Degradation prediction model and stem cell growth of gelatin-PEG composite hydrogel.

PubMed

Zhou, Nan; Liu, Chang; Lv, Shijie; Sun, Dongsheng; Qiao, Qinglong; Zhang, Rui; Liu, Yang; Xiao, Jing; Sun, Guangwei

2016-12-01

Gelatin hydrogel has great potential in regenerative medicine. The degradation of gelatin hydrogel is important to control the release profile of encapsulated biomolecules and regulate in vivo tissue repair process. As a plasticizer, PEG can significantly improve the mechanical property of gelatin hydrogel. However, how preparation parameters affect the degradation rate of gelatin-PEG composite hydrogel is still not clear. In this study, the significant effect factor, glutaraldehyde (GA) concentration, was confirmed by means of Plackett-Burman method. Then a mathematical model was built to predict the degradation rate of composite hydrogels under different preparation conditions using the response surface method (RSM), which was helpful to prepare the certain composite hydrogel with desired degradation rate. In addition, it was found that gelatin-PEG composite hydrogel surface well supported the adhesion and growth of human mesenchymal stem cells (MSCs). Moreover, PEG concentration not only could adjust hydrogel degradation more subtly, but also might increase the cross-linking degree and affect the cell migration. Therefore, these results would be useful to optimize the preparation of gelatin-PEG composite hydrogel for drug delivery or tissue engineering. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3149-3156, 2016. © 2016 Wiley Periodicals, Inc.

Myocardial matrix-polyethylene glycol hybrid hydrogels for tissue engineering

NASA Astrophysics Data System (ADS)

Grover, Gregory N.; Rao, Nikhil; Christman, Karen L.

2014-01-01

Similar to other protein-based hydrogels, extracellular matrix (ECM) based hydrogels, derived from decellularized tissues, have a narrow range of mechanical properties and are rapidly degraded. These hydrogels contain natural cellular adhesion sites, form nanofibrous networks similar to native ECM, and are biodegradable. In this study, we expand the properties of these types of materials by incorporating poly(ethylene glycol) (PEG) into the ECM network. We use decellularized myocardial matrix as an example of a tissue specific ECM derived hydrogel. Myocardial matrix-PEG hybrids were synthesized by two different methods, cross-linking the proteins with an amine-reactive PEG-star and photo-induced radical polymerization of two different multi-armed PEG-acrylates. We show that both methods allow for conjugation of PEG to the myocardial matrix by gel electrophoresis and infrared spectroscopy. Scanning electron microscopy demonstrated that the hybrid materials still contain a nanofibrous network similar to unmodified myocardial matrix and that the fiber diameter is changed by the method of PEG incorporation and PEG molecular weight. PEG conjugation also decreased the rate of enzymatic degradation in vitro, and increased material stiffness. Hybrids synthesized with amine-reactive PEG had gelation rates of 30 min, similar to the unmodified myocardial matrix, and incorporation of PEG did not prevent cell adhesion and migration through the hydrogels, thus offering the possibility to have an injectable ECM hydrogel that degrades more slowly in vivo. The photo-polymerized radical systems gelled in 4 min upon irradiation, allowing 3D encapsulation and culture of cells, unlike the soft unmodified myocardial matrix. This work demonstrates that PEG incorporation into ECM-based hydrogels can expand material properties, thereby opening up new possibilities for in vitro and in vivo applications.

Poly(ethylene glycol)-containing hydrogels promote the release of primary granules from human blood-derived polymorphonuclear leukocytes

PubMed Central

Cohen, Hannah Caitlin; Lieberthal, Tyler Jacob; Kao, W. John

2014-01-01

Polymorphonuclear leukocytes (PMNs) are recruited to sites of injury and biomaterial implants. Once activated, PMNs can exocytose their granule subsets to recruit monocytes (MCs) and mediate MC/macrophage activation. We investigated the release of myeloperoxidase (MPO), a primary granule marker, and matrix metalloproteinase-9 (MMP-9), a tertiary granule marker, from human blood-derived PMNs cultured on poly(ethylene glycol) (PEG) hydrogels, polydimethylsiloxane (PDMS), tissue culture polystyrene (TCPS) and gelatin-PEG (GP) hydrogels, with and without the presence of the bacterial peptide formyl-Met-Leu-Phe. Supernatants from PMN cultures on PEG-containing hydrogels (i.e., PEG and GP hydrogels) had higher concentrations of MPO than those from PMN cultures on PDMS or TCPS at 2 hours. PMNs on all biomaterials released comparable levels of MMP-9 at 2 hours, indicating that PMNs cultured on PEG-containing hydrogels have different mechanisms of release for primary and tertiary granules. Src family kinases were involved in the release of MPO from PMNs cultured on PEG hydrogels, TCPS and GP hydrogels and in the release of MMP-9 from PMNs cultured on all four materials. The increased release of primary granules from PMNs on PEG-containing hydrogels did not significantly increase MC chemotaxis, indicating that additional co-effectors in the dynamic inflammatory milieu in vivo modulate PMN-mediated MC recruitment. PMID:24497370

Bioprinting 3D cell-laden hydrogel microarray for screening human periodontal ligament stem cell response to extracellular matrix.

PubMed

Ma, Yufei; Ji, Yuan; Huang, Guoyou; Ling, Kai; Zhang, Xiaohui; Xu, Feng

2015-12-22

Periodontitis is an inflammatory disease negatively affecting up to 15% of adults worldwide. Periodontal ligament stem cells (PDLSCs) hold great promises for periodontal tissue regeneration, where it is necessary to find proper extracellular matrix (ECM) materials (e.g., composition, concentration). In this study, we proposed a bioprinting-based approach to generate nano-liter sized three-dimensional (3D) cell-laden hydrogel array with gradient of ECM components, through controlling the volume ratio of two hydrogels, such as gelatin methacrylate (GelMA) and poly(ethylene glycol) (PEG) dimethacrylate. The resulting cell-laden array with a gradient of GelMA/PEG composition was used to screen human PDLSC response to ECM. The behavior (e.g., cell viability, spreading) of human PDLSCs in GelMA/PEG array were found to be depended on the volume ratios of GelMA/PEG, with cell viability and spreading area decreased along with increasing the ratio of PEG. The developed approach would be useful for screening cell-biomaterial interaction in 3D and promoting regeneration of functional tissue.

Hydrogel Design for Supporting Neurite Outgrowth and Promoting Gene Delivery to Maximize Neurite Extension

PubMed Central

Shepard, Jaclyn A.; Stevans, Alyson C.; Holland, Samantha; Wang, Christine E.; Shikanov, Ariella; Shea, Lonnie D.

2012-01-01

Hydrogels capable of gene delivery provide a combinatorial approach for nerve regeneration, with the hydrogel supporting neurite outgrowth and gene delivery inducing the expression of inductive factors. This report investigates the design of hydrogels that balance the requirements for supporting neurite growth with those requirements for promoting gene delivery. Enzymatically-degradable PEG hydrogels encapsulating dorsal root ganglia explants, fibroblasts, and lipoplexes encoding nerve growth factor were gelled within channels that can physically guide neurite outgrowth. Transfection of fibroblasts increased with increasing concentration of Arg-Gly-Asp (RGD) cell adhesion sites and decreasing PEG content. The neurite length increased with increasing RGD concentration within 10% PEG hydrogels, yet was maximal within 7.5% PEG hydrogels at intermediate RGD levels. Delivering lipoplexes within the gel produced longer neurites than culture in NGF-supplemented media or co-culture with cells exposed to DNA prior to encapsulation. Hydrogels designed to support neurite outgrowth and deliver gene therapy vectors locally may ultimately be employed to address multiple barriers that limit regeneration. PMID:22038654

Photo-crosslinked PDMSstar-PEG Hydrogels: Synthesis, Characterization, and Potential Application for Tissue Engineering Scaffolds

PubMed Central

Hou, Yaping; Schoener, Cody A.; Regan, Katherine R.; Munoz-Pinto, Dany; Hahn, Mariah S.; Grunlan, Melissa A.

2010-01-01

Inorganic-organic hydrogels with tunable chemical and physical properties were prepared from methacrylated star polydimethylsiloxane (PDMSstar-MA) and diacrylated poly(ethylene glycol) (PEG-DA) for use as tissue engineering scaffolds. Eighteen compositionally unique hydrogels were prepared by photo-crosslinking varying weight ratios of PEG-DA and PDMSstar-MA of different molecular weights (Mn): PEG-DA (Mn = 3.4k and 6k g/mol) and PDMSstar-MA (Mn = 1.8k, 5k and 7k g/mol). Introduction of PDMSstar-MA caused formation of discrete PDMS-enriched microparticles dispersed within the PEG matrix. The swelling ratio, mechanical properties in tension and compression, non-specific protein adhesion, controlled introduction of bioactivity and cytotoxicity of hydrogels were studied. This library of inorganic-organic hydrogels with tunable properties provides a useful platform to study the effect of scaffold properties on cell behavior. PMID:20146518

The effects of cross-linked thermo-responsive PNIPAAm-based hydrogel injection on retinal function.

PubMed

Turturro, Sanja B; Guthrie, Micah J; Appel, Alyssa A; Drapala, Pawel W; Brey, Eric M; Pérez-Luna, Victor H; Mieler, William F; Kang-Mieler, Jennifer J

2011-05-01

There is significant interest in biomaterials that provide sustained release of therapeutic molecules to the retina. Poly(N-isopropylacrylamide) (PNIPAAm)-based materials have received significant attention as injectable drug delivery platforms due to PNIPAAm's thermo-responsive properties at approximately 32 °C. While the drug delivery properties of PNIPAAm materials have been studied extensively, there is a need to evaluate the safety effects of hydrogel injection on retinal function. The purpose of this study was to examine the effect of poly(ethylene glycol) diacrylate (PEG-DA) crosslinked PNIPAAm hydrogel injection on retinal function. Utilizing scanning laser ophthalmoscopy (SLO), optical coherent tomography (OCT), and electroretinography (ERG), retinal function was assessed following hydrogel injection. In region near the hydrogel, there was a significant decrease in arterial and venous diameters (∼4%) and an increase in venous blood velocity (∼8%) 1 week post-injection. Retinal thickness decreased (∼6%) at 1 week and the maximum a- and b-wave amplitudes of ERG decreased (∼15%). All data returned to baseline values after week 1. These data suggest that the injection of PEG-DA crosslinked PNIPAAm hydrogel results in a small transient effect on retinal function without any long-term effects. These results further support the potential of PNIPAAm-based materials as an ocular drug delivery platform. Copyright © 2011 Elsevier Ltd. All rights reserved.

Cyclodextrin modified hydrogels of PVP/PEG for sustained drug release.

PubMed

Nielsen, Anne Louise; Madsen, Flemming; Larsen, Kim Lambertsen

2009-02-01

Hydrogels are water swollen networks of polymers and especially hydrogels consisting of poly vinylpyrrolidone/poly ethyleneglycol-dimethacrylate (PVP/PEG-DMA) blends show promising wound care properties. Enhanced functionality of the hydrogels can be achieved by incorporating drugs and other substances that may assist wound healing into the gel matrix. Controlling the release of active compounds from the hydrogels may be possible by carefully modifying the polymer matrix. For this purpose, cyclodextrins (CD) were grafted to the polymer matrix in 4-5 w/w% in an attempt to retard the release of water-soluble drugs. Ibuprofenate (IBU) was chosen as model drug and loaded in IBU/CD ratios of 0.6, 1.2, and 2.5. Vinyl derivatives of alpha-, beta- and gamma-CD were produced, added to the prepolymer blend and cured by UV-light. During this curing process the CD derivatives were covalently incorporated into the hydrogel matrix. The modified hydrogels were loaded with ibuprofenate by swelling. The release of the model drug from CD modified hydrogels show that especially covalently bonded beta-cyclodextrin can change both the release rate and the release profile of ibuprofen.

Antibacterial anti-oxidant electroactive injectable hydrogel as self-healing wound dressing with hemostasis and adhesiveness for cutaneous wound healing.

PubMed

Zhao, Xin; Wu, Hao; Guo, Baolin; Dong, Ruonan; Qiu, Yusheng; Ma, Peter X

2017-04-01

Injectable self-healing hydrogel dressing with multifunctional properties including anti-infection, anti-oxidative and conductivity promoting wound healing process will be highly desired in wound healing application and its design is still a challenge. We developed a series of injectable conductive self-healed hydrogels based on quaternized chitosan-g-polyaniline (QCSP) and benzaldehyde group functionalized poly(ethylene glycol)-co-poly(glycerol sebacate) (PEGS-FA) as antibacterial, anti-oxidant and electroactive dressing for cutaneous wound healing. These hydrogels presented good self-healing, electroactivity, free radical scavenging capacity, antibacterial activity, adhesiveness, conductivity, swelling ratio, and biocompatibility. Interestingly, the hydrogel with an optimal crosslinker concentration of 1.5 wt% PEGS-FA showed excellent in vivo blood clotting capacity, and it significantly enhanced in vivo wound healing process in a full-thickness skin defect model than quaternized chitosan/PEGS-FA hydrogel and commercial dressing (Tegaderm™ film) by upregulating the gene expression of growth factors including VEGF, EGF and TGF-β and then promoting granulation tissue thickness and collagen deposition. Taken together, the antibacterial electroactive injectable hydrogel dressing prolonged the lifespan of dressing relying on self-healing ability and significantly promoted the in vivo wound healing process attributed to its multifunctional properties, meaning that they are excellent candidates for full-thickness skin wound healing. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evaluation of BSA protein release from hollow hydroxyapatite microspheres into PEG hydrogel

PubMed Central

Fu, Hailuo; Rahaman, Mohamed N.; Brown, Roger F.; Day, Delbert E.

2013-01-01

Implants that simultaneously function as an osteoconductive matrix and as a device for local drug or growth factor delivery could provide an attractive system for bone regeneration. In our previous work, we prepared hollow hydroxyapatite (abbreviated HA) microspheres with a high surface area, mesoporous shell wall and studied the release of a model protein, bovine serum albumin (BSA), from the microspheres into phosphate-buffered saline (PBS). The present work is an extension of our previous work to study the release of BSA from similar HA microspheres into a biocompatible hydrogel, poly(ethylene glycol) (PEG). BSA-loaded HA microspheres were placed in a PEG solution which was rapidly gelled using ultraviolet radiation. The BSA release rate into the PEG hydrogel, measured using a spectrophotometric method, was slower than into PBS, and it was dependent on the initial BSA loading and on the microstructure of the microsphere shell wall. A total of 35–40% of the BSA initially loaded into the microspheres was released into PEG over ~14 days. The results indicate that these hollow HA microspheres have promising potential as an osteoconductive device for local drug or growth factor delivery in bone regeneration and in the treatment of bone diseases. PMID:23498254

Synthetic PEG Hydrogel for Engineering the Environment of Ovarian Follicles.

PubMed

Mendez, Uziel; Zhou, Hong; Shikanov, Ariella

2018-01-01

The functional unit within the ovary is the ovarian follicle, which is also a morphological unit composed of three basic cell types: the oocyte, granulosa, and theca cells. Similar to human ovarian follicles, mouse follicles can be isolated from their ovarian environment and cultured in vitro to study folliculogenesis, or follicle development for days or weeks. Over the course of the last decade, follicle culture in a three-dimensional (3D) environment exponentially improved the outcomes of in vitro folliculogenesis. Follicle culture in 3D environments preserves follicle architecture and promotes the cross talk between cells in the follicle. Hydrogels, such as polyethylene glycol (PEG), have been used for various physiological systems for regenerative purposes because they provide a 3D environment similar to soft tissues, allow diffusion of nutrients, and can be readily modified to present biological signals, including cell adhesion ligands and proteolytic degradation facilitated by enzymes secreted by the encapsulated cells. This chapter outlines the application of PEG hydrogels to the follicle culture, including the procedures to isolate, encapsulate, and culture mouse ovarian follicles. The tunable properties of PEG hydrogels support co-encapsulation of ovarian follicles with somatic cells, which further promote follicle survival and growth in vitro through paracrine and juxtacrine interactions.

Biomaterials differentially regulate Src kinases and phosphoinositide 3-kinase-γ in polymorphonuclear leukocyte primary and tertiary granule release

PubMed Central

Cohen, Hannah Caitlin; Frost, Dustin C.; Lieberthal, Tyler Jacob; Li, Lingjun; Kao, W. John

2018-01-01

In the foreign body response, infiltrating PMNs exocytose granule subsets to influence subsequent downstream inflammatory and wound healing events. In previous studies, we found that PMNs cultured on poly(ethylene glycol) (PEG)-containing hydrogels (i.e., PEG and gelatin + PEG hydrogels) had enhanced primary granule release, yet similar tertiary granule release compared with PMNs cultured on polydimethylsiloxane or tissue culture polystyrene. PMN primary granules contain microbicidal proteins and proteases, which can potentially injure bystander cells, degrade the extracellular matrix, and promote inflammation. Here, we sought to understand the mechanism of the enhanced primary granule release from PMNs on PEG hydrogels. We found that primary granule release from PMNs on PEG hydrogels was adhesion mediated and involved Src family kinases and PI3K-γ. The addition of gelatin to PEG hydrogels did not further enhance PMN primary granule release. Using stable-isotope dimethyl labeling-based shotgun proteomics, we identified many serum proteins – including Ig gamma constant chain region proteins and alpha-1-acid glycoprotein 1 – that were absorbed/adsorbed in higher quantities on PEG hydrogels than on TCPS, and may be involved in mediating PMN primary granule release. Ultimately, this mechanistic knowledge can be used to direct inflammation and wound healing following biomaterial implantation to promote a more favorable healing response. PMID:25736495

Development of injectable hydrogels for nucleus pulposus replacement

NASA Astrophysics Data System (ADS)

Thomas, Jonathan D.

Intervertebral disc degeneration has been reported as the underlying cause for 75% of cases of lower back pain and is marked by dehydration of the nucleus pulposus within the intervertebral disc. There have been many implant designs to replace the nucleus pulposus. Some researchers have proposed the replacement of the nucleus pulposus with hydrogel materials. The insertion of devices made from these materials further compromises the annulus of the disc. An ideal nucleus replacement could be injected into the disc space and form a solid in vivo. However, injectable replacements using curing elastomers and thermoplastic materials are not ideal because of the potentially harmful exothermic heat evolved from their reactions and the toxicity of the reactants used. We propose a hydrogel system that can be injected as a liquid at 25°C and solidified to yield a hydrogel within the intervertebral disc at 37°C. In aqueous solutions, these polymers have Lower Critical Solution Temperatures (LCST) between 25-37°C, making them unique candidate materials for this application. Poly(N-isopropylacrylamide) (PNIPAAm) is the most widely studied LCST polymer due to its drastic transition near body temperature. However, by itself, pure PNIPAAm forms a hydrogel that has low water content and can readily undergo plastic deformation. To increase the water content and impart elasticity to PNIPAAm hydrogels, grafted and branched hydrogel systems were created that incorporated the thermogelling PNIPAAm and hydrophilic poly(ethylene glycol) (PEG). In this research, the effects of polymer composition and monomer to initiator ratio, which controls polymer MW, on the in vitro swelling properties (mass, chemical, and compressive mechanical stability) of hydrogels formed from aqueous solutions of these polymers were evaluated. Immersion studies were also conducted in solutions to simulate the osmotic environment of the nucleus pulposus. The effects of repeated compression and unloading cycles on the water content and dimensional recovery of hydrogels made from three candidate polymer formulations were also determined. Unlike PNIPAAm and PEG grafted PNIPAAm hydrogels, PEG branched hydrogels have covalently linked networks. Addition of 7 mol% PEG branches to PNIPAAm resulted in a hydrogel with a higher water content and better elastic recovery than hydrogels made from pure PNIPAAm. PEG branched PNIPAAm hydrogels were shown to have mass, chemical, and compressive mechanical stability in vitro. Furthermore, these hydrogels showed superior dimensional recovery after compressive cycling than pure PNIPAAm and PEG grafted PNIPAAm hydrogels. The 7 mol% PEG branched PNIPAAm hydrogels have suitable swelling and mechanical properties to potentially serve as a nucleus pulposus replacement.

3D-Hydrogel Based Polymeric Nanoreactors for Silver Nano-Antimicrobial Composites Generation.

PubMed

Soto-Quintero, Albanelly; Romo-Uribe, Ángel; Bermúdez-Morales, Víctor H; Quijada-Garrido, Isabel; Guarrotxena, Nekane

2017-08-01

This study underscores the development of Ag hydrogel nanocomposites, as smart substrates for antibacterial uses, via innovative in situ reactive and reduction pathways. To this end, two different synthetic strategies were used. Firstly thiol-acrylate (PSA) based hydrogels were attained via thiol-ene and radical polymerization of polyethylene glycol (PEG) and polycaprolactone (PCL). As a second approach, polyurethane (PU) based hydrogels were achieved by condensation polymerization from diisocyanates and PCL and PEG diols. In fact, these syntheses rendered active three-dimensional (3D) hydrogel matrices which were used as nanoreactors for in situ reduction of AgNO₃ to silver nanoparticles. A redox chemistry of stannous catalyst in PU hydrogel yielded spherical AgNPs formation, even at 4 °C in the absence of external reductant; and an appropriate thiol-functionalized polymeric network promoted spherical AgNPs well dispersed through PSA hydrogel network, after heating up the swollen hydrogel at 103 °C in the presence of citrate-reductant. Optical and swelling behaviors of both series of hydrogel nanocomposites were investigated as key factors involved in their antimicrobial efficacy over time. Lastly, in vitro antibacterial activity of Ag loaded hydrogels exposed to Pseudomona aeruginosa and Escherichia coli strains indicated a noticeable sustained inhibitory effect, especially for Ag-PU hydrogel nanocomposites with bacterial inhibition growth capabilities up to 120 h cultivation.

Hydrogel formulation determines cell fate of fetal and adult neural progenitor cells

PubMed Central

Wagner, Jennifer L.; Shandas, Robin; Bjugstad, Kimberly B.

2014-01-01

Hydrogels provide a unique tool for neural tissue engineering. These materials can be customized for certain functions, i.e. to provide cell/drug delivery or act as a physical scaffold. Unfortunately, hydrogel complexities can negatively impact their biocompatibility, resulting in unintended consequences. These adverse effects may be combated with a better understanding of hydrogel chemical, physical, and mechanical properties, and how these properties affect encapsulated neural cells. We defined the polymerization and degradation rates and compressive moduli of 25 hydrogels formulated from different concentrations of hyaluronic acid (HA) and poly(ethylene glycol) (PEG). Changes in compressive modulus were driven primarily by the HA concentration. The in vitro biocompatibility of fetal-derived (fNPC) and adult-derived (aNPC) neural progenitor cells was dependent on hydrogel formulation. Acute survival of fNPC benefited from hydrogel encapsulation. NPC differentiation was divergent: fNPC differentiated into mostly glial cells, compared with neuronal differentiation of aNPC. Differentiation was influenced in part by the hydrogel mechanical properties. This study indicates that there can be a wide range of HA and PEG hydrogels compatible with NPC. Additionally, this is the first study comparing hydrogel encapsulation of NPC derived from different aged sources, with data suggesting that fNPC and aNPC respond dissimilarly within the same hydrogel formulation. PMID:24141109

Hydrogels of poly(ethylene glycol): mechanical characterization and release of a model drug.

PubMed

Iza, M; Stoianovici, G; Viora, L; Grossiord, J L; Couarraze, G

1998-03-02

Thermosensitive polymer networks were synthesized from poly(ethylene glycol), hexamethylene diisocyanate and 1,2,6-hexanetriol in stoichiometric proportions. By varying the amount of 1,2,6-hexanetriol and the molar mass of the poly(ethylene glycol), a wide range of networks with different crosslinking densities was prepared. The networks obtained were characterized by the temperature dependence of their degree of equilibrium swelling in water and by their Young's moduli. For each network, the molecular weight between crosslinks was estimated. The structure of the hydrogels was analysed with respect to scaling laws, and it was found that the results obtained with PEG 1500 and PEG 6000 hydrogels are in agreement with theoretical predictions, whereas those obtained with PEG 400 hydrogels are in disagreement. The release properties of PEG hydrogels were studied by the determination of the diffusion coefficient for acebutolol chlorhydrate and by an analysis of the effect of temperature on these coefficients. Finally, these release properties were correlated with the swelling and structural properties of the hydrogels.

Effects of bevacizumab loaded PEG-PCL-PEG hydrogel intracameral application on intraocular pressure after glaucoma filtration surgery.

PubMed

Han, Qian; Wang, Yuqi; Li, Xiabin; Peng, Ribo; Li, Ailing; Qian, Zhiyong; Yu, Ling

2015-08-01

PEG-PCL-PEG (PECE) hydrogel for intracameral injection as a sustained delivery system can get a stable release of the medication and achieve an effective local concentration. The injectable PECE hydrogel is thermosensitive nano-material which is flowing sol at low temperature and can shift to nonflowing gel at body temperature. This study evaluated the intracameral injection of bevacizumab combined with a PECE hydrogel drug release system on postoperative scarring and bleb survival after experimental glaucoma filtration surgery. The best result was achieved in the bevacizumab loaded PECE hydrogels group, which presented the lowest IOP values after surgery. And the blebs were significantly more persistent in this group. Histology, Massion trichrome staining and immunohistochemistry further demonstrated that glaucoma filtration surgery in combination with bevacizumab loaded PECE hydrogel resulted in good bleb survival due to scar formation inhibition. In conclusions, this study demonstrated that bevacizumab-loaded PECE hydrogel for intracameral injection as a sustained delivery system provide a great opportunity to increase the therapeutic efficacy of glaucoma filtration surgery.

Water-in-Water Emulsion Based Synthesis of Hydrogel Nanospheres with Tunable Release Kinetics

NASA Astrophysics Data System (ADS)

Aydın, Derya; Kızılel, Seda

2017-07-01

Poly(ethylene glycol) (PEG) micro/nanospheres have several unique advantages as polymer based drug delivery systems (DDS) such as tunable size, large surface area to volume ratio, and colloidal stability. Emulsification is one of the widely used methods for facile synthesis of micro/nanospheres. Two-phase aqueous system based on polymer-polymer immiscibility is a novel approach for preparation of water-in-water (w/w) emulsions. This method is promising for the synthesis of PEG micro/nanospheres for biological systems, since the emulsion is aqueous and do not require organic solvents or surfactants. Here, we report the synthesis of nano-scale PEG hydrogel particles using w/w emulsions using phase separation of dextran and PEG prepolymer. Dynamic light scattering (DLS) and scaning electron microscopy (SEM) results demonstrated that nano-scale hydrogel spheres could be obtained with this approach. We investigated the release kinetics of a model drug, pregabalin (PGB) from PEG nanospheres and demonstrated the influence of polymerization conditions on loading and release of the drug as well as the morphology and size distribution of PEG nanospheres. The experimental drug release data was fitted to a stretched exponential function which suggested high correlation with experimental results to predict half-time and drug release rates from the model equation. The biocompatibility of nanospheres on human dermal fibroblasts using cell-survival assay suggested that PEG nanospheres with altered concentrations are non-toxic, and can be considered for controlled drug/molecule delivery.

Evaluation of an in situ chemically crosslinked hydrogel as a long-term vitreous substitute material.

PubMed

Tao, Yong; Tong, Xinming; Zhang, Yan; Lai, Jingjing; Huang, Yanbin; Jiang, Yan-Rong; Guo, Bao-Hua

2013-02-01

Currently there is no material that can be used as a long-term vitreous substitute, and this remains an unmet clinical need in ophthalmology. In this study, we developed an injectable, in situ chemically crosslinked hydrogel system and evaluated it in a rabbit model. The system consisted of two components, both based on multi-functional poly(ethylene glycol) (PEG) but with complementarily reactive end groups of thiol and active vinyl groups, respectively. The two components are mixed and injected as a solution mixture, react in vivo via the Michael addition route and form a chemically crosslinked hydrogel in situ. The linkages between the end groups and the backbone PEG chains are specially designed to ensure that the final network structure is hydrolysis-resistant. In the rabbit study and with an optimized operation protocol, we demonstrated that the hydrogel indeed formed in situ after injection, and remained transparent and stable during the study period of 9 months without significant adverse reactions. In addition, the hydrogel formed in situ showed rheological properties very similar to the natural vitreous. Therefore, our study demonstrated that this in situ chemically crosslinked PEG gel system is suitable as a potential long-term vitreous substitute. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

Liposome-Cross-Linked Hybrid Hydrogels for Glutathione-Triggered Delivery of Multiple Cargo Molecules.

PubMed

Liang, Yingkai; Kiick, Kristi L

2016-02-08

Novel, liposome-cross-linked hybrid hydrogels cross-linked by the Michael-type addition of thiols with maleimides were prepared via the use of maleimide-functionalized liposome cross-linkers and thiolated polyethylene glycol (PEG) polymers. Gelation of the materials was confirmed by oscillatory rheology experiments. These hybrid hydrogels are rendered degradable upon exposure to thiol-containing molecules such as glutathione (GSH), via the incorporation of selected thioether succinimide cross-links between the PEG polymers and liposome nanoparticles. Dynamic light scattering (DLS) characterization confirmed that intact liposomes were released upon network degradation. Owing to the hierarchical structure of the network, multiple cargo molecules relevant for chemotherapies, namely doxorubicin (DOX) and cytochrome c, were encapsulated and simultaneously released from the hybrid hydrogels, with differential release profiles that were driven by degradation-mediated release and Fickian diffusion, respectively. This work introduces a facile approach for the development of advanced, hybrid drug delivery vehicles that exhibit novel chemical degradation.

Thermoreversible hydrogels based on triblock copolymers of poly(ethylene glycol) and carboxyl functionalized poly(ε-caprolactone): The effect of carboxyl group substitution on the transition temperature and biocompatibility in plasma.

PubMed

Safaei Nikouei, Nazila; Vakili, Mohammad Reza; Bahniuk, Markian S; Unsworth, Larry; Akbari, Ali; Wu, Jianping; Lavasanifar, Afsaneh

2015-01-01

In this study we report on the development, characterization and plasma protein interaction of novel thermoresponsive in situ hydrogels based on triblock copolymers of poly(ethylene glycol) (PEG) and poly(α-carboxyl-co-benzyl carboxylate)-ε-caprolactone (PCBCL) having two different degrees of carboxyl group substitution on the PCBCL block. Block copolymers were synthesized through ring-opening polymerization of α-benzyl carboxylate-ε-caprolactone by dihydroxy PEG, leading to the production of poly(α-benzyl carboxylate-ε-caprolactone)-PEG-poly(α-benzyl carboxylate-ε-caprolactone) (PBCL-PEG-PBCL). This was followed by partial debenzylation of PBCL blocks under controlled conditions, leading to the preparation of PCBCL-PEG-PCBCL triblock copolymers with 30 and 54mol.% carboxyl group substitution. Prepared PCBCL-PEG-PCBCL block copolymers have been shown to have a concentration-dependent sol to gel transition as a result of an increase in temperature above ∼29°C, as evidenced by the inverse flow method, differential scanning calorimetry and dynamic mechanical analysis. The sol-gel transition temperature/concentration and dynamic mechanical properties of the gel were found to be dependent on the level of carboxyl group substitution. Both hydrogels (30 and 54mol.% carboxyl group substitution) showed similar amounts of protein adsorption but striking differences in the profiles of the adsorbed proteome. Additionally, the two systems showed similarities in their clot formation kinetics but substantial differences in clot endpoints. The results show great promise for the above-mentioned thermoreversible in situ hydrogels as biocompatible materials for biomedical applications. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Cyclodextrin-cross-linked diaminotriazine-based hydrogen bonding strengthened hydrogels for drug and reverse gene delivery.

PubMed

Hu, Xiufeng; Wang, Ning; Liu, Lu; Liu, Wenguang

2013-01-01

A hydrogen bonding strengthened hydrogel was prepared by radical copolymerization of poly(ethylene glycol) methacrylated β-cyclodextrin (PEG-β-CD) and 2-vinyl-4,6-diamino-1,3,5-triazine (VDT) monomer. PEG-β-CD served not only as a cross-linker, but also as a built-in solubilizing agent of the hydrophobic drug in the gel. Increasing VDT content resulted in a notable enhancement in the mechanical strengths of hydrogels whose equilibrium water contents could be modulated from 75% to 85% by varying the ratio of PEG-β-CD cross-linker. It was shown that copolymerizing more PEG-β-CDs could load higher amount of ibuprofen (IBU) in the gels and contribute to a slower release rate of IBU. Plasmid DNA could be anchored onto the surface of hydrogels due to the hydrogen bonding between the base pairs and diaminotriazine, thereby mediating efficient reverse gene transfection of luciferase gene in COS-7 cells cultured on the gel surface. The cytocompatible PEG-β-CD-cross-linked PVDT hydrogels with multifunction of drug and gene delivery hold a potential as tissue engineering scaffold.

Photoinitiator-Free Synthesis of Endothelial Cell Adhesive and Enzymatically Degradable Hydrogels

PubMed Central

Jones, Derek R.; Marchant, Roger E.; von Recum, Horst; Gupta, Anirban Sen; Kottke-Marchant, Kandice

2015-01-01

We report on a photoinitiator-free synthetic method of incorporating bioactivity into poly(ethylene glycol) (PEG) hydrogels in order to control physical properties, enzymatic biodegradability and cell-specific adhesiveness of the polymer network, while eliminating the need for UV-mediated photopolymerization. To accomplish this, hydrogel networks were polymerized using Michael addition with four-arm PEG acrylate (10 kDa), using a collagenase sensitive peptide (CSP) as a crosslinker, and introducing an endothelial cell adhesive peptide either terminally (RGD) or attached to the crosslinking peptide sequence (CSP-RGD). The efficiency of the Michael addition reactions were determined by NMR and Ellman’s assay. Successful decoupling of cell adhesivity and physical properties was demonstrated by quantifying and comparing the swelling ratios and Young’s Moduli of various hydrogel formulations. Degradation profiles were established by incubating functionalized hydrogels in collagenase solutions (0.0 – 1.0 µg/mL), demonstrating that functionalized hydrogels degraded at a rate dependent upon collagenase concentration. Moreover, it was shown that the degradation rate was independent of CSP-RGD concentration. Cell attachment and proliferation on functionalized hydrogels were compared for various RGD concentrations, providing evidence that cell attachment and proliferation were directly related to relative amounts of the CSP-RGD combination peptide. An increase in cell viability was achieved using Michael addition techniques when compared to UV-polymerization, and was assessed by a LIVE/DEAD fluorescence assay. This photoinitiator-free method shows promise in creating hydrogel-based tissue engineering scaffolds allow for decoupled cell adhesivity and physical properties and that render greater cell viability. PMID:25462848

Temperature-responsive in situ nanoparticle hydrogels based on hydrophilic pendant cyclic ether modified PEG-PCL-PEG.

PubMed

Feng, Zujian; Zhao, Junqiang; Li, Yin; Xu, Shuxin; Zhou, Junhui; Zhang, Jianhua; Deng, Liandong; Dong, Anjie

2016-10-20

Thermo-sensitive injectable hydrogels based on poly(ε-caprolactone)/poly(ethylene glycol) (PCL/PEG) block copolymers have attracted considerable attention for sustained drug release and tissue engineering applications. Previously, we have reported a thermo-sensitive hydrogel of P(CL-co-TOSUO)-PEG-P(CL-co-TOSUO) (PECT) triblock copolymers modified by hydrophilic cyclic ether pendant groups 1,4,8-trioxa-[4.6]spiro-9-undecanone (TOSUO). Unfortunately, the low gel modulus of PECT (only 50-70 Pa) may limit its applications. Herein, another kind of thermogelling triblock copolymer of a pendant cyclic ether-modified caprolactonic poloxamer analog, PEG-P(CL-co-TOSUO)-PEG (PECTE), was successfully prepared by control of the hydrophilicity/hydrophobicity balance and chemical compositions of the copolymers. PECTE powder could directly disperse in water to form a stable nanoparticle (NP) aqueous dispersion and underwent sol-gel-sol transition behavior at a higher concentration with the temperature increasing from ambient or lower temperatures. Significantly, the microstructure parameters (e.g., different chemical compositions of the hydrophobic block and topology) played a critical role in the phase transition behavior. Furthermore, comparison studies on PECTE and PEG-PCL-PEG (PECE) showed that the introduction of pendant cyclic ether groups into PCL blocks could avoid unexpected ahead-of-time gelling of the PECE aqueous solution. In addition, the rheological analysis of PECTE and PECT indicated that the storage modulus of the PECTE hydrogel could be 100 times greater than that of the PECT hydrogel under the same mole ratios of TOSUO/CL and lower molecular weight. Consequently, PECTE thermal hydrogel systems are believed to be promising as in situ gel-forming biomaterials for drug delivery and tissue engineering.

Synthesis, characterization, and application of reversible PDLLA-PEG-PDLLA copolymer thermogels in vitro and in vivo

PubMed Central

Shi, Kun; Wang, Ya-Li; Qu, Ying; Liao, Jin-Feng; Chu, Bing-Yang; Zhang, Hua-Ping; Luo, Feng; Qian, Zhi-Yong

2016-01-01

In this study, a series of injectable thermoreversible and thermogelling PDLLA-PEG-PDLLA copolymers were developed and a systematic evaluation of the thermogelling system both in vitro and in vivo was performed. The aqueous PDLLA-PEG-PDLLA solutions above a critical gel concentration could transform into hydrogel spontaneously within 2 minutes around the body temperature in vitro or in vivo. Modulating the molecular weight, block length and polymer concentration could adjust the sol-gel transition behavior and the mechanical properties of the hydrogels. The gelation was thermally reversible due to the physical interaction of copolymer micelles and no crystallization formed during the gelation. Little cytotoxicity and hemolysis of this polymer was found, and the inflammatory response after injecting the hydrogel to small-animal was acceptable. In vitro and in vivo degradation experiments illustrated that the physical hydrogel could retain its integrity as long as several weeks and eventually be degraded by hydrolysis. A rat model of sidewall defect-bowel abrasion was employed, and a significant reduction of post-operative adhesion has been found in the group of PDLLA-PEG-PDLLA hydrogel-treated, compared with untreated control group and commercial hyaluronic acid (HA) anti-adhesion hydrogel group. As such, this PDLLA-PEG-PDLLA hydrogel might be a promising candidate of injectable biomaterial for medical applications. PMID:26752008

3D-Hydrogel Based Polymeric Nanoreactors for Silver Nano-Antimicrobial Composites Generation

PubMed Central

Soto-Quintero, Albanelly; Romo-Uribe, Ángel; Bermúdez-Morales, Víctor H.; Quijada-Garrido, Isabel

2017-01-01

This study underscores the development of Ag hydrogel nanocomposites, as smart substrates for antibacterial uses, via innovative in situ reactive and reduction pathways. To this end, two different synthetic strategies were used. Firstly thiol-acrylate (PSA) based hydrogels were attained via thiol-ene and radical polymerization of polyethylene glycol (PEG) and polycaprolactone (PCL). As a second approach, polyurethane (PU) based hydrogels were achieved by condensation polymerization from diisocyanates and PCL and PEG diols. In fact, these syntheses rendered active three-dimensional (3D) hydrogel matrices which were used as nanoreactors for in situ reduction of AgNO3 to silver nanoparticles. A redox chemistry of stannous catalyst in PU hydrogel yielded spherical AgNPs formation, even at 4 °C in the absence of external reductant; and an appropriate thiol-functionalized polymeric network promoted spherical AgNPs well dispersed through PSA hydrogel network, after heating up the swollen hydrogel at 103 °C in the presence of citrate-reductant. Optical and swelling behaviors of both series of hydrogel nanocomposites were investigated as key factors involved in their antimicrobial efficacy over time. Lastly, in vitro antibacterial activity of Ag loaded hydrogels exposed to Pseudomona aeruginosa and Escherichia coli strains indicated a noticeable sustained inhibitory effect, especially for Ag–PU hydrogel nanocomposites with bacterial inhibition growth capabilities up to 120 h cultivation. PMID:28763050

Synthesis and characterization of biodegradable poly (ethylene glycol) and poly (caprolactone diol) end capped poly (propylene fumarate) cross linked amphiphilic hydrogel as tissue engineering scaffold material.

PubMed

Krishna, Lekshmi; Jayabalan, Muthu

2009-12-01

Biodegradable poly (caprolactone diol-co-propylene fumarate-co-ethylene glycol) amphiphilic polymer with poly (ethylene glycol) and poly (caprolactone diol) chain ends (PCL-PPF-PEG) was prepared. PCL-PPF-PEG undergoes fast setting with acrylamide (aqueous solution) by free radical polymerization and produces a crosslinked hydrogel. The cross linked and freeze-dried amphiphilic material has porous and interconnected network. It undergoes higher degree of swelling and water absorption to form hydrogel with hydrophilic and hydrophobic domains at the surface and appreciable tensile strength. The present hydrogel is compatible with L929 fibroblast cells. PCL-PPF-PEG/acrylamide hydrogel is a candidate scaffold material for tissue engineering applications.

Fast and facile fabrication of antifouling and hemocompatible PVDF membrane tethered with amino-acid modified PEG film

NASA Astrophysics Data System (ADS)

Zhang, Shuyou; Cao, Jingjing; Ma, Na; You, Meng; Wang, Xushan; Meng, Jianqiang

2018-01-01

A fast and facile protocol is reported aiming at improving the antifouling property and hemocompatibility of poly(vinylidene fluoride) (PVDF) membranes by tethering PEG hydrogel and zwitterion immobilization. The coated PEG hydrogel was first prepared by interfacial polymerization and tethered on an alkali treated PVDF membrane (PVDFA) surface via a simultaneous thio-ene and thiol-epoxy reaction. Then, the thiol groups of cysteine reacted with the epoxy groups in PEG hydrogel to fabricate the PVDFA-g-Cys membrane. The membrane fabrication was complete within less than 20 min and was conducted in mild conditions. The successful preparation of PVDFA-g-Cys membrane was confirmed by ATR-FTIR and XPS. Raman spectroscopy showed that the hydrogels covalently bonded to the PVDF membrane surface. The membrane retained its mechanical strength after modification. The SEM measurements suggested that the membrane became denser after hydrogel coating, meanwhile, the EDX test verified that the functional species uniformly distributed in the membrane matrix. Water contact angle (WCA), protein adsorption and protein filtration tests showed significant improvements in hydrophilicity and antifouling properties for the modified membrane. The negativity of the membrane surface measured by the streaming potential method provides a basis for protein resistance and hemocompatibility. Moreover, the suppressed platelet adhesion and prolonged plasma coagulant time show that the PVDFA-g-Cys membrane has ultralow thrombotic potential and better hemocompatibility. The reported surface modification method combing thio-ene and thio-epoxy chemistry not only facilitates fabrication of hemocompatible PVDF membrane but also provide an universal chemical platform for multifunctionalization of porous membranes.

Glucose-Responsive Trehalose Hydrogel for Insulin Stabilization and Delivery.

PubMed

Lee, Juneyoung; Ko, Jeong Hoon; Mansfield, Kathryn M; Nauka, Peter C; Bat, Erhan; Maynard, Heather D

2018-05-01

Effective delivery of therapeutic proteins is important for many biomedical applications. Yet, the stabilization of proteins during delivery and long-term storage remains a significant challenge. Herein, a trehalose-based hydrogel is reported that stabilizes insulin to elevated temperatures prior to glucose-triggered release. The hydrogel is synthesized using a polymer with trehalose side chains and a phenylboronic acid end-functionalized 8-arm poly(ethylene glycol) (PEG). The hydroxyls of the trehalose side chains form boronate ester linkages with the PEG boronic acid cross-linker to yield hydrogels without any further modification of the original trehalose polymer. Dissolution of the hydrogel is triggered upon addition of glucose as a stronger binder to boronic acid (K b = 2.57 vs 0.48 m -1 for trehalose), allowing the insulin that is entrapped during gelation to be released in a glucose-responsive manner. Moreover, the trehalose hydrogel stabilizes the insulin as determined by immunobinding after heating up to 90 °C. After 30 min heating, 74% of insulin is detected by enzyme-linked immunosorbent assay in the presence of the trehalose hydrogel, whereas only 2% is detected without any additives. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PEG-chitosan hydrogel with tunable stiffness for study of drug response of breast cancer cells

PubMed Central

Chang, Fei-Chien; Tsao, Ching-Ting; Lin, Anqi; Zhang, Mengying; Levengood, Sheeny Lan; Zhang, Miqin

2016-01-01

Mechanical properties of the extracellular matrix have a profound effect on the behavior of anchorage-dependent cells. However, the mechanisms that define the effects of matrix stiffness on cell behavior remains unclear. Therefore, the development and fabrication of synthetic matrices with well-defined stiffness is invaluable for studying the interactions of cells with their biophysical microenvironment in vitro. We demonstrate a methoxypolyethylene glycol (mPEG)-modified chitosan hydrogel network where hydrogel stiffness can be easily modulated under physiological conditions by adjusting the degree of mPEG grafting onto chitosan (PEGylation). We show that the storage modulus of the hydrogel increases as PEGylation decreases and the gels exhibit instant self-recovery after deformation. Breast cancer cells cultured on the stiffest hydrogels adopt a more malignant phenotype with increased resistance to doxorubicin as compared with cells cultured on tissue culture polystyrene or Matrigel. This work demonstrates the utility of mPEG-modified chitosan hydrogel, with tunable mechanical properties, as an improved replacement of conventional culture system for in vitro characterization of breast cancer cell phenotype and evaluation of cancer therapies. PMID:27595012

Controlled Thermoresponsive Hydrogels by Stereocomplexed PLA-PEG-PLA Prepared via Hybrid Micelles of Pre-Mixed Copolymers with Different PEG Lengths

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abebe, Daniel G.; Fujiwara, Tomoko

2012-09-05

The stereocomplexed hydrogels derived from the micelle mixture of two enantiomeric triblock copolymers, PLLA-PEG-PLLA and PDLA-PEG-PDLA, reported in 2001 exhibited sol-to-gel transition at approximately body temperature upon heating. However, the showed poor storage modulus (ca. 1000 Pa) determined their insufficiency as injectable implant biomaterials for many applications. In this study, the mechanical property of these hydrogels was significantly improved by the modifications of molecular weights and micelle structure. Co-micelles composed of block copolymers with two sizes of PEG block length were shown to possess unique and dissimilar properties from the micelles composed of single-sized block copolymers. The stereomixture of PLA-PEG-PLAmore » comicelles showed a controllable sol-to-gel transition at a wide temperature range of 4 and 80 C. The sol-gel phase diagram displays a linear relationship of temperature versus copolymer composition; hence, a transition at body temperature can be readily achieved by adjusting the mixed copolymer ratio. The resulting thermoresponsive hydrogels exhibit a storage modulus notably higher (ca. 6000 Pa) than that of previously reported hydrogels. As a physical network solely governed by self-reorganization of micelles, followed by stereocomplexation, this unique system offers practical, safe, and simple implantable biomaterials.« less

Injectable dual redox responsive diselenide-containing poly(ethylene glycol) hydrogel.

PubMed

Gong, Chu; Shan, Meng; Li, Bingqiang; Wu, Guolin

2017-09-01

An injectable dual redox responsive diselenide-containing poly(ethylene glycol) (PEG) hydrogel was successfully developed by combining the conceptions of injectable hydrogels and dual redox responsive diselenides. In the first step, four-armed PEG was modified with N-hydroxysuccinimide (NHS)-activated esters and thereafter, crosslinked by selenocystamine crosslinkers to form injectable hydrogels via the rapid reaction between NHS-activated esters and amino groups. The cross-sectional morphology, mechanical properties, and crosslinking modes of hydrogels were well characterized via scanning electron microscope (SEM), rheological measurements, and Fourier transform infrared spectra, respectively. In addition, the oxidation- and reduction-responsive degradation behaviors of hydrogels were observed and analyzed. The model drug, rhodamine B, was encapsulated in the hydrogel. The drug-loaded hydrogel exhibited a dual redox responsive release profile, which was consistent with the degradation experiments. The results of all experiments indicated that the formulated injectable dual redox responsive diselenide-containing PEG hydrogel can have potential applications in various biomedical fields such as drug delivery and stimuli-responsive drug release. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2451-2460, 2017. © 2017 Wiley Periodicals, Inc.

Release mechanisms of acetaminophen from polyethylene oxide/polyethylene glycol matrix tablets utilizing magnetic resonance imaging.

PubMed

Tajiri, Tomokazu; Morita, Shigeaki; Sakamoto, Ryosaku; Suzuki, Masazumi; Yamanashi, Shigeyuki; Ozaki, Yukihiro; Kitamura, Satoshi

2010-08-16

Release mechanism of acetaminophen (AAP) from extended-release tablets of hydrogel polymer matrices containing polyethylene oxide (PEO) and polyethylene glycol (PEG) were achieved using flow-through cell with magnetic resonance imaging (MRI). The hydrogel forming abilities are observed characteristically and the layer thickness which is corresponding to the diffusion length of AAP has a good correlation with the drug release profiles. In addition, polymeric erosion contribution to AAP releasing from hydrogel matrix tablets was directly quantified using size-exclusion chromatography (SEC). The matrix erosion profile indicates that the PEG erosion kinetic depends primarily on the composition ratio of PEG to PEO. The present study has confirmed that the combination of in situ MRI and SEC should be well suited to investigate the drug release mechanisms of hydrogel matrix such as PEO/PEG. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Immobilization of Cell-Adhesive Laminin Peptides in Degradable PEGDA Hydrogels Influences Endothelial Cell Tubulogenesis

PubMed Central

Ali, Saniya; Saik, Jennifer E.; Gould, Dan J.; Dickinson, Mary E.

2013-01-01

Abstract Attachment, spreading, and organization of endothelial cells into tubule networks are mediated by interactions between cells in the extracellular microenvironment. Laminins are key extracellular matrix components and regulators of cell adhesion, migration, and proliferation. In this study, laminin-derived peptides were conjugated to poly(ethylene glycol) (PEG) monoacrylate and covalently incorporated into degradable PEG diacrylate (PEGDA) hydrogels to investigate the influence of these peptides on endothelial cellular adhesion and function in organizing into tubule networks. Degradable PEGDA hydrogels were synthesized by incorporating a matrix metalloproteinase (MMP)–sensitive peptide, GGGPQGIWGQGK (abbreviated PQ), into the polymer backbone. The secretion of MMP-2 and MMP-9 by endothelial cells promotes polymer degradation and consequently cell migration. We demonstrate the formation of extensive networks of tubule-like structures by encapsulated human umbilical vein endothelial cells in hydrogels with immobilized synthetic peptides. The resulting structures were stabilized by pericyte precursor cells (10T1/2s) in vitro. During tubule formation and stabilization, extracellular matrix proteins such as collagen IV and laminin were deposited. Tubules formed in the matrix of metalloproteinase sensitive hydrogels were visualized from 7 days to 4 weeks in response to different combination of peptides. Moreover, hydrogels functionalized with laminin peptides and transplanted in a mouse cornea supported the ingrowth and attachment of endothelial cells to the hydrogel during angiogenesis. Results of this study illustrate the use of laminin-derived peptides as potential candidates for modification of biomaterials to support angiogenesis. PMID:23914330

Hybrid Elastin-like Polypeptide–Polyethylene Glycol (ELP-PEG) Hydrogels with Improved Transparency and Independent Control of Matrix Mechanics and Cell Ligand Density

PubMed Central

2015-01-01

Hydrogels have been developed as extracellular matrix (ECM) mimics both for therapeutic applications and basic biological studies. In particular, elastin-like polypeptide (ELP) hydrogels, which can be tuned to mimic several biochemical and physical characteristics of native ECM, have been constructed to encapsulate various types of cells to create in vitro mimics of in vivo tissues. However, ELP hydrogels become opaque at body temperature because of ELP’s lower critical solution temperature behavior. This opacity obstructs light-based observation of the morphology and behavior of encapsulated cells. In order to improve the transparency of ELP hydrogels for better imaging, we have designed a hybrid ELP-polyethylene glycol (PEG) hydrogel system that rapidly cross-links with tris(hydroxymethyl) phosphine (THP) in aqueous solution via Mannich-type condensation. As expected, addition of the hydrophilic PEG component significantly improves the light transmittance. Coherent anti-Stokes Raman scattering (CARS) microscopy reveals that the hybrid ELP-PEG hydrogels have smaller hydrophobic ELP aggregates at 37 °C. Importantly, this hydrogel platform enables independent tuning of adhesion ligand density and matrix stiffness, which is desirable for studies of cell–matrix interactions. Human fibroblasts encapsulated in these hydrogels show high viability (>98%) after 7 days of culture. High-resolution confocal microscopy of encapsulated fibroblasts reveals that the cells adopt a more spread morphology in response to higher RGD ligand concentrations and softer gel mechanics. PMID:25111283

Hybrid elastin-like polypeptide-polyethylene glycol (ELP-PEG) hydrogels with improved transparency and independent control of matrix mechanics and cell ligand density.

PubMed

Wang, Huiyuan; Cai, Lei; Paul, Alexandra; Enejder, Annika; Heilshorn, Sarah C

2014-09-08

Hydrogels have been developed as extracellular matrix (ECM) mimics both for therapeutic applications and basic biological studies. In particular, elastin-like polypeptide (ELP) hydrogels, which can be tuned to mimic several biochemical and physical characteristics of native ECM, have been constructed to encapsulate various types of cells to create in vitro mimics of in vivo tissues. However, ELP hydrogels become opaque at body temperature because of ELP's lower critical solution temperature behavior. This opacity obstructs light-based observation of the morphology and behavior of encapsulated cells. In order to improve the transparency of ELP hydrogels for better imaging, we have designed a hybrid ELP-polyethylene glycol (PEG) hydrogel system that rapidly cross-links with tris(hydroxymethyl) phosphine (THP) in aqueous solution via Mannich-type condensation. As expected, addition of the hydrophilic PEG component significantly improves the light transmittance. Coherent anti-Stokes Raman scattering (CARS) microscopy reveals that the hybrid ELP-PEG hydrogels have smaller hydrophobic ELP aggregates at 37 °C. Importantly, this hydrogel platform enables independent tuning of adhesion ligand density and matrix stiffness, which is desirable for studies of cell-matrix interactions. Human fibroblasts encapsulated in these hydrogels show high viability (>98%) after 7 days of culture. High-resolution confocal microscopy of encapsulated fibroblasts reveals that the cells adopt a more spread morphology in response to higher RGD ligand concentrations and softer gel mechanics.

Keratocyte behavior in three-dimensional photopolymerizable poly(ethylene glycol) hydrogels

PubMed Central

Thibault, Richard; Ambrose, Winnette McIntosh; Schein, Oliver D.; Chakravarti, Shukti; Elisseeff, Jennifer

2015-01-01

The goal of this study was to evaluate three-dimensional (3-D) poly(ethylene glycol) (PEG) hydrogels as a culture system for studying corneal keratocytes. Bovine keratocytes were subcultured in DMEM/F-12 containing 10% fetal bovine serum (FBS) through passage 5. Primary keratocytes (P0) and corneal fibroblasts from passages 1 (P1) and 3 (P3) were photoencapsulated at various cell concentrations in PEG hydrogels via brief exposure to light. Additional hydrogels contained adhesive YRGDS and nonadhesive YRDGS peptides. Hydrogel constructs were cultured in DMEM/F-12 with 10% FBS for 2 and 4 weeks. Cell viability was assessed by DNA quantification and vital staining. Biglycan, type I collagen, type III collagen, keratocan and lumican expression were determined by reverse transcriptase–polymerase chain reaction. Deposition of type I collagen, type III collagen and keratan sulfate (KS)-containing matrix components was visualized using confocal microscopy. Keratocytes in a monolayer lost their stellate morphology and keratocan expression, displayed elongated cell bodies, and up-regulated biglycan, type I collagen and type III collagen characteristic of corneal fibroblasts. Encapsulated keratocytes remained viable for 4 weeks with spherical morphologies. Hydrogels supported production of KS, type I collagen and type III collagen matrix components. PEG-based hydrogels can support keratocyte viability and matrix production. 3-D hydrogel culture can stabilize but not restore the keratocyte phenotype. This novel application of PEG hydrogels has potential use in the study of corneal keratocytes in a 3-D environment. PMID:18567550

Chitosan cross-linked with poly(ethylene glycol)dialdehyde via reductive amination as effective controlled release carriers for oral protein drug delivery.

PubMed

Jing, Zi-Wei; Ma, Zhi-Wei; Li, Chen; Jia, Yi-Yang; Luo, Min; Ma, Xi-Xi; Zhou, Si-Yuan; Zhang, Bang-Le

2017-02-15

The covalently cross-linked chitosan-poly(ethylene glycol) 1540 derivatives have been developed as a controlled release system with potential for the delivery of protein drug. The swelling characteristics of the hydrogels based on these derivatives as the function of different PEG content and the release profiles of a model protein (bovine serum albumin, BSA) from the hydrogels were evaluated in simulated gastric fluid with or without enzyme in order to simulate the gastrointestinal tract conditions. The derivatives cross-linked with difunctional PEG 1540 -dialdehyde via reductive amination can swell in alkaline pH and remain insoluble in acidic medium. The cumulative release amount of BSA was relatively low in the initial 2h and increased significantly at pH 7.4 with intestinal lysozyme for additional 12h. The results proved that the release-and-hold behavior of the cross-linked CS-PEG 1540 H-CS hydrogel provided a swell and intestinal enzyme controlled release carrier system, which is suitable for oral protein drug delivery. Copyright © 2016 Elsevier Ltd. All rights reserved.

Tough stimuli-responsive supramolecular hydrogels with hydrogen-bonding network junctions.

PubMed

Guo, Mingyu; Pitet, Louis M; Wyss, Hans M; Vos, Matthijn; Dankers, Patricia Y W; Meijer, E W

2014-05-14

Hydrogels were prepared with physical cross-links comprising 2-ureido-4[1H]-pyrimidinone (UPy) hydrogen-bonding units within the backbone of segmented amphiphilic macromolecules having hydrophilic poly(ethylene glycol) (PEG). The bulk materials adopt nanoscopic physical cross-links composed of UPy-UPy dimers embedded in segregated hydrophobic domains dispersed within the PEG matrix as comfirmed by cryo-electron microscopy. The amphiphilic network was swollen with high weight fractions of water (w(H2O) ≈ 0.8) owing to the high PEG weight fraction within the pristine polymers (w(PEG) ≈ 0.9). Two different PEG chain lengths were investigated and illustrate the corresponding consequences of cross-link density on mechanical properties. The resulting hydrogels exhibited high strength and resilience upon deformation, consistent with a microphase separated network, in which the UPy-UPy interactions were adequately shielded within hydrophobic nanoscale pockets that maintain the network despite extensive water content. The cumulative result is a series of tough hydrogels with tunable mechanical properties and tractable synthetic preparation and processing. Furthermore, the melting transition of PEG in the dry polymer was shown to be an effective stimulus for shape memory behavior.

Hydrogel Tethering Enhances Interdomain Stabilization of Single-Chain Antibodies.

PubMed

Xiong, Yijia; Ford, Nicole R; Hecht, Karen A; Roesijadi, Guritno; Squier, Thomas C

2017-11-15

Here, we identify the importance of molecular crowding agents in the functional stabilization of scFv antibodies. Antibodies were tethered through an engineered calmodulin (CaM)-binding peptide into a stimulus-responsive hydrogel composed of poly(ethylene glycol) (PEG)-functionalized CaM. Macromolecular crowding is modulated by transient heating, which decreases effective pore sizes. Using a fluorescent ligand bound to the scFv, frequency-domain fluorescence spectroscopy was used to assess the structural coupling between the V H and the V L domains and relationships with functional stabilization. There is minimal structural coupling between the V H and the V L domains in solution, as is apparent from the substantial rotational mobility for the bound ligand, that is suggestive of an independent mobility for the V H and the V L domains. In comparison, the hydrogel matrix acts to structurally couple the V H and the V L domains, resulting in a reduction in rotational mobility and a retention of ligand binding in the presence of 8.0 M urea. Under these same conditions, ligand binding is disrupted for scFv antibodies in solution. Increases in the stabilization of scFv antibodies in hydrogels is not simply the result of molecular crowding because decreases in pore size act to destabilize ligand binding. Rather, our results suggest that the functional stabilization of the scFv antibody within the PEG hydrogel matrix includes important factors involving protein solvation that stabilize interdomain interactions between the V H and the V L domains necessary for ligand binding.

Mussel-inspired histidine-based transient network metal coordination hydrogels

PubMed Central

Fullenkamp, Dominic E.; He, Lihong; Barrett, Devin G.; Burghardt, Wesley R.; Messersmith, Phillip B.

2013-01-01

Transient network hydrogels cross-linked through histidine-divalent cation coordination bonds were studied by conventional rheologic methods using histidine-modified star poly(ethylene glycol) (PEG) polymers. These materials were inspired by the mussel, which is thought to use histidine-metal coordination bonds to impart self-healing properties in the mussel byssal thread. Hydrogel viscoelastic mechanical properties were studied as a function of metal, pH, concentration, and ionic strength. The equilibrium metal-binding constants were determined by dilute solution potentiometric titration of monofunctional histidine-modified methoxy-PEG and were found to be consistent with binding constants of small molecule analogs previously studied. pH-dependent speciation curves were then calculated using the equilibrium constants determined by potentiometric titration, providing insight into the pH dependence of histidine-metal ion coordination and guiding the design of metal coordination hydrogels. Gel relaxation dynamics were found to be uncorrelated with the equilibrium constants measured, but were correlated to the expected coordination bond dissociation rate constants. PMID:23441102

Hyaluronic Acid (HA)-Polyethylene glycol (PEG) as injectable hydrogel for intervertebral disc degeneration patients therapy

NASA Astrophysics Data System (ADS)

Putri Kwarta, Cityta; Widiyanti, Prihartini; Siswanto

2017-05-01

Chronic Low Back Pain (CLBP) is one health problem that is often encountered in a community. Inject-able hydrogels are the newest way to restore the disc thickness and hydration caused by disc degeneration by means of minimally invasive surgery. Thus, polymers can be combined to improve the characteristic properties of inject-able hydrogels, leading to use of Hyaluronic Acid (a natural polymer) and Polyethylene glycol (PEG) with Horse Radish Peroxide (HRP) cross linker enzymes. The swelling test results, which approaches were the ideal disc values, were sampled with variation of enzyme concentrations of 0.25 µmol/min/mL. The enzyme concentrations were 33.95%. The degradation test proved that the sample degradation increased along with the decrease of the HRP enzyme concentration. The results of the cytotoxicity assay with MTT assay method showed that all samples resulted in the 90% of living cells are not toxic. In vitro injection, models demonstrated that higher concentration of the enzymes was less state of gel which would rupture when released from the agarose gel. The functional group characterization shows the cross linking bonding in sample with enzyme adding. The conclusion of this study is PEG-HA-HRP enzyme are safe polymer composites which have a potential to be applied as an injectable hydrogel for intervertebral disc degeneration.

Production of bioinspired and rationally designed polymer hydrogels for controlled delivery of therapeutic proteins

NASA Astrophysics Data System (ADS)

Kim, Sung Hye

Hydrogel systems for controlled delivery therapeutic growth factors have been developed in a wide spectrum of strategies: these systems aim for the release of growth factors via a passive diffusion, electrostatic interaction, degradation of hydrogels, and responsiveness to external stimuli. Heparin, a highly sulfated glycosaminoglycan (GAG), was employed for a targeted delivery system of vascular endothelial growth factor (VEGF) to endothelial cells overexpressing a relevant receptor VEGFR-2. Addition of dimeric VEGF to 4-arm star-shaped poly(ethylene glycol) (PEG) immobilized with low-molecular weight heparin (LMWH) afforded a non-covalently assembled hydrogel via interaction between heparin and VEGF, with storage modulus 10 Pa. The release of VEGF and hydrogel erosion reached maximum 100 % at day 4 in the presence of VEGFR-2 overexpressing pocine aortic endothelial cell (PAE/KDR), while those of 80% were achieved via passive release at day 5 in the presence of PAE cell lacking VEGFR-2 or in the absence of cell, indicating that the release of VEGF was in targeted manner toward cell receptor. The proliferation of PAE/KDR in the presence of [PEG-LMWH/VEGF] hydrogel was greater by ca. 30% at day 4 compared to that of PAE, confirming that the release of VEGF was in response to the cellular demand. The phosphorylation fraction of VEGFR-2 on PAE/KDR was greater in the presence of [PEG-LMWH/VEGF] hydrogel, increasing from 0.568 at day 1 to 0.790 at day 4, whereas it was maintained at 0.230 at day 4 in the presence of [PEG-LMWH] hydrogel. This study has proven that this hydrogel, assembled via bio-inspired non-covalent interaction, liberating VEGFon celluar demand to target cell, eroding upon VEGF release, and triggering endothelial cell proliferation, could be used in multiple applications including targeted delivery and angiogenesis. Heparin has been widely exploited in growth factor delivery systems owing to its ability to bind many growth factors through the flexible patterns of functional groups. However, heterogeneity in the composition and in the polydispersity of heparin has been problematic in controlled delivery system and thus motivated the development of homogeneous heparin mimics. Peptides of appropriate sequence and chemical function have therefore recently emerged as potential replacements for heparin in select applications. Studied was the assessment of the binding affinities of multiple sulfated peptides (SPs) for a set of heparin-binding peptides (HBPs) and for VEGF; these binding partners have application in the selective immobilization of proteins and in hydrogel formation through non-covalent interactions. Sulfated peptides were produced via solid-phase methods, and their affinity for the HBPs and VEGF was assessed via affinity liquid chromatography (ALC), surface plasmon resonance (SPR), and in select cases, isothermal titration calorimetry (ITC). The shortest peptide, SPa, showed the highest affinity binding of HBPs and VEGF165 in both ALC and SPR measurements, with slight exceptions. Of the investigated HBPs, a peptide based on the heparin-binding domain of human platelet factor 4 showed greatest binding affinities toward all of the SPs, consistent with its stronger binding to heparin. The affinity between SPa and PF4ZIP was indicated via SPR ( KD = 5.27 muM) and confirmed via ITC (KD = 8.09 muM). The binding by SPa of both VEGF and HBPs suggests its use as a binding partner to multiple species, and the use of these interactions in assembly of materials. Given that the peptide sequences can be varied to control binding affinity and selectivity, opportunities are also suggested for the production of a wider array of matrices with selective binding and release properties useful for biomaterials applications. Hydrogel consisting of SPa was formed via a covalent Michael Addition reaction between maleimide- and thiol-terminated multi-arm PEGs and Cys-SPa. The mechanical property of hydrogel was tunable from ca. 186 to 1940 Pa. by varing the cross-linking density, suggesting its flexible applications depending on matrix needs. The non-anti-coagulative property of SPa, assessed via activated partial thromboplastin time (APTT) and HeptestRTM in comparison to LMWH, implied its usefulness in applications without excessive bleeding. The VEGF released from [PEG-SPa] hydrogel showed up to ca. 400% greater bioactivity on proliferation of human umbilical vein endothelical cell (HUVEC) compared to the VEGF incubated in solution for the same period: this was significantly higher than that of [PEG] hydrogel (ca. 280%), suggesting the SPa may protect the bioactivity of VEGF when bound. The release of dual growth factor, i.e. VEGF and fibroblast growth factor-2 (FGF-2), were investigated on [PEG-SPa] hydrogel: the release of bFGF was lower than that of VEGF due to weaker binding affinity to matrix-bound SPa. The HUVEC culture on dual growth factor loaded [PEG-SPa] showed that the synergistic effects of dual system in select concentrations, suggesting the opportunity of manipulating cell responses. Given that sulfated peptides for various binding targets with desired affinity can be identified, applications are suggested in multiple growth factors delivery where an integrated action of multiple growth factors is required, such as angiogenesis.

Hydrogel Macroporosity and the Prolongation of Transgene Expression and the Enhancement of Angiogenesis

PubMed Central

Shepard, Jaclyn A.; Virani, Farrukh R.; Goodman, Ashley G.; Gossett, Timothy D.; Shin, Seungjin; Shea, Lonnie D.

2012-01-01

The utility of hydrogels for regenerative medicine can be improved through localized gene delivery to enhance their bioactivity. However, current systems typically lead to low-level transgene expression located in host tissue surrounding the implant. Herein, we investigated the inclusion of macropores into hydrogels to facilitate cell ingrowth and enhance gene delivery within the macropores in vivo. Macropores were created within PEG hydrogels by gelation around gelatin microspheres, with gelatin subsequently dissolved by incubation at 37°C. The macropores were interconnected, as evidenced by homogeneous cell seeding in vitro and complete cell infiltration in vivo. Lentivirus loaded within hydrogels following gelation retained its activity relative to the unencapsulated control virus. In vivo, macroporous PEG demonstrated sustained, elevated levels of transgene expression for 6 weeks, while hydrogels without macropores had transient expression. Transduced cells were located throughout the macroporous structure, while non-macroporous PEG hydrogels had transduction only in the adjacent host tissue. Delivery of lentivirus encoding for VEGF increased vascularization relative to the control, with vessels throughout the macropores of the hydrogel. The inclusion of macropores within the hydrogel to enhance cell infiltration enhances transduction and influences tissue development, which has implications for multiple regenerative medicine applications. PMID:22800542

Nondestructive evaluation of a new hydrolytically degradable and photo-clickable PEG hydrogel for cartilage tissue engineering.

PubMed

Neumann, Alexander J; Quinn, Timothy; Bryant, Stephanie J

2016-07-15

Photopolymerizable and hydrolytically labile poly(ethylene glycol) (PEG) hydrogels formed from photo-clickable reactions were investigated as cell delivery platforms for cartilage tissue engineering (TE). PEG hydrogels were formed from thiol-norbornene PEG macromers whereby the crosslinks contained caprolactone segments with hydrolytically labile ester linkages. Juvenile bovine chondrocytes encapsulated in the hydrogels were cultured for up to four weeks and assessed biochemically and histologically, using standard destructive assays, and for mechanical and ultrasound properties, as nondestructive assays. Bulk degradation of acellular hydrogels was confirmed by a decrease in compressive modulus and an increase in mass swelling ratio over time. Chondrocytes deposited increasing amounts of sulfated glycosaminoglycans and collagens in the hydrogels with time. Spatially, collagen type II and aggrecan were present in the neotissue with formation of a territorial matrix beginning at day 21. Nondestructive measurements revealed an 8-fold increase in compressive modulus from days 7 to 28, which correlated with total collagen content. Ultrasound measurements revealed changes in the constructs over time, which differed from the mechanical properties, and appeared to correlate with ECM structure and organization shown by immunohistochemical analysis. Overall, non-destructive and destructive measurements show that this new hydrolytically degradable PEG hydrogel is promising for cartilage TE. Designing synthetic hydrogels whose degradation matches tissue growth is critical to maintaining mechanical integrity as the hydrogel degrades and new tissue forms, but is challenging due to the nature of the hydrogel crosslinks that inhibit diffusion of tissue matrix molecules. This study details a promising, new, photo-clickable and synthetic hydrogel whose degradation supports cartilaginous tissue matrix growth leading to the formation of a territorial matrix, concomitant with an increase in mechanical properties. Nondestructive assays based on mechanical and ultrasonic properties were also investigated using a novel instrument and found to correlate with matrix deposition and evolution. In sum, this study presents a new hydrogel platform combined with nondestructive assessments, which together have potential for in vitro cartilage tissue engineering. Copyright © 2016 Acta Materialia Inc. All rights reserved.

Tough Supramolecular Hydrogel Based on Strong Hydrophobic Interactions in a Multiblock Segmented Copolymer

PubMed Central

2017-01-01

We report the preparation and structural and mechanical characterization of a tough supramolecular hydrogel, based exclusively on hydrophobic association. The system consists of a multiblock, segmented copolymer of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic dimer fatty acid (DFA) building blocks. A series of copolymers containing 2K, 4K, and 8K PEG were prepared. Upon swelling in water, a network is formed by self-assembly of hydrophobic DFA units in micellar domains, which act as stable physical cross-link points. The resulting hydrogels are noneroding and contain 75–92 wt % of water at swelling equilibrium. Small-angle neutron scattering (SANS) measurements showed that the aggregation number of micelles ranges from 2 × 102 to 6 × 102 DFA units, increasing with PEG molecular weight. Mechanical characterization indicated that the hydrogel containing PEG 2000 is mechanically very stable and tough, possessing a tensile toughness of 4.12 MJ/m3. The high toughness, processability, and ease of preparation make these hydrogels very attractive for applications where mechanical stability and load bearing features of soft materials are required. PMID:28469284

Design of a vascularized synthetic poly(ethylene glycol) macroencapsulation device for islet transplantation.

PubMed

Weaver, Jessica D; Headen, Devon M; Hunckler, Michael D; Coronel, Maria M; Stabler, Cherie L; García, Andrés J

2018-07-01

The use of immunoisolating macrodevices in islet transplantation confers the benefit of safety and translatability by containing transplanted cells within a single retrievable device. To date, there has been limited development and characterization of synthetic poly(ethylene glycol) (PEG)-based hydrogel macrodevices for islet encapsulation and transplantation. Herein, we describe a two-component synthetic PEG hydrogel macrodevice system, designed for islet delivery to an extrahepatic islet transplant site, consisting of a hydrogel core cross-linked with a non-degradable PEG dithiol and a vasculogenic outer layer cross-linked with a proteolytically sensitive peptide to promote degradation and enhance localized vascularization. Synthetic PEG macrodevices exhibited equivalent passive molecular transport to traditional microencapsulation materials (e.g., alginate) and long-term stability in the presence of proteases in vitro and in vivo, out to 14 weeks in rats. Encapsulated islets demonstrated high viability within the device in vitro and the incorporation of RGD adhesive peptides within the islet encapsulating PEG hydrogel improved insulin responsiveness to a glucose challenge. In vivo, the implementation of a vasculogenic, degradable hydrogel layer at the outer interface of the macrodevice enhanced vascular density within the rat omentum transplant site, resulting in improved encapsulated islet viability in a syngeneic diabetic rat model. These results highlight the benefits of the facile PEG platform to provide controlled presentation of islet-supportive ligands, as well as degradable interfaces for the promotion of engraftment and overall graft efficacy. Copyright © 2018 Elsevier Ltd. All rights reserved.

Mussel-Inspired Dopamine and Carbon Nanotube Leading to a Biocompatible Self-Rolling Conductive Hydrogel Film.

PubMed

Jiang, Junzi; Huang, Yong; Wang, Yitian; Xu, Hui; Xing, Malcolm; Zhong, Wen

2017-08-18

We report a novel self-rolling, conductive, and biocompatible multiwall carbon nanotube (MWCNT)-dopamine-polyethylene glycol (PEG) hydrogel film. The gel can self-fold into a thin tube when it is transferred from a glass slide to an aqueous environment, regardless of the concentrations of the MWCNT. The film presents a highly organized pattern, which results from the self-assembly of hydrophilic dopamine and hydrophobic carbon nanotubes. By exploring the biomedical potential, we found that MWCNT-included rolled film is nontoxic and can promote cell growth. For further functional verification by qPCR (quantitative polymerase chain reaction), bone marrow derived mesenchymal cells present higher levels of osteogenic differentiations in response to a higher concentration of CNTs. The results suggest that the self-rolling, conductive CNT-dopamine-PEG hydrogel could have multiple potentials, including biomedical usage and as a conductive biosensor.

A PEG-Based Hydrogel for Effective Wound Care Management

PubMed Central

Chen, Sen-Lu; Fu, Ru-Huei; Liao, Shih-Fei; Liu, Shih-Ping; Lin, Shinn-Zong; Wang, Yu-Chi

2018-01-01

It is extremely challenging to achieve strong adhesion in soft tissues while minimizing toxicity, tissue damage, and other side effects caused by wound sealing materials. In this study, flexible synthetic hydrogel sealants were prepared based on polyethylene glycol (PEG) materials. PEG is a synthetic material that is nontoxic and inert and, thus, suitable for use in medical products. We evaluated the in vitro biocompatibility tests of the dressings to assess cytotoxicity and irritation, sensitization, pyrogen toxicity, and systemic toxicity following the International Organization for Standardization 10993 standards and the in vivo effects of the hydrogel samples using Coloskin liquid bandages as control samples for potential in wound closure. PMID:29637814

Isolated Reporter Bacteria in Supramolecular Hydrogel Microwell Arrays

PubMed Central

2017-01-01

The combination of supramolecular hydrogels formed by low molecular weight gelator self-assembly via noncovalent interactions within a scaffold derived from polyethylene glycol (PEG) affords an interesting approach to immobilize fully functional, isolated reporter bacteria in novel microwell arrays. The PEG-based scaffold serves as a stabilizing element and provides physical support for the self-assembly of the C2-phenyl-derived gelator on the micrometer scale. Supramolecular hydrogel microwell arrays with various shapes and sizes were used to isolate single or small numbers of Escherichia coli TOP10 pTetR-LasR-pLuxR-GFP. In the presence of the autoinducer N-(3-oxododecanoyl) homoserine lactone, the entrapped E. coli in the hydrogel microwell arrays showed an increased GFP expression. The shape and size of microwell arrays did not influence the fluorescence intensity and the projected size of the bacteria markedly, while the population density of seeded bacteria affected the number of bacteria expressing GFP per well. The hydrogel microwell arrays can be further used to investigate quorum sensing, reflecting communication in inter- and intraspecies bacterial communities for biology applications in the field of biosensors. In the future, these self-assembled hydrogel microwell arrays can also be used as a substrate to detect bacteria via secreted autoinducers. PMID:28486805

Isolated Reporter Bacteria in Supramolecular Hydrogel Microwell Arrays.

PubMed

Li, Ping; Dou, Xiaoqiu; Feng, Chuanliang; Müller, Mareike; Chang, Matthew Wook; Frettlöh, Martin; Schönherr, Holger

2017-08-08

The combination of supramolecular hydrogels formed by low molecular weight gelator self-assembly via noncovalent interactions within a scaffold derived from polyethylene glycol (PEG) affords an interesting approach to immobilize fully functional, isolated reporter bacteria in novel microwell arrays. The PEG-based scaffold serves as a stabilizing element and provides physical support for the self-assembly of the C 2 -phenyl-derived gelator on the micrometer scale. Supramolecular hydrogel microwell arrays with various shapes and sizes were used to isolate single or small numbers of Escherichia coli TOP10 pTetR-LasR-pLuxR-GFP. In the presence of the autoinducer N-(3-oxododecanoyl) homoserine lactone, the entrapped E. coli in the hydrogel microwell arrays showed an increased GFP expression. The shape and size of microwell arrays did not influence the fluorescence intensity and the projected size of the bacteria markedly, while the population density of seeded bacteria affected the number of bacteria expressing GFP per well. The hydrogel microwell arrays can be further used to investigate quorum sensing, reflecting communication in inter- and intraspecies bacterial communities for biology applications in the field of biosensors. In the future, these self-assembled hydrogel microwell arrays can also be used as a substrate to detect bacteria via secreted autoinducers.

Fabrication of micropatterned hydrogels for neural culture systems using dynamic mask projection photolithography.

PubMed

Curley, J Lowry; Jennings, Scott R; Moore, Michael J

2011-02-11

Increasingly, patterned cell culture environments are becoming a relevant technique to study cellular characteristics, and many researchers believe in the need for 3D environments to represent in vitro experiments which better mimic in vivo qualities. Studies in fields such as cancer research, neural engineering, cardiac physiology, and cell-matrix interaction have shown cell behavior differs substantially between traditional monolayer cultures and 3D constructs. Hydrogels are used as 3D environments because of their variety, versatility and ability to tailor molecular composition through functionalization. Numerous techniques exist for creation of constructs as cell-supportive matrices, including electrospinning, elastomer stamps, inkjet printing, additive photopatterning, static photomask projection-lithography, and dynamic mask microstereolithography. Unfortunately, these methods involve multiple production steps and/or equipment not readily adaptable to conventional cell and tissue culture methods. The technique employed in this protocol adapts the latter two methods, using a digital micromirror device (DMD) to create dynamic photomasks for crosslinking geometrically specific poly-(ethylene glycol) (PEG) hydrogels, induced through UV initiated free radical polymerization. The resulting "2.5D" structures provide a constrained 3D environment for neural growth. We employ a dual-hydrogel approach, where PEG serves as a cell-restrictive region supplying structure to an otherwise shapeless but cell-permissive self-assembling gel made from either Puramatrix or agarose. The process is a quick simple one step fabrication which is highly reproducible and easily adapted for use with conventional cell culture methods and substrates. Whole tissue explants, such as embryonic dorsal root ganglia (DRG), can be incorporated into the dual hydrogel constructs for experimental assays such as neurite outgrowth. Additionally, dissociated cells can be encapsulated in the photocrosslinkable or self polymerizing hydrogel, or selectively adhered to the permeable support membrane using cell-restrictive photopatterning. Using the DMD, we created hydrogel constructs up to ~1mm thick, but thin film (<200 μm) PEG structures were limited by oxygen quenching of the free radical polymerization reaction. We subsequently developed a technique utilizing a layer of oil above the polymerization liquid which allowed thin PEG structure polymerization. In this protocol, we describe the expeditious creation of 3D hydrogel systems for production of microfabricated neural cell and tissue cultures. The dual hydrogel constructs demonstrated herein represent versatile in vitro models that may prove useful for studies in neuroscience involving cell survival, migration, and/or neurite growth and guidance. Moreover, as the protocol can work for many types of hydrogels and cells, the potential applications are both varied and vast.

Poly(acrylic acid)/polyethylene glycol hygrogel prepared by using gamma-ray irradiation for mucosa adhesion

NASA Astrophysics Data System (ADS)

Nho, Young-Chang; Park, Jong-Seok; Shin, Jung-Woong; Lim, Youn-Mook; Jeong, Sung-In; Shin, Young-Min; Gwon, Hui-Jeong; Khil, Myung-Seob; Lee, Deok-Won; Ahn, Sung-Jun

2015-01-01

A buccal delivery system provides a much milder environment for drug delivery compared to an oral delivery which presents a hostile environment for drugs, especially proteins and polypeptides, owing to acid hydrolysis. Local delivery in an oral cavity has particular applications in the treatment of toothaches, periodontal disease, and bacterial infections. Poly(acrylic acid) (PAA)-based hydrogels prepared using a chemical initiator have been attempted for a mucoadhesive system owing to their flexibility and excellent bioadhesion. In this experiment, PAA and polyethylene glycol (PEG) were selected to prepare using a radiation process a bioadhesive hydrogel for adhesion to mucosal surfaces. PAA and PEG were dissolved in purified water to prepare a homogeneous PAA/PEG solution, and the solution was then irradiated using an electron beam at dose up to 70 kGy to make the hydrogels. Their physical properties, such as gel percent, swelling percent, and adhesive strength to mucosal surfaces, were investigated. In this experiment, various amounts of PEG were incorporated into the PAA to enhance the mucoadhesive property of the hydrogels. The effect of the molecular weight of PEG on the mucoadhesion was also examined.

A Biosynthetic Scaffold that Facilitates Chondrocyte-Mediated Degradation and Promotes Articular Cartilage Extracellular Matrix Deposition.

PubMed

Sridhar, Balaji V; Dailing, Eric A; Brock, J Logan; Stansbury, Jeffrey W; Randolph, Mark A; Anseth, Kristi S

2015-12-01

Articular cartilage remains a significant clinical challenge to repair because of its limited self-healing capacity. Interest has grown in the delivery of autologous chondrocytes to cartilage defects, and combining cell-based therapies with scaffolds that capture aspects of native tissue and allow cell-mediated remodeling could improve outcomes. Currently, scaffold-based therapies with encapsulated chondrocytes permit matrix production; however, resorption of the scaffold often does not match the rate of matrix production by chondrocytes, which can limit functional tissue regeneration. Here, we designed a hybrid biosynthetic system consisting of poly (ethylene glycol) (PEG) endcapped with thiols and crosslinked by norbornene-functionalized gelatin via a thiol-ene photopolymerization. The protein crosslinker was selected to facilitate chondrocyte-mediated scaffold remodeling and matrix deposition. Gelatin was functionalized with norbornene to varying degrees (~4-17 norbornenes/gelatin), and the shear modulus of the resulting hydrogels was characterized (<0.1-0.5 kPa). Degradation of the crosslinked PEG-gelatin hydrogels by chondrocyte-secreted enzymes was confirmed by gel permeation chromatography. Finally, chondrocytes encapsulated in these biosynthetic scaffolds showed significantly increased glycosaminoglycan deposition over just 14 days of culture, while maintaining high levels of viability and producing a distributed matrix. These results indicate the potential of a hybrid PEG-gelatin hydrogel to permit chondrocyte-mediated remodeling and promote articular cartilage matrix production. Tunable scaffolds that can easily permit chondrocyte-mediated remodeling may be useful in designing treatment options for cartilage tissue engineering applications.

A Biosynthetic Scaffold that Facilitates Chondrocyte-Mediated Degradation and Promotes Articular Cartilage Extracellular Matrix Deposition

PubMed Central

Sridhar., Balaji V.; Dailing, Eric A.; Brock, J. Logan; Stansbury, Jeffrey W.; Randolph, Mark A.; Anseth, Kristi S.

2015-01-01

Articular cartilage remains a significant clinical challenge to repair because of its limited self-healing capacity. Interest has grown in the delivery of autologous chondrocytes to cartilage defects, and combining cell-based therapies with scaffolds that capture aspects of native tissue and allow cell-mediated remodeling could improve outcomes. Currently, scaffold-based therapies with encapsulated chondrocytes permit matrix production; however, resorption of the scaffold often does not match the rate of matrix production by chondrocytes, which can limit functional tissue regeneration. Here, we designed a hybrid biosynthetic system consisting of poly (ethylene glycol) (PEG) endcapped with thiols and crosslinked by norbornene-functionalized gelatin via a thiol-ene photopolymerization. The protein crosslinker was selected to facilitate chondrocyte-mediated scaffold remodeling and matrix deposition. Gelatin was functionalized with norbornene to varying degrees (~4–17 norbornenes/gelatin), and the shear modulus of the resulting hydrogels was characterized (<0.1–0.5 kPa). Degradation of the crosslinked PEG-gelatin hydrogels by chondrocyte-secreted enzymes was confirmed by gel permeation chromatography. Finally, chondrocytes encapsulated in these biosynthetic scaffolds showed significantly increased glycosaminoglycan deposition over just 14 days of culture, while maintaining high levels of viability and producing a distributed matrix. These results indicate the potential of a hybrid PEG-gelatin hydrogel to permit chondrocyte-mediated remodeling and promote articular cartilage matrix production. Tunable scaffolds that can easily permit chondrocyte-mediated remodeling may be useful in designing treatment options for cartilage tissue engineering applications. PMID:26900597

Collagen-Based Fillers as Alternatives to Cyanoacrylate Glue for the Sealing of Large Corneal Perforations.

PubMed

Samarawickrama, Chameen; Samanta, Ayan; Liszka, Aneta; Fagerholm, Per; Buznyk, Oleksiy; Griffith, May; Allan, Bruce

2018-05-01

To describe the use of collagen-based alternatives to cyanoacrylate glue for the sealing of acute corneal perforations. A collagen analog comprising a collagen-like peptide conjugated to polyethylene glycol (CLP-PEG) and its chemical crosslinker were tested for biocompatibility. These CLP-PEG hydrogels, which are designed to act as a framework for corneal tissue regeneration, were then tested as potential fillers in ex vivo human corneas with surgically created full-thickness perforations. Bursting pressures were measured in each of 3 methods (n = 10 for each condition) of applying a seal: 1) cyanoacrylate glue with a polyethylene patch applied ab externo (gold standard); 2) a 100-μm thick collagen hydrogel patch applied ab interno, and 3) the same collagen hydrogel patch applied ab interno supplemented with CLP-PEG hydrogel molded in situ to fill the remaining corneal stromal defect. Cyanoacrylate gluing achieved a mean bursting pressure of 325.9 mm Hg, significantly higher than the ab interno patch alone (46.3 mm Hg) and the ab interno patch with the CLP-PEG filler (86.6 mm Hg). All experimental perforations were sealed effectively using 100 μm hydrogel sheets as an ab interno patch, whereas conventional ab externo patching with cyanoacrylate glue failed to provide a seal in 30% (3/10) cases. An ab interno patch system using CLP-PEG hydrogels designed to promote corneal tissue regeneration may be a viable alternative to conventional cyanoacrylate glue patching for the treatment of corneal perforation. Further experimentation and material refinement is required in advance of clinical trials.

A Genome-wide Analysis of Human Pluripotent Stem Cell-Derived Endothelial Cells in 2D or 3D Culture.

PubMed

Zhang, Jue; Schwartz, Michael P; Hou, Zhonggang; Bai, Yongsheng; Ardalani, Hamisha; Swanson, Scott; Steill, John; Ruotti, Victor; Elwell, Angela; Nguyen, Bao Kim; Bolin, Jennifer; Stewart, Ron; Thomson, James A; Murphy, William L

2017-04-11

A defined protocol for efficiently deriving endothelial cells from human pluripotent stem cells was established and vascular morphogenesis was used as a model system to understand how synthetic hydrogels influence global biological function compared with common 2D and 3D culture platforms. RNA sequencing demonstrated that gene expression profiles were similar for endothelial cells and pericytes cocultured in polyethylene glycol (PEG) hydrogels or Matrigel, while monoculture comparisons identified distinct vascular signatures for each cell type. Endothelial cells cultured on tissue-culture polystyrene adopted a proliferative phenotype compared with cells cultured on or encapsulated in PEG hydrogels. The proliferative phenotype correlated to increased FAK-ERK activity, and knockdown or inhibition of ERK signaling reduced proliferation and expression for cell-cycle genes while increasing expression for "3D-like" vasculature development genes. Our results provide insight into the influence of 2D and 3D culture formats on global biological processes that regulate cell function. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Injectable Self-Healing Hydrogel with Antimicrobial and Antifouling Properties.

PubMed

Li, Lin; Yan, Bin; Yang, Jingqi; Huang, Weijuan; Chen, Lingyun; Zeng, Hongbo

2017-03-22

Microbial adhesion, biofilm formation and associated microbial infection are common challenges faced by implanted biomaterials (e.g., hydrogels) in bioengineering applications. In this work, an injectable self-healing hydrogel with antimicrobial and antifouling properties was prepared through self-assembly of an ABA triblock copolymer employing catechol functionalized polyethylene glycol (PEG) as A block and poly{[2-(methacryloyloxy)-ethyl] trimethylammonium iodide}(PMETA) as B block. This hydrogel exhibits excellent thermosensitivity, and can effectively inhibit the growth of E. coli (>99.8% killing efficiency) and prevent cell attachment. It can also heal autonomously from repeated damage, through mussel-inspired catechol-mediated hydrogen bonding and aromatic interactions, exhibiting great potential in bioengineering applications.

Design of poly(mPEGMA-co-MAA) hydrogel-based mPEG-b-PCL nanoparticles for oral meloxicam delivery.

PubMed

Shi, Yongli; Liu, Zhaomin; Yang, Yaxing; Xu, Xiaojie; Li, Yan; Li, Tong

2017-07-01

To enhance the therapeutic effects of meloxicam (MLX), we developed an oral MLX-loaded poly(ethylene glycol)-b-poly(ε-caprolactone) nanoparticles@hydrogel (MLX-NPs@hydrogel) preparation. The MLX-NPs were fabricated via a solvent evaporation method, and their morphologies were observed by a JEM-1011 transmission electron microscope (TEM). The poly(mPEGMA-co-MAA) hydrogels were synthesized, and studies on their pH sensibilities were carried out in pH1.2, 6.8, and 7.4 buffers. The final MLX-NPs@hydrogel preparation was obtained by immersing the hydrogels in the MLX-NPs suspensions (pH7.4) for 48h. The thermodynamic properties and cytotoxicity of the MLX-NPs@hydrogel preparation were also studied. TEM images illustrated that mPEG-b-PCL NPs had a uniform size distribution. The poly(mPEGMA-co-MAA) hydrogels showed an excellent pH-sensibility. Thermal gravity analysis (TGA) data suggested that the protection of hydrogels improved the stability of mPEG-b-PCL NPs. The release studies revealed that MLX-NPs@hydrogel could deliver the MLX-NPs into alkalescent environment (e.g. intestinal tract). Then, the medicated NPs released MLX at a sustained release profile. Such preparation could overcome the drawbacks of oral MLX, and enhance its therapeutic effects. Therefore, the NPs@hydrogel was a promising sustained-controlled release matrix. Copyright © 2017 Elsevier B.V. All rights reserved.

Clonazepam release from bioerodible hydrogels based on semi-interpenetrating polymer networks composed of poly(epsilon-caprolactone) and poly(ethylene glycol) macromer.

PubMed

Cho, C S; Han, S Y; Ha, J H; Kim, S H; Lim, D Y

1999-04-30

Poly(ethylene glycol)(PEG) macromers terminated with acrylate groups and semi-interpenetrating polymer networks (SIPNs) composed of poly(epsilon-caprolactone)(PCL) and PEG macromer were synthesized to obtain a bioerodible hydrogel. Polymerization of PEG macromer resulted in the formation of cross-linked gels due to the multifunctionality of macromer. Glass transition temperature (Tg) and melting temperature (Tm) of PEG networks and PCL in the SIPNs were inner-shifted, indicating an interpenetration of PCL and PEG chains. Water content in the SIPNs increased with increasing PEG weight fraction due to the hydrophilicity of PEG. The amount of clonazepam (CNZ) released from the SIPNs increased with higher content in the SIPNs, lower drug loading, lower concentration of PEG macromer during the SIPNs preparation, and higher molecular weight of PEG. In particular, a combination with low PEG content and low CNZ solubility in water led to long-term constant release from these matrices in vitro and in vivo. Copyright.

Controlled drug delivery through a novel PEG hydrogel encapsulated silica aerogel system.

PubMed

Giray, Seda; Bal, Tuğba; Kartal, Ayse M; Kızılel, Seda; Erkey, Can

2012-05-01

A novel composite material consisting of a silica aerogel core coated by a poly(ethylene) glycol (PEG) hydrogel was developed. The potential of this novel composite as a drug delivery system was tested with ketoprofen as a model drug due to its solubility in supercritical carbon dioxide. The results indicated that both drug loading capacity and drug release profiles could be tuned by changing hydrophobicity of aerogels, and that drug loading capacity increased with decreased hydrophobicity, while slower release rates were achieved with increased hydrophobicity. Furthermore, higher concentration of PEG diacrylate in the prepolymer solution of the hydrogel coating delayed the release of the drug which can be attributed to the lower permeability at higher PEG diacrylate concentrations. The novel composite developed in this study can be easily implemented to achieve the controlled delivery of various drugs and/or proteins for specific applications. Copyright © 2012 Wiley Periodicals, Inc.

An Injectable Hydrogel Prepared Using a PEG/Vitamin E Copolymer Facilitating Aqueous-Driven Gelation.

PubMed

Zhang, Jianfeng; Muirhead, Ben; Dodd, Megan; Liu, Lina; Xu, Fei; Mangiacotte, Nicole; Hoare, Todd; Sheardown, Heather

2016-11-14

Hydrogels have been widely explored for biomedical applications, with injectable hydrogels being of particular interest for their ability to precisely deliver drugs and cells to targets. Although these hydrogels have demonstrated satisfactory properties in many cases, challenges still remain for commercialization. In this paper, we describe a simple injectable hydrogel based on poly(ethylene glycol) (PEG) and a vitamin E (Ve) methacrylate copolymer prepared via simple free radical polymerization and delivered in a solution of low molecular weight PEG and Ve as the solvent instead of water. The hydrogel formed immediately in an aqueous environment with a controllable gelation time. The driving force for gelation is attributed to the self-assembly of hydrophobic Ve residues upon exposure to water to form a physically cross-linked polymer network via polymer chain rearrangement and subsequent phase separation, a spontaneous process with water uptake. The hydrogels can be customized to give the desired water content, mechanical strength, and drug release kinetics simply by formulating the PEGMA-co-Ve polymer with an appropriate solvent mixture or by varying the molecular weight of the polymer. The hydrogels exhibited no significant cytotoxicity in vitro using fibroblasts and good tissue compatibility in the eye and when injected subcutaneously. These polymers thus have the potential to be used in a variety of applications where injection of a drug or cell containing depot would be desirable.

Poly(n-vinylpyrrolidone) hydrogels: 2.Hydrogel composites as wound dressing for tropical environment

NASA Astrophysics Data System (ADS)

Himly, N.; Darwis, D.; Hardiningsih, L.

1993-10-01

POLY(N-VINYLPYRROLIDONE) HYDROGELS: 2. HYDROGEL COMPOSITES AS WOUND DRESSING FOR TROPICAL ENVIRONMENT. The effects of irradiation on hydration and other properties of poly(vinylpyrrolidone) (PVP) hydrogel composites have been investigated. The aqueous solution of vinylpyrrolidone (VP) 10 wt % was mixed with several additives such as agar and polyethylen glycol (PEG). The solution was then irradiated with gamma rays from Cobalt-60 source at room temperature. Several parameters such as elongation at break (EB), tensile strength (TS), degree of swelling (DS), water vapor transmission rate (WVTR), equilibrium water content (EWC), microbial growth and penetration test, and water activity (Aw) were analysed at room temperature of 29 ±2°C humidity of 80 ± 10%. Results show that elongation at break of hydrogel membranes with initial composition of VP with agar, VP with agar and PEG were 240 % and 250 % kGy, the equilibrium water content of membranes were 96 to 90%, whereas degree of swelling were 55 to 10. The WVTR of hydrogel membranes with initial composition of VP with agar and PEG was 70 g m -2h -1, while the water activity was 0.9. Such hydrogel membranes exhibits the following properties: They are elastic, transparent, flexible, impermeable for bacteria. They absopt a high capacity of water, attached to healthy skin but not to the wound and they are easy to remove. These properties of the hydrogel membranes allow for applying as a wound dressings in tropical environment.

Development of a cellularly degradable PEG hydrogel to promote articular cartilage extracellular matrix deposition.

PubMed

Sridhar, Balaji V; Brock, John L; Silver, Jason S; Leight, Jennifer L; Randolph, Mark A; Anseth, Kristi S

2015-04-02

Healing articular cartilage remains a significant clinical challenge because of its limited self-healing capacity. While delivery of autologous chondrocytes to cartilage defects has received growing interest, combining cell-based therapies with scaffolds that capture aspects of native tissue and promote cell-mediated remodeling could improve outcomes. Currently, scaffold-based therapies with encapsulated chondrocytes permit matrix production; however, resorption of the scaffold does not match the rate of production by cells leading to generally low extracellular matrix outputs. Here, a poly (ethylene glycol) (PEG) norbornene hydrogel is functionalized with thiolated transforming growth factor (TGF-β1) and cross-linked by an MMP-degradable peptide. Chondrocytes are co-encapsulated with a smaller population of mesenchymal stem cells, with the goal of stimulating matrix production and increasing bulk mechanical properties of the scaffold. The co-encapsulated cells cleave the MMP-degradable target sequence more readily than either cell population alone. Relative to non-degradable gels, cellularly degraded materials show significantly increased glycosaminoglycan and collagen deposition over just 14 d of culture, while maintaining high levels of viability and producing a more widely-distributed matrix. These results indicate the potential of an enzymatically degradable, peptide-functionalized PEG hydrogel to locally influence and promote cartilage matrix production over a short period. Scaffolds that permit cell-mediated remodeling may be useful in designing treatment options for cartilage tissue engineering applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Lamellar Biogels: Fluid-Membrane-Based Hydrogels Containing Polymer Lipids

NASA Astrophysics Data System (ADS)

Warriner, Heidi E.; Idziak, Stefan H. J.; Slack, Nelle L.; Davidson, Patrick; Safinya, Cyrus R.

1996-02-01

A class of lamellar biological hydrogels comprised of fluid membranes of lipids and surfactants with small amounts of low molecular weight poly(ethylene glycol)-derived polymer lipids (PEG-lipids) were studied by x-ray diffraction, polarized light microscopy, and rheometry. In contrast to isotropic hydrogels of polymer networks, these membrane-based birefringent liquid crystalline biogels, labeled Lα,g, form the gel phase when water is added to the liquid-like lamellar L_α phase, which reenters a liquid-like mixed phase upon further dilution. Furthermore, gels with larger water content require less PEG-lipid to remain stable. Although concentrated (~50 weight percent) mixtures of free PEG (molecular weight, 5000) and water do not gel, gelation does occur in mixtures containing as little as 0.5 weight percent PEG-lipid. A defining signature of the Lα,g regime as it sets in from the fluid lamellar L_α phase is the proliferation of layer-dislocation-type defects, which are stabilized by the segregation of PEG-lipids to the defect regions of high membrane curvature that connect the membranes.

Smart hydrogel-functionalized textile system with moisture management property for skin application

NASA Astrophysics Data System (ADS)

Wang, Xiaowen; Hu, Huawen; Yang, Zongyue; He, Liang; Kong, Yeeyee; Fei, Bin; Xin, John H.

2014-12-01

In this study, a functional textile-based material for topical skin application was fabricated by coating a thermoresponsive hydrogel onto one side of absorbent nonwoven fabric. The thermoresponsive hydrogel was synthesized easily through coupling of poly (ethylene glycol) (PEG) and poly (ɛ-caprolactone) (PCL) with hexamethylene diisocyanate (HMDI) as a chemical linker. The chemical structure of the as-prepared triblock copolymer hydrogel was unraveled by FTIR and 1H NMR analysis. The hydrogel showed a temperature-triggered sol-gel transition behavior and high potential for use as drug controlled release. When the surrounding temperature was close to the skin temperature of around 34 °C, it became a moisture management system where the liquids including sweat, blood, and other body fluids can be transported unidirectionally from one fabric side with the hydrophobic hydrogel coating to the untreated opposite side. This thereby showed that the thermoresponsive hydrogel-coated textile materials had a function to keep topical skin area clean, breathable, and comfortable, thus suggesting a great potential and significance for long-term skin treatment application. The structure and surface morphology of the thermoresponsive hydrogel, in vitro drug release behavior, and the mechanism of unidirectional water transport were investigated in detail. Our success in preparation of the functional textile composites will pave the way for development of various polymer- or textile-based functional materials that are applicable in the real world.

Synthesis and Characterization of Degradable Bioconjugated Hydrogels with Hyperbranched Multifunctional Crosslinkers

PubMed Central

Pedrón, Sara; Peinado, Carmen; Bosch, Paula; S.Anseth, Kristi

2010-01-01

Hyperbranched poly(ester amide) polymer (Hybrane™ S1200; Mn 1200 g/mol) was functionalized with maleic anhydride (MA) and propylene sulfide, to obtain multifunctional crosslinkers with fumaric and thiol-end groups, S1200MA and S1200SH, respectively. The degree of substitution of maleic acid groups (DS) was controlled by varying the molar ratio of MA to S1200 in the reaction mixture. Hydrogels were obtained by UV crosslinking of functionalized S1200 and poly(ethyleneglycol) diacrylate (PEGDA) in aqueous solutions. Compressive modulus increased with decreasing the S1200/PEG ratio and also depended on the DS of the multifunctional crosslinker (S1200). Also, heparin-based macromonomers together with functionalized hyperbranched polymers were used to construct novel functional hydrogels. The multivalent hyperbranched polymers allowed high crosslinking densities in heparin modified gels while introducing biodegradation sites. Both heparin presence and acrylate/thiol ratio have an impact on degradation profiles and morphologies. Hyperbranched crosslinked hydrogels showed no evidence of cell toxicity. Overall, the multifunctional crosslinkers afford hydrogels with promising properties that suggest that these may be suitable for tissue engineering applications. PMID:20561601

Reinforcement of mono- and bi-layer poly(ethylene glycol) hydrogels with a fibrous collagen scaffold

PubMed Central

Kinneberg, K. R. C.; Nelson, A.; Stender, M.; Aziz, A. H.; Mozdzen, L. C.; Harley, B. A. C.; Bryant, S. J.; Ferguson, V. L.

2015-01-01

Biomaterial-based tissue engineering strategies hold great promise for osteochondral tissue repair. Yet significant challenges remain in joining highly dissimilar materials to achieve a biomimetic, mechanically robust design for repairing interfaces between soft tissue and bone. This study sought to improve interfacial properties and function in a bilayer, multi-phase hydrogel interpenetrated with a fibrous collagen scaffold. ‘Soft’ 10% (w/w) and ‘stiff’ 30% (w/w) PEGDM was formed into mono- or bilayer hydrogels possessing a sharp diffusional interface. Hydrogels were evaluated as single- (hydrogel only) or multi-phase (hydrogel+fibrous scaffold penetrating throughout the stiff layer and extending >500μm into the soft layer). Including a fibrous scaffold into both soft and stiff single-phase hydrogels significantly increased tangent modulus and toughness and decreased lateral expansion under compressive loading. In multi-phase hydrogels, finite element simulations predict substantially reduced stress and strain gradients across the soft—stiff hydrogel interface. When combining two low moduli constituent material, composites theory poorly predicts the observed, large modulus increases. These results suggest material structure associated with the fibrous scaffold penetrating within the PEG hydrogel as the major contributor to improved properties and function – the hydrogel bore compressive loads and the 3D fibrous scaffold was loaded in tension thus resisting lateral expansion. PMID:26001970

Chondrogenesis of Human Bone Marrow Mesenchymal Stem Cells in 3-Dimensional, Photocrosslinked Hydrogel Constructs: Effect of Cell Seeding Density and Material Stiffness

PubMed Central

Sun, Aaron X.; Lin, Hang; Fritch, Madalyn R.; Shen, He; Alexander, Pete G.; DeHart, Michael; Tuan, Rocky S.

2018-01-01

Three-dimensional hydrogel constructs incorporated with live stem cells that support chondrogenic differentiation and maintenance offer a promising regenerative route towards addressing the limited self-repair capabilities of articular cartilage. In particular, hydrogel scaffolds that augment chondrogenesis and recapitulate the native physical properties of cartilage, such as compressive strength, can potentially be applied in point-of-care procedures. We report here the synthesis of two new materials, [poly-L-lactic acid/polyethylene glycol/poly-L-lactic acid] (PLLA-PEG 1000) and [poly-D,L-lactic acid/polyethylene glycol/poly-D,L-lactic acid] (PDLLA-PEG 1000), that are biodegradable, biocompatible (>80% viability post fabrication), and possess high, physiologically relevant mechanical strength (~1,500 to 1,800 kPa). This study examined the effects of physiologically relevant cell densities (4, 8, 20, and 50 × 106/mL) and hydrogel stiffnesses (~150kPa to ~1,500 kPa Young’s moduli) on chondrogenesis of human bone marrow stem cells incorporated in hydrogel constructs fabricated with these materials and a previously characterized PDLLA-PEG 4000. Results showed that 20 × 106 cells/mL, under a static culture condition, was the most efficient cell seeding density for extracellular matrix (ECM) production on the basis of hydroxyproline and glycosaminoglycan content. Interestingly, material stiffness did not significantly affect chondrogenesis, but rather material concentration was correlated to chondrogenesis with increasing levels at lower concentrations based on ECM production, chondrogenic gene expression, and histological analysis. These findings establish optimal cell densities for chondrogenesis within three-dimensional cell-incorporated hydrogels, inform hydrogel material development for cartilage tissue engineering, and demonstrate the efficacy and potential utility of PDLLA-PEG 1000 for point-of-care treatment of cartilage defects. PMID:28611002

Synthesis of stiffness-tunable and cell-responsive Gelatin-poly(ethylene glycol) hydrogel for three-dimensional cell encapsulation.

PubMed

Cao, Ye; Lee, Bae Hoon; Peled, Havazelet Bianco; Venkatraman, Subbu S

2016-10-01

Biosynthetic poly(ethylene glycol) (PEG)-based hydrogels have been extensively investigated as extracellular matrix (ECM) mimicking gels as they retain the benefits of both ECM (biological cues) and synthetic hydrogels (tunable mechanical properties). In this article, we developed and characterized a new gelatin-PEG (GP) hydrogel that retains the benefits of gelatin and synthetic hydrogels. In this strategy, the thiolation of gelatin was accomplished by reacting with Traut's reagent; the thiolated gelatin was then conjugated to one end of PEG diacrylate (PEGDA) by Michael-type addition reaction. Two kinds of GP precursors, GP30 and GP60, were synthesized by changing the amount of Traut's reagent, while the weight ratio between thiolated-gelatin and PEGDA of GP30 and GP60 was 1.451:1 and 0.785:1, respectively. Finally, neonatal human dermal fibroblasts were encapsulated into the hydrogel by cross-linking the remaining double bonds of precursor under ultraviolet light. These GP hydrogels can encapsulate the fibroblasts in situ with high cell viability. Moreover, the behaviors of cells within the GP hydrogels can be modulated by varying the cross-linking density of GP hydrogel (storage modulus from 40 to 2000 Pa). In particular, this article showed that a minimum amount of cell-binding motifs (gelatin >2.30 wt/vol % and 44.0% dry weight percentage) are required for attachment; and appropriate initial rheological and structural properties (storage modulus <∼100 Pa and mesh size >∼150 nm) can accelerate the attachment of cells and improve cell viability. Hence, this mixed-hydrogel platform allows an easily control hydrogel structure and modulates cell behavior to reconstruct new tissue in the three-dimensional microenvironments. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2401-2411, 2016. © 2016 Wiley Periodicals, Inc.

Synthesis of photodegradable hydrogels as dynamically tunable cell culture platforms

PubMed Central

Kloxin, April M.; Tibbitt, Mark W.; Anseth, Kristi S.

2013-01-01

We describe a detailed procedure to create photolabile, poly(ethylene glycol)-based (PEG) hydrogels and manipulate material properties in situ. The cytocompatible chemistry and degradation process enable dynamic, tunable changes for applications in 2D or 3D cell culture. The materials are created by synthesizing an o-nitrobenzylether-based photodegradable monomer that can be coupled to primary amines. Here, we provide coupling procedures to PEG-bis-amine to form a photodegradable crosslinker or to the fibronectin-derived peptide RGDS to form a photoreleasable tether. Hydrogels are synthesized with the photodegradable crosslinker in the presence or absence of cells, allowing direct encapsulation or seeding on surfaces. Cell-material interactions can be probed in 2D or 3D by spatiotemporally controlling the gel microenvironment, which allows unique experiments to be performed to monitor cell response to changes in their niche. Degradation is readily achieved with cytocompatible wavelengths of low intensity flood irradiation (365 to 420 nm) in minutes or with highintensity laser irradiation (405 nm) in seconds. In this protocol, synthesis and purification of the photodegradable monomers take approximately 2 weeks, but can be substantially shortened by purchasing the o-nitrobenzylether precursor. Preparation of the sterile solutions for hydrogel fabrication takes hours, while the reaction to form the final hydrogel is complete in minutes. Hydrogel degradation occurs on-demand, in seconds to minutes, with user-directed light exposure. This comprehensive protocol is useful for controlling peptide presentation and substrate modulus during cell culture on or within an elastic matrix. These PEG-based materials are useful for probing the dynamic influence of cell-cell and cell-material interactions on cell function in 2D or 3D. While other protocols are available for controlling peptide presentation or modulus, few allow manipulation of material properties in situ and in the presence of cells down to the micrometer scale. PMID:21127482

Effect of grafting RGD and BMP-2 protein-derived peptides to a hydrogel substrate on osteogenic differentiation of marrow stromal cells.

PubMed

He, Xuezhong; Ma, Junyu; Jabbari, Esmaiel

2008-11-04

Osteogenic differentiation and mineralization of bone marrow stromal (BMS) cells depends on the cells' interactions with bioactive peptides associated with the matrix proteins. The RGD peptides of ECM proteins interact with BMS cells through integrin surface receptors to facilitate cell spreading and adhesion. The BMP peptide corresponding to residues 73-92 of bone morphogenetic protein-2 promotes differentiation and mineralization of BMS cells. The objective of this work was to investigate the effects of RGD and BMP peptides, grafted to a hydrogel substrate, on osteogenic differentiation and mineralization of BMS cells. RGD peptide was acrylamide-terminated by reacting acrylic acid with the N-terminal amine group of the peptide to produce the functionalized Ac-GRGD peptide. The PEGylated BMP peptide was reacted with 4-carboxybenzenesulfonazide to produce an azide functionalized Az-mPEG-BMP peptide. Poly (lactide-co-ethylene oxide- co-fumarate) (PLEOF) macromer was cross-linked with Ac-GRGD peptide and propargyl acrylate to produce an RGD conjugated hydrogel. Az-mPEG-BMP peptide was grafted to the hydrogel by "click chemistry". The RGD and BMP peptide density on the hydrogel surface was 1.62+/-0.37 and 5.2+/-0.6 pmol/cm2, respectively. BMS cells were seeded on the hydrogels and the effect of RGD and BMP peptides on osteogenesis was evaluated by measuring ALPase activity and calcium content with incubation time. BMS cells cultured on RGD conjugated, BMP peptide grafted, and RGD+BMP peptide modified hydrogels showed 3, 2.5, and 5-fold increase in ALPase activity after 14 days incubation. BMS cells seeded on RGD+BMP peptides modified hydrogel showed 4.9- and 11.8-fold increase in calcium content after 14 and 21 days, respectively, which was significantly higher than RGD conjugated or BMP grafted hydrogels. These results demonstrate that RGD and BMP peptides, grafted to a hydrogel substrate, act synergistically to enhance osteogenic differentiation and mineralization of BMS cells. These findings are potentially useful in developing engineered scaffolds for bone regeneration.

Injectable Dopamine-Modified Poly(ethylene glycol) Nanocomposite Hydrogel with Enhanced Adhesive Property and Bioactivity

PubMed Central

2015-01-01

A synthetic mimic of mussel adhesive protein, dopamine-modified four-armed poly(ethylene glycol) (PEG-D4), was combined with a synthetic nanosilicate, Laponite (Na0.7+(Mg5.5Li0.3Si8)O20(OH)4)0.7–), to form an injectable naoncomposite tissue adhesive hydrogel. Incorporation of up to 2 wt % Laponite significantly reduced the cure time while enhancing the bulk mechanical and adhesive properties of the adhesive due to strong interfacial binding between dopamine and Laponite. The addition of Laponite did not alter the degradation rate and cytocompatibility of PEG-D4 adhesive. On the basis of subcutaneous implantation in rat, PEG-D4 nanocomposite hydrogels elicited minimal inflammatory response and exhibited an enhanced level of cellular infiltration as compared to Laponite-free samples. The addition of Laponite is potentially a simple and effective method for promoting bioactivity in a bioinert, synthetic PEG-based adhesive while simultaneously enhancing its mechanical and adhesive properties. PMID:25222290

Micropatterning of a nanoporous alumina membrane with poly(ethylene glycol) hydrogel to create cellular micropatterns on nanotopographic substrates.

PubMed

Lee, Hyun Jong; Kim, Dae Nyun; Park, Saemi; Lee, Yeol; Koh, Won-Gun

2011-03-01

In this paper, we describe a simple method for fabricating micropatterned nanoporous substrates that are capable of controlling the spatial positioning of mammalian cells. Micropatterned substrates were prepared by fabricating poly(ethylene glycol) (PEG) hydrogel microstructures on alumina membranes with 200 nm nanopores using photolithography. Because hydrogel precursor solution could infiltrate and become crosslinked within the nanopores, the resultant hydrogel micropatterns were firmly anchored on the substrate without the use of adhesion-promoting monolayers, thereby allow tailoring of the surface properties of unpatterned nanoporous areas. For mammalian cell patterning, arrays of microwells of different dimensions were fabricated. These microwells were composed of hydrophilic PEG hydrogel walls surrounding nanoporous bottoms that were modified with cell-adhesive Arg-Gly-Asp (RGD) peptides. Because the PEG hydrogel was non-adhesive towards proteins and cells, cells adhered selectively and remained viable within the RGD-modified nanoporous regions, thereby creating cellular micropatterns. Although the morphology of cell clusters and the number of cells inside one microwell were dependent on the lateral dimension of the microwells, adhered cells that were in direct contact with nanopores were able to penetrate into the nanopores by small extensions (filopodia) for all the different sizes of microwells evaluated. Copyright © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Process Extension from Embryonic Stem Cell-Derived Motor Neurons through Synthetic Extracellular Matrix Mimics

NASA Astrophysics Data System (ADS)

McKinnon, Daniel Devaud

This thesis focuses on studying the extension of motor axons through synthetic poly(ethylene glycol) PEG hydrogels that have been modified with biochemical functionalities to render them more biologically relevant. Specifically, the research strategy is to encapsulate embryonic stem cell-derived motor neurons (ESMNs) in synthetic PEG hydrogels crosslinked through three different chemistries providing three mechanisms for dynamically tuning material properties. First, a covalently crosslinked, enzymatically degradable hydrogel is developed and exploited to study the biophysical dynamics of axon extension and matrix remodeling. It is demonstrated that dispersed motor neurons require a battery of adhesive peptides and growth factors to maintain viability and extend axons while those in contact with supportive neuroglial cells do not. Additionally, cell-degradable crosslinker peptides and a soft modulus mimicking that of the spinal cord are requirements for axon extension. However, because local degradation of the hydrogel results in a cellular environment significantly different than that of the bulk, enzymatically degradable peptide crosslinkers were replaced with reversible covalent hydrazone bonds to study the effect of hydrogel modulus on axon extension. This material is characterized in detail and used to measure forces involved in axon extension. Finally, a hydrogel with photocleavable linkers incorporated into the network structure is exploited to explore motor axon response to physical channels. This system is used to direct the growth of motor axons towards co-cultured myotubes, resulting in the formation of an in vitro neural circuit.

Thermo-responsive hydrogels for intravitreal injection and biomolecule release

NASA Astrophysics Data System (ADS)

Drapala, Pawel

In this dissertation, we develop an injectable polymer system to enable localized and prolonged release of therapeutic biomolecules for improved treatment of Age-Related Macular Degeneration (AMD). Thermo-responsive hydrogels derived from N-isopropylacrylamide (NIPAAm) and cross-linked with poly(ethylene glycol) (PEG) poly(L-Lactic acid) (PLLA) copolymer were synthesized via free-radical polymerization. These materials were investigated for (a) phase change behavior, (b) in-vitro degradation, (c) capacity for controlled drug delivery, and (d) biocompatibility. The volume-phase transition temperature (VPTT) of the PNIPAAm- co-PEG-b-PLLA hydrogels was adjusted using hydrophilic and hydrophobic moieties so that it is ca. 33°C. These hydrogels did not initially show evidence of degradation at 37°C due to physical cross-links of collapsed PNIPAAm. Only after addition of glutathione chain transfer agents (CTA)s to the precursor did the collapsed hydrogels become fully soluble at 37°C. CTAs significantly affected the release kinetics of biomolecules; addition of 1.0 mg/mL glutathione to 3 mM cross-linker accelerated hydrogel degradation, resulting in 100% release in less than 2 days. This work also explored the effect of PEGylation in order to tether biomolecules to the polymer matrix. It was demonstrated that non-site-specific PEGylation can postpone the burst release of solutes (up to 10 days in hydrogels with 0.5 mg/mL glutathione). Cell viability assays showed that at least two 20-minute buffer extraction steps were needed to remove cytotoxic elements from the hydrogels. Clinically-used therapeutic biomolecules LucentisRTM and AvastinRTM were demonstrated to be both stable and bioactive after release form PNIPAAm-co-PEG-b-PLLA hydrogels. The thermo-responsive hydrogels presented here offer a promising platform for the localized delivery of proteins such as recombinant antibodies.

Culture of preantral follicles in poly(ethylene) glycol-based, three-dimensional hydrogel: a relationship between swelling ratio and follicular developments

PubMed Central

Ahn, Jong Il; Kim, Gil Ah; Kwon, Hyo Suk; Ahn, Ji Yeon; Hubbell, Jeffrey A; Song, Yong Sang; Lee, Seung Tae; Lim, Jeong Mook

2015-01-01

This study was undertaken to examine how the softness of poly(ethylene) glycol (PEG)-based hydrogels, creating a three-dimensional (3D) microenvironment, influences the in vitro growth of mouse ovarian follicles. Early secondary, preantral follicles of 2 week-old mice were cultured in a crosslinked four-arm PEG hydrogel. The hydrogel swelling ratio, which relates to softness, was modified within the range 25.7–15.5 by increasing the reactive PEG concentration in the precursor solution from 5% to 15% w/v, but it did not influence follicular growth to form the pseudoantrum (60–80%; p = 0.76). Significant (p < 0.04) model effects, however, were detected in the maturation and developmental competence of the follicle-derived oocytes. A swelling ratio of > 21.4 yielded better oocyte maturation than other levels, while the highest competence to develop pronuclear and blastocyst formation was detected at 20.6. In conclusion, gel softness, as reflected in swelling ratio, was one of the essential factors for supporting folliculogenesis in vivo within a hydrogel-based, 3D microenvironment. © 2014 The Authors. Journal of Tissue Engineering and Regenerative Medicine published by John Wiley & Sons, Ltd. PMID:24493269

The influence of polymer molecular weight in lamellar gels based on PEG-lipids.

PubMed Central

Warriner, H E; Keller, S L; Idziak, S H; Slack, N L; Davidson, P; Zasadzinski, J A; Safinya, C R

1998-01-01

We report x-ray scattering, rheological, and freeze-fracture and polarizing microscopy studies of a liquid crystalline hydrogel called Lalpha,g. The hydrogel, found in DMPC, pentanol, water, and PEG-DMPE mixtures, differs from traditional hydrogels, which require high MW polymer, are disordered, and gel only at polymer concentrations exceeding an "overlap" concentration. In contrast, the Lalpha,g uses very low-molecular-weight polymer-lipids (1212, 2689, and 5817 g/mole), shows lamellar order, and requires a lower PEG-DMPE concentration to gel as water concentration increases. Significantly, the Lalpha,g contains fluid membranes, unlike Lbeta' gels, which gel via chain ordering. A recent model of gelation in Lalpha phases predicts that polymer-lipids both promote and stabilize defects; these defects, resisting shear in all directions, then produce elasticity. We compare our observations to this model, with particular attention to the dependence of gelation on the PEG MW used. We also use x-ray lineshape analysis of scattering from samples spanning the fluid-gel transition to obtain the elasticity coefficients kappa and B; this analysis demonstrates that although B in particular depends strongly on PEG-DMPE concentration, gelation is uncorrelated to changes in membrane elasticity. PMID:9649387

Synthetically Simple, Highly Resilient Hydrogels

PubMed Central

Cui, Jun; Lackey, Melissa A.; Madkour, Ahmad E.; Saffer, Erika M.; Griffin, David M.; Bhatia, Surita R.; Crosby, Alfred J.; Tew, Gregory N.

2014-01-01

Highly resilient synthetic hydrogels were synthesized by using the efficient thiol-norbornene chemistry to cross-link hydrophilic poly(ethylene glycol) (PEG) and hydrophobic polydimethylsiloxane (PDMS) polymer chains. The swelling and mechanical properties of the hydrogels were well-controlled by the relative amounts of PEG and PDMS. In addition, the mechanical energy storage efficiency (resilience) was more than 97% at strains up to 300%. This is comparable with one of the most resilient materials known: natural resilin, an elastic protein found in many insects, such as in the tendons of fleas and the wings of dragonflies. The high resilience of these hydrogels can be attributed to the well-defined network structure provided by the versatile chemistry, low cross-link density, and lack of secondary structure in the polymer chains. PMID:22372639

Influence of three-dimensional hyaluronic acid microenvironments on mesenchymal stem cell chondrogenesis.

PubMed

Chung, Cindy; Burdick, Jason A

2009-02-01

Mesenchymal stem cells (MSCs) are multipotent progenitor cells whose plasticity and self-renewal capacity have generated significant interest for applications in tissue engineering. The objective of this study was to investigate MSC chondrogenesis in photo-cross-linked hyaluronic acid (HA) hydrogels. Because HA is a native component of cartilage, and MSCs may interact with HA via cell surface receptors, these hydrogels could influence stem cell differentiation. In vitro and in vivo cultures of MSC-laden HA hydrogels permitted chondrogenesis, measured by the early gene expression and production of cartilage-specific matrix proteins. For in vivo culture, MSCs were encapsulated with and without transforming growth factor beta-3 (TGF-beta3) or pre-cultured for 2 weeks in chondrogenic medium before implantation. Up-regulation of type II collagen, aggrecan, and sox 9 was observed for all groups over MSCs at the time of encapsulation, and the addition of TGF-beta3 further enhanced the expression of these genes. To assess the influence of scaffold chemistry on chondrogenesis, HA hydrogels were compared with relatively inert poly(ethylene glycol) (PEG) hydrogels and showed enhanced expression of cartilage-specific markers. Differences between HA and PEG hydrogels in vivo were most noticeable for MSCs and polymer alone, indicating that hydrogel chemistry influences the commitment of MSCs to undergo chondrogenesis (e.g., approximately 43-fold up-regulation of type II collagen of MSCs in HA over PEG hydrogels). Although this study investigated only early markers of tissue regeneration, these results emphasize the importance of material cues in MSC differentiation microenvironments, potentially through interactions between scaffold materials and cell surface receptors.

The effect of matrix stiffness of injectable hydrogels on the preservation of cardiac function after a heart attack.

PubMed

Plotkin, Marian; Vaibavi, Srirangam Ramanujam; Rufaihah, Abdul Jalil; Nithya, Venkateswaran; Wang, Jing; Shachaf, Yonatan; Kofidis, Theo; Seliktar, Dror

2014-02-01

This study compares the effect of four injectable hydrogels with different mechanical properties on the post-myocardial infarction left ventricle (LV) remodeling process. The bioactive hydrogels were synthesized from Tetronic-fibrinogen (TF) and PEG-fibrinogen (PF) conjugates; each hydrogel was supplemented with two levels of additional cross-linker to increase the matrix stiffness as measured by the shear storage modulus (G'). Infarcts created by ligating the left anterior descending coronary artery in a rodent model were treated with the hydrogels, and all four treatment groups showed an increase in wall thickness, arterial density, and viable cardiac tissue in the peri-infarct areas of the LV. Echocardiography and hemodynamics data of the PF/TF treated groups showed significant improvement of heart function associated with the attenuated effects of the remodeling process. Multi-factorial regression analysis indicated that the group with the highest modulus exhibited the best rescue of heart function and highest neovascularization. The results of this study demonstrate that multiple properties of an injectable bioactive biomaterial, and notably the matrix stiffness, provide the multifaceted stimulation necessary to preserve cardiac function and prevent adverse remodeling following a heart attack. Copyright © 2013 Elsevier Ltd. All rights reserved.

Water-Responsive Shape Recovery Induced Buckling in Biodegradable Photo-Cross-Linked Poly(ethylene glycol) (PEG) Hydrogel.

PubMed

Salvekar, Abhijit Vijay; Huang, Wei Min; Xiao, Rui; Wong, Yee Shan; Venkatraman, Subbu S; Tay, Kiang Hiong; Shen, Ze Xiang

2017-02-21

The phenomenon of recovering the permanent shape from a severely deformed temporary shape, but only in the presence of the right stimulus, is known as the shape memory effect (SME). Materials with such an interesting effect are known as shape memory materials (SMMs). Typical stimuli to trigger shape recovery include temperature (heating or cooling), chemical (including water/moisture and pH value), and light. As a SMM is able not only to maintain the temporary shape but also to respond to the right stimulus when it is applied, via shape-shifting, a seamless integration of sensing and actuation functions is achieved within one single piece of material. Hydrogels are defined by their ability to absorb a large amount of water (from 10-20% up to thousands of times their dry weight), which results in significant swelling. On the other hand, dry hydrogels indeed belong to polymers, so they exhibit heat- and chemoresponsive SMEs as most polymers do. While heat-responsive SMEs have been spotted in a handful of wet hydrogels, so far, most dry hydrogels evince the heat and water (moisture)-responsive SMEs. Since water is one of the major components in living biological systems, water-responsive SMMs hold great potential for various implantable applications, including wound healing, intravascular devices, soft tissue reconstruction, and controlled drug delivery. This provides motivation to combine water-activated SMEs and swelling in hydrogels together to enhance the performance. In many applications, such as vascular occlusion via minimally invasive surgery for liver cancer treatment, the operation time (for both start and finish) is required to be well controlled. Due to the gradual and slow manner of water absorption for water-activated SMEs and swelling in hydrogels, even a combination of both effects encounters many difficulties to meet the timerequirements in real procedures of vascular occlusion. Recently, we have reported a bioabsorbable radiopaque water-responsive shape memory embolization plug for temporary vascular occlusion. The plug consists of a composite with a poly(dl-lactide-co-glycolide) (PLGA) core (loaded with radiopaque filler) and cross-linked poly(ethylene glycol) (PEG) hydrogel outer layer. The device can be activated by body fluid (or water) after about 2 min of immersion in water. The whole occlusion process is completed within a few dozens of seconds. The underlying mechanism is water-responsive shape recovery induced buckling, which occurs in an expeditious manner within a short time period and does not require complete hydration of the whole hydrogel. In this paper, we experimentally and analytically investigate the water-activated shape recovery induced buckling in this biodegradable PEG hydrogel to understand the fundamentals in precisely controlling the buckling time. The molecular mechanism responsible for the water-induced SME in PEG hydrogel is also elucidated. The original diameter and amount of prestretching are identified as two influential parameters to tailor the buckling time between 1 and 4 min as confirmed by both experiments and simulation. The phenomenon reported here, chemically induced buckling via a combination of the SME and swelling, is generic, and the study reported here should be applicable to other water- and non-water-responsive gels.

Novel Injectable Pentablock Copolymer Based Thermoresponsive Hydrogels for Sustained Release Vaccines.

PubMed

Bobbala, Sharan; Tamboli, Viral; McDowell, Arlene; Mitra, Ashim K; Hook, Sarah

2016-01-01

The need for multiple vaccinations to enhance the immunogenicity of subunit vaccines may be reduced by delivering the vaccine over an extended period of time. Here, we report two novel injectable pentablock copolymer based thermoresponsive hydrogels made of polyethyleneglycol-polycaprolactone-polylactide-polycaprolactone-polyethyleneglycol (PEG-PCL-PLA-PCL-PEG) with varying ratios of polycaprolactone (PCL) and polylactide (PLA), as single shot sustained release vaccines. Pentablock copolymer hydrogels were loaded with vaccine-encapsulated poly lactic-co-glycolic acid nanoparticles (PLGA-NP) or with the soluble vaccine components. Incorporation of PLGA-NP into the thermoresponsive hydrogels increased the complex viscosity of the gels, lowered the gelation temperature, and minimized the burst release of antigen and adjuvants. The two pentablock hydrogels stimulated both cellular and humoral responses. The addition of PLGA-NP to the hydrogels sustained immune responses for up to 49 days. The polymer with a higher ratio of PCL to PLA formed a more rigid gel, induced stronger immune responses, and stimulated effective anti-tumor responses in a prophylactic melanoma tumor model.

Cell-Responsive Hydrogel for Encapsulation of Vascular Cells

PubMed Central

Kraehenbuehl, Thomas P.; Ferreira, Lino S.; Zammaretti, Prisca; Hubbell, Jeffrey A.; Langer, Robert

2014-01-01

The in vitro potential of a synthetic matrix metalloproteinase (MMP)-responsive polyethylene glycol) (PEG)-based hydrogel as a bioactive co-encapsulation system for vascular cells and a small bioactive peptide, thymosin β4 (Tp4), was examined. We show that the physical incorporation of Tβ4 in this bioactive matrix creates a three-dimensional (3D) environment conducive for human umbilical vein endothelial cell (HUVEC) adhesion, survival, migration and organization. Gels with entrapped Tβ4 increased the survival of HUVEC compared to gels without Tp4, and significantly up-regulated the endothelial genes vascular endothelial-cadherin and angiopoietin-2, whereas von Willebrand factor was significantly down-regulated. Incorporation of Tβ4 significantly increased MMP-2 and MMP-9 secretion of encapsulated HUVEC. The gel acts as a controlled Tβ4-release system, as MMP-2 and MMP-9 enzymes trigger the release. In addition, Tβ4 facilitated HUVEC attachment and induced vascular-like network formation upon the PEG-hydrogels. These MMP-responsive PEG-hydrogels may thus serve as controlled co-encapsulation system of vascular cells and bioactive factors for in situ regeneration of ischemic tissues. PMID:19500842

RNA interfering molecule delivery from in situ forming biodegradable hydrogels for enhancement of bone formation in rat calvarial bone defects.

PubMed

Nguyen, Minh K; Jeon, Oju; Dang, Phuong N; Huynh, Cong T; Varghai, Davood; Riazi, Hooman; McMillan, Alexandra; Herberg, Samuel; Alsberg, Eben

2018-06-06

RNA interference (RNAi) may be an effective and valuable tool for promoting the growth of functional tissue, as short interfering RNA (siRNA) and microRNA (miRNA) can block the expression of genes that have negative effects on tissue regeneration. Our group has recently reported that the localized and sustained presentation of siRNA against noggin (siNoggin) and miRNA-20a from in situ forming poly(ethylene glycol) (PEG) hydrogels enhanced osteogenic differentiation of encapsulated human bone marrow-derived mesenchymal stem cells (hMSCs). Here, the capacity of the hydrogel system to accelerate bone formation in a rat calvarial bone defect model is presented. After 12 weeks post-implantation, the hydrogels containing encapsulated hMSCs and miRNA-20a resulted in more bone formation in the defects than the hydrogels containing hMSCs without siRNA or with negative control siRNA. This localized and sustained RNA interfering molecule delivery system may provide an excellent platform for healing bony defects and other tissues. Delivery of RNAi molecules may be a valuable strategy to guide cell behavior for tissue engineering applications, but to date there have been no reports of a biomaterial system capable of both encapsulation of cells and controlled delivery of incorporated RNA. Here, we present PEG hydrogels that form in situ via Michael type reaction, and that permit encapsulation of hMSCs and the concomitant controlled delivery of siNoggin and/or miRNA-20a. These RNAs were chosen to suppress noggin, a BMP-2 antagonist, and/or PPAR-γ, a negative regulator of BMP-2-mediated osteogenesis, and therefore promote osteogenic differentiation of hMSCs and subsequent bone repair in critical-sized rat calvarial defects. Simultaneous delivery of hMSCs and miRNA-20a enhanced repair of these defects compared to hydrogels containing hMSCs without siRNA or with negative control siRNA. This in situ forming PEG hydrogel system offers an exciting platform for healing critical-sized bone defects by localized, controlled delivery of RNAi molecules to encapsulated hMSCs and surrounding cells. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Functionalizable hydrogel microparticles of tunable size and stiffness for soft-tissue filler applications

PubMed Central

Chan, Ka Man Carmen; Li, Randolph H.; Chapman, Joseph W.; Trac, Eric M.; Kobler, James B.; Zeitels, Steven M.; Langer, Robert; Karajanagi, Sandeep S.

2014-01-01

Particle size, stiffness and surface functionality are important in determining the injection site, safety and efficacy of injectable soft-tissue fillers. Methods to produce soft injectable biomaterials with controlled particle characteristics are therefore desirable. Here we report a method based on suspension photopolymerization and semi-interpenetrating network (semi-IPN) to synthesize soft, functionalizable, spherical hydrogel microparticles (MP) of independently tunable size and stiffness. MP were prepared using acrylated forms of polyethylene glycol (PEG), gelatin and hyaluronic acid. Semi-IPN MP of PEG-diacrylate and PEG were used to study the effect of process parameters on particle characteristics. The process parameters were systematically varied to produce MP with size ranging from 115 to 515 μm and stiffness ranging from 190 to 1600 Pa. In vitro studies showed that the MP thus prepared were cytocompatible. The ratio and identity of the polymers used to make the semi-IPN MP were varied to control their stiffness and to introduce amine groups for potential functionalization. Slow-release polymeric particles loaded with Rhodamine or dexamethasone were incorporated in the MP as a proof-of-principle of drug incorporation and release from the MP. This work has implications in preparing injectable biomaterials of natural or synthetic polymers for applications as soft-tissue fillers. PMID:24561708

Hyaluronic Acid and Polyethylene Glycol Hybrid Hydrogel Encapsulating Nanogel with Hemostasis and Sustainable Antibacterial Property for Wound Healing.

PubMed

Zhu, Jie; Li, Faxue; Wang, Xueli; Yu, Jianyong; Wu, Dequn

2018-04-25

Immediate hemorrhage control and anti-infection play important roles in the wound management. Besides, a moist environment is also beneficial for wound healing. Hydrogels are promising materials in urgent hemostasis and drug release. However, hydrogels have the disadvantage of rapid release profiles, leading to the exposure to high drug concentrations. In this study, we constructed hybrid hydrogels with rapid hemostasis and sustainable antibacterial property combining aminoethyl methacrylate hyaluronic acid (HA-AEMA) and methacrylated methoxy polyethylene glycol (mPEG-MA) hybrid hydrogels and chlorhexidine diacetate (CHX)-loaded nanogels. The CHX-loaded nanogels (CLNs) were prepared by the enzyme degradation of CHX-loaded lysine-based hydrogels. The HA-AEMA and mPEG-MA hybrid hydrogel loaded with CLNs (labeled as Gel@CLN) displayed a three-dimensional microporous structure and exhibited excellent swelling, mechanical property, and low cytotoxicity. The Gel@CLN hydrogel showed a prolonged release period of CHX over 240 h and the antibacterial property over 10 days. The hemostasis and wound-healing properties were evaluated in vivo using a mouse model. The results showed that hydrogel had the rapid hemostasis capacity and accelerated wound healing. In summary, CLN-loaded hydrogels may be excellent candidates as hemostasis and anti-infection materials for the wound dressing application.

The effect of lysophosphatidic acid using a hydrogel or collagen sponge carrier on bone healing in dogs.

PubMed

Might, Kelly R; Martinez, Steven A; Karin, Norman; Lin, Genyao; Tarasevich, Barbara; Pool, Roy R

2016-07-19

The purposes of this study were to determine: 1) the efficacy of polycaprolactone-g-polyethylene glycol (PCL-g-PEG) and polylactic-co-glycolic acid (PLGA-g-PEG) hydrogels and an absorbable collagen sponge (ACS) as carriers for lysophosphatidic acid (LPA), 2) the effect of LPA on bone healing in dogs, and 3) the ideal dose of LPA to maximally stimulate bone healing. Bilateral ulnar ostectomies were performed on purpose bred dogs. Control defects were filled with a PCL-g-PEG or PLGA-g-PEG hydrogel, or a saline soaked ACS. Contralateral defects were filled with a PCL-g-PEG or PLGA-g-PEG hydrogel, or an ACS with each carrying differing concentrations of an LPA solution. Dual-energy X-ray absorptiometry (DXA) was performed. Total bone area (TBA), mineral density (BMD), and mineral content (BMC) were determined at each time point. Relationships between the effect of treatment over time on TBA, BMC and BMD were determined. Phase 1 - There was no significant difference in DXA-based TBA (p = 0.09), BMC (p = 0.33), or BMD (p = 0.74) over time between LPA treatments, or between the LPA treated and control groups TBA (p = 0.95), BMC (p = 0.99), or BMD (p = 0.46). Phase 2 - There was no significant difference over time between LPA treatments in DXA-based TBA (p = 0.33), BMC (p = 0.45), or BMD (p = 0.43), or between the LPA treated and control groups TBA (p = 0.94), BMC (p = 0.38), or BMD (p = 0.17). Phase 3 - There was no significant difference over time between LPA treatments in DXA-based TBA (p = 0.78), BMC (p = 0.88), or BMD (p = 0.35), or between the LPA treated and control groups TBA (p = 0.07), BMC (p = 0.85), or BMD (p = 0.06). There was a significant increase in TBA (p <0.0001) and BMC (p = 0.0014), but a significant decrease in BMD (p <0.0001) was noted over time when all groups were combined. Although LPA has shown promise as an osteoinductive agent in research, its performance as a bone graft substitute, as utilized in this study, is unsupported. Further studies are necessary to determine the incorporation and elution kinetics of LPA from the PLGA-g-PEG hydrogel and from an ACS. Hydrogels may have clinical applications for delaying or preventing bone formation.

Engineering the bone-ligament interface using polyethylene glycol diacrylate incorporated with hydroxyapatite.

PubMed

Paxton, Jennifer Z; Donnelly, Kenneth; Keatch, Robert P; Baar, Keith

2009-06-01

Ligaments and tendons have previously been tissue engineered. However, without the bone attachment, implantation of a tissue-engineered ligament would require it to be sutured to the remnant of the injured native tissue. Due to slow repair and remodeling, this would result in a chronically weak tissue that may never return to preinjury function. In contrast, orthopaedic autograft reconstruction of the ligament often uses a bone-to-bone technique for optimal repair. Since bone-to-bone repairs heal better than other methods, implantation of an artificial ligament should also occur from bone-to-bone. The aim of this study was to investigate the use of a poly(ethylene glycol) diacrylate (PEGDA) hydrogel incorporated with hydroxyapatite (HA) and the cell-adhesion peptide RGD (Arg-Gly-Asp) as a material for creating an in vitro tissue interface to engineer intact ligaments (i.e., bone-ligament-bone). Incorporation of HA into PEG hydrogels reduced the swelling ratio but increased mechanical strength and stiffness of the hydrogels. Further, HA addition increased the capacity for cell growth and interface formation. RGD incorporation increased the swelling ratio but decreased mechanical strength and stiffness of the material. Optimum levels of cell attachment were met using a combination of both HA and RGD, but this material had no better mechanical properties than PEG alone. Although adherence of the hydrogels containing HA was achieved, failure occurs at about 4 days with 5% HA. Increasing the proportion of HA improved interface formation; however, with high levels of HA, the PEG HA composite became brittle. This data suggests that HA, by itself or with other materials, might be well suited for engineering the ligament-bone interface.

Phenotypic Characterization of Prostate Cancer LNCaP Cells Cultured within a Bioengineered Microenvironment

PubMed Central

Sieh, Shirly; Taubenberger, Anna V.; Rizzi, Simone C.; Sadowski, Martin; Lehman, Melanie L.; Rockstroh, Anja; An, Jiyuan; Clements, Judith A.; Nelson, Colleen C.; Hutmacher, Dietmar W.

2012-01-01

Biophysical and biochemical properties of the microenvironment regulate cellular responses such as growth, differentiation, morphogenesis and migration in normal and cancer cells. Since two-dimensional (2D) cultures lack the essential characteristics of the native cellular microenvironment, three-dimensional (3D) cultures have been developed to better mimic the natural extracellular matrix. To date, 3D culture systems have relied mostly on collagen and Matrigel™ hydrogels, allowing only limited control over matrix stiffness, proteolytic degradability, and ligand density. In contrast, bioengineered hydrogels allow us to independently tune and systematically investigate the influence of these parameters on cell growth and differentiation. In this study, polyethylene glycol (PEG) hydrogels, functionalized with the Arginine-glycine-aspartic acid (RGD) motifs, common cell-binding motifs in extracellular matrix proteins, and matrix metalloproteinase (MMP) cleavage sites, were characterized regarding their stiffness, diffusive properties, and ability to support growth of androgen-dependent LNCaP prostate cancer cells. We found that the mechanical properties modulated the growth kinetics of LNCaP cells in the PEG hydrogel. At culture periods of 28 days, LNCaP cells underwent morphogenic changes, forming tumor-like structures in 3D culture, with hypoxic and apoptotic cores. We further compared protein and gene expression levels between 3D and 2D cultures upon stimulation with the synthetic androgen R1881. Interestingly, the kinetics of R1881 stimulated androgen receptor (AR) nuclear translocation differed between 2D and 3D cultures when observed by immunofluorescent staining. Furthermore, microarray studies revealed that changes in expression levels of androgen responsive genes upon R1881 treatment differed greatly between 2D and 3D cultures. Taken together, culturing LNCaP cells in the tunable PEG hydrogels reveals differences in the cellular responses to androgen stimulation between the 2D and 3D environments. Therefore, we suggest that the presented 3D culture system represents a powerful tool for high throughput prostate cancer drug testing that recapitulates tumor microenvironment. PMID:22957009

Experimental and Computational Investigation of the Effect of Hydrophobicity on Aggregation and Osteoinductive Potential of BMP-2-Derived Peptide in a Hydrogel Matrix

PubMed Central

Moeinzadeh, Seyedsina; Barati, Danial; Sarvestani, Samaneh K.; Karimi, Tahereh

2015-01-01

An attractive approach to reduce the undesired side effects of bone morphogenetic proteins (BMPs) in regenerative medicine is to use osteoinductive peptide sequences derived from BMPs. Although the structure and function of BMPs have been studied extensively, there is limited data on structure and activity of BMP-derived peptides immobilized in hydrogels. The objective of this work was to investigate the effect of concentration and hydrophobicity of the BMP-2 peptide, corresponding to residues 73–92 of the knuckle epitope of BMP-2 protein, on peptide aggregation and osteogenic differentiation of human mesenchymal stem cells encapsulated in a polyethylene glycol (PEG) hydrogel. The peptide hydrophobicity was varied by capping PEG chain ends with short lactide segments. The BMP-2 peptide with a positive index of hydrophobicity had a critical micelle concentration (CMC) and formed aggregates in aqueous solution. Based on simulation results, there was a slight increase in the concentration of free peptide in solution with 1000-fold increase in peptide concentration. The dose-osteogenic response curve of the BMP-2 peptide was in the 0.0005–0.005 mM range, and osteoinductive potential of the BMP-2 peptide was significantly less than that of BMP-2 protein even at 1000-fold higher concentrations, which was attributed to peptide aggregation. Further, the peptide or PEG-peptide aggregates had significantly higher interaction energy with the cell membrane compared with the free peptide, which led to a higher nonspecific interaction with the cell membrane and loss of osteoinductive potential. Conjugation of the BMP-2 peptide to PEG increased CMC and osteoinductive potential of the peptide whereas conjugation to lactide-capped PEG reduced CMC and osteoinductive potential of the peptide. Experimental and simulation results revealed that osteoinductive potential of the BMP-2 peptide is correlated with its CMC and the free peptide concentration in aqueous medium and not the total concentration. PMID:25051457

Effects of precursor composition and mode of crosslinking on mechanical properties of graphene oxide reinforced composite hydrogels.

PubMed

Jang, Jinhyeong; Hong, Jisu; Cha, Chaenyung

2017-05-01

Graphene oxide (GO) is increasingly investigated as a reinforcing nanofiller for various hydrogels for biomedical applications for its superior mechanical strength. However, the reinforcing mechanism of GO in different hydrogel conditions has not been extensively explored and elucidated to date. Herein, we systematically examine the effects of various types of precursor molecules (monomers vs. macromers) as well as mode of GO incorporation (physical vs. covalent) on the mechanical properties of resulting composite hydrogels. Two hydrogel types, (1) polyacrylamide hydrogels with varying concentrations of acrylamide monomers and (2) poly(ethylene glycol) (PEG) hydrogels with varying molecular weights of PEG macromers, are used as model systems. In addition, incorporation of GO is also controlled by using either unmodified GO or methacrylic GO (MGO) which allows for covalent incorporation. The results in this study demonstrate that the interaction between GO and the surrounding network and its effect on the mechanical properties (i.e. rigidity and toughness) of composite hydrogels are highly dependent on both the type and concentration of precursors and the mode of crosslinking. We expect this study will provide an important guideline for future research efforts on controlling the mechanical properties of GO-based composite hydrogels. Copyright © 2017 Elsevier Ltd. All rights reserved.

Transdermal thiol-acrylate polyethylene glycol hydrogel synthesis using near infrared light

NASA Astrophysics Data System (ADS)

Chung, Solchan; Lee, Hwangjae; Kim, Hyung-Seok; Kim, Min-Gon; Lee, Luke P.; Lee, Jae Young

2016-07-01

Light-induced polymerization has been widely applied for hydrogel synthesis, which conventionally involves the use of ultraviolet or visible light to activate a photoinitiator for polymerization. However, with these light sources, transdermal gelation is not efficient and feasible due to their substantial interactions with biological systems, and thus a high power is required. In this study, we used biocompatible and tissue-penetrating near infrared (NIR) light to remotely trigger a thiol-acrylate reaction for efficient in vivo gelation with good controllability. Our gelation system includes gold nanorods as a photothermal agent, a thermal initiator, diacrylate polyethylene glycol (PEG), and thiolated PEG. Irradiation with a low-power NIR laser (0.3 W cm-2) could induce gelation via a mixed-mode reaction with a small increase in temperature (~5 °C) under the optimized conditions. We also achieved successful transdermal gelation via the NIR-assisted photothermal thiol-acryl reactions. This new type of NIR-assisted thiol-acrylate polymerization provides new opportunities for in situ hydrogel formation for injectable hydrogels and delivery of drugs/cells for various biomedical applications.Light-induced polymerization has been widely applied for hydrogel synthesis, which conventionally involves the use of ultraviolet or visible light to activate a photoinitiator for polymerization. However, with these light sources, transdermal gelation is not efficient and feasible due to their substantial interactions with biological systems, and thus a high power is required. In this study, we used biocompatible and tissue-penetrating near infrared (NIR) light to remotely trigger a thiol-acrylate reaction for efficient in vivo gelation with good controllability. Our gelation system includes gold nanorods as a photothermal agent, a thermal initiator, diacrylate polyethylene glycol (PEG), and thiolated PEG. Irradiation with a low-power NIR laser (0.3 W cm-2) could induce gelation via a mixed-mode reaction with a small increase in temperature (~5 °C) under the optimized conditions. We also achieved successful transdermal gelation via the NIR-assisted photothermal thiol-acryl reactions. This new type of NIR-assisted thiol-acrylate polymerization provides new opportunities for in situ hydrogel formation for injectable hydrogels and delivery of drugs/cells for various biomedical applications. Electronic supplementary information (ESI) available: FE-SEM image of thiol-acrylate hydrogels; UV/Vis spectra of Ellman's assay; the temperature increase during transdermal photothermal hydrogelation. See DOI: 10.1039/c6nr01956k

Biocompatibility of poly(ethylene glycol) and poly(acrylic acid) interpenetrating network hydrogel by intrastromal implantation in rabbit cornea

PubMed Central

Zheng, Luo Luo; Vanchinathan, Vijay; Dalal, Roopa; Noolandi, Jaan; Waters, Dale J.; Hartmann, Laura; Cochran, Jennifer R.; Frank, Curtis W.; Yu, Charles Q.; Ta, Christopher N.

2015-01-01

We evaluated the biocompatibility of a poly(ethylene glycol) and poly(acrylic acid) (PEG/PAA) interpenetrating network hydrogel designed for artificial cornea in a rabbit model. PEG/PAA hydrogel measuring 6 mm in diameter was implanted in the corneal stroma of twelve rabbits. Stromal flaps were created with a microkeratome. Randomly, six rabbits were assigned to bear the implant for 2 months, two rabbits for 6 months, two rabbits for 9 months, one rabbit for 12 months, and one rabbit for 16 months. Rabbits were evaluated monthly. After the assigned period, eyes were enucleated, and corneas were processed for histology and immunohistochemistry. There were clear corneas in three of six rabbits that had implantation of hydrogel for 2 months. In the six rabbits with implant for 6 months or longer, the corneas remained clear in four. There was a high rate of epithelial defect and corneal thinning in these six rabbits. One planned 9-month rabbit developed extrusion of implant at 4 months. The cornea remained clear in the 16-month rabbit but histology revealed epithelial in-growth. Intrastromal implantation of PEG/PAA resulted in a high rate of long-term complications. PMID:25778285

Encoding Hydrogel Mechanics via Network Cross-Linking Structure.

PubMed

Schweller, Ryan M; West, Jennifer L

2015-05-11

The effects of mechanical cues on cell behaviors in 3D remain difficult to characterize as the ability to tune hydrogel mechanics often requires changes in the polymer density, potentially altering the material's biochemical and physical characteristics. Additionally, with most PEG diacrylate (PEGDA) hydrogels, forming materials with compressive moduli less than ∼10 kPa has been virtually impossible. Here, we present a new method of controlling the mechanical properties of PEGDA hydrogels independent of polymer chain density through the incorporation of additional vinyl group moieties that interfere with the cross-linking of the network. This modification can tune hydrogel mechanics in a concentration dependent manner from <1 to 17 kPa, a more physiologically relevant range than previously possible with PEG-based hydrogels, without altering the hydrogel's degradation and permeability. Across this range of mechanical properties, endothelial cells (ECs) encapsulated within MMP-2/MMP-9 degradable hydrogels with RGDS adhesive peptides revealed increased cell spreading as hydrogel stiffness decreased in contrast to behavior typically observed for cells on 2D surfaces. EC-pericyte cocultures exhibited vessel-like networks within 3 days in highly compliant hydrogels as compared to a week in stiffer hydrogels. These vessel networks persisted for at least 4 weeks and deposited laminin and collagen IV perivascularly. These results indicate that EC morphogenesis can be regulated using mechanical cues in 3D. Furthermore, controlling hydrogel compliance independent of density allows for the attainment of highly compliant mechanical regimes in materials that can act as customizable cell microenvironments.

Development of polymer-polysaccharide hydrogels for controlling drug delivery

NASA Astrophysics Data System (ADS)

Baldwin, Aaron David

The use of polymers as biomaterials has evolved over the past several decades, encompassing an expanding synthetic toolbox and many bio-mimetic approaches. Both synthetic and natural polymers have been used as components for biomaterials as their unique chemical structures can provide specific functions for desired applications. Of these materials, heparin, a highly sulfated naturally occurring polysaccharide, has been investigated extensively as a core component in drug delivery platforms and tissue engineering. The goal of this work was to further explore the use of heparin via conjugation with synthetic polymers for applications in drug delivery. We begin by investigating low molecular weight heparin (LMWH), a depolymerized heparin that is used medicinally in the prevention of thrombosis by subcutaneous injection or intravenous drip. Certain disease states or disorders require frequent administration with invasive delivery modalities leading to compliance issues for individuals on prolonged therapeutic courses. To address these issues, a long-term delivery method was developed for LMWH via subcutaneous injection of in situ hydrogelators. This therapy was accomplished by chemical modification of LMWH with maleimide functionality so that it may be crosslinked into continuous hydrogel networks with four-arm thiolated polyethylene glycol (PEG-SH). These hydrogels degrade via hydrolysis over a period of weeks and release bioactive LMWH with first-order kinetics as determined by in vitro and in vivo models, thus indicating the possibility of an alternative means of heparin delivery over current accepted methodologies. Evaluation of the maleimide-thiol chemistries applied in the LMWH hydrogels revealed reversibility for some conjugates under reducing conditions. Addition chemistries, such as maleimide-thiol reactions, are widely employed in biological conjugates and are generally accepted as stable. Here we show that the resulting succinimide thioether formed by the Michael type addition of thiol derivatives to N-ethylmaleimide (NEM) undergoes retro and exchange reactions in the presence of other thiol compounds at physiological pH and temperature. Model studies of NEM conjugated to various thiols (4-mercaptophenylacetic acid (MPA), N-acetylcysteine, or 3-mercaptopropionic acid (MP)), incubated with a naturally occurring reducing agent, glutathione, showed half-lives from 20-80 hrs with extents of conversion from 20-90% for MPA and N-acetylcysteine conjugates. The kinetics of the retro reactions and extent of exchange can be modulated by the Michael donor's reactivity; therefore the degradation of maleimide-thiol adducts could be tuned for controlled release of drugs or degradation of materials at timescales different than those currently possible via disulfide-mediated release. The reduction sensitive maleimide-thiol chemistry was then investigated as a crosslinking mechanism for LMWH hydrogels. Crosslinking maleimide functionalized LMWH with PEG functionalized with thiophenyl functionalities imparted glutathione sensitivity. 4-mercaptophenylpropionic acid and 2,2-dimethyl-3-(4-mercaptophenyl)propionic acid, induced sensitivity to glutathione as shown by a decrease in degradation time of 4x and 5x respectively. The pseudo-first order retro reaction constants were approximately an order of magnitude slower than hydrogels crosslinked via disulfide linkages, indicating the potential use of the retro succinimide-thioether covalent bonds for reduction mediated release and/or degradation with increased blood stability and prolonged drug delivery timescales compared to disulfide chemistries. In summary, this work highlights the use of polymer-polysaccharide hydrogels composed of LMWH and PEG as investigated for drug delivery and as a tool for elucidating a novel reduction sensitive controlled release mechanism.

Design and evaluation of novel fast forming pilocarpine-loaded ocular hydrogels for sustained pharmacological response

PubMed Central

Anumolu, SivaNaga S.; Singh, Yashveer; Gao, Dayuan; Stein, Stanley; Sinko, Patrick J.

2009-01-01

Fast forming hydrogels prepared by crosslinking a poly(ethylene glycol) (PEG)-based copolymer containing multiple thiol (SH) groups were evaluated for the controlled ocular delivery of pilocarpine and subsequent pupillary constriction. Physical properties of the hydrogels were characterized using UV-Vis spectrophotometry, transmission electron microscopy (TEM), rheometry, and swelling kinetics. Pilocarpine loading efficiency and release properties were measured in simulated tear fluid. The hydrogel formulations exhibited high drug loading efficiency (~74%). Pilocarpine release was found to be biphasic with release half times of ~2 and 94 h, respectively, and 85–100% of the drug was released over 8-days. Pilocarpine-loaded (2% w/v) hydrogels were evaluated in a rabbit model and compared to a similar dose of drug in aqueous solution. The hydrogels were retained in the eye for the entire period of the study with no observed irritation. Pilocarpine-loaded hydrogels sustained pupillary constriction for 24 h after administration as compared to 3 h for the solution, an 8-fold increase in duration of action. A strong correlation between pilocarpine release and pupillary response was observed. In conclusion, the current studies demonstrate that in situ forming PEG hydrogels possess the viscoelastic, retention, and sustained delivery properties required for an efficient ocular drug delivery system. PMID:19341773

Poly(ethylene glycol) hydrogel microstructures encapsulating living cells

NASA Technical Reports Server (NTRS)

Koh, Won-Gun; Revzin, Alexander; Pishko, Michael V.

2002-01-01

We present an easy and effective method for the encapsulation of cells inside PEG-based hydrogel microstructures fabricated using photolithography. High-density arrays of three-dimensional microstructures were created on substrates using this method. Mammalian cells were encapsulated in cylindrical hydrogel microstructures of 600 and 50 micrometers in diameter or in cubic hydrogel structures in microfluidic channels. Reducing lateral dimension of the individual hydrogel microstructure to 50 micrometers allowed us to isolate 1-3 cells per microstructure. Viability assays demonstrated that cells remained viable inside these hydrogels after encapsulation for up to 7 days.

Mechanomimetic hydrogels for vocal fold lamina propria regeneration.

PubMed

Kutty, Jaishankar K; Webb, Ken

2009-01-01

Vocal fold injury commonly leads to reduced vocal quality due to scarring-induced alterations in matrix composition and tissue biomechanics. The long-term hypothesis motivating our work is that rapid restoration of phonation and the associated dynamic mechanical environment will reduce scarring and promote regenerative healing. Toward this end, the objective of this study was to develop mechanomimetic, degradable hydrogels approximating the viscoelastic properties of the vocal ligament and mucosa that may be photopolymerized in situ to restore structural integrity to vocal fold tissues. The tensile and rheological properties of hydrogels (targeting the vocal ligament and mucosa, respectively) were varied as a function of macromer concentration. PEG diacrylate-based hydrogels exhibited linear stress-strain response and elastic modulus consistent with the properties of the vocal ligament at low strains (0-15%), but did not replicate the non-linear behavior observed in native tissue at higher strains. Methacrylated hyaluronic acid hydrogels displayed dynamic viscosity consistent with native vocal mucosa, while elastic shear moduli values were several-fold higher. Cell culture studies indicated that both hydrogels supported spreading, proliferation and collagen/proteoglycan matrix deposition by encapsulated fibroblasts throughout the 3D network.

A biohybrid hydrogel for the urate-responsive release of urate oxidase.

PubMed

Geraths, Christian; Daoud-El Baba, Marie; Charpin-El Hamri, Ghislaine; Weber, Wilfried

2013-10-10

Functional biomaterials that detect and correct pathological parameters hold high promises for biomedical application. In this study we describe a biohybrid hydrogel that detects elevated concentrations of uric acid and responds by dissolution and the release of uric acid-degrading urate oxidase. This material was synthesized by incorporating PEG-stabilized urate oxidase into a polyacrylamide hydrogel that was crosslinked by the uric acid-sensitive interaction between the uric acid transcription factor HucR and its operator hucO. We characterize the uric acid responsiveness of the material and demonstrate that it can effectively be applied to counteract flares of uric acid in a mouse model. This approach might be a first step towards a biomedical device autonomously managing uric acid burst associated to gouty arthritis and the tumor lysis syndrome. © 2013.

Therapeutic application of injectable thermosensitive hydrogel in preventing local breast cancer recurrence and improving incision wound healing in a mouse model

NASA Astrophysics Data System (ADS)

Lei, Na; Gong, Changyang; Qian, Zhiyong; Luo, Feng; Wang, Cheng; Wang, Helan; Wei, Yuquan

2012-08-01

Many drug delivery systems (DDSs) have been investigated for local targeting of malignant disease with the intention of increasing anti-tumor activity and minimizing systemic toxicity. An injectable thermosensitive hydrogel was applied to prevent locoregional recurrence of 4T1 breast cancer in a mouse model. The presented hydrogel, which is based on poly(ethyleneglycol)-poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE), flows freely at normal temperature, forms a gel within seconds in situ at body temperature, and eventually releases the drug in a consistent and sustained fashion as it gradually biodegrades. Locoregional recurrence after primary tumor removal was significantly inhibited in mice treated with the paclitaxel (PTX)-loaded PECE hydrogel subcutaneously (9.1%) administered, compared with the blank hydrogel (80.0%), systemic (77.8%) and locally (75.0%) administered PTX, and the control group (100%) (P < 0.01). In addition, tensile strength measurements of the surgical incisions showed that the PECE hydrogel accelerates wound healing at postoperative day 7 (P < 0.05), and days 4 and 14 (P > 0.05), in agreement with histopathological examinations. This novel DDSs represents a promising approach for local adjuvant therapy in malignant disease.

Tuning mechanical performance of poly(ethylene glycol) and agarose interpenetrating network hydrogels for cartilage tissue engineering.

PubMed

Rennerfeldt, Deena A; Renth, Amanda N; Talata, Zsolt; Gehrke, Stevin H; Detamore, Michael S

2013-11-01

Hydrogels are attractive for tissue engineering applications due to their incredible versatility, but they can be limited in cartilage tissue engineering applications due to inadequate mechanical performance. In an effort to address this limitation, our team previously reported the drastic improvement in the mechanical performance of interpenetrating networks (IPNs) of poly(ethylene glycol) diacrylate (PEG-DA) and agarose relative to pure PEG-DA and agarose networks. The goal of the current study was specifically to determine the relative importance of PEG-DA concentration, agarose concentration, and PEG-DA molecular weight in controlling mechanical performance, swelling characteristics, and network parameters. IPNs consistently had compressive and shear moduli greater than the additive sum of either single network when compared to pure PEG-DA gels with a similar PEG-DA content. IPNs withstood a maximum stress of up to 4.0 MPa in unconfined compression, with increased PEG-DA molecular weight being the greatest contributing factor to improved failure properties. However, aside from failure properties, PEG-DA concentration was the most influential factor for the large majority of properties. Increasing the agarose and PEG-DA concentrations as well as the PEG-DA molecular weight of agarose/PEG-DA IPNs and pure PEG-DA gels improved moduli and maximum stresses by as much as an order of magnitude or greater compared to pure PEG-DA gels in our previous studies. Although the viability of encapsulated chondrocytes was not significantly affected by IPN formulation, glycosaminoglycan (GAG) content was significantly influenced, with a 12-fold increase over a three-week period in gels with a lower PEG-DA concentration. These results suggest that mechanical performance of IPNs may be tuned with partial but not complete independence from biological performance of encapsulated cells. © 2013 Elsevier Ltd. All rights reserved.

Extracellular-Matrix-Based and Arg-Gly-Asp–Modified Photopolymerizing Hydrogels for Cartilage Tissue Engineering

PubMed Central

Kim, Hwan D.; Heo, Jiseung; Hwang, Yongsung; Kwak, Seon-Yeong; Park, Ok Kyu; Kim, Hyunbum; Varghese, Shyni

2015-01-01

Articular cartilage damage is a persistent and increasing problem with the aging population. Strategies to achieve complete repair or functional restoration remain a challenge. Photopolymerizing-based hydrogels have long received an attention in the cartilage tissue engineering, due to their unique bioactivities, flexible method of synthesis, range of constituents, and desirable physical characteristics. In the present study, we have introduced unique bioactivity within the photopolymerizing-based hydrogels by copolymerizing polyethylene glycol (PEG) macromers with methacrylated extracellular matrix (ECM) molecules (hyaluronic acid and chondroitin sulfate [CS]) and integrin binding peptides (RGD peptide). Results indicate that cellular morphology, as observed by the actin cytoskeleton structures, was strongly dependent on the type of ECM component as well as the presence of integrin binding moieties. Further, CS-based hydrogel with integrin binding RGD moieties increased the lubricin (or known as superficial zone protein [SZP]) gene expression of the encapsulated chondrocytes. Additionally, CS-based hydrogel displayed cell-responsive degradation and resulted in increased DNA, GAG, and collagen accumulation compared with other hydrogels. This study demonstrates that integrin-mediated interactions within CS microenvironment provide an optimal hydrogel scaffold for cartilage tissue engineering application. PMID:25266634

Free radical scavenging injectable hydrogels for regenerative therapy.

PubMed

Komeri, Remya; Thankam, Finosh Gnanaprakasam; Muthu, Jayabalan

2017-02-01

Pathological free radicals generated from inflamed and infarcted cardiac tissues interferes natural tissue repair mechanisms. Hypoxic microenvironment at the injured zone of non-regenerating cardiac tissues hinders the therapeutic attempts including cell therapy. Here we report an injectable, cytocompatible, free radical scavenging synthetic hydrogel formulation for regenerative therapy. New hydrogel (PEAX-P) is prepared with D-xylitol-co-fumarate-co-poly ethylene adipate-co-PEG comaromer (PEAX) and PEGDiacrylate. PEAX-P hydrogel swells 4.9 times the initial weight and retains 100.07kPa Young modulus at equilibrium swelling, which is suitable for cardiac applications. PEAX-P hydrogel retains elastic nature even at 60% compressive strain, which is favorable to fit with the dynamic and elastic natural tissue counterparts. PEAX-P hydrogel scavenges 51% DPPH radical, 40% hydroxyl radicals 41% nitrate radicals with 31% reducing power. The presence of hydrogel protects 62% cardiomyoblast cells treated with stress inducing media at LD 50 concentration. The free hydroxyl groups in sugar alcohols of the comacromer influence the free radical scavenging. Comparatively, PEAX-P hydrogel based on xylitol evinces slightly lower scavenging characteristics than with previously reported PEAM-P hydrogel containing mannitol having more hydroxyl groups. The possible free radical scavenging mechanism of the present hydrogel relies on the free π electrons associated with uncrosslinked fumarate bonds, hydrogen atoms associated with sugar alcohols/PEG and radical dilution by free water in the matrix. Briefly, the present PEAX-P hydrogel is a potential injectable system for combined antioxidant and regenerative therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

Synthesis and preparation of biodegradable hybrid dextran hydrogel incorporated with biodegradable curcumin nanomicelles for full thickness wound healing.

PubMed

Alibolandi, Mona; Mohammadi, Marzieh; Taghdisi, Seyed Mohammad; Abnous, Khalil; Ramezani, Mohammad

2017-10-30

There is a clinical need for a novel, more efficient therapy for full thickness wound healing. In the current study, curcumin encapsulated PEG-PLA [poly(lactide)-block-poly(ethylene glycol)] nanomicelles were incorporated into dextran hydrogel for a full thickness dermal wound healing application. To assess the application of the hydrogel as a therapeutic wound dressing, its morphology, swelling pattern, kinetics of degradation, and capacity to control curcumin release were evaluated. It was found that the prepared hybrid hydrogel had acceptable biocompatibility, incorporation capacity of curcumin nanomicelles, and mechanical properties. An in vitro release experiment also demonstrated the sustained release of curcumin from dextran hydrogel, which was first controlled by the diffusion of curcumin from hydrogel and continued through hydrogel matrix erosion at the terminal phase. An in vivo wound healing experiment was carried out using dressing hydrogels on full thickness wounds in BALB/c mice. An histological study demonstrated that the application of curcumin nanomicelles incorporated hydrogel could significantly augment the re-epithelialization of epidermis and collagen deposition in the wound area. Expression of CD31 and vimentin in wound tissue was investigated using immunohistochemistry tests on the eighth day post wounding. The results obtained demonstrated that curcumin nanomicelles incorporated hydrogel could significantly accelerate angiogenesis, fibroblast accumulation, and the process of wound healing. Together, the data indicate that the prepared hybrid curcumin PEG-PLA nanomicelles incorporated dextran hydrogel is a promising candidate for full thickness wound treatment that increases re-epithelialization, collagen deposition, angiogenesis, and tissue granulation. Copyright © 2017 Elsevier B.V. All rights reserved.

Enhancement of surface graft density of MPEG on alginate/chitosan hydrogel microcapsules for protein repellency.

PubMed

Zheng, Jiani; Xie, Hongguo; Yu, Weiting; Tan, Mingqian; Gong, Faquan; Liu, Xiudong; Wang, Feng; Lv, Guojun; Liu, Wanfa; Zheng, Guoshuang; Yang, Yan; Xie, Weiyang; Ma, Xiaojun

2012-09-18

Alginate/chitosan/alginate (ACA) hydrogel microcapsules were modified with methoxy poly(ethylene glycol) (MPEG) to improve protein repellency and biocompatibility. Increased MPEG surface graft density (n(S)) on hydrogel microcapsules was achieved by controlling the grafting parameters including the buffer layer substrate, membrane thickness, and grafting method. X-ray photoelectron spectroscopy (XPS) model was employed to quantitatively analyze n(S) on this three-dimensional (3D) hydrogel network structure. Our results indicated that neutralizing with alginate, increasing membrane thickness, and in situ covalent grafting could increase n(S) effectively. ACAC(PEG) was more promising than ACC(PEG) in protein repellency because alginate supplied more -COO(-) negative binding sites and prevented MPEG from diffusing. The n(S) increased with membrane thickness, showing better protein repellency. Moreover, the in situ covalent grafting provided an effective way to enhance n(S), and 1.00 ± 0.03 chains/nm(2) was achieved, exhibiting almost complete immunity to protein adsorption. This antifouling hydrogel biomaterial is expected to be useful in transplantation in vivo.

Monodisperse Polyethylene Glycol Diacrylate Hydrogel Microsphere Formation by Oxygen-Controlled Photopolymerization in a Microfluidic Device

PubMed Central

Krutkramelis, K.; Xia, B.; Oakey, J.

2016-01-01

PEG-based hydrogels have become widely used as drug delivery and tissue scaffolding materials. Common among PEG hydrogel-forming polymers are photopolymerizable acrylates such as polyethylene glycol diacrylate (PEGDA). Microfluidics and microfabrication technologies have recently enabled the miniaturization of PEGDA structures, thus enabling many possible applications for nano- and micro- structured hydrogels. The presence of oxygen, however, dramatically inhibits the photopolymerization of PEGDA, which in turn frustrates hydrogel formation in environments of persistently high oxygen concentration. Using PEGDA that has been emulsified in fluorocarbon oil via microfluidic flow focusing within polydimethylsiloxane (PDMS) devices, we show that polymerization is completely inhibited below critical droplet diameters. By developing an integrated model incorporating reaction kinetics and oxygen diffusion, we demonstrate that the critical droplet diameter is largely determined by the oxygen transport rate, which is dictated by the oxygen saturation concentration of the continuous oil phase. To overcome this fundamental limitation, we present a nitrogen micro-jacketed microfluidic device to reduce oxygen within the droplet, enabling the continuous on-chip photopolymerization of microscale PEGDA particles. PMID:26987384

Immobilizing enzymes onto electrode arrays by hydrogel photolithography to fabricate multi-analyte electrochemical biosensors.

PubMed

Yan, Jun; Pedrosa, Valber A; Simonian, Aleksandr L; Revzin, Alexander

2010-03-01

This paper describes a biomaterial microfabrication approach for interfacing functional biomolecules (enzymes) with electrode arrays. Poly (ethylene glycol) (PEG) hydrogel photopatterning was employed to integrate gold electrode arrays with the enzymes glucose oxidase (GOX) and lactate oxidase (LOX). In this process, PEG diacrylate (DA)-based prepolymer containing enzyme molecules as well as redox species (vinylferrocene) was spin-coated, registered, and UV cross-linked on top of an array of gold electrodes. As a result, enzyme-carrying circular hydrogel structures (600 microm diameter) were fabricated on top of 300 microm diameter gold electrodes. Importantly, when used with multiple masks, hydrogel photolithography allowed us to immobilize GOX and LOX molecules on adjacent electrodes within the same electrode array. Cyclic voltammetry and amperometry were used to characterize biosensor electrode arrays. The response of the biosensor array was linear for up to 20 mM glucose with sensitivity of 0.9 microA cm(-2) mM(-1) and 10 mM lactate with sensitivity of 1.1 microA cm(-2) mM(-1). Importantly, simultaneous detection of glucose and lactate from the same electrode array was demonstrated. A novel strategy for integrating biological and electrical components of a biosensor described in this paper provides the flexibility to spatially resolve and register different biorecognition elements with individual members of a miniature electrode array. Of particular interest to us are future applications of these miniature electrodes for real-time monitoring of metabolite fluxes in the vicinity of living cells.

Nano-hydrogels of methoxy polyethylene glycol-grafted branched polyethyleneimine via biodegradable cross-linking of Zn2+-ionomer micelle template

NASA Astrophysics Data System (ADS)

Abolmaali, Samira Sadat; Tamaddon, Ali Mohammad; Dinarvand, Rasoul

2013-12-01

Soft polymeric nanomaterials were synthesized by the template-assisted method involving self-association of methoxy polyethylene glycol- g-branched polyethyleneimine (mPEG- g-branched PEI) ionomer by transition metal ions such as Zn2+ followed by chemical cross-linking of the polyamine core by dithiopropionic acid. The formation of donor-acceptor complexes of Zn2+ and PEI ionomer was characterized by FT-IR spectroscopy and potentiometric titration. Turbidimetry was performed to study the solution property of the complexes which depended on pH, relative weight fraction of mPEG, and the molar ratio of Zn2+. The cross-linking reaction was studied by TNBS assay, 1H-NMR, and size exclusion chromatography. Upon removal of Zn2+ from cl-mPEG- g-branched PEI/Zn2+ at pH 3 by dialysis, the resulting cross-linked self-assembly represented a uniform, stable, and less positively charged hydrogel-like nanosphere with an intensity-averaged size ranging from 150 to 250 nm as determined by a Zetasizer. Atomic forced microscopy imaging was performed in intermittent contact mode in air that revealed discrete and oval-to-spherically shaped particles with average sizes ranging from 40 to 50 nm depending on the degree of cross-linking. This functional nanocarrier is expected to exhibit some key features such as active encapsulation of negatively charged hydrophilic agents in the swollen core of polyamine network and a hydrophilic mPEG shell which provides an increased solubility and passive targeting of active pharmaceutical agents to impaired tissues. The nano-hydrogels especially at 12 % degrees of cross-link demonstrated excellent biocompatibility determined by different experiments such as albumin aggregation, erythrocyte aggregation, hemolysis, and MTT cytotoxicity assay. Moreover, biodegradability of the cross-links as shown by the Ellman assay can offer a time-dependent degradation and redox-stimulated release of active agents.

Programmable Hydrogel Ionic Circuits for Biologically Matched Electronic Interfaces.

PubMed

Zhao, Siwei; Tseng, Peter; Grasman, Jonathan; Wang, Yu; Li, Wenyi; Napier, Bradley; Yavuz, Burcin; Chen, Ying; Howell, Laurel; Rincon, Javier; Omenetto, Fiorenzo G; Kaplan, David L

2018-06-01

The increased need for wearable and implantable medical devices has driven the demand for electronics that interface with living systems. Current bioelectronic systems have not fully resolved mismatches between engineered circuits and biological systems, including the resulting pain and damage to biological tissues. Here, salt/poly(ethylene glycol) (PEG) aqueous two-phase systems are utilized to generate programmable hydrogel ionic circuits. High-conductivity salt-solution patterns are stably encapsulated within PEG hydrogel matrices using salt/PEG phase separation, which route ionic current with high resolution and enable localized delivery of electrical stimulation. This strategy allows designer electronics that match biological systems, including transparency, stretchability, complete aqueous-based connective interface, distribution of ionic electrical signals between engineered and biological systems, and avoidance of tissue damage from electrical stimulation. The potential of such systems is demonstrated by generating light-emitting diode (LED)-based displays, skin-mounted electronics, and stimulators that deliver localized current to in vitro neuron cultures and muscles in vivo with reduced adverse effects. Such electronic platforms may form the basis of future biointegrated electronic systems. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Intradiscal application of a PCLA-PEG-PCLA hydrogel loaded with celecoxib for the treatment of back pain in canines: What's in it for humans?

PubMed

Tellegen, Anna R; Willems, Nicole; Beukers, Martijn; Grinwis, Guy C M; Plomp, Saskia G M; Bos, Clemens; van Dijk, Maarten; de Leeuw, Mike; Creemers, Laura B; Tryfonidou, Marianna A; Meij, Björn P

2018-03-01

Chronic low back pain is a common clinical problem in both the human and canine population. Current pharmaceutical treatment often consists of oral anti-inflammatory drugs to alleviate pain. Novel treatments for degenerative disc disease focus on local application of sustained released drug formulations. The aim of this study was to determine safety and feasibility of intradiscal application of a poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-bpoly(ε-caprolactone-co-lactide) PCLA-PEG-PCLA hydrogel releasing celecoxib, a COX-2 inhibitor. Biocompatibility was evaluated after subcutaneous injection in mice, and safety of intradiscal injection of the hydrogel was evaluated in experimental dogs with early spontaneous intervertebral disc (IVD) degeneration. COX-2 expression was increased in IVD samples surgically obtained from canine patients, indicating a role of COX-2 in clinical IVD disease. Ten client-owned dogs with chronic low back pain related to IVD degeneration received an intradiscal injection with the celecoxib-loaded hydrogel. None of the dogs showed adverse reactions after intradiscal injection. The hydrogel did not influence magnetic resonance imaging signal at long-term follow-up. Clinical improvement was achieved by reduction of back pain in 9 of 10 dogs, as was shown by clinical examination and owner questionnaires. In 3 of 10 dogs, back pain recurred after 3 months. This study showed the safety and effectiveness of intradiscal injections in vivo with a thermoresponsive PCLA-PEG-PCLA hydrogel loaded with celecoxib. In this set-up, the dog can be used as a model for the development of novel treatment modalities in both canine and human patients with chronic low back pain. Copyright © 2017 John Wiley & Sons, Ltd.

Fabrication of poly(ethylene glycol) hydrogel microstructures using photolithography

NASA Technical Reports Server (NTRS)

Revzin, A.; Russell, R. J.; Yadavalli, V. K.; Koh, W. G.; Deister, C.; Hile, D. D.; Mellott, M. B.; Pishko, M. V.

2001-01-01

The fabrication of hydrogel microstructures based upon poly(ethylene glycol) diacrylates, dimethacrylates, and tetraacrylates patterned photolithographically on silicon or glass substrates is described. A silicon/silicon dioxide surface was treated with 3-(trichlorosilyl)propyl methacrylate to form a self-assembled monolayer (SAM) with pendant acrylate groups. The SAM presence on the surface was verified using ellipsometry and time-of-flight secondary ion mass spectrometry. A solution containing an acrylated or methacrylated poly(ethylene glycol) derivative and a photoinitiator (2,2-dimethoxy-2-phenylacetophenone) was spin-coated onto the treated substrate, exposed to 365 nm ultraviolet light through a photomask, and developed with either toluene, water, or supercritical CO2. As a result of this process, three-dimensional, cross-linked PEG hydrogel microstructures were immobilized on the surface. Diameters of cylindrical array members were varied from 600 to 7 micrometers by the use of different photomasks, while height varied from 3 to 12 micrometers, depending on the molecular weight of the PEG macromer. In the case of 7 micrometers diameter elements, as many as 400 elements were reproducibly generated in a 1 mm2 square pattern. The resultant hydrogel patterns were hydrated for as long as 3 weeks without delamination from the substrate. In addition, micropatterning of different molecular weights of PEG was demonstrated. Arrays of hydrogel disks containing an immobilized protein conjugated to a pH sensitive fluorophore were also prepared. The pH sensitivity of the gel-immobilized dye was similar to that in an aqueous buffer, and no leaching of the dye-labeled protein from the hydrogel microstructure was observed over a 1 week period. Changes in fluorescence were also observed for immobilized fluorophore labeled acetylcholine esterase upon the addition of acetyl acholine.

A simple approach to hybrid inorganic–organic step-growth hydrogels with scalable control of physicochemical properties and biodegradability† †Electronic supplementary information (ESI) available: Experimental details and characterization data as mentioned in the text. See DOI: 10.1039/c4py01789g Click here for additional data file.

PubMed Central

Alves, F.

2015-01-01

We prepared new and scalable, hybrid inorganic–organic step-growth hydrogels with polyhedral oligomeric silsesquioxane (POSS) network knot construction elements and hydrolytically degradable poly(ethylene glycol) (PEG) di-ester macromonomers by in situ radical-mediated thiol–ene photopolymerization. The physicochemical properties of the gels are fine-tailored over orders of magnitude including functionalization of their interior, a hierarchical gel structure, and biodegradability. PMID:25821524

Live RB51 vaccine lyophilized hydrogel formulations with increased shelf life for practical ballistic delivery

USDA-ARS?s Scientific Manuscript database

Ballistic delivery capability is essential to delivering vaccines and other therapeutics effectively to both livestock and wildlife in many global scenarios. Here, lyophilized poly(ethylene glycol) (PEG)-glycolide dimethacrylate crosslinked but degradable hydrogels were assessed as payload vehicles ...

Synthesis and Characterization of Carboxymethylcellulose-Methacrylate Hydrogel Cell Scaffolds

PubMed Central

Reeves, Robert; Ribeiro, Andreia; Lombardo, Leonard; Boyer, Richard; Leach, Jennie B.

2012-01-01

Many carbohydrates pose advantages for tissue engineering applications due to their hydrophilicity, degradability, and availability of chemical groups for modification. For example, carboxymethylcellulose (CMC) is a water-soluble cellulose derivative that is degradable by cellulase. Though this enzyme is not synthesized by mammalian cells, cellulase and the fragments derived from CMC degradation are biocompatible. With this in mind, we created biocompatible, selectively degradable CMC-based hydrogels that are stable in routine culture, but degrade when exposed to exogenous cellulase. Solutions of CMC-methacrylate and polyethylene glycol dimethacrylate (PEG-DM) were co-crosslinked to form stable hydrogels; we found that greater CMC-methacrylate content resulted in increased gel swelling, protein diffusion and rates of degradation by cellulase, as well as decreased gel shear modulus. CMC-methacrylate/PEG-DM gels modified with the adhesive peptide RGD supported fibroblast adhesion and viability. We conclude that hydrogels based on CMC-methacrylate are suitable for bioengineering applications where selective degradability may be favorable, such as cell scaffolds or controlled release devices. PMID:22708058

Bone augmentation at peri-implant dehiscence defects comparing a synthetic polyethylene glycol hydrogel matrix vs. standard guided bone regeneration techniques.

PubMed

Thoma, Daniel S; Jung, Ui-Won; Park, Jin-Young; Bienz, Stefan P; Hüsler, Jürg; Jung, Ronald E

2017-07-01

The aim of the study was to test whether or not the use of a polyethylene glycol (PEG) hydrogel with or without the addition of an arginylglycylaspartic acid (RGD) sequence applied as a matrix in combination with hydroxyapatite/tricalciumphosphate (HA/TCP) results in similar peri-implant bone regeneration as traditional guided bone regeneration procedures. In 12 beagle dogs, implant placement and peri-implant bone regeneration were performed 2 months after tooth extraction in the maxilla. Two standardized box-shaped defects were bilaterally created, and dental implants were placed in the center of the defects with a dehiscence of 4 mm. Four treatment modalities were randomly applied: i)HA/TCP mixed with a synthetic PEG hydrogel, ii)HA/TCP mixed with a synthetic PEG hydrogel supplemented with an RGD sequence, iii)HA/TCP covered with a native collagen membrane (CM), iv)and no bone augmentation (empty). After a healing period of 8 or 16 weeks, micro-CT and histological analyses were performed. Histomorphometric analysis revealed a greater relative augmented area for groups with bone augmentation (43.3%-53.9% at 8 weeks, 31.2%-42.8% at 16 weeks) compared to empty controls (22.9% at 8 weeks, 1.1% at 16 weeks). The median amount of newly formed bone was greatest in group CM at both time-points. Regarding the first bone-to-implant contact, CM was statistically significantly superior to all other groups at 8 weeks. Bone can partially be regenerated at peri-implant buccal dehiscence defects using traditional guided bone regeneration techniques. The use of a PEG hydrogel applied as a matrix mixed with a synthetic bone substitute material might lack a sufficient stability over time for this kind of defect. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

New biodegradable dextran-based hydrogels for protein delivery: Synthesis and characterization.

PubMed

Pacelli, Settimio; Paolicelli, Patrizia; Casadei, Maria Antonietta

2015-08-01

A new derivative of dextran grafted with polyethylene glycol methacrylate through a carbonate bond (DEX-PEG-MA) has been synthesized and characterized. The photo-crosslinking reaction of DEX-PEG-MA allowed the obtainment of biodegradable networks tested for their mechanical and release properties. The new hydrogels were compared with those made of dextran methacrylate (DEX-MA), often employed as drug delivery systems of small molecules. The inclusion of PEG as a spacer created additional interactions among the polymeric chains improving the extreme fragility and lack of hardness typical of gels made of DEX-MA. Moreover, the different behavior in terms of swelling and degradability of the networks was able to affect the release of a model macromolecule over time, making DEX-PEG-MA matrices suitable candidates for the delivery of high molecular weight peptides. Interestingly, the combination of the two dextran derivatives showed intermediate ability to modulate the release of high molecular weight macromolecules. Copyright © 2015 Elsevier Ltd. All rights reserved.

A microfabricated platform with hydrogel arrays for 3D mechanical stimulation of cells.

PubMed

Liu, Haijiao; Usprech, Jenna; Sun, Yu; Simmons, Craig A

2016-04-01

Cellular microenvironments present cells with multiple stimuli, including not only soluble biochemical and insoluble matrix cues but also mechanical factors. Biomaterial array platforms have been used to combinatorially and efficiently probe and define two-dimensional (2D) and 3D microenvironmental cues to guide cell functions for tissue engineering applications. However, there are few examples of array platforms that include dynamic mechanical forces, particularly to enable stretching of 3D cell-seeded biomaterials, which is relevant to engineering connective and cardiovascular tissues. Here we present a deformable membrane platform that enables 3D dynamic mechanical stretch of arrayed biomaterial constructs. Cell-seeded polyethylene glycol norbornene (PEG-NB) hydrogels were bound to miniaturized deformable membranes via a thiol-ene reaction with off-stoichiometry thiol-ene based polydimethylsiloxane (OSTE-PDMS) as the membrane material. Bonding to OSTE-PDMS enabled the 3D hydrogel microconstructs to be cyclically deformed and stretched by the membrane. As a first demonstration, human mesenchymal stromal cells (MSCs) embedded in PEG-NB were stretched for several days. They were found to be viable, spread in the 3D hydrogels, and exhibited a contractile myofibroblast phenotype when exposed to dynamic 3D mechanical deformation. This platform, which is readily scalable to larger arrays, enables systematic interrogation of the relationships between combinations of 3D mechanobiological cues and cellular responses, and thus has the potential to identify strategies to predictably control the construction of functional engineered tissues. Current high-throughput biomaterial screening approaches fail to consider the effects of dynamic mechanical stimulation, despite its importance in a wide variety of regenerative medicine applications. To meet this need, we developed a deformable membrane platform that enables 3D dynamic stretch of arrayed biomaterial constructs. Our approach combines microtechnologies fabricated with off-stoichiometry thiol-ene based polydimethylsiloxane membranes that can covalently bond cell-seeded polyethylene glycol norbornene 3D hydrogels, a model biomaterial with tunable adhesive, elastic and degradation characteristics. As a first demonstration, we show that human mesenchymal stromal cells embedded in hydrogels and subjected to dynamic mechanical stimulation undergo myofibroblast differentiation. This system is readily scaled up to larger arrays, and will enable systematic and efficient screening of combinations of 3D mechanobiological and biomaterial cues on cell fate and function. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Balancing Cell Migration with Matrix Degradation Enhances Gene Delivery to Cells Cultured Three-Dimensionally Within Hydrogels

PubMed Central

Shepard, Jaclyn A.; Huang, Alyssa; Shikanova, Ariella; Shea, Lonnie D.

2010-01-01

In regenerative medicine, hydrogels are employed to fill defects and support the infiltration of cells that can ultimately regenerate tissue. Gene delivery within hydrogels targeting infiltrating cells has the potential to promote tissue formation, but the delivery efficiency of nonviral vectors within hydrogels is low hindering their applicability in tissue regeneration. To improve their functionality, we have conducted a mechanistic study to investigate the contribution of cell migration and matrix degradation on gene delivery. In this report, lipoplexes were entrapped within hydrogels based on poly(ethylene glycol) (PEG) crosslinked with peptides containing matrix metalloproteinase degradable sequences. The mesh size of these hydrogels is substantially less than the size of the entrapped lipoplexes, which can function to retain vectors. Cell migration and transfection were simultaneously measured within hydrogels with varying density of cell adhesion sites (Arg-Gly-Asp peptides) and solids content. Increasing RGD density increased expression levels up to 100-fold, while greater solids content sustained expression levels for 16 days. Increasing RGD density and decreasing solids content increased cell migration, which indicates expression levels increase with increased cell migration. Initially exposing cells to vector resulted in transient expression that declined after 2 days, verifying the requirement of migration to sustain expression. Transfected cells were predominantly located within the population of migrating cells for hydrogels that supported cell migration. Although the small mesh size retained at least 70% of the lipoplexes in the absence of cells after 32 days, the presence of cells decreased retention to 10% after 16 days. These results indicate that vectors retained within hydrogels contact migrating cells, and that persistent cell migration can maintain elevated expression levels. Thus matrix degradation and cell migration are fundamental design parameters for maximizing gene delivery from hydrogels. PMID:20450944

Attachment and spatial organisation of human mesenchymal stem cells on poly(ethylene glycol) hydrogels.

PubMed

Chahal, Aman S; Schweikle, Manuel; Heyward, Catherine A; Tiainen, Hanna

2018-08-01

Strategies that enable hydrogel substrates to support cell attachment typically incorporate either entire extracellular matrix proteins or synthetic peptide fragments such as the RGD (arginine-glycine-aspartic acid) motif. Previous studies have carefully analysed how material characteristics can affect single cell morphologies. However, the influence of substrate stiffness and ligand presentation on the spatial organisation of human mesenchymal stem cells (hMSCs) have not yet been examined. In this study, we assessed how hMSCs organise themselves on soft (E = 7.4-11.2 kPa) and stiff (E = 27.3-36.8 kPa) poly(ethylene glycol) (PEG) hydrogels with varying concentrations of RGD (0.05-2.5 mM). Our results indicate that hMSCs seeded on soft hydrogels clustered with reduced cell attachment and spreading area, irrespective of RGD concentration and isoform. On stiff hydrogels, in contrast, cells spread with high spatial coverage for RGD concentrations of 0.5 mM or higher. In conclusion, we identified that an interplay of hydrogel stiffness and the availability of cell attachment motifs are important factors in regulating hMSC organisation on PEG hydrogels. Understanding how cells initially interact and colonise the surface of this material is a fundamental prerequisite for the design of controlled platforms for tissue engineering and mechanobiology studies. Copyright © 2018 Elsevier Ltd. All rights reserved.

One-pot synthesis and lubricity of fluorescent carbon dots applied on PCL-PEG-PCL hydrogel.

PubMed

Guo, Junde; Mei, Tangjie; Li, Yue; Hafezi, Mahshid; Lu, Hailin; Li, Jianhui; Dong, Guangneng

2018-06-12

This work presents a method for one-pot synthesis of N-doped nanometer-size carbon dots, which can be assembled with thermosensitive poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) hydrogel to achieve slow-release lubricity. The typical property of this green production was studied by fourier transform infrared (FT-IR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and transmission electron microscope (TEM). The photoluminescence of composite PCEC/CDs hydrogel and its released solutions were characterized by ultraviolet spectrum, and the rheological properties were tested by rotary rheometer. Tribological performance of the released solution from composite PCEC/CDs hydrogel was obtained to compare with PBS and pure CDs solution. The experimental results reveal that the CDs contain the chemical groups of N-H, C-OH/C-O-C and -COOH, etc. In addition, the diameter of the CDs is in the range of 6~8 nm. The phase transition behavior of PCEC/CDs hydrogel can be still kept and its viscoelasticity hydrogel is improved by approximatively 7%. Furthermore, friction coefficient of the released solution from composite PCEC/CDs hydrogel decreases by about 70% than that of PBS. Besides, the wear condition can be improved by a lubricating transfer film formed by released CDs. This novel strategy for slow-release application is valuable for drug delivery and bio-tribology.

Amphiphilic Polyurethane Hydrogels as Smart Carriers for Acidic Hydrophobic Drugs.

PubMed

Fonseca, Lucas P; Trinca, Rafael B; Isabel Felisberti, Maria

2018-05-14

Amphiphilic hydrogels are widely reported as systems with great potential for controlled drug release. Nevertheless, the majority of studies make use of functionalization or attachment of drugs to the polymer chains. In this study, we propose a strategy of combining amphiphilic polyurethanes with pH-responsive drugs to develop smart drug carriers. While the amphiphilic character of the polymer imparts an efficient load of hydrophobic and hydrophilic drugs, the drug's characteristics determine the selectivity of the medium delivery. Drug loading and release behavior as well as hydrolytic degradation of chemically crosslinked polyurethane hydrogels based on PEG and PCL-triol (PU (polyurethane) hydrogels) synthesized by an easy one-pot route were studied. PU hydrogels have been shown to successfully load the hydrophobic acidic drug sodium diclofenac, reaching a partition coefficient of 8 between the most hydrophobic PU and diclofenac/ethanol solutions. Moreover, an oral administration simulation was conducted by changing the environment from an acidic to a neutral medium. PU hydrogels release less than 5 % of the drug in an acidic medium; however, in a PBS pH 7.4 solution, diclofenac is delivered in a sustained fashion for up to 40 hours, achieving 80% of cumulative release. Copyright © 2018. Published by Elsevier B.V.

Development of (acrylic acid/ polyethylene glycol)-zinc oxide mucoadhesive nanocomposites for buccal administration of propranolol HCl

NASA Astrophysics Data System (ADS)

Mahmoud, Ghada A.; Ali, Amr El-Hag; Raafat, Amany I.; Badawy, Nagwa A.; Elshahawy, Mai. F.

2018-06-01

A series of mucoadhesive nanocomposites with self disinfection properties composed of acrylic acid, polyethylene glycol and ZnO nanoparticles (AAc/PEG)-ZnO were developed for localized buccal Propranolol HCl delivery. γ-irradiation as a clean tool for graft copolymerization process was used for the preparation of (AAc/PEG) hydrogels. In suite precipitation technique was used for ZnO nanoparticles immobilization within (AAc/PEG) hydrogels. The developed (AAc/PEG)-ZnO nanocomposites were characterized by X-ray diffraction (XRD), UV-Vis spectrophotometer, energy dispersive X-ray spectroscopy (EDX) and scanning electron microscopy (SEM) to confirm the success of ZnO nanoparticles formation within the (AAc/PEG) matrices. The presence of ZnO nanoparticles improves the thermal stability as indicated using thermogravimetric analysis (TGA). The mucoadhesion characteristics such as hydration degree, surface pH, and mucoadhesive strength were evaluated in artificial saliva solution. The self disinfection property of the developed (AAc/PEG)-ZnO nanocomposites was investigated by examining their resistance to pathogenic microorganisms such as Staphylococcus aureus, Bacillus subtilis, and Escherichia coli using disc diffusion method. The release of Propranolol -HCl drug in artificial saliva was found to obey a non-Fickian diffusion mechanism. The obtained results suggests that (AAc/PEG)-ZnO nanocomposites could be used as mucoadhesive carrier for buccal drug delivery with efficient antibacterial properties.

Accelerated cell sheet detachment by copolymerizing hydrophilic PEG side chains into PNIPAm nanocomposite hydrogels.

PubMed

Liu, Dan; Wang, Tao; Liu, Xinxing; Tong, Zhen

2012-10-01

One-end-connected short poly(ethylene glycol) (PEG) side chains were facilely introduced into the poly(N-isopropylacrylamide) (PNIPAm) nanocomposite hydrogel (NC gel) via in situ copolymerization of NIPAm monomer and PEG macromonomer in the aqueous suspension of hectorite clay Laponite XLS. The NC gels were characterized with Fourier transform infrared and x-ray photoelectron spectroscopy for the composition, DSC and transmittance for the phase separation temperature, dynamic mechanical spectra and swelling ratio for the interaction. Increasing the PEG content led to a small increase in the storage modulus and the lower critical solution temperature (LCST) of the copolymerized NC gels, and the LCST of the copolymerized NC gels was still below 37 °C. The L929 cell adhesion and proliferation on the surface of these NC gels were not suppressed by the incorporation of hydrophilic PEG side chains. By lowering temperature below the LCST, the cell sheet spontaneously detached from the copolymerized NC gels. The surface morphology and surface wettability of the NC gels were detected by atom force microscope and contact angle measurement. A rough and hydrophilic surface induced by a small amount of PEG side chains was found to be favorable to accelerate the cell sheet detachment, probably due to the enhanced water permeation into the gel-cell sheet interface.

Characterization and tribology of PEG-like coatings on UHMWPE for total hip replacements.

PubMed

Kane, Sheryl R; Ashby, Paul D; Pruitt, Lisa A

2010-03-15

A crosslinked hydrogel coating similar to poly(ethylene glycol) (PEG) was covalently bonded to the surface of ultrahigh molecular weight polyethylene (UHMWPE) to improve the lubricity and wear resistance of the UHWMPE for use in total joint replacements. The chemistry, hydrophilicity, and protein adsorption resistance of the coatings were determined, and the wear behavior of the PEG-like coating was examined by two methods: pin-on-disk tribometry to evaluate macroscale behavior, and atomic force microscopy (AFM) to simulate asperity wear. As expected, the coating was found to be highly PEG-like, with approximately 83% ether content by x-ray photoelectron spectroscopy and more hydrophilic and resistant to protein adsorption than uncoated UHMWPE. Pin-on-disk testing showed that the PEG-like coating could survive 3 MPa of contact pressure, comparable to that experienced by total hip replacements. AFM nanoscratching experiments uncovered three damage mechanisms for the coatings: adhesion/microfracture, pure adhesion, and delamination. The latter two mechanisms appear to correlate well with wear patterns induced by pin-on-disk testing and evaluated by attenuated total reflection Fourier transform infrared spectroscopy mapping. Understanding the mechanisms by which the PEG-like coatings wear is critical for improving the behavior of subsequent generations of wear-resistant hydrogel coatings. (c) 2009 Wiley Periodicals, Inc.

Application of a Dense Gas Technique for Sterilizing Soft Biomaterials

PubMed Central

Karajanagi, Sandeep S.; Yoganathan, Roshan; Mammucari, Raffaella; Park, Hyoungshin; Cox, Julian; Zeitels, Steven M.; Langer, Robert; Foster, Neil R.

2017-01-01

Sterilization of soft biomaterials such as hydrogels is challenging because existing methods such as gamma irradiation, steam sterilization, or ethylene oxide sterilization, while effective at achieving high sterility assurance levels (SAL), may compromise their physicochemical properties and biocompatibility. New methods that effectively sterilize soft biomaterials without compromising their properties are therefore required. In this report, a dense-carbon dioxide (CO2)-based technique was used to sterilize soft polyethylene glycol (PEG)-based hydrogels while retaining their structure and physicochemical properties. Conventional sterilization methods such as gamma irradiation and steam sterilization severely compromised the structure of the hydrogels. PEG hydrogels with high water content and low elastic shear modulus (a measure of stiffness) were deliberately inoculated with bacteria and spores and then subjected to dense CO2. The dense CO2-based methods effectively sterilized the hydrogels achieving a SAL of 10−7 without compromising the viscoelastic properties, pH, water-content, and structure of the gels. Furthermore, dense CO2-treated gels were biocompatible and non-toxic when implanted subcutaneously in ferrets. The application of novel dense CO2-based methods to sterilize soft biomaterials has implications in developing safe sterilization methods for soft biomedical implants such as dermal fillers and viscosupplements. PMID:21337339

Rapid 3D printing of anatomically accurate and mechanically heterogeneous aortic valve hydrogel scaffolds

PubMed Central

Hockaday, L A; Kang, K H; Colangelo, N W; Cheung, P Y C; Duan, B; Malone, E; Wu, J; Girardi, L N; Bonassar, L J; Lipson, H; Chu, C C; Butcher, J T

2013-01-01

The aortic valve exhibits complex three-dimensional (3D) anatomy and heterogeneity essential for long-term efficient biomechanical function. These are, however, challenging to mimic in de novo engineered living tissue valve strategies. We present a novel simultaneous 3D-printing/photocrosslinking technique for rapidly engineering complex, heterogeneous aortic valve scaffolds. Native anatomic and axisymmetric aortic valve geometries (root wall and tri-leaflets) with 12 to 22 mm inner diameters (ID) were 3D printed with poly-ethylene glycol-diacrylate (PEG-DA) hydrogels (700 or 8000 MW) supplemented with alginate. 3D printing geometric accuracy was quantified and compared using Micro-CT. Porcine aortic valve interstitial cells (PAVIC) seeded scaffolds were cultured for up to 21 days. Results showed that blended PEG-DA scaffolds could achieve over 10-fold range in elastic modulus (5.3±0.9 to 74.6±1.5 kPa). 3D printing times for valve conduits with mechanically contrasting hydrogels were optimized to 14 to 45 minutes, increasing linearly with conduit diameter. Larger printed valves had greater shape fidelity (93.3±2.6, 85.1±2.0, and 73.3±5.2% for 22, 17, and 12 mm ID porcine valves; 89.1±4.0, 84.1±5.6, and 66.6±5.2% for simplified valves). PAVIC seeded scaffolds maintained near 100% viability over 21 days. These results demonstrate that 3D hydrogel printing with controlled photocrosslinking can rapidly fabricate anatomical heterogeneous valve conduits that support cell engraftment. PMID:22914604

The bridging conformations of double-end anchored polymer-surfactants destabilize a hydrogel of lipid membranes

NASA Astrophysics Data System (ADS)

Slack, N. L.; Davidson, P.; Chibbaro, M. A.; Jeppesen, C.; Eiselt, P.; Warriner, H. E.; Schmidt, H.-W.; Pincus, P.; Safinya, C. R.

2001-10-01

Double-end-anchored poly-ethylene-glycol-surfactants (DEA-PEG-surfactants) induce the gelation of lyotropic lamellar Lα phases stabilized by undulation forces. The physical hydrogel (Lα,g) derives its viscoelasticity from the proliferation of defects at a mesoscopic level. The DEA-PEG-surfactants assume both looping and bridging conformations. The existence of novel bridging conformations is indicated by the coexistence of two lamellar phases and the limited swelling of the Lα and Lα,g phases. Modeling of the polymer decorated membranes demonstrates the existence of bridging and yields a rapidly decreasing density of bridging conformations with increasing interlayer spacing.

Assessment of PLGA-PEG-PLGA Copolymer Hydrogel for Sustained Drug Delivery in the Ear

PubMed Central

Feng, Liang; Ward, Jonette A.; Li, S. Kevin; Tolia, Gaurav; Hao, Jinsong; Choo, Daniel I.

2014-01-01

Temperature sensitive copolymer systems were previously studied using modified diffusion cells in vitro for intratympanic injection, and the PLGA-PEG-PLGA copolymer systems were found to provide sustained drug delivery for several days. The objectives of the present study were to assess the safety of PLGA-PEG-PLGA copolymers in intratympanic injection in guinea pigs in vivo and to determine the effects of additives glycerol and poloxamer in PLGA-PEG-PLGA upon drug release in the diffusion cells in vitro for sustained inner ear drug delivery. In the experiments, the safety of PLGA-PEG-PLGA copolymers to inner ear was evaluated using auditory brainstem response (ABR). The effects of the additives upon drug release from PLGA-PEG-PLGA hydrogel were investigated in the modified Franz diffusion cells in vitro with cidofovir as the model drug. The phase transition temperatures of the PLGA-PEG-PLGA copolymers in the presence of the additives were also determined. In the ABR safety study, the PLGA-PEG-PLGA copolymer alone did not affect hearing when delivered at 0.05-mL dose but caused hearing loss after 0.1-mL injection. In the drug release study, the incorporation of the bioadhesive additive, poloxamer, in the PLGA-PEG-PLGA formulations was found to decrease the rate of drug release whereas the increase in the concentration of the humectant additive, glycerol, provided the opposite effect. In summary, the PLGA-PEG-PLGA copolymer did not show toxicity to the inner ear at the 0.05-mL dose and could provide sustained release that could be controlled by using the additives for inner ear applications. PMID:24438444

Uniform neural tissue models produced on synthetic hydrogels using standard culture techniques.

PubMed

Barry, Christopher; Schmitz, Matthew T; Propson, Nicholas E; Hou, Zhonggang; Zhang, Jue; Nguyen, Bao K; Bolin, Jennifer M; Jiang, Peng; McIntosh, Brian E; Probasco, Mitchell D; Swanson, Scott; Stewart, Ron; Thomson, James A; Schwartz, Michael P; Murphy, William L

2017-11-01

The aim of the present study was to test sample reproducibility for model neural tissues formed on synthetic hydrogels. Human embryonic stem (ES) cell-derived precursor cells were cultured on synthetic poly(ethylene glycol) (PEG) hydrogels to promote differentiation and self-organization into model neural tissue constructs. Neural progenitor, vascular, and microglial precursor cells were combined on PEG hydrogels to mimic developmental timing, which produced multicomponent neural constructs with 3D neuronal and glial organization, organized vascular networks, and microglia with ramified morphologies. Spearman's rank correlation analysis of global gene expression profiles and a comparison of coefficient of variation for expressed genes demonstrated that replicate neural constructs were highly uniform to at least day 21 for samples from independent experiments. We also demonstrate that model neural tissues formed on PEG hydrogels using a simplified neural differentiation protocol correlated more strongly to in vivo brain development than samples cultured on tissue culture polystyrene surfaces alone. These results provide a proof-of-concept demonstration that 3D cellular models that mimic aspects of human brain development can be produced from human pluripotent stem cells with high sample uniformity between experiments by using standard culture techniques, cryopreserved cell stocks, and a synthetic extracellular matrix. Impact statement Pluripotent stem (PS) cells have been characterized by an inherent ability to self-organize into 3D "organoids" resembling stomach, intestine, liver, kidney, and brain tissues, offering a potentially powerful tool for modeling human development and disease. However, organoid formation must be quantitatively reproducible for applications such as drug and toxicity screening. Here, we report a strategy to produce uniform neural tissue constructs with reproducible global gene expression profiles for replicate samples from multiple experiments.

Component effect of stem cell-loaded thermosensitive polypeptide hydrogels on cartilage repair.

PubMed

Liu, He; Cheng, Yilong; Chen, Jinjin; Chang, Fei; Wang, Jincheng; Ding, Jianxun; Chen, Xuesi

2018-06-01

Biophysical properties of the desired biomimetic scaffolds, such as porosity and elasticity, have been proven associated with the efficacy of cartilage regeneration. In this work, the copolymers of poly(l-alanine)-block-poly(ethylene glycol)-block-poly(l-alanine) (PA-PEG-PA) and poly(l-alanine-co-l-phenylalanine)-block-poly(ethylene glycol)-block-poly(l-alanine-co-l-phenylalanine) (PAF-PEG-PAF) with different ratios of alanine to phenylalanine were synthesized. The introduction of a hydrophobic amino acid, i.e., phenylalanine, into polyalanine-based thermosensitive hydrogel led to the enhanced gelation behaviors and upregulated mechanical properties. Moreover, the increase of phenylalanine content resulted in the enlarged pore size and enhanced mechanical strength of PAF-PEG-PAF thermogel, followed by the regeneration of hyaline-like cartilage with reduced fibrous tissue formation in vivo. The findings indicated the great potential of thermosensitive polypeptide hydrogels in cartilage tissue engineering. Articular cartilage defect has limited self-repair ability due to the lack of blood supply and innervation, which may lead to knee osteoarthritis afterwards. Injectable hydrogels are demonstrated possessing outstanding properties as biomimetic scaffolds in cartilage tissue engineering, while the effect of biophysical properties on the efficacy of cartilage regeneration has not been revealed. Herein, the poly(ethylene glycol)-polypeptide triblock copolymers with different ratios of alanine to phenylalanine were synthesized. The sol-to-gel transition temperature and the critical gelation concentration decreased as the increased amount of phenylalanine unit, resulting in the enlarged pore size and enhanced mechanical strength. These features lead to better regeneration of hyaline-like cartilage with reduced fibrous tissue formation, indicating great potential of thermosensitive polypeptide hydrogels for efficient cartilage repair. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Improving Joint Function Using Photochemical Hydrogels for Articular Surface Repair

DTIC Science & Technology

2013-10-01

riboflavin and blue light in hypoxic conditions. Control gels were not photochemically crosslinked . New cartilage matrix was formed in vivo in mice after 4...Sections were probed with AlexaFluor 568- conjugated secondary antibodies and counterstained with DAPI for cell nuclei. All samples were processed at...calcium deposits demonstrated with von Kossa stains; 2) A degradable form of photochemically crosslinked PEG norbomene gel was formulated and growth

Characterization and manipulation of the in vivo host response and in vitro macrophage response to synthetic hydrogels

NASA Astrophysics Data System (ADS)

Lynn, Aaron David

Tissue engineering hope to fill the donor gap between patient needing transplantation and donors able to provide organs. Many challenges exist in the engineering of replacement tissues such as cell sourcing and scaffold design. A particularly promising group of scaffolds used extensively in tissue engineering research are based on cross-linked poly(ethylene glycol) (PEG) hydrogels. Materials based on these gels have been selected for their tissue-like high water content, low cell toxicty, mild polymerization conditions and the ease with which their mechanical and chemical properties can be tuned. However, all materials which will ultimately be implanted into will elicit a host response. This reaction is initiated when a wound is created. It leads to bathing of the material in proteins from the blood, recruitment, attachment and interrogation of the material by macrophages, attempted degradation and phagocytosis, macrophage fusion into foreign body giant cells (FBGCs) and ultimately the "walling off" of the implant as a dense collagenous capsule surrounds the material restricting further interactions with the host. This foreign body response (FBR) is well studied and contributes significantly to premature failure of implanted medical devices. The research presented in this thesis aims to characterize the FBR to PEG-based tissue engineering scaffolds with the intention of uncovering mechanisms by which the response can be attenuated. To this end, implantation studies have been performed to gauge the severity of the foreign body response to these hydrogels and to establish to what degree modifications with the cell adhesion peptide alter this reaction in vivo. Additionally, in vitro models were established to study characteristics of the the early (< 1 week), middle (1-2 weeks) and late phases (> 2 weeks) of the FBR. Studies were performed to determine the potentially detrimental effects of macrophage interrogation of a PEG-based skin tissue engineering system containing encapsulated fibroblasts. Finally, preliminary work has been done on a strategy for manipulating macrophage interactions with tissue engineering hydrogels utilizing a novel hydrogel coating system. This provides some of the first correlations between in vivo host responses and in vitro macrophage responses to PEG-based tissue engineering materials.

Development of a thermosensitive HAMA-containing bio-ink for the fabrication of composite cartilage repair constructs.

PubMed

Mouser, V H M; Abbadessa, A; Levato, R; Hennink, W E; Vermonden, T; Gawlitta, D; Malda, J

2017-03-23

Fine-tuning of bio-ink composition and material processing parameters is crucial for the development of biomechanically relevant cartilage constructs. This study aims to design and develop cartilage constructs with tunable internal architectures and relevant mechanical properties. More specifically, the potential of methacrylated hyaluronic acid (HAMA) added to thermosensitive hydrogels composed of methacrylated poly[N-(2-hydroxypropyl)methacrylamide mono/dilactate] (pHPMA-lac)/polyethylene glycol (PEG) triblock copolymers, to optimize cartilage-like tissue formation by embedded chondrocytes, and enhance printability was explored. Additionally, co-printing with polycaprolactone (PCL) was performed for mechanical reinforcement. Chondrocyte-laden hydrogels composed of pHPMA-lac-PEG and different concentrations of HAMA (0%-1% w/w) were cultured for 28 d in vitro and subsequently evaluated for the presence of cartilage-like matrix. Young's moduli were determined for hydrogels with the different HAMA concentrations. Additionally, hydrogel/PCL constructs with different internal architectures were co-printed and analyzed for their mechanical properties. The results of this study demonstrated a dose-dependent effect of HAMA concentration on cartilage matrix synthesis by chondrocytes. Glycosaminoglycan (GAG) and collagen type II content increased with intermediate HAMA concentrations (0.25%-0.5%) compared to HAMA-free controls, while a relatively high HAMA concentration (1%) resulted in increased fibrocartilage formation. Young's moduli of generated hydrogel constructs ranged from 14 to 31 kPa and increased with increasing HAMA concentration. The pHPMA-lac-PEG hydrogels with 0.5% HAMA were found to be optimal for cartilage-like tissue formation. Therefore, this hydrogel system was co-printed with PCL to generate porous or solid constructs with different mesh sizes. Young's moduli of these composite constructs were in the range of native cartilage (3.5-4.6 MPa). Interestingly, the co-printing procedure influenced the mechanical properties of the final constructs. These findings are relevant for future bio-ink development, as they demonstrate the importance of selecting proper HAMA concentrations, as well as appropriate print settings and construct designs for optimal cartilage matrix deposition and final mechanical properties of constructs, respectively.

Non-Covalent Photo-Patterning of Gelatin Matrices Using Caged Collagen Mimetic Peptides

PubMed Central

Li, Yang; Hoa San, Boi; L. Kessler, Julian; Hwan Kim, Jin; Xu, Qingguo; Hanes, Justin; Yu, Seungju Michael

2015-01-01

Advancements in photolithography have enabled us to spatially encode biochemical cues in biocompatible platforms such as synthetic hydrogels. Conventional patterning works through photo-activated chemical reactions on inert polymer networks. However, these techniques cannot be directly applied to protein hydrogels without chemically altering the protein scaffolds. To this end, we developed a non-covalent photo-patterning strategy for gelatin (denatured collagen) hydrogels utilizing a caged collagen mimetic peptide (caged CMP) which binds to gelatin strands through UV activated, triple helix hybridization. Here we present 2D and 3D photo-patterning of gelatin hydrogels enabled by the caged CMPs as well as creation of concentration gradients of CMPs. We show that photo-patterning of PEG-conjugated caged CMPs can be used to spatially control cell adhesion on gelatin films. CMP’s specificity for binding to gelatin allows patterning of almost any synthetic or natural gelatin-containing matrix, such as zymograms, gelatin-methacrylate hydrogels, and even a corneal tissue. Since the CMP is a chemically and biologically inert peptide which is proven to be an ideal carrier for bioactive molecules, our patterning method provides a radically new tool for immobilizing drugs to natural tissues and for functionalizing scaffolds for complex tissue formation. PMID:25476588

Characterization of protein release from photocrosslinkable hyaluronic acid-polyethylene glycol hydrogel tissue engineering scaffolds.

PubMed

Leach, Jennie B; Schmidt, Christine E

2005-01-01

The goal of this work was to utilize the naturally derived bioactive polymer hyaluronic acid (HA) to create a combination tissue engineering scaffold and protein delivery device. HA is a non-immunogenic, non-adhesive glycosaminoglycan that plays significant roles in several cellular processes, including angiogenesis and the regulation of inflammation. In previous work, we created photopolymerizable glycidyl methacrylate-hyaluronic acid (GMHA) hydrogels that had controlled degradation rates, were cytocompatible, and were able to be modified with peptide moieties. In the present studies, we characterized the release of a model protein, bovine serum albumin (BSA), from GMHA and GMHA-polyethylene glycol (PEG) hydrogels. Although BSA could be released rapidly (> 60% within 6 h) from 1% GMHA hydrogels, we found that increasing either the GMHA or the PEG concentrations could lengthen the duration of protein delivery. Preliminary size exclusion chromatography studies indicated that the released BSA was almost entirely in its native monomeric form. Lastly, protein release was extended to several weeks by suspending BSA-poly(lactic-co-glycolic acid) microspheres within the hydrogel bulk. These initial studies indicate that the naturally derived biopolymer HA can be employed to design novel photopolymerizable composites that are suitable for delivering stable proteins from scaffolding in tissue engineering applications.

Selective adsorption of carbohydrates and glycoproteins via molecularly imprinted hydrogels: application to visible detection by a boronic acid monomer.

PubMed

Kubo, Takuya; Furuta, Hayato; Naito, Toyohiro; Sano, Tomoharu; Otsuka, Koji

2017-06-29

Selective adsorption of carbohydrates and glycoproteins was effectively achieved by molecularly imprinted hydrogels (MIHs) with a poly(ethylene glycol) (PEG)-based crosslinker and 4-vinylphenylboronic acid. In addition, an MIH with a novel boronic acid monomer provided selective adsorption and enabled visible detection of fructose.

In Vitro and In Vivo Evaluation of a Hydrogel Reservoir as a Continuous Drug Delivery System for Inner Ear Treatment

PubMed Central

Hessler, Roland; Stöver, Timo; Esser, Karl-Heinz; Möller, Martin; Lenarz, Thomas; Jolly, Claude; Groll, Jürgen; Scheper, Verena

2014-01-01

Fibrous tissue growth and loss of residual hearing after cochlear implantation can be reduced by application of the glucocorticoid dexamethasone-21-phosphate-disodium-salt (DEX). To date, sustained delivery of this agent to the cochlea using a number of pharmaceutical technologies has not been entirely successful. In this study we examine a novel way of continuous local drug application into the inner ear using a refillable hydrogel functionalized silicone reservoir. A PEG-based hydrogel made of reactive NCO-sP(EO-stat-PO) prepolymers was evaluated as a drug conveying and delivery system in vitro and in vivo. Encapsulating the free form hydrogel into a silicone tube with a small opening for the drug diffusion resulted in delayed drug release but unaffected diffusion of DEX through the gel compared to the free form hydrogel. Additionally, controlled DEX release over several weeks could be demonstrated using the hydrogel filled reservoir. Using a guinea-pig cochlear trauma model the reservoir delivery of DEX significantly protected residual hearing and reduced fibrosis. As well as being used as a device in its own right or in combination with cochlear implants, the hydrogel-filled reservoir represents a new drug delivery system that feasibly could be replenished with therapeutic agents to provide sustained treatment of the inner ear. PMID:25105670

Gel structure has an impact on pericellular and extracellular matrix deposition, which subsequently alters metabolic activities in chondrocyte-laden PEG hydrogels.

PubMed

Nicodemus, G D; Skaalure, S C; Bryant, S J

2011-02-01

While designing poly(ethylene glycol) hydrogels with high moduli suitable for in situ placement is attractive for cartilage regeneration, the impact of a tighter crosslinked structure on the organization and deposition of the matrix is not fully understood. The objectives of this study were to characterize the composition and spatial organization of new matrix as a function of gel crosslinking and study its impact on chondrocytes in terms of anabolic and catabolic gene expression and catabolic activity. Bovine articular chondrocytes were encapsulated in hydrogels with three crosslinking densities (compressive moduli 60, 320 and 590 kPa) and cultured for 25 days. Glycosaminoglycan production increased with culture time and was greatest in the gels with lowest crosslinking. Collagens II and VI, aggrecan, link protein and decorin were localized to pericellular regions in all gels, but their presence decreased with increasing gel crosslinking. Collagen II and aggrecan expression were initially up-regulated in gels with higher crosslinking, but increased similarly up to day 15. Matrix metalloproteinase (MMP)-1 and MMP-13 expression were elevated (∼25-fold) in gels with higher crosslinking throughout the study, while MMP-3 was unaffected by gel crosslinking. The presence of aggrecan and collagen degradation products confirmed MMP activity. These findings indicate that chondrocytes synthesized the major cartilage components within PEG hydrogels, however, gel structure had a significant impact on the composition and spatial organization of the new tissue and on how chondrocytes responded to their environment, particularly with respect to their catabolic expression. Copyright © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Cellularized cylindrical fiber/hydrogel composites for ligament tissue engineering.

PubMed

Thayer, Patrick S; Dimling, Anna F; Plessl, Daniel S; Hahn, Mariah R; Guelcher, Scott A; Dahlgren, Linda A; Goldstein, Aaron S

2014-01-13

Electrospun meshes suffer from poor cell infiltration and limited thickness, which restrict their use to thin tissue applications. Herein, we demonstrate two complementary processes to overcome these limitations and achieve elastomeric composites that may be suitable for ligament repair. First, C3H10T1/2 mesenchymal stem cells were incorporated into electrospun meshes using a hybrid electrospinning/electrospraying process. Second, electrospun meshes were rolled and formed into composites with an interpenetrating polyethylene glycol (PEG) hydrogel network. Stiffer composites were formed from poly(lactic-co-glycolic acid) (PLGA) meshes, while softer and more elastic composites were formed from poly(ester-urethane urea) (PEUUR) meshes. As-spun PLGA and PEUUR rolled meshes had tensile moduli of 19.2 ± 1.9 and 0.86 ± 0.34 MPa, respectively, which changed to 11.6 ± 4.8 and 1.05 ± 0.39 MPa with the incorporation of a PEG hydrogel phase. In addition, cyclic tensile testing indicated that PEUUR-based composites deformed elastically to at least 10%. Finally, C3H10T1/2 cells incorporated into electrospun meshes survived the addition of the PEG phase and remained viable for up to 5 days. These results indicate that the fabricated cellularized composites are support cyclic mechanical conditioning, and have potential application in ligament repair.

Difference in suitable mechanical properties of three-dimensional, synthetic scaffolds for self-renewing mouse embryonic stem cells of different genetic backgrounds.

PubMed

Lee, Myungook; Ahn, Jong Il; Ahn, Ji Yeon; Yang, Woo Sub; Hubbell, Jeffrey A; Lim, Jeong Mook; Lee, Seung Tae

2017-11-01

We evaluated whether the genetic background of embryonic stem cells (ESCs) affects the properties suitable for three-dimensional (3D) synthetic scaffolds for cell self-renewal. Inbred R1 and hybrid B6D2F1 mouse ESC lines were cultured for 7 days in hydrogel scaffolds with different properties derived from conjugating 7.5, 10, 12.5, or 15% (wt/vol) vinylsulfone-functionalized three-, four-, or eight-arm polyethylene glycol (PEG) with dicysteine-containing crosslinkers with an intervening matrix metalloproteinase-specific cleavage sites. Cell proliferation and expression of self-renewal-related genes and proteins by ESCs cultured in feeder-free or containing 2D culture plate or 3D hydrogel were monitored. As a preliminary experiment, the E14 ESC-customized synthetic 3D microenvironment did not maintain self-renewal of either the R1 or B6D2F1 ESCs. The best R1 cell proliferation (10.04 vs. 0.16-4.39; p < 0.0001) was observed in the four-arm 7.5% PEG-based hydrogels than those with other properties, whereas the F1 ESCs showed better proliferation when they were embedded in the three-arm 10% hydrogels. Self-renewal-related gene and protein expression by ESCs after feeder-free 3D culture was generally maintained compared with the feeder-containing 2D culture, but expression patterns and quantities differed. However, the feeder-free 3D culture yielded better expression than the feeder-free 2D culture. In conclusion, genetic background determined the suitability of hydrogel scaffolds for self-renewal of ESCs, which requires customization for the mechanical properties of each cell line. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2261-2268, 2017. © 2016 Wiley Periodicals, Inc.

Improving Joint Function Using Photochemical Hydrogels for Articular Surface Repair

DTIC Science & Technology

2012-10-01

with thrombin previously has been reported as a favorable scaffold for cartilage formation by encapsulated chondrocytes [10]. Studies over the past...during the photochemical crosslinking process. A full scale study is planned for the first quarter of year 3 to evaluate the fully formed cartilage ...Perform initial study of collagen and PEG gels with stem cells implanted in mice  Bone marrow MSCs were harvested from donor swine and grown in culture

In vitro drug release behavior from a novel thermosensitive composite hydrogel based on Pluronic f127 and poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene glycol) copolymer

PubMed Central

Gong, Chang Yang; Shi, Shuai; Dong, Peng Wei; Zheng, Xiu Ling; Fu, Shao Zhi; Guo, Gang; Yang, Jing Liang; Wei, Yu Quan; Qian, Zhi Yong

2009-01-01

Background Most conventional methods for delivering chemotherapeutic agents fail to achieve therapeutic concentrations of drugs, despite reaching toxic systemic levels. Novel controlled drug delivery systems are designed to deliver drugs at predetermined rates for predefined periods at the target organ and overcome the shortcomings of conventional drug formulations therefore could diminish the side effects and improve the life quality of the patients. Thus, a suitable controlled drug delivery system is extremely important for chemotherapy. Results A novel biodegradable thermosensitive composite hydrogel, based on poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) and Pluronic F127 copolymer, was successfully prepared in this work, which underwent thermosensitive sol-gel-sol transition. And it was flowing sol at ambient temperature but became non-flowing gel at body temperature. By varying the composition, sol-gel-sol transition and in vitro drug release behavior of the composite hydrogel could be adjusted. Cytotoxicity of the composite hydrogel was conducted by cell viability assay using human HEK293 cells. The 293 cell viability of composite hydrogel copolymers were yet higher than 71.4%, even when the input copolymers were 500 μg per well. Vitamin B12 (VB12), honokiol (HK), and bovine serum albumin (BSA) were used as model drugs to investigate the in vitro release behavior of hydrophilic small molecular drug, hydrophobic small molecular drug, and protein drug from the composite hydrogel respectively. All the above-mentioned drugs in this work could be released slowly from composite hydrogel in an extended period. Chemical composition of composite hydrogel, initial drug loading, and hydrogel concentration substantially affected the drug release behavior. The higher Pluronic F127 content, lower initial drug loading amount, or lower hydrogel concentration resulted in higher cumulative release rate. Conclusion The results showed that composite hydrogel prepared in this paper were biocompatible with low cell cytotoxicity, and the drugs in this work could be released slowly from composite hydrogel in an extended period, which suggested that the composite hydrogel might have great potential applications in biomedical fields. PMID:19210779

In vitro and in vivo co-culture of chondrocytes and bone marrow stem cells in photocrosslinked PCL-PEG-PCL hydrogels enhances cartilage formation.

PubMed

Ko, Chao-Yin; Ku, Kuan-Lin; Yang, Shu-Rui; Lin, Tsai-Yu; Peng, Sydney; Peng, Yu-Shiang; Cheng, Ming-Huei; Chu, I-Ming

2016-10-01

Chondrocytes (CH) and bone marrow stem cells (BMSCs) are sources that can be used in cartilage tissue engineering. Co-culture of CHs and BMSCs is a promising strategy for promoting chondrogenic differentiation. In this study, articular CHs and BMSCs were encapsulated in PCL-PEG-PCL photocrosslinked hydrogels for 4 weeks. Various ratios of CH:BMSC co-cultures were investigated to identify the optimal ratio for cartilage formation. The results thus obtained revealed that co-culturing CHs and BMSCs in hydrogels provides an appropriate in vitro microenvironment for chondrogenic differentiation and cartilage matrix production. Co-culture with a 1:4 CH:BMSC ratio significantly increased the synthesis of GAGs and collagen. In vivo cartilage regeneration was evaluated using a co-culture system in rabbit models. The co-culture system exhibited a hyaline chondrocyte phenotype with excellent regeneration, resembling the morphology of native cartilage. This finding suggests that the co-culture of these two cell types promotes cartilage regeneration and that the system, including the hydrogel scaffold, has potential in cartilage tissue engineering. Copyright © 2013 John Wiley & Sons, Ltd. Copyright © 2013 John Wiley & Sons, Ltd.

Multiscale approach for the construction of equilibrated all-atom models of a poly(ethylene glycol)-based hydrogel

PubMed Central

Li, Xianfeng; Murthy, N. Sanjeeva; Becker, Matthew L.; Latour, Robert A.

2016-01-01

A multiscale modeling approach is presented for the efficient construction of an equilibrated all-atom model of a cross-linked poly(ethylene glycol) (PEG)-based hydrogel using the all-atom polymer consistent force field (PCFF). The final equilibrated all-atom model was built with a systematic simulation toolset consisting of three consecutive parts: (1) building a global cross-linked PEG-chain network at experimentally determined cross-link density using an on-lattice Monte Carlo method based on the bond fluctuation model, (2) recovering the local molecular structure of the network by transitioning from the lattice model to an off-lattice coarse-grained (CG) model parameterized from PCFF, followed by equilibration using high performance molecular dynamics methods, and (3) recovering the atomistic structure of the network by reverse mapping from the equilibrated CG structure, hydrating the structure with explicitly represented water, followed by final equilibration using PCFF parameterization. The developed three-stage modeling approach has application to a wide range of other complex macromolecular hydrogel systems, including the integration of peptide, protein, and/or drug molecules as side-chains within the hydrogel network for the incorporation of bioactivity for tissue engineering, regenerative medicine, and drug delivery applications. PMID:27013229

End-Group Effects on the Properties of PEG-co-PGA Hydrogels

PubMed Central

Bencherif, Sidi A.; Srinivasan, Abiraman; Sheehan, Jeffrey A.; Walker, Lynn M.; Gayathri, Chakicherla; Gil, Roberto; Hollinger, Jeffrey O.; Matyjaszewski, Krzysztof; Washburn, Newell R.

2009-01-01

A series of resorbable poly(ethylene glycol)-co-poly(glycolic acid) macromonomers have been synthesized with the chemistries from three different photopolymerizable end-groups (acrylates, methacrylates, and urethane methacrylates). The aim of the study is to examine the effects of the chemistry of the cross-linker group on the properties of photocross-linkable hydrogels. PEG-co-PGA (4KG5) hydrogels were prepared by photopolymerization with high vinyl group conversion as confirmed by 1H NMR spectroscopy using DOSY 1D pulse sequence. Our study reveals that the nature of end-groups in a moderately amphiphilic polymer can adjust the distribution and size of the micellar configuration in water leading to changes in the macroscopic structure of hydrogels. By varying the chemistry of the cross-linker group (diacrylates; DA, dimethacrylates; DM, and urethane dimethacrylates; UDM), we determined that the hydrophobocity of a single core polymer consisting of poly(glycolic acid) could be fine-tuned leading to significant variations in the mechanical, swelling, and degradation properties of the gels. In addition, the effects of cross-linker chemistry on cytotoxicity and proliferation were examined. Cytotoxicity assays showed that all the three types of hydrogels (4KG5 DA, DM, and UDM) were biocompatible and the introduction of RGD ligand enhanced cell adhesion. However, differences in gel properties and stability differentially affected the spreading and proliferation of myoblast C2C12 cells. PMID:19328754

Dental pulp stem cell-derived chondrogenic cells demonstrate differential cell motility in type I and type II collagen hydrogels.

PubMed

Yao, Li; Flynn, Nikol

2018-06-01

Advances in the development of biomaterials and stem cell therapy provide a promising approach to regenerating degenerated discs. The normal nucleus pulposus (NP) cells exhibit similar phenotype to chondrocytes. Because dental pulp stem cells (DPSCs) can be differentiated into chondrogenic cells, the DPSCs and DPSCs-derived chondrogenic cells encapsulated in type I and type II collagen hydrogels can potentially be transplanted into degenerated NP to repair damaged tissue. The motility of transplanted cells is critical because the cells need to migrate away from the hydrogels containing the cells of high density and disperse through the NP tissue after implantation. The purpose of this study was to determine the motility of DPSC and DPSC-derived chondrogenic cells in type I and type II collagen hydrogels. The time lapse imaging that recorded cell migration was analyzed to quantify the cell migration velocity and distance. The cell viability of DPSCs in native or poly(ethylene glycol) ether tetrasuccinimidyl glutarate (4S-StarPEG)-crosslinked type I and type II collagen hydrogels was determined using LIVE/DEAD cell viability assay and AlamarBlue assay. DPSCs were differentiated into chondrogenic cells. The migration of DPSCs and DPSC-derived chondrogenic cells in these hydrogels was recorded using a time lapse imaging system. This study was funded by the Regional Institute on Aging and Wichita Medical Research and Education Foundation, and the authors declare no competing interest. DPSCs showed high cell viability in non-crosslinked and crosslinked collagen hydrogels. DPSCs migrated in collagen hydrogels, and the cell migration speed was not significantly different in either type I collagen or type II collagen hydrogels. The migration speed of DPSC-derived chondrogenic cells was higher in type I collagen hydrogel than in type II collagen hydrogel. Crosslinking of type I collagen with 4S-StarPEG significantly reduced the cell migration speed of DPSC-derived chondrogenic cells. After implantation of collagen hydrogels encapsulating DPSCs or DPSC-derived chondrogenic cells, the cells can potentially migrate from the hydrogels and migrate into the NP tissue. This study also explored the differential cell motility of DPSCs and DPSC-derived chondrogenic cells in these collagen hydrogels. Copyright © 2018 Elsevier Inc. All rights reserved.

Hydrogel Delivery of Mesenchymal Stem Cell–Expressing Bone Morphogenetic Protein-2 Enhances Bone Defect Repair

PubMed Central

Hsiao, Hui-Yi; Yang, Shu-Rui; Brey, Eric M.; Chu, I-Ming

2016-01-01

Background: The application of bone tissue engineering for repairing bone defects has gradually shown some satisfactory progress. One of the concerns raising scientific attention is the poor supply of growth factors. A number of growth factor delivery approaches have been developed for promoting bone formation. However, there is no systematic comparison of those approaches on efficiency of neobone formation. In this study, the approaches using periosteum, direct supply of growth factors, or gene transfection of growth factors were evaluated to determine the osteogenic capacity on the repair of bone defect. Methods: In total, 42 male 21-week-old Sprague-Dawley rats weighing 250 to 400 g were used as the bone defect model to evaluate the bone repair efficiency. Various tissue engineered constructs of poly(ethylene glycol)-poly(l-lactic acid) (PEG-PLLA) copolymer hydrogel with periosteum, with external supply of bone morphogenetic protein-2 (BMP2), or with BMP2-transfected bone marrow–derived mesenchymal stem cells (BMMSCs) were filled in a 7-mm bone defect region. Animals were euthanized at 3 months, and the hydrogel constructs were harvested. The evaluation with histological staining and radiography analysis were performed for the volume of new bone formation. Results: The PEG-PLLA scaffold with BMMSCs promotes bone regeneration with the addition of periosteum. The group with BMP2-transfected BMMSCs demonstrated the largest volume of new bone among all the testing groups. Conclusions: Altogether, the results of this study provide the evidence that the combination of PEG-PLLA hydrogels with BMMSCs and sustained delivery of BMP2 resulted in the maximal bone regeneration. PMID:27622106

Bioprinting Cellularized Constructs Using a Tissue-specific Hydrogel Bioink

PubMed Central

Skardal, Aleksander; Devarasetty, Mahesh; Kang, Hyun-Wook; Seol, Young-Joon; Forsythe, Steven D.; Bishop, Colin; Shupe, Thomas; Soker, Shay; Atala, Anthony

2016-01-01

Bioprinting has emerged as a versatile biofabrication approach for creating tissue engineered organ constructs. These constructs have potential use as organ replacements for implantation in patients, and also, when created on a smaller size scale as model "organoids" that can be used in in vitro systems for drug and toxicology screening. Despite development of a wide variety of bioprinting devices, application of bioprinting technology can be limited by the availability of materials that both expedite bioprinting procedures and support cell viability and function by providing tissue-specific cues. Here we describe a versatile hyaluronic acid (HA) and gelatin-based hydrogel system comprised of a multi-crosslinker, 2-stage crosslinking protocol, which can provide tissue specific biochemical signals and mimic the mechanical properties of in vivo tissues. Biochemical factors are provided by incorporating tissue-derived extracellular matrix materials, which include potent growth factors. Tissue mechanical properties are controlled combinations of PEG-based crosslinkers with varying molecular weights, geometries (linear or multi-arm), and functional groups to yield extrudable bioinks and final construct shear stiffness values over a wide range (100 Pa to 20 kPa). Using these parameters, hydrogel bioinks were used to bioprint primary liver spheroids in a liver-specific bioink to create in vitro liver constructs with high cell viability and measurable functional albumin and urea output. This methodology provides a general framework that can be adapted for future customization of hydrogels for biofabrication of a wide range of tissue construct types. PMID:27166839

Microfluidic-enhanced 3D bioprinting of aligned myoblast-laden hydrogels leads to functionally organized myofibers in vitro and in vivo.

PubMed

Costantini, Marco; Testa, Stefano; Mozetic, Pamela; Barbetta, Andrea; Fuoco, Claudia; Fornetti, Ersilia; Tamiro, Francesco; Bernardini, Sergio; Jaroszewicz, Jakub; Święszkowski, Wojciech; Trombetta, Marcella; Castagnoli, Luisa; Seliktar, Dror; Garstecki, Piotr; Cesareni, Gianni; Cannata, Stefano; Rainer, Alberto; Gargioli, Cesare

2017-07-01

We present a new strategy for the fabrication of artificial skeletal muscle tissue with functional morphologies based on an innovative 3D bioprinting approach. The methodology is based on a microfluidic printing head coupled to a co-axial needle extruder for high-resolution 3D bioprinting of hydrogel fibers laden with muscle precursor cells (C2C12). To promote myogenic differentiation, we formulated a tailored bioink with a photocurable semi-synthetic biopolymer (PEG-Fibrinogen) encapsulating cells into 3D constructs composed of aligned hydrogel fibers. After 3-5 days of culture, the encapsulated myoblasts started migrating and fusing, forming multinucleated myotubes within the 3D bioprinted fibers. The obtained myotubes showed high degree of alignment along the direction of hydrogel fiber deposition, further revealing maturation, sarcomerogenesis, and functionality. Following subcutaneous implantation in the back of immunocompromised mice, bioprinted constructs generated organized artificial muscle tissue in vivo. Finally, we demonstrate that our microfluidic printing head allows to design three dimensional multi-cellular assemblies with an exquisite compartmentalization of the encapsulated cells. Our results demonstrate an enhanced myogenic differentiation with the formation of parallel aligned long-range myotubes. The approach that we report here represents a robust and valid candidate for the fabrication of macroscopic artificial muscle to scale up skeletal muscle tissue engineering for human clinical application. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Bioprinting Cellularized Constructs Using a Tissue-specific Hydrogel Bioink.

PubMed

Skardal, Aleksander; Devarasetty, Mahesh; Kang, Hyun-Wook; Seol, Young-Joon; Forsythe, Steven D; Bishop, Colin; Shupe, Thomas; Soker, Shay; Atala, Anthony

2016-04-21

Bioprinting has emerged as a versatile biofabrication approach for creating tissue engineered organ constructs. These constructs have potential use as organ replacements for implantation in patients, and also, when created on a smaller size scale as model "organoids" that can be used in in vitro systems for drug and toxicology screening. Despite development of a wide variety of bioprinting devices, application of bioprinting technology can be limited by the availability of materials that both expedite bioprinting procedures and support cell viability and function by providing tissue-specific cues. Here we describe a versatile hyaluronic acid (HA) and gelatin-based hydrogel system comprised of a multi-crosslinker, 2-stage crosslinking protocol, which can provide tissue specific biochemical signals and mimic the mechanical properties of in vivo tissues. Biochemical factors are provided by incorporating tissue-derived extracellular matrix materials, which include potent growth factors. Tissue mechanical properties are controlled combinations of PEG-based crosslinkers with varying molecular weights, geometries (linear or multi-arm), and functional groups to yield extrudable bioinks and final construct shear stiffness values over a wide range (100 Pa to 20 kPa). Using these parameters, hydrogel bioinks were used to bioprint primary liver spheroids in a liver-specific bioink to create in vitro liver constructs with high cell viability and measurable functional albumin and urea output. This methodology provides a general framework that can be adapted for future customization of hydrogels for biofabrication of a wide range of tissue construct types.

Microscale Bioadhesive Hydrogel Arrays for Cell Engineering Applications.

PubMed

Patel, Ravi Ghanshyam; Purwada, Alberto; Cerchietti, Leandro; Inghirami, Giorgio; Melnick, Ari; Gaharwar, Akhilesh K; Singh, Ankur

2014-09-01

Bioengineered hydrogels have been explored in cell and tissue engineering applications to support cell growth and modulate its behavior. A rationally designed scaffold should allow for encapsulated cells to survive, adhere, proliferate, remodel the niche, and can be used for controlled delivery of biomolecules. Here we report a microarray of composite bioadhesive microgels with modular dimensions, tunable mechanical properties and bulk modified adhesive biomolecule composition. Composite bioadhesive microgels of maleimide functionalized polyethylene glycol (PEG-MAL) with interpenetrating network (IPN) of gelatin ionically cross-linked with silicate nanoparticles were engineered by integrating microfabrication with Michael-type addition chemistry and ionic gelation. By encapsulating clinically relevant anchorage-dependent cervical cancer cells and suspension leukemia cells as cell culture models in these composite microgels, we demonstrate enhanced cell spreading, survival, and metabolic activity compared to control gels. The composite bioadhesive hydrogels represent a platform that could be used to study independent effect of stiffness and adhesive ligand density on cell survival and function. We envision that such microarrays of cell adhesive microenvironments, which do not require harsh chemical and UV crosslinking conditions, will provide a more efficacious cell culture platform that can be used to study cell behavior and survival, function as building blocks to fabricate 3D tissue structures, cell delivery systems, and high throughput drug screening devices.

Microscale Bioadhesive Hydrogel Arrays for Cell Engineering Applications

PubMed Central

PATEL, RAVI GHANSHYAM; PURWADA, ALBERTO; CERCHIETTI, LEANDRO; INGHIRAMI, GIORGIO; MELNICK, ARI; GAHARWAR, AKHILESH K.; SINGH, ANKUR

2014-01-01

Bioengineered hydrogels have been explored in cell and tissue engineering applications to support cell growth and modulate its behavior. A rationally designed scaffold should allow for encapsulated cells to survive, adhere, proliferate, remodel the niche, and can be used for controlled delivery of biomolecules. Here we report a microarray of composite bioadhesive microgels with modular dimensions, tunable mechanical properties and bulk modified adhesive biomolecule composition. Composite bioadhesive microgels of maleimide functionalized polyethylene glycol (PEG-MAL) with interpenetrating network (IPN) of gelatin ionically cross-linked with silicate nanoparticles were engineered by integrating microfabrication with Michael-type addition chemistry and ionic gelation. By encapsulating clinically relevant anchorage-dependent cervical cancer cells and suspension leukemia cells as cell culture models in these composite microgels, we demonstrate enhanced cell spreading, survival, and metabolic activity compared to control gels. The composite bioadhesive hydrogels represent a platform that could be used to study independent effect of stiffness and adhesive ligand density on cell survival and function. We envision that such microarrays of cell adhesive microenvironments, which do not require harsh chemical and UV crosslinking conditions, will provide a more efficacious cell culture platform that can be used to study cell behavior and survival, function as building blocks to fabricate 3D tissue structures, cell delivery systems, and high throughput drug screening devices. PMID:25328548

A thermoreversible hydrogel as a biosynthetic bandage for corneal wound repair.

PubMed

Pratoomsoot, Chayanin; Tanioka, Hidetoshi; Hori, Kuniko; Kawasaki, Satoshi; Kinoshita, Shigeru; Tighe, Patrick J; Dua, Harminder; Shakesheff, Kevin M; Rose, Felicity Rosamari A J

2008-01-01

Ocular trauma and disorders that lead to corneal blindness account for over 2 million new cases of monocular blindness every year. A popular ocular surface reconstruction therapy, amniotic membrane transplantation, has been shown to aid corneal wound repair. However, the success rates of the procedure are variable. Here, we proposed to bioengineer a novel synthetic material that would serve as a biomimetic corneal bandage. The PLGA-PEG-PLGA triblock copolymer was synthesised via ring-opening polymerisation. Thermoreversible gelation behaviour was investigated at different polymer concentrations (23%, 30%, 35%, 40%, 45%, w/v) at temperatures ranging between 5 and 60 degrees C. Viscoelastic properties were studied in dynamic mechanical analysis with 1 degrees C/min temperature ramp. Cryo-SEM revealed a porous hydrogel with interconnecting networks. No adverse cytotoxicity was observed with an in vitro scratch-wound assay and in in vivo biocompatibility tests. We have demonstrated that the PLGA-PEG-PLGA hydrogel possessed a suitable gelling profile and, for the first time, the biocompatibility properties for this application as a potential bandage for corneal wound repair.

Lamellar Biogels: Fluid-Membrane Based Hydrogels Containing Polymer-Lipids

NASA Astrophysics Data System (ADS)

Warriner, Heidi E.; Davidson, P.; Slack, N. L.; Idziak, S. H. J.; Schmidt, H. W.; Safinya, C. R.

1996-03-01

A new class of lamellar biogels containing low molecular weight (MW 5181, 2053 and 576 g/mole) polyethylene glycol-surfactants is described (H. Warriner et. al., Science, (in press)). The gels were formed in 7 different systems using two types of polymer-surfactants: (i) polymer-lipids based on the lipid DMPE covalently attached to the different MW of PEG (ii) polymer-surfactants of the two largest PEG MW covalently attached to double-tailed phenyl surfactants with 14 or 18 carbon tails. Unlike isotropic hydrogels of polymer networks, these membrane-based liquid crystalline biogels, labeled L_α,g, form through the addition of water to a liquid-like L_α phase. The signature of the L_α,g regime in these systems is a dramatic increase in layer-dislocation defects, stabilized by aggregation of the PEG-surfactants to the high curvature defect regions. These regions connect and "entangle" the membranes, causing gelation. A simple model describing these phenomena is that the inclusion of the polymer-surfactants in lamellar membranes softens the free energy of high curvature line-defects, leading to proliferation and gelation.

Tracking hypoxic signaling within encapsulated cell aggregates.

PubMed

Skiles, Matthew L; Sahai, Suchit; Blanchette, James O

2011-12-16

In Diabetes mellitus type 1, autoimmune destruction of the pancreatic β-cells results in loss of insulin production and potentially lethal hyperglycemia. As an alternative treatment option to exogenous insulin injection, transplantation of functional pancreatic tissue has been explored. This approach offers the promise of a more natural, long-term restoration of normoglycemia. Protection of the donor tissue from the host's immune system is required to prevent rejection and encapsulation is a method used to help achieve this aim. Biologically-derived materials, such as alginate and agarose, have been the traditional choice for capsule construction but may induce inflammation or fibrotic overgrowth which can impede nutrient and oxygen transport. Alternatively, synthetic poly(ethylene glycol) (PEG)-based hydrogels are non-degrading, easily functionalized, available at high purity, have controllable pore size, and are extremely biocompatible. As an additional benefit, PEG hydrogels may be formed rapidly in a simple photo-crosslinking reaction that does not require application of non-physiological temperatures. Such a procedure is described here. In the crosslinking reaction, UV degradation of the photoinitiator, 1-[4-(2-Hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propane-1-one (Irgacure 2959), produces free radicals which attack the vinyl carbon-carbon double bonds of dimethacrylated PEG (PEGDM) inducing crosslinking at the chain ends. Crosslinking can be achieved within 10 minutes. PEG hydrogels constructed in such a manner have been shown to favorably support cells, and the low photoinitiator concentration and brief exposure to UV irradiation is not detrimental to viability and function of the encapsulated tissue. While we methacrylate our PEG with the method described below, PEGDM can also be directly purchased from vendors such as Sigma. An inherent consequence of encapsulation is isolation of the cells from a vascular network. Supply of nutrients, notably oxygen, is therefore reduced and limited by diffusion. This reduced oxygen availability may especially impact β-cells whose insulin secretory function is highly dependent on oxygen. Capsule composition and geometry will also impact diffusion rates and lengths for oxygen. Therefore, we also describe a technique for identifying hypoxic cells within our PEG capsules. Infection of the cells with a recombinant adenovirus allows for a fluorescent signal to be produced when intracellular hypoxia-inducible factor (HIF) pathways are activated. As HIFs are the primary regulators of the transcriptional response to hypoxia, they represent an ideal target marker for detection of hypoxic signaling. This approach allows for easy and rapid detection of hypoxic cells. Briefly, the adenovirus has the sequence for a red fluorescent protein (Ds Red DR from Clontech) under the control of a hypoxia-responsive element (HRE) trimer. Stabilization of HIF-1 by low oxygen conditions will drive transcription of the fluorescent protein (Figure 1). Additional details on the construction of this virus have been published previously. The virus is stored in 10% glycerol at -80° C as many 150 μL aliquots in 1.5 mL centrifuge tubes at a concentration of 3.4 x 10(10) pfu/mL. Previous studies in our lab have shown that MIN6 cells encapsulated as aggregates maintain their viability throughout 4 weeks of culture in 20% oxygen. MIN6 aggregates cultured at 2 or 1% oxygen showed both signs of necrotic cells (still about 85-90% viable) by staining with ethidium bromide as well as morphological changes relative to cells in 20% oxygen. The smooth spherical shape of the aggregates displayed at 20% was lost and aggregates appeared more like disorganized groups of cells. While the low oxygen stress does not cause a pronounced drop in viability, it is clearly impacting MIN6 aggregation and function as measured by glucose-stimulated insulin secretion. Western blot analysis of encapsulated cells in 20% and 1% oxygen also showed a significant increase in HIF-1α for cells cultured in the low oxygen conditions which correlates with the expression of the DsRed DR protein.

Micro- and Nanoscale Hydrogel Systems for Drug Delivery and Tissue Engineering

PubMed Central

Schwall, Christine T.; Banerjee, Ipsita A.

2009-01-01

The pursuit for targeted drug delivery systems has led to the development of highly improved biomaterials with enhanced biocompatibility and biodegradability properties. Micro- and nanoscale components of hydrogels prepared from both natural and artificial components have been gaining significant importance due to their potential uses in cell based therapies, tissue engineering, liquid micro-lenses, cancer therapy, and drug delivery. In this review some of the recent methodologies used in the preparation of a number of synthetic hydrogels such as poly(N-isopropylacrylamide) (pNIPAm), poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), polyvinyl alcohol methylacrylate co-polymers (PVA-MA) and polylactic acid (PLA), as well as some of the natural hydrogels and their applications have been discussed in detail.

Using selective withdrawal to encapsulate pancreatic islets for immunoisolation

NASA Astrophysics Data System (ADS)

Wyman, Jason; Murphy, William; Mrksich, Milan

2005-11-01

We apply selective-withdrawal for encapsulating insulin-producing pancreatic islets within thin poly(ethylene glycol) (PEG) coats. Islets placed in an aqueous PEG solution are drawn into the selective-withdrawal spout which then breaks up, leaving the islets surrounded by a thin, 20μm, polymer coat. These coats, whose thickness is independent of the size of the encapsulated islet, are photo-crosslinked to form hydrogel capsules. We can apply multiple coats of varying chemical composition. These coats provide a semi-permeable membrane which allows the islets to respond to changes in glucose concentration by producing insulin in a manner similar to that of unencapsulated islets. Furthermore, the hydrogel capsules exclude large molecules the size of the smallest antibodies. Our results suggest that this microencapsulation technique may be useful for the transplantation of islets for treatment of Type I diabetes.

Development of a self-cleaning sensor membrane for implantable biosensors.

PubMed

Gant, Rebecca M; Hou, Yaping; Grunlan, Melissa A; Coté, Gerard L

2009-09-01

Fibrous tissue encapsulation may slow the diffusion of the target analyte to an implanted sensor and compromise the optical signal. Poly(N-isopropylacrylamide) (PNIPAAm) hydrogels are thermoresponsive, exhibiting temperature-modulated swelling behavior that could be used to prevent biofouling. Unfortunately, PNIPAAm hydrogels are limited by poor mechanical strength. In this study, a unique thermoresponsive nanocomposite hydrogel was developed to create a mechanically robust self-cleaning sensor membrane for implantable biosensors. This hydrogel was prepared by the photochemical cure of an aqueous solution of NIPAAm and copoly(dimethylsiloxane/methylvinylsiloxane) colloidal nanoparticles ( approximately 219 nm). At temperatures above the volume phase transition temperature (VPTT) of approximately 33-34 degrees C, the hydrogel deswells and becomes hydrophobic, whereas lowering the temperature below the VPTT causes the hydrogel to swell and become hydrophilic. The potential of this material to minimize biofouling via temperature-modulation while maintaining sensor viability was investigated using glucose as a target analyte. PNIPAAm composite hydrogels with and without poration were compared to a pure PNIPAAm hydrogel and a nonthermoresponsive poly(ethylene glycol) (PEG) hydrogel. Poration led to a substantial increase in diffusion. Cycling the temperature of the nanocomposite hydrogels around the VPTT caused significant detachment of GFP-H2B 3T3 fibroblast cells.

Preparation, optimization and property of PVA-HA/PAA composite hydrogel.

PubMed

Chen, Kai; Liu, Jinlong; Yang, Xuehui; Zhang, Dekun

2017-09-01

PVA-HA/PAA composite hydrogel is prepared by freezing-thawing, PEG dehydration and annealing method. Orthogonal design method is used to choose the optimization combination. Results showed that HA and PVA have the maximum effect on water content. PVA and freezing-thawing cycles have the maximum effect on creep resistance and stress relaxation rate of hydrogel. Annealing temperature and freezing-thawing cycles have the maximum effect on compressive elastic modulus of hydrogel. Comparing with the water content and mechanical properties of 16 kinds of combination, PVA-HA/PAA composite hydrogel with freezing-thawing cycles of 3, annealing temperature of 120°C, PVA of 16%, HA of 2%, PAA of 4% has the optimization comprehensive properties. PVA-HA/PAA composite hydrogel has a porous network structure. There are some interactions between PVA, HA and PAA in hydrogel and the properties of hydrogel are strengthened. The annealing treatment improves the crystalline and crosslinking of hydrogel. Therefore, the annealing PVA-HA/PAA composite hydrogel has good thermostability, strength and mechanical properties. It also has good lubrication property and its friction coefficient is relative low. Copyright © 2017 Elsevier B.V. All rights reserved.

Modulation of hydrogel nanoparticle intracellular trafficking by multivalent surface engineering with tumor targeting peptide

NASA Astrophysics Data System (ADS)

Karamchand, Leshern; Kim, Gwangseong; Wang, Shouyan; Hah, Hoe Jin; Ray, Aniruddha; Jiddou, Ruba; Koo Lee, Yong-Eun; Philbert, Martin A.; Kopelman, Raoul

2013-10-01

Surface engineering of a hydrogel nanoparticle (NP) with the tumor-targeting ligand, F3 peptide, enhances both the NP's binding affinity for, and internalization by, nucleolin overexpressing tumor cells. Remarkably, the F3-functionalized NPs consistently exhibited significantly lower trafficking to the degradative lysosomes than the non-functionalized NPs, in the tumor cells, after internalization. This is attributed to the non-functionalized NPs, but not the F3-functionalized NPs, being co-internalized with Lysosome-associated Membrane Protein-1 (LAMP1) from the surface of the tumor cells. Furthermore, it is shown that the intracellular trafficking of the F3-functionalized NPs differs significantly from that of the molecular F3 peptides (untethered to NPs). This has important implications for designing effective, chemically-responsive, controlled-release and multifunctional nanodrugs for multi-drug-resistant cancers.Surface engineering of a hydrogel nanoparticle (NP) with the tumor-targeting ligand, F3 peptide, enhances both the NP's binding affinity for, and internalization by, nucleolin overexpressing tumor cells. Remarkably, the F3-functionalized NPs consistently exhibited significantly lower trafficking to the degradative lysosomes than the non-functionalized NPs, in the tumor cells, after internalization. This is attributed to the non-functionalized NPs, but not the F3-functionalized NPs, being co-internalized with Lysosome-associated Membrane Protein-1 (LAMP1) from the surface of the tumor cells. Furthermore, it is shown that the intracellular trafficking of the F3-functionalized NPs differs significantly from that of the molecular F3 peptides (untethered to NPs). This has important implications for designing effective, chemically-responsive, controlled-release and multifunctional nanodrugs for multi-drug-resistant cancers. Electronic supplementary information (ESI) available: Effect of Potassium depletion on F3 peptide subcellular localization, MTT cytotoxicity data for endocytic inhibitors, size and morphology characterizations of hydrogel PAA nanocarriers, and optimization data for nanocarrier surface functionalization with PEG molecules and F3 peptides. See DOI: 10.1039/c3nr00908d

Modeling Alveolar Epithelial Cell Behavior In Spatially Designed Hydrogel Microenvironments

NASA Astrophysics Data System (ADS)

Lewis, Katherine Jean Reeder

The alveolar epithelium consists of two cell phenotypes, elongated alveolar type I cells (AT1) and rounded alveolar type II cells (ATII), and exists in a complex three-dimensional environment as a polarized cell layer attached to a thin basement membrane and enclosing a roughly spherical lumen. Closely surrounding the alveolar cysts are capillary endothelial cells as well as interstitial pulmonary fibroblasts. Many factors are thought to influence alveolar epithelial cell differentiation during lung development and wound repair, including physical and biochemical signals from the extracellular matrix (ECM), and paracrine signals from the surrounding mesenchyme. In particular, disrupted signaling between the alveolar epithelium and local fibroblasts has been implicated in the progression of several pulmonary diseases. However, given the complexity of alveolar tissue architecture and the multitude of signaling pathways involved, designing appropriate experimental platforms for this biological system has been difficult. In order to isolate key factors regulating cellular behavior, the researcher ideally should have control over biophysical properties of the ECM, as well as the ability to organize multiple cell types within the scaffold. This thesis aimed to develop a 3D synthetic hydrogel platform to control alveolar epithelial cyst formation, which could then be used to explore how extracellular cues influence cell behavior in a tissue-relevant cellular arrangement. To accomplish this, a poly(ethylene glycol) (PEG) hydrogel network containing enzymatically-degradable crosslinks and bioadhesive pendant peptides was employed as a base material for encapsulating primary alveolar epithelial cells. First, an array of microwells of various cross-sectional shapes was photopatterned into a PEG gel containing photo-labile crosslinks, and primary ATII cells were seeded into the wells to examine the role of geometric confinement on differentiation and multicellular arrangement. Aggregate formation in these microwells motivated us to develop a templating technique to create hollow cyst-like epithelial structures within PEG hydrogels. Photodegradable microspheres were used to form spherical epithelial layers, which were then encapsulated in a PEG hydrogel followed by template erosion with cytocompatible light. With these model alveoli, we investigated the interplay between the epithelium and mesenchyme by co-encapsulating healthy and diseased pulmonary fibroblasts with healthy and diseased epithelial cysts and measuring important cellular behaviors (i.e. proliferation, migration, and protein expression). This model of alveolar tissue represents a significant advance in culture platforms available to researchers interested in identifying the mechanisms involved in disease progression and for testing potential therapeutics in a controlled, tissue-appropriate setting.

3D Bioprinting of Self-Standing Silk-Based Bioink.

PubMed

Zheng, Zhaozhu; Wu, Jianbing; Liu, Meng; Wang, Heng; Li, Chunmei; Rodriguez, María J; Li, Gang; Wang, Xiaoqin; Kaplan, David L

2018-03-01

Silk/polyethylene glycol (PEG) hydrogels are studied as self-standing bioinks for 3D printing for tissue engineering. The two components of the bioink, silk fibroin protein (silk) and PEG, are both Food and Drug Administration approved materials in drug and medical device products. Mixing PEG with silk induces silk β-sheet structure formation and thus gelation and water insolubility due to physical crosslinking. A variety of constructs with high resolution, high shape fidelity, and homogeneous gel matrices are printed. When human bone marrow mesenchymal stem cells are premixed with the silk solution prior to printing and the constructs are cultured in this medium, the cell-loaded constructs maintain their shape over at least 12 weeks. Interestingly, the cells grow faster in the higher silk concentration (10%, w/v) gel than in lower ones (7.5 and 5%, w/v), likely due to the difference in material stiffness and the amount of residual PEG remaining in the gel related to material hydrophobicity. Subcutaneous implantation of 7.5% (w/v) bioink gels with and without printed fibroblast cells in mice reveals that the cells survive and proliferate in the gel matrix for at least 6 week postimplantation. The results suggest that these silk/PEG bioink gels may provide suitable scaffold environments for cell printing and function. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

An Intriguing Method for Fabricating Arbitrarily Shaped “Matreshka” Hydrogels Using a Self-Healing Template

PubMed Central

Sato, Takeshi; Uto, Koichiro; Aoyagi, Takao; Ebara, Mitsuhiro

2016-01-01

This work describes an intriguing strategy for the creation of arbitrarily shaped hydrogels utilizing a self-healing template (SHT). A SHT was loaded with a photo-crosslinkable monomer, PEG diacrylate (PEGDA), and then ultraviolet light (UV) crosslinked after first shaping. The SHT template was removed by simple washing with water, leaving behind the hydrogel in the desired physical shape. A hierarchical 3D structure such as “Matreshka” boxes were successfully prepared by simply repeating the “self-healing” and “photo-irradiation” processes. We have also explored the potential of the SHT system for the manipulation of cells. PMID:28773983

Folic acid conjugated cross-linked acrylic polymer (FA-CLAP) hydrogel for site specific delivery of hydrophobic drugs to cancer cells.

PubMed

Pillai, Jisha Jayadevan; Thulasidasan, Arun Kumar Theralikattu; Anto, Ruby John; Chithralekha, Devika Nandan; Narayanan, Ashwanikumar; Kumar, Gopalakrishnapillai Sankaramangalam Vinod

2014-07-15

The hydrogel based system is found to be rarely reported for the delivery of hydrophobic drug due to the incompatibility of hydrophilicity of the polymer network and the hydrophobicity of drug. This problem can be solved by preparing semi-interpenetrating network of cross-linked polymer for tuning the hydrophilicity so as to entrap the hydrophobic drugs. The current study is to develop a folic acid conjugated cross-linked pH sensitive, biocompatible polymeric hydrogel to achieve a site specific drug delivery. For that, we have synthesized a folic acid conjugated PEG cross-linked acrylic polymer (FA-CLAP) hydrogel and investigated its loading and release of curcumin. The formed polymer hydrogel was then conjugated with folic acid for the site specific delivery of curcumin to cancer cells and then further characterized and conducted the cell uptake and cytotoxicity studies on human cervical cancer cell lines (HeLa). In this study, we synthesized folic acid conjugated cross-linked acrylic hydrogel for the delivery of hydrophobic drugs to the cancer site. Poly (ethyleneglycol) (PEG) diacrylate cross-linked acrylic polymer (PAA) was prepared via inverse emulsion polymerization technique and later conjugated it with folic acid (FA-CLAP). Hydrophobic drug curcumin is entrapped into it and investigated the entrapment efficiency. Characterization of synthesized hydogel was done by using Fourier Transform-Infrared spectroscopy (FT-IR), Transmission Electron Microscopy (TEM), Differential Scanning Calorimetry (DSC). Polymerization and folate conjugation was confirmed by FT-IR spectroscopy. The release kinetics of drug from the entrapped form was studied which showed initial burst release followed by sustained release due to swelling and increased cross-linking. In vitro cytotoxicity and cell uptake studies were conducted in human cervical cancer (HeLa) cell lines. Results showed that curcumin entrapped folate conjugated cross-linked acrylic polymer (FA-CLAP) hydrogel showed higher cellular uptake than the non folate conjugated form. So this can be suggested as a better delivery system for site specific release of hydrophobic cancer drugs.

Incorporation of Active DNA/Cationic Polymer Polyplexes into Hydrogel Scaffolds

PubMed Central

Lei, Yuguo; Huang, Suxian; Sharif-Kashani, Pooria; Chen, Yong; Kavehpour, Pirouz; Segura, Tatiana

2010-01-01

The effective and sustained delivery of DNA and siRNAs locally would increase the applicability of gene therapy in tissue regeneration and cancer therapy. One promising approach is to use hydrogel scaffolds to encapsulate and deliver nucleotides in the form of nanoparticles to the disease sites. However, this approach is currently limited by the inability to load concentrated and active gene delivery nanoparticles into the hydrogels due to the severe nanoparticle aggregation during the loading process. Here, we present a process to load concentrated and un-aggregated non-viral gene delivery nanoparticles, using DNA/polyethylene imine (PEI) polyplexes as an example, into neutral polyethylene glycol (PEG), negatively charged hyaluronic acid (HA) and protein fibrin hydrogels crosslinked through various chemistries. The encapsulated polyplexes are highly active both in vitro and in vivo. We believe this process will significantly advance the applications of hydrogel scaffold mediated non-viral gene delivery in tissue regeneration and cancer therapy. PMID:20822811

Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing

PubMed Central

Johnson, Christopher T.; Wroe, James A.; Agarwal, Rachit; Martin, Karen E.; Guldberg, Robert E.; Donlan, Rodney M.; Westblade, Lars F.; García, Andrés J.

2018-01-01

Orthopedic implant infections are a significant clinical problem, with current therapies limited to surgical debridement and systemic antibiotic regimens. Lysostaphin is a bacteriolytic enzyme with high antistaphylococcal activity. We engineered a lysostaphin-delivering injectable PEG hydrogel to treat Staphylococcus aureus infections in bone fractures. The injectable hydrogel formulation adheres to exposed tissue and fracture surfaces, ensuring efficient, local delivery of lysostaphin. Lysostaphin encapsulation within this synthetic hydrogel maintained enzyme stability and activity. Lysostaphin-delivering hydrogels exhibited enhanced antibiofilm activity compared with soluble lysostaphin. Lysostaphin-delivering hydrogels eradicated S. aureus infection and outperformed prophylactic antibiotic and soluble lysostaphin therapy in a murine model of femur fracture. Analysis of the local inflammatory response to infections treated with lysostaphin-delivering hydrogels revealed indistinguishable differences in cytokine secretion profiles compared with uninfected fractures, demonstrating clearance of bacteria and associated inflammation. Importantly, infected fractures treated with lysostaphin-delivering hydrogels fully healed by 5 wk with bone formation and mechanical properties equivalent to those of uninfected fractures, whereas fractures treated without the hydrogel carrier were equivalent to untreated infections. Finally, lysostaphin-delivering hydrogels eliminate methicillin-resistant S. aureus infections, supporting this therapy as an alternative to antibiotics. These results indicate that lysostaphin-delivering hydrogels effectively eliminate orthopedic S. aureus infections while simultaneously supporting fracture repair. PMID:29760099

An interpenetrating HA/G/CS biomimic hydrogel via Diels-Alder click chemistry for cartilage tissue engineering.

PubMed

Yu, Feng; Cao, Xiaodong; Zeng, Lei; Zhang, Qing; Chen, Xiaofeng

2013-08-14

In order to mimic the natural cartilage extracellular matrix, a novel biological degradable interpenetrating network hydrogel was synthesized from the gelatin (G), hyaluronic acid (HA) and chondroitin sulfate (CS) by Diels-Alder "click" chemistry. HA was modified with furylamine and G was modified with furancarboxylic acid respectively. (1)H NMR spectra and elemental analysis showed that the substitution degrees of HA-furan and G-furan were 71.5% and 44.5%. Then the hydrogels were finally synthesized by cross-linking furan-modified HA and G derivatives with dimaleimide poly(ethylene glycol) (MAL-PEG-MAL). The mechanical and degradation properties of the hydrogels could be tuned simply through varying the molar ratio between furan and maleimide. Rheological, mechanical and degradation studies demonstrated that the Diels-Alder "click" chemistry is an efficient method for preparing high performance biological interpenetrating hydrogels. This biomimic hydrogel with improved mechanical properties could have great potential applications in cartilage tissue engineering. Copyright © 2013 Elsevier Ltd. All rights reserved.

Human iPSC-Derived Endothelial Cell Sprouting Assay in ...

EPA Pesticide Factsheets

Activation of vascular endothelial cells (ECs) by growth factors initiates a cascade of events in vivo consisting of EC tip cell selection, sprout formation, EC stalk cell proliferation, and ultimately vascular stabilization by support cells. Although EC functional assays can recapitulate one or more aspects of angiogenesis in vitro, they are often limited by a lack of definition to the substratum and lack of dependence on key angiogenic signaling axes. Here, we designed and characterized a chemically-defined model of endothelial sprouting behavior in vitro using human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs). Thiol-ene photopolymerization was used to rapidly encapsulate iPSC-ECs at high density in poly(ethylene glycol) (PEG) hydrogel spheres and subsequently to rapidly encapsulate iPSC-EC-containing hydrogel spheres in a cell-free over-layer. The hydrogel sprouting array here maintained pro-angiogenic phenotype of iPSC-ECs and supported growth factor-dependent proliferation and sprouting behavior. The sprouting model responded appropriately to several reference pharmacological angiogenesis inhibitors, which suggests the functional role of vascular endothelial growth factor, NF-κB, matrix metalloproteinase-2/9, protein kinase activity, and β-tubulin in endothelial sprouting. A blinded screen of 38 putative vascular disrupting compounds (pVDCs) from the US Environmental Protection Agency’s ToxCast library identified five compounds th

Tunable separations based on a molecular size effect for biomolecules by poly(ethylene glycol) gel-based capillary electrophoresis.

PubMed

Kubo, Takuya; Nishimura, Naoki; Furuta, Hayato; Kubota, Kei; Naito, Toyohiro; Otsuka, Koji

2017-11-10

We report novel capillary gel electrophoresis (CGE) with poly(ethylene glycol) (PEG)-based hydrogels for the effective separations of biomolecules containing sugars and DNAs based on a molecular size effect. The gel capillaries were prepared in a fused silica capillary modified with 3-(trimethoxysilyl)propylmethacrylate using a variety of the PEG-based hydrogels. After the fundamental evaluations in CGE regarding the separation based on the molecular size effect depending on the crosslinking density, the optimized capillary provided the efficient separation of glucose ladder (G1 to G20). In addition, another capillary showed the successful separation of DNA ladder in the range of 10-1100 base pair, which is superior to an authentic acrylamide-based gel capillary. For both glucose and DNA ladders, the separation ranges against the molecular size were simply controllable by alteration of the concentration and/or units of ethylene oxide in the PEG-based crosslinker. Finally, we demonstrated the separations of real samples, which included sugars carved out from monoclonal antibodies, mAbs, and then the efficient separations based on the molecular size effect were achieved. Copyright © 2017 Elsevier B.V. All rights reserved.

Injectable hyperbranched poly(β-amino ester) hydrogels with on-demand degradation profiles to match wound healing processes.

PubMed

Xu, Qian; Guo, Linru; A, Sigen; Gao, Yongsheng; Zhou, Dezhong; Greiser, Udo; Creagh-Flynn, Jack; Zhang, Hong; Dong, Yixiao; Cutlar, Lara; Wang, Fagang; Liu, Wenguang; Wang, Wei; Wang, Wenxin

2018-02-28

Adjusting biomaterial degradation profiles to match tissue regeneration is a challenging issue. Herein, biodegradable hyperbranched poly(β-amino ester)s (HP-PBAEs) were designed and synthesized via "A2 + B4" Michael addition polymerization, and displayed fast gelation with thiolated hyaluronic acid (HA-SH) via a "click" thiol-ene reaction. HP-PBAE/HA-SH hydrogels showed tunable degradation profiles both in vitro and in vivo using diamines with different alkyl chain lengths and poly(ethylene glycol) diacrylates with varied PEG spacers. The hydrogels with optimized degradation profiles encapsulating ADSCs were used as injectable hydrogels to treat two different types of humanized excisional wounds - acute wounds with faster healing rates and diabetic wounds with slower healing and neo-tissue formation. The fast-degrading hydrogel showed accelerated wound closure in acute wounds, while the slow-degrading hydrogel showed better wound healing for diabetic wounds. The results demonstrate that the new HP-PBAE-based hydrogel in combination with ADSCs can be used as a well-controlled biodegradable skin substitute, which demonstrates a promising approach in the treatment of various types of skin wounds.

Transient Dynamic Mechanical Analysis of Resilin-based Elastomeric Hydrogels

NASA Astrophysics Data System (ADS)

Li, Linqing; Kiick, Kristi

2014-04-01

The outstanding high-frequency properties of emerging resilin-like polypeptides (RLPs) have motivated their development for vocal fold tissue regeneration and other applications. Recombinant RLP hydrogels show efficient gelation, tunable mechanical properties, and display excellent extensibility, but little has been reported about their transient mechanical properties. In this manuscript, we describe the transient mechanical behavior of new RLP hydrogels investigated via both sinusoidal oscillatory shear deformation and uniaxial tensile testing. Oscillatory stress relaxation and creep experiments confirm that RLP-based hydrogels display significantly reduced stress relaxation and improved strain recovery compared to PEG-based control hydrogels. Uniaxial tensile testing confirms the negligible hysteresis, reversible elasticity and superior resilience (up to 98%) of hydrated RLP hydrogels, with Young’s modulus values that compare favorably with those previously reported for resilin and that mimic the tensile properties of the vocal fold ligament at low strain (< 15%). These studies expand our understanding of the properties of these RLP materials under a variety of conditions, and confirm the unique applicability, for mechanically demanding tissue engineering applications, of a range of RLP hydrogels.

Aptamer-based hydrogel barcodes for the capture and detection of multiple types of pathogenic bacteria.

PubMed

Xu, Yueshuang; Wang, Huan; Luan, Chengxin; Liu, Yuxiao; Chen, Baoan; Zhao, Yuanjin

2018-02-15

Rapid and sensitive diagnosing hematological infections based on the separation and detection of pathogenic bacteria in the patient's blood is a significant challenge. To address this, we herein present a new barcodes technology that can simultaneously capture and detect multiple types of pathogenic bacteria from a complex sample. The barcodes are poly (ethylene glycol) (PEG) hydrogel inverse opal particles with characteristic reflection peak codes that remain stable during bacteria capture on their surfaces. As the spherical surface of the particles has ordered porous nanostructure, the barcodes can provide not only more surface area for probe immobilization and reaction, but also a nanopatterned platform for highly efficient bioreactions. In addition, the PEG hydrogel scaffold could decrease the non-specificity adsorption by its anti-adhesive effect, and the decorated aptamer probes in the scaffolds could increase the sensitivity, reliability, and specificity of the bacteria capture and detection. Moreover, the tagged magnetic nanoparticles in the PEG scaffold could impart the barcodes with controllable movement under magnetic fields, which can be used to significantly increase the reaction speed and simplify the processing of the bioassays. Based on the describe barcodes, it was demonstrated that the bacteria could be captured and identified even at low bacterial concentrations (100 CFU mL -1 ) within 2.5h, which is effectively shortened in comparison with the "gold standard" in clinic. These features make the barcodes ideal for capturing and detecting multiple bacteria from clinical samples for hematological infection diagnostics. Copyright © 2017 Elsevier B.V. All rights reserved.

Efficient antitumor effect of co-drug-loaded nanoparticles with gelatin hydrogel by local implantation

PubMed Central

Zhang, Hao; Tian, Yong; Zhu, Zhenshu; Xu, Huae; Li, Xiaolin; Zheng, Donghui; Sun, Weihao

2016-01-01

Tetrandrine (Tet) could enhance the antitumor effect of Paclitaxel (Ptx) by increasing intracellular Reactive Oxygen Species (ROS) levels, which leads to the possibility of co-delivery of both drugs for synergistic antitumor effect. In the current study, we reported an efficient, local therapeutic strategy employing effective Tet and Ptx delivery with a nanoparticle-loaded gelatin system. Tet- and Ptx co-loaded mPEG-PCL nanoparticles (P/T-NPs) were encapsulated into the physically cross-linked gelatin hydrogel and then implanted on the tumor site for continuous drug release. The drug-loaded gelatin hydrogel underwent a phase change when the temperature slowly increased. In vitro study showed that Tet/Ptx-loaded PEG-b-PCL nanoparticles encapsulated within a gelatin hydrogel (P/T-NPs-Gelatin) inhibited the growth and invasive ability of BGC-823 cells more effectively than the combination of free drugs or P/T-NPs. In vivo study validated the therapeutic potential of P/T-NPs-Gelatin. P/T-NPs-Gelatin significantly inhibited the activation of p-Akt and the downstream anti-apoptotic Bcl-2 protein and also inducing the activation of pro-apoptotic Bax protein. Moreover, the molecular-modulating effect of P/T-NPs-Gelatin on related proteins varied slightly under the influence of NAC, which was supported by the observations of the tumor volumes and weights. Based on these findings, local implantation of P/T-NPs-Gelatin may be a promising therapeutic strategy for the treatment of gastric cancer. PMID:27226240

Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing.

PubMed

Johnson, Christopher T; Wroe, James A; Agarwal, Rachit; Martin, Karen E; Guldberg, Robert E; Donlan, Rodney M; Westblade, Lars F; García, Andrés J

2018-05-29

Orthopedic implant infections are a significant clinical problem, with current therapies limited to surgical debridement and systemic antibiotic regimens. Lysostaphin is a bacteriolytic enzyme with high antistaphylococcal activity. We engineered a lysostaphin-delivering injectable PEG hydrogel to treat Staphylococcus aureus infections in bone fractures. The injectable hydrogel formulation adheres to exposed tissue and fracture surfaces, ensuring efficient, local delivery of lysostaphin. Lysostaphin encapsulation within this synthetic hydrogel maintained enzyme stability and activity. Lysostaphin-delivering hydrogels exhibited enhanced antibiofilm activity compared with soluble lysostaphin. Lysostaphin-delivering hydrogels eradicated S. aureus infection and outperformed prophylactic antibiotic and soluble lysostaphin therapy in a murine model of femur fracture. Analysis of the local inflammatory response to infections treated with lysostaphin-delivering hydrogels revealed indistinguishable differences in cytokine secretion profiles compared with uninfected fractures, demonstrating clearance of bacteria and associated inflammation. Importantly, infected fractures treated with lysostaphin-delivering hydrogels fully healed by 5 wk with bone formation and mechanical properties equivalent to those of uninfected fractures, whereas fractures treated without the hydrogel carrier were equivalent to untreated infections. Finally, lysostaphin-delivering hydrogels eliminate methicillin-resistant S. aureus infections, supporting this therapy as an alternative to antibiotics. These results indicate that lysostaphin-delivering hydrogels effectively eliminate orthopedic S. aureus infections while simultaneously supporting fracture repair. Copyright © 2018 the Author(s). Published by PNAS.

Gene Therapy Vectors with Enhanced Transfection Based on Hydrogels Modified with Affinity Peptides

PubMed Central

Shepard, Jaclyn A.; Wesson, Paul J.; Wang, Christine E.; Stevans, Alyson C.; Holland, Samantha J.; Shikanov, Ariella; Grzybowski, Bartosz A.; Shea, Lonnie D.

2011-01-01

Regenerative strategies for damaged tissue aim to present biochemical cues that recruit and direct progenitor cell migration and differentiation. Hydrogels capable of localized gene delivery are being developed to provide a support for tissue growth, and as a versatile method to induce the expression of inductive proteins; however, the duration, level, and localization of expression isoften insufficient for regeneration. We thus investigated the modification of hydrogels with affinity peptides to enhance vector retention and increase transfection within the matrix. PEG hydrogels were modified with lysine-based repeats (K4, K8), which retained approximately 25% more vector than control peptides. Transfection increased 5- to 15-fold with K8 and K4 respectively, over the RDG control peptide. K8- and K4-modified hydrogels bound similar quantities of vector, yet the vector dissociation rate was reduced for K8, suggesting excessive binding that limited transfection. These hydrogels were subsequently applied to an in vitro co-culture model to induce NGF expression and promote neurite outgrowth. K4-modified hydrogels promoted maximal neurite outgrowth, likely due to retention of both the vector and the NGF. Thus, hydrogels modified with affinity peptides enhanced vector retention and increased gene delivery, and these hydrogels may provide a versatile scaffold for numerous regenerative medicine applications. PMID:21514659

Synthesis of PEG-rich PLGA-PEG-PLGA for the PLGA-PEG-PLGA/laponite hydrogels with thermoresponsive sol-gel transitions

NASA Astrophysics Data System (ADS)

Tanimoto, Keishi; Maeda, Tomoki; Hotta, Atsushi

Poly (D,L-lactide-co-glycolide)-b-poly (ethylene glycol)-b-poly (D,L-lactide-co-glycolide) (PLGA-PEG-PLGA) possesses moderate biocompatibility originating from the relatively shorter PEG block in its polymeric molecule. For the maximum utilization of the highly biocompatible PEG block, the PEG block should be relatively longer, and thus the PEG/PLGA ratio, the molecular weight ratio of PEG and PLGA, should be higher. In addition, for the wider use of PLGA-PEG-PLGA in the biological fields, the aqueous PLGA-PEG-PLGA solution should transfer from sol to gel states in response to the increase in temperature. It was reported, however, through the previous researches, that the PLGA-PEG-PLGA solution with a high PEG/PLGA ratio (above 0.5) would not exhibit thermoresponsive sol-gel transitions. In this work, PLGA-PEG-PLGAs with higher PEG/PLGA ratios were synthesized and the laponite, an inorganic nanoparticle, was added to the solutions to realize the thermoresponsive sol-gel transition. It was found that the PLGA-PEG-PLGA with the high PEG/PLGA ratio of 3.0 could exhibit the thermoresponsive sol-gel transition by adding laponite at 1.25 weight percent. The physical characteristics of the gel were also studied by the dynamic mechanical analysis (DMA) This work was supported by a Grant-in-Aid for Scientific Research (A) (No. 15H02298 to A.H.) and a Grant-in-Aid for Research Activity Start-up (No.15H06586 to T.M.) from JSPS: KAKENHI\\x9D.

Hyaluronic acid based hydrogel system for soft tissue regeneration and drug delivery

NASA Astrophysics Data System (ADS)

Jha, Amit Kumar

We have developed hyaluronic acid (HA)-based, biomimetic hydrogel matrices that are hierarchically structured, mechanically robust and biologically active. Specifically, HA-based hydrogel particles (HGPs) with controlled sizes, defined porosity, and improved stability were synthesized using different inverse emulsion systems and crosslinking chemistries. The resultant particles either contained residual functional groups or were rendered reactive by subsequent chemical modifications. HA-based doubly crosslinked networks (DXNs) were synthesized via covalent crosslinking of HA HGPs with soluble HA macromers carrying mutually reactive functional groups. These hybrid matrices are hierarchical in nature, consisting of densely crosslinked HGPs integrated in a loosely connected secondary matrix. Their mechanical properties and degradation kinetics can be readily tuned by varying the particle size, functional group density, intra- and interparticle crosslinking. To improve the biological functions of HA HGPs, perlecan domain I (PlnDI), a basement membrane proteoglycan that has strong affinity for various heparin binding growth factors (HBGFs), was successfully conjugated to the particles through the core protein via a flexible poly(ethylene glycol) (PEG) linker. The immobilized PlnDI maintains its ability to bind bone morphogenetic proteins (BMP-2) and modulates its in vitro release. A similar, sustained release of BMP-2 was achieved by encapsulating BMP-2-loaded HGPs within a photocrosslinked HA matrix. When encapsulated in HA DXNs, primary bovine chondrocytes were able to maintain their phenotype, proliferate readily and produce abundant glycosaminoglycan. Finally, cell-adhesive HA DXNs were fabricated by encapsulating gelatin-decorated HA HGPs in a secondary HA matrix. Human MSCs were shown to adhere to the composite matrix through the focal adhesion sites clustered on particle surface. The cell-adhesive composite matrices supported hMSC proliferation and migration into the gels. Human MSCs were undifferentiated during the early time points of culture, however differentiated into osteoblast phenotype after 28 days of culture. In summary, the HA-based hydrogel matrices are hierarchically structured, mechanically robust and enzymatically stable, capable of mediating cellular functions through the spatial and temporal presentation of defined biological cues. These hydrogel systems are promising candidates for soft tissue regeneration.

Polyethylene glycol hydrogel rectal spacer implantation in patients with prostate cancer undergoing combination high-dose-rate brachytherapy and external beam radiotherapy.

PubMed

Yeh, Jekwon; Lehrich, Brandon; Tran, Carolyn; Mesa, Albert; Baghdassarian, Ruben; Yoshida, Jeffrey; Torrey, Robert; Gazzaniga, Michael; Weinberg, Alan; Chalfin, Stuart; Ravera, John; Tokita, Kenneth

2016-01-01

To present rectal toxicity rates in patients administered a polyethylene glycol (PEG) hydrogel rectal spacer in conjunction with combination high-dose-rate brachytherapy and external beam radiotherapy. Between February 2010 and April 2015, 326 prostate carcinoma patients underwent combination high-dose-rate brachytherapy of 16 Gy (average dose 15.5 Gy; standard deviation [SD] = 1.6 Gy) and external beam radiotherapy of 59.4 Gy (average dose 60.2 Gy; SD = 2.9 Gy). In conjunction with the radiation therapy regimen, each patient was injected with 10 mL of a PEG hydrogel in the anterior perirectal fat space. The injectable spacer (rectal spacer) creates a gap between the prostate and the rectum. The rectum is displaced from the radiation field, and rectal dose is substantially reduced. The goal is a reduction in rectal radiation toxicity. Clinical efficacy was determined by measuring acute and chronic rectal toxicity using the National Cancer Center Institute Common Terminology Criteria for Adverse Events v4.0 grading scheme. Median followup was 16 months. The mean anterior-posterior separation achieved was 1.6 cm (SD = 0.4 cm). Rates of acute Grade 1 and 2 rectal toxicity were 37.4% and 2.8%, respectively. There were no acute Grade 3/4 toxicities. Rates of late Grade 1, 2, and 3 rectal toxicity were 12.7%, 1.4%, and 0.7%, respectively. There were no late Grade 4 toxicities. PEG rectal spacer implantation is safe and well tolerated. Acute and chronic rectal toxicities are low despite aggressive dose escalation. Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Development of a P((MAA-co-NVP)-g-EG) Hydrogel Platform for Oral Protein Delivery: Effects of Hydrogel Composition on Environmental Response and Protein Partitioning.

PubMed

Steichen, Stephanie; O'Connor, Colleen; Peppas, Nicholas A

2017-01-01

Hydrogels based upon terpolymers of methacrylic acid, N-vinyl pyrrolidone, and poly(ethylene glycol) are developed and characterized for their ability to respond to changes in environmental pH and to partition protein therapeutics of varying molecular weights and isoelectric points. P((MAA-co-NVP)-g-EG) hydrogels are synthesized with PEG-based cross-linking agents of varying length and incorporation densities. The composition is confirmed using FT-IR spectroscopy and shows peak shifts indicating hydrogen bonding. Scanning electron microscopy reveals microparticles with an irregular, planar morphology. The pH-responsive behavior of the hydrogels is confirmed under equilibrium and dynamic conditions, with the hydrogel collapsed at acidic pH and swollen at neutral pH. The ability of the hydrogels to partition model protein therapeutics at varying pH and ionic strength is evaluated using three model proteins: insulin, porcine growth hormone, and ovalbumin. Finally, the microparticles are evaluated for adverse interactions with two model intestinal cell lines and show minimal cytotoxicity at concentrations below 5 mg mL -1 . © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Poly(2-oxazoline) hydrogels as next generation three-dimensional cell supports

PubMed Central

Dargaville, Tim R; Hollier, Brett G; Shokoohmand, Ali; Hoogenboom, Richard

2014-01-01

Synthetic hydrogels selectively decorated with cell adhesion motifs are rapidly emerging as promising substrates for 3D cell culture. When cells are grown in 3D they experience potentially more physiologically relevant cell–cell interactions and physical cues compared with traditional 2D cell culture on stiff surfaces. A newly developed polymer based on poly(2-oxazoline)s has been used for the first time to control attachment of fibroblast cells and is discussed here for its potential use in 3D cell culture with particular focus on cancer cells toward the ultimate aim of high-throughput screening of anticancer therapies. Advantages and limitations of using poly(2-oxazoline) hydrogels are discussed and compared with more established polymers, especially polyethylene glycol (PEG). PMID:24714592

Self-Healing Nanocomposite Hydrogel with Well-Controlled Dynamic Mechanics

NASA Astrophysics Data System (ADS)

Li, Qiaochu; Mishra, Sumeet; Chen, Pangkuan; Tracy, Joseph; Holten-Andersen, Niels

Network dynamics is a crucial factor that determines the macroscopic self-healing rate and efficiency in polymeric hydrogel materials, yet its controllability is seldom studied in most reported self-healing hydrogel systems. Inspired by mussel's adhesion chemistry, we developed a novel approach to assemble inorganic nanoparticles and catechol-decorated PEG polymer into a hydrogel network. When utilized as reversible polymer-particle crosslinks, catechol-metal coordination bonds yield a unique gel network with dynamic mechanics controlled directly by interfacial crosslink structure. Taking advantage of this structure-property relationship at polymer-particle interfaces, we next designed a hierarchically structured hybrid gel with two distinct relaxation timescales. By tuning the relative contribution of the two hierarchical relaxation modes, we are able to finely control the gel's dynamic mechanical behavior from a viscoelastic fluid to a stiff solid, yet preserving its fast self-healing property without the need for external stimuli.

3D cell entrapment in crosslinked thiolated gelatin-poly(ethylene glycol) diacrylate hydrogels

PubMed Central

Fu, Yao; Xu, Kedi; Zheng, Xiaoxiang; Giacomin, A. Jeffrey; Mix, Adam W.; Kao, Weiyuan John

2012-01-01

The combined use of natural ECM components and synthetic materials offers an attractive alternative to fabricate hydrogel-based tissue engineering scaffolds to study cell-matrix interactions in three-dimensions (3D). A facile method was developed to modify gelatin with cysteine via a bifunctional PEG linker, thus introducing free thiol groups to gelatin chains. A covalently crosslinked gelatin hydrogel was fabricated using thiolated gelatin and poly(ethylene glycol) diacrylate (PEGdA) via thiol-ene reaction. Unmodified gelatin was physically incorporated in a PEGdA-only matrix for comparison. We sought to understand the effect of crosslinking modality on hydrogel physicochemical properties and the impact on 3D cell entrapment. Compared to physically incorporated gelatin hydrogels, covalently crosslinked gelatin hydrogels displayed higher maximum weight swelling ratio (Qmax), higher water content, significantly lower cumulative gelatin dissolution up to 7 days, and lower gel stiffness. Furthermore, fibroblasts encapsulated within covalently crosslinked gelatin hydrogels showed extensive cytoplasmic spreading and the formation of cellular networks over 28 days. In contrast, fibroblasts encapsulated in the physically incorporated gelatin hydrogels remained spheroidal. Hence, crosslinking ECM protein with synthetic matrix creates a stable scaffold with tunable mechanical properties and with long-term cell anchorage points, thus supporting cell attachment and growth in the 3D environment. PMID:21955690

Protease-degradable PEG-maleimide coating with on-demand release of IL-1Ra to improve tissue response to neural electrodes

PubMed Central

Gutowski, Stacie M.; Shoemaker, James T.; Templeman, Kellie L.; Wei, Yang; Latour, Robert A.; Bellamkonda, Ravi V.; LaPlaca, Michelle C.; García, Andrés J.

2015-01-01

Neural electrodes are an important part of brain-machine interface devices that can restore functionality to patients with sensory and movement disorders. Chronically implanted neural electrodes induce an unfavorable tissue response which includes inflammation, scar formation, and neuronal cell death, eventually causing loss of electrode function. We developed a poly(ethylene glycol) hydrogel coating for neural electrodes with non-fouling characteristics, incorporated an anti-inflammatory agent, and engineered a stimulus-responsive degradable portion for on-demand release of the anti-inflammatory agent in response to inflammatory stimuli. This coating reduces in vitro glial cell adhesion, cell spreading, and cytokine release compared to uncoated controls. We also analyzed the in vivo tissue response using immunohistochemistry and microarray qRT-PCR. Although no differences were observed among coated and uncoated electrodes for inflammatory cell markers, lower IgG penetration into the tissue around PEG+IL-1Ra coated electrodes indicates an improvement in blood-brain barrier integrity. Gene expression analysis showed higher expression of IL-6 and MMP-2 around PEG+IL-1Ra samples, as well as an increase in CNTF expression, an important marker for neuronal survival. Importantly, increased neuronal survival around coated electrodes compared to uncoated controls was observed. Collectively, these results indicate promising findings for an engineered coating to increase neuronal survival and improve tissue response around implanted neural electrodes. PMID:25617126

Lamellar biogels comprising fluid membranes with a newly synthesized class of polyethylene glycol-surfactants

NASA Astrophysics Data System (ADS)

Warriner, Heidi E.; Davidson, Patrick; Slack, Nelle L.; Schellhorn, Matthias; Eiselt, Petra; Idziak, Stefan H. J.; Schmidt, Hans-Werner; Safinya, Cyrus R.

1997-09-01

A series of four polymer-surfactant macromolecules, each consisting of a double-chain hydrophobic moiety attached onto a monofunctional polyethylene glycol (PEG) polymer chain, were synthesized in order to study their effect upon the fluid lamellar liquid crystalline (Lα) phase of the dimyristoylphosphatidylcholine/pentanol/water system. The main finding of this study is that the addition of these compounds induces a new lamellar gel, called Lα,g. We have determined the phase diagrams as a function of PEG-surfactant concentration, cPEG, and weight fraction water, ΦW. All phase diagrams are qualitatively similar and show the existence of the gel. Unlike more common polymer physical gels, this gel can be induced either by increasing cPEG or by adding water at constant cPEG. In particular, less polymer is required for gelation as water concentration increases. Moreover, the gel phase is attained at concentrations of PEG-surfactant far below that required for classical polymer gels and is stable at temperatures comparable to the lower critical solution temperature of free PEG-water mixtures. Small angle x-ray experiments demonstrate the lamellar structure of the gel phase, while wide angle x-ray scattering experiments prove that the structure is Lα, not Lβ' (a common chain-ordered phase which is also a gel). The rheological behavior of the Lα,g phase demonstrates the existence of three dimensional elastic properties. Polarized light microscopy of Lα,g samples reveals that the Lα,g is induced by a proliferation of defect structures, including whispy lines, spherulitic defects, and a nematiclike Schlieren texture. We propose a model of topological defects created by the aggregation of PEG-surfactant into highly curved regions within the membranes. This model accounts for both the inverse relationship between ΦW and cPEG observed along the gel transition line and the scaling dependence of the interlayer spacing at the gel transition with the PEG molecular weight. These Lα hydrogels could serve as the matrix for membrane-anchored peptides, proteins or other drug molecules, creating a "bioactive gel" with mechanical stability deriving from the polymer-lipid minority component.

Interleukin-15 and cisplatin co-encapsulated thermosensitive polypeptide hydrogels for combined immuno-chemotherapy.

PubMed

Wu, Xilong; Wu, Yundi; Ye, Hongbo; Yu, Shuangjiang; He, Chaoliang; Chen, Xuesi

2017-06-10

In situ-forming thermosensitive hydrogels based on poly(ethylene glycol)-poly(γ-ethyl-l-glutamate) diblock copolymers (mPEG-b-PELG) were prepared for the co-delivery of interleukin-15 (IL-15) and cisplatin (CDDP). The polypeptide-based hydrogels as local drug delivery carriers could reduce the systemic toxicity, degrade thoroughly within 3weeks after subcutaneous injection into rats and display an acceptable biocompatibility. When incubated with mouse melanoma B16 cells, only the CDDP-treated groups had significant effects on the S phase cell-cycle arrest in melanoma cells. After a single peritumoral injection of the hydrogel containing IL-15/CDDP in C57BL/6 mice inoculated with B16F0-RFP melanoma cells, the dual drug-loaded hydrogels displayed synergistic anticancer efficacy, which was resulted from a combination of CDDP-mediated S arrest and IL-15/CDDP-induced recovery of CD8 + T cell and NK cell populations to reduce immunosuppression and enhance antitumor immunity. Hence, the as-prepared thermosensitive polypeptide hydrogels for localized and sustained co-delivery of IL-15 and CDDP may have potential for efficient treatment of melanoma. Copyright © 2017 Elsevier B.V. All rights reserved.

Multiplex Immunoassay Platforms Based on Shape-Coded Poly(ethylene glycol) Hydrogel Microparticles Incorporating Acrylic Acid

PubMed Central

Park, Saemi; Lee, Hyun Jong; Koh, Won-Gun

2012-01-01

A suspension protein microarray was developed using shape-coded poly(ethylene glycol) (PEG) hydrogel microparticles for potential applications in multiplex and high-throughput immunoassays. A simple photopatterning process produced various shapes of hydrogel micropatterns that were weakly bound to poly(dimethylsiloxane) (PDMS)-coated substrates. These micropatterns were easily detached from substrates during the washing process and were collected as non-spherical microparticles. Acrylic acids were incorporated into hydrogels, which could covalently immobilize proteins onto their surfaces due to the presence of carboxyl groups. The amount of immobilized protein increased with the amount of acrylic acid due to more available carboxyl groups. Saturation was reached at 25% v/v of acrylic acid. Immunoassays with IgG and IgM immobilized onto hydrogel microparticles were successfully performed with a linear concentration range from 0 to 500 ng/mL of anti-IgG and anti-IgM, respectively. Finally, a mixture of two different shapes of hydrogel microparticles immobilizing IgG (circle) and IgM (square) was prepared and it was demonstrated that simultaneous detection of two different target proteins was possible without cross-talk using same fluorescence indicator because each immunoassay was easily identified by the shapes of hydrogel microparticles. PMID:22969408

Injectable hyperbranched poly(β-amino ester) hydrogels with on-demand degradation profiles to match wound healing processes† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc03913a

PubMed Central

Xu, Qian; Guo, Linru; A, Sigen; Gao, Yongsheng; Zhou, Dezhong; Greiser, Udo; Creagh-Flynn, Jack; Zhang, Hong; Dong, Yixiao; Cutlar, Lara; Wang, Fagang; Liu, Wenguang

2018-01-01

Adjusting biomaterial degradation profiles to match tissue regeneration is a challenging issue. Herein, biodegradable hyperbranched poly(β-amino ester)s (HP-PBAEs) were designed and synthesized via “A2 + B4” Michael addition polymerization, and displayed fast gelation with thiolated hyaluronic acid (HA-SH) via a “click” thiol–ene reaction. HP-PBAE/HA-SH hydrogels showed tunable degradation profiles both in vitro and in vivo using diamines with different alkyl chain lengths and poly(ethylene glycol) diacrylates with varied PEG spacers. The hydrogels with optimized degradation profiles encapsulating ADSCs were used as injectable hydrogels to treat two different types of humanized excisional wounds – acute wounds with faster healing rates and diabetic wounds with slower healing and neo-tissue formation. The fast-degrading hydrogel showed accelerated wound closure in acute wounds, while the slow-degrading hydrogel showed better wound healing for diabetic wounds. The results demonstrate that the new HP-PBAE-based hydrogel in combination with ADSCs can be used as a well-controlled biodegradable skin substitute, which demonstrates a promising approach in the treatment of various types of skin wounds. PMID:29719691

Articular cartilage generation applying PEG-LA-DM/PEGDM copolymer hydrogels.

PubMed

Zhao, Xing; Papadopoulos, Anestis; Ibusuki, Shinichi; Bichara, David A; Saris, Daniel B; Malda, Jos; Anseth, Kristi S; Gill, Thomas J; Randolph, Mark A

2016-06-03

Injuries to the human native cartilage tissue are particularly problematic because cartilage has little to no ability to heal or regenerate itself. Employing a tissue engineering strategy that combines suitable cell sources and biomimetic hydrogels could be a promising alternative to achieve cartilage regeneration. However, the weak mechanical properties may be the major drawback to use fully degradable hydrogels. Besides, most of the fully degradable hydrogels degrade too fast to permit enough extracellular matrix (ECM) production for neocartilage formation. In this study, we demonstrated the feasibility of neocartilage regeneration using swine articular chondrocytes photoencapsualted into poly (ethylene glycol) dimethacrylate (PEGDM) copolymer hydrogels composed of different degradation profiles: degradable (PEG-LA-DM) and nondegradable (PEGDM) macromers in molar ratios of 50/50, 60/40, 70/30, 80/20, and 90/10. Articular chondrocytes were isolated enzymatically from juvenile Yorkshire swine cartilage. 6 × 10(7) cells cells were added to each milliliter of macromer/photoinitiator (I2959) solution. Nonpolymerized gel containing the cells (100 μL) was placed in cylindrical molds (4.5 mm diameter × 6.5 mm in height). The macromer/photoinitiator/chondrocyte solutions were polymerized using ultraviolet (365 nm) light at 10 mW/cm(2) for 10 mins. Also, an articular cartilaginous ring model was used to examine the capacity of the engineered cartilage to integrate with native cartilage. Samples in the pilot study were collected at 6 weeks. Samples in the long-term experimental groups (60/40 and 70/30) were implanted into nude mice subcutaneously and harvested at 6, 12 and 18 weeks. Additionally, cylindrical constructs that were not implanted used as time zero controls. All of the harvested specimens were examined grossly and analyzed histologically and biochemically. Histologically, the neocartilage formed in the photochemically crosslinked gels resembled native articular cartilage with chondrocytes in lacunae and surrounded by new ECM. Increases in total DNA, glycosaminoglycan, and hydroxyproline were observed over the time periods studied. The neocartilage integrated with existing native cartilage. Articular cartilage generation was achieved using swine articular chondrocytes photoencapsulated in copolymer PEGDM hydrogels, and the neocartilage tissue had the ability to integrate with existing adjacent native cartilage.

3D‐Bioprinted Osteoblast‐Laden Nanocomposite Hydrogel Constructs with Induced Microenvironments Promote Cell Viability, Differentiation, and Osteogenesis both In Vitro and In Vivo

PubMed Central

Zhai, Xinyun; Ma, Yufei; Cheng, Delin; Wu, Mingming; Liu, Wenguang; Zhao, Xiaoli

2017-01-01

Abstract An osteoblast‐laden nanocomposite hydrogel construct, based on polyethylene glycol diacrylate (PEGDA)/laponite XLG nanoclay ([Mg5.34Li0.66Si8O20(OH)4]Na0.66, clay)/hyaluronic acid sodium salt (HA) bio‐inks, is developed by a two‐channel 3D bioprinting method. The novel biodegradable bio‐ink A, comprised of a poly(ethylene glycol) (PEG)–clay nanocomposite crosslinked hydrogel, is used to facilitate 3D‐bioprinting and enables the efficient delivery of oxygen and nutrients to growing cells. HA with encapsulated primary rat osteoblasts (ROBs) is applied as bio‐ink B with a view to improving cell viability, distribution uniformity, and deposition efficiency. The cell‐laden PEG–clay constructs not only encapsulated osteoblasts with more than 95% viability in the short term but also exhibited excellent osteogenic ability in the long term, due to the release of bioactive ions (magnesium ions, Mg2+ and silicon ions, Si4+), which induces the suitable microenvironment to promote the differentiation of the loaded exogenous ROBs, both in vitro and in vivo. This 3D‐bioprinting method holds much promise for bone tissue regeneration in terms of cell engraftment, survival, and ultimately long‐term function. PMID:29593958

PLGA-PEG-PLGA hydrogel for ocular drug delivery of dexamethasone acetate.

PubMed

Gao, Yuan; Sun, Yan; Ren, Fuzheng; Gao, Shen

2010-10-01

This study aims to investigate the suitability of thermosensitive triblock polymer poly-(DL-lactic acid-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-PLGA as a matrix material for ocular delivery of dexamethasone acetate (DXA). The copolymer was synthesized and evaluated for its thermosensitive and gelation properties. DXA in situ gel-forming solution based on PLGA-PEG-PLGA copolymer of 20% (w/w) was prepared and evaluated for ocular pharmacokinetics in rabbit according to the microdialysis method, which was compared to the normal eye drop. The copolymer with 20% (w/w) had a low critical solution temperature of 32 degrees C, which is close to the surface temperature of the eye. The C(max) of DXA in the anterior chamber for the PLGA-PEG-PLGA solution was 125.2 microg/mL, which is sevenfold higher than that of the eye drop, along with greater area under the concentration-time curves (AUC). These results suggest that the PLGA-PEG-PLGA copolymer is potential thermosensitive in situ gel-forming material for ocular drug delivery, and it may improve the bioavailability, efficacy of some eye drugs.

Adjustment of surface chemical and physical properties with functionalized polymers to control cell adhesion

NASA Astrophysics Data System (ADS)

Zhou, Zhaoli

Cell-surface interaction is crucial in many cellular functions such as movement, growth, differentiation, proliferation and survival. In the present work, we have developed several strategies to design and prepare synthetic polymeric materials with selected cues to control cell attachment. To promote neuronal cell adhesion on the surfaces, biocompatible, non-adhesive PEG-based materials were modified with neurotransmitter acetylcholine functionalities to produce hydrogels with a range of porous structures, swollen states, and mechanical strengths. Mice hippocampal cells cultured on the hydrogels showed differences in number, length of processes and exhibited different survival rates, thereby highlighting the importance of chemical composition and structure in biomaterials. Similar strategies were used to prepare polymer brushes to assess how topographical cues influence neuronal cell behaviors. The brushes were prepared using the "grown from" method through surface-initiated atom transfer radical polymerization (SI-ATRP) reactions and further patterned via UV photolithography. Protein absorption tests and hippocampal neuronal cell culture of the brush patterns showed that both protein and neuronal cells can adhere to the patterns and therefore can be guided by the patterns at certain length scales. We also prepared functional polymers to discourage attachment of undesirable cells on the surfaces. For example, we synthesized PEG-perfluorinated alkyl amphiphilic surfactants to modify polystyrene-block-poly(ethylene-ran-butylene)- block-polyisoprene (SEBI or K3) triblock copolymers for marine antifouling/fouling release surface coatings. Initial results showed that the polymer coated surfaces can facilitate removal of Ulva sporelings on the surfaces. In addition, we prepared both bioactive and dual functional biopassive/bioactive antimicrobial coatings based on SEBI polymers. Incubating the polymer coated surfaces with gram-positive bacteria (S. aureus), gram-negative bacteria (E. coli) and marine bacteria (C. marina ) species demonstrated that, unlike biopassive surfaces, the dual functionality polymer coated surfaces can significantly reduce both live and dead cells, without killing the cells in the culture media. The knowledge gained from those studies offers opportunities for further modification and potential applications of those types of polymers in the future.

Facile preparation of mussel-inspired polyurethane hydrogel and its rapid curing behavior.

PubMed

Sun, Peiyu; Wang, Jing; Yao, Xiong; Peng, Ying; Tu, Xiaoxiong; Du, Pengfei; Zheng, Zhen; Wang, Xinling

2014-08-13

A facile method was found to incorporate a mussel-inspired adhesive moiety into synthetic polymers, and mussel mimetic polyurethanes were developed as adhesive hydrogels. In these polymers, a urethane backbone was substituted for the polyamide chain of mussel adhesive proteins, and dopamine was appended to mimic the adhesive moiety of adhesive proteins. A series of mussel mimetic polyurethanes were created through a step-growth polymerization based on hexamethylene diisocyanate as a hard segment, PEG having different molecular weights as a soft segment, and lysine-dopamine as a chain extender. Upon a treatment with Fe(3+), the aqueous mussel mimetic polyurethane solutions can be triggered by pH adjustment to form adhesive hydrogels instantaneously; these materials can be used as injectable adhesive hydrogels. Upon a treatment with NaIO4, the mussel mimetic polyurethane solutions can be cured in a controllable period of time. The successful combination of the unique mussel-inspired adhesive moiety with a tunable polyurethane structure can result in a new kind of mussel-inspired adhesive polymers.

Injectable biodegradable temperature-responsive PLGA-PEG-PLGA copolymers: synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels.

PubMed

Qiao, Mingxi; Chen, Dawei; Ma, Xichen; Liu, Yanjun

2005-04-27

Injectable biodegradable temperature-responsive poly(DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymers with DL-lactide/glycolide molar ratio ranging from 6/1 to 15/l were synthesized from monomers of DL-lactide, glycolide and polyethylene glycol and characterized by 1H NMR. The resulting copolymers are soluble in water to form free flowing fluid at room temperature but become hydrogels at body temperature. The hydrophobicity of the copolymer increased with the increasing of DL-lactide/glycolide molar ratio. In vitro dissolution studies with two different hydrophobic drugs (5-fluorouracil and indomethacin) were performed to study the effect of DL-lactide/glycolide molar ratio on drug release and to elucidate drug release mechanism. The release mechanism for hydrophilic 5-fluorouracil was diffusion-controlled, while hydrophobic indomethacin showed an biphasic profile comprising of an initial diffusion-controlled stage followed by the hydrogel erosion-dominated stage. The effect of DL-lactide/glycolide molar ratio on drug release seemed to be dependent on the drug release mechanism. It has less effect on the drug release during the diffusion-controlled stage, but significantly affected drug release during the hydrogel erosion-controlled stage. Compared with ReGel system, the synthesized copolymers showed a higher gelation temperature and longer period of drug release. The copolymers can solubilize the hydrophobic indomethacin and the solubility (13.7 mg/ml) was increased 3425-fold compared to that in water (4 microg/ml, 25 degrees C). Two methods of physical mixing method and solvent evaporation method were used for drug solubilization and the latter method showed higher solubilization efficiency.

Protein adsorption and cell adhesion on nanoscale bioactive coatings formed from poly(ethylene glycol) and albumin microgels

PubMed Central

Scott, Evan A.; Nichols, Michael D.; Cordova, Lee H.; George, Brandon J.; Jun, Young-Shin; Elbert, Donald L.

2008-01-01

Late-term thrombosis on drug-eluting stents is an emerging problem that might be addressed using extremely thin, biologically-active hydrogel coatings. We report a dip-coating strategy to covalently link poly(ethylene glycol) (PEG) to substrates, producing coatings with <≈100 nm thickness. Gelation of PEG-octavinylsulfone with amines in either bovine serum albumin (BSA) or PEG-octaamine was monitored by dynamic light scattering (DLS), revealing the presence of microgels before macrogelation. NMR also revealed extremely high end group conversions prior to macrogelation, consistent with the formation of highly crosslinked microgels and deviation from Flory-Stockmayer theory. Before macrogelation, the reacting solutions were diluted and incubated with nucleophile-functionalized surfaces. Using optical waveguide lightmode spectroscopy (OWLS) and quartz crystal microbalance with dissipation (QCM-D), we identified a highly hydrated, protein-resistant layer with a thickness of approximately 75 nm. Atomic force microscopy in buffered water revealed the presence of coalesced spheres of various sizes but with diameters less than about 100 nm. Microgel-coated glass or poly(ethylene terephthalate) exhibited reduced protein adsorption and cell adhesion. Cellular interactions with the surface could be controlled by using different proteins to cap unreacted vinylsulfone groups within the coating. PMID:18771802

PEG Molecular Net-Cloth Grafted on Polymeric Substrates and Its Bio-Merits

NASA Astrophysics Data System (ADS)

Zhao, Changwen; Lin, Zhifeng; Yin, Huabing; Ma, Yuhong; Xu, Fujian; Yang, Wantai

2014-05-01

Polymer brushes and hydrogels are sensitive to the environment, which can cause uncontrolled variations on their performance. Herein, for the first time, we report a non-swelling ``PEG molecular net-cloth'' on a solid surface, fabricated using a novel ``visible light induced surface controlled graft cross-linking polymerization'' (VSCGCP) technique. Via this method, we show that 1) the 3D-network structure of the net-cloth can be precisely modulated and its thickness controlled; 2) the PEG net-cloth has excellent resistance to non-specific protein adsorption and cell adhesion; 3) the mild polymerization conditions (i.e. visible light and room temperature) provided an ideal tool for in situ encapsulation of delicate biomolecules such as enzymes; 4) the successive grafting of reactive three-dimensional patterns on the PEG net-cloth enables the creation of protein microarrays with high signal to noise ratio. Importantly, this strategy is applicable to any C-H containing surface, and can be easily tailored for a broad range of applications.

Controlled release of bioactive PDGF-AA from a hydrogel/nanoparticle composite.

PubMed

Elliott Donaghue, Irja; Shoichet, Molly S

2015-10-01

Polymer excipients, such as low molar mass poly(ethylene glycol) (PEG), have shown contradictory effects on protein stability when co-encapsulated in polymeric nanoparticles. To gain further insight into these effects, platelet-derived growth factor (PDGF-AA) was encapsulated in polymeric nanoparticles with vs. without PEG. PDGF-AA is a particularly compelling protein, as it has been demonstrated to promote cell survival and induce the oligodendrocyte differentiation of neural stem/progenitor cells (NSPCs) both in vitro and in vivo. Here we show, for the first time, the controlled release of bioactive PDGF-AA from an injectable nanoparticle/hydrogel drug delivery system (DDS). PDGF-AA was encapsulated, with high efficiency, in poly(lactide-co-glycolide) nanoparticles, and its release from the drug delivery system was followed over 21 d. Interestingly, the co-encapsulation of low molecular weight poly(ethylene glycol) increased the PDGF-AA loading but, unexpectedly, accelerated the aggregation of PDGF-AA, resulting in reduced activity and detection by enzyme-linked immunosorbent assay (ELISA). In the absence of PEG, released PDGF-AA remained bioactive as demonstrated with NSPC oligodendrocyte differentiation, similar to positive controls, and significantly different from untreated controls. This work presents a novel delivery method for differentiation factors, such as PDGF-AA, and provides insights into the contradictory effects reported in the literature of excipients, such as PEG, on the loading and release of proteins from polymeric nanoparticles. Previously, the polymer poly(ethylene glycol) (PEG) has been used in many biomaterials applications, from surface coatings to the encapsulation of proteins. In this work, we demonstrate that, unexpectedly, low molecular weight PEG has a deleterious effect on the release of the encapsulated protein platelet-derived growth factor AA (PDGF-AA). We also demonstrate release of bioactive PDGF-AA (in the absence of PEG). Specifically, we demonstrate the differentiation of neural stem and progenitor cells to oligodendrocytes, similar to what is observed with the addition of fresh PDGFAA. A differentiated oligodendrocyte population is a key strategy in central nervous system regeneration. This work is the first demonstration of controlled PDGF-AA release, and also brings new insights to the broader field of protein encapsulation. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

The effect of glutathione as chain transfer agent in PNIPAAm-based thermo-responsive hydrogels for controlled release of proteins.

PubMed

Drapala, Pawel W; Jiang, Bin; Chiu, Yu-Chieh; Mieler, William F; Brey, Eric M; Kang-Mieler, Jennifer J; Pérez-Luna, Victor H

2014-03-01

To control degradation and protein release using thermo-responsive hydrogels for localized delivery of anti-angiogenic proteins. Thermo-responsive hydrogels derived from N-isopropylacrylamide (NIPAAm) and crosslinked with poly(ethylene glycol)-co-(L-lactic acid) diacrylate (Acry-PLLA-b-PEG-b-PLLA-Acry) were synthesized via free radical polymerization in the presence of glutathione, a chain transfer agent (CTA) added to modulate their degradation and release properties. Immunoglobulin G (IgG) and the recombinant proteins Avastin® and Lucentis® were encapsulated in these hydrogels and their release was studied. The encapsulation efficiency of IgG was high (75-87%) and decreased with CTA concentration. The transition temperature of these hydrogels was below physiological temperature, which is important for minimally invasive therapies involving these materials. The toxicity from unreacted monomers and free radical initiators was eliminated with a minimum of three buffer extractions. Addition of CTA accelerated degradation and resulted in complete protein release. Glutathione caused the degradation products to become solubilized even at 37°C. Hydrogels prepared without glutathione did not disintegrate nor released protein completely after 3 weeks at 37°C. PEGylation of IgG postponed the burst release effect. Avastin® and Lucentis® released from degraded hydrogels retained their biological activity. These systems offer a promising platform for the localized delivery of proteins.

Microfluidic bioassay system based on microarrays of hydrogel sensing elements entrapping quantum dot-enzyme conjugates.

PubMed

Jang, Eunji; Kim, Sinyoung; Koh, Won-Gun

2012-01-15

This paper presents a simple method to fabricate a microfluidic biosensor that is able to detect substrates for H(2)O(2)-generating oxidase. The biosensor consists of three components (quantum dot-enzyme conjugates, hydrogel microstructures, and a set of microchannels) that were hierarchically integrated into a microfluidic device. The quantum dot (QD)-enzyme conjugates were entrapped within the poly(ethylene glycol) (PEG)-based hydrogel microstructures that were fabricated within the microchannels by a photopatterning process. Glucose oxidase (GOX) and alcohol oxidase (AOX) were chosen as the model oxidase enzymes, conjugated to carboxyl-terminated CdSe/ZnS QDs, and entrapped within the hydrogel microstructures, which resulted in a fluorescent hydrogel microarray that was responsive to glucose or alcohol. The hydrogel-entrapped GOX and AOX were able to perform enzyme-catalyzed oxidation of glucose and alcohol, respectively, to produce H(2)O(2), which subsequently quenched the fluorescence of the conjugated QDs. The fluorescence intensity of the hydrogel microstructures decreased as the glucose and alcohol concentrations increased, and the detection limits of this system were found to be 50 μM of glucose and 70 μM of alcohol. Because each microchannel was able to carry out different assays independently, the simultaneous detection of glucose and alcohol was possible using our novel microfluidic device composed of multiple microchannels. Copyright © 2011 Elsevier B.V. All rights reserved.

Biomimetic hydrogels for biosensor implant biocompatibility: electrochemical characterization using micro-disc electrode arrays (MDEAs).

PubMed

Justin, Gusphyl; Finley, Stephen; Abdur Rahman, Abdur Rub; Guiseppi-Elie, Anthony

2009-02-01

Our interest is in the development of engineered microdevices for continuous remote monitoring of intramuscular lactate, glucose, pH and temperature during post-traumatic hemorrhaging. Two important design considerations in the development of such devices for in vivo diagnostics are discussed; the utility of micro-disc electrode arrays (MDEAs) for electrochemical biosensing and the application of biomimetic, bioactive poly(HEMA)-based hydrogel composites for implant biocompatibility. A poly(HEMA)-based hydrogel membrane containing polyethylene glycol (PEG) was UV cross-linked with tetraethyleneglycol diacrylate following application to MDEAs (50 mum discs) and to 250 mum diameter gold electrodes within 8-well culture ware. Cyclic voltammetry (CV) of the MDEAs revealed a reduction in the apparent diffusion coefficient of ferrocenemonocarboxylic acid (FcCO(2)H), from 6.68 x 10(-5) to 6.74 x 10(-6) cm(2)/s for the uncoated and 6 mum thick hydrogel coated devices, respectively. Single frequency (4 kHz) temporal impedance measurements of the hydrogels in the 8-well culture ware showed a reversible 5% change in the absolute impedance of the hydrogels when exposed to a pH change between 6.1 to 7.2 and a 20% drop between pH 6.1 and 8.8.

PEGDA hydrogels as a replacement for animal tissues in mucoadhesion testing.

PubMed

Eshel-Green, Tal; Eliyahu, Shaked; Avidan-Shlomovich, Shlomit; Bianco-Peled, Havazelet

2016-06-15

Utilization of animal parts in ex-vivo mucoadhesion assays is a common approach that presents many difficulties due to animal rights issues and large variance between animals. This study examines the suitability of two PEGDA (poly(ethylene glycol) diacrylate) based hydrogels to serve as tissue mimetics for mucoadhesion evaluation. One hydrogel, termed PEGDA-QT, was composed of pentaerythritol tetrakis (3-mercaptopropionate) and PEG and contained free thiol groups mimicking those found in natural mucosa. The other hydrogel was formed by UV (ultraviolet) curing of PEGDA and mimicked the mechanical property of mucosa but not its chemical constitute. When ranking different first generation mucoadhesive polymers using a tensile assay, both hydrogels showed good agreement with the ranking achieved for porcine small intestine. However, only PEGDA-QT and porcine small intestine shared a similar displacement curve. The same ranking for PEGDA-QT and porcine small intestine was also observed when comparing a second-generation mucoadhesive polymer, thiolated alginate, to native alginate. Our findings suggest that PEGDA-QT could serve as a replacement for porcine small intestine in both mucoadhesion evaluations using a tensile machine and the flow-through method for first and second-generation mucoadhesive polymers. Copyright © 2016 Elsevier B.V. All rights reserved.

Fabrication of Apigenin loaded gellan gum-chitosan hydrogels (GGCH-HGs) for effective diabetic wound healing.

PubMed

Shukla, Rajesh; Kashaw, Sushil K; Jain, Alok Pal; Lodhi, Santram

2016-10-01

The Apigenin (APN) was isolated from ethanolic extract of M. alba leaves and screened by in-vivo wound models (Diabetic and Dead space) in rats. Apigenin loaded hydrogel (HGs) was prepared using gellan gum-chitosan (GGCH) with PEG as a cross linker and characterized for various parameter like AFM, swelling property, entrapment efficiency and drug release. Further performance of hydrogel was evaluated by wound healing activity tested against wound contraction, collagen content, dried granuloma weights and antioxidant activity. The percent entrapment efficiency of optimized hydrogel found to be 87.15±1.20. APN loaded GGCH-HGs were able to release 96.11% APN in 24h. The level of superoxide dismutase (SOD) and catalase were found increased significantly in granuloma tissue of APN treated group. APN GGCH-HGs found higher wound healing effect in diabetic as well as normal wound tissues with significant antioxidant activity. Results proven the utility of prepared hydrogel (APN loaded GGCH-HGs) seems to be highly suitable for wound healing due to its unique properties of biocompatibility, biodegradability, moist nature and antioxidant effectiveness. Copyright © 2016 Elsevier B.V. All rights reserved.

Lubricin is expressed in chondrocytes derived from osteoarthritic cartilage encapsulated in poly (ethylene glycol) diacrylate scaffold

PubMed Central

Musumeci, G.; Loreto, C.; Carnazza, M.L.; Coppolino, F.; Cardile, V.; Leonardi, R.

2011-01-01

Osteoarthritis (OA) is characterized by degenerative changes within joints that involved quantitative and/or qualitative alterations of cartilage and synovial fluid lubricin, a mucinous glycoprotein secreted by synovial fibroblasts and chondrocytes. Modern therapeutic methods, including tissue-engineering techniques, have been used to treat mechanical damage of the articular cartilage but to date there is no specific and effective treatment. This study aimed at investigating lubricin immunohistochemical expression in cartilage explant from normal and OA patients and in cartilage constructions formed by Poly (ethylene glycol) (PEG) based hydrogels (PEG-DA) encapsulated OA chondrocytes. The expression levels of lubricin were studied by immunohistochemistry: i) in tissue explanted from OA and normal human cartilage; ii) in chondrocytes encapsulated in hydrogel PEGDA from OA and normal human cartilage. Moreover, immunocytochemical and western blot analysis were performed in monolayer cells from OA and normal cartilage. The results showed an increased expression of lubricin in explanted tissue and in monolayer cells from normal cartilage, and a decreased expression of lubricin in OA cartilage. The chondrocytes from OA cartilage after 5 weeks of culture in hydrogels (PEGDA) showed an increased expression of lubricin compared with the control cartilage. The present study demonstrated that OA chondrocytes encapsulated in PEGDA, grown in the scaffold and were able to restore lubricin biosynthesis. Thus our results suggest the possibility of applying autologous cell transplantation in conjunction with scaffold materials for repairing cartilage lesions in patients with OA to reduce at least the progression of the disease. PMID:22073377

Controlling Properties and Cytotoxicity of Chitosan Nanocapsules by Chemical Grafting

PubMed Central

De Matteis, Laura; Alleva, Maria; Serrano-Sevilla, Inés; García-Embid, Sonia; Stepien, Grazyna; Moros, María; de la Fuente, Jesús M.

2016-01-01

The tunability of the properties of chitosan-based carriers opens new ways for the application of drugs with low water-stability or high adverse effects. In this work, the combination of a nanoemulsion with a chitosan hydrogel coating and the following poly (ethylene glycol) (PEG) grafting is proven to be a promising strategy to obtain a flexible and versatile nanocarrier with an improved stability. Thanks to chitosan amino groups, a new easy and reproducible method to obtain nanocapsule grafting with PEG has been developed in this work, allowing a very good control and tunability of the properties of nanocapsule surface. Two different PEG densities of coverage are studied and the nanocapsule systems obtained are characterized at all steps of the optimization in terms of diameter, Z potential and surface charge (amino group analysis). Results obtained are compatible with a conformation of PEG molecules laying adsorbed on nanoparticle surface after covalent linking through their amino terminal moiety. An improvement in nanocapsule stability in physiological medium is observed with the highest PEG coverage density obtained. Cytotoxicity tests also demonstrate that grafting with PEG is an effective strategy to modulate the cytotoxicity of developed nanocapsules. Such results indicate the suitability of chitosan as protective coating for future studies oriented toward drug delivery. PMID:27706041

Rapid Self-healing Nanocomposite Hydrogel with Tunable Dynamic Mechanics

NASA Astrophysics Data System (ADS)

Li, Qiaochu; Mishra, Sumeet; Chapman, Brian; Chen, Pangkuan; Tracy, Joseph; Holten-Andersen, Niels

The macroscopic healing rate and efficiency in self-repairing hydrogel materials are largely determined by the dissociation dynamics of their polymer network, which is hardly achieved in a controllable manner. Inspired by mussel's adhesion chemistry, we developed a novel approach to assemble inorganic nanoparticles and catechol-decorated PEG polymer into a hydrogel network. When utilized as reversible polymer-particle crosslinks, catechol-metal coordination bonds yield a unique gel network with dynamic mechanics controlled directly by interfacial crosslink structure. Taking advantage of this structure-property relationship at polymer-particle interfaces, we designed a hierarchically structured hybrid gel with two distinct relaxation timescales. By tuning the relative contribution of the two relaxation modes, we are able to finely control the gel's dynamic mechanical behavior from a viscoelastic fluid to a stiff solid, yet preserving its rapid self-healing property without the need for external stimuli.

Storage stability of biodegradable polyethylene glycol microspheres

NASA Astrophysics Data System (ADS)

Jain, Era; Sheth, Saahil; Polito, Kristen; Sell, Scott A.; Zustiak, Silviya P.

2017-10-01

Degradable hydrogel microspheres are popular choices for multiple biomedical applications, including drug, protein, or cell carriers for minimally invasive delivery. Clinical transitioning of such new, sensitive pharmaceutical preparations requires investigation of storage methods that retain key properties for extended time. In this study, we sought to determine the influence of seven common storage conditions on the physical and mechanical properties of degradable polyethylene glycol (PEG) hydrogel microspheres: 25 °C, 4 °C, -80 °C, lyophilization/-20 °C, dimethyl sulfoxide/-80 °C, dimethyl sulfoxide/lyophilization/-20 °C, vacuum/-20 °C. We have outlined the storage conditions in detail and explained their effect on swelling ratio, stiffness and degradation rate post-storage. Additionally, we have implemented protein-loaded hydrogels to evaluate the effect of storage conditions on diffusivity as well as protein stability post-storage. We found that hydrogels could be stored short-term (1-4 d) under moist conditions (i.e. storage without drying) without a substantial loss of properties. For extended storage (7-28 d), they could be stored either at  -80 °C (moist condition) or vacuum drying (dry condition).

Dual Affinity Heparin-Based Hydrogels Achieve Pro-Regenerative Immunomodulation and Microvascular Remodeling.

PubMed

Ogle, Molly E; Krieger, Jack R; Tellier, Liane E; McFaline-Figueroa, Jennifer; Temenoff, Johnna S; Botchwey, Edward A

2018-04-09

The immune response to biomaterial implants critically regulates functional outcomes such as vascularization, transplant integration/survival, and fibrosis. To create "immunologically smart" materials, the host-material response may be engineered to optimize the recruitment of pro-regenerative leukocyte subsets which mature into corresponding wound-healing macrophages. We have recently identified a unique feature of pro-regenerative Ly6C low monocytes that is a higher expression of both the bioactive lipid receptor sphingosine-1-phosphate receptor 3 (S1PR3) and the stromal derived factor-1α (SDF-1α) receptor CXCR4. Therefore, we designed a bifunctional hydrogel to harnesses a mechanistic synergy between these signaling axes to enhance the recruitment of endogenous pro-regenerative monocytes. To overcome the challenge of codelivering two physiochemically distinct molecules-a large hydrophilic protein and hydrophobic small molecule-we engineered a dual affinity hydrogel that exploits the growth factor affinity of a heparin derivative (Hep -N ) and lipid chaperone activity of albumin. The sphingosine analog FTY720 and SDF-1α are successfully loaded and coreleased from the Hep -N -functionalized PEG-DA hydrogels while maintaining bioactivity. Placement of these hydrogels into a murine partial thickness skin wound demonstrates that corelease of FTY720 and SDF-1α yields superior recruitment of myeloid cells to the implant interface compared to either factor alone. Although in vivo delivery of FTY720 or SDF-1α individually promotes the enhanced recruitment of Ly-6C low anti-inflammatory monocytes, codelivery enhances the early accumulation and persistence of the differentiated wound healing CD206 + macrophages in the tissue surrounding the gel. Co-delivery similarly promoted the synergistic expansion of vasculature adjacent to the implant, a key step in tissue healing. Taken together, these findings suggest that the combination of chemotactic molecules may provide additional maturation signals to the infiltrating leukocytes to facilitate macrophage transition and vascular network expansion, thus, ultimately, potentiating tissue repair. The coupling of multiple pro-regenerative biological cues provides a foundation for more fine-tuned immunoregenerative modulation to facilitate tissue repair.

The influence of matrix properties on growth and morphogenesis of human pancreatic ductal epithelial cells in 3D

PubMed Central

Raza, Asad; Ki, Chang Seok; Lin, Chien-Chi

2013-01-01

A highly tunable synthetic biomimetic hydrogel platform was developed to study the growth and morphogenesis of pancreatic ductal epithelial cells (PDEC) under the influence of a myriad of instructive cues. A PDEC line, PANC-1, was used as a model system to illustrate the importance of matrix compositions on cell fate determination. PANC-1 is an immortalized ductal epithelial cell line widely used in the study of pancreatic tumor cell behaviors. PANC-1 cells are also increasingly explored as a potential cell source for endocrine differentiation. Thus far, most studies related to PANC-1, among other PDEC lines, are performed on 2D culture surfaces. Here, we evaluated the effect of matrix compositions on PANC-1 cell growth and morphogenesis in 3D. Specifically, PANC-1 cells were encapsulated in PEG-based hydrogels prepared by step-growth thiol-ene photopolymerization. It was found that thiol-ene hydrogels provided a cytocompatible environment for encapsulation and 3D culture of PANC-1 cells. In contrast to a monolayer morphology on 2D culture surfaces, PANC-1 cells formed clusters in 3D thiol-ene hydrogels within 4 days of culture. After culturing for 10 days, however, the growth and structures of these clusters were significantly impacted by gel matrix properties, including sensitivity of the matrix to proteases, stiffness of the matrix, and ECM-mimetic motifs. The use of matrix metalloproteinase (MMP) sensitive linker or the immobilization of fibronectin-derived RGDS ligand in the matrix promoted PANC-1 cell growth and encouraged them to adopt ductal cyst-like structures. On the other hand, the encapsulated cells formed smaller and more compact aggregates in non-MMP responsive gels. The incorporation of laminin-derived YIGSR peptide did not enhance cell growth and caused the cells to form compact aggregates. Immobilized YIGSR also enhanced the expression of epithelial cell markers including β-catenin and E-cadherin. These studies have established PEG-peptide hydrogels formed by thiol-ene photo-click reaction as a suitable platform for studying and manipulating pancreatic epithelial cell growth and morphogenesis in 3D. PMID:23602364

Evaluation of a novel biodegradable thermosensitive keto-hydrogel for improving postoperative pain in a rat model.

PubMed

Wu, Meng-Huang; Shih, Ming-Hung; Hsu, Wei-Bin; Dubey, Navneet Kumar; Lee, Wen-Fu; Lin, Tsai-Yu; Hsieh, Meng-Yow; Chen, Chin-Fu; Peng, Kuo-Ti; Huang, Tsung-Jen; Shi, Chung-Sheng; Guo, Ren-Shyang; Cai, Chang-Jhih; Chung, Chiu-Yen; Wong, Chung-Hang

2017-01-01

This study evaluates the sustained analgesic effect of ketorolac-eluting thermosensitive biodegradable hydrogel in the plantar incisional pain model of the rat hind-paw. A ketorolac-embedded 2, 2'-Bis (2-oxazolin) (BOX) linking methoxy-poly(ethylene glycol) and poly(lactide-co-glycolide) (mPEG-PLGA) diblock copolymer (BOX copolymer) was synthesized as keto-hydrogel based on optimal sol-gel phase transition and in vitro drug release profile. The effect of keto-hydrogel on postoperative pain (POP) was assessed using the established plantar incisional pain model in hind-paw of rats and compared to that of ketorolac solution. Pain and sensory threshold, as well as pain scoring, were evaluated with behavioral tests by means of anesthesiometer and incapacitance apparatus, respectively. Pro-inflammatory cytokine levels (TNF-α, IL-6, VEGF, and IL-1β) around incisional wounds were measured by ELISA. Tissue histology was assessed using hematoxylin and eosin and Masson's trichrome staining. Ten mg/mL (25 wt%) keto-hydrogel showed a sol-gel transition at 26.4°C with a 10-day sustained drug release profile in vitro. Compared to ketorolac solution group, the concentration of ketorolac in tissue fluid was higher in the keto-hydrogel group during the first 18 h of application. Keto-hydrogel elevated pain and sensory threshold, increased weight-bearing capacity, and significantly reduced the levels of TNF-α, IL-6, and IL-1β while enhanced VEGF in tissue fluid. Histologic analysis reveals greater epithelialization and collagen deposition around wound treated with keto-hydrogel. In conclusion, our study suggests that keto-hydrogel is an ideal compound to treat POP with a secondary gain of improved incisional wound healing.

Disruption of Cell-Cell Contact-mediated Notch Signaling via Hydrogel Encapsulation Reduces Mesenchymal Stem Cell Chondrogenic Potential

PubMed Central

Chen, Amanda X.; Hoffman, Michael D.; Chen, Caressa S.; Shubin, Andrew D.; Reynolds, Daniel S.; Benoit, Danielle S. W.

2015-01-01

Cell-cell contact-mediated Notch signaling is essential for mesenchymal stem cell (MSC) chondrogenesis during development. However, subsequent deactivation of Notch signaling is also required to allow for stem cell chondrogenic progression. Recent literature has shown that Notch signaling can also influence Wnt/β-catenin signaling, critical for MSC differentiation, through perturbations in cell-cell contacts. Traditionally, abundant cell-cell contacts, consistent with development, are emulated in vitro using pellet cultures for chondrogenesis. However, cells are often encapsulated within biomaterials-based scaffolds, such as hydrogels, to improve therapeutic cell localization in vivo. To explore the role of Notch and Wnt/β-catenin signaling in the context of hydrogel-encapsulated MSC chondrogenesis, we compared signaling and differentiation capacity of MSCs in both hydrogels and traditional pellet cultures. We demonstrate that encapsulation within poly(ethylene glycol) (PEG) hydrogels reduces cell-cell contacts, and both Notch (7.5-fold) and Wnt/β-catenin (84.7-fold) pathway activation. Finally, we demonstrate that following establishment of cell-cell contacts and transient Notch signaling in pellet cultures, followed by Notch signaling deactivation, resulted in a 1.5-fold increase in MSC chondrogenesis. Taken together, these findings support that cellular condensation, and the establishment of initial cell-cell contacts is critical for MSC chondrogenesis, and this process is inhibited by hydrogel encapsulation. PMID:25504509

A thermosensitive hydrogel based on biodegradable amphiphilic poly(ethylene glycol) polycaprolactone poly(ethylene glycol) block copolymers

NASA Astrophysics Data System (ADS)

Gong, Chang Yang; Qian, Zhi Yong; Liu, Cai Bing; Juan Huang, Mei; Gu, Ying Chun; Wen, Yan Jun; Kan, Bing; Wang, Ke; Dai, Mei; Li, Xing Yi; Gou, Ma Ling; Tu, Ming Jing; Wei, Yu Quan

2007-06-01

A series of low molecular weight poly(ethylene glycol)-polycaprolactone-poly(ethylene glycol) (PEG-PCL-PEG) biodegradable block copolymers were successfully synthesized using isophorone diisocyanate (IPDI) as the coupling agent, and were characterized using 1H NMR and Fourier transform infrared spectroscopy. The aqueous solutions of the PEG-PCL-PEG copolymers displayed a special thermosensitive gel-sol transition when the concentration was above the corresponding critical gel concentration. Gel-sol phase diagrams were recorded using the test-tube-inversion method; they depended on the hydrophilic/hydrophobic balance in the macromolecular structure, as well as some other factors, including the heating history, volume, and the ageing time of the copolymer aqueous solutions and dissolution temperature of the copolymers. As a result, the gel-sol transition temperature range could be altered, which might be very useful for application in injectable drug delivery systems. This work was financially supported by the Chinese Key Basic Research Program (2004CB518800 and 2004CB518807), and the Sichuan Key Project of Science and Technology (06(05SG022-021-02)).

Biodegradable hyperbranched amphiphilic polyurethane multiblock copolymers consisting of poly(propylene glycol), poly(ethylene glycol), and polycaprolactone as in situ thermogels.

PubMed

Li, Zibiao; Zhang, Zhongxing; Liu, Kerh Li; Ni, Xiping; Li, Jun

2012-12-10

This paper reports the synthesis and characterization of new hyperbranched amphiphilic polyurethane multiblock copolymers consisting of poly(propylene glycol) (PPG), poly(ethylene glycol) (PEG), and polycaprolactone (PCL) segments as in situ thermogels. The hyperbranched poly(PPG/PEG/PCL urethane)s, termed as HBPEC copolymers, were synthesized from PPG-diol, PEG-diol, and PCL-triol by using 1,6-hexamethylene diisocyanate (HMDI) as a coupling agent. The compositions and structures of HBPEC copolymers were determined by GPC and 1H NMR spectroscopy. We carried out comparative studies of the new hyperbranched copolymers with their linear counterparts, the linear poly(PPG/PEG/PCL urethane) (LPEC) copolymer and Pluronic F127 PEG-PPG-PEG block copolymer, in terms of their self-assembly and aggregation behaviors and thermoresponsive properties. HBPEC copolymers were found to show thermoresponsive micelle formation and aggregation behaviors. Particularly, the lower critical solution temperature (LCST) of the copolymers was significantly affected by the copolymer architecture. HBPEC copolymers showed much lower LCST than LPEC, the linear counterpart. Our studies revealed that the effect of hyperbranch architecture was more prominent in the gelation of the copolymers. The aqueous solutions of HBPEC copolymers exhibited thermogelling behaviors at critical gelation concentrations (CGCs) ranging from 4.3 to 7.4 wt %. These values are much lower than those reported on other PCL-contained linear thermogelling copolymers and Pluronic F127 copolymer. In addition, the CGC of HBPEC copolymers is much lower than the control LPEC copolymer. More interestingly, at high temperatures, while LPEC and other linear thermogelling copolymers formed turbid sol, HBPEC formed a dehydrated gel. Our data suggest that these phenomena are caused by the hyperbranched structure of HBPEC copolymers, which could increase the interaction of copolymer branches and enhance the chain association through synergetic hydrogen bonding effect. The thermogelling behavior of HBPEC block copolymers was further evidenced by the 1H NMR molecular dynamic study and rheological study, which further support the above hypothesis. The hydrolytic degradation study showed that the HBPEC copolymer hydrogels are biodegradable under physiological conditions. Together with the good cell biocompatibility demonstrated by the cytotoxicity study, the new thermogelling copolymers reported in this paper could potentially be used as in situ-forming hydrogels for biomedical applications.

A pH- and temperature-responsive bioresorbable injectable hydrogel based on polypeptide block copolymers for the sustained delivery of proteins in vivo.

PubMed

Turabee, Md Hasan; Thambi, Thavasyappan; Duong, Huu Thuy Trang; Jeong, Ji Hoon; Lee, Doo Sung

2018-02-27

Sustained delivery of protein therapeutics is limited owing to the fragile nature of proteins. Despite its great potential, delivery of proteins without any loss of bioactivity remains a challenge in the use of protein therapeutics in the clinic. To surmount this shortcoming, we report a pH- and temperature-responsive in situ-forming injectable hydrogel based on comb-type polypeptide block copolymers for the controlled delivery of proteins. Polypeptide block copolymers, composed of hydrophilic polyethylene glycol (PEG), temperature-responsive poly(γ-benzyl-l-glutamate) (PBLG), and pH-responsive oligo(sulfamethazine) (OSM), exhibit pH- and temperature-induced sol-to-gel transition behavior in aqueous solutions. Polypeptide block copolymers were synthesized by combining N-carboxyanhydride-based ring-opening polymerization and post-functionalization of the chain-end using N-hydroxy succinimide ester activated OSM. The physical properties of polypeptide-based hydrogels were tuned by varying the composition of temperature- and pH-responsive PBLG and OSM in block copolymers. Polypeptide block copolymers were non-toxic to human embryonic kidney cells at high concentrations (2000 μg mL -1 ). Subcutaneous administration of polypeptide block copolymer sols formed viscoelastic gel instantly at the back of Sprague-Dawley (SD) rats. The in vivo gels exhibited sustained degradation and were found to be bioresorbable in 6 weeks without any noticeable inflammation at the injection site. Anionic characteristics of hydrogels allow efficient loading of a cationic model protein, lysozyme, through electrostatic interaction. Lysozyme-loaded polypeptide block copolymer sols readily formed a viscoelastic gel in vivo and sustained lysozyme release for at least a week. Overall, the results demonstrate an elegant approach to control the release of certain charged proteins and open a myriad of therapeutic possibilities in protein therapeutics.

Improved properties of bone and cartilage tissue from 3D inkjet-bioprinted human mesenchymal stem cells by simultaneous deposition and photocrosslinking in PEG-GelMA.

PubMed

Gao, Guifang; Schilling, Arndt F; Hubbell, Karen; Yonezawa, Tomo; Truong, Danh; Hong, Yi; Dai, Guohao; Cui, Xiaofeng

2015-11-01

Bioprinting of bone and cartilage suffers from low mechanical properties. Here we have developed a unique inkjet bioprinting approach of creating mechanically strong bone and cartilage tissue constructs using poly(ethylene glycol) dimethacrylate, gelatin methacrylate, and human MSCs. The printed hMSCs were evenly distributed in the polymerized PEG-GelMA scaffold during layer-by-layer assembly. The procedure showed a good biocompatibility with >80% of the cells surviving the printing process and the resulting constructs provided strong mechanical support to the embedded cells. The printed mesenchymal stem cells showed an excellent osteogenic and chondrogenic differentiation capacity. Both osteogenic and chondrogenic differentiation as determined by specific gene and protein expression analysis (RUNX2, SP7, DLX5, ALPL, Col1A1, IBSP, BGLAP, SPP1, Col10A1, MMP13, SOX9, Col2A1, ACAN) was improved by PEG-GelMA in comparison to PEG alone. These observations were consistent with the histological evaluation. Inkjet bioprinted-hMSCs in simultaneously photocrosslinked PEG-GelMA hydrogel scaffolds demonstrated an improvement of mechanical properties and osteogenic and chondrogenic differentiation, suggesting its promising potential for usage in bone and cartilage tissue engineering.

Effectiveness of a new gelatin sealant system for dural closure.

PubMed

Kawai, Hisashi; Nakagawa, Ichiro; Nishimura, Fumihiko; Motoyama, Yasushi; Park, Young-Su; Nakamura, Mitsutoshi; Nakase, Hiroyuki; Suzuki, Shuko; Ikada, Yoshito

2014-10-01

Watertight dural closure is imperative after neurosurgical procedures because inadequately treated leakage of cerebrospinal fluid (CSF) can have serious consequences. In this study, the authors test the use of a new gelatin glue as a dural sealant in in vitro and in vivo canine models of transdural CSF leakage. The in vitro model was sutured semicircles of canine dura mater and artificial dural substitute. The sutures were sealed with gelatin glue (n  =  20), fibrin glue (n  =  20), or a polyethylene glycol (PEG)-based hydrogel sealant (n  =  20). Each sample was set in a device to measure water pressure, and pressure was increased until leakage occurred. Bonding strength was subjectively evaluated. The in vivo model was dogs who underwent dural excision and received either no sealant (control group; n  =  5) or gelatin glue sealant (n  =  5) before dural closure. Twenty-eight days post-surgery, the maximum intracranial pressure was measured at the cisterna magna using Valsalva maneuver and tissue adhesion was evaluated. The water pressure at which leakage occurred in the in vitro model was higher with gelatin glue (76·5 ± 39·8 mmHg) than with fibrin glue (38·3 ± 27·4 mmHg, P < 0·001) or the PEG-based hydrogel sealant (46·3 ± 20·9 mmHg, P  =  0·007). Bonding strength was higher for the gelatin glue than fibrin glue (P < 0·001) or PEG-based hydrogel sealant (P  =  0·001). The maximum intracranial pressure in the in vivo model was higher for the gelatin glue group (59·0 ± 2·2 mmHg) than the control group (13·8 ± 4·0 mmHg, P < 0·001). Tissue adhesion was lower for the gelatin glue group than the control group (P  =  0·005). The new gelatin glue provides an effective watertight closure when used as an adjunct to sutured dural repair.

Spatially localized recruitment of anti-inflammatory monocytes by SDF-1α-releasing hydrogels enhances microvascular network remodeling.

PubMed

Krieger, J R; Ogle, M E; McFaline-Figueroa, J; Segar, C E; Temenoff, J S; Botchwey, E A

2016-01-01

Tissue repair processes are characterized by the biphasic recruitment of distinct subpopulations of blood monocytes, including classical ("inflammatory") monocytes (IMs, Ly6C(hi)Gr1(+)CX3CR1(lo)) and non-classical anti-inflammatory monocytes (AMs, Ly6C(lo)Gr1(-)CX3CR1(hi)). Drug-eluting biomaterial implants can be used to tune the endogenous repair process by the preferential recruitment of pro-regenerative cells. To enhance recruitment of AMs during inflammatory injury, a novel N-desulfated heparin-containing poly(ethylene glycol) diacrylate (PEG-DA) hydrogel was engineered to deliver exogenous stromal derived factor-1α (SDF-1α), utilizing the natural capacity of heparin to sequester and release growth factors. SDF-1α released from the hydrogels maintained its bioactivity and stimulated chemotaxis of bone marrow cells in vitro. Intravital microscopy and flow cytometry demonstrated that SDF-1α hydrogels implanted in a murine dorsal skinfold window chamber promoted spatially-localized recruitment of AMs relative to unloaded internal control hydrogels. SDF-1α delivery stimulated arteriolar remodeling that was correlated with AM enrichment in the injury niche. SDF-1α, but not unloaded control hydrogels, supported sustained arteriogenesis and microvascular network growth through 7 days. The recruitment of AMs correlated with parameters of vascular remodeling suggesting that tuning the innate immune response by biomaterial SDF-1α release is a promising strategy for promoting vascular remodeling in a spatially controlled manner. Copyright © 2015 Elsevier Ltd. All rights reserved.

Biomimetic, ultrathin and elastic hydrogels regulate human neutrophil extravasation across endothelial-pericyte bilayers.

PubMed

Lauridsen, Holly M; Gonzalez, Anjelica L

2017-01-01

The vascular basement membrane-a thin, elastic layer of extracellular matrix separating and encasing vascular cells-provides biological and mechanical cues to endothelial cells, pericytes, and migrating leukocytes. In contrast, experimental scaffolds typically used to replicate basement membranes are stiff and bio-inert. Here, we present thin, porated polyethylene glycol hydrogels to replicate human vascular basement membranes. Like commercial transwells, our hydrogels are approximately 10μm thick, but like basement membranes, the hydrogels presented here are elastic (E: 50-80kPa) and contain a dense network of small pores. Moreover, the inclusion of bioactive domains introduces receptor-mediated biochemical signaling. We compare elastic hydrogels to common culture substrates (E: >2GPa) for human endothelial cell and pericyte monolayers and bilayers to replicate postcapillary venules in vitro. Our data demonstrate that substrate elasticity facilitates differences in vascular phenotype, supporting expression of vascular markers that are increasingly replicative of venules. Endothelial cells differentially express vascular markers, like EphB4, and leukocyte adhesion molecules, such as ICAM-1, with decreased mechanical stiffness. With porated PEG hydrogels we demonstrate the ability to evaluate and observe leukocyte recruitment across endothelial cell and pericyte monolayers and bilayers, reporting that basement membrane scaffolds can significantly alter the rate of vascular migration in experimental systems. Overall, this study demonstrates the creation and utility of a new and accessible method to recapture the mechanical and biological complexity of human basement membranes in vitro.

Design of multimodal degradable hydrogels for controlled therapeutic delivery

NASA Astrophysics Data System (ADS)

Kharkar, Prathamesh Madhav

Hydrogels are of growing interest for the delivery of therapeutics to specific sites in the body. For localized drug delivery, hydrophilic polymeric precursors often are laden with bioactive moieties and then directly injected to the site of interest for in situ gel formation. The release of physically entrapped cargo is dictated by Fickian diffusion, degradation of the drug carrier, or a combination of both. The goal of this work was to design and characterize degradable hydrogel formulations that are responsive to multiple biologically relevant stimuli for degradation-mediated delivery of cargo molecules such as therapeutic proteins, growth factors, and immunomodulatory agents. We began by demonstrating the use of cleavable click linkages formed by Michael-type addition reactions in conjunction with hydrolytically cleavable functionalities for the degradation of injectable hydrogels by endogenous stimuli for controlled protein release. Specifically, the reaction between maleimides and thiols was utilized for hydrogel formation, where thiol selection dictates the degradability of the resulting linkage under thiol-rich reducing conditions. Relevant microenvironments where degradation would occur in vivo include those rich in glutathione (GSH), a tripeptide that is found at elevated concentrations in carcinoma tissues. Degradation of the hydrogels was monitored with rheometry and volumetric swelling measurements. Arylthiol-based thioether succinimide linkages underwent degradation via click cleavage and thiol exchange reaction in the presence of GSH and via ester hydrolysis, whereas alkylthiol-based thioether succinimide linkages only undergo degradation by only ester hydrolysis. The resulting control over the degradation rate within a reducing microenvironment resulted in 2.5 fold differences in the release profile of the model protein, a fluorescently-labeled bovine serum albumin, from dually degradable hydrogels compared to non-degradable hydrogels, where the thiol exchange reaction facilitated rapid and responsive protein release in the presence of GSH. A photolabile o-nitrobenzyl ether group (o-NB) was subsequently incorporated within the PEG-based, gel-forming monomers to demonstrate cargo release triggered by exogenous stimuli for patient-specific therapies. Upon the application of cytocompatible doses of light, the photolabile o-NB linkage underwent irreversible cleavage yielding ketone and carboxylic acid-based cleavage products. Hydrogel degradation kinetics was characterized in response to externally applied cytocompatible light or GSH in aqueous microenvironments. By incorporating a photodegradable o-nitrobenzyl ether group, a thiol-sensitive succinimide thioether linkage, and ester linkages within the hydrogels, we demonstrated unique control over degradation via surface erosion or bulk degradation mechanisms, respectively, with degradation rate constants ranging from 10-1 min-1 to 10-4 min-1. As a proof of concept, the controlled release of nanobeads from the hydrogel was demonstrated in a preprogrammed and stimuli-responsive fashion. The multimodal degradable hydrogels were then investigated for the local controlled release of small molecular weight proteins, which are of interest for regulating various cellular functions and fates in vivo. Low molecular weight heparin, a highly sulfated polysaccharide was incorporated within the hydrogel network by Michael-type reaction due to its affinity with biologics such as growth factors and immunomodulatory proteins. Incorporation of reduction-sensitive linkages resulted in 2.3 fold differences in the release profile of fibroblast growth factor-2 (FGF-2) in the presence of GSH compared to non-reducing microenvironment. Bioactivity of released FGF-2 was comparable to pristine FGF-2, indicating the ability of the hydrogel to retain bioactivity of cargo molecules during encapsulation and release. Further, preliminary in vivo studies demonstrated control over hydrogel degradation by varying % degradable contents. Collectively, this research developed injectable hydrogels that are responsive to various endogenous and exogenous stimuli, establishing a platform for stimuli-responsive drug delivery carriers.

Microfabricated Multianalyte Sensor Arrays for Metabolic Monitoring

DTIC Science & Technology

2006-09-01

aqueous in vivo-like surrounding15-18 to entrap both the redox polymer and glucose oxidase on polyimide sheets. We have used biocompatible PEG-DA hydrogel...arrays were fabricated on gold electrodes on flexible polyimide sheets by cross-linking glucose oxidase and redox polymer using UV-initiated free...cyclic voltammetry. We have fabricated an array of glucose sensors on flexible polyimide sheets that exhibit the desired linear response in the

Micropatterned cell-cell interactions enable functional encapsulation of primary hepatocytes in hydrogel microtissues.

PubMed

Li, Cheri Y; Stevens, Kelly R; Schwartz, Robert E; Alejandro, Brian S; Huang, Joanne H; Bhatia, Sangeeta N

2014-08-01

Drug-induced liver injury is a major cause of drug development failures and postmarket withdrawals. In vitro models that incorporate primary hepatocytes have been shown to be more predictive than model systems which rely on liver microsomes or hepatocellular carcinoma cell lines. Methods to phenotypically stabilize primary hepatocytes ex vivo often rely on mimicry of hepatic microenvironmental cues such as cell-cell interactions and cell-matrix interactions. In this work, we sought to incorporate phenotypically stable hepatocytes into three-dimensional (3D) microtissues, which, in turn, could be deployed in drug-screening platforms such as multiwell plates and diverse organ-on-a-chip devices. We first utilize micropatterning on collagen I to specify cell-cell interactions in two-dimensions, followed by collagenase digestion to produce well-controlled aggregates for 3D encapsulation in polyethylene glycol (PEG) diacrylate. Using this approach, we examined the influence of homotypic hepatocyte interactions and composition of the encapsulating hydrogel, and achieved the maintenance of liver-specific function for over 50 days. Optimally preaggregated structures were subsequently encapsulated using a microfluidic droplet-generator to produce 3D microtissues. Interactions of engineered hepatic microtissues with drugs was characterized by flow cytometry, and yielded both induction of P450 enzymes in response to prototypic small molecules and drug-drug interactions that give rise to hepatotoxicity. Collectively, this study establishes a pipeline for the manufacturing of 3D hepatic microtissues that exhibit stabilized liver-specific functions and can be incorporated into a wide array of emerging drug development platforms.

Minocycline enhances the mesenchymal stromal/stem cell pro-healing phenotype in triple antimicrobial-loaded hydrogels.

PubMed

Guerra, Alberto Daniel; Rose, Warren E; Hematti, Peiman; Kao, W John

2017-03-15

Mesenchymal stromal/stem cells (MSCs) have demonstrated pro-healing properties including an anti-inflammatory cytokine profile and the promotion of angiogenesis via expression of growth factors in pre-clinical models. MSCs encapsulated in poly(ethylene glycol) diacrylate (PEGdA) and thiolated gelatin poly(ethylene glycol) (Gel-PEG-Cys) crosslinked hydrogels have led to controlled cellular presentation at wound sites with favorable wound healing outcomes. However, the therapeutic potential of MSC-loaded hydrogels may be limited by non-specific protein adsorption on the delivery matrix that could facilitate the initial adhesion of microorganisms and subsequent virulent biofilm formation. Antimicrobials loaded concurrently in the hydrogels with MSCs could reduce microbial bioburden and promote healing, but the antimicrobial effect on the MSC wound healing capacity and the antibacterial efficacy of the hydrogels is unknown. We demonstrate that minocycline specifically induces a favorable change in MSC migration capacity, proliferation, gene expression, extracellular matrix (ECM) attachment, and adhesion molecule and growth factor release with subsequent increased angiogenesis. We then demonstrate that hydrogels loaded with MSCs, minocycline, vancomycin, and linezolid can significantly decrease bacterial bioburden. Our study suggests that minocycline can serve as a dual mechanism for the regenerative capacity of MSCs and the reduction of bioburden in triple antimicrobial-loaded hydrogels. Wound healing is a complex biological process that can be hindered by bacterial infection, excessive inflammation, and inadequate microvasculature. In this study, we develop a new formulation of poly(ethylene glycol) diacrylate and thiolated gelatin poly(ethylene glycol) crosslinked hydrogels loaded with minocycline, vancomycin, linezolid, and mesenchymal stromal/stem cells that induces a favorable wound healing phenotype in mesenchymal stromal/stem cells and prevents bacterial bioburden on the hydrogel. This combinatorial approach to biomaterial development has the potential to impact wound healing for contaminated full thickness cutaneous wounds. Copyright © 2017. Published by Elsevier Ltd.

Development of a High-Throughput Ultrasound Technique for the Analysis of Tissue Engineering Constructs

PubMed Central

Stukel, Jessica; Goss, Monika; Zhou, Haoyan; Zhou, Wenda; Willits, Rebecca; Exner, Agata A.

2015-01-01

Development of hydrogel-based tissue engineering constructs is growing at a rapid rate, yet translation to patient use has been sluggish. Years of costly preclinical tests are required to predict clinical performance and safety of these devices. The tests are invasive, destructive to the samples and, in many cases, are not representative of the ultimate in vivo scenario. Biomedical imaging has the potential to facilitate biomaterial development by enabling longitudinal noninvasive device characterization directly in situ. Among the various available imaging modalities, ultrasound stands out as an excellent candidate due to low cost, wide availability, and a favorable safety profile. The overall goal of this work was to demonstrate the utility of clinical ultrasound in longitudinal characterization of 3D hydrogel matrices supporting cell growth. Specifically, we developed a quantitative technique using clinical B-mode ultrasound to differentiate collagen content and fibroblast density within poly(ethylene glycol) (PEG) hydrogels and validated it in an in vitro phantom environment. By manipulating the hydrogel gelation, differences in ultrasound signal intensity were found between gels with collagen fibers and those with non-fiber forming collagen, indicating that the technique was sensitive to the configuration of the protein. At a collagen density of 2.5 mg/mL collagen, fiber forming collagen had a significantly increased signal intensity of 14.90± 2.58*10−5 a.u. compared to non-fiber forming intensity at 2.74± 0.36*10−5 a.u. Additionally, differences in intensity were found between living and fixed fibroblasts, with an increased signal intensity detected in living cells (5 ± 0.8*10−5 a.u. in 1 day live cells compared to 2.26 ± 0.39*10−5 a.u. in fixed cells at a concentration of 1*106 cells/mL in gels containing collagen). Overall, there was a linear correlation >0.90 for ultrasound intensity with increasing cell density. Results demonstrate the feasibility of using clinical ultrasound for characterization of PEG-based hydrogels in a tissue-mimicking phantom. The approach is clinically-relevant and could, with further validation, be utilized to nondestructively monitor in vivo performance of implanted tissue engineering scaffolds over time in preclinical and clinical settings. PMID:26577255

Development of a High-Throughput Ultrasound Technique for the Analysis of Tissue Engineering Constructs.

PubMed

Stukel, Jessica M; Goss, Monika; Zhou, Haoyan; Zhou, Wenda; Willits, Rebecca Kuntz; Exner, Agata A

2016-03-01

Development of hydrogel-based tissue engineering constructs is growing at a rapid rate, yet translation to patient use has been sluggish. Years of costly preclinical tests are required to predict clinical performance and safety of these devices. The tests are invasive, destructive to the samples and, in many cases, are not representative of the ultimate in vivo scenario. Biomedical imaging has the potential to facilitate biomaterial development by enabling longitudinal noninvasive device characterization directly in situ. Among the various available imaging modalities, ultrasound stands out as an excellent candidate due to low cost, wide availability, and a favorable safety profile. The overall goal of this work was to demonstrate the utility of clinical ultrasound in longitudinal characterization of 3D hydrogel matrices supporting cell growth. Specifically, we developed a quantitative technique using clinical B-mode ultrasound to differentiate collagen content and fibroblast density within poly(ethylene glycol) (PEG) hydrogels and validated it in an in vitro phantom environment. By manipulating the hydrogel gelation, differences in ultrasound signal intensity were found between gels with collagen fibers and those with non-fiber forming collagen, indicating that the technique was sensitive to the configuration of the protein. At a collagen density of 2.5 mg/mL collagen, fiber forming collagen had a significantly increased signal intensity of 14.90 ± 2.58 × 10(-5) a.u. compared to non-fiber forming intensity at 2.74 ± 0.36 × 10(-5) a.u. Additionally, differences in intensity were found between living and fixed fibroblasts, with an increased signal intensity detected in living cells (5.00 ± 0.80 × 10(-5) a.u. in 1 day live cells compared to 2.26 ± 0.39 × 10(-5) a.u.in fixed cells at a concentration of 1 × 10(6) cells/mL in gels containing collagen). Overall, there was a linear correlation >0.90 for ultrasound intensity with increasing cell density. Results demonstrate the feasibility of using clinical ultrasound for characterization of PEG-based hydrogels in a tissue-mimicking phantom. The approach is clinically-relevant and could, with further validation, be utilized to nondestructively monitor in vivo performance of implanted tissue engineering scaffolds over time in preclinical and clinical settings.

A lateral ridge augmentation study to evaluate a synthetic membrane for guided bone regeneration: an experiment in the canine mandible.

PubMed

Vierra, Matthew; Mau, Lian Ping; Huynh-Ba, Guy; Schoolfield, John; Cochran, David L

2016-01-01

To evaluate guided bone regeneration outcomes in defects protected with an in situ formed polyethylene glycol (PEG) hydrogel membrane as compared to a non-cross-linked collagen membrane (CM). Four mandibular alveolar ridge defects were created in eight hound dogs. Regenerative procedures were randomly allocated to one of four groups consisting of freeze-dried bone allograft, which is referred to in this study as freeze-dried bone xenograft (FDBX) + PEG, autogenous bone (AB) + PEG, AB + CM, and AB alone. After 8 weeks, titanium dental implants were placed into augmented sites. After 8 weeks of allowed time for osseointegration, the animals were sacrificed to harvest block specimens for bone-to-implant contact (BIC) and ridge width histomorphometric analysis. Polyethylene glycol membranes had an exposure rate of 50% as compared to 12.5% for sites grafted with CM. Regenerative outcomes with respect to implant placement were least favorable for FDBX + PEG which had implants placed in 37.5% of augmented sites compared to 100% implant placement for all other groups. No statistically significant differences were noted between groups for ridge width measurements in implant and non-implant histologic sections (P > 0.05). Buccal BIC (%) values between treatment groups also failed to reach statistical significant difference (FDBX + PEG [60.2 ± 9.4]; AB + PEG [58.8 ± 8.5]; AB + CM [57.9 ± 12.8]; AB [61.0 ± 10.2]). When used in conjunction with FDBX, PEG had unpredictable bone formation and in most cases negatively impacted future implant placement. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effects of sterilization on poly(ethylene glycol) hydrogels.

PubMed

Kanjickal, Deenu; Lopina, Stephanie; Evancho-Chapman, M Michelle; Schmidt, Steven; Donovan, Duane

2008-12-01

The past few decades have witnessed a dramatic increase in the development of polymeric biomaterials. These biomaterials have to undergo a sterilization procedure before implantation. However, many sterilization procedures have been shown to profoundly affect polymer properties. Poly(ethylene glycol) hydrogels have gained increasing importance in the controlled delivery of therapeutics and in tissue engineering. We evaluated the effect of ethylene oxide (EtO), hydrogen peroxide (H(2)O(2)), and gamma sterilization of poly(ethylene glycol) hydrogels on properties relevant to controlled drug delivery and tissue engineering. We observed that the release of cyclosporine (CyA) (an immunosuppressive drug that is effective in combating tissue rejection following organ transplantation) was significantly affected by the type of sterilization. However, that was not the case with rhodamine B, a dye. Hence, the drug release characteristics were observed to be dependent not only on the sterilization procedure but also on the type of agent that needs to be delivered. In addition, differences in the swelling ratios for the sterilized and unsterilized hydrogels were statistically significant for 1:1 crosslinked hydrogels derived from the 8000 MW polymer. Significant differences were also observed for gamma sterilization for 1:1 crosslinked hydrogels derived from the 3350 MW polymer and also the 2:1 crosslinked hydrogels derived from the 8000 MW polymer. Atomic force microscopy (AFM) studies revealed that the roughness parameter for the unsterilized and EtO-sterilized PEG hydrogels remained similar. However, a statistically significant reduction of the roughness parameter was observed for the H(2)O(2) and gamma-sterilized samples. Electron spin resonance (ESR) studies on the unsterilized and the sterilized samples revealed the presence of the peroxy and the triphenyl methyl carbon radical in the samples. The gamma and the H(2)O(2)-sterilized samples were observed to have a much higher concentration of the radical pecies when compared with the EtO and the unsterilized samples. (c) 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2008.

Degradable Hydrogels and Nanogels for the Delivery of Cells and Therapeutics

NASA Astrophysics Data System (ADS)

Boehnke, Natalie

Degradable polymeric materials such as hydrogels are extensively utilized as delivery vehicles due to their biocompatibility and tunable properties. Encapsulating therapeutic agents inside hydrogels stabilizes the cargo by preventing degradation, extending circulation time, and also allows for targeted release and delivery. Due to their small size and tunable properties, nano-scale hydrogels, or nanogels, are frequently utilized to deliver therapeutics to areas difficult to reach, such as tumors and the cytoplasm, through traditional means. To control hydro- and nanogel function, degradable cross-links can be installed, allowing for cargo release in response to specific stimuli, such as hydrolysis or reduction. This dissertation offers three degradable strategies that can be applied to synthesize hydrogels and nanogels for the stabilization and release of therapeutic cargo. In the first example, mixed imine cross-linking chemistry was applied to synthesize poly(ethylene glycol) (PEG)-based hydrogels with tunable degradability to encapsulate and deliver cells. Time to degradation of the gels could be controlled from 24 hours to more than 7 days by varying the hydrazone structure and the ratio of hydrazone and oxime cross-links. Encapsulated cells exhibited high viability up to at least 7 days, suggesting this system may be useful for cell delivery applications. In the second example, disulfide cross-links were utilized to form redox-responsive nanogels comprised of trehalose copolymers. The synthesis of a methacrylate trehalose monomer (TrMA) was optimized, improving the overall yield from 14% to 42%. TrMA was subsequently copolymerized with pyridyl disulfide ethyl methacrylate (PDSMA) using free radical polymerization conditions to form copolymers with two monomer ratios (1:1 and 2:1) which were cross-linked with 1 kDa PEG-dithiol via disulfide exchange to form uniform nanogels approximately 9 nm in diameter. The addition of a cross-linker eliminated the need to add reducing agent to facilitate cross-linking and nanogel formation, making this approach ideal for the encapsulation of sensitive therapeutic agents. Next, PDSMA-co-TrMA nanogels were utilized to encapsulate, stabilize, and release glucagon, an unstable peptide hormone used to treat hypoglycemia. The amines on glucagon were modified with thiol groups while retaining their positive charges for reversible conjugation and cross-linking. Glucagon-nanogel conjugates were synthesized with >80% conjugation yield, and the reversible disulfide linkage between peptide and polymer allowed for efficient cargo release under mild reducing conditions. The nanogels stabilized glucagon against aggregation in solution up to five days as well as solubilized the peptide at neutral pH. In vitro bioactivity of the modified peptide was found to be comparable to native glucagon, suggesting this may be a promising formulation strategy for further in vivo study. Finally, a series of dual-enzyme responsive peptides was synthesized by masking the epsilon-amine of lysine with protease substrates. After unmasking the amine by enzymatic cleavage, a second enzyme was able to cleave at the C terminus of lysine, which was monitored colorimetrically. Three different dual-enzyme responsive peptides were prepared, (AcAAF)K-pNA, (AcFG)K-pNA, and (AcDEVD)K-pNA, for chymotrypsin, papain, and caspase 3 sensitivity, respectively, followed by trypsin sensitivity after cleavage by the first enzyme. This modular peptide design could be useful for selective drug delivery, studies on dual enzyme activity, as well as for diagnostic enzyme screening.

The effect of desulfation of chondroitin sulfate on interactions with positively charged growth factors and upregulation of cartilaginous markers in encapsulated MSCs.

PubMed

Lim, Jeremy J; Temenoff, Johnna S

2013-07-01

Sulfated glycosaminoglycans (GAGs) are known to interact electrostatically with positively charged growth factors to modulate signaling. Therefore, regulating the degree of sulfation of GAGs may be a promising approach to tailor biomaterial carriers for controlled growth factor delivery and release. For this study, chondroitin sulfate (CS) was first desulfated to form chondroitin, and resulting crosslinked CS and chondroitin hydrogels were examined in vitro for release of positively charged model protein (histone) and for their effect on cartilaginous differentiation of encapsulated human mesenchymal stem cells (MSCs). Desulfation significantly increased the release of histone from chondroitin hydrogels (30.6 ± 2.3 μg released over 8 days, compared to natively sulfated CS with 20.2 ± 0.8 μg), suggesting that sulfation alone plays a significant role in modulating protein interactions with GAG hydrogels. MSCs in chondroitin hydrogels significantly upregulated gene expression of collagen II and aggrecan by day 21 in chondrogenic medium (115 ± 100 and 23.1 ± 7.9 fold upregulation of collagen II and aggrecan, respectively), compared to CS hydrogels and PEG-based swelling controls, indicating that desulfation may actually enhance the response of MSCs to soluble chondrogenic cues, such as TGF-β1. Thus, desulfated chondroitin materials present a promising biomaterial tool to further investigate electrostatic GAG/growth factor interactions, especially for repair of cartilaginous tissues. Copyright © 2013 Elsevier Ltd. All rights reserved.

Synthesis and characterization of injectable, thermosensitive, and biocompatible acellular bone matrix/poly(ethylene glycol)-poly (ε-caprolactone)-poly(ethylene glycol) hydrogel composite.

PubMed

Ni, Pei-Yan; Fan, Min; Qian, Zhi-Yong; Luo, Jing-Cong; Gong, Chang-Yang; Fu, Shao-Zhi; Shi, Shuai; Luo, Feng; Yang, Zhi-Ming

2012-01-01

In orthopedic tissue engineering, the extensively applied acellular bone matrix (ABM) can seldom be prefabricated just right to mold the cavity of the diverse defects, might induce severe inflammation on account of the migration of small granules and usually bring the patients great pain in the treatment. In this study, a new injectable thermosensitive ABM/PECE composite with good biocompatibility was designed and prepared by adding the ABM granules into the triblock copolymer poly(ethylene eglycol)-poly(ε-caprolactone)-poly(ethylene eglycol) (PEG-PCL-PEG, PECE). The PECE was synthesized by ring-opening copolymerization and characterized by ¹H NMR. The ABM was prepared by acellular treatment of natural bone and ground to fine granules. The obtained ABM/PECE composite showed the most important absorption bands of ABM and PECE copolymer in FT-IR spectroscopy and underwent sol-gel phage transition from solution to nonflowing hydrogel at 37°C. SEM results indicated that the ABM/PECE composite with different ABM contents all presented similar porous 3D structure. ABM/PECE composite presented mild cytotoxicity to rat MSCs in vitro and good biocompatibility in the BALB/c mice subcutis up to 4 weeks. In conclusion, all the results confirmed that the injectable thermosensitive ABM/PECE composite was a promising candidate for orthopedic tissue engineering in a minimally-invasive way. Copyright © 2011 Wiley Periodicals, Inc.

Magneto-thermally responsive hydrogels for bladder cancer treatment: Therapeutic efficacy and in vivo biodistribution.

PubMed

Jaiswal, Manish K; Pradhan, Lina; Vasavada, Shaleen; De, Mrinmoy; Sarma, H D; Prakash, Anand; Bahadur, D; Dravid, Vinayak P

2015-12-01

Bladder cancer is one of the deadliest forms of cancer in modern medicine which despite recent progress has remained incurable and challenging for researchers. There is unmet need to address this endemic as the number of patients are growing by about 10,000 every year world-wide. Here, we report a minimally invasive magnetic chemotherapy method to address this problem where polyethylene glycol (PEG) functionalized Fe3O4 magnetic nanostructures (MNS) are homogeneously embedded in thermally responsive poly(N-isopropylacrylamide, NIPAAm) hydrogels (HG). The system (HG-MNS) loaded with anti-cancer drug doxorubicin (DOX) incubated with cancer cell lines subjected to external radiofrequency (RF) field can remotely stimulate the release of drug smartly at the site. The in vitro efficacy investigated on bladder cancer (T-24) cell lines showed the potential of the system in dealing with the disease successfully. Further, the materials preferential accumulation via systemic delivery was studied using swiss mice model. Vital tissue organs like liver, lung and heart were analysed by magnetic resonance imaging (MRI). A detail accounts of the materials optimization, cytotoxicity and anti-proliferation activity tests with apoptosis analysis by flow cytometry after RF exposure (250 kHz) to the cells and in vivo biodistribution data are discussed in the paper. Copyright © 2015 Elsevier B.V. All rights reserved.

Micropatterned Cell–Cell Interactions Enable Functional Encapsulation of Primary Hepatocytes in Hydrogel Microtissues

PubMed Central

Li, Cheri Y.; Stevens, Kelly R.; Schwartz, Robert E.; Alejandro, Brian S.; Huang, Joanne H.

2014-01-01

Drug-induced liver injury is a major cause of drug development failures and postmarket withdrawals. In vitro models that incorporate primary hepatocytes have been shown to be more predictive than model systems which rely on liver microsomes or hepatocellular carcinoma cell lines. Methods to phenotypically stabilize primary hepatocytes ex vivo often rely on mimicry of hepatic microenvironmental cues such as cell–cell interactions and cell–matrix interactions. In this work, we sought to incorporate phenotypically stable hepatocytes into three-dimensional (3D) microtissues, which, in turn, could be deployed in drug-screening platforms such as multiwell plates and diverse organ-on-a-chip devices. We first utilize micropatterning on collagen I to specify cell–cell interactions in two-dimensions, followed by collagenase digestion to produce well-controlled aggregates for 3D encapsulation in polyethylene glycol (PEG) diacrylate. Using this approach, we examined the influence of homotypic hepatocyte interactions and composition of the encapsulating hydrogel, and achieved the maintenance of liver-specific function for over 50 days. Optimally preaggregated structures were subsequently encapsulated using a microfluidic droplet-generator to produce 3D microtissues. Interactions of engineered hepatic microtissues with drugs was characterized by flow cytometry, and yielded both induction of P450 enzymes in response to prototypic small molecules and drug–drug interactions that give rise to hepatotoxicity. Collectively, this study establishes a pipeline for the manufacturing of 3D hepatic microtissues that exhibit stabilized liver-specific functions and can be incorporated into a wide array of emerging drug development platforms. PMID:24498910

Synthesis and characterization of lactose-based homopolymers, hydrophilic/hydrophobic copolymers, and hydrogels

NASA Astrophysics Data System (ADS)

Zhou, Wenjing

The focus of this dissertation is the synthesis and characterization of lactose-based functional polymers. Currently 60% of lactose, a by-product from the cheese industry, is being utilized and the remaining fraction represents a serious disposal problem because of the high biological oxygen demand. Therefore, further development of utilization of lactose is an important issue both for industry and environment. Herein, the syntheses of lactose-based polymers such glycopolymers, hydrophilic/hydrophobic copolymers, and hydrogels are reported. A brief review of lactose formation, physical properties, and production is presented in Chapter 1. Syntheses and applications of lactose derivatives such as lactitol, lactulose, lactaime, lactosylurea, lactosylamine, lactone, and barbituric derivative are documented. Previous work in lactose-based polymers include: (1) hydrogels from cross linking of LPEP, borate complexation of lactose-containing polymer, and copolymerization of lactose monomer with crosslinkers; (2) lactose-based polyurethane rigid foams and adhesives; and (3) lactose-containing glycopolymers are also included. Chapter 2 documents the synthesis of acrylamidolactamine and the free radical copolymerization of this monomer with N-isopropylacrylamide in the presence of BisA to make hydrogels. Swelling behavior of the hydrogels at different temperatures as well as DSC study of these hydrogels are also carried out to characterize the swelling transition and the organization of water in the copolymer hydrogels. In Chapter 3, novel monomer syntheses of N-lactosyl- N'-(4-vinylbenzyl)urea or N '-lactosyl-N,N-methyl(4-vinylbenzyl)urea are described. Polymerization of these new urea monomers using a redox initiator gave water-soluble homopolymers with molecular weights in the range of 1.9 x 103 to 5.3 x 106. Synthesis and polymerization of lactose-O-(p-vinylbenzyl)hydroxime are documented in Chapter 4. The resulting polymers had high molecular weight (106) and narrow polydispersity (Mw/Mn: 1.20--1.35). The Mark-Houwink equation was obtained as [eta] = 2.15 x 10-4Mv0.73. Hydrogels produced in the presence of N,N'-methylenebisacrylamide swelled as much as 21-fold in deionized water. Copolymerization of styrene with lactose-O-(vinylbenzyl)oxime in dimethylsulfoxide-toluene (1:1, v/v) using 2,2'-azobisisobutyronitrile as the initiator are discussed in Chapter 5. The resulting hydrophilic/hydrophobic copolymers were characterized by viscometry, TGA, DSC, GPC, and solubility tests in solvents of varied polarities. Chapter 6 documents the preparation of polystyrene beads with different length of oligo(ethylene glycol) crosslinkers. Swelling in different solvents, solvent accessibility, and reagent diffusion of these beads with different crosslinking density were studied and the results indicated that the PEG-crosslinked polymers showed slightly better solvent accessibility in polar solvents than the analogous DVB-crosslinked networks.

Oral Delivery of Nanoparticles Loaded With Ginger Active Compound, 6-Shogaol, Attenuates Ulcerative Colitis and Promotes Wound Healing in a Murine Model of Ulcerative Colitis.

PubMed

Zhang, Mingzhen; Xu, Changlong; Liu, Dandan; Han, Moon Kwon; Wang, Lixin; Merlin, Didier

2018-01-24

Oral drug delivery is the most attractive pathway for ulcerative colitis [UC] therapy, since it has many advantages. However, this strategy has encountered many challenges, including the instability of drugs in the gastrointestinal tract [GT], low targeting of disease tissues, and severe adverse effects. Nanoparticles capable of colitis tissue-targeted delivery and site-specific drug release may offer a unique and therapeutically effective system that addresses these formidable challenges. We used a versatile single-step surface-functionalising technique to prepare PLGA/PLA-PEG-FA nanoparticles loaded with the ginger active compound, 6-shogaol [NPs-PEG-FA/6-shogaol]. The therapeutic efficacy of NPs-PEG-FA/6-shogaol was evaluated in the well-established mouse model of dextran sulphate sodium [DSS]-induced colitis. NPs-PEG-FA exhibited very good biocompatibility both in vitro and in vivo. Subsequent cellular uptake experiments demonstrated that NPs-PEG-FA could undergo efficient receptor-mediated uptake by colon-26 cells and activated Raw 264.7 macrophage cells. In vivo, oral administration of NPs-PEG-FA/6-shogaol encapsulated in a hydrogel system [chitosan/alginate] significantly alleviated colitis symptoms and accelerated colitis wound repair in DSS-treated mice by regulating the expression levels of pro-inflammatory [TNF-α, IL-6, IL-1β, and iNOS] and anti-inflammatory [Nrf-2 and HO-1] factors. Our study demonstrates a convenient, orally administered 6-shogaol drug delivery system that effectively targets colitis tissue, alleviates colitis symptoms, and accelerates colitis wound repair. This system may represent a promising therapeutic approach for treating inflammatory bowel disease [IBD]. Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com

Design and characterization of tunable hydrogels to examine microenvironmental regulation of breast cancer recurrence

NASA Astrophysics Data System (ADS)

Sawicki, Lisa A.

Late recurrence of breast cancer within distant metastatic tissue sites is often difficult to diagnose and treat, resulting in poor prognosis for patients. It is hypothesized that cells may go dormant by interactions with or lack of adhesion to the extracellular matrix (ECM) within these tissues, which differs from native breast tissue. The metastatic ECM is a complex microenvironment, containing a mixture of mechanical and chemical cues to which cells respond. To investigate how the ECM regulates cancer recurrence, two-dimensional (2D, plates) and three-dimensional (3D, naturally-derived scaffolds) in vitro culture models have been used. However, lack of complexity (2D), mechanical property control (2D, 3D), and chemical property control (3D) makes it challenging to identify key factors involved in regulating dormancy or activation in these systems. The development of synthetic polymer-based scaffolds in recent years provides an alternate route to investigating cellular response to the presentation of microenvironmental cues in 3D. Initially bioinert, these scaffolds may be modified with chemical ligands to permit cell-matrix interactions and their mechanical properties may be precisely tuned to mimic different tissue sites. The goal of this dissertation is to develop and characterize a novel synthetic material for cell culture applications and to examine how physical and chemical factors in this microenvironment regulate breast cancer activation. Specifically, we have developed a novel poly(ethylene glycol) (PEG)-based hydrogel scaffold for in vitro cell culture. PEG modified with thiols and peptides containing alloxycarbonyl-protected lysines (containing a reactive vinyl) react rapidly upon the application of light in the presence of a photoinitiator, lithium acylphosphinate ( minutes). Scaffold mechanical properties are tuned by varying macromer concentration to mimic soft metastatic site tissue ECMs (Young's modulus 600 - 6000 Pa). These properties remain stable during long-term culture ( weeks). We also demonstrate the covalent attachment and spatial presentation of peptides mimicking proteins found within metastatic tissue ECMs in these scaffolds. All cell lines remain viable (>70%) after encapsulation, with many at greater than 90% viability, indicating minimal negative effects of light and radicals on cell survival post-polymerization. While initially well-defined, the properties of synthetic hydrogel scaffolds change as cells secrete soluble factors that permit cell-cell signaling and synthesize new proteins that provide additional binding sites with which cells may interact. To investigate these chemical property changes, we developed a shotgun proteomics technique to isolate and identify large proteins secreted within synthetic, polymer-based hydrogel scaffolds. Metastatic niche cells (adult human mesenchymal stem cells, hMSCs) were cultured within hydrogel scaffolds and large proteins, including fibronectin and collagen VI were identified. Additionally, a bead-based multiplex assay identified several soluble factors secreted by hMSCs (VEGF, IL-8), which may play a role in regulating cell function and fate. Finally, the response and activation of estrogen receptor negative (MDA-MB-231) and estrogen receptor positive (T-47D) breast cancer cells cultured within synthetic hydrogels with discrete mechanical and chemical properties was determined. The highly aggressive MDA-MB-231 cells demonstrated the greatest levels of activation and spread within these synthetic matrices, while T-47D cells, which have been associated with a dormant phenotype, exhibited only minimal response and formed multicellular spheroids. Specifically, hydrogels with high stiffness and matrix density restricted cancer cell growth, resulting in decreased spreading and smaller cell cluster volume. Individual and mixtures of peptides (GFOGER, RGDS, IKVAV) mimicking ECM proteins found within metastatic tissue sites and targeting cell surface receptors were also shown to affect response. GFOGER and RGDS, targeting integrin ?1, among others, resulted in the highest levels of activation observed within microenvironments. Collectively, this work describes the development of a novel material scaffold with well-defined chemical and physical properties that may be used to identify critical factors in metastatic microenvironments that regulate breast cancer activation toward development of new treatments for recurrent cancers.

Biofunctionalized aligned microgels provide 3D cell guidance to mimic complex tissue matrices.

PubMed

Rose, Jonas C; Gehlen, David B; Haraszti, Tamás; Köhler, Jens; Licht, Christopher J; De Laporte, Laura

2018-05-01

Natural healing is based on highly orchestrated processes, in which the extracellular matrix plays a key role. To resemble the native cell environment, we introduce an artificial extracellular matrix (aECM) with the capability to template hierarchical and anisotropic structures in situ, allowing a minimally-invasive application via injection. Synthetic, magnetically responsive, rod-shaped microgels are locally aligned and fixed by a biocompatible surrounding hydrogel, creating a hybrid anisotropic hydrogel (Anisogel), of which the physical, mechanical, and chemical properties can be tailored. The microgels are rendered cell-adhesive with GRGDS and incorporated either inside a cell-adhesive fibrin or bioinert poly(ethylene glycol) hydrogel to strongly interact with fibroblasts. GRGDS-modified microgels inside a fibrin-based Anisogel enhance fibroblast alignment and lead to a reduction in fibronectin production, indicating successful replacement of structural proteins. In addition, YAP-translocation to the nucleus increases with the concentration of microgels, indicating cellular sensing of the overall anisotropic mechanical properties of the Anisogel. For bioinert surrounding PEG hydrogels, GRGDS-microgels are required to support cell proliferation and fibronectin production. In contrast to fibroblasts, primary nerve growth is not significantly affected by the biomodification of the microgels. In conclusion, this approach opens new opportunities towards advanced and complex aECMs for tissue regeneration. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

The Effect of Desulfation of Chondroitin Sulfate on Interactions with Positively Charged Growth Factors and Upregulation of Cartilaginous Markers in Encapsulated MSCs

PubMed Central

Lim, Jeremy J.; Temenoff, Johnna S.

2013-01-01

Sulfated glycosaminoglycans (GAGs) are known to interact electrostatically with positively charged growth factors to modulate signaling. Therefore, regulating the degree of sulfation of GAGs may be a promising approach to tailor biomaterial carriers for controlled growth factor delivery and release. For this study, chondroitin sulfate (CS) was first desulfated to form chondroitin, and resulting crosslinked CS and chondroitin hydrogels were examined in vitro for release of positively charged model protein (histone) and for their effect on cartilaginous differentiation of encapsulated human mesenchymal stem cells (MSCs). Desulfation significantly increased the release of histone from chondroitin hydrogels (30.6±2.3 ìg released over 8 days, compared to natively sulfated CS with 20.2±0.8 ìg), suggesting that sulfation alone plays a significant role in modulating protein interactions with GAG hydrogels. MSCs in chondroitin hydrogels significantly upregulated gene expression of collagen II and aggrecan by day 21 in chondrogenic medium (115±100 and 23.1±7.9 fold upregulation of collagen II and aggrecan, respectively), compared to CS and PEG-based swelling controls, indicating that desulfation may actually enhance the response of MSCs to soluble chondrogenic cues, such as TGF-â1. Thus, desulfated chondroitin materials present a promising biomaterial tool to further investigate electrostatic GAG/growth factor interactions, especially for repair of cartilaginous tissues. PMID:23570717

Tissue engineering approaches for studying the effect of biochemical and physiological stimuli on cell behavior

NASA Astrophysics Data System (ADS)

Jimenez Vergara, Andrea Carolina

Tissue engineering (TE) approaches have emerged as an alternative to traditional tissue and organ replacements. The aim of this work was to contribute to the understanding of the effects of cell-material and endothelial cell (EC) paracrine signaling on cell responses using poly(ethylene glycol) diacrylate (PEGDA) hydrogels as a material platform. Three TE applications were explored. First, the effect of glycosaminoglycan (GAG) identity was evaluated for vocal fold restoration. Second, the influence of GAG identity was explored and a novel approach for stable endothelialization was developed for vascular graft applications. Finally, EC paracrine signaling in the presence of cyclic stretch, and hydrophobicity and inorganic content were studied for osteogenic applications. In terms of vocal fold restoration, it was found that vocal fold fibroblast (VFF) phenotype and extracellular matrix (ECM) production were impacted by GAG identity. VFF phenotype was preserved in long-term cultured hydrogels containing high molecular weight hyaluronan (HAHMW). Furthermore, collagen I deposition, fibronectin production and smooth muscle α-actin (SM-α-actin) expression in PEG-HA, PEG-chondroitin sulfate C and PEG-heparan sulfate (HS) gels suggest that CSC and HS may be undesirable for vocal fold implants. Regarding vascular graft applications, the impact of GAG identity on smooth muscle cell (SMC) foam cell formation was explored. Results support the increasing body of literature that suggests a critical role for dermatan sulfate (DS)-bearing proteoglycans in early atherosclerosis. In addition, an approach for fabricating bi-layered tissue engineering vascular grafts (TEVGs) with stable endothelialization was validated using PEGDA as an intercellular “cementing” agent between adjacent endothelial cells (ECs). Finally, mesenchymal stem cell (MSC) differentiation toward osteogenic like cells was evaluated. ECM and cell phenotypic data showed that elevated scaffold inorganic content and hydrophobicity were indeed correlated with increased osteogenic differentiation. Moreover, the present results suggest that EC paracrine signaling enhances MSC osteogenesis in the presence of cyclic stretch.

Continuous gradient scaffolds for rapid screening of cell-material interactions and interfacial tissue regeneration

PubMed Central

Bailey, Brennan M.; Nail, Lindsay N.; Grunlan, Melissa A.

2013-01-01

In tissue engineering, the physical and chemical properties of the scaffold mediates cell behavior including regeneration. Thus, a strategy that permits rapid screening of cell-scaffold interactions is critical. Herein, we have prepared eight “hybrid” hydrogel scaffolds in the form of continuous gradients such that a single scaffold contains spatially varied properties. These scaffolds are based on combining an inorganic macromer [methacrylated star polydimethylsiloxane, PDMSstar-MA] and organic macromer [poly(ethylene glycol)diacrylate, PEG-DA] as well both aqueous and organic fabrication solvents. Having previously demonstrated its bioactivity and osteoinductivity, PDMSstar-MA is a particularly powerful component to incorporate into instructive gradient scaffolds based on PEG-DA. The following parameters were varied to produce the different gradients or gradual transitions in: (1) the wt% ratio of PDMSstar-MA to PEG-DA macromers, (2) the total wt% macromer concentration, (3) the number average molecular weight (Mn) of PEG-DA and (4) the Mn of PDMSstar-MA. Upon dividing each scaffold into four “zones” perpendicular to the gradient, we were able to demonstrate the spatial variation in morphology, bioactivity, swelling and modulus. Among these gradient scaffolds are those in which swelling and modulus are conveniently decoupled. In addition to rapid screening of cell-material interactions, these scaffolds are well-suited for regeneration of interfacial tissues (e.g. osteochondral tissues) that transition from one tissue type to another. PMID:23707502

Deciphering the Combinatorial Roles of Geometric, Mechanical, and Adhesion Cues in Regulation of Cell Spreading

PubMed Central

Harris, Greg M.; Shazly, Tarek; Jabbarzadeh, Ehsan

2013-01-01

Significant effort has gone towards parsing out the effects of surrounding microenvironment on macroscopic behavior of stem cells. Many of the microenvironmental cues, however, are intertwined, and thus, further studies are warranted to identify the intricate interplay among the conflicting downstream signaling pathways that ultimately guide a cell response. In this contribution, by patterning adhesive PEG (polyethylene glycol) hydrogels using Dip Pen Nanolithography (DPN), we demonstrate that substrate elasticity, subcellular elasticity, ligand density, and topography ultimately define mesenchymal stem cells (MSCs) spreading and shape. Physical characteristics are parsed individually with 7 kilopascal (kPa) hydrogel islands leading to smaller, spindle shaped cells and 105 kPa hydrogel islands leading to larger, polygonal cell shapes. In a parallel effort, a finite element model was constructed to characterize and confirm experimental findings and aid as a predictive tool in modeling cell microenvironments. Signaling pathway inhibition studies suggested that RhoA is a key regulator of cell response to the cooperative effect of the tunable substrate variables. These results are significant for the engineering of cell-extra cellular matrix interfaces and ultimately decoupling matrix bound cues presented to cells in a tissue microenvironment for regenerative medicine. PMID:24282570

Novel cryomilled physically cross-linked biodegradable hydrogel microparticles as carriers for inhalation therapy.

PubMed

El-Sherbiny, I M; Smyth, H D C

2010-01-01

In this study, novel biodegradable physically cross-linked hydrogel microparticles were developed and evaluated in-vitro as potential carriers for inhalation therapy. These hydrogel microparticles were prepared to be respirable (desired aerodynamic size) when dry and also designed to avoid the macrophage uptake (attain large swollen size once deposited in lung). The swellable microparticles, prepared using cryomilling, were based on Pluronic® F-108 in combination with PEG grafted onto both chitosan (Cs) and its N-phthaloyl derivative (NPHCs). Polymers synthesized in the study were characterized using EA, FTIR, 2D-XRD and DSC. Morphology, particle size, density, biodegradation and moisture content of the microparticles were quantified. Swelling characteristics for both drug-free and drug-loaded microparticles showed excellent size increases (between 700-1300%) and the release profiles indicated sustained release could be achieved for up to 20 days. The respirable microparticles showed drug loading efficiency up to 92%. The enzymatic degradation of developed microparticles started within the first hour and only ∼10% weights were remaining after 10 days. In conclusion, these respirable microparticles demonstrated promising in-vitro performance for potential sustained release vectors in pulmonary drug delivery.

Effect of Immobilized Antithrombin III on the Thromboresistance of Polycarbonate Urethane.

PubMed

Lukas, Karin; Stadtherr, Karin; Gessner, Andre; Wehner, Daniel; Schmid, Thomas; Wendel, Hans Peter; Schmid, Christof; Lehle, Karla

2017-03-24

The surface of foils and vascular grafts made from a thermoplastic polycarbonate urethanes (PCU) (Chronoflex AR) were chemically modified using gas plasma treatment, binding of hydrogels-(1) polyethylene glycol bisdiamine and carboxymethyl dextran (PEG-DEX) and (2) polyethyleneimine (PEI)-and immobilization of human antithrombin III (AT). Their biological impact was tested in vitro under static and dynamic conditions. Static test methods showed a significantly reduced adhesion of endothelial cells, platelets, and bacteria, compared to untreated PCU. Modified PCU grafts were circulated in a Chandler-Loop model for 90 min at 37 °C with human blood. Before and after circulation, parameters of the hemostatic system (coagulation, platelets, complement, and leukocyte activation) were analyzed. PEI-AT significantly inhibited the activation of both coagulation and platelets and prevented the activation of leukocytes and complement. In conclusion, both modifications significantly reduce coagulation activation, but only PEI-AT creates anti-bacterial and anti-thrombogenic functionality.

Holographic lithography for biomedical applications

NASA Astrophysics Data System (ADS)

Stankevicius, E.; Balciunas, E.; Malinauskas, M.; Raciukaitis, G.; Baltriukiene, D.; Bukelskiene, V.

2012-06-01

Fabrication of scaffolds for cell growth with appropriate mechanical characteristics is top-most important for successful creation of tissue. Due to ability of fast fabrication of periodic structures with a different period, the holographic lithography technique is a suitable tool for scaffolds fabrication. The scaffolds fabricated by holographic lithography can be used in various biomedical investigations such as the cellular adhesion, proliferation and viability. These investigations allow selection of the suitable material and geometry of scaffolds which can be used in creation of tissue. Scaffolds fabricated from di-acrylated poly(ethylene glycol) (PEG-DA-258) over a large area by holographic lithography technique are presented in this paper. The PEG-DA scaffolds fabricated by holographic lithography showed good cytocompatibility for rabbit myogenic stem cells. It was observed that adult rabbit muscle-derived myogenic stem cells grew onto PEG-DA scaffolds. They were attached to the pillars and formed cell-cell interactions. It demonstrates that the fabricated structures have potential to be an interconnection channel network for cell-to-cell interactions, flow transport of nutrients and metabolic waste as well as vascular capillary ingrowth. These results are encouraging for further development of holographic lithography by improving its efficiency for microstructuring three-dimensional scaffolds out of biodegradable hydrogels

ReSure Sealant for Pars Plana Vitrectomy Wound Closure.

PubMed

Ho, Vincent Y; Shah, Gaurav K; Liu, Enchun M

2015-01-01

ReSure Sealant (Ocular Therapeutix, Bedford, MA) is an ocular sealant that demonstrated both safety and effectiveness in a prospective, randomized clinical trial for sealing clear corneal incisions following cataract surgery and intraocular lens placement in adults.1 PATIENTS AND METHODS: This is the first literature report of ReSure Sealant used for the closure of 23-gauge (G) pars plana vitrectomy (PPV) sclerotomies. A 70-year-old pseudophakic female with a history of epiretinal membrane and branch retinal vein occlusion of the right eye underwent 23-G PPV, membrane peel, and air-fluid exchange and was found to have leaking subconjunctival air at the end of the case. A linear conjunctival incision was performed to access the sclerotomy site. The incisions were then carefully dried before the sealant was applied to seal both the sclera and conjunctiva. After polymerization, the sealant formed a polyethylene glycol (PEG) hydrogel that was 89% water and 9.44% PEG. PEG is a synthetic material that is non-toxic and inert and, thus, suitable for use in medical products. ReSure Sealant may be a safe, quick method to close sclerotomy wounds in select cases. [ Copyright 2015, SLACK Incorporated.

Effect of the Addition of a Labile Gelatin Component on the Degradation and Solute Release Kinetics of a Stable PEG Hydrogel

PubMed Central

Waldeck, H.; Kao, W. J.

2013-01-01

Characterization of the degradation mechanisms and resulting products of biodegradable materials is critical in understanding the behavior of the material including solute transport and biological response. Previous mathematical analyses of a semi-interpenetrating network (sIPN) containing both labile gelatin and a stable cross-linked poly(ethylene glycol) (PEG) network found that diffusion-based models alone were unable to explain the release kinetics of solutes from the system. In this study, degradation of the sIPN and its effect on solute release and swelling kinetics were investigated. The kinetics of the primary mode of degradation, gelatin dissolution, was dependent on temperature, preparation methods, PEGdA and gelatin concentration, and the weight ratio between the gelatin and PEG. The gelatin dissolution rate positively correlated with both matrix swelling and the release kinetics of high-molecular-weight model compound, FITC-dextran. Coupled with previous in vitro studies, the kinetics of sIPN degradation provided insights into the time-dependent changes in cellular response including adhesion and protein expression. These results provide a facile guide in material formulation to control the delivery of high-molecular-weight compounds with concomitant modulation of cellular behavior. PMID:21801489

Electrochemical immunoassay for tumor markers based on hydrogels.

PubMed

Yin, Shuang; Ma, Zhanfang

2018-05-08

Hydrogel-based electrochemical immunoassays exhibit a large surface-to-volume ratio, excellent biocompatibility, unique stimuli-responsive behavior, high permeability and hydrophilicity and, thus, have shown great potential in the sensitive and accurate detection of tumor markers. Electrochemical immunosensing techniques for tumor markers based on hydrogels have greatly progressed in recent years. Areas covered: In this review, the authors describe the recent advances of hydrogel-based electrochemical immunosensing interface of tumor markers based on the different functions of hydrogels including conductive, catalytic, redox, stimuli-responsive and antifouling hydrogels. Expert commentary: Hydrogels have been successfully employed in electrochemical immunoassay of tumor markers, which is accountable to their unique properties. For further exploitation of hydrogel-based electrochemical biosensors, more variety of hydrogels need be fabricated with improved functionality.

Foamed oligo(poly(ethylene glycol)fumarate) hydrogels as versatile prefabricated scaffolds for tissue engineering.

PubMed

Henke, Matthias; Baumer, Julia; Blunk, Torsten; Tessmar, Joerg

2014-03-01

Radically cross-linked hydrogels are frequently used as cell carriers due to their excellent biocompatibility and their tissue-like mechanical properties. Through frequent investigation, PEG-based polymers such as oligo(poly(ethylene glycol)fumarate [OPF] have proven to be especially suitable as cell carriers by encapsulating cells during hydrogel formation. In some cases, NaCl or biodegradable gelatin microparticles were added prior to cross-linking in order to provide space for the proliferating cells, which would otherwise stay embedded in the hydrogel matrix. However, all of these immediate cross-linking procedures involve time consuming sample preparation and sterilization directly before cell culture and often show notable swelling after their preparation. In this study, ready to use OPF-hydrogel scaffolds were prepared by gas foaming, freeze drying, individual packing into bags and subsequent γ-sterilization. The scaffolds could be stored and used "off-the-shelf" without any need for further processing prior to cell culture. Thus the handling was simplified and the sterility of the cell carrier was assured. Further improvement of the gel system was achieved using a two component injectable system, which may be used for homogenous injection molding in order to create individually shaped three dimensional scaffolds. In order to evaluate the suitability of the scaffolds for tissue engineering, constructs were seeded with juvenile bovine chondrocytes and cultured for 28 days. Cross-sections of the respective constructs showed an intense and homogenous red staining of GAG with safranin O, indicating a homogenous cell distribution within the scaffolds and the production of substantial amounts of GAG-rich matrix. Copyright © 2012 John Wiley & Sons, Ltd.

Structural analysis of binding functionality of folic acid-PEG dendrimers against folate receptor.

PubMed

Sampogna-Mireles, Diana; Araya-Durán, Ingrid D; Márquez-Miranda, Valeria; Valencia-Gallegos, Jesús A; González-Nilo, Fernando D

2017-03-01

Dendrimers functionalized with folic acid (FA) are drug delivery systems that can selectively target cancer cells with folate receptors (FR-α) overexpression. Incorporation of polyethylene glycol (PEG) can enhance dendrimers solubility and pharmacokinetics, but ligand-receptor binding must not be affected. In this work we characterized, at atomic level, the binding functionality of conventional site-specific dendrimers conjugated with FA with PEG 750 or PEG 3350 as a linker. After Molecular Dynamics simulation, we observed that both PEG's did not interfere over ligand-receptor binding functionality. Although binding kinetics could be notably affected, the folate fragment from both dendrimers remained exposed to the solvent before approaching selectively to FR-α. PEG 3350 provided better solubility and protection from enzymatic degradation to the dendrimer than PEG 750. Also, FA-PEG3350 dendrimer showed a slightly better interaction with FR-α than FA-PEG750 dendrimer. Therefore, theoretical evidence supports that both dendrimers are suitable as drug delivery systems for cancer therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Laccase-assisted formation of bioactive chitosan/gelatin hydrogel stabilized with plant polyphenols.

PubMed

Rocasalbas, Guillem; Francesko, Antonio; Touriño, Sonia; Fernández-Francos, Xavier; Guebitz, Georg M; Tzanov, Tzanko

2013-02-15

Laccase-assisted simultaneous cross-linking and functionalization of chitosan/gelatin blends with phenolic compounds from Hamamelis virginiana was investigated for the development of bioactive hydrogel dressings. The potential of these hydrogels for chronic wound treatment was evaluated in vitro, assessing their antibacterial and inhibitory effect on myeloperoxidase and collagenase. Rheological studies revealed that the mechanical properties of the hydrogels were a function of the enzymatic reaction time. Stable hydrogels and resistant to lysozyme degradation were achieved after 2 h laccase reaction. The inhibitory capacity of the hydrogel for myeloperoxidase and collagenase was 32% and 79% respectively after 24 h incubation. Collagenase activity was additionally suppressed by adsorption (20%) of the enzyme onto the hydrogel. Therefore, the bioactive properties of the hydrogels were due to the effect of both released phenolic compounds and the permanently functionalized platform itself. The hydrogels showed antibacterial activity against Pseudomonas aeruginosa and Staphylococcus aureus. Copyright © 2012 Elsevier Ltd. All rights reserved.

Tailoring vessel morphology in vivo

NASA Astrophysics Data System (ADS)

Gould, Daniel Joseph

Tissue engineering is a rapidly growing field which seeks to provide alternatives to organ transplantation in order to address the increasing need for transplantable tissues. One huge hurdle in this effort is the provision of thick tissues; this hurdle exists because currently there is no way to provide prevascularized or rapidly vascularizable scaffolds. To design thick, vascularized tissues, scaffolds are needed that can induce vessels which are similar to the microvasculature found in normal tissues. Angiogenic biomaterials are being developed to provide useful scaffolds to address this problem. In this thesis angiogenic and cell signaling and adhesion factors were incorporated into a biomimetic poly(ethylene glycol) (PEG) hydrogel system. The composition of these hydrogels was precisely tuned to induce the formation of differing vessel morphology. To sensitively measure induced microvascular morphology and to compare it to native microvessels in several tissues, this thesis developed an image-based tool for quantification of scale invariant and classical measures of vessel morphology. The tool displayed great utility in the comparison of native vessels and remodeling vessels in normal tissues. To utilize this tool to tune the vessel response in vivo, Flk1::myr-mCherry fluorescently labeled mice were implanted with Platelet Derived Growth Factor-BB (PDGF-BB) and basic Fibroblast Growth Factor (FGF-2) containing PEG-based hydrogels in a modified mouse corneal angiogenesis assay. Resulting vessels were imaged with confocal microscopy, analyzed with the image based tool created in this thesis to compare morphological differences between treatment groups, and used to create a linear relationship between space filling parameters and dose of growth factor release. Morphological parameters of native mouse tissue vessels were then compared to the linear fit to calculate the dose of growth factors needed to induce vessels similar in morphology to native vessels. Resulting induced vessels did match in morphology to the target vessels. Several other covalently bound signals were then analyzed in the assay and resulting morphology of vessels was compared in several studies which further highlighted the utility of the micropocket assay in conjunction with the image based tool for vessel morphological quantification. Finally, an alternative method to provide rapid vasculature to the constructs, which relied on pre-seeded hydrogels encapsulated endothelial cells was also developed and shown to allow anastamosis between induced host vessels and the implanted construct within 48 hours. These results indicate great promise in the rational design of synthetic, bioactive hydrogels, which can be used as a platform to study microvascular induction for regenerative medicine and angiogenesis research. Future applications of this research may help to develop therapeutic strategies to ameliorate human disease by replacing organs or correcting vessel morphology in the case of ischemic diseases and cancer.

Incorporating functionalized polyethylene glycol lipids into reprecipitated conjugated polymer nanoparticles for bioconjugation and targeted labeling of cells

NASA Astrophysics Data System (ADS)

Kandel, Prakash K.; Fernando, Lawrence P.; Ackroyd, P. Christine; Christensen, Kenneth A.

2011-03-01

We report a simple and rapid method to prepare extremely bright, functionalized, stable, and biocompatible conjugated polymer nanoparticles incorporating functionalized polyethylene glycol (PEG) lipids by reprecipitation. These nanoparticles retain the fundamental spectroscopic properties of conjugated polymer nanoparticles prepared without PEG lipid, but demonstrate greater hydrophilicity and quantum yield compared to unmodified conjugated polymer nanoparticles. The sizes of these nanoparticles, as determined by TEM, were 21-26 nm. Notably, these nanoparticles were prepared with several PEG lipid functional end groups, including biotin and carboxy moieties that can be easily conjugated to biomolecules. We have demonstrated the availability of these end groups for functionalization using the interaction of biotin PEG lipid conjugated polymer nanoparticles with streptavidin. Biotinylated PEG lipid conjugated polymer nanoparticles bound streptavidin-linked magnetic beads, while carboxy and methoxy PEG lipid modified nanoparticles did not. Similarly, biotinylated PEG lipid conjugated polymer nanoparticles bound streptavidin-coated glass slides and could be visualized as diffraction-limited spots, while nanoparticles without PEG lipid or with non-biotin PEG lipid end groups were not bound. To demonstrate that nanoparticle functionalization could be used for targeted labelling of specific cellular proteins, biotinylated PEG lipid conjugated polymer nanoparticles were bound to biotinylated anti-CD16/32 antibodies on J774A.1 cell surface receptors, using streptavidin as a linker. This work represents the first demonstration of targeted delivery of conjugated polymer nanoparticles and demonstrates the utility of these new nanoparticles for fluorescence based imaging and sensing.We report a simple and rapid method to prepare extremely bright, functionalized, stable, and biocompatible conjugated polymer nanoparticles incorporating functionalized polyethylene glycol (PEG) lipids by reprecipitation. These nanoparticles retain the fundamental spectroscopic properties of conjugated polymer nanoparticles prepared without PEG lipid, but demonstrate greater hydrophilicity and quantum yield compared to unmodified conjugated polymer nanoparticles. The sizes of these nanoparticles, as determined by TEM, were 21-26 nm. Notably, these nanoparticles were prepared with several PEG lipid functional end groups, including biotin and carboxy moieties that can be easily conjugated to biomolecules. We have demonstrated the availability of these end groups for functionalization using the interaction of biotin PEG lipid conjugated polymer nanoparticles with streptavidin. Biotinylated PEG lipid conjugated polymer nanoparticles bound streptavidin-linked magnetic beads, while carboxy and methoxy PEG lipid modified nanoparticles did not. Similarly, biotinylated PEG lipid conjugated polymer nanoparticles bound streptavidin-coated glass slides and could be visualized as diffraction-limited spots, while nanoparticles without PEG lipid or with non-biotin PEG lipid end groups were not bound. To demonstrate that nanoparticle functionalization could be used for targeted labelling of specific cellular proteins, biotinylated PEG lipid conjugated polymer nanoparticles were bound to biotinylated anti-CD16/32 antibodies on J774A.1 cell surface receptors, using streptavidin as a linker. This work represents the first demonstration of targeted delivery of conjugated polymer nanoparticles and demonstrates the utility of these new nanoparticles for fluorescence based imaging and sensing. Electronic supplementary information (ESI) available: Additional TEM data, supplemental light scattering measurements, absorbance and fluorescence emission spectra, and photostability measurements. See DOI: 10.1039/c0nr00746c

Continuous gradient scaffolds for rapid screening of cell-material interactions and interfacial tissue regeneration.

PubMed

Bailey, Brennan M; Nail, Lindsay N; Grunlan, Melissa A

2013-09-01

In tissue engineering, the physical and chemical properties of the scaffold mediates cell behavior, including regeneration. Thus a strategy that permits rapid screening of cell-scaffold interactions is critical. Herein, we have prepared eight "hybrid" hydrogel scaffolds in the form of continuous gradients such that a single scaffold contains spatially varied properties. These scaffolds are based on combining an inorganic macromer (methacrylated star polydimethylsiloxane, PDMSstar-MA) and organic macromer (poly(ethylene glycol)diacrylate, PEG-DA) as well as both aqueous and organic fabrication solvents. Having previously demonstrated its bioactivity and osteoinductivity, PDMSstar-MA is a particularly powerful component to incorporate into instructive gradient scaffolds based on PEG-DA. The following parameters were varied to produce the different gradients or gradual transitions in: (1) the wt.% ratio of PDMSstar-MA to PEG-DA macromers, (2) the total wt.% macromer concentration, (3) the number average molecular weight (Mn) of PEG-DA and (4) the Mn of PDMSstar-MA. Upon dividing each scaffold into four "zones" perpendicular to the gradient, we were able to demonstrate the spatial variation in morphology, bioactivity, swelling and modulus. Among these gradient scaffolds are those in which swelling and modulus are conveniently decoupled. In addition to rapid screening of cell-material interactions, these scaffolds are well suited for regeneration of interfacial tissues (e.g. osteochondral tissues) that transition from one tissue type to another. Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Synthesis, characterization and application in biomedicine of a novel chondroitin sulfate based hydrogel and bioadhesive

NASA Astrophysics Data System (ADS)

Strehin, Iossif

Clinically, there exists a need for adhesive biomaterials. There is room to improve upon what is currently on the market as it is either too toxic, lacks the required adhesive strength and/or lacks the desired degradation properties. The general goals of this thesis all focused on designing a biomaterial which would improve upon these shortcomings while at the same time allow for modifications to meet the needs for the specific application of interest. To accomplish this task, it was important to choose the appropriate composition and crosslinking chemistry which will allow the most flexibility. Chondroitin sulfate (CS) was chosen as the principle component of the hydrogel because it is a ubiquitous glycosaminoglycan (GAG) found in almost all tissues in the body. Many variants of CS exist with each one possessing unique biological activity allowing for tight control over these properties of the material. To modulate cell migration through the adhesive, polyethylene glycol (PEG) or blood was used as the second constituent. The former made the scaffold act as a cell barrier while the ladder could be used in varying concentrations to modulate cell adhesion and migration into the biomaterial. Also, the CS and blood components are both biodegradable and degradation can be controlled using various methods. While the constituents were chosen to allow flexibility in the biological activity and cell migration into the scaffold, the crosslinking chemistry was chosen to allow control over the mechanical properties as well as to increase tissue adhesion. By functionalizing the carboxyl groups of the GAG with N-hydroxysuccinimide (NHS), the resulting chondroitin sulfate succinimidyl succinate (CS-NHS) molecule could react with primary amines on polymers to form a hydrogel as well as the primary amines on proteins comprising tissue to anchor the hydrogel to the tissue. The material has been characterized and optimized for several applications. The applications described here include sealing of corneal wounds following cataract surgery, wound healing of the skin, and chondrogenic differentiation of hMSCs for treatment of arthritic conditions. In these applications, the CS based adhesive has shown considerable promise.

Microfluidic hydrogels for tissue engineering.

PubMed

Huang, Guo You; Zhou, Li Hong; Zhang, Qian Cheng; Chen, Yong Mei; Sun, Wei; Xu, Feng; Lu, Tian Jian

2011-03-01

With advanced properties similar to the native extracellular matrix, hydrogels have found widespread applications in tissue engineering. Hydrogel-based cellular constructs have been successfully developed to engineer different tissues such as skin, cartilage and bladder. Whilst significant advances have been made, it is still challenging to fabricate large and complex functional tissues due mainly to the limited diffusion capability of hydrogels. The integration of microfluidic networks and hydrogels can greatly enhance mass transport in hydrogels and spatiotemporally control the chemical microenvironment of cells, mimicking the function of native microvessels. In this review, we present and discuss recent advances in the fabrication of microfluidic hydrogels from the viewpoint of tissue engineering. Further development of new hydrogels and microengineering technologies will have a great impact on tissue engineering.

Hybrid lipid-based nanostructures

NASA Astrophysics Data System (ADS)

Dayani, Yasaman

Biological membranes serve several important roles, such as structural support of cells and organelles, regulation of ionic and molecular transport, barriers to non-mediated transport, contact between cells within tissues, and accommodation of membrane proteins. Membrane proteins and other vital biomolecules incorporated into the membrane need a lipid membrane to function. Due to importance of lipid bilayers and their vital function in governing many processes in the cell, the development of various models as artificial lipid membranes that can mimic cell membranes has become a subject of great interest. Using different models of artificial lipid membranes, such as liposomes, planar lipid bilayers and supported or tethered lipid bilayers, we are able to study many biophysical processes in biological membranes. The ability of different molecules to interact with and change the structure of lipid membranes can be also investigated in artificial lipid membranes. An important application of lipid bilayer-containing interfaces is characterization of novel membrane proteins for high throughput drug screening studies to investigate receptor-drug interactions and develop biosensor systems. Membrane proteins need a lipid bilayer environment to preserve their stability and functionality. Fabrication of materials that can interact with biomolecules like proteins necessitates the use of lipid bilayers as a mimic of cell membranes. The objective of this research is to develop novel hybrid lipid-based nanostructures mimicking biological membranes. Toward this aim, two hybrid biocompatible structures are introduced: lipid bilayer-coated multi-walled carbon nanotubes (MWCNTs) and hydrogel-anchored liposomes with double-stranded DNA anchors. These structures have potential applications in biosensing, drug targeting, drug delivery, and biophysical studies of cell membranes. In the first developed nanostructure, lipid molecules are covalently attached to the surfaces of MWCNTs, and then, using a sonication process, a uniform lipid bilayer that supports the incorporation of membrane proteins is formed. These bilayer-coated carbon nanotubes are highly dispersible and stable in aqueous solution, and they can be used in development of various biosensors and energy producing devices. In the other hybrid nanostructure, the lipid bilayer of a liposome is covalently anchored to a biocompatible poly(ethylene) glycol (PEG) hydrogel core using double-stranded DNA (dsDNA) linkers. Release studies shows that nano-size hydrogel-anchored liposomes are exceptionally stable, and they can be used as biomimetic model membranes that mimic the connectivity between the cytoskeleton and the plasma membrane. After lipid bilayer removal, dsDNA linkers can provide programmable nanogels decorated with oligonucleotides with potential sites for further molecular assembly. These stable nanostructures can be useful for oligonucleotide and drug delivery applications. The developed hydrogel-anchored liposomes are exploited for encapsulation and intracellular delivery of therapeutic peptide. Peptides with anti-cancer properties are successfully encapsulated in hydrogel core of pH-sensitive liposomes during rehydration process. Liposomes release their cargo at acidic pH. Confocal microscopy confirms the intracellular delivery of liposomes through an endocytotic pathway.

Polyamidoamine dendrimer hydrogel for enhanced delivery of antiglaucoma drugs.

PubMed

Holden, Christopher A; Tyagi, Puneet; Thakur, Ashish; Kadam, Rajendra; Jadhav, Gajanan; Kompella, Uday B; Yang, Hu

2012-07-01

Dendrimer hydrogel (DH), made from ultraviolet-cured polyamidoamine dendrimer G3.0 tethered with three polyethylene glycol (PEG, 12,000 Da)-acrylate chains (8.1% w/v) in pH 7.4 phosphate buffered saline (PBS), was studied for the delivery of brimonidine (0.1% w/v) and timolol maleate (0.5% w/v), two antiglaucoma drugs. DH was found to be mucoadhesive to mucin particles and nontoxic to human corneal epithelial cells. DH increased the PBS solubility of brimonidine by 77.6% and sustained the in vitro release of both drugs over 56-72 hours. As compared to eye drop formulations (PBS-drug solutions), DH brought about substantially higher human corneal epithelial cells uptake and significantly increased bovine corneal transport for both drugs. DH increased timolol maleate uptake in bovine corneal epithelium, stroma, and endothelium by 0.4- to 4.6-fold. This work demonstrated that DH can enhance the delivery of antiglaucoma drugs in multiple aspects and represents a novel platform for ocular drug delivery. Dendrimer hydrogel was studied as agent for simultaneous delivery of two anti-glaucoma drugs, one hydrophobic and one hydrophilic. Superiority over standard PBS-based formulation was clearly demonstrated for both drugs. The work may be a novel platform for ocular drug delivery. Copyright © 2012 Elsevier Inc. All rights reserved.

A Drosera-bioinspired hydrogel for catching and killing cancer cells

PubMed Central

Li, Shihui; Chen, Niancao; Gaddes, Erin R.; Zhang, Xiaolong; Dong, Cheng; Wang, Yong

2015-01-01

A variety of bioinspired materials have been successfully synthesized to mimic the sophisticated structures or functions of biological systems. However, it is still challenging to develop materials with multiple functions that can be performed synergistically or sequentially. The purpose of this work was to demonstrate a novel bioinspired hydrogel that can interact with cancer cells, functionally similar to Drosera in catching and killing prey. This hydrogel had two layers with the top one functionalized with oligonucleotide aptamers and the bottom one functionalized with double-stranded DNA. The results show that the top hydrogel layer was able to catch target cells with high efficiency and specificity, and that the bottom hydrogel layer could sequester doxorubicin (Dox) for sustained drug release. Importantly, the released Dox could kill 90% of the cells after 1-h residence of the cells on the hydrogel. After the cell release, this bifunctional hydrogel could be regenerated for continuous cell catching and killing. Therefore, the data presented in this study has successfully demonstrated the potential of developing a material system with the functions of attracting, catching and killing diseased cells (e.g., circulating tumor cells) or even invading microorganisms (e.g., bacteria). PMID:26396063

Dual-Functional Hydrazide-Reactive and Anhydride-Containing Oligomeric Hydrogel Building Blocks.

PubMed

Kascholke, Christian; Loth, Tina; Kohn-Polster, Caroline; Möller, Stephanie; Bellstedt, Peter; Schulz-Siegmund, Michaela; Schnabelrauch, Matthias; Hacker, Michael C

2017-03-13

Biomimetic hydrogels are advanced biomaterials that have been developed following different synthetic routes. Covalent postfabrication functionalization is a promising strategy to achieve efficient matrix modification decoupled of general material properties. To this end, dual-functional macromers were synthesized by free radical polymerization of maleic anhydride with diacetone acrylamide (N-(1,1-dimethyl-3-oxobutyl)acrylamide) and pentaerythritol diacrylate monostearate. Amphiphilic oligomers (M n < 7.5 kDa) with anhydride contents of 7-20% offered cross-linking reactivity to yield rigid hydrogels with gelatinous peptides (E = 4-13 kPa) and good cell adhesion properties. Mildly reactive methyl ketones as second functionality remained intact during hydrogel formation and potential of covalent matrix modification was shown using hydrazide and hydrazine model compounds. Successful secondary dihydrazide cross-linking was demonstrated by an increase of hydrogel stiffness (>40%). Efficient hydrazide/hydrazine immobilization depending on solution pH, hydrogel ketone content as well as ligand concentration for bioconjugation was shown and reversibility of hydrazone formation was indicated by physiologically relevant hydrazide release over 7 days. Proof-of-concept experiments with hydrazido-functionalized hyaluronan demonstrated potential for covalent aECM immobilization. The presented dual-functional macromers have perspective as reactive hydrogel building blocks for various biomedical applications.

Hydrophilic polyurethane matrix promotes chondrogenesis of mesenchymal stem cells☆

PubMed Central

Nalluri, Sandeep M.; Krishnan, G. Rajesh; Cheah, Calvin; Arzumand, Ayesha; Yuan, Yuan; Richardson, Caley A.; Yang, Shuying; Sarkar, Debanjan

2016-01-01

Segmental polyurethanes exhibit biphasic morphology and can control cell fate by providing distinct matrix guided signals to increase the chondrogenic potential of mesenchymal stem cells (MSCs). Polyethylene glycol (PEG) based hydrophilic polyurethanes can deliver differential signals to MSCs through their matrix phases where hard segments are cell-interactive domains and PEG based soft segments are minimally interactive with cells. These coordinated communications can modulate cell–matrix interactions to control cell shape and size for chondrogenesis. Biphasic character and hydrophilicity of polyurethanes with gel like architecture provide a synthetic matrix conducive for chondrogenesis of MSCs, as evidenced by deposition of cartilage-associated extracellular matrix. Compared to monophasic hydrogels, presence of cell interactive domains in hydrophilic polyurethanes gels can balance cell–cell and cell–matrix interactions. These results demonstrate the correlation between lineage commitment and the changes in cell shape, cell–matrix interaction, and cell–cell adhesion during chondrogenic differentiation which is regulated by polyurethane phase morphology, and thus, represent hydrophilic polyurethanes as promising synthetic matrices for cartilage regeneration. PMID:26046282

Skin-inspired hydrogel-elastomer hybrids with robust interfaces and functional microstructures

NASA Astrophysics Data System (ADS)

Yuk, Hyunwoo; Zhang, Teng; Parada, German Alberto; Liu, Xinyue; Zhao, Xuanhe

2016-06-01

Inspired by mammalian skins, soft hybrids integrating the merits of elastomers and hydrogels have potential applications in diverse areas including stretchable and bio-integrated electronics, microfluidics, tissue engineering, soft robotics and biomedical devices. However, existing hydrogel-elastomer hybrids have limitations such as weak interfacial bonding, low robustness and difficulties in patterning microstructures. Here, we report a simple yet versatile method to assemble hydrogels and elastomers into hybrids with extremely robust interfaces (interfacial toughness over 1,000 Jm-2) and functional microstructures such as microfluidic channels and electrical circuits. The proposed method is generally applicable to various types of tough hydrogels and diverse commonly used elastomers including polydimethylsiloxane Sylgard 184, polyurethane, latex, VHB and Ecoflex. We further demonstrate applications enabled by the robust and microstructured hydrogel-elastomer hybrids including anti-dehydration hydrogel-elastomer hybrids, stretchable and reactive hydrogel-elastomer microfluidics, and stretchable hydrogel circuit boards patterned on elastomer.

Enzymatic regulation of functional vascular networks using gelatin hydrogels

PubMed Central

Chuang, Chia-Hui; Lin, Ruei-Zeng; Tien, Han-Wen; Chu, Ya-Chun; Li, Yen-Cheng; Melero-Martin, Juan M.; Chen, Ying-Chieh

2015-01-01

To manufacture tissue engineering-based functional tissues, scaffold materials that can be sufficiently vascularized to mimic the functionality and complexity of native tissues are needed. Currently, vascular network bioengineering is largely carried out using natural hydrogels as embedding scaffolds, but most natural hydrogels have poor mechanical stability and durability, factors that critically limit their widespread use. In this study, we examined the suitability of gelatin-phenolic hydroxyl (gelatin-Ph) hydrogels that can be enzymatically crosslinked, allowing tuning of the storage modulus and the proteolytic degradation rate, for use as injectable hydrogels to support the human progenitor cell-based formation of a stable and mature vascular network. Porcine gelatin-Ph hydrogels were found to be cytocompatible with human blood-derived endothelial colony-forming cells and white adipose tissue-derived mesenchymal stem cells, resulting in >87% viability, and cell proliferation and spreading could be modulated by using hydrogels with different proteolytic degradability and stiffness. In addition, gelatin was extracted from mouse dermis and murine gelatin-Ph hydrogels were prepared. Importantly, implantation of human cell-laden porcine or murine gelatin-Ph hydrogels into immunodeficient mice resulted in the rapid formation of functional anastomoses between the bioengineered human vascular network and the mouse vasculature. Furthermore, the degree of enzymatic crosslinking of the gelatin-Ph hydrogels could be used to modulate cell behavior and the extent of vascular network formation in vivo. Our report details a technique for the synthesis of gelatin-Ph hydrogels from allogeneic or xenogeneic dermal skin and suggests that these hydrogels can be used for biomedical applications that require the formation of microvascular networks, including the development of complex engineered tissues. PMID:25749296

Effect of DSPE-PEG on compound action potential, injury potential and ion concentration following compression in ex vivo spinal cord.

PubMed

Wang, Aihua; Huo, Xiaolin; Zhang, Guanghao; Wang, Xiaochen; Zhang, Cheng; Wu, Changzhe; Rong, Wei; Xu, Jing; Song, Tao

2016-05-04

It has been shown that polyethylene glycol (PEG) can reseal membrane disruption on the spinal cord, but only high concentrations of PEG have been shown to have this effect. Therefore, the effect of PEG is somewhat limited, and it is necessary to investigate a new approach to repair spinal cord injury. This study assesses the ability of 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(poly (ethylene glycol)) 2000] (DSPE-PEG) to recover physiological function and attenuate the injury-induced influx of extracellular ions in ex vivo spinal cord injury. Isolated spinal cords were subjected to compression injury and treated with PEG or DSPE-PEG immediately after injury. The compound action potential (CAP) was recorded before and after injury to assess the functional recovery. Furthermore, injury potential, the difference in gap potentials before and after compression, and the concentration of intracellular ions were used to evaluate the effect of DSPE-PEG on reducing ion influx. Data showed that the injury potential and ion concentration of the untreated, PEG and DSPE-PEG group, without significant difference among them, are remarkably higher than those of the intact group. Moreover, the CAP recovery of the DSPE-PEG and PEG treated spinal cords was significantly greater than that of the untreated spinal cords. The level of CAP recovery in the DSPE-PEG and PEG treated groups was the same, but the concentration of DSPE-PEG used was much lower than the concentration of PEG. These results suggest that instant application of DSPE-PEG could effectively repair functional disturbance in SCI at a much lower concentration than PEG. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Mussel-inspired fabrication of konjac glucomannan/microcrystalline cellulose intelligent hydrogel with pH-responsive sustained release behavior.

PubMed

Wang, Lin; Du, Yu; Yuan, Yi; Mu, Ruo-Jun; Gong, Jingni; Ni, Yongsheng; Pang, Jie; Wu, Chunhua

2018-07-01

Intelligent hydrogels are attractive biomaterials for various applications, however, fabricating a hydrogel with both adequate self-healing ability and mechanical properties remains a challenge. Herein, a series of novel intelligent konjac glucomannan (KGM)/microcrystalline cellulose (MCC) hydrogels were prepared vis the mussel-inspired chemistry. MCC was firstly functionalized by the oxidative polymerization of dopamine, and the intelligent hydrogels were obtained by mixing aqueous solutions of KGM and functionalized MCC (PDMCC). By introducing PDMCC, a more compact interconnected porous structure formed for the resulting hydrogels. The self-healing ability and mechanical properties of intelligent hydrogels were dependence on the PDMCC content. Compared with KGM hydrogels, KGM/PDMCC hydrogels exhibited a more distinct pH sensitivity and a lower initial burst release, which was attributed to the compact structure and strong intermolecular hydrogen bond interaction between PDMCC and KGM. These results suggest that the KGM/PDMCC intelligent hydrogels may be promising carriers for controlled drug delivery. Copyright © 2018 Elsevier B.V. All rights reserved.

PNA-PEG modified silicon platforms as functional bio-interfaces for applications in DNA microarrays and biosensors.

PubMed

Cattani-Scholz, Anna; Pedone, Daniel; Blobner, Florian; Abstreiter, Gerhard; Schwartz, Jeffrey; Tornow, Marc; Andruzzi, Luisa

2009-03-09

The synthesis and characterization of two types of silicon-based biofunctional interfaces are reported; each interface bonds a dense layer of poly(ethylene glycol) (PEG(n)) and peptide nucleic acid (PNA) probes. Phosphonate self-assembled monolayers were derivatized with PNA using a maleimido-terminated PEG(45). Similarly, siloxane monolayers were functionalized with PNA using a maleimido-terminated PEG(45) spacer and were subsequently modified with a shorter methoxy-terminated PEG(12) ("back-filling"). The long PEG(45) spacer was used to distance the PNA probe from the surface and to minimize undesirable nonspecific adsorption of DNA analyte. The short PEG(12) "back-filler" was used to provide additional passivation of the surface against nonspecific DNA adsorption. X-ray photoelectron spectroscopic (XPS) analysis near the C 1s and N 1s ionization edges was done to characterize chemical groups formed in the near-surface region, which confirmed binding of PEG and PNA to the phosphonate and silane films. XPS also indicated that additional PEG chains were tethered to the surface during the back-filling process. Fluorescence hybridization experiments were carried out with complementary and noncDNA strands; both phosphonate and siloxane biofunctional surfaces were effective for hybridization of cDNA strands and significantly reduced nonspecific adsorption of the analyte. Spatial patterns were prepared by polydimethylsiloxane (PDMS) micromolding on the PNA-functionalized surfaces; selective hybridization of fluorescently labeled DNA was shown at the PNA functionalized regions, and physisorption at the probe-less PEG-functionalized regions was dramatically reduced. These results show that PNA-PEG derivatized phosphonate monolayers hold promise for the smooth integration of device surface chemistry with semiconductor technology for the fabrication of DNA biosensors. In addition, our results confirm that PNA-PEG derivatized self-assembled carboxyalkylsiloxane films are promising substrates for DNA microarray applications.

Plasma-mediated grafting of poly(ethylene glycol) on polyamide and polyester surfaces and evaluation of antifouling ability of modified substrates.

PubMed

Dong, Baiyan; Jiang, Hongquan; Manolache, Sorin; Wong, Amy C Lee; Denes, Ferencz S

2007-06-19

A simple cold plasma technique was developed to functionalize the surfaces of polyamide (PA) and polyester (PET) for the grafting of polyethylene glycol (PEG) with the aim of reducing biofilm formation. The surfaces of PA and PET were treated with silicon tetrachloride (SiCl4) plasma, and PEG was grafted onto plasma-functionalized substrates (PA-PEG, PET-PEG). Different molecular weights of PEG and grafting times were tested to obtain optimal surface coverage by PEG as monitored by electron spectroscopy for chemical analysis (ESCA). The presence of a predominant C-O peak on the PEG-modified substrates indicated that the grafting was successful. Data from hydroxyl group derivatization and water contact angle measurement also indicated the presence of PEG after grafting. The PEG-grafted PA and PET under optimal conditions had similar chemical composition and hydrophilicity; however, different morphology changes were observed after grafting. Both PA-PEG and PET-PEG surfaces developed under optimal plasma conditions showed about 96% reduction in biofilm formation by Listeria monocytogenes compared with that of the corresponding unmodified substrates. This plasma functionalization method provided an efficient way to graft PEG onto PA and PET surfaces. Because of the high reactivity of Si-Cl species, this method could potentially be applied to other polymeric materials.

Structural and functional consequences of antigenic modulation of red blood cells with methoxypoly(ethylene glycol).

PubMed

Murad, K L; Mahany, K L; Brugnara, C; Kuypers, F A; Eaton, J W; Scott, M D

1999-03-15

We previously showed that the covalent modification of the red blood cell (RBC) surface with methoxypoly(ethylene glycol) [mPEG; MW approximately 5 kD] could significantly attenuate the immunologic recognition of surface antigens. However, to make these antigenically silent RBC a clinically viable option, the mPEG-modified RBC must maintain normal cellular structure and functions. To this end, mPEG-derivatization was found to have no significant detrimental effects on RBC structure or function at concentrations that effectively blocked antigenic recognition of a variety of RBC antigens. Importantly, RBC lysis, morphology, and hemoglobin oxidation state were unaffected by mPEG-modification. Furthermore, as shown by functional studies of Band 3, a major site of modification, PEG-binding does not affect protein function, as evidenced by normal SO4- flux. Similarly, Na+ and K+ homeostasis were unaffected. The functional aspects of the mPEG-modified RBC were also maintained, as evidenced by normal oxygen binding and cellular deformability. Perhaps most importantly, mPEG-derivatized mouse RBC showed normal in vivo survival ( approximately 50 days) with no sensitization after repeated transfusions. These data further support the hypothesis that the covalent attachment of nonimmunogenic materials (eg, mPEG) to intact RBC may have significant application in transfusion medicine, especially for the chronically transfused and/or allosensitized patient.

Influence of Different ECM-Like Hydrogels on Neurite Outgrowth Induced by Adipose Tissue-Derived Stem Cells

PubMed Central

Oliveira, E.; Assunção-Silva, R. C.; Teixeira, F. G.

2017-01-01

Mesenchymal stem cells (MSCs) have been proposed for spinal cord injury (SCI) applications due to their capacity to secrete growth factors and vesicles—secretome—that impacts important phenomena in SCI regeneration. To improve MSC survival into SCI sites, hydrogels have been used as transplantation vehicles. Herein, we hypothesized if different hydrogels could interact differently with adipose tissue-derived MSCs (ASCs). The efficacy of three natural hydrogels, gellan gum (functionalized with a fibronectin peptide), collagen, and a hydrogel rich in laminin epitopes (NVR-gel) in promoting neuritogenesis (alone and cocultured with ASCs), was evaluated in the present study. Their impact on ASC survival, metabolic activity, and gene expression was also evaluated. Our results indicated that all hydrogels supported ASC survival and viability, being this more evident for the functionalized GG hydrogels. Moreover, the presence of different ECM-derived biological cues within the hydrogels appears to differently affect the mRNA levels of growth factors involved in neuronal survival, differentiation, and axonal outgrowth. All the hydrogel-based systems supported axonal growth mediated by ASCs, but this effect was more robust in functionalized GG. The data herein presented highlights the importance of biological cues within hydrogel-based biomaterials as possible modulators of ASC secretome and its effects for SCI applications. PMID:29333166

A glucose-sensitive block glycopolymer hydrogel based on dynamic boronic ester bonds for insulin delivery.

PubMed

Cai, Baoqi; Luo, Yanping; Guo, Qianqian; Zhang, Xinge; Wu, Zhongming

2017-06-05

Hydrogels are good candidates to satisfy many needs for functional and tunable biomaterials. How to precisely control the gel structure and functions is crucial for the construction of sophisticated soft biomaterials comprising the hydrogels, which facilitates the impact of the surrounding environment on a unique biological function occurring. Here, glucose-responsive hydrogels comprised of 3-acrylamidophenyl boronic acid copolymerized with 2-lactobionamidoethyl methacrylate (p(APBA-b-LAMA)) were synthesized, and further evaluated as carriers for insulin delivery. The formation of (p(APBA-b-LAMA)) hydrogel was based on dynamic covalent bond using the association of boronic acid with diols. P(APBA-b-LAMA) hydrogel with the typical porous structure showed a rapid increase in equilibrium of swelling, which was up to 1856% after incubation with aqueous solution. Using insulin as a model protein therapeutic, p(APBA-b-LAMA) hydrogel exhibited high drug loading capability up to 15.6%, and also displayed glucose-dependent insulin release under physiological conditions. Additionally, the viability of NIH3T3 cells was more than 90% after treated with p(APBA-b-LAMA) hydrogel, indicating that the hydrogel had no cytotoxicity. Consequently, the novel p(APBA-b-LAMA) hydrogel has a practical application for diabetes treatment. Copyright © 2017. Published by Elsevier Ltd.

A comparative study on collagen type I and hyaluronic acid dependent cell behavior for osteochondral tissue bioprinting.

PubMed

Park, Ju Young; Choi, Jong-Cheol; Shim, Jin-Hyung; Lee, Jung-Seob; Park, Hyoungjun; Kim, Sung Won; Doh, Junsang; Cho, Dong-Woo

2014-09-01

Bioprinting is a promising technique for engineering composite tissues, such as osteochondral tissues. In this study, as a first step toward bioprinting-based osteochondral tissue regeneration, we systematically examined the behavior of chondrocytes and osteoblasts to hyaluronic acid (HA) and type I collagen (Col-1) hydrogels. First, we demonstrated that cells on hydrogels that were comprised of major native tissue extracellular matrix (ECM) components (i.e. chondrocytes on HA hydrogels and osteoblasts on Col-1 hydrogels) exhibited better proliferation and cell function than cells on non-native ECM hydrogels (i.e., chondrocytes on Col-1 hydrogels and osteoblasts on HA hydrogels). In addition, cells located near their native ECM hydrogels migrated towards them. Finally, we bioprinted three-dimensional (3D) osteochondral tissue-mimetic structures composed of two compartments, osteoblast-encapsulated Col-1 hydrogels and chondrocyte-encapsulated HA hydrogels, and found viability and functions of each cell type were well maintained within the 3D structures up to 14 days in vitro. These results suggest that with proper choice of hydrogel materials, bioprinting-based approaches can be successfully applied for osteochondral tissue regeneration.

Platelet-Rich Plasma-Loaded Poly(d,l-lactide)-Poly(ethylene glycol)-Poly(d,l-lactide) Hydrogel Dressing Promotes Full-Thickness Skin Wound Healing in a Rodent Model

PubMed Central

Qiu, Manle; Chen, Daoyun; Shen, Chaoyong; Shen, Ji; Zhao, Huakun; He, Yaohua

2016-01-01

Traditional therapeutic methods for skin wounds have many disadvantages, and new wound dressings that can facilitate the healing process are thus urgently needed. Platelet-rich plasma (PRP) contains multiple growth factors (GFs) and shows a significant capacity to heal soft tissue wounds. However, these GFs have a short half-life and deactivate rapidly; we therefore need a sustained delivery system to overcome this shortcoming. In this study, poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PDLLA-PEG-PDLLA: PLEL) hydrogel was successfully created as delivery vehicle for PRP GFs and was evaluated systematically. PLEL hydrogel was injectable at room temperature and exhibited a smart thermosensitive in situ gel-formation behavior at body temperature. In vitro cell culture showed PRP-loaded PLEL hydrogel (PRP/PLEL) had little cytotoxicity, and promoted EaHy926 proliferation, migration and tube formation; the factor release assay additionally indicated that PLEL realized the controlled release of PRP GFs for as long as 14 days. When employed to treat rodents’ full-thickness skin defects, PRP/PLEL showed a significantly better ability to raise the number of both newly formed and mature blood vessels compared to the control, PLEL and PRP groups. Furthermore, the PRP/PLEL-treated group displayed faster wound closure, better reepithelialization and collagen formation. Taken together, PRP/PLEL provides a promising strategy for promoting angiogenesis and skin wound healing, which extends the potential of this dressing for clinical application. PMID:27347938

Functionalized graphene hydrogel-based high-performance supercapacitors.

PubMed

Xu, Yuxi; Lin, Zhaoyang; Huang, Xiaoqing; Wang, Yang; Huang, Yu; Duan, Xiangfeng

2013-10-25

Functionalized graphene hydrogels are prepared by a one-step low-temperature reduction process and exhibit ultrahigh specific capacitances and excellent cycling stability in the aqueous electrolyte. Flexible solid-state supercapacitors based on functionalized graphene hydrogels are demonstrated with superior capacitive performances and extraordinary mechanical flexibility. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Raman scattering studies on PEG functionalized hydroxyapatite nanoparticles

NASA Astrophysics Data System (ADS)

Yamini, D.; Devanand Venkatasubbu, G.; Kumar, J.; Ramakrishnan, V.

2014-01-01

The pure hydroxyapatite (HAP) nanoparticles (NPs) have been synthesized by wet chemical precipitation method. Raman spectral measurements have been made for pure HAP, pure Polyethylene glycol (PEG) 6000 and PEG coated HAP in different mass ratios (sample 1, sample 2 and sample 3). The peaks observed in Raman spectrum of pure HAP and the XRD pattern have confirmed the formation of HAP NPs. Vibrational modes have been assigned for pure HAP and pure PEG 6000. The observed variation in peak position of Raman active vibrational modes of PEG in PEG coated HAP has been elucidated in this work, in terms of intermolecular interactions between PEG and HAP. Further these results suggest that the functionalization of nanoparticles may be independent of PEG mass.

Programmable hydrogels.

PubMed

Wang, Yong

2018-03-05

Programmable hydrogels are defined as hydrogels that are able to change their properties and functions periodically, reversibly and/or sequentially on demand. They are different from those responsive hydrogels whose changes are passive or cannot be stopped or reversed once started and vice versa. The purpose of this review is to summarize major progress in developing programmable hydrogels from the viewpoints of principles, functions and biomedical applications. The principles are first introduced in three categories including biological, chemical and physical stimulation. With the stimulation, programmable hydrogels can undergo functional changes in dimension, mechanical support, cell attachment and molecular sequestration, which are introduced in the middle of this review. The last section is focused on the introduction and discussion of four biomedical applications including mechanistic studies in mechanobiology, tissue engineering, cell separation and protein delivery. Copyright © 2018 Elsevier Ltd. All rights reserved.

Hydrogels from biopolymer hybrid for biomedical, food, and functional food applications

USDA-ARS?s Scientific Manuscript database

Hybrid hydrogels from biopolymers have been applied for various indications across a wide range of biomedical, pharmaceutical, and functional food industries. In particular, hybrid hydrogels synthesized from two biopolymers have attracted increasing attention. The inclusion of a second biopolymer st...

Bioprinting Cartilage Tissue from Mesenchymal Stem Cells and PEG Hydrogel.

PubMed

Gao, Guifang; Hubbell, Karen; Schilling, Arndt F; Dai, Guohao; Cui, Xiaofeng

2017-01-01

Bioprinting based on thermal inkjet printing is one of the most attractive enabling technologies for tissue engineering and regeneration. During the printing process, cells, scaffolds , and growth factors are rapidly deposited to the desired two-dimensional (2D) and three-dimensional (3D) locations. Ideally, the bioprinted tissues are able to mimic the native anatomic structures in order to restore the biological functions. In this study, a bioprinting platform for 3D cartilage tissue engineering was developed using a commercially available thermal inkjet printer with simultaneous photopolymerization . The engineered cartilage demonstrated native zonal organization, ideal extracellular matrix (ECM ) composition, and proper mechanical properties. Compared to the conventional tissue fabrication approach, which requires extended UV exposure, the viability of the printed cells with simultaneous photopolymerization was significantly higher. Printed neocartilage demonstrated excellent glycosaminoglycan (GAG) and collagen type II production, which was consistent with gene expression profile. Therefore, this platform is ideal for anatomic tissue engineering with accurate cell distribution and arrangement.

Hydraulic hydrogel actuators and robots optically and sonically camouflaged in water

PubMed Central

Yuk, Hyunwoo; Lin, Shaoting; Ma, Chu; Takaffoli, Mahdi; Fang, Nicolas X.; Zhao, Xuanhe

2017-01-01

Sea animals such as leptocephali develop tissues and organs composed of active transparent hydrogels to achieve agile motions and natural camouflage in water. Hydrogel-based actuators that can imitate the capabilities of leptocephali will enable new applications in diverse fields. However, existing hydrogel actuators, mostly osmotic-driven, are intrinsically low-speed and/or low-force; and their camouflage capabilities have not been explored. Here we show that hydraulic actuations of hydrogels with designed structures and properties can give soft actuators and robots that are high-speed, high-force, and optically and sonically camouflaged in water. The hydrogel actuators and robots can maintain their robustness and functionality over multiple cycles of actuations, owing to the anti-fatigue property of the hydrogel under moderate stresses. We further demonstrate that the agile and transparent hydrogel actuators and robots perform extraordinary functions including swimming, kicking rubber-balls and even catching a live fish in water. PMID:28145412

Composites of Polymer Hydrogels and Nanoparticulate Systems for Biomedical and Pharmaceutical Applications

PubMed Central

Zhao, Fuli; Yao, Dan; Guo, Ruiwei; Deng, Liandong; Dong, Anjie; Zhang, Jianhua

2015-01-01

Due to their unique structures and properties, three-dimensional hydrogels and nanostructured particles have been widely studied and shown a very high potential for medical, therapeutic and diagnostic applications. However, hydrogels and nanoparticulate systems have respective disadvantages that limit their widespread applications. Recently, the incorporation of nanostructured fillers into hydrogels has been developed as an innovative means for the creation of novel materials with diverse functionality in order to meet new challenges. In this review, the fundamentals of hydrogels and nanoparticles (NPs) were briefly discussed, and then we comprehensively summarized recent advances in the design, synthesis, functionalization and application of nanocomposite hydrogels with enhanced mechanical, biological and physicochemical properties. Moreover, the current challenges and future opportunities for the use of these promising materials in the biomedical sector, especially the nanocomposite hydrogels produced from hydrogels and polymeric NPs, are discussed. PMID:28347111

Hydraulic hydrogel actuators and robots optically and sonically camouflaged in water.

PubMed

Yuk, Hyunwoo; Lin, Shaoting; Ma, Chu; Takaffoli, Mahdi; Fang, Nicolas X; Zhao, Xuanhe

2017-02-01

Sea animals such as leptocephali develop tissues and organs composed of active transparent hydrogels to achieve agile motions and natural camouflage in water. Hydrogel-based actuators that can imitate the capabilities of leptocephali will enable new applications in diverse fields. However, existing hydrogel actuators, mostly osmotic-driven, are intrinsically low-speed and/or low-force; and their camouflage capabilities have not been explored. Here we show that hydraulic actuations of hydrogels with designed structures and properties can give soft actuators and robots that are high-speed, high-force, and optically and sonically camouflaged in water. The hydrogel actuators and robots can maintain their robustness and functionality over multiple cycles of actuations, owing to the anti-fatigue property of the hydrogel under moderate stresses. We further demonstrate that the agile and transparent hydrogel actuators and robots perform extraordinary functions including swimming, kicking rubber-balls and even catching a live fish in water.

Hydraulic hydrogel actuators and robots optically and sonically camouflaged in water

NASA Astrophysics Data System (ADS)

Yuk, Hyunwoo; Lin, Shaoting; Ma, Chu; Takaffoli, Mahdi; Fang, Nicolas X.; Zhao, Xuanhe

2017-02-01

Sea animals such as leptocephali develop tissues and organs composed of active transparent hydrogels to achieve agile motions and natural camouflage in water. Hydrogel-based actuators that can imitate the capabilities of leptocephali will enable new applications in diverse fields. However, existing hydrogel actuators, mostly osmotic-driven, are intrinsically low-speed and/or low-force; and their camouflage capabilities have not been explored. Here we show that hydraulic actuations of hydrogels with designed structures and properties can give soft actuators and robots that are high-speed, high-force, and optically and sonically camouflaged in water. The hydrogel actuators and robots can maintain their robustness and functionality over multiple cycles of actuations, owing to the anti-fatigue property of the hydrogel under moderate stresses. We further demonstrate that the agile and transparent hydrogel actuators and robots perform extraordinary functions including swimming, kicking rubber-balls and even catching a live fish in water.

Stimuli-Responsive DNA-Based Hydrogels: From Basic Principles to Applications.

PubMed

Kahn, Jason S; Hu, Yuwei; Willner, Itamar

2017-04-18

The base sequence of nucleic acids encodes structural and functional information into the DNA biopolymer. External stimuli such as metal ions, pH, light, or added nucleic acid fuel strands provide triggers to reversibly switch nucleic acid structures such as metal-ion-bridged duplexes, i-motifs, triplex nucleic acids, G-quadruplexes, or programmed double-stranded hybrids of oligonucleotides (DNA). The signal-triggered oligonucleotide structures have been broadly applied to develop switchable DNA nanostructures and DNA machines, and these stimuli-responsive assemblies provide functional scaffolds for the rapidly developing area of DNA nanotechnology. Stimuli-responsive hydrogels undergoing signal-triggered hydrogel-to-solution transitions or signal-controlled stiffness changes attract substantial interest as functional matrices for controlled drug delivery, materials exhibiting switchable mechanical properties, acting as valves or actuators, and "smart" materials for sensing and information processing. The integration of stimuli-responsive oligonucleotides with hydrogel-forming polymers provides versatile means to exploit the functional information encoded in the nucleic acid sequences to yield stimuli-responsive hydrogels exhibiting switchable physical, structural, and chemical properties. Stimuli-responsive DNA-based nucleic acid structures are integrated in acrylamide polymer chains and reversible, switchable hydrogel-to-solution transitions of the systems are demonstrated by applying external triggers, such as metal ions, pH-responsive strands, G-quadruplex, and appropriate counter triggers that bridge and dissociate the polymer chains. By combining stimuli-responsive nucleic acid bridges with thermosensitive poly(N-isopropylacrylamide) (pNIPAM) chains, systems undergoing reversible solution ↔ hydrogel ↔ solid transitions are demonstrated. Specifically, by bridging acrylamide polymer chains by two nucleic acid functionalities, where one type of bridging unit provides a stimuli-responsive element and the second unit acts as internal "bridging memory", shape-memory hydrogels undergoing reversible and switchable transitions between shaped hydrogels and shapeless quasi-liquid states are demonstrated. By using stimuli-responsive hydrogel cross-linking units that can assemble the bridging units by two different input signals, the orthogonally-triggered functions of the shape-memory were shown. Furthermore, a versatile approach to assemble stimuli-responsive DNA-based acrylamide hydrogel films on surfaces is presented. The method involves the activation of the hybridization chain-reaction (HCR) by a surface-confined promoter strand, in the presence of acrylamide chains modified with two DNA hairpin structures and appropriate stimuli-responsive tethers. The resulting hydrogel-modified surfaces revealed switchable stiffness properties and signal-triggered catalytic functions. By applying the method to assemble the hydrogel microparticles, substrate-loaded, stimuli-responsive microcapsules are prepared. The signal-triggered DNA-based hydrogel microcapsules are applied as drug carriers for controlled release. The different potential applications and future perspectives of stimuli responsive hydrogels are discussed. Specifically, the use of these smart materials and assemblies as carriers for controlled drug release and as shape-memory matrices for information storage and inscription and the use of surface-confined stimuli-responsive hydrogels, exhibiting switchable stiffness properties, for catalysis and controlled growth of cells are discussed.

Adaptable Hydrogel Networks with Reversible Linkages for Tissue Engineering

PubMed Central

Wang, Huiyuan

2015-01-01

Adaptable hydrogels have recently emerged as a promising platform for three-dimensional (3D) cell encapsulation and culture. In conventional, covalently crosslinked hydrogels, degradation is typically required to allow complex cellular functions to occur, leading to bulk material degradation. In contrast, adaptable hydrogels are formed by reversible crosslinks. Through breaking and re-forming of the reversible linkages, adaptable hydrogels can be locally modified to permit complex cellular functions while maintaining their long-term integrity. In addition, these adaptable materials can have biomimetic viscoelastic properties that make them well suited for several biotechnology and medical applications. In this review, adaptable hydrogel design considerations and linkage selections are overviewed, with a focus on various cell compatible crosslinking mechanisms that can be exploited to form adaptable hydrogels for tissue engineering. PMID:25989348

In vitro model alveoli from photodegradable microsphere templates†

PubMed Central

Lewis, Katherine J. R.; Tibbitt, Mark W.; Zhao, Yi; Branchfield, Kelsey; Sun, Xin; Balasubramaniam, Vivek; Anseth, Kristi S.

2016-01-01

Recreating the 3D cyst-like architecture of the alveolar epithelium in vitro has been challenging to achieve in a controlled fashion with primary lung epithelial cells. Here, we demonstrate model alveoli formed within a tunable synthetic biomaterial platform using photodegradable microspheres as templates to create physiologically relevant, cyst structures. Poly(ethylene glycol) (PEG)-based hydrogels were polymerized in suspension to form microspheres on the order of 120 μm in diameter. The gel chemistry was designed to allow erosion of the microspheres with cytocompatible light doses (≤15 min exposure to 10 mW cm−2 of 365 nm light) via cleavage of a photolabile nitrobenzyl ether crosslinker. Epithelial cells were incubated with intact microspheres, modified with adhesive peptide sequences to facilitate cellular attachment to and proliferation on the surface. A tumor-derived alveolar epithelial cell line, A549, completely covered the microspheres after only 24 hours, whereas primary mouse alveolar epithelial type II (ATII) cells took ~3 days. The cell-laden microsphere structures were embedded within a second hydrogel formulation at user defined densities; the microsphere templates were subsequently removed with light to render hollow epithelial cysts that were cultured for an additional 6 days. The resulting primary cysts stained positive for cell–cell junction proteins (β-catenin and ZO-1), indicating the formation of a functional epithelial layer. Typically, primary ATII cells differentiated in culture to the alveolar epithelial type I (ATI) phenotype; however, each cyst contained ~1–5 cells that stained positive for an ATII marker (surfactant protein C), which is consistent with ATII cell numbers in native mouse alveoli. This biomaterial-templated alveoli culture system should be useful for future experiments to study lung development and disease progression, and is ideally suited for co-culture experiments where pulmonary fibroblasts or endothelial cells could be presented in the hydrogel surrounding the epithelial cysts. PMID:26221842

Dextran hydrogels by crosslinking with amino acid diamines and their viscoelastic properties.

PubMed

O'Connor, Naphtali A; Jitianu, Mihaela; Nunez, Greisly; Picard, Quentin; Wong, Madeline; Akpatsu, David; Negrin, Adam; Gharbaran, Rajendra; Lugo, Daniel; Shaker, Sundus; Jitianu, Andrei; Redenti, Stephen

2018-05-01

Amine functionalized polysaccharide hydrogels such as those based on chitosan are widely examined as biomaterials. Here we set out to develop a facile procedure for developing such hydrogels by crosslinking dextran with amino acid diamines. The dextran-amino acid gels were formed by the addition of the amino acid diamines to a dextran and epichlorohydrin solution once it became homogeneous. This was demonstrated with three amino acid diamines, lysine, lysine methyl ester, and cystine dimethyl ester. Hydrogel networks with albumin entrapped were also demonstrated. These hydrogels were characterized by FTIR, SEM, rotational rheometry, swelling studies and cell biocompatibility analysis. These hydrogels showed the unexpected pH-responsive behavior of greater swelling at more basic pH, similar to that of an anionic hydrogel. This is uncharacteristic for amine functionalized gels as they typically exhibit cationic hydrogel behavior. All hydrogels showed similar biocompatibility to that of dextran crosslinked without amino acids. Copyright © 2018 Elsevier B.V. All rights reserved.

Elective gastrostomy, nutritional status and quality of life in advanced head and neck cancer patients receiving chemoradiotherapy.

PubMed

Morton, Randall P; Crowder, Victoria L; Mawdsley, Robert; Ong, Esther; Izzard, Mark

2009-10-01

Chemoradiotherapy for treatment of advanced head and neck cancer (HNC) is used to achieve organ preservation without compromising survival. Because chemoradiotherapy usually impacts adversely on nutritional and functional status, feeding by percutaneous endoscopic gastrostomy (PEG) is often part of the management regimen for these patients, but the presence of a PEG tube can also be associated with reduced quality of life (QOL). This study aimed to examine the factors associated with PEG insertion and the effects of PEG use on QOL and functional outcomes in HNC patients receiving chemoradiotherapy. Survey of 36 consecutive patients treated by primary chemoradiotherapy for HNC. Patient weight, age, tumour type, details of PEG insertion, feeding regimens and treatment were noted. The survey comprised the Performance Status Scale, the Functional Measure for Swallowing, Nutritional Mode and a self-assessment of QOL. PEG insertion within 1 month of treatment was associated with smaller fall in body mass index at 12 months than PEG insertion 1 month or more after the start of the treatment (P < 0.05). Body mass index change was inversely correlated with health-related quality of life and significantly related to lower speech and swallowing function scores. Longer PEG duration correlated with poorer performance status and swallowing function (P < 0.01). Longer PEG duration also predicted poorer overall QOL (P < 0.01) and poorer swallowing (P < 0.01) and speech (P < 0.05). Nutritional mode was related to overall QOL (P < 0.01). Nutritional support for HNC patients undergoing chemoradiotherapy is an essential component of patient care. Early PEG insertion and shorter PEG duration are associated with more favourable QOL-related outcomes.

Functionalized core-shell hydrogel microsprings by anisotropic gelation with bevel-tip capillary

PubMed Central

Yoshida, Koki; Onoe, Hiroaki

2017-01-01

This study describes a novel microfluidic-based method for the synthesis of hydrogel microsprings that are capable of encapsulating various functional materials. A continuous flow of alginate pre-gel solution can spontaneously form a hydrogel microspring by anisotropic gelation around the bevel-tip of the capillary. This technique allows fabrication of hydrogel microsprings using only simple capillaries and syringe pumps, while their complex compartmentalization characterized by a laminar flow inside the capillary can contribute to the optimization of the microspring internal structure and functionality. Encapsulation of several functional materials including magnetic-responsive nanoparticles or cell dispersed collagen for tissue scaffold was demonstrated to functionalize the microsprings. Our core-shell hydrogel microsprings have immense potential for application in a number of fields, including biological/chemical microsensors, biocompatible soft robots/microactuators, drug release, self-assembly of 3D structures and tissue engineering. PMID:28378803

Nanoscale functionalization and characterization of surfaces with hydrogel patterns and biomolecules

NASA Astrophysics Data System (ADS)

Dinakar, Hariharasudhan Chirra

The advent of numerous tools, ease of techniques, and concepts related to nanotechnology, in combination with functionalization via simple chemistry has made gold important for various biomedical applications. In this dissertation, the development and characterization of planar gold surfaces with responsive hydrogel patterns for rapid point of care sensing and the functionalization of gold nanoparticles for drug delivery are highlighted. Biomedical micro- and nanoscale devices that are spatially functionalized with intelligent hydrogels are typically fabricated using conventional UV-lithography. Herein, precise 3-D hydrogel patterns made up of temperature responsive crosslinked poly(N-isopropylacrylamide) over gold were synthesized. The XY control of the hydrogel was achieved using microcontact printing, while thickness control was achieved using atom transfer radical polymerization (ATRP). Atomic force microscopy analysis showed that to the ATRP reaction time governed the pattern growth. The temperature dependent swelling ratio was tailored by tuning the mesh size of the hydrogel. While nanopatterns exhibited a broad lower critical solution temperature (LCST) transition, surface roughness showed a sharp LCST transition. Quartz crystal microbalance with dissipation showed rapid response behavior of the thin films, which makes them applicable as functional components in biomedical devices. The easy synthesis, relative biocompatibility, inertness, and easy functionalization of gold nanoparticles (GNPs) have made them useful for various biomedical applications. Although ATRP can be successfully carried out over GNPs, the yield of stable solution based GNPs for biomedical applications prove to be low. As an alternative approach, a novel method of ISOlating, FUnctionalizing, and REleasing nanoparticles (ISOFURE) was proposed. Biodegradable poly(beta-amino ester) hydrogels were used to synthesize ISOFURE-GNP composites. ATRP was performed inside the composite, and the final hydrogel coated GNPs were released via matrix degradation. Response analysis confirmed that the ISOFURE method led to the increased stability and yield of the hydrogel coated ISOFURE-GNPs. The ISOFURE protocol was also utilized in functionalizing GNPs with enzyme catalase in the absence of a stabilizing reagent. Biotin-streptavidin affinity was used as the bioconjugation method. Activity analysis of the conjugated enzyme showed that the ISOFURE-GNPs showed enhanced biomolecular loading relative to solution based stabilizing reagent passivated GNPs. KEYWORDS: Hydrogel, Gold nanoparticle, ISOFURE, Atom transfer radical polymerization, Microcontact printing

Raman scattering studies on PEG functionalized hydroxyapatite nanoparticles.

PubMed

Yamini, D; Devanand Venkatasubbu, G; Kumar, J; Ramakrishnan, V

2014-01-03

The pure hydroxyapatite (HAP) nanoparticles (NPs) have been synthesized by wet chemical precipitation method. Raman spectral measurements have been made for pure HAP, pure Polyethylene glycol (PEG) 6000 and PEG coated HAP in different mass ratios (sample 1, sample 2 and sample 3). The peaks observed in Raman spectrum of pure HAP and the XRD pattern have confirmed the formation of HAP NPs. Vibrational modes have been assigned for pure HAP and pure PEG 6000. The observed variation in peak position of Raman active vibrational modes of PEG in PEG coated HAP has been elucidated in this work, in terms of intermolecular interactions between PEG and HAP. Further these results suggest that the functionalization of nanoparticles may be independent of PEG mass. Copyright © 2013 Elsevier B.V. All rights reserved.

Creating Stiff, Tough, and Functional Hydrogel Composites with Low-Melting-Point Alloys.

PubMed

Takahashi, Riku; Sun, Tao Lin; Saruwatari, Yoshiyuki; Kurokawa, Takayuki; King, Daniel R; Gong, Jian Ping

2018-04-01

Reinforcing hydrogels with a rigid scaffold is a promising method to greatly expand the mechanical and physical properties of hydrogels. One of the challenges of creating hydrogel composites is the significant stress that occurs due to swelling mismatch between the water-swollen hydrogel matrix and the rigid skeleton in aqueous media. This stress can cause physical deformation (wrinkling, buckling, or fracture), preventing the fabrication of robust composites. Here, a simple yet versatile method is introduced to create "macroscale" hydrogel composites, by utilizing a rigid reinforcing phase that can relieve stress-induced deformation. A low-melting-point alloy that can transform from a load-bearing solid state to a free-deformable liquid state at relatively low temperature is used as a reinforcing skeleton, which enables the release of any swelling mismatch, regardless of the matrix swelling degree in liquid media. This design can generally provide hydrogels with hybridized functions, including excellent mechanical properties, shape memory, and thermal healing, which are often difficult or impossible to achieve with single-component hydrogel systems. Furthermore, this technique enables controlled electrochemical reactions and channel-structure templating in hydrogel matrices. This work may play an important role in the future design of soft robots, wearable electronics, and biocompatible functional materials. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Extracellular matrix hydrogels from decellularized tissues: Structure and function.

PubMed

Saldin, Lindsey T; Cramer, Madeline C; Velankar, Sachin S; White, Lisa J; Badylak, Stephen F

2017-02-01

Extracellular matrix (ECM) bioscaffolds prepared from decellularized tissues have been used to facilitate constructive and functional tissue remodeling in a variety of clinical applications. The discovery that these ECM materials could be solubilized and subsequently manipulated to form hydrogels expanded their potential in vitro and in vivo utility; i.e. as culture substrates comparable to collagen or Matrigel, and as injectable materials that fill irregularly-shaped defects. The mechanisms by which ECM hydrogels direct cell behavior and influence remodeling outcomes are only partially understood, but likely include structural and biological signals retained from the native source tissue. The present review describes the utility, formation, and physical and biological characterization of ECM hydrogels. Two examples of clinical application are presented to demonstrate in vivo utility of ECM hydrogels in different organ systems. Finally, new research directions and clinical translation of ECM hydrogels are discussed. More than 70 papers have been published on extracellular matrix (ECM) hydrogels created from source tissue in almost every organ system. The present manuscript represents a review of ECM hydrogels and attempts to identify structure-function relationships that influence the tissue remodeling outcomes and gaps in the understanding thereof. There is a Phase 1 clinical trial now in progress for an ECM hydrogel. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

In Vitro Characterization of a Stem-Cell-Seeded Triple-Interpenetrating-Network Hydrogel for Functional Regeneration of the Nucleus Pulposus

PubMed Central

Smith, Lachlan J.; Gorth, Deborah J.; Showalter, Brent L.; Chiaro, Joseph A.; Beattie, Elizabeth E.; Elliott, Dawn M.; Mauck, Robert L.; Chen, Weiliam

2014-01-01

Intervertebral disc degeneration is implicated as a major cause of low-back pain. There is a pressing need for new regenerative therapies for disc degeneration that restore native tissue structure and mechanical function. To that end we investigated the therapeutic potential of an injectable, triple-interpenetrating-network hydrogel comprised of dextran, chitosan, and teleostean, for functional regeneration of the nucleus pulposus (NP) of the intervertebral disc in a series of biomechanical, cytotoxicity, and tissue engineering studies. Biomechanical properties were evaluated as a function of gelation time, with the hydrogel reaching ∼90% of steady-state aggregate modulus within 10 h. Hydrogel mechanical properties evaluated in confined and unconfined compression were comparable to native human NP properties. To confirm containment within the disc under physiological loading, toluidine-blue-labeled hydrogel was injected into human cadaveric spine segments after creation of a nucleotomy defect, and the segments were subjected to 10,000 cycles of loading. Gross analysis demonstrated no implant extrusion, and further, that the hydrogel interdigitated well with native NP. Constructs were next surface-seeded with NP cells and cultured for 14 days, confirming lack of hydrogel cytotoxicity, with the hydrogel maintaining NP cell viability and promoting proliferation. Next, to evaluate the potential of the hydrogel to support cell-mediated matrix production, constructs were seeded with mesenchymal stem cells (MSCs) and cultured under prochondrogenic conditions for up to 42 days. Importantly, the hydrogel maintained MSC viability and promoted proliferation, as evidenced by increasing DNA content with culture duration. MSCs differentiated along a chondrogenic lineage, evidenced by upregulation of aggrecan and collagen II mRNA, and increased GAG and collagen content, and mechanical properties with increasing culture duration. Collectively, these results establish the therapeutic potential of this novel hydrogel for functional regeneration of the NP. Future work will confirm the ability of this hydrogel to normalize the mechanical stability of cadaveric human motion segments, and advance the material toward human translation using preclinical large-animal models. PMID:24410394

Biomimetic poly(amidoamine) hydrogels as synthetic materials for cell culture

PubMed Central

Jacchetti, Emanuela; Emilitri, Elisa; Rodighiero, Simona; Indrieri, Marco; Gianfelice, Antonella; Lenardi, Cristina; Podestà, Alessandro; Ranucci, Elisabetta; Ferruti, Paolo; Milani, Paolo

2008-01-01

Background Poly(amidoamine)s (PAAs) are synthetic polymers endowed with many biologically interesting properties, being highly biocompatible, non toxic and biodegradable. Hydrogels based on PAAs can be easily modified during the synthesis by the introduction of functional co-monomers. Aim of this work is the development and testing of novel amphoteric nanosized poly(amidoamine) hydrogel film incorporating 4-aminobutylguanidine (agmatine) moieties to create RGD-mimicking repeating units for promoting cell adhesion. Results A systematic comparative study of the response of an epithelial cell line was performed on hydrogels with agmatine and on non-functionalized amphoteric poly(amidoamine) hydrogels and tissue culture plastic substrates. The cell adhesion on the agmatine containing substrates was comparable to that on plastic substrates and significantly enhanced with respect to the non-functionalized controls. Interestingly, spreading and proliferation on the functionalized supports are slower than on plastic exhibiting the possibility of an easier control of the cell growth kinetics. In order to favor the handling of the samples, a procedure for the production of bi-layered constructs was also developed by means the deposition via spin coating of a thin layer of hydrogel on a pre-treated cover slip. Conclusion The obtained results reveal that PAAs hydrogels can be profitably functionalized and, in general, undergo physical and chemical modifications to meet specific requirements. In particular the incorporation of agmatine warrants good potential in the field of cell culturing and the development of supported functionalized hydrogels on cover glass are very promising substrates for applications in cell screening devices. PMID:19014710

Glycol chitosan/oxidized hyaluronic acid hydrogels functionalized with cartilage extracellular matrix particles and incorporating BMSCs for cartilage repair.

PubMed

Liu, Chun; Liu, Deshuai; Wang, Yingying; Li, Yun; Li, Tao; Zhou, Zhiyou; Yang, Zhijian; Wang, Jianhua; Zhang, Qiqing

2018-02-05

In this article, we fabricated a bioactive hydrogel composed of glycol chitosan (G-CS) and oxidized hyaluronic acid (OHA) via Schiff base reaction. Cartilage extracellular matrix (ECM) particles with different concentrations were used to functionalize G-CS/OHA (S1) hydrogel. The results demonstrated that S3 (G-CS/OHA/ECM 2% w/v) hydrogel exhibited the most suitable compression strength and provided the optimal environment for proliferation of bone marrow mesenchymal stem cells (BMSCs). To assess the chondroinductivity of ECM in vitro, we compared the chondrogenesis of BMSCs in S1 (G-CS/OHA) and S3 (G-CS/OHA/ECM 2% w/v) hydrogels. The results confirmed that the higher levels of glycosaminoglycans (GAGs) and collagen type II (COL II) were accumulated in S3 hydrogel. In vivo, cartilage defects of rats generated most mature tissue within BMSCs-laden S3 hydrogel (S3/BMSCs group). The tissues were more integrative and contained higher levels of COL II and GAGs compared to the other groups. All these results suggested that the G-CS/OHA hydrogel functionalized with ECM particles is a good candidate biomaterial to be applied in cartilage tissue engineering.

A simple and high-resolution stereolithography-based 3D bioprinting system using visible light crosslinkable bioinks.

PubMed

Wang, Zongjie; Abdulla, Raafa; Parker, Benjamin; Samanipour, Roya; Ghosh, Sanjoy; Kim, Keekyoung

2015-12-22

Bioprinting is a rapidly developing technique for biofabrication. Because of its high resolution and the ability to print living cells, bioprinting has been widely used in artificial tissue and organ generation as well as microscale living cell deposition. In this paper, we present a low-cost stereolithography-based bioprinting system that uses visible light crosslinkable bioinks. This low-cost stereolithography system was built around a commercial projector with a simple water filter to prevent harmful infrared radiation from the projector. The visible light crosslinking was achieved by using a mixture of polyethylene glycol diacrylate (PEGDA) and gelatin methacrylate (GelMA) hydrogel with eosin Y based photoinitiator. Three different concentrations of hydrogel mixtures (10% PEG, 5% PEG + 5% GelMA, and 2.5% PEG + 7.5% GelMA, all w/v) were studied with the presented systems. The mechanical properties and microstructure of the developed bioink were measured and discussed in detail. Several cell-free hydrogel patterns were generated to demonstrate the resolution of the solution. Experimental results with NIH 3T3 fibroblast cells show that this system can produce a highly vertical 3D structure with 50 μm resolution and 85% cell viability for at least five days. The developed system provides a low-cost visible light stereolithography solution and has the potential to be widely used in tissue engineering and bioengineering for microscale cell patterning.

Fibrin hydrogels functionalized with cartilage extracellular matrix and incorporating freshly isolated stromal cells as an injectable for cartilage regeneration.

PubMed

Almeida, H V; Eswaramoorthy, R; Cunniffe, G M; Buckley, C T; O'Brien, F J; Kelly, D J

2016-05-01

Freshly isolated stromal cells can potentially be used as an alternative to in vitro expanded cells in regenerative medicine. Their use requires the development of bioactive hydrogels or scaffolds which provide an environment to enhance their proliferation and tissue-specific differentiation in vivo. The goal of the current study was to develop an injectable fibrin hydrogel functionalized with cartilage ECM microparticles and transforming growth factor (TGF)-β3 as a putative therapeutic for articular cartilage regeneration. ECM microparticles were produced by cryomilling and freeze-drying porcine articular cartilage. Up to 2% (w/v) ECM could be incorporated into fibrin without detrimentally affecting its capacity to form stable hydrogels. To access the chondroinductivity of cartilage ECM, we compared chondrogenesis of infrapatellar fat pad-derived stem cells in fibrin hydrogels functionalized with either particulated ECM or control gelatin microspheres. Cartilage ECM particles could be used to control the delivery of TGF-β3 to IFP-derived stem cells within fibrin hydrogels in vitro, and furthermore, led to higher levels of sulphated glycosaminoglycan (sGAG) and collagen accumulation compared to control constructs loaded with gelatin microspheres. In vivo, freshly isolated stromal cells generated a more cartilage-like tissue within fibrin hydrogels functionalized with cartilage ECM particles compared to the control gelatin loaded constructs. These tissues stained strongly for type II collagen and contained higher levels of sGAGs. These results support the use of fibrin hydrogels functionalized with cartilage ECM components in single-stage, cell-based therapies for joint regeneration. An alternative to the use of in vitro expanded cells in regenerative medicine is the use of freshly isolated stromal cells, where a bioactive scaffold or hydrogel is used to provide an environment that enhances their proliferation and tissue-specific differentiation in vivo. The objective of this study was to develop an injectable fibrin hydrogel functionalized with cartilage ECM micro-particles and the growth factor TGF-β3 as a therapeutic for articular cartilage regeneration. This study demonstrates that freshly isolated stromal cells generate cartilage tissue in vivo when incorporated into such a fibrin hydrogels functionalized with cartilage ECM particles. These findings open up new possibilities for in-theatre, single-stage, cell-based therapies for joint regeneration. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Tough Hydrogel Robots: High-Speed, High-Force and Opto-sonically Invisible in Water

NASA Astrophysics Data System (ADS)

Zhao, Xuanhe

Sea animals such as leptocephali develop tissues and organs composed of active transparent hydrogels to achieve agile motions and natural camouflage in water. Hydrogel-based actuators that can imitate the capabilities of leptocephali will enable new applications in diverse fields. However, existing hydrogel actuators, mostly osmotic-driven, are intrinsically low-speed and/or low-force; and their camouflage capabilities have not been explored. Here we show that hydraulic actuations of tough hydrogels with designed structures and properties can give soft actuators and robots that are high-speed, high-force, and optically and sonically camouflaged in water. We invent a simple method capable of assembling physically-crosslinked hydrogel parts followed by covalent crosslinking to fabricate large-scale hydraulic hydrogel actuators and robots with robust bodies and interfaces. The hydrogel actuators and robots can maintain their robustness and functionality over multiple cycles of actuations, owning to the anti-fatigue property of the hydrogel under moderate stresses. A multiscale theoretical framework has been developed to guide the design and optimization of the hydrogel robots. We further demonstrate that the agile and transparent hydrogel actuators and robots perform extraordinary functions including swimming, kicking rubber-balls and catching a live fish in water. The work was supported by NSF(No. CMMI- 1253495) and ONR (No. N00014-14-1-0528).

A study in the adsorption of Fe(2+) and NO(3)(-) on pine needles based hydrogels.

PubMed

Chauhan, Ghanshyam S; Chauhan, Sandeep; Kumar, Sunil; Kumari, Anita

2008-09-01

Novel supports for use as cation and anion adsorbents were prepared from lignocellulosics using pine needles and their carboxymethylated forms by network/hydrogel formation with acrylamide and N,N-methylene bisacrylamide. The hydrogels thus prepared were further functionalized by partial alkaline hydrolysis with 0.5 N NaOH and were characterized by FTIR, SEM and nitrogen analysis. Adsorption of Fe(2+) on these hydrogels was carried as a function of time, temperature, pH and ionic strength. The hydrogel having the maximum adsorption capacity was loaded with Fe(2+) at the conditions those afforded maximum uptake and was used as novel anionic adsorbent for NO(3)(-). The water uptake capacities and biodegradability of the hydrogels before and after the ion loading was studied to evaluate the possible end-uses of these hydrogels as alternate materials in the removal of ionic species from water.

Dynamic modeling of the hydrogel molecular filter in a metamaterial biosensing system for glucose concentration estimation.

PubMed

Teutsch, T; Mesch, M; Giessen, H; Tarin, C

2014-01-01

We present a novel concept for ophthalmic glucose sensing using a biosensing system that consists of plasmonic dipole metamaterial covered by a layer of functionalized hydrogel. The metamaterial together with the hydrogel can be integrated into a contact lens. This optical sensor changes its properties such as reflectivity upon the ambient glucose concentration, which allows in situ measurements in the eye. The functionalization of the sensor with hydrogel allows for a glucose-specific detection, providing both selectivity and sensitivity. As a result of the presented work we derive a dynamic model of the hydrogel that can be used for further simulation studies.

Glucose-Sensitive Hydrogel Optical Fibers Functionalized with Phenylboronic Acid.

PubMed

Yetisen, Ali K; Jiang, Nan; Fallahi, Afsoon; Montelongo, Yunuen; Ruiz-Esparza, Guillermo U; Tamayol, Ali; Zhang, Yu Shrike; Mahmood, Iram; Yang, Su-A; Kim, Ki Su; Butt, Haider; Khademhosseini, Ali; Yun, Seok-Hyun

2017-04-01

Hydrogel optical fibers are utilized for continuous glucose sensing in real time. The hydrogel fibers consist of poly(acrylamide-co-poly(ethylene glycol) diacrylate) cores functionalized with phenylboronic acid. The complexation of the phenylboronic acid and cis-diol groups of glucose enables reversible changes of the hydrogel fiber diameter. The analyses of light propagation loss allow for quantitative glucose measurements within the physiological range. © 2017 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Macroporous biohybrid cryogels for co-housing pancreatic islets with mesenchymal stromal cells.

PubMed

Borg, Danielle J; Welzel, Petra B; Grimmer, Milauscha; Friedrichs, Jens; Weigelt, Marc; Wilhelm, Carmen; Prewitz, Marina; Stißel, Aline; Hommel, Angela; Kurth, Thomas; Freudenberg, Uwe; Bonifacio, Ezio; Werner, Carsten

2016-10-15

Intrahepatic transplantation of allogeneic pancreatic islets offers a promising therapy for type 1 diabetes. However, long-term insulin independency is often not achieved due to severe islet loss shortly after transplantation. To improve islet survival and function, extrahepatic biomaterial-assisted transplantation of pancreatic islets to alternative sites has been suggested. Herein, we present macroporous, star-shaped poly(ethylene glycol) (starPEG)-heparin cryogel scaffolds, covalently modified with adhesion peptides, for the housing of pancreatic islets in three-dimensional (3D) co-culture with adherent mesenchymal stromal cells (MSC) as accessory cells. The implantable biohybrid scaffolds provide efficient transport properties, mechanical protection, and a supportive extracellular environment as a desirable niche for the islets. MSC colonized the cryogel scaffolds and produced extracellular matrix proteins that are important components of the natural islet microenvironment known to facilitate matrix-cell interactions and to prevent cellular stress. Islets survived the seeding procedure into the cryogel scaffolds and secreted insulin after glucose stimulation in vitro. In a rodent model, intact islets and MSC could be visualized within the scaffolds seven days after subcutaneous transplantation. Overall, this demonstrates the potential of customized macroporous starPEG-heparin cryogel scaffolds in combination with MSC to serve as a multifunctional islet supportive carrier for transplantation applications. Diabetes results in the insufficient production of insulin by the pancreatic β-cells in the islets of Langerhans. Transplantation of pancreatic islets offers valuable options for treating the disease; however, many transplanted islets often do not survive the transplantation or die shortly thereafter. Co-transplanted, supporting cells and biomaterials can be instrumental for improving islet survival, function and protection from the immune system. In the present study, islet supportive hydrogel sponges were explored for the co-transplantation of islets and mesenchymal stromal cells. Survival and continued function of the supported islets were demonstrated in vitro. The in vivo feasibility of the approach was shown by transplantation in a mouse model. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Polyethyleneglycol/silver functionalized reduced graphene oxide aerogel for environmental application

NASA Astrophysics Data System (ADS)

Kumari, G. Vanitha; Asha, S.; Ananth, A. Nimrodh; Rajan, M. A. Jothi; Mathavan, T.

2018-04-01

Polyethylene glycol (PEG)/Silver (Ag) functionalized reduced graphene oxide aerogel (RGOA) was synthesized. PEG/Ag decorated reduced graphene oxide aerogel was characterized using XRD, Raman spectroscopy, Fourier transform infrared spectroscopy (FT-IR). The surface morphology of PEG/Ag/RGOA was analyzed using scanning electron microscope. The non-covalent interaction between reduced graphene oxide layers and the interaction between PEG and Ag on RGOA were studied by FT-IR spectra. It was observed that the interaction between Ag and PEG could enhance the properties of RGOA. Methyl Orange (MO) dye degradation was observed from UV-Vis Spectra. The process was studied by monitoring the simultaneous decrease in the height of UV-Vis absorption peak of dye solution. The results show that PEG/RGOA and PEG/Ag/RGOA are an efficient catalyst for dye degradation.

Role of oxygen functional groups in reduced graphene oxide for lubrication

PubMed Central

Gupta, Bhavana; Kumar, Niranjan; Panda, Kalpataru; Kanan, Vigneshwaran; Joshi, Shailesh; Visoly-Fisher, Iris

2017-01-01

Functionalized and fully characterized graphene-based lubricant additives are potential 2D materials for energy-efficient tribological applications in machine elements, especially at macroscopic contacts. Two different reduced graphene oxide (rGO) derivatives, terminated by hydroxyl and epoxy-hydroxyl groups, were prepared and blended with two different molecular weights of polyethylene glycol (PEG) for tribological investigation. Epoxy-hydroxyl-terminated rGO dispersed in PEG showed significantly smaller values of the friction coefficient. In this condition, PEG chains intercalate between the functionalized graphene sheets, and shear can take place between the PEG and rGO sheets. However, the friction coefficient was unaffected when hydroxyl-terminated rGO was coupled with PEG. This can be explained by the strong coupling between graphene sheets through hydroxyl units, causing the interaction of PEG with the rGO to be non- effective for lubrication. On the other hand, antiwear properties of hydroxyl-terminated rGO were significantly enhanced compared to epoxy-hydroxyl functionalized rGO due to the integrity of graphene sheet clusters. PMID:28344337

Injectable supramolecular hydrogel formed from α-cyclodextrin and PEGylated arginine-functionalized poly(l-lysine) dendron for sustained MMP-9 shRNA plasmid delivery.

PubMed

Lin, Qianming; Yang, Yumeng; Hu, Qian; Guo, Zhong; Liu, Tao; Xu, Jiake; Wu, Jianping; Kirk, Thomas Brett; Ma, Dong; Xue, Wei

2017-02-01

Hydrogels have attracted much attention in cancer therapy and tissue engineering due to their sustained gene delivery ability. To obtain an injectable and high-efficiency gene delivery hydrogel, methoxypolyethylene glycol (MPEG) was used to conjugate with the arginine-functionalized poly(l-lysine) dendron (PLLD-Arg) by click reaction, and then the synthesized MPEG-PLLD-Arg interacted with α-cyclodextrin (α-CD) to form the supramolecular hydrogel by the host-guest interaction. The gelation dynamics, hydrogel strength and shear viscosity could be modulated by α-CD content in the hydrogel. MPEG-PLLD-Arg was confirmed to bind and deliver gene effectively, and its gene transfection efficiency was significantly higher than PEI-25k under its optimized condition. After gelation, MMP-9 shRNA plasmid (pMMP-9) could be encapsulated into the hydrogel matrix in situ and be released from the hydrogels sustainedly, as the release rate was dependent on α-CD content. The released MPEG-PLLD-Arg/pMMP-9 complex still showed better transfection efficiency than PEI-25k and induced sustained tumor cell apoptosis. Also, in vivo assays indicated that this pMMP-9-loaded supramolecular hydrogel could result in the sustained tumor growth inhibition meanwhile showed good biocompatibility. As an injectable, sustained and high-efficiency gene delivery system, this supramolecular hydrogel is a promising candidate for long-term gene therapy. To realize the sustained gene delivery for gene therapy, a supramolecular hydrogel with high-efficiency gene delivery ability was prepared through the host-guest interaction between α-cyclodextrin and PEGylated arginine-functionalized poly(l-lysine) dendron. The obtained hydrogel was injectable and biocompatible with adjustable physicochemical property. More importantly, the hydrogel showed the high-efficiency and sustained gene transfection to our used cells, better than PEI-25k. The supramolecular hydrogel resulted in the sustained tumor growth inhibition meanwhile keep good biocompatibility. As an injectable, sustained and high-efficiency gene delivery system, this supramolecular hydrogel is a promising candidate in long-term gene therapy and tissue engineering. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

S. pombe CLASP needs dynein, not EB1 or CLIP170, to induce microtubule instability and slows polymerization rates at cell tips in a dynein-dependent manner

PubMed Central

Grallert, Agnes; Beuter, Christoph; Craven, Rachel A.; Bagley, Steve; Wilks, Deepti; Fleig, Ursula; Hagan, Iain M.

2006-01-01

The Schizosaccharomyces pombe CLIP170-associated protein (CLASP) Peg1 was identified in a screen for mutants with spindle formation defects and a screen for molecules that antagonized EB1 function. The conditional peg1.1 mutant enabled us to identify key features of Peg1 function. First, Peg1 was required to form a spindle and astral microtubules, yet destabilized interphase microtubules. Second, Peg1 was required to slow the polymerization rate of interphase microtubules that establish end-on contact with the cortex at cell tips. Third, Peg1 antagonized the action of S. pombe CLIP170 (Tip1) and EB1 (Mal3). Fourth, although Peg1 resembled higher eukaryotic CLASPs by physically associating with both Mal3 and Tip1, neither Tip1 nor Mal3 was required for Peg1 to destabilize interphase microtubules or for it to associate with microtubules. Conversely, neither Mal3 nor Tip1 required Peg1 to associate with microtubules or cell tips. Consistently, while mal3.Δ and tip1.Δ disrupted linear growth, corrupting peg1 + did not. Fifth, peg1.1 phenotypes resembled those arising from deletion of the single heavy or both light chains of fission yeast dynein. Furthermore, all interphase phenotypes arising from peg1 + manipulation relied on dynein function. Thus, the impact of S. pombe CLASP on interphase microtubule behavior is more closely aligned to dynein than EB1 or CLIP170. PMID:16951255

Hydrophilic polyurethane matrix promotes chondrogenesis of mesenchymal stem cells.

PubMed

Nalluri, Sandeep M; Krishnan, G Rajesh; Cheah, Calvin; Arzumand, Ayesha; Yuan, Yuan; Richardson, Caley A; Yang, Shuying; Sarkar, Debanjan

2015-09-01

Segmental polyurethanes exhibit biphasic morphology and can control cell fate by providing distinct matrix guided signals to increase the chondrogenic potential of mesenchymal stem cells (MSCs). Polyethylene glycol (PEG) based hydrophilic polyurethanes can deliver differential signals to MSCs through their matrix phases where hard segments are cell-interactive domains and PEG based soft segments are minimally interactive with cells. These coordinated communications can modulate cell-matrix interactions to control cell shape and size for chondrogenesis. Biphasic character and hydrophilicity of polyurethanes with gel like architecture provide a synthetic matrix conducive for chondrogenesis of MSCs, as evidenced by deposition of cartilage-associated extracellular matrix. Compared to monophasic hydrogels, presence of cell interactive domains in hydrophilic polyurethanes gels can balance cell-cell and cell-matrix interactions. These results demonstrate the correlation between lineage commitment and the changes in cell shape, cell-matrix interaction, and cell-cell adhesion during chondrogenic differentiation which is regulated by polyurethane phase morphology, and thus, represent hydrophilic polyurethanes as promising synthetic matrices for cartilage regeneration. Copyright © 2015 Elsevier B.V. All rights reserved.

An Injectable, Self-Healing Hydrogel to Repair the Central Nervous System.

PubMed

Tseng, Ting-Chen; Tao, Lei; Hsieh, Fu-Yu; Wei, Yen; Chiu, Ing-Ming; Hsu, Shan-hui

2015-06-17

An injectable, self-healing hydrogel (≈1.5 kPa) is developed for healing nerve-system deficits. Neurosphere-like progenitors proliferate in the hydrogel and differentiate into neuron-like cells. In the zebrafish injury model, the central nervous system function is partially rescued by injection of the hydrogel and significantly rescued by injection of the neurosphere-laden hydrogel. The self-healing hydrogel may thus potentially repair the central nervous system. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Carbon nanotube-incorporated collagen hydrogels improve cell alignment and the performance of cardiac constructs

PubMed Central

Sun, Hongyu; Zhou, Jing; Huang, Zhu; Qu, Linlin; Lin, Ning; Liang, Chengxiao; Dai, Ruiwu; Tang, Lijun; Tian, Fuzhou

2017-01-01

Carbon nanotubes (CNTs) provide an essential 2-D microenvironment for cardiomyocyte growth and function. However, it remains to be elucidated whether CNT nanostructures can promote cell–cell integrity and facilitate the formation of functional tissues in 3-D hydrogels. Here, single-walled CNTs were incorporated into collagen hydrogels to fabricate (CNT/Col) hydrogels, which improved mechanical and electrical properties. The incorporation of CNTs (up to 1 wt%) exhibited no toxicity to cardiomyocytes and enhanced cell adhesion and elongation. Through the use of immunohistochemical staining, transmission electron microscopy, and intracellular calcium-transient measurement, the incorporation of CNTs was found to improve cell alignment and assembly remarkably, which led to the formation of engineered cardiac tissues with stronger contraction potential. Importantly, cardiac tissues based on CNT/Col hydrogels were noted to have better functionality. Collectively, the incorporation of CNTs into the Col hydrogels improved cell alignment and the performance of cardiac constructs. Our study suggests that CNT/Col hydrogels offer a promising tissue scaffold for cardiac constructs, and might serve as injectable biomaterials to deliver cell or drug molecules for cardiac regeneration following myocardial infarction in the near future. PMID:28450785

Functional nucleic acid-based hydrogels for bioanalytical and biomedical applications

PubMed Central

Mo, Liuting; Lu, Chun-Hua; Fu, Ting

2016-01-01

Hydrogels are crosslinked hydrophilic polymers that can absorb a large amount of water. By their hydrophilic, biocompatible and highly tunable nature, hydrogels can be tailored for applications in bioanalysis and biomedicine. Of particular interest are DNA-based hydrogels owing to the unique features of nucleic acids. Since the discovery of DNA double helical structure, interest in DNA has expanded beyond its genetic role to applications in nanotechnology and materials science. In particular, DNA-based hydrogels present such remarkable features as stability, flexibility, precise programmability, stimuli-responsive DNA conformations, facile synthesis and modification. Moreover, functional nucleic acids (FNAs) have allowed the construction of hydrogels based on aptamers, DNAzymes, i-motif nanostructures, siRNAs and CpG oligodeoxynucleotides to provide additional molecular recognition, catalytic activities and therapeutic potential, making them key players in biological analysis and biomedical applications. To date, a variety of applications have been demonstrated with FNA-based hydrogels, including biosensing, environmental analysis, controlled drug release, cell adhesion and targeted cancer therapy. In this review, we focus on advances in the development of FNA-based hydrogels, which have fully incorporated both the unique features of FNAs and DNA-based hydrogels. We first introduce different strategies for constructing DNA-based hydrogels. Subsequently, various types of FNAs and the most recent developments of FNA-based hydrogels for bioanalytical and biomedical applications are described with some selected examples. Finally, the review provides an insight into the remaining challenges and future perspectives of FNA-based hydrogels. PMID:26758955

Assessing the Potential of Folded Globular Polyproteins As Hydrogel Building Blocks

PubMed Central

2016-01-01

The native states of proteins generally have stable well-defined folded structures endowing these biomolecules with specific functionality and molecular recognition abilities. Here we explore the potential of using folded globular polyproteins as building blocks for hydrogels. Photochemically cross-linked hydrogels were produced from polyproteins containing either five domains of I27 ((I27)5), protein L ((pL)5), or a 1:1 blend of these proteins. SAXS analysis showed that (I27)5 exists as a single rod-like structure, while (pL)5 shows signatures of self-aggregation in solution. SANS measurements showed that both polyprotein hydrogels have a similar nanoscopic structure, with protein L hydrogels being formed from smaller and more compact clusters. The polyprotein hydrogels showed small energy dissipation in a load/unload cycle, which significantly increased when the hydrogels were formed in the unfolded state. This study demonstrates the use of folded proteins as building blocks in hydrogels, and highlights the potential versatility that can be offered in tuning the mechanical, structural, and functional properties of polyproteins. PMID:28006103

Hybrid hydrogels containing vertically aligned carbon nanotubes with anisotropic electrical conductivity for muscle myofiber fabrication.

PubMed

Ahadian, Samad; Ramón-Azcón, Javier; Estili, Mehdi; Liang, Xiaobin; Ostrovidov, Serge; Shiku, Hitoshi; Ramalingam, Murugan; Nakajima, Ken; Sakka, Yoshio; Bae, Hojae; Matsue, Tomokazu; Khademhosseini, Ali

2014-03-19

Biological scaffolds with tunable electrical and mechanical properties are of great interest in many different fields, such as regenerative medicine, biorobotics, and biosensing. In this study, dielectrophoresis (DEP) was used to vertically align carbon nanotubes (CNTs) within methacrylated gelatin (GelMA) hydrogels in a robust, simple, and rapid manner. GelMA-aligned CNT hydrogels showed anisotropic electrical conductivity and superior mechanical properties compared with pristine GelMA hydrogels and GelMA hydrogels containing randomly distributed CNTs. Skeletal muscle cells grown on vertically aligned CNTs in GelMA hydrogels yielded a higher number of functional myofibers than cells that were cultured on hydrogels with randomly distributed CNTs and horizontally aligned CNTs, as confirmed by the expression of myogenic genes and proteins. In addition, the myogenic gene and protein expression increased more profoundly after applying electrical stimulation along the direction of the aligned CNTs due to the anisotropic conductivity of the hybrid GelMA-vertically aligned CNT hydrogels. We believe that platform could attract great attention in other biomedical applications, such as biosensing, bioelectronics, and creating functional biomedical devices.

Hybrid hydrogels containing vertically aligned carbon nanotubes with anisotropic electrical conductivity for muscle myofiber fabrication

PubMed Central

Ahadian, Samad; Ramón-Azcón, Javier; Estili, Mehdi; Liang, Xiaobin; Ostrovidov, Serge; Shiku, Hitoshi; Ramalingam, Murugan; Nakajima, Ken; Sakka, Yoshio; Bae, Hojae; Matsue, Tomokazu; Khademhosseini, Ali

2014-01-01

Biological scaffolds with tunable electrical and mechanical properties are of great interest in many different fields, such as regenerative medicine, biorobotics, and biosensing. In this study, dielectrophoresis (DEP) was used to vertically align carbon nanotubes (CNTs) within methacrylated gelatin (GelMA) hydrogels in a robust, simple, and rapid manner. GelMA-aligned CNT hydrogels showed anisotropic electrical conductivity and superior mechanical properties compared with pristine GelMA hydrogels and GelMA hydrogels containing randomly distributed CNTs. Skeletal muscle cells grown on vertically aligned CNTs in GelMA hydrogels yielded a higher number of functional myofibers than cells that were cultured on hydrogels with randomly distributed CNTs and horizontally aligned CNTs, as confirmed by the expression of myogenic genes and proteins. In addition, the myogenic gene and protein expression increased more profoundly after applying electrical stimulation along the direction of the aligned CNTs due to the anisotropic conductivity of the hybrid GelMA-vertically aligned CNT hydrogels. We believe that platform could attract great attention in other biomedical applications, such as biosensing, bioelectronics, and creating functional biomedical devices. PMID:24642903

Hybrid hydrogels containing vertically aligned carbon nanotubes with anisotropic electrical conductivity for muscle myofiber fabrication

NASA Astrophysics Data System (ADS)

Ahadian, Samad; Ramón-Azcón, Javier; Estili, Mehdi; Liang, Xiaobin; Ostrovidov, Serge; Shiku, Hitoshi; Ramalingam, Murugan; Nakajima, Ken; Sakka, Yoshio; Bae, Hojae; Matsue, Tomokazu; Khademhosseini, Ali

2014-03-01

Biological scaffolds with tunable electrical and mechanical properties are of great interest in many different fields, such as regenerative medicine, biorobotics, and biosensing. In this study, dielectrophoresis (DEP) was used to vertically align carbon nanotubes (CNTs) within methacrylated gelatin (GelMA) hydrogels in a robust, simple, and rapid manner. GelMA-aligned CNT hydrogels showed anisotropic electrical conductivity and superior mechanical properties compared with pristine GelMA hydrogels and GelMA hydrogels containing randomly distributed CNTs. Skeletal muscle cells grown on vertically aligned CNTs in GelMA hydrogels yielded a higher number of functional myofibers than cells that were cultured on hydrogels with randomly distributed CNTs and horizontally aligned CNTs, as confirmed by the expression of myogenic genes and proteins. In addition, the myogenic gene and protein expression increased more profoundly after applying electrical stimulation along the direction of the aligned CNTs due to the anisotropic conductivity of the hybrid GelMA-vertically aligned CNT hydrogels. We believe that platform could attract great attention in other biomedical applications, such as biosensing, bioelectronics, and creating functional biomedical devices.

Arginine-glycine-aspartic acid functional branched semi-interpenetrating hydrogels.

PubMed

Plenderleith, Richard A; Pateman, Christopher J; Rodenburg, Cornelia; Haycock, John W; Claeyssens, Frederik; Sammon, Chris; Rimmer, Stephen

2015-10-14

For the first time a series of functional hydrogels based on semi-interpenetrating networks with both branched and crosslinked polymer components have been prepared and we show the successful use of these materials as substrates for cell culture. The materials consist of highly branched poly(N-isopropyl acrylamide)s with peptide functionalised end groups in a continuous phase of crosslinked poly(vinyl pyrrolidone). Functionalisation of the end groups of the branched polymer component with the GRGDS peptide produces a hydrogel that supports cell adhesion and proliferation. The materials provide a new synthetic functional biomaterial that has many of the features of extracellular matrix, and as such can be used to support tissue regeneration and cell culture. This class of high water content hydrogel material has important advantages over other functional hydrogels in its synthesis and does not require post-processing modifications nor are functional-monomers, which change the polymerisation process, required. Thus, the systems are amenable to large scale and bespoke manufacturing using conventional moulding or additive manufacturing techniques. Processing using additive manufacturing is exemplified by producing tubes using microstereolithography.

Quantitative analysis of PEG-functionalized colloidal gold nanoparticles using charged aerosol detection.

PubMed

Smith, Mackensie C; Crist, Rachael M; Clogston, Jeffrey D; McNeil, Scott E

2015-05-01

Surface characteristics of a nanoparticle, such as functionalization with polyethylene glycol (PEG), are critical to understand and achieve optimal biocompatibility. Routine physicochemical characterization such as UV-vis spectroscopy (for gold nanoparticles), dynamic light scattering, and zeta potential are commonly used to assess the presence of PEG. However, these techniques are merely qualitative and are not sensitive enough to distinguish differences in PEG quantity, density, or presentation. As an alternative, two methods are described here which allow for quantitative measurement of PEG on PEGylated gold nanoparticles. The first, a displacement method, utilizes dithiothreitol to displace PEG from the gold surface. The dithiothreitol-coated gold nanoparticles are separated from the mixture via centrifugation, and the excess dithiothreitol and dissociated PEG are separated through reversed-phase high-performance liquid chromatography (RP-HPLC). The second, a dissolution method, utilizes potassium cyanide to dissolve the gold nanoparticles and liberate PEG. Excess CN(-), Au(CN)2 (-), and free PEG are separated using RP-HPLC. In both techniques, the free PEG can be quantified against a standard curve using charged aerosol detection. The displacement and dissolution methods are validated here using 2-, 5-, 10-, and 20-kDa PEGylated 30-nm colloidal gold nanoparticles. Further value in these techniques is demonstrated not only by quantitating the total PEG fraction but also by being able to be adapted to quantitate the free unbound PEG and the bound PEG fractions. This is an important distinction, as differences in the bound and unbound PEG fractions can affect biocompatibility, which would not be detected in techniques that only quantitate the total PEG fraction.

Intracellular production of hydrogels and synthetic RNA granules by multivalent molecular interactions

NASA Astrophysics Data System (ADS)

Nakamura, Hideki; Lee, Albert A.; Afshar, Ali Sobhi; Watanabe, Shigeki; Rho, Elmer; Razavi, Shiva; Suarez, Allister; Lin, Yu-Chun; Tanigawa, Makoto; Huang, Brian; Derose, Robert; Bobb, Diana; Hong, William; Gabelli, Sandra B.; Goutsias, John; Inoue, Takanari

2018-01-01

Some protein components of intracellular non-membrane-bound entities, such as RNA granules, are known to form hydrogels in vitro. The physico-chemical properties and functional role of these intracellular hydrogels are difficult to study, primarily due to technical challenges in probing these materials in situ. Here, we present iPOLYMER, a strategy for a rapid induction of protein-based hydrogels inside living cells that explores the chemically inducible dimerization paradigm. Biochemical and biophysical characterizations aided by computational modelling show that the polymer network formed in the cytosol resembles a physiological hydrogel-like entity that acts as a size-dependent molecular sieve. We functionalize these polymers with RNA-binding motifs that sequester polyadenine-containing nucleotides to synthetically mimic RNA granules. These results show that iPOLYMER can be used to synthetically reconstitute the nucleation of biologically functional entities, including RNA granules in intact cells.

Programmable display of DNA-protein chimeras for controlling cell-hydrogel interactions via reversible intermolecular hybridization.

PubMed

Zhang, Zhaoyang; Li, Shihui; Chen, Niancao; Yang, Cheng; Wang, Yong

2013-04-08

Extensive studies have been recently carried out to achieve dynamic control of cell-material interactions primarily through physicochemical stimulation. The purpose of this study was to apply reversible intermolecular hybridization to program cell-hydrogel interactions in physiological conditions based on DNA-antibody chimeras and complementary oligonucleotides. The results showed that DNA oligonucleotides could be captured to and released from the immobilizing DNA-functionalized hydrogels with high specificity via DNA hybridization. Accordingly, DNA-antibody chimeras were captured to the hydrogels, successfully inducing specific cell attachment. The cell attachment to the hydrogels reached the plateau at approximately half an hour after the functionalized hydrogels and the cells were incubated together. The attached cells were rapidly released from the bound hydrogels when triggering complementary oligonucleotides were introduced to the system. However, the capability of the triggering complementary oligonucleotides in releasing cells was affected by the length of intermolecular hybridization. The length needed to be at least more than 20 base pairs in the current experimental setting. Notably, because the procedure of intermolecular hybridization did not involve any harsh condition, the released cells maintained the same viability as that of the cultured cells. The functionalized hydrogels also exhibited the potential to catch and release cells repeatedly. Therefore, this study demonstrates that it is promising to regulate cell-material interactions dynamically through the DNA-programmed display of DNA-protein chimeras.

Biodegradable hyaluronic acid hydrogels to control release of dexamethasone through aqueous Diels-Alder chemistry for adipose tissue engineering.

PubMed

Fan, Ming; Ma, Ye; Zhang, Ziwei; Mao, Jiahui; Tan, Huaping; Hu, Xiaohong

2015-11-01

A robust synthetic strategy of biopolymer-based hydrogels has been developed where hyaluronic acid derivatives reacted through aqueous Diels-Alder chemistry without the involvement of chemical catalysts, allowing for control and sustain release of dexamethasone. To conjugate the hydrogel, furan and maleimide functionalized hyaluronic acid were synthesized, respectively, as well as furan functionalized dexamethasone, for the covalent immobilization. Chemical structure, gelation time, morphologies, swelling kinetics, weight loss, compressive modulus and dexamethasone release of the hydrogel system in PBS at 37°C were studied. The results demonstrated that the aqueous Diels-Alder chemistry provides an extremely selective reaction and proceeds with high efficiency for hydrogel conjugation and covalent immobilization of dexamethasone. Cell culture results showed that the dexamethasone immobilized hydrogel was noncytotoxic and preserved proliferation of entrapped human adipose-derived stem cells. This synthetic approach uniquely allows for the direct fabrication of biologically functionalized gel scaffolds with ideal structures for adipose tissue engineering, which provides a competitive alternative to conventional conjugation techniques such as copper mediated click chemistry. Copyright © 2015. Published by Elsevier B.V.

Autonomously Self-Adhesive Hydrogels as Building Blocks for Additive Manufacturing.

PubMed

Deng, Xudong; Attalla, Rana; Sadowski, Lukas P; Chen, Mengsu; Majcher, Michael J; Urosev, Ivan; Yin, Da-Chuan; Selvaganapathy, P Ravi; Filipe, Carlos D M; Hoare, Todd

2018-01-08

We report a simple method of preparing autonomous and rapid self-adhesive hydrogels and their use as building blocks for additive manufacturing of functional tissue scaffolds. Dynamic cross-linking between 2-aminophenylboronic acid-functionalized hyaluronic acid and poly(vinyl alcohol) yields hydrogels that recover their mechanical integrity within 1 min after cutting or shear under both neutral and acidic pH conditions. Incorporation of this hydrogel in an interpenetrating calcium-alginate network results in an interfacially stiffer but still rapidly self-adhesive hydrogel that can be assembled into hollow perfusion channels by simple contact additive manufacturing within minutes. Such channels withstand fluid perfusion while retaining their dimensions and support endothelial cell growth and proliferation, providing a simple and modular route to produce customized cell scaffolds.

Cytarabine-AOT catanionic vesicle-loaded biodegradable thermosensitive hydrogel as an efficient cytarabine delivery system.

PubMed

Liu, Jing; Jiang, Yue; Cui, Yuting; Xu, Chuanshan; Ji, Xiaoqing; Luan, Yuxia

2014-10-01

Carrier with high drug loading content is one of the most important issues in drug delivery system. In the present work, an ion-pair amphiphilic molecule composed of anticancer drug cation and surfactant anion is used for straightforward fabricating vesicles for cancer therapy. Anticancer drug (cytarabine hydrochloride) and anionic surfactant (AOT) are selected for the fabrication of ion-pair amphiphilic molecule. One amphiphilic molecule contains one drug cation, thus the drug loading content is 50% (mol/mol) in theory. The in vitro drug release study shows that the release time of cytarabine is about 3 times of the pure cytarabine solution and the permeability of cytarabine has been improved about 160 times tested by parallel artificial membrane permeability assay model. However, the hemolytic toxicity is largely decreased in the studied concentration range. The in vitro cytotoxicity results show that cytarabine-AOT amphiphiles have a much lower IC50 (drug concentration resulting in 50% cell death) value and a higher cell inhibition rate comparing with their respective components, indicating its effective therapy for leukemic cells. To obtain a longer and a convenient drug release system, the prepared vesicles are further incorporated into the thermosensitive PLGA-PEG-PLGA hydrogel to prepare a subcutaneous administration. The in vivo drug release results indicate that cytarabine-AOT vesicle-loaded hydrogel is a good injectable delivery system for controlled release of cytarabine for cancer therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

Three dimensional living neural networks

NASA Astrophysics Data System (ADS)

Linnenberger, Anna; McLeod, Robert R.; Basta, Tamara; Stowell, Michael H. B.

2015-08-01

We investigate holographic optical tweezing combined with step-and-repeat maskless projection micro-stereolithography for fine control of 3D positioning of living cells within a 3D microstructured hydrogel grid. Samples were fabricated using three different cell lines; PC12, NT2/D1 and iPSC. PC12 cells are a rat cell line capable of differentiation into neuron-like cells NT2/D1 cells are a human cell line that exhibit biochemical and developmental properties similar to that of an early embryo and when exposed to retinoic acid the cells differentiate into human neurons useful for studies of human neurological disease. Finally induced pluripotent stem cells (iPSC) were utilized with the goal of future studies of neural networks fabricated from human iPSC derived neurons. Cells are positioned in the monomer solution with holographic optical tweezers at 1064 nm and then are encapsulated by photopolymerization of polyethylene glycol (PEG) hydrogels formed by thiol-ene photo-click chemistry via projection of a 512x512 spatial light modulator (SLM) illuminated at 405 nm. Fabricated samples are incubated in differentiation media such that cells cease to divide and begin to form axons or axon-like structures. By controlling the position of the cells within the encapsulating hydrogel structure the formation of the neural circuits is controlled. The samples fabricated with this system are a useful model for future studies of neural circuit formation, neurological disease, cellular communication, plasticity, and repair mechanisms.

A new route to fabricate biocompatible hydrogels with controlled drug delivery behavior.

PubMed

Hu, Xiaohong; Gong, Xiao

2016-05-15

Hydrogels for drug delivery have attracted extensive interests since they can be used for biomaterials such as contact lenses. Here, we report that biocompatible hydrogels for contact lenses with controlled drug delivery behavior can be fabricated using copolymer hydrogels and Layer-by-Layer (LbL) surface modification technique. Methyl acrylic anhydride (MAA) modified β-cyclodextrin (β-CD) (MA-β-CD) was synthesized and copolymerized with hydroxyethyl methacrylate (HEMA) to form copolymer hydrogel. The introduction of second monomer of MA-β-CD would accelerate the polymerization of hydrogel, leading to increase of residual CC groups. The structure of copolymers was characterized by differential scanning calorimetry (DSC). Transparence, equilibrium swelling ratio and contact angle of copolymer hydrogel were also detailed discussed in the work. In vitro drug release results showed that copolymer hydrogel with higher MA-β-CD content exhibited a better drug loading capacity and drug release behaviors could be tuned by MA-β-CD/monomer ratio. Finally, alkynyl functional hyaluronic acid (HA-BP) and nitrine functional chitosan (CS-N3) were synthesized and covalently cross-linked to copolymer hydrogel surface using LbL technique through click chemistry. The successful LbL multilayers were confirmed by X-ray Photoelectron Spectroscopy (XPS). Resultsofcytotoxicityexperiment revealed that the hydrogels were biocompatible since they could support the growth of cells. Copyright © 2016 Elsevier Inc. All rights reserved.

Bioinspired Smart Actuator Based on Graphene Oxide-Polymer Hybrid Hydrogels.

PubMed

Wang, Tao; Huang, Jiahe; Yang, Yiqing; Zhang, Enzhong; Sun, Weixiang; Tong, Zhen

2015-10-28

Rapid response and strong mechanical properties are desired for smart materials used in soft actuators. A bioinspired hybrid hydrogel actuator was designed and prepared by series combination of three trunks of tough polymer-clay hydrogels to accomplish the comprehensive actuation of "extension-grasp-retraction" like a fishing rod. The hydrogels with thermo-creep and thermo-shrinking features were successively irradiated by near-infrared (NIR) to execute extension and retraction, respectively. The GO in the hydrogels absorbed the NIR energy and transformed it into thermo-energy rapidly and effectively. The hydrogel with adhesion or magnetic force was adopted as the "hook" of the hybrid hydrogel actuator for grasping object. The hook of the hybrid hydrogel actuator was replaceable according to applications, even with functional materials other than hydrogels. This study provides an innovative concept to explore new soft actuators through combining response hydrogels and programming the same stimulus.

Hydrogel-based three-dimensional cell culture for organ-on-a-chip applications.

PubMed

Lee, Seung Hwan; Shim, Kyu Young; Kim, Bumsang; Sung, Jong Hwan

2017-05-01

Recent studies have reported that three-dimensionally cultured cells have more physiologically relevant functions than two-dimensionally cultured cells. Cells are three-dimensionally surrounded by the extracellular matrix (ECM) in complex in vivo microenvironments and interact with the ECM and neighboring cells. Therefore, replicating the ECM environment is key to the successful cell culture models. Various natural and synthetic hydrogels have been used to mimic ECM environments based on their physical, chemical, and biological characteristics, such as biocompatibility, biodegradability, and biochemical functional groups. Because of these characteristics, hydrogels have been combined with microtechnologies and used in organ-on-a-chip applications to more closely recapitulate the in vivo microenvironment. Therefore, appropriate hydrogels should be selected depending on the cell types and applications. The porosity of the selected hydrogel should be controlled to facilitate the movement of nutrients and oxygen. In this review, we describe various types of hydrogels, external stimulation-based gelation of hydrogels, and control of their porosity. Then, we introduce applications of hydrogels for organ-on-a-chip. Last, we also discuss the challenges of hydrogel-based three-dimensional cell culture techniques and propose future directions. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:580-589, 2017. © 2017 American Institute of Chemical Engineers.

Development of hydrogels for regenerative engineering.

PubMed

Guan, Xiaofei; Avci-Adali, Meltem; Alarçin, Emine; Cheng, Hao; Kashaf, Sara Saheb; Li, Yuxiao; Chawla, Aditya; Jang, Hae Lin; Khademhosseini, Ali

2017-05-01

The aim of regenerative engineering is to restore complex tissues and biological systems through convergence in the fields of advanced biomaterials, stem cell science, and developmental biology. Hydrogels are one of the most attractive biomaterials for regenerative engineering, since they can be engineered into tissue mimetic 3D scaffolds to support cell growth due to their similarity to native extracellular matrix. Advanced nano- and micro-technologies have dramatically increased the ability to control properties and functionalities of hydrogel materials by facilitating biomimetic fabrication of more sophisticated compositions and architectures, thus extending our understanding of cell-matrix interactions at the nanoscale. With this perspective, this review discusses the most commonly used hydrogel materials and their fabrication strategies for regenerative engineering. We highlight the physical, chemical, and functional modulation of hydrogels to design and engineer biomimetic tissues based on recent achievements in nano- and micro-technologies. In addition, current hydrogel-based regenerative engineering strategies for treating multiple tissues, such as musculoskeletal, nervous and cardiac tissue, are also covered in this review. The interaction of multiple disciplines including materials science, cell biology, and chemistry, will further play an important role in the design of functional hydrogels for the regeneration of complex tissues. Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and Characterization of Elastin-Mimetic Hybrid Polymers with Multiblock, Alternating Molecular Architecture and Elastomeric Properties

PubMed Central

Grieshaber, Sarah E.; Farran, Alexandra J. E.; Lin-Gibson, Sheng; Kiick, Kristi L.; Jia, Xinqiao

2009-01-01

We are interested in developing elastin–mimetic hybrid polymers (EMHPs) that capture the multiblock molecular architecture of tropoelastin as well as the remarkable elasticity of mature elastin. In this study, multiblock EMHPs containing flexible synthetic segments based on poly(ethylene glycol) (PEG) alternating with alanine-rich, lysine-containing peptides were synthesized by step-growth polymerization using α,ω-azido-PEG and alkyne-terminated AKA3KA (K = lysine, A = alanine) peptide, employing orthogonal click chemistry. The resulting EMHPs contain an estimated three to five repeats of PEG and AKA3KA and have an average molecular weight of 34 kDa. While the peptide alone exhibited α-helical structures at high pH, the fractional helicity for EMHPs was reduced. Covalent cross-linking of EMHPs with hexamethylene diisocyanate (HMDI) through the lysine residue in the peptide domain afforded an elastomeric hydrogel (xEMHP) with a compressive modulus of 0.12 MPa when hydrated. The mechanical properties of xEMHP are comparable to a commercial polyurethane elastomer (Tecoflex SG80A) under the same conditions. In vitro toxicity studies showed that while the soluble EMHPs inhibited the growth of primary porcine vocal fold fibroblasts (PVFFs) at concentrations ≥0.2 mg/mL, the cross-linked hybrid elastomers did not leach out any toxic reagents and allowed PVFFs to grow and proliferate normally. The hybrid and modular approach provides a new strategy for developing elastomeric scaffolds for tissue engineering. PMID:19763157

Extension arm facilitated pegylation of alphaalpha-hemoglobin with modifications targeted exclusively to amino groups: functional and structural advantages of free Cys-93(beta) in the PEG-Hb adduct.

PubMed

Li, Dongxia; Hu, Tao; Manjula, Belur N; Acharya, Seetharama A

2009-11-01

Cys-93(beta) of hemoglobin (Hb) was reversibly protected as a mixed disulfide with thiopyridine during extension arm facilitated (EAF) PEGylation and its influence on the structural and functional properties of the EAF-PEG-Hb has been investigated. Avoiding PEGylation of Cys-93(beta) in the EAF-PEG-Hb lowers the level of perturbation of heme pocket, alpha1beta2 interface, autoxidation, heme loss, and the O(2) affinity, as compared to the EAF-PEG-Hb with PEGylation of Cys-93(beta).The structural and functional advantages of reversible protection of Cys-93(beta) during EAF PEGylation of oxy-Hb has been compared with Euro PEG-Hb generated by EAF PEGylation of deoxy Hb where Cys-93(beta) is free in the final product. The alphaalpha-fumaryl cross-linking and EAF PEGylation targeted exclusively to Lys residues has been combined together for generation of second-generation EAF-PEG-Hb with lower oxygen affinity. The PEG chains engineered on Lys as well as PEGylation of Cys-93(beta) independently contribute to the stabilization of oxy conformation of Hb and hence increase the oxygen affinity of Hb. However, oxygen affinity of the EAF-PEG-alphaalpha-Hb is more sensitive to the presence of PEGylation on Cys-93(beta) than that of the EAF-PEG-Hb. The present modified EAF PEGylation platform is expected to facilitate the design of novel versions of the EAF-PEG-Hbs that can now integrate the advantages of avoiding PEGylation of Cys-93(beta).

Hydrogels constructed via self-assembly of beta-hairpin molecules

NASA Astrophysics Data System (ADS)

Ozbas, Bulent

There is a recent and growing interest in hydrogel materials that are formed via peptide self-assembly for tissue engineering applications. Peptide based materials are excellent candidates for diverse applications in biomedical field due to their responsive behavior and complex self-assembled structures. However, there is very limited information on the self-assembly and resultant network and mechanical properties of these types of hydrogels. The main goal of this dissertation is to investigate the self-assembly mechanism and viscoelastic properties of hydrogels that can be altered by changing solution conditions as well as the primary structure of the peptide. These hydrogels are formed via intramolecular folding and consequent self-assembly of 20 amino acid long beta-hairpin peptide molecules (Max1). The peptide molecules are locally amphiphilic with two linear strands of alternating hydrophobic valine and hydrophilic lysine amino acids connected with a Dproline-LProline turn sequence. Circular dichroism and FTIR spectroscopy show that at physiological conditions peptides are unfolded in the absence of salt. By raising the ionic strength of the solution electrostatic interactions between charged lysines are screened and the peptide arms are forced into a beta-sheet secondary structure stabilized by the turn sequence. These folded molecules intermolecularly assemble via hydrophobic collapse and hydrogen bonding into a three dimensional network. Folding and self-assembly of these molecules can also be triggered by increasing temperature and/or pH of the peptide solution. In addition, the random-coil to beta-sheet transition of the beta-hairpin peptides is pH and, with proper changes in the peptide sequence, thermally reversible. Rheological measurements demonstrate that the resultant supramolecular structure forms an elastic material, whose structure, and thus modulus, can be tuned by magnitude of the stimulus. Hydrogels recover their initial viscoelastic properties after cessation of high magnitude of strain due to the physically crosslinked network structure and strong inter-fibrillar interactions. These interactions can be turned off by either condensing anions or covalently attaching PEG chains on lysine-decorated fibrillar surfaces. TEM, SANS, and rheological data reveal that the elasticity arises from a network consisting of semiflexible fibrillar assemblies that are monodisperse in width. The experimental results are compared with scaling relationships developed for permanently crosslinked semiflexible biopolymer networks. (Abstract shortened by UMI.)

Silk protein-based hydrogels: Promising advanced materials for biomedical applications.

PubMed

Kapoor, Sonia; Kundu, Subhas C

2016-02-01

Hydrogels are a class of advanced material forms that closely mimic properties of the soft biological tissues. Several polymers have been explored for preparing hydrogels with structural and functional features resembling that of the extracellular matrix. Favourable material properties, biocompatibility and easy processing of silk protein fibers into several forms make it a suitable material for biomedical applications. Hydrogels made from silk proteins have shown a potential in overcoming limitations of hydrogels prepared from conventional polymers. A great deal of effort has been made to control the properties and to integrate novel topographical and functional characteristics in the hydrogel composed from silk proteins. This review provides overview of the advances in silk protein-based hydrogels with a primary emphasis on hydrogels of fibroin. It describes the approaches used to fabricate fibroin hydrogels. Attempts to improve the existing properties or to incorporate new features in the hydrogels by making composites and by improving fibroin properties by genetic engineering approaches are also described. Applications of the fibroin hydrogels in the realms of tissue engineering and controlled release are reviewed and their future potentials are discussed. This review describes the potentiality of silk fibroin hydrogel. Silk Fibroin has been widely recognized as an interesting biomaterial. Due to its properties including high mechanical strength and excellent biocompatibility, it has gained wide attention. Several groups are exploring silk-based materials including films, hydrogels, nanofibers and nanoparticles for different biomedical applications. Although there is a good amount of literature available on general properties and applications of silk based biomaterials, there is an inadequacy of extensive review articles that specifically focus on silk based hydrogels. Silk-based hydrogels have a strong potential to be utilized in biomedical applications. Our work is an effort to highlight the research that has been done in the area of silk-based hydrogels. It aims to provide an overview of the advances that have been made and the future course available. It will provide an overview of the silk-based hydrogels as well as may direct the readers to the specific areas of application. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Clinical efficacy and safety of polyethylene glycol 3350 versus liquid paraffin in the treatment of pediatric functional constipation.

PubMed

Rafati, Mr; Karami, H; Salehifar, E; Karimzadeh, A

2011-01-01

Functional constipation is prevalent in children. Recently polyethylene glycol has been introduced as an effective and safe drug to treat chronic constipation. There are only a few clinical trials on comparison of PEG and liquid paraffin in childhood constipation. The purpose of this study was to evaluate clinical efficacy and safety of PEG 3350 solution and liquid paraffin in the treatment of children with functional constipation in Sari Toba clinic during the period of 2008-2009. Children with a history of functional constipation were subjects of this study. One hundred and sixty children of 2-12 years old with functional constipation were randomized in two PEG and paraffin treatment groups. Patients received either 1.0-1.5 g/kg/day PEG 3350 or 1.0-1.5 ml/kg/day liquid paraffin for 4 months. Clinical efficacy was evaluated by stool and encopresis frequency/week and overall treatment success rate was compared in two groups. Compared with the baseline, defecation frequency/ week increased significantly and encopresis frequency meaningfully decreased in two groups during the period of the study. Patients using PEG 3350 had more success rate (mean: 95.3%±3.7) compared with the patients in paraffin group (mean: 87.2%±7.1) (p=0.087). Administration of PEG 3350 were associated with less adverse events than liquid paraffin. In conclusion in treatment of pediatric functional constipation, regarding clinical efficacy and safety, PEG 3350 were at least as effective as liquid paraffin and but less adverse drug events.

Silk Fibroin Aqueous-Based Adhesives Inspired by Mussel Adhesive Proteins.

PubMed

Burke, Kelly A; Roberts, Dane C; Kaplan, David L

2016-01-11

Silk fibroin from the domesticated silkworm Bombyx mori is a naturally occurring biopolymer with charged hydrophilic terminal regions that end-cap a hydrophobic core consisting of repeating sequences of glycine, alanine, and serine residues. Taking inspiration from mussels that produce proteins rich in L-3,4-dihydroxyphenylalanine (DOPA) to adhere to a variety of organic and inorganic surfaces, the silk fibroin was functionalized with catechol groups. Silk fibroin was selected for its high molecular weight, tunable mechanical and degradation properties, aqueous processability, and wide availability. The synthesis of catechol-functionalized silk fibroin polymers containing varying amounts of hydrophilic polyethylene glycol (PEG, 5000 g/mol) side chains was carried out to balance silk hydrophobicity with PEG hydrophilicity. The efficiency of the catechol functionalization reaction did not vary with PEG conjugation over the range studied, although tuning the amount of PEG conjugated was essential for aqueous solubility. Adhesive bonding and cell compatibility of the resulting materials were investigated, where it was found that incorporating as little as 6 wt % PEG prior to catechol functionalization resulted in complete aqueous solubility of the catechol conjugates and increased adhesive strength compared with silk lacking catechol functionalization. Furthermore, PEG-silk fibroin conjugates maintained their ability to form β-sheet secondary structures, which can be exploited to reduce swelling. Human mesenchymal stem cells (hMSCs) proliferated on the silks, regardless of PEG and catechol conjugation. These materials represent a protein-based approach to catechol-based adhesives, which we envision may find applicability as biodegradable adhesives and sealants.

[Thromboresistance of glucose-containing hydrogels].

PubMed

Valuev, I L; Valuev, L I; Vanchugova, L V; Obydennova, I V; Valueva, T A

2013-01-01

The thromboresistance of glucose-sensitive polymer hydrogels, modeling one of the functions of the pancreas, namely, the ability to secrete insulin in response to the introduction of glucose into the environment, has been studied. Hydrogels were synthesized by the copolymerization of hydroxyethyl methacrylate with N-acryloyl glucosamine in the presence of a cross-linking agent and subsequently treated with concanavalin A. Introduction of glucose residues into the hydrogel did not result in significant changes in either the number of trombocytes adhered to the hydrogel or the degree of denaturation of blood plasma proteins interacting with the hydrogel. Consequently, the biological activity of insulin did not change after release from the hydrogel. The use of glucose-sensitive hydrogels is supposed to contribute to the development of a novel strategy for the treatment of diabetes.

Multifunctional 3D printing of heterogeneous hydrogel structures

NASA Astrophysics Data System (ADS)

Nadernezhad, Ali; Khani, Navid; Skvortsov, Gözde Akdeniz; Toprakhisar, Burak; Bakirci, Ezgi; Menceloglu, Yusuf; Unal, Serkan; Koc, Bahattin

2016-09-01

Multimaterial additive manufacturing or three-dimensional (3D) printing of hydrogel structures provides the opportunity to engineer geometrically dependent functionalities. However, current fabrication methods are mostly limited to one type of material or only provide one type of functionality. In this paper, we report a novel method of multimaterial deposition of hydrogel structures based on an aspiration-on-demand protocol, in which the constitutive multimaterial segments of extruded filaments were first assembled in liquid state by sequential aspiration of inks into a glass capillary, followed by in situ gel formation. We printed different patterned objects with varying chemical, electrical, mechanical, and biological properties by tuning process and material related parameters, to demonstrate the abilities of this method in producing heterogeneous and multi-functional hydrogel structures. Our results show the potential of proposed method in producing heterogeneous objects with spatially controlled functionalities while preserving structural integrity at the switching interface between different segments. We anticipate that this method would introduce new opportunities in multimaterial additive manufacturing of hydrogels for diverse applications such as biosensors, flexible electronics, tissue engineering and organ printing.

Multifunctional 3D printing of heterogeneous hydrogel structures

PubMed Central

Nadernezhad, Ali; Khani, Navid; Skvortsov, Gözde Akdeniz; Toprakhisar, Burak; Bakirci, Ezgi; Menceloglu, Yusuf; Unal, Serkan; Koc, Bahattin

2016-01-01

Multimaterial additive manufacturing or three-dimensional (3D) printing of hydrogel structures provides the opportunity to engineer geometrically dependent functionalities. However, current fabrication methods are mostly limited to one type of material or only provide one type of functionality. In this paper, we report a novel method of multimaterial deposition of hydrogel structures based on an aspiration-on-demand protocol, in which the constitutive multimaterial segments of extruded filaments were first assembled in liquid state by sequential aspiration of inks into a glass capillary, followed by in situ gel formation. We printed different patterned objects with varying chemical, electrical, mechanical, and biological properties by tuning process and material related parameters, to demonstrate the abilities of this method in producing heterogeneous and multi-functional hydrogel structures. Our results show the potential of proposed method in producing heterogeneous objects with spatially controlled functionalities while preserving structural integrity at the switching interface between different segments. We anticipate that this method would introduce new opportunities in multimaterial additive manufacturing of hydrogels for diverse applications such as biosensors, flexible electronics, tissue engineering and organ printing. PMID:27630079

Surface functionalization of gold nanoparticles using hetero-bifunctional poly(ethylene glycol) spacer for intracellular tracking and delivery

PubMed Central

Shenoy, Dinesh; Fu, Wei; Li, Jane; Crasto, Curtis; Jones, Graham; DiMarzio, Charles; Sridhar, Srinivas; Amiji, Mansoor

2006-01-01

For the development of surface-functionalized gold nanoparticles as cellular probes and delivery agents, we have synthesized hetero-bifunctional poly(ethylene glycol) (PEG, MW 1500) having a thiol group on one terminus and a reactive functional group on the other for use as a flexible spacer. Coumarin, a model fluorescent dye, was conjugated to one end of the PEG spacer and gold nanoparticles were modified with coumarin-PEG-thiol. Surface attachment of coumarin through the PEG spacer decreased the fluorescence quenching effect of gold nanoparticles. The results of cellular cytotoxicity and fluorescence confocal analyses showed that the PEG spacer-modified nanoparticles were essentially non-toxic and could be efficiently internalized in the cells within 1 hour of incubation. Intracellular particle tracking using a Keck 3-D Fusion Microscope System showed that the functionalized gold nanoparticles were rapidly internalized in the cells and localized in the peri-nuclear region. Using the PEG spacer, the gold nano-platform can be conjugated with a variety of biologically relevant ligands such as fluorescent dyes, antibodies, etc in order to target, probe, and induce a stimulus at the target site. PMID:16467923

Intraspinal Delivery of Polyethylene Glycol-coated Gold Nanoparticles Promotes Functional Recovery After Spinal Cord Injury.

PubMed

Papastefanaki, Florentia; Jakovcevski, Igor; Poulia, Nafsika; Djogo, Nevena; Schulz, Florian; Martinovic, Tamara; Ciric, Darko; Loers, Gabrielle; Vossmeyer, Tobias; Weller, Horst; Schachner, Melitta; Matsas, Rebecca

2015-06-01

Failure of the mammalian central nervous system (CNS) to regenerate effectively after injury leads to mostly irreversible functional impairment. Gold nanoparticles (AuNPs) are promising candidates for drug delivery in combination with tissue-compatible reagents, such as polyethylene glycol (PEG). PEG administration in CNS injury models has received interest for potential therapy, but toxicity and low bioavailability prevents clinical application. Here we show that intraspinal delivery of PEG-functionalized 40-nm-AuNPs at early stages after mouse spinal cord injury is beneficial for recovery. Positive outcome of hind limb motor function was accompanied by attenuated inflammatory response, enhanced motor neuron survival, and increased myelination of spared or regrown/sprouted axons. No adverse effects, such as body weight loss, ill health, or increased mortality were observed. We propose that PEG-AuNPs represent a favorable drug-delivery platform with therapeutic potential that could be further enhanced if PEG-AuNPs are used as carriers of regeneration-promoting molecules.

Glutathione-mediated release of Bodipy® from PEG cofunctionalized gold nanoparticles

PubMed Central

Kumar, Dhiraj; Meenan, Brian J; Dixon, Dorian

2012-01-01

Gold nanoparticles synthesized via sodium citrate reduction of chloroauric acid (HAuCl4) were functionalized with either various concentrations of thiol-terminated Bodipy® FL L-cystine (0.5, 1.0, 1.5, and 2.0 μg/mL) or Bodipy-poly(ethylene glycol) at concentrations of 0.5–18.75, 1.0–12.50, and 1.5–6.25 μg/mL to form a mixed monolayer of BODIPY-PEG. Thiol-terminated Bodipy, a fluorescing molecule, was used as the model drug, while PEG is widely used in drug-delivery applications to shield nanoparticles from unwanted immune responses. Understanding the influence of PEG-capping on payload release is critical because it is the most widely used type of nanoparticle functionalization in drug delivery studies. It has been previously reported that glutathione can trigger release of thiol-bound payloads from gold nanoparticles. Bodipy release from Bodipy capped and from Bodipy-PEG functionalized gold nanoparticles was studied at typical intracellular glutathione levels. It was observed that the addition of PEG capping inhibits the initial burst release observed in gold nanoparticles functionalized only with Bodipy and inhibits nanoparticle aggregation. Efficient and controlled payload release was observed in gold nanoparticles cofunctionalized with only a limited amount of PEG, thus enabling the coattachment of large amounts of drug, targeting groups or other payloads. PMID:22915847

In vivo biofunctional evaluation of hydrogels for disc regeneration.

PubMed

Reitmaier, Sandra; Kreja, Ludwika; Gruchenberg, Katharina; Kanter, Britta; Silva-Correia, Joana; Oliveira, Joaquim Miguel; Reis, Rui Luís; Perugini, Valeria; Santin, Matteo; Ignatius, Anita; Wilke, Hans-Joachim

2014-01-01

Regenerative strategies aim to restore the original biofunctionality of the intervertebral disc. Different biomaterials are available, which might support disc regeneration. In the present study, the prospects of success of two hydrogels functionalized with anti-angiogenic peptides and seeded with bone marrow derived mononuclear cells (BMC), respectively, were investigated in an ovine nucleotomy model. In a one-step procedure iliac crest aspirates were harvested and, subsequently, separated BMC were seeded on hydrogels and implanted into the ovine disc. For the cell-seeded approach a hyaluronic acid-based hydrogel was used. The anti-angiogenic potential of newly developed VEGF-blockers was investigated on ionically crosslinked metacrylated gellan gum hydrogels. Untreated discs served as nucleotomy controls. 24 adult merino sheep were used. After 6 weeks histological, after 12 weeks histological and biomechanical analyses were conducted. Biomechanical tests revealed no differences between any of the implanted and nucleotomized discs. All implanted discs significantly degenerated compared to intact discs. In contrast, there was no marked difference between implanted and nucleotomized discs. In tendency, albeit not significant, degeneration score and disc height index deteriorated for all but not for the cell-seeded hydrogels from 6 to 12 weeks. Cell-seeded hydrogels slightly decelerated degeneration. None of the hydrogel configurations was able to regenerate biofunctionality of the intervertebral disc. This might presumably be caused by hydrogel extrusion. Great importance should be given to the development of annulus sealants, which effectively exploit the potential of (cell-seeded) hydrogels for biological disc regeneration and restoration of intervertebral disc functioning.

One-step fabrication of PEGylated fluorescent nanodiamonds through the thiol-ene click reaction and their potential for biological imaging

NASA Astrophysics Data System (ADS)

Huang, Hongye; Liu, Meiying; Tuo, Xun; Chen, Junyu; Mao, Liucheng; Wen, Yuanqing; Tian, Jianwen; Zhou, Naigen; Zhang, Xiaoyong; Wei, Yen

2018-05-01

Over the past years, fluorescent carbon nanoparticles have got growing interest for biological imaging. Fluorescent nanodiamonds (FNDs) are novel fluorescent carbon nanoparticles with multitudinous useful properties, including remarkable fluorescence properties, extremely low toxicity and high refractive index. However, facile preparation of FNDs with designable properties and functions from non-fluorescent detonation nanodiamonds (DNDs) has demonstrated to be challengeable. In this work, we reported for the first time that preparation of Polyethylene glycol (PEG) functionalized FNDs through a one-step thiol-ene click reaction using thiol containing PEG (PEG-SH) as the coating agent. Based on the characterization results, we demonstrated that PEG-SH could be efficiently introduced on DNDs to obtain FNDs through the thiol-ene click chemistry. The resultant FND-PEG composites showed high water dispersibility, strong fluorescence and low cytotoxicity. Moreover, FND-PEG composites could be internalized by cells and displayed good cell dyeing performance. All of these features implied that FND-PEG composites are of great potential for biological imaging. Taken together, a facile one-step strategy based on the one-step thiol-ene click reaction has been developed for efficient preparation of FND-PEG composites from non-fluorescent DNDs. The strategy should be also useful for fabrication of many other functional FNDs via using different thiol containing compounds for the universality of thiol-ene click reaction.

Inkjet-Spray Hybrid Printing for 3D Freeform Fabrication of Multilayered Hydrogel Structures.

PubMed

Yoon, Sejeong; Park, Ju An; Lee, Hwa-Rim; Yoon, Woong Hee; Hwang, Dong Soo; Jung, Sungjune

2018-04-30

Here, a new bioprinting process by combining drop-on-demand inkjet printing with a spray-coating technique, which enables the high-resolution, high-speed, and freeform fabrication of large-scale cell-laden hydrogel structures is reported. Hydrogel structures with various shapes and composed of different materials, including alginate, cellulose nanofiber, and fibrinogen, are fabricated using the inkjet-spray printing. To manufacture cell-friendly hydrogel structures with controllable stiffness, gelatine methacryloyl is saponified to stabilize jet formation and is subsequently mixed with sodium alginate to prepare blend inks. The hydrogels crosslinked from the blend inks are characterized by assessing physical properties including the microstructure and mechanical stiffness and cellular responses including the cell viability, metabolic activity, and functionality of human dermal fibroblasts within the hydrogel. Cell-laden hydrogel structures are generated on a large scale and collagen type I secretion and spreading of cells within the hydrogels are assessed. The results demonstrate that the inkjet-spray printing system will ensure the formation of a cell-laden hydrogel structure with high shape fidelity in a rapid and reliable manner. Ultimately, the proposed printing technique and the blend bioink to be used to fabricate 3D laminated large-scale tissue equivalents that potentially mimic the function of native tissues is expected. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Facile synthesis of degradable and electrically conductive polysaccharide hydrogels.

PubMed

Guo, Baolin; Finne-Wistrand, Anna; Albertsson, Ann-Christine

2011-07-11

Degradable and electrically conductive polysaccharide hydrogels (DECPHs) have been synthesized by functionalizing polysaccharide with conductive aniline oligomers. DECPHs based on chitosan (CS), aniline tetramer (AT), and glutaraldehyde were obtained by a facile one-pot reaction by using the amine group of CS and AT under mild conditions, which avoids the multistep reactions and tedious purification involved in the synthesis of degradable conductive hydrogels in our previous work. Interestingly, these one-pot hydrogels possess good film-forming properties, electrical conductivity, and a pH-sensitive swelling behavior. The chemical structure and morphology before and after swelling of the hydrogels were verified by FT-IR, NMR, and SEM. The conductivity of the hydrogels was tuned by adjusting the content of AT. The swelling ratio of the hydrogels was altered by the content of tetraaniline and cross-linker. The hydrogels underwent slow degradation in a buffer solution. The hydrogels obtained by this facile approach provide new possibilities in biomedical applications, for example, biodegradable conductive hydrogels, films, and scaffolds for cardiovascular tissue engineering and controlled drug delivery.

On the development of multifunctional luminescent supramolecular hydrogel of gold and egg white

NASA Astrophysics Data System (ADS)

Patra, Sudeshna; Ravulapalli, Sathyavathi; Hahm, Myung Gwan; Tadi, Kiran Kumar; Narayanan, Tharangattu N.

2016-10-01

Highly stable, luminescent, and printable/paintable supramolecular egg white hydrogel-based surface enhanced Raman scattering (SERS) matrix is created by an in situ synthesis of gold clusters inside a luminescent egg white hydrogel (Au-Gel). The synthesis of stable luminescent egg-white-based hydrogel, where the hydrogel can act as a three dimensional (3D) matrix, using a simple cross-linking chemistry, has promising application in the biomedical field including in 3D cell culturing. Furthermore, this functional hydrogel is demonstrated for micromolar-level detection of Rhodamine 6G using the SERS technique, where Au-Gel is painted over a flexible cellulose pad.

Dual-responsive and Multi-functional Plasmonic Hydrogel Valves and Biomimetic Architectures Formed with Hydrogel and Gold Nanocolloids

PubMed Central

Song, Ji Eun; Cho, Eun Chul

2016-01-01

We present a straightforward approach with high moldability for producing dual-responsive and multi-functional plasmonic hydrogel valves and biomimetic architectures that reversibly change volumes and colors in response to temperature and ion variations. Heating of a mixture of hybrid colloids (gold nanoparticles assembled on a hydrogel colloid) and hydrogel colloids rapidly induces (within 30 min) the formation of hydrogel architectures resembling mold shapes (cylinder, fish, butterfly). The biomimetic fish and butterfly display reversible changes in volumes and colors with variations of temperature and ionic conditions in aqueous solutions. The cylindrical plasmonic valves installed in flow tubes rapidly control water flow rate in on-off manner by responding to these stimuli. They also report these changes in terms of their colors. Therefore, the approach presented here might be helpful in developing new class of biomimetic and flow control systems where liquid conditions should be visually notified (e.g., glucose or ion concentration changes). PMID:27703195

Intracellular production of hydrogels and synthetic RNA granules by multivalent enhancers

PubMed Central

Nakamura, Hideki; Lee, Albert A.; Afshar, Ali Sobhi; Watanabe, Shigeki; Rho, Elmer; Razavi, Shiva; Suarez, Allison; Lin, Yu-Chun; Tanigawa, Makoto; Huang, Brian; DeRose, Robert; Bobb, Diana; Hong, William; Gabelli, Sandra B.; Goutsias, John; Inoue, Takanari

2018-01-01

Non-membrane bound, hydrogel-like entities, such as RNA granules, nucleate essential cellular functions through their unique physico-chemical properties. However, these intracellular hydrogels have not been as extensively studied as their extracellular counterparts, primarily due to technical challenges in probing these materials in situ. Here, by taking advantage of a chemically inducible dimerization paradigm, we developed iPOLYMER, a strategy for rapid induction of protein-based hydrogels inside living cells. A series of biochemical and biophysical characterizations, in conjunction with computational modeling, revealed that the polymer network formed in the cytosol resembles a physiological hydrogel-like entity that behaves as a size-dependent molecular sieve. We studied several properties of the gel and functionalized it with RNA binding motifs that sequester polyadenine-containing nucleotides to synthetically mimic RNA granules. Therefore, we here demonstrate that iPOLYMER presents a unique and powerful approach to synthetically reconstitute hydrogel-like structures including RNA granules in intact cells. PMID:29115293

Development of chitosan/β-glycerophosphate/glycerol hydrogel as a thermosensitive coupling agent.

PubMed

Huang, Chih-Ling; Chen, Yu-Bin; Lo, Yu-Lung; Lin, Yi-Hsiang

2016-08-20

This work develops a dual-function thermosensitive hydrogel to prevent overheating, a side effect of focused ultrasound therapy. The proposed hydrogel has the components of chitosan, β-glycerophosphate, and glycerol. Its thermosensitive sol-to-gel transition gives an instant signal of overheating without the need of any awkward sensing device. Impacts of varying component concentrations on the sol-to-gel temperature, rate, and degree of transparency are also investigated. Chemical structures and ultrasonic coefficients after heating are obtained with a Fourier transform infrared spectroscopy and ultrasonic measurement, respectively. Optimized formula of the proposed hydrogel is 0.5% chitosan, 5% β-glycerophosphate, and 25% glycerol. This hydrogel has a high acoustic impedance (Z=1.8 Mrayl) close to that of human skin, high ultrasonic transmission (T=99%, which is normalized to water) from 25 to 55°C, and low attenuation coefficient (α=4.0Np/m). These properties assure the success of dual functions of the hydrogel developed in this work. Copyright © 2016 Elsevier Ltd. All rights reserved.

Polyethylene glycol 3350 without electrolytes for the treatment of functional constipation in infants and toddlers.

PubMed

Loening-Baucke, Vera; Krishna, Rachana; Pashankar, Dinesh S

2004-11-01

We have recently reported the safety and efficacy of polyethylene glycol 3350 without electrolytes (PEG) for the daily treatment of constipation in older children. Because there are very few data available on the use of PEG in infants and toddlers, we evaluated the efficacy and safety of PEG for the treatment of constipation in children <2 years of age. This is a retrospective chart review of 75 constipated children <2 years of age at start of PEG therapy. PEG was started at an average dose of 1 g/kg body weight/d and parents were asked to adjust the dose to yield 1 to 2 soft painless stools/d. Data from the history and physical examination were collected initially and at short-term (or=6 months) follow-up. 75 otherwise healthy children received PEG for functional constipation. The mean age was 17 months (range, 1 to 24 months) and the mean duration of constipation was 10 months (range, 0.5 to 23 months). The mean duration of short-term follow-up was 2 months and mean duration of long-term follow-up was 11 months. The mean effective short-term PEG dose was 1.1 g/kg body weight/d and the mean long-term dose was 0.8 g/kg body weight/d. Constipation was relieved in 85% with short-term and in 91% with long-term PEG therapy. Adverse effects were mild and included diarrhea, which disappeared with lowering the dose. No subjects stopped PEG because of adverse effects. PEG is effective, well tolerated and appeared safe for the treatment of functional constipation in children <2 years of age.

Safety Evaluation of Polyethylene Glycol (PEG) Compounds for Cosmetic Use

PubMed Central

Shin, Chan Young; Kim, Kyu-Bong

2015-01-01

Polyethylene glycols (PEGs) are products of condensed ethylene oxide and water that can have various derivatives and functions. Since many PEG types are hydrophilic, they are favorably used as penetration enhancers, especially in topical dermatological preparations. PEGs, together with their typically nonionic derivatives, are broadly utilized in cosmetic products as surfactants, emulsifiers, cleansing agents, humectants, and skin conditioners. The compounds studied in this review include PEG/PPG-17/6 copolymer, PEG-20 glyceryl triisostearate, PEG-40 hydrogenated castor oil, and PEG-60 hydrogenated castor oil. Overall, much of the data available in this review are on PEGylated oils (PEG-40 and PEG-60 hydrogenated castor oils), which were recommended as safe for use in cosmetics up to 100% concentration. Currently, PEG-20 glyceryl triisostearate and PEGylated oils are considered safe for cosmetic use according to the results of relevant studies. Additionally, PEG/PPG-17/6 copolymer should be further studied to ensure its safety as a cosmetic ingredient. PMID:26191379

Bio-inspired self-healing structural color hydrogel

PubMed Central

Fu, Fanfan; Chen, Zhuoyue; Zhao, Ze; Wang, Huan; Shang, Luoran; Gu, Zhongze

2017-01-01

Biologically inspired self-healing structural color hydrogels were developed by adding a glucose oxidase (GOX)- and catalase (CAT)-filled glutaraldehyde cross-linked BSA hydrogel into methacrylated gelatin (GelMA) inverse opal scaffolds. The composite hydrogel materials with the polymerized GelMA scaffold could maintain the stability of an inverse opal structure and its resultant structural colors, whereas the protein hydrogel filler could impart self-healing capability through the reversible covalent attachment of glutaraldehyde to lysine residues of BSA and enzyme additives. A series of unprecedented structural color materials could be created by assembling and healing the elements of the composite hydrogel. In addition, as both the GelMA and the protein hydrogels were derived from organisms, the composite materials presented high biocompatibility and plasticity. These features of self-healing structural color hydrogels make them excellent functional materials for different applications. PMID:28533368

Glucose-functionalized Au nanoprisms for optoacoustic imaging and near-infrared photothermal therapy

NASA Astrophysics Data System (ADS)

Han, Jishu; Zhang, Jingjing; Yang, Meng; Cui, Daxiang; de La Fuente, Jesus M.

2015-12-01

Targeted imaging and tumor therapy using nanomaterials has stimulated research interest recently, but the high cytotoxicity and low cellular uptake of nanomaterials limit their bioapplication. In this paper, glucose (Glc) was chosen to functionalize Au nanoprisms (NPrs) for improving the cytotoxicity and cellular uptake of Au@PEG-Glc NPrs into cancer cells. Glucose is a primary source of energy at the cellular level and at cellular membranes for cell recognition. A coating of glucose facilitates the accumulation of Au@PEG-Glc NPrs in a tumor region much more than Au@PEG NPrs. Due to the high accumulation and excellent photoabsorbing property of Au@PEG-Glc NPrs, enhanced optoacoustic imaging of a tumor in vivo was achieved, and visualization of the tumor further guided cancer treatment. Based on the optical-thermal conversion performance of Au@PEG-Glc NPrs, the tumor in vivo was effectively cured through photothermal therapy. The current work demonstrates the great potential of Au@PEG-Glc NPrs in optoacoustic imaging and photothermal cancer therapy in future.Targeted imaging and tumor therapy using nanomaterials has stimulated research interest recently, but the high cytotoxicity and low cellular uptake of nanomaterials limit their bioapplication. In this paper, glucose (Glc) was chosen to functionalize Au nanoprisms (NPrs) for improving the cytotoxicity and cellular uptake of Au@PEG-Glc NPrs into cancer cells. Glucose is a primary source of energy at the cellular level and at cellular membranes for cell recognition. A coating of glucose facilitates the accumulation of Au@PEG-Glc NPrs in a tumor region much more than Au@PEG NPrs. Due to the high accumulation and excellent photoabsorbing property of Au@PEG-Glc NPrs, enhanced optoacoustic imaging of a tumor in vivo was achieved, and visualization of the tumor further guided cancer treatment. Based on the optical-thermal conversion performance of Au@PEG-Glc NPrs, the tumor in vivo was effectively cured through photothermal therapy. The current work demonstrates the great potential of Au@PEG-Glc NPrs in optoacoustic imaging and photothermal cancer therapy in future. Electronic supplementary information (ESI) available: The evolution of the UV-vis absorption of Au NPrs by centrifugation, TEM image of PEG-capped Au NPrs, the UV-vis absorption of glucose, cytotoxicity of Au@PEG-Glc NPrs, gastric cell viabilities versus the concentration of Au@PEG-Glc NPrs and gastric cell viabilities filled with 80 μg Au@PEG-Glc NPrs versus the irradiation time, optoacoustic signals of Au NPr solution and Au@PEG NPrs. See DOI: 10.1039/c5nr06261f

Biomimetic Hydrogel Materials

DOEpatents

Bertozzi, Carolyn , Mukkamala, Ravindranath , Chen, Oing , Hu, Hopin , Baude, Dominique

2003-04-22

Novel biomimetic hydrogel materials and methods for their preparation. Hydrogels containing acrylamide-functionalized carbohydrate, sulfoxide, sulfide or sulfone copolymerized with a hydrophilic or hydrophobic copolymerizing material selected from the group consisting of an acrylamide, methacrylamide, acrylate, methacrylate, vinyl and a derivative thereof present in concentration from about 1 to about 99 wt %. and methods for their preparation. The method of use of the new hydrogels for fabrication of soft contact lenses and biomedical implants.

Biomimetic hydrogel materials

DOEpatents

Bertozzi, Carolyn; Mukkamala, Ravindranath; Chen, Qing; Hu, Hopin; Baude, Dominique

2000-01-01

Novel biomimetic hydrogel materials and methods for their preparation. Hydrogels containing acrylamide-functionalized carbohydrate, sulfoxide, sulfide or sulfone copolymerized with a hydrophilic or hydrophobic copolymerizing material selected from the group consisting of an acrylamide, methacrylamide, acrylate, methacrylate, vinyl and a derivative thereof present in concentration from about 1 to about 99 wt %. and methods for their preparation. The method of use of the new hydrogels for fabrication of soft contact lenses and biomedical implants.

Modulation of cultured neural networks using neurotrophin release from hydrogel-coated microelectrode arrays

NASA Astrophysics Data System (ADS)

Jun, Sang Beom; Hynd, Matthew R.; Dowell-Mesfin, Natalie M.; Al-Kofahi, Yousef; Roysam, Badrinath; Shain, William; Kim, Sung June

2008-06-01

Polyacrylamide and poly(ethylene glycol) diacrylate hydrogels were synthesized and characterized for use as drug release and substrates for neuron cell culture. Protein release kinetics was determined by incorporating bovine serum albumin (BSA) into hydrogels during polymerization. To determine if hydrogel incorporation and release affect bioactivity, alkaline phosphatase was incorporated into hydrogels and a released enzyme activity determined using the fluorescence-based ELF-97 assay. Hydrogels were then used to deliver a brain-derived neurotrophic factor (BDNF) from hydrogels polymerized over planar microelectrode arrays (MEAs). Primary hippocampal neurons were cultured on both control and neurotrophin-containing hydrogel-coated MEAs. The effect of released BDNF on neurite length and process arborization was investigated using automated image analysis. An increased spontaneous activity as a response to the released BDNF was recorded from the neurons cultured on the top of hydrogel layers. These results demonstrate that proteins of biological interest can be incorporated into hydrogels to modulate development and function of cultured neural networks. These results also set the stage for development of hydrogel-coated neural prosthetic devices for local delivery of various biologically active molecules.

Injectable biodegradable hydrogels for embryonic stem cell transplantation: improved cardiac remodelling and function of myocardial infarction

PubMed Central

Wang, Haibin; Liu, Zhiqiang; Li, Dexue; Guo, Xuan; Kasper, F Kurtis; Duan, Cuimi; Zhou, Jin; Mikos, Antonios G; Wang, Changyong

2012-01-01

Abstract In this study, an injectable, biodegradable hydrogel composite of oligo[poly(ethylene glycol) fumarate] (OPF) was investigated as a carrier of mouse embryonic stem cells (mESCs) for the treatment of myocardial infarction (MI). The OPF hydrogels were used to encapsulate mESCs. The cell differentiation in vitro over 14 days was determined via immunohistochemical examination. Then, mESCs encapsulated in OPF hydrogels were injected into the LV wall of a rat MI model. Detailed histological analysis and echocardiography were used to determine the structural and functional consequences after 4 weeks of transplantation. With ascorbic acid induction, mESCs could differentiate into cardiomyocytes and other cell types in all three lineages in the OPF hydrogel. After transplantation, both the 24-hr cell retention and 4-week graft size were significantly greater in the OPF + ESC group than that of the PBS + ESC group (P < 0.01). Four weeks after transplantation, OPF hydrogel alone significantly reduced the infarct size and collagen deposition and improved the cardiac function. The heart function and revascularization improved significantly, while the infarct size and fibrotic area decreased significantly in the OPF + ESC group compared with that of the PBS + ESC, OPF and PBS groups (P < 0.01). All treatments had significantly reduced MMP2 and MMP9 protein levels compared to the PBS control group, and the OPF + ESC group decreased most by Western blotting. Transplanted mESCs expressed cardiovascular markers. This study suggests the potential of a method for heart regeneration involving OPF hydrogels for stem cell encapsulation and transplantation. PMID:21838774

Clinical efficacy and safety of polyethylene glycol 3350 versus liquid paraffin in the treatment of pediatric functional constipation

PubMed Central

Rafati, MR.; Karami, H.; Salehifar, E.; Karimzadeh, A.

2011-01-01

Background and the purpose of the study Functional constipation is prevalent in children. Recently polyethylene glycol has been introduced as an effective and safe drug to treat chronic constipation. There are only a few clinical trials on comparison of PEG and liquid paraffin in childhood constipation. The purpose of this study was to evaluate clinical efficacy and safety of PEG 3350 solution and liquid paraffin in the treatment of children with functional constipation in Sari Toba clinic during the period of 2008–2009. Methods Children with a history of functional constipation were subjects of this study. One hundred and sixty children of 2–12 years old with functional constipation were randomized in two PEG and paraffin treatment groups. Patients received either 1.0–1.5 g/kg/day PEG 3350 or 1.0–1.5 ml/kg/day liquid paraffin for 4 months. Clinical efficacy was evaluated by stool and encopresis frequency/week and overall treatment success rate was compared in two groups. Results and major conclusion Compared with the baseline, defecation frequency/ week increased significantly and encopresis frequency meaningfully decreased in two groups during the period of the study. Patients using PEG 3350 had more success rate (mean: 95.3%±3.7) compared with the patients in paraffin group (mean: 87.2%±7.1) (p=0.087). Administration of PEG 3350 were associated with less adverse events than liquid paraffin. In conclusion in treatment of pediatric functional constipation, regarding clinical efficacy and safety, PEG 3350 were at least as effective as liquid paraffin and but less adverse drug events. PMID:22615652

Controlled Breast Cancer Microarrays for the Deconvolution of Cellular Multilayering and Density Effects upon Drug Responses

PubMed Central

Håkanson, Maria; Kobel, Stefan; Lutolf, Matthias P.; Textor, Marcus; Cukierman, Edna; Charnley, Mirren

2012-01-01

Background Increasing evidence shows that the cancer microenvironment affects both tumorigenesis and the response of cancer to drug treatment. Therefore in vitro models that selectively reflect characteristics of the in vivo environment are greatly needed. Current methods allow us to screen the effect of extrinsic parameters such as matrix composition and to model the complex and three-dimensional (3D) cancer environment. However, 3D models that reflect characteristics of the in vivo environment are typically too complex and do not allow the separation of discrete extrinsic parameters. Methodology/Principal Findings In this study we used a poly(ethylene glycol) (PEG) hydrogel-based microwell array to model breast cancer cell behavior in multilayer cell clusters that allows a rigorous control of the environment. The innovative array fabrication enables different matrix proteins to be integrated into the bottom surface of microwells. Thereby, extrinsic parameters including dimensionality, type of matrix coating and the extent of cell-cell adhesion could be independently studied. Our results suggest that cell to matrix interactions and increased cell-cell adhesion, at high cell density, induce independent effects on the response to Taxol in multilayer breast cancer cell clusters. In addition, comparing the levels of apoptosis and proliferation revealed that drug resistance mediated by cell-cell adhesion can be related to altered cell cycle regulation. Conversely, the matrix-dependent response to Taxol did not correlate with proliferation changes suggesting that cell death inhibition may be responsible for this effect. Conclusions/Significance The application of the PEG hydrogel platform provided novel insight into the independent role of extrinsic parameters controlling drug response. The presented platform may not only become a useful tool for basic research related to the role of the cancer microenvironment but could also serve as a complementary platform for in vitro drug development. PMID:22792141

Chemical Interactions of Polyethylene Glycols (PEG) and Glycerol with Protein Functional Groups: Applications to PEG, Glycerol Effects on Protein Processes

PubMed Central

Knowles, DB; Shkel, Irina A; Phan, Noel M; Sternke, Matt; Lingeman, Emily; Cheng, Xian; Cheng, Lixue; O’Connor, Kevin; Record, M. Thomas

2015-01-01

Here we obtain the data needed to predict chemical interactions of polyethylene glycols (PEGs) and glycerol with proteins and related organic compounds, and thereby interpret or predict chemical effects of PEGs on protein processes. To accomplish this we determine interactions of glycerol and tetraEG with >30 model compounds displaying the major C, N, and O functional groups of proteins. Analysis of these data yields coefficients (α-values) quantifying interactions of glycerol, tetraEG and PEG end (-CH2OH) and interior (-CH2OCH2-) groups with these groups, relative to interactions with water. TetraEG (strongly) and glycerol (weakly) interact favorably with aromatic C, amide N, and cationic N, but unfavorably with amide O, carboxylate O and salt ions. Strongly unfavorable O and salt anion interactions help make both small and large PEGs effective protein precipitants. Interactions of tetraEG and PEG interior groups with aliphatic C are quite favorable, while interactions of glycerol and PEG end groups with aliphatic C are not. Hence tetraEG and PEG 300 favor unfolding of the DNA-binding domain of lac repressor (lacDBD) while glycerol, di- and mono-ethylene glycol are stabilizers. Favorable interactions with aromatic and aliphatic C explain why PEG400 greatly increases the solubility of aromatic hydrocarbons and steroids. PEG400-steroid interactions are unusually favorable, presumably because of simultaneous interactions of multiple PEG interior groups with the fused ring system of the steroid. Using α-values reported here, chemical contributions to PEG m-values can be predicted or interpreted in terms of changes in water-accessible surface area (ΔASA), and separated from excluded volume effects. PMID:25962980

Functionalized graphene oxide quantum dot-PVA hydrogel: a colorimetric sensor for Fe2+, Co2+ and Cu2+ ions

NASA Astrophysics Data System (ADS)

Baruah, Upama; Chowdhury, Devasish

2016-04-01

Functionalized graphene oxide quantum dots (GOQDs)-poly(vinyl alcohol) (PVA) hybrid hydrogels were prepared using a simple, facile and cost-effective strategy. GOQDs bearing different surface functional groups were introduced as the cross-linking agent into the PVA matrix thereby resulting in gelation. The four different types of hybrid hydrogels were prepared using graphene oxide, reduced graphene oxide, ester functionalized graphene oxide and amine functionalized GOQDs as cross-linking agents. It was observed that the hybrid hydrogel prepared with amine functionalized GOQDs was the most stable. The potential applicability of using this solid sensing platform has been subsequently explored in an easy, simple, effective and sensitive method for optical detection of M2+ (Fe2+, Co2+ and Cu2+) in aqueous media involving colorimetric detection. Amine functionalized GOQDs-PVA hybrid hydrogel when put into the corresponding solution of Fe2+, Co2+ and Cu2+ renders brown, orange and blue coloration respectively of the solution detecting the presence of Fe2+, Co2+ and Cu2+ ions in the solution. The minimum detection limit observed was 1 × 10-7 M using UV-visible spectroscopy. Further, the applicability of the sensing material was also tested for a mixture of co-existing ions in solution to demonstrate the practical applicability of the system. Insight into the probable mechanistic pathway involved in the detection process is also being discussed.

Functional Self-Assembling Peptide Nanofiber Hydrogels Designed for Nerve Degeneration.

PubMed

Sun, Yuqiao; Li, Wen; Wu, Xiaoli; Zhang, Na; Zhang, Yongnu; Ouyang, Songying; Song, Xiyong; Fang, Xinyu; Seeram, Ramakrishna; Xue, Wei; He, Liumin; Wu, Wutian

2016-01-27

Self-assembling peptide (SAP) RADA16-I (Ac-(RADA)4-CONH2) has been suffering from a main drawback associated with low pH, which damages cells and host tissues upon direct exposure. In this study, we presented a strategy to prepare nanofiber hydrogels from two designer SAPs at neutral pH. RADA16-I was appended with functional motifs containing cell adhesion peptide RGD and neurite outgrowth peptide IKVAV. The two SAPs were specially designed to have opposite net charges at neutral pH, the combination of which created a nanofiber hydrogel (-IKVAV/-RGD) characterized by significantly higher G' than G″ in a viscoelasticity examination. Circular dichroism, Fourier transform infrared spectroscopy, and Raman measurements were performed to investigate the secondary structure of the designer SAPs, indicating that both the hydrophobic/hydrophilic properties and electrostatic interactions of the functional motifs play an important role in the self-assembling behavior of the designer SAPs. The neural progenitor cells (NPCs)/stem cells (NSCs) fully embedded in the 3D-IKVAV/-RGD nanofiber hydrogel survived, whereas those embedded within the RADA 16-I hydrogel hardly survived. Moreover, the -IKVAV/-RGD nanofiber hydrogel supported NPC/NSC neuron and astrocyte differentiation in a 3D environment without adding extra growth factors. Studies of three nerve injury models, including sciatic nerve defect, intracerebral hemorrhage, and spinal cord transection, indicated that the designer -IKVAV/-RGD nanofiber hydrogel provided a more permissive environment for nerve regeneration than the RADA 16-I hydrogel. Therefore, we reported a new mechanism that might be beneficial for the synthesis of SAPs for in vitro 3D cell culture and nerve regeneration.

Pegylated Interferon α-2a Triggers NK-Cell Functionality and Specific T-Cell Responses in Patients with Chronic HBV Infection without HBsAg Seroconversion

PubMed Central

Bruder Costa, Juliana; Dufeu-Duchesne, Tania; Leroy, Vincent; Bertucci, Inga; Bouvier-Alias, Magali; Pouget, Noelle; Brevot-Lutton, Ophelie; Bourliere, Marc; Zoulim, Fabien

2016-01-01

Pegylated interferon α-2a (Peg-IFN-α) represents a therapeutic alternative to the prolonged use of nucleos(t)ide analog (NA) in chronic hepatitis B (CHB) infection. The mechanisms leading to a positive clinical outcome remain unclear. As immune responses are critical for virus control, we investigated the effects of Peg-IFN-α on both innate and adaptive immunity, and related it to the clinical evolution. The phenotypic and functional features of the dendritic cells (DCs), natural killer (NK) cells and HBV-specific CD4/CD8 T cells were analyzed in HBeAg-negative CHB patients treated for 48-weeks with NA alone or together with Peg-IFN-α, before, during and up to 2-years after therapy. Peg-IFN-α induced an early activation of DCs, a potent expansion of the CD56bright NK subset, and enhanced the activation and functionality of the CD56dim NK subset. Peg-IFN-α triggered an increase in the frequencies of Th1- and Th17-oriented HBV-specific CD4/CD8 T cells. Peg-IFN-α reversed the unresponsiveness of patients to a specific stimulation. Most of the parameters returned to baseline after the stop of Peg-IFN-α therapy. Peg-IFN-α impacts both innate and adaptive immunity, overcoming dysfunctional immune responses in CHB patients. These modulations were not associated with seroconversion, which questioned the benefit of the add-on Peg-IFN-α treatment. PMID:27348813

An analysis of prognostic factors after percutaneous endoscopic gastrostomy placement in Japanese patients with amyotrophic lateral sclerosis.

PubMed

Nagashima, Kazuaki; Furuta, Natsumi; Makioka, Kouki; Fujita, Yukio; Ikeda, Masaki; Ikeda, Yoshio

2017-05-15

A percutaneous endoscopic gastrostomy (PEG) is an useful intervention for feeding of amyotrophic lateral sclerosis (ALS) patients who have lost oral intake function. The aim of this study was to investigate the risk factors for early death and the survival after PEG placement. A total of 102 ALS patients who underwent PEG placement were enrolled in this study. Patients were divided into two groups; the poor prognosis group included patients who died or needed permanent mechanical ventilation within 30days after PEG placement, and the good prognosis group included patients who did not meet the criteria of the poor prognosis group. Clinical characteristics, respiratory function, and nutritional parameters were compared for the two groups to assess the correlations between clinical and laboratory variables and early death after PEG placement. Multivariate analysis between two groups revealed that higher arterial carbon dioxide pressure (PaCO 2 ) and aphagia before PEG placement were significantly associated with the poor prognosis group. Multivariate analysis for survival also revealed that higher PaCO 2 and shorter duration from onset to PEG placement were significantly associated with shorter survival after PEG placement. In conclusion, respiratory and nutritional parameters are revealed to be important prognostic factors for ALS patients who undergo PEG placement. Copyright © 2017 Elsevier B.V. All rights reserved.

Supramolecular hydrogel formation between chitosan and hydroxypropyl β-cyclodextrin via Diels-Alder reaction and its drug delivery.

PubMed

Zhang, Mengke; Wang, Jinpeng; Jin, Zhengyu

2018-07-15

Chitosan-cyclodextrin hydrogel (CFCD) was prepared via Diels-Alder reaction between furfural functionalized chitosan (CF) and N-maleoyl alanine functionalized hydroxypropyl β-cyclodextrin (HPCD-AMI) in aqueous media without any catalyst or initiator. The CF and HPCD-AMI were confirmed by Fourier transform infrared spectroscopy and 1 H nuclear magnetic resonance spectroscopy. The resultant CFCD hydrogel was characterized in terms of thermal peripteries, microstructure, rheology behavior, and swelling capacity. The rheology analysis found that the storage modulus G' ranged from 1pa to 1200pa as the degree of furfural substitute on chitosan increased from 2.6% to 28.3%, indicating the hydrogel strength can be tuned readily by reaction stoichiometry. The swelling behaviors proved that CFCD hydrogel was pH-responsive with low swelling capacity, which would be preferable for drug delivery. Drug adsorption analysis showed the introduction of cyclodextrin into CFCD hydrogels promoted drug adsorption capacity. In addition, methyl orange cumulative release in PBS buffer was only 48.85% after 24h, suggesting CFCD hydrogel had good sustained release capacity on the loaded drug. Copyright © 2018 Elsevier B.V. All rights reserved.

Thermal Stabilization of Biologics with Photoresponsive Hydrogels.

PubMed

Sridhar, Balaji V; Janczy, John R; Hatlevik, Øyvind; Wolfson, Gabriel; Anseth, Kristi S; Tibbitt, Mark W

2018-03-12

Modern medicine, biological research, and clinical diagnostics depend on the reliable supply and storage of complex biomolecules. However, biomolecules are inherently susceptible to thermal stress and the global distribution of value-added biologics, including vaccines, biotherapeutics, and Research Use Only (RUO) proteins, requires an integrated cold chain from point of manufacture to point of use. To mitigate reliance on the cold chain, formulations have been engineered to protect biologics from thermal stress, including materials-based strategies that impart thermal stability via direct encapsulation of the molecule. While direct encapsulation has demonstrated pronounced stabilization of proteins and complex biological fluids, no solution offers thermal stability while enabling facile and on-demand release from the encapsulating material, a critical feature for broad use. Here we show that direct encapsulation within synthetic, photoresponsive hydrogels protected biologics from thermal stress and afforded user-defined release at the point of use. The poly(ethylene glycol) (PEG)-based hydrogel was formed via a bioorthogonal, click reaction in the presence of biologics without impact on biologic activity. Cleavage of the installed photolabile moiety enabled subsequent dissolution of the network with light and release of the encapsulated biologic. Hydrogel encapsulation improved stability for encapsulated enzymes commonly used in molecular biology (β-galactosidase, alkaline phosphatase, and T4 DNA ligase) following thermal stress. β-galactosidase and alkaline phosphatase were stabilized for 4 weeks at temperatures up to 60 °C, and for 60 min at 85 °C for alkaline phosphatase. T4 DNA ligase, which loses activity rapidly at moderately elevated temperatures, was protected during thermal stress of 40 °C for 24 h and 60 °C for 30 min. These data demonstrate a general method to employ reversible polymer networks as robust excipients for thermal stability of complex biologics during storage and shipment that additionally enable on-demand release of active molecules at the point of use.

Hydrogel ionotronics

NASA Astrophysics Data System (ADS)

Yang, Canhui; Suo, Zhigang

2018-06-01

An ionotronic device functions by a hybrid circuit of mobile ions and mobile electrons. Hydrogels are stretchable, transparent, ionic conductors that can transmit electrical signals of high frequency over long distance, enabling ionotronic devices such as artificial muscles, skins and axons. Moreover, ionotronic luminescent devices, ionotronic liquid crystal devices, touchpads, triboelectric generators, artificial eels and gel-elastomer-oil devices can be designed based on hydrogels. In this Review, we discuss first-generation hydrogel ionotronic devices and the challenges associated with the mechanical properties and the chemistry of the materials. We examine how strong and stretchable adhesion between hydrophilic and hydrophobic polymer networks can be achieved, how water can be retained in hydrogels and how to design hydrogels that resist fatigue under cyclic loads. Finally, we highlight applications of hydrogel ionotronic devices and discuss the future of the field.

A precision structured smart hydrogel for sensing applications

NASA Astrophysics Data System (ADS)

Menges, J.; Kleinschmidt, P.; Bart, H.-J.; Oesterschulze, E.

2017-10-01

We report on a macroinitiator based smart hydrogel film applied on a microcantilever for sensing applications. The studied hydrogel features a comparatively wide dynamic range for changes in the electrolyte's ionic strength. Furthermore, it offers a simple spin coating process for thin film deposition as well as the capability to obtain high aspect ratio microstructures by reactive ion etching. This makes the hydrogel compatible to microelectromechanical system integration. As a proof of concept, we study the response of hydrogel functionalized cantilevers in aqueous sodium chloride solutions of varying ionic strength. In contrast to the majority of hydrogel materials reported in the literature, we found that our hydrogel still responds in high ionic strength environments. This may be of future interest for sensing e.g., in sea water or physiological environments like urine.

Degradable Bone Graft Substitute for Effective Delivery of Multiple Growth Factors in the Treatment of Nonunion Fractures

DTIC Science & Technology

2011-10-01

During this reporting period, a more general set of hydrogel synthesis steps were defined which enables the incorporation of chitosan from multiple...sources and suppliers and still produce a consistent material. Functional behavior of the hydrogel was confirmed with a new source of chitosan ...inducing tissue ingrowth into a subcutaneously injected scaffold loaded with the composite xylan/ chitosan hydrogel. Delivery of new hydrogel treatment for

Characterization of superabsorbent hydrogel based on epichlorohydrin crosslink and carboxymethyl functionalization of cassava starch

NASA Astrophysics Data System (ADS)

Muharam, S.; Yuningsih, L. M.; Sumitra, M. R.

2017-07-01

Superabsorbent hydrogel was prepared by epichlorohydrin crosslink of cassava starch. Their swelling improved with added carboxymethyl group on the starch-epichlorohydrin structure. The structure and properties of starch-epichlorohydrin-carboxymethyl hydrogel were measured by SEM, FTIR, water and physiological solution absorption test and water retention test. The result showed that hydrogel displayed macroporous with heterogenous distribution and irregular surface was formed by epichlorohydrin and carboxymethyl bond in the structure of hydrogel. It was confirmed also by the FTIR spectra. The swelling ratio of starch-epichlorohydrin hydrogel to the water is 518 % and increased to 1,028.5 % with carboxymethyl addition on the structure. The best influence of the physiological solution to the swelling ratio of starch-epichlorohydrin-carboxymethyl hydrogel is urea solution. The water retention of starch-epichlorohydrin-carboxymethyl hydrogel in NaCl solution is better than in CaCl2 solution.

Hydrogel-coated feed spacers in two-phase flow cleaning in spiral wound membrane elements: a novel platform for eco-friendly biofouling mitigation.

PubMed

Wibisono, Yusuf; Yandi, Wetra; Golabi, Mohsen; Nugraha, Roni; Cornelissen, Emile R; Kemperman, Antoine J B; Ederth, Thomas; Nijmeijer, Kitty

2015-03-15

Biofouling is still a major challenge in the application of nanofiltration and reverse osmosis membranes. Here we present a platform approach for environmentally friendly biofouling control using a combination of a hydrogel-coated feed spacer and two-phase flow cleaning. Neutral (polyHEMA-co-PEG10MA), cationic (polyDMAEMA) and anionic (polySPMA) hydrogels have been successfully grafted onto polypropylene (PP) feed spacers via plasma-mediated UV-polymerization. These coatings maintained their chemical stability after 7 days incubation in neutral (pH 7), acidic (pH 5) and basic (pH 9) environments. Anti-biofouling properties of these coatings were evaluated by Escherichia coli attachment assay and nanofiltration experiments at a TMP of 600 kPag using tap water with additional nutrients as feed and by using optical coherence tomography. Especially the anionic polySPMA-coated PP feed spacer shows reduced attachment of E. coli and biofouling in the spacer-filled narrow channels resulting in delayed biofilm growth. Employing this highly hydrophilic coating during removal of biofouling by two-phase flow cleaning also showed enhanced cleaning efficiency, feed channel pressure drop and flux recoveries. The strong hydrophilic nature and the presence of negative charge on polySPMA are most probably responsible for the improved antifouling behavior. A combination of polySPMA-coated PP feed spacers and two-phase flow cleaning therefore is promising and an environmentally friendly approach to control biofouling in NF/RO systems employing spiral-wound membrane modules. Copyright © 2015 Elsevier Ltd. All rights reserved.

Swellable microparticles as carriers for sustained pulmonary drug delivery.

PubMed

El-Sherbiny, Ibrahim M; McGill, Shayna; Smyth, Hugh D C

2010-05-01

In this investigation, novel biodegradable physically crosslinked hydrogel microparticles were developed and evaluated in vitro as potential carriers for sustained pulmonary drug delivery. To facilitate sustained release in the lungs, aerosols must first navigate past efficient aerodynamic filtering to penetrate to the deep lung (requires small particle size) where they must then avoid rapid macrophage clearance (enhanced by large particle size). The strategy suggested in this study to solve this problem is to deliver drug-loaded hydrogel microparticles with aerodynamic characteristics allowing them to be respirable when dry but attain large swollen sizes once deposited on moist lung surfaces to reduce macrophage uptake rates. The microparticles are based on PEG graft copolymerized onto chitosan in combination with Pluronic(R) F-108 and were prepared via cryomilling. The synthesized polymers used in preparation of the microparticles were characterized using FTIR, EA, 2D-XRD, and differential scanning calorimetry (DSC). The microparticles size, morphology, moisture content, and biodegradation rates were investigated. Swelling studies and in vitro drug release profiles were determined. An aerosolization study was conducted and macrophage uptake rates were evaluated against controls. The microparticles showed a respirable fraction of approximately 15% when prepared as dry powders. Enzymatic degradation of microparticles started within the first hour and about 7-41% weights were remaining after 240 h. Microparticles showed sustained release up to 10 and 20 days in the presence and absence of lysozyme, respectively. Preliminary macrophage interaction studies indicate that the developed hydrogel microparticles significantly delayed phagocytosis and may have the potential for sustained drug delivery to the lung.

25th Anniversary Article: Rational Design and Applications of Hydrogels in Regenerative Medicine

PubMed Central

Annabi, Nasim; Tamayol, Ali; Uquillas, Jorge Alfredo; Akbari, Mohsen; Bertassoni, Luiz E.; Cha, Chaenyung; Camci-Unal, Gulden; Dokmeci, Mehmet R.

2014-01-01

Hydrogels are hydrophilic polymer-based materials with high water content and physical characteristics that resemble the native extracellular matrix. Because of their remarkable properties, hydrogel systems are used for a wide range of biomedical applications, such as three-dimensional (3D) matrices for tissue engineering, drug-delivery vehicles, composite biomaterials, and as injectable fillers in minimally invasive surgeries. In addition, the rational design of hydrogels with controlled physical and biological properties can be used to modulate cellular functionality and tissue morphogenesis. Here, the development of advanced hydrogels with tunable physiochemical properties is highlighted, with particular emphasis on elastomeric, light-sensitive, composite, and shape-memory hydrogels. Emerging technologies developed over the past decade to control hydrogel architecture are also discussed and a number of potential applications and challenges in the utilization of hydrogels in regenerative medicine are reviewed. It is anticipated that the continued development of sophisticated hydrogels will result in clinical applications that will improve patient care and quality of life. PMID:24741694

Efficient adsorption of Au(CN)2- from gold cyanidation with graphene oxide-polyethylenimine hydrogel as adsorbent

NASA Astrophysics Data System (ADS)

Yang, Lang; Jia, Feifei; Yang, Bingqiao; Song, Shaoxian

The adsorption of gold cyanide complex ion (Au(CN)2-) on graphene oxide-polyethylenimine hydrogel (GO/PEI hydrogel) from gold cyanidation has been studied to explore the possibility of the application of GO/PEI hydrogel in gold cyanidation process for extracting gold from ores. The adsorption was carried out in artificial Au(CN)2- aqueous solution with GO/PEI hydrogel as adsorbent. The experimental results, as well as IR, XPS and SEM-EDS, have shown that GO/PEI hydrogel exhibited a high adsorption capacity and a fast adsorption rate of Au(CN)2-, suggesting that GO/PEI hydrogel might be a good adsorbent for the recovery of Au(CN)2-. The adsorption of Au(CN)2- on GO/PEI hydrogel obeyed the Langmuir isotherm model and fitted well with the pseudo second order model. The good recovery of Au(CN)2- was largely related to the porous structure, large specific surface area, as well as the oxygenous functional groups on the surface of GO/PEI hydrogel.

Peptide-Modified Zwitterionic Porous Hydrogels for Endothelial Cell and Vascular Engineering

PubMed Central

Lin, Chih-Yeh; Wang, Yi-Ren; Lin, Che-Wei; Wang, Shih-Wen; Chien, Hsiu-Wen; Cheng, Nai-Chen; Tsai, Wei-Bor

2014-01-01

Abstract Hydrogels allow control of gel composition and mechanics, and permit incorporation of cells and a wide variety of molecules from nanoparticles to micromolecules. Peptide-linked hydrogels should tune the basic polymer into a more bioactive template to influence cellular activities. In this study, we first introduced the generation of 2D poly-(sulfobetaine methacrylate [SBMA]) hydrogel surfaces. By incorporating with functional peptide RGD and vascular endothelial growth factor-mimicking peptide KLTWQELYQLKYKG (QK) peptides, endothelial cells attached to the surface well and proliferated in a short-term culturing. However, the mechanical property, which plays a crucial role directing the cellular functions and supporting the structures, decreased when peptides graft onto hydrogels. Manipulating the mechanical property was thus necessary, and the most related factor was the monomer concentration. From our results, the higher amount of SBMA caused greater stiffness in hydrogels. Following the 2D surface studies, we fabricated 3D porous hydrogels for cell scaffolds by several methods. The salt/particle leaching method showed a more reliable way than gas-foaming method to fabricate homogeneous and open-interconnected pores within the hydrogel. Using the salt/particle leaching method, we can control the pore size before leaching. Morphology of endothelial cells within scaffolds was also investigated by scanning electron microscopy, and histological analysis was conducted in vitro and in vivo to test the biocompatibility of SB hydrogel and its potential as a therapeutic reagent for ischemic tissue repair in mice. PMID:25469315

3-Dimensional functionalized polycaprolactone-hyaluronic acid hydrogel constructs for bone tissue engineering.

PubMed

Hamlet, Stephen M; Vaquette, Cedryck; Shah, Amit; Hutmacher, Dietmar W; Ivanovski, Saso

2017-04-01

Alveolar bone regeneration remains a significant clinical challenge in periodontology and dental implantology. This study assessed the mineralized tissue forming potential of 3-D printed medical grade polycaprolactone (mPCL) constructs containing osteoblasts (OB) encapsulated in a hyaluronic acid (HA)-hydrogel incorporating bone morphogenetic protein-7 (BMP-7). HA-hydrogels containing human OB ± BMP-7 were prepared. Cell viability, osteogenic gene expression, mineralized tissue formation and BMP-7 release in vitro, were assessed by fluorescence staining, RT-PCR, histological/μ-CT examination and ELISA respectively. In an athymic rat model, subcutaneous ectopic mineralized tissue formation in mPCL-hydrogel constructs was assessed by μ-CT and histology. Osteoblast encapsulation in HA-hydrogels did not detrimentally effect cell viability, and 3-D culture in osteogenic media showed mineralized collagenous matrix formation after 6 weeks. BMP-7 release from the hydrogel was biphasic, sustained and increased osteogenic gene expression in vitro. After 4 weeks in vivo, mPCL-hydrogel constructs containing BMP-7 formed significantly more volume (mm 3 ) of vascularized bone-like tissue. Functionalized mPCL-HA hydrogel constructs provide a favourable environment for bone tissue engineering. Although encapsulated cells contributed to mineralized tissue formation within the hydrogel in vitro and in vivo, their addition did not result in an improved outcome compared to BMP-7 alone. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hydrogel Bioprinted Microchannel Networks for Vascularization of Tissue Engineering Constructs

PubMed Central

Bertassoni, Luiz E.; Cecconi, Martina; Manoharan, Vijayan; Nikkhah, Mehdi; Hjortnaes, Jesper; Cristino, Ana Luiza; Barabaschi, Giada; Demarchi, Danilo; Dokmeci, Mehmet R.; Yang, Yunzhi; Khademhosseini, Ali

2014-01-01

Vascularization remains a critical challenge in tissue engineering. The development of vascular networks within densely populated and metabolically functional tissues facilitate transport of nutrients and removal of waste products, thus preserving cellular viability over a long period of time. Despite tremendous progress in fabricating complex tissue constructs in the past few years, approaches for controlled vascularization within hydrogel based engineered tissue constructs have remained limited. Here, we report a three dimensional (3D) micromolding technique utilizing bioprinted agarose template fibers to fabricate microchannel networks with various architectural features within photo cross linkable hydrogel constructs. Using the proposed approach, we were able to successfully embed functional and perfusable microchannels inside methacrylated gelatin (GelMA), star poly (ethylene glycol-co-lactide) acrylate (SPELA), poly (ethylene glycol) dimethacrylate (PEGDMA) and poly (ethylene glycol) diacrylate (PEGDA) hydrogels at different concentrations. In particular, GelMA hydrogels were used as a model to demonstrate the functionality of the fabricated vascular networks in improving mass transport, cellular viability and differentiation within the cell-laden tissue constructs. In addition, successful formation of endothelial monolayers within the fabricated channels was confirmed. Overall, our proposed strategy represents an effective technique for vascularization of hydrogel constructs with useful applications in tissue engineering and organs on a chip. PMID:24860845

Nanocomposite Hydrogels: 3D Polymer-Nanoparticle Synergies for On-Demand Drug Delivery.

PubMed

Merino, Sonia; Martín, Cristina; Kostarelos, Kostas; Prato, Maurizio; Vázquez, Ester

2015-05-26

Considerable progress in the synthesis and technology of hydrogels makes these materials attractive structures for designing controlled-release drug delivery systems. In particular, this review highlights the latest advances in nanocomposite hydrogels as drug delivery vehicles. The inclusion/incorporation of nanoparticles in three-dimensional polymeric structures is an innovative means for obtaining multicomponent systems with diverse functionality within a hybrid hydrogel network. Nanoparticle-hydrogel combinations add synergistic benefits to the new 3D structures. Nanogels as carriers for cancer therapy and injectable gels with improved self-healing properties have also been described as new nanocomposite systems.

Investigation of the role of hydrophilic chain length in amphiphilic perfluoropolyether/poly(ethylene glycol) networks: towards high-performance antifouling coatings.

PubMed

Wang, Yapei; Pitet, Louis M; Finlay, John A; Brewer, Lenora H; Cone, Gemma; Betts, Douglas E; Callow, Maureen E; Callow, James A; Wendt, Dean E; Hillmyer, Marc A; DeSimonea, Joseph M

2011-01-01

The facile preparation of amphiphilic network coatings having a hydrophobic dimethacryloxy-functionalized perfluoropolyether (PFPE-DMA; M(w) = 1500 g mol(-1)) crosslinked with hydrophilic monomethacryloxy functionalized poly(ethylene glycol) macromonomers (PEG-MA; M(w) = 300, 475, 1100 g mol(-1)), intended as non-toxic high-performance marine coatings exhibiting antifouling characteristics is demonstrated. The PFPE-DMA was found to be miscible with the PEG-MA. Photo-cured blends of these materials containing 10 wt% of PEG-MA oligomers did not swell significantly in water. PFPE-DMA crosslinked with the highest molecular weight PEG oligomer (ie PEG1100) deterred settlement (attachment) of algal cells and cypris larvae of barnacles compared to a PFPE control coating. Dynamic mechanical analysis of these networks revealed a flexible material. Preferential segregation of the PEG segments at the polymer/air interface resulted in enhanced antifouling performance. The cured amphiphilic PFPE/PEG films showed decreased advancing and receding contact angles with increasing PEG chain length. In particular, the PFPE/PEG1100 network had a much lower advancing contact angle than static contact angle, suggesting that the PEG1100 segments diffuse to the polymer/water interface quickly. The preferential interfacial aggregation of the larger PEG segments enables the coating surface to have a substantially enhanced resistance to settlement of spores of the green seaweed Ulva, cells of the diatom Navicula and cypris larvae of the barnacle Balanus amphitrite as well as low adhesion of sporelings (young plants) of Ulva, adhesion being lower than to a polydimethyl elastomer, Silastic T2.

Electron-beam-initiated polymerization of poly(ethylene glycol)-based wood impregnants.

PubMed

Trey, Stacy M; Netrval, Julia; Berglund, Lars; Johansson, Mats

2010-11-01

The current study demonstrates that methacrylate and acrylate poly(ethylene glycol) (PEG) functional oligomers can be effectively impregnated into wood blocks, and cured efficiently to high conversions without catalyst by e-beam radiation, allowing for less susceptibility to leaching, and favorable properties including higher Brinell hardness values. PEG based monomers were chosen because there is a long history of this water-soluble monomer being able to penetrate the cell wall, thus bulking it and decreasing the uptake of water which further protects the wood from fungal attack. Diacrylate, dimethacrylate, and dihydroxyl functional PEG of M(w) 550-575, of concentrations 0, 30, 60, and 100 wt % in water, were vacuum pressure impregnated into Scots Pine blocks of 15 × 25 × 50 mm in an effort to bulk the cell wall. The samples were then irradiated and compared with nonirradiated samples. It was shown by IR, DSC that the acrylate polymers were fully cured to much higher conversions than can be reached with conventional methods. Leaching studies indicated a much lower amount of oligomer loss from the cured vinyl functional PEG chains in comparison to hydroxyl functional PEG indicating a high degree of fastening of the polymer in the wood. The Brinell hardness indicated a significant increase in hardness to hardwood levels in the modified samples compared to the samples of hydroxyl functional PEG and uncured vinyl PEG samples, which actually became softer than the untreated Scots Pine. By monitoring the dimensions of the sample it was found by weight percent gain calculations (WPG %) that water helps to swell the wood structure and allow better access of the oligomers into the cell wall. Further, the cure shrinkage of the wood samples demonstrated infiltration of the oligomers into the cell wall as this was not observed for methyl methacrylate which is well-documented to remain in the lumen. However, dimensional stability of the vinyl polymer modified blocks when placed in water was not observed to the same extent as PEG.

Biomimetic hydrogels direct spinal progenitor cell differentiation and promote functional recovery after spinal cord injury.

PubMed

Geissler, Sydney A; Sabin, Alexandra L; Besser, Rachel R; Gooden, Olivia M; Shirk, Bryce D; Nguyen, Quan M; Khaing, Zin Z; Schmidt, Christine E

2018-04-01

Demyelination that results from disease or traumatic injury, such as spinal cord injury (SCI), can have a devastating effect on neural function and recovery. Many researchers are examining treatments to minimize demyelination by improving oligodendrocyte availability in vivo. Transplantation of stem and oligodendrocyte progenitor cells is a promising option, however, trials are plagued by undirected differentiation. Here we introduce a biomaterial that has been optimized to direct the differentiation of neural progenitor cells (NPCs) toward oligodendrocytes as a cell delivery vehicle after SCI. A collagen-based hydrogel was modified to mimic the mechanical properties of the neonatal spinal cord, and components present in the developing extracellular matrix were included to provide appropriate chemical cues to the NPCs to direct their differentiation toward oligodendrocytes. The hydrogel with cells was then transplanted into a unilateral cervical contusion model of SCI to examine the functional recovery with this treatment. Six behavioral tests and histological assessment were performed to examine the in vivo response to this treatment. Our results demonstrate that we can achieve a significant increase in oligodendrocyte differentiation of NPCs compared to standard culture conditions using a three-component biomaterial composed of collagen, hyaluronic acid, and laminin that has mechanical properties matched to those of neonatal neural tissue. Additionally, SCI rats with hydrogel transplants, with and without NPCs, showed functional recovery. Animals transplanted with hydrogels with NPCs showed significantly increased functional recovery over six weeks compared to the media control group. The three-component hydrogel presented here has the potential to provide cues to direct differentiation in vivo to encourage regeneration of the central nervous system.

Biodistribution and toxicological study of PEGylated single-wall carbon nanotubes in the zebrafish (Danio rerio) nervous system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weber, Gisele E.B.; Dal Bosco, Lidiane; Programa de Pós-graduação em Ciências Fisiológicas–Fisiologia Animal Comparada, FURG, Rio Grande, RS, 96210-900

Nanotechnology has been proven to be increasingly compatible with pharmacological and biomedical applications. Therefore, we evaluated the biological interactions of single-wall carbon nanotubes functionalized with polyethylene glycol (SWNT-PEG). For this purpose, we analyzed biochemical, histological, behavioral and biodistribution parameters to understand how this material behaves in vitro and in vivo using the fish Danio rerio (zebrafish) as a biological model. The in vitro results for fish brain homogenates indicated that SWNT-PEG had an effect on lipid peroxidation and GSH (reduced glutathione) content. However, after intraperitoneal exposure, SWNT-PEG proved to be less biocompatible and formed aggregates, suggesting that the PEG usedmore » for the nanoparticle functionalization was of an inappropriate size for maintaining product stability in a biological environment. This problem with functionalization may have contributed to the low or practically absent biodistribution of SWNT-PEG in zebrafish tissues, as verified by Raman spectroscopy. There was an accumulation of material in the abdominal cavity that led to inflammation and behavioral disturbances, as evaluated by a histological analysis and an open field test, respectively. These results provide evidence of a lack of biocompatibility of SWNTs modified with short chain PEGs, which leads to the accumulation of the material, tissue damage and behavioral alterations in the tested subjects. - Highlights: • In vitro brain exposure diminished lipid peroxidation. • In vitro brain exposure depletes the GSH content. • SWNT-PEG was not biocompatible and formed aggregates after the exposure. • Practically absent biodistribution of SWNT-PEG was observed by Raman spectroscopy. • SWNT-PEG exposure lead to tissue damage and inflammatory responses.« less

The role of environmental factors in regulating the development of cartilaginous grafts engineered using osteoarthritic human infrapatellar fat pad-derived stem cells.

PubMed

Liu, Yurong; Buckley, Conor T; Downey, Richard; Mulhall, Kevin J; Kelly, Daniel J

2012-08-01

Engineering functional cartilaginous grafts using stem cells isolated from osteoarthritic human tissue is of fundamental importance if autologous tissue engineering strategies are to be used in the treatment of diseased articular cartilage. It has previously been demonstrated that human infrapatellar fat pad (IFP)-derived stem cells undergo chondrogenesis in pellet culture; however, the ability of such cells to generate functional cartilaginous grafts has not been adequately addressed. The objective of this study was to explore how environmental conditions regulate the functional development of cartilaginous constructs engineered using diseased human IFP-derived stem cells (FPSCs). FPSCs were observed to display a diminished chondrogenic potential upon encapsulation in a three-dimensional hydrogel compared with pellet culture, synthesizing significantly lower levels of glycosaminoglycan and collagen on a per cell basis. To engineer more functional cartilaginous grafts, we next explored whether additional biochemical and biophysical stimulations would enhance chondrogenesis within the hydrogels. Serum stimulation was observed to partially recover the diminished chondrogenic potential within hydrogel culture. Over 42 days, stem cells that had first been expanded in a low-oxygen environment proliferated extensively on the outer surface of the hydrogel in response to serum stimulation, assembling a dense type II collagen-positive cartilaginous tissue resembling that formed in pellet culture. The application of hydrostatic pressure did not further enhance extracellular matrix synthesis within the hydrogels, but did appear to alter the spatial accumulation of extracellular matrix leading to the formation of a more compact tissue with superior mechanically functionality. Further work is required in order to recapitulate the environmental conditions present during pellet culture within scaffolds or hydrogels in order to engineer more functional cartilaginous grafts using human osteoarthritic FPSCs.

Strong tissue glue with tunable elasticity.

PubMed

Kelmansky, Regina; McAlvin, Brian J; Nyska, Abraham; Dohlman, Jenny C; Chiang, Homer H; Hashimoto, Michinao; Kohane, Daniel S; Mizrahi, Boaz

2017-04-15

Many bio-adhesive materials adhere weakly to tissue due to their high water content and weak structural integrity. Others provide desirable adhesive strength but suffer from rigid structure and lack of elasticity after administration. We have developed two water-free, liquid four-armed PEG pre-polymers modified with NHS or with NH 2 end groups which upon mixing changed from liquids to an elastic solid. The sealant and adhesive properties increased with the amount of the %v/v PEG 4 -NHS pre-polymer, and achieved adhesive properties comparable to those of cyanoacrylate glues. All mixtures showed minimal cytotoxicity in vitro. Mixtures of 90%v/v PEG 4 -NHS were retained in the subcutaneous space in vivo for up to 14days with minimal inflammation. This material's combination of desirable mechanical properties and biocompatibility has potential in numerous biomedical applications. Many bio-adhesive materials adhere weakly to tissue (e.g. hydrogels) due to their high water content and weak structural integrity. Others provide desirable mechanical properties but suffer from poor biocompatibility (e.g. cyanoacrylates). This study proposes a new concept for the formation of super strong and tunable tissue glues. Our bio-materials' enhanced performance is the product of new neat (without water or other solvents) liquid polymers that solidify after administration while allowing interactions with the tissue. Moreover, the elastic modulus of these materials could easily be tuned without compromising biocompatibility. This system could be an attractive alternative to sutures and staples since it can be applied more quickly, causes less pain and may require less equipment while maintaining the desired adhesion strength. Copyright © 2017 Acta Materialia Inc. All rights reserved.

Synthesis and evaluation of functional alginate hydrogels based on click chemistry for drug delivery applications.

PubMed

García-Astrain, Clara; Avérous, Luc

2018-06-15

Environment-sensitive alginate-based hydrogels for drug delivery applications are receiving increasing attention. However, most work in this field involves traditional cross-linking strategies which led to hydrogels with poor long-term stability. Herein, a series of chemically cross-linked alginate hydrogels was synthesized via click chemistry using Diels-Alder reaction by reacting furan-modified alginate and bifunctional cross-linkers. Alginate was successfully functionalized with furfurylamine. Then, 3D architectures were synthesized with water-soluble bismaleimides. Different substitution degrees were achieved in order to study the effect of alginate modification and the cross-linking extent over the behaviour of the hydrogels. The ensuing hydrogels were analysed in terms of microstructure, swelling, structure modification and rheological behaviour. The materials response to external stimuli such as pH was also investigated, revealing a pulsatile behaviour in a large pH range (1-13) and a clear pH-dependent swelling. Finally, vanillin release studies were conducted to demonstrate the potential of these biobased materials for drug delivery applications. Copyright © 2018 Elsevier Ltd. All rights reserved.

Silver nanoparticles-containing dual-function hydrogels based on a guar gum-sodium borohydride system

PubMed Central

Dai, Lei; Nadeau, Ben; An, Xingye; Cheng, Dong; Long, Zhu; Ni, Yonghao

2016-01-01

Dual-function hydrogels, possessing both stimuli-responsive and self-healing properties, have recently attracted attention of both chemists and materials scientists. Here we report a new paradigm using natural polymer (guar gum, GG) and sodium borohydride (NaBH4), for the preparation of silver nanoparticles (AgNPs)-containing smart hydrogels in a simple, fast and economical way. NaBH4 performs as a reducing agent for AgNPs synthesis using silver nitrate (AgNO3) as the precursor. Meanwhile, sodium metaborate (NaBO2) (from NaBH4) behaves as a cross-linking agent between GG molecular chains. The AgNPs/GG hydrogels with excellent viscoelastic properties can be obtained within 3 min at room temperature without the addition of other cross-linkers. The resultant AgNPs/GG hydrogels are flowable and injectable, and they possess excellent pH/thermal responsive properties. Additionally, they exhibit rapid self-healing capacity. This work introduces a facile and scale-up way to prepare a class of hydrogels that can have great potential to biomedical and other industrial applications. PMID:27819289

Fluorescent Dendritic Micro-Hydrogels: Synthesis, Analysis and Use in Single-Cell Detection.

PubMed

Christadore, Lisa; Grinstaff, Mark W; Schaus, Scott E

2018-04-18

Hydrogels are of keen interest for a wide range of medical and biotechnological applications including as 3D substrate structures for the detection of proteins, nucleic acids, and cells. Hydrogel parameters such as polymer wt % and crosslink density are typically altered for a specific application; now, fluorescence can be incorporated into such criteria by specific macromonomer selection. Intrinsic fluorescence was observed at λ max 445 nm from hydrogels polymerized from lysine and aldehyde- terminated poly(ethylene glycol) macromonomers upon excitation with visible light. The hydrogel’s photochemical properties are consistent with formation of a nitrone functionality. Printed hydrogels of 150 μm were used to detect individual cell adherence via a decreased in fluorescence. The use of such intrinsically fluorescent hydrogels as a platform for cell sorting and detection expands the current repertoire of tools available.

DNA Hydrogel with Tunable pH-Responsive Properties Produced by Rolling Circle Amplification.

PubMed

Xu, Wanlin; Huang, Yishun; Zhao, Haoran; Li, Pan; Liu, Guoyuan; Li, Jing; Zhu, Chengshen; Tian, Leilei

2017-12-22

Recently, smart DNA hydrogels, which are generally formed by the self-assembly of oligonucleotides or through the cross-linking of oligonucleotide-polymer hybrids, have attracted tremendous attention. However, the difficulties of fabricating DNA hydrogels limit their practical applications. We report herein a novel method for producing pH-responsive hydrogels by rolling circle amplification (RCA). In this method, pH-sensitive cross-linking sites were introduced into the polymeric DNA chains during DNA synthesis. As the DNA sequence can be precisely defined by its template, the properties of such hydrogels can be finely tuned in a very facile way through template design. We have investigated the process of hydrogel formation and pH-responsiveness to provide rationales for functional hydrogel design based on the RCA reaction. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Combinatorial screening of 3D biomaterial properties that promote myofibrogenesis for mesenchymal stromal cell-based heart valve tissue engineering.

PubMed

Usprech, Jenna; Romero, David A; Amon, Cristina H; Simmons, Craig A

2017-08-01

The physical and chemical properties of a biomaterial integrate with soluble cues in the cell microenvironment to direct cell fate and function. Predictable biomaterial-based control of integrated cell responses has been investigated with two-dimensional (2D) screening platforms, but integrated responses in 3D have largely not been explored systematically. To address this need, we developed a screening platform using polyethylene glycol norbornene (PEG-NB) as a model biomaterial with which the polymer wt% (to control elastic modulus) and adhesion peptide types (RGD, DGEA, YIGSR) and densities could be controlled independently and combinatorially in arrays of 3D hydrogels. We applied this platform and regression modeling to identify combinations of biomaterial and soluble biochemical (TGF-β1) factors that best promoted myofibrogenesis of human mesenchymal stromal cells (hMSCs) in order to inform our understanding of regenerative processes for heart valve tissue engineering. In contrast to 2D culture, our screens revealed that soft hydrogels (low PEG-NB wt%) best promoted spread myofibroblastic cells that expressed high levels of α-smooth muscle actin (α-SMA) and collagen type I. High concentrations of RGD enhanced α-SMA expression in the presence of TGF-β1 and cell spreading regardless of whether TGF-β1 was in the culture medium. Strikingly, combinations of peptides that maximized collagen expression depended on the presence or absence of TGF-β1, indicating that biomaterial properties can modulate MSC response to soluble signals. This combination of a 3D biomaterial array screening platform with statistical modeling is broadly applicable to systematically identify combinations of biomaterial and microenvironmental conditions that optimally guide cell responses. We present a novel screening platform and methodology to model and identify how combinations of biomaterial and microenvironmental conditions guide cell phenotypes in 3D. Our approach to systematically identify complex relationships between microenvironmental cues and cell responses enables greater predictive power over cell fate in conditions with interacting material design factors. We demonstrate that this approach not only predicts that mesenchymal stromal cell (MSC) myofibrogenesis is promoted by soft, porous 3D biomaterials, but also generated new insights which demonstrate how biomaterial properties can differentially modulate MSC response to soluble signals. An additional benefit of the process includes utilizing both parametric and non parametric analyses which can demonstrate dominant significant trends as well as subtle interactions between biochemical and biomaterial cues. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

A Functional Iron Oxide Nanoparticles Modified with PLA-PEG-DG as Tumor-Targeted MRI Contrast Agent.

PubMed

Xiong, Fei; Hu, Ke; Yu, Haoli; Zhou, Lijun; Song, Lina; Zhang, Yu; Shan, Xiuhong; Liu, Jianping; Gu, Ning

2017-08-01

Tumor targeting could greatly promote the performance of magnetic nanomaterials as MRI (Magnetic Resonance Imaging) agent for tumor diagnosis. Herein, we reported a novel magnetic nanoparticle modified with PLA (poly lactic acid)-PEG (polyethylene glycol)-DG (D-glucosamine) as Tumor-targeted MRI Contrast Agent. In this work, we took use of the D-glucose passive targeting on tumor cells, combining it on PLA-PEG through amide reaction, and then wrapped the PLA-PEG-DG up to the Fe 3 O 4 @OA NPs. The stability and anti phagocytosis of Fe 3 O 4 @OA@PLA-PEG-DG was tested in vitro; the MRI efficiency and toxicity was also detected in vivo. These functional magnetic nanoparticles demonstrated good biocompatibility and stability both in vitro and in vivo. Cell experiments showed that Fe 3 O 4 @OA@PLA-PEG-DG nanoparticles exist good anti phagocytosis and high targetability. In vivo MRI images showed that the contrast effect of Fe 3 O 4 @OA@PLA-PEG-DG nanoparticles prevailed over the commercial non tumor-targeting magnetic nanomaterials MRI agent at a relatively low dose. The DG can validly enhance the tumor-targetting effect of Fe 3 O 4 @OA@PLA-PEG nanoparticle. Maybe MRI agents with DG can hold promise as tumor-targetting development in the future.

Functionalized graphene oxide nanoparticles for cancer cell-specific delivery of antitumor drug.

PubMed

Zhao, Xubo; Yang, Liangwei; Li, Xiaorui; Jia, Xu; Liu, Lei; Zeng, Jin; Guo, Jinshan; Liu, Peng

2015-01-21

The unique reduction-triggered functional graphene oxide nanoparticles (GON) with well-defined size and uniform distribution were designed as an innovative drug delivery platform for cancer treatment for the first time, via the redox radical polymerization of methacrylic acid from the polyethylene glycol (PEG) modified GON (GON-PEG), following by cross-linking with cystamine. Thermogravimetric analysis demonstrates that the typical PMAA2-GON-PEG carriers contain about 16 wt % PEG segments and 33 wt % poly(methacrylic acid) (PMAA) brushes. PEG moieties are incorporated to make the drug delivery platforms stealthy during blood circulation. Notably, introducing the cross-linked PMAA brushes efficiently minimizes the premature release of doxorubicin (DOX) in the stimulated normal tissues, and accelerates DOX release in the stimulated tumor tissues through response to reduce agent. The carriers showed a 6-fold faster releasing rate at pH 5.0 in the presence of 10 mM glutathione (GSH) (stimulated tumor tissues) than at pH 7.4 with 10 μM GSH (stimulated normal tissues). In vitro cytotoxicity test also showed that the cross-linked PMAA2-GON-PEG (CPMAA2-GON-PEG) carriers had remarkable cytocompatibility, and that the DOX-loaded CPMAA2-GON-PEG had excellent killing capability to SiHa cells.

Programmable release of multiple protein drugs from aptamer-functionalized hydrogels via nucleic acid hybridization.

PubMed

Battig, Mark R; Soontornworajit, Boonchoy; Wang, Yong

2012-08-01

Polymeric delivery systems have been extensively studied to achieve localized and controlled release of protein drugs. However, it is still challenging to control the release of multiple protein drugs in distinct stages according to the progress of disease or treatment. This study successfully demonstrates that multiple protein drugs can be released from aptamer-functionalized hydrogels with adjustable release rates at predetermined time points using complementary sequences (CSs) as biomolecular triggers. Because both aptamer-protein interactions and aptamer-CS hybridization are sequence-specific, aptamer-functionalized hydrogels constitute a promising polymeric delivery system for the programmable release of multiple protein drugs to treat complex human diseases.

Functional and Anatomical Outcomes of Facial Nerve Injury With Application of Polyethylene Glycol in a Rat Model.

PubMed

Brown, Brandon L; Asante, Tony; Welch, Haley R; Sandelski, Morgan M; Drejet, Sarah M; Shah, Kishan; Runge, Elizabeth M; Shipchandler, Taha Z; Jones, Kathryn J; Walker, Chandler L

2018-05-17

Functional and anatomical outcomes after surgical repair of facial nerve injury may be improved with the addition of polyethylene glycol (PEG) to direct suture neurorrhaphy. The application of PEG has shown promise in treating spinal nerve injuries, but its efficacy has not been evaluated in treatment of cranial nerve injuries. To determine whether PEG in addition to neurorrhaphy can improve functional outcomes and synkinesis after facial nerve injury. In this animal experiment, 36 rats underwent right facial nerve transection and neurorrhaphy with addition of PEG. Weekly behavioral scoring was done for 10 rats for 6 weeks and 14 rats for 16 weeks after the operations. In the 16-week study, the buccal branches were labeled and tissue analysis was performed. In the 6-week study, the mandibular and buccal branches were labeled and tissue analysis was performed. Histologic analysis was performed for 10 rats in a 1-week study to assess the association of PEG with axonal continuity and Wallerian degeneration. Six rats served as the uninjured control group. Data were collected from February 8, 2016, through July 10, 2017. Polyethylene glycol applied to the facial nerve after neurorrhaphy. Functional recovery was assessed weekly for the 16- and 6-week studies, as well as motoneuron survival, amount of regrowth, specificity of regrowth, and aberrant branching. Short-term effects of PEG were assessed in the 1-week study. Among the 40 male rats included in the study, PEG addition to neurorrhaphy showed no functional benefit in eye blink reflex (mean [SEM], 3.57 [0.88] weeks; 95% CI, -2.8 to 1.9 weeks; P = .70) or whisking function (mean [SEM], 4.00 [0.72] weeks; 95% CI, -3.6 to 2.4 weeks; P = .69) compared with suturing alone at 16 weeks. Motoneuron survival was not changed by PEG in the 16-week (mean, 132.1 motoneurons per tissue section; 95% CI, -21.0 to 8.4; P = .13) or 6-week (mean, 131.1 motoneurons per tissue section; 95% CI, -11.0 to 10.0; P = .06) studies. Compared with controls, neither surgical group showed differences in buccal branch regrowth at 16 (36.9 motoneurons per tissue section; 95% CI, -14.5 to 22.0; P = .28) or 6 (36.7 motoneurons per tissue section; 95% CI, -7.8 to 18.5; P = .48) weeks or in the mandibular branch at 6 weeks (25.2 motoneurons per tissue section; 95% CI, -14.5 to 15.5; P = .99). Addition of PEG had no advantage in regrowth specificity compared with suturing alone at 16 weeks (15.3% buccal branch motoneurons with misguided projections; 95% CI, -7.2% to 11.0%; P = .84). After 6 weeks, the number of motoneurons with misguided projections to the mandibular branch showed no advantage of PEG treatment compared with suturing alone (12.1% buccal branch motoneurons with misguided projections; 95% CI, -8.2% to 9.2%; P = .98). In the 1-week study, improved axonal continuity and muscular innervation were not observed in PEG-treated rats. Although PEG has shown efficacy in treating other nervous system injuries, PEG in addition to neurorraphy was not beneficial in a rat model of facial nerve injury. The addition of PEG to suturing may not be warranted in the surgical repair of facial nerve injury. NA.

Protein-based hydrogels for tissue engineering

PubMed Central

Schloss, Ashley C.; Williams, Danielle M.; Regan, Lynne J.

2017-01-01

The tunable mechanical and structural properties of protein-based hydrogels make them excellent scaffolds for tissue engineering and repair. Moreover, using protein-based components provides the option to insert sequences associated with the promoting both cellular adhesion to the substrate and overall cell growth. Protein-based hydrogel components are appealing for their structural designability, specific biological functionality, and stimuli-responsiveness. Here we present highlights in the field of protein-based hydrogels for tissue engineering applications including design requirements, components, and gel types. PMID:27677513

Peripheral Nerve Repair in Rats Using Composite Hydrogel-Filled Aligned Nanofiber Conduits with Incorporated Nerve Growth Factor

PubMed Central

Jin, Jenny; Limburg, Sonja; Joshi, Sunil K.; Landman, Rebeccah; Park, Michelle; Zhang, Qia; Kim, Hubert T.

2013-01-01

Repair of peripheral nerve defects with current synthetic, tubular nerve conduits generally shows inferior recovery when compared with using nerve autografts, the current gold standard. We tested the ability of composite collagen and hyaluronan hydrogels, with and without the nerve growth factor (NGF), to stimulate neurite extension on a promising aligned, nanofiber poly-L-lactide-co-caprolactone (PLCL) scaffold. In vitro, the hydrogels significantly increased neurite extension from dorsal root ganglia explants. Consistent with these results, the addition of hydrogels as luminal fillers within aligned, nanofiber tubular PLCL conduits led to improved sensory function compared to autograft repair in a critical-size defect in the sciatic nerve in a rat model. Sensory recovery was assessed 3 and 12 weeks after repair using a withdrawal assay from thermal stimulation. The addition of hydrogel did not enhance recovery of motor function in the rat model. The NGF led to dose-dependent improvements in neurite out-growth in vitro, but did not have a significant effect in vivo. In summary, composite collagen/hyaluronan hydrogels enhanced sensory neurite outgrowth in vitro and sensory recovery in vivo. The use of such hydrogels as luminal fillers for tubular nerve conduits may therefore be useful in assisting restoration of protective sensation following peripheral nerve injury. PMID:23659607

Preparation of new GO-based slide ring hydrogel through a convenient one-pot approach as methylene blue absorbent.

PubMed

Soleimani, Khadijeh; Dadkhah Tehrani, Abbas; Adeli, Mohsen

2018-05-01

Slide ring hydrogels (SRHG) with supramolecular structures are a new class of hydrogels that contrary to the traditional hydrogels comprise dynamic cross-linking points. Herein, we reported on the fabrication of a new slide ring hydrogel through a very convenient one-pot approach. In this regard, isocyanate functionalized GO was synthesized and used as a stopper as well as cross-linker in the presence of a polypseudorotaxane of cyclodextrin threaded on poly(ethylene glycol) (PR). The surface of the resulting SRHG modified via graft polymerization with polyacrylamide (PAAm) and its application as a new type of absorbent for wastewater treatment was studied. Due to its porous structure and its high content of surface functional groups, the synthesized hydrogel was able to efficiently remove cationic dye methylene blue (MB) from wastewater in a short time. The maximum adsorption capacity of the resulting hydrogel was 92.3 mg/g which exhibited an almost 100% increment as compared to that of untreated GO. The adsorption mechanism of MB was also investigated. The kinetic data, obtained at the optimum pH 7, were fitted well with the pseudo-second-order model. Results from degradation and recycling experiments toward MB showed that the SRHG was stable and reusable. Copyright © 2018 Elsevier Ltd. All rights reserved.

Designer Self-Assembling Peptide Nanofiber Scaffolds Containing Link Protein N-Terminal Peptide Induce Chondrogenesis of Rabbit Bone Marrow Stem Cells

PubMed Central

Wang, Baichuan; Sun, Caixia; Shao, Zengwu; Yang, Shuhua; Che, Biao; Wu, Qiang; Liu, Jianxiang

2014-01-01

Designer self-assembling peptide nanofiber hydrogel scaffolds have been considered as promising biomaterials for tissue engineering because of their excellent biocompatibility and biofunctionality. Our previous studies have shown that a novel designer functionalized self-assembling peptide nanofiber hydrogel scaffold (RLN/RADA16, LN-NS) containing N-terminal peptide sequence of link protein (link N) can promote nucleus pulposus cells (NPCs) adhesion and three-dimensional (3D) migration and stimulate biosynthesis of type II collagen and aggrecan by NPCs in vitro. The present study has extended these investigations to determine the effects of this functionalized LN-NS on bone marrow stem cells (BMSCs), a potential cell source for NP regeneration. Although the functionalized LN-NS cannot promote BMSCs proliferation, it significantly promotes BMSCs adhesion compared with that of the pure RADA16 hydrogel scaffold. Moreover, the functionalized LN-NS remarkably stimulates biosynthesis and deposition of type II collagen and aggrecan. These data demonstrate that the functionalized peptide nanofiber hydrogel scaffold containing link N peptide as a potential matrix substrate will be very useful in the NP tissue regeneration. PMID:25243141

Hyaluronic Acid-Serum Hydrogels Rapidly Restore Metabolism of Encapsulated Stem Cells and Promote Engraftment

PubMed Central

Chan, Angel T.; Karakas, Mehmet F.; Vakrou, Styliani; Afzal, Junaid; Rittenbach, Andrew; Lin, Xiaoping; Wahl, Richard L.; Pomper, Martin G.; Steenbergen, Charles J.; Tsui, Benjamin M.W.; Elisseeff, Jennifer H.; Abraham, M. Roselle

2015-01-01

Background Cell death due to anoikis, necrosis and cell egress from transplantation sites limits functional benefits of cellular cardiomyoplasty. Cell dissociation and suspension, which are a pre-requisite for most cell transplantation studies, lead to depression of cellular metabolism and anoikis, which contribute to low engraftment. Objective We tissue engineered scaffolds with the goal of rapidly restoring metabolism, promoting viability, proliferation and engraftment of encapsulated stem cells. Methods The carboxyl groups of HA were functionalized with N-hydroxysuccinimide (NHS) to yield HA succinimidyl succinate (HA-NHS) groups that react with free amine groups to form amide bonds. HA-NHS was cross-linked by serum to generate HA:Serum (HA:Ser) hydrogels. Physical properties of HA:Ser hydrogels were measured. Effect of encapsulating cardiosphere-derived cells (CDCs) in HA:Ser hydrogels on viability, proliferation, glucose uptake and metabolism was assessed in vitro. In vivo acute intra-myocardial cell retention of 18FDG-labeled CDCs encapsulated in HA:Ser hydrogels was quantified. Effect of CDC encapsulation in HA:Ser hydrogels on in vivo metabolism and engraftment at 7 days was assessed by serial, dual isotope SPECT-CT and bioluminescence imaging of CDCs expressing the Na-iodide symporter and firefly luciferase genes respectively. Effect of HA:Ser hydrogels +/− CDCs on cardiac function was assessed at 7 days & 28 days post-infarct. Results HA:Ser hydrogels are highly bio-adhesive, biodegradable, promote rapid cell adhesion, glucose uptake and restore bioenergetics of encapsulated cells within 1 h of encapsulation, both in vitro and in vivo. These metabolic scaffolds can be applied epicardially as a patch to beating hearts or injected intramyocardially. HA:Ser hydrogels markedly increase acute intramyocardial retention (~6 fold), promote in vivo viability, proliferation, engraftment of encapsulated stem cells and angiogenesis. Conclusion HA:Ser hydrogels serve as ‘synthetic stem cell niches’ that rapidly restore metabolism of encapsulated stem cells, promote stem cell engraftment and angiogenesis. These first ever, tissue engineered metabolic scaffolds hold promise for clinical translation in conjunction with CDCs and possibly other stem cell types. PMID:26378976

Genipin-crosslinked catechol-chitosan mucoadhesive hydrogels for buccal drug delivery.

PubMed

Xu, Jinke; Strandman, Satu; Zhu, Julian X X; Barralet, Jake; Cerruti, Marta

2015-01-01

Drug administration via buccal mucosa is an attractive drug delivery strategy due to good patient compliance, prolonged localized drug effect, and avoidance of gastrointestinal drug metabolism and first-pass elimination. Buccal drug delivery systems need to maintain an intimate contact with the mucosa lining in the wet conditions of the oral cavity for long enough to allow drug release and absorption. For decades, mucoadhesive polymers such as chitosan (CS) and its derivatives have been explored to achieve this. In this study, inspired by the excellent wet adhesion of marine mussel adhesive protein, we developed a buccal drug delivery system using a novel catechol-functionalized CS (Cat-CS) hydrogel. We covalently bonded catechol functional groups to the backbone of CS, and crosslinked the polymer with a non-toxic crosslinker genipin (GP). We achieved two degrees of catechol conjugation (9% and 19%), forming Cat9-CS/GP and Cat19-CS/GP hydrogels, respectively. We confirmed covalent bond formation during the catechol functionalization and GP crosslinking during the gel formation. The gelation time and the mechanical properties of Cat-CS hydrogels are similar to those of CS only hydrogels. Catechol groups significantly enhanced mucoadhesion in vitro (7 out of the 10 Cat19-CS hydrogels were still in contact with porcine mucosal membrane after 6 h, whereas all of the CS hydrogels lost contact after 1.5 h). The new hydrogel systems sustained the release of lidocaine for about 3 h. In-vivo, we compared buccal patches made of Cat19-CS/GP and CS/GP adhered to rabbit buccal mucosa. We were able to detect lidocaine in the rabbit's serum at concentration about 1 ng/ml only from the Cat19-CS patch, most likely due to the intimate contact provided by mucoadhesive Cat19-CS/GP systems. No inflammation was observed on the buccal tissue in contact with any of the patches tested. These results show that the proposed catechol-modified CS hydrogel is a promising mucoadhesive and biocompatible hydrogel system for buccal drug delivery. Copyright © 2014 Elsevier Ltd. All rights reserved.

Photo-crosslinked alginate hydrogels support enhanced matrix accumulation by nucleus pulposus cells in vivo.

PubMed

Chou, A I; Akintoye, S O; Nicoll, S B

2009-10-01

Intervertebral disc (IVD) degeneration is a major health concern in the United States. Replacement of the nucleus pulposus (NP) with injectable biomaterials represents a potential treatment strategy for IVD degeneration. The objective of this study was to characterize the extracellular matrix (ECM) assembly and functional properties of NP cell-encapsulated, photo-crosslinked alginate hydrogels in comparison to ionically crosslinked alginate constructs. Methacrylated alginate was synthesized by esterification of hydroxyl groups with methacrylic anhydride. Bovine NP cells were encapsulated in alginate hydrogels by ionic crosslinking using CaCl(2) or through photo-crosslinking upon exposure to long-wave UV light in the presence of a photoinitiator. The hydrogels were evaluated in vitro by gross and histological analysis and in vivo using a murine subcutaneous pouch model. In vivo samples were analyzed for gene expression, ECM localization and accumulation, and equilibrium mechanical properties. Ionically crosslinked hydrogels exhibited inferior proteoglycan accumulation in vitro and were unable to maintain structural integrity in vivo. In further studies, photo-crosslinked alginate hydrogels were implanted for up to 8 weeks to examine NP tissue formation. Photo-crosslinked hydrogels displayed temporal increases in gene expression and assembly of type II collagen and proteoglycans. Additionally, hydrogels remained intact over the duration of the study and the equilibrium Young's modulus increased from 1.24+/-0.09 kPa to 4.31+/-1.39 kPa, indicating the formation of functional matrix with properties comparable to those of the native NP. These findings support the use of photo-crosslinked alginate hydrogels as biomaterial scaffolds for NP replacement.

Hydrogels with Modulated Ionic Load for Mammalian Cell Harvesting with Reduced Bacterial Adhesion.

PubMed

Gallardo, Alberto; Martínez-Campos, Enrique; García, Carolina; Cortajarena, Aitziber L; Rodríguez-Hernández, Juan

2017-05-08

In this manuscript, we describe the fabrication of hydrogel supports for mammalian cell handling that can simultaneously prevent materials from microbial contamination and therefore allow storage in aqueous media. For that purpose, hydrogels based on the antifouling polymer polyvinylpyrrolidone (PVP) were functionalized with different ionic groups (anionic, cationic, or two types of zwitterions). In order to prevent bacterial adhesion in the long-term, we took advantage of the synergistic effect of inherently antifouling PVP and additional antifouling moieties incorporated within the hydrogel structure. We evaluated, in a separated series of experiments, both the capability of the materials to act as supports for the growth of mammalian cell monolayers for transplantation (using C-166-GFP endothelial cell line), as well their antifouling properties against Staphylococcus aureus, were studied. All of the hydrogels are structurally pseudodouble networks with high swelling (around 90%) and similar mechanical properties (in the low range for hydrogel materials with Young modulus below 1250 kPa). With some differences, all the charged hydrogels were capable of hosting mouse endothelial cell line C166-GFP to confluence, as well as a monolayer detachment and transplantation through simple mechanical agitation. On the contrary, the uncharged hydrogel was not capable to detach a full monolayer for transplantation. Bacterial adhesion and proliferation was highly sensitive to the functionality (type of charge and density). In particular, we evidenced that monomers bearing zwitterionic sulfobetaine groups, those negatively charged as well as "electro neutral" hydrogels fabricated from stoichiometric amounts of positive and negative units, exhibit excellent antifouling properties both at initial adhesion times and during longer periods up to 72 h.

Timing effect of intramyocardial hydrogel injection for positively impacting left ventricular remodeling after myocardial infarction

PubMed Central

Yoshizumi, Tomo; Zhu, Yang; Jiang, Hongbin; D’Amore, Antonio; Sakaguchi, Hirokazu; Tchao, Jason; Tobita, Kimimasa; Wagner, William R.

2016-01-01

Intramyocardial injection of various injectable hydrogel materials has shown benefit in positively impacting the course of left ventricular (LV) remodeling after myocardial infarction (MI). However, since LV remodeling is a complex, time dependent process, the most efficacious time of hydrogel injection is not clear. In this study, we injected a relatively stiff, thermoresponsive and bioabsorbable hydrogel in rat hearts at 3 different time points - immediately after MI (IM), 3 d post-MI (3D), and 2 w post-MI (2W), corresponding to the beginnings of the necrotic, fibrotic and chronic remodeling phases. The employed left anterior descending coronary artery ligation model showed expected infarction responses including functional loss, inflammation and fibrosis with distinct time dependent patterns. Changes in LV geometry and contractile function were followed by longitudinal echocardiography for 10 w post-MI. While all injection times positively affected LV function and wall thickness, the 3D group gave better functional outcomes than the other injection times and also exhibited more local vascularization and less inflammatory markers than the earlier injection time. The results indicate an important role for injection timing in the increasingly explored concept of post-MI biomaterial injection therapy and suggest that for hydrogels with mechanical support as primary function, injection at the beginning of the fibrotic phase may provide improved outcomes. PMID:26774561

Timing effect of intramyocardial hydrogel injection for positively impacting left ventricular remodeling after myocardial infarction.

PubMed

Yoshizumi, Tomo; Zhu, Yang; Jiang, Hongbin; D'Amore, Antonio; Sakaguchi, Hirokazu; Tchao, Jason; Tobita, Kimimasa; Wagner, William R

2016-03-01

Intramyocardial injection of various injectable hydrogel materials has shown benefit in positively impacting the course of left ventricular (LV) remodeling after myocardial infarction (MI). However, since LV remodeling is a complex, time dependent process, the most efficacious time of hydrogel injection is not clear. In this study, we injected a relatively stiff, thermoresponsive and bioabsorbable hydrogel in rat hearts at 3 different time points - immediately after MI (IM), 3 d post-MI (3D), and 2 w post-MI (2W), corresponding to the beginnings of the necrotic, fibrotic and chronic remodeling phases. The employed left anterior descending coronary artery ligation model showed expected infarction responses including functional loss, inflammation and fibrosis with distinct time dependent patterns. Changes in LV geometry and contractile function were followed by longitudinal echocardiography for 10 w post-MI. While all injection times positively affected LV function and wall thickness, the 3D group gave better functional outcomes than the other injection times and also exhibited more local vascularization and less inflammatory markers than the earlier injection time. The results indicate an important role for injection timing in the increasingly explored concept of post-MI biomaterial injection therapy and suggest that for hydrogels with mechanical support as primary function, injection at the beginning of the fibrotic phase may provide improved outcomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

A study on the swelling behavior of poly(acrylic acid) hydrogels obtained by electron beam crosslinking

NASA Astrophysics Data System (ADS)

Sheikh, N.; Jalili, L.; Anvari, F.

2010-06-01

Poly(acrylic acid) (PAA) hydrogels were prepared by using electron beam (EB) crosslinking of PAA homopolymer from its aqueous solutions. The swelling behavior of the hydrogels was studied as a function of the concentration of PAA solution, radiation dose, pH of the swelling medium and swelling time. Also the environmental pH effect on the water diffusion mode into hydrogels was investigated. These hydrogels clearly showed pH-sensitive swelling behavior with Fickian type of diffusion in the stomach-like pH medium (pH 1.3) and non-Fickian type in the intestine-like pH medium (pH 6.8).

A novel honeycomb cell assay kit designed for evaluating horizontal cell migration in response to functionalized self-assembling peptide hydrogels

NASA Astrophysics Data System (ADS)

Guan, Fengyi; Lu, Jiaju; Wang, Xiumei

2017-03-01

A clear understanding on cell migration behaviors contributes to designing novel biomaterials in tissue engineering and elucidating related tissue regeneration processes. Many traditional evaluation methods on cell migration including scratch assay and transwell migration assay possess all kinds of limitations. In this study, a novel honeycomb cell assay kit was designed and made of photosensitive resin by 3D printing. This kit has seven hexagonal culture chambers so that it can evaluate the horizontal cell migration behavior in response to six surrounding environments simultaneously, eliminating the effect of gravity on cells. Here this cell assay kit was successfully applied to evaluate endothelial cell migration cultured on self-assembling peptide (SAP) RADA (AcN-RADARADARADARADA-CONH2) nanofiber hydrogel toward different functionalized SAP hydrogels. Our results indicated that the functionalized RADA hydrogels with different concentration of bioactive motifs of KLT or PRG could induce cell migration in a dose-dependent manner. The total number and migration distance of endothelial cells on functionalized SAP hydrogels significantly increased with increasing concentration of bioactive motif PRG or KLT. Therefore, the honeycomb cell assay kit provides a simple, efficient and convenient tool to investigate cell migration behavior in response to multi-environments simultaneously.

Engineering tough, highly compressible, biodegradable hydrogels by tuning the network architecture.

PubMed

Gu, Dunyin; Tan, Shereen; Xu, Chenglong; O'Connor, Andrea J; Qiao, Greg G

2017-06-20

By precisely tuning the network architecture, tough, highly compressible hydrogels were engineered. The hydrogels were made by interconnecting high-functionality hydrophobic domains through linear tri-block chains, consisting of soft hydrophilic middle blocks, flanked with flexible hydrophobic blocks. In showing their applicability, the efficient encapsulation and prolonged release of hydrophobic drugs were achieved.

Implications of poly(N-isopropylacrylamide)-g-poly(ethylene glycol) with codissolved brain-derived neurotrophic factor injectable scaffold on motor function recovery rate following cervical dorsolateral funiculotomy in the rat

PubMed Central

Grous, Lauren Conova; Vernengo, Jennifer; Jin, Ying; Himes, B. Timothy; Shumsky, Jed S.; Fischer, Itzhak; Lowman, Anthony

2016-01-01

Object In a follow-up study to their prior work, the authors evaluated a novel delivery system for a previously established treatment for spinal cord injury (SCI), based on a poly(N-isopropylacrylamide) (PNIPAAm), lightly cross-linked with a polyethylene glycol (PEG) injectable scaffold. The primary aim of this work was to assess the recovery of both spontaneous and skilled forelimb function following a cervical dorsolateral funiculotomy in the rat. This injury ablates the rubrospinal tract (RST) but spares the dorsal and ventral corticospinal tract and can severely impair reaching and grasping abilities. Methods Animals received an implant of either PNIPAAm-g-PEG or PNIPAAm-g-PEG + brain-derived neurotrophic factor (BDNF). The single-pellet reach-to-grasp task and the staircase-reaching task were used to assess skilled motor function associated with reaching and grasping abilities, and the cylinder task was used to assess spontaneous motor function, both before and after injury. Results Because BDNF can stimulate regenerating RST axons, the authors showed that animals receiving an implant of PNIPAAm-g-PEG with codissolved BDNF had an increased recovery rate of fine motor function when compared with a control group (PNIPAAm-g-PEG only) on both a staircase-reaching task at 4 and 8 weeks post-SCI and on a single-pellet reach-to-grasp task at 5 weeks post-SCI. In addition, spontaneous motor function, as measured in the cylinder test, recovered to preinjury values in animals receiving PNIPAAm-g-PEG + BDNF. Fluorescence immunochemistry indicated the presence of both regenerating axons and BDA-labeled fibers growing up to or within the host-graft interface in animals receiving PNIPAAm-g-PEG + BDNF. Conclusions Based on their results, the authors suggest that BDNF delivered by the scaffold promoted the growth of RST axons into the lesion, which may have contributed in part to the increased recovery rate. PMID:23581453

Design and synthesis of multifunctional poly(ethylene glycol)s using enzymatic catalysis for multivalent cancer drug delivery

NASA Astrophysics Data System (ADS)

Seo, Kwang Su

The objective of this research was to design and synthesize multifunctional poly(ethylene glycol)s (PEG)s using enzyme-catalyzed reactions for multivalent targeted drug delivery. Based on computer simulation for optimum folate binding, a four-arm PEG star topology with Mn = 1000 g/mol was proposed. First, a four-functional core based on tetraethylene glycol (TEG) was designed and synthesized using transesterification and Michael addition reactions in the presence of Candida antarctica lipase B (CALB) as a biocatalyst. The four-functional core (HO)2-TEG-(OH)2 core was successfully prepared by the CALB-catalyzed transesterification of vinyl acrylate (VA) with TEG and then Michael addition of diethanolamine to the resulting TEG diacrylate with/without the use of solvent. The functional PEG arms with fluorescein isothiocyanate (FITC) and folic acid (FA) were prepared using both traditional organic chemistry and enzyme-catalyzed reactions. FITC was reacted with the amine group of H2N-PEG-OH in the presence of triethylamine via nucleophilic addition onto the isothiocyanate group. Then, divinyl adipate (DVA) was transesterified with the FITC-PEG-OH product in the presence of CALB to produce the FITC-PEG vinyl ester that will be attached to the four-functional core via CALC-catalyzed transesterification. For the synthesis of FA-PEG vinyl ester arm, DVA was first reacted with PEG-monobenzyl ether (BzPEG-OH) in bulk in the presence of CALB. The BzPEG vinyl ester was then transesterified with 12-bromo-1-dodecanol in the presence of CALB. Finally, BzPEG-Br was attached to FA exclusively in the gamma position using a new method. The thesis also discusses fundamental studies that were carried out in order to get better understanding of enzyme catalyzed transesterification and Michael addition reactions. First, in an effort to investigate the effects of reagent and enzyme concentrations in transesterification, vinyl methacrylate (VMA) was reacted with 2-(hydroxyethyl) acrylate (2HEA) in the presence of CALB. When the reaction was performed in tetrahydrofuran (THF) with a 2HEA concentration of 0.10 mol/L, only 19% conversion was observed within 4 hours, whereas complete conversion was achieved under solventless conditions. The effect of enzyme concentration in reactions with and without solvent was also studied. The effect of DVA concentration on the CALB-catalyzed transesterification with TEG was studied under solventless conditions. When 1.5 molar equivalent of DVA per OH in TEG was used, 42% divinyl-functionalized product was observed together with 56.5% oligomerized (di-, tri-, tetra- and pentamer) products. At 10 eq. of DVA, only 18.4% oligomerized products were obtained. The effect of diol molecular weight was also investigated. At 10.0 eq. DVA per OH only 2% dimer was observed with PEG Mn=1000 g/mol, and a single divinyl functionalized product was obtained with M n=2000 g/mol. The effects of polymer molecular weight and DVA concentration were also studied in the reaction of DVA with PEG monomethyl ether (MPEG-OH, Mn=1100 g/mol and 2000 g/mol). The extent of coupling decreased from 35% to 0.4% when the DVA concentration was increased from 1.5 to 10 per -OH in the MPEG-OH. No coupling was observed with MPEG-OH Mn=2000 g/mol at 5 eq. DVA per -OH. Following these fundamental studies, TEGs and PEGs were enzymatically functionalized. TEGs were transesterified with VMA and vinyl crotonate in the presence of CALB under solventless conditions within 4 hours of reaction time. Benzyl protected TEG-OHs were also successfully functionalized with VMA and vinyl crotonate in the presence of CALB under solventless conditions within 2 hours. An eight-functional molecule was also synthesized from (HO)2-TEG-(OH) 2. First an alpha-vinyl-o-acrylate linker was prepared by the transesterification of DVA with 2HEA. This linker was then transesterified with (HO)-TEG-(OH)2, followed by Michael addition of DEA to the tetra-acrylated TEG. (Abstract shortened by UMI.)

Hydrogels in a historical perspective: from simple networks to smart materials.

PubMed

Buwalda, Sytze J; Boere, Kristel W M; Dijkstra, Pieter J; Feijen, Jan; Vermonden, Tina; Hennink, Wim E

2014-09-28

Over the past decades, significant progress has been made in the field of hydrogels as functional biomaterials. Biomedical application of hydrogels was initially hindered by the toxicity of crosslinking agents and limitations of hydrogel formation under physiological conditions. Emerging knowledge in polymer chemistry and increased understanding of biological processes resulted in the design of versatile materials and minimally invasive therapies. Hydrogel matrices comprise a wide range of natural and synthetic polymers held together by a variety of physical or chemical crosslinks. With their capacity to embed pharmaceutical agents in their hydrophilic crosslinked network, hydrogels form promising materials for controlled drug release and tissue engineering. Despite all their beneficial properties, there are still several challenges to overcome for clinical translation. In this review, we provide a historical overview of the developments in hydrogel research from simple networks to smart materials. Copyright © 2014 Elsevier B.V. All rights reserved.

Optimizing Double-Network Hydrogel for Biomedical Soft Robots.

PubMed

Banerjee, Hritwick; Ren, Hongliang

2017-09-01

Double-network hydrogel with standardized chemical parameters demonstrates a reasonable and viable alternative to silicone in soft robotic fabrication due to its biocompatibility, comparable mechanical properties, and customizability through the alterations of key variables. The most viable hydrogel sample in our article shows tensile strain of 851% and maximum tensile strength of 0.273 MPa. The elasticity and strength range of this hydrogel can be customized according to application requirements by simple alterations in the recipe. Furthermore, we incorporated Agar/PAM hydrogel into our highly constrained soft pneumatic actuator (SPA) design and eventually produced SPAs with escalated capabilities, such as larger range of motion, higher force output, and power efficiency. Incorporating SPAs made of Agar/PAM hydrogel resulted in low viscosity, thermos-reversibility, and ultralow elasticity, which we believe can help to combine with the other functions of hydrogel, tailoring a better solution for fabricating biocompatible soft robots.

Nano-graphene oxide composite for in vivo imaging

PubMed Central

Oh, Seo Yeong; Vilian, AT Ezhil; Lee, Ilsong; Han, Young-Kyu; Park, Jeong Hoon; Roh, Changhyun; Huh, Yun Suk

2018-01-01

Introduction Positron emission tomography (PET) tracers has the potential to revolutionize cancer imaging and diagnosis. PET tracers offer non-invasive quantitative imaging in biotechnology and biomedical applications, but it requires radioisotopes as radioactive imaging tracers or radiopharmaceuticals. Method This paper reports the synthesis of 18F-nGO-PEG by covalently functionalizing PEG with nano-graphene oxide, and its excellent stability in physiological solutions. Using a green synthesis route, nGO is then functionalized with a biocompatible PEG polymer to acquire high stability in PBS and DMEM. Results and discussion The radiochemical safety of 18F-nGO-PEG was measured by a reactive oxygen species and cell viability test. The biodistribution of 18F-nGO-PEG could be observed easily by PET, which suggested the significantly high sensitivity tumor uptake of 18F-nGO-PEG and in a tumor bearing CT-26 mouse compared to the control. 18F-nGO-PEG was applied successfully as an efficient radiotracer or drug agent in vivo using PET imaging. This article is expected to assist many researchers in the fabrication of 18F-labeled graphene-based bio-conjugates with high reproducibility for applications in the biomedicine field. PMID:29379283

Shape-Memory Hydrogels: Evolution of Structural Principles To Enable Shape Switching of Hydrophilic Polymer Networks.

PubMed

Löwenberg, Candy; Balk, Maria; Wischke, Christian; Behl, Marc; Lendlein, Andreas

2017-04-18

The ability of hydrophilic chain segments in polymer networks to strongly interact with water allows the volumetric expansion of the material and formation of a hydrogel. When polymer chain segments undergo reversible hydration depending on environmental conditions, smart hydrogels can be realized, which are able to shrink/swell and thus alter their volume on demand. In contrast, implementing the capacity of hydrogels to switch their shape rather than volume demands more sophisticated chemical approaches and structural concepts. In this Account, the principles of hydrogel network design, incorporation of molecular switches, and hydrogel microstructures are summarized that enable a spatially directed actuation of hydrogels by a shape-memory effect (SME) without major volume alteration. The SME involves an elastic deformation (programming) of samples, which are temporarily fixed by reversible covalent or physical cross-links resulting in a temporary shape. The material can reverse to the original shape when these molecular switches are affected by application of a suitable stimulus. Hydrophobic shape-memory polymers (SMPs), which are established with complex functions including multiple or reversible shape-switching, may provide inspiration for the molecular architecture of shape-memory hydrogels (SMHs), but cannot be identically copied in the world of hydrophilic soft materials. For instance, fixation of the temporary shape requires cross-links to be formed also in an aqueous environment, which may not be realized, for example, by crystalline domains from the hydrophilic main chains as these may dissolve in presence of water. Accordingly, dual-shape hydrogels have evolved, where, for example, hydrophobic crystallizable side chains have been linked into hydrophilic polymer networks to act as temperature-sensitive temporary cross-links. By incorporating a second type of such side chains, triple-shape hydrogels can be realized. Considering the typically given light permeability of hydrogels and the fully hydrated state with easy permeation by small molecules, other types of stimuli like light, pH, or ions can be employed that may not be easily used in hydrophobic SMPs. In some cases, those molecular switches can respond to more than one stimulus, thus increasing the number of opportunities to induce actuation of these synthetic hydrogels. Beyond this, biopolymer-based hydrogels can be equipped with a shape switching function when facilitating, for example, triple helix formation in proteins or ionic interactions in polysaccharides. Eventually, microstructured SMHs such as hybrid or porous structures can combine the shape-switching function with an improved performance by helping to overcome frequent shortcomings of hydrogels such as low mechanical strength or volume change upon temporary cross-link cleavage. Specifically, shape switching without major volume alteration is possible in porous SMHs by decoupling small volume changes of pore walls on the microscale and the macroscopic sample size. Furthermore, oligomeric rather than short aliphatic side chains as molecular switches allow stabilization of the sample volumes. Based on those structural principles and switching functionalities, SMHs have already entered into applications as soft actuators and are considered, for example, for cell manipulation in biomedicine. In the context of those applications, switching kinetics, switching forces, and reversibility of switching are aspects to be further explored.

Effect of commonly used vehicles on gastrointestinal, renal, and liver function in rats.

PubMed

Pestel, Sabine; Martin, Hans-Juergen; Maier, Gerd-Michael; Guth, Brian

2006-01-01

Solubility is often a limiting factor when testing new compounds in animal experiments. Various solubilizing agents may be used, but each have their own pharmacological effects. We investigated the effects of selected vehicles having different chemical characteristics on gastrointestinal, renal, and liver function. Rats were treated orally, intravenously or intraperitoneally and gastric emptying, intestinal transit, renal, and liver function were investigated. Gastrointestinal motility was influenced by hydroxyethylcellulose, hydroxypropyl-beta-cyclodextrin (HPbetaCD), HPgammaCD, DMSO, polyethylene glycol 400 (PEG 400), fat emulsion, and the corresponding emulsifier. Liver function was affected by HPbetaCD, HPgammaCD, DMSO, PEG 400, Polysorbate 80, Cremophor RH 40, and fat emulsion. An increase in liver enzymes was observed after PEG 400 and Polysorbate 80. DMSO interfered with clinical chemistry measurements in serum. Urinary function was modified by HPgammaCD, DMSO, PEG 400, and Polysorbate 80, while enhanced urine enzyme excretion was observed after HPbetaCD, HPgammaCD, DMSO, PEG 400, and Polysorbate 80. Most of the investigated vehicles changed gastrointestinal, renal, and/or liver parameters after application of a certain threshold dose for each assay. No "best" vehicle could be identified that may be used in each test system. Thus, vehicles must be selected not only on their chemical characteristics but also on their potential pharmacological activity in a given test system.

Anti-Inflammatory Peptide Functionalized Hydrogels for Insulin-Secreting Cell Encapsulation

PubMed Central

Su, Jing; Hu, Bi-Huang; Lowe, William L.; Kaufman, Dixon B.; Messersmith, Phillip B.

2009-01-01

Pancreatic islet encapsulation within semi-permeable materials has been proposed for transplantation therapy of Type I diabetes mellitus. Polymer hydrogel networks used for this purpose have been shown to provide protection from islet destruction by immunoreactive cells and antibodies. However, one of the fundamental deficiencies with current encapsulation methods is that the permselective barriers cannot protect islets from cytotoxic molecules of low molecular weight that are diffusible into the capsule material, which subsequently results in β-cell destruction. Use of materials that can locally inhibit the interaction between the permeable small cytotoxic factors and islet cells may prolong the viability and function of encapsulated islet grafts. Here we report the design of anti-inflammatory hydrogels supporting islet cell survival in the presence of diffusible pro-inflammatory cytokines. We demonstrated that a poly(ethylene glycol)-containing hydrogel network, formed by native chemical ligation and presenting an inhibitory peptide for islet cell surface IL-1 receptor, was able to maintain the viability of encapsulated islet cells in the presence of a combination of cytokines including IL-1β, TNF-α, and INF-γ. In stark contrast, cells encapsulated in unmodified hydrogels were mostly destroyed by cytokines which diffused into the capsules. At the same time, these peptide-modified hydrogels were able to efficiently protect encapsulated cells against β-cell specific T-lymphocytes and maintain glucose-stimulated insulin release by islet cells. With further development, the approach of encapsulating cells and tissues within hydrogels presenting anti-inflammatory agents may represent a new strategy to improve cell and tissue graft function in transplantation and tissue engineering applications. PMID:19782393

Biohydrogels with magnetic nanoparticles as crosslinker: characteristics and potential use for controlled antitumor drug-delivery.

PubMed

Barbucci, Rolando; Giani, Gabriele; Fedi, Serena; Bottari, Severino; Casolaro, Mario

2012-12-01

Hybrid magnetic hydrogels are of interest for applications in biomedical science as controlled drug-delivery systems. We have developed a strategy to obtain novel hybrid hydrogels with magnetic nanoparticles (NPs) of CoFe(2)O(3) and Fe(3)O(4) as crosslinker agents of carboxymethylcellulose (CMC) or hyaluronic acid (HYAL) polymers and we have tested these systems for controlled doxorubicin release. The magnetic NPs are functionalized with (3-aminopropyl)trimethoxysilane (APTMS) in order to introduce amino groups on the surface. The amino coating is determined and quantified by standard Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy methods, and by cyclic voltammetry, a novel approach that permits us to look at the solution properties of the functionalized NPs. The gel formation involves the creation of an amide bond between the carboxylic groups of CMC or HYAL and the amine groups of functionalized NPs, which work as crosslinking agents of the polymer chains. The hybrid hydrogels are chemically and morphologically characterized. The rheological and the water uptake properties of the hydrogels are also investigated. Under the application of an alternating magnetic field, the CMC-HYAL hybrid hydrogel previously loaded with doxorubicin shows a drug release greater than that showed by the CMC-HYAL hydrogel crosslinked with 1,3-diaminopropane. In conclusion, the presence of magnetic NPs makes the synthesized hybrid hydrogels suitable for application as a drug-delivery system by means of alternating magnetic fields. Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Polyisocyanopeptide hydrogels: A novel thermo-responsive hydrogel supporting pre-vascularization and the development of organotypic structures.

PubMed

Zimoch, Jakub; Padial, Joan Simó; Klar, Agnes S; Vallmajo-Martin, Queralt; Meuli, Martin; Biedermann, Thomas; Wilson, Christopher J; Rowan, Alan; Reichmann, Ernst

2018-04-01

Molecular and mechanical interactions with the 3D extracellular matrix are essential for cell functions such as survival, proliferation, migration, and differentiation. Thermo-responsive biomimetic polyisocyanopeptide (PIC) hydrogels are promising new candidates for 3D cell, tissue, and organ cultures. This is a synthetic, thermo-responsive and stress-stiffening material synthesized via polymerization of the corresponding monomers using a nickel perchlorate as a catalyst. It can be tailored to meet various demands of cells by modulating its stiffness and through the decoration of the polymer with short GRGDS peptides using copper free click chemistry. These peptides make the hydrogels biocompatible by mimicking the binding sites of certain integrins. This study focuses on the optimization of the PIC polymer properties for efficient cell, tissue and organ development. Screening for the optimal stiffness of the hydrogel and the ideal concentration of the GRGDS ligand conjugated with the polymer, enabled cell proliferation, migration and differentiation of various primary cell types of human origin. We demonstrate that fibroblasts, endothelial cells, adipose-derived stem cells and melanoma cells, do survive, thrive and differentiate in optimized PIC hydrogels. Importantly, these hydrogels support the spontaneous formation of complex structures like blood capillaries in vitro. Additionally, we utilized the thermo-responsive properties of the hydrogels for a rapid and gentle recovery of viable cells. Finally, we show that organotypic structures of human origin grown in PIC hydrogels can be successfully transplanted subcutaneously onto immune-compromised rats, on which they survive and integrate into the surrounding tissue. Molecular and mechanical interactions with the surrounding environment are essential for cell functions. Although 2D culture systems greatly contributed to our understanding of complex biological phenomena, they cannot substitute for crucial interaction that take place in 3D. 3D culture systems aim to overcome limitations of the 2D cultures and answer new questions about cell functions. Thermo-responsive biomimetic polyisocyanopeptide (PIC) hydrogels are promising new candidates for 3D cell, tissue, and organ cultures. They are synthetic and can be tailor to meet certain experimental demands. Additionally, they are characterized by strain-stiffening, a feature crucial for cell behaviour, but rare in hydrogels. Their thermos-responsive properties enable quick recovery of the cells by a simple procedure of lowering the temperature. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Three-Dimensional Bioprinting of Oppositely Charged Hydrogels with Super Strong Interface Bonding.

PubMed

Li, Huijun; Tan, Yu Jun; Liu, Sijun; Li, Lin

2018-04-04

A novel strategy to improve the adhesion between printed layers of three-dimensional (3D) printed constructs is developed by exploiting the interaction between two oppositely charged hydrogels. Three anionic hydrogels [alginate, xanthan, and κ-carrageenan (Kca)] and three cationic hydrogels [chitosan, gelatin, and gelatin methacrylate (GelMA)] are chosen to find the optimal combination of two oppositely charged hydrogels for the best 3D printability with strong interface bonding. Rheological properties and printability of the hydrogels, as well as structural integrity of printed constructs in cell culture medium, are studied as functions of polymer concentration and the combination of hydrogels. Kca2 (2 wt % Kca hydrogel) and GelMA10 (10 wt % GelMA hydrogel) are found to be the best combination of oppositely charged hydrogels for 3D printing. The interfacial bonding between a Kca layer and a GelMA layer is proven to be significantly higher than that of the bilayered Kca or bilayered GelMA because of the formation of polyelectrolyte complexes between the oppositely charged hydrogels. A good cell viability of >96% is obtained for the 3D-bioprinted Kca-GelMA construct. This novel strategy has a great potential for 3D bioprinting of layered constructs with a strong interface bonding.

Biomimetic hydrogels direct spinal progenitor cell differentiation and promote functional recovery after spinal cord injury

NASA Astrophysics Data System (ADS)

Geissler, Sydney A.; Sabin, Alexandra L.; Besser, Rachel R.; Gooden, Olivia M.; Shirk, Bryce D.; Nguyen, Quan M.; Khaing, Zin Z.; Schmidt, Christine E.

2018-04-01

Objective. Demyelination that results from disease or traumatic injury, such as spinal cord injury (SCI), can have a devastating effect on neural function and recovery. Many researchers are examining treatments to minimize demyelination by improving oligodendrocyte availability in vivo. Transplantation of stem and oligodendrocyte progenitor cells is a promising option, however, trials are plagued by undirected differentiation. Here we introduce a biomaterial that has been optimized to direct the differentiation of neural progenitor cells (NPCs) toward oligodendrocytes as a cell delivery vehicle after SCI. Approach. A collagen-based hydrogel was modified to mimic the mechanical properties of the neonatal spinal cord, and components present in the developing extracellular matrix were included to provide appropriate chemical cues to the NPCs to direct their differentiation toward oligodendrocytes. The hydrogel with cells was then transplanted into a unilateral cervical contusion model of SCI to examine the functional recovery with this treatment. Six behavioral tests and histological assessment were performed to examine the in vivo response to this treatment. Main results. Our results demonstrate that we can achieve a significant increase in oligodendrocyte differentiation of NPCs compared to standard culture conditions using a three-component biomaterial composed of collagen, hyaluronic acid, and laminin that has mechanical properties matched to those of neonatal neural tissue. Additionally, SCI rats with hydrogel transplants, with and without NPCs, showed functional recovery. Animals transplanted with hydrogels with NPCs showed significantly increased functional recovery over six weeks compared to the media control group. Significance. The three-component hydrogel presented here has the potential to provide cues to direct differentiation in vivo to encourage regeneration of the central nervous system.

Poly(ethylene glycol)s as grinding additives in the mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins.

PubMed

Mascitti, Andrea; Lupacchini, Massimiliano; Guerra, Ruben; Taydakov, Ilya; Tonucci, Lucia; d'Alessandro, Nicola; Lamaty, Frederic; Martinez, Jean; Colacino, Evelina

2017-01-01

The mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins was investigated in the presence of various poly(ethylene) glycols (PEGs), as safe grinding assisting agents (liquid-assisted grinding, LAG). A comparative study under dry-grinding conditions was also performed. The results showed that the cyclization reaction was influenced by the amount of the PEG grinding agents. In general, cleaner reaction profiles were observed in the presence of PEGs, compared to dry-grinding procedures.

Poly(ethylene glycol)s as grinding additives in the mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins

PubMed Central

Guerra, Ruben; Taydakov, Ilya; Tonucci, Lucia; d’Alessandro, Nicola; Lamaty, Frederic; Martinez, Jean

2017-01-01

The mechanochemical preparation of highly functionalized 3,5-disubstituted hydantoins was investigated in the presence of various poly(ethylene) glycols (PEGs), as safe grinding assisting agents (liquid-assisted grinding, LAG). A comparative study under dry-grinding conditions was also performed. The results showed that the cyclization reaction was influenced by the amount of the PEG grinding agents. In general, cleaner reaction profiles were observed in the presence of PEGs, compared to dry-grinding procedures. PMID:28179944

Avidin-biotin-PEG-CPA complexes as potential EPR-directed therapeutic protein carriers: preparation and characterization.

PubMed

Ke, Shan; Wright, John C; Kwon, Glen S

2007-01-01

Bovine carboxypeptidase A (CPA) conjugated with biotinylated poly(ethylene glycol) (PEG) has been synthesized and characterized in terms of stoichiometry and half-life of the avidin-biotin-PEG(s)-CPA complex. The half-lives for dissociation are 3.34 days for the avidin-biotin-PEG(3400)-CPA 1:1 complex, 3.65 days for the avidin-biotin-PEG(5000)-CPA 1:1 complex, 3.91 days for the avidin-biotin-PEG(3400)-CPA-PEG(2000) 1:1 complex, and 2.74 days for the avidin-biotin-PEG(5000)-CPA-PEG(2000) 1:1 complex. The slow dissociation demonstrates the stability of complexes using a PEGylated biotin terminus as a linker with avidin. The stoichiometry of the biotin-PEGylated CPA with avidin was determined by the 2,6-ANS method, and the results are consistent with measurements of the stoichiometry using size exclusion chromatography. The stoichiometries are 1:2 for the avidin-biotin-PEG(3400)-CPA complex and the avidin-biotin-PEG(3400)-CPA-PEG(2000) complex, 1:1 for the avidin-biotin-PEG(5000)-CPA complex, and 1:4 for the avidin-biotin-PEG(5000)-CPA-PEG(2000) complex. These findings stress both the importance of the length of a PEG chain as an appropriate spacer between the biotin terminus and a functional group, and the great potential of the avidin-biotin-PEGylated-protein complex as a therapeutic protein delivery system for solid tumor prodrug targeting.

A Hydrogel of Ultrathin Pure Polyaniline Nanofibers: Oxidant-Templating Preparation and Supercapacitor Application.

PubMed

Zhou, Kun; He, Yuan; Xu, Qingchi; Zhang, Qin'e; Zhou, An'an; Lu, Zihao; Yang, Li-Kun; Jiang, Yuan; Ge, Dongtao; Liu, Xiang Yang; Bai, Hua

2018-05-15

Although challenging, fabrication of porous conducting polymeric materials with excellent electronic properties is crucial for many applications. We developed a fast in situ polymerization approach to pure polyaniline (PANI) hydrogels, with vanadium pentoxide hydrate nanowires as both the oxidant and sacrifice template. A network comprised of ultrathin PANI nanofibers was generated during the in situ polymerization, and the large aspect ratio of these PANI nanofibers allowed the formation of hydrogels at a low solid content of 1.03 wt %. Owing to the ultrathin fibril structure, PANI hydrogels functioning as a supercapacitor electrode display a high specific capacitance of 636 F g -1 , a rate capability, and good cycling stability (∼83% capacitance retention after 10,000 cycles). This method was also extended to the preparation of polypyrrole and poly(3,4-ethylenedioxythiophene) hydrogels. This template polymerization method represents a rational strategy for design of conducing polymer networks, which can be readily integrated in high-performance devices or a further platform for functional composites.

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function

PubMed Central

Murakami, Tetsuro; Qamar, Seema; Lin, Julie Qiaojin; Schierle, Gabriele S. Kaminski; Rees, Eric; Miyashita, Akinori; Costa, Ana R.; Dodd, Roger B.; Chan, Fiona T.S.; Michel, Claire H.; Kronenberg-Versteeg, Deborah; Li, Yi; Yang, Seung-Pil; Wakutani, Yosuke; Meadows, William; Ferry, Rodylyn Rose; Dong, Liang; Tartaglia, Gian Gaetano; Favrin, Giorgio; Lin, Wen-Lang; Dickson, Dennis W.; Zhen, Mei; Ron, David; Schmitt-Ulms, Gerold; Fraser, Paul E.; Shneider, Neil A.; Holt, Christine; Vendruscolo, Michele; Kaminski, Clemens F.; St George-Hyslop, Peter

2015-01-01

Summary The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins. PMID:26526393

Stable environmentally sensitive cationic hydrogels for controlled delivery applications.

PubMed

Deo, Namita; Ruetsch, S; Ramaprasad, K R; Kamath, Y

2010-01-01

New thermosensitive, cationic hydrogels were synthesized by the dispersion copolymerization of N-isopropylacrylamide (NIPAM) and (3-acrylamidopropyl)trimethylammonium chloride (AAPTAC). In the polymerization protocol, an amide-based comonomer, (3-acrylamidopropyl)trimethylammonium chloride, was reacted as a new alternative monomer for introducing positive charges into the thermosensitive hydrogel. The hydrogels were synthesized without making any pH adjustment in the aqueous medium. These hydrogel particles exhibited colloidal stability in the pH range of 1.5 to 11.0, while similar cationic hydrogels were reported to be unstable at pHs higher than 6. The stronger cationic character of the selected comonomer provided higher colloidal stability to the poly(NIPAM-co-AAPTAC) hydrogels. Furthermore, these hydrogels displayed sensitivity towards temperature, pH, and salt concentration. Interestingly, the particle size of hydrogels was found to be decreased significantly with an increase in temperature and salt concentration. In addition, using pyrene fluorescence spectroscopy, it was established that the hydrophobicity/hydrophilicity of the hydrogel particles was largely controlled by both pH and temperature. The thermosensitive hydrogels reported in this paper may be suitable for delivering different actives for cosmetic and medical applications. Although direct application of these hydrogel particles in cosmetics has not been shown at this stage, the methodology of making them and controlling their absorption and release properties as a function of temperature and pH has been demonstrated. Furthermore, these hydrogels may also have applications in scavenging organic and inorganic toxics.

Short-Chain PEG Mixed-Monolayer Protected Gold Clusters Increase Clearance and Red Blood Cell Counts

PubMed Central

Simpson, Carrie A.; Agrawal, Amanda C.; Balinski, Andrzej; Harkness, Kellen M.; Cliffel, David E.

2011-01-01

Monolayer-protected gold nanoparticles have great potential as novel building blocks for the design of new drugs and therapeutics based on the easy ability to multifunctionalize them for biological targeting and drug activity. In order to create nanoparticles that are biocompatible in vivo, poly-ethylene glycol functional groups have been added to many previous multifunctionalized particles to eliminate non-specific binding. Recently, monolayer-protected gold nanoparticles with mercaptoglycine functionalities were shown to elicit deleterious effects on the kidney in vivo that were eliminated by incorporating a long-chain, mercapto-undecyl-tetraethylene glycol, at very high loadings into a mixed monolayer. These long-chain PEGs induced an immune response to the particle presumably generating an anti-PEG antibody as seen in other long-chain PEG-ylated nanoparticles in vivo. In the present work, we explore the in vivo effects of high and low percent ratios of a shorter chain, mercapto-tetraethylene glycol, within the monolayer using simple place-exchange reactions. The shorter chain PEG MPCs were expected to have better water solubility due to elimination of the alkyl chain, no toxicity, and long-term circulation in vivo. Shorter chain lengths at lower concentrations should not trigger the immune system into creating an anti-PEG antibody. We found that a 10% molar exchange of this short chain PEG within the monolayer met three of the desired goals: high water solubility, no toxicity, and no immune response as measured by white blood cell counts, but none of the short chain PEG mixed monolayer compositions enabled the nanoparticles to have a long circulation time within the blood as compared to mercapto-undecyl-ethylene glycol, which had a residence time of 4 weeks. We also compared the effects of a hydroxyl versus a carboxylic acid terminal functional group on the end of the PEG thiol on both clearance and immune response. The results indicate that short-chain length PEGs, regardless of termini, increase clearance rates compared to the previous long-chain PEG studies while carboxylated-termini increase red blood cell counts at high loadings. Given these findings, short-chain, alcohol-terminated PEG, exchanged at 10% was identified as a potential nanoparticle for further in vivo applications requiring short circulation lifetimes with desired features of no toxicity, no immune response, and high water solubility. PMID:21473648

Adverse eff ects of polymeric nanoparticle poly(ethylene glycol)- block-polylactide methyl ether (PEG-b-PLA) on steroid hormone secretion by porcine granulosa cells.

PubMed

Scsukova, Sona; Bujnakova, Mlynarcikova A; Kiss, A; Rollerova, E

2017-04-25

Development of nanoparticles (NPs) for biomedical applications, including medical imaging and drug delivery, is currently undergoing a dramatic expansion. Diverse effects of different type NPs relating to mammalian reproductive tissues have been demonstrated. Th e objective of this study was to explore the in vitro effects of polymeric nanoparticle poly(ethylene glycol)-blockpolylactide methyl ether (PEG-b-PLA NPs) on functional state and viability of ovarian granulosa cells (GCs), which play an important role in maintaining ovarian function and female fertility. The GCs isolated from porcine ovarian follicles were incubated with the different concentrations of PEG-b-PLA NPs (PEG average Mn=350 g/mol and PLA average Mn=1000 g/mol; 0.2-100 μg/ml) or poly(ethylene glycol) with an average molecular weight of 300 (PEG-300; 0.2- 40 mg/ml) in the presence or absence of stimulators, follicle-stimulating hormone (FSH; 1 μg/ml), androstenedione (100 nM), forskolin (10 μM) or 8Br-cAMP (100 μM), for different time periods (24, 48, 72 h). At the end of the incubation, progesterone and estradiol levels produced by GCs were measured in the culture media by radioimmunoassay. Th e viability of GCs was determined by the method using a colorimetric assay with MTT. Treatment of GCs with PEG-b-PLA NPs induced a significant decrease in basal as well as FSH-stimulated progesterone secretion above the concentration of 20 and 4 μg/ml, respectively. Moreover, PEG-b-PLA NPs reduced forskolin-stimulated, but not cAMP-stimulated progesterone production by GCs. A dose-dependent inhibition of androstenedione-stimulated estradiol release by GCs was found by the action of PEG-b-PLA NPs. Incubation of GCs with PEG-300 significantly inhibited basal as well as FSH-stimulated progesterone secretion above the concentration of 40 mg/ml. PEG-b-PLA NPs and PEG-300 significantly reduced the viability of GCs at the highest tested concentrations (100 μg/ml and 40 mg/ml, respectively). The obtained results indicate that polymeric NPs PEG-b-PLA might induce alterations in steroid hormone production by ovarian GCs and thereby could modify reproductive functions.

Viability and neuronal differentiation of neural stem cells encapsulated in silk fibroin hydrogel functionalized with an IKVAV peptide.

PubMed

Sun, Wei; Incitti, Tania; Migliaresi, Claudio; Quattrone, Alessandro; Casarosa, Simona; Motta, Antonella

2017-05-01

Three-dimensional (3D) porous scaffolds combined with therapeutic stem cells play vital roles in tissue engineering. The adult brain has very limited regeneration ability after injuries such as trauma and stroke. In this study, injectable 3D silk fibroin-based hydrogel scaffolds with encapsulated neural stem cells were developed, aiming at supporting brain regeneration. To improve the function of the hydrogel towards neural stem cells, silk fibroin was modified by an IKVAV peptide through covalent binding. Both unmodified and modified silk fibroin hydrogels were obtained, through sonication, with mechanical stiffness comparable to that of brain tissue. Human neural stem cells were encapsulated in both hydrogels and the effects of IKVAV peptide conjugation on cell viability and neural differentiation were assessed. The silk fibroin hydrogel modified by IKVAV peptide showed increased cell viability and an enhanced neuronal differentiation capability, which contributed to understanding the effects of IKVAV peptide on the behaviour of neural stem cells. For these reasons, IKVAV-modified silk fibroin is a promising material for brain tissue engineering. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Bio-functionalized silk hydrogel microfluidic systems.

PubMed

Zhao, Siwei; Chen, Ying; Partlow, Benjamin P; Golding, Anne S; Tseng, Peter; Coburn, Jeannine; Applegate, Matthew B; Moreau, Jodie E; Omenetto, Fiorenzo G; Kaplan, David L

2016-07-01

Bio-functionalized microfluidic systems were developed based on a silk protein hydrogel elastomeric materials. A facile multilayer fabrication method using gelatin sacrificial molding and layer-by-layer assembly was implemented to construct interconnected, three dimensional (3D) microchannel networks in silk hydrogels at 100 μm minimum feature resolution. Mechanically activated valves were implemented to demonstrate pneumatic control of microflow. The silk hydrogel microfluidics exhibit controllable mechanical properties, long-term stability in various environmental conditions, tunable in vitro and in vivo degradability in addition to optical transparency, providing unique features for cell/tissue-related applications than conventional polydimethylsiloxane (PDMS) and existing hydrogel-based microfluidic options. As demonstrated in the work here, the all aqueous-based fabrication process at ambient conditions enabled the incorporation of active biological substances in the bulk phase of these new silk microfluidic systems during device fabrication, including enzymes and living cells, which are able to interact with the fluid flow in the microchannels. These silk hydrogel-based microfluidic systems offer new opportunities in engineering active diagnostic devices, tissues and organs that could be integrated in vivo, and for on-chip cell sensing systems. Copyright © 2016 Elsevier Ltd. All rights reserved.

Controlled release of functional proteins through designer self-assembling peptide nanofiber hydrogel scaffold

PubMed Central

Koutsopoulos, Sotirios; Unsworth, Larry D.; Nagai, Yusuke; Zhang, Shuguang

2009-01-01

The release kinetics for a variety of proteins of a wide range of molecular mass, hydrodynamic radii, and isoelectric points through a nanofiber hydrogel scaffold consisting of designer self-assembling peptides were studied by using single-molecule fluorescence correlation spectroscopy (FCS). In contrast to classical diffusion experiments, the single-molecule approach allowed for the direct determination of diffusion coefficients for lysozyme, trypsin inhibitor, BSA, and IgG both inside the hydrogel and after being released into the solution. The results of the FCS analyses and the calculated pristine in-gel diffusion coefficients were compared with the values obtained from the Stokes–Einstein equation, Fickian diffusion models, and the literature. The release kinetics suggested that protein diffusion through nanofiber hydrogels depended primarily on the size of the protein. Protein diffusivities decreased, with increasing hydrogel nanofiber density providing a means of controlling the release kinetics. Secondary and tertiary structure analyses and biological assays of the released proteins showed that encapsulation and release did not affect the protein conformation and functionality. Our results show that this biocompatible and injectable designer self-assembling peptide hydrogel system may be useful as a carrier for therapeutic proteins for sustained release applications. PMID:19273853

Microarray profiling of human white adipose tissue after exogenous leptin injection.

PubMed

Taleb, S; Van Haaften, R; Henegar, C; Hukshorn, C; Cancello, R; Pelloux, V; Hanczar, B; Viguerie, N; Langin, D; Evelo, C; Zucker, J; Clément, K; Saris, W H M

2006-03-01

Leptin is a secreted adipocyte hormone that plays a key role in the regulation of body weight homeostasis. The leptin effect on human white adipose tissue (WAT) is still debated. The aim of this study was to assess whether the administration of polyethylene glycol-leptin (PEG-OB) in a single supraphysiological dose has transcriptional effects on genes of WAT and to identify its target genes and functional pathways in WAT. Blood samples and WAT biopsies were obtained from 10 healthy nonobese men before treatment and 72 h after the PEG-OB injection, leading to an approximate 809-fold increase in circulating leptin. The WAT gene expression profile before and after the PEG-OB injection was compared using pangenomic microarrays. Functional gene annotations based on the gene ontology of the PEG-OB regulated genes were performed using both an 'in house' automated procedure and GenMAPP (Gene Microarray Pathway Profiler), designed for viewing and analyzing gene expression data in the context of biological pathways. Statistical analysis of microarray data revealed that PEG-OB had a major down-regulated effect on WAT gene expression, as we obtained 1,822 and 100 down- and up-regulated genes, respectively. Microarray data were validated using reverse transcription quantitative PCR. Functional gene annotations of PEG-OB regulated genes revealed that the functional class related to immunity and inflammation was among the most mobilized PEG-OB pathway in WAT. These genes are mainly expressed in the cell of the stroma vascular fraction in comparison with adipocytes. Our observations support the hypothesis that leptin could act on WAT, particularly on genes related to inflammation and immunity, which may suggest a novel leptin target pathway in human WAT.

Radiofrequency treatment enhances the catalytic function of an immobilized nanobiohybrid catalyst

NASA Astrophysics Data System (ADS)

San, Boi Hoa; Ha, Eun-Ju; Paik, Hyun-Jong; Kim, Kyeong Kyu

2014-05-01

Biocatalysis, the use of enzymes in chemical transformation, has undergone intensive development for a wide range of applications. As such, maximizing the functionality of enzymes for biocatalysis is a major priority to enable industrial use. To date, many innovative technologies have been developed to address the future demand of enzymes for these purposes, but maximizing the catalytic activity of enzymes remains a challenge. In this study, we demonstrated that the functionality of a nanobiocatalyst could be enhanced by combining immobilization and radiofrequency (RF) treatment. Aminopeptidase PepA-encapsulating 2 nm platinum nanoparticles (PepA-PtNPs) with the catalytic activities of hydrolysis and hydrogenation were employed as multifunctional nanobiocatalysts. Immobilizing the nanobiocatalysts in a hydrogel using metal chelation significantly enhanced their functionalities, including catalytic power, thermal-stability, pH tolerance, organic solvent tolerance, and reusability. Most importantly, RF treatment of the hydrogel-immobilized PepA-PtNPs increased their catalytic power by 2.5 fold greater than the immobilized PepA. Our findings indicate that the catalytic activities and functionalities of PepA-PtNPs are greatly enhanced by the combination of hydrogel-immobilization and RF treatment. Based on our findings, we propose that RF treatment of nanobiohybrid catalysts immobilized on the bulk hydrogel represents a new strategy for achieving efficient biocatalysis.Biocatalysis, the use of enzymes in chemical transformation, has undergone intensive development for a wide range of applications. As such, maximizing the functionality of enzymes for biocatalysis is a major priority to enable industrial use. To date, many innovative technologies have been developed to address the future demand of enzymes for these purposes, but maximizing the catalytic activity of enzymes remains a challenge. In this study, we demonstrated that the functionality of a nanobiocatalyst could be enhanced by combining immobilization and radiofrequency (RF) treatment. Aminopeptidase PepA-encapsulating 2 nm platinum nanoparticles (PepA-PtNPs) with the catalytic activities of hydrolysis and hydrogenation were employed as multifunctional nanobiocatalysts. Immobilizing the nanobiocatalysts in a hydrogel using metal chelation significantly enhanced their functionalities, including catalytic power, thermal-stability, pH tolerance, organic solvent tolerance, and reusability. Most importantly, RF treatment of the hydrogel-immobilized PepA-PtNPs increased their catalytic power by 2.5 fold greater than the immobilized PepA. Our findings indicate that the catalytic activities and functionalities of PepA-PtNPs are greatly enhanced by the combination of hydrogel-immobilization and RF treatment. Based on our findings, we propose that RF treatment of nanobiohybrid catalysts immobilized on the bulk hydrogel represents a new strategy for achieving efficient biocatalysis. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr00407h

Emulating Native Periosteum Cell Population and Subsequent Paracrine Factor Production To Promote Tissue Engineered Periosteum-Mediated Allograft Healing

PubMed Central

Hoffman, Michael D.

2015-01-01

Emulating autograft healing within the context of decellularized bone allografts has immediate clinical applications in the treatment of critical-sized bone defects. The periosteum, a thin, osteogenic tissue that surrounds bone, houses a heterogeneous population of stem cells and osteoprogenitors. There is evidence that periosteum-cell derived paracrine factors, specifically vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2), orchestrate autograft healing through host cell recruitment and subsequent tissue elaboration. In previous work, we demonstrated that the use of poly(ethylene glycol) (PEG) hydrogels as a tissue engineered (T.E.) periosteum to localize mesenchymal stem cells (MSCs) to the surface of decellularized bone enhances allograft healing and integration. Herein, we utilize a mixed population of 50:50 MSCs and osteoprogenitor cells to better mimic native periosteum cell population and paracrine factor production to further promote allograft healing. This mixed cell population was localized to the surface of decellularized allografts within degradable hydrogels and shown to expedite allograft healing. Specifically, bone callus formation and biomechanical graft-host integration are increased as compared to unmodified allografts. These results demonstrate the dual importance of periosteum-mediated paracrine factors orchestrating host cell recruitment as well as new bone formation while developing clinically translatable strategies for allograft healing and integration. PMID:25818449

Chromatic biosensor for detection of phosphinothricin acetyltransferase by use of polydiacetylene vesicles encapsulated within automatically generated immunohydrogel beads.

PubMed

Jung, Sung-Ho; Jang, Huisoo; Lim, Min-Cheol; Kim, Jae-Hwan; Shin, Kong-Sik; Kim, Sun Min; Kim, Hae-Yeong; Kim, Young-Rok; Jeon, Tae-Joon

2015-02-17

We developed a simple and sensitive colorimetric biosensor in the form of microparticles by using polydiacetylene (PDA) vesicles encapsulated within a hydrogel matrix for the detection of phosphinothricin acetyltransferase (PAT) protein, which is one of the most important marker proteins in genetically modified (GM) crops. Although PDA is commonly used as a sensing material due to its unique colorimetric properties, existing PDA biosensors are ineffective due to their low sensitivity as well as their lack of robustness. To overcome these disadvantages, we devised immunohydrogel beads made of anti-PAT-conjugated PDA vesicles embedded at high density within a poly(ethylene glycol) diacrylate (PEG-DA) hydrogel matrix. In addition, the construction of immunohydrogel beads was automated by use of a microfluidic device. In the immunoreaction, the sensitivity of antibody-conjugated PDA vesicles was significantly amplified, as monitored by the unaided eye. The limit of detection for target molecules reached as low as 20 nM, which is sufficiently low enough to detect target materials in GM organisms. Collectively, the results show that immunohydrogel beads constitute a promising colorimetric sensing platform for onsite testing in a number of fields, such as the food and medical industries, as well as warfare situations.

Nanocomposite hydrogels stabilized by self-assembled multivalent bisphosphonate-magnesium nanoparticles mediate sustained release of magnesium ion and promote in-situ bone regeneration.

PubMed

Zhang, Kunyu; Lin, Sien; Feng, Qian; Dong, Chaoqun; Yang, Yanhua; Li, Gang; Bian, Liming

2017-12-01

Hydrogels are appealing biomaterials for applications in regenerative medicine due to their tunable physical and bioactive properties. Meanwhile, therapeutic metal ions, such as magnesium ion (Mg 2+ ), not only regulate the cellular behaviors but also stimulate local bone formation and healing. However, the effective delivery and tailored release of Mg 2+ remains a challenge, with few reports on hydrogels being used for Mg 2+ delivery. Bisphosphonate exhibits a variety of specific bioactivities and excellent binding affinity to multivalent cations such as Mg 2+ . Herein, we describe a nanocomposite hydrogel based on hyaluronic acid and self-assembled bisphosphonate-magnesium (BP-Mg) nanoparticles. These nanoparticles bearing acrylate groups on the surface not only function as effective multivalent crosslinkers to strengthen the hydrogel network structure, but also promote the mineralization of hydrogels and mediate sustained release of Mg 2+ . The released Mg 2+ ions facilitate stem cell adhesion and spreading on the hydrogel substrates in the absence of cell adhesion ligands, and promote osteogenesis of the seeded hMSCs in vitro. Furthermore, the acellular porous hydrogels alone can support in situ bone regeneration without using exogenous cells and inductive agents, thereby greatly simplifying the approaches of bone regeneration therapy. In this study, we developed a novel bioactive nanocomposite hydrogel based on hyaluronic acid and self-assembled bisphosphonate-magnesium (BP-Mg) nanoparticles. Such hydrogels are stabilized by the multivalent crosslinking domains formed by the aggregation of Ac-BP-Mg NPs, and therefore show enhanced mechanical properties, improved capacity for mineralization, and controlled release kinetics of Mg 2+ . Moreover, the released Mg 2+ can enhance cell adhesion and spreading, and further promote the osteogenic differentiation of hMSCs. Owing to these unique properties, these acellular hydrogels alone can well facilitate the in vivo bone regeneration at the intended sites. We believe that the strategy reported in this work opens up a new route to develop biopolymer-based nanocomposite hydrogels with enhanced physical and biological functionalities for regenerative medicine. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Gold nanoparticles and polyethylene glycols functionalized conducting polyaniline nanowires for ultrasensitive and low fouling immunosensing of alpha-fetoprotein.

PubMed

Hui, Ni; Sun, Xiaotian; Song, Zhiling; Niu, Shuyan; Luo, Xiliang

2016-12-15

An ultrasensitive biosensor for alpha-fetoprotein was developed based on electrochemically synthesized polyaniline (PANI) nanowires, which were functionalized with gold nanoparticles (AuNPs) and polyethylene glycols (PEG). The prepared PEG/AuNPs/PANI composite, combining the electrical conductivity of the AuNPs/PANI with the robust antifouling ability of PEG, offered an ideal substrate for the development of low fouling electrochemical biosensors. Alpha-fetoprotein (AFP), a well-known hepatocellular carcinoma biomarker, was used as a model analyte, and its antibody was immobilized on the PEG/AuNPs/PANI for the construction of the AFP immunosensor. Using the redox current of PANI as the sensing signal, in addition to the good biocompatibility of PEG/AuNPs and the anti-biofouling property of PEG, the developed immunosensor showed improved biosensing performances, such as wide linear range and ultralow detection limit (0.007pgmL(-1)). More importantly, it is label-free, reagentless and low fouling, making it capable of assaying AFP in real serum samples without suffering from significant interference or biofouling. Copyright © 2016 Elsevier B.V. All rights reserved.

Separation of polyethylene glycols and amino-terminated polyethylene glycols by high-performance liquid chromatography under near critical conditions.

PubMed

Wei, Y-Z; Zhuo, R-X; Jiang, X-L

2016-05-20

The separation and characterization of polyethylene glycols (PEGs) and amino-substituted derivatives on common silica-based reversed-phase packing columns using isocratic elution is described. This separation is achieved by liquid chromatography under the near critical conditions (LCCC), based on the number of amino functional end groups without obvious effect of molar mass for PEGs. The mobile phase is acetonitrile in water with an optimal ammonium acetate buffer. The separation mechanism of PEG and amino-substituted PEG under the near LCCC on silica-based packing columns is confirmed to be ion-exchange interaction. Under the LCCC of PEG backbone, with fine tune of buffer concentration, the retention factor ratios for benzylamine and phenol in buffered mobile phases, α(benzylamine/phenol)-values, were used to assess the ion-exchange capacity on silica-based reversed-phase packing columns. To the best of our knowledge, this is the first report on separation of amino-functional PEGs independent of the molar mass by isocratic elution using common C18 or phenyl reversed-phase packing columns. Copyright © 2016 Elsevier B.V. All rights reserved.

An injectable particle-hydrogel hybrid system for glucose-regulatory insulin delivery.

PubMed

Zhao, Fuli; Wu, Di; Yao, Dan; Guo, Ruiwei; Wang, Weiwei; Dong, Anjie; Kong, Deling; Zhang, Jianhua

2017-12-01

Long-term and daily subcutaneous injections of insulin for the treatment of insulin-dependent diabetic patients often lead to poor patient compliance and undesired complications. Phenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, their applications are limited by clinically irrelevant glucose-responsive range, slow response rate, low tissue-adhesiveness and poor biodegradability, undesirable leakage at normoglycemic state. Herein, we report a novel implantable insulin hydrogel for glucose-regulated delivery of insulin based on a unique particle-hydrogel hybrid platform featuring fast glucose responsiveness at physiological pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, and full biodegradability for safe use. The system was thoroughly characterized both in vitro and in vivo and was demonstrated to hold these unique functions. Using streptozotocin-induced diabetic mice as a model, it was shown that a single subcutaneous injection of the insulin-loaded particle-hydrogel formulation led to quasi-steady-state blood glucose levels within the normal range for about two weeks. In addition, the preparation of the formulation only involved simple mixing and self-assembling processes, and thus it had great scalability and reproducibility for practical use. The highly feasible preparation, excellent performance, inherent biocompatibility and biodegradability make this novel composite hydrogel promising platform for diabetes therapy. Phenylboronic acid (PBA)-based polymeric hydrogels have been widely considered as one of the most promising insulin delivery system to replace the frequent insulin injections. However, these hydrogels, mostly based on a variety of PBA-containing acrylamide monomers, are still far from clinical reality. Building upon a unique particle-hydrogel hybrid platform, herein we report a novel implantable insulin storage and delivery system with multifunctionalities including fast glucose-sensitiveness at physiological pH, shear-thinning behavior for injection, tissue-adhesive function for long-lasting adherence, biodegradable materials for safe use and well-controlled insulin release. These unique functions were demonstrated through research both in vitro and in vivo. In addition, the preparation of the formulation was simple, and thus it had great scalability and reproducibility for practical use. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Mechanically enhanced nested-network hydrogels as a coating material for biomedical devices.

PubMed

Wang, Zhengmu; Zhang, Hongbin; Chu, Axel J; Jackson, John; Lin, Karen; Lim, Chinten James; Lange, Dirk; Chiao, Mu

2018-04-01

Well-organized composite formations such as hierarchical nested-network (NN) structure in bone tissue and reticular connective tissue present remarkable mechanical strength and play a crucial role in achieving physical and biological functions for living organisms. Inspired by these delicate microstructures in nature, an analogous scaffold of double network hydrogel was fabricated by creating a poly(2-hydroxyethyl methacrylate) (pHEMA) network in the porous structure of alginate hydrogels. The resulting hydrogel possessed hierarchical NN structure and showed significantly improved mechanical strength but still maintained high elasticity comparable to soft tissues due to a mutual strengthening effect between the two networks. The tough hydrogel is also self-lubricated, exhibiting a surface friction coefficient comparable with polydimethylsiloxane (PDMS) substrates lubricated by a commercial aqueous lubricant (K-Y Jelly) and other low surface friction hydrogels. Additional properties of this hydrogel include high hydrophilicity, good biocompatibility, tunable cell adhesion and bacterial resistance after incorporation of silver nanoparticles. Firm bonding of the hydrogel on silicone substrates could be achieved through facile chemical modification, thus enabling the use of this hydrogel as a versatile coating material for biomedical applications. In this study, we developed a tough hydrogel by crosslinking HEMA monomers in alginate hydrogels and forming a well-organized structure of hierarchical nested network (NN). Different from most reported stretchable alginate-based hydrogels, the NN hydrogel shows higher compressive strength but retains comparable softness to alginate counterparts. This work further demonstrated the good integration of the tough hydrogel with silicone substrates through chemical modification and micropillar structures. Other properties including surface friction, biocompatibility and bacterial resistance were investigated and the hydrogel shows a great promise as a versatile coating material for biomedical applications. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Chitosan-g-MPEG-modified alginate/chitosan hydrogel microcapsules: a quantitative study of the effect of polymer architecture on the resistance to protein adsorption.

PubMed

Zheng, Jia N; Xie, Hong G; Yu, Wei T; Liu, Xiu D; Xie, Wei Y; Zhu, Jing; Ma, Xiao J

2010-11-16

The chemical modification of the alginate/chitosan/alginate (ACA) hydrogel microcapsule with methoxy poly(ethylene glycol) (MPEG) was investigated to reduce nonspecific protein adsorption and improve biocompatibility in vivo. The graft copolymer chitosan-g-MPEG (CS-g-MPEG) was synthesized, and then alginate/chitosan/alginate/CS-g-MPEG (ACAC(PEG)) multilayer hydrogel microcapsules were fabricated by the layer-by-layer (LBL) polyelectrolyte self-assembly method. A quantitative study of the modification was carried out by the gel permeation chromatography (GPC) technique, and protein adsorption on the modified microcapsules was also investigated. The results showed that the apparent graft density of the MPEG side chain on the microcapsules decreased with increases in the degree of substitution (DS) and the MPEG chain length. During the binding process, the apparent graft density of CS-g-MPEG showed rapid growth-plateau-rapid growth behavior. CS-g-MPEG was not only bound to the surface but also penetrated a certain depth into the microcapsule membranes. The copolymers that penetrated the microcapsules made a smaller contribution to protein repulsion than did the copolymers on the surfaces of the microcapsules. The protein repulsion ability decreased with the increase in DS from 7 to 29% with the same chain length of MPEG 2K. CS-g-MPEG with MPEG 2K was more effective at protein repulsion than CS-g-MPEG with MPEG 550, having a similar DS below 20%. In this study, the microcapsules modified with CS-g-MPEG2K-DS7% had the lowest IgG adsorption of 3.0 ± 0.6 μg/cm(2), a reduction of 61% compared to that on the chitosan surface.

Repair of full-thickness articular cartilage defect using stem cell-encapsulated thermogel.

PubMed

Zhang, Yanbo; Zhang, Jin; Chang, Fei; Xu, Weiguo; Ding, Jianxun

2018-07-01

Cartilage defect repair by hydrogel-based tissue engineering is becoming one of the most potential treatment strategies. In this work, a thermogel of triblock copolymer poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) was prepared as scaffold of bone marrow mesenchymal stem cells (BMMSCs) for repair of full-thickness articular cartilage defect. At first, the copolymer solution showed a reversible sol-gel transition at physiological temperature range, and the mechanical properties of such thermogel were high enough to support the repair of cartilage. Additionally, excellent biodegradability and biocompatibility of the thermogel were demonstrated. By implanting the BMMSC-encapsulated thermogel into the full-thickness articular cartilage defect (5.0 mm in diameter and 4.0 mm in depth) in the rabbit, it was found that the regenerated cartilage integrated well with the surrounding normal cartilage and subchondral bone at 12 weeks post-surgery. The upregulated expression of glycosaminoglycan and type II collagen in the repaired cartilage, and the comparable biomechanical properties with normal cartilage suggested that the cell-encapsulated PLGA-PEG-PLGA thermogel had great potential in serving as the promising scaffold for cartilage regeneration. Copyright © 2018 Elsevier B.V. All rights reserved.

Dose-dependent sustained local release of dexamethasone from biodegradable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers in the possible prevention of TMJ re-ankylosis (Arakeri's TMJ release technique).

PubMed

Arakeri, Gururaj; Brennan, Peter A

2012-05-01

Temporomandibular joint (TMJ) ankylosis is a devastating anatomico-pathological condition which severely affects the quality of human health. Over the last 70 years various treatments have been described to treat this distressing condition. But no single method has uniformly produced successful results. Although various surgical techniques have been improved periodically, the treatment results remain inefficient due to its recurrence as TMJ re-adhesion. Since recurrence remains as a problem in many cases, the TMJ ankylosis presents a major therapeutic challenge in head and neck surgery. The re-ankylosis is a unique phenomenon that so far has defied a full and logical explanation, based upon biological and mechanical factors that are linked together in a coherent fashion. Many factors have been implicated in the development of re-adhesion following TMJ surgery. But still the mechanism by which the TMJ re-adhesion develops is unclear. Hence, TMJ ankylosis demands an alternative effective treatment modality to prevent its recurrence as re-ankylosis. This paper postulates some critical biological factors responsible for re-ankylosis based on which a novel treatment modality is also proposed. Copyright © 2012 Elsevier Ltd. All rights reserved.

Polyelectrolyte hydrogel instabilities in ionic solutions

NASA Astrophysics Data System (ADS)

English, Anthony E.; Tanaka, Toyoichi; Edelman, Elazer R.

1996-12-01

The phase behavior of polyelectrolyte hydrogels has been examined as a function of relative charge composition, bath salt concentration, and solvent quality. Nonlinear swelling instabilities of 2-hydroxyethyl methacrylate (HEMA) and methacrylic acid (MAAc) copolymer hydrogels manifested themselves as discontinuous first order swelling transitions as a function of bath salt concentration. A modified Flory-Huggins model was used to describe the regions of instability when bath salt concentration and solvent quality are considered as control variables. The role of ion dissociation equilibrium in the change from local or smooth transitions to nonlocal or discontinuous swelling transitions is illustrated within the framework of our model.

Controlling the Porosity and Microarchitecture of Hydrogels for Tissue Engineering

PubMed Central

Annabi, Nasim; Nichol, Jason W.; Zhong, Xia; Ji, Chengdong; Koshy, Sandeep; Khademhosseini, Ali

2010-01-01

Tissue engineering holds great promise for regeneration and repair of diseased tissues, making the development of tissue engineering scaffolds a topic of great interest in biomedical research. Because of their biocompatibility and similarities to native extracellular matrix, hydrogels have emerged as leading candidates for engineered tissue scaffolds. However, precise control of hydrogel properties, such as porosity, remains a challenge. Traditional techniques for creating bulk porosity in polymers have demonstrated success in hydrogels for tissue engineering; however, often the conditions are incompatible with direct cell encapsulation. Emerging technologies have demonstrated the ability to control porosity and the microarchitectural features in hydrogels, creating engineered tissues with structure and function similar to native tissues. In this review, we explore the various technologies for controlling the porosity and microarchitecture within hydrogels, and demonstrate successful applications of combining these techniques. PMID:20121414

Mission planning, mission analysis and software formulation. Level C requirements for the shuttle mission control center orbital guidance software

NASA Technical Reports Server (NTRS)

Langston, L. J.

1976-01-01

The formulation of Level C requirements for guidance software was reported. Requirements for a PEG supervisor which controls all input/output interfaces with other processors and determines which PEG mode is to be utilized were studied in detail. A description of the two guidance modes for which Level C requirements have been formulated was presented. Functions required for proper execution of the guidance software were defined. The requirements for a navigation function that is used in the prediction logic of PEG mode 4 were discussed. It is concluded that this function is extracted from the current navigation FSSR.

Fabrication and characterization of graphene hydrogel via hydrothermal approach as a scaffold for preliminary study of cell growth

PubMed Central

Lim, HN; Huang, NM; Lim, SS; Harrison, I; Chia, CH

2011-01-01

Background Three-dimensional assembly of graphene hydrogel is rapidly attracting the interest of researchers because of its wide range of applications in energy storage, electronics, electrochemistry, and waste water treatment. Information on the use of graphene hydrogel for biological purposes is lacking, so we conducted a preliminary study to determine the suitability of graphene hydrogel as a substrate for cell growth, which could potentially be used as building blocks for biomolecules and tissue engineering applications. Methods A three-dimensional structure of graphene hydrogel was prepared via a simple hydrothermal method using two-dimensional large-area graphene oxide nanosheets as a precursor. Results The concentration and lateral size of the graphene oxide nanosheets influenced the structure of the hydrogel. With larger-area graphene oxide nanosheets, the graphene hydrogel could be formed at a lower concentration. X-ray diffraction patterns revealed that the oxide functional groups on the graphene oxide nanosheets were reduced after hydrothermal treatment. The three-dimensional graphene hydrogel matrix was used as a scaffold for proliferation of a MG63 cell line. Conclusion Guided filopodia protrusions of MG63 on the hydrogel were observed on the third day of cell culture, demonstrating compatibility of the graphene hydrogel structure for bioapplications. PMID:21931479

Biodegradable HEMA-based hydrogels with enhanced mechanical properties.

PubMed

Moghadam, Mohamadreza Nassajian; Pioletti, Dominique P

2016-08-01

Hydrogels are widely used in the biomedical field. Their main purposes are either to deliver biological active agents or to temporarily fill a defect until they degrade and are followed by new host tissue formation. However, for this latter application, biodegradable hydrogels are usually not capable to sustain any significant load. The development of biodegradable hydrogels presenting load-bearing capabilities would open new possibilities to utilize this class of material in the biomedical field. In this work, an original formulation of biodegradable photo-crosslinked hydrogels based on hydroxyethyl methacrylate (HEMA) is presented. The hydrogels consist of short-length poly(2-hydroxyethyl methacrylate) (PHEMA) chains in a star shape structure, obtained by introducing a tetra-functional chain transfer agent in the backbone of the hydrogels. They are cross-linked with a biodegradable N,O-dimethacryloyl hydroxylamine (DMHA) molecule sensitive to hydrolytic cleavage. We characterized the degradation properties of these hydrogels submitted to mechanical loadings. We showed that the developed hydrogels undergo long-term degradation and specially meet the two essential requirements of a biodegradable hydrogel suitable for load bearing applications: enhanced mechanical properties and low molecular weight degradation products. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1161-1169, 2016. © 2015 Wiley Periodicals, Inc.

Application of Hydrogels in Heart Valve Tissue Engineering

PubMed Central

Zhang, Xing; Xu, Bin; Puperi, Daniel S.; Wu, Yan; West, Jennifer L.; Grande-Allen, K. Jane

2015-01-01

With an increasing number of patients requiring valve replacement, there is heightened interest in advancing heart valve tissue engineering (HVTE) to provide solutions to the many limitations of current surgical treatments. A variety of materials have been developed as scaffolds for HVTE including natural polymers, synthetic polymers, and decellularized valvular matrices. Among them, biocompatible hydrogels are generating growing interest. Natural hydrogels, such as collagen and fibrin, generally show good bioactivity, but poor mechanical durability. Synthetic hydrogels, on the other hand, have tunable mechanical properties; however, appropriate cell-matrix interactions are difficult to obtain. Moreover, hydrogels can be used as cell carriers when the cellular component is seeded into the polymer meshes or decellularized valve scaffolds. In this review, we discuss current research strategies for HVTE with an emphasis on hydrogel applications. The physicochemical properties and fabrication methods of these hydrogels, as well as their mechanical properties and bioactivities are described. Performance of some hydrogels including in vitro evaluation using bioreactors and in vivo tests in different animal models are also discussed. For future HVTE, it will be compelling to examine how hydrogels can be constructed from composite materials to replicate mechanical properties and mimic biological functions of the native heart valve. PMID:25955010

Superabsorbent hydrogel composite based on copolymer cellulose/poly (vinyl alcohol)/CNT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khoerunnisa, Fitri, E-mail: fitri.khoerunnisa@gmail.com; Hendrawan,; Sonjaya, Yaya

2016-04-19

Superabsorbent hydrogels are cross-linked hydrophilic polymers that can absorb and retain a large volume of water, saline solution, or physiological fluids. A distinctive superabsorbent hydrogel composite based on cellulose/ poly (vinyl alcohol)/ carbon nanotubes was successfully synthesized via the graft bio-copolymerization in an aqueous medium with glutaraldehide as a crosslinking agent. The effect of carbon nanotubes (CNT) on water absorption capacity and mechanical properties of superabsorbent composite were particularly investigated. The Fourier transform infrared spectra showed the evidence of copolymerization of hydrogel precursors as well as the interaction of CNT filler with the hydrogel matrices, as indicated by the shiftingmore » of peak intensity and position of several functional groups (O-H, C-H sp{sup 3}, C=O, C-N, C-O). The modification of hydrogel surface morphology and porosity owing to CNT insertion was also confirmed by scanning electron microscopy images. The CNT insertion improved the mechanical strength of superabsorbent hydrogel composites. Moreover, insertion of CNT into hydrogel matrix remarkably increased the swelling capacity of superabsorbent composites up to 840%. This huge water absorption capacity of hydrogel composites offers promising applications in development of superabsorbent polymers.« less

Sensitive and rapid detection of anti-PEG in blood using surface plasmon resonance sensor (Conference Presentation)

NASA Astrophysics Data System (ADS)

Sun, Fang; Jiang, Shaoyi; Yu, Qiuming

2016-03-01

Polyethylene glycol (PEG) is widely used to modify many therapeutic proteins and nanoparticles to reduce their immunogenicity and to improve their pharmacokinetic and therapeutic properties. It is generally accepted that PEG is non-immunogenic and non-antigenic. However, an emerging of literature and studies shows that the immune system can generate specific antibodies binding PEG. These anti-PEG antibodies not only correlate with adverse reactions appeared after patient infusions, but are also found to be the reason for therapeutic efficacy loss during chronical administrations. In addition, because of constant exposure to PEG in daily consumer products including detergents, processed food and cosmetics, a substantial proportion of the population has likely developed anti-PEG immunity. Thus a method to quickly and accurately measure the anti-PEG antibody level is desired. Nevertheless, the gold standard to detect anti-PEG antibodies is ELISA, which is costly and time-consuming especially for quantification. Herein, we demonstrated the anti-PEG measurement in blood serum using surface plasmon resonance (SPR) sensor. Several PEG-based surface functionalization on SPR sensor chip were studied in terms of protein resistance and the limit of detection (LOD) of anti-PEG. The quantitative detection can be achieved in less than 30 min with LOD comparable to ELISA. Furthermore, the IgG and IgM of anti-PEG can be differentiated by following the secondary antibody.

Creating Polymer Hydrogel Microfibres with Internal Alignment via Electrical and Mechanical Stretching

PubMed Central

Zhang, Shuming; Liu, Xi; Barreto-Ortiz, Sebastian F.; Yu, Yixuan; Ginn, Brian; DeSantis, Nicholas; Hutton, Daphne L; Grayson, Warren; Cui, Fu-Zhai; Korgel, Brian A.; Gerecht, Sharon; Mao, Hai-Quan

2014-01-01

Hydrogels have been widely used for 3-dimensional (3D) cell culture and tissue regeneration due to their tunable biochemical and physicochemical properties as well as their high water content, which resembles the aqueous microenvironment of the natural extracellular matrix. While many properties of natural hydrogel matrices are modifiable, their intrinsic isotropic structure limits the control over cellular organization, which is critical to restore tissue function. Here we report a generic approach to incorporate alignment topography inside the hydrogel matrix using a combination of electrical and mechanical stretching. Hydrogel fibres with uniaxial alignment were prepared from aqueous solutions of natural polymers such as alginate, fibrin, gelatin, and hyaluronic acid under ambient conditions. The unique internal alignment feature drastically enhances the mechanical properties of the hydrogel microfibres. Furthermore, the facile, organic solvent-free processing conditions are amenable to the incorporation of live cells within the hydrogel fibre or on the fibre surface; both approaches effectively induce cellular alignment. This work demonstrates a versatile and scalable strategy to create aligned hydrogel microfibres from various natural polymers. PMID:24439410

Synthesis of a chitosan-based photo-sensitive hydrogel and its biocompatibility and biodegradability.

PubMed

He, Ming; Han, Baoqin; Jiang, Zhiwen; Yang, Yan; Peng, Yanfei; Liu, Wanshun

2017-06-15

Hydroxyethyl chitosan (HECTS) is one of the most important water soluble derivatives of chitosan. In this study, photo-sensitive azidehydroxyethyl chitosan (AZ-HECTS) was synthesized with grafting degree 3.4%, and its water solution resulted in an insoluble hydrogel by 254nm UV irradiation for 90s. AZ-HECTS hydrogels, with water absorption 86.21%, had little impact on growth of mouse fibroblast (L929) and presented good cell biocompatibility. Obvious sudden degradation stage, slow degradation stage and no apparent toxicity was observed after AZ-HECTS hydrogels implanted into rats, and tissue inflammation was slighter, which indicated favorable biological safety. Furthermore, AZ-HECTS hydrogels was loaded with heparin, and released 50% of heparin accumulated 14d. AZ-HECTS-heparin hydrogels showed inhibitory effects on L929, and pro-growth functions within vascular endothelial cells seeded on the hydrogels, meanwhile a positive influence on vascular endothelial growth factor expression. In conclusion, AZ-HECTS hydrogels possessed favorable biocompatibility and biodegradability and had good potential as drug carrier. Copyright © 2017 Elsevier Ltd. All rights reserved.

Hierarchical nanostructured conducting polymer hydrogel with high electrochemical activity

PubMed Central

Pan, Lijia; Yu, Guihua; Zhai, Dongyuan; Lee, Hye Ryoung; Zhao, Wenting; Liu, Nian; Wang, Huiliang; Tee, Benjamin C.-K.; Shi, Yi; Cui, Yi; Bao, Zhenan

2012-01-01

Conducting polymer hydrogels represent a unique class of materials that synergizes the advantageous features of hydrogels and organic conductors and have been used in many applications such as bioelectronics and energy storage devices. They are often synthesized by polymerizing conductive polymer monomer within a nonconducting hydrogel matrix, resulting in deterioration of their electrical properties. Here, we report a scalable and versatile synthesis of multifunctional polyaniline (PAni) hydrogel with excellent electronic conductivity and electrochemical properties. With high surface area and three-dimensional porous nanostructures, the PAni hydrogels demonstrated potential as high-performance supercapacitor electrodes with high specific capacitance (∼480 F·g-1), unprecedented rate capability, and cycling stability (∼83% capacitance retention after 10,000 cycles). The PAni hydrogels can also function as the active component of glucose oxidase sensors with fast response time (∼0.3 s) and superior sensitivity (∼16.7 μA·mM-1). The scalable synthesis and excellent electrode performance of the PAni hydrogel make it an attractive candidate for bioelectronics and future-generation energy storage electrodes. PMID:22645374

Automated real time peg and tool detection for the FLS trainer box.

PubMed

Nemani, Arun; Sankaranarayanan, Ganesh

2012-01-01

This study proposes a method that effectively tracks trocar tool and peg positions in real time to allow real time assessment of the peg transfer task of the Fundamentals of Laparoscopic Surgery (FLS). By utilizing custom code along with OpenCV libraries, tool and peg positions can be accurately tracked without altering the original setup conditions of the FLS trainer box. This is achieved via a series of image filtration sequences, thresholding functions, and Haar training methods.

Green polymer chemistry: The role of Candida antarctica lipase B in polymer functionalization

NASA Astrophysics Data System (ADS)

Castano Gil, Yenni Marcela

The synthesis of functional polymers with well-defined structure, end-group fidelity and physico-chemical properties useful for biomedical applications has proven challenging. Chemo-enzymatic methods are an alternative strategy to increase the diversity of functional groups in polymeric materials. Specifically, enzyme-catalyzed polymer functionalization carried out under solventless conditions is a great advancement in the design of green processes for biomedical applications, where the toxicity of solvents and catalyst residues need to be considered. Enzymes offer several distinct advantages, including high efficiency, catalyst recyclability, and mild reaction conditions. This reseach aimed to precisely functionalized polymers using two methods: enzyme-catalyzed functionalization via polymerization and chemo-enzymatic functionalization of pre-made polymers for drug delivery. In the first method, well-defined poly(caprolactone)s were generated using alkyne-based initiating systems catalyzed by CALB. Propargyl alcohol and 4-dibenzocyclooctynol (DIBO) were shown to efficiently initiate the ring opening polymerization of epsilon-caprolactone under metal free conditions and yielded polymers with Mn ~4 to 24 KDa and relatively narrow molecular mass distribution. In the second methodology, we present quantitative enzyme-catalyzed transesterification of vinyl esters and ethyl esters with poly(ethylene glycol)s (PEG)s that will serve as building blocks for dendrimer synthesis, followed by introducing a new process for the exclusive gamma-conjugation of folic acid. Specifically, fluorescein-acrylate was enzymatically conjugated with PEG. Additionally, halo-ester functionalized PEGs were successfully prepared by the transesterification of alkyl halo-esters with PEGs. 1H and 13C NMR spectroscopy, SEC and MALDI-ToF mass spectrometry confirmed the structure and purity of the products.

Developing of a novel antibacterial agent by functionalization of graphene oxide with guanidine polymer with enhanced antibacterial activity

NASA Astrophysics Data System (ADS)

Li, Ping; Sun, Shiyu; Dong, Alideertu; Hao, Yanping; Shi, Shuangqiang; Sun, Zijia; Gao, Ge; Chen, Yuxin

2015-11-01

New materials with excellent antibacterial activity attract numerous research interests. Herein, a facile synthetic method of polyethylene glycol (PEG) and polyhexamethylene guanidine hydrochloride (PHGC) dual-polymer-functionalized graphene oxide (GO) (GO-PEG-PHGC), a novel antibacterial material, was reported. The as-prepared products were characterized by scanning electron microscopy (SEM), Fourier transform infrared (FTIR), thermogravimetric analysis (TGA), X-ray pattern (XRD) and elemental analysis. The antibacterial effect on the bacterial strain was investigated by incubating both Gram-negative bacteria (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus). The results show that GO-PEG-PHGC has enhanced antibacterial activity when compared to GO, GO-PEG or GO-PHGC alone. The improved antibacterial activity was described to be related to a better dispersion of GO-PEG-PHGC in the presence of PEG. This better dispersion leads to a greater contact between the bacteria membrane and nanomaterials, therefore leading to greater cell damage. Not only Gram-negative bacteria but also Gram-positive bacteria are greatly inhibited by this antibacterial agent. With the powerful antibacterial activity as well as its low cost and facile preparation, the GO-PEG-PHGC as a novel antibacterial agent can find potential application in the areas of healthcare and environmental engineering.

Evaluation of an injectable hydrogel and polymethyl methacrylate in restoring mechanics to compressively fractured spine motion segments.

PubMed

Balkovec, Christian; Vernengo, Andrea J; Stevenson, Peter; McGill, Stuart M

2016-11-01

Compressive fracture can produce profound changes to the mechanical profile of a spine segment. Minimally invasive repair has the potential to restore both function and structural integrity to an injured spine. Use of both hydrogels to address changes to the disc, combined with polymethyl methacrylate (PMMA) to address changes to the vertebral body, has the potential to facilitate repair. The purpose of this investigation was to determine if the combined use of hydrogel injection and PMMA could restore the mechanical profile of an axially injured spinal motion segment. This is a basic science study evaluating a combination of hydrogel injection and vertebroplasty on restoring mechanics to compressively injured porcine spine motion segments. Fourteen porcine spine motion segments were subject to axial compression until fracture using a dynamic servohydraulic testing apparatus. Rotational and compressive stiffness was measured for each specimen under the following conditions: initial undamaged, fractured, fatigue loading under compression, hydrogel injection, PMMA injection, and fatigue loading under compression. Group 1 received hydrogel injection followed by PMMA injection, whereas Group 2 received PMMA injection followed by hydrogel injection. This study was funded under a Natural Sciences and Engineering Research Council of Canada discovery grant. PMMA injection was found to alter the compressive stiffness properties of axially injured spine motion segments, restoring values from Groups 1 and 2 to 89.3%±29.3% and 81%±27.9% of initial values respectively. Hydrogel injection was found to alter the rotational stiffness properties, restoring specimens in Groups 1 and 2 to 151.5%±81% and 177.2%±54.9% of initial values respectively. Prolonged restoration of function was not possible, however, after further fatigue loading. Using this repair technique, replication of the mechanism of injury appears to cause a rapid deterioration in function of the motion segments. Containment of the hydrogel appears to be an issue with large breaches in the end plate, as it is posited to migrate into the cancellous bone of the vertebral body. Future work should attempt to evaluate methods in fully sealing the disc space. Copyright © 2016 Elsevier Inc. All rights reserved.

Near-infrared (1550 nm) in vivo bioimaging based on rare-earth doped ceramic nanophosphors modified with PEG-b-poly(4-vinylbenzylphosphonate)

NASA Astrophysics Data System (ADS)

Kamimura, Masao; Kanayama, Naoki; Tokuzen, Kimikazu; Soga, Kohei; Nagasaki, Yukio

2011-09-01

A novel poly(ethylene glycol) (PEG)-based block copolymer possessing a 4-vinylbenzylphosphonate repeating unit in another segment (PEG-block-poly(4-vinylbenzylphosphonate)) (PEG-b-PVBP) was designed and successfully synthesized. As a control, an end-functionalized PEG possessing a mono-phosphonate group (PEG-PO3H2) was also synthesized. The surface of near-infrared (NIR) phosphors (i.e., ytterbium (Yb) and erbium (Er) ion-codoped Y2O3 nanoparticles (YNPs)) were modified with PEG-b-PVBP (PEG-YNP(b)s) and PEG-PO3H2 (PEG-YNP(1)s). The adsorption of PEG-b-PVBP and PEG-PO3H2 was estimated by Fourier transform infrared (FT-IR) measurements and thermal gravimetric analysis (TGA). The physicochemical characteristics of the obtained YNP samples were analyzed by ζ-potential and dynamic light scattering (DLS) measurements. The ζ-potentials of YNPs modified by these polymers were close to zero, indicating the effective coverage of the YNP surface by our new PEG derivatives. However, the dispersion stability of the PEGylated YNPs was strongly affected by the structure of the PEG terminus. The average diameter of the PEG-YNP(1)s increased, and aggregates precipitated after less than 1 h in phosphate buffer saline (PBS). In contrast, the size did not change at all in the case of PEG-YNP(b)s and the dispersion in PBS was stable for over 1 week. PEG-YNP(b)s also showed high erosion resistance under acidic conditions. The multiple coordinated PVBP segment of the block copolymer on the YNP surface plays a substantial role in improving such dispersion stability. The excellent dispersion stability and strong NIR luminescence of the obtained PEG-YNP(b)s were also confirmed in fetal bovine serum (FBS) solution over 1 week. Furthermore, in vivo NIR imaging of live mice was performed, and the 1550 nm NIR emission of PEG-YNP(b)s from the organ of live mice was confirmed without dissection.A novel poly(ethylene glycol) (PEG)-based block copolymer possessing a 4-vinylbenzylphosphonate repeating unit in another segment (PEG-block-poly(4-vinylbenzylphosphonate)) (PEG-b-PVBP) was designed and successfully synthesized. As a control, an end-functionalized PEG possessing a mono-phosphonate group (PEG-PO3H2) was also synthesized. The surface of near-infrared (NIR) phosphors (i.e., ytterbium (Yb) and erbium (Er) ion-codoped Y2O3 nanoparticles (YNPs)) were modified with PEG-b-PVBP (PEG-YNP(b)s) and PEG-PO3H2 (PEG-YNP(1)s). The adsorption of PEG-b-PVBP and PEG-PO3H2 was estimated by Fourier transform infrared (FT-IR) measurements and thermal gravimetric analysis (TGA). The physicochemical characteristics of the obtained YNP samples were analyzed by ζ-potential and dynamic light scattering (DLS) measurements. The ζ-potentials of YNPs modified by these polymers were close to zero, indicating the effective coverage of the YNP surface by our new PEG derivatives. However, the dispersion stability of the PEGylated YNPs was strongly affected by the structure of the PEG terminus. The average diameter of the PEG-YNP(1)s increased, and aggregates precipitated after less than 1 h in phosphate buffer saline (PBS). In contrast, the size did not change at all in the case of PEG-YNP(b)s and the dispersion in PBS was stable for over 1 week. PEG-YNP(b)s also showed high erosion resistance under acidic conditions. The multiple coordinated PVBP segment of the block copolymer on the YNP surface plays a substantial role in improving such dispersion stability. The excellent dispersion stability and strong NIR luminescence of the obtained PEG-YNP(b)s were also confirmed in fetal bovine serum (FBS) solution over 1 week. Furthermore, in vivo NIR imaging of live mice was performed, and the 1550 nm NIR emission of PEG-YNP(b)s from the organ of live mice was confirmed without dissection. Electronic supplementary information (ESI) available: 1H-NMR spectra of PEG-b-PCMS, PEG-b-PDEVBP and PEG-b-PVBP, 31P-NMR spectra of PEG-b-PDEVBP and PEG-b-PVBP, schematic representation of PEG-PO3H2 synthesis, 1H-NMR spectra of PEG-PO3Et2 and PEG-PO3H2, FT-IR spectra of YNP samples, PEG brush density on the YNP surface, and size distribution of YNP samples under acidic conditions are described. See DOI: 10.1039/c1nr10466g

Crosslinkable hydrogels derived from cartilage, meniscus, and tendon tissue.

PubMed

Visser, Jetze; Levett, Peter A; te Moller, Nikae C R; Besems, Jeremy; Boere, Kristel W M; van Rijen, Mattie H P; de Grauw, Janny C; Dhert, Wouter J A; van Weeren, P René; Malda, Jos

2015-04-01

Decellularized tissues have proven to be versatile matrices for the engineering of tissues and organs. These matrices usually consist of collagens, matrix-specific proteins, and a set of largely undefined growth factors and signaling molecules. Although several decellularized tissues have found their way to clinical applications, their use in the engineering of cartilage tissue has only been explored to a limited extent. We set out to generate hydrogels from several tissue-derived matrices, as hydrogels are the current preferred cell carriers for cartilage repair. Equine cartilage, meniscus, and tendon tissue was harvested, decellularized, enzymatically digested, and functionalized with methacrylamide groups. After photo-cross-linking, these tissue digests were mechanically characterized. Next, gelatin methacrylamide (GelMA) hydrogel was functionalized with these methacrylated tissue digests. Equine chondrocytes and mesenchymal stromal cells (MSCs) (both from three donors) were encapsulated and cultured in vitro up to 6 weeks. Gene expression (COL1A1, COL2A1, ACAN, MMP-3, MMP-13, and MMP-14), cartilage-specific matrix formation, and hydrogel stiffness were analyzed after culture. The cartilage, meniscus, and tendon digests were successfully photo-cross-linked into hydrogels. The addition of the tissue-derived matrices to GelMA affected chondrogenic differentiation of MSCs, although no consequent improvement was demonstrated. For chondrocytes, the tissue-derived matrix gels performed worse compared to GelMA alone. This work demonstrates for the first time that native tissues can be processed into crosslinkable hydrogels for the engineering of tissues. Moreover, the differentiation of encapsulated cells can be influenced in these stable, decellularized matrix hydrogels.

Visible light induced electropolymerization of suspended hydrogel bioscaffolds in a microfluidic chip.

PubMed

Li, Pan; Yu, Haibo; Liu, Na; Wang, Feifei; Lee, Gwo-Bin; Wang, Yuechao; Liu, Lianqing; Li, Wen Jung

2018-05-23

The development of microengineered hydrogels co-cultured with cells in vitro could advance in vivo bio-systems in both structural complexity and functional hierarchy, which holds great promise for applications in regenerative tissues or organs, drug discovery and screening, and bio-sensors or bio-actuators. Traditional hydrogel microfabrication technologies such as ultraviolet (UV) laser or multiphoton laser stereolithography and three-dimensional (3D) printing systems have advanced the development of 3D hydrogel micro-structures but need either expensive and complex equipment, or harsh material selection with limited photoinitiators. Herein, we propose a simple and flexible hydrogel microfabrication method based on a ubiquitous visible-light projection system combined with a custom-designed photosensitive microfluidic chip, to rapidly (typically several to tens of seconds) fabricate various two-dimensional (2D) hydrogel patterns and 3D hydrogel constructs. A theoretical layer-by-layer model that involves continuous polymerizing-delaminating-polymerizing cycles is presented to explain the polymerization and structural formation mechanism of hydrogels. A large area of hydrogel patterns was efficiently fabricated without the usage of costly laser systems or photoinitiators, i.e., a stereoscopic mesh-like hydrogel network with intersecting hydrogel micro-belts was fabricated via a series of dynamic-changing digital light projections. The pores and gaps of the hydrogel network are tunable, which facilitates the supply of nutrients and discharge of waste in the construction of 3D thick bio-models. Cell co-culture experiments showed the effective regulation of cell spreading by hydrogel scaffolds fabricated by the new method presented here. This visible light enabled hydrogel microfabrication method may provide new prospects for designing cell-based units for advanced biomedical studies, e.g., for 3D bio-models or bio-actuators in the future.

Engineering Protein Hydrogels Using SpyCatcher-SpyTag Chemistry.

PubMed

Gao, Xiaoye; Fang, Jie; Xue, Bin; Fu, Linglan; Li, Hongbin

2016-09-12

Constructing hydrogels from engineered proteins has attracted significant attention within the material sciences, owing to their myriad potential applications in biomedical engineering. Developing efficient methods to cross-link tailored protein building blocks into hydrogels with desirable mechanical, physical, and functional properties is of paramount importance. By making use of the recently developed SpyCatcher-SpyTag chemistry, we successfully engineered protein hydrogels on the basis of engineered tandem modular elastomeric proteins. Our resultant protein hydrogels are soft but stable, and show excellent biocompatibility. As the first step, we tested the use of these hydrogels as a drug carrier, as well as in encapsulating human lung fibroblast cells. Our results demonstrate the robustness of the SpyCatcher-SpyTag chemistry, even when the SpyTag (or SpyCatcher) is flanked by folded globular domains. These results demonstrate that SpyCatcher-SpyTag chemistry can be used to engineer protein hydrogels from tandem modular elastomeric proteins that can find applications in tissue engineering, in fundamental mechano-biological studies, and as a controlled drug release vehicle.

Cellulose fibers extracted from rice and oat husks and their application in hydrogel.

PubMed

Oliveira, Jean Paulo de; Bruni, Graziella Pinheiro; Lima, Karina Oliveira; Halal, Shanise Lisie Mello El; Rosa, Gabriela Silveira da; Dias, Alvaro Renato Guerra; Zavareze, Elessandra da Rosa

2017-04-15

The commercial cellulose fibers and cellulose fibers extracted from rice and oat husks were analyzed by chemical composition, morphology, functional groups, crystallinity and thermal properties. The cellulose fibers from rice and oat husks were used to produce hydrogels with poly (vinyl alcohol). The fibers presented different structural, crystallinity, and thermal properties, depending on the cellulose source. The hydrogel from rice cellulose fibers had a network structure with a similar agglomeration sponge, with more homogeneous pores compared to the hydrogel from oat cellulose fibers. The hydrogels prepared from the cellulose extracted from rice and oat husks showed water absorption capacity of 141.6-392.1% and high opacity. The highest water absorption capacity and maximum stress the compression were presented by rice cellulose hydrogel at 25°C. These results show that the use of agro-industrial residues is promising for the biomaterial field, especially in the preparation of hydrogels. Copyright © 2016 Elsevier Ltd. All rights reserved.

Synthesis and characterization of psyllium-NVP based drug delivery system through radiation crosslinking polymerization

NASA Astrophysics Data System (ADS)

Singh, Baljit; Kumar, S.

2008-08-01

In order to develop the hydrogels meant for the drug delivery, we have prepared psyllium- N-vinylpyrrolidone (NVP) based hydrogels by radiation induced crosslinking. Polymers were characterized with SEMs, FTIR and swelling studies. Swelling of the hydrogels was studied as a function of monomer concentration, total radiation dose, temperature, pH and [NaCl] of the swelling medium. The swelling kinetics of the hydrogels and release dynamics of anticancer model drug (5-fluorouracil) from the hydrogels have been carried out for the evaluation of swelling and drug release mechanism. It has been observed that diffusion exponent ' n' have 0.8, 0.9, 0.8 and gel characteristics constant ' k' have 9.22 × 10 -3, 2.06 × 10 -3, 11.72 × 10 -3 values for the release of drug from the drug loaded hydrogels in distilled water, pH 2.2 buffer and pH 7.4 buffer, respectively. The present study shows that the release of drug from the hydrogels occurred through Non-Fickian diffusion mechanism.

Targeting In-Stent-Stenosis with RGD- and CXCL1-Coated Mini-Stents in Mice.

PubMed

Simsekyilmaz, Sakine; Liehn, Elisa A; Weinandy, Stefan; Schreiber, Fabian; Megens, Remco T A; Theelen, Wendy; Smeets, Ralf; Jockenhövel, Stefan; Gries, Thomas; Möller, Martin; Klee, Doris; Weber, Christian; Zernecke, Alma

2016-01-01

Atherosclerotic lesions that critically narrow the artery can necessitate an angioplasty and stent implantation. Long-term therapeutic effects, however, are limited by excessive arterial remodeling. We here employed a miniaturized nitinol-stent coated with star-shaped polyethylenglycole (star-PEG), and evaluated its bio-functionalization with RGD and CXCL1 for improving in-stent stenosis after implantation into carotid arteries of mice. Nitinol foils or stents (bare metal) were coated with star-PEG, and bio-functionalized with RGD, or RGD/CXCL1. Cell adhesion to star-PEG-coated nitinol foils was unaltered or reduced, whereas bio-functionalization with RGD but foremost RGD/CXCL1 increased adhesion of early angiogenic outgrowth cells (EOCs) and endothelial cells but not smooth muscle cells when compared with bare metal foils. Stimulation of cells with RGD/CXCL1 furthermore increased the proliferation of EOCs. In vivo, bio-functionalization with RGD/CXCL1 significantly reduced neointima formation and thrombus formation, and increased re-endothelialization in apoE-/- carotid arteries compared with bare-metal nitinol stents, star-PEG-coated stents, and stents bio-functionalized with RGD only. Bio-functionalization of star-PEG-coated nitinol-stents with RGD/CXCL1 reduced in-stent neointima formation. By supporting the adhesion and proliferation of endothelial progenitor cells, RGD/CXCL1 coating of stents may help to accelerate endothelial repair after stent implantation, and thus may harbor the potential to limit the complication of in-stent restenosis in clinical approaches.

Targeting In-Stent-Stenosis with RGD- and CXCL1-Coated Mini-Stents in Mice

PubMed Central

Weinandy, Stefan; Schreiber, Fabian; Megens, Remco T. A.; Theelen, Wendy; Smeets, Ralf; Jockenhövel, Stefan; Gries, Thomas; Möller, Martin; Klee, Doris; Weber, Christian; Zernecke, Alma

2016-01-01

Atherosclerotic lesions that critically narrow the artery can necessitate an angioplasty and stent implantation. Long-term therapeutic effects, however, are limited by excessive arterial remodeling. We here employed a miniaturized nitinol-stent coated with star-shaped polyethylenglycole (star-PEG), and evaluated its bio-functionalization with RGD and CXCL1 for improving in-stent stenosis after implantation into carotid arteries of mice. Nitinol foils or stents (bare metal) were coated with star-PEG, and bio-functionalized with RGD, or RGD/CXCL1. Cell adhesion to star-PEG-coated nitinol foils was unaltered or reduced, whereas bio-functionalization with RGD but foremost RGD/CXCL1 increased adhesion of early angiogenic outgrowth cells (EOCs) and endothelial cells but not smooth muscle cells when compared with bare metal foils. Stimulation of cells with RGD/CXCL1 furthermore increased the proliferation of EOCs. In vivo, bio-functionalization with RGD/CXCL1 significantly reduced neointima formation and thrombus formation, and increased re-endothelialization in apoE-/- carotid arteries compared with bare-metal nitinol stents, star-PEG-coated stents, and stents bio-functionalized with RGD only. Bio-functionalization of star-PEG-coated nitinol-stents with RGD/CXCL1 reduced in-stent neointima formation. By supporting the adhesion and proliferation of endothelial progenitor cells, RGD/CXCL1 coating of stents may help to accelerate endothelial repair after stent implantation, and thus may harbor the potential to limit the complication of in-stent restenosis in clinical approaches. PMID:27192172

Pharmacokinetic analysis of multi PEG-theophylline conjugates.

PubMed

Grassi, Mario; Bonora, Gian Maria; Drioli, Sara; Cateni, Francesca; Zacchigna, Marina

2012-10-01

In the attempt of prolonging the effect of drugs, a new branched, high-molecular weight multimeric poly(ethylene glycol) (MultiPEG), synthesized with a simple assembling procedure that devised the introduction of functional groups with divergent and selective reactivity, was employed as drug carrier. In particular, the attention was focused on the study of theophylline (THEO) and THEO-MultiPEG conjugates pharmacokinetic after oral administration in rabbit. Pharmacokinetic behavior was studied according to an ad hoc developed mathematical model accounting for THEO-MultiPEG in vivo absorption and decomposition into drug (THEO) and carrier (MultiPEG). The branched high-molecular weight MultiPEG proved to be a reliable drug delivery system able to prolong theophylline staying in the blood after oral administration of a THEO-MultiPEG solution. The analysis of experimental data by means of the developed mathematical model revealed that the prolongation of THEO effect was essentially due to the low THEO-MultiPEG permeability in comparison to that of pure THEO. Copyright © 2012 Elsevier Ltd. All rights reserved.

Safety of polyethylene glycol 3350 for the treatment of chronic constipation in children.

PubMed

Pashankar, Dinesh S; Loening-Baucke, Vera; Bishop, Warren P

2003-07-01

To assess the clinical and biochemical safety profile of long-term polyethylene glycol 3350 (PEG) therapy in children with chronic constipation and to assess pediatric patient acceptance of PEG therapy. Prospective observational study. Pediatric clinics at a referral center. Patients Eighty-three children (44 with chronic constipation, 39 with constipation and encopresis) receiving PEG therapy for more than 3 months. Clinical adverse effects related to PEG therapy and acceptance and compliance with PEG therapy. Serum electrolyte levels, osmolality, albumin levels, and liver and renal function test results were measured. At the time of evaluation, the mean duration of PEG therapy was 8.7 months, and the mean PEG dose was 0.75 g/kg daily. There were no major clinical adverse effects. All blood test results were normal, except for transient minimal alanine aminotransferase elevation unrelated to therapy in 9 patients. All children preferred PEG to previously used laxatives, and daily compliance was measured as good in 90% of children. Long-term PEG therapy is safe and is well accepted by children with chronic constipation with and without encopresis.

Multi-Functional Macromers for Hydrogel Design in Biomedical Engineering and Regenerative Medicine

PubMed Central

Hacker, Michael C.; Nawaz, Hafiz Awais

2015-01-01

Contemporary biomaterials are expected to provide tailored mechanical, biological and structural cues to encapsulated or invading cells in regenerative applications. In addition, the degradative properties of the material also have to be adjustable to the desired application. Oligo- or polymeric building blocks that can be further cross-linked into hydrogel networks, here addressed as macromers, appear as the prime option to assemble gels with the necessary degrees of freedom in the adjustment of the mentioned key parameters. Recent developments in the design of multi-functional macromers with two or more chemically different types of functionalities are summarized and discussed in this review illustrating recent trends in the development of advanced hydrogel building blocks for regenerative applications. PMID:26610468

Multi-Functional Macromers for Hydrogel Design in Biomedical Engineering and Regenerative Medicine.

PubMed

Hacker, Michael C; Nawaz, Hafiz Awais

2015-11-19

Contemporary biomaterials are expected to provide tailored mechanical, biological and structural cues to encapsulated or invading cells in regenerative applications. In addition, the degradative properties of the material also have to be adjustable to the desired application. Oligo- or polymeric building blocks that can be further cross-linked into hydrogel networks, here addressed as macromers, appear as the prime option to assemble gels with the necessary degrees of freedom in the adjustment of the mentioned key parameters. Recent developments in the design of multi-functional macromers with two or more chemically different types of functionalities are summarized and discussed in this review illustrating recent trends in the development of advanced hydrogel building blocks for regenerative applications.

Enzymetically regulating the self-healing of protein hydrogels with high healing efficiency.

PubMed

Gao, Yuzhou; Luo, Quan; Qiao, Shanpeng; Wang, Liang; Dong, Zeyuan; Xu, Jiayun; Liu, Junqiu

2014-08-25

Enzyme-mediated self-healing of dynamic covalent bond-driven protein hydrogels was realized by the synergy of two enzymes, glucose oxidase (GOX) and catalase (CAT). The reversible covalent attachment of glutaraldehyde to lysine residues of GOX, CAT, and bovine serum albumin (BSA) led to the formation and functionalization of the self-healing protein hydrogel system. The enzyme-mediated protein hydrogels exhibit excellent self-healing properties with 100% recovery. The self-healing process was reversible and effective with an external glucose stimulus at room temperature. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Supramolecular Hydrogel Based on Polyglycerol Dendrimer-Specific Amino Group Recognition.

PubMed

Cho, Ik Sung; Ooya, Tooru

2018-05-24

Dendrimer-based supramolecular hydrogels have gained attention in biomedical fields. While biocompatible dendrimers were used to prepare hydrogels via physical and/or chemical crosslinking, smart functions such as pH and molecular control remain undeveloped. Here, we present polyglycerol dendrimer-based supramolecular hydrogel formation induced by a specific interaction between the polyglycerol dendrimer and an amino group of glycol chitosan. Gelation was achieved by mixing the two aqueous solutions. Hydrogel formation was controlled by varying the polyglycerol dendrimer generation. The hydrogel showed pH-dependent swelling; strongly acidic conditions induced degradation via dissociation of the specific interaction. It also showed unique L-arginine-responsive degradation capability due to competitive exchange of the amino groups of glycol chitosan and L-arginine. These polyglycerol dendrimer-based supramolecular characteristics allow multimodal application in smart biomaterials. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Advances in the Fabrication of Antimicrobial Hydrogels for Biomedical Applications.

PubMed

González-Henríquez, Carmen M; Sarabia-Vallejos, Mauricio A; Rodriguez-Hernandez, Juan

2017-02-26

This review describes, in an organized manner, the recent developments in the elaboration of hydrogels that possess antimicrobial activity. The fabrication of antibacterial hydrogels for biomedical applications that permits cell adhesion and proliferation still remains as an interesting challenge, in particular for tissue engineering applications. In this context, a large number of studies has been carried out in the design of hydrogels that serve as support for antimicrobial agents (nanoparticles, antibiotics, etc.). Another interesting approach is to use polymers with inherent antimicrobial activity provided by functional groups contained in their structures, such as quaternary ammonium salt or hydrogels fabricated from antimicrobial peptides (AMPs) or natural polymers, such as chitosan. A summary of the different alternatives employed for this purpose is described in this review, considering their advantages and disadvantages. Finally, more recent methodologies that lead to more sophisticated hydrogels that are able to react to external stimuli are equally depicted in this review.

Advances in the Fabrication of Antimicrobial Hydrogels for Biomedical Applications

PubMed Central

González-Henríquez, Carmen M.; Sarabia-Vallejos, Mauricio A.; Rodriguez-Hernandez, Juan

2017-01-01

This review describes, in an organized manner, the recent developments in the elaboration of hydrogels that possess antimicrobial activity. The fabrication of antibacterial hydrogels for biomedical applications that permits cell adhesion and proliferation still remains as an interesting challenge, in particular for tissue engineering applications. In this context, a large number of studies has been carried out in the design of hydrogels that serve as support for antimicrobial agents (nanoparticles, antibiotics, etc.). Another interesting approach is to use polymers with inherent antimicrobial activity provided by functional groups contained in their structures, such as quaternary ammonium salt or hydrogels fabricated from antimicrobial peptides (AMPs) or natural polymers, such as chitosan. A summary of the different alternatives employed for this purpose is described in this review, considering their advantages and disadvantages. Finally, more recent methodologies that lead to more sophisticated hydrogels that are able to react to external stimuli are equally depicted in this review. PMID:28772591

Mussel-inspired synthesis of polydopamine-functionalized graphene oxide hydrogel as broad-spectrum antimicrobial material

NASA Astrophysics Data System (ADS)

Wang, Xinpeng; Liu, Zhiming; Zhong, Huiqing; Guo, Zhouyi; Yuan, Xiaochan

2014-09-01

Recently, three-dimensional GO-based hydrogels have attracted great attention due to the unique advantages. It is generally know that bacteria are everywhere and many of them could cause the diseases and threaten human health. However, developing new antibacterial materials with high-efficiency, low cost, broad-spectrum, and easy recycling is still a great challenge. Herein, inspired by mussel, we synthesized benzalkonium bromide/polydopamine/reduced graphene oxide hydrogel (BKB/PDA/rGOG). The as-prepared three-dimensional hydrogels were characterized by scanning eletron microscope (SEM), Fourier transform infrared spectroscopy (FT-IR) and Raman spectroscopy. The resultant hydrogels exhibited strong antibacterial effects to both Gram-negative and Gram-positive bacteria due to the synergistic effect of graphene oxide and benzalkonium bromide. In addition, the resultant hydrogels could be removed easily from the resolution, which was undoubtedly good news for industry application.

Polymer-induced compression of biological hydrogels

NASA Astrophysics Data System (ADS)

Datta, Sujit; Preska Steinberg, Asher; Ismagilov, Rustem

Hydrogels - such as mucus, blood clots, and the extracellular matrix - provide critical functions in biological systems. However, little is known about how their structure is influenced by many of the polymeric materials they come into contact with regularly. Here, we focus on one critically important biological hydrogel: colonic mucus. While several biological processes are thought to potentially regulate the mucus hydrogel structure, the polymeric composition of the gut environment has been ignored. We use Flory-Huggins solution theory to characterize polymer-mucus interactions. We find that gut polymers, including those small enough to penetrate the mucus hydrogel, can in fact alter mucus structure, changing its equilibrium degree of swelling and forcing it to compress. The extent of compression increases with increasing polymer concentration and size. We use experiments on mice to verify these predictions with common dietary and therapeutic gut polymers. Our results provide a foundation for investigating similar, previously overlooked, polymer-induced effects in other biological hydrogels.

Light-guiding hydrogels for cell-based sensing and optogenetic synthesis in vivo

NASA Astrophysics Data System (ADS)

Choi, Myunghwan; Choi, Jin Woo; Kim, Seonghoon; Nizamoglu, Sedat; Hahn, Sei Kwang; Yun, Seok Hyun

2013-12-01

Polymer hydrogels are widely used as cell scaffolds for biomedical applications. Although the biochemical and biophysical properties of hydrogels have been investigated extensively, little attention has been paid to their potential photonic functionalities. Here, we report cell-integrated polyethylene glycol-based hydrogels for in vivo optical-sensing and therapy applications. Hydrogel patches containing cells were implanted in awake, freely moving mice for several days and shown to offer long-term transparency, biocompatibility, cell viability and light-guiding properties (loss of <1 dB cm-1). Using optogenetic, glucagon-like peptide-1 secreting cells, we conducted light-controlled therapy using the hydrogel in a mouse model with diabetes and obtained improved glucose homeostasis. Furthermore, real-time optical readout of encapsulated heat-shock-protein-coupled fluorescent reporter cells made it possible to measure the nanotoxicity of cadmium-based bare and shelled quantum dots (CdTe; CdSe/ZnS) in vivo.

Synthesis of chitosan-PEO hydrogels via mesylation and regioselective Cu(I)-catalyzed cycloaddition.

PubMed

Tirino, Pasquale; Laurino, Rosaria; Maglio, Giovanni; Malinconico, Mario; d'Ayala, Giovanna Gomez; Laurienzo, Paola

2014-11-04

In this work, a well-defined hydrogel was developed by coupling chitosan with PEO through "click chemistry". Azide functionalities were introduced onto chitosan, through mesylation of C-6 hydroxyl groups, and reacted with a di-alkyne PEO by a regioselective Cu(I)-catalyzed cycloaddition. This synthetic approach allowed us to obtain a hydrogel with a controlled crosslinking degree. In fact, the extent of coupling is strictly dependent on the amount of azido groups on chitosan, which in turn can be easily modulated. The obtained hydrogel, with a crosslinking degree of around 90%, showed interesting swelling properties. With respect to chitosan hydrogels reported in literature, a considerably higher equilibrium uptake was reached (940%). The possibility to control the crosslinking degree of hydrogel and its capability to rapidly absorb high amounts of water make this material suitable for several applications, such as controlled drug release and wound healing. Copyright © 2014. Published by Elsevier Ltd.

Hierarchical structures based on self-assembling beta-hairpin peptides and their application as biomaterials and hybrid materials

NASA Astrophysics Data System (ADS)

Altunbas, Aysegul

Self-assembly represents a robust and powerful paradigm for the bottom-up construction of nanostructures. Self-assembled peptide hydrogels are emerging as promising routes to novel multifunctional materials. The 20 amino acid MAX1and MAX8 peptides self-assemble into a three dimensional network of entangled, branched fibrils rich in beta-sheet secondary structure with a high density of lysine groups exposed on the fibril-surfaces. These hydrogels form self-supporting structures that shear thin upon application of shear and then immediately recover to a solid hydrogel upon cessation of shear which facilitates the local delivery of the hydrogel into a site in vivo. Templated condensation of silica precursors on self-assembled nanoscale peptide fibrils with various surface functionalities can be used to mimic biosilicification. This template-defined approach towards biomineralization was utilized for the controlled fabrication of 3D hybrid nanostructures. We report a study on the structure-property relationship of self-assembled peptide hydrogels where mineralization of individual fibrils through sol-gel chemistry was achieved. The nanostructure and consequent mechanical characteristics of these hybrid networks can be modulated by changing the stoichiometric parameters of the sol-gel process. Construction of such organic-inorganic hybrid networks by sol-gel processing of self-assembled peptide hydrogels has improved mechanical properties and resulted in materials with ˜ 3 orders of magnitude higher stiffness. The physical characterization of the hybrid networks via electron microscopy and small angle scattering is detailed and correlated with changes in the network mechanical behavior. The resultant high fidelity templating process suggests that the peptide substrate can be used to template the coating of other functional inorganic materials. Self-assembling peptide hydrogels encapsulating an anti-tumorigenic drug, curcumin, have been prepared and demonstrated to be an effective vehicle for the localized delivery of curcumin over sustained periods of time in vitro. The curcumin-hydrogel is prepared in-situ where curcumin encapsulation within the hydrogel network is accomplished concurrently with peptide self-assembly. Physical characterization methods and in vitro biological studies were used to demonstrate the effectiveness of curcumin-loaded beta-hairpin hydrogels as injectable agents for localized curcumin delivery. Notably, rheological characterization of the curcumin loaded hydrogel before and after shear flow have indicated solid-like properties even at high curcumin payloads. In vitro experiments with a medulloblastoma cell line confirm that the encapsulation of the curcumin within the hydrogel does not have an adverse effect on its bioactivity. Most importantly, the rate of curcumin release and its consequent therapeutic efficacy can be conveniently modulated by changing the morphological characteristics of the peptide hydrogel network. Lastly, MAX8 hydrogel cytocompatibility and biocompatibility was assessed with the future aim of utilizing this hydrogel as a scaffold in liver regeneration studies in rats. MAX8 hydrogel cytotoxity was evaluated using MC3T3-E1 and MG63 cell lines. Encapsulation, syringe delivery and subsequent viability of MG63 cells in hydrogels was also assessed to study the feasibility of using hydrogel/cell constructs as minimally invasive cell delivery vehicles. Biocompatibility was evaluated by monitoring inflammatory response induced by the MAX8 hydrogel via a subcutaneous mice model. Biocompatibility of MAX8 hydrogels at sites other than the subcutaneous region was also investigated using a cylindrical punch resection model in rat liver. The preliminary biocompatibility studies provide an elemental understanding of MAX8 hydrogel behavior in vivo.

Analysis of peg formation in cucumber seedlings grown on clinostats and in a microgravity (space) environment.

PubMed

Link, B M; Cosgrove, D J

1999-12-01

In young cucumber seedlings, the peg is a polar out-growth of tissue that functions by snagging the seed coat, thereby freeing the cotyledons. Previous studies have indicated that peg formation is gravity dependent. In this study we analyzed peg formation in cucumber seedlings (Cucumis sativus L. cv Burpee Hybrid II) grown under conditions of normal gravity, microgravity, and simulated microgravity (clinostat rotation). Seeds were germinated on the ground, in clinostats and on board the space shuttle (STS 95) for 1-2 days, frozen and subsequently examined for their stage of development, degree of hook formation, number of pegs formed, and peg morphology. The frequency of peg formation in space grown seedlings was found to be nearly identical to that of clinostat grown seedlings and to differ from that of seedlings germinated under normal gravity only in a minority of cases; approximately 6% of the seedlings formed two pegs and nearly 2% of the seedlings lacked pegs, whereas such abnormalities did not occur in ground controls. The degree of hook formation was found to be less pronounced for space grown seedlings, compared to clinostat grown seedlings, indicating a greater degree of decoupling between peg formation and hook formation in space. Nonetheless, in all seedlings having single pegs and a hook, the peg was found to be positioned correctly on the inside of the hook, showing that there is coordinate development even in microgravity environments. Peg morphologies were altered in space grown samples, with the pegs having a blunt appearance and many pegs showing alterations in expansion, with the peg extending out over the edges of the seed coat and downwards. These phenotypes were not observed in clinostat or ground grown seedlings.

Analysis of peg formation in cucumber seedlings grown on clinostats and in a microgravity (space) environment

NASA Technical Reports Server (NTRS)

Link, B. M.; Cosgrove, D. J.

1999-01-01

In young cucumber seedlings, the peg is a polar out-growth of tissue that functions by snagging the seed coat, thereby freeing the cotyledons. Previous studies have indicated that peg formation is gravity dependent. In this study we analyzed peg formation in cucumber seedlings (Cucumis sativus L. cv Burpee Hybrid II) grown under conditions of normal gravity, microgravity, and simulated microgravity (clinostat rotation). Seeds were germinated on the ground, in clinostats and on board the space shuttle (STS 95) for 1-2 days, frozen and subsequently examined for their stage of development, degree of hook formation, number of pegs formed, and peg morphology. The frequency of peg formation in space grown seedlings was found to be nearly identical to that of clinostat grown seedlings and to differ from that of seedlings germinated under normal gravity only in a minority of cases; approximately 6% of the seedlings formed two pegs and nearly 2% of the seedlings lacked pegs, whereas such abnormalities did not occur in ground controls. The degree of hook formation was found to be less pronounced for space grown seedlings, compared to clinostat grown seedlings, indicating a greater degree of decoupling between peg formation and hook formation in space. Nonetheless, in all seedlings having single pegs and a hook, the peg was found to be positioned correctly on the inside of the hook, showing that there is coordinate development even in microgravity environments. Peg morphologies were altered in space grown samples, with the pegs having a blunt appearance and many pegs showing alterations in expansion, with the peg extending out over the edges of the seed coat and downwards. These phenotypes were not observed in clinostat or ground grown seedlings.

Effects of local application of methylprednisolone delivered by the C/GP-hydrogel on the recovery of facial nerves.

PubMed

Chao, Xiuhua; Fan, Zhaomin; Han, Yuechen; Wang, Yan; Li, Jianfeng; Chai, Renjie; Xu, Lei; Wang, Haibo

2015-01-01

Local administration of MP delivered by the C/GP-MP-hydrogel can improve the recovery of facial nerve following crush injury. The findings suggested that locally injected MP delivered by C/GP-hydrogel might be a promising treatment for facial nerve damage. In this study, the aim is to assess the effectiveness of locally administrating methylprednisolone(MP) loaded by chitosan-β-glycerophosphate hydrogel (C/GP-hydrogel) on the regeneration of facial nerve crush injury. After the crush of left facial nerves, Wistar rats were randomly divided into four different groups. Then, four different therapies were used to treat the damaged facial nerves. At the 1(st), 2(nd), 3(rd), and 4(th) week after injury, the functional recovery of facial nerves and the morphological changes of facial nerves were assessed. The expression of growth associated protein-43 (GAP-43) protein in the facial nucleus were also evaluated. Locally injected MP delivered by C/GP-hydrogel effectively accelerated the facial functional recovery. In addition, the regenerated facial nerves in the C/GP-MP group were more mature than those in the other groups. The expression of GAP-43 protein was also improved by the MP, especially in the C/GP-MP group.

Characterization of Particle Translocation through Mucin Hydrogels

PubMed Central

Lieleg, Oliver; Vladescu, Ioana; Ribbeck, Katharina

2010-01-01

Abstract Biological functional entities surround themselves with selective barriers that control the passage of certain classes of macromolecules while rejecting others. A prominent example of such a selective permeability barrier is given by mucus. Mucus is a biopolymer-based hydrogel that lines all wet epithelial surfaces of the human body. It regulates the uptake of nutrients from our gastrointestinal system, adjusts itself with the menstrual cycle to control the passage of sperm, and shields the underlying cells from pathogens such as bacteria and viruses. In the case of drug delivery, the mucus barrier needs to be overcome for successful medical treatment. Despite its importance for both physiology and medical applications, the underlying principles which regulate the permeability of mucus remain enigmatic. Here, we analyze the mobility of microscopic particles in reconstituted mucin hydrogels. We show that electrostatic interactions between diffusing particles and mucin polymers regulate the permeability properties of reconstituted mucin hydrogels. As a consequence, various parameters such as particle surface charge and mucin density, and buffer conditions such as pH and ionic strength, can modulate the microscopic barrier function of the mucin hydrogel. Our findings suggest that the permeability of a biopolymer-based hydrogel such as native mucus can be tuned to a wide range of settings in different compartments of our bodies. PMID:20441741

The use of hydrogel as an electrode-skin interface for electrode array FES applications.

PubMed

Cooper, Glen; Barker, Anthony T; Heller, Ben W; Good, Tim; Kenney, Laurence P J; Howard, David

2011-10-01

Functional electrical stimulation is commonly used to restore function in post-stroke patients in upper and lower limb applications. Location of the electrodes can be a problem hence some research groups have begun to experiment with electrode arrays. Electrode arrays are interfaced with a thin continuous hydrogel sheet which is high resistivity to reduce transverse currents between electrodes in the array. Research using electrode arrays has all been conducted in a laboratory environment over short time periods but it is suspected that this approach will not be feasible over longer time periods due to changes in hydrogel resistivity. High resistivity hydrogel samples were tested by leaving them in contact with the skin over a seven day period. The samples became extremely conductive with resistivities reaching around 10-50 Ωm. The effect of these resistivity changes was studied using finite element analysis to solve for the stationary current quasi-static electric field gradient in the tissue. Electrical stimulation efficiency and focality were calculated for both a high and low resistivity electrode-skin interface layer at different tissue depths. The results showed that low resistivity hydrogel produced significant decreases in stimulation efficiency and focality compared to high resistivity hydrogel. Copyright © 2011 IPEM. Published by Elsevier Ltd. All rights reserved.

Chondrogenic potential of injectable κ-carrageenan hydrogel with encapsulated adipose stem cells for cartilage tissue-engineering applications.

PubMed

Popa, Elena G; Caridade, Sofia G; Mano, João F; Reis, Rui L; Gomes, Manuela E

2015-05-01

Due to the limited self-repair capacity of cartilage, regenerative medicine therapies for the treatment of cartilage defects must use a significant amount of cells, preferably applied using a hydrogel system that can promise their delivery and functionality at the specific site. This paper discusses the potential use of κ-carrageenan hydrogels for the delivery of stem cells obtained from adipose tissue in the treatment of cartilage tissue defects. The developed hydrogels were produced by an ionotropic gelation method and human adipose stem cells (hASCs) were encapsulated in 1.5% w/v κ-carrageenan solution at a cell density of 5 × 10(6) cells/ml. The results from the analysis of the cell-encapsulating hydrogels, cultured for up to 21 days, indicated that κ-carrageenan hydrogels support the viability, proliferation and chondrogenic differentiation of hASCs. Additionally, the mechanical analysis demonstrated an increase in stiffness and viscoelastic properties of κ-carrageenan gels with their encapsulated cells with increasing time in culture with chondrogenic medium. These results allowed the conclusion that κ-carrageenan exhibits properties that enable the in vitro functionality of encapsulated hASCs and thus may provide the basis for new successful approaches for the treatment of cartilage defects. Copyright © 2013 John Wiley & Sons, Ltd.

Biocompatibility and inflammatory response in vitro and in vivo to gelatin-based biomaterials with tailorable elastic properties.

PubMed

Ullm, Sandra; Krüger, Anne; Tondera, Christoph; Gebauer, Tim P; Neffe, Axel T; Lendlein, Andreas; Jung, Friedrich; Pietzsch, Jens

2014-12-01

Hydrogels prepared from gelatin and lysine diisocyanate ethyl ester provide tailorable elastic properties and degradation behavior. Their interaction with human aortic endothelial cells (HAEC) as well as human macrophages (Mɸ) and granulocytes (Gɸ) were explored. The experiments revealed a good biocompatibility, appropriate cell adhesion, and cell infiltration. Direct contact to hydrogels, but not contact to hydrolytic or enzymatic hydrogel degradation products, resulted in enhanced cyclooxygenase-2 (COX-2) expression in all cell types, indicating a weak inflammatory activation in vitro. Only Mɸ altered their cytokine secretion profile after direct hydrogel contact, indicating a comparably pronounced inflammatory activation. On the other hand, in HAEC the expression of tight junction proteins, as well as cytokine and matrix metalloproteinase secretion were not influenced by the hydrogels, suggesting a maintained endothelial cell function. This was in line with the finding that in HAEC increased thrombomodulin synthesis but no thrombomodulin membrane shedding occurred. First in vivo data obtained after subcutaneous implantation of the materials in immunocompetent mice revealed good integration of implants in the surrounding tissue, no progredient fibrous capsule formation, and no inflammatory tissue reaction in vivo. Overall, the study demonstrates the potential of gelatin-based hydrogels for temporal replacement and functional regeneration of damaged soft tissue. Copyright © 2014 Elsevier Ltd. All rights reserved.

Chromatographic matrix based on hydrogel-coated reticulated polyurethane foams, prepared by gamma irradiation

NASA Astrophysics Data System (ADS)

Sánchez, Mirna L.; Giménez, Claudia Y.; Delgado, Juan F.; Martínez, Leandro J.; Grasselli, Mariano

2017-12-01

Novel chromatographic materials for protein purification with high adsorption capacity and fouling resistance are highly demanded to improve downstream processes. Here, we describe a novel adsorptive material based on reticulated polyurethane foam (rPUF) coated with a functional hydrogel layer. rPUF provides physical rigidity through its macroscopic structure, whereas the hydrogel layer provides capacity to adsorb proteins by specific interactions. The hydrogel coating process was performed by the dip-coating method, using a polyvinyl alcohol (PVA) solution. The PVA hydrogel was linked to the rPUF material by using a radiation-induced crosslinking process in aqueous ethanol solution. The ethanol in the solvent mixture allowed a balance between PVA swelling and PVA dissolution during the irradiation step. The resulting material showed higher thermal stability than the non-irradiated one. In addition, a simultaneous radiation-induced grafting polymerization (SRIGP) was done by simple addition of glycidyl methacrylate monomer into the irradiation solution. In a further step, sulfonic ligands were included specifically in the hydrogel layer, which contained around 200% of PVA respect to the original rPUF. Materials were characterized by FT-IR, thermogravimetric analysis, SEM microscopy and EDX analysis. The cation-exchange rPUF material was functionally characterized by the Langmuir isotherm and a dynamic adsorption experiment to analyze the chromatographic properties for protein purification processes.

Synthesis and characterization of arginine-NIPAAm hybrid hydrogel as wound dressing: In vitro and in vivo study.

PubMed

Wu, De-Qun; Zhu, Jie; Han, Hua; Zhang, Jun-Zhi; Wu, Fei-Fei; Qin, Xiao-Hong; Yu, Jian-Yong

2018-01-01

A multi-functional hybrid hydrogel P(M-Arg/NIPAAm) with temperature response, anti-protein adsorption and antibacterial properties was prepared and applied as wound dressing. The hydrogel was carried out by free radical copolymerization of methacrylate arginine (M-Arg) and N-isopropyl acrylamide (NIPAAm) monomers using N,N'-methylene bisacrylamide as a crosslinker, and ammonium persulfate/N,N,N', N'-tetramethylethylenediamine as the redox initiator. To endow the antimicrobial property, chlorhexidine diacetate (CHX) was preloaded into the hydrogel and polyhexamethylene guanidine phosphate (PHMG) was grafted on the hydrogel surface, respectively. The antimicrobial property of two series of hydrogels was evaluated and compared. The successful synthesis of M-Arg, PHMG and hydrogels was proved by 13 C NMR, 1 H NMR and FTIR spectroscopy. The hydrogel morphology characterized by scanning electron microscopy confirmed that the homogeneous porous and interconnected structures of the hydrogels. The swelling, protein adsorption property, in vitro release of CHX, antimicrobial assessment, cell viability as well as in vivo wound healing in a mouse model were studied. The results showed the nontoxicity and antimicrobial P(M-Arg/NIPAAm) hydrogel accelerated the full-thickness wound healing process and had the potential application in wound dressing. Despite the zwitterionic characteristic and biocompatible property of arginine based hydrogels, the brittle behavior and non-transparency still remain as a significant problem for wound dressing. Furthermore promoting the antibacterial property of the zwitterionic hydrogel is also necessary to prevent the bacterial colonization and subsequent wound infection. Therefore, we created a hybrid hydrogel combined methacrylate arginine (M-Arg) and N-isopropyl acrylamide (NIPAAm). NIPAAm improves transparency and mechanical property as well as acts as a temperature-response drug release system. Additionally, chlorhexidine (CHX) was preloaded into the hydrogels and polyhexamethylene guanidine phosphate (PHMG) was grafted on the hydrogel surface, respectively, which make the hydrogel useful as a favorable antibacterial dressing. The hybrid hydrogel has a combination effect of biocompatibility, environmentally responsive transformation behavior, biodegradability, anti-protein adsorption and antimicrobial properties. This report proposes the preparation of P(M-Arg/NIPAAm) hydrogel that has a great potential for wound healing. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Doxorubicin-loaded micelles based on multiarm star-shaped PLGA-PEG block copolymers: influence of arm numbers on drug delivery.

PubMed

Ma, Guilei; Zhang, Chao; Zhang, Linhua; Sun, Hongfan; Song, Cunxian; Wang, Chun; Kong, Deling

2016-01-01

Star-shaped block copolymers based on poly(D,L-lactide-co-glycolide) (PLGA) and poly(ethylene glycol) (PEG) (st-PLGA-PEG) were synthesized with structural variation on arm numbers in order to investigate the relationship between the arm numbers of st-PLGA-PEG copolymers and their micelle properties. st-PLGA-PEG copolymers with arm numbers 3, 4 and 6 were synthesized by using different cores such as trimethylolpropane, pentaerythritol and dipentaerythritol, and were characterized by nuclear magnetic resonance and gel permeation chromatography. The critical micelle concentration decreased with increasing arm numbers in st-PLGA-PEG copolymers. The doxorubicin-loaded st-PLGA-PEG micelles were prepared by a modified nanoprecipitation method. Micellar properties such as particle size, drug loading content and in vitro drug release behavior were investigated as a function of the number of arms and compared with each other. The doxorubicin-loaded 4-arm PLGA-PEG micelles were found to have the highest cellular uptake efficiency and cytotoxicity compared with 3-arm PLGA-PEG micelles and 6-arm PLGA-PEG micelles. The results suggest that structural tailoring of arm numbers from st-PLGA-PEG copolymers could provide a new strategy for designing drug carriers of high efficiency. Structural tailoring of arm numbers from star shaped-PLGA-PEG copolymers (3-arm/4-arm/6-arm-PLGA-PEG) could provide a new strategy for designing drug carriers of high efficiency.

Mechanical testing of hydrogels in cartilage tissue engineering: beyond the compressive modulus.

PubMed

Xiao, Yinghua; Friis, Elizabeth A; Gehrke, Stevin H; Detamore, Michael S

2013-10-01

Injuries to articular cartilage result in significant pain to patients and high medical costs. Unfortunately, cartilage repair strategies have been notoriously unreliable and/or complex. Biomaterial-based tissue-engineering strategies offer great promise, including the use of hydrogels to regenerate articular cartilage. Mechanical integrity is arguably the most important functional outcome of engineered cartilage, although mechanical testing of hydrogel-based constructs to date has focused primarily on deformation rather than failure properties. In addition to deformation testing, as the field of cartilage tissue engineering matures, this community will benefit from the addition of mechanical failure testing to outcome analyses, given the crucial clinical importance of the success of engineered constructs. However, there is a tremendous disparity in the methods used to evaluate mechanical failure of hydrogels and articular cartilage. In an effort to bridge the gap in mechanical testing methods of articular cartilage and hydrogels in cartilage regeneration, this review classifies the different toughness measurements for each. The urgency for identifying the common ground between these two disparate fields is high, as mechanical failure is ready to stand alongside stiffness as a functional design requirement. In comparing toughness measurement methods between hydrogels and cartilage, we recommend that the best option for evaluating mechanical failure of hydrogel-based constructs for cartilage tissue engineering may be tensile testing based on the single edge notch test, in part because specimen preparation is more straightforward and a related American Society for Testing and Materials (ASTM) standard can be adopted in a fracture mechanics context.