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Sample records for acid plga microbubbles

  1. Magnetite loaded Polypeptide-PLGA multifunctional microbubbles for dual-mode US/MR imaging.

    PubMed

    Sun, Ying; Zhu, Yunkai; Huang, Can; Li, Rongxin; Chen, Yaqing; Duan, Yourong

    2016-01-01

    Magnetite loaded Polypeptide-PLGA multifunctional microbubbles (Fe3O4 /Polypeptide-PLGA MMBs) that show superparamagnetic properties were prepared by a modified double emulsion method and employed as imaging agent for dual-mode Ultrasound/Magnetic resonance (US/MR) imaging of prostatic cancer. The successful synthesis of MMBs was determined by Fourier Transform Infrared Spectrometer (FTIR), X-ray diffraction (XRD), Transmission Electron Microscope (TEM), Scanning Electron Microscope (SEM), Atomic Absorption Spectroscopy (AAS) and vibrating sample magnetometer (VSM). The as-prepared MMBs had a diameter of 700 nm and were quite safe as confirmed by MTT assays. Prussian Blue Staining showed that targeted Fe3O4 /Polypeptide-PLGA MMBs enhanced the cellular uptake efficiency. In cell attachment study, adherence of MMBs was significantly higher to LNCaP cells compared with negative control PC3 cells. The in vitro results demonstrated that these MMBs could enhance both US and MR imaging of prostatic cancer.

  2. Nucleic acid delivery with microbubbles and ultrasound

    PubMed Central

    Rychak, Joshua J.; Klibanov, Alexander L.

    2014-01-01

    Nucleic acid-based therapy is a growing field of drug delivery research. Although ultrasound has been suggested to enhance transfection decades ago, it took a combination of ultrasound with nucleic acid carrier systems (microbubbles, liposomes, polyplexes, viral carriers) to achieve reasonable nucleic acid delivery efficacy. Microbubbles serve as foci for local deposition of ultrasound energy near the target cell, and greatly enhance sonoporation. Major advantage of this approach is in the minimal transfection in the non-insonated non-target tissues. Microbubbles can be simply co-administered with the nucleic acid carrier or can be modified to carry nucleic acid themselves. Liposomes with embedded gas or gas precursor particles can also be used to carry nucleic acid, release and deliver it by the ultrasound trigger. Successful testing in a wide variety of animal models (myocardium, solid tumors, skeletal muscle, pancreas) proves the potential usefulness of this technique for nucleic acid drug delivery. PMID:24486388

  3. Doxorubicin loaded superparamagnetic PLGA-iron oxide multifunctional microbubbles for dual-mode US/MR imaging and therapy of metastasis in lymph nodes.

    PubMed

    Niu, Chengcheng; Wang, Zhigang; Lu, Guangming; Krupka, Tianyi M; Sun, Yang; You, Yufang; Song, Weixiang; Ran, Haitao; Li, Pan; Zheng, Yuanyi

    2013-03-01

    Current strategies for tumor-induced sentinel lymph node detection and metastasis therapy have limitations. In this work, we co-encapsulated iron oxide nanoparticles and chemotherapeutic drug into poly(lactic-co-glycolic acid) (PLGA) microbubbles to form multifunctional polymer microbubbles (MPMBs) for both tumor lymph node imaging and therapy. Fe(3)O(4) nanoparticles and doxorubicin (DOX) co-encapsulated PLGA microbubbles were prepared and filled with perfluorocarbon gas. Enhancement of ultrasound (US)/magnetic resonance (MR) imaging and US triggered drug delivery were evaluated both in vitro and in vivo. The MPMBs exhibited characters like narrow size distribution and smooth surface with a mean diameter of 868.0 ± 68.73 nm. In addition, varying the concentration of Fe(3)O(4) nanoparticles in the bubbles did not significantly influence the DOX encapsulation efficiency or drug loading efficiency. Our in vitro results demonstrated that these MPMBs could enhance both US and MR imaging which was further validated in vivo showing that these MPMBs enhanced tumor lymph nodes signals. The anti-tumor effect of MPMBs mediated chemotherapy was assessed in vivo using end markers like tumor proliferation index, micro blood vessel density and micro lymphatic vessel density, which were shown consistently the lowest after the MPMBs plus sonication treatment compared to controls. In line with these findings, the tumor cell apoptotic index was found the largest after the MPMBs plus sonication treatment. In conclusion, we have successfully developed a doxorubicin loaded superparamagnetic PLGA-Iron Oxide multifunctional theranostic agent for dual-mode US/MR Imaging of lymph node, and for low frequency US triggered therapy of metastasis in lymph nodes, which might provide a strategy for the imaging and chemotherapy of primary tumor and their metastases.

  4. Multifunctional microbubbles and nanobubbles for photoacoustic and ultrasound imaging

    PubMed Central

    Kim, Chulhong; Qin, Ruogu; Xu, Jeff S.; Wang, Lihong V.; Xu, Ronald

    2010-01-01

    We develop a novel dual-modal contrast agent—encapsulated-ink poly(lactic-co-glycolic acid) (PLGA) microbubbles and nanobubbles—for photoacoustic and ultrasound imaging. Soft gelatin phantoms with embedded tumor simulators of encapsulated-ink PLGA microbubbles and nanobubbles in various concentrations are clearly shown in both photoacoustic and ultrasound images. In addition, using photoacoustic imaging, we successfully image the samples positioned below 1.8-cm-thick chicken breast tissues. Potentially, simultaneous photoacoustic and ultrasound imaging enhanced by encapsulated-dye PLGA microbubbles or nanobubbles can be a valuable tool for intraoperative assessment of tumor boundaries and therapeutic margins. PMID:20210423

  5. Multifunctional microbubbles and nanobubbles for photoacoustic and ultrasound imaging.

    PubMed

    Kim, Chulhong; Qin, Ruogu; Xu, Jeff S; Wang, Lihong V; Xu, Ronald

    2010-01-01

    We develop a novel dual-modal contrast agent-encapsulated-ink poly(lactic-co-glycolic acid) (PLGA) microbubbles and nanobubbles-for photoacoustic and ultrasound imaging. Soft gelatin phantoms with embedded tumor simulators of encapsulated-ink PLGA microbubbles and nanobubbles in various concentrations are clearly shown in both photoacoustic and ultrasound images. In addition, using photoacoustic imaging, we successfully image the samples positioned below 1.8-cm-thick chicken breast tissues. Potentially, simultaneous photoacoustic and ultrasound imaging enhanced by encapsulated-dye PLGA microbubbles or nanobubbles can be a valuable tool for intraoperative assessment of tumor boundaries and therapeutic margins.

  6. Ultrasound-Mediated Microbubble Destruction (UMMD) Facilitates the Delivery of CA19-9 Targeted and Paclitaxel Loaded mPEG-PLGA-PLL Nanoparticles in Pancreatic Cancer

    PubMed Central

    Xing, Lingxi; Shi, Qiusheng; Zheng, Kailiang; Shen, Ming; Ma, Jing; Li, Fan; Liu, Yang; Lin, Lizhou; Tu, Wenzhi; Duan, Yourong; Du, Lianfang

    2016-01-01

    Pancreatic cancer, one of the most lethal human malignancies with dismal prognosis, is refractory to existing radio-chemotherapeutic treatment modalities. There is a critical unmet need to develop effective approaches, especially for targeted pancreatic cancer drug delivery. Targeted and drug-loaded nanoparticles (NPs) combined with ultrasound-mediated microbubble destruction (UMMD) have been shown to significantly increase the cellular uptake in vitro and drug retention in vivo, suggesting a promising strategy for cancer therapy. In this study, we synthesized pancreatic cancer-targeting organic NPs that were modified with anti CA19-9 antibody and encapsulated paclitaxol (PTX). The three-block copolymer methoxy polyethylene glycol-polylacticco-glycolic acid-polylysine (mPEG-PLGA-PLL) constituted the skeleton of the NPs. We speculated that the PTX-NPs-anti CA19-9 would circulate long-term in vivo, "actively target" pancreatic cancer cells, and sustainably release the loaded PTX while UMMD would "passively target" the irradiated tumor and effectively increase the permeability of cell membrane and capillary gaps. Our results demonstrated that the combination of PTX-NPs-anti CA19-9 with UMMD achieved a low IC50, significant cell cycle arrest, and cell apoptosis in vitro. In mouse pancreatic tumor xenografts, the combined application of PTX-NP-anti CA19-9 NPs with UMMD attained the highest tumor inhibition rate, promoted the pharmacokinetic profile by increasing AUC, t1/2, and mean residence time (MRT), and decreased clearance. Consequently, the survival of the tumor-bearing nude mice was prolonged without obvious toxicity. The dynamic change in cellular uptake, targeted real-time imaging, and the concentration of PTX in the plasma and tumor were all closely associated with the treatment efficacy both in vitro and in vivo. Our study suggests that PTX-NP-anti CA19-9 NPs combined with UMMD is a promising strategy for the treatment of pancreatic cancer. PMID:27446491

  7. [Characteristics of acid red 3R wastewater treatment by ozone microbubbles].

    PubMed

    Zhang, Jing; Du, Ya-Wei; Liu, Xiao-Jing; Zhou, Yu-Wen; Liu, Chun; Yang, Jing-Liang; Zhang, Lei

    2015-02-01

    The application of microbubble technology for ozonation wastewater treatment could enhance ozone mass transfer, improve ozonation performance and increase ozone utilization efficiency. The ozone microbubbles were used to treat synthetic acid red 3R wastewater in the present study, and compared to ozone conventional bubbles. The ozone mass transfer and ozonation characteristics of acid red 3R were investigated when ozone microbubbles and ozone conventional bubbles were applied. The results confirmed the enhanced ozone mass transfer using microbubbles. The ozone mass transfer coefficient using microbubbles was 3.6 times higher than that using conventional bubbles under the same conditions. Simultaneously, the ozone decomposition coefficient using microbubbles was 6.2 times higher than that using conventional bubbles, which would be favorable for *OH generation. The ozonation rate and mineralization efficiency of acid red 3R could be improved significantly using ozone microbubbles. A TOC removal efficiency of 78.0% was achieved using ozone microbubbles, which was about 2 times higher than that using ozone conventional bubbles. The ozone utilization efficiency using microbubbles was much higher that using conventional bubbles during ozonation treatment of acid red 3R. The average ozone utilization efficiencies were 97.8% and 69.3% when microbubbles and conventional bubbles were used, respectively. The oxidative ability of ozone microbubbles could be increased by enhancing *OH generation, and as a result, the oxidative reaction of degradation intermediates was accelerated by ozone microbubbles. Especially, the mineralization ability of small organic acid intermediates using ozone microbubbles was about 1.6 times higher than that using ozone conventional bubbles.

  8. Enhanced Osteoblast Functions on Nanophase Titania in Poly-lactic-co-glycolic Acid (PLGA) Composites

    DTIC Science & Technology

    2005-01-01

    Poly - lactic -co-glycolic Acid (PLGA) Composites Huinan Liu’, Elliott B. Slamovich’ and Thomas J. Webster’ 2 1School of Materials Engineering, 501...collagen matrix. For this purpose, poly - lactic -co- glycolic acid (PLGA) was dissolved in chloroform and nanometer grain size titania was dispersed by...gelatin, fibrin or collagen [4-6]), synthetic bioresorbable polymers (e.g., polylactic acid , polyglycolic acid and poly - lactic -co-glycolic acid [7-9

  9. Hyaluronic Acid/PLGA Core/Shell Fiber Matrices Loaded with EGCG Beneficial to Diabetic Wound Healing.

    PubMed

    Shin, Yong Cheol; Shin, Dong-Myeong; Lee, Eun Ji; Lee, Jong Ho; Kim, Ji Eun; Song, Sung Hwa; Hwang, Dae-Youn; Lee, Jun Jae; Kim, Bongju; Lim, Dohyung; Hyon, Suong-Hyu; Lim, Young-Jun; Han, Dong-Wook

    2016-12-01

    During the last few decades, considerable research on diabetic wound healing strategies has been performed, but complete diabetic wound healing remains an unsolved problem, which constitutes an enormous biomedical burden. Herein, hyaluronic acid (HA)/poly(lactic-co-glycolic acid, PLGA) core/shell fiber matrices loaded with epigallocatechin-3-O-gallate (EGCG) (HA/PLGA-E) are fabricated by coaxial electrospinning. HA/PLGA-E core/shell fiber matrices are composed of randomly-oriented sub-micrometer fibers and have a 3D porous network structure. EGCG is uniformly dispersed in the shell and sustainedly released from the matrices in a stepwise manner by controlled diffusion and PLGA degradation over four weeks. EGCG does not adversely affect the thermomechanical properties of HA/PLGA-E matrices. The number of human dermal fibroblasts attached on HA/PLGA-E matrices is appreciably higher than that on HA/PLGA counterparts, while their proliferation is steadily retained on HA/PLGA-E matrices. The wound healing activity of HA/PLGA-E matrices is evaluated in streptozotocin-induced diabetic rats. After two weeks of surgical treatment, the wound areas are significantly reduced by the coverage with HA/PLGA-E matrices resulting from enhanced re-epithelialization/neovascularization and increased collagen deposition, compared with no treatment or HA/PLGA. In conclusion, the HA/PLGA-E matrices can be potentially exploited to craft strategies for the acceleration of diabetic wound healing and skin regeneration.

  10. Effects of lactic acid and glycolic acid on human osteoblasts: a way to understand PLGA involvement in PLGA/calcium phosphate composite failure.

    PubMed

    Meyer, Florent; Wardale, John; Best, Serena; Cameron, Ruth; Rushton, Neil; Brooks, Roger

    2012-06-01

    The use of degradable composite materials in orthopedics remains a field of intense research due to their ability to support new bone formation and degrade in a controlled manner, broadening their use for orthopedic applications. Poly (lactide-co-glycolide) acid (PLGA), a degradable biopolymer, is now a popular material for different orthopedic applications and is proposed for use in tissue engineering scaffolds either alone or combined with bioactive ceramics. Interference screws composed of calcium phosphates and PLGA are readily available in the market. However, some reports highlight problems of screw migration or aseptic cyst formation following screw degradation. In order to understand these phenomena and to help to improve implant formulation, we have evaluated the effects of PLGA degradation products: lactic acid and glycolic acid on human osteoblasts in vitro. Cell proliferation, differentiation, and matrix mineralization, important for bone healing were studied. It was found that the toxicity of polymer degradation products under buffering conditions was limited to high concentrations. However, non-toxic concentrations led to a decrease in cell proliferation, rapid cell differentiation, and mineralization failure. Calcium, whilst stimulating cell proliferation was not able to overcome the negative effects of high concentrations of lactic and glycolic acids on osteoblasts. These effects help to explain recently reported clinical failures of calcium phosphate/PLGA composites, but further in vitro analyses are needed to mimic the dynamic situation which occurs in the body by, for example, culture of osteoblasts with materials that have been pre-degraded to different extents and thus be able to relate these findings to the degradation studies that have been performed previously.

  11. Interaction between dimethyldioctadecylammonium bromide-modified PLGA microspheres and hyaluronic acid

    NASA Astrophysics Data System (ADS)

    Mulia, Kamarza; Devi, Krisanti, Elsa

    2017-02-01

    In application of intravitreal injection, an extended drug delivery system is desired so that the frequency of injection to treat diabetic retinopathy may be reduced. Poly(lactic-co-glycolic acid) polymer (PLGA) was used to encapsulate a model drug in the form of microspheres. The zeta potential of dimethyldioctadecylammonium bromide (DDAB)-modified PLGA microspheres in water was proportional to the DDAB concentration used in the preparation step, up to +57.8 mV. The scanning electron microscope pictures and the zeta potential data (SEM) confirmed that the surface of the PLGA has been modified by the cationic surfactant and that electrostatic interaction between the positively charged microspheres and the negatively charged vitreous were present.

  12. Development and characterization of hyaluronic acid decorated PLGA nanoparticles for delivery of 5-fluorouracil.

    PubMed

    Yadav, Awesh K; Agarwal, Abhinav; Rai, Gopal; Mishra, Pradeep; Jain, Sanyog; Mishra, Anil K; Agrawal, Himanshu; Agrawal, Govind P

    2010-11-01

    The present investigation was aimed to develop and explore the prospective of engineered PLGA nanoparticles as vehicles for targeted delivery of 5-fluorouracil (5-FU). Nanoparticles of 5-FU-loaded hyaluronic acid-poly(ethylene glycol)-poly(lactide-co-glycolide) (HA-PEG-PLGA-FU) copolymer were prepared and characterized by FTIR, NMR, transmission electron microscopy, particle size analysis, DSC, and X-ray diffractometer measurement studies. The nanoparticulate formulation was evaluated for in vitro release, hemolytic toxicity, and hematological toxicity. Cytotoxicity studies were performed on Ehrlich ascites tumor (EAT) cell lines using MTT cell proliferation assay. Biodistribution studies of 99m Tc labeled formulation were conducted on EAT-bearing mice. The in vivo tumor inhibition study was also performed after i.v. administration of HA-PEG-PLGA-FU nanoparticles. The HA conjugated formulation was found to be less hemolytic but more cytotoxic as compared to free drug. The hematological data suggested that HA-PEG-PLGA-FU formulation was less immunogenic compared to plain drug. The tissue distribution studies displayed that HA-PEG-PLGA-FU were able to deliver a higher concentration of 5-FU in the tumor mass. In addition, the HA-PEG-PLGA-FU nanoparticles reduced tumor volume significantly in comparison with 5-FU. Thus, it was concluded that the conjugation of HA imparts targetability to the formulation, and enhanced permeation and retention effect ruled out its access to the non-tumor tissues, at the same time favored selective entry in tumors, thereby reducing the side-effects both in vitro and in vivo.

  13. Glycolic acid-catalyzed deamidation of asparagine residues in degrading PLGA matrices: a computational study.

    PubMed

    Manabe, Noriyoshi; Kirikoshi, Ryota; Takahashi, Ohgi

    2015-03-31

    Poly(lactic-co-glycolic acid) (PLGA) is a strong candidate for being a drug carrier in drug delivery systems because of its biocompatibility and biodegradability. However, in degrading PLGA matrices, the encapsulated peptide and protein drugs can undergo various degradation reactions, including deamidation at asparagine (Asn) residues to give a succinimide species, which may affect their potency and/or safety. Here, we show computationally that glycolic acid (GA) in its undissociated form, which can exist in high concentration in degrading PLGA matrices, can catalyze the succinimide formation from Asn residues by acting as a proton-transfer mediator. A two-step mechanism was studied by quantum-chemical calculations using Ace-Asn-Nme (Ace = acetyl, Nme = NHCH3) as a model compound. The first step is cyclization (intramolecular addition) to form a tetrahedral intermediate, and the second step is elimination of ammonia from the intermediate. Both steps involve an extensive bond reorganization mediated by a GA molecule, and the first step was predicted to be rate-determining. The present findings are expected to be useful in the design of more effective and safe PLGA devices.

  14. Spontaneous arrangement of a tumor targeting hyaluronic acid shell on irinotecan loaded PLGA nanoparticles.

    PubMed

    Giarra, Simona; Serri, Carla; Russo, Luisa; Zeppetelli, Stefania; De Rosa, Giuseppe; Borzacchiello, Assunta; Biondi, Marco; Ambrosio, Luigi; Mayol, Laura

    2016-04-20

    The arrangement of tumor targeting hyaluronic acid (HA) moieties on irinotecan (IRIN)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) has been directed by means of a gradient of lipophilicity between the oil and water phases of the emulsion used to produce the NPs. PLGA constitutes the NP bulk while HA is superficially exposed, with amphiphilic poloxamers acting as a bridge between PLGA and HA. Differential scanning calorimetry, zeta potential analyses and ELISA tests were employed to support the hypothesis of polymer assembly in NP formulations. The presence of flexible HA chains on NP surface enhances NP size stability over time due to an increased electrostatic repulsion between NPs and a higher degree of hydration of the device surface. IRIN in vitro release kinetics can be sustained up to 7-13 days. In vitro biologic studies indicated that HA-containing NPs were more toxic than bare PLGA NPs against CD44-overexpressing breast carcinoma cells (HS578T), therefore indicating their ability to target CD44 receptor.

  15. Novel Simvastatin-Loaded Nanoparticles Based on Cholic Acid-Core Star-Shaped PLGA for Breast Cancer Treatment.

    PubMed

    Wu, Yanping; Wang, Zhongyuan; Liu, Gan; Zeng, Xiaowei; Wang, Xusheng; Gao, Yongfeng; Jiang, Lijuan; Shi, Xiaojun; Tao, Wei; Huang, Laiqiang; Mei, Lin

    2015-07-01

    A novel nanocarrier system of cholic acid (CA) core, star-shaped polymer consisting of poly(D,L-lactide-co-glycolide) (PLGA) was developed for sustained and controlled delivery of simvastatin for chemotherapy of breast adenocarcinoma. The star-shaped polymer CA-PLGA with three branch arms was synthesized successfully through the core-first approach. The simvastatin-loaded star-shaped CA-PLGA nanoparticles were prepared through a modified nanoprecipitation method. The data showed that the fluorescence star-shaped CA-PLGA nanoparticles could be internalized into MDA-MB-231 and MDA-MB-468 human breast cancer cells. The simvastatin-loaded star-shaped CA-PLGA nanoparticles achieved significantly higher level of cytotoxicity than pristine simvastatin and simvastatin-loaded linear PLGA nanoparticles. Moreover, the expression of the cell cycle protein cyclin D1 was dramatically inhibited by simvastatin in both cells, with simvastatin-loaded star-shaped CA-PLGA nanoparticles having the greatest effect. MDA-MB-231 xenograft tumor model on BALB/c nude mice showed that simvastatin-loaded star-shaped CA-PLGA nanoformulations could effectively inhibit the growth of tumor over a longer period of time than pristine simvastatin and simvastatin-loaded linear PLGA nanoformulations at the same dose. In agreement with these, the nuclear expression of proliferation marker Ki-67 in simvastatin-loaded star-shaped CA-PLGA nanoparticles group was reduced to a most extent among four groups through tumor frozen section immunohistochemistry. In conclusion, the star-shaped CA-PLGA polymers could serve as a novel polymeric nanocarrier for breast cancer chemotherapy.

  16. Nanoscaled buffering zone of charged (PLGA)n-b-bPEI micelles in acidic microclimate for potential protein delivery application

    PubMed Central

    Kang, Han Chang; Lee, Ji Eun; Bae, You Han

    2012-01-01

    Poly(lactide-co-glycolide) (PLGA) has most often been employed for the controlled release of protein formulations because of its safety profile with non-toxic degradation products. Nevertheless, such formulations have been plagued by a local acidic microenvironment and protein-polymer interactions, which result in chemical and physical denaturation of loaded proteins and often unfavorable release profiles. This study investigated the pH change of inner PLGA microsphere (MS) using charged (PLGA)n-b-branched polyethyleneimine (bPEI) micelles. The designed micelles can be transformed into either micelle or reverse micelle (RM) depending on the solvent and RM can form microspheres. In addition, (PLGA)n-b-bPEI can be modified into (PLGA)n-b-(carboxylated bPEI) via carboxylation of the primary amines. Cationic micelle (CM) or anionic micelle (AM) were complexed with counter-charged proteins leading to nanosized particles (approximately 100 nm). In the micelle/protein complexes, the micelles mostly maintained their proton buffering capacity, and consequently, prevented or delayed the typical decrease in pH caused by degradation of PLGA in aqueous solution. Reconstitutable micelle/protein complexes allowed for increased and fine-tuned protein loading (~20 wt% when using CM1 (CM prepared from PLGA36kDa-b-bPEI25kDa)/insulin complexes) in PLGA MS. In CM2 (CM prepared from (PLGA36kDa)2-b-bPEI25kDa)/insulin (4 of weight ratio (WR) of micelle to protein; WR4)-loaded PLGA MS, CM2 strongly prevented the micellar nanoenvironmental pH (pH 6.6 within 5 days and then approximately pH 8.5) to be acidified in PLGA MS for 9 weeks, unlike CM2-free PLGA MS. In conclusion, our findings propose that the proton buffering capacity and protein loading in PLGA MS can be tuned by controlling the complexation ratios of micelles and proteins, polymeric architectures of (PLGA)n-b-bPEI copolymers and WR of micelle/protein complexes and PLGA (or RM). PMID:22405902

  17. van der Waals force-induced loading of proangiogenic nanoparticles on microbubbles for enhanced neovascularization

    NASA Astrophysics Data System (ADS)

    Chen, Jinrong; Lee, Min Kyung; Qin, Ellen; Misra, Sanjay; Kong, Hyunjoon

    2015-10-01

    Nanoparticles emerged as carriers of promising diagnostic and therapeutic molecules due to their unique size, injectability, and potential to sustainably release molecular cargos. However, with local injection of particles into target tissue, the significant particle loss caused by external biomechanical forces is a great challenge yet to be resolved to date. We hypothesized that nanoparticles associated with tissue-adherent microbubbles in the form of core-shell particles due to van der Waals attractive forces would stably remain on an implanted site and significantly increase therapeutic efficacy of drug cargos. To examine this hypothesis, we used 100 nm diameter nanoparticles made of poly(lactide-co-glycolic acid) (PLGA) as a model nanoparticle and 50 μm diameter microbubbles made of poly(2-hydroxyethyl aspartamide) (PHEA) grafted with octadecyl chains, PHEA-g-C18, as a model microbubble. Simple mixing of PLGA nanoparticles and PHEA-g-C18 microbubbles resulted in the core-shell particles. Following implantation, the PHEA-g-C18 microbubbles acted as glue to minimize the displacement of PLGA nanoparticles, because of the association between the octadecyl chains on PHEA-g-C18 and the epithelium of the tissue. As a consequence, the core-shell particles prepared with Angiopoietin-1 (Ang1)-encapsulated PLGA nanoparticles significantly promoted vascularization in the implanted tissue. Overall, the results of this study provide a simple but advanced strategy for improving therapeutic efficacy of drug-carrying nanoparticles without altering their surface chemistry and potential.Nanoparticles emerged as carriers of promising diagnostic and therapeutic molecules due to their unique size, injectability, and potential to sustainably release molecular cargos. However, with local injection of particles into target tissue, the significant particle loss caused by external biomechanical forces is a great challenge yet to be resolved to date. We hypothesized that nanoparticles

  18. Drug release behavior of poly (lactic-glycolic acid) grafting from sodium alginate (ALG-g-PLGA) prepared by direct polycondensation.

    PubMed

    Shi, Gang; Ding, Yuanyuan; Zhang, Xin; Wu, Luyan; He, Fei; Ni, Caihua

    2015-01-01

    Hydrophobically modified sodium alginate, poly (lactic-glycolic acid) grafting from sodium alginate (ALG-g-PLGA), was successfully synthesized through direct one-step polymerization of sodium alginate, glycolic acid, and lactic acid. ALG-g-PLGA self-assembled to colloidal nanoparticles and subsequently hydrogel microspheres were obtained by crosslinking ALG-g-PLGA nanoparticles in the solution of calcium chloride. The modified hydrogel microspheres could be used as the drug delivery vehicles for a hydrophobic ibuprofen. Compared with sodium alginate, ALG-g-PLGA demonstrated an improved drug loading rate, encapsulation efficiency, and prolonged release speed. The products, as novel and highly promising biomaterials, have potential applications.

  19. An overview of poly(lactic-co-glycolic) acid (PLGA)-based biomaterials for bone tissue engineering.

    PubMed

    Gentile, Piergiorgio; Chiono, Valeria; Carmagnola, Irene; Hatton, Paul V

    2014-02-28

    Poly(lactic-co-glycolic) acid (PLGA) has attracted considerable interest as a base material for biomedical applications due to its: (i) biocompatibility; (ii) tailored biodegradation rate (depending on the molecular weight and copolymer ratio); (iii) approval for clinical use in humans by the U.S. Food and Drug Administration (FDA); (iv) potential to modify surface properties to provide better interaction with biological materials; and (v) suitability for export to countries and cultures where implantation of animal-derived products is unpopular. This paper critically reviews the scientific challenge of manufacturing PLGA-based materials with suitable properties and shapes for specific biomedical applications, with special emphasis on bone tissue engineering. The analysis of the state of the art in the field reveals the presence of current innovative techniques for scaffolds and material manufacturing that are currently opening the way to prepare biomimetic PLGA substrates able to modulate cell interaction for improved substitution, restoration, or enhancement of bone tissue function.

  20. An Overview of Poly(lactic-co-glycolic) Acid (PLGA)-Based Biomaterials for Bone Tissue Engineering

    PubMed Central

    Gentile, Piergiorgio; Chiono, Valeria; Carmagnola, Irene; Hatton, Paul V.

    2014-01-01

    Poly(lactic-co-glycolic) acid (PLGA) has attracted considerable interest as a base material for biomedical applications due to its: (i) biocompatibility; (ii) tailored biodegradation rate (depending on the molecular weight and copolymer ratio); (iii) approval for clinical use in humans by the U.S. Food and Drug Administration (FDA); (iv) potential to modify surface properties to provide better interaction with biological materials; and (v) suitability for export to countries and cultures where implantation of animal-derived products is unpopular. This paper critically reviews the scientific challenge of manufacturing PLGA-based materials with suitable properties and shapes for specific biomedical applications, with special emphasis on bone tissue engineering. The analysis of the state of the art in the field reveals the presence of current innovative techniques for scaffolds and material manufacturing that are currently opening the way to prepare biomimetic PLGA substrates able to modulate cell interaction for improved substitution, restoration, or enhancement of bone tissue function. PMID:24590126

  1. Stabilization of Human Immunoglobulin G Encapsulated within Biodegradable Poly (Cyclohexane-1, 4-diyl Acetone Dimethylene Ketal) (PCADK)/ Poly (Lactic-co-Glycolic Acid) (PLGA) Blend Microspheres.

    PubMed

    Wang, Chenhui; Yu, Changhui; Liu, Jiaxin; Sun, Fengying; Teng, Lesheng; Li, Youxin

    2015-01-01

    The aim of this study was to prepare PCADK/PLGA-blend microspheres for improving the stability of human immunoglobulin G (IgG). The short half-life of antibodies limit their development as therapeutic agents, thus PLGA microspheres were prepared to sustained release antibodies and prolong their half-life. However, the acidic intra-microsphere environment causes the loss of antibody stability and activity. In this study, the effect of PCADK or PLGA degradation products on IgG was investigated by size exclusion chromatography (SEC-HPLC), circular dichroism (CD), fluorescence spectroscopy and antigenicity detection. The degradation products of PCADK exerted a larger influence on IgG than that of PLGA. Then PCADK/PLGA microspheres were prepared by the emulsionsolvent evaporation method and systematically characterized and 20% PCADK were selected as the optimal proportion. In addition, the release profile of microspheres and the stability of the released IgG were investigated. The stability of the IgG released from the PCADK/PLGA microspheres was better than that of IgG released from the PLGA microspheres. Confocal laser scanning microscopy (CLSM) was used to determine the pH inside the microspheres. The IgG-loaded PCADK/PLGA microspheres have important advantages over the PLGA microspheres in terms of IgG stability and could be a good carrier to deliver antibodies for the treatment of disease.

  2. Humidity-dependent compression-induced glass transition of the air-water interfacial Langmuir films of poly(D,L-lactic acid-ran-glycolic acid) (PLGA).

    PubMed

    Kim, Hyun Chang; Lee, Hoyoung; Jung, Hyunjung; Choi, Yun Hwa; Meron, Mati; Lin, Binhua; Bang, Joona; Won, You-Yeon

    2015-07-28

    Constant rate compression isotherms of the air-water interfacial Langmuir films of poly(D,L-lactic acid-ran-glycolic acid) (PLGA) show a distinct feature of an exponential increase in surface pressure in the high surface polymer concentration regime. We have previously demonstrated that this abrupt increase in surface pressure is linked to the glass transition of the polymer film, but the detailed mechanism of this process is not fully understood. In order to obtain a molecular-level understanding of this behavior, we performed extensive characterizations of the surface mechanical, structural and rheological properties of Langmuir PLGA films at the air-water interface, using combined experimental techniques including the Langmuir film balance, X-ray reflectivity and double-wall-ring interfacial rheometry methods. We observed that the mechanical and structural responses of the Langmuir PLGA films are significantly dependent on the rate of film compression; the glass transition was induced in the PLGA film only at fast compression rates. Surprisingly, we found that this deformation rate dependence is also dependent on the humidity of the environment. With water acting as a plasticizer for the PLGA material, the diffusion of water molecules through the PLGA film seems to be the key factor in the determination of the glass transformation properties and thus the mechanical response of the PLGA film against lateral compression. Based on our combined results, we hypothesize the following mechanism for the compression-induced glass transformation of the Langmuir PLGA film; (1) initially, a humidified/non-glassy PLGA film is formed in the full surface-coverage region (where the surface pressure shows a plateau) during compression; (2) further compression leads to the collapse of the PLGA chains and the formation of new surfaces on the air side of the film, and this newly formed top layer of the PLGA film is transiently glassy in character because the water evaporation rate

  3. Cellular uptake, antioxidant and antiproliferative activity of entrapped α-tocopherol and γ-tocotrienol in poly (lactic-co-glycolic) acid (PLGA) and chitosan covered PLGA nanoparticles (PLGA-Chi).

    PubMed

    Alqahtani, Saeed; Simon, Lacey; Astete, Carlos E; Alayoubi, Alaadin; Sylvester, Paul W; Nazzal, Sami; Shen, Yixiao; Xu, Zhimin; Kaddoumi, Amal; Sabliov, Cristina M

    2015-05-01

    The aim of this study was to formulate and characterize α-tocopherol (α-T) and tocotrienol-rich fraction (TRF) entrapped in poly (lactide-co-glycolide) (PLGA) and chitosan covered PLGA (PLGA-Chi) based nanoparticles. The resultant nanoparticles were characterized and the effect of nanoparticles entrapment on the cellular uptake, antioxidant, and antiproliferative activity of α-T and TRF were tested. In vitro uptake studies in Caco2 cells showed that PLGA and PLGA-Chi nanoparticles displayed a greater enhancement in the cellular uptake of α-T and TRF when compared with the control without causing toxicity to the cells (p<0.0001). Furthermore, the cellular internalization of both PLGA and PLGA-Chi nanoparticles labeled with FITC was investigated by fluorescence microscopy; both types of nanoparticles were able to get internalized into the cells with reasonable amounts. However, PLGA-Chi nanoparticles showed significantly higher (3.5-fold) cellular uptake compared to PLGA nanoparticles. The antioxidant activity studies demonstrated that entrapment of α-T and TRF in PLGA and PLGA-Chi nanoparticles exhibited greater ability in inhibiting cholesterol oxidation at 48 h compared to the control. In vitro antiproliferative studies confirmed marked cytotoxicity of TRF on MCF-7 and MDA-MB-231 cell lines when delivered by PLGA and PLGA-Chi nanoparticles after 48 h incubation compared to control. In summary, PLGA and PLGA-Chi nanoparticles may be considered as an attractive and promising approach to enhance the bioavailability and activity of poorly water soluble compounds such as α-tocopherol and tocotrienols.

  4. Hyaluronic acid grafted PLGA copolymer nanoparticles enhance the targeted delivery of Bromelain in Ehrlich's Ascites Carcinoma.

    PubMed

    Bhatnagar, Priyanka; Pant, Aditya Bhushan; Shukla, Yogeshwer; Panda, Amulya; Gupta, Kailash Chand

    2016-08-01

    Rapidly increasing malignant neoplastic disease demands immediate attention. Several dietary compounds have recently emerged as strong anti-cancerous agents. Among, Bromelain (BL), a protease from pineapple plant, was used to enhance its anti-cancerous efficacy using nanotechnology. In lieu of this, hyaluronic acid (HA) grafted PLGA copolymer, having tumor targeting ability, was developed. BL was encapsulated in copolymer to obtain BL-copolymer nanoparticles (NPs) that ranged between 140 to 281nm in size. NPs exhibited higher cellular uptake and cytotoxicity in cells with high CD44 expression as compared with non-targeted NPs. In vivo results on tumor bearing mice showed that NPs were efficient in suppressing the tumor growth. Hence, the formulation could be used as a self-targeting drug delivery cargo for the remission of cancer.

  5. Aspartic acid-based modified PLGA-PEG nanoparticles for bone targeting: in vitro and in vivo evaluation.

    PubMed

    Fu, Yin-Chih; Fu, Tzu-Fun; Wang, Hung-Jen; Lin, Che-Wei; Lee, Gang-Hui; Wu, Shun-Cheng; Wang, Chih-Kuang

    2014-11-01

    Nanoparticles (NP) that target bone tissue were developed using PLGA-PEG (poly(lactic-co-glycolic acid)-polyethylene glycol) diblock copolymers and bone-targeting moieties based on aspartic acid, (Asp)(n(1,3)). These NP are expected to enable the transport of hydrophobic drugs. The molecular structures were examined by (1)H NMR or identified using mass spectrometry and Fourier transform infrared (FT-IR) spectra. The NP were prepared using the water miscible solvent displacement method, and their size characteristics were evaluated using transmission electron microscopy (TEM) and dynamic light scattering. The bone targeting potential of the NP was evaluated in vitro using hydroxyapatite affinity assays and in vivo using fluorescent imaging in zebrafish and rats. It was confirmed that the average particle size of the NP was <200 nm and that the dendritic Asp3 moiety of the PLGA-PEG-Asp3 NP exhibited the best apatite mineral binding ability. Preliminary findings in vivo bone affinity assays in zebrafish and rats indicated that the PLGA-PEG-ASP3 NP may display increased bone-targeting efficiency compared with other PLGA-PEG-based NP that lack a dendritic Asp3 moiety. These NP may act as a delivery system for hydrophobic drugs, warranting further evaluation of the treatment of bone disease.

  6. Multifunctional PLGA particles containing poly(l-glutamic acid)-capped silver nanoparticles and ascorbic acid with simultaneous antioxidative and prolonged antimicrobial activity.

    PubMed

    Stevanović, Magdalena; Bračko, Ines; Milenković, Marina; Filipović, Nenad; Nunić, Jana; Filipič, Metka; Uskoković, Dragan P

    2014-01-01

    A water-soluble antioxidant (ascorbic acid, vitamin C) was encapsulated together with poly(l-glutamic acid)-capped silver nanoparticles (AgNpPGA) within a poly(lactide-co-glycolide) (PLGA) polymeric matrix and their synergistic effects were studied. The PLGA/AgNpPGA/ascorbic acid particles synthesized by a physicochemical method with solvent/non-solvent systems are spherical, have a mean diameter of 775 nm and a narrow size distribution with a polydispersity index of 0.158. The encapsulation efficiency of AgNpPGA/ascorbic acid within PLGA was determined to be >90%. The entire amount of encapsulated ascorbic acid was released in 68 days, and the entire amount of AgNpPGAs was released in 87 days of degradation. The influence of PLGA/AgNpPGA/ascorbic acid on cell viability, generation of reactive oxygen species (ROS) in HepG2 cells, as well as antimicrobial activity against seven different pathogens was investigated. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay indicated good biocompatibility of these PLGA/AgNpPGA/ascorbic acid particles. We measured the kinetics of ROS formation in HepG2 cells by a DCFH-DA assay, and found that PLGA/AgNpPGA/ascorbic acid caused a significant decrease in DCF fluorescence intensity, which was 2-fold lower than that in control cells after a 5h exposure. This indicates that the PLGA/AgNpPGA/ascorbic acid microspheres either act as scavengers of intracellular ROS and/or reduce their formation. Also, the results of antimicrobial activity of PLGA/AgNpPGA/ascorbic acid obtained by the broth microdilution method showed superior and extended activity of these particles. The samples were characterized using Fourier transform infrared spectroscopy, field-emission scanning electron microscopy, transmission electron microscopy, zeta potential and particle size analysis. This paper presents a new approach to the treatment of infection that at the same time offers a very pronounced antioxidant effect.

  7. Highly Stable PEGylated Poly(lactic-co-glycolic acid) (PLGA) Nanoparticles for the Effective Delivery of Docetaxel in Prostate Cancers

    NASA Astrophysics Data System (ADS)

    Cao, Long-Bin; Zeng, Sha; Zhao, Wei

    2016-06-01

    In the present study, a highly stable luteinizing-hormone-releasing hormone (LHRH)-conjugated PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles were developed for the successful treatment of prostate cancers. We have demonstrated that a unique combination of targeted drug delivery and controlled drug release is effective against prostate cancer therapy. The docetaxel (DTX)/PLGA-LHRH micelles possessed a uniform spherical shape with an average diameter of ~170 nm. The micelles exhibited a controlled drug release for up to 96 h which can minimize the non-specific systemic spread of toxic drugs during circulation while maximizing the efficiency of tumor-targeted drug delivery. The LHRH-conjugated micelles showed enhanced cellular uptake and exhibited significantly higher cytotoxicity against LNCaP cancer cells. We have showed that PLGA-LHRH induced greater caspase-3 activity indicating its superior apoptosis potential. Consistently, LHRH-conjugated micelles induced threefold and twofold higher G2/M phase arrest than compared to free DTX or PLGA NP-treated groups. Overall, results indicate that use of LHRH-conjugated nanocarriers may potentially be an effective nanocarrier to effectively treat prostate cancer.

  8. New Perspective in the Formulation and Characterization of Didodecyldimethylammonium Bromide (DMAB) Stabilized Poly(Lactic-co-Glycolic Acid) (PLGA) Nanoparticles

    PubMed Central

    Gossmann, Rebecca; Langer, Klaus; Mulac, Dennis

    2015-01-01

    Over the last few decades the establishment of nanoparticles as suitable drug carriers with the transport of drugs across biological barriers such as the gastrointestinal barrier moved into the focus of many research groups. Besides drug transport such carrier systems are well suited for the protection of drugs against enzymatic and chemical degradation. The preparation of biocompatible and biodegradable nanoparticles based on poly(lactic-co-glycolic acid) (PLGA) is intensively described in literature, while especially nanoparticles with cationic properties show a promising increased cellular uptake. This is due to the electrostatic interaction between the cationic surface and the negatively charged lipid membrane of the cells. Even though several studies achieved the successful preparation of nanoparticles stabilized with the cationic surfactants such as didodecyldimethylammonium bromide (DMAB), in most cases insufficient attention was paid to a precise analytical characterization of the nanoparticle system. The aim of the present work was to overcome this deficit by presenting a new perspective in the formulation and characterization of DMAB-stabilized PLGA nanoparticles. Therefore these nanoparticles were carefully examined with regard to particle diameter, zeta potential, the effect of variation in stabilizer concentration, residual DMAB content, and electrolyte stability. Without any steric stabilization, the DMAB-modified nanoparticles were sensitive to typical electrolyte concentrations of biological environments due to compression of the electrical double layer in conjunction with a decrease in zeta potential. To handle this problem, the present study proposed two modifications to enable electrolyte stability. Both polyvinyl alcohol (PVA) and polyethylene glycol (PEG) modified DMAB-PLGA-nanoparticles were stable during electrolyte addition. Furthermore, in contrast to unmodified DMAB-PLGA-nanoparticles and free DMAB, such modifications led to a lower

  9. Improved insulin loading in poly(lactic-co-glycolic) acid (PLGA) nanoparticles upon self-assembly with lipids.

    PubMed

    García-Díaz, María; Foged, Camilla; Nielsen, Hanne Mørck

    2015-03-30

    Polymeric nanoparticles are widely investigated as drug delivery systems for oral administration. However, the hydrophobic nature of many polymers hampers effective loading of the particles with hydrophilic macromolecules such as insulin. Thus, the aim of this work was to improve the loading of insulin into poly(lactic-co-glycolic) acid (PLGA) nanoparticles by pre-assembly with amphiphilic lipids. Insulin was complexed with soybean phosphatidylcholine or sodium caprate by self-assembly and subsequently loaded into PLGA nanoparticles by using the double emulsion-solvent evaporation technique. The nanoparticles were characterized in terms of size, zeta potential, insulin encapsulation efficiency and loading capacity. Upon pre-assembly with lipids, there was an increased distribution of insulin into the organic phase of the emulsion, eventually resulting in significantly enhanced encapsulation efficiencies (90% as compared to 24% in the absence of lipids). Importantly, the insulin loading capacity was increased up to 20% by using the lipid-insulin complexes. The results further showed that a main fraction of the lipid was incorporated into the nanoparticles and remained associated to the polymer during release studies in buffers, whereas insulin was released in a non-complexed form as a burst of approximately 80% of the loaded insulin. In conclusion, the protein load in PLGA nanoparticles can be significantly increased by employing self-assembled protein-lipid complexes.

  10. Electrospun aligned PLGA and PLGA/gelatin nanofibers embedded with silica nanoparticles for tissue engineering.

    PubMed

    Mehrasa, Mohammad; Asadollahi, Mohammad Ali; Ghaedi, Kamran; Salehi, Hossein; Arpanaei, Ayyoob

    2015-08-01

    Aligned poly lactic-co-glycolic acid (PLGA) and PLGA/gelatin nanofibrous scaffolds embedded with mesoporous silica nanoparticles (MSNPs) were fabricated using electrospinning method. The mean diameters of nanofibers were 641±24 nm for the pure PLGA scaffolds vs 418±85 nm and 267±58 nm for the PLGA/10 wt% MSNPs and the PLGA/gelatin/10 wt% MSNPs scaffolds, respectively. The contact angle measurement results (102°±6.7 for the pure PLGA scaffold vs 81°±6.8 and 18°±8.7 for the PLGA/10 wt% MSNPs and the PLGA/gelatin/10 wt% MSNPs scaffolds, respectively) revealed enhanced hydrophilicity of scaffolds upon incorporation of gelatin and MSNPs. Besides, embedding the scaffolds with MSNPs resulted in improved tensile mechanical properties. Cultivation of PC12 cells on the scaffolds demonstrated that introduction of MSNPs into PLGA and PLGA/gelatin matrices leads to the improved cell attachment and proliferation as well as long cellular processes. DAPI staining results indicated that cell proliferations on the PLGA/10 wt% MSNPs and the PLGA/gelatin/10 wt% MSNPs scaffolds were strikingly (nearly 2.5 and 3 folds, respectively) higher than that on the aligned pure PLGA scaffolds. These results suggest superior properties of silica nanoparticles-incorporated PLGA/gelatin eletrospun nanofibrous scaffolds for the stem cell culture and tissue engineering applications.

  11. Covalently Linking Poly(Lactic-co-Glycolic Acid) Nanoparticles to Microbubbles Before Intravenous Injection Improves Their Ultrasound-Targeted Delivery to Skeletal Muscle

    PubMed Central

    Burke, Caitlin W.; Hsiang, Yu-Han J.; Alexander, Eben; Kilbanov, Alexander L.; Price, Richard J.

    2011-01-01

    Intravenously-injected nanoparticles can be delivered to skeletal muscle through capillary pores created by the activation of microbubbles with ultrasound; however, strategies that utilize co-injections of free microbubbles and nanoparticles are limited by nanoparticle dilution in the bloodstream. Here, we tested whether fluorescently-labeled (VT680; far-red fluorophore) nanoparticle [~150nm; poly(lactic-co-glycolic acid)] delivery to skeletal muscle can be improved by covalently linking them to albumin-shelled microbubbles in a composite agent formulation. Studies were performed using an experimental model of peripheral arterial disease, wherein the right and left femoral arteries of BalbC mice were surgically ligated. Four days after arterial ligation, composite agents, co-injected microbubbles and nanoparticles, or nanoparticles alone were administered intravenously and 1 MHz pulsed ultrasound was applied to the left hindlimb. Nanoparticle delivery was assessed at 0, 1, 4, and 24 hrs post-treatment by fluorescence-mediated tomography. Within the co-injection group, as expected, both microbubbles and ultrasound were required for nanoparticle delivery to skeletal muscle. Within the composite agent group, nanoparticle delivery was enhanced 8- to 18-fold over “no ultrasound” controls, depending on the time of measurement. A maximum of 7.2% of initial nanoparticle dose per gram tissue (ID/g) was delivered at 1 hr in the composite agent group, which was significantly greater than in the co-injection group (3.6% ID/g). We conclude that covalently linking 150 nm diameter poly(lactic-co-glycolic acid) nanoparticles to microbubbles before intravenous injection can improve their delivery to skeletal muscle. PMID:21456081

  12. Particulate Systems Based on Poly(Lactic-co-Glycolic)Acid (pLGA) for Immunotherapy of Cancer.

    PubMed

    Rahimian, Sima; Fransen, Marieke F; Kleinovink, Jan Willem; Amidi, Maryam; Ossendorp, Ferry; Hennink, Wim E

    2015-01-01

    Immunotherapy of cancer is a promising therapeutic approach which aims to eliminate malignancies by inducing or enhancing an immune response against the tumor. Immunotherapy, however, faces several challenges such as local immunosuppression in the tumor area leading to immunological tolerance. To overcome these challenges, particulate formulations such as nano- and microparticles containing immunotherapeutics have been developed to increase therapeutic efficacy and reduce toxicity of immunotherapy. Particulate formulations based on biodegradable aliphatic polyesters such as poly(lactic-co-glycolic acid) (pLGA) have been extensively used with promising results. In this review, we addressed the potential of pLGA-based particulate formulations for immunotherapy of cancer. The discussion was focused on cancer vaccines and delivery of immunomodulatory antibodies. Features and drawbacks of pLGA systems were discussed together with several examples of recently developed therapeutic cancer vaccines and antibody-loaded particulate systems. Various strategies to overcome the drawbacks and optimize the formulations were given. In conclusion, pLGA-based particulate systems are attractive carriers for development of clinically acceptable formulations in immunotherapy of cancer.

  13. Applications of Magnetic Microbubbles for Theranostics

    PubMed Central

    Cai, Xiaowei; Yang, Fang; Gu, Ning

    2012-01-01

    Compared with other diagnostic methods, ultrasound is proven to be a safe, simple, non-invasive and cost-effective imaging technique, but the resolution is not comparable to that of magnetic resonance imaging (MRI). Contrast-enhanced ultrasound employing microbubbles can gain a better resolution and is now widely used to diagnose a number of diseases in the clinic. For the last decade, microbubbles have been widely used as ultrasound contrast agents, drug delivery systems and nucleic acid transfection tools. However, microbubbles are not fairly stable enough in some conditions and are not well administrated distributed in the circulation system. On the other hand, magnetic nanoparticles, as MRI contrast agents, can non-specifically penetrate into normal tissues because of their relatively small sizes. By taking advantage of these two kinds of agents, the magnetic microbubbles which couple magnetic iron oxides nanoparticles in the microbubble structure have been explored. The stability of microbubbles can be raised by encapsulating magnetic nanoparticles into the bubble shells and with the guidance of magnetic field, magnetic microbubbles can be delivered to regions of interest, and after appropriate ultrasound exposure, the nanoparticles can be released to the desired area while the magnetic microbubbles collapse. In this review, we summarize magnetic microbubbles used in diagnostic and therapeutic fields, and predict the potential applications of magnetic microbubbles in the future. PMID:22287990

  14. Poly(Lactide-co-glycolide) ultrasonographic microbubbles carrying Sudan black for preoperative and intraoperative localization of lymph nodes.

    PubMed

    Niu, Chengcheng; Wang, Zhigang; Zuo, Guoqing; Krupka, Tianyi M; Ran, Haitao; Zhang, Ping; Li, Pan; Chen, Yu; Chen, Hangrong; Zheng, Yuanyi

    2012-06-01

    Lymph node (LN) examination plays a critical role in the staging and treatment of several kinds of cancer such as lesions of the breast. However current strategies have limitations. This study aimed to develop a novel imaging agent, a polymeric ultrasonographic contrast agent carrying Sudan black (SB), for ultrasonographic imaging of the regional LNs before surgery and to directly localize the LNs during surgery. The poly(lactide-co-glycolide) (PLGA) ultrasonographic microbubbles carrying Sudan black B (SB) (SB-PLGA microbubbles) were prepared by the double emulsion method. The SB-PLGA microbubbles had a diameter of 1.5 ± 0.5 μm and the SB encapsulation efficiency was (86.2 ± 1.56%). Results from MTT assays suggested that these bubbles have little cytotoxicity to mouse macrophages after incubation. Confocal laser scanning microscopy showed that the PLGA microbubbles carrying the fluorescent dye rhodamine 6G were taken up by macrophages after 2-hour incubation. In addition, these SB-PLGA microbubbles were able to enhance ultrasonographic contrast of 12 popliteal LNs of 6 rabbits. Furthermore, the LNs were easily identifiable by the naked eye during surgery because of the blue color of the SB-PLGA microbubbles inside the LNs. By cryosectioning and hematoxylin and eosin (H&E) staining of LN tissue, our results showed that these SB-PLGA microbubbles were internalized inside the macrophages of the LNs. To conclude, the SB-PLGA microbubbles could be a suitable imaging agent for preoperative and intraoperative localization of LNs as well as for a preoperative ultrasonographically guided core needle biopsy of suspicious sentinel lymph nodes (SLNs) in cancer patients, hence enhancing treatment outcome.

  15. Acid-Sensitive Sheddable PEGylated PLGA Nanoparticles Increase the Delivery of TNF-α siRNA in Chronic Inflammation Sites

    PubMed Central

    Aldayel, Abdulaziz M; Naguib, Youssef W; O'Mary, Hannah L; Li, Xu; Niu, Mengmeng; Ruwona, Tinashe B; Cui, Zhengrong

    2016-01-01

    There has been growing interest in utilizing small interfering RNA (siRNA) specific to pro-inflammatory cytokines, such as tumor necrosis factor-α ( TNF-α), in chronic inflammation therapy. However, delivery systems that can increase the distribution of the siRNA in chronic inflammation sites after intravenous administration are needed. Herein we report that innovative functionalization of the surface of siRNA-incorporated poly (lactic-co-glycolic) acid (PLGA) nanoparticles significantly increases the delivery of the siRNA in the chronic inflammation sites in a mouse model. The TNF-α siRNA incorporated PLGA nanoparticles were prepared by the standard double emulsion method, but using stearoyl-hydrazone-polyethylene glycol 2000, a unique acid-sensitive surface active agent, as the emulsifying agent, which renders (i) the nanoparticles PEGylated and (ii) the PEGylation sheddable in low pH environment such as that in chronic inflammation sites. In a mouse model of lipopolysaccharide-induced chronic inflammation, the acid-sensitive sheddable PEGylated PLGA nanoparticles showed significantly higher accumulation or distribution in chronic inflammation sites than PLGA nanoparticles prepared with an acid-insensitive emulsifying agent (i.e., stearoyl-amide-polyethylene glycol 2000) and significantly increased the distribution of the TNF-α siRNA incorporated into the nanoparticles in inflamed mouse foot. PMID:27434685

  16. Microspheres prepared with different co-polymers of poly(lactic-glycolic acid) (PLGA) or with chitosan cause distinct effects on macrophages.

    PubMed

    Bitencourt, Claudia da Silva; Silva, Letícia Bueno da; Pereira, Priscilla Aparecida Tartari; Gelfuso, Guilherme Martins; Faccioli, Lúcia Helena

    2015-12-01

    Microencapsulation of bioactive molecules for modulating the immune response during infectious or inflammatory events is a promising approach, since microspheres (MS) protect these labile biomolecules against fast degradation, prolong the delivery over longer periods of time and, in many situations, target their delivery to site of action, avoiding toxic side effects. Little is known, however, about the influence of different polymers used to prepare MS on macrophages. This paper aims to address this issue by evaluating in vitro cytotoxicity, phagocytosis profile and cytokines release from alveolar macrophages (J-774.1) treated with MS prepared with chitosan, and four different co-polymers of PLGA [poly (lactic-co-glycolic acid)]. The five MS prepared presented similar diameter and zeta potential each other. Chitosan-MS showed to be cytotoxic to J-774.1 cells, in contrast to PLGA-MS, which were all innocuous to this cell linage. PLGA 5000-MS was more efficiently phagocytized by macrophages compared to the other MS tested. PLGA 5000-MS and 5002-MS induced significant production of TNF-α, while 5000-MS, 5004-MS and 7502-MS decreased spontaneous IL-6 release. Nevertheless, only PLGA 5002-MS induced significant NFkB/SEAP activation. These findings together show that MS prepared with distinct PLGA co-polymers are differently recognized by macrophages, depending on proportion of lactic and glycolic acid in polymeric chain, and on molecular weight of the co-polymer used. Selection of the most adequate polymer to prepare a microparticulate drug delivery system to modulate immunologic system may take into account, therefore, which kind of immunomodulatory response is more adequate for the required treatment.

  17. Down-regulation of Th2 immune responses by sublingual administration of poly (lactic-co-glycolic) acid (PLGA)-encapsulated allergen in BALB/c mice.

    PubMed

    Salari, Farhad; Varasteh, Abdol-Reza; Vahedi, Fatemeh; Hashemi, Maryam; Sankian, Mojtaba

    2015-12-01

    The goal of this study was to investigate whether poly (lactic-co-glycolic) acid (PLGA) nanoparticles could enhance sublingual immunotherapy (SLIT) efficacy. BALB/c mice sensitized to rChe a 3 were treated sublingually either with soluble rChe a 3 (100μg/dose) or PLGA-encapsulated rChe a 3 (5, 25, or 50μg/dose). SLIT with PLGA-encapsulated rChe a 3 (equivalent to 25 and 50μg rChe a 3 per dose) led to significantly increased antigen-specific IgG2a, along with no effect on allergen-specific IgE and IgG1 antibody levels. In addition, interleukin 4 (IL-4) levels in restimulated splenocytes were significantly less, while interferon-γ (IFN-γ), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β) levels, as well as Foxp3 expression, were significantly greater than in the control groups. Our findings suggest that PLGA nanoparticle-based vaccination may help rational development of sublingual immunotherapy through reduction of the needed allergen doses and also significantly enhanced systemic T regulatory (Treg) and T helper 1 (Th1) immune responses.

  18. Lectin-Conjugated Clarithromycin and Acetohydroxamic Acid-Loaded PLGA Nanoparticles: a Novel Approach for Effective Treatment of H. pylori.

    PubMed

    Jain, Sunil K; Haider, Tanweer; Kumar, Amrish; Jain, Akhlesh

    2016-10-01

    Helicobacter pylori infection remains challenging as it mainly colonized beneath the deep gastric mucosa and adheres to epithelial cells of the stomach. Concanavalin-A (Con-A)-conjugated gastro-retentive poly (lactic-co-glycolic acid) (PLGA) nanoparticles of acetohydroxamic acid (AHA) and clarithromycin (CLR) were prepared and evaluated under in vitro conditions. Solvent evaporation method was employed for preparation of nanoparticles and characterized for particle size distribution, surface morphology, percent drug entrapment, and in vitro drug release in simulated gastric fluid. Optimized nanoparticles were conjugated with Con-A and further characterized for Con-A conjugation efficiency and mucoadhesion and tested for in vitro anti-H. pylori activity. The conjugation with Con-A further sustained the drug release over a period of 8 h when compared to non-conjugated nanoparticles of AHA and CLR. In vitro anti H. pylori study confirmed that Con-A-conjugated nanoparticles containing both drugs, i.e., CLR and AHA, had shown maximum zone of inhibition compared to other formulations. In a nut shell, results suggest that the developed systems could be used for better therapeutic activity against H. pylori infection.

  19. Immune activity and biodistribution of polypeptide K237 and folic acid conjugated amphiphilic PEG-PLGA copolymer nanoparticles radiolabeled with 99mTc

    PubMed Central

    Wu, Yufeng; Huang, Xuanzhang; Chen, Jie; Xia, Junyong; Jiang, Hao; Ma, Jing; Wu, Jian

    2016-01-01

    In a previous study, amphiphilic copolymer, polypeptide K237 (HTMYYHHYQHHL) and folic acid (FA) modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (K237/FA-PEG-PLGA) nanoparticles were developed and studied as a drug carrier. To further promote the clinical application of K237/FA-PEG-PLGA nanoparticles and provide guidance for future research, we need to examine their specific biodistribution in vivo. In this study, K237/FA-PEG-PLGA nanoparticles were effectively labeled by a direct method with Technetium-99m (99mTc) using stannous chloride as a reducing agent. The optimal stability of the labeled nanoparticles was determined by evaluating their radiochemical purity in serum, physiological saline, diethylenetriaminepentaacetic acid (DTPA) and cysteine solutions. The affinity of ligands and receptors was elicited by cell binding and blocking experiments in KDR/folate receptor high expressing SKOV-3 ovarian cancer cells. The nanoparticles biodistribution was studied after intravenous administration in healthy mice xenografted with SKOV-3 cells. A higher percent injected dose per gram of tissue (% ID/g) was observed in liver, kidney, spleen, blood and tumor at 3 and 9 h post-injection. Scintigraphic images revealed that the radioactivity was mainly concentrated in tumor, liver, kidney and bladder; and in the heart, lung, and muscle was significantly lower at 3 h. The radioactivity distribution in the images is consistent with the in vivo biodistribution data. Our works demonstrated that K237/FA-PEG-PLGA nanoparticles have great potential as biodegradable drug carriers, especially for tumors expressing the folate and KDr receptor. PMID:27791199

  20. Comparative evaluation of antibacterial activity of caffeic acid phenethyl ester and PLGA nanoparticle formulation by different methods

    NASA Astrophysics Data System (ADS)

    Arasoglu, Tülin; Derman, Serap; Mansuroglu, Banu

    2016-01-01

    The aim of the present study was to evaluate the antimicrobial activity of nanoparticle and free formulations of the CAPE compound using different methods and comparing the results in the literature for the first time. In parallel with this purpose, encapsulation of CAPE with the PLGA nanoparticle system (CAPE-PLGA-NPs) and characterization of nanoparticles were carried out. Afterwards, antimicrobial activity of free CAPE and CAPE-PLGA-NPs was determined using agar well diffusion, disk diffusion, broth microdilution and reduction percentage methods. P. aeroginosa, E. coli, S. aureus and methicillin-resistant S. aureus (MRSA) were chosen as model bacteria since they have different cell wall structures. CAPE-PLGA-NPs within the range of 214.0 ± 8.80 nm particle size and with an encapsulation efficiency of 91.59 ± 4.97% were prepared using the oil-in-water (o-w) single-emulsion solvent evaporation method. The microbiological results indicated that free CAPE did not have any antimicrobial activity in any of the applied methods whereas CAPE-PLGA-NPs had significant antimicrobial activity in both broth dilution and reduction percentage methods. CAPE-PLGA-NPs showed moderate antimicrobial activity against S. aureus and MRSA strains particularly in hourly measurements at 30.63 and 61.25 μg ml-1 concentrations (both p < 0.05), whereas they failed to show antimicrobial activity against Gram-negative bacteria (P. aeroginosa and E. coli, p > 0.05). In the reduction percentage method, in which the highest results of antimicrobial activity were obtained, it was observed that the antimicrobial effect on S. aureus was more long-standing (3 days) and higher in reduction percentage (over 90%). The appearance of antibacterial activity of CAPE-PLGA-NPs may be related to higher penetration into cells due to low solubility of free CAPE in the aqueous medium. Additionally, the biocompatible and biodegradable PLGA nanoparticles could be an alternative to solvents such as ethanol

  1. Comparative evaluation of antibacterial activity of caffeic acid phenethyl ester and PLGA nanoparticle formulation by different methods.

    PubMed

    Arasoglu, Tülin; Derman, Serap; Mansuroglu, Banu

    2016-01-15

    The aim of the present study was to evaluate the antimicrobial activity of nanoparticle and free formulations of the CAPE compound using different methods and comparing the results in the literature for the first time. In parallel with this purpose, encapsulation of CAPE with the PLGA nanoparticle system (CAPE-PLGA-NPs) and characterization of nanoparticles were carried out. Afterwards, antimicrobial activity of free CAPE and CAPE-PLGA-NPs was determined using agar well diffusion, disk diffusion, broth microdilution and reduction percentage methods. P. aeroginosa, E. coli, S. aureus and methicillin-resistant S. aureus (MRSA) were chosen as model bacteria since they have different cell wall structures. CAPE-PLGA-NPs within the range of 214.0 ± 8.80 nm particle size and with an encapsulation efficiency of 91.59 ± 4.97% were prepared using the oil-in-water (o-w) single-emulsion solvent evaporation method. The microbiological results indicated that free CAPE did not have any antimicrobial activity in any of the applied methods whereas CAPE-PLGA-NPs had significant antimicrobial activity in both broth dilution and reduction percentage methods. CAPE-PLGA-NPs showed moderate antimicrobial activity against S. aureus and MRSA strains particularly in hourly measurements at 30.63 and 61.25 μg ml(-1) concentrations (both p < 0.05), whereas they failed to show antimicrobial activity against Gram-negative bacteria (P. aeroginosa and E. coli, p > 0.05). In the reduction percentage method, in which the highest results of antimicrobial activity were obtained, it was observed that the antimicrobial effect on S. aureus was more long-standing (3 days) and higher in reduction percentage (over 90%). The appearance of antibacterial activity of CAPE-PLGA-NPs may be related to higher penetration into cells due to low solubility of free CAPE in the aqueous medium. Additionally, the biocompatible and biodegradable PLGA nanoparticles could be an alternative to solvents such as ethanol

  2. Development and characterization of sorafenib-loaded PLGA nanoparticles for the systemic treatment of liver fibrosis.

    PubMed

    Lin, Ts-Ting; Gao, Dong-Yu; Liu, Ya-Chi; Sung, Yun-Chieh; Wan, Dehui; Liu, Jia-Yu; Chiang, Tsaiyu; Wang, Liying; Chen, Yunching

    2016-01-10

    Sorafenib is a tyrosine kinase inhibitor that has recently been shown to be a potential antifibrotic agent. However, a narrow therapeutic window limits the clinical use and therapeutic efficacy of sorafenib. Herein, we have developed and optimized nanoparticle (NP) formulations prepared from a mixture of poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (PEG-PLGA) copolymers with poly(lactic-co-glycolic acid) (PLGA) for the systemic delivery of sorafenib into the fibrotic livers of CCl4-induced fibrosis mouse models. We characterized and compared the pharmaceutical and biological properties of two different PLGA nanoparticles (NPs)--PEG-PLGA NPs (PEG-PLGA/PLGA=10/0) and PEG-PLGA/PLGA NPs (PEG-PLGA/PLGA=5/5). Increasing the PLGA content in the PEG-PLGA/PLGA mixture led to increases in the particle size and drug encapsulation efficacy and a decrease in the drug release rate. Both PEG-PLGA and PEG-PLGA/PLGA NPs significantly prolonged the blood circulation of the cargo and increased the uptake by the fibrotic livers. The systemic administration of PEG-PLGA or PEG-PLGA/PLGA NPs containing sorafenib twice per week for a period of 4 weeks efficiently ameliorated liver fibrosis, as indicated by decreased α-smooth muscle actin (α-SMA) content and collagen production in the livers of CCl4-treated mice. Furthermore, sorafenib-loaded PLGA NPs significantly shrank the abnormal blood vessels and decreased microvascular density (MVD), leading to vessel normalization in the fibrotic livers. In conclusion, our results reflect the clinical potential of sorafenib-loaded PLGA NPs for the prevention and treatment of liver fibrosis.

  3. Surface Mechanical and Rheological Behaviors of Biocompatible Poly((D,L-lactic acid-ran-glycolic acid)-block-ethylene glycol) (PLGA-PEG) and Poly((D,L-lactic acid-ran-glycolic acid-ran-ε-caprolactone)-block-ethylene glycol) (PLGACL-PEG) Block Copolymers at the Air-Water Interface.

    PubMed

    Kim, Hyun Chang; Lee, Hoyoung; Khetan, Jawahar; Won, You-Yeon

    2015-12-29

    Air-water interfacial monolayers of poly((D,L-lactic acid-ran-glycolic acid)-block-ethylene glycol) (PLGA-PEG) exhibit an exponential increase in surface pressure under high monolayer compression. In order to understand the molecular origin of this behavior, a combined experimental and theoretical investigation (including surface pressure-area isotherm, X-ray reflectivity (XR) and interfacial rheological measurements, and a self-consistent field (SCF) theoretical analysis) was performed on air-water monolayers formed by a PLGA-PEG diblock copolymer and also by a nonglassy analogue of this diblock copolymer, poly((D,L-lactic acid-ran-glycolic acid-ran-caprolactone)-block-ethylene glycol) (PLGACL-PEG). The combined results of this study show that the two mechanisms, i.e., the glass transition of the collapsed PLGA film and the lateral repulsion of the PEG brush chains that occur simultaneously under lateral compression of the monolayer, are both responsible for the observed PLGA-PEG isotherm behavior. Upon cessation of compression, the high surface pressure of the PLGA-PEG monolayer typically relaxes over time with a stretched exponential decay, suggesting that in this diblock copolymer situation, the hydrophobic domain formed by the PLGA blocks undergoes glass transition in the high lateral compression state, analogously to the PLGA homopolymer monolayer. In the high PEG grafting density regime, the contribution of the PEG brush chains to the high monolayer surface pressure is significantly lower than what is predicted by the SCF model because of the many-body attraction among PEG segments (referred to in the literature as the "n-cluster" effects). The end-grafted PEG chains were found to be protein resistant even under the influence of the "n-cluster" effects.

  4. Biodistribution of PLGA and PLGA/chitosan nanoparticles after repeat-dose oral delivery in F344 rats for 7 days

    PubMed Central

    Navarro, Sara M; Darensbourg, Caleb; Cross, Linda; Stout, Rhett; Coulon, Diana; Astete, Carlos E; Morgan, Timothy; Sabliov, Cristina M

    2015-01-01

    Aim To quantify in vivo the biodistribution of poly(lactic-co-glycolic) acid (PLGA) and PLGA/chitosan nanoparticles (PLGA/Chi NPs) and assess if the positive charge of chitosan significantly enhances nanoparticle absorption in the GI tract. Material & methods PLGA and PLGA/Chi NPs covalently linked to tetramethylrhodamine-5-isothiocyanate (TRITC) were orally administered to F344 rats for 7 days, and the biodistribution of fluorescent NPs was analyzed in different organs. Results The highest amount of particles (% total dose/g) was detected for both treatments in the spleen, followed by intestine and kidney, and then by liver, lung, heart and brain, with no significant difference between PLGA and PLGA/Chi NPs. Conclusion Only a small percentage of orally delivered NPs was detected in the analyzed organs. The positive charge conferred by chitosan was not sufficient to improve the absorption of the PLGA/Chi NPs over that of PLGA NPs. PMID:25491670

  5. A novel cationic microbubble coated with stearic acid-modified polyethylenimine to enhance DNA loading and gene delivery by ultrasound.

    PubMed

    Jin, Qiaofeng; Wang, Zhiyong; Yan, Fei; Deng, Zhiting; Ni, Fei; Wu, Junru; Shandas, Robin; Liu, Xin; Zheng, Hairong

    2013-01-01

    A novel cationic microbubble (MB) for improvement of the DNA loading capacity and the ultrasound-mediated gene delivery efficiency has been developed; it has been prepared with commercial lipids and a stearic acid modified polyethylenimine 600 (Stearic-PEI600) polymer synthesized via acylation reaction of branched PEI600 and stearic acid mediated by N, N'-carbonyldiimidazole (CDI). The MBs' concentration, size distribution, stability and zeta potential (ζ-potential) were measured and the DNA loading capacity was examined as a function of the amount of Stearic-PEI600. The gene transfection efficiency and cytotoxicity were also examined using breast cancer MCF-7 cells via the reporter plasmid pCMV-Luc, encoding the firefly luciferase gene. The results showed that the Stearic-PEI600 polymer caused a significant increase in magnitude of ζ-potential of MBs. The addition of DNA into cationic MBs can shift ζ-potentials from positive to negative values. The DNA loading capacity of the MBs grew linearly from (5±0.2) ×10⁻³ pg/µm² to (20±1.8) ×10⁻³ pg/µm² when Stearic-PEI600 was increased from 5 mol% to 30 mol%. Transfection of MCF-7 cells using 5% PEI600 MBs plus ultrasound exposure yielded 5.76±2.58×10³ p/s/cm²/sr average radiance intensity, was 8.97- and 7.53-fold higher than those treated with plain MBs plus ultrasound (6.41±5.82) ×10² p/s/cm²/sr, (P<0.01) and PEI600 MBs without ultrasound (7.65±6.18) ×10² p/s/cm²/sr, (P<0.01), respectively. However, the PEI600 MBs showed slightly higher cytotoxicity than plain MBs. The cells treated with PEI600-MBs and plain MBs plus ultrasound showed 59.5±6.1% and 71.4±7.1% cell viability, respectively. In conclusion, our study demonstrated that the novel cationic MBs were able to increase DNA loading capacity and gene transfection efficiency and could be potentially applied in targeted gene delivery and therapy.

  6. Hemocompatibility of folic-acid-conjugated amphiphilic PEG-PLGA copolymer nanoparticles for co-delivery of cisplatin and paclitaxel: treatment effects for non-small-cell lung cancer.

    PubMed

    He, Zelai; Shi, Zengfang; Sun, Wenjie; Ma, Jing; Xia, Junyong; Zhang, Xiangyu; Chen, Wenjun; Huang, Jingwen

    2016-06-01

    In this study, we used folic-acid-modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (FA-PEG-PLGA) to encapsulate cisplatin and paclitaxel (separately or together), and evaluated their antitumor effects against lung cancer; this study was conducted in order to investigate the antitumor effects of the co-delivery of cisplatin and paclitaxel by a targeted drug delivery system. Blood compatibility assays and complement activation tests revealed that FA-PEG-PLGA nanoparticles did not induce blood hemolysis, blood clotting, or complement activation. The results also indicated that FA-PEG-PLGA nanoparticles had no biotoxic effects, the drug delivery system allowed controlled release of the cargo molecules, and the co-delivery of cisplatin and paclitaxel efficiently induces cancer cell apoptosis and cell cycle retardation. In addition, co-delivery of cisplatin and paclitaxel showed the ability to suppress xenograft lung cancer growth and prolong the survival time of xenografted mice. These results implied that FA-PEG-PLGA nanoparticles can function as effective carriers of cisplatin and paclitaxel, and that co-delivery of cisplatin and paclitaxel by FA-PEG-PLGA nanoparticles results in more effective antitumor effects than the combination of free-drugs or single-drug-loaded nanoparticles.

  7. Humidity-dependent compression-induced glass transition of the air–water interfacial Langmuir films of poly(D,L-lactic acid-ran-glycolic acid) (PLGA)

    SciTech Connect

    Kim, Hyun Chang; Lee, Hoyoung; Jung, Hyunjung; Choi, Yun -Hwa; Meron, Mati; Lin, Binhua; Bang, Joona; Won, You -Yeon

    2015-08-26

    Constant rate compression isotherms of the air–water interfacial Langmuir films of poly(D,L-lactic acid-ran-glycolic acid) (PLGA)show a distinct feature of an exponential increase in surface pressure in the high surface polymer concentration regime. We have previously demonstrated that this abrupt increase in surface pressure is linked to the glass transition of the polymer film, but the detailed mechanism of this process is not understood. In order to obtain a molecular-level understanding of this behavior, we performed extensive characterizations of the surface mechanical, structural and rheological properties of Langmuir PLGA films at the air–water interface, using combined experimental techniques including the Langmuir film balance, X-ray reflectivity and double-wall-ring interfacial rheometry methods.

  8. Inertial cavitation threshold of nested microbubbles.

    PubMed

    Wallace, N; Dicker, S; Lewin, Peter; Wrenn, S P

    2015-04-01

    Cavitation of ultrasound contrast agents (UCAs) promotes both beneficial and detrimental bioeffects in vivo (Radhakrishnan et al., 2013) [1]. The ability to determine the inertial cavitation threshold of UCA microbubbles has potential application in contrast imaging, development of therapeutic agents, and evaluation of localized effects on the body (Ammi et al., 2006) [2]. This study evaluates a novel UCA and its inertial cavitation behavior as determined by a home built cavitation detection system. Two 2.25 MHz transducers are placed at a 90° angle to one another where one transducer is driven by a high voltage pulser and the other transducer receives the signal from the oscillating microbubble. The sample chamber is placed in the overlap of the focal region of the two transducers where the microbubbles are exposed to a pulser signal consisting of 600 pulse trains per experiment at a pulse repetition frequency of 5 Hz where each train has four pulses of four cycles. The formulation being analyzed is comprised of an SF6 microbubble coated by a DSPC PEG-3000 monolayer nested within a poly-lactic acid (PLA) spherical shell. The effect of varying shell diameters and microbubble concentration on cavitation threshold profile for peak negative pressures ranging from 50 kPa to 2 MPa are presented and discussed in this paper. The nesting shell decreases inertial cavitation events from 97.96% for an un-nested microbubble to 19.09% for the same microbubbles nested within a 2.53 μm shell. As shell diameter decreases, the percentage of inertially cavitating microbubbles also decreases. For nesting formulations with average outer capsule diameters of 20.52, 14.95, 9.95, 5.55, 2.53, and 1.95 μm, the percentage of sample destroyed at 1 MPa was 51.02, 38.94, 33.25, 25.27, 19.09, and 5.37% respectively.

  9. ICG-loaded microbubbles for multimodal billiary imaging in cholecystectomy

    NASA Astrophysics Data System (ADS)

    Qin, Ruogu; Melvin, Scott; Xu, Ronald X.

    2012-12-01

    A dual-mode imaging technique has been developed for intraoperative imaging of bile ducts and real-time identification of iatrogenic injuries in cholecystectomy. The technique is based on ultrasound (US) and fluorescence (FL) imaging of a dual-mode microbubble (MB) agent comprising a poly (lactic-co-glycolic acid) (PLGA) shell and a core of Indocyanine Green. During cholecystectomy, a clinical US probe is used to localize the bile duct structure after bolus injection of dual-mode MBs. As the surrounding adipose tissue is removed and the Calot's triangle is exposed, FL imaging is used to identify the MB distribution and to determine the potential bile duct injury. The contrast-enhanced bile duct imaging technique has been demonstrated in both a surgical simulation model and an ex vivo porcine tissue model under two surgical scenarios. The first scenario simulates the correct procedure where the cystic duct is clipped. The second scenario simulates the incorrect procedure where the common bile duct is clipped, leading to consequent bile duct injury. Benchtop experiments in both the phantom and the ex vivo models show that the dual-mode imaging technique is able to identify the potential bile duct injury during cholecystectomy. A phantom system has also been established for future device calibration and surgical training in image-guided cholecystectomy. Further in vivo animal validation tests are necessary before the technique can be implemented in a clinical setting.

  10. PLGA/alginate composite microspheres for hydrophilic protein delivery.

    PubMed

    Zhai, Peng; Chen, X B; Schreyer, David J

    2015-11-01

    Poly(lactic-co-glycolic acid) (PLGA) microspheres and PLGA/alginate composite microspheres were prepared by a novel double emulsion and solvent evaporation technique and loaded with bovine serum albumin (BSA) or rabbit anti-laminin antibody protein. The addition of alginate and the use of a surfactant during microsphere preparation increased the encapsulation efficiency and reduced the initial burst release of hydrophilic BSA. Confocal laser scanning microcopy (CLSM) of BSA-loaded PLGA/alginate composite microspheres showed that PLGA, alginate, and BSA were distributed throughout the depths of microspheres; no core/shell structure was observed. Scanning electron microscopy revealed that PLGA microspheres erode and degrade more quickly than PLGA/alginate composite microspheres. When loaded with anti-laminin antibody, the function of released antibody was well preserved in both PLGA and PLGA/alginate composite microspheres. The biocompatibility of PLGA and PLGA/alginate microspheres were examined using four types of cultured cell lines, representing different tissue types. Cell survival was variably affected by the inclusion of alginate in composite microspheres, possibly due to the sensitivity of different cell types to excess calcium that may be released from the calcium cross-linked alginate.

  11. Microbubbles Reforming Endothelium

    NASA Astrophysics Data System (ADS)

    van Wamel, Annemieke; Kooiman, Klazina; Harteveld, Miranda; Emmer, Marcia; ten Cate, Folkert J.; Versluis, Michel; de Jong, Nico

    2006-05-01

    Ultrasound contrast microbubbles have the ability to enhance cell permeability and thus may be used as a new way to deliver drugs inter-vascular. It facilitates the transfer of extracellular molecules into cells through ultrasound-activated microbubbles. The present study is designed to correlate the relationship between microbubble induced cell deformation and enhanced cell membrane permeability. Propidium Iodide was used as a membrane integrity probe. Using high-speed imaging of vibrating microbubbles against endothelial cells and imaging transport of Propidium Iodide into these cells showed a direct correlation between cell deformation and resulting cell membrane permeability. The membrane permeabilization lasted for a short period without affecting aortic endothelial cells viability. We identified that microbubbles are crucial to enhance transient cell membrane permeability.

  12. PEG-b-PLA micelles and PLGA-b-PEG-b-PLGA sol-gels for drug delivery.

    PubMed

    Cho, Hyunah; Gao, Jieming; Kwon, Glen S

    2016-10-28

    Poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) micelles and poly(D,L-lactic-co-glycolic acid)-block-polyethylene glycol)-block-poly(D,L-lactic-co-glycolic acid) (PLGA-b-PEG-b-PLGA) sol-gels have been extensively researched for systemic and localized drug delivery applications, respectively, and they have both progressed into humans for paclitaxel, an important yet poorly water-soluble chemotherapeutic agent. In this review article, preclinical and clinical research on PEG-b-PLA micelles and PLGA-b-PEG-b-PLGA sol-gels that has focused on paclitaxel will be updated, and recent research on other poorly water-soluble anticancer agents and delivery of drug combinations (i.e. multi-drug delivery) that seeks synergistic anticancer efficacy will be summarized. PEG-b-PLA micelles are a first-generation platform for the systemic multi-delivery of poorly water soluble anticancer agents. PLGA-b-PEG-b-PLGA sol-gels are a first-generation platform for the localized multi-drug delivery of water-soluble and/or poorly water-soluble anticancer agents. In summary, PEG-b-PLA micelles and PLGA-b-PEG-b-PLGA sol-gels may safely enable pre-clinical evaluation and clinical translation of poorly water-soluble anticancer agents, especially for promising, rapidly emerging anticancer combinations.

  13. Tailoring magnetic PLGA nanoparticles suitable for doxorubicin delivery

    NASA Astrophysics Data System (ADS)

    Tansık, Gülistan; Yakar, Arzu; Gündüz, Ufuk

    2014-01-01

    One of the main problems of current cancer chemotherapy is the lack of selectivity of anti-cancer drugs to tumor cells, which leads to systemic toxicity and adverse side effects. In order to overcome these limitations, researches on controlled drug delivery systems have gained much attention. Nanoscale-based drug delivery systems provide tumor targeting. Among many types of nanocarriers, superparamagnetic nanoparticles with their biocompatible polymer coatings can be targeted to an intented site by an external magnetic field. Thus, the drug can be carried to the targeted site safely. The aim of this study is to prepare poly( dl-lactic- co-glycolic acid) (PLGA)-coated magnetic nanoparticles and load anti-cancer drug, doxorubicin to them. For this purpose, magnetite (Fe3O4) iron oxide nanoparticles were synthesized as a magnetic core material (MNP) and then coated with oleic acid. Oleic acid-coated MNP (OA-MNP) was encapsulated into PLGA. Effects of different OA-MNP/PLGA ratios on magnetite entrapment efficiency were investigated. Doxorubicin-loaded magnetic polymeric nanoparticles (DOX-PLGA-MNP) were prepared. After the characterization of prepared nanoparticles, their cytotoxic effects on MCF-7 cell line were studied. PLGA-coated magnetic nanoparticles (PLGA-MNP) had a proper size and superparamagnetic character. The highest magnetite entrapment efficiency of PLGA-MNP was estimated as 63 % at 1:8 ratio. Cytotoxicity studies of PLGA-MNP did not indicate any notable cell death between the concentration ranges of 2 and 125 μg/ml. Drug loading efficiency was estimated as 32 %, and it was observed that DOX-PLGA-MNP showed significant cytotoxicity on MCF-7 cells compared to PLGA-MNP. The results showed that prepared nanoparticles have desired size and superparamagnetic characteristics without serious toxic effects on cells. These nanoparticles may be suitable for targeted drug delivery applications.

  14. Mesenchymal stem cells attenuated PLGA-induced inflammatory responses by inhibiting host DC maturation and function.

    PubMed

    Zhu, Heng; Yang, Fei; Tang, Bo; Li, Xi-Mei; Chu, Ya-Nan; Liu, Yuan-Lin; Wang, Shen-Guo; Wu, De-Cheng; Zhang, Yi

    2015-01-01

    The poly lactic-co-glycolic acid (PLGA) bio-scaffold is a biodegradable scaffold commonly used for tissue repair. However, implanted PLGA scaffolds usually cause serious inflammatory responses around grafts. To improve PLGA scaffold-based tissue repair, it is important to control the PLGA-mediated inflammatory responses. Recent evidence indicated that PLGA induce dendritic cell (DC) maturation in vitro, which may initiate host immune responses. In the present study, we explored the modulatory effects of mesenchymal stem cells (MSC) on PLGA-induced DCs (PLGA-DC). We found that mouse MSCs inhibited PLGA-DC dendrite formation, as well as co-stimulatory molecule and pro-inflammatory factor expression. Functionally, MSC-educated PLGA-DCs promoted Th2 and regulatory T cell differentiation but suppressed Th1 and Th17 cell differentiation. Mechanistically, we determined that PLGA elicited DC maturation via inducing phosphorylation of p38/MAPK and ERK/MAPK pathway proteins in DCs. Moreover, MSCs suppressed PLGA-DCs by partially inactivating those pathways. Most importantly, we found that the MSCs were capable of suppressing DC maturation and immune function in vivo. Also, the proportion of mature DCs in the mice that received MSC-PLGA constructs greatly decreased compared with that of their PLGA-film implantation counterparts. Additionally, MSCs co-delivery increased regulatory T and Th2 cells but decreased the Th1 and Th17 cell numbers in the host spleens. Histological analysis showed that MSCs alleviated the inflammatory responses around the grafted PLGA scaffolds. In summary, our findings reveal a novel function for MSCs in suppressing PLGA-induced host inflammatory response and suggest that DCs are a new cellular target in improving PLGA scaffold-based tissue repair.

  15. An HPLC method for microanalysis and pharmacokinetics of marine sulfated polysaccharide PSS-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles in rat plasma.

    PubMed

    Li, Peng-Li; Li, Chun-Xia; Xue, Yi-Ting; Li, Hai-Hua; Liu, Hong-Bing; He, Xiao-Xi; Yu, Guang-Li; Guan, Hua-Shi

    2013-04-02

    This study was aimed at developing a sensitive and selective HPLC method with postcolumn fluorescence derivatization for the detection of propylene glycol alginate sodium sulfate (PSS) in rat plasma. Plasma samples were prepared by a simple and fast ultrafiltration method. PSS was extracted from rat plasma with D-glucuronic acid as internal standard. Isocratic chromatographic separation was performed on a TSKgel G2500 PWxL column with the mobile phase of 0.1 M sodium sulfate at a flow rate of 0.5 mL/min. Analyte detection was achieved by fluorescence detection (FLD) at 250 nm (excitation) and 435 nm (emission) using guanidine hydrochloride as postcolumn derivatizing reagent in an alkaline medium at 120 °C. The calibration curve was linear over a concentration range of 1-500 μg/mL, and the lower limit of detection (LLOD) was found to be 250 ng/mL. This validated method was applied successfully to the pharmacokinetic study of PSS and PSS-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles (PSS-NP) in rat plasma after a single intravenous (PSS only) and oral administration (PSS and PSS-NP). Significant differences in the main pharmacokinetic parameters of PSS and PSS-NP were observed. The relative bioavailability of PSS-NP was 190.10% compared with PSS which shows that PSS-NP can improve oral bioavailability.

  16. An HPLC Method for Microanalysis and Pharmacokinetics of Marine Sulfated Polysaccharide PSS-Loaded Poly Lactic-co-Glycolic Acid (PLGA) Nanoparticles in Rat Plasma

    PubMed Central

    Li, Peng-Li; Li, Chun-Xia; Xue, Yi-Ting; Li, Hai-Hua; Liu, Hong-Bing; He, Xiao-Xi; Yu, Guang-Li; Guan, Hua-Shi

    2013-01-01

    This study was aimed at developing a sensitive and selective HPLC method with postcolumn fluorescence derivatization for the detection of propylene glycol alginate sodium sulfate (PSS) in rat plasma. Plasma samples were prepared by a simple and fast ultrafiltration method. PSS was extracted from rat plasma with d-glucuronic acid as internal standard. Isocratic chromatographic separation was performed on a TSKgel G2500 PWxL column with the mobile phase of 0.1 M sodium sulfate at a flow rate of 0.5 mL/min. Analyte detection was achieved by fluorescence detection (FLD) at 250 nm (excitation) and 435 nm (emission) using guanidine hydrochloride as postcolumn derivatizing reagent in an alkaline medium at 120 °C. The calibration curve was linear over a concentration range of 1–500 μg/mL, and the lower limit of detection (LLOD) was found to be 250 ng/mL. This validated method was applied successfully to the pharmacokinetic study of PSS and PSS-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles (PSS-NP) in rat plasma after a single intravenous (PSS only) and oral administration (PSS and PSS-NP). Significant differences in the main pharmacokinetic parameters of PSS and PSS-NP were observed. The relative bioavailability of PSS-NP was 190.10% compared with PSS which shows that PSS-NP can improve oral bioavailability. PMID:23549283

  17. Co-delivery of cisplatin and paclitaxel by folic acid conjugated amphiphilic PEG-PLGA copolymer nanoparticles for the treatment of non-small lung cancer

    PubMed Central

    He, Zelai; Huang, Jingwen; Xu, Yuanyuan; Zhang, Xiangyu; Teng, Yanwei; Huang, Can; Wu, Yufeng; Zhang, Xi; Zhang, Huijun; Sun, Wenjie

    2015-01-01

    An amphiphilic copolymer, folic acid (FA) modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (FA-PEG-PLGA) was prepared and explored as a nanometer carrier for the co-delivery of cisplatin (cis-diaminodichloroplatinum, CDDP) and paclitaxel (PTX). CDDP and PTX were encapsulated inside the hydrophobic inner core and chelated to the middle shell, respectively. PEG provided the outer corona for prolonged circulation. An in vitro release profile of the CDDP + PTX-encapsulated nanoparticles revealed that the PTX chelation cross-link prevented an initial burst release of CDDP. After an incubation period of 24 hours, the CDDP+PTX-encapsulated nanoparticles exhibited a highly synergistic effect for the inhibition of A549 (FA receptor negative) and M109 (FA receptor positive) lung cancer cell line proliferation. Pharmacokinetic experiment and distribution research shows that nanoparticles have longer circulation time in the blood and can prolong the treatment times of chemotherapeutic drugs. For the in vivo treatment of A549 cells xeno-graft lung tumor, the CDDP+PTX-encapsulated nanoparticles displayed an obvious tumor inhibiting effect with an 89.96% tumor suppression rate (TSR). This TSR was significantly higher than that of free chemotherapy drug combination or nanoparticles with a single drug. For M109 cells xeno-graft tumor, the TSR was 95.03%. In vitro and in vivo experiments have all shown that the CDDP+PTX-encapsulated nanoparticles have better targeting and antitumor effects in M109 cells than CDDP+PTX-loaded PEG-PLGA nanoparticles (p < 0.05). In addition, more importantly, the enhanced anti-tumor efficacy of the CDDP+PTX-encapsulated nanoparticles came with reduced side-effects. No obvious body weight loss or functional changes occurred within blood components, liver, or kidneys during the treatment of A549 and M109 tumor-bearing mice with the CDDP+PTX-encapsulated nanoparticles. Thus, the FA modified amphiphilic copolymer-based combination of CDDP and

  18. Enhanced ozonation of simulated dyestuff wastewater by microbubbles.

    PubMed

    Chu, Li-Bing; Xing, Xin-Hui; Yu, An-Feng; Zhou, Yu-Nan; Sun, Xu-Lin; Jurcik, Benjamin

    2007-08-01

    The ozonation of synthetic wastewater containing azo dye, CI Reactive Black 5, was investigated using a microbubble generator and a conventional bubble contactor. The microbubble generator produced a milky and high intensity microbubble solution in which the bubbles had a mean diameter of less than 58 microm and a numerical density of more than 2.9 x 10(4) counts ml(-1) at a gas flow rate of less than 0.5 l min(-1). Compared with the bubble contactor, the total mass transfer coefficient was 1.8 times higher and the pseudo-first order rate constant was 3.2-3.6 times higher at the same initial dye concentration of 100 mg l(-1), 230 mg l(-1) and 530 mg l(-1) in the proposed microbubble system. The amount of total organic carbon removed per g of ozone consumed was about 1.3 times higher in the microbubble system than in the bubble contactor. The test using terephthalic acid as the chemical probe implied that more hydroxyl radicals were produced in the microbubble system, which contributed to the degradation of the dye molecules. The results suggested that in addition to the enhancement of mass transfer, microbubbles, which had higher inner pressure, could accelerate the formation of hydroxyl radicals and hence improve the oxidation of dye molecules.

  19. Hyaluronic acid-decorated dual responsive nanoparticles of Pluronic F127, PLGA, and chitosan for targeted co-delivery of doxorubicin and irinotecan to eliminate cancer stem-like cells

    PubMed Central

    Wang, Hai; Agarwal, Pranay; Zhao, Shuting; Xu, Ronald X.; Yu, Jianhua; Lu, Xiongbin; He, Xiaoming

    2016-01-01

    Dual responsive nanoparticles are developed for co-delivery of multiple anticancer drugs to target the drug resistance mechanisms of cancer stem-like cells (CSCs). The nanoparticles consist of four polymers approved by the Food and Drug Administration (FDA) for medical use: Poly(D,L-lactide-co-glycolide) (PLGA), Pluronic F127 (PF127), chitosan, and hyaluronic acid (HA). By combining PLGA and PF127 together, more stable and uniform-sized nanoparticles can be obtained than using PLGA or PF127 alone. The HA is used for not only actively targeting CSCs to reduce their drug resistance due to dormancy (i.e., slow metabolism), but also replacing the commonly used poly(vinyl alcohol) as a stabilizing agent to synthesize the nanoparticles using the double-emulsion approach and to allow for acidic pH-triggered drug release and thermal responsiveness. Besides minimizing drug efflux from CSCs, the nanoparticles encapsulated with doxorubicin hydrochloride (DOX, hydrophilic) and irinotecan (CPT, hydrophobic) to inhibit the activity of topoisomerases II and I, respectively, can fight against the CSC drug resistance associated with their enhanced DNA repair and anti-apoptosis. Ultimately, the two drugs-laden nanoparticles can be used to efficiently destroy the CSCs both in vitro and in vivo with up to ~500 times of enhancement compared to the simple mixture of the two drugs. PMID:26344365

  20. PEGylated apoptotic protein-loaded PLGA microspheres for cancer therapy

    PubMed Central

    Byeon, Hyeong Jun; Kim, Insoo; Choi, Ji Su; Lee, Eun Seong; Shin, Beom Soo; Youn, Yu Seok

    2015-01-01

    The aim of the current study was to investigate the antitumor potential of poly (D,L-lactic-co-glycolic acid) microspheres (PLGA MSs) containing polyethylene glycol (PEG)-conjugated (PEGylated) tumor necrosis factor–related apoptosis-inducing ligand (PEG-TRAIL). PEG-TRAIL PLGA MSs were prepared by using a water-in-oil-in-water double-emulsion method, and the apoptotic activities of supernatants released from the PLGA MSs at days 1, 3, and 7 were examined. The antitumor effect caused by PEG-TRAIL PLGA MSs was evaluated in pancreatic Mia Paca-2 cell-xenografted mice. PEG-TRAIL PLGA MS was found to be spherical and 14.4±1.06 μm in size, and its encapsulation efficiency was significantly greater than that of TRAIL MS (85.7%±4.1% vs 43.3%±10.9%, respectively). The PLGA MS gradually released PEG-TRAIL for 14 days, and the released PEG-TRAIL was shown to have clear apoptotic activity in Mia Paca-2 cells, whereas TRAIL released after 1 day had a negligible activity. Finally, PEG-TRAIL PLGA MS displayed remarkably greater antitumor efficacy than blank or TRAIL PLGA MS in Mia Paca-2 cell-xenografted mice in terms of tumor volume and weight, apparently due to increased stability and well-retained apoptotic activity of PEG-TRAIL in PLGA MS. We believe that this PLGA MS system, combined with PEG-TRAIL, should be considered a promising candidate for treating pancreatic cancer. PMID:25632232

  1. PEGylated apoptotic protein-loaded PLGA microspheres for cancer therapy.

    PubMed

    Byeon, Hyeong Jun; Kim, Insoo; Choi, Ji Su; Lee, Eun Seong; Shin, Beom Soo; Youn, Yu Seok

    2015-01-01

    The aim of the current study was to investigate the antitumor potential of poly (D,L-lactic-co-glycolic acid) microspheres (PLGA MSs) containing polyethylene glycol (PEG)-conjugated (PEGylated) tumor necrosis factor-related apoptosis-inducing ligand (PEG-TRAIL). PEG-TRAIL PLGA MSs were prepared by using a water-in-oil-in-water double-emulsion method, and the apoptotic activities of supernatants released from the PLGA MSs at days 1, 3, and 7 were examined. The antitumor effect caused by PEG-TRAIL PLGA MSs was evaluated in pancreatic Mia Paca-2 cell-xenografted mice. PEG-TRAIL PLGA MS was found to be spherical and 14.4±1.06 μm in size, and its encapsulation efficiency was significantly greater than that of TRAIL MS (85.7%±4.1% vs 43.3%±10.9%, respectively). The PLGA MS gradually released PEG-TRAIL for 14 days, and the released PEG-TRAIL was shown to have clear apoptotic activity in Mia Paca-2 cells, whereas TRAIL released after 1 day had a negligible activity. Finally, PEG-TRAIL PLGA MS displayed remarkably greater antitumor efficacy than blank or TRAIL PLGA MS in Mia Paca-2 cell-xenografted mice in terms of tumor volume and weight, apparently due to increased stability and well-retained apoptotic activity of PEG-TRAIL in PLGA MS. We believe that this PLGA MS system, combined with PEG-TRAIL, should be considered a promising candidate for treating pancreatic cancer.

  2. Radiolabeling of Poly(lactic-co-glycolic acid) (PLGA) Nanoparticles with Biotinylated F-18 Prosthetic Groups and Imaging of Their Delivery to the Brain with Positron Emission Tomography

    PubMed Central

    2015-01-01

    The avidin–biotin interaction permits rapid and nearly irreversible noncovalent linkage between biotinylated molecules and avidin-modified substrates. We designed a biotinylated radioligand intended for use in the detection of avidin-modified polymer nanoparticles in tissue with positron emission tomography (PET). Using an F-18 labeled prosthetic group, [18F]4-fluorobenzylamine, and a commercially available biotin derivate, NHS-PEG4-biotin, [18F]-fluorobenzylamide-poly(ethylene glycol)4-biotin ([18F]NPB4) was prepared with high purity and specific activity. The attachment of the [18F]NPB4 radioligand to avidin-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles was tested by using PET imaging to measure the kinetics of convection-enhanced delivery (CED) of nanoparticles of varying size to the rat brain. PET imaging enabled the direct observation of nanoparticle delivery by measurement of the spatial volume of distribution of radiolabeled nanoparticles as a function of time, both during and after the infusion. This work thus validates new methods for radiolabeling PEG-biotin derivatives and also provides insight into the fate of nanoparticles that have been infused directly into the brain. PMID:25322194

  3. [Experimental study on application recombinant human bone morphogenetic protein 2(rhBMP-2)/poly-lactide-co-glycolic acid (PLGA)/fibrin sealant(FS) on repair of rabbit radial bone defect].

    PubMed

    Fan, Zhongkai; Cao, Yang; Zhang, Zhe; Zhang, Mingchao; Lu, Wei; Tang, Lei; Yao, Qi; Lu, Gang

    2012-10-01

    This paper is aimed to investigate the repair of rabbit radial bone defect by the recombinant human bone morphogenetic protein 2/poly-lactideco-glycolic acid microsphere with fibrin sealant (rhBMP-2/PLGA/FS). The radial bone defect models were prepared using New Zealand white rabbits, which were randomly divided into 3 groups, experiment group which were injected with eMP-2/PLGA/FS at bone defect location, control group which were injected with FS at bone defect location, and blank control group without treatment. The ability of repairing bone defect was evaluated with X-ray radiograph. Bone mineral density in the defect regions was analysed using the level of ossification. The osteogenetic ability of repairing bone defect, the degradation of the material, the morphologic change and the bone formation were assessed by HE staining and Masson staining. The result showed that rhBMP-2/PLGA/FS had overwhelming superiority in the osteogenetic ability and quality of bone defect over the control group, and it could promote the repair of bone defect and could especially repair the radial bone defect of rabbit well. It may be a promising and efficient synthetic bone graft.

  4. Polypyrrole-Coated Electrospun PLGA Nanofibers for Neural Tissue Applications

    PubMed Central

    Lee, Jae Young; Bashur, Chris A.; Goldstein, Aaron S.; Schmidt, Christine E.

    2009-01-01

    Electrospinning is a promising approach to create nanofiber structures that are capable of supporting adhesion and guiding extension of neurons for nerve regeneration. Concurrently, electrical stimulation of neurons in the absence of topographical features also has been shown to guide axonal extension. Therefore, the goal of this study was to form electrically conductive nanofiber structures and to examine the combined effect of nanofiber structures and electrical stimulation. Conductive meshes were produced by growing polypyrrole (PPy) on random and aligned electrospun poly(lactic-co-glycolic acid) (PLGA) nanofibers, as confirmed by scanning electron micrographs and X-ray photon spectroscopy. PPy-PLGA electrospun meshes supported the growth and differentiation of rat pheochromocytoma 12 (PC12) cells and hippocampal neurons comparable to non-coated PLGA control meshes, suggesting that PPy-PLGA may be suitable as conductive nanofibers for neuronal tissue scaffolds. Electrical stimulation studies showed that PC12 cells, stimulated with a potential of 10 mV/cm on PPy-PLGA scaffolds, exhibited 40–50% longer neurites and 40–90% more neurite formation compared to unstimulated cells on the same scaffolds. In addition, stimulation of the cells on aligned PPy-PLGA fibers resulted in longer neurites and more neurite-bearing cells than stimulation on random PPy-PLGA fibers, suggesting a combined effect of electrical stimulation and topographical guidance and the potential use of these scaffolds for neural tissue applications. PMID:19501901

  5. Thermodynamic phase behaviour of indomethacin/PLGA formulations.

    PubMed

    Prudic, Anke; Lesniak, Anna-Katharina; Ji, Yuanhui; Sadowski, Gabriele

    2015-06-01

    In the current study, the phase behaviour of indomethacin and poly(lactic-co-glycolic acid) (PLGA) formulations was investigated as a function of the molecular weight and the copolymer composition of PLGA. The formulations were prepared by ball milling, and the phase behaviour, comprised of the glass-transition temperature of the formulations and the solubility of indomethacin in PLGA, was measured using modulated differential scanning calorimetry (mDSC). The results determined that the solubility of indomethacin in PLGA at room temperature was very low and increased with a corresponding decrease in the molecular weight of PLGA. The copolymer composition of PLGA had a minor effect on the indomethacin solubility. The effect of PLGA's molecular weight and copolymer composition on the solubility of indomethacin could be modelled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) with a high degree of accuracy when compared with the experimental data. The glass-transition temperatures had a negative deviation from the weighted mean of the glass-transition temperatures of the pure substances, which could be described by the Kwei-equation.

  6. Interaction of PLGA and trimethyl chitosan modified PLGA nanoparticles with mixed anionic/zwitterionic phospholipid bilayers studied using molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Novak, Brian; Astete, Carlos; Sabliov, Cristina; Moldovan, Dorel

    2012-02-01

    Poly(lactic-co-glycolic acid) (PLGA) is a biodegradable polymer. Nanoparticles of PLGA are commonly used for drug delivery applications. The interaction of the nanoparticles with the cell membrane may influence the rate of their uptake by cells. Both PLGA and cell membranes are negatively charged, so adding positively charged polymers such as trimethyl chitosan (TMC) which adheres to the PLGA particles improves their cellular uptake. The interaction of 3 nm PLGA and TMC-modified-PLGA nanoparticles with lipid bilayers composed of mixtures of phosphatidylcholine and phosphatidylserine lipids was studied using molecular dynamics simulations. The free energy profiles as function of nanoparticles position along the normal direction to the bilayers were calculated, the distribution of phosphatidylserine lipids as a function of distance of the particle from the bilayer was calculated, and the time scale for particle motion in the directions parallel to the bilayer surface was estimated.

  7. Engineering a freestanding biomimetic cardiac patch using biodegradable poly(lactic-co-glycolic acid) (PLGA) and human embryonic stem cell-derived ventricular cardiomyocytes (hESC-VCMs).

    PubMed

    Chen, Yin; Wang, Junping; Shen, Bo; Chan, Camie W Y; Wang, Chaoyi; Zhao, Yihua; Chan, Ho N; Tian, Qian; Chen, Yangfan; Yao, Chunlei; Hsing, I-Ming; Li, Ronald A; Wu, Hongkai

    2015-03-01

    Microgrooved thin PLGA film (≈30 μm) is successfully fabricated on a Teflon mold, which could be readily peeled off and is used for the construction of a biomimetic cardiac patch. The contraction of it is studied with optical mapping on transmembrane action potential. Our results suggest that steady-state contraction could be easily established on it under regular electrical stimuli. Besides, the biomimetic cardiac patch recapitulates the anisotropic electrophysiological feature of native cardiac tissue and is much more refractory to premature stimuli than the random one constructed with non-grooved PLGA film, as proved by the reduced incidence of arrhythmia. Considering the good biocompatibility of PLGA as demonstrated in our study and the biodegradability of it, our biomimetic cardiac patch may find applications in the treatment of myocardial infarction. Moreover, the Teflon mold could be applied in the fabrication of various scaffolds with fine features for other tissues.

  8. [Transport of PLGA nanoparticles across Caco-2/HT29-MTX co-cultured cells].

    PubMed

    Wen, Zhen; Li, Gang; Lin, Dong-Hai; Wang, Jun-Teng; Qin, Li-Fang; Guo, Gui-Ping

    2013-12-01

    The present study is to establish Caco-2/HT29-MTX co-cultured cells and investigate the transport capability of PLGA nanoparticles with different surface chemical properties across Caco-2/HT29-MTX co-cultured cells. PLGA-NPs, mPEG-PLGA-NPs and chitosan coated PLGA-NPs were prepared by nanoprecipitation method using poly(lactic-co-glycolic acid) as carrier material with surface modified by methoxy poly(ethylene glycol) and chitosan. The particle size and zeta potential of nanoparticles were measured by dynamic light scattering. Coumarin 6 was used as a fluorescent marker in the transport of nanoparticles investigated by confocal laser scanning microscopy. The transport of furanodiene (FDE) loaded nanoparticles was quantitively determined by high performance liquid chromatography. Colchicine and nocodazole were used in the transport study to explore the involved endocytosis mechanisms of nanoparticles. Distribution of the tight junction proteins ZO-1 was also analyzed by immunofluorescence staining. The results showed that the nanoparticles dispersed uniformly. The zeta potential of PLGA-NPs was negative, the mPEG-PLGA-NPs was close to neutral and the CS-PLGA-NPs was positive. The entrapment efficiency of FDE in all nanoparticles was higher than 75%. The transport capability of mPEG-PLGA-NPs across Caco-2/HT29-MTX co-cultured cells was higher than that of PLGA-NPs and CS-PLGA-NPs. Colchicine and nocodazole could significantly decrease the transport amount of nanoparticles. mPEG-PLGA-NPs could obviously reduce the distribution of ZO-1 protein than PLGA-NPs and CS-PLGA-NPs. The transport mechanism of PLGA-NPs and mPEG-PLGA-NPs were indicated to be a combination of endocytosis and paracellular way, while CS-PLGA-NPs mainly relied on the endocytosis way. PEG coating could shield the surface charge and enhance the hydrophilicity of PLGA nanoparticles, which leads mPEG-PLGA-NPs to possess higher anti-adhesion activity. As a result, mPEG-PLGA-NPs could penetrate the mucus

  9. Phase-Shifted PFH@PLGA/Fe3O4 Nanocapsules for MRI/US Imaging and Photothermal Therapy with near-Infrared Irradiation.

    PubMed

    Zhao, Yajing; Song, Weixiang; Wang, Dong; Ran, Haitao; Wang, Ronghui; Yao, Yuanzhi; Wang, Zhigang; Zheng, Yuanyi; Li, Pan

    2015-07-08

    Photothermal therapy (PTT) utilizes photothermal conversion reagents to generate heat energy from absorbed light to effectively treat various malignant diseases. This approach has attracted broad and increasing interest in cancer treatment. Near-infrared (NIR)-induced PTT is particularly attractive because of its minimal absorbance by normal tissue and relatively deep tissue penetration. To improve the efficacy of PTT, we have developed nanocapsules encapsulating superparamagnetic iron oxide (Fe3O4) as synergistic agents for NIR-induced PTT. In this study, phase-shift and NIR photoabsorbing poly(lactic-co-glycolic acid) (PLGA) nanocapsules (perfluorohexane (PFH)@PLGA/Fe3O4) were fabricated for MRI/US dual-modal imaging-guided PTT. The multifunctional nanocapsules can be used not only to increase the local tumor temperature by absorbing the NIR energy but also as bimodal contrast agents for both MRI and US imaging. Such nanocapsules can be converted into microbubbles under NIR irradiation, which produces excellent contrast for US imaging and enhanced cancer ablation. We refer to the nanocapsule phase transition process induced by the infrared lamp as NIR radiation droplet vaporization (NIRDV).

  10. Effect of Temperature and Pressure on the Stability of Protein Microbubbles.

    PubMed

    Rovers, Tijs A M; Sala, Guido; van der Linden, Erik; Meinders, Marcel B J

    2016-01-13

    Protein microbubbles are air bubbles with a network of interacting proteins at the air-water interface. Protein microbubbles are commonly used in medical diagnostic and therapeutic research. They have also recently gained interest in the research area of food as they can be used as structural elements to control texture, allowing for the manufacture of healthier foods with increased consumer perception. For the application of microbubbles in the food industry, it is important to gain insights into their stability under food processing conditions. In this study, we tested the stability of protein microbubbles against heating and pressurization. Microbubbles could be heated to 50 °C for 2 min or pressurized to 100 kPa overpressure for 15 s without significantly affecting their stability. At higher pressures and temperatures, the microbubbles became unstable and buckled. Buckling was observed above a critical pressure and was influenced by the shell modulus. The addition of cross-linkers like glutaraldehyde and tannic acid resulted in microbubbles that were stable against all tested temperatures and overpressures, more specifically, up to 120 °C and 470 kPa, respectively. We found a relation between the storage temperatures of microbubble dispersions (4, 10, 15, and 21 °C) and a decrease in the number of microbubbles with the highest decrease at the highest storage temperature. The average rupture time of microbubbles stored at different storage temperatures followed an Arrhenius relation with an activation energy for rupture of the shell of approximately 27 kT. This strength ensures applicability of microbubbles in food processes only at moderate temperatures and storage for a moderate period of time. After the proteins in the shell are cross-linked, the microbubbles can withstand pressures and temperatures that are representative of food processes.

  11. Fabricating multifunctional microbubbles and nanobubbles for concurrent ultrasound and photoacoustic imaging

    NASA Astrophysics Data System (ADS)

    Qin, Ruogu; Xu, Jeff; Xu, Ronald; Kim, Chulhong; Wang, Lihong V.

    2010-02-01

    Background: Clinical ultrasound (US) uses ultrasonic scattering contrast to characterize subcutaneous anatomic structures. Photoacoustic (PA) imaging detects the functional properties of thick biological tissue with high optical contrast. In the case of image-guided cancer ablation therapy, simultaneous US and PA imaging can be useful for intraoperative assessment of tumor boundaries and ablation margins. In this regard, accurate co-registration between imaging modalities and high sensitivity to cancer cells are important. Methods: We synthesized poly-lactic-co-glycolic acid (PLGA) microbubbles (MBs) and nanobubbles (NBs) encapsulating India ink or indocyanine green (ICG). Multiple tumor simulators were fabricated by entrapping ink MBs or NBs at various concentrations in gelatin phantoms for simultaneous US and PA imaging. MBs and NBs were also conjugated with CC49 antibody to target TAG-72, a human glycoprotein complex expressed in many epithelial-derived cancers. Results: Accurate co-registration and intensity correlation were observed in US and PA images of MB and NB tumor simulators. MBs and NBs conjugating with CC49 effectively bound with over-expressed TAG-72 in LS174T colon cancer cell cultures. ICG was also encapsulated in MBs and NBs for the potential to integrate US, PA, and fluorescence imaging. Conclusions: Multifunctional MBs and NBs can be potentially used as a general contrast agent for multimodal intraoperative imaging of tumor boundaries and therapeutic margins.

  12. Preparation and characterization of bee venom-loaded PLGA particles for sustained release.

    PubMed

    Park, Min-Ho; Jun, Hye-Suk; Jeon, Jong-Woon; Park, Jin-Kyu; Lee, Bong-Joo; Suh, Guk-Hyun; Park, Jeong-Sook; Cho, Cheong-Weon

    2016-12-14

    Bee venom-loaded poly(lactic-co-glycolic acid) (PLGA) particles were prepared by double emulsion-solvent evaporation, and characterized for a sustained-release system. Factors such as the type of organic solvent, the amount of bee venom and PLGA, the type of PLGA, the type of polyvinyl alcohol, and the emulsification method were considered. Physicochemical properties, including the encapsulation efficiency, drug loading, particle size, zeta-potential and surface morphology were examined by Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD). The size of the bee venom-loaded PLGA particles was 500 nm (measured using sonication). Zeta-potentials of the bee venom-loaded PLGA particles were negative owing to the PLGA. FT-IR results demonstrated that the bee venom was completely encapsulated in the PLGA particles, indicated by the disappearance of the amine and amide peaks. In addition, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis indicated that the bee venom in the bee venom-loaded PLGA particles was intact. In vitro release of the bee venom from the bee venom-loaded PLGA particles showed a sustained-release profile over 1 month. Bee venom-loaded PLGA particles can help improve patients' quality of life by reducing the number of injections required.

  13. Surface Mechanical and Rheological Behaviors of Biocompatible Poly((D,L-lactic acid-ran-glycolic acid)-block-ethylene glycol) (PLGA-PEG) and Poly((D,L-lactic acid-ran-glycolic acid-ran-ε-caprolactone)-block-ethylene glycol) (PLGACL-PEG) Block Copolymers at the Air-Water Interface

    SciTech Connect

    Kim, Hyun Chang; Lee, Hoyoung; Khetan, Jawahar; Won, You-Yeon

    2016-02-01

    Air–water interfacial monolayers of poly((d,l-lactic acid-ran-glycolic acid)-block-ethylene glycol) (PLGA–PEG) exhibit an exponential increase in surface pressure under high monolayer compression. In order to understand the molecular origin of this behavior, a combined experimental and theoretical investigation (including surface pressure–area isotherm, X-ray reflectivity (XR) and interfacial rheological measurements, and a self-consistent field (SCF) theoretical analysis) was performed on air–water monolayers formed by a PLGA–PEG diblock copolymer and also by a nonglassy analogue of this diblock copolymer, poly((d,l-lactic acid-ran-glycolic acid-ran-caprolactone)-block-ethylene glycol) (PLGACL–PEG). The combined results of this study show that the two mechanisms, i.e., the glass transition of the collapsed PLGA film and the lateral repulsion of the PEG brush chains that occur simultaneously under lateral compression of the monolayer, are both responsible for the observed PLGA–PEG isotherm behavior. Upon cessation of compression, the high surface pressure of the PLGA–PEG monolayer typically relaxes over time with a stretched exponential decay, suggesting that in this diblock copolymer situation, the hydrophobic domain formed by the PLGA blocks undergoes glass transition in the high lateral compression state, analogously to the PLGA homopolymer monolayer. In the high PEG grafting density regime, the contribution of the PEG brush chains to the high monolayer surface pressure is significantly lower than what is predicted by the SCF model because of the many-body attraction among PEG segments (referred to in the literature as the “n-cluster” effects). The end-grafted PEG chains were found to be protein resistant even under the influence of the “n-cluster” effects.

  14. Engineering of lipid-coated PLGA nanoparticles with a tunable payload of diagnostically active nanocrystals for medical imaging†

    PubMed Central

    Mieszawska, Aneta J.; Gianella, Anita; Cormode, David P.; Zhao, Yiming; Meijerink, Andries; Langer, Robert; Farokhzad, Omid C.; Fayad, Zahi A.; Mulder, Willem J. M.

    2013-01-01

    Polylactic-co-glycolic acid (PLGA) based nanoparticles are biocompatible and biodegradable and therefore have been extensively investigated as therapeutic carriers. Here, we engineered diagnostically active PLGA nanoparticles that incorporate high payloads of nanocrystals into their core for tunable bioimaging features. We accomplished this through esterification reactions of PLGA to generate polymers modified with nanocrystals. The PLGA nanoparticles formed from modified PLGA polymers that were functionalized with either gold nanocrystals or quantum dots exhibited favorable features for computed tomography and optical imaging, respectively. PMID:22555311

  15. Microbubble cavitation imaging.

    PubMed

    Vignon, Francois; Shi, William T; Powers, Jeffry E; Everbach, E Carr; Liu, Jinjin; Gao, Shunji; Xie, Feng; Porter, Thomas R

    2013-04-01

    Ultrasound cavitation of microbubble contrast agents has a potential for therapeutic applications such as sonothrombolysis (STL) in acute ischemic stroke. For safety, efficacy, and reproducibility of treatment, it is critical to evaluate the cavitation state (moderate oscillations, stable cavitation, and inertial cavitation) and activity level in and around a treatment area. Acoustic passive cavitation detectors (PCDs) have been used to this end but do not provide spatial information. This paper presents a prototype of a 2-D cavitation imager capable of producing images of the dominant cavitation state and activity level in a region of interest. Similar to PCDs, the cavitation imaging described here is based on the spectral analysis of the acoustic signal radiated by the cavitating microbubbles: ultraharmonics of the excitation frequency indicate stable cavitation, whereas elevated noise bands indicate inertial cavitation; the absence of both indicates moderate oscillations. The prototype system is a modified commercially available ultrasound scanner with a sector imaging probe. The lateral resolution of the system is 1.5 mm at a focal depth of 3 cm, and the axial resolution is 3 cm for a therapy pulse length of 20 μs. The maximum frame rate of the prototype is 2 Hz. The system has been used for assessing and mapping the relative importance of the different cavitation states of a microbubble contrast agent. In vitro (tissue-mimicking flow phantom) and in vivo (heart, liver, and brain of two swine) results for cavitation states and their changes as a function of acoustic amplitude are presented.

  16. Muscle regeneration by adipose tissue-derived adult stem cells attached to injectable PLGA spheres.

    PubMed

    Kim, MiJung; Choi, Yu Suk; Yang, Seung Hye; Hong, Hea-Nam; Cho, Sung-Woo; Cha, Sang Myun; Pak, Jhang Ho; Kim, Chan Wha; Kwon, Seog Woon; Park, Chan Jeoung

    2006-09-22

    The [corrected] use of adult stem cells for cell-based tissue engineering and regeneration strategies represents a promising approach for skeletal muscle repair. We have evaluated the combination of adipose tissue-derived adult stem cells (ADSCs) obtained from autologous liposuction and injectable poly(lactic-co-glycolic acid) (PLGA) spheres for muscle regeneration. ADSCs attached to PLGA spheres and PLGA spheres alone were cultured in myogenic medium for 21 days and injected subcutaneously into the necks of nude mice. After 30 and 60 days, the mice were sacrificed, and newly formed tissues were analyzed by immunostaining, H and E staining, and RT-PCR. We found that ADSCs attached to PLGA spheres, but not PLGA spheres alone, were able to generate muscle tissue. These findings suggest that ADSCs and PLGA spheres are useful materials for muscle tissue engineering and that their combination can be used in clinical settings for muscle regeneration.

  17. High Yielding Microbubble Production Method

    PubMed Central

    Fiabane, Joe; Prentice, Paul; Pancholi, Ketan

    2016-01-01

    Microfluidic approaches to microbubble production are generally disadvantaged by low yield and high susceptibility to (micro)channel blockages. This paper presents an alternative method of producing microbubbles of 2.6 μm mean diameter at concentrations in excess of 30 × 106 mL−1. In this method, the nitrogen gas flowing inside the liquid jet is disintegrated into spray of microbubble when air surrounding this coflowing nitrogen gas-liquid jet passes through a 100 μm orifice at high velocity. Resulting microbubble foam has the polydispersity index of 16%. Moreover, a ratio of mean microbubble diameter to channel width ratio was found to be less than 0.025, which substantially alleviates the occurrence of blockages during production. PMID:27034935

  18. Formulations for modulation of protein release from large-size PLGA microparticles for tissue engineering.

    PubMed

    Qodratnama, Roozbeh; Serino, Lorenzo Pio; Cox, Helen C; Qutachi, Omar; White, Lisa J

    2015-02-01

    In this study we present an approach to pre-program lysozyme release from large size (100-300 μm) poly(DL-lactic acid-co-glycolic acid) (PLGA) microparticles. This approach involved blending in-house synthesized triblock copolymers with a PLGA 85:15. In this work it is demonstrated that the lysozyme release rate and the total release are related to the mass of triblock copolymer present in polymer formulation. Two triblock copolymers (PLGA-PEG1500-PLGA and PLGA-PEG1000-PLGA) were synthesized and used in this study. In a like-for-like comparison, these two triblock copolymers appeared to have similar effects on the release of lysozyme. It was shown that blending resulted in the increase of the total lysozyme release and shortened the release period (70% release within 30 days). These results demonstrated that blending PLGA-PEG-PLGA triblock copolymer with PLGA 85:15 can be used as a method to pre-program protein release from microparticles. These microparticles with modulated protein release properties may be used to create microparticle-based tissue engineering constructs with pre-programmed release properties.

  19. Systemic delivery to central nervous system by engineered PLGA nanoparticles

    PubMed Central

    Cai, Qiang; Wang, Long; Deng, Gang; Liu, Junhui; Chen, Qianxue; Chen, Zhibiao

    2016-01-01

    Neurological disorders are an important global public health problem, but pharmaceutical treatments are limited due to drug access to the central nervous system being restricted by the blood-brain barrier (BBB). Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) are one of the most promising drug and gene delivery systems for crossing the BBB. While these systems offer great promise, PLGA NPs also have some intrinsic drawbacks and require further engineering for clinical and research applications. Multiple strategies have been developed for using PLGA NPs to deliver compounds across the BBB. We classify these strategies into three categories according to the adaptations made to the PLGA NPs (1) to facilitate travel from the injection site (pre-transcytosis strategies); (2) to enhance passage across the brain endothelial cells (BBB transcytosis strategies) and (3) to achieve targeting of the impaired nervous system cells (post-transcytosis strategies). PLGA NPs modified according to these three strategies are denoted first, second, and third generation NPs, respectively. We believe that fusing these three strategies to engineer multifunctional PLGA NPs is the only way to achieve translational applications. PMID:27158367

  20. Synthesis and characterization of magnetite/PLGA/chitosan nanoparticles

    NASA Astrophysics Data System (ADS)

    Ibarra, Jaime; Melendres, Julio; Almada, Mario; Burboa, María G.; Taboada, Pablo; Juárez, Josué; Valdez, Miguel A.

    2015-09-01

    In this work, we report the synthesis and characterization of a new hybrid nanoparticles system performed by magnetite nanoparticles, loaded in a PLGA matrix, and stabilized by different concentrations of chitosan. Magnetite nanoparticles were hydrophobized with oleic acid and entrapped in a PLGA matrix by the emulsion solvent evaporation method, after that, magnetite/PLGA/chitosan nanoparticles were obtained by adding dropwise magnetite/PLGA nanoparticles in chitosan solutions. Magnetite/PLGA nanoparticles produced with different molar ratios did not show significant differences in size and the 3:1 molar ratio showed best spherical shapes as well as uniform particle size. Isothermal titration calorimetry studies demonstrated that the first stage of PLGA-chitosan interaction is mostly regulated by electrostatic forces. Based on a single set of identical sites model, we obtained for the average number of binding sites a value of 3.4, which can be considered as the number of chitosan chains per nanoparticle. This value was confirmed by using a model based on the DLVO theory and fitting zeta potential measurements of magnetite/PLGA/chitosan nanoparticles. From the adjusted parameters, we found that an average number of chitosan molecules of 3.6 per nanoparticle are attached onto the surface of the PLGA matrix. Finally, we evaluated the effect of surface charge of nanoparticles on a membrane model of endothelial cells performed by a mixture of three phospholipids at the air-water interface. Different isotherms and adsorption curves show that cationic surface of charged nanoparticles strongly interact with the phospholipids mixture and these results can be the basis of future experiments to understand the nanoparticles- cell membrane interaction.

  1. Bone Regeneration from PLGA Micro-Nanoparticles

    PubMed Central

    Ortega-Oller, Inmaculada; Padial-Molina, Miguel; Galindo-Moreno, Pablo; O'Valle, Francisco; Jódar-Reyes, Ana Belén; Peula-García, Jose Manuel

    2015-01-01

    Poly-lactic-co-glycolic acid (PLGA) is one of the most widely used synthetic polymers for development of delivery systems for drugs and therapeutic biomolecules and as component of tissue engineering applications. Its properties and versatility allow it to be a reference polymer in manufacturing of nano- and microparticles to encapsulate and deliver a wide variety of hydrophobic and hydrophilic molecules. It additionally facilitates and extends its use to encapsulate biomolecules such as proteins or nucleic acids that can be released in a controlled way. This review focuses on the use of nano/microparticles of PLGA as a delivery system of one of the most commonly used growth factors in bone tissue engineering, the bone morphogenetic protein 2 (BMP2). Thus, all the needed requirements to reach a controlled delivery of BMP2 using PLGA particles as a main component have been examined. The problems and solutions for the adequate development of this system with a great potential in cell differentiation and proliferation processes under a bone regenerative point of view are discussed. PMID:26509156

  2. Thermo-sensitive hydrogel PLGA-PEG-PLGA as a vaccine delivery system for intramuscular immunization.

    PubMed

    Wang, Xiaoyan; Zhang, Yu; Xue, Wei; Wang, Hong; Qiu, Xiaozhong; Liu, Zonghua

    2016-11-25

    In this work, we explored the potential of thermo-sensitive PLGA-PEG-PLGA with sol-gel transition temperature around 32℃ as an intramuscular vaccine delivery system by using ovalbumin as a model antigen. First, in vitro release test showed that the PLGA-PEG-PLGA-deriving hydrogels could release ovalbumin in vitro in a more sustainable way. From fluorescence living imaging, 50-200 mg/mL of PLGA-PEG-PLGA formulations could release antigen in a sustainable manner in vivo, suggesting that the PLGA-PEG-PLGA hydrogel worked as an antigen-depot. Further, the sustainable antigen release from the PLGA-PEG-PLGA hydrogels increased antigen availability in the spleens of the immunized mice. The intramuscular immunization results showed that 50-200 mg/mL of PLGA-PEG-PLGA formulations promoted significantly more potent antigen-specific IgG immune response. In addition, 200 mg/mL of PLGA-PEG-PLGA formulation significantly enhanced the secretion of both Th1 and Th2 cytokines. From in vitro splenocyte proliferation assay, 50-200 mg/mL of PLGA-PEG-PLGA formulations all initiated significantly higher splenocyte activation. These results indicate that the thermo-sensitive and injectable PLGA-PEG-PLGA hydrogels (particularly, 200 mg/mL of PLGA-PEG-PLGA-based hydrogel) own promising potential as an intramuscular vaccine delivery system.

  3. Degreasing of Solid Surfaces by Microbubble Cleaning

    NASA Astrophysics Data System (ADS)

    Miyamoto, Makoto; Ueyama, Satoshi; Hinomoto, Nobuhide; Saitoh, Tadashi; Maekawa, Shigeki; Hirotsuji, Junji

    2007-03-01

    It is increasingly required to reduce the environmental impact and cost in the field of industrial cleaning. As a substitute for conventional degreasing technology using organic solvents, acids, and alkalis, the authors have developed a new cleaning technology that uses microbubbles having an average diameter of about 70 μm. Grease being adsorbed onto a bubble’s surface and grease being separated from a solid surface by its buoyancy were captured using a high-speed microscopic video camera to demonstrate the degreasing capability of bubbles. High-density microbubbles were generated by adding a trace amount of a specific chemical (0.1% weight or less). The cleaning performance using microbubbles was found to be highly improved compared with that using normal bubbles. It was also revealed that the grease removal efficiency was strongly dependent on the viscosity of the grease. Raising the temperature of the cleaning solution is an effective method of improving cleaning performance by reducing the viscosity. Finally, the degreasing of about 150 machining metal parts at the same time was demonstrated to exceed the common target cleaning level (5-20 μg/cm2) in only 2 min because of their large surface area. Furthermore, the high degreasing performance was maintained even after repeated use of the cleaning solution because of the separation of grease due to buoyancy.

  4. The onset of microbubble vibration.

    PubMed

    Emmer, Marcia; van Wamel, Annemieke; Goertz, Dave E; de Jong, Nico

    2007-06-01

    A linear relationship between the relative expansion of an off-resonance ultrasound contrast microbubble and low acoustic pressures is expected. In this study, high-speed optical recordings of individual phospholipid-coated microbubbles were used to investigate this relationship for microbubbles ranging from 2 to 11 microm and for acoustic pressures ranging from 20 to 250 kPa at a driving frequency of 1.7 MHz. For microbubbles larger than 5 microm, the relative expansion (DeltaD/D0) increased linearly with applied acoustic pressure, starting at the origin. The response of smaller microbubbles (<5 microm) also increased linearly with the applied acoustic pressure. However, linearity started at an acoustic pressure threshold value of 30 to 120 kPa for the different individual microbubbles. Below these pressure values, little or no oscillation was observed. The results may be explained by size-dependent mechanical properties of the phospholipid shells. An imaging technique such as power modulation imaging could profit from the presence of an acoustic pressure threshold in the microbubble response.

  5. Periodontal tissue regeneration by transplantation of rat adipose-derived stromal cells in combination with PLGA-based solid scaffolds.

    PubMed

    Akita, Daisuke; Morokuma, Masakazu; Saito, Yoko; Yamanaka, Katsuyuki; Akiyama, Yuko; Sato, Momoko; Mashimo, Takayuki; Toriumi, Taku; Arai, Yoshinori; Kaneko, Tadashi; Tsukimura, Naoki; Isokawa, Keitaro; Ishigami, Tomohiko; Honda, Masaki J

    2014-01-01

    Regeneration of damaged periodontium is challenging due to its multi-tissue composition. Mesenchymalstem cell-based approaches using adipose-derived stromal cells (ASCs) may contribute to periodontal reconstruction, particularly when combined with the use of scaffolds to maintain a space for new tissue growth. The aim of this study was to assess the regenerative potential of ASCs derived from inbred or outbred rats in combination with novel solid scaffolds composed of PLGA (Poly D,L-lactic-co-glycolic acid) (PLGA-scaffolds). Cultured ASCs seeded onto PLGA scaffolds (ASCs/PLGA) or PLGA-scaffolds (PLGA) alone were transplanted into periodontal fenestration defects created in F344 or Sprague Dawley (SD) rats. Micro-CT analysis showed a significantly higher percentage of bone growth in the ASCs/PLGA groups compared with the PLGA-alone groups at five weeks after surgery. Similarly, histomorphometric analysis demonstrated thicker growth of periodontal ligament and cementum layers in the ASCs/PLGA-groups compared with the PLGA-alone groups. In addition, transplanted DiI-labeled ASCs were observed in the periodontal regenerative sites. The present investigation demonstrated the marked ability of ASCs in combination with PLGA scaffolds to repair periodontal defects.

  6. Acoustic detection of microbubble resonance

    NASA Astrophysics Data System (ADS)

    Thomas, D. H.; Looney, P.; Steel, R.; Pelekasis, N.; McDicken, W. N.; Anderson, T.; Sboros, V.

    2009-06-01

    Large numbers of acoustic signals from single lipid-shelled Definity® microbubbles have been measured using a calibrated microacoustic system and a two population response observed. Theoretical results based on the Mooney-Rivlin strain softening shell model have been used to identify these populations as primary resonant and off-primary resonant scatter. An experimentally measured size distribution was used to provide the initial resting radius for the simulations, and the responses agree well with the experimental data. In this way, the primary resonant or off-primary resonant behavior of a microbubble can be studied, with potential benefits to both signal processing techniques and microbubble manufacture.

  7. Biodegradable double-targeted PTX-mPEG-PLGA nanoparticles for ultrasound contrast enhanced imaging and antitumor therapy in vitro

    PubMed Central

    Sun, Ying; Duan, You Rong; Du, Lian Fang

    2016-01-01

    A porous-structure nano-scale ultrasound contrast agent (UCA) was made of monomethoxypoly (ethylene glycol)-poly (lactic-co-glycolic acid) (mPEG-PLGA), and modified by double-targeted antibody: anti-carcinoembryonic antigen (CEA) and anti-carbohydrate antigen 19-9 (CA19-9), as a double-targeted nanoparticles (NPs). Anti-tumor drug paclitaxel (PTX) was encapsulated in the double-targeted nanoparticles (NPs). The morphor and release curve were characterized. We verified a certain anticancer effect of PTX-NPs through cytotoxicity experiments. The cell uptake result showed much more NPs may be facilitated to ingress the cells or tissues with ultrasound (US) or ultrasound targeted microbubble destruction (UTMD) transient sonoporation in vitro. Ultrasound contrast-enhanced images in vitro and in vivo were investigated. Compared with SonoVue, the NPs prolonged imaging time in rabbit kidneys and tumor of nude mice, which make it possible to further enhance anti-tumor effects by extending retention time in the tumor region. The novel double-targeted NPs with the function of ultrasound contrast enhanced imaging and anti-tumor therapy can be a promising way in clinic. PMID:27835907

  8. Understanding greater cardiomyocyte functions on aligned compared to random carbon nanofibers in PLGA.

    PubMed

    Asiri, Abdullah M; Marwani, Hadi M; Khan, Sher Bahadar; Webster, Thomas J

    2015-01-01

    Previous studies have demonstrated greater cardiomyocyte density on carbon nanofibers (CNFs) aligned (compared to randomly oriented) in poly(lactic-co-glycolic acid) (PLGA) composites. Although such studies demonstrated a closer mimicking of anisotropic electrical and mechanical properties for such aligned (compared to randomly oriented) CNFs in PLGA composites, the objective of the present in vitro study was to elucidate a deeper mechanistic understanding of how cardiomyocyte densities recognize such materials to respond more favorably. Results showed lower wettability (greater hydrophobicity) of CNFs embedded in PLGA compared to pure PLGA, thus providing evidence of selectively lower wettability in aligned CNF regions. Furthermore, the results correlated these changes in hydrophobicity with increased adsorption of fibronectin, laminin, and vitronectin (all proteins known to increase cardiomyocyte adhesion and functions) on CNFs in PLGA compared to pure PLGA, thus providing evidence of selective initial protein adsorption cues on such CNF regions to promote cardiomyocyte adhesion and growth. Lastly, results of the present in vitro study further confirmed increased cardiomyocyte functions by demonstrating greater expression of important cardiomyocyte biomarkers (such as Troponin-T, Connexin-43, and α-sarcomeric actin) when CNFs were aligned compared to randomly oriented in PLGA. In summary, this study provided evidence that cardiomyocyte functions are improved on CNFs aligned in PLGA compared to randomly oriented in PLGA since CNFs are more hydrophobic than PLGA and attract the adsorption of key proteins (fibronectin, laminin, and vironectin) that are known to promote cardiomyocyte adhesion and expression of important cardiomyocyte functions. Thus, future studies should use this knowledge to further design improved CNF:PLGA composites for numerous cardiovascular applications.

  9. HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages.

    PubMed

    Sanchez-Gaytan, Brenda L; Fay, Francois; Lobatto, Mark E; Tang, Jun; Ouimet, Mireille; Kim, YongTae; van der Staay, Susanne E M; van Rijs, Sarian M; Priem, Bram; Zhang, Liangfang; Fisher, Edward A; Moore, Kathryn J; Langer, Robert; Fayad, Zahi A; Mulder, Willem J M

    2015-03-18

    High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and the phospholipid corona make the HDL platform an attractive nanocarrier. To realize controlled release properties, we developed a hybrid polymer/HDL nanoparticle composed of a lipid/apolipoprotein coating that encapsulates a poly(lactic-co-glycolic acid) (PLGA) core. This novel HDL-like nanoparticle (PLGA-HDL) displayed natural HDL characteristics, including preferential uptake by macrophages and a good cholesterol efflux capacity, combined with a typical PLGA nanoparticle slow release profile. In vivo studies carried out with an ApoE knockout mouse model of atherosclerosis showed clear accumulation of PLGA-HDL nanoparticles in atherosclerotic plaques, which colocalized with plaque macrophages. This biomimetic platform integrates the targeting capacity of HDL biomimetic nanoparticles with the characteristic versatility of PLGA-based nanocarriers.

  10. In vivo biocompatibility of the PLGA microparticles in parotid gland

    PubMed Central

    Cantín, Mario; Miranda, Patricio; Suazo Galdames, Iván; Zavando, Daniela; Arenas, Patricia; Velásquez, Luis; Vilos, Cristian

    2013-01-01

    Poly(lactic-co-glycolic acid) (PLGA) microparticles are used in various disorders for the controlled or sustained release of drugs, with the management of salivary gland pathologies possible using this technology. There is no record of the response to such microparticles in the glandular parenchyma. The purpose of this study was to assess the morphological changes in the parotid gland when injected with a single dose of PLGA microparticles. We used 12 adult female Sprague Dawley rats (Rattus norvegicus) that were injected into their right parotid gland with sterile vehicle solution (G1, n=4), 0.5 mg PLGA microparticles (G2, n=4), and 0.75 mg PLGA microparticles (G3, n=4); the microparticles were dissolved in a sterile vehicle solution. The intercalar and striated ducts lumen, the thickness of the acini and the histology aspect in terms of the parenchyma organization, cell morphology of acini and duct system, the presence of polymeric residues, and inflammatory response were determined at 14 days post-injection. The administration of the compound in a single dose modified some of the morphometric parameters of parenchyma (intercalar duct lumen and thickness of the glandular acini) but did not induce tissue inflammatory response, despite the visible presence of polymer waste. This suggests that PLGA microparticles are biocompatible with the parotid tissue, making it possible to use intraglandular controlled drug administration. PMID:24228103

  11. Fabrication and in vitro biocompatibility of biomorphic PLGA/nHA composite scaffolds for bone tissue engineering.

    PubMed

    Qian, Junmin; Xu, Weijun; Yong, Xueqing; Jin, Xinxia; Zhang, Wei

    2014-03-01

    In this study, biomorphic poly(dl-lactic-co-glycolic acid)/nano-hydroxyapatite (PLGA/nHA) composite scaffolds were successfully prepared using cane as a template. The porous morphology, phase, compression characteristics and in vitro biocompatibility of the PLGA/nHA composite scaffolds and biomorphic PLGA scaffolds as control were investigated. The results showed that the biomorphic scaffolds preserved the original honeycomb-like architecture of cane and exhibited a bimodal porous structure. The average channel diameter and micropore size of the PLGA/nHA composite scaffolds were 164 ± 52 μm and 13 ± 8 μm, respectively, with a porosity of 89.3 ± 1.4%. The incorporation of nHA into PLGA decreased the degree of crystallinity of PLGA, and significantly improved the compressive modulus of biomorphic scaffolds. The in vitro biocompatibility evaluation with MC3T3-E1 cells demonstrated that the biomorphic PLGA/nHA composite scaffolds could better support cell attachment, proliferation and differentiation than the biomorphic PLGA scaffolds. The localization depth of MC3T3-E1 cells within the channels of the biomorphic PLGA/nHA composite scaffolds could reach approximately 400 μm. The results suggested that the biomorphic PLGA/nHA composite scaffolds were promising candidates for bone tissue engineering.

  12. In vitro biocompatibility of polypyrrole/PLGA conductive nanofiber scaffold with cultured rat hepatocytes

    NASA Astrophysics Data System (ADS)

    Chu, Xue-Hui; Xu, Qian; Feng, Zhang-Qi; Xiao, Jiang-Qiang; Li, Qiang; Sun, Xi-Tai; Cao, Yang; Ding, Yi-Tao

    2014-09-01

    To intruduce conductive biomaterial into liver tissue engineering, a conductive nanofiber scaffold, polypyrrole/poly(lactic-co-glycolic)acid(PLGA), was designed and prepared via electro-spinning and oxidative polymerization. Effects of the scaffold on hepatocyte adhesion, viability and function were then investigated. SEM revealed pseudopodium formation and abundant extracellular matrix on the surface of PLGA membrane and polypyrrole/PLGA membrane. The adhesion rate, cellular activity, urea synthesis and albumin secretion of the hepatocytes cultured on polypyrrole/PLGA group were similar to those on the PLGA group, but were significantly higher than those on the control group. There were no significant differences in concentrations of LDH and TNF-α among three groups. These results suggested the potential application of this conductive nanofiber scaffold as a suitable substratum for hepatocyte culturing in liver tissue engineering.

  13. Fabrication of pillared PLGA microvessel scaffold using femtosecond laser ablation

    PubMed Central

    Wang, Hsiao-Wei; Cheng, Chung-Wei; Li, Ching-Wen; Chang, Han-Wei; Wu, Ping-Han; Wang, Gou-Jen

    2012-01-01

    One of the persistent challenges confronting tissue engineering is the lack of intrinsic microvessels for the transportation of nutrients and metabolites. An artificial microvascular system could be a feasible solution to this problem. In this study, the femtosecond laser ablation technique was implemented for the fabrication of pillared microvessel scaffolds of polylactic-co-glycolic acid (PLGA). This novel scaffold facilitates implementation of the conventional cell seeding process. The progress of cell growth can be observed in vitro by optical microscopy. The problems of becoming milky or completely opaque with the conventional PLGA scaffold after cell seeding can be resolved. In this study, PLGA microvessel scaffolds consisting of 47 μm × 80 μm pillared branches were produced. Results of cell culturing of bovine endothelial cells demonstrate that the cells adhere well and grow to surround each branch of the proposed pillared microvessel networks. PMID:22605935

  14. Elucidation of the physicomechanical and ab initio quantum energy transitions of a crosslinked PLGA scaffold.

    PubMed

    Sibambo, Sibongile R; Pillay, Viness; Choonara, Yahya E; Khan, Riaz A; Sweet, Joe L

    2007-09-01

    This study elucidated the in vitro physicomechanical transitions of a crosslinked polylactic-co-glycolic acid (PLGA) scaffold, utilizing quantum mechanics to compute the ab initio energy requirements of a salted-out and subsequently crosslinked PLGA scaffold interacting with simulated physiological fluid, phosphate buffered saline (PBS) (pH 7.4, 37 degrees C) at a molecular level. Twenty-six salted-out PLGA scaffolds were formulated using a four factor, two centerpoint quadratic Face-Centered Central Composite Design (FCCD). PLGA molecular mass, PLGA concentration, water volume and salting-out reaction time were the dependant formulation variables. Subsequent to PLGA solubilization in dimethyl formamide (DMF), protonated water was added to induce salting-out of PLGA into a scaffolds that were immersed in PBS, oscillated at 100 rpm, and analyzed at pre-determined time intervals for their physicomechanical and ab initio quantum energy transitions. Results indicated that the matrix resilience (MR) decreased with longer incubation periods (MR=35-45%) at day 30. Scaffolds salted-out using higher PLGA concentrations exhibited minimal changes in MR and the matrix ability to absorb energy was found to closely correlate with the scaffold residence time in PBS. Spartan-based ab initio quantum energy predictions elucidated the potential scaffold stability from a molecular viewpoint and its suitability for use in rate-modulated drug delivery.

  15. Surface modification of PLGA nanoparticles by carbopol to enhance mucoadhesion and cell internalization.

    PubMed

    Surassmo, Suvimol; Saengkrit, Nattika; Ruktanonchai, Uracha Rungsardthong; Suktham, Kunat; Woramongkolchai, Noppawan; Wutikhun, Tuksadon; Puttipipatkhachorn, Satit

    2015-06-01

    Mucoadhesive poly (lactic-co-glycolic acid) (PLGA) nanoparticles having a modified shell-matrix derived from polyvinyl alcohol (PVA) and Carbopol (CP), a biodegradable polymer coating, to improve the adhesion and cell transfection properties were developed. The optimum formulations utilized a CP concentration in the range of 0.05-0.2%w/v, and were formed using modified emulsion-solvent evaporation technique. The resulting CP-PLGA nanoparticles were characterized in terms of their physical and chemical properties. The absorbed CP on the PLGA shell-matrix was found to affect the particle size and surface charge, with 0.05% CP giving rise to smooth spherical particles (0.05CP-PLGA) with the smallest size (285.90 nm), and strong negative surface charge (-25.70 mV). The introduction of CP results in an enhancement of the mucoadhesion between CP-PLGA nanoparticles and mucin particles. In vitro cell internalization studies highlighted the potential of 0.05CP-PLGA nanoparticles for transfection into SiHa cells, with uptake being time dependent. Additionally, cytotoxicity studies of CP-PLGA nanoparticles against SiHa cancer cells indicated that low concentrations of the nanoparticles were non-toxic to cells (cell viability >80%). From the various formulations studied, 0.05CP-PLGA nanoparticles proved to be the optimum model carrier having the required mucoadhesive profile and could be an alternative therapeutic efficacy carrier for targeted mucosal drug delivery systems with biodegradable polymer.

  16. PLGA nanoparticles loaded with host defense peptide LL37 promote wound healing.

    PubMed

    Chereddy, Kiran Kumar; Her, Charles-Henry; Comune, Michela; Moia, Claudia; Lopes, Alessandra; Porporato, Paolo E; Vanacker, Julie; Lam, Martin C; Steinstraesser, Lars; Sonveaux, Pierre; Zhu, Huijun; Ferreira, Lino S; Vandermeulen, Gaëlle; Préat, Véronique

    2014-11-28

    Wound treatment remains one of the most prevalent and economically burdensome healthcare issues in the world. Poly (lactic-co-glycolic acid) (PLGA) supplies lactate that accelerates neovascularization and promotes wound healing. LL37 is an endogenous human host defense peptide that modulates wound healing and angiogenesis and fights infection. Hence, we hypothesized that the administration of LL37 encapsulated in PLGA nanoparticles (PLGA-LL37 NP) promotes wound closure due to the sustained release of both LL37 and lactate. In full thickness excisional wounds, the treatment with PLGA-LL37 NP significantly accelerated wound healing compared to PLGA or LL37 administration alone. PLGA-LL37 NP-treated wounds displayed advanced granulation tissue formation by significant higher collagen deposition, re-epithelialized and neovascularized composition. PLGA-LL37 NP improved angiogenesis, significantly up-regulated IL-6 and VEGFa expression, and modulated the inflammatory wound response. In vitro, PLGA-LL37 NP induced enhanced cell migration but had no effect on the metabolism and proliferation of keratinocytes. It displayed antimicrobial activity on Escherichia coli. In conclusion, we developed a biodegradable drug delivery system that accelerated healing processes due to the combined effects of lactate and LL37 released from the nanoparticles.

  17. PLGA nanometer surface features manipulate fibronectin interactions for improved vascular cell adhesion.

    PubMed

    Miller, Derick C; Haberstroh, Karen M; Webster, Thomas J

    2007-06-01

    The largest cause of mortality in the Western world is atherosclerotic vascular disease. Many of these diseases require synthetic vascular grafts; however, their patency rate is only 30% in small (<6 mm) diameter vascular grafts after 5 years of implantation. In an effort to increase small diameter vascular graft success, researchers have been designing random nanostructured surface features which enhance vascular cell functions. However, for the present study, highly-controllable, nanostructured features on poly(lactic-co-glycolic acid) (PLGA) surfaces were formulated. To create ordered nanostructured roughness on PLGA surfaces, either 500, 200, or 100 nm polystyrene nanospheres were separately placed onto mica. These were then used as a template for creating an inverse poly(dimethylsiloxane) mold which was utilized to cast PLGA. Compared to all other PLGA films formulated, AFM results demonstrated greater initial fibronectin spreading on PLGA which possessed spherical 200 nm features. Compared to smooth PLGA, PLGA with 500 or 100 nm surface features, results further showed that PLGA with 200 nm spherical features promoted vascular cell (specifically, endothelial, and smooth muscle cell) adhesion. In this manner, the present study demonstrated a specific nanometer surface feature size that promoted fibronectin spreading and subsequent vascular cell adhesion; criteria critical to vascular graft success.

  18. Preparation, characterization, and anticancer efficacy of evodiamine-loaded PLGA nanoparticles.

    PubMed

    Zou, Lidi; Chen, Fengqian; Bao, Jiaolin; Wang, Shengpeng; Wang, Lu; Chen, Meiwan; He, Chengwei; Wang, Yitao

    2016-01-01

    Evodiamine (EVO) is a plant-derived indolequinazoline alkaloid with potential anticancer activity. However, low bioavailability caused by its poor water solubility limits it anticancer efficacy in clinic. To enhance the solubility and improve the bioavailability of EVO, a delivery system based on poly (lactic-co-glycolic acid) (PLGA) nanoparticles loaded with EVO (EVO-PLGA NPs) for treating breast cancer was prepared in this study. The physicochemical characterization and in vitro antitumor evaluation of EVO-PLGA NPs were determined. EVO-PLGA NPs could persistently control the release of EVO for 180 h. 3-[4,5-Dimethyl-2-thiazolyl]-2,5-diphenyl tetrazolium bromide (MTT) assessment and colony formation assay showed that EVO-PLGA NPs could enhance the toxicity and the proliferation inhibition effect of EVO on MCF-7 breast cancer cells. EVO-PLGA NPs did not strengthen G2/M arrest effect of EVO-treated cells after 24h incubation. Meanwhile, EVO-PLGA NPs could increase the expression of cyclin B1 and decrease the expression of β-actin. Taken together, these results suggested that -PLGA NPs is promising for improving anticancer efficacy of EVO in breast cancer therapy.

  19. Development of Risperidone PLGA Microspheres

    PubMed Central

    D'Souza, Susan; Faraj, Jabar A.; Giovagnoli, Stefano; DeLuca, Patrick P.

    2014-01-01

    The aim of this study was to design and evaluate biodegradable PLGA microspheres for sustained delivery of Risperidone, with an eventual goal of avoiding combination therapy for the treatment of schizophrenia. Two PLGA copolymers (50 : 50 and 75 : 25) were used to prepare four microsphere formulations of Risperidone. The microspheres were characterized by several in vitro techniques. In vivo studies in male Sprague-Dawley rats at 20 and 40 mg/kg doses revealed that all formulations exhibited an initial burst followed by sustained release of the active moiety. Additionally, formulations prepared with 50 : 50 PLGA had a shorter duration of action and lower cumulative AUC levels than the 75 : 25 PLGA microspheres. A simulation of multiple dosing at weekly or 15-day regimen revealed pulsatile behavior for all formulations with steady state being achieved by the second dose. Overall, the clinical use of Formulations A, B, C, or D will eliminate the need for combination oral therapy and reduce time to achieve steady state, with a smaller washout period upon cessation of therapy. Results of this study prove the suitability of using PLGA copolymers of varying composition and molecular weight to develop sustained release formulations that can tailor in vivo behavior and enhance pharmacological effectiveness of the drug. PMID:24616812

  20. Preparation, characterization and in vivo evaluation of a combination delivery system based on hyaluronic acid/jeffamine hydrogel loaded with PHBV/PLGA blend nanoparticles for prolonged delivery of Teriparatide.

    PubMed

    Bahari Javan, Nika; Montazeri, Hamed; Rezaie Shirmard, Leila; Jafary Omid, Nersi; Barbari, Ghullam Reza; Amini, Mohsen; Ghahremani, Mohammad Hossein; Rafiee-Tehrani, Morteza; Abedin Dorkoosh, Farid

    2017-04-01

    In the current study, biodegradable PHBV/PLGA blend nanoparticles (NPs) containing Teriparatide were loaded in hyaluronic acid/jeffamine (HA-JEF ED-600) hydrogel to prepare a combination delivery system (CDS) for prolonged delivery of Teriparatide. The principal purpose of the present study was to formulate an effective and prolonged Teriparatide delivery system in order to reduce the frequency of injection and thus enhance patient's compliance. Morphological properties, swelling behaviour, crosslinking efficiency and rheological characterization of HA-JEF ED-600 hydrogel were evaluated. The CDS was acquired by adding PHBV/PLGA NPs to HA-JEF ED-600 hydrogel simultaneously with crosslinking reaction. The percentage of NPs incorporation within the hydrogel as well as the loading capacity and morphology of Teriparatide loaded CDS were examined. Intrinsic fluorescence and circular dichroism spectroscopy proved that Teriparatide remains stable after processing. The release profile represented 63% Teriparatide release from CDS within 50days with lower burst release compared to NPs and hydrogel. MTT assay was conducted by using NIH3T3 cell line and no sign of reduction in cell viability was observed. Based on Miller and Tainter method, LD50 of Teriparatide loaded CDS was 131.8mg/kg. In vivo studies demonstrated that Teriparatide loaded CDS could effectively increase serum calcium level after subcutaneous injection in mice. Favourable results in the current study introduced CDS as a promising candidate for controlled delivery of Teriparatide and pave the way for future investigations in the field of designing prolonged delivery systems for other peptides and proteins.

  1. Investigation on the ion pair amphiphiles and their in vitro release of amantadine drug based on PLGA-PEG-PLGA gel

    NASA Astrophysics Data System (ADS)

    Yang, Xiaoxia; Ji, Xiaoqing; Shi, Chunhuan; Liu, Jing; Wang, Haiyang; Luan, Yuxia

    2014-12-01

    The amantadine drug and oleic acid surfactant are used to form amantadine-based ion pair amphiphiles based on proton transfer reaction between the drug and the surfactant molecules. The ion pair amphiphiles are characterized by 1H-nuclear magnetic resonance, Fourier transform infrared spectroscopy, and X-ray diffraction. Self-assembly properties of amantadine-based ion pair amphiphiles are studied by surface tension determination, transmission electron microscopy, zeta potential, and dynamic light scattering. The aggregation behavior studies indicate that the as-prepared ion pair amphiphiles can self-assemble into vesicles with the size of 200-300 nm in aqueous solution. The drug release results show that the amantadine release rate could be well controlled by incorporating the amantadine-based ion pair vesicles in poly (lactic-co-glycolic acid)-poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PLGA-PEG-PLGA) copolymer hydrogel. The drug release from the AT-OA vesicle-loaded PLGA-PEG-PLGA hydrogel is significantly inhibited in comparison with the AT-loaded PLGA-PEG-PLGA hydrogel. The present work thus demonstrates that the vesicle-loaded hydrogel is a good candidate for the drug delivery system with long-term controlled drug release behavior.

  2. [Transport of mPEG-PLGA nanoparticles across the rat nasal mucosa].

    PubMed

    Wang, Jun-Teng; Lin, Dong-Hai; Qin, Li-Fang; Wen, Zhen; Guo, Gui-Ping

    2013-05-01

    To investigate the effects of particle size, mPEG molecular weight, coating density and zeta potential of monomethoxyl poly(ethylene glycol)-poly(lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles on their transportation across the rat nasal mucosa, mPEG-PLGA-NPs with different mPEG molecular weights (M(r) 1 000, 2 000) and coating density (0, 5%, 10%, 15%) and chitosan coated PLGA-NP, which loaded coumarin-6 as fluorescent marker, were prepared with the nanoprecipitation method and emulsion-solvent evaporation method, and determine their particle size, zeta potential, the efficiency of fluorescent labeling, in vitro leakage rate and the stability with the lysozyme were determined. The effects of physical and chemical properties on the transmucosal transport of the fluorescent nanoparticles were investigated by confocal laser scanning microscopy (CLSM). The result showed that the size of nanoparticles prepared with nanoprecipitation method varied between 120 and 200 nm; the size of nanoparticles prepared with emulsion-solvent evaporation method varied between 420 and 450 nm. Nanoparticles dispersed uniformly; the zeta potential of PLGA-NPs was negative; mPEG-PLGA-NPs was close to neutral; chitosan coated PLGA-NPs was positive; and the efficiency of fluorescent labeling were higher than 80%. In vitro leak was less than 5% within 4 h and nanoparticles were basically stable with lysozyme. The CLSM results show that the transportation efficiency of mPEG-PLGA-NPs with a high PEG coating density and high mPEG molecular weight was significantly higher than that of uncoated PLGA nanoparticles and also that of chitosan coated PLGA-NPs (P < 0.05). The hydrophilcity, zeta potential and particle size of nanoparticles play important roles on the efficiency of mPEG-PLGA nanoparticles to transport across the rat nasal mucosa.

  3. Microbubble tunneling in gel phantoms

    PubMed Central

    Caskey, Charles F.; Qin, Shengping; Dayton, Paul A.; Ferrara, Katherine W.

    2009-01-01

    Insonified microbubbles were observed in vessels within a gel with a Young’s modulus similar to that of tissue, demonstrating shape instabilities, liquid jets, and the formation of small tunnels. In this study, tunnel formulation occurred in the direction of the propagating ultrasound wave, where radiation pressure directed the contact of the bubble and gel, facilitating the activity of the liquid jets. Combinations of ultrasonic parameters and microbubble concentrations that are relevant for diagnostic imaging and drug delivery and that lead to tunnel formation were applied and the resulting tunnel formation was quantified. PMID:19425620

  4. High Q silica microbubble resonators

    NASA Astrophysics Data System (ADS)

    Farnesi, D.; Barucci, A.; Berneschi, S.; Brenci, M.; Cosi, F.; Nunzi Conti, G.; Pelli, S.; Righini, G. C.; Soria, S.

    2012-01-01

    Microbubble resonators (MBRs) combine the unique properties of whispering gallery mode resonators with the intrinsic capability of integrated microfluidics. Here an improved fabrication method of MBRs is presented, based on the heating of a slightly pressurized capillary by a rotating arc discharge. Rotation of the electrodes ensures an homogeneous distribution of the heat all over the capillary surface. The demonstrated MBRs have Q factors up to 107 at 773 nm. Microbubbles were filled with water and aqueous solutions of ethanol in order to test the refractive index sensing capabilities of such resonators, which also show a good temporal stability.

  5. Tracking the in vivo release of bioactive NRG from PLGA and PEG-PLGA microparticles in infarcted hearts.

    PubMed

    Pascual-Gil, S; Simón-Yarza, T; Garbayo, E; Prosper, F; Blanco-Prieto, M J

    2015-12-28

    The growth factor neuregulin (NRG) is one of the most promising candidates in protein therapy as potential treatment for myocardial infarction (MI). In the last few years, biomaterial based delivery systems, such as polymeric microparticles (MPs) made of poly(lactic co glycolic acid) and polyethylene glycol (PLGA and PEG-PLGA MPs), have improved the efficacy of protein therapy in preclinical studies. However, no cardiac treatment based on MPs has yet been commercialized since this is a relatively new field and total characterization of polymeric MPs remains mandatory before they reach the clinical arena. Therefore, the objective of this study was to characterize the in vivo release, bioactivity and biodegradation of PLGA and PEG-PLGA MPs loaded with biotinylated NRG in a rat model of MI. The effect of PEGylation in the clearance of the particles from the cardiac tissue was also evaluated. Interestingly, MPs were detected in the cardiac tissue for up to 12 weeks after administration. In vivo release analysis showed that bNRG was released in a controlled manner throughout the twelve week study. Moreover, the biological cardiomyocyte receptor (ErbB4) for NRG was detected in its activated form only in those animals treated with bNRG loaded MPs. On the other hand, the PEGylation strategy was effective in diminishing phagocytosis of these MPs compared to noncoated MPs in the long term (12 weeks after injection). Taking all this together, we report new evidence in favor of the use of polymeric PLGA and PEG-PLGA MPs as delivery systems for treating MI, which could be soon included in clinical trials.

  6. PLGA nanofiber membranes loaded with epigallocatechin-3-O-gallate are beneficial to prevention of postsurgical adhesions

    PubMed Central

    Shin, Yong Cheol; Yang, Won Jun; Lee, Jong Ho; Oh, Jin-Woo; Kim, Tai Wan; Park, Jong-Chul; Hyon, Suong-Hyu; Han, Dong-Wook

    2014-01-01

    This study concentrates on the development of biodegradable nanofiber membranes with controlled drug release to ensure reduced tissue adhesion and accelerated healing. Nanofibers of poly(lactic-co-glycolic acid) (PLGA) loaded with epigallocatechin-3-O-gallate (EGCG), the most bioactive polyphenolic compound in green tea, were electrospun. The physicochemical and biomechanical properties of EGCG-releasing PLGA (E-PLGA) nanofiber membranes were characterized by atomic force microscopy, EGCG release and degradation profiles, and tensile testing. In vitro antioxidant activity and hemocompatibility were evaluated by measuring scavenged reactive oxygen species levels and activated partial thromboplastin time, respectively. In vivo antiadhesion efficacy was examined on the rat peritonea with a surgical incision. The average fiber diameter of E-PLGA membranes was approximately 300–500 nm, which was almost similar to that of pure PLGA equivalents. E-PLGA membranes showed sustained EGCG release mediated by controlled diffusion and PLGA degradation over 28 days. EGCG did not adversely affect the tensile strength of PLGA membranes, whereas it significantly decreased the elastic modulus and increased the strain at break. E-PLGA membranes were significantly effective in both scavenging reactive oxygen species and extending activated partial thromboplastin time. Macroscopic observation after 1 week of surgical treatment revealed that the antiadhesion efficacy of E-PLGA nanofiber membranes was significantly superior to those of untreated controls and pure PLGA equivalents, which was comparable to that of a commercial tissue-adhesion barrier. In conclusion, the E-PLGA hybrid nanofiber can be exploited to craft strategies for the prevention of postsurgical adhesions. PMID:25187710

  7. PLGA nanofiber membranes loaded with epigallocatechin-3-O-gallate are beneficial to prevention of postsurgical adhesions.

    PubMed

    Shin, Yong Cheol; Yang, Won Jun; Lee, Jong Ho; Oh, Jin-Woo; Kim, Tai Wan; Park, Jong-Chul; Hyon, Suong-Hyu; Han, Dong-Wook

    2014-01-01

    This study concentrates on the development of biodegradable nanofiber membranes with controlled drug release to ensure reduced tissue adhesion and accelerated healing. Nanofibers of poly(lactic-co-glycolic acid) (PLGA) loaded with epigallocatechin-3-O-gallate (EGCG), the most bioactive polyphenolic compound in green tea, were electrospun. The physicochemical and biomechanical properties of EGCG-releasing PLGA (E-PLGA) nanofiber membranes were characterized by atomic force microscopy, EGCG release and degradation profiles, and tensile testing. In vitro antioxidant activity and hemocompatibility were evaluated by measuring scavenged reactive oxygen species levels and activated partial thromboplastin time, respectively. In vivo antiadhesion efficacy was examined on the rat peritonea with a surgical incision. The average fiber diameter of E-PLGA membranes was approximately 300-500 nm, which was almost similar to that of pure PLGA equivalents. E-PLGA membranes showed sustained EGCG release mediated by controlled diffusion and PLGA degradation over 28 days. EGCG did not adversely affect the tensile strength of PLGA membranes, whereas it significantly decreased the elastic modulus and increased the strain at break. E-PLGA membranes were significantly effective in both scavenging reactive oxygen species and extending activated partial thromboplastin time. Macroscopic observation after 1 week of surgical treatment revealed that the antiadhesion efficacy of E-PLGA nanofiber membranes was significantly superior to those of untreated controls and pure PLGA equivalents, which was comparable to that of a commercial tissue-adhesion barrier. In conclusion, the E-PLGA hybrid nanofiber can be exploited to craft strategies for the prevention of postsurgical adhesions.

  8. Improving Protein Stability and Controlling Protein Release by Adding Poly (Cyclohexane-1, 4-Diyl Acetone Dimethylene Ketal) to PLGA Microspheres.

    PubMed

    Wang, Chenhui; Yu, Changhui; Yu, Kongtong; Teng, Lesheng; Liu, Jiaxin; Wang, Xuesong; Sun, Fengying; Li, Youxin

    2015-01-01

    The use of biodegradable polymers such as PLGA to encapsulate therapeutic proteins for their controlled release has received tremendous interest. However, an acidic environment caused by PLGA degradation productions leads to protein incomplete release and chemical degradation. The aim of this study was to develop novel PCADK/PLGA microspheres to improve protein stability and release behavior. Bovine serum albumin (BSA) incubated in PCADK and PLGA degradation products was investigated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), size exclusion chromatography (SEC-HPLC), circular dichroism (CD) and fluorescence spectroscopy. Blended microspheres of PCADK/PLGA were prepared in different ratios and the release behaviors of the microspheres and the protein stability were then measured. The degradation properties of the microspheres and the pH inside the microspheres were systematically investigated by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) to examine the mechanism of autocatalytic degradation and protein stability. BSA was more stable in the presence of PCADK monomers than it was in the presence of PLGA monomers, revealing that PCADK is highly compatible with this protein. PCADK/PLGA microspheres were successfully prepared, and 2/8 was determined to be the optimal ratio. Further, 43% of the BSA formed water-insoluble aggregates in the presence of PCADK/PLGA microspheres, compared with 57% for the PLGA microspheres, demonstrating that the BSA encapsulated in PCADK/PLGA blended microspheres was more stable than in PLGA microspheres. The PCADK/PLGA blended microspheres improved protein stability and release behavior, providing a promising protein drug delivery system.

  9. Encapsulated microbubbles and echogenic liposomes for contrast ultrasound imaging and targeted drug delivery

    PubMed Central

    Paul, Shirshendu; Nahire, Rahul; Mallik, Sanku; Sarkar, Kausik

    2014-01-01

    Micron- to nanometer-sized ultrasound agents, like encapsulated microbubbles and echogenic liposomes, are being developed for diagnostic imaging and ultrasound mediated drug/gene delivery. This review provides an overview of the current state of the art of the mathematical models of the acoustic behavior of ultrasound contrast microbubbles. We also present a review of the in vitro experimental characterization of the acoustic properties of microbubble based contrast agents undertaken in our laboratory. The hierarchical two-pronged approach of modeling contrast agents we developed is demonstrated for a lipid coated (Sonazoid™) and a polymer shelled (poly D-L-lactic acid) contrast microbubbles. The acoustic and drug release properties of the newly developed echogenic liposomes are discussed for their use as simultaneous imaging and drug/gene delivery agents. Although echogenicity is conclusively demonstrated in experiments, its physical mechanisms remain uncertain. Addressing questions raised here will accelerate further development and eventual clinical approval of these novel technologies. PMID:26097272

  10. Efficient production of retroviruses using PLGA/bPEI-DNA nanoparticles and application for reprogramming somatic cells.

    PubMed

    Seo, Eun Jin; Jang, Il Ho; Do, Eun Kyoung; Cheon, Hyo Cheon; Heo, Soon Chul; Kwon, Yang Woo; Jeong, Geun Ok; Kim, Ba Reun; Kim, Jae Ho

    2013-01-01

    Reprogramming of somatic cells to pluripotent cells requires the introduction of factors driving fate switches. Viral delivery has been the most efficient method for generation of induced pluripotent stem cells. Transfection, which precedes virus production, is a commonly-used process for delivery of nucleic acids into cells. The aim of this study is to evaluate the efficiency of PLGA/ bPEI nanoparticles in transfection and virus production. Using a modified method of producing PLGA nanoparticles, PLGA/bPEI-DNA nanoparticles were examined for transfection efficiency and virus production yield in comparison with PLGA-DNA, bPEI-DNA nanoparticles or liposome-DNA complexes. After testing various ratios of PLGA, bPEI, and DNA, the ratio of 6:3:1 (PLGA:bPEI:DNA, w/w/w) was determined to be optimal, with acceptable cellular toxicity. PLGA/bPEI-DNA (6:3:1) nanoparticles showed superior transfection efficiency, especially in multiple gene transfection, and viral yield when compared with liposome-DNA complexes. The culture supernatants of HEK293FT cells transfected with PLGA/bPEI-DNA of viral constructs containing reprogramming factors (Oct4, Sox2, Klf4, or c-Myc) successfully and more efficiently generated induced pluripotent stem cell colonies from mouse embryonic fibroblasts. These results strongly suggest that PLGA/bPEI-DNA nanoparticles can provide significant advantages in studying the effect of multiple factor delivery such as in reprogramming or direct conversion of cell fate.

  11. Multiparameter evaluation of in vivo gene delivery using ultrasound-guided, microbubble-enhanced sonoporation.

    PubMed

    Shapiro, Galina; Wong, Andrew W; Bez, Maxim; Yang, Fang; Tam, Sarah; Even, Lisa; Sheyn, Dmitriy; Ben-David, Shiran; Tawackoli, Wafa; Pelled, Gadi; Ferrara, Katherine W; Gazit, Dan

    2016-02-10

    More than 1800 gene therapy clinical trials worldwide have targeted a wide range of conditions including cancer, cardiovascular diseases, and monogenic diseases. Biological (i.e. viral), chemical, and physical approaches have been developed to deliver nucleic acids into cells. Although viral vectors offer the greatest efficiency, they also raise major safety concerns including carcinogenesis and immunogenicity. The goal of microbubble-mediated sonoporation is to enhance the uptake of drugs and nucleic acids. Insonation of microbubbles is thought to facilitate two mechanisms for enhanced uptake: first, deflection of the cell membrane inducing endocytotic uptake, and second, microbubble jetting inducing the formation of pores in the cell membrane. We hypothesized that ultrasound could be used to guide local microbubble-enhanced sonoporation of plasmid DNA. With the aim of optimizing delivery efficiency, we used nonlinear ultrasound and bioluminescence imaging to optimize the acoustic pressure, microbubble concentration, treatment duration, DNA dosage, and number of treatments required for in vivo Luciferase gene expression in a mouse thigh muscle model. We found that mice injected with 50μg luciferase plasmid DNA and 5×10(5) microbubbles followed by ultrasound treatment at 1.4MHz, 200kPa, 100-cycle pulse length, and 540 Hz pulse repetition frequency (PRF) for 2min exhibited superior transgene expression compared to all other treatment groups. The bioluminescent signal measured for these mice on Day 4 post-treatment was 100-fold higher (p<0.0001, n=5 or 6) than the signals for controls treated with DNA injection alone, DNA and microbubble injection, or DNA injection and ultrasound treatment. Our results indicate that these conditions result in efficient gene delivery and prolonged gene expression (up to 21days) with no evidence of tissue damage or off-target delivery. We believe that these promising results bear great promise for the development of microbubble

  12. Preparation and characterization of gadolinium-loaded PLGA particles surface modified with RGDS for the detection of thrombus

    PubMed Central

    Zhang, Yu; Zhou, Jun; Guo, Dajing; Ao, Meng; Zheng, Yuanyi; Wang, Zhigang

    2013-01-01

    Thrombotic disease is a leading cause of death and disability worldwide. The development of magnetic resonance molecular imaging provides potential promise for early disease diagnosis. In this study, we explore the preparation and characterization of gadolinium (Gd)-loaded poly (lactic-co-glycolic acid) (PLGA) particles surface modified with the Arg-Gly-Asp-Ser (RGDS) peptide for the detection of thrombus. PLGA was employed as the carrier-delivery system, and a double emulsion solvent-evaporation method (water in oil in water) was used to prepare PLGA particles encapsulating the magnetic resonance contrast agent Gd diethylenetriaminepentaacetic acid (DTPA). To synthesize the Gd-PLGA/chitosan (CS)-RGDS particles, carbodiimide-mediated amide bond formation was used to graft the RGDS peptide to CS to form a CS-RGDS film that coated the surface of the PLGA particles. Blank PLGA, Gd-PLGA, and Gd-PLGA/CS particles were fabricated using the same water in oil in water method. Our results indicated that the RGDS peptide successfully coated the surface of the Gd-PLGA/CS-RGDS particles. The particles had a regular shape, smooth surface, relatively uniform size, and did not aggregate. The high electron density of the Gd-loaded particles and a translucent film around the particles coated with the CS and CS-RGDS films could be observed by transmission electron microscopy. In vitro experiments demonstrated that the Gd-PLGA/CS-RGDS particles could target thrombi and could be imaged using a clinical magnetic resonance scanner. Compared with the Gd-DTPA solution, the longitudinal relaxation time of the Gd-loaded particles was slightly longer, and as the Gd-load concentration increased, the longitudinal relaxation time values decreased. These results suggest the potential of the Gd-PLGA/CS-RGDS particles for the sensitive and specific detection of thrombus at the molecular level. PMID:24124363

  13. In vitro evaluation of the genotoxicity of a family of novel MeO-PEG-poly(D,L-lactic-co-glycolic acid)-PEG-OMe triblock copolymer and PLGA nanoparticles

    NASA Astrophysics Data System (ADS)

    He, Lili; Yang, Likai; Zhang, Zhi-rong; Gong, Tao; Deng, Li; Gu, Zhongwei; Sun, Xun

    2009-11-01

    Despite the booming development of nanoparticle materials for pharmaceutical applications, studies on their genotoxicity are few. In our previous efforts to develop an intravenous nanoparticle material, a family of novel monomethoxy(polyethylene glycol)-poly(D,L-lactic-co-glycolic acid)-monomethoxy (PELGE) polymers was synthesized. The cytotoxicity and genotoxicity of nine kinds of selected blank PELGE and PLGA (poly(D,L-lactic and glycolic acid)) nanoparticles were evaluated using methyl thiazolyl tetrazolium (MTT), micronucleus (MN) and sister chromatid exchange (SCE) assays with or without the addition of a metabolic activation system (S9 mix), using Chinese hamster ovary (CHO) cells. The cytotoxicity of nanoparticles exhibited a dose-dependent response, with a concentration of 5 mg ml-1 being the turning point. The frequencies of MN observed in samples treated with various nanoparticles were not statistically different from those seen in the negative controls in the presence or absence of the S9 mix. Also, no cell cycle delay was observed. The numbers of SCE per cell observed in samples treated with five kinds of PELGE nanoparticles were significantly greater than those found in the negative controls with or without the S9 mix. The discrepancies found in the two assays suggest that the five kinds of nanoparticles may produce only a weakly clastogenic response.

  14. Assessment of PLGA-PEG-PLGA copolymer hydrogel for sustained drug delivery in the ear.

    PubMed

    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-PEGPLGA 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.

  15. Bone induction by biomimetic PLGA-(PEG-ASP)n copolymer loaded with a novel synthetic BMP-2-related peptide in vitro and in vivo.

    PubMed

    Lin, Zhen-Yu; Duan, Zhi-Xia; Guo, Xiao-Dong; Li, Jing-Feng; Lu, Hong-Wei; Zheng, Qi-Xin; Quan, Da-Ping; Yang, Shu-Hua

    2010-06-01

    BMP-2 is one of the most important growth factors of bone regeneration. Polylactide-co-glycolic acid (PLGA), which is used as a biodegradable scaffold for delivering therapeutic agents, has been intensively investigated. In previous studies, we synthesized a novel BMP-2-related peptide (designated P24) and found that it could enhance the osteoblastic differentiation of bone marrow stromal cells (BMSCs). The objective of this study was to construct a biomimetic composite by incorporating P24 into a modified PLGA-(PEG-ASP)n copolymer to promote bone formation. In vitro, our results demonstrated that PLGA-(PEG-ASP)n scaffolds were shown to be an efficient system for sustained release of P24. Significantly more BMSCs attached to the P24/PLGA-(PEG-ASP)n and PLGA-(PEG-ASP)n membranes than to PLGA, and the cells in the two groups subsequently proliferated more vigorously than those in the PLGA group. The expression of osteogenic markers in P24/PLGA-(PEG-ASP)n group was stronger than that in the PLGA-(PEG-ASP)n and PLGA groups. Radiographic and histological examination, Western blotting and RT-PCR showed that P24/PLGA-(PEG-ASP)n scaffold could induce more effective ectopic bone formation in vivo, as compared with PLGA-(PEG-ASP)n or gelatin sponge alone. It is concluded that the PLGA-(PEG-ASP)n copolymer is a good P24 carrier and can serve as a good scaffold for controlled release of P24. This novel P24/PLGA-(PEG-ASP)n composite promises to be an excellent biomaterial for inducing bone regeneration.

  16. Preparation, physicochemical properties and biocompatibility of PBLG/PLGA/bioglass composite scaffolds.

    PubMed

    Cui, Ning; Qian, Junmin; Wang, Jinlei; Ji, Chuanlei; Xu, Weijun; Wang, Hongjie

    2017-02-01

    In this study, novel poly(γ-benzyl l-glutamate)/poly(lactic-co-glycolic acid)/bioglass (PBLG/PLGA/BG) composite scaffolds with different weight ratios were fabricated using a negative NaCl-templating method. The morphology, compression modulus and degradation kinetics of the scaffolds were characterized. The results showed that the PBLG/PLGA/BG composite scaffolds with a weight ratio of 5:5:1, namely PBLG5PLGA5BG composite scaffolds, displayed a pore size range of 50-500μm, high compressive modulus (566.6±8.8kPa), suitable glass transition temperature (46.8±0.2°C) and low degradation rate (>8weeks). The in vitro biocompatibility of the scaffolds was evaluated with MC3T3-E1 cells by live-dead staining, MTT and ALP activity assays. The obtained results indicated that the PBLG5PLGA5BG composite scaffolds were more conducive to the adhesion, proliferation and osteoblastic differentiation of MC3T3-E1 cells than PBLG and PBLG/PLGA composite scaffolds. The in vivo biocompatibility of the scaffolds was evaluated in both SD rat subcutaneous model and rabbit tibia defect model. The results of H&E, Masson's trichrome and CD34 staining assays demonstrated that the PBLG5PLGA5BG composite scaffolds allowed the ingrowth of tissue and microvessels more effectively than PBLG/PLGA composite scaffolds. The results of digital radiography confirmed that the PBLG5PLGA5BG composite scaffolds significantly improved in vivo osteogenesis. Collectively, the PBLG5PLGA5BG composite scaffolds could be a promising candidate for tissue engineering applications.

  17. PLGA-Mesoporous Silicon Microspheres for the in Vivo Controlled Temporospatial Delivery of Proteins.

    PubMed

    Minardi, Silvia; Pandolfi, Laura; Taraballi, Francesca; De Rosa, Enrica; Yazdi, Iman K; Liu, Xeuwu; Ferrari, Mauro; Tasciotti, Ennio

    2015-08-05

    In regenerative medicine, the temporospatially controlled delivery of growth factors (GFs) is crucial to trigger the desired healing mechanisms in the target tissues. The uncontrolled release of GFs has been demonstrated to cause severe side effects in the surrounding tissues. The aim of this study was to optimize a translational approach for the fine temporal and spatial control over the release of proteins, in vivo. Hence, we proposed a newly developed multiscale composite microsphere based on a core consisting of the nanostructured silicon multistage vector (MSV) and a poly(dl-lactide-co-glycolide) acid (PLGA) outer shell. Both of the two components of the resulting composite microspheres (PLGA-MSV) can be independently tailored to achieve multiple release kinetics contributing to the control of the release profile of a reporter protein in vitro. The influence of MSV shape (hemispherical or discoidal) and size (1, 3, or 7 μm) on PLGA-MSV's morphology and size distribution was investigated. Second, the copolymer ratio of the PLGA used to fabricate the outer shell of PLGA-MSV was varied. The composites were fully characterized by optical microscopy, scanning electron microscopy, ζ potential, Fourier transform infrared spectroscopy, and thermogravimetric analysis-differential scanning calorimetry, and their release kinetics over 30 days. PLGA-MSV's biocompatibility was assessed in vitro with J774 macrophages. Finally, the formulation of PLGA-MSV was selected, which concurrently provided the most consistent microsphere size and allowed for a zero-order release kinetic. The selected PLGA-MSVs were injected in a subcutaneous model in mice, and the in vivo release of the reporter protein was followed over 2 weeks by intravital microscopy, to assess if the zero-order release was preserved. PLGA-MSV was able to retain the payload over 2 weeks, avoiding the initial burst release typical of most drug delivery systems. Finally, histological evaluation assessed the

  18. Porous magnesium/PLGA composite scaffolds for enhanced bone regeneration following tooth extraction.

    PubMed

    Brown, Andrew; Zaky, Samer; Ray, Herbert; Sfeir, Charles

    2015-01-01

    Sixty percent of implant-supported dental prostheses require bone grafting to enhance bone quantity and quality prior to implant placement. We have developed a metallic magnesium particle/PLGA composite scaffold to overcome the limitations of currently used dental bone grafting materials. This is the first report of porous metallic magnesium/PLGA scaffolds synthesized using a solvent casting, salt leaching method. We found that incorporation of varying amounts of magnesium into the PLGA scaffolds increased the compressive strength and modulus, as well as provided a porous structure suitable for cell infiltration, as measured by mercury intrusion porosimetry. Additionally, combining basic-degrading magnesium with acidic-degrading PLGA led to an overall pH buffering effect and long-term release of magnesium over the course of a 10-week degradation assay, as measured with inductively coupled plasma-atomic emission spectroscopy. Using an indirect proliferation assay adapted from ISO 10993:5, it was found that extracts of medium from degrading magnesium/PLGA scaffolds increased bone marrow stromal cell proliferation in vitro, a phenomenon observed by other groups investigating magnesium's impact on cells. Finally, magnesium/PLGA scaffold biocompatibility was assessed in a canine socket preservation model. Micro-computed tomography and histological analysis showed the magnesium/PLGA scaffolds to be safer and more effective at preserving bone height than empty controls. Three-dimensional magnesium/PLGA composite scaffolds show promise for dental socket preservation and also, potentially, orthopedic bone regeneration. These scaffolds could decrease inflammation observed with clinically used PLGA devices, as well as enhance osteogenesis, as observed with previously studied magnesium devices.

  19. Surface modification of PLGA nanoparticles via human serum albumin conjugation for controlled delivery of docetaxel

    PubMed Central

    2013-01-01

    Background Poly lactic-co-glycolic acid (PLGA) based nanoparticles are considered to be a promising drug carrier in tumor targeting but suffer from the high level of opsonization by reticuloendothelial system due to their hydrophobic structure. As a result surface modification of these nanoparticles has been widely studied as an essential step in their development. Among various surface modifications, human serum albumin (HSA) possesses advantages including small size, hydrophilic surface and accumulation in leaky vasculature of tumors through passive targeting and a probable active transport into tumor tissues. Methods PLGA nanoparticles of docetaxel were prepared by emulsification evaporation method and were surface conjugated with human serum albumin. Fourier transform infrared spectrum was used to confirm the conjugation reaction where nuclear magnetic resonance was utilized for conjugation ratio determination. In addition, transmission electron microscopy showed two different contrast media in conjugated nanoparticles. Furthermore, cytotoxicity of free docetaxel, unconjugated and conjugated PLGA nanoparticles was studied in HepG2 cells. Results Size, zeta potential and drug loading of PLGA nanoparticles were about 199 nm, −11.07 mV, and 4%, respectively where size, zeta potential and drug loading of conjugated nanoparticles were found to be 204 nm, −5.6 mV and 3.6% respectively. Conjugated nanoparticles represented a three-phasic release pattern with a 20% burst effect for docetaxel on the first day. Cytotoxicity experiment showed that the IC50 of HSA conjugated PLGA nanoparticles (5.4 μg) was significantly lower than both free docetaxel (20.2 μg) and unconjugated PLGA nanoparticles (6.2 μg). Conclusion In conclusion surface modification of PLGA nanoparticles through HSA conjugation results in more cytotoxicity against tumor cell lines compared with free docetaxel and unconjugated PLGA nanoparticles. Albumin conjugated PLGA nanoparticles may

  20. Microbubbling by co-axial electrohydrodynamic atomization.

    PubMed

    Farook, U; Stride, E; Edirisinghe, M J; Moaleji, R

    2007-08-01

    The preparation of microbubble suspensions is an important feature of medical engineering research. Recently, co-axial electrohydrodynamic atomization was used in our laboratory for the first time to prepare microbubble suspensions. In this paper, using a model glycerol-air system, we investigate in detail the characteristics of this microbubbling process. Modes of microbubbling are elucidated with respect to applied voltage and liquid and air flow rates. Thus, a parametric plot is constructed to identify a liquid and gas flow rate regime, which allows continuous microbubbling. This map provides a basis for the selection of a suitable combination of liquid and gas flow rates particularly in relation to yield and bubble size. The mechanism of microbubbling in microfluidic systems is compared with that of microbubbling by co-axial electrohydrodynamic atomization to identify the advantages and the limiting factors of the latter. Stability of microbubbles prepared by this method in terms of variation of diameter as a function of time is compared with previous literature on the dissolution of microbubbles with an air core and suggests the need for further work to stabilize the bubbles.

  1. Measurement of PLGA-NP interaction with single smooth muscle cells using optical tweezers

    NASA Astrophysics Data System (ADS)

    Gu, Ling; Mondal, Argha; Homayoni, Homa; Nguyen, Kytai; Mohanty, Samarendra

    2012-10-01

    For intervention of cardiovascular diseases, biodegradable and biocompatible, poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) are emerging as agents of choice for controlled and targeted drug delivery. Therefore development of PLGA-NP with optimal physico-chemical properties will allow efficient binding and thus delivery of drug to targeted cells under various patho-physiological conditions. The force kinetics and its dependence on size of the NPs will be crucial for designing the NPs. Since optical tweezers allow non-contact, highly sensitive force measurement with high spatial and temporal resolution, we utilized it for studying interaction forces between magnetic PLGA nanoparticles with smooth muscle cells (SMC). In order to investigate effect of size, interaction force for 200 to 1100nm PLGA NP was measured. For similar interaction duration, the force was found to be higher with increase in size. The rupture force was found to depend on time of interaction of SMC with NPs.

  2. In vitro performance of lipid-PLGA hybrid nanoparticles as an antigen delivery system: lipid composition matters

    NASA Astrophysics Data System (ADS)

    Hu, Yun; Ehrich, Marion; Fuhrman, Kristel; Zhang, Chenming

    2014-08-01

    Due to the many beneficial properties combined from both poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and liposomes, lipid-PLGA hybrid NPs have been intensively studied as cancer drug delivery systems, bio-imaging agent carriers, as well as antigen delivery vehicles. However, the impact of lipid composition on the performance of lipid-PLGA hybrid NPs as a delivery system has not been well investigated. In this study, the influence of lipid composition on the stability of the hybrid NPs and in vitro antigen release from NPs under different conditions was examined. The uptake of hybrid NPs with various surface charges by dendritic cells (DCs) was carefully studied. The results showed that PLGA NPs enveloped by a lipid shell with more positive surface charges could improve the stability of the hybrid NPs, enable better controlled release of antigens encapsulated in PLGA NPs, as well as enhance uptake of NPs by DC.

  3. Fabrication of PLGA/MWNTs composite electrospun fibrous scaffolds for improved myogenic differentiation of C2C12 cells.

    PubMed

    Xu, Jiazhu; Xie, Ya; Zhang, Hongbo; Ye, Zhaoyang; Zhang, Wenjun

    2014-11-01

    Electrically conducting scaffolds have attracted tremendous attention in skeletal muscle tissue engineering. In this paper, poly(lactic-co-glycolic acid) (PLGA)/multi-wall carbon nanotubes (MWNTs) composite fibrous scaffolds were fabricated using the electrospinning technique. The physical properties of the composite fibers were characterized and proliferation and differentiation of C2C12 cells on these scaffolds were examined. It was found that the addition of MWNTs modulated the physical properties of PLGA fibers including morphology, fiber diameter, degradation, tensile strength and electrical conductivity, depending on the amount of MWNTs. These fibrous scaffolds were cytocompatible and supported the proliferation of C2C12 cells. Importantly, C2C12 cells showed more mature myotube formation on PLGA/MWNTs composite fibrous scaffolds compared to PLGA scaffolds. These results indicate that PLGA/MWNTs composite electrospun fibers have great potential in skeletal muscle tissue engineering.

  4. Treating cutaneous squamous cell carcinoma using ALA PLGA nanoparticle-mediated photodynamic therapy in a mouse model

    NASA Astrophysics Data System (ADS)

    Wang, Xiaojie; Shi, Lei; Tu, Qingfeng; Wang, Hongwei; Zhang, Haiyan; Wang, Peiru; Zhang, Linglin; Huang, Zheng; Wang, Xiuli; Zhao, Feng; Luan, Hansen

    2015-03-01

    Background: Squamous cell carcinoma (SCC) is a common skin cancer and its treatment is still difficult. The aim of this study was to evaluate the effectiveness of nanoparticle (NP)-assisted ALA delivery for topical photodynamic therapy (PDT) of cutaneous SCC. Methods: UV-induced cutaneous SCCs were established in hairless mice. ALA loaded polylactic-co-glycolic acid (PLGA) NPs were prepared and characterized. The kinetics of ALA PLGA NPs-induced protoporphyrin IX (PpIX) fluorescence in SCCs, therapeutic efficacy of ALA NP-mediated PDT, and immune responses were examined. Results: PLGA NPs could enhance PpIX production in SCC. ALA PLGA NP mediated topical PDT was more effective than free ALA of the same concentration in treating cutaneous SCC. Conclusion: PLGA NPs provide a promising strategy for delivering ALA in topical PDT of cutaneous SCC.

  5. Gamma Irradiation of Active Self-healing PLGA Microspheres for Efficient Aqueous Encapsulation of Vaccine Antigens

    PubMed Central

    Desai, Kashappa-Goud H.; Kadous, Samer; Schwendeman, Steven P.

    2013-01-01

    Purpose To investigate the effect of γ-irradiation of poly(lactic-co-glycolic acid) (PLGA)/Al(OH)3/0 or 5 wt% diethyl phthalate (DEP) microspheres for active self-healing encapsulation of vaccine antigens. Methods Microspheres were irradiated with 60Co at 2.5 and 1.8 MRad and 0.37 and 0.20 MRad/h. Encapsulation of tetanus toxoid (TT) was achieved by mixing Al(OH)3-PLGA microspheres with TT solution at 10-38°C. Electron paramagnetic resonance (EPR) spectroscopy was used to examine free radical formation. Glass transition temperature (Tg) and molecular weight of PLGA was measured by differential scanning calorimetry and gel permeation chromatography, respectively. Loading and release of TT were examined by modified Bradford, amino acid analysis, and ELISA assays. Results EPR spectroscopy results indicated absence of free radicals in PLGA microspheres after γ-irradiation. Antigen-sorbing capacity, encapsulation efficiency, and Tg of the polymer were also not adversely affected. When DEP-loaded microspheres were irradiated at 0.2 MRad/h, some PLGA pores healed during irradiation and PLGA healing during encapsulation was suppressed. The molecular weight of PLGA was slightly reduced when DEP-loaded microspheres were irradiated at the same dose rate. These trends were not observed at 0.37 MRad/h. Gamma irradiation slightly increased TT initial burst release. Apart from the slightly higher polymer molecular weight decline caused by higher irradiation dose in case of DEP-loaded microspheres, the small increase in total irradiation dose from 1.8 to 2.5 MRad had insignificant effect on the polymer and microspheres properties analyzed. Conclusion Gamma irradiation is a plausible approach to provide a terminally sterilized, self-healing encapsulation PLGA excipient for vaccine delivery. PMID:23515830

  6. Superharmonic microbubble Doppler effect in ultrasound therapy.

    PubMed

    Pouliopoulos, Antonios N; Choi, James J

    2016-08-21

    The introduction of microbubbles in focused ultrasound therapies has enabled a diverse range of non-invasive technologies: sonoporation to deliver drugs into cells, sonothrombolysis to dissolve blood clots, and blood-brain barrier opening to deliver drugs into the brain. Current methods for passively monitoring the microbubble dynamics responsible for these therapeutic effects can identify the cavitation position by passive acoustic mapping and cavitation mode by spectral analysis. Here, we introduce a new feature that can be monitored: microbubble effective velocity. Previous studies have shown that echoes from short imaging pulses had a Doppler shift that was produced by the movement of microbubbles. Therapeutic pulses are longer (>1 000 cycles) and thus produce a larger alteration of microbubble distribution due to primary and secondary acoustic radiation force effects which cannot be monitored using pulse-echo techniques. In our experiments, we captured and analyzed the Doppler shift during long therapeutic pulses using a passive cavitation detector. A population of microbubbles (5  ×  10(4)-5  ×  10(7) microbubbles ml(-1)) was embedded in a vessel (inner diameter: 4 mm) and sonicated using a 0.5 MHz focused ultrasound transducer (peak-rarefactional pressure: 75-366 kPa, pulse length: 50 000 cycles or 100 ms) within a water tank. Microbubble acoustic emissions were captured with a coaxially aligned 7.5 MHz passive cavitation detector and spectrally analyzed to measure the Doppler shift for multiple harmonics above the 10th harmonic (i.e. superharmonics). A Doppler shift was observed on the order of tens of kHz with respect to the primary superharmonic peak and is due to the axial movement of the microbubbles. The position, amplitude and width of the Doppler peaks depended on the acoustic pressure and the microbubble concentration. Higher pressures increased the effective velocity of the microbubbles up to 3 m s(-1), prior to the onset

  7. Superharmonic microbubble Doppler effect in ultrasound therapy

    NASA Astrophysics Data System (ADS)

    Pouliopoulos, Antonios N.; Choi, James J.

    2016-08-01

    The introduction of microbubbles in focused ultrasound therapies has enabled a diverse range of non-invasive technologies: sonoporation to deliver drugs into cells, sonothrombolysis to dissolve blood clots, and blood-brain barrier opening to deliver drugs into the brain. Current methods for passively monitoring the microbubble dynamics responsible for these therapeutic effects can identify the cavitation position by passive acoustic mapping and cavitation mode by spectral analysis. Here, we introduce a new feature that can be monitored: microbubble effective velocity. Previous studies have shown that echoes from short imaging pulses had a Doppler shift that was produced by the movement of microbubbles. Therapeutic pulses are longer (>1 000 cycles) and thus produce a larger alteration of microbubble distribution due to primary and secondary acoustic radiation force effects which cannot be monitored using pulse-echo techniques. In our experiments, we captured and analyzed the Doppler shift during long therapeutic pulses using a passive cavitation detector. A population of microbubbles (5  ×  104-5  ×  107 microbubbles ml-1) was embedded in a vessel (inner diameter: 4 mm) and sonicated using a 0.5 MHz focused ultrasound transducer (peak-rarefactional pressure: 75-366 kPa, pulse length: 50 000 cycles or 100 ms) within a water tank. Microbubble acoustic emissions were captured with a coaxially aligned 7.5 MHz passive cavitation detector and spectrally analyzed to measure the Doppler shift for multiple harmonics above the 10th harmonic (i.e. superharmonics). A Doppler shift was observed on the order of tens of kHz with respect to the primary superharmonic peak and is due to the axial movement of the microbubbles. The position, amplitude and width of the Doppler peaks depended on the acoustic pressure and the microbubble concentration. Higher pressures increased the effective velocity of the microbubbles up to 3 m s-1, prior to the onset of

  8. Microbubble Compositions, Properties and Biomedical Applications

    PubMed Central

    Sirsi, Shashank

    2010-01-01

    Over the last decade, there has been significant progress towards the development of microbubbles as theranostics for a wide variety of biomedical applications. The unique ability of microbubbles to respond to ultrasound makes them useful agents for contrast ultrasound imaging, molecular imaging, and targeted drug and gene delivery. The general composition of a microbubble is a gas core stabilized by a shell comprised of proteins, lipids or polymers. Each type of microbubble has its own unique advantages and can be tailored for specialized functions. In this review, different microbubbles compositions and physiochemical properties are discussed in the context of current progress towards developing novel constructs for biomedical applications, with specific emphasis on molecular imaging and targeted drug/gene delivery. PMID:20574549

  9. Current strategies in modification of PLGA-based gene delivery system.

    PubMed

    Ramezani, Mohammad; Ebrahimian, Mahboubeh; Hashemi, Maryam

    2016-12-05

    The successful gene therapy has been limited by safe and efficient delivery of nucleic acid to the target cells. Poly (d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) are able to deliver drugs and gene efficiently. This formulation has several advantages in comparison with other formulations including improvement of solubility, stability, controlling of degradation and release of the entrapped agents. For application of PLGA as gene carrier, there exist many challenges. PLGA nanoparticles could protect the encapsulated DNA from in vivo degradation but the DNA release is slowl and their negative charge acts as a barrier to DNA incorporation and delivery. Also, during the preparation process, DNA could be exposed to high shear stress and organic solvents which could result in its inactivation. Moreover, PLGA NPs could be modified with different agents to reduce its cytotoxicity, to enhance the delivery efficiency and to target it to specific tissues/cells. This review summarizes different methods used for the preparation of PLGA NPs as gene carriers and recent strategies for modification of PLGA particles applied in gene therapy.

  10. pH-Responsive PLGA Nanoparticle for Controlled Payload Delivery of Diclofenac Sodium

    PubMed Central

    Khanal, Shalil; Adhikari, Udhab; Rijal, Nava P.; Bhattarai, Shanta R.; Sankar, Jagannathan; Bhattarai, Narayan

    2016-01-01

    Poly(lactic-co-glycolic acid) (PLGA) based nanoparticles have gained increasing attention in delivery applications due to their capability for controlled drug release characteristics, biocompatibility, and tunable mechanical, as well as degradation, properties. However, thorough study is always required while evaluating potential toxicity of the particles from dose dumping, inconsistent release and drug-polymer interactions. In this research, we developed PLGA nanoparticles modified by chitosan (CS), a cationic and pH responsive polysaccharide that bears repetitive amine groups in its backbone. We used a model drug, diclofenac sodium (DS), a nonsteroidal anti-inflammatory drug (NSAID), to study the drug loading and release characteristics. PLGA nanoparticles were synthesized by double-emulsion solvent evaporation technique. The nanoparticles were evaluated based on their particle size, surface charge, entrapment efficacy, and effect of pH in drug release profile. About 390–420 nm of average diameters and uniform morphology of the particles were confirmed by scanning electron microscope (SEM) imaging and dynamic light scattering (DLS) measurement. Chitosan coating over PLGA surface was confirmed by FTIR and DLS. Drug entrapment efficacy was up to 52%. Chitosan coated PLGA showed a pH responsive drug release in in vitro. The release was about 45% more at pH 5.5 than at pH 7.4. The results of our study indicated the development of chitosan coating over PLGA nanoparticle for pH dependent controlled release DS drug for therapeutic applications. PMID:27490577

  11. In vivo study of ALA PLGA nanoparticles-mediated PDT for treating cutaneous squamous cell carcinoma

    NASA Astrophysics Data System (ADS)

    Wang, Xiaojie; Shi, Lei; Huang, Zheng; Wang, Xiuli

    2014-09-01

    Background: Squamous cell carcinoma (SCC) is a common skin cancer and its treatment is still a challenge. Although topical photodynamic therapy (PDT) is effective for treating in situ and superficial SCC, the effectiveness of topical ALA delivery to thick SCC can be limited by its bioavailability. Polylactic-co-glycolic acid nanopartieles (PLGA NPs) might provide a promising ALA delivery strategy. The aim of this study was to evaluate the efficacy of ALA PLGA NPs PDT for the treatment of cutaneous SCC in a mouse model. Methods: ALA loaded PLGA NPs were prepared and characterized. The therapeutic efficacy of ALA PLGA NP mediated PDT in treating UV-induced cutaneous SCC in the mice model were examined. Results: In vivo study showed that ALA PLGA NPs PDT were more effective than free ALA of the same concentration in treating mouse cutaneous SCC. Conclusion: ALA PLGA NPs provides a promising strategy for delivering ALA and treating cutaneous SCC.

  12. Biomimetic Hybrid Nanofiber Sheets Composed of RGD Peptide-Decorated PLGA as Cell-Adhesive Substrates.

    PubMed

    Shin, Yong Cheol; Lee, Jong Ho; Kim, Min Jeong; Park, Ji Hoon; Kim, Sung Eun; Kim, Jin Su; Oh, Jin-Woo; Han, Dong-Wook

    2015-05-29

    In biomedical applications, there is a need for tissue engineering scaffolds to promote and control cellular behaviors, including adhesion, proliferation and differentiation. In particular, the initial adhesion of cells has a great influence on those cellular behaviors. In this study, we concentrate on developing cell-adhesive substrates applicable for tissue engineering scaffolds. The hybrid nanofiber sheets were prepared by electrospinning poly(lactic-co-glycolic acid) (PLGA) and M13 phage, which was genetically modified to enhance cell adhesion thru expressing RGD peptides on their surface. The RGD peptide is a specific motif of extracellular matrix (ECM) for integrin receptors of cells. RGD peptide-decorated PLGA (RGD-PLGA) nanofiber sheets were characterized by scanning electron microscopy, immunofluorescence staining, contact angle measurement and differential scanning calorimetry. In addition, the initial adhesion and proliferation of four different types of mammalian cells were determined in order to evaluate the potential of RGD-PLGA nanofiber sheets as cell-adhesive substrates. Our results showed that the hybrid nanofiber sheets have a three-dimensional porous structure comparable to the native ECM. Furthermore, the initial adhesion and proliferation of cells were significantly enhanced on RGD-PLGA sheets. These results suggest that biomimetic RGD-PLGA nanofiber sheets can be promising cell-adhesive substrates for application as tissue engineering scaffolds.

  13. Multifunctional Bi2S3/PLGA nanocapsule for combined HIFU/radiation therapy.

    PubMed

    Yao, Ming-hua; Ma, Ming; Chen, Yu; Jia, Xiao-qing; Xu, Guang; Xu, Hui-xiong; Chen, Hang-rong; Wu, Rong

    2014-09-01

    A multifunctional organic-inorganic hybrid nanocapsule based on Bi2S3-embedded poly (lactic-co-glycolic acid) (PLGA) nanocapsule has been elaborately designed to combine the merits of both polymeric shell structure and Bi2S3 nanoparticles. Hydrophobic Bi2S3 nanoparticles were successfully introduced into the PLGA nanocapsules via a facile and efficient water/oil/water (W/O/W) emulsion strategy. The elastic polymeric PLGA shell provides the excellent capability of ultrasound contrast imaging to the Bi2S3/PLGA. Meanwhile, the potential of these microcapsules to enhance the high intensity focused ultrasound (HIFU) therapy was demonstrated. Importantly, this research provided the first example of both in vitro and in vivo to demonstrate the radiosensitization effect of Bi2S3-embedded PLGA hybrid nanocapsules against prostate cancer under external X-ray irradiation. Thus, the successful integration of the Bi2S3 and PLGA nanocapsules provided an alternative strategy for the highly efficient ultrasound guided HIFU/RT synergistic therapy.

  14. BMP-2 Grafted nHA/PLGA Hybrid Nanofiber Scaffold Stimulates Osteoblastic Cells Growth

    PubMed Central

    Haider, Adnan; Kim, Sukyoung; Huh, Man-Woo; Kang, Inn-Kyu

    2015-01-01

    Biomaterials play a pivotal role in regenerative medicine, which aims to regenerate and replace lost/degenerated tissues or organs. Natural bone is a hierarchical structure, comprised of various cells having specific functions that are regulated by sophisticated mechanisms. However, the regulation of the normal functions in damaged or injured cells is disrupted. In order to address this problem, we attempted to artificially generate a scaffold for mimicking the characteristics of the extracellular matrix at the nanoscale level to trigger osteoblastic cell growth. For this purpose, we have chemically grafted bone morphogenetic protein (BMP-2) onto the surface of L-glutamic acid modified hydroxyapatite incorporated into the PLGA nanofiber matrix. After extensive characterization using various spectroscopic techniques, the BMP-g-nHA/PLGA hybrid nanofiber scaffolds were subjected to various in vitro cytocompatibility tests. The results indicated that BMP-2 on BMP-g-nHA/PLGA hybrid nanofiber scaffolds greatly stimulated osteoblastic cells growth, contrary to the nHA/PLGA and pristine PLGA nanofiber scaffold, which are used as control. These results suggest that BMP-g-nHA/PLGA hybrid nanofiber scaffold can be used as a nanodrug carrier for the controlled and targeted delivery of BMP-2, which will open new possibilities for enhancing bone tissue regeneration and will help in the treatment of various bone-related diseases in the future. PMID:26539477

  15. [Experimental research on the prevention of rabbit postoperative abdominal cavity adhesion with PLGA membrane].

    PubMed

    Pang, Xiubing; Pan, Yongming; Hua, Fei; Sun, Chaoying; Chen, Liang; Chen, Fangming; Zhu, Keyan; Xu, Jianqin; Chen, Minli

    2015-02-01

    The aim of this paper is to explore the prevention of rabbit postoperative abdominal cavity adhesion with poly (lactic-co-glycotic acid) (PLGA) membrane and the mechanism of this prevention function. Sixty-six Japanese white rabbits were randomly divided into normal control group, model control group and PLGA membrane group. The rabbits were treated with multifactor methods to establish the postoperative abdominal cavity adhesion models except for those in the normal control group. PLGA membrane was used to cover the wounds of rabbits in the PLGA membrane group and nothing covered the wounds of rabbits in the model control group. The hematologic parameters, liver and kidney functions and fibrinogen contents were detected at different time. The rabbit were sacrificed 1, 2, 4, 6, 12 weeks after the operations, respectively. The adhesions were graded blindly, and Masson staining and immunohistochemistry methods were used to observe the proliferation of collagen fiber and the expression of transforming growth factor β1 (TGF-β1) on the cecal tissues, respectively. The grade of abdominal cavity adhesion showed that the PLGA membrane-treated group was significant lower than that in the model control group, and it has no influence on liver and kidney function and hematologic parameters. But the fibrinogen content and the number of white blood cell in the PLGA membrane group were significant lower than those of model control group 1 week and 2 weeks after operation, respectively. The density of collagen fiber and optical density of TGF-β1 in the PLGA membrane group were significant lower than those of model control group. The results demonstrated that PLGA membrane could be effective in preventing the abdominal adhesions in rabbits, and it was mostly involved in the reducing of fibrinogen exudation, and inhibited the proliferation of collagen fiber and over-expression of TGF-β1.

  16. In-vitro anticancer and antimicrobial activities of PLGA/silver nanofiber composites prepared by electrospinning.

    PubMed

    Almajhdi, Fahad N; Fouad, H; Khalil, Khalil Abdelrazek; Awad, Hanem M; Mohamed, Sahar H S; Elsarnagawy, T; Albarrag, Ahmed M; Al-Jassir, Fawzi F; Abdo, Hany S

    2014-04-01

    In the present work, a series of 0, 1 and 7 wt% silver nano-particles (Ag NPs) incorporated poly lactic-co-glycolic acid (PLGA) nano-fibers were synthesized by the electrospinning process. The PLGA/Ag nano-fibers sheets were characterized using SEM, TEM and DSC analyses. The three synthesized PLGA/silver nano-fiber composites were screened for anticancer activity against liver cancer cell line using MTT and LDH assays. The anticancer activity of PLGA nano-fibers showed a remarkable improvement due to increasing the concentration of the Ag NPs. In addition to the given result, PLGA nano-fibers did not show any cytotoxic effect. However, PLGA nano-fibers that contain 1 % nano silver showed anticancer activity of 8.8 %, through increasing the concentration of the nano silver to 7 % onto PLGA nano-fibers, the anticancer activity was enhanced to a 67.6 %. Furthermore, the antibacterial activities of these three nano-fibers, against the five bacteria strains namely; E.coli o157:H7 ATCC 51659, Staphylococcus aureus ATCC 13565, Bacillus cereus EMCC 1080, Listeria monocytogenes EMCC 1875 and Salmonella typhimurium ATCC25566 using the disc diffusion method, were evaluated. Sample with an enhanced inhibitory effect was PLGA/Ag NPs (7 %) which inhibited all strains (inhibition zone diameter 10 mm); PLGA/Ag NPs (1 %) sample inhibited only one strain (B. cereus) with zone diameter 8 mm. The PLGA nano-fiber sample has not shown any antimicrobial activity. Based on the anticancer as well as the antimicrobial results in this study, it can be postulated that: PLGA nanofibers containing 7 % nano silver are suitable as anticancer- and antibiotic-drug delivery systems, as they will increase the anticancer as well as the antibiotic drug potency without cytotoxicity effect on the normal cells. These findings also suggest that Ag NPs, of the size (5-10 nm) evaluated in the present study, are appropriate for therapeutic application from a safety standpoint.

  17. In Vitro Evaluation of the Biological Responses of Canine Macrophages Challenged with PLGA Nanoparticles Containing Monophosphoryl Lipid A

    PubMed Central

    Guldner, Delphine; Hwang, Julianne K.; Cardieri, Maria Clara D.; Eren, Meaghan; Ziaei, Parissa; Norton, M. Grant; Souza, Cleverson D.

    2016-01-01

    Poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) have been considerably studied as a promising biodegradable delivery system to induce effective immune responses and to improve stability, safety, and cost effectiveness of vaccines. The study aimed at evaluating early inflammatory effects and cellular safety of PLGA NPs, co-encapsulating ovalbumin (PLGA/OVA NPs), as a model antigen and the adjuvant monophosphoryl lipid A (PLGA/MPLA NPs) as an adjuvant, on primary canine macrophages. The PLGA NPs constructs were prepared following the emulsion-solvent evaporation technique and further physic-chemically characterized. Peripheral blood mononuclear cells were isolated from canine whole blood by magnetic sorting and further cultured to generate macrophages. The uptake of PLGA NP constructs by macrophages was demonstrated by flow cytometry, transmission electron microscopy and confocal microscopy. Macrophage viability and morphology were evaluated by trypan blue exclusion and light microscopy. Macrophages were immunophenotyped for the expression of MHC-I and MHC-II and gene expression of Interleukin-10 (IL-10), Interleukin-12 (IL-12p40), and tumor necrosis factor alpha (TNF-α) were measured. The results showed that incubation of PLGA NP constructs with macrophages revealed effective early uptake of the PLGA NPs without altering the viability of macrophages. PLGA/OVA/MPLA NPs strongly induced TNF-α and IL-12p40 expression by macrophages as well as increase relative expression of MHC-I but not MHC-II molecules. Taken together, these results indicated that PLGA NPs with addition of MPLA represent a good model, when used as antigen carrier, for further, in vivo, work aiming to evaluate their potential to induce strong, specific, immune responses in dogs. PMID:27835636

  18. Micro/Nano Multilayered Scaffolds of PLGA and Collagen by Alternately Electrospinning for Bone Tissue Engineering

    NASA Astrophysics Data System (ADS)

    Kwak, Sanghwa; Haider, Adnan; Gupta, Kailash Chandra; Kim, Sukyoung; Kang, Inn-Kyu

    2016-07-01

    The dual extrusion electrospinning technique was used to fabricate multilayered 3D scaffolds by stacking microfibrous meshes of poly(lactic acid-co-glycolic acid) (PLGA) in alternate fashion to micro/nano mixed fibrous meshes of PLGA and collagen. To fabricate the multilayered scaffold, 35 wt% solution of PLGA in THF-DMF binary solvent (3:1) and 5 wt% solution of collagen in hexafluoroisopropanol (HFIP) with and without hydroxyapatite nanorods (nHA) were used. The dual and individual electrospinning of PLGA and collagen were carried out at flow rates of 1.0 and 0.5 mL/h, respectively, at an applied voltage of 20 kV. The density of collagen fibers in multilayered scaffolds has controlled the adhesion, proliferation, and osteogenic differentiation of MC3T3-E1 cells. The homogeneous dispersion of glutamic acid-modified hydroxyapatite nanorods (nHA-GA) in collagen solution has improved the osteogenic properties of fabricated multilayered scaffolds. The fabricated multilayered scaffolds were characterized using FT-IR, X-ray photoelectron spectroscopy, and transmission electron microscopy (TEM). The scanning electron microscopy (FE-SEM) was used to evaluate the adhesion and spreads of MC3T3-E1 cells on multilayered scaffolds. The activity of MC3T3-E1 cells on the multilayered scaffolds was evaluated by applying MTT, alkaline phosphatase, Alizarin Red, von Kossa, and cytoskeleton F-actin assaying protocols. The micro/nano fibrous PLGA-Col-HA scaffolds were found to be highly bioactive in comparison to pristine microfibrous PLGA and micro/nano mixed fibrous PLGA and Col scaffolds.

  19. Micro/Nano Multilayered Scaffolds of PLGA and Collagen by Alternately Electrospinning for Bone Tissue Engineering.

    PubMed

    Kwak, Sanghwa; Haider, Adnan; Gupta, Kailash Chandra; Kim, Sukyoung; Kang, Inn-Kyu

    2016-12-01

    The dual extrusion electrospinning technique was used to fabricate multilayered 3D scaffolds by stacking microfibrous meshes of poly(lactic acid-co-glycolic acid) (PLGA) in alternate fashion to micro/nano mixed fibrous meshes of PLGA and collagen. To fabricate the multilayered scaffold, 35 wt% solution of PLGA in THF-DMF binary solvent (3:1) and 5 wt% solution of collagen in hexafluoroisopropanol (HFIP) with and without hydroxyapatite nanorods (nHA) were used. The dual and individual electrospinning of PLGA and collagen were carried out at flow rates of 1.0 and 0.5 mL/h, respectively, at an applied voltage of 20 kV. The density of collagen fibers in multilayered scaffolds has controlled the adhesion, proliferation, and osteogenic differentiation of MC3T3-E1 cells. The homogeneous dispersion of glutamic acid-modified hydroxyapatite nanorods (nHA-GA) in collagen solution has improved the osteogenic properties of fabricated multilayered scaffolds. The fabricated multilayered scaffolds were characterized using FT-IR, X-ray photoelectron spectroscopy, and transmission electron microscopy (TEM). The scanning electron microscopy (FE-SEM) was used to evaluate the adhesion and spreads of MC3T3-E1 cells on multilayered scaffolds. The activity of MC3T3-E1 cells on the multilayered scaffolds was evaluated by applying MTT, alkaline phosphatase, Alizarin Red, von Kossa, and cytoskeleton F-actin assaying protocols. The micro/nano fibrous PLGA-Col-HA scaffolds were found to be highly bioactive in comparison to pristine microfibrous PLGA and micro/nano mixed fibrous PLGA and Col scaffolds.

  20. AUGMENTATION OF LIMB PERFUSION AND REVERSAL OF TISSUE ISCHEMIA PRODUCED BY ULTRASOUND-MEDIATED MICROBUBBLE CAVITATION

    PubMed Central

    Belcik, J. Todd; Mott, Brian H.; Xie, Aris; Zhao, Yan; Kim, Sajeevani; Lindner, Nathan J.; Ammi, Azzdine; Linden, Joel M.; Lindner, Jonathan R.

    2015-01-01

    Background Ultrasound can increase tissue blood flow in part through the intravascular shear produced by oscillatory pressure fluctuations. We hypothesized that ultrasound-mediated increases in perfusion can be augmented by microbubble contrast agents that undergo ultrasound-mediated cavitation, and sought to characterize the biologic mediators. Methods and Results Contrast ultrasound perfusion imaging of hindlimb skeletal muscle and femoral artery diameter measurement were performed in non-ischemic mice after unilateral 10 min exposure to intermittent ultrasound alone (mechanical index [MI] 0.6 or 1.3) or ultrasound with lipid microbubbles (2×108 I.V.). Studies were also performed after inhibiting shear- or pressure-dependent vasodilator pathways, and in mice with hindlimb ischemia. Ultrasound alone produced a 2-fold increase (p<0.05) in muscle perfusion regardless of ultrasound power. Ultrasound-mediated augmentation in flow was greater with microbubbles (3-fold and 10-fold higher than control for MI 0.6 and 1.3, respectively; p<0.05), as was femoral artery dilation. Inhibition of endothelial nitric oxide synthase (eNOS) attenuated flow augmentation produced by ultrasound and microbubbles by 70% (p<0.01), whereas inhibition of adenosine-A2a receptors and epoxyeicosatrienoic acids had minimal effect. Limb nitric oxide (NO) production and muscle phospho-eNOS increased in a stepwise fashion by ultrasound and ultrasound with microbubbles. In mice with unilateral hindlimb ischemia (40–50% reduction in flow), ultrasound (MI 1.3) with microbubbles increased perfusion by 2-fold to a degree that was greater than the control non-ischemic limb. Conclusions Increases in muscle blood flow during high-power ultrasound are markedly amplified by the intravascular presence of microbubbles and can reverse tissue ischemia. These effects are most likely mediated by cavitation-related increases in shear and activation of eNOS. PMID:25834183

  1. Micro-bubbles seeding for flow characterization

    NASA Astrophysics Data System (ADS)

    Aumelas, V.; Lecoffre, Y.; Maj, G.; Franc, J.-P.

    2016-11-01

    Micro-bubbles injection has long been used in hydrodynamic facilities for the control of dissolved and free air. In some cavitation tunnels [9], very large quantities of microbubbles (billions per second) are injected for rapid degassing and, in smaller quantities (millions per second), for cavitation nuclei seeding. Micro-bubbles can also be used as tracers for optical measurements including visualization, LDV or PIV. For these applications, bubbles must be sufficiently small to faithfully follow the flow. Depending on the quality and spatial characteristics of the micro-bubbles seeding, several optical methods can be applied: simple visualization gives access to semi-quantitative information on the behaviour of flows; LASER velocimetry provides information on the mean velocity and other temporal local characteristics of the flow. This paper presents some new micro-bubbles seeding devices recently developed by YLEC Consultants. These devices have been designed to fulfill specific requirements related to integration into cavitation tunnels and permit optical velocimetry measurement techniques such as Particle Image Velocimetry (PIV). The LEGI cavitation tunnel is the first tunnel which has been equipped with these microbubbles seeding systems dedicated to optical velocimetry. This paper presents the final integration schemes selected for micro-bubbles seeding into LEGI tunnel and discuss about practical concerns related to the use of the injection system for optical velocimetry.

  2. In vitro and in vivo effects of rat kidney vascular endothelial cells on osteogenesis of rat bone marrow mesenchymal stem cells growing on polylactide-glycoli acid (PLGA) scaffolds.

    PubMed

    Sun, Hongchen; Qu, Zhe; Guo, Ying; Zang, Guangxiang; Yang, Bai

    2007-11-04

    It is well established that vascularization is critical for osteogenesis. However, adequate vascularization also remains one of the major challenges in tissue engineering of bone. This problem is further accentuated in regeneration of large volume of tissue. Although a complex process, vascularization involves reciprocal regulation and functional interaction between endothelial and osteoblast-like cells during osteogenesis. This prompted us to investigate the possibility of producing bone tissue both in vitro and ectopically in vivo using vascular endothelial cells because we hypothesized that the direct contact or interaction between vascular endothelial cells and bone marrow mesenchymal stem cells are of benefit to osteogenesis in vitro and in vivo. For that purpose we co-cultured rat bone marrow mesenchymal stem cells (MSC) and kidney vascular endothelial cells (VEC) with polylactide-glycolic acid scaffolds. In vitro experiments using alkaline phosphatase and osteocalcin assays demonstrated the proliferation and differentiation of MSC into osteoblast-like cells, especially the direct contact between VEC and MSC. In addition, histochemical analysis with CD31 and von-Willebrand factor staining showed that VEC retained their endothelial characteristics. In vivo implantation of MSC and VEC co-cultures into rat's muscle resulted in pre-vascular network-like structure established by the VEC in the PLGA. These structures developed into vascularized tissue, and increased the amount and size of the new bone compared to the control group (p < 0.05). These results suggest that the vascular endothelial cells could efficiently stimulate the in vitro proliferation and differentiation of osteoblast-like cells and promote osteogenesis in vivo by the direct contact or interaction with the MSC. This technique for optimal regeneration of bone should be further investigated.

  3. In vitro drug release behavior, mechanism and antimicrobial activity of rifampicin loaded low molecular weight PLGA-PEG-PLGA triblock copolymeric nanospheres.

    PubMed

    Gajendiran, M; Divakar, S; Raaman, N; Balasubramanian, S

    2013-12-01

    Poly (lactic-co-glycolic acid) (PLGA (92:8)) and a series of PLGA-PEG-PLGA tri block copolymers were synthesized by direct melt polycondensation. The copolymers were characterized by FTIR, and 1HNMR spectroscopic techniques, viscosity, gel permeation chromatography (GPC) and powder x-ray diffraction (XRD). The rifampicin (RIF) loaded polymeric nanospheres (NPs) were prepared by ultrasonication-W/O emulsification technique. The NPs have been characterized by field emission scanning electron microscopy (FESEM), TEM, powder X-ray diffraction (XRD), UVvisible spectroscopy and DLS measurements. The drug loaded triblock copolymeric NPs have five folds higher drug content and drug loading efficiency than that of PLGA microspheres (MPs). The in vitro drug release study shows that the drug loaded NPs showed an initial burst release after that sustained release up to 72 h. All the triblock copolymeric NPs follow anomalous drug diffusion mechanism while the PLGA MPs follow non-Fickian super case-II mechanism up to 12 h. The overall in-vitro release follows second order polynomial kinetics up to 72 h. The antimicrobial activity of the RIF loaded polymer NPs was compared with that of pure RIF and tetracycline (TA). The RIF loaded triblock copolymeric NPs inhibited the bacterial growth more effectively than the pure RIF and TA.

  4. Biosurfactants for Microbubble Preparation and Application

    PubMed Central

    Xu, Qingyi; Nakajima, Mitsutoshi; Liu, Zengshe; Shiina, Takeo

    2011-01-01

    Biosurfactants can be classified by their chemical composition and their origin. This review briefly describes various classes of biosurfactants based on their origin and introduces a few of the most widely used biosurfactants. The current status and future trends in biosurfactant production are discussed, with an emphasis on those derived from plants. Following a brief introduction of the properties of microbubbles, recent progress in the application of microbubble technology to molecular imaging, wastewater treatment, and aerobic fermentation are presented. Several studies on the preparation, characterization and applications of biosurfactant-based microbubbles are reviewed. PMID:21339998

  5. Spark discharge in conductive liquid with microbubbles

    NASA Astrophysics Data System (ADS)

    Vetchinin, S. P.; Vasilyak, L. M.; Pecherkin, V. Ya; Panov, V. A.; Son, E. E.

    2016-11-01

    Pulse electrical breakdown in 15% water solution of Isopropyl alcohol with air microbubbles from a pointed anode has been studied experimentally. It is shown, that the breakdown is always initiated from the bright region near the anode (anode “spot”). Detailed investigation into dynamic current-voltage characteristics and synchronized images reveals that it is thermal instability in the near anode region that causes spark channel initiation and development. The breakdown voltage, spark channel propagation speed and short-circuit current increase when the microbubbles are presented in the solution. The spark channel propagation speed is about 4-12 m/s and grows along with microbubbles concentration.

  6. Resonance and streaming of armored microbubbles

    NASA Astrophysics Data System (ADS)

    Spelman, Tamsin; Bertin, Nicolas; Stephen, Olivier; Marmottant, Philippe; Lauga, Eric

    2015-11-01

    A new experimental technique involves building a hollow capsule which partially encompasses a microbubble, creating an ``armored microbubble'' with long lifespan. Under acoustic actuation, such bubble produces net streaming flows. In order to theoretically model the induced flow, we first extend classical models of free bubbles to describe the streaming flow around a spherical body for any known axisymmetric shape oscillation. A potential flow model is then employed to determine the resonance modes of the armored microbubble. We finally use a more detailed viscous model to calculate the surface shape oscillations at the experimental driving frequency, and from this we predict the generated streaming flows.

  7. Biosurfactants for microbubble preparation and application.

    PubMed

    Xu, Qingyi; Nakajima, Mitsutoshi; Liu, Zengshe; Shiina, Takeo

    2011-01-17

    Biosurfactants can be classified by their chemical composition and their origin. This review briefly describes various classes of biosurfactants based on their origin and introduces a few of the most widely used biosurfactants. The current status and future trends in biosurfactant production are discussed, with an emphasis on those derived from plants. Following a brief introduction of the properties of microbubbles, recent progress in the application of microbubble technology to molecular imaging, wastewater treatment, and aerobic fermentation are presented. Several studies on the preparation, characterization and applications of biosurfactant-based microbubbles are reviewed.

  8. Bioerodable PLGA-Based Microparticles for Producing Sustained-Release Drug Formulations and Strategies for Improving Drug Loading

    PubMed Central

    Han, Felicity Y.; Thurecht, Kristofer J.; Whittaker, Andrew K.; Smith, Maree T.

    2016-01-01

    Poly(lactic-co-glycolic acid) (PLGA) is the most widely used biomaterial for microencapsulation and prolonged delivery of therapeutic drugs, proteins and antigens. PLGA has excellent biodegradability and biocompatibility and is generally recognized as safe by international regulatory agencies including the United States Food and Drug Administration and the European Medicines Agency. The physicochemical properties of PLGA may be varied systematically by changing the ratio of lactic acid to glycolic acid. This in turn alters the release rate of microencapsulated therapeutic molecules from PLGA microparticle formulations. The obstacles hindering more widespread use of PLGA for producing sustained-release formulations for clinical use include low drug loading, particularly of hydrophilic small molecules, high initial burst release and/or poor formulation stability. In this review, we address strategies aimed at overcoming these challenges. These include use of low-temperature double-emulsion methods to increase drug-loading by producing PLGA particles with a small volume for the inner water phase and a suitable pH of the external phase. Newer strategies for producing PLGA particles with high drug loading and the desired sustained-release profiles include fabrication of multi-layered microparticles, nanoparticles-in-microparticles, use of hydrogel templates, as well as coaxial electrospray, microfluidics, and supercritical carbon dioxide methods. Another recent strategy with promise for producing particles with well-controlled and reproducible sustained-release profiles involves complexation of PLGA with additives such as polyethylene glycol, poly(ortho esters), chitosan, alginate, caffeic acid, hyaluronic acid, and silicon dioxide. PMID:27445821

  9. HDL-Mimetic PLGA Nanoparticle To Target Atherosclerosis Plaque Macrophages

    PubMed Central

    Sanchez-Gaytan, Brenda L.; Fay, Francois; Lobatto, Mark E.; Tang, Jun; Ouimet, Mireille; Kim, YongTae; van der Staay, Susanne E. M.; van Rijs, Sarian M.; Priem, Bram; Zhang, Liangfang; Fisher, Edward A; Moore, Kathryn J.; Langer, Robert; Fayad, Zahi A.; Mulder, Willem J M

    2015-01-01

    High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and the phospholipid corona make the HDL platform an attractive nanocarrier. To realize controlled release properties, we developed a hybrid polymer/HDL nanoparticle composed of a lipid/apolipoprotein coating that encapsulates a poly(lactic-co-glycolic acid) (PLGA) core. This novel HDL-like nanoparticle (PLGA–HDL) displayed natural HDL characteristics, including preferential uptake by macrophages and a good cholesterol efflux capacity, combined with a typical PLGA nanoparticle slow release profile. In vivo studies carried out with an ApoE knockout mouse model of atherosclerosis showed clear accumulation of PLGA–HDL nanoparticles in atherosclerotic plaques, which colocalized with plaque macrophages. This biomimetic platform integrates the targeting capacity of HDL biomimetic nanoparticles with the characteristic versatility of PLGA-based nanocarriers. PMID:25650634

  10. Heuristic modeling of macromolecule release from PLGA microspheres

    PubMed Central

    Szlęk, Jakub; Pacławski, Adam; Lau, Raymond; Jachowicz, Renata; Mendyk, Aleksander

    2013-01-01

    Dissolution of protein macromolecules from poly(lactic-co-glycolic acid) (PLGA) particles is a complex process and still not fully understood. As such, there are difficulties in obtaining a predictive model that could be of fundamental significance in design, development, and optimization for medical applications and toxicity evaluation of PLGA-based multiparticulate dosage form. In the present study, two models with comparable goodness of fit were proposed for the prediction of the macromolecule dissolution profile from PLGA micro- and nanoparticles. In both cases, heuristic techniques, such as artificial neural networks (ANNs), feature selection, and genetic programming were employed. Feature selection provided by fscaret package and sensitivity analysis performed by ANNs reduced the original input vector from a total of 300 input variables to 21, 17, 16, and eleven; to achieve a better insight into generalization error, two cut-off points for every method was proposed. The best ANNs model results were obtained by monotone multi-layer perceptron neural network (MON-MLP) networks with a root-mean-square error (RMSE) of 15.4, and the input vector consisted of eleven inputs. The complicated classical equation derived from a database consisting of 17 inputs was able to yield a better generalization error (RMSE) of 14.3. The equation was characterized by four parameters, thus feasible (applicable) to standard nonlinear regression techniques. Heuristic modeling led to the ANN model describing macromolecules release profiles from PLGA microspheres with good predictive efficiency. Moreover genetic programming technique resulted in classical equation with comparable predictability to the ANN model. PMID:24348037

  11. PLGA Nanoparticles as Subconjunctival Injection for Management of Glaucoma.

    PubMed

    Salama, Hamed A; Ghorab, Mahmoud; Mahmoud, Azza A; Abdel Hady, Mayssa

    2017-02-21

    Nanoparticles fabricated from the biodegradable and biocompatible polymer, polylactic-co-glycolic acid (PLGA), could be a promising system for targeting ocular drug delivery. The objective of this work was to investigate the possibility of encapsulating brinzolamide in PLGA nanoparticles in order to be applied as a subconjunctival injection that could represent a starting point for developing new therapeutic strategies against increase in ocular pressure. The brinzolamide-loaded PLGA nanoparticles were fabricated using emulsion-diffusion-evaporation method with varying concentrations of Tween 80 or poloxamer 188 (Plx) in aqueous and organic phases. The nanoparticles were characterized in terms of particle size and size distribution, entrapment efficiency and in-vitro drug release pattern as well as DSC and X-ray analysis. Nanoparticles prepared using Tween 80 in the aqueous phase showed higher encapsulation efficiency and smaller particle size-values compared to those prepared using Plx. Furthermore, the addition of Plx 188 or Brij 97 to the organic phase in the formulation containing Tween 80 in the aqueous phase led to an increase in the particle diameter-values of the obtained nanoparticles. The nanoparticles had the capacity to release the brinzolamide in a biphasic release profile. The nanoparticles were spherical in shape and the drug was entraped in the nanoparticles in an amorphous form. Selected nanoparticles, injected subconjunctivally in normotensive Albino rabbits, were able to reduce the IOP for up to 10 days. Nanoparticles loaded with brinzolamide with lower particle size were able to reduce the IOP for longer period compared to those with higher particle size. Histopathological studies for the anterior cross sections of the rabbits' eyes revealed that the tested nanoparticles were compatible with the ocular tissue. The overall results support that PLGA nanoparticles, applied as subconjunctival injection, can be considered as a promising carrier for

  12. PLGA-PEG-PLGA triblock copolymeric micelles as oral drug delivery system: In vitro drug release and in vivo pharmacokinetics assessment.

    PubMed

    Chen, Xiufen; Chen, Jianzhong; Li, Bowen; Yang, Xiang; Zeng, Rongjie; Liu, Yajun; Li, Tao; Ho, Rodney J Y; Shao, Jingwei

    2017-03-15

    Poly (d,l-lactide-co-glycolide)-poly (ethylene glycol)-poly (d,l-lactide-co-glycolide) triblock copolymers (PLGA-PEG-PLGA) has been proven to be desirable for anti-cancer drug delivery by intravenous administration. But till now there is no report of developing this micelle as a sustained oral formulation for cancer therapy. 3β-acetoxy-urs-12-en-28-oic acid hexamethylenediamine (US597), a derivative of natural product ursolic acid has been developed as a novel cancer metastasis chemopreventive agent by us. Herein, we developed a new oral dosage formulation of PLGA-PEG-PLGA tri-block micelles loaded with US597 (US597@micelles). US597@micelles was prepared by a double emulsion solvent evaporation method, and characterized in regards to mean diameter (<100nm), drug loading (25.9-28.5%), zeta potential (5.76-10.65mV) and encapsulation efficiency (55.7-74.3%), respectively. In vitro, US597@micelles could ameliorate sustained drug release, inhibit cell proliferation by inducing apoptosis (46.6% of late apoptosis), and influence the integrity of nuclei and mitochondrial on HepG2. Moreover, in vivo pharmacokinetic study by UPLC/MS/MS method demonstrated better absorption, metabolism and elimination characters of US597@micelles as an oral dosage form (Cmax=53±49ng/mL, t1/2=8.716±7.033h) over free US597 (Cmax=14±11ng/mL, t1/2=16.433±8.821h). In conclusion, PLGA-PEG-PLGA micelles as a promising oral drug delivery system are able to improve the bioavailability and efficacy of US597 in cancer therapy.

  13. An endothelial cultured condition medium embedded porous PLGA scaffold for the enhancement of mouse embryonic stem cell differentiation.

    PubMed

    Li, Ching-Wen; Pan, Wei-Ting; Ju, Jyh-Cherng; Wang, Gou-Jen

    2016-04-12

    In this study, we have developed a microporous poly(lactic-co-glycolic acid) (PLGA) scaffold that combines a continuous release property and a three-dimensional (3D) scaffolding technique for the precise and efficient formation of endothelial cell lineage from embryonic stem cells (ESCs). Eight PLGA scaffolds (14.29%, 16.67%, 20% and 25% concentrations of PLGA solutions) mixed with two crystal sizes of sodium chloride (NaCl) were fabricated by leaching. Then, vascular endothelial cell conditioned medium (ECCM) mixed with gelatin was embedded into the scaffold for culturing of mouse embryonic stem cells (mESCs). The 14.29% PLGA scaffolds fabricated using non-ground NaCl particles (NG-PLGA) and the 25% PLGA containing scaffolds fabricated using ground NaCl particles (G-PLGA) possessed minimum and maximum moisture content and bovine serum albumin (BSA) content properties, respectively. These two groups of scaffolds were used for future experiments in this study. Cell culture results demonstrated that the proposed porous scaffolds without growth factors were sufficient to induce mouse ESCs to differentiate into endothelial-like cells in the early culture stages, and combined with embedded ECCM could provide a long-term inducing system for ESC differentiation.

  14. Impact of PEG and PEG-b-PAGE modified PLGA on nanoparticle formation, protein loading and release.

    PubMed

    Rietscher, René; Czaplewska, Justyna A; Majdanski, Tobias C; Gottschaldt, Michael; Schubert, Ulrich S; Schneider, Marc; Lehr, Claus-Michael

    2016-03-16

    The effect of modifying the well-established pharmaceutical polymer PLGA by different PEG-containing block-copolymers on the preparation of ovalbumin (OVA) loaded PLGA nanoparticles (NPs) was studied. The used polymers contained poly(d,l-lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG) and poly(allyl glycidyl ether) (PAGE) as building blocks. The double emulsion technique yielded spherical NPs in the size range from 170 to 220 nm (PDI<0.15) for all the differently modified polymers, allowing to directly compare protein loading of and release. PEGylation is usually believed to increase the hydrophilic character of produced particles, favoring encapsulation of hydrophilic substances. However, in this study simple PEGylation of PLGA had only a slight effect on protein release. In contrast, incorporating a PAGE block between the PEG and PLGA units, also eventually enabling active targeting introducing a reactive group, led to a significantly higher loading (+25%) and release rate (+100%), compared to PLGA and PEG-b-PLGA NPs.

  15. cmRNA/lipoplex encapsulation in PLGA microspheres enables transfection via calcium phosphate cement (CPC)/PLGA composites.

    PubMed

    Utzinger, Maximilian; Jarzebinska, Anita; Haag, Nicolas; Schweizer, Martin; Winter, Gerhard; Dohmen, Christian; Rudolph, Carsten; Plank, Christian

    2017-03-10

    In this study lipoplexes containing chemically modified messenger RNA (cmRNA) were incorporated into poly (lactic-co-glycolic acid) (PLGA) microspheres via water-in-oil-in-water (W/O/W) double emulsion solvent evaporation technique. The nanoparticle encapsulation by microparticle formation was optimized to achieve lipoplex release and maximum transfection efficiency in surrounding cells. It was possible to adjust characteristic features in surface topology and size of the PLGA-microspheres by varying the extent of lipoplex loading into the polymer matrix. The partial release of lipids and mRNA out of the microparticle system, their accumulation in cells and the production of encoded protein were visualized via fluorescence microscopy. These bioactive microspheres, containing cmRNA bearing lipoplexes, were developed for the incorporation of a therapeutic component into injectable calcium phosphate cements (CPC). Due to the incorporation of PLGA/lipoplex microspheres as a degradable entity, the porosity of the cement phase could additionally be adjusted. This approach of complex nanoparticle incorporation into polymer/cement composites represents a promising example for combining transcript therapy with biomechanical engineering.

  16. PLGA based drug delivery systems: Promising carriers for wound healing activity.

    PubMed

    Chereddy, Kiran Kumar; Vandermeulen, Gaëlle; Préat, Véronique

    2016-03-01

    Wound treatment remains one of the most prevalent and economically burdensome healthcare issues in the world. Current treatment options are limited and require repeated administrations which led to the development of new therapeutics to satisfy the unmet clinical needs. Many potent wound healing agents were discovered but most of them are fragile and/or sensitive to in vivo conditions. Poly(lactic-co-glycolic acid) (PLGA) is a widely used biodegradable polymer approved by food and drug administration and European medicines agency as an excipient for parenteral administrations. It is a well-established drug delivery system in various medical applications. The aim of the current review is to elaborate the applications of PLGA based drug delivery systems carrying different wound healing agents and also present PLGA itself as a wound healing promoter. PLGA carriers encapsulating drugs such as antibiotics, anti-inflammatory drugs, proteins/peptides, and nucleic acids targeting various phases/signaling cycles of wound healing, are discussed with examples. The combined therapeutic effects of PLGA and a loaded drug on wound healing are also mentioned.

  17. Development of a porous PLGA-based scaffold for mastoid air cell regeneration

    PubMed Central

    Gould, Toby W. A.; Birchall, John P.; Mallick, Ali S.; Alliston, Tamara; Lustig, Lawrence R.; Shakesheff, Kevin M.

    2015-01-01

    Objective To develop a porous, biodegradable scaffold for mastoid air cell regeneration. Study Design In vitro development of a temperature-sensitive poly(DL-lactic acid-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) scaffold tailored for this application. Methods Human mastoid bone microstructure and porosity was investigated using micro-computed tomography. PLGA/PEG-alginate scaffolds were developed and scaffold porosity was assessed. Human bone marrow mesenchymal stem cells (hBM-MSCs) were cultured on the scaffolds in vitro. Scaffolds were loaded with ciprofloxacin and release of ciprofloxacin over time in vitro was assessed. Results Porosity of human mastoid bone was measured at 83% with an average pore size of 1.3mm. PLGA/PEG-alginate scaffold porosity ranged from 43–78% depending on the alginate bead content. hBM-MSCs proliferate on the scaffolds in vitro, and release of ciprofloxacin from the scaffolds was demonstrated over 7–10 weeks. Conclusion The PLGA/PEG-alginate scaffolds developed in this study demonstrate similar structural features to human mastoid bone, support cell growth and display sustained antibiotic release. These scaffolds may be of potential clinical use in mastoid air cell regeneration. Further in vivo studies to assess the suitability of PLGA/PEG-alginate scaffolds for this application are required. PMID:23670365

  18. Microbubble generation by microplasma in water

    NASA Astrophysics Data System (ADS)

    Xiao, Peng; Staack, David

    2014-09-01

    A microscale plasma and a spherical microscale bubble were generated by the application of a single pulsed discharge in water with no pre-existing bubble. The microscale corona discharges were created at the tip of a microelectrode by applying a voltage at around -11 kV with a rise time of around 20 ns. The energy inputs for microplasma generation were controlled by varying the durations of the discharges from nanoseconds to microseconds. Two different energy inputs of 103 and 0.5 mJ were studied in detail and the differences in the microplasma-generated microbubbles, such as the maximum radii, numbers of oscillations and durations of the bubble were observed. These microbubbles were visualized using a microscope based optical system with two different high speed cameras. Images of the discharges were captured by a nanosecond gated intensified charge-coupled device (CCD) camera, and the microbubbles' dynamics were recorded by a million-frame-per-second CCD video camera. A Rayleigh-Plesset (RP) model considering both condensable (water vapour) and incondensable (H2 and O2) gases in the microbubble predicts the bubbles' dynamics accurately. Comparisons of the experimental results and the RP models allow estimation of the thermodynamic states of the microplasmas and microbubbles. The energies in the microbubbles are analysed quantitatively from the model and rough approximations for energy dissipation and the energy of the microplasma are made. The microplasma energy can be significantly less than the applied energy input. Such low initiation energy is the reason that the size of microplasmas is at the micron scale and all microplasmas are confined in a spherical microbubble. All the microbubbles reported in this paper are spherical. The low energy also provides conditions for non-equilibrium plasmas in liquid.

  19. Hydrodynamic Forces on Microbubbles under Ultrasound Excitation

    NASA Astrophysics Data System (ADS)

    Clark, Alicia; Aliseda, Alberto

    2014-11-01

    Ultrasound (US) pressure waves exert a force on microbubbles that can be used to steer them in a flow. To control the motion of microbubbles under ultrasonic excitation, the coupling between the volume oscillations induced by the ultrasound pressure and the hydrodynamic forces needs to be well understood. We present experimental results for the motion of small, coated microbubbles, with similar sizes and physico-chemical properties as clinically-available ultrasound contrast agents (UCAs). The size distribution for the bubbles, resulting from the in-house manufacturing process, was characterized by analysis of high magnification microscopic images and determined to be bimodal. More than 99% of the volume is contained in microbubbles less than 10 microns in diameter, the size of a red blood cell. The motion of the microbubbles in a pulsatile flow, at different Reynolds and Womersley numbers, is studied from tracking of high-speed shadowgraphy. The influence of ultrasound forcing, at or near the resonant frequency of the bubbles, on the hydrodynamic forces due to the pulsatile flow is determined from the experimental measurements of the trajectories. Previous evidence of a sign reversal in Saffman lift is the focus of particular attention, as this is frequently the only hydrodynamic force acting in the direction perpendicular to the flow pathlines. Application of the understanding of this physical phenomenon to targeted drug delivery is analyzed in terms of the transport of the microbubbles. NSF GRFP.

  20. Rifapentine-loaded PLGA microparticles for tuberculosis inhaled therapy: Preparation and in vitro aerosol characterization.

    PubMed

    Parumasivam, Thaigarajan; Leung, Sharon S Y; Quan, Diana Huynh; Triccas, Jamie A; Britton, Warwick J; Chan, Hak-Kim

    2016-06-10

    Inhaled delivery of drugs incorporated into poly (lactic-co-glycolic acid) (PLGA) microparticles allows a sustained lung concentration and encourages phagocytosis by alveolar macrophages that harboring Mycobacterium tuberculosis. However, limited data are available on the effects of physicochemical properties of PLGA, including the monomer ratio (lactide:glycide) and molecular weight (MW) on the aerosol performance, macrophage uptake, and toxicity profile. The present study aims to address this knowledge gap, using PLGAs with monomer ratios of 50:50, 75:25 and 85:15, MW ranged 24 - 240kDa and an anti-tuberculosis (TB) drug, rifapentine. The PLGA-rifapentine powders were produced through a solution spray drying technique. The particles were spherical with a smooth surface and a volume median diameter around 2μm (span ~2). When the powders were dispersed using an Osmohaler(®) at 100L/min for 2.4s, the fine particle fraction (FPFtotal, wt.% particles in aerosol <5μm relative to the total recovered drug mass) was ranged between 52 and 57%, with no significant difference between the formulations. This result suggests that the monomer ratio and MW are not crucial parameters for the aerosol performance of PLGA. The phagocytosis analysis was performed using Thp-1 monocyte-derived macrophages. The highest rate of uptake was observed in PLGA 85:15 followed by 75:25 and 50:50 with about 90%, 80% and 70%, respectively phagocytosis over 4h of exposure. Furthermore, the cytotoxicity analysis on Thp-1 and human lung adenocarcinoma epithelial cells demonstrated that PLGA concentration up to 1.5mg/mL, regardless of the monomer composition and MW, were non-toxic. In conclusion, the monomer ratio and MW are not crucial in determining the aerosol performance and cytotoxicity profile of PLGA however, the particles with high lactide composition have a superior tendency for macrophage uptake.

  1. Knockdown of STAT3 expression in SKOV3 cells by biodegradable siRNA-PLGA/CSO conjugate micelles.

    PubMed

    Zhao, Yunchun; Zheng, Caihong; Zhang, Li; Chen, Yue; Ye, Yiqing; Zhao, Mengdan

    2015-03-01

    Biodegradable and biocompatible poly(d,l-lactic-co-glycolic acid) (PLGA)was conjugated to the 5'-thiol end of signal transducer and activator of transcription 3 (STAT3) small interfering RNA (STAT3-siRNA) via a disulfide bond. In aqueous environments, these siRNA-PLGA conjugates can spontaneously form core/shell type spherical micelles with a particle size of about 200 nm. A biodegradable, low molecular weight cationic polymer, chitosan oligosaccharide (CSO), was added to the siRNA-PLGA micelles at different nitrogen to phosphate (N/P) ratios to form stable, spherical siRNA-PLGA/CSO micelles with sizes of 150-180 nm. The siRNA-PLGA/CSO micelles were produced via ionic complexation between negatively charged siRNA and positively charged CSO on the outer shell of the micelles. The siRNA-PLGA/CSO micelles exhibited superior cellular uptake and STAT3 gene silencing efficiency in SKOV3 ovarian cancer cells when compared with siRNA/CSO complexes at the same N/P ratios with no significant differences with lipofectamine 2000. Furthermore, the siRNA-PLGA/CSO micelles showed that the efficiencies of cellular uptake and STAT3 gene silencing gradually increased with increasing N/P ratios. The siRNA-PLGA/CSO micelles also inhibited the growth of SKOV3 cells, as well as, promoted apoptosis of the cells. These results indicate that siRNA-PLGA/CSO micelles can be utilized as a novel and efficient siRNA carrier to treat a variety of diseases.

  2. TPGS2k/PLGA nanoparticles for overcoming multidrug resistance by interfering mitochondria of human alveolar adenocarcinoma cells.

    PubMed

    Wang, Dong-Fang; Rong, Wen-Ting; Lu, Yu; Hou, Jie; Qi, Shan-Shan; Xiao, Qing; Zhang, Jue; You, Jin; Yu, Shu-Qin; Xu, Qian

    2015-02-25

    In this study, we successfully synthesized d-α-tocopheryl polyethylene glycol 2000 succinate (TPGS2k) and prepared TPGS2k-modified poly(lactic-co-glycolic acid) nanoparticles (TPGS2k/PLGA NPs) loaded with 7-ethyl-10-hydroxycamptothecin (SN-38), designated TPGS2k/PLGA/SN-38 NPs. Characterization measurements showed that TPGS2k/PLGA/SN-38 NPs displayed flat and spheroidal particles with diameters of 80-104 nm. SN-38 was encapsulated in TPGS2k emulsified PLGA NPs with the entrapment efficiency and loading rates of SN-38 83.6 and 7.85%, respectively. SN-38 could release constantly from TPGS2k/PLGA/SN-38 NPs in vitro. TPGS2k/PLGA/SN-38 NPs induced significantly higher cytotoxicity on A549 cells and the multidrug resistance (MDR) cell line (A549/DDP cells and A549/Taxol cells) compared with free SN-38. Further studies on the mechanism of the NPs in increasing the death of MDR cells showed that following the SN-38 releasing into cytoplasm the remaining TPGS2k/PLGA NPs could reverse the P-gp mediated MDR via interfering with the structure and function of mitochondria and rather than directly inhibiting the enzymatic activity of P-gp ATPase. Therefore, TPGS2k/PLGA NPs can reduce the generation of ATP and the release of energy for the requisite of P-gp efflux transporters. The results indicated that TPGS2k/PLGA NPs could become the nanopharmaceutical materials with the capability to reversal MDR and improve anticancer effects of some chemotherapy drugs as P-gp substrates.

  3. Microencapsulation of a synbiotic into PLGA/alginate multiparticulate gels.

    PubMed

    Cook, Michael T; Tzortzis, George; Charalampopoulos, Dimitris; Khutoryanskiy, Vitaliy V

    2014-05-15

    Probiotic bacteria have gained popularity as a defence against disorders of the bowel. However, the acid sensitivity of these cells results in a loss of viability during gastric passage and, consequently, a loss of efficacy. Probiotic treatment can be supplemented using 'prebiotics', which are carbohydrates fermented specifically by probiotic cells in the body. This combination of probiotic and prebiotic is termed a 'synbiotic'. Within this article a multiparticulate dosage form has been developed, consisting of poly(d,l-lactic-co-glycolic acid) (PLGA) microcapsules containing prebiotic Bimuno™ incorporated into an alginate-chitosan matrix containing probiotic Bifidobacterium breve. The aim of this multiparticulate was that, in vivo, the probiotic would be protected against gastric acid and the release of the prebiotic would occur in the distal colon. After microscopic investigation, this synbiotic multiparticulate was shown to control the release of the prebiotic during in vitro gastrointestinal transit, with the release of galacto-oligosaccharides (GOS) initially occurred over 6h, but with a triphasic release pattern giving further release over 288 h. Encapsulation of B. breve in multiparticulates resulted in a survival of 8.0 ± 0.3 logCFU/mL cells in acid, an improvement over alginate-chitosan microencapsulation of 1.4 logCFU/mL. This was attributed to increased hydrophobicity by the incorporation of PLGA particles.

  4. Apatite coating of electrospun PLGA fibers using a PVA vehicle system carrying calcium ions.

    PubMed

    Kim, In Ae; Rhee, Sang-Hoon

    2010-01-01

    A novel method to coat electrospun poly(D,L-lactic-co-glycolic acid) (PLGA) fiber surfaces evenly and efficiently with low-crystalline carbonate apatite crystals using a poly(vinyl alcohol) (PVA) vehicle system carrying calcium ions was presented. A non-woven PLGA fabric was prepared by electrospinning: a 10 wt% PLGA solution was prepared using 1,1,3,3-hexafluoro-2-propanol as a solvent and electrospun under a electrical field of 1 kV/cm using a syringe pump with a flowing rate of 3 ml/h. The non-woven PLGA fabric, 12 mm in diameter and 1 mm in thickness, was cut and then coated with a PVA solution containing calcium chloride dihydrate (specimen PPC). As controls, pure non-woven PLGA fabric (specimen P) and fabric coated with a calcium chloride dihydrate solution without PVA (specimen PC) were also prepared. Three specimens were exposed to simulated body fluid for 1 week and this exposure led to form uniform and complete apatite coating layer on the fiber surfaces of specimen PPC. However, no apatite had formed to the fiber surfaces of specimen P and only inhomogeneous coating occurred on the fiber surfaces of specimen PC. These results were explained in terms of the calcium chelating and adhesive properties of PVA vehicle system. The practical implication of the results is that this method provides a simple but efficient technique for coating the fiber surface of an initially non-bioactive material with low-crystalline carbonate apatite.

  5. Ozone Gas as a Benign Sterilization Treatment for PLGA Nanofiber Scaffolds

    PubMed Central

    de Jesus Andreoli Pinto, Terezinha; Bou-Chacra, Nadia Araci; Galante, Raquel; de Araújo, Gabriel Lima Barros; do Nascimento Pedrosa, Tatiana; Maria-Engler, Silvya Stuchi

    2016-01-01

    The use of electrospun nanofibers for tissue engineering and regenerative medicine applications is a growing trend as they provide improved support for cell proliferation and survival due, in part, to their morphology mimicking that of the extracellular matrix. Sterilization is a critical step in the fabrication process of implantable biomaterial scaffolds for clinical use, but many of the existing methods used to date can negatively affect scaffold properties and performance. Poly(lactic-co-glycolic acid) (PLGA) has been widely used as a biodegradable polymer for 3D scaffolds and can be significantly affected by current sterilization techniques. The aim of this study was to investigate pulsed ozone gas as an alternative method for sterilizing PLGA nanofibers. The morphology, mechanical properties, physicochemical properties, and response of cells to PLGA nanofiber scaffolds were assessed following different degrees of ozone gas sterilization. This treatment killed Geobacillus stearothermophilus spores, the most common biological indicator used for validation of sterilization processes. In addition, the method preserved all of the characteristics of nonsterilized PLGA nanofibers at all degrees of sterilization tested. These findings suggest that ozone gas can be applied as an alternative method for sterilizing electrospun PLGA nanofiber scaffolds without detrimental effects. PMID:26757850

  6. In vitro hemocompatibility and cytocompatibility of dexamethasone-eluting PLGA stent coatings

    NASA Astrophysics Data System (ADS)

    Zhang, Jiang; Liu, Yang; Luo, Rifang; Chen, Si; Li, Xin; Yuan, Shuheng; Wang, Jin; Huang, Nan

    2015-02-01

    Drug-eluting stents (DESs) have been an important breakthrough for interventional cardiology applications since 2002. Though successful in reducing restenosis, some adverse clinical problems still emerged, which were mostly caused by the bare-metal stents and non-biodegradable polymer coatings, associated with the delayed endothelialization process. In this study, dexamethasone-loaded poly (lactic-co-glycolic acid) (PLGA) coatings were developed to explore the potential application of dexamethasone-eluting stents. Dexamethasone-eluting PLGA stents were prepared using ultrasonic atomization spray method. For other tests like stability and cytocompatibility and hemocompatibility tests, dexamethasone loaded coatings were deposited on 316L SS wafers. Fourier transform-infrared spectroscopy (FT-IR) results demonstrated that there was no chemical reaction between PLGA and dexamethasone. The balloon expansion experiment and surface morphology observation suggested that the stent coatings were smooth and uniform, and could also withstand the compressive and tensile strains imparted without cracking after stent expansion. The drug release behavior in vitro indicated that dexamethasone existed burst release within 1 day, but it presented linear release characteristics after 6 days. In vitro platelets adhesion, activation test and APTT test were also done, which showed that after blending dexamethasone into PLGA, the hemocompatibility was improved. Besides, dexamethasone and dexamethasone-loaded PLGA coatings could significantly inhibit the attachment and proliferation of smooth muscle cells.

  7. In vitro characterization of hepatocyte growth factor release from PHBV/PLGA microsphere scaffold.

    PubMed

    Zhu, Xin Hao; Wang, Chi-Hwa; Tong, Yen Wah

    2009-05-01

    Polymer scaffolds which can support cells to grow as well as deliver growth factors to the cells simultaneously have great potential for the successful regeneration of failed tissues. As popularly used vehicles to deliver anti-cancer drugs and growth factors, microspheres also show many advantages as substrates to guide the growth of cells. Therefore, we aimed to examine the feasibility of using microspheres as ideal scaffolds for liver tissue engineering. To determine the capabilities of previously used microsphere scaffold to deliver growth factors simultaneously, this work investigated a long-term (about three months) release of bovine serum albumin (BSA) from microsphere scaffolds fabricated by using two different polymers, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV, 8% PHV), poly(lactide-co-glycolide) acid (PLGA, 5050) and a blend of PLGA and PHBV. BSA served as a model for hepatocyte growth factor (HGF) since both proteins have similar molecular weights and hydrophilicity. Furthermore, HGF was encapsulated into the PLGA/PHBV composite microsphere with a core-shell structure, and sustained delivery of HGF with maintained bioactivity was achieved for at least 40 days. The moderate degradation rate (about 55% loss of the initial mass) and well-preserved structure after three months of incubation indicated that the PLGA/PHBV composite microspheres would therefore be more suitable than the pure PHBV or PLGA microspheres as a scaffold for engineering liver tissue.

  8. PHBV microspheres--PLGA matrix composite scaffold for bone tissue engineering.

    PubMed

    Huang, Wei; Shi, Xuetao; Ren, Li; Du, Chang; Wang, Yingjun

    2010-05-01

    Polymer scaffolds, particularly in the form of microspheres, have been employed to support cells growth and deliver drugs or growth factors in tissue engineering. In this study, we have established a scaffold by embedding poly (beta-hydroxybutyrate-co-beta-hydroxyvalerate) (PHBV) microspheres into poly (L-lactic-co-glycolic acid) (PLGA) matrix, according to their different solubility in acetone, with the aim of repairing bone defects. PLGA/PHBV scaffolds had good pore parameters, for example, the porosity of PLGA/30% PHBV scaffold can reach to 81.273 +/- 2.192%. Besides, the pore size distribution of the model was evaluated and the results revealed that the pore size mainly distributed between 50 mum and 200 mum. With increasing the amount of PHBV microspheres, the compressive strength of the PLGA/PHBV scaffold enhanced. The morphology of the hybrid scaffold was rougher than that of pure PLGA scaffold, which had no significant effect on the cell behavior. The in vitro evaluation suggested that the model is suitable as a scaffold for engineering bone tissue, and has the potential for further applications in drug delivery system.

  9. Biodegradable effect of PLGA membrane in alveolar bone regeneration on beagle dog.

    PubMed

    Hua, Nan; Ti, Vivian Lao; Xu, Yuanzhi

    2014-11-01

    Guided bone regeneration (GBR) is a principle adopted from guided tissue regeneration (GTR). Wherein, GBR is used for the healing of peri-implant bony dehiscences, for the immediate placement of implants into extraction sockets and for the augmentation of atrophic alveolar ridges. This procedure is done by the placement of a resorbable or non-resorbable membrane that will exclude undesirable types of tissue growth between the extraction socket and the soft tissue to allow only bone cells to regenerate in the surgically treated lesion. Here, we investigated the biodegradable effect of polylactic-co-glycolic acid (PLGA) membrane in the alveolar bone on Beagle dogs. Results show that both collagen and PLGA membrane had been fully resorbed, biodegraded, at four weeks post-operative reentry into the alveolar bone. Histological results under light microscopy revealed formation of new bone trabeculae in the extraction sites on both collagen and PLGA membrane. In conclusion, PLGA membrane could be a potential biomaterials for use on GBR and GTR. Nevertheless, further studies will be necessary to elucidate the efficiency and cost effectiveness of PLGA as GBR membrane in clinical.

  10. Ozone Gas as a Benign Sterilization Treatment for PLGA Nanofiber Scaffolds.

    PubMed

    Rediguieri, Carolina Fracalossi; Pinto, Terezinha de Jesus Andreoli; Bou-Chacra, Nadia Araci; Galante, Raquel; de Araújo, Gabriel Lima Barros; Pedrosa, Tatiana do Nascimento; Maria-Engler, Silvya Stuchi; De Bank, Paul A

    2016-04-01

    The use of electrospun nanofibers for tissue engineering and regenerative medicine applications is a growing trend as they provide improved support for cell proliferation and survival due, in part, to their morphology mimicking that of the extracellular matrix. Sterilization is a critical step in the fabrication process of implantable biomaterial scaffolds for clinical use, but many of the existing methods used to date can negatively affect scaffold properties and performance. Poly(lactic-co-glycolic acid) (PLGA) has been widely used as a biodegradable polymer for 3D scaffolds and can be significantly affected by current sterilization techniques. The aim of this study was to investigate pulsed ozone gas as an alternative method for sterilizing PLGA nanofibers. The morphology, mechanical properties, physicochemical properties, and response of cells to PLGA nanofiber scaffolds were assessed following different degrees of ozone gas sterilization. This treatment killed Geobacillus stearothermophilus spores, the most common biological indicator used for validation of sterilization processes. In addition, the method preserved all of the characteristics of nonsterilized PLGA nanofibers at all degrees of sterilization tested. These findings suggest that ozone gas can be applied as an alternative method for sterilizing electrospun PLGA nanofiber scaffolds without detrimental effects.

  11. Anticancer Activity of Nanoparticles Based on PLGA and its Co-polymer: In-vitro Evaluation

    PubMed Central

    Amjadi, Issa; Rabiee, Mohammad; Hosseini, Motahare-Sadat

    2013-01-01

    Attempts have been made to prepare nanoparticles based on poly(lactic-co-glycolic acid) (PLGA) and doxorubicin. Biological evaluation and physio-chemical characterizations were performed to elucidate the effects of initial drug loading and polymer composition on nanoparticle properties and its antitumor activity. PLGA nanoparticles were formulated by sonication method. Lactide/glycolide ratio and doxorubicin amounts have been tailored. Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) were employed to identify the presence of doxorubicin within nanospheres. The in vitro release studies were performed to determine the initial ant net release rates over 24 h and 20 days, respectively. Furthermore, cytotoxicity assay was measured to evaluate therapeutic potency of doxorubicin-loaded nanoparticles. Spectroscopy and thermal results showed that doxorubicin was loaded into the particles successfully. It was observed that lactide/glycolide content of PLGA nanoparticles containing doxorubicin has more prominent role in tuning particle characteristics. Doxorubicin release profiles from PLGA 75 nanospheres demonstrated that the cumulative release rate increased slightly and higher initial burst was detected in comparison to PLGA 50 nanoparticles. MTT data revealed doxorubicin induced antitumor activity was enhanced by encapsulation process, and increasing drug loading and glycolide portion. The results led to the conclusion that by controlling the drug loading and the polymer hydrophilicity, we can adjust the drug targeting and blood clearance, which may play a more prominent role for application in chemotherapy. PMID:24523742

  12. Porous nano-hydroxyapatite/collagen scaffold containing drug-loaded ADM-PLGA microspheres for bone cancer treatment.

    PubMed

    Rong, Zi-Jie; Yang, Lian-Jun; Cai, Bao-Ta; Zhu, Li-Xin; Cao, Yan-Lin; Wu, Guo-Feng; Zhang, Zan-Jie

    2016-05-01

    To develop adriamycin (ADM)-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles in a porous nano-hydroxyapatite/collagen scaffold (ADM-PLGA-NHAC). To provide novel strategies for future treatment of osteosarcoma, the properties of the scaffold, including its in vitro extended-release properties, the inhibition effects of ADM-PLGA-NHAC on the osteosarcoma MG63 cells, and its bone repair capacity, were investigated in vivo and in vitro. The PLGA copolymer was utilized as a drug carrier to deliver ADM-PLGA nanoparticles (ADM-PLGA-NP). Porous nano-hydroxyapatite and collagen were used to materials to produce the porous nano-hydroxyapatite/collagen scaffold (NHAC), into which the ADM-PLGA-NP was loaded. The performance of the drug-carrying scaffold was assessed using multiple techniques, including scanning electron microscopy and in vitro extended release. The antineoplastic activities of scaffold extracts on the human osteosarcoma MG63 cell line were evaluated in vitro using the cell counting kit-8 (CCK8) method and live-dead cell staining. The bone repair ability of the scaffold was assessed based on the establishment of a femoral condyle defect model in rabbits. ADM-PLGA-NHAC and NHAC were implanted into the rat muscle bag for immune response experiments. A tumor-bearing nude mice model was created, and the TUNEL and HE staining results were observed under optical microscopy to evaluate the antineoplastic activity and toxic side effects of the scaffold. The composite scaffold demonstrated extraordinary extended-release properties, and its extracts also exhibited significant inhibition of the growth of osteosarcoma MG63 cells. In the bone repair experiment, no significant difference was observed between ADM-PLGA-NHAC and NHAC by itself. In the immune response experiments, ADM-PLGA-NHAC exhibited remarkable biocompatibility. The in vivo antitumor experiment revealed that the implantation of ADM-PLGA-NHAC in the tumor resulted in a improved antineoplastic

  13. PLGA particulate delivery systems for subunit vaccines: Linking particle properties to immunogenicity.

    PubMed

    Silva, A L; Soema, P C; Slütter, B; Ossendorp, F; Jiskoot, W

    2016-04-02

    Among the emerging subunit vaccines are recombinant protein- and synthetic peptide-based vaccine formulations. However, proteins and peptides have a low intrinsic immunogenicity. A common strategy to overcome this is to co-deliver (an) antigen(s) with (an) immune modulator(s) by co-encapsulating them in a particulate delivery system, such as poly(lactic-co-glycolic acid) (PLGA) particles. Particulate PLGA formulations offer many advantages for antigen delivery as they are biocompatible and biodegradable; can protect the antigens from degradation and clearance; allow for co-encapsulation of antigens and immune modulators; can be targeted to antigen presenting cells; and their particulate nature can increase uptake and cross-presentation by mimicking the size and shape of an invading pathogen. In this review we discuss the pros and cons of using PLGA particulate formulations for subunit vaccine delivery and provide an overview of formulation parameters that influence their adjuvanticity and the ensuing immune response.

  14. PLGA particulate delivery systems for subunit vaccines: Linking particle properties to immunogenicity

    PubMed Central

    Silva, A. L.; Soema, P. C.; Slütter, B.; Ossendorp, F.; Jiskoot, W.

    2016-01-01

    ABSTRACT Among the emerging subunit vaccines are recombinant protein- and synthetic peptide-based vaccine formulations. However, proteins and peptides have a low intrinsic immunogenicity. A common strategy to overcome this is to co-deliver (an) antigen(s) with (an) immune modulator(s) by co-encapsulating them in a particulate delivery system, such as poly(lactic-co-glycolic acid) (PLGA) particles. Particulate PLGA formulations offer many advantages for antigen delivery as they are biocompatible and biodegradable; can protect the antigens from degradation and clearance; allow for co-encapsulation of antigens and immune modulators; can be targeted to antigen presenting cells; and their particulate nature can increase uptake and cross-presentation by mimicking the size and shape of an invading pathogen. In this review we discuss the pros and cons of using PLGA particulate formulations for subunit vaccine delivery and provide an overview of formulation parameters that influence their adjuvanticity and the ensuing immune response. PMID:26752261

  15. Effects of Microemulsion Preparation Conditions on Drug Encapsulation Efficiency of PLGA Nanoparticles

    NASA Astrophysics Data System (ADS)

    Ng, Set Hui; Ooi, Ing Hong

    2011-12-01

    Emulsion solvent evaporation technique is widely used to prepare nanoparticles of many organic polymer drug carriers. The mechanism of nanoparticle generation by this technique involves oil-in-water (O/W) microemulsion formation followed by solvent evaporation. Various microemulsion preparation conditions can affect the encapsulation efficiency of drug in the nanoparticulate carrier. In this study, emulsifying speed, emulsifying temperature, and organic-to-aqueous phase ratio were varied and the resulting encapsulation efficiency of a model drug in Poly(Lactide-co-Glycolide) (PLGA) nanoparticles was determined. The organic phase containing PLGA and a model drug dissolved in chloroform was first dispersed in an aqueous solution containing 0.5 %(w/v) Poly(vinyl alcohol) (PVA), which was then homogenized at high speeds. The resulting O/W microemulsion was subsequently subjected to stirring at room temperature for four hours during which the solvent diffused and evaporated gradually. The fine white suspension was centrifuged and freeze-dried. The model drug loading in the PLGA nanoparticles was determined using UV spectrophotometry. Results showed that the encapsulation efficiency of a model drug, salicylic acid, ranged from 8.5% to 17% depending on the microemulsion preparation conditions. Under the same temperature (15 °C) and homogenization speed (19000 rpm) conditions studied, a relatively high organic-to-aqueous phase ratio (1:5) provided salicylic acid loaded PLGA nanoparticles with significantly higher drug encapsulation efficiency. In addition, under all microemulsion preparation conditions, PLGA nanoparticles obtained after solvent evaporation and freeze drying were spherical and aggregation between the nanoparticles was not observed under a high power microscope. This indicates that PLGA nanoparticles with desirable amount of drug and with anticipated size and shape can be realized by controlling emulsification process conditions.

  16. Pilot-scale testing of microbubble flotation

    SciTech Connect

    Yoon, R.H.; Adel, G.T.; Luttrell, G.H.

    1991-01-01

    Fundamental investigations into the effect of bubble size on coal flotation have established that the use of microbubbles can improve the recovery of fine coal during flotation while, at the same time, increasing the rejection of ash-forming mineral matter. When used in conjunction with the quiescent conditions provided by a column, the microbubble flotation process has been demonstrated on a laboratory scale to be capable of producing superclean coal containing less than 1 or 2% ash and very little pyritic sulfur. The main objective of this project is to demonstrate the microbubble column flotation process on a pilot-scale. A 500 lb/hr pilot plant is being constructed for the purpose of: 910 demonstrating the feasibility of the microbubble flotation process for producing superclean coal, (2) collecting scale-up data for designing commercial-scale microbubble flotation columns, and (3) collecting cost data for an economic evaluation of the process. In addition to micronized coal, the process is also being tested on coarse coal and refuse pond material. 20 figs.

  17. Lead-silicate glass optical microbubble resonator

    SciTech Connect

    Wang, Pengfei; Ward, Jonathan; Yang, Yong; Chormaic, Síle Nic; Feng, Xian; Brambilla, Gilberto; Farrell, Gerald

    2015-02-09

    Microbubble whispering gallery resonators have the potential to become key components in a variety of active and passive photonic circuit devices by offering a range of significant functionalities. Here, we report on the fabrication, optical characterization, and theoretical analysis of lead-silicate glass and optical microbubble resonators. Evanescent field coupling to the microbubbles was achieved using a 1 μm diameter, silica microfiber at a wavelength of circa 775 nm. High Q-factor modes were efficiently excited in both single-stem and two-stem, lead-silicate glass, and microbubble resonators, with bubble diameters of 38 μm (single-stem) and 48 μm (two-stem). Whispering gallery mode resonances with Q-factors as high as 2.3 × 10{sup 5} (single-stem) and 7 × 10{sup 6} (two-stem) were observed. By exploiting the high-nonlinearity of the lead-silicate glass, this work will act as a catalyst for studying a range of nonlinear optical effects in microbubbles, such as Raman scattering and four-wave mixing, at low optical powers.

  18. Use of microbubble dispersion for soil scouring

    SciTech Connect

    Longe, T.A.; Bouillard, J.X.; Michelsen, D.L.

    1995-12-31

    Techniques for generating a microbubble dispersion (colloidal gas aphrons) have been developed. The microbubbles typically consist of 60 to 70% dispersion of 55-{micro} microbubbles in water, although dispersion up to 90 to 95% can be generated continuously. A number of laboratory soil column flow studies have been completed to define the potential of using these microbubbles to scour and release dispersed organics for subsequent pumping and removal or to enhance in situ degradation. The higher viscosity foams flow forward and fill up larger channels. The pressure drop builds up in the channel, resulting in foam flow into less accessible spill zones. In scouring hexadecane from columns containing 50- to 70-mesh sand, following a water preflush, up to 80% of the remaining organic could be flushed using a 70% CGA quality (70% air, 30% liquid). The technique was less effective at lower CGA quality. In genera, a surfactant concentration of 1,000 to 5,000 ppm was needed to generate the microbubbles.

  19. Lactosylated PLGA nanoparticles containing ϵ-polylysine for the sustained release and liver-targeted delivery of the negatively charged proteins.

    PubMed

    Zhou, Ping; An, Tong; Zhao, Chuan; Li, Yuan; Li, Rongshan; Yang, Rui; Wang, Yinsong; Gao, Xiujun

    2015-01-30

    The acidic internal pH environment, initial burst release and lack of targeting property are main limitations of poly(lactide-co-glycolide) (PLGA) nanoparticles for carrying proteins. In this study, ϵ-polylysine (ϵ-PL) was used as an anti-acidic agent and a protein protectant to prepare PLGA nanoparticles for the protein delivery. To obtain the liver-targeting capability, lactosylated PLGA (Lac-PLGA) was synthesized by conjugation of lactose acid to PLGA at both ends, and then used to prepare nanoparticles containing ϵ-PL by the nanoprecipitation method. Bovine serumal bumin (BSA), a negatively charged protein, was efficiently loaded into Lac-PLGA/ϵ-PL nanoparticles and exhibited significant decreased burst release in vitro, sustained release in the blood and increased liver distribution in mice after intravenous injections. The enhanced stability of BSA was due to its electrical interaction with ϵ-PL and the neutralized internal environment of nanoparticles. In conclusion, Lac-PLGA/ϵ-PL nanoparticle system can be used as a promising carrier for the negatively charged proteins.

  20. On the acoustic response of microbubbles in arteriole sized vessels

    NASA Astrophysics Data System (ADS)

    Butler, Mairead B.; Thomas, David H.; Silva, Nadia; Pye, Stephen D.; Sboros, Vassilis

    2011-11-01

    Microbubbles are used to improve ultrasound imaging of the vascular bed. Optical microscopy has shown microbubbles in different size tubes which have different responses to ultrasound. The acoustic scatter associated with such differences has not been previously measured. Echoes from two types of microbubbles, in narrow tubes, were collected at incident ultrasound parameters relevant to diagnostic imaging. Microbubbles were found to have increased second harmonic signatures in 50 μm diameter tubes compared to 200 μm. There was decreased survival of lipid microbubbles in the smaller tube. Understanding scatter mechanisms in narrow tubes is useful for signal processing optimisation for imaging applications.

  1. Ultrasound microbubble contrast and current clinical applications.

    PubMed

    Dindyal, Shiva; Kyriakides, Constantinos

    2011-01-01

    Ultrasound imaging is widely used worldwide principally because it is cheap, easily available and contains no exposure to ionizing radiation. The advent of microbubble ultrasound contrast has further increased the diagnostic sensitivity and specificity of this technique thus widening its clinical applications. The third generation of ultrasound contrast agents consist of sulphur hexafluoride microbubbles encased in a phospholipid shell. This review will elaborate on the pharmacology, safety profile and method of action of these agents. We also aim to discuss the ever expanding uses for contrast enhanced ultrasound in a number of clinical specialities which include the liver, kidney, prostate, sentinel node detection, vascular tree and endovascular stent surveillance. We will also discuss some of the recent patents regarding the future uses of ultrasound microbubble contrast and recent technological advances in clinical applications.

  2. Dynamics of micro-bubble sonication inside a phantom vessel

    NASA Astrophysics Data System (ADS)

    Qamar, Adnan; Samtaney, Ravi; Bull, Joseph L.

    2013-01-01

    A model for sonicated micro-bubble oscillations inside a phantom vessel is proposed. The model is not a variant of conventional Rayleigh-Plesset equation and is obtained from reduced Navier-Stokes equations. The model relates the micro-bubble oscillation dynamics with geometric and acoustic parameters in a consistent manner. It predicts micro-bubble oscillation dynamics as well as micro-bubble fragmentation when compared to the experimental data. For large micro-bubble radius to vessel diameter ratios, predictions are damped, suggesting breakdown of inherent modeling assumptions for these cases. Micro-bubble response with acoustic parameters is consistent with experiments and provides physical insight to the micro-bubble oscillation dynamics.

  3. Dynamics of micro-bubble sonication inside a phantom vessel

    PubMed Central

    Qamar, Adnan; Samtaney, Ravi; Bull, Joseph L.

    2013-01-01

    A model for sonicated micro-bubble oscillations inside a phantom vessel is proposed. The model is not a variant of conventional Rayleigh-Plesset equation and is obtained from reduced Navier-Stokes equations. The model relates the micro-bubble oscillation dynamics with geometric and acoustic parameters in a consistent manner. It predicts micro-bubble oscillation dynamics as well as micro-bubble fragmentation when compared to the experimental data. For large micro-bubble radius to vessel diameter ratios, predictions are damped, suggesting breakdown of inherent modeling assumptions for these cases. Micro-bubble response with acoustic parameters is consistent with experiments and provides physical insight to the micro-bubble oscillation dynamics. PMID:23405034

  4. Bone-Healing Capacity of PCL/PLGA/Duck Beak Scaffold in Critical Bone Defects in a Rabbit Model

    PubMed Central

    Lee, Jae Yeon; Son, Soo Jin; Son, Jun Sik; Kang, Seong Soo; Choi, Seok Hwa

    2016-01-01

    Bone defects are repaired using either natural or synthetic bone grafts. Poly(ϵ-caprolactone) (PCL), β-tricalcium phosphate (TCP), and poly(lactic-co-glycolic acid) (PLGA) are widely used as synthetic materials for tissue engineering. This study aimed to investigate the bone-healing capacity of PCL/PLGA/duck beak scaffold in critical bone defects and the oxidative stress status of the graft site in a rabbit model. The in vivo performance of 48 healthy New Zealand White rabbits, weighing between 2.5 and 3.5 kg, was evaluated. The rabbits were assigned to the following groups: group 1 (control), group 2 (PCL/PLGA hybrid scaffolds), group 3 (PCL/PLGA/TCP hybrid scaffolds), and group 4 (PCL/PLGA/DB hybrid scaffolds). A 5 mm critical defect was induced in the diaphysis of the left radius. X-ray, micro-CT, and histological analyses were conducted at (time 0) 4, 8, and 12 weeks after implantation. Furthermore, bone formation markers (bone-specific alkaline phosphatase, carboxyterminal propeptide of type I procollagen, and osteocalcin) were measured and oxidative stress status was determined. X-ray, micro-CT, biochemistry, and histological analyses revealed that the PCL/PLGA/duck beak scaffold promotes new bone formation in rabbit radius by inducing repair, suggesting that it could be a good option for the treatment of fracture. PMID:27042660

  5. pH-dependent antibacterial effects on oral microorganisms through pure PLGA implants and composites with nanosized bioactive glass.

    PubMed

    Hild, Nora; Tawakoli, Pune N; Halter, Jonas G; Sauer, Bärbel; Buchalla, Wolfgang; Stark, Wendelin J; Mohn, Dirk

    2013-11-01

    Biomaterials made of biodegradable poly(α-hydroxyesters) such as poly(lactide-co-glycolide) (PLGA) are known to decrease the pH in the vicinity of the implants. Bioactive glass (BG) is being investigated as a counteracting agent buffering the acidic degradation products. However, in dentistry the question arises whether an antibacterial effect is rather obtained from pure PLGA or from BG/PLGA composites, as BG has been proved to be antimicrobial. In the present study the antimicrobial properties of electrospun PLGA and BG45S5/PLGA fibres were investigated using human oral bacteria (specified with mass spectrometry) incubated for up to 24 h. BG45S5 nanoparticles were prepared by flame spray synthesis. The change in colony-forming units (CFU) of the bacteria was correlated with the pH of the medium during incubation. The morphology and structure of the scaffolds as well as the appearance of the bacteria were followed bymicroscopy. Additionally, we studied if the presence of BG45S5 had an influence on the degradation speed of the polymer. Finally, it turned out that the pH increase induced by the presence of BG45S5 in the scaffold did not last long enough to show a reduction in CFU. On the contrary, pure PLGA demonstrated antibacterial properties that should be taken into consideration when designing biomaterials for dental applications.

  6. Transferrin surface-modified PLGA nanoparticles-mediated delivery of a proteasome inhibitor to human pancreatic cancer cells.

    PubMed

    Frasco, Manuela F; Almeida, Gabriela M; Santos-Silva, Filipe; Pereira, Maria do Carmo; Coelho, Manuel A N

    2015-04-01

    The aim of this study was to develop a drug delivery system based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles for an efficient and targeted action of the proteasome inhibitor bortezomib against pancreatic cancer cells. The PLGA nanoparticles were formulated with a poloxamer, and further surface-modified with transferrin for tumor targeting. The nanoparticles were characterized as polymer carriers of bortezomib, and the cellular uptake and growth inhibitory effects were evaluated in pancreatic cells. Cellular internalization of nanoparticles was observed in normal and cancer cells, but with higher uptake by cancer cells. The sustained release of the loaded bortezomib from PLGA nanoparticles showed cytotoxic effects against pancreatic normal and cancer cells. Noteworthy differential cytotoxicity was attained by transferrin surface-modified PLGA nanoparticles since significant cell growth inhibition by delivered bortezomib was only observed in cancer cells. These findings demonstrate that the ligand transferrin enhanced the targeted delivery of bortezomib-loaded PLGA nanoparticles to pancreatic cancer cells. These in vitro results highlight the transferrin surface-modified PLGA nanoparticles as a promising system for targeted delivery of anticancer drugs.

  7. Neoangiogenesis of human mesenchymal stem cells transfected with peptide-loaded and gene-coated PLGA nanoparticles.

    PubMed

    Park, Ji Sun; Yang, Han Na; Yi, Se Won; Kim, Jae-Hwan; Park, Keun-Hong

    2016-01-01

    Several factors are involved in angiogenesis. To form new blood vessels, we fabricated vehicles carrying an angiogenesis-related peptide (apelin) and gene (vascular endothelial growth factor (VEGF)165) that were internalized by human mesenchymal stem cells (hMSCs). These non-toxic poly-(DL)-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) easily entered hMSCs without cytotoxicity. The negatively charged outer surface of PLGA NPs can be easily complexed with highly positively charged polyethylenimine (PEI) to deliver genes into cells. PLGA NPs complexed with PEI could be coated with negatively charged VEGF plasmid DNA and loaded with apelin. The physical characteristics of these PLGA NPs were determined by size distribution, gel retardation, and morphological analyses. Transfection of VEGF-coated apelin-loaded PLGA NPs resulted in the differentiation of hMSCs into endothelial cells and vascular formation in Matrigel in vitro. Following injection of hMSCs transfected with these PLGA NPs into an ischemic hind limb mouse model, these cells differentiated into endothelial cells and accelerated neovascularization.

  8. The Influence of Side Group Modification in Polyphosphazenes on Hydrolysis and Cell Adhesion of Blends with PLGA

    PubMed Central

    Krogman, Nicholas R.; Weikel, Arlin L.; Kristhart, Katherine A.; Nukavaropu, Syam P.; Deng, Meng; Nair, Lakshmi S.; Laurencin, Cato T.; Allcock, Harry R.

    2009-01-01

    Polyphosphazenes have been synthesized with tris(hydroxymethyl)amino methane (THAM) side groups and with co-substituents glycine ethyl ester and alanine ethyl ester. The THAM side group was linked to the polyphosphazene backbone via the amino function. The three pendent hydroxyl functions on each THAM side group were utilized for hydrogen bonding association with poly(glycolic-lactic acid) (PLGA). Co-substitution of the polyphosphazene with both THAM and glycine or alanine ethyl esters was employed to avoid the insolubility of the single-substituent THAM -substituted polyphosphazenes. Both poly[(tris(hydroxymethyl)aminomethane)(ethyl glycinato)phosphazene] and poly[(tris(hydroxymethyl)aminomethane)(ethyl alanato)phosphazene] (1:1 ratio of side groups) were blended with PLGA (50:50) or PLGA (85:15). DSC analysis indicated miscible blend formation, irrespective of the detailed molecular structure of the polyphosphazene or the composition of PLGA in the blend. Hydrolysis studies of the polyphosphazene:PLGA (50:50) blends indicated that the PLGA component hydrolyzed more rapidly than the polyphosphazene. Primary osteoblast cell studies showed good cell adhesion to the polymer blends during 14 days, but subsequent limited cell spreading due to increased surface roughness as the two polymers eroded at different rates. PMID:19345410

  9. Fabrication and in vivo evaluation of Nelfinavir loaded PLGA nanoparticles for enhancing oral bioavailability and therapeutic effect

    PubMed Central

    Venkatesh, D. Nagasamy; Baskaran, Mahendran; Karri, Veera Venkata Satyanarayana Reddy; Mannemala, Sai Sandeep; Radhakrishna, Kollipara; Goti, Sandip

    2015-01-01

    Nelfinavir mesylate (NFV) is an anti-viral drug, used in the treatment of Acquired Immunodeficiency Syndrome (AIDS). Poor oral bioavailability and shorter half-life (3.5–5 h) remain a major clinical limitation of NFV leading to unpredictable drug bioavailability and frequent dosing. In this context, the objective of the present study was to formulate NFV loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), which can increase the solubility and oral bioavailability along with sustained release of the drug. NFV loaded PLGA-NPs were prepared by nanoprecipitation method using PLGA and Poloxomer 407. The prepared NPs were evaluated for particle size, zeta potential, morphology, drug content, entrapment efficiency (EE) and in vitro dissolution studies. Oral bioavailability studies were carried out in New Zealand rabbits by administering developed NFV PLGA-NPs and pure drug suspension. PLGA-NPs prepared by using 1:4 ratio of drug and PLGA, with a stirring rate of 1500 rpm for 4 h. The prepared NPs were in the size of 185 ± 0.83 nm with a zeta potential of 28.7 ± 0.09 mV. The developed NPs were found to be spherical with uniform size distribution. The drug content and EE of the optimized formulation were found to be 36 ± 0.19% and 72 ± 0.47% respectively. After oral administration of NFV PLGA-NPs, the relative bioavailability was enhanced about 4.94 fold compared to NFV suspension as a control. The results describe an effective strategy for oral delivery of NFV loaded PLGA NPs that helps in enhancing bioavailability and reduce the frequency of dosing. PMID:26702262

  10. Cationic nanoparticles with quaternary ammonium-functionalized PLGA-PEG-based copolymers for potent gene transfection

    NASA Astrophysics Data System (ADS)

    Wang, Yan-Hsung; Fu, Yin-Chih; Chiu, Hui-Chi; Wang, Chau-Zen; Lo, Shao-Ping; Ho, Mei-Ling; Liu, Po-Len; Wang, Chih-Kuang

    2013-11-01

    The objective of the present work was to develop new cationic nanoparticles (cNPs) with amphiphilic cationic copolymers for the delivery of plasmid DNA (pDNA). Cationic copolymers were built on the synthesis of quaternary ammonium salt compounds from diethylenetriamine (DETA) to include the positively charged head group and amphiphilic multi-grafts. PLGA- phe-PEG- qDETA (PPD), phe-PEG- qDETA-PLGA (PDP), and PLGA- phe-PEG- qDETA-PLGA (PPDP) cationic copolymers were created by this moiety of DETA quaternary ammonium, heterobifunctional polyethylene glycol (COOH-PEG-NH2), phenylalanine ( phe), and poly(lactic- co-glycolic acid) (PLGA). These new cNPs were prepared by the water miscible solvent displacement method. They exhibit good pDNA binding ability, as shown in a retardation assay that occurred at a particle size of 217 nm. The zeta potential was approximately +21 mV when the cNP concentration was 25 mg/ml. The new cNPs also have a better buffering capacity than PLGA NPs. However, the pDNA binding ability was demonstrated starting at a weight ratio of approximately 6.25 cNPs/pDNA. Gene transfection results showed that these cNPs had transfection effects similar to those of Lipofectamine 2000 in 293T cells. Furthermore, cNPs can also transfect human adipose-derived stem cells. The results indicate that the newly developed cNP is a promising candidate for a novel gene delivery vehicle.

  11. Biodegradable PLGA- b-PEG polymeric nanoparticles: synthesis, properties, and nanomedical applications as drug delivery system

    NASA Astrophysics Data System (ADS)

    Locatelli, Erica; Comes Franchini, Mauro

    2012-12-01

    During the past decades many synthetic polymers have been studied for nanomedicine applications and in particular as drug delivery systems. For this purpose, polymers must be non-toxic, biodegradable, and biocompatible. Polylactic- co-glycolic acid (PLGA) is one of the most studied polymers due to its complete biodegradability and ability to self-assemble into nanometric micelles that are able to entrap small molecules like drugs and to release them into body in a time-dependent manner. Despite fine qualities, using PLGA polymeric nanoparticles for in vivo applications still remains an open challenge due to many factors such as poor stability in water, big diameter (150-200 nm), and the removal of these nanocarriers from the blood stream by the liver and spleen thus reducing the concentration of drugs drastically in tumor tissue. Polyethylene glycol (PEG) is the most used polymers for drug delivery applications and the first PEGylated product is already on the market for over 20 years. This is due to its stealth behavior that inhibits the fast recognition by the immune system (opsonization) and generally leads to a reduced blood clearance of nanocarriers increasing blood circulation time. Furthermore, PEG is hydrophilic and able to stabilize nanoparticles by steric and not ionic effects especially in water. PLGA-PEG block copolymer is an emergent system because it can be easily synthesized and it possesses all good qualities of PLGA and also PEG capability so in the last decade it arose as one of the most promising systems for nanoparticles formation, drug loading, and in vivo drug delivery applications. This review will discuss briefly on PLGA- b-PEG synthesis and physicochemical properties, together with its improved qualities with respect to the single PLGA and PEG polymers. Moreover, we will focus on but in particular will treat nanoparticles formation and uses as new drug delivery system for nanomedical applications.

  12. A comparative study of gelatin sponge scaffolds and PLGA scaffolds transplanted to completely transected spinal cord of rat.

    PubMed

    Du, Bao-ling; Zeng, Chen-guang; Zhang, Wei; Quan, Da-ping; Ling, Eng-ang; Zeng, Yuan-shan

    2014-06-01

    This study sought to investigate whether gelatin sponge (GS) scaffold would produce less acidic medium in injured spinal cord, as compared with poly(lactic-co-glycolic acid) (PLGA) scaffold, to determine which of the two scaffolds as the biomaterial is more suitable for transplantation into spinal cord. GS scaffold or PLGA scaffold was transplanted into a transected spinal cord in this study. Two months after transplantation of scaffolds, acid sensing ion channel 1a (ASIC1a) positive cells expressing microtubule associated protein 2 (Map2) were observed as well as expressing adenomatous polyposis coli (APC) in spinal cord. GFAP positive cells were distributed at the rostral and caudal of the injury/graft area in the GS and PLGA groups. Western blot showed ASIC1a and GFAP expression of injured spinal cord was downregulated in the GS group. The number of CD68 positive cells was fewer and NF nerve fibers were more in the GS group. Nissl staining and cell counting showed that the number of survival neurons was comparable between the GS and PLGA groups in the pyramidal layer of sensorimotor cortex and the red nucleus of midbrain. However, in the Clarke's nucleus at L1 spinal segment, the surviving neurons in the GS group were more numerous than that in the PLGA group. H&E staining showed that the tissue cavities in the GS group were smaller in size than that in the PLGA group. The results suggest that GS scaffold is more suitable for transplantation to promote the recovery of spinal cord injury compared with PLGA scaffold.

  13. Ultrasound contrast agent fabricated from microbubbles containing instant adhesives, and its ultrasound imaging ability

    NASA Astrophysics Data System (ADS)

    Makuta, T.; Tamakawa, Y.

    2012-04-01

    Non-invasive surgery techniques and drug delivery system with acoustic characteristics of ultrasound contrast agent have been studied intensively in recent years. Ultrasound contrast agent collapses easily under the blood circulating and the ultrasound irradiating because it is just a stabilized bubble without solid-shell by surface adsorption of surfactant or lipid. For improving the imaging stability, we proposed the fabrication method of the hollow microcapsule with polymer shell, which can be fabricated just blowing vapor of commonly-used instant adhesive (Cyanoacrylate monomer) into water as microbubbles. Therefore, the cyanoacrylate vapor contained inside microbubble initiates polymerization on the gasliquid interface soon after microbubbles are generated in water. Consequently, hollow microspheres coated by cyanoacrylate thin film are generated. In this report, we revealed that diameter distributions of microbubbles and microcapsules were approximately same and most of them were less than 10 μm, that is, smaller than blood capillary. In addition, we also revealed that hollow microcapsules enhanced the acoustic signal especially in the harmonic contrast imaging and were broken or agglomerated under the ultrasound field. As for the yield of hollow microcapsules, we revealed that sodium dodecyl sulfate addition to water phase instead of deoxycolic acid made the fabrication yield increased.

  14. Electrospun PDLLA/PLGA composite membranes for potential application in guided tissue regeneration.

    PubMed

    Zhang, Ershuai; Zhu, Chuanshun; Yang, Jun; Sun, Hong; Zhang, Xiaomin; Li, Suhua; Wang, Yonglan; Sun, Lu; Yao, Fanglian

    2016-01-01

    With the aim to explore a membrane system with appropriate degradation rate and excellent cell-occlusiveness for guided tissue regeneration (GTR), a series of poly(D, L-lactic acid) (PDLLA)/poly(D, L-lactic-co-glycolic acid) (PLGA) (100/0, 70/30, 50/50, 30/70, 0/100, w/w) composite membranes were fabricated via electrospinning. The fabricated membranes were evaluated by morphological characterization, water contact angle measurement and tensile test. In vitro degradation was characterized in terms of the weight loss and the morphological change. Moreover, in vitro cytologic research revealed that PDLLA/PLGA composite membranes could efficiently inhibit the infiltration of 293 T cells. Finally, subcutaneous implant test on SD rat in vivo showed that PDLLA/PLGA (70/30, 50/50) composite membranes could function well as a physical barrier to prevent cellular infiltration within 13 weeks. These results suggested that electrospun PDLLA/PLGA (50/50) composite membranes could serve as a promising barrier membrane for guided tissue regeneration due to suitable biodegradability, preferable mechanical properties and excellent cellular shielding effects.

  15. Peptide/protein vaccine delivery system based on PLGA particles

    PubMed Central

    Allahyari, Mojgan; Mohit, Elham

    2016-01-01

    abstract Due to the excellent safety profile of poly (D,L-lactide-co-glycolide) (PLGA) particles in human, and their biodegradability, many studies have focused on the application of PLGA particles as a controlled-release vaccine delivery system. Antigenic proteins/peptides can be encapsulated into or adsorbed to the surface of PLGA particles. The gradual release of loaded antigens from PLGA particles is necessary for the induction of efficient immunity. Various factors can influence protein release rates from PLGA particles, which can be defined intrinsic features of the polymer, particle characteristics as well as protein and environmental related factors. The use of PLGA particles encapsulating antigens of different diseases such as hepatitis B, tuberculosis, chlamydia, malaria, leishmania, toxoplasma and allergy antigens will be described herein. The co-delivery of antigens and immunostimulants (IS) with PLGA particles can prevent the systemic adverse effects of immunopotentiators and activate both dendritic cells (DCs) and natural killer (NKs) cells, consequently enhancing the therapeutic efficacy of antigen-loaded PLGA particles. We will review co-delivery of different TLR ligands with antigens in various models, highlighting the specific strengths and weaknesses of the system. Strategies to enhance the immunotherapeutic effect of DC-based vaccine using PLGA particles can be designed to target DCs by functionalized PLGA particle encapsulating siRNAs of suppressive gene, and disease specific antigens. Finally, specific examples of cellular targeting where decorating the surface of PLGA particles target orally administrated vaccine to M-cells will be highlighted. PMID:26513024

  16. Pharmacokinetics and distributions of bevacizumab by intravitreal injection of bevacizumab-PLGA microspheres in rabbits

    PubMed Central

    Ye, Zhuo; Ji, Yan-Li; Ma, Xiang; Wen, Jian-Guo; Wei, Wei; Huang, Shu-Man

    2015-01-01

    AIM To investigate the pharmacokinetics and distributions of bevacizumab by intravitreal injection of prepared bevacizumab-poly (L-lactic-co-glycolic acid) (PLGA) microspheres in rabbits, to provide evidence for clinical application of this kind of bevacizumab sustained release dosage form. METHODS Bevacizumab was encapsulated into PLGA microsphere via the solid-in-oil-in-hydrophilic oil (S/O/hO) method. Fifteen healthy New Zealand albino-rabbits were used in experiments. The eyes of each rabbit received an intravitreal injection. The left eyes were injected with prepared bevacizumab-PLGA microspheres and the right eyes were injected with bevacizumab solution. After intravitreal injection, rabbits were randomly selected at days 3, 7, 14, 28 and 42 respectively, three animals each day. Then we used immunofluorescence staining to observe the distribution and duration of bevacizumab in rabbit eye tissues, and used the sandwich ELISA to quantify the concentration of free bevacizumab from the rabbit aqueous humor and vitreous after intravitreal injection. RESULTS The results show that the concentration of bevacizumab in vitreous and aqueous humor after administration of PLGA formulation was higher than that of bevacizumab solution. The T1/2 of intravitreal injection of bevacizumab-PLGA microspheres is 9.6d in vitreous and 10.2d in aqueous humor, and the T1/2 of intravitreal injection of soluble bevacizumab is 3.91d in vitreous and 4.1d in aqueous humor. There were statistical significant difference for comparison the results of the bevacizumab in vitreous and aqueous humor between the left and right eyes (P<0.05). The AUC0-t of the sustained release dosage form was 1-fold higher than that of the soluble form. The relative bioavailability was raised significantly. The immunofluorescence staining of PLGA-encapsulated bevacizumab (b-PLGA) in rabbit eye tissues was still observed up to 42d. It was longer than that of the soluble form. CONCLUSION The result of this study

  17. Long lived microbubbles for oxygen delivery.

    PubMed

    Gerber, Frédéric; Waton, Gilles; Krafft, Marie Pierre; Vandamme, Thierry F

    2007-01-01

    Exceptionally long lived microbubbles containing a fluorocarbon as part of their filling gas have been obtained by using a fluorinated phospholipid instead of a standard phospholipid as shell component. An unexpected, strong synergistic effect between the fluorocarbon gas and the fluorinated phospholipid has been discovered. Such bubbles could be used for in vivo oxygen delivery, ultrasound contrast imaging and drug delivery.

  18. A Targeting Microbubble for Ultrasound Molecular Imaging

    PubMed Central

    Yeh, James Shue-Min; Sennoga, Charles A.; McConnell, Ellen; Eckersley, Robert; Tang, Meng-Xing; Nourshargh, Sussan; Seddon, John M.; Haskard, Dorian O.; Nihoyannopoulos, Petros

    2015-01-01

    Rationale Microbubbles conjugated with targeting ligands are used as contrast agents for ultrasound molecular imaging. However, they often contain immunogenic (strept)avidin, which impedes application in humans. Although targeting bubbles not employing the biotin-(strept)avidin conjugation chemistry have been explored, only a few reached the stage of ultrasound imaging in vivo, none were reported/evaluated to show all three of the following properties desired for clinical applications: (i) low degree of non-specific bubble retention in more than one non-reticuloendothelial tissue; (ii) effective for real-time imaging; and (iii) effective for acoustic quantification of molecular targets to a high degree of quantification. Furthermore, disclosures of the compositions and methodologies enabling reproduction of the bubbles are often withheld. Objective To develop and evaluate a targeting microbubble based on maleimide-thiol conjugation chemistry for ultrasound molecular imaging. Methods and Results Microbubbles with a previously unreported generic (non-targeting components) composition were grafted with anti-E-selectin F(ab’)2 using maleimide-thiol conjugation, to produce E-selectin targeting microbubbles. The resulting targeting bubbles showed high specificity to E-selectin in vitro and in vivo. Non-specific bubble retention was minimal in at least three non-reticuloendothelial tissues with inflammation (mouse heart, kidneys, cremaster). The bubbles were effective for real-time ultrasound imaging of E-selectin expression in the inflamed mouse heart and kidneys, using a clinical ultrasound scanner. The acoustic signal intensity of the targeted bubbles retained in the heart correlated strongly with the level of E-selectin expression (|r|≥0.8), demonstrating a high degree of non-invasive molecular quantification. Conclusions Targeting microbubbles for ultrasound molecular imaging, based on maleimide-thiol conjugation chemistry and the generic composition described

  19. Galactose decorated PLGA nanoparticles for hepatic delivery of acyclovir.

    PubMed

    Gupta, Swati; Agarwal, Abhinav; Gupta, Nishant Kumar; Saraogi, Gauravkant; Agrawal, Himanshu; Agrawal, G P

    2013-12-01

    The present study explores prospective of surface tailored nanoparticles for targeted delivery of acyclovir along with the interception of minimal side effects. Acyclovir loaded plain and galactosylated poly lectic co glycolic acid (PLGA) nanoparticles were efficiently prepared and characterized by Fourier transform infrared spectroscopy, scanning electron microscopy (SEM), size, polydispersity index, zeta potential, and entrapment efficiency. The formulations were evaluated for in vitro drug release and hemolysis. Further, biodistribution study and fluorescent microscopic studies were carried out to determine the targeting potential of formulations. SEM revealed smooth morphology and spherical shape of the nanoparticles. In vitro, the galactosylated nanoparticles were found to be least hemolytic and exhibited a sustained release pattern. In vivo studies exhibited an augmented bioavailability, increased residence time and enhanced delivery of acyclovir to the liver upon galactosylation. It may therefore be concluded that galactose conjugated PLGA nanoparticles can be used suitably as vehicles for delivery of bioactives specifically to the hepatic tissues and may be thus exploited in the effective management of various liver disorders.

  20. Development of Microbubble Contrast Agents with Biochemical Recognition and Tunable Acoustic Response

    NASA Astrophysics Data System (ADS)

    Nakatsuka, Matthew Allan Masao

    Microbubbles, consisting of gas-filled cores encapsulated within phospholipid or polymer shells, are the most widely used ultrasound contrast agents in the world. Because of their acoustic impedance mismatch with surrounding tissues and compressible gaseous interiors, they have high echogenicities that allow for efficient backscatter of ultrasound. They can also generate unique harmonic frequencies when insonated near their resonance frequency, depending on physical microbubble properties such as the stiffness and thickness of the encapsulating shell. Microbubbles are used to detect a number of cardiovascular diseases, but current methodologies lack the ability to detect and distinguish small, rapidly growing abnormalities that do not produce visible blockage or slowing of blood flow. This work describes the development, formulation, and validation of microbubbles with various polymer shell architectures designed to modulate their acoustic ability. We demonstrate that the addition of a thick disulfide crosslinked, poly(acrylic acid) encapsulating shell increases a bubble's resistance to cavitation and changes its resonance frequency. Modification of this shell architecture to use hybridized DNA strands to form crosslinks between the polymer chains allows for tuning of the bubble acoustic response. When the DNA crosslinks are in place, shell stiffness is increased so the bubbles do not oscillate and acoustic signal is muted. Subsequently, when these DNA strands are displaced, partial acoustic activity is restored. By using aptamer sequences with a specific affinity towards the biomolecule thrombin as the DNA crosslinking strand, this acoustic "ON/OFF" behavior can be specifically tailored towards the presence of a specific biomarker, and produces a change in acoustic signal at concentrations of thrombin consistent with acute deep venous thrombosis. Incorporation of the emulsifying agent poly(ethylene glycol) into the encapsulating shell improves microbubble yield

  1. Effect of n-HA with different surface-modified on the properties of n-HA/PLGA composite

    NASA Astrophysics Data System (ADS)

    Liuyun, Jiang; Chengdong, Xiong; Dongliang, Chen; Lixin, Jiang; xiubing, Pang

    2012-10-01

    Three different surface modification methods for nano-hydroxyapatite (n-HA) of stearic acid, grafted with L-lactide, combining stearic acid and surface-grafting L-lactic were adopted, respectively. The surface modification reaction and the effect of different methods were evaluated by Fourier transformation infrared (FTIR), X-ray photoelectron spectra (XPS), thermal gravimetric analysis (TGA), transmission electron microscopy (TEM). The results showed that n-HA surfaces were all successful modified, and the modification method of combining stearic acid and surface-grafting L-lactic had the greatest grafting amount and the best dispersion among the three modification methods. Then, the n-HA with three different surface modification and unmodified n-HA were introduced into PLGA, respectively, and a serials of n-HA/PLGA composites with 3% n-HA amount in weight were prepared by solution mixing, and the properties of n-HA/PLGA composites were also investigated by electromechanical universal tester and scanning electron microscope(SEM), comparing with PLGA. The results showed that the n-HA/PLGA composite with the n-HA surface modified by combining stearic acid and surface-grafting L-lactic had the highest bending strength and the best dispersion and interfacial adhesion among the three different modification methods, suggesting the surface modification of combining stearic acid and surface-grafting L-lactic was the most ideal method in this study, which has a great deal of enhancement of bending strength than PLGA, and it would be potential to be used in the field of bone fracture internal fixation in future.

  2. In vitro and in vivo evaluation of calcium phosphate composite scaffolds containing BMP-VEGF loaded PLGA microspheres for the treatment of avascular necrosis of the femoral head.

    PubMed

    Zhang, Hao-Xuan; Zhang, Xiu-Ping; Xiao, Gui-Yong; Hou, Yong; Cheng, Lei; Si, Meng; Wang, Shuai-Shuai; Li, Yu-Hua; Nie, Lin

    2016-03-01

    Avascular necrosis of the femoral head (ANFH) is difficult to treat due to high pressure and hypoxia, and reduced levels of growth factors such as bone morphogenetic protein (BMP), and vascular endothelial growth factor (VEGF). We generated a novel calcium phosphate (CPC) composite scaffold, which contains BMP-VEGF-loaded poly-lactic-co-glycolic acid (PLGA) microspheres (BMP-VEGF-PLGA-CPC). The BMP-VEGF-loaded microspheres have an encapsulation efficiency of 89.15% for BMP, and 78.55% for VEGF. The BMP-VEGF-PLGA-CPC scaffold also demonstrated a porosity of 62% with interconnected porous structures, and pore sizes of 219 μm and compressive strength of 6.60 MPa. Additionally, bone marrow mesenchymal stem cells (BMSCs) were seeded on scaffolds in vitro. Further characterization showed that the BMP-VEGF-PLGA-CPC scaffolds were biocompatible and enhanced osteogenesis and angiogenesis in vitro. Using a rabbit model of ANFH, BMP-VEGF-PLGA-CPC scaffolds were implanted into the bone tunnels of core decompression in the femoral head for 6 and 12 weeks. Radiographic and histological analysis demonstrated that the BMP-VEGF-PLGA-CPC scaffolds exhibited good biocompatibility, and osteogenic and angiogenic activity in vivo. These results indicate that the BMP-VEGF-PLGA-CPC scaffold may improve the therapeutic effect of core decompression surgery and be used as a treatment for ANFH.

  3. Microbubbles in Ultrasound-Triggered Drug and Gene Delivery

    PubMed Central

    Hernot, Sophie; Klibanov, Alexander L.

    2008-01-01

    Ultrasound contrast agents, in the form of gas-filled microbubbles, are becoming popular in perfusion monitoring; they are employed as molecular imaging agents. Microbubbles are manufactured from biocompatible materials, they can be injected intravenously, and some are approved for clinical use. Microbubbles can be destroyed by ultrasound irradiation. This destruction phenomenon can be applied to targeted drug delivery and enhancement of drug action. The ultrasonic field can be focused at the target tissues and organs; thus, selectivity of the treatment can be improved, reducing undesirable side effects. Microbubbles enhance ultrasound energy deposition in the tissues and serve as cavitation nuclei, increasing intracellular drug delivery. DNA delivery and successful tissue transfection is observed in the areas of the body where ultrasound is applied after intravascular administration of microbubbles and plasmid DNA. Accelerated blood clot dissolution in the areas of insonation by cooperative action of thrombolytic agents and microbubbles is demonstrated in several clinical trials. PMID:18486268

  4. Optical Scattering Measurement of Microbubble Cloud Dynamics in Ultrasound

    NASA Astrophysics Data System (ADS)

    Takashi Miwa,; Yoshiki Yamakoshi,; Tomoharu Mashiyama,

    2010-07-01

    The manipulation of microbubbles by ultrasonic waves has the potential to be a useful technique in therapeutic ultrasound, such as for drug delivery systems and gene delivery systems. The Bjerknes force, which is an acoustic radiation force produced by microbubbles, acts as a driving force on the microbubbles; however, the two types of Bjerknes force make the resultant bubble movement very complex. In this paper, the evaluation of microbubble dynamics under ultrasonic wave radiation based on a laser diffraction method is proposed. The relationship between the microbubble spatial distribution and the diffracted light intensity is discussed on the basis of both theoretical analysis and numerical simulations. Experiments are carried out using ultrasonic wave contrast agent as microbubbles.

  5. Mapping microbubble viscosity using fluorescence lifetime imaging of molecular rotors

    PubMed Central

    Hosny, Neveen A.; Mohamedi, Graciela; Rademeyer, Paul; Owen, Joshua; Wu, Yilei; Tang, Meng-Xing; Eckersley, Robert J.; Stride, Eleanor; Kuimova, Marina K.

    2013-01-01

    Encapsulated microbubbles are well established as highly effective contrast agents for ultrasound imaging. There remain, however, some significant challenges to fully realize the potential of microbubbles in advanced applications such as perfusion mapping, targeted drug delivery, and gene therapy. A key requirement is accurate characterization of the viscoelastic surface properties of the microbubbles, but methods for independent, nondestructive quantification and mapping of these properties are currently lacking. We present here a strategy for performing these measurements that uses a small fluorophore termed a “molecular rotor” embedded in the microbubble surface, whose fluorescence lifetime is directly related to the viscosity of its surroundings. We apply fluorescence lifetime imaging to show that shell viscosities vary widely across the population of the microbubbles and are influenced by the shell composition and the manufacturing process. We also demonstrate that heterogeneous viscosity distributions exist within individual microbubble shells even with a single surfactant component. PMID:23690599

  6. Electrospinning of PLGA/gum tragacanth nanofibers containing tetracycline hydrochloride for periodontal regeneration.

    PubMed

    Ranjbar-Mohammadi, Marziyeh; Zamani, M; Prabhakaran, M P; Bahrami, S Hajir; Ramakrishna, S

    2016-01-01

    Controlled drug release is a process in which a predetermined amount of drug is released for longer period of time, ranging from days to months, in a controlled manner. In this study, novel drug delivery devices were fabricated via blend electrospinning and coaxial electrospinning using poly lactic glycolic acid (PLGA), gum tragacanth (GT) and tetracycline hydrochloride (TCH) as a hydrophilic model drug in different compositions and their performance as a drug carrier scaffold was evaluated. Scanning electron microscopy (SEM) results showed that fabricated PLGA, blend PLGA/GT and core shell PLGA/GT nanofibers had a smooth and bead-less morphology with the diameter ranging from 180 to 460 nm. Drug release studies showed that both the fraction of GT within blend nanofibers and the core-shell structure can effectively control TCH release rate from the nanofibrous membranes. By incorporation of TCH into core-shell nanofibers, drug release was sustained for 75 days with only 19% of burst release within the first 2h. The prolonged drug release, together with proven biocompatibility, antibacterial and mechanical properties of drug loaded core shell nanofibers make them a promising candidate to be used as drug delivery system for periodontal diseases.

  7. Effect of blending HA-g-PLLA on xanthohumol-loaded PLGA fiber membrane.

    PubMed

    Qiao, Tiankui; Jiang, Suchen; Song, Ping; Song, Xiaofeng; Liu, Qimin; Wang, Lijuan; Chen, Xuesi

    2016-10-01

    Electropsun poly (lactide-co-glycolide) (PLGA) fiber membrane loaded xanthohumol (XN) has been developed using a co-solvent system of chloroform and dimethylformamide. To enhance its biological functionality as bone tissue engineering scaffolds, 5wt% hydroxyapatite grafted poly (l-lactic acid) (HA-g-PLLA) is blended into the spinning solution. The purpose of the present work is to disclose the effect of blending HA-g-PLLA on the corresponding properties of the medicated fiber membrane including morphology, thermodynamics, wettability, drug release, mechanics as well as cytotoxicity. XN and HA-g-PLLA can be well blended with PLGA to make fibers. Blending HA-g-PLLA not only turns amorphous XN/PLGA fiber membrane into crystal structure, but also changes the membranous wettability. Various medicated membranes exhibit the sustained release profiles. Drug release rate of the ternary membrane with HA-g-PLLA is slower compared to the binary XN/PLGA, and for the ternary membrane, the drug release accelerates with increasing XN content. A model is proposed to account for the drug release process. Tensile testing shows that at 10% of XN, the comprehensive mechanics of the ternary is preferable to the binary. At the same time, these fiber membranes are no cytotoxicity.

  8. PLGA-Listeriolysin O microspheres: Opening the gate for cytosolic delivery of cancer antigens.

    PubMed

    Gilert, Ariel; Baruch, Limor; Bronshtein, Tomer; Machluf, Marcelle

    2016-04-01

    Strategies for cancer protein vaccination largely aim to activate the cellular arm of the immune system against cancer cells. This approach, however, is limited since protein vaccines mostly activate the system's humoral arm instead. One way to overcome this problem is to enhance the cross-presentation of such proteins by antigen-presenting cells, which may consequently lead to intense cellular response. Here we examined the ability of listeriolysin O (LLO) incorporated into poly-lactic-co-glycolic acid (PLGA) microspheres to modify the cytosolic delivery of low molecular weight peptides and enhance their cross-presentation. PLGA microspheres were produced in a size suitable for uptake by phagocytic cells. The peptide encapsulation and release kinetics were improved by adding NaCl to the preparation. PLGA microspheres loaded with the antigenic peptide and incorporated with LLO were readily up-taken by phagocytic cells, which exhibited an increase in the expression of peptide-MHC-CI complexes on the cell surface. Furthermore, this system enhanced the activation of a specific T hybridoma cell line, thus simulating cytotoxic T cells. These results establish, for the first time, a proof of concept for the use of PLGA microspheres incorporated with a pore-forming agent and the antigen peptide of choice as a unique cancer protein vaccination delivery platform.

  9. Development and optimization of quercetin-loaded PLGA nanoparticles by experimental design

    PubMed Central

    TEFAS, LUCIA RUXANDRA; TOMUŢĂ, IOAN; ACHIM, MARCELA; VLASE, LAURIAN

    2015-01-01

    Background and aims Quercetin is a flavonoid with good antioxidant activity, and exhibits various important pharmacological effects. The aim of the present work was to study the influence of formulation factors on the physicochemical properties of quercetin-loaded polymeric nanoparticles in order to optimize the formulation. Materials and methods The nanoparticles were prepared by the nanoprecipitation method. A 3-factor, 3-level Box-Behnken design was employed in this study considering poly(D,L-lactic-co-glycolic) acid (PLGA) concentration, polyvinyl alcohol (PVA) concentration and the stirring speed as independent variables. The responses were particle size, polydispersity index, zeta potential and encapsulation efficiency. Results The PLGA concentration seemed to be the most important factor influencing quercetin-nanoparticle characteristics. Increasing PLGA concentration led to an increase in particle size, as well as encapsulation efficiency. On the other hand, it exhibited a negative influence on the polydispersity index and zeta potential. The PVA concentration and the stirring speed had only a slight influence on particle size and polydispersity index. However, PVA concentration had an important negative effect on the encapsulation efficiency. Based on the results obtained, an optimized formulation was prepared, and the experimental values were comparable to the predicted ones. Conclusions The overall results indicated that PLGA concentration was the main factor influencing particle size, while entrapment efficiency was predominantly affected by the PVA concentration. PMID:26528074

  10. Microbubble resonators as enhancement platforms for linear and nonlinear applications

    NASA Astrophysics Data System (ADS)

    Farnesi, Daniele; Berneschi, Simone; Righini, Giancarlo C.; Nunzi Conti, Gualtiero; Quercioli, Franco; Soria, Silvia

    2015-07-01

    We present linear and non linear optical applications of solid and hollow silica microresonators. Hollow microresonators or microbubble resonators combine the unique properties of whispering gallery mode resonators (WGMR) with the intrinsic capability of integrated microfluidics. Microbubbles were filled with water and aqueous solutions of ethanol in order to test the refractive index sensing capabilities of such resonators. We also tested the potential of microbubbles as nonlinear enhancement platform of both the filling material (Rhodamine 6G and Fluorescein) and the glass bubble.

  11. Docetaxel-loaded PLGA and PLGA-PEG nanoparticles for intravenous application: pharmacokinetics and biodistribution profile

    PubMed Central

    Rafiei, Pedram; Haddadi, Azita

    2017-01-01

    Docetaxel is a highly potent anticancer agent being used in a wide spectrum of cancer types. There are important matters of concern regarding the drug’s pharmacokinetics related to the conventional formulation. Poly(lactide-co-glycolide) (PLGA) is a biocompatible/biodegradable polymer with variable physicochemical characteristics, and its application in human has been approved by the United States Food and Drug Administration. PLGA gives polymeric nanoparticles with unique drug delivery characteristics. The application of PLGA nanoparticles (NPs) as intravenous (IV) sustained-release delivery vehicles for docetaxel can favorably modify pharmacokinetics, biofate, and pharmacotherapy of the drug in cancer patients. Surface modification of PLGA NPs with poly(ethylene glycol) (PEG) can further enhance NPs’ long-circulating properties. Herein, an optimized fabrication approach has been used for the preparation of PLGA and PLGA–PEG NPs loaded with docetaxel for IV application. Both types of NP formulations demonstrated in vitro characteristics that were considered suitable for IV administration (with long-circulating sustained-release purposes). NP formulations were IV administered to an animal model, and docetaxel’s pharmacokinetic and biodistribution profiles were determined and compared between study groups. PLGA and PEGylated PLGA NPs were able to modify the pharmacokinetics and biodistribution of docetaxel. Accordingly, the mode of changes made to pharmacokinetics and biodistribution of docetaxel is attributed to the size and surface properties of NPs. NPs contributed to increased blood residence time of docetaxel fulfilling their role as long-circulating sustained-release drug delivery systems. Surface modification of NPs contributed to more pronounced docetaxel blood concentration, which confirms the role of PEG in conferring long-circulation properties to NPs. PMID:28184163

  12. Ultrasound Gene Transfer into Fibroblast Cells using Microbubbles

    NASA Astrophysics Data System (ADS)

    Nakamura, Yoji; Hirayama, Kota; Yoshinaka, Kiyoshi; Tei, Yuichi; Takagi, Shu; Matsumoto, Yoichiro

    2009-04-01

    Ultrasound is widely applied in the medical field and offers the strong advantages of non-invasiveness and high-selectivity. Gene transfer using ultrasound, which is called sonoporation, is one application. Ultrasound has the potential to deliver therapeutic materials such as genes, drugs or proteins into cells. Microbubbles are known to be able to improve delivery efficiency. This is attributed to therapeutic materials passing through the cell membrane after permeability is increased by destruction or oscillation of microbubbles. The present study tried to deliver the GFP plasmids into fibroblast cells. Cells were cultured in 6-well culture plates and exposed to ultrasound (frequency, 2.1 MHz; wave pattern, duty cycle 10%; intensity, 0-26 W/cm2; time, 0-200 s) transmitted through medium containing microbubbles (Levovist® (void fraction, 8×10-5) or Sonazoid® (void fraction, 0-24×10-4)) and GFP plasmids at a concentration of 15 μg/mL. Density of microbubbles after ultrasound irradiation was measured. When ultrasound intensity was increased with Levovist® 8×10-4, transfection efficiency increased, cell viability decreased and microbubbles disappeared. With Sonazoid®, transfection efficiency and cell viability were basically unchanged and microbubbles decreased, but did not disappear. Transfection efficiency also improved with increased ultrasound irradiation time or microbubble density. Microbubble destruction appeared to have the main effect on gene transfection under Levovist® and microbubble oscillation had the main effect under Sonazoid®.

  13. Optical and acoustical dynamics of microbubble contrast agents inside neutrophils.

    PubMed Central

    Dayton, P A; Chomas, J E; Lum, A F; Allen, J S; Lindner, J R; Simon, S I; Ferrara, K W

    2001-01-01

    Acoustically active microbubbles are used for contrast-enhanced ultrasound assessment of organ perfusion. In regions of inflammation, contrast agents are captured and phagocytosed by activated neutrophils adherent to the venular wall. Using direct optical observation with a high-speed camera and acoustical interrogation of individual bubbles and cells, we assessed the physical and acoustical responses of both phagocytosed and free microbubbles. Optical analysis of bubble radial oscillations during insonation demonstrated that phagocytosed microbubbles experience viscous damping within the cytoplasm and yet remain acoustically active and capable of large volumetric oscillations during an acoustic pulse. Fitting a modified version of the Rayleigh-Plesset equation that describes mechanical properties of thin shells to optical radius-time data of oscillating bubbles provided estimates of the apparent viscosity of the intracellular medium. Phagocytosed microbubbles experienced a viscous damping approximately sevenfold greater than free microbubbles. Acoustical comparison between free and phagocytosed microbubbles indicated that phagocytosed microbubbles produce an echo with a higher mean frequency than free microbubbles in response to a rarefaction-first single-cycle pulse. Moreover, this frequency increase is predicted using the modified Rayleigh-Plesset equation. We conclude that contrast-enhanced ultrasound can detect distinct acoustic signals from microbubbles inside of neutrophils and may provide a unique tool to identify activated neutrophils at sites of inflammation. PMID:11222315

  14. Ozone micro-bubble disinfection method for wastewater reuse system.

    PubMed

    Sumikura, M; Hidaka, M; Murakami, H; Nobutomo, Y; Murakami, T

    2007-01-01

    Reuse of wastewater is regarded as one important way to deal with the world's shortage of potable water. The authors focused on a disinfection system using micro-bubbles and evaluated its capability for wastewater reuse. This paper reports experimental results from examination of the basic characteristics of micro-bubbles and disinfection of secondary effluent by air or ozone micro-bubbles. The results suggest that when micro-bubbles are applied in an ozonation system it is possible to reduce the reactor size, the amount of ozone decomposition equipment needed and the ozone dose rate.

  15. mZD7349 peptide-conjugated PLGA nanoparticles directed against VCAM-1 for targeted delivery of simvastatin to restore dysfunctional HUVECs.

    PubMed

    Imanparast, Fatemeh; Faramarzi, Mohammad Ali; Vatannejad, Akram; Paknejad, Maliheh; Deiham, Behnas; Kobarfard, Farzad; Amani, Amir; Doosti, Mahmood

    2017-02-02

    Endothelial dysfunction is initial and critical step of atherosclerosis. Impaired bioavailability of endothelial nitric oxide synthase (eNOS) is one of the main reasons of endothelial dysfunction. Improving bioavailability of eNOS by increasing its expression or activity using statins is an effective therapeutic strategy in restoring endothelial dysfunction. In this study, simvastatin (SIM) as a poorly water-soluble drug was loaded in poly (lactic-co-glycolic acid) (PLGA) nanoparticles (SIM-PLGA-NPs). NPs were then conjugated with mZD7349 peptide (mZD7349-SIM-PLGA-NPs) and directed against vascular cell adhesion molecule 1 (VCAM-1). In vitro evaluation of the NPs for targeted delivery of SIM was performed on activated Human Umbilical Cord Vascular Endothelial Cells (HUVECs) by tumor necrosis factor alpha (TNF-α). Effect of mZD7349-SIM-PLGA-NPs and SIM-PLGA-NPs was compared on eNOS phosphorylation (ser-1177). Results of western blot showed SIM post-treatment increased significantly phosphor-eNOS (Ser1177) expression but no total eNOS expression. The study showed that mZD7349-SIM-PLGA-NPs have particle size, zeta potential value, polydispersity index (PDI) and encapsulation efficacy % of 233±18nm, -9.6±1.1mV, 0.59±0.066 and 69±17.3%, respectively. Also phosphor-eNOS (Ser1177) expression in activated HUVECs treated with mZD7349-SIM-PLGA-NPs was significantly (p<0.05) better than treated cells with SIM-PLGA-NPs. The results suggest that mZD7349-SIM-PLGA-NPs may be usable as an appropriate drug carrier for restoring endothelial dysfunction.

  16. Microbubbles loaded with nanoparticles: a route to multiple imaging modalities.

    PubMed

    Park, Jai Il; Jagadeesan, Dinesh; Williams, Ross; Oakden, Wendy; Chung, Siyon; Stanisz, Greg J; Kumacheva, Eugenia

    2010-11-23

    We report a single-step approach to producing small and stable bubbles functionalized with nanoparticles. The strategy includes the following events occurring in sequence: (i) a microfluidic generation of bubbles from a mixture of CO(2) and a minute amount of gases with low solubility in water, in an aqueous solution of a protein, a polysaccharide, and anionic nanoparticles; (ii) rapid dissolution of CO(2) leading to the shrinkage of bubbles and an increase in acidity of the medium in the vicinity of the bubbles; and (iii) co-deposition of the biopolymers and nanoparticles at the bubble-liquid interface. The proposed approach yielded microbubbles with a narrow size distribution, long-term stability, and multiple functions originating from the attachment of metal oxide, metal, or semiconductor nanoparticles onto the bubble surface. We show the potential applications of these bubbles in ultrasound and magnetic resonance imaging.

  17. Coalescence preference in densely packed microbubbles

    SciTech Connect

    Kim, Yeseul; Lim, Su Jin; Gim, Bopil; Weon, Byung Mook

    2015-01-13

    A bubble merged from two parent bubbles with different size tends to be placed closer to the larger parent. This phenomenon is known as the coalescence preference. Here we demonstrate that the coalescence preference can be blocked inside a densely packed cluster of bubbles. We utilized high-speed high-resolution X-ray microscopy to clearly visualize individual coalescence events inside densely packed microbubbles with a local packing fraction of ~40%. Thus, the surface energy release theory predicts an exponent of 5 in a relation between the relative coalescence position and the parent size ratio, whereas our observation for coalescence in densely packed microbubbles shows a different exponent of 2. We believe that this result would be important to understand the reality of coalescence dynamics in a variety of packing situations of soft matter.

  18. Cavitation microstreaming and material transport around microbubbles

    NASA Astrophysics Data System (ADS)

    Manasseh, Richard; Tho, Paul; Ooi, Andrew; Petkovic-Duran, Karolina; Zhu, Yonggang

    2010-01-01

    It has been suggested that cavitation microstreaming plays a role in the therapeutic action of microbubbles driven by ultrasound, such as the sonothrombolytic and sonoporative phenomena. Microscopic particle-image velocimetry experiments are presented, showing that many different microstreaming patterns are possible around a microbubble when it is on a surface. Each pattern is associated with a particular oscillation mode of the bubble and generates a different shear stress distribution. It was found that it is possible to change the flow pattern by changing the sound frequency. Microstreaming flows around bubbles could be responsible for mixing therapeutic agents into the surrounding blood, as well as assisting sonoporative delivery of molecules across cell membranes. Appropriate tuning of the driving frequency may benefit therapies.

  19. Microbubbles and ultrasound: a bird's eye view.

    PubMed

    Kaul, Sanjiv

    2004-01-01

    Gas-filled microbubbles were initially used as ultrasound contrast agent because of their intravascular rheology, which is similar to that of red blood cells. Their transit through tissue can thus be quantified with ultrasound. More recently, these bubbles have been successfully used for molecular imaging by incorporating ligands on their surfaces that will adhere to cellular and other components within the microvasculature and can be detected by ultrasound. These bubbles have also been used for delivery of genes and drugs which can be released locally by disruption of the bubbles with high-energy ultrasound. Finally, bioeffects produced by localized ultrasound disruption of microbubbles have been shown to induce angiogenesis. This brief review will provide a bird's eye view of these applications.

  20. Computational Intelligence Modeling of the Macromolecules Release from PLGA Microspheres-Focus on Feature Selection.

    PubMed

    Zawbaa, Hossam M; Szlȩk, Jakub; Grosan, Crina; Jachowicz, Renata; Mendyk, Aleksander

    2016-01-01

    Poly-lactide-co-glycolide (PLGA) is a copolymer of lactic and glycolic acid. Drug release from PLGA microspheres depends not only on polymer properties but also on drug type, particle size, morphology of microspheres, release conditions, etc. Selecting a subset of relevant properties for PLGA is a challenging machine learning task as there are over three hundred features to consider. In this work, we formulate the selection of critical attributes for PLGA as a multiobjective optimization problem with the aim of minimizing the error of predicting the dissolution profile while reducing the number of attributes selected. Four bio-inspired optimization algorithms: antlion optimization, binary version of antlion optimization, grey wolf optimization, and social spider optimization are used to select the optimal feature set for predicting the dissolution profile of PLGA. Besides these, LASSO algorithm is also used for comparisons. Selection of crucial variables is performed under the assumption that both predictability and model simplicity are of equal importance to the final result. During the feature selection process, a set of input variables is employed to find minimum generalization error across different predictive models and their settings/architectures. The methodology is evaluated using predictive modeling for which various tools are chosen, such as Cubist, random forests, artificial neural networks (monotonic MLP, deep learning MLP), multivariate adaptive regression splines, classification and regression tree, and hybrid systems of fuzzy logic and evolutionary computations (fugeR). The experimental results are compared with the results reported by Szlȩk. We obtain a normalized root mean square error (NRMSE) of 15.97% versus 15.4%, and the number of selected input features is smaller, nine versus eleven.

  1. In vivo uptake and acute immune response to orally administered chitosan and PEG coated PLGA nanoparticles

    SciTech Connect

    Semete, B.; Booysen, L.I.J.; Kalombo, L.; Venter, J.D.; Katata, L.; Ramalapa, B.; Verschoor, J.A.; Swai, H.

    2010-12-01

    Nanoparticulate drug delivery systems offer great promise in addressing challenges of drug toxicity, poor bioavailability and non-specificity for a number of drugs. Much progress has been reported for nano drug delivery systems for intravenous administration, however very little is known about the effects of orally administered nanoparticles. Furthermore, the development of nanoparticulate systems necessitates a thorough understanding of the biological response post exposure. This study aimed to elucidate the in vivo uptake of chitosan and polyethylene glycol (PEG) coated Poly, DL, lactic-co-glycolic Acid (PLGA) nanoparticles and the immunological response within 24 h of oral and peritoneal administration. These PLGA nanoparticles were administered orally and peritoneally to female Balb/C mice, they were taken up by macrophages of the peritoneum. When these particles were fluorescently labelled, intracellular localisation was observed. The expression of pro-inflammatory cytokines IL-2, IL-6, IL-12p70 and TNF-{alpha} in plasma and peritoneal lavage was found to remain at low concentration in PLGA nanoparticles treated mice as well as ZnO nanoparticles during the 24 hour period. However, these were significantly increased in lipopolysaccharide (LPS) treated mice. Of these pro-inflammatory cytokines, IL-6 and IL-12p70 were produced at the highest concentration in the positive control group. The anti-inflammatory cytokines IL-10 and chemokines INF-{gamma}, IL-4, IL-5 remained at normal levels in PLGA treated mice. IL-10 and INF-{gamma} were significantly increased in LPS treated mice. MCP-1 was found to be significantly produced in all groups in the first hours, except the saline treated mice. These results provide the first report to detail the induction of cytokine production by PLGA nanoparticles engineered for oral applications.

  2. Computational Intelligence Modeling of the Macromolecules Release from PLGA Microspheres—Focus on Feature Selection

    PubMed Central

    Zawbaa, Hossam M.; Szlȩk, Jakub; Grosan, Crina; Jachowicz, Renata; Mendyk, Aleksander

    2016-01-01

    Poly-lactide-co-glycolide (PLGA) is a copolymer of lactic and glycolic acid. Drug release from PLGA microspheres depends not only on polymer properties but also on drug type, particle size, morphology of microspheres, release conditions, etc. Selecting a subset of relevant properties for PLGA is a challenging machine learning task as there are over three hundred features to consider. In this work, we formulate the selection of critical attributes for PLGA as a multiobjective optimization problem with the aim of minimizing the error of predicting the dissolution profile while reducing the number of attributes selected. Four bio-inspired optimization algorithms: antlion optimization, binary version of antlion optimization, grey wolf optimization, and social spider optimization are used to select the optimal feature set for predicting the dissolution profile of PLGA. Besides these, LASSO algorithm is also used for comparisons. Selection of crucial variables is performed under the assumption that both predictability and model simplicity are of equal importance to the final result. During the feature selection process, a set of input variables is employed to find minimum generalization error across different predictive models and their settings/architectures. The methodology is evaluated using predictive modeling for which various tools are chosen, such as Cubist, random forests, artificial neural networks (monotonic MLP, deep learning MLP), multivariate adaptive regression splines, classification and regression tree, and hybrid systems of fuzzy logic and evolutionary computations (fugeR). The experimental results are compared with the results reported by Szlȩk. We obtain a normalized root mean square error (NRMSE) of 15.97% versus 15.4%, and the number of selected input features is smaller, nine versus eleven. PMID:27315205

  3. Two-step nanoprecipitation for the production of protein-loaded PLGA nanospheres

    PubMed Central

    Morales-Cruz, Moraima; Flores-Fernández, Giselle M.; Morales-Cruz, Myreisa; Orellano, Elsie A.; Rodriguez-Martinez, José A.; Ruiz, Mercedes; Griebenow, Kai

    2012-01-01

    One of the first methods to encapsulate drugs within polymer nanospheres was developed by Fessi and coworkers in 1989 and consisted of one-step nanoprecipitation based on solvent displacement. However, proteins are poorly encapsulated within polymer nanoparticles using this method because of their limited solubility in organic solvents. To overcome this limitation, we developed a two-step nanoprecipitation method and encapsulated various proteins with high efficiency into poly(lactic-co-glycolic)acid (PLGA) nanospheres (NP). In this method, a protein nanoprecipitation step is used first followed by a second polymer nanoprecipitation step. Two model enzymes, lysozyme and α-chymotrypsin, were used for the optimization of the method. We obtained encapsulation efficiencies of >70%, an amount of buffer-insoluble protein aggregates of typically <2%, and a high residual activity of typically >90%. The optimum conditions identified for lysozyme were used to successfully encapsulate cytochrome c(Cyt-c), an apoptosis-initiating basic protein of similar size, to verify reproducibility of the encapsulation procedure. The size of the Cyt-c loaded-PLGA nanospheres was around 300–400 nm indicating the potential of the delivery system to passively target tumors. Cell viability studies, using a human cervical cancer cell line (HeLa), demonstrate excellent biocompatibility of the PLGA nanoparticles. PLGA nanoparticles carrying encapsulated Cyt-c were not efficient in causing apoptosis presumably because PLGA nanoparticles are not efficiently taken up by the cells. Future systems will have to be optimized to ascertain efficient cellular uptake of the nanoparticles by, e.g., surface modification with receptor ligands. PMID:23316451

  4. RGD peptide-displaying M13 bacteriophage/PLGA nanofibers as cell-adhesive matrices for smooth muscle cells

    NASA Astrophysics Data System (ADS)

    Shin, Yong Cheol; Lee, Jong Ho; Jin, Oh Seong; Lee, Eun Ji; Jin, Lin Hua; Kim, Chang-Seok; Hong, Suck Won; Han, Dong-Wook; Kim, Chuntae; Oh, Jin-Woo

    2015-01-01

    Extracellular matrices (ECMs) are network structures that play an essential role in regulating cellular growth and differentiation. In this study, novel nanofibrous matrices were fabricated by electrospinning M13 bacteriophage and poly(lactic- co-glycolic acid) (PLGA) and were shown to be structurally and functionally similar to natural ECMs. A genetically-engineered M13 bacteriophage was constructed to display Arg-Gly-Asp (RGD) peptides on its surface. The physicochemical properties of RGD peptide-displaying M13 bacteriophage (RGD-M13 phage)/PLGA nanofibers were characterized by using scanning electron microscopy and Fourier-transform infrared spectroscopy. We used immunofluorescence staining to confirm that M13 bacteriophages were homogenously distributed in RGD-M13 phage/PLGA matrices. Furthermore, RGD-M13 phage/PLGA nanofibrous matrices, having excellent biocompatibility, can enhance the behaviors of vascular smooth muscle cells. This result suggests that RGD-M13 phage/PLGA nanofibrous matrices have potentials to serve as tissue engineering scaffolds.

  5. The use of BMP-2 coupled - Nanosilver-PLGA composite grafts to induce bone repair in grossly infected segmental defects.

    PubMed

    Zheng, Zhong; Yin, Wei; Zara, Janette N; Li, Weiming; Kwak, Jinny; Mamidi, Rachna; Lee, Min; Siu, Ronald K; Ngo, Richard; Wang, Joyce; Carpenter, Doug; Zhang, Xinli; Wu, Benjamin; Ting, Kang; Soo, Chia

    2010-12-01

    Healing of contaminated/infected bone defects is a significant clinical challenge. Prevalence of multi-antibiotic resistant organisms has renewed interest in the use of antiseptic silver as an effective, but less toxic antimicrobial with decreased potential for bacterial resistance. In this study, we demonstrated that metallic nanosilver particles (with a size of 20-40nm)-poly(lactic-co-glycolic acid) (PLGA) composite grafts have strong antibacterial properties. In addition, nanosilver particles-PLGA composite grafts did not inhibit adherence, proliferation, alkaline phosphatase activity, or mineralization of ongrowth MC3T3-E1 pre-osteoblasts compared to PLGA controls. Furthermore, nanosilver particles did not affect the osteoinductivity of bone morphogenetic protein 2 (BMP-2). Infected femoral defects implanted with BMP-2 coupled 2.0% nanosilver particles-PLGA composite grafts healed in 12 weeks without evidence of residual bacteria. In contrast, BMP-2 coupled PLGA control grafts failed to heal in the presence of continued bacterial colonies. Our results indicate that nanosilver of defined particle size is bactericidal without discernable in vitro and in vivo cytotoxicity or negative effects on BMP-2 osteoinductivity, making it an ideal antimicrobial for bone regeneration in infected wounds.

  6. A mechanistic model for drug release in PLGA biodegradable stent coatings coupled with polymer degradation and erosion.

    PubMed

    Zhu, Xiaoxiang; Braatz, Richard D

    2015-07-01

    Biodegradable poly(d,l-lactic-co-glycolic acid) (PLGA) coating for applications in drug-eluting stents has been receiving increasing interest as a result of its unique properties compared with biodurable polymers in delivering drug for reducing stents-related side effects. In this work, a mathematical model for describing the PLGA degradation and erosion and coupled drug release from PLGA stent coating is developed and validated. An analytical expression is derived for PLGA mass loss that predicts multiple experimental studies in the literature. An analytical model for the change of the number-average degree of polymerization [or molecular weight (MW)] is also derived. The drug transport model incorporates simultaneous drug diffusion through both the polymer solid and the liquid-filled pores in the coating, where an effective drug diffusivity model is derived taking into account factors including polymer MW change, stent coating porosity change, and drug partitioning between solid and aqueous phases. The model is used to describe in vitro sirolimus release from PLGA stent coating, and demonstrates the significance of simultaneous sirolimus release via diffusion through both polymer solid and pore space. The proposed model is compared to existing drug transport models, and the impact of model parameters, limitations and possible extensions of the model are also discussed.

  7. A three-layered nano-carbonated hydroxyapatite/collagen/PLGA composite membrane for guided tissue regeneration.

    PubMed

    Liao, Susan; Wang, Wei; Uo, Motohiro; Ohkawa, Shoji; Akasaka, Tsukasa; Tamura, Kazuchika; Cui, Fuzhai; Watari, Fumio

    2005-12-01

    Functional graded materials (FGM) provided us one new concept for guided tissue regeneration (GTR) membrane design with graded component and graded structure where one face of the membrane is porous thereby allowing cell growth thereon and the opposite face of the membrane is smooth, thereby inhibiting cell adhesion in periodontal therapy. The goal of the present study was to develop a three-layered graded membrane, with one face of 8% nano-carbonated hydroxyapatite/collagen/poly(lactic-co-glycolic acid) (nCHAC/PLGA) porous membrane, the opposite face of pure PLGA non-porous membrane, the middle layer of 4% nCHAC/PLGA as the transition through layer-by-layer casting method. Then the three layers were combined well with each other with flexibility and enough high mechanical strength as membrane because the three layers all contained PLGA polymer that can be easily used for practical medical application. This high biocompatibility and osteoconductivity of this biodegraded composite membrane was enhanced by the nCHAC addition, for the same component and nano-level crystal size with natural bone tissue. The osteoblastic MC3T3-E1 cells were cultured on the three-layered composite membrane, the primary result shows the positive response compared with pure PLGA membrane.

  8. Effects of gatifloxaine content in gatifloxacine-loaded PLGA and β-tricalcium phosphate composites on efficacy in treating osteomyelitis.

    PubMed

    Kimishima, Kaori; Matsuno, Tomonori; Makiishi, Jun; Tamazawa, Gaku; Sogo, Yu; Ito, Atsuo; Satoh, Tazuko

    2016-01-01

    Composites of gatifloxacin (GFLX)-loaded poly (lactic-co-glycolic) acid (PLGA) and β-tricalcium phosphate (βTCP) containing 0, 1, and 10 wt % GFLX (0, 1, and 10 wt % GFLX composites), and GFLX-loaded PLGA containing 1, 5, and 10 wt % GFLX (1, 5, and 10wt % GFLX-PLGA) as controls were fabricated and characterized in vitro and in vivo. On in vitro evaluation, the 10 wt % GFLX composite released GFLX over at least 28 days in Hanks' balanced solution and exhibited clinically sufficient bactericidal activities against Streptococcus milleri and Bacteroides fragilis from 1 h to 10 days. The 0, 1, and 10 wt % GFLX composites and 10 wt % GFLX-PLGA were implanted in bone defects created by debridement of osteomyelitis lesions induced by S. milleri and B. fragilis in the mandible of rabbits (n = 5). Four weeks after implantation of the 10 wt % GFLX composite, inflammation in the debrided area disappeared in all the rabbits, while inflammation remained in all the rabbits after implantation of the 0 wt % GFLX composite and 10 wt % GFLX-PLGA, and in three rabbits after implantation of the 1 wt % GFLX composite. Bone formation appears to be less intense for the 10 wt % GFLX composite than for the 1 wt % GFLX composite probably owing to the rapid degradation of the 10 wt % GFLX composite. These findings show that the GFLX composite is effective for the local treatment of osteomyelitis.

  9. Thermodynamic Insights and Conceptual Design of Skin-Sensitive Chitosan Coated Ceramide/PLGA Nanodrug for Regeneration of Stratum Corneum on Atopic Dermatitis

    PubMed Central

    Jung, Sang-Myung; Yoon, Gwang Heum; Lee, Hoo Chul; Jung, Moon Hee; Yu, Sun Il; Yeon, Seung Ju; Min, Seul Ki; Kwon, Yeo Seon; Hwang, Jin Ha; Shin, Hwa Sung

    2015-01-01

    Atopic dermatitis (AD) is a complex skin disease primarily characterized by psoriasis of the stratum corneum. AD drugs have usually been used in acidic and hydrophilic solvents to supply moisture and prevent lipid defects. Ceramide is a typical treatment agent to regenerate the stratum corneum and relieve symptoms of AD. However, ceramide has limitation on direct use for skin because of its low dispersion properties in hydrophilic phase and side effects at excessive treatment. In this study, ceramide imbedded PLGA nanoparticles were developed with chitosan coating (Chi-PLGA/Cer) to overcome this problem. The chitosan coating enhanced initial adherence to the skin and prevented the initial burst of ceramide, but was degraded by the weakly acidic nature of skin, resulting in controlled release of ceramide with additional driving force of the squeezed PLGA nanoparticles. Additionally, the coating kinetics of chitosan were controlled by manipulating the reaction conditions and then mathematically modeled. The Chi-PLGA/Cer was not found to be cytotoxic and ceramide release was controlled by pH, temperature, and chitosan coating. Finally, Chi-PLGA/Cer was demonstrated to be effective at stratum corneum regeneration in a rat AD model. Overall, the results presented herein indicated that Chi-PLGA/Cer is a novel nanodrug for treatment of AD. PMID:26666701

  10. Thermodynamic Insights and Conceptual Design of Skin-Sensitive Chitosan Coated Ceramide/PLGA Nanodrug for Regeneration of Stratum Corneum on Atopic Dermatitis.

    PubMed

    Jung, Sang-Myung; Yoon, Gwang Heum; Lee, Hoo Chul; Jung, Moon Hee; Yu, Sun Il; Yeon, Seung Ju; Min, Seul Ki; Kwon, Yeo Seon; Hwang, Jin Ha; Shin, Hwa Sung

    2015-12-15

    Atopic dermatitis (AD) is a complex skin disease primarily characterized by psoriasis of the stratum corneum. AD drugs have usually been used in acidic and hydrophilic solvents to supply moisture and prevent lipid defects. Ceramide is a typical treatment agent to regenerate the stratum corneum and relieve symptoms of AD. However, ceramide has limitation on direct use for skin because of its low dispersion properties in hydrophilic phase and side effects at excessive treatment. In this study, ceramide imbedded PLGA nanoparticles were developed with chitosan coating (Chi-PLGA/Cer) to overcome this problem. The chitosan coating enhanced initial adherence to the skin and prevented the initial burst of ceramide, but was degraded by the weakly acidic nature of skin, resulting in controlled release of ceramide with additional driving force of the squeezed PLGA nanoparticles. Additionally, the coating kinetics of chitosan were controlled by manipulating the reaction conditions and then mathematically modeled. The Chi-PLGA/Cer was not found to be cytotoxic and ceramide release was controlled by pH, temperature, and chitosan coating. Finally, Chi-PLGA/Cer was demonstrated to be effective at stratum corneum regeneration in a rat AD model. Overall, the results presented herein indicated that Chi-PLGA/Cer is a novel nanodrug for treatment of AD.

  11. Aromatic proteinaceous surfactants stabilize long-lived gas microbubbles from natural sources

    NASA Technical Reports Server (NTRS)

    Darrigo, J. S.

    1981-01-01

    Three different types of protein-specific chemical tests were performed on long-lived gas microbubbles derived from aqueous solutions of agarose powder and from filtered aqueous extracts of Hawaiian forest soil. The separate protein-specific tests involved use of either 0.3% (w/v) ninhydrin, 100 microM methylene blue dye, or 0.7-1.0 M 2-hydroxy-5-nitrobenzyl bromide. The chemical test results obtained with each of the two natural substances, i.e., agarose powder and Hawaiian forest soil, were very similar and indicate that the biological surfactants which surround and stabilize long-lived gas microbubbles are proteinaceous compounds that contain, and whose surface activity depends upon, aromatic amino acid residues, particularly tryptophan.

  12. Heating Location Control of HIFU Treatment Enhanced with Microbubbles

    NASA Astrophysics Data System (ADS)

    Nishihara, T.; Utashiro, H.; Ichiyanagi, M.; Yoshinaka, K.; Takagi, S.; Matsumoto, Y.

    2011-09-01

    High-intensity focused ultrasound (HIFU) treatment using ultrasound contrast microbubbles for enhancing the heating effect has been developed with the aim of realising a less invasive tumor therapy. The focused sound waves result in an increase in temperature and increased thermal absorption, which necroses tumor cells. In addition, microbubbles are used as contrast agents for ultrasound imaging, and, in a previous study, we used microbubbles to enhance the heating effect. However, when microbubbles exist in the ultrasound pathway, they disturb ultrasound propagation and distort the acoustic field. Distortion of the acoustic field leads to defocusing and causes unexpected damage to tissue in the body. The objective of the present study is to propose a method by which to destroy microbubbles in the ultrasound pathway and to focus the thermal energy only at the focal point. The proposed method consists of two steps. The first step is to use repetitive high-intensity, short-burst waves (20 waves) to destroy the microbubbles in the pathway. In the second step, low amplitude continuous waves are sent in order to heat the focal point. This method was successful for a gel containing microbubbles with a void fraction on the order of 10-4. The results of the present study indicate that more microbubbles were destroyed as the non-exposure time and the pulse number were increased during the first step.

  13. Light propagation in a turbid medium with insonified microbubbles.

    PubMed

    Leung, Terence S; Honeysett, Jack E; Stride, Eleanor; Deng, Jing

    2013-01-01

    Surfactant stabilized microbubbles are widely used clinical contrast agents for ultrasound imaging. In this work, the light propagation through a turbid medium in the presence of microbubbles has been investigated. Through a series of experiments, it has been found that the optical attenuation is increased when the microbubbles in a turbid medium are insonified by ultrasound. Such microbubble enhanced optical attenuation is a function of both applied ultrasound pressure and microbubble concentration. To understand the mechanisms involved, a Monte Carlo (MC) model has been developed. Under ultrasound exposure, the sizes of microbubbles vary in space and time, and their dynamics are modeled by the Rayleigh-Plesset equation. By using Mie theory, the spatially and temporally varying optical scattering and scattering efficiency of microbubbles are determined based on the bubble sizes and internal refractive indices. The MC model is shown to effectively describe a medium with rapidly changing optical scattering, and the results are validated against both computational results using an N-layered diffusion equation model and experimental results using a clinical microbubble contrast agent (SonoVue®).

  14. Intracellular delivery of peptides and siRNAs using microbubble enhanced focused ultrasound

    NASA Astrophysics Data System (ADS)

    Kinoshita, Manabu; Hynynen, Kullervo

    2006-05-01

    Bioactive substances such as peptides and nucleic acid based agents have attracted great attention for the next generation drug for various diseases. However, the greatest challenge for using these bioactive substances is the development of their delivery system, especially the method for delivering these substances through the cell membrane. With the advancement of ultrasound and ultrasound contrast agent technology, it has become possible to transiently change the permeability of the cell membrane. Moreover, using a focused ultrasound transducer, it is possible to narrow and focus the ultrasound energy within a small target, avoiding damage to the surrounding tissue. In this research we have searched the possibility of delivering the Bak BH3 peptide, the death domain of the Bc1-2 family of proteins, or the short interfering RNA (siRNA) targeting the enhanced green fluorescent protein (EGFP) using microbubble-enhanced focused ultrasound in an in vitro setting. Using a 1.696 MHz focused ultrasound and a microbubble ultrasound contrast agent OPTISON®, we first tested the stability of BH3 peptide under microbubble-enhanced focused ultrasound exposure and proved that the peptide is stable under these circumstances. Next, we have tested the cell-killing effect of the intracellularly delivered Bak BH3 peptide in HeLa and BJAB cell line and observed a statistically enhanced cell death in BJAB cells but not in HeLa cells, leading to the conclusion that intracellularly delivered BH3 peptide by microbubble-enhanced ultrasound can exert its cell killing effect in some cells. We also investigated if we can silence the EGFP expression in the cell by delivering siRNA targeting the EGFP in both transient and stable EGFP expression cell line. Using a 1.653 MHz focused ultrasound and OPTISON®, in both cases, intracellularly delivered siRNA by microbubble-enhanced ultrasound was able to knock down the EGFP expression, which demonstrates the feasibility of using this novel method

  15. Surface-assembled poly(I:C) on PEGylated PLGA microspheres as vaccine adjuvant: APC activation and bystander cell stimulation.

    PubMed

    Hafner, Annina M; Corthésy, Blaise; Textor, Marcus; Merkle, Hans P

    2016-11-30

    Biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres are potential vehicles to deliver antigens for vaccination. Because they lack the full capacity to activate professional antigen presenting cells (APCs), combination with an immunostimulatory adjuvant may be considered. A candidate is the synthetic TLR3 ligand polyriboinosinic acid-polyribocytidylic acid, poly(I:C), which drives cell-mediated immunity. However, poly(I:C) has also been linked to the pathogenesis of autoimmunity, as affected by widespread stimulation of non-hematopoietic bystander cells. To address this aspect, we propose to minimize the poly(I:C) dose as well as to control the stimulation of non-immune bystander cells by poly(I:C). To facilitate the maturation of APCs with minimal poly(I:C) doses, we surface-assembled poly(I:C) onto PLGA microspheres. The microspheres' surface was further modified by poly(ethylene glycol) (PEG) coronas with varying PEG-densities. PLGA microspheres loaded with tetanus toxoid (tt) as model antigen were manufactured by microextrusion-based solvent extraction. The negatively charged PLGA(tt) microspheres were coated with polycationic poly(l-lysine) (PLL) polymers, either PLL itself or PEG-grafted PLL (PLL-g-PEG) with varying grafting ratios (g=2.2 and g=10.1). Stable surface assembly of poly(I:C) was achieved by subsequent incubation of polymer-coated PLGA microspheres with aqueous poly(I:C) solutions. We evaluated the immunostimulatory potential of such PLGA(tt) microsphere formulations on monocyte-derived dendritic cells (MoDCs) as well as human foreskin fibroblasts (HFFs) as model for non-hematopoietic bystander cells. Formulations with surface-assembled poly(I:C) readily activated MoDCs with respect to the expression of maturation-related surface markers, proinflammatory cytokine secretion and directed migration. When surface-assembled, poly(I:C) enhanced its immunostimulatory activity by more than one order of magnitude as compared to free poly

  16. Ultrasound triggered drug delivery with liposomal nested microbubbles.

    PubMed

    Wallace, N; Wrenn, S P

    2015-12-01

    When ultrasound contrast agent microbubbles are nested within a liposome, damage to the liposome membrane caused by both stable and inertial cavitation of the microbubble allows for release of the aqueous core of the liposome. Triggered release was not accomplished unless microbubbles were present within the liposome. Leakage was tested using fluorescence assays developed specifically for this drug delivery vehicle and qualitative measurements using an optical microscope. These studies were done using a 1 MHz focused ultrasound transducer while varying parameters including peak negative ultrasound pressure, average liposome diameter, and microbubble concentration. Two regimes exist for membrane disruption caused by cavitating microbubbles. A faster release rate, as well as permanent membrane damage are seen for samples exposed to high pressure (2.1-3.7 MPa). A slower release rate and dilation/temporary poration are characteristic of stable cavitation for low pressure studies (0.54-1.7 MPa).

  17. High Q silica microbubble resonators fabricated by arc discharge

    NASA Astrophysics Data System (ADS)

    Berneschi, S.; Farnesi, D.; Cosi, F.; Nunzi Conti, G.; Pelli, S.; Righini, G. C.; Soria, S.

    2011-09-01

    Microbubble resonators combine the unique properties of whispering gallery mode resonators with the intrinsic capability of integrated microfluidics. Here an improved fabrication method of microbubble resonators is presented, based on the heating of a slightly pressurized capillary by a rotating arc discharge. Rotation of the electrodes, moved out of a fiber splicer, ensures a homogeneous distribution of the heat all over the capillary surface. The demonstrated microbubble resonators have Q factors up to 6×107 at 1550nm. Microbubbles were filled with water and aqueous solutions of ethanol in order to test the refractive index sensing capabilities of such resonators, which also show a good temporal stability. The limit of detection of our microbubble resonator sensor is 10-6RIU.

  18. High Q silica microbubble resonators fabricated by arc discharge.

    PubMed

    Berneschi, S; Farnesi, D; Cosi, F; Conti, G Nunzi; Pelli, S; Righini, G C; Soria, S

    2011-09-01

    Microbubble resonators combine the unique properties of whispering gallery mode resonators with the intrinsic capability of integrated microfluidics. Here an improved fabrication method of microbubble resonators is presented, based on the heating of a slightly pressurized capillary by a rotating arc discharge. Rotation of the electrodes, moved out of a fiber splicer, ensures a homogeneous distribution of the heat all over the capillary surface. The demonstrated microbubble resonators have Q factors up to 6×10(7) at 1550 nm. Microbubbles were filled with water and aqueous solutions of ethanol in order to test the refractive index sensing capabilities of such resonators, which also show a good temporal stability. The limit of detection of our microbubble resonator sensor is 10(-6) RIU.

  19. Individual lipid encapsulated microbubble radial oscillations: Effects of fluid viscosity

    PubMed Central

    Helfield, Brandon; Chen, Xucai; Qin, Bin; Villanueva, Flordeliza S.

    2016-01-01

    Ultrasound-stimulated microbubble dynamics have been shown to be dependent on intrinsic bubble properties, including size and shell characteristics. The effect of the surrounding environment on microbubble response, however, has been less investigated. In particular, microbubble optimization studies are generally conducted in water/saline, characterized by a 1 cP viscosity, for application in the vasculature (i.e., 4 cP). In this study, ultra-high speed microscopy was employed to investigate fluid viscosity effects on phospholipid encapsulated microbubble oscillations at 1 MHz, using a single, eight-cycle pulse at peak negative pressures of 100 and 250 kPa. Microbubble oscillations were shown to be affected by fluid viscosity in a size- and pressure-dependent manner. In general, the oscillation amplitudes exhibited by microbubbles between 3 and 6 μm in 1 cP fluid were larger than in 4 cP fluid, reaching a maximum of 1.7-fold at 100 kPa for microbubbles 3.8 μm in diameter and 1.35-fold at 250 kPa for microbubbles 4.8 μm in diameter. Simulation results were in broad agreement at 250 kPa, however generally underestimated the effect of fluid viscosity at 100 kPa. This is the first experimental demonstration documenting the effects of surrounding fluid viscosity on microbubble oscillations, resulting in behavior not entirely predicted by current microbubble models. PMID:26827018

  20. Individual lipid encapsulated microbubble radial oscillations: Effects of fluid viscosity.

    PubMed

    Helfield, Brandon; Chen, Xucai; Qin, Bin; Villanueva, Flordeliza S

    2016-01-01

    Ultrasound-stimulated microbubble dynamics have been shown to be dependent on intrinsic bubble properties, including size and shell characteristics. The effect of the surrounding environment on microbubble response, however, has been less investigated. In particular, microbubble optimization studies are generally conducted in water/saline, characterized by a 1 cP viscosity, for application in the vasculature (i.e., 4 cP). In this study, ultra-high speed microscopy was employed to investigate fluid viscosity effects on phospholipid encapsulated microbubble oscillations at 1 MHz, using a single, eight-cycle pulse at peak negative pressures of 100 and 250 kPa. Microbubble oscillations were shown to be affected by fluid viscosity in a size- and pressure-dependent manner. In general, the oscillation amplitudes exhibited by microbubbles between 3 and 6 μm in 1 cP fluid were larger than in 4 cP fluid, reaching a maximum of 1.7-fold at 100 kPa for microbubbles 3.8 μm in diameter and 1.35-fold at 250 kPa for microbubbles 4.8 μm in diameter. Simulation results were in broad agreement at 250 kPa, however generally underestimated the effect of fluid viscosity at 100 kPa. This is the first experimental demonstration documenting the effects of surrounding fluid viscosity on microbubble oscillations, resulting in behavior not entirely predicted by current microbubble models.

  1. PLGA nanoparticle encapsulation reduces toxicity while retaining the therapeutic efficacy of EtNBS-PDT in vitro

    PubMed Central

    Hung, Hsin-I; Klein, Oliver J.; Peterson, Sam W.; Rokosh, Sarah R.; Osseiran, Sam; Nowell, Nicholas H.; Evans, Conor L.

    2016-01-01

    Photodynamic therapy regimens, which use light-activated molecules known as photosensitizers, are highly selective against many malignancies and can bypass certain challenging therapeutic resistance mechanisms. Photosensitizers such as the small cationic molecule EtNBS (5-ethylamino-9-diethyl-aminobenzo[a]phenothiazinium chloride) have proven potent against cancer cells that reside within acidic and hypoxic tumour microenvironments. At higher doses, however, these photosensitizers induce “dark toxicity” through light-independent mechanisms. In this study, we evaluated the use of nanoparticle encapsulation to overcome this limitation. Interestingly, encapsulation of the compound within poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGA-EtNBS) was found to significantly reduce EtNBS dark toxicity while completely retaining the molecule’s cytotoxicity in both normoxic and hypoxic conditions. This dual effect can be attributed to the mechanism of release: EtNBS remains encapsulated until external light irradiation, which stimulates an oxygen-independent, radical-mediated process that degrades the PLGA nanoparticles and releases the molecule. As these PLGA-encapsulated EtNBS nanoparticles are capable of penetrating deeply into the hypoxic and acidic cores of 3D spheroid cultures, they may enable the safe and efficacious treatment of otherwise unresponsive tumour regions. PMID:27686626

  2. PLGA nanoparticle encapsulation reduces toxicity while retaining the therapeutic efficacy of EtNBS-PDT in vitro

    NASA Astrophysics Data System (ADS)

    Hung, Hsin-I.; Klein, Oliver J.; Peterson, Sam W.; Rokosh, Sarah R.; Osseiran, Sam; Nowell, Nicholas H.; Evans, Conor L.

    2016-09-01

    Photodynamic therapy regimens, which use light-activated molecules known as photosensitizers, are highly selective against many malignancies and can bypass certain challenging therapeutic resistance mechanisms. Photosensitizers such as the small cationic molecule EtNBS (5-ethylamino-9-diethyl-aminobenzo[a]phenothiazinium chloride) have proven potent against cancer cells that reside within acidic and hypoxic tumour microenvironments. At higher doses, however, these photosensitizers induce “dark toxicity” through light-independent mechanisms. In this study, we evaluated the use of nanoparticle encapsulation to overcome this limitation. Interestingly, encapsulation of the compound within poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGA-EtNBS) was found to significantly reduce EtNBS dark toxicity while completely retaining the molecule’s cytotoxicity in both normoxic and hypoxic conditions. This dual effect can be attributed to the mechanism of release: EtNBS remains encapsulated until external light irradiation, which stimulates an oxygen-independent, radical-mediated process that degrades the PLGA nanoparticles and releases the molecule. As these PLGA-encapsulated EtNBS nanoparticles are capable of penetrating deeply into the hypoxic and acidic cores of 3D spheroid cultures, they may enable the safe and efficacious treatment of otherwise unresponsive tumour regions.

  3. Nanobody conjugated PLGA nanoparticles for active targeting of African Trypanosomiasis.

    PubMed

    Arias, José L; Unciti-Broceta, Juan D; Maceira, José; Del Castillo, Teresa; Hernández-Quero, José; Magez, Stefan; Soriano, Miguel; García-Salcedo, José A

    2015-01-10

    Targeted delivery of therapeutics is an alternative approach for the selective treatment of infectious diseases. The surface of African trypanosomes, the causative agents of African trypanosomiasis, is covered by a surface coat consisting of a single variant surface glycoprotein, termed VSG. This coat is recycled by endocytosis at a very high speed, making the trypanosome surface an excellent target for the delivery of trypanocidal drugs. Here, we report the design of a drug nanocarrier based on poly ethylen glycol (PEG) covalently attached (PEGylated) to poly(D,L-lactide-co-glycolide acid) (PLGA) to generate PEGylated PLGA nanoparticles. This nanocarrier was coupled to a single domain heavy chain antibody fragment (nanobody) that specifically recognizes the surface of the protozoan pathogen Trypanosoma brucei. Nanoparticles were loaded with pentamidine, the first-line drug for T. b. gambiense acute infection. An in vitro effectiveness assay showed a 7-fold decrease in the half-inhibitory concentration (IC50) of the formulation relative to free drug. Furthermore, in vivo therapy using a murine model of African trypanosomiasis demonstrated that the formulation cured all infected mice at a 10-fold lower dose than the minimal full curative dose of free pentamidine and 60% of mice at a 100-fold lower dose. This nanocarrier has been designed with components approved for use in humans and loaded with a drug that is currently in use to treat the disease. Moreover, this flexible nanobody-based system can be adapted to load any compound, opening a range of new potential therapies with application to other diseases.

  4. Thermogelling Biodegradable Polymers with Hydrophilic Backbones: PEG-g-PLGA

    SciTech Connect

    Jeong, Byeongmoon; Kibbey, Merinda R.; Birnbaum, Jerome C.; Won, You-Yeong; Gutowska, Anna

    2000-10-31

    The aqueous solutions of poly(ethylene glycol)grafted with poly(lactic acid-co-glycolic acid) flow freely at room temperature but form gels at higher temperature. The existence of micelles in water at low polymer concentration was confirmed by Cro-transmission electron microscopy and dye solubilization studies. The micellar diameter and critical micelle concentration are about 9 nm and 0.47 wt.% respectively. The critical gel concentration, above which a gel phase appears was 16 wt.% and sol-to-gel transition temperature was slightly affected by the concentration in the range of 16 {approx} 25 wt.%. At sol-to-gel transition, viscosity increased abruptly and C-NMR showed molecular motion of hydrophilic poly(lactic acid-co-glycolic acid) side-chains increased. The hydrogel of PEG-g-PLGA with hydrophilic backbones was transparent during degradation and remained a gel for one week, suggesting a promising material for short-term drug delivery.

  5. Improving bone repair of femoral and radial defects in rabbit by incorporating PRP into PLGA/CPC composite scaffold with unidirectional pore structure.

    PubMed

    He, Fupo; Chen, Yan; Li, Jiyan; Lin, Bomiao; Ouyang, Yi; Yu, Bo; Xia, Yuanyou; Yu, Bo; Ye, Jiandong

    2015-04-01

    In this study, a platelet-rich plasma poly(lactic-co-glycolic acid) (PRP-PLGA)/calcium phosphate cement (CPC) composite scaffold was prepared by incorporating PRP into PLGA/CPC scaffold with unidirectional pore structure, which was fabricated by the unidirectional freeze casting of CPC slurry and the following infiltration of PLGA. The results from in vitro cell experiments and in vivo implantation in femoral defects manifested that incorporation of PRP into PLGA/CPC scaffold improved in vitro cell response (cell attachment, proliferation, and differentiation), and markedly boosted bone formation, angiogenesis and material degradation. The incorporation of PRP into scaffold showed more outstanding improvement in osteogenesis as the scaffolds were used to repair the segmental radial defects, especially at the early stage. The new bone tissues grew along the unidirectional lamellar pores of scaffold. At 12 weeks postimplantation, the segmental radial defects treated with PRP-PLGA/CPC scaffold had almost recuperated, whereas treated with the scaffold without PRP was far from healed. Taken together, the PRP-PLGA/CPC scaffold with unidirectional pore structure is a promising candidate to repair bone defects at various sites.

  6. Multifunctional SPIO/DOX-loaded A54 Homing Peptide Functionalized Dextran-g-PLGA Micelles for Tumor Therapy and MR Imaging

    NASA Astrophysics Data System (ADS)

    Situ, Jun-Qing; Wang, Xiao-Juan; Zhu, Xiu-Liang; Xu, Xiao-Ling; Kang, Xu-Qi; Hu, Jing-Bo; Lu, Chen-Ying; Ying, Xiao-Ying; Yu, Ri-Sheng; You, Jian; Du, Yong-Zhong

    2016-10-01

    Specific delivery of chemotherapy drugs and magnetic resonance imaging (MRI) contrast agent into tumor cells is one of the issues to highly efficient tumor targeting therapy and magnetic resonance imaging. Here, A54 peptide-functionalized poly(lactic-co-glycolic acid)-grafted dextran (A54-Dex-PLGA) was synthesized. The synthesized A54-Dex-PLGA could self-assemble to form micelles with a low critical micelle concentration of 22.51 μg. mL‑1 and diameter of about 50 nm. The synthetic A54-Dex-PLGA micelles can encapsulate doxorubicin (DOX) as a model anti-tumor drug and superparamagnetic iron oxide (SPIO) as a contrast agent for MRI. The drug-encapsulation efficiency was about 80% and the in vitro DOX release was prolonged to 72 hours. The DOX/SPIO-loaded micelles could specifically target BEL-7402 cell line. In vitro MRI results also proved the specific binding ability of A54-Dex-PLGA/DOX/SPIO micelles to hepatoma cell BEL-7402. The in vivo MR imaging experiments using a BEL-7402 orthotopic implantation model further validated the targeting effect of DOX/SPIO-loaded micelles. In vitro and in vivo anti-tumor activities results showed that A54-Dex-PLGA/DOX/SPIO micelles revealed better therapeutic effects compared with Dex-PLGA/DOX/SPIO micelles and reduced toxicity compared with commercial adriamycin injection.

  7. Multifunctional SPIO/DOX-loaded A54 Homing Peptide Functionalized Dextran-g-PLGA Micelles for Tumor Therapy and MR Imaging

    PubMed Central

    Situ, Jun-Qing; Wang, Xiao-Juan; Zhu, Xiu-Liang; Xu, Xiao-Ling; Kang, Xu-Qi; Hu, Jing-Bo; Lu, Chen-Ying; Ying, Xiao-Ying; Yu, Ri-Sheng; You, Jian; Du, Yong-Zhong

    2016-01-01

    Specific delivery of chemotherapy drugs and magnetic resonance imaging (MRI) contrast agent into tumor cells is one of the issues to highly efficient tumor targeting therapy and magnetic resonance imaging. Here, A54 peptide-functionalized poly(lactic-co-glycolic acid)-grafted dextran (A54-Dex-PLGA) was synthesized. The synthesized A54-Dex-PLGA could self-assemble to form micelles with a low critical micelle concentration of 22.51 μg. mL−1 and diameter of about 50 nm. The synthetic A54-Dex-PLGA micelles can encapsulate doxorubicin (DOX) as a model anti-tumor drug and superparamagnetic iron oxide (SPIO) as a contrast agent for MRI. The drug-encapsulation efficiency was about 80% and the in vitro DOX release was prolonged to 72 hours. The DOX/SPIO-loaded micelles could specifically target BEL-7402 cell line. In vitro MRI results also proved the specific binding ability of A54-Dex-PLGA/DOX/SPIO micelles to hepatoma cell BEL-7402. The in vivo MR imaging experiments using a BEL-7402 orthotopic implantation model further validated the targeting effect of DOX/SPIO-loaded micelles. In vitro and in vivo anti-tumor activities results showed that A54-Dex-PLGA/DOX/SPIO micelles revealed better therapeutic effects compared with Dex-PLGA/DOX/SPIO micelles and reduced toxicity compared with commercial adriamycin injection. PMID:27775017

  8. Modified poly(lactic-co-glycolic acid) nanoparticles for enhanced cellular uptake and gene editing in the lung.

    PubMed

    Fields, Rachel J; Quijano, Elias; McNeer, Nicole Ali; Caputo, Christina; Bahal, Raman; Anandalingam, Kavi; Egan, Marie E; Glazer, Peter M; Saltzman, W Mark

    2015-02-18

    Surface-modified poly(lactic-co-glycolic acid) (PLGA)/poly(β-aminoester)(PBAE)nanoparticles (NPs) have shown great promise in gene delivery. In this work, the pulmonary cellular uptake of these NPs is evaluated and surface-modified PLGA/PBAE NPs are shown to achieve higher cellular association and gene editing than traditional NPs composed of PLGA or PLGA/PBAE blends alone.

  9. Enhanced singlet oxygen generation from PLGA loaded with verteporfin and gold nanoparticles

    NASA Astrophysics Data System (ADS)

    Deng, Wei; Kautzka, Zofia; Goldys, Ewa M.

    2016-12-01

    In this study, poly(lactic-co-glycolic acid) (PLGA) nanocomposites were developed by incorporating a photosensitizer, verteporfin and gold nanoparticles into this polymeric matrix and utilised for enhanced photoynamic therapy. Both enhanced fluorescence and singlet oxygen generation from verteporfin were observed in this new formulation under both 425nm LED and 405nm laser illumination. A maximum enhancement factor of 2.5 for fluorescence and 1.84 for 1O2 generation was obtained when the molar ratio of gold:VP was 5:1 and excited at 425 nm, compared with PLGA doped with verteporfin only. The experiment results could be explained by the local electric field enhancement of gold nanoparticles. Furthermore, in vitro cell-killing effect on human pancreatic cancer cells was also demonstrated by using this new formulation following light exposure, indicating the utility of these nanocomposites for enhanced photodynamic therapy.

  10. PLGA-loaded nanomedicines in melanoma treatment: Future prospect for efficient drug delivery

    PubMed Central

    Das, Sreemanti; Khuda-Bukhsh, Anisur Rahman

    2016-01-01

    Current treatment methods for melanoma have some limitations such as less target-specific action, severe side effects and resistance to drugs. Significant progress has been made in exploring novel drug delivery systems based on suitable biochemical mechanisms using nanoparticles ranging from 10 to 400 nm for drug delivery and imaging, utilizing their enhanced penetration and retention properties. Poly-lactide-co-glycolide (PLGA), a copolymer of poly-lactic acid and poly-glycolic acid, provides an ideally suited performance-based design for better penetration into skin cells, thereby having a greater potential for the treatment of melanoma. Moreover, encapsulation protects the drug from deactivation by biological reactions and interactions with biomolecules, ensuring successful delivery and bioavailability for effective treatment. Controlled and sustained delivery of drugs across the skin barrier that otherwise prohibits entry of larger molecules can be successfully made with adequately stable biocompatible nanocarriers such as PLGA for taking drugs through the small cutaneous pores permitting targeted deposition and prolonged drug action. PLGA is now being extensively used in photodynamic therapy and targeted therapy through modulation of signal proteins and drug-DNA interactions. Recent advances made on these nanomedicines and their advantages in the treatment of skin melanoma are highlighted and discussed in this review. PMID:27934796

  11. Prediction of dexamethasone release from PLGA microspheres prepared with polymer blends using a design of experiment approach.

    PubMed

    Gu, Bing; Burgess, Diane J

    2015-11-10

    Hydrophobic drug release from poly (lactic-co-glycolic acid) (PLGA) microspheres typically exhibits a tri-phasic profile with a burst release phase followed by a lag phase and a secondary release phase. High burst release can be associated with adverse effects and the efficacy of the formulation cannot be ensured during a long lag phase. Accordingly, the development of a long-acting microsphere product requires optimization of all drug release phases. The purpose of the current study was to investigate whether a blend of low and high molecular weight polymers can be used to reduce the burst release and eliminate/minimize the lag phase. A single emulsion solvent evaporation method was used to prepare microspheres using blends of two PLGA polymers (PLGA5050 (25 kDa) and PLGA9010 (113 kDa)). A central composite design approach was applied to investigate the effect of formulation composition on dexamethasone release from these microspheres. Mathematical models obtained from this design of experiments study were utilized to generate a design space with maximized microsphere drug loading and reduced burst release. Specifically, a drug loading close to 15% can be achieved and a burst release less than 10% when a composition of 80% PLGA9010 and 90 mg of dexamethasone is used. In order to better describe the lag phase, a heat map was generated based on dexamethasone release from the PLGA microsphere/PVA hydrogel composite coatings. Using the heat map an optimized formulation with minimum lag phase was selected. The microspheres were also characterized for particle size/size distribution, thermal properties and morphology. The particle size was demonstrated to be related to the polymer concentration and the ratio of the two polymers but not to the dexamethasone concentration.

  12. Ultrasound-stimulated peripheral nerve regeneration within asymmetrically porous PLGA/Pluronic F127 nerve guide conduit.

    PubMed

    Park, Sang Chul; Oh, Se Heang; Seo, Tae Beom; Namgung, Uk; Kim, Jin Man; Lee, Jin Ho

    2010-08-01

    Recently, we developed a novel method to fabricate a nerve guide conduit (NGC) with asymmetrical pore structure and hydrophilicity using poly(lactic-co-glycolic acid) (PLGA) and Pluronic F127 by a modified immersion precipitation method. From the animal study using a rat model (sciatic nerve defect of rat), we recognized that the unique PLGA/Pluronic F127 tube provided good environments for nerve regeneration. In this study, we applied low-intensity pulsed ultrasound as a simple and noninvasive stimulus at the PLGA/F127 NGC-implanted site transcutaneously in rats to investigate the feasibility of ultrasound for the enhanced nerve regeneration through the tube. The nerve regeneration behaviors within the ultrasound-stimulated PLGA/Pluronic F127 NGCs were compared with the NGCs without the ultrasound treatment as well as normal nerve by histological and immunohistochemical observations. It was observed that the PLGA/Pluronic F127 tube-implanted group applied with the ultrasound had more rapid nerve regeneration behavior (approximately 0.71 mm/day) than the tube-implanted group without the ultrasound treatment (approximately 0.48 mm/day). The ultrasound-treated tube group also showed greater neural tissue area as well as larger axon diameter and thicker myelin sheath than the tube group without the ultrasound treatment, indicating better nerve regeneration. The better nerve regeneration behavior in the our NGC/ultrasound system may be caused by the synergistic effect of the asymmetrically porous PLGA/Pluronic F127 tube with unique properties (selective permeability, hydrophilicity, and structural stability, which can provide good environment for nerve regeneration) and physical stimulus (stimulation of the Schwann cells and activation of the neurotrophic factors).

  13. Graphene oxide-stimulated myogenic differentiation of C2C12 cells on PLGA/RGD peptide nanofiber matrices

    NASA Astrophysics Data System (ADS)

    Shin, Y. C.; Lee, J. H.; Kim, M. J.; Hong, S. W.; Oh, J.-W.; Kim, C.-S.; Kim, B.; Hyun, J. K.; Kim, Y.-J.; Han, D.-W.

    2015-07-01

    During the last decade, much attention has been paid to graphene-based nanomaterials because they are considered as potential candidates for biomedical applications such as scaffolds for tissue engineering and substrates for the differentiation of stem cells. Until now, electrospun matrices composed of various biodegradable copolymers have been extensively developed for tissue engineering and regeneration; however, their use in combination with graphene oxide (GO) is novel and challenging. In this study, nanofiber matrices composed of poly(lactic-co-glycolic acid, PLGA) and M13 phage with RGD peptide displayed on its surface (RGD peptide-M13 phage) were prepared as extracellular matrix (ECM)-mimicking substrates. RGD peptide is a tripeptide (Arg-Gly-Asp) found on ECM proteins that promotes various cellular behaviors. The physicochemical properties of PLGA and RGD peptide-M13 phage (PLGA/RGD peptide) nanofiber matrices were characterized by atomic force microscopy, Fourier-transform infrared spectroscopy and thermogravimetric analysis. In addition, the growth of C2C12 mouse myoblasts on the PLGA/RGD peptide matrices was examined by measuring the metabolic activity. Moreover, the differentiation of C2C12 mouse myoblasts on the matrices when treated with GO was evaluated. The cellular behaviors, including growth and differentiation of C2C12 mouse myoblasts, were substantially enhanced on the PLGA/RGD peptide nanofiber matrices when treated with GO. Overall, these findings suggest that the PLGA/RGD peptide nanofiber matrices can be used in combination with GO as a novel strategy for skeletal tissue regeneration.

  14. Comparison of three different methods for effective introduction of platelet-rich plasma on PLGA woven mesh.

    PubMed

    Lee, Ji-Hye; Nam, Jinwoo; Kim, Hee Joong; Yoo, Jeong Joon

    2015-03-11

    For successful tissue regeneration, effective cell delivery to defect site is very important. Various types of polymer biomaterials have been developed and applied for effective cell delivery. PLGA (poly lactic-co-glycolic acid), a synthetic polymer, is a commercially available and FDA approved material. Platelet-rich plasma (PRP) is an autologous growth factor cocktail containing various growth factors including PDGF, TGFβ-1 and BMPs, and has shown positive effects on cell behaviors. We hypothesized that PRP pretreatment on PLGA mesh using different methods would cause different patterns of platelet adhesion and stages which would modulate cell adhesion and proliferation on the PLGA mesh. In this study, we pretreated PRP on PLGA using three different methods including simple dripping (SD), dynamic oscillation (DO) and centrifugation (CE), then observed the amount of adhered platelets and their activation stage distribution. The highest amount of platelets was observed on CE mesh and calcium treated CE mesh. Moreover, calcium addition after PRP coating triggered dramatic activation of platelets which showed large and flat morphologies of platelets with rich fibrin networks. Human chondrocytes (hCs) and human bone marrow stromal cells (hBMSCs) were next cultured on PRP-pretreated PLGA meshes using different preparation methods. CE mesh showed a significant increase in the initial cell adhesion of hCs and proliferation of hBMSCs compared with SD and DO meshes. The results demonstrated that the centrifugation method can be considered as a promising coating method to introduce PRP on PLGA polymeric material which could improve cell-material interaction using a simple method.

  15. Sustained delivery of rhBMP-2 via PLGA microspheres: cranial bone regeneration without heterotopic ossification or craniosynostosis

    PubMed Central

    Wink, Jason D.; Gerety, Patrick A.; Sherif, Rami D.; Lim, Youngshin; A.Clarke, Nadya; Rajapakse, Chamith S.; Nah, Hyun-Duck; Taylor, Jesse A.

    2014-01-01

    Background Commercially available recombinant human bone morphogenetic protein 2 (rhBMP2) has demonstrated efficacy in bone regeneration, but not without significant side effects. In this study, we utilize rhBMP2 encapsulated in PLGA microspheres (PLGA-rhBMP2) placed in a rabbit cranial defect model to test whether low-dose, sustained, delivery can effectively induce bone regeneration. Methods rhBMP2 was encapsulated in 15% poly (lactic-co-glycolic acid), using a double emulsion, solvent extraction/evaporation technique, and its release kinetics and bioactivity were tested. Two critical-size defects (10mm) were created in the calvarium of New Zealand White rabbits (5-7 mos of age, M/F) and filled with a collagen scaffold containing one of four groups: 1) no implant, 2) collagen scaffold only, 3) PLGA-rhBMP2(0.1ug/implant), or 4) free rhBMP2 (0.1ug/implant). After 6 weeks, the rabbits were sacrificed and defects were analyzed by μCT, histology, and finite element analysis. Results RhBMP2 delivered via bioactive PLGA microspheres resulted in higher volumes and surface area coverage of new bone than an equal dose of free rhBMP2 by μCT and histology (p=0.025, 0.025). FEA indicated that the mechanical competence using the regional elastic modulus did not differ with rhBMP2 exposure (p=0.70). PLGA-rhBMP2 did not demonstrate heterotopic ossification, craniosynostosis, or seroma formation. Conclusions Sustained delivery via PLGA microspheres can significantly reduce the rhBMP2 dose required for de novo bone formation. Optimization of the delivery system may be a key to reduce the risk for recently reported rhBMP2 related adverse effects. Level of Evidence Animal Study PMID:24622573

  16. Effects of designed PLLA and 50:50PLGA scaffold architectures on bone formation in vivo

    PubMed Central

    Saito, Eiji; Liao, Elly E.; Hu, Wei-Wen; Krebsbach, Paul H.; Hollister, Scott J.

    2015-01-01

    Biodegradable porous scaffolds have been investigated as an alternative approach to current metal, ceramic, and polymer bone graft substitutes for lost or damaged bone tissues. Although there have been many studies investigating the effects of scaffold architecture on bone formation, many of these scaffolds were fabricated using conventional methods, such as salt leaching and phase separation, and were constructed without designed architecture. To study the effects of both designed architecture and material on bone formation, we designed and fabricated three types of porous scaffold architecture from two biodegradable materials, poly (L-lactic acid) (PLLA) and 50:50Poly (lactic-co-glycolic acid) (PLGA) using image based design and indirect solid freeform fabrication techniques, seeded them with bone morphogenic protein-7 transduced human gingival fibroblasts and implanted them subcutaneously into mice for 4 and 8 weeks. Micro-computed tomography data confirmed that the fabricated porous scaffolds replicated the designed architectures. Histological analysis revealed that the 50:50PLGA scaffolds degraded and did not maintain their architecture after 4 weeks. The PLLA scaffolds maintained their architecture at both time points and showed improved bone ingrowth which followed the internal architecture of the scaffolds. Mechanical properties of both PLLA and 50:50PLGA scaffolds decreased, but PLLA scaffolds maintained greater mechanical properties than 50:50PLGA after implantation. The increase of mineralized tissue helped to support mechanical properties of bone tissue and scaffold constructs from 4 to 8 weeks. The results indicated the importance of choice of scaffold materials and computationally designed scaffolds to control tissue formation and mechanical properties for desired bone tissue regeneration. PMID:22162220

  17. Optical manipulation in optofluidic microbubble resonators

    NASA Astrophysics Data System (ADS)

    Wang, HaoTian; Wu, Xiang

    2015-11-01

    An optical manipulation system based on optofluidic microbubble resonators (MBR) is proposed. As the high- Q whispering gallery modes (WGMs) are excited in an MBR, the buildup of the field intensity inside the resonator is large enough to trap nanoscale particles. The optical gradient forces generated by the WGMs with different radial orders are investigated numerically. The negative effect of the resonance detuning induced by the particles is taken into account to investigate the optical gradient forces exerting on the particles. By the stability analysis, the WGMs with high radial orders show a better trapping stability under Brownian motion since most of the optical fields reside within the water core.

  18. MODELING MICROBUBBLE DYNAMICS IN BIOMEDICAL APPLICATIONS*

    PubMed Central

    CHAHINE, Georges L.; HSIAO, Chao-Tsung

    2012-01-01

    Controlling microbubble dynamics to produce desirable biomedical outcomes when and where necessary and avoid deleterious effects requires advanced knowledge, which can be achieved only through a combination of experimental and numerical/analytical techniques. The present communication presents a multi-physics approach to study the dynamics combining viscous- in-viscid effects, liquid and structure dynamics, and multi bubble interaction. While complex numerical tools are developed and used, the study aims at identifying the key parameters influencing the dynamics, which need to be included in simpler models. PMID:22833696

  19. Novel PLGA-based nanoparticles for the oral delivery of insulin

    PubMed Central

    Malathi, Sampath; Nandhakumar, Perumal; Pandiyan, Velayudham; Webster, Thomas J; Balasubramanian, Sengottuvelan

    2015-01-01

    Background Insulin is the drug therapy for patients with insulin-dependent diabetes mellitus. A number of attempts have been made in the past to overcome the problems associated with the oral delivery of insulin, but with little success. Orally administered insulin has encountered with many difficulties such as rapid degradation and poor intestinal absorption. The potential use of D-α-tocopherol poly(ethylene glycol) 1000 succinate (TPGS)-emulsified poly(ethylene glycol) (PEG)-capped poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) was investigated for sustained delivery of insulin (IS). Objective To investigate the efficacy of TPGS-emulsified PEG-capped PLGA NPs (TPPLG NPs) as a potential drug carrier for the oral delivery of insulin. Methods A series of biodegradable low-molecular-weight PLGA (80/20 [PLG4] and 70/30 [PLG6]) copolymers were synthesized by melt polycondensation. The commercial insulin-loaded TPGS-emulsified PEG-capped PLGA NPs (ISTPPLG NPs) were synthesized by water–oil–water emulsion solvent evaporation method. The physical and chemical properties of PLGA copolymers, particle size, zeta potential, and morphology of the NPs were examined. The in vivo studies of ISTPPLG NPs were carried out in diabetic rats by oral administration. Results The maximum encapsulation efficiency of ISTPPLG6 NPs was 78.6%±1.2%, and the mean diameter of the NPs was 180±20 nm. The serum glucose level was significantly (twofold) decreased on treatment with ISTPPLG NPs, and there was a threefold decrease with insulin-loaded PLGA (70/30) NPs when compared to that of free insulin-treated diabetic rats. The results show that the oral administration of ISTPPLG6 NPs is an effective method of reducing serum glucose level for a period of 24 hours. Histopathological studies reveal that ISTPPLG NPs could restore the damage caused by streptozotocin in the liver, kidneys, and pancreas, indicating its biocompatibility and regenerative effects. Conclusion ISTPPLG6 NPs can

  20. The influence of distance between microbubbles on the fluid flow produced during ultrasound exposure.

    PubMed

    Schutt, Carolyn E; Ibsen, Stuart D; Thrift, William; Esener, Sadik C

    2014-12-01

    The collapse dynamics of lipid monolayer-coated microbubbles in the clinically-relevant size range under 6 μm in diameter have not been studied directly due to their small size obscuring the collapse visualization. This study investigates the influence of inter-microbubble distance on the shape of lipid debris clouds created by the collapse of the microbubble destroying the microbubble lipid monolayer. The shape was highly influenced by the fluid motion that occurred as the microbubbles collapsed. It was observed that at inter-microbubble distances smaller than 37 μm the microbubbles began to interact with one another resulting in distorted and ellipsoid-shaped debris clouds. At inter-microbubble distances less than 10 μm, significantly elongated debris clouds were observed that extended out from the original microbubble location in a single direction. These distortions show a significant distance-dependent interaction between microbubbles. It was observed that microbubbles in physical contact with one another behaved in the same manner as separate microbubbles less than 10 μm apart creating significantly elongated debris clouds. It can be hypothesized that small inter-microbubble distances influence the microbubble to collapse asymmetrically resulting in the creation of fluid jets that contribute to the formation of debris fields that are elongated in a single direction.

  1. Research spotlight: microbubbles for therapeutic delivery.

    PubMed

    Peyman, Sally A; Abou-Saleh, Radwa H; Evans, Stephen D

    2013-05-01

    Systemic injection of chemotherapy agents for treating cancer can cause severe side effects for the patient, as well as being a relatively inefficient use of expensive and highly toxic drugs. The area of targeted drug delivery in which drugs are delivered utilizing a specialized carrier directly to the cancerous tumor via immuno-recognition has gained much interest in recent years. Such an approach reduces the side effects of systemic injection and also provides a localized, high-concentration treatment directly to the cancer. Our group at the University of Leeds (Leeds, UK) is developing therapeutic microbubbles that double as both agents for contrast-enhanced ultrasound imaging and drug-delivery vehicles that are targeted to specific cancer cell receptors. Ultimately, a large amplitude sound wave will be used to destroy the bubbles and trigger release of the drug at the targeted tumor. Theranostic microbubbles are a simple and versatile drug-delivery technique that could potentially improve cancer treatment, both in terms of patient experience and overall drug efficiency. Importantly, they offer new ways of delivering hydrophobic drugs, which have traditionally been difficult to deliver efficiently.

  2. Microbubble generation by piezotransducer for biological studies

    NASA Astrophysics Data System (ADS)

    Zhu, W.; Alkhazal, M.; Cho, M.; Xiao, S.

    2015-12-01

    Bubbles induced by blast waves or shocks are speculated to be the major cause of damages in biological cells in mild traumatic brain injuries. Microbubble collapse was found to induce noticeable cell detachment from the cell substrate, changes in focal adhesion and biomechanics. To better understand the bubble mechanism, we would like to construct a system, which allows us to clearly differentiate the impact of bubbles from that of shocks. Such a generator needs to be low profile in order to place under a microscope. A piezoelectric transducer system was designed to meet the need. The system uses either a flat or a spherical focusing piezoelectric transducer to produce microbubbles in a cuvette loaded with cell-culture medium. The transducer is placed on the side of the cuvette with its axis lining horizontally. A cover slip is placed on the top of the cuvette. The impact of the waves to the cells is minimized as the cover slip is parallel to the direction of the wave. Only bubbles from the medium reach the cover slip and interact with cells. The effect of bubbles therefore can be separated that of pressure waves. The bubbles collected on a cover slip range in size from 100 μm to 10 μm in radius, but the dominant size is 20-30 μm.

  3. A Biomimetic Approach to Active Self-Microencapsulation of Proteins in PLGA

    PubMed Central

    Shah, Ronak B.; Schwendeman, Steven P.

    2014-01-01

    A biomimetic approach to organic solvent-free microencapsulation of proteins based on the self-healing capacity of poly (DL)-lactic-co-glycolic acid (PLGA) microspheres containing glycosaminoglycan-like biopolymers (BPs), was examined. To screen BPs, aqueous solutions of BP [high molecular weight dextran sulfate (HDS), low molecular weight dextran sulfate (LDS), chondroitin sulfate (CS), heparin (HP), hyaluronic acid (HA), chitosan (CH)] and model protein lysozyme (LYZ) were combined in different molar and mass ratios, at 37 °C and pH 7. The BP-PLGA microspheres (20–63 µm) were prepared by a double water-oil-water emulsion method with a range of BP content, and trehalose and MgCO3 to control microclimate pH and to create percolating pores for protein. Biomimetic active self-encapsulation (ASE) of proteins [LYZ, vascular endothelial growth factor165 (VEGF) and fibroblast growth factor (FgF-20)] was accomplished by incubating blank BP-PLGA microspheres in low concentration protein solutions at ~24 °C, for 48 h. Pore closure was induced at 42.5 °C under mild agitation for 42 h. Formulation parameters of BP-PLGA microspheres and loading conditions were studied to optimize protein loading and subsequent release. LDS and HP were found to bind >95% LYZ at BP:LYZ >0.125 w/w, whereas HDS and CS bound > 80% LYZ at BP:LYZ of 0.25–1 and < 0.33, respectively. HA-PLGA microspheres were found to be not ideal for obtaining high protein loading (>2% w/w of LYZ). Sulfated BP-PLGA microspheres were capable of loading LYZ (~2–7 % w/w), VEGF (~ 4% w/w), and FgF-20 (~2% w/w) with high efficiency. Protein loading was found to be dependent on the loading solution concentration, with higher protein loading obtained at higher loading solution concentration within the range investigated. Loading also increased with content of sulfated BP in microspheres. Release kinetics of proteins was evaluated in-vitro with complete release media replacement. Rate and extent of release were

  4. A biomimetic approach to active self-microencapsulation of proteins in PLGA.

    PubMed

    Shah, Ronak B; Schwendeman, Steven P

    2014-12-28

    A biomimetic approach to organic solvent-free microencapsulation of proteins based on the self-healing capacity of poly (DL)-lactic-co-glycolic acid (PLGA) microspheres containing glycosaminoglycan-like biopolymers (BPs), was examined. To screen BPs, aqueous solutions of BP [high molecular weight dextran sulfate (HDS), low molecular weight dextran sulfate (LDS), chondroitin sulfate (CS), heparin (HP), hyaluronic acid (HA), chitosan (CH)] and model protein lysozyme (LYZ) were combined in different molar and mass ratios, at 37 °C and pH7. The BP-PLGA microspheres (20-63 μm) were prepared by a double water-oil-water emulsion method with a range of BP content, and trehalose and MgCO3 to control microclimate pH and to create percolating pores for protein. Biomimetic active self-encapsulation (ASE) of proteins [LYZ, vascular endothelial growth factor165 (VEGF) and fibroblast growth factor (FgF-20)] was accomplished by incubating blank BP-PLGA microspheres in low concentration protein solutions at ~24 °C, for 48 h. Pore closure was induced at 42.5 °C under mild agitation for 42h. Formulation parameters of BP-PLGA microspheres and loading conditions were studied to optimize protein loading and subsequent release. LDS and HP were found to bind >95% LYZ at BP:LYZ>0.125 w/w, whereas HDS and CS bound >80% LYZ at BP:LYZ of 0.25-1 and <0.33, respectively. HA-PLGA microspheres were found to be not ideal for obtaining high protein loading (>2% w/w of LYZ). Sulfated BP-PLGA microspheres were capable of loading LYZ (~2-7% w/w), VEGF (~4% w/w), and FgF-20 (~2% w/w) with high efficiency. Protein loading was found to be dependent on the loading solution concentration, with higher protein loading obtained at higher loading solution concentration within the range investigated. Loading also increased with content of sulfated BP in microspheres. Release kinetics of proteins was evaluated in-vitro with complete release media replacement. Rate and extent of release were found to depend

  5. Surface characteristics of PLA and PLGA films

    NASA Astrophysics Data System (ADS)

    Paragkumar N, Thanki; Edith, Dellacherie; Six, Jean-Luc

    2006-12-01

    Surface segregation and restructuring in polylactides (poly( D, L-lactide) and poly( L-lactide)) and poly( D,L-lactide-co-glycolide) (PLGA) films of various thicknesses were investigated using both attenuated total reflection FTIR (ATR-FTIR) and contact angle relaxation measurements. In case of poly( D,L-lactide) (DLPLA), it was observed that the surface segregation and the surface restructuring of methyl side groups are influenced by the polymer film thickness. This result has been confirmed by X-ray photoelectron spectroscopy (XPS). In the same way, PLGA thick films were also characterized by an extensive surface segregation of methyl side groups. Finally, surface restructuring was investigated by dynamic contact angle measurements and it was observed when film surface comes into contact with water. In parallel, we also found that poly( L-lactide) (PLLA) thin and clear films with thickness ˜15 μm undergo conformational changes on the surface upon solvent treatment with certain solvents. The solvent treated surface of PLLA becomes hazy and milky white and its hydrophobicity increases compared to untreated surface. FTIR spectroscopic analysis indicated that polymer chains at the surface undergo certain conformational changes upon solvent treatment. These changes are identified as the restricted motions of C-O-C segments and more intense and specific vibrations of methyl side groups. During solvent treatment, the change in water contact angle and FTIR spectrum of PLLA is well correlated.

  6. Process and apparatus for separating fine particles by microbubble flotation together with a process and apparatus for generation of microbubbles

    DOEpatents

    Yoon, R.H.; Adel, G.T.; Luttrell, G.H.

    1991-01-01

    A method and apparatus are disclosed for the microbubble flotation separation of very fine particles, especially coal, so as to produce a high purity and large recovery efficiently. This is accomplished through the use of a high aspect ratio flotation column, microbubbles, and a countercurrent use of wash water to gently wash the froth. Also, disclosed are unique processes and apparatus for generating microbubbles for flotation in a high efficient and inexpensive manner using either a porous tube or an in-line static generator. 23 figures.

  7. Process and apparatus for separating fine particles by microbubble flotation together with a process and apparatus for generation of microbubbles

    DOEpatents

    Yoon, Roe-Hoan; Adel, Gregory T.; Luttrell, Gerald H.

    1991-01-01

    A method and apparatus are disclosed for the microbubble flotation separation of very fine particles, especially coal, so as to produce a high purity and large recovery efficiently. This is accomplished through the use of a high aspect ratio flotation column, microbubbles, and a countercurrent use of wash water to gently wash the froth. Also, disclosed are unique processes and apparatus for generating microbubbles for flotation in a high efficient and inexpensive manner using either a porous tube or an in-line static generator.

  8. Encapsulation-free controlled release: Electrostatic adsorption eliminates the need for protein encapsulation in PLGA nanoparticles

    PubMed Central

    Pakulska, Malgosia M.; Elliott Donaghue, Irja; Obermeyer, Jaclyn M.; Tuladhar, Anup; McLaughlin, Christopher K.; Shendruk, Tyler N.; Shoichet, Molly S.

    2016-01-01

    Encapsulation of therapeutic molecules within polymer particles is a well-established method for achieving controlled release, yet challenges such as low loading, poor encapsulation efficiency, and loss of protein activity limit clinical translation. Despite this, the paradigm for the use of polymer particles in drug delivery has remained essentially unchanged for several decades. By taking advantage of the adsorption of protein therapeutics to poly(lactic-co-glycolic acid) (PLGA) nanoparticles, we demonstrate controlled release without encapsulation. In fact, we obtain identical, burst-free, extended-release profiles for three different protein therapeutics with and without encapsulation in PLGA nanoparticles embedded within a hydrogel. Using both positively and negatively charged proteins, we show that short-range electrostatic interactions between the proteins and the PLGA nanoparticles are the underlying mechanism for controlled release. Moreover, we demonstrate tunable release by modifying nanoparticle concentration, nanoparticle size, or environmental pH. These new insights obviate the need for encapsulation and offer promising, translatable strategies for a more effective delivery of therapeutic biomolecules. PMID:27386554

  9. Peripheral nerve regeneration within an asymmetrically porous PLGA/Pluronic F127 nerve guide conduit.

    PubMed

    Oh, Se Heang; Kim, Jun Ho; Song, Kyu Sang; Jeon, Byeong Hwa; Yoon, Jin Hwan; Seo, Tae Beom; Namgung, Uk; Lee, Il Woo; Lee, Jin Ho

    2008-04-01

    Asymmetrically porous tubes with selective permeability and hydrophilicity as nerve guide conduits (NGCs) were fabricated using poly(lactic-co-glycolic acid) (PLGA) and Pluronic F127 by a modified immersion precipitation method. The inner surface of the tube had nano-size pores ( approximately 50nm) which can effectively prevent from fibrous tissue infiltration but permeate nutrients and retain neurotrophic factors, while the outer surface had micro-size pores ( approximately 50microm) which can allow vascular ingrowth for effective supply of nutrients into the tube. From the animal study using a rat model, the hydrophilized PLGA/F127 (3wt%) tube showed better nerve regeneration behavior than the control silicone or hydrophobic PLGA tubes, as investigated by immunohistochemical observation (by fluorescent microscopy with anti-neurofilament staining), histological observations (by light microscopy with toluidine blue staining and transmission electron microscopy), and electrophysiological evaluation (by compound muscle action potential measurement). This is probably owing to the effective permeation of nutrients and prevention of fibrous scar tissue invasion as well as the good mechanical strength of the tube to maintain a stable support structure for the nerve regeneration.

  10. Collagen/silk fibroin composite scaffold incorporated with PLGA microsphere for cartilage repair.

    PubMed

    Wang, Jianhua; Yang, Qiu; Cheng, Niangmei; Tao, Xiaojun; Zhang, Zhihua; Sun, Xiaomin; Zhang, Qiqing

    2016-04-01

    For cartilage repair, ideal scaffolds should mimic natural extracellular matrix (ECM) exhibiting excellent characteristics, such as biocompatibility, suitable porosity, and good cell affinity. This study aimed to prepare a collagen/silk fibroin composite scaffold incorporated with poly-lactic-co-glycolic acid (PLGA) microsphere that can be applied in repairing cartilage. To obtain optimum conditions for manufacturing a composite scaffold, a scaffold composed of different collagen-to-silk fibroin ratios was evaluated by determining porosity, water absorption, loss rate in hot water, and cell proliferation. Results suggested that the optimal ratio of collagen and silk fibroin composite scaffold was 7:3. The microstructure and morphological characteristics of the obtained scaffold were also examined through scanning electron microscopy and Fourier transform infrared spectroscopy. The results of in vitro fluorescence staining of bone marrow stromal cells revealed that collagen/silk fibroin composite scaffold enhanced cell proliferation without eliciting side effects. The prepared composite scaffold incorporated with PLGA microsphere was implanted in fully thick articular cartilage defects in rabbits. Collagen/silk fibroin composite scaffold with PLGA microspheres could enhance articular cartilage regeneration and integration between the repaired cartilage and the surrounding cartilage. Therefore, this composite will be a promising material for cartilage repair and regeneration.

  11. In vitro and in vivo performance of dexamethasone loaded PLGA microspheres prepared using polymer blends.

    PubMed

    Gu, Bing; Wang, Yan; Burgess, Diane J

    2015-12-30

    The foreign body reaction is the major cause of the dysfunction and relatively short lifetime associated with implanted glucose biosensors. An effective strategy to maintain sensor functionality is to apply biocompatible coatings that elute drug to counter the negative tissue reactions. This has been achieved using dexamethasone releasing poly(lactic-co-glycolic acid) (PLGA) microspheres embedded in a polyvinyl alcohol (PVA) hydrogel coating. Accordingly, the biosensor lifetime relies on the duration and dose of drug release from the coating. To achieve long-term drug release mixed populations of microspheres have been used. In the current study, microspheres were prepared by blending low (25KDa) and high (113KDa) molecular weight PLGA at different mass ratios to overcome problems associated with mixing multiple populations of microspheres. "Real-time" in vitro studies demonstrated dexamethasone release for approximately 5 months. An accelerated method with discriminatory ability was developed to shorten drug release to less than 2 weeks. An in vivo pharmacodynamics study demonstrated efficacy against the foreign body reaction for 4.5 months. Such composite coatings composed of PLGA microspheres prepared using polymer blends could potentially be used to ensure long-term performance of glucose sensors.

  12. Biological activity of rhBMP-2 released from PLGA microspheres.

    PubMed

    Oldham, J B; Lu, L; Zhu, X; Porter, B D; Hefferan, T E; Larson, D R; Currier, B L; Mikos, A G; Yaszemski, M J

    2000-06-01

    Human recombinant bone morphogenetic protein-2 (rhBMP-2) has been proven effective in stimulating the regeneration of bone in both skeletal and extraskeletal locations. Through encapsulation within, and release from, biodegradable poly(DL-lactic-co-glycolic acid) (PLGA) microspheres, a proven vehicle for sustained delivery of various proteins, the local concentrations of rhBMP-2 could be maintained at optimal levels to stimulate bone regeneration and remodeling at the site of healing in diverse clinical settings. Thus the purpose of this work was to investigate the encapsulation of rhBMP-2 in PLGA microspheres and its biologic activity upon release. Using in vitro tests in simulated body fluids, the effect of rhBMP-2 released from PLGA microspheres upon osteoblast cell cultures was found to be statistically similar to the effect produced by positive controls consisting of nonencapsulated aqueous rhBMP-2 in simulated body fluids. This clarifies an important step in skeletal tissue engineering strategies aimed at the use of encapsulated rhBMP-2 to stimulate bone regeneration and remodeling.

  13. Phagocytosis of PLGA Microparticles in Rat Peritoneal Exudate Cells: A Time-Dependent Study

    NASA Astrophysics Data System (ADS)

    Gomes, Anderson De Jesus; Nain Lunardi, Claure; Henrique Caetano, Flávio; Orive Lunardi, Laurelúcia; da Hora Machado, Antonio Eduardo

    2006-07-01

    With the purpose of enhancing the efficacy of microparticle-encapsulated therapeutic agents, in this study we evaluated the phagocytic ability of rat peritoneal exudate cells and the preferential location of poly(D,L-lactide-co-glycolic acid) (PLGA) microparticles inside these cells. The microparticles used were produced by a solvent evaporation method and were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). Size distribution analysis using DLS and SEM showed that the particles were spherical, with diameters falling between 0.5 and 1.5 [mu]m. Results from cell adhesion by SEM assay, indicated that the PLGA microparticles are not toxic to cells and do not cause any distinct damage to them as confirmed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. Among the large variety of cell populations found in the peritoneal exudates (neutrophils, eosinophils, monocytes, and macrophages), TEM showed that only the latter phagocytosed PLGA microparticles, in a time-dependent manner. The results obtained indicate that the microparticles studied show merits as possible carriers of drugs for intracellular delivery.

  14. Electrospun PLGA/gelatin fibrous tubes for the application of biodegradable intestinal stent in rat model.

    PubMed

    Son, So-Ra; Franco, Rose-Ann; Bae, Sang-Ho; Min, Young-Ki; Lee, Byong-Taek

    2013-08-01

    A biodegradable fibrous tube was fabricated by electrospinning method using a combination of Poly(lactic-co-glycolic acid) (PLGA) and gelatin dissolved in trifluoroethanol (TFE). Different ratios of the two polymers (PLGA/Gelatin: 1/9, 3/7, 5/5) were used for electrospinning to determine the optimum condition appropriate for intestinal stent application. Fiber morphology was visualized and analyzed using a scanning electron microscope (SEM). Characterizations of physical properties were done according to its tensile strength, surface hydrophilicity, swelling ability, and biodegradability. Biocompatibility of the scaffolds was investigated in vitro using IEC-18 (Rat intestinal epithelial cell). Cell proliferation was quantified using MTT assay and cell adhesion behavior was visualized by SEM and confocal laser scanning microscope. PLGA/Gelatin (5/5) was determined to have adequate material properties and sufficient in vitro biocompatibility. This was then implanted in a male Sprague-Dawley rat for 14 days to determine in vivo behavior of the sample. Histological examination on the intestinal tissue surrounding the graft showed normal morphology comparable to non-implanted intestine.

  15. Gelsolin Amyloidogenesis Is Effectively Modulated by Curcumin and Emetine Conjugated PLGA Nanoparticles

    PubMed Central

    Goel, Surbhi; Kundu, Bishwajit; Mishra, Prashant; Fnu, Ashish

    2015-01-01

    Small molecule based therapeutic intervention of amyloids has been limited by their low solubility and poor pharmacokinetic characteristics. We report here, the use of water soluble poly lactic-co-glycolic acid (PLGA)-encapsulated curcumin and emetine nanoparticles (Cm-NPs and Em-NPs, respectively), as potential modulators of gelsolin amyloidogenesis. Using the amyloid-specific dye Thioflavin T (ThT) as an indicator along with electron microscopic imaging we show that the presence of Cm-NPs augmented amyloid formation in gelsolin by skipping the pre-fibrillar assemblies, while Em-NPs induced non-fibrillar aggregates. These two types of aggregates differed in their morphologies, surface hydrophobicity and secondary structural signatures, confirming that they followed distinct pathways. In spite of differences, both these aggregates displayed reduced toxicity against SH-SY5Y human neuroblastoma cells as compared to control gelsolin amyloids. We conclude that the cytotoxicity of gelsolin amyloids can be reduced by either stalling or accelerating its fibrillation process. In addition, Cm-NPs increased the fibrillar bulk while Em-NPs defibrillated the pre-formed gelsolin amyloids. Moreover, amyloid modulation happened at a much lower concentration and at a faster rate by the PLGA encapsulated compounds as compared to their free forms. Thus, besides improving pharmacokinetic and biocompatible properties of curcumin and emetine, PLGA conjugation elevates the therapeutic potential of both small molecules against amyloid fibrillation and toxicity. PMID:25996685

  16. Flowing microbubble manipulation in blood vessel phantom using ultrasonic standing wave with stepwise frequency

    NASA Astrophysics Data System (ADS)

    Shi, Aiwei; Min, Yu; Wan, Mingxi

    2013-10-01

    An approach was demonstrated to gather, fix, and controllably shift flowing microbubbles in a blood vessel phantom. An ultrasonic standing wave field was generated by the superposition of the emission of a 5 MHz conventional transducer and the reflection from a bone surface. The acoustic radiation force gathered flowing microbubbles into the nodes, fixed some accumulated microbubble clusters in the flow condition, and shifted microbubbles to target site with stepwise frequency. The resolution of microbubble shift was approximately 4 μm, and the low acoustic pressure range was from 4 to 16 kPa to avoid microbubble rupture.

  17. Reconstructing jaw defects with MSCs and PLGA-encapsulated growth factors

    PubMed Central

    Tee, Boon Ching; Desai, Kashappa Goud H; Kennedy, Kelly S; Sonnichsen, Brittany; Kim, Do-Gyoon; Fields, Henry W; Mallery, Susan R; Schwendeman, Steven P; Sun, Zongyang

    2016-01-01

    Cell and growth factor-based tissue engineering has shown great potentials for skeletal regeneration. This study tested its feasibility in reconstructing large mandibular defects and compared the efficacy of varied construction materials and sealing methods. Bilateral mandibular critical-size (5-cm3) defects were created on six 4-month-old domestic pigs, and grafted with β-tricalcium phosphate (βTCP) only (Group-A), βTCP with autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) (Group-B), and βTCP with BM-MSCs and biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres containing bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) (Group-C). The buccal sides of Groups-B/-C were either sealed by fibrin sealant or by a biodegradable PLGA barrier membrane before soft-tissue closure. Computed tomography (CT), microCT and histology analyses were performed 12 weeks postoperatively. In vitro data demonstrated that BM-MSCs, with MSC properties confirmed, remained vital after integration with βTCP; and PLGA microspheres exhibited an initial burst followed by slow and continuous release of growth factors over a period of 28 days. In vivo data demonstrated that Group-B/-C sites had significantly greater gap obliteration, higher tissue mineral densities and more residual βTCP granules (p<0.05, Kruskal-Wallis tests). Qualitatively, Group-B/-C defect sites had started remodeling while Group-A sites were mainly forming new bone to bridge the gaps. Furthermore, βTCP degradation was not mediated by macrophages or osteoclasts, and was significantly slowed down by sealing the defects with barrier membrane. Combined, these data present a promising formulation composed of βTCP granules, autologous MSCs, controlled-release growth factors and biodegradable PLGA barrier membrane for the reconstruction of critical-size mandibular defects. PMID:27398152

  18. Studies on the preparation, characterization and pharmacological evaluation of tolterodine PLGA microspheres.

    PubMed

    Sun, Fengying; Sui, Cheng; Teng, Lesheng; Liu, Ximing; Teng, Lirong; Meng, Qingfan; Li, Youxin

    2010-09-15

    In this study, poly(d,l-lactide-co-glycolide) (PLGA) microspheres of tolterodine depot formulation were prepared using oil in water (o/w) method to investigate their potential pharmacokinetic and pharmacodynamic advantages over tolterodine l-tartrate tablets. Morphological studies of the microspheres showed a spherical shape and smooth surface with mean size of 50.69-83.01 microm, and the encapsulation efficiency was improved from 62.55 to 79.10% when the polymer concentration increased from 180 to 230 mg/ml. The addition of stearic or palmitic acids could significantly raise the drug entrapment efficiency but only slightly affected the in vitro release. A low initial burst followed by a proximately constant release of tolterodine was noticed in the in vitro release profiles. The in vivo study was carried out by intramuscular (i.m.) administration of tolterodine-loaded microspheres on beagle dogs, and a sustained release of drug from the PLGA microspheres was achieved until the 18th day with a low initial burst. Since the absence of hepatic first pass metabolism, only a single active compound-tolterodine was detected in the plasma. This avoided the coexistence of two active compounds in plasma in the case of oral administration of tolterodine, which may lead to a difficulty in dose control due to the different metabolic capacity of patients. In the pharmacodynamic study, the influence of tolterodine PLGA microspheres on the inhibition of carbachol-induced rat urinary bladder contraction was more significant than that of tolterodine l-tartrate tablets. There were invisible changes in rat bladder slices between tolterodine-loaded PLGA microspheres group and tolterodine l-tartrate tablets group. These results indicate that the continuous inhibition of muscarinic receptor may offer an alternative therapy of urge incontinence.

  19. Algal cell disruption using microbubbles to localize ultrasonic energy.

    PubMed

    Krehbiel, Joel D; Schideman, Lance C; King, Daniel A; Freund, Jonathan B

    2014-12-01

    Microbubbles were added to an algal solution with the goal of improving cell disruption efficiency and the net energy balance for algal biofuel production. Experimental results showed that disruption increases with increasing peak rarefaction ultrasound pressure over the range studied: 1.90 to 3.07 MPa. Additionally, ultrasound cell disruption increased by up to 58% by adding microbubbles, with peak disruption occurring in the range of 10(8)microbubbles/ml. The localization of energy in space and time provided by the bubbles improve efficiency: energy requirements for such a process were estimated to be one-fourth of the available heat of combustion of algal biomass and one-fifth of currently used cell disruption methods. This increase in energy efficiency could make microbubble enhanced ultrasound viable for bioenergy applications and is expected to integrate well with current cell harvesting methods based upon dissolved air flotation.

  20. Enhancing antibiofilm efficacy in antimicrobial photodynamic therapy: effect of microbubbles

    NASA Astrophysics Data System (ADS)

    Kishen, Anil; George, Saji

    2013-02-01

    In this study, we tested the hypothesis that a microbubble containing photosensitizer when activated with light would enable comprehensive disinfection of bacterial biofilms in infected root dentin by antimicrobial photodynamic therapy (APDT). Experiments were conducted in two stages. In the stage-1, microbubble containing photosensitizing formulation was tested for its photochemical properties. In the stage-2, the efficacy of microbubble containing photosensitizing formulation was tested on in vitro infected root canal model, developed with monospecies biofilm models of Enterococcus faecalis on root dentin substrate. The findings from this study showed that the microbubble containing photosensitizing formulation was overall the most effective formulation for photooxidation, generation of singlet oxygen, and in disinfecting the biofilm bacteria in the infected root canal model. This modified photosensitizing formulation will have potential advantages in eliminating bacterial biofilms from infected root dentin.

  1. Modeling photothermal and acoustical induced microbubble generation and growth.

    PubMed

    Krasovitski, Boris; Kislev, Hanoch; Kimmel, Eitan

    2007-12-01

    Previous experimental studies showed that powerful heating of nanoparticles by a laser pulse using energy density greater than 100 mJ/cm(2), could induce vaporization and generate microbubbles. When ultrasound is introduced at the same time as the laser pulse, much less laser power is required. For therapeutic applications, generation of microbubbles on demand at target locations, e.g. cells or bacteria can be used to induce hyperthermia or to facilitate drug delivery. The objective of this work is to develop a method capable of predicting photothermal and acoustic parameters in terms of laser power and acoustic pressure amplitude that are needed to produce stable microbubbles; and investigate the influence of bubble coalescence on the thresholds when the microbubbles are generated around nanoparticles that appear in clusters. We develop and solve here a combined problem of momentum, heat and mass transfer which is associated with generation and growth of a microbubble, filled with a mixture of non-vaporized gas (air) and water vapor. The microbubble's size and gas content vary as a result of three mechanisms: gas expansion or compression, evaporation or condensation on the bubble boundary, and diffusion of dissolved air in the surrounding water. The simulations predict that when ultrasound is applied relatively low threshold values of laser and ultrasound power are required to obtain a stable microbubble from a single nanoparticle. Even lower power is required when microbubbles are formed by coalescence around a cluster of 10 nanoparticles. Laser pulse energy density of 21 mJ/cm(2) is predicted for instance together with acoustic pressure of 0.1 MPa for a cluster of 10 or 62 mJ/cm(2) for a single nanoparticle. Those values are well within the safety limits, and as such are most appealing for targeted therapeutic purposes.

  2. Design and characterization of a conductive nanostructured polypyrrole-polycaprolactone coated magnesium/PLGA composite for tissue engineering scaffolds.

    PubMed

    Liu, Haixia; Wang, Ran; Chu, Henry K; Sun, Dong

    2015-09-01

    A novel biodegradable and conductive composite consisting of magnesium (Mg), polypyrrole-block-ploycaprolactone (PPy-PCL), and poly(lactic-co-glycolic acid) (PLGA) is synthesized in a core-shell-skeleton manner for tissue engineering applications. Mg particles in the composite are first coated with a conductive nanostructured PPy-PCL layer for corrosion resistance via the UV-induced photopolymerization method. PLGA matrix is then added to tailor the biodegradability of the resultant composite. Composites with different composition ratios are examined through experiments, and their material properties are characterized. The in vitro experiments on culture of 293FT-GFP cells show that the composites are suitable for cell growth and culture. Biodegradability of the composite is also evaluated. By adding PLGA matrix to the composite, the degrading time of the composite can last for more than eight weeks, hence providing a longer period for tissue formation as compared to Mg composites or alloys. The findings of this research will offer a new opportunity to utilize a conductive, nanostructured-coated Mg/PLGA composite as the scaffold material for implants and tissue regeneration.

  3. Salidroside promotes peripheral nerve regeneration based on tissue engineering strategy using Schwann cells and PLGA: in vitro and in vivo

    PubMed Central

    Liu, Hui; Lv, Peizhen; Zhu, Yongjia; Wu, Huayu; Zhang, Kun; Xu, Fuben; Zheng, Li; Zhao, Jinmin

    2017-01-01

    Salidriside (SDS), a phenylpropanoid glycoside derived from Rhodiola rosea L, has been shown to be neuroprotective in many studies, which may be promising in nerve recovery. In this study, the neuroprotective effects of SDS on engineered nerve constructed by Schwann cells (SCs) and Poly (lactic-co-glycolic acid) (PLGA) were studied in vitro. We further investigated the effect of combinational therapy of SDS and PLGA/SCs based tissue engineering on peripheral nerve regeneration based on the rat model of nerve injury by sciatic transection. The results showed that SDS dramatically enhanced the proliferation and function of SCs. The underlying mechanism may be that SDS affects SCs growth through the modulation of neurotrophic factors (BDNF, GDNF and CNTF). 12 weeks after implantation with a 12 mm gap of sciatic nerve injury, SDS-PLGA/SCs achieved satisfying outcomes of nerve regeneration, as evidenced by morphological and functional improvements upon therapy by SDS, PLGA/SCs or direct suture group assessed by sciatic function index, nerve conduction assay, HE staining and immunohistochemical analysis. Our results demonstrated the significant role of introducing SDS into neural tissue engineering to promote nerve regeneration. PMID:28054637

  4. Interactions of PLGA nanoparticles with blood components: protein adsorption, coagulation, activation of the complement system and hemolysis studies.

    PubMed

    Fornaguera, Cristina; Calderó, Gabriela; Mitjans, Montserrat; Vinardell, Maria Pilar; Solans, Conxita; Vauthier, Christine

    2015-04-14

    The intravenous administration of poly(lactic-co-glycolic) acid (PLGA) nanoparticles has been widely reported as a promising alternative for delivery of drugs to specific cells. However, studies on their interaction with diverse blood components using different techniques are still lacking. Therefore, in the present work, the interaction of PLGA nanoparticles with blood components was described using different complementary techniques. The influence of different encapsulated compounds/functionalizing agents on these interactions was also reported. It is worth noting that all these techniques can be simply performed, without the need for highly sophisticated apparatus or skills. Moreover, their transference to industries and application of quality control could be easily performed. Serum albumin was adsorbed onto all types of tested nanoparticles. The saturation concentration was dependent on the nanoparticle size. In contrast, fibrinogen aggregation was dependent on nanoparticle surface charge. The complement activation was also influenced by the nanoparticle functionalization; the presence of a functionalizing agent increased complement activation, while the addition of an encapsulated compound only caused a slight increase. None of the nanoparticles influenced the coagulation cascade at low concentrations. However, at high concentrations, cationized nanoparticles did activate the coagulation cascade. Interactions of nanoparticles with erythrocytes did not reveal any hemolysis. Interactions of PLGA nanoparticles with blood proteins depended both on the nanoparticle properties and the protein studied. Independent of their loading/surface functionalization, PLGA nanoparticles did not influence the coagulation cascade and did not induce hemolysis of erythrocytes; they could be defined as safe concerning induction of embolization and cell lysis.

  5. Salidroside promotes peripheral nerve regeneration based on tissue engineering strategy using Schwann cells and PLGA: in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Liu, Hui; Lv, Peizhen; Zhu, Yongjia; Wu, Huayu; Zhang, Kun; Xu, Fuben; Zheng, Li; Zhao, Jinmin

    2017-01-01

    Salidriside (SDS), a phenylpropanoid glycoside derived from Rhodiola rosea L, has been shown to be neuroprotective in many studies, which may be promising in nerve recovery. In this study, the neuroprotective effects of SDS on engineered nerve constructed by Schwann cells (SCs) and Poly (lactic-co-glycolic acid) (PLGA) were studied in vitro. We further investigated the effect of combinational therapy of SDS and PLGA/SCs based tissue engineering on peripheral nerve regeneration based on the rat model of nerve injury by sciatic transection. The results showed that SDS dramatically enhanced the proliferation and function of SCs. The underlying mechanism may be that SDS affects SCs growth through the modulation of neurotrophic factors (BDNF, GDNF and CNTF). 12 weeks after implantation with a 12 mm gap of sciatic nerve injury, SDS-PLGA/SCs achieved satisfying outcomes of nerve regeneration, as evidenced by morphological and functional improvements upon therapy by SDS, PLGA/SCs or direct suture group assessed by sciatic function index, nerve conduction assay, HE staining and immunohistochemical analysis. Our results demonstrated the significant role of introducing SDS into neural tissue engineering to promote nerve regeneration.

  6. Magnetic hyperthermia efficiency and 1H-NMR relaxation properties of iron oxide/paclitaxel-loaded PLGA nanoparticles

    NASA Astrophysics Data System (ADS)

    Ruggiero, Maria R.; Geninatti Crich, Simonetta; Sieni, Elisabetta; Sgarbossa, Paolo; Forzan, Michele; Cavallari, Eleonora; Stefania, Rachele; Dughiero, Fabrizio; Aime, Silvio

    2016-07-01

    Magnetic iron oxide nanoparticles (Fe-NPs) can be exploited in biomedicine as agents for magnetic fluid hyperthermia (MFH) treatments and as contrast enhancers in magnetic resonance imaging. New, oleate-covered, iron oxide particles have been prepared either by co-precipitation or thermal decomposition methods and incorporated into poly(lactic-co-glycolic acid) nanoparticles (PLGA-Fe-NPs) to improve their biocompatibility and in vivo stability. Moreover, the PLGA-Fe-NPs have been loaded with paclitaxel to pursue an MFH-triggered drug release. Remarkably, it has been found that the nanoparticle formulations are characterized by peculiar 1H nuclear magnetic relaxation dispersion (NMRD) profiles that directly correlate with their heating potential when exposed to an alternating magnetic field. By prolonging the magnetic field exposure to 30 min, a significant drug release was observed for PLGA-Fe-NPs in the case of the larger-sized magnetic nanoparticles. Furthermore, the immobilization of lipophilic Fe-NPs in PLGA-NPs also made it possible to maintain Néel relaxation as the dominant relaxation contribution in the presence of large iron oxide cores (diameters of 15-20 nm), with the advantage of preserving their efficiency when they are entrapped in the intracellular environment. The results reported herein show that NMRD profiles are a useful tool for anticipating the heating capabilities of Fe-NPs designed for MFH applications.

  7. Magnetic targeting of microbubbles against physiologically relevant flow conditions

    PubMed Central

    Owen, Joshua; Rademeyer, Paul; Chung, Daniel; Cheng, Qian; Holroyd, David; Coussios, Constantin; Friend, Peter; Pankhurst, Quentin A.; Stride, Eleanor

    2015-01-01

    The localization of microbubbles to a treatment site has been shown to be essential to their effectiveness in therapeutic applications such as targeted drug delivery and gene therapy. A variety of different strategies for achieving localization has been investigated, including biochemical targeting, acoustic radiation force, and the incorporation of superparamagnetic nanoparticles into microbubbles to enable their manipulation using an externally applied magnetic field. The third of these strategies has the advantage of concentrating microbubbles in a target region without exposing them to ultrasound, and can be used in conjunction with biochemical targeting to achieve greater specificity. Magnetic microbubbles have been shown to be effective for therapeutic delivery in vitro and in vivo. Whether this technique can be successfully applied in humans however remains an open question. The aim of this study was to determine the range of flow conditions under which targeting could be achieved. In vitro results indicate that magnetic microbubbles can be retained using clinically acceptable magnetic fields, for both the high shear rates (approx. 104 s−1) found in human arterioles and capillaries, and the high flow rates (approx. 3.5 ml s−1) of human arteries. The potential for human in vivo microbubble retention was further demonstrated using a perfused porcine liver model. PMID:26442137

  8. Effect of electrical potential of microbubbles on ozone dissolution

    NASA Astrophysics Data System (ADS)

    Hasegawa, H.; Kataoka, H.; Asano, K.

    2009-02-01

    Microbubbles make ozone water generation effective due to the high dissolution rate of gas in contrast to a conventional generating method. Therefore, it is presumable that ozone water generation using microbubbles can be achieved by the low concentration ozone gas. In our previous study, a compact and low power microbubble generator was developed. The microbubbles are generated by the local shear stress in the flow through a pipe with slits. In the present study, in order to investigate the relationship between the electrical potential of the gas-water interface and the cleaning of cloth using ozone microbubbles, two models with different slit angles (θ=30 and 60 deg) were installed. High concentration ozone water is produced for θ = 60 deg in contrast to the θ=30 deg case. When a cloth is washed in the θ=60 deg case, the soiled cloth can be cleaned easily in comparison with the θ=30 deg case, because the zeta potential of microbubbles for θ=60 deg is larger than that for θ=30 deg.

  9. Stability of microbubbles prepared by co-axial electrohydrodynamic atomisation.

    PubMed

    Farook, U; Stride, Eleanor; Edirisinghe, M J

    2009-06-01

    Previous studies have indicated that microbubbles prepared by co-axial electrohydrodynamic atomisation (CEHDA) are less stable than those prepared by other methods such as sonication and microfluidic techniques. The aim of this investigation was to determine the reasons for this observation and how this might be addressed in future work. Microbubbles were prepared by CEHDA using (i) a glycerol-air system, (ii) a glycerol-Tween 80-air system and (iii) a glycerol-zirconia-air system and also by simple agitation of (i) and (ii), in order to compare the effect upon the dissolution rate of microbubbles of different materials and processing methods. Both theoretical examination and the experimental results indicated that all three quantities were important in controlling the rate of microbubble dissolution, namely: surface tension at the gas/liquid interface, the effective diffusivity of gas through this interface and the initial concentration of gas dissolved in the surrounding liquid. However, it was the difference in gas concentration in the surrounding liquid that was indicated as the primary reason for the differences in stability observed with different processing methods. It was concluded, therefore, that improved stability could be achieved for microbubbles prepared using CEHDA by saturating the collecting fluid with gas and/or maintaining a high concentration of microbubbles during collection.

  10. Targeted oral delivery of BmpB vaccine using porous PLGA microparticles coated with M cell homing peptide-coupled chitosan.

    PubMed

    Jiang, Tao; Singh, Bijay; Li, Hui-Shan; Kim, You-Kyoung; Kang, Sang-Kee; Nah, Jae-Woon; Choi, Yun-Jaie; Cho, Chong-Su

    2014-02-01

    M cells, the key players of the mucosal immunity induction, are one of the intestinal barriers for the efficient delivery of vaccines to mucosal immune tissues. To overcome the barrier, we have developed an efficient oral vaccine carrier that constitutes poly (lactic-co-glycolic acid) (PLGA) microparticle coated with M cell targeting peptide. In this study, a membrane protein B of Brachyspira hyodysenteriae (BmpB) as a model vaccine against swine dysentery was loaded into porous PLGA microparticles (MPs). The PLGA MPs were further coated with the water-soluble chitosan (WSC) conjugated with M cell homing peptide (CKS9) to prepare BmpB-CKS9-WSC-PLGA MPs. Oral immunization of BmpB vaccine with CKS9-WSC-PLGA MPs in mice showed elevated secretory IgA responses in the mucosal tissues and systemic IgG antibody responses, providing a complete immune response. Specifically, the immunization with these MPs demonstrated to induce both Th1- and Th2-type responses based on elevated IgG1 and IgG2a titers. The elevated immune responses were attributed to the enhanced M cell targeting and transcytosis ability of CKS9-WSC-PLGA MPs to Peyer's patch regions. The high binding affinity of CKS9-WSC-PLGA MPs with the M cells to enter into the Peyer's patch regions of mouse small intestine was investigated by closed ileal loop assay and it was further confirmed by confocal laser scanning microscopy. These results suggest that the M cell targeting approach used in this study is a promising tool for targeted oral vaccine delivery.

  11. Nonlinear response to ultrasound of encapsulated microbubbles.

    PubMed

    Jiménez-Fernández, J

    2012-08-01

    The acoustic backscatter of encapsulated gas-filled microbubbles immersed in a weak compressible liquid and irradiated by ultrasound fields of moderate to high pressure amplitudes is investigated theoretically. The problem is formulated by considering, for the viscoelastic shell of finite thickness, an isotropic hyperelastic neo-Hookean model for the elastic contribution in addition to a Newtonian viscous component. First and second harmonic scattering cross-sections have been evaluated and the quantitative influence of the driving pressure amplitude on the harmonic resonance frequencies for different initial equilibrium bubble sizes and for different encapsulating physical properties has been determined. Conditions for optimal second harmonic imaging have been also investigated and some regions in the parameters space where the second harmonic intensity is dominant over the fundamental have been identified. Results have been obtained for albumin, lipid and polymer encapsulating shells, respectively.

  12. Coalescence preference in densely packed microbubbles

    DOE PAGES

    Kim, Yeseul; Lim, Su Jin; Gim, Bopil; ...

    2015-01-13

    A bubble merged from two parent bubbles with different size tends to be placed closer to the larger parent. This phenomenon is known as the coalescence preference. Here we demonstrate that the coalescence preference can be blocked inside a densely packed cluster of bubbles. We utilized high-speed high-resolution X-ray microscopy to clearly visualize individual coalescence events inside densely packed microbubbles with a local packing fraction of ~40%. Thus, the surface energy release theory predicts an exponent of 5 in a relation between the relative coalescence position and the parent size ratio, whereas our observation for coalescence in densely packed microbubblesmore » shows a different exponent of 2. We believe that this result would be important to understand the reality of coalescence dynamics in a variety of packing situations of soft matter.« less

  13. Microbubble ultrasound contrast agents: a review.

    PubMed

    Stride, E; Saffari, N

    2003-01-01

    The superior scattering properties of gas bubbles compared with blood cells have made microbubble ultrasound contrast agents important tools in ultrasound diagnosis. Over the past 2 years they have become the focus of a wide and rapidly expanding field of research, with their benefits being repeatedly demonstrated, both in ultrasound image enhancement, and more recently in drug and gene delivery applications. However, despite considerable investigation, their behaviour is by no means fully understood and, while no definite evidence of harmful effects has been obtained, there remain some concerns as to their safety. In this review the existing theoretical and experimental evidence is examined in order to clarify the extent to which contrast agents are currently understood and to identify areas for future research. In particular the disparity between the conditions considered in theoretical models and those encountered both in vitro, and more importantly in vivo is discussed, together with the controversy regarding the risk of harmful bio-effects.

  14. Design and Control of Functional Microbubbles for Medical Applications of Ultrasound

    NASA Astrophysics Data System (ADS)

    Takagi, Shu; Osaki, Taichi; Ariyoshi, Takuya; Azuma, Takashi; Ichiyanagi, Mitsuhisa; Kinefuchi, Ikuya

    2015-11-01

    Microbubbles are used as a contrast agent for ultrasound diagnosis. It is also expected to be use for the treatment. One of the possible applications is microbubble DDS. For that purpose, microbubbles need to be well-controlled for the generating process and manipulation. In this talk, for the design and control of the functional microbubbles, an experimental study on generation and surface modification of microbubbles are explained. Using a T-junction type microchannel, small bubbles about 5 μm size are successfully generated. For the surface modification, Biotin-coated microbubbles are tried to adhere the Avidin-coated wall. Furthermore, the manipulation of the microbubbles using ultrasound is also discussed. Plane-wave and focused ultrasound is used to manipulate a microbubble and bubble clusters. The experimental results are shown in the presentation. Supported by JSPS KAKENHI Grant Number 15K13865.

  15. A Novel High Mechanical Property PLGA Composite Matrix Loaded with Nanodiamond-Phospholipid Compound for Bone Tissue Engineering.

    PubMed

    Zhang, Fan; Song, Qingxin; Huang, Xuan; Li, Fengning; Wang, Kun; Tang, Yixing; Hou, Canglong; Shen, Hongxing

    2016-01-20

    A potential bone tissue engineering material was produced from a biodegradable polymer, poly(lactic-co-glycolic acid) (PLGA), loaded with nanodiamond phospholipid compound (NDPC) via physical mixing. On the basis of hydrophobic effects and physical absorption, we modified the original hydrophilic surface of the nanodiamond (NDs) with phospholipids to be amphipathic, forming a typical core-shell structure. The ND-phospholipid weight ratio was optimized to generate sample NDPC50 (i.e., ND-phospholipid weight ratio of 100:50), and NDPC50 was able to be dispersed in a PLGA matrix at up to 20 wt %. Compared to a pure PLGA matrix, the introduction of 10 wt % of NDPC (i.e., sample NDPC50-PF10) resulted in a significant improvement in the material's mechanical and surface properties, including a decrease in the water contact angle from 80 to 55°, an approximately 100% increase in the Young's modulus, and an approximate 550% increase in hardness, thus closely resembling that of human cortical bone. As a novel matrix supporting human osteoblast (hFOB1.19) growth, NDPC50-PFs with different amounts of NDPC50 demonstrated no negative effects on cell proliferation and osteogenic differentiation. Furthermore, we focused on the behaviors of NDPC-PFs implanted into mice for 8 weeks and found that NDPC-PFs induced acceptable immune response and can reduce the rapid biodegradation of PLGA matrix. Our results represent the first in vivo research on ND (or NDPC) as nanofillers in a polymer matrix for bone tissue engineering. The high mechanical properties, good in vitro and in vivo biocompatibility, and increased mineralization capability suggest that biodegradable PLGA composite matrices loaded with NDPC may potentially be useful for a variety of biomedical applications, especially bone tissue engineering.

  16. Exploring the dark side of MTT viability assay of cells cultured onto electrospun PLGA-based composite nanofibrous scaffolding materials.

    PubMed

    Qi, Ruiling; Shen, Mingwu; Cao, Xueyan; Guo, Rui; Tian, Xuejiao; Yu, Jianyong; Shi, Xiangyang

    2011-07-21

    One major method used to evaluate the biocompatibility of porous tissue engineering scaffolding materials is MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The MTT cell viability assay is based on the absorbance of the dissolved MTT formazan crystals formed in living cells, which is proportional to the number of viable cells. Due to the strong dye sorption capability of porous scaffolding materials, we propose that the cell viability determined from the MTT assay is likely to give a false negative result. In this study, we aim to explore the effect of the adsorption of MTT formazan on the accuracy of the viability assay of cells cultured onto porous electrospun poly(lactic-co-glycolic acid) (PLGA) nanofibers, HNTs (halloysite nanotubes)/PLGA, and CNTs (multiwalled carbon nanotubes)/PLGA composite nanofibrous mats. The morphology of electrospun nanofibers and L929 mouse fibroblasts cultured onto the nanofibrous scaffolds were observed using scanning electron microscopy. The viability of cells proliferated for 3 days was evaluated through the MTT assay. In the meantime, the adsorption of MTT formazan onto the same electrospun nanofibers was evaluated and the standard concentration-absorbance curve was obtained in order to quantify the contribution of the adsorbed MTT formazan during the MTT cell viability assay. We show that the PLGA, and the HNTs- or CNTs-doped PLGA nanofibers display appreciable MTT formazan dye sorption, corresponding to 35.6-50.2% deviation from the real cell viability assay data. The better dye sorption capability of the nanofibers leads to further deviation from the real cell viability. Our study gives a general insight into accurate MTT cytotoxicity assessment of various porous tissue engineering scaffolding materials, and may be applicable to other colorimetric assays for analyzing the biological properties of porous scaffolding materials.

  17. Delivery of multiple siRNAs using lipid-coated PLGA nanoparticles for treatment of prostate cancer.

    PubMed

    Hasan, Warefta; Chu, Kevin; Gullapalli, Anuradha; Dunn, Stuart S; Enlow, Elizabeth M; Luft, J Christopher; Tian, Shaomin; Napier, Mary E; Pohlhaus, Patrick D; Rolland, Jason P; DeSimone, Joseph M

    2012-01-11

    Nanotechnology can provide a critical advantage in developing strategies for cancer management and treatment by helping to improve the safety and efficacy of novel therapeutic delivery vehicles. This paper reports the fabrication of poly(lactic acid-co-glycolic acid)/siRNA nanoparticles coated with lipids for use as prostate cancer therapeutics made via a unique soft lithography particle molding process called Particle Replication In Nonwetting Templates (PRINT). The PRINT process enables high encapsulation efficiency of siRNA into neutral and monodisperse PLGA particles (32-46% encapsulation efficiency). Lipid-coated PLGA/siRNA PRINT particles were used to deliver therapeutic siRNA in vitro to knockdown genes relevant to prostate cancer.

  18. Delivery of Multiple siRNAs Using Lipid-coated PLGA Nanoparticles for Treatment of Prostate Cancer

    PubMed Central

    Hasan, Warefta; Chu, Kevin; Gullapalli, Anuradha; Dunn, Stuart S.; Enlow, Elizabeth M.; Luft, J. Christopher; Tian, Shaomin; Napier, Mary E.; Pohlhaus, Patrick D.; Rolland, Jason P.; DeSimone, Joseph M.

    2012-01-01

    Nanotechnology can provide a critical advantage in developing strategies for cancer management and treatment by helping to improve the safety and efficacy of novel therapeutic delivery vehicles. This paper reports the fabrication of poly(lactic acid-co-glycolic acid)/siRNA nanoparticles coated with lipids for use as prostate cancer therapeutics made via a unique soft lithography particle molding process called PRINT (Particle Replication In Nonwetting Templates). The PRINT process enables high encapsulation efficiency of siRNA into neutral and monodisperse PLGA particles (32–46% encapsulation efficiency). Lipid-coated PLGA/siRNA PRINT particles were used to deliver therapeutic siRNA in vitro to knockdown genes relevant to prostate cancer. PMID:22165988

  19. Protective efficacy of PLGA microspheres loaded with divalent DNA vaccine encoding the ompA gene of Aeromonas veronii and the hly gene of Aeromonas hydrophila in mice.

    PubMed

    Gao, Shanshan; Zhao, Na; Amer, Said; Qian, Mingming; Lv, Mengxi; Zhao, Yuliang; Su, Xin; Cao, Jieying; He, Hongxuan; Zhao, Baohua

    2013-11-19

    In the present study, poly (lactic-co-glycolic) acid (PLGA) was used as a carrier for a divalent fusion DNA vaccine encoding the Aeromonas veronii outer membrane protein A (ompA) and Aeromonas hydrophila hemolysins (hly) protein. The recombinant pET-28a-ompA-hly was constructed by inserting the ompA gene and hly gene into a pET-28a expression vector. Loading of ompA-hly antigen module on PLGA microspheres were accomplished by water-in-oil-in-water (W/O/W) encapsulation. The molecular weight and specificity of pET-28a-ompA-hly were detected by dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting. The microspheres showed an average particle size of 100-150 μm and a loading efficiency (LE) of 68.8%. Mice received ompA-hly antigen-loaded PLGA microspheres by intraperitoneal or intragastric administration mounted strong and sustained IgG response, which was significantly higher (p<0.05) than those achieved by pET-28a-ompA-hly antigen alone. OmpA-hly antigen-loaded PLGA microsphere vaccine uniquely conferred a long lasting (30 days) sterile immunity against challenge infection. Results indicated that ompA-hly antigen-loaded PLGA microsphere vaccine is a qualified candidate vector system for sterile protective immunity against A. hydrophila and A. veronii infections.

  20. Evaluation of PLGA containing anti-CTLA4 inhibited endometriosis progression by regulating CD4+CD25+Treg cells in peritoneal fluid of mouse endometriosis model.

    PubMed

    Liu, Qi; Ma, Pingchuan; Liu, Lanxia; Ma, Guilei; Ma, Jingjing; Liu, Xiaoxuan; Liu, Yijin; Lin, Wanjun; Zhu, Yingjun

    2017-01-01

    Our study investigated poly(lactic-co-glycolic acid) (PLGA) as protein delivery vehicles encapsulate CTLA-4-antibody (anti-CTLA-4) which is essential for CD4+CD25+Treg cells suppressive function exposing superior potential for inhibiting endometriosis progress in mouse model than single anti-CTLA-4. Anti-CTLA-4 loaded PLGA combined to ligands CTLA-4 in surface of CD4+CD25+Treg cells which distributed in peritoneal fluid of mouse endometriosis model. The particle size, zeta potential of the anti-CTLA-4 loaded nanoparticles was detected by dynamic light scattering. Morphology of nanoparticles was evaluated by transmission electron microscopy (TEM). Confocal laser scanning microscopy (CLSM) indicated distribution of anti-CTLA-4 with PLGA or without in peritoneal fluid. Cumulative anti-CTLA-4 release from nanoparticles was evaluated by Micro BCA assay. The percentage of CD4+CD25+Treg cells in peritoneal fluid was demonstrated by flow cytometer. In vitro experiment we co-culture ectopic endometrial cells (EEC) with isolated CD4+CD25+Treg cells in peritoneal fluid (PF), proliferation and invasion of ectopic endometrial cells (EEC) was measured by BrdU ELISA assay and Matrigel invasion assay. In comparison with anti-CTLA-4 without nanoparticles, the bioconjugates PLGA/anti-CTLA-4 were tolerated in peritoneal fluid with a controlled release of anti-CTLA-4 in 3, 7, 14days. Moreover, PLGA/anti-CTLA-4 had superior protective regulation ability to reduce level of CD4+CD25+Treg cells in peritoneal fluid. Most strikingly, in vitro experiment, PLGA/anti-CTLA-4 exhibited better ability in inhibiting proliferation and invasion of ectopic endometrial cells in co-culture system compared with anti-CTLA-4. Progressively, PLGA/anti-CTLA-4 had better suppressive activity to inhibited IL-10 and TGF-beta secreted by CD4+CD25+Treg cells which indicating that PLGA/anti-CTLA-4 suppressed cells proliferation and invasion through reduced IL-10 and TGF-beta production. Thus, PLGA/anti-CTLA-4 may

  1. Thermal property and assessment of biocompatibility of poly(lactic-co-glycolic) acid/graphene nanocomposites

    NASA Astrophysics Data System (ADS)

    Adhikari, Ananta R.; Rusakova, Irene; Haleh, Ardebili; Luisi, Jonathan; Panova, Neli I.; Laezza, Fernanda; Chu, Wei-Kan

    2014-02-01

    Polymer-matrix nanocomposites based on Poly(lactic-co-glycolic) acid (PLGA) and Graphene platelets (GNPs) were studied. GNPs, nanomaterials with a 2D flat surface, were chosen with or without chemical modification in PLGA/GNP nanocomposites and their microstructure, thermal property, and their compatibility as scaffolds for cell growth were investigated. PLGA/GNP nanocomposites (0, 1, and 5 wt. % of GNPs) were prepared using a solution based technique. Transmission electron microscopy, X-ray diffraction, Differential scanning calorimeter, and Thermogravimetric analyzer were used to analyze morphology and thermal properties. This work demonstrated the role of GNPs flat surface to provide a favorable platform resulting in an enhanced PLGA crystallization. Functionalized GNPs suppress both the thermal stability and the crystallization of PLGA. Finally, to determine the potential usefulness of these scaffolds for biomedical applications, mammalian cells were cultured on various PLGA/GNP nanocomposites (0, 1, and 5 wt. % GNPs). 1 wt. % PLGA/GNP nanocomposites showed better biocompatibility for cell growth with/without graphenes functionalization compared to pure PLGA and 5 wt. % PLGA/GNP. The function of GNPs in PLGA/GNPs (1 wt. %) composites is to provide a stage for PLGA crystallization where cell growth is favored. These results provide strong evidence for a new class of materials that could be important for biomedical applications.

  2. Thermal property and assessment of biocompatibility of poly(lactic-co-glycolic) acid/graphene nanocomposites

    SciTech Connect

    Adhikari, Ananta R.; Rusakova, Irene; Chu, Wei-Kan; Haleh, Ardebili; Luisi, Jonathan; Panova, Neli I.; Laezza, Fernanda

    2014-02-07

    Polymer-matrix nanocomposites based on Poly(lactic-co-glycolic) acid (PLGA) and Graphene platelets (GNPs) were studied. GNPs, nanomaterials with a 2D flat surface, were chosen with or without chemical modification in PLGA/GNP nanocomposites and their microstructure, thermal property, and their compatibility as scaffolds for cell growth were investigated. PLGA/GNP nanocomposites (0, 1, and 5 wt. % of GNPs) were prepared using a solution based technique. Transmission electron microscopy, X-ray diffraction, Differential scanning calorimeter, and Thermogravimetric analyzer were used to analyze morphology and thermal properties. This work demonstrated the role of GNPs flat surface to provide a favorable platform resulting in an enhanced PLGA crystallization. Functionalized GNPs suppress both the thermal stability and the crystallization of PLGA. Finally, to determine the potential usefulness of these scaffolds for biomedical applications, mammalian cells were cultured on various PLGA/GNP nanocomposites (0, 1, and 5 wt. % GNPs). 1 wt. % PLGA/GNP nanocomposites showed better biocompatibility for cell growth with/without graphenes functionalization compared to pure PLGA and 5 wt. % PLGA/GNP. The function of GNPs in PLGA/GNPs (1 wt. %) composites is to provide a stage for PLGA crystallization where cell growth is favored. These results provide strong evidence for a new class of materials that could be important for biomedical applications.

  3. Janus nanogels of PEGylated Taxol and PLGA-PEG-PLGA copolymer for cancer therapy

    NASA Astrophysics Data System (ADS)

    Wei, Jun; Wang, Huaimin; Zhu, Meifeng; Ding, Dan; Li, Dongxia; Yin, Zhinan; Wang, Lianyong; Yang, Zhimou

    2013-09-01

    Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy.Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy. Electronic supplementary information (ESI) available: Synthesis and characterization of compounds, dynamic time sweep, H

  4. Preparation of microbubble suspensions by co-axial electrohydrodynamic atomization.

    PubMed

    Farook, U; Zhang, H B; Edirisinghe, M J; Stride, E; Saffari, N

    2007-09-01

    In this paper we report a novel method, based on co-axial electrohydrodynamic jetting, for the preparation of microbubble suspensions containing bubbles <10 microm in size and having a narrow size distribution. No selective filtration is necessary and the suspensions are produced directly by the process. To demonstrate the method, glycerol was used as the liquid medium, flowing in the outer needle of the co-axial twin needle arrangement and undergoing electrohydrodynamic atomization in the stable cone-jet mode while air flowed through the inner needle at the same time. At zero applied voltage a hollow stream of liquid flowed from the outer needle. When the applied voltage was increased, eventually the hollow stream became a stable cone-jet and emitted a microthread of bubbles, which were collected in a container of glycerol to obtain microbubble suspensions. The size of the microbubbles was measured via optical microscopy and laser diffractometry. Several microbubble suspensions were prepared and characterised and the size distribution was found to be critically dependent on the ratio (n) of flow rates of liquid/air and, in particular the flow rate of the air. At n=1.5, with the flow rate of air set at approximately 1.7 microl/s, a microbubble suspension containing bubbles in the size range 2-8 microm was obtained.

  5. Macroscopic acousto-mechanical analogy of a microbubble.

    PubMed

    Chaline, Jennifer; Jiménez, Noé; Mehrem, Ahmed; Bouakaz, Ayache; Dos Santos, Serge; Sánchez-Morcillo, Víctor J

    2015-12-01

    Microbubbles, either in the form of free gas bubbles surrounded by a fluid or encapsulated bubbles used currently as contrast agents for medical echography, exhibit complex dynamics under specific acoustic excitations. Nonetheless, considering their micron size and the complexity of their interaction phenomenon with ultrasound waves, expensive and complex experiments and/or simulations are required for their analysis. The behavior of a microbubble along its equator can be linked to a system of coupled oscillators. In this study, the oscillatory behavior of a microbubble has been investigated through an acousto-mechanical analogy based on a ring-shaped chain of coupled pendula. Observation of parametric vibration modes of the pendula ring excited at frequencies between 1 and 5 Hz is presented. Simulations have been carried out and show mode mixing phenomena. The relevance of the analogy between a microbubble and the macroscopic acousto-mechanical setup is discussed and suggested as an alternative way to investigate the complexity of microbubble dynamics.

  6. Enhancement of Focused Ultrasound Treatment by Acoustically Generated Microbubbles

    NASA Astrophysics Data System (ADS)

    Umemura, Shin-ichiro; Yoshizawa, Shin; Takagi, Ryo; Inaba, Yuta; Yasuda, Jun

    2013-07-01

    Microbubbles, whether introduced from outside the body or ultrasonically generated in situ, are known to significantly enhance the biological effects of ultrasound, including the mechanical, thermal, and sonochemical effects. Phase-change nanodroplets, which selectively accumulate in tumor tissue and whose phase changes to microbubbles can be induced by ultrasonic stimulation, have been proposed for high-intensity focused ultrasound (HIFU) tumor treatment with enhanced selectivity and efficiency. In this paper, a purely acoustic approach to generate microbubble clouds in the tissue to be treated is proposed. Short pulses of focused ultrasound with extremely high intensity, named trigger pulses, are used for exposure. They are immediately followed by focused ultrasound for heating with an intensity similar to or less than that of normal HIFU treatment. The localized generation of microbubble clouds by the trigger pulses is observed in a polyarylamide gel by a high-speed camera, and the effectiveness of the generated clouds in accelerating ultrasonically induced thermal coagulation is confirmed in excised chicken breast tissue. The use of second-harmonic superimposed waves as the trigger pulses is also proposed. The highly reproducible initiation of cavitation by waves with the negative peak pressure emphasized and the efficient expansion of the generated microbubble clouds by waves with the positive peak pressure emphasized are also observed by a high-speed camera in partially degassed water.

  7. Mechanisms for microvascular damage induced by ultrasound-activated microbubbles

    SciTech Connect

    Chen Hong; Brayman, Andrew A.; Evan, Andrew P.; Matula, Thomas J.

    2012-10-03

    To provide insight into the mechanisms of microvascular damage induced by ultrasound-activated microbubbles, experimental studies were performed to correlate microvascular damage to the dynamics of bubble-vessel interactions. High-speed photomicrography was used to record single microbubbles interacting with microvessels in ex vivo tissue, under the exposure of short ultrasound pulses with a center frequency of 1 MHz and peak negative pressures (PNP) ranging from 0.8-4 MPa. Vascular damage associated with observed bubble-vessel interactions was either indicated directly by microbubble extravasation or examined by transmission electron microscopy (TEM) analyses. As observed previously, the high-speed images revealed that ultrasound-activated microbubbles could cause distention and invagination of adjacent vessel walls, and could form liquid jets in microvessels. Vessel distention, invagination, and liquid jets were associated with the damage of microvessels whose diameters were smaller than those of maximally expanded microbubbles. However, vessel invagination appeared to be the dominant mechanism for the damage of relative large microvessels.

  8. A Novel Method for Preparing Surface-Modified Fluocinolone Acetonide Loaded PLGA Nanoparticles for Ocular Use: In Vitro and In Vivo Evaluations.

    PubMed

    Salama, Alaa H; Mahmoud, Azza A; Kamel, Rabab

    2016-10-01

    Our objective was to prepare nanoparticulate system using a simple yet attractive innovated method as an ophthalmic delivery system for fluocinolone acetonide to improve its ocular bioavailability. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were prepared by adopting thin film hydration method using PLGA/poloxamer 407 in weight ratios of 1:5 and 1:10. PLGA was used in 75/25 and 50/50 copolymer molar ratio of DL-lactide/glycolide. Results revealed that using PLGA with lower glycolic acid monomer ratio exhibited high particle size (PS), zeta potential (ZP) and drug encapsulation efficiency (EE) values with slow drug release pattern. Also, doubling the drug concentration during nanoparticles preparation ameliorated its EE to reach almost 100%. Furthermore, studies for separating the un-entrapped drug in nanoparticles using centrifugation method at 20,000 rpm for 30 min showed that the separated clear supernatant contained nanoparticles encapsulating an important drug amount. Therefore, separation of un-entrapped drug was carried out by filtrating the preparation using 20-25 μm pore size filter paper to avoid drug loss. Aiming to increase the PLGA nanoparticles mucoadhesion ability, surface modification of selected formulation was done using different amount of stearylamine and chitosan HCl. Nanoparticles coated with 0.1% w/v chitosan HCl attained most suitable results of PS, ZP and EE values as well as high drug release properties. Transmission electron microphotographs illustrated the deposition of chitosan molecules on the nanoparticles surfaces. Pharmacokinetic studies on Albino rabbit's eyes using HPLC indicated that the prepared novel chitosan-coated PLGA nanoparticles subjected to separation by filtration showed rapid and extended drug delivery to the eye.

  9. Mechanisms of in vivo release of triamcinolone acetonide from PLGA microspheres.

    PubMed

    Doty, Amy C; Weinstein, David G; Hirota, Keiji; Olsen, Karl F; Ackermann, Rose; Wang, Yan; Choi, Stephanie; Schwendeman, Steven P

    2017-03-22

    Little is known about the underlying effects controlling in vitro-in vivo correlations (IVIVCs) for biodegradable controlled release microspheres. Most reports of IVIVCs that exist are empirical in nature, typically based on a mathematical relationship between in vitro and in vivo drug release, with the latter often estimated by deconvolution of pharmacokinetic data. In order to improve the ability of in vitro release tests to predict microsphere behavior in vivo and develop more meaningful IVIVCs, the in vivo release mechanisms need to be characterized. Here, two poly(lactic-co-glycolic acid) (PLGA) microsphere formulations encapsulating the model steroid triamcinolone acetonide (Tr-A) were implanted subcutaneously in rats by using a validated cage model, allowing for free fluid and cellular exchange and microsphere retrieval during release. Release kinetics, as well as mechanistic indicators of release such as hydrolysis and mass loss, was measured by direct analysis of the recovered microspheres. Release of Tr-A from both formulations was greatly accelerated in vivo compared to in vitro using agitated phosphate buffered saline +0.02% Tween 80 pH7.4, including rate of PLGA hydrolysis, mass loss and water uptake. Both microsphere formulations exhibited erosion-controlled release in vitro, indicated by similar polymer mass loss kinetics, but only one of the formulations (low molecular weight, free acid terminated) exhibited the same mechanism in vivo. The in vivo release of Tr-A from microspheres made of a higher molecular weight, ester end-capped PLGA displayed an osmotically induced/pore diffusion mechanism based on confocal micrographs of percolating pores in the polymer, not previously observed in vitro. This research indicates the need to fully understand the in vivo environment and how it causes drug release from biodegradable microspheres. This understanding can then be applied to develop in vitro release tests which better mimic this environment and cause

  10. Characterization of individual ultrasound microbubble dynamics with a light-scattering system

    PubMed Central

    Hsu, Mark J.; Eghtedari, Mohammad; Goodwin, Andrew P.; Hall, David J.; Mattrey, Robert F.; Esener, Sadik C.

    2011-01-01

    Ultrasound microbubbles are contrast agents used for diagnostic ultrasound imaging and as carriers for noninvasive payload delivery. Understanding the acoustic properties of individual microbubble formulations is important for optimizing the ultrasound imaging parameters for improved image contrast and efficient payload delivery. We report here a practical and simple optical tool for direct real-time characterization of ultrasound contrast microbubble dynamics based on light scattering. Fourier transforms of raw linear and nonlinear acoustic oscillations, and microbubble cavitations are directly recorded. Further, the power of this tool is demonstrated by comparing clinically relevant microbubble cycle-to-cycle dynamics and their corresponding Fourier transforms. PMID:21721823

  11. Recombinant Protein-Stabilized Monodisperse Microbubbles with Tunable Size Using a Valve-Based Microfluidic Device

    PubMed Central

    2015-01-01

    Microbubbles are used as contrast enhancing agents in ultrasound sonography and more recently have shown great potential as theranostic agents that enable both diagnostics and therapy. Conventional production methods lead to highly polydisperse microbubbles, which compromise the effectiveness of ultrasound imaging and therapy. Stabilizing microbubbles with surfactant molecules that can impart functionality and properties that are desirable for specific applications would enhance the utility of microbubbles. Here we generate monodisperse microbubbles with a large potential for functionalization by combining a microfluidic method and recombinant protein technology. Our microfluidic device uses an air-actuated membrane valve that enables production of monodisperse microbubbles with narrow size distribution. The size of microbubbles can be precisely tuned by dynamically changing the dimension of the channel using the valve. The microbubbles are stabilized by an amphiphilic protein, oleosin, which provides versatility in controlling the functionalization of microbubbles through recombinant biotechnology. We show that it is critical to control the composition of the stabilizing agents to enable formation of highly stable and monodisperse microbubbles that are echogenic under ultrasound insonation. Our protein-shelled microbubbles based on the combination of microfluidic generation and recombinant protein technology provide a promising platform for ultrasound-related applications. PMID:25265041

  12. Photothermal generation of microbubbles on plasmonic nanostructures inside microfluidic channels

    NASA Astrophysics Data System (ADS)

    Li, Jingting; Li, Ming; Santos, Greggy M.; Zhao, Fusheng; Shih, Wei-Chuan

    2016-03-01

    Microbubbles have been utilized as micro-pumps, micro-mixers, micro-valves, micro-robots and surface cleaners. Various generation techniques can be found in the literature, including resistive heating, hydrodynamic methods, illuminating patterned metal films and noble metal nanoparticles of Au or Ag. We present photothermal microbubble generation by irradiating nanoporous gold disk covered microfluidic channels. The size of the microbubble can be controlled by adjusting the laser power. The dynamics of both bubble growth and shrinkage are studied. The advantages of this technique are flexible bubble generation locations, long bubble lifetimes, no need for light-adsorbing dyes, high controllability over bubble size, low power consumption, etc. This technique has the potential to provide new flow control functions in microfluidic devices.

  13. Sonication-microfluidics for fabrication of nanoparticle-stabilized microbubbles.

    PubMed

    Chen, Haosheng; Li, Jiang; Zhou, Weizheng; Pelan, Eddie G; Stoyanov, Simeon D; Arnaudov, Luben N; Stone, Howard A

    2014-04-22

    An approach based upon sonication-microfluidics is presented to fabricate nanoparticle-coated microbubbles. The gas-in-liquid slug flow formed in a microchannel is subjected to ultrasound, leading to cavitation at the gas-liquid interface. Therefore, microbubbles are formed and then stabilized by the nanoparticles contained in the liquid. Compared to the conventional sonication method, this sonication-microfluidics continuous flow approach has unlimited gas nuclei for cavitation that yields continuous production of foam with shorter residence time. By controlling the flow rate ratios of the gas to the liquid, this method also achieves a higher production volume, smaller bubble size, and less waste of the nanoparticles needed to stabilize the microbubbles.

  14. Observation of spontaneous combustion of hydrogen and oxygen in microbubbles

    NASA Astrophysics Data System (ADS)

    Postnikov, A. V.; Uvarov, I. V.; Prokaznikov, A. V.; Svetovoy, V. B.

    2016-03-01

    Experimental evidence is presented that combustion can ignite at room temperature spontaneously inside microbubbles filled with mixture of hydrogen and oxygen. We perform water electrolysis in a closed microchamber by voltage pulses of alternating polarity at repetition frequencies ≥100 kHz to pump the gases rapidly into the electrolyte and produce extreme supersaturation with both gases. After a delay of 300 -600 μs , we observe stroboscopically microbubbles of 5 -20 μm in diameter that appear in between the electrodes for several microseconds. Each event is accompanied by a pressure jump of 0.1 -1 bar that is measured interferometrically. The pressure jumps are attributed to combustion of the gases in the microbubbles.

  15. Molecular sonography with targeted microbubbles: current investigations and potential applications.

    PubMed

    Hwang, Misun; Lyshchik, Andrej; Fleischer, Arthur C

    2010-06-01

    Sonography using targeted microbubbles affords a variety of diagnostic and potentially therapeutic clinical applications. It provides a whole new world of functional information at the cellular and molecular level. This information can then be used to diagnose and possibly prevent diseases at early stages as well as devise therapeutic strategies at the molecular level. It is also useful in monitoring tumor response to therapy and devising treatment timing and plans based on the molecular state of an individual's health. Moreover, targeted microbubble-enhanced sonography has several advantages over other imaging modalities, including widespread availability, low cost, fast acquisition times, and lack of radiation risk. These traits are likely to advance it as one of the imaging methods of choice in future clinical trials examining the impact of molecular imaging on treatment outcome. This review describes the fundamental concepts of targeted microbubble-enhanced sonography as well as its potential clinical applications.

  16. Size distribution of microbubbles as a function of shell composition.

    PubMed

    Dicker, Stephen; Mleczko, Michał; Schmitz, Georg; Wrenn, Steven P

    2013-09-01

    The effect of modifying the shell composition of a population of microbubbles on their size demonstrated through experiment. Specifically, these variations include altering both the mole fraction and molecular weight of functionalized polymer, polyethylene glycol (PEG) in the microbubble phospholipid monolayer shell (1-15 mol% PEG, and 1000-5000 g/mole, respectively). The size distribution is measured with an unbiased image segmentation program written in MATLAB which identifies and sizes bubbles from micrographs. For a population of microbubbles with a shell composition of 5 mol% PEG2000, the mean diameter is 1.42 μm with a variance of 0.244 μm. For the remainder of the shell compositions studied herein, we find that the size distributions do not show a statistically significant correlation to either PEG molecular weight or mole fraction. All the measured distributions are nearly Gaussian in shape and have a monomodal peak.

  17. Acoustic behavior of microbubbles and implications for drug delivery.

    PubMed

    Kooiman, Klazina; Vos, Hendrik J; Versluis, Michel; de Jong, Nico

    2014-06-01

    Ultrasound contrast agents are valuable in diagnostic ultrasound imaging, and they increasingly show potential for drug delivery. This review focuses on the acoustic behavior of flexible-coated microbubbles and rigid-coated microcapsules and their contribution to enhanced drug delivery. Phenomena relevant to drug delivery, such as non-spherical oscillations, shear stress, microstreaming, and jetting will be reviewed from both a theoretical and experimental perspective. Further, the two systems for drug delivery, co-administration and the microbubble as drug carrier system, are reviewed in relation to the microbubble behavior. Finally, future prospects are discussed that need to be addressed for ultrasound contrast agents to move from a pre-clinical tool into a clinical setting.

  18. Epigallocatechin-3-O-Gallate-Loaded Poly(lactic-co-glycolic acid) Fibrous Sheets as Anti-Adhesion Barriers.

    PubMed

    Lee, Jong Ho; Shin, Yong Cheol; Yang, Won Jun; Park, Jong-chul; Hyon, Suong-hyu; Han, Dong-wook

    2015-08-01

    Epigallocatechin-3-O-gallate (EGCG), the main polyphenolic component of green tea, has a wide range of pharmacological activities, including antioxidant, anti-inflammatory, and anti-fibrotic effects. In this study, EGCG-loaded poly(lactic-co-glycolic acid) (PLGA) sheets were prepared by electrospinning nanofibers and evaluating their potential as tissue-adhesion barriers. EGCG-loaded PLGA (E-PLGA) fibrous sheets were electrospun from a PLGA solution containing 8% (w/v) EGCG. The average diameter of E-PLGA fibers was 397 ± 159 nm, which was comparable to that of pure PLGA fibers (459 ± 154 nm). EGCG was uniformly dispersed in E-PLGA sheets without direct chemical interactions. E-PLGA fibrous sheets showed sustained release of EGCG by controlled diffusion and PLGA degradation. The attachment and proliferation of L-929 fibroblastic cells were significantly (p < 0.05) suppressed in E-PLGA sheets. Furthermore, E-PLGA fibrous sheets did not induce any inflammatory response to J774A.1 macrophages. The anti-adhesion efficacy of E-PLGA fibrous sheets was evaluated in the intraperitoneal adhesion model in rats. Two weeks after surgical treatment, macroscopic adhesion (extent and severity) scores and histopathological tissue responses of E-PLGA fibrous sheets were significantly lower than those of non-treated controls and pure PLGA sheets. The results suggest that the scores are comparable, and in some cases superior, to those of other commercialized tissue-adhesion barriers. In conclusion, our study findings suggest that E-PLGA fibrous sheets may be exploited as potential tissue-adhesion barriers for the prevention of post-surgical adhesion formation.

  19. Dynamic interactions between microbubbles in water.

    PubMed

    Vakarelski, Ivan U; Manica, Rogerio; Tang, Xiaosong; O'Shea, Sean J; Stevens, Geoffrey W; Grieser, Franz; Dagastine, Raymond R; Chan, Derek Y C

    2010-06-22

    The interaction between moving bubbles, vapor voids in liquid, can arguably represent the simplest dynamical system in continuum mechanics as only a liquid and its vapor phase are involved. Surprisingly, and perhaps because of the ephemeral nature of bubbles, there has been no direct measurement of the time-dependent force between colliding bubbles which probes the effects of surface deformations and hydrodynamic flow on length scales down to nanometers. Using ultrasonically generated microbubbles (approximately 100 microm size) that have been accurately positioned in an atomic force microscope, we have made direct measurements of the force between two bubbles in water under controlled collision conditions that are similar to Brownian particles in solution. The experimental results together with detailed modeling reveal the nature of hydrodynamic boundary conditions at the air/water interface, the importance of the coupling of hydrodynamic flow, attractive van der Waals-Lifshitz forces, and bubble deformation in determining the conditions and mechanisms that lead to bubble coalescence. The observed behavior differs from intuitions gained from previous studies conducted using rigid particles. These direct force measurements reveal no specific ion effects at high ionic strengths or any special role of thermal fluctuations in film thickness in triggering the onset of bubble coalescence.

  20. Dynamic interactions between microbubbles in water

    PubMed Central

    Vakarelski, Ivan U.; Manica, Rogerio; Tang, Xiaosong; O’Shea, Sean J.; Stevens, Geoffrey W.; Grieser, Franz; Dagastine, Raymond R.; Chan, Derek Y. C.

    2010-01-01

    The interaction between moving bubbles, vapor voids in liquid, can arguably represent the simplest dynamical system in continuum mechanics as only a liquid and its vapor phase are involved. Surprisingly, and perhaps because of the ephemeral nature of bubbles, there has been no direct measurement of the time-dependent force between colliding bubbles which probes the effects of surface deformations and hydrodynamic flow on length scales down to nanometers. Using ultrasonically generated microbubbles (∼100 μm size) that have been accurately positioned in an atomic force microscope, we have made direct measurements of the force between two bubbles in water under controlled collision conditions that are similar to Brownian particles in solution. The experimental results together with detailed modeling reveal the nature of hydrodynamic boundary conditions at the air/water interface, the importance of the coupling of hydrodynamic flow, attractive van der Waals–Lifshitz forces, and bubble deformation in determining the conditions and mechanisms that lead to bubble coalescence. The observed behavior differs from intuitions gained from previous studies conducted using rigid particles. These direct force measurements reveal no specific ion effects at high ionic strengths or any special role of thermal fluctuations in film thickness in triggering the onset of bubble coalescence. PMID:20534552

  1. Controlled release of simvastatin-loaded thermo-sensitive PLGA-PEG-PLGA hydrogel for bone tissue regeneration: in vitro and in vivo characteristics.

    PubMed

    Yan, Qi; Xiao, Li-Qun; Tan, Lei; Sun, Wei; Wu, Tao; Chen, Liang-Wen; Mei, Yan; Shi, Bin

    2015-11-01

    Reports on the local delivery of drug loaded injectable hydrogels for bone regeneration are currently limited. This study assessed the effect of controlled simvastatin (SIM) release from a thermo-sensitive hydrogel in vitro and in vivo. We successfully manufactured and evaluated thermo-sensitive poly(d,l-lactide-co-glycolide)-poly(ethylene glycol)-poly(d,l-lactide-co-glycolide) triblock copolymers (PLGA-PEG-PLGA) loaded with SIM. The osteogenic effect of this hydrogel was tested in vitro and in vivo. MC-3T3 E1 cells proliferation and osteoblastic differentiation was analyzed after cultivation with the hydrogel extracts. Cells co-cultured with SIM/PLGA-PEG-PLGA extracts showed an increase in mineralization and osteogenic gene expression compared to the other two groups. Additionally, the characteristics of this composite in vivo were demonstrated using a rat bone defect model. The bone defects injected with SIM/PLGA-PEG-PLGA hydrogel showed increased new bone formation compared to samples treated with PLGA-PEG-PLGA and control samples. The results of this study suggest that SIM/PLGA-PEG-PLGA might provide potential therapeutic value for bone healing.

  2. Ultrasound imaging of the mouse pancreatic duct using lipid microbubbles

    NASA Astrophysics Data System (ADS)

    Banerjee, B.; McKeown, K. R.; Skovan, B.; Ogram, E.; Ingram, P.; Ignatenko, N.; Paine-Murrieta, G.; Witte, R.; Matsunaga, T. O.

    2012-03-01

    Research requiring the murine pancreatic duct to be imaged is often challenging due to the difficulty in selectively cannulating the pancreatic duct. We have successfully catheterized the pancreatic duct through the common bile duct in severe combined immune deficient (SCID) mice and imaged the pancreatic duct with gas filled lipid microbubbles that increase ultrasound imaging sensitivity due to exquisite scattering at the gas/liquid interface. A SCID mouse was euthanized by CO2, a midline abdominal incision made, the common bile duct cut at its midpoint, a 2 cm, 32 gauge tip catheter was inserted about 1 mm into the duct and tied with suture. The duodenum and pancreas were excised, removed in toto, embedded in agar and an infusion pump was used to instill normal saline or lipid-coated microbubbles (10 million / ml) into the duct. B-mode images before and after infusion of the duct with microbubbles imaged the entire pancreatic duct (~ 1 cm) with high contrast. The microbubbles were cavitated by high mechanical index (HMI) ultrasound for imaging to be repeated. Our technique of catheterization and using lipid microbubbles as a contrast agent may provide an effective, affordable technique of imaging the murine pancreatic duct; cavitation with HMI ultrasound would enable repeated imaging to be performed and clustering of targeted microbubbles to receptors on ductal cells would allow pathology to be localized accurately. This research was supported by the Experimental Mouse Shared Service of the AZ Cancer Center (Grant Number P30CA023074, NIH/NCI and the GI SPORE (NIH/NCI P50 CA95060).

  3. Photoprotective efficiency of PLGA-curcumin nanoparticles versus curcumin through the involvement of ERK/AKT pathway under ambient UV-R exposure in HaCaT cell line.

    PubMed

    Chopra, Deepti; Ray, Lipika; Dwivedi, Ashish; Tiwari, Shashi Kant; Singh, Jyoti; Singh, Krishna P; Kushwaha, Hari Narayan; Jahan, Sadaf; Pandey, Ankita; Gupta, Shailendra K; Chaturvedi, Rajnish Kumar; Pant, Aditya Bhushan; Ray, Ratan Singh; Gupta, Kailash Chand

    2016-04-01

    Curcumin (Cur) has been demonstrated to have wide pharmacological window including anti-oxidant and anti-inflammatory properties. However, phototoxicity under sunlight exposure and poor biological availability limits its applicability. We have synthesized biodegradable and non-toxic polymer-poly (lactic-co-glycolic) acid (PLGA) encapsulated formulation of curcumin (PLGA-Cur-NPs) of 150 nm size range. Photochemically free curcumin generates ROS, lipid peroxidation and induces significant UVA and UVB mediated impaired mitochondrial functions leading to apoptosis/necrosis and cell injury in two different origin cell lines viz., mouse fibroblasts-NIH-3T3 and human keratinocytes-HaCaT as compared to PLGA-Cur-NPs. Molecular docking studies suggested that intact curcumin from nanoparticles, bind with BAX in BIM SAHB site and attenuate it to undergo apoptosis while upregulating anti-apoptotic genes like BCL2. Real time studies and western blot analysis with specific phosphorylation inhibitor of ERK1 and AKT1/2/3 confirm the involvement of ERK/AKT signaling molecules to trigger the survival cascade in case of PLGA-Cur-NPs. Our finding demonstrates that low level sustained release of curcumin from PLGA-Cur-NPs could be a promising way to protect the adverse biological interactions of photo-degradation products of curcumin upon the exposure of UVA and UVB. Hence, the applicability of PLGA-Cur-NPs could be suggested as prolonged radical scavenging ingredient in curcumin containing products.

  4. Effect of microbubble size on fundamental mode high frequency ultrasound imaging in mice.

    PubMed

    Sirsi, Shashank; Feshitan, Jameel; Kwan, James; Homma, Shunichi; Borden, Mark

    2010-06-01

    High-frequency ultrasound imaging using microbubble (MB) contrast agents is becoming increasingly popular in pre-clinical and small animal studies of anatomy, flow and vascular expression of molecular epitopes. Currently, in vivo imaging studies rely on highly polydisperse microbubble suspensions, which may provide a complex and varied acoustic response. To study the effect of individual microbubble size populations, microbubbles of 1-2 microm, 4-5 microm and 6-8 microm diameter were isolated using the technique of differential centrifugation. Size-selected microbubbles were imaged in the mouse kidney over a range of concentrations using a Visualsonics Vevo 770 ultrasound imaging system (Visualsonics, Toronto, Ontario, Canada) with a 40-MHz probe in fundamental mode. Results demonstrate that contrast enhancement and circulation persistence are strongly dependent on microbubble size and concentration. Large microbubbles (4-5 and 6-8 microm) strongly enhanced the ultrasound image with positive contrast, while 1-2 microm microbubbles showed little enhancement. For example, the total integrated contrast enhancement, measured by the area under the time-intensity curve (AUC), increased 16-fold for 6-8 microm diameter microbubbles at 5 x 10(7) MB/bolus compared with 4-5 microm microbubbles at the same concentration. Interestingly, 1-2 microm diameter microbubbles, at any concentration, did not measurably enhance the integrated ultrasound signal at tissue depth, but did noticeably attenuate the signal, indicating that they had a low scattering-to-attenuation ratio. When concentration matched, larger microbubbles were more persistent in circulation. However, when volume matched, all microbubble sizes had a similar circulation half-life. These results indicated that dissolution of the gas core plays a larger role in contrast elimination than filtering by the lungs and spleen. The results of this study show that microbubbles can be tailored for optimal contrast enhancement in

  5. Effect of Microbubble Size on Fundamental Mode High Frequency Ultrasound Imaging in Mice

    PubMed Central

    Sirsi, Shashank; Feshitan, Jameel; Kwan, James; Homma, Shunichi; Borden, Mark

    2010-01-01

    High-frequency ultrasound imaging using microbubble (MB) contrast agents is becoming increasingly popular in pre-clinical and small animal studies of anatomy, flow and vascular expression of molecular epitopes. Currently, in vivo imaging studies rely on highly polydisperse microbubble suspensions, which may provide a complex and varied acoustic response. In order to study the effect of individual microbubble size populations, microbubbles of 1-2 μm, 4-5 μm, and 6-8 μm diameter were isolated using the technique of differential centrifugation. Size-selected microbubbles were imaged in the mouse kidney over a range of concentrations using a Visualsonics Vevo 770 ultrasound imaging system with a 40-MHz probe in fundamental mode. Results demonstrate that contrast enhancement and circulation persistence are strongly dependent on microbubble size and concentration. Large microbubbles (4-5 and 6-8 μm) strongly enhanced the ultrasound image with positive contrast, while 1-2 μm microbubbles showed little enhancement. For example, the total integrated contrast enhancement, measured by the area under the time-intensity curve (AUC), increased 16-fold for 6-8 μm diameter microbubbles at 5×107 MB/bolus compared to 4-5 μm microbubbles at the same concentration. Interestingly, 1-2 μm diameter microbubbles, at any concentration, did not measurably enhance the integrated ultrasound signal at tissue depth, but did noticeably attenuate the signal, indicating that they had a low scattering-to-attenuation ratio. When concentration matched, larger microbubbles were more persistent in circulation. However, when volume matched, all microbubble sizes had a similar circulation half-life. These results indicated that dissolution of the gas core plays a larger role in contrast elimination than filtering by the lungs and spleen. The results of this study show that microbubbles can be tailored for optimal contrast enhancement in fundamental mode imaging. PMID:20447755

  6. Experimental microbubble generation by sudden pressure drop and fluidics

    NASA Astrophysics Data System (ADS)

    Franco Gutierrez, Fernando; Figueroa Espinoza, Bernardo; Aguilar Corona, Alicia; Vargas Correa, Jesus; Solorio Diaz, Gildardo

    2014-11-01

    Mass and heat transfer, as well as chemical species in bubbly flow are of importance in environmental and industrial applications. Microbubbles are well suited to these applications due to the large interface contact area and residence time. The objective of this investigation is to build devices to produce microbubbles using two methods: pressure differences and fluidics. Some characteristics, advantages and drawbacks of both methods are briefly discussed, as well as the characterization of the bubbly suspensions in terms of parameters such as the pressure jump and bubble equivalent diameter distribution. The authors acknowledge the support of Consejo Nacional de Ciencia y Tecnología.

  7. In-plant testing of microbubble column flotation

    SciTech Connect

    Yoon, R.H.; Luttrell, G.H.; Adel, G.T.; Mankosa, M.J.

    1990-01-01

    During the past year, a joint project between the US Department of Energy (DOE), the Virginia Center for Coal and Minerals Processing (VCCMP) and the Shell Mining Corporation (SMC) was initiated to implement the testing of a full-scale microbubble flotation column. The work is being carried out at the Marrowbone Preparation Plant, located near Naugatuck in southwestern West Virginia. The primary objective of this effort was to determine the feasibility of using microbubble column flotation for the recovery of coal fines from a classifying cyclone overflow stream that is presently being discarded as refuse.

  8. Dopamine-conjugated poly(lactic-co-glycolic acid) nanoparticles for protein delivery to macrophages.

    PubMed

    Lee, Song Yi; Cho, Hyun-Jong

    2017-03-15

    Poly(lactic-co-glycolic acid)-dopamine (PLGA-D)-based nanoparticles (NPs) were developed for the delivery of protein to macrophages. PLGA-D was synthesized via amide bond formation between the amine group of D and the carboxylic acid group of PLGA. Bovine serum albumin (BSA, model protein) was encapsulated in PLGA NPs and PLGA-D NPs, which had an approximately 200nm mean diameter, <0.2 polydispersity index, and negative zeta potential value. There was no increment in the mean diameters of BSA-loaded NPs after 24h of incubation in biological fluid-simulated media (i.e., aqueous buffer and serum media). The primary, secondary, and tertiary structures of BSA released from the NPs were studied by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism, and fluorescence spectrophotometry; the structural stability of BSA was preserved during its encapsulation in the NPs and release from the NPs. PLGA/BSA NPs and PLGA-D/BSA NPs did not induce serious cytotoxicity in RAW 264.7 cells (mouse macrophage cell line) in an established concentration range. In RAW 264.7 cells, the intracellular accumulation of PLGA-D NPs was 2-fold higher than that of PLGA NPs. All of these findings indicated that PLGA-D NPs are a promising system for delivering proteins to macrophages.

  9. Effect of polymer porosity on aqueous self-healing encapsulation of proteins in PLGA microspheres.

    PubMed

    Reinhold, Samuel E; Schwendeman, Steven P

    2013-12-01

    Self-healing (SH) poly(lactic-co-glycolic acid) (PLGA) microspheres are a unique class of functional biomaterials capable of microencapsulating process-sensitive proteins by simple mixing and heating the drug-free polymer in aqueous protein solution. Drug-free SH microspheres of PLGA 50/50 with percolating pore networks of varying porosity (ϵ = 0.49-73) encapsulate increasing lysozyme (≈1 to 10% w/w) with increasing ϵ, with typically ≈20 to 25% pores estimated accessible to entry by the enzyme from the external solution. Release kinetics of lysozyme under physiological conditions is continuous over more than two weeks and most strongly influenced by ϵ and protein loading before reaching a lag phase until 28 d at the study completion. Recovered enzyme after release is typically predominantly monomeric and active. Formulations containing acid-neutralizing MgCO3 at ≥ 4.3% exhibit >97% monomeric and active protein after the release with full mass balance recovery. Hence, control of SH polymer ϵ is a key parameter to development of this new class of biomaterials.

  10. Injectable and porous PLGA microspheres that form highly porous scaffolds at body temperature.

    PubMed

    Qutachi, Omar; Vetsch, Jolanda R; Gill, Daniel; Cox, Helen; Scurr, David J; Hofmann, Sandra; Müller, Ralph; Quirk, Robin A; Shakesheff, Kevin M; Rahman, Cheryl V

    2014-12-01

    Injectable scaffolds are of interest in the field of regenerative medicine because of their minimally invasive mode of delivery. For tissue repair applications, it is essential that such scaffolds have the mechanical properties, porosity and pore diameter to support the formation of new tissue. In the current study, porous poly(dl-lactic acid-co-glycolic acid) (PLGA) microspheres were fabricated with an average size of 84±24μm for use as injectable cell carriers. Treatment with ethanolic sodium hydroxide for 2min was observed to increase surface porosity without causing the microsphere structure to disintegrate. This surface treatment also enabled the microspheres to fuse together at 37°C to form scaffold structures. The average compressive strength of the scaffolds after 24h at 37°C was 0.9±0.1MPa, and the average Young's modulus was 9.4±1.2MPa. Scaffold porosity levels were 81.6% on average, with a mean pore diameter of 54±38μm. This study demonstrates a method for fabricating porous PLGA microspheres that form solid porous scaffolds at body temperature, creating an injectable system capable of supporting NIH-3T3 cell attachment and proliferation in vitro.

  11. Microencapsulation of curcumin in PLGA microcapsules by coaxial flow focusing

    NASA Astrophysics Data System (ADS)

    Lei, Fan; Si, Ting; Luo, Xisheng; Xu, Ronald X.

    2014-03-01

    Curcumin-loaded PLGA microcapsules are fabricated by a liquid-driving coaxial flow focusing device. In the process, a stable coaxial cone-jet configuration is formed under the action of a coflowing liquid stream and the coaxial liquid jet eventually breaks up into microcapsules because of flow instability. This process can be well controlled by adjusting the flow rates of three phases including the driving PVA water solution, the outer PLGA ethyl acetate solution and the inner curcumin propylene glycol solution. Confocal and SEM imaging methods clearly indicate the core-shell structure of the resultant microcapsules. The encapsulation rate of curcumin in PLGA is measured to be more than 70%, which is much higher than the tranditional methods such as emulsion. The size distribution of resultant microcapsules under different conditions is presented and compared. An in vitro release simulation platform is further developed to verify the feasibility and reliability of the method.

  12. Evaluation of 3D printed PCL/PLGA/β-TCP versus collagen membranes for guided bone regeneration in a beagle implant model.

    PubMed

    Won, J-Y; Park, C-Y; Bae, J-H; Ahn, G; Kim, C; Lim, D-H; Cho, D-W; Yun, W-S; Shim, J-H; Huh, J-B

    2016-10-07

    Here, we compared 3D-printed polycaprolactone/poly(lactic-co-glycolic acid)/β-tricalcium phosphate (PCL/PLGA/β-TCP) membranes with the widely used collagen membranes for guided bone regeneration (GBR) in beagle implant models. For mechanical property comparison in dry and wet conditions and cytocompatibility determination, we analyzed the rate and pattern of cell proliferation of seeded fibroblasts and preosteoblasts using the cell counting kit-8 assay and scanning electron microscopy. Osteogenic differentiation was verified using alizarin red S staining. At 8 weeks following implantation in vivo using beagle dogs, computed tomography and histological analyses were performed after sacrifice. Cell proliferation rates in vitro indicated that early cell attachment was higher in collagen than in PCL/PLGA/β-TCP membranes; however, the difference subsided by day 7. Similar outcomes were found for osteogenic differentiation, with approximately 2.5 times greater staining in collagen than PCL/PLGA/β-TCP, but without significant difference by day 14. In vivo, bone regeneration in the defect area, represented by new bone formation and bone-to-implant contact, paralleled those associated with collagen membranes. However, tensile testing revealed that whereas the PCL/PLGA/β-TCP membrane mechanical properties were conserved in both wet and dry states, the tensile property of collagen was reduced by 99% under wet conditions. Our results demonstrate in vitro and in vivo that PCL/PLGA/β-TCP membranes have similar levels of biocompatibility and bone regeneration as collagen membranes. In particular, considering that GBR is always applied to a wet environment (e.g. blood, saliva), we demonstrated that PCL/PLGA/β-TCP membranes maintained their form more reliably than collagen membranes in a wet setting, confirming their appropriateness as a GBR membrane.

  13. Entrapment of H1N1 Influenza Virus Derived Conserved Peptides in PLGA Nanoparticles Enhances T Cell Response and Vaccine Efficacy in Pigs

    PubMed Central

    Hiremath, Jagadish; Kang, Kyung-il; Xia, Ming; Elaish, Mohamed; Binjawadagi, Basavaraj; Ouyang, Kang; Dhakal, Santosh; Arcos, Jesus; Torrelles, Jordi B.; Jiang, X.; Lee, Chang Won; Renukaradhya, Gourapura J.

    2016-01-01

    Pigs are believed to be one of the important sources of emerging human and swine influenza viruses (SwIV). Influenza virus conserved peptides have the potential to elicit cross-protective immune response, but without the help of potent adjuvant and delivery system they are poorly immunogenic. Biodegradable polylactic-co-glycolic acid (PLGA) nanoparticle (PLGA-NP) based vaccine delivery system enhances cross-presentation of antigens by the professional antigen presenting cells. In this study, Norovirus P particle containing SwIV M2e (extracellular domain of the matrix protein 2) chimera and highly conserved two each of H1N1 peptides of pandemic 2009 and classical human influenza viruses were entrapped in PLGA-NPs. Influenza antibody-free pigs were vaccinated with PLGA-NPs peptides cocktail vaccine twice with or without an adjuvant, Mycobacterium vaccae whole cell lysate, intranasally as mist. Vaccinated pigs were challenged with a virulent heterologous zoonotic SwIV H1N1, and one week later euthanized and the lung samples were analyzed for the specific immune response and viral load. Clinically, pigs vaccinated with PLGA-NP peptides vaccine had no fever and flu symptoms, and the replicating challenged SwIV was undetectable in the bronchoalveolar lavage fluid. Immunologically, PLGA-NP peptides vaccination (without adjuvant) significantly increased the frequency of antigen-specific IFNγ secreting CD4 and CD8 T cells response in the lung lymphocytes, despite not boosting the antibody response both at pre- and post-challenge. In summary, our data indicated that nanoparticle-mediated delivery of conserved H1N1 influenza peptides induced the virus specific T cell response in the lungs and reduced the challenged heterologous virus load in the airways of pigs. PMID:27093541

  14. Dry powders based on PLGA nanoparticles for pulmonary delivery of antibiotics: modulation of encapsulation efficiency, release rate and lung deposition pattern by hydrophilic polymers.

    PubMed

    Ungaro, Francesca; d'Angelo, Ivana; Coletta, Ciro; d'Emmanuele di Villa Bianca, Roberta; Sorrentino, Raffaella; Perfetto, Brunella; Tufano, Maria Antonietta; Miro, Agnese; La Rotonda, Maria Immacolata; Quaglia, Fabiana

    2012-01-10

    Although few experimental studies have been handled so far to exploit the potential of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) in the production of dry powders for antibiotic inhalation, there has been no comprehensive study on the role played by NP composition. In this work, we try to shed light on this aspect by designing and developing a pulmonary delivery system for antibiotics, such as tobramycin (Tb), based on PLGA NPs embedded in an inert microcarrier made of lactose, referred to as nano-embedded micro-particles (NEM). At nanosize level, helper hydrophilic polymers were used to impart the desired surface, bulk and release properties to PLGA NPs prepared by a modified emulsion-solvent diffusion technique. Results showed that poly(vinyl alcohol) (PVA) and chitosan (CS) are essential to optimise the size and modulate the surface properties of Tb-loaded PLGA NPs, whereas the use of alginate (Alg) allows efficient Tb entrapment within NPs and its release up to one month. Optimized formulations display good in vitro antimicrobial activity against P. aeruginosa planktonic cells. Furthermore, spray-drying of the NPs with lactose yielded NEM with peculiar but promising flow and aerosolization properties, while preserving the peculiar NP features. Nonetheless, in vivo biodistribution studies showed that PVA-modified Alg/PLGA NPs reached the deep lung, while CS-modified NPs were found in great amounts in the upper airways, lining lung epithelial surfaces. In conclusion, PLGA NP composition appears to play a crucial role in determining not only the technological features of NPs but, once processed in the form of NEM, also their in vitro/in vivo deposition pattern.

  15. Entrapment of H1N1 Influenza Virus Derived Conserved Peptides in PLGA Nanoparticles Enhances T Cell Response and Vaccine Efficacy in Pigs.

    PubMed

    Hiremath, Jagadish; Kang, Kyung-il; Xia, Ming; Elaish, Mohamed; Binjawadagi, Basavaraj; Ouyang, Kang; Dhakal, Santosh; Arcos, Jesus; Torrelles, Jordi B; Jiang, X; Lee, Chang Won; Renukaradhya, Gourapura J

    2016-01-01

    Pigs are believed to be one of the important sources of emerging human and swine influenza viruses (SwIV). Influenza virus conserved peptides have the potential to elicit cross-protective immune response, but without the help of potent adjuvant and delivery system they are poorly immunogenic. Biodegradable polylactic-co-glycolic acid (PLGA) nanoparticle (PLGA-NP) based vaccine delivery system enhances cross-presentation of antigens by the professional antigen presenting cells. In this study, Norovirus P particle containing SwIV M2e (extracellular domain of the matrix protein 2) chimera and highly conserved two each of H1N1 peptides of pandemic 2009 and classical human influenza viruses were entrapped in PLGA-NPs. Influenza antibody-free pigs were vaccinated with PLGA-NPs peptides cocktail vaccine twice with or without an adjuvant, Mycobacterium vaccae whole cell lysate, intranasally as mist. Vaccinated pigs were challenged with a virulent heterologous zoonotic SwIV H1N1, and one week later euthanized and the lung samples were analyzed for the specific immune response and viral load. Clinically, pigs vaccinated with PLGA-NP peptides vaccine had no fever and flu symptoms, and the replicating challenged SwIV was undetectable in the bronchoalveolar lavage fluid. Immunologically, PLGA-NP peptides vaccination (without adjuvant) significantly increased the frequency of antigen-specific IFNγ secreting CD4 and CD8 T cells response in the lung lymphocytes, despite not boosting the antibody response both at pre- and post-challenge. In summary, our data indicated that nanoparticle-mediated delivery of conserved H1N1 influenza peptides induced the virus specific T cell response in the lungs and reduced the challenged heterologous virus load in the airways of pigs.

  16. Layering PLGA-based electrospun membranes and cell sheets for engineering cartilage-bone transition.

    PubMed

    Mouthuy, P-A; El-Sherbini, Y; Cui, Z; Ye, H

    2016-04-01

    It is now widely acknowledged that implants that have been designed with an effort towards reconstructing the transition between tissues might improve their functionality and integration in vivo. This paper contributes to the development of improved treatment for articular cartilage repair by exploring the potential of the combination of electrospinning technology and cell sheet engineering to create cartilage tissue. Poly(lactic-co-glycolic acid) (PLGA) was used to create the electrospun membranes. The focus being on the cartilage-bone transition, collagen type I and hydroxyapatite (HA) were also added to the scaffolds to increase the histological biocompatibility. Human mesenchymal stem cells (hMSCs) were cultured in thermoresponsive dishes to allow non-enzymatic removal of an intact cell layer after reaching confluence. The tissue constructs were created by layering electrospun membranes with sheets of hMSCs and were cultured under chondrogenic conditions for up to 21 days. High viability was found to be maintained in the multilayered construct. Under chondrogenic conditions, reverse-transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry have shown high expression levels of collagen type X, a form of collagen typically found in the calcified zone of articular cartilage, suggesting an induction of chondrocyte hypertrophy in the PLGA-based scaffolds. To conclude, this paper suggests that layering electrospun scaffolds and cell sheets is an efficient approach for the engineering of tissue transitions, and in particular the cartilage-bone transition. The use of PLGA-based scaffold might be particularly useful for the bone-cartilage reconstruction, since the differentiated tissue constructs seem to show characteristics of calcified cartilage.

  17. Preparation and in vitro evaluation of thienorphine-loaded PLGA nanoparticles.

    PubMed

    Yang, Yang; Xie, Xiang Yang; Mei, Xing Guo

    2016-01-01

    Poly (d,l-lactic-co-glycolide) nanoparticles (PLGA-NPs) have attracted considerable interest as new delivery vehicles for small molecules, with the potential to overcome issue such as poor drug solubility and cell permeability. However, their negative surface charge decreases bioavailability under oral administration. Recently, cationically modified PLGA-NPs has been introduced as novel carriers for oral delivery. In this study, our aim was to introduce and evaluate the physiochemical characteristics and bioadhesion of positively charged chitosan-coated PLGA-NPs (CS-PLGA-NPs), using thienorphine as a model drug. These results indicated that both CS-PLGA-NPs and PLGA-NPs had a narrow size distribution, averaging less than 130 nm. CS-PLGA-NPs was positively charged (+42.1 ± 0.4 mV), exhibiting the cationic nature of chitosan, whereas PLGA-NPs showed a negative surface charge (-2.01 ± 0.3 mV). CS-PLGA-NPs exhibited stronger bioadhesive potency than PLGA-NPs. Furthermore, the transport of thienorphine-CS-PLGA-NPs by Caco-2 cells was higher than thienorphine-PLGA-NPs or thienorphine solution. CS-PLGA-NPs were also found to significantly enhance cellular uptake compared with PLGA-NPs on Caco-2 cells. An evaluation of cytotoxicity showed no increase in toxicity in either kind of nanoparticles during the formulation process. The study proves that CS-PLGA-NPs can be used as a vector in oral drug delivery systems for thienorphine due to its positive surface charge and bioadhesive properties.

  18. Degradation behavior of hydroxyapatite/poly(lactic-co-glycolic) acid nanocomposite in simulated body fluid

    SciTech Connect

    Liuyun, Jiang; Chengdong, Xiong; Lixin, Jiang; Lijuan, Xu

    2013-10-15

    Graphical abstract: In this manuscript, we initiated a systematic study to investigate the effect of HA on thermal properties, inner structure, reduction of mechanical strength, surface morphology and the surface deposit of n-HA/PLGA composite with respect to the soaking time. The results showed that n-HA played an important role in improving the degradation behavior of n-HA/PLGA composite, which can accelerate the degradation of n-HA/PLGA composite and endow it with bioactivity, after n-HA was detached from PLGA during the degradation, so that n-HA/PLGA composite may have a more promising prospect of the clinical application than pure PLGA as bone fracture internal fixation materials, and the results would be of reference significance to predict the in vivo degradation and biological properties. - Highlights: • Effect of n-HA on degradation behavior of n-HA/PLGA composite was investigated. • Degradation behaviors of n-HA/PLGA and PLGA were carried out in SBF for 6 months. • Viscosity, thermal properties, inner structure and bending strength were tested. • n-HA can accelerate the degradation and endows it with bioactivity. - Abstract: To investigate the effect of hydroxyapatite(HA) on the degradation behavior of hydroxyapatite/poly(lactic-co-glycolic) acid (HA/PLGA) nanocomposite, the degradation experiment of n-HA/PLGA composite and pure PLGA were carried out by soaking in simulated body fluid(SBF) at 37 °C for 1, 2, 4 and 6 months. The change of intrinsic viscosity, thermal properties, inner structure, bending strength reduction, surface morphology and the surface deposit of n-HA/PLGA composite and pure PLGA with respect to the soaking time were investigated by means of UbbeloHde Viscometer, differential scanning calorimeter (DSC), scanning electron microscope(SEM), electromechanical universal tester, a conventional camera and X-ray diffraction (XRD). The results showed that n-HA played an important role in improving the degradation behavior of n-HA/PLGA

  19. Development of poly(lactic-co-glycolic) acid nanoparticles-embedded hyaluronic acid-ceramide-based nanostructure for tumor-targeted drug delivery.

    PubMed

    Park, Ju-Hwan; Lee, Jae-Young; Termsarasab, Ubonvan; Yoon, In-Soo; Ko, Seung-Hak; Shim, Jae-Seong; Cho, Hyun-Jong; Kim, Dae-Duk

    2014-10-01

    A hyaluronic acid-ceramide (HACE) nanostructure embedded with docetaxel (DCT)-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) was fabricated for tumor-targeted drug delivery. NPs with a narrow size distribution and negative zeta potential were prepared by embedding DCT-loaded PLGA NPs into a HACE nanostructure (DCT/PLGA/HACE). DCT-loaded PLGA and DCT/PLGA/HACE NPs were characterized by solid-state techniques, including Fourier-transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). A sustained drug release pattern from the NPs developed was observed and negligible cytotoxicity was seen in NIH3T3 cells (normal fibroblast, CD44 receptor negative) and MDA-MB-231 cells (breast cancer cells, CD44 receptor positive). PLGA/HACE NPs containing coumarin 6, used as a fluorescent dye, exhibited improved cellular uptake efficiency, based on the HA-CD44 receptor interaction, compared to plain PLGA NPs. Cyanine 5.5 (Cy5.5)-labeled PLGA/HACE NPs were injected intravenously into a MDA-MB-231 tumor xenograft mouse model and demonstrated enhanced tumor targetability, compared with Cy5.5-PLGA NPs, according to a near-infrared fluorescence (NIRF) imaging study. Considering these experimental results, the DCT/PLGA/HACE NPs developed may be useful as a tumor-targeted drug delivery system.

  20. Ultrasound contrast microbubbles in imaging and therapy: physical principles and engineering

    PubMed Central

    Qin, Shengping; Caskey, Charles F; Ferrara, Katherine W

    2010-01-01

    Microbubble contrast agents and the associated imaging systems have developed over the past twenty-five years, originating with manually-agitated fluids introduced for intra-coronary injection. Over this period, stabilizing shells and low diffusivity gas materials have been incorporated in microbubbles, extending stability in vitro and in vivo. Simultaneously, the interaction of these small gas bubbles with ultrasonic waves has been extensively studied, resulting in models for oscillation and increasingly sophisticated imaging strategies. Early studies recognized that echoes from microbubbles contained frequencies that are multiples of the microbubble resonance frequency. Although individual microbubble contrast agents cannot be resolved—given that their diameter is on the order of microns—nonlinear echoes from these agents are used to map regions of perfused tissue and to estimate the local microvascular flow rate. Such strategies overcome a fundamental limitation of previous ultrasound blood flow strategies; the previous Doppler-based strategies are insensitive to capillary flow. Further, the insonation of resonant bubbles results in interesting physical phenomena that have been widely studied for use in drug and gene delivery. Ultrasound pressure can enhance gas diffusion, rapidly fragment the agent into a set of smaller bubbles or displace the microbubble to a blood vessel wall. Insonation of a microbubble can also produce liquid jets and local shear stress that alter biological membranes and facilitate transport. In this review, we focus on the physical aspects of these agents, exploring microbubble imaging modes, models for microbubble oscillation and the interaction of the microbubble with the endothelium. PMID:19229096

  1. TOPICAL REVIEW: Ultrasound contrast microbubbles in imaging and therapy: physical principles and engineering

    NASA Astrophysics Data System (ADS)

    Qin, Shengping; Caskey, Charles F.; Ferrara, Katherine W.

    2009-03-01

    Microbubble contrast agents and the associated imaging systems have developed over the past 25 years, originating with manually-agitated fluids introduced for intra-coronary injection. Over this period, stabilizing shells and low diffusivity gas materials have been incorporated in microbubbles, extending stability in vitro and in vivo. Simultaneously, the interaction of these small gas bubbles with ultrasonic waves has been extensively studied, resulting in models for oscillation and increasingly sophisticated imaging strategies. Early studies recognized that echoes from microbubbles contained frequencies that are multiples of the microbubble resonance frequency. Although individual microbubble contrast agents cannot be resolved—given that their diameter is on the order of microns—nonlinear echoes from these agents are used to map regions of perfused tissue and to estimate the local microvascular flow rate. Such strategies overcome a fundamental limitation of previous ultrasound blood flow strategies; the previous Doppler-based strategies are insensitive to capillary flow. Further, the insonation of resonant bubbles results in interesting physical phenomena that have been widely studied for use in drug and gene delivery. Ultrasound pressure can enhance gas diffusion, rapidly fragment the agent into a set of smaller bubbles or displace the microbubble to a blood vessel wall. Insonation of a microbubble can also produce liquid jets and local shear stress that alter biological membranes and facilitate transport. In this review, we focus on the physical aspects of these agents, exploring microbubble imaging modes, models for microbubble oscillation and the interaction of the microbubble with the endothelium.

  2. Ultrasound contrast microbubbles in imaging and therapy: physical principles and engineering.

    PubMed

    Qin, Shengping; Caskey, Charles F; Ferrara, Katherine W

    2009-03-21

    Microbubble contrast agents and the associated imaging systems have developed over the past 25 years, originating with manually-agitated fluids introduced for intra-coronary injection. Over this period, stabilizing shells and low diffusivity gas materials have been incorporated in microbubbles, extending stability in vitro and in vivo. Simultaneously, the interaction of these small gas bubbles with ultrasonic waves has been extensively studied, resulting in models for oscillation and increasingly sophisticated imaging strategies. Early studies recognized that echoes from microbubbles contained frequencies that are multiples of the microbubble resonance frequency. Although individual microbubble contrast agents cannot be resolved-given that their diameter is on the order of microns-nonlinear echoes from these agents are used to map regions of perfused tissue and to estimate the local microvascular flow rate. Such strategies overcome a fundamental limitation of previous ultrasound blood flow strategies; the previous Doppler-based strategies are insensitive to capillary flow. Further, the insonation of resonant bubbles results in interesting physical phenomena that have been widely studied for use in drug and gene delivery. Ultrasound pressure can enhance gas diffusion, rapidly fragment the agent into a set of smaller bubbles or displace the microbubble to a blood vessel wall. Insonation of a microbubble can also produce liquid jets and local shear stress that alter biological membranes and facilitate transport. In this review, we focus on the physical aspects of these agents, exploring microbubble imaging modes, models for microbubble oscillation and the interaction of the microbubble with the endothelium.

  3. Oral Delivery of DMAB-Modified Docetaxel-Loaded PLGA-TPGS Nanoparticles for Cancer Chemotherapy

    NASA Astrophysics Data System (ADS)

    Chen, Hongbo; Zheng, Yi; Tian, Ge; Tian, Yan; Zeng, Xiaowei; Liu, Gan; Liu, Kexin; Li, Lei; Li, Zhen; Mei, Lin; Huang, Laiqiang

    2011-12-01

    Three types of nanoparticle formulation from biodegradable PLGA-TPGS random copolymer were developed in this research for oral administration of anticancer drugs, which include DMAB-modified PLGA nanoparticles, unmodified PLGA-TPGS nanoparticles and DMAB-modified PLGA-TPGS nanoparticles. Firstly, the PLGA-TPGS random copolymer was synthesized and characterized. DMAB was used to increase retention time at the cell surface, thus increasing the chances of particle uptake and improving oral drug bioavailability. Nanoparticles were found to be of spherical shape with an average particle diameter of around 250 nm. The surface charge of PLGA-TPGS nanoparticles was changed to positive after DMAB modification. The results also showed that the DMAB-modified PLGA-TPGS nanoparticles have significantly higher level of the cellular uptake than that of DMAB-modified PLGA nanoparticles and unmodified PLGA-TPGS nanoparticles. In vitro, cytotoxicity experiment showed advantages of the DMAB-modified PLGA-TPGS nanoparticle formulation over commercial Taxotere® in terms of cytotoxicity against MCF-7 cells. In conclusion, oral chemotherapy by DMAB-modified PLGA-TPGS nanoparticle formulation is an attractive and promising treatment option for patients.

  4. The preosteoblast response of electrospinning PLGA/PCL nanofibers: effects of biomimetic architecture and collagen I

    PubMed Central

    Qian, Yunzhu; Chen, Hanbang; Xu, Yang; Yang, Jianxin; Zhou, Xuefeng; Zhang, Feimin; Gu, Ning

    2016-01-01

    Constructing biomimetic structure and incorporating bioactive molecules is an effective strategy to achieve a more favorable cell response. To explore the effect of electrospinning (ES) nanofibrous architecture and collagen I (COL I)-incorporated modification on tuning osteoblast response, a resorbable membrane composed of poly(lactic-co-glycolic acid)/poly(caprolactone) (PLGA/PCL; 7:3 w/w) was developed via ES. COL I was blended into PLGA/PCL solution to prepare composite ES membrane. Notably, relatively better cell response was delivered by the bioactive ES-based membrane which was fabricated by modification of 3,4-dihydroxyphenylalanine and COL I. After investigation by field emission scanning electron microscopy, Fourier transform infrared spectroscopy, contact angle measurement, and mechanical test, polyporous three-dimensional nanofibrous structure with low tensile force and the successful integration of COL I was obtained by the ES method. Compared with traditional PLGA/PCL membrane, the surface hydrophilicity of collagen-incorporated membranes was largely enhanced. The behavior of mouse preosteoblast MC3T3-E1 cell infiltration and proliferation on membranes was studied at 24 and 48 hours. The negative control was fabricated by solvent casting. Evaluation of cell adhesion and morphology demonstrated that all the ES membranes were more favorable for promoting the cell adhesion and spreading than the casting membrane. Cell Counting Kit-8 assays revealed that biomimetic architecture, surface topography, and bioactive properties of membranes were favorable for cell growth. Analysis of β1 integrin expression level by immunofluorescence indicated that such biomimetic architecture, especially COL I-grafted surface, plays a key role in cell adhesion and proliferation. The real-time polymerase chain reaction suggested that both surface topography and bioactive properties could facilitate the cell adhesion. The combined effect of biomimetic architecture with enhanced

  5. The preosteoblast response of electrospinning PLGA/PCL nanofibers: effects of biomimetic architecture and collagen I.

    PubMed

    Qian, Yunzhu; Chen, Hanbang; Xu, Yang; Yang, Jianxin; Zhou, Xuefeng; Zhang, Feimin; Gu, Ning

    Constructing biomimetic structure and incorporating bioactive molecules is an effective strategy to achieve a more favorable cell response. To explore the effect of electrospinning (ES) nanofibrous architecture and collagen I (COL I)-incorporated modification on tuning osteoblast response, a resorbable membrane composed of poly(lactic-co-glycolic acid)/poly(caprolactone) (PLGA/PCL; 7:3 w/w) was developed via ES. COL I was blended into PLGA/PCL solution to prepare composite ES membrane. Notably, relatively better cell response was delivered by the bioactive ES-based membrane which was fabricated by modification of 3,4-dihydroxyphenylalanine and COL I. After investigation by field emission scanning electron microscopy, Fourier transform infrared spectroscopy, contact angle measurement, and mechanical test, polyporous three-dimensional nanofibrous structure with low tensile force and the successful integration of COL I was obtained by the ES method. Compared with traditional PLGA/PCL membrane, the surface hydrophilicity of collagen-incorporated membranes was largely enhanced. The behavior of mouse preosteoblast MC3T3-E1 cell infiltration and proliferation on membranes was studied at 24 and 48 hours. The negative control was fabricated by solvent casting. Evaluation of cell adhesion and morphology demonstrated that all the ES membranes were more favorable for promoting the cell adhesion and spreading than the casting membrane. Cell Counting Kit-8 assays revealed that biomimetic architecture, surface topography, and bioactive properties of membranes were favorable for cell growth. Analysis of β1 integrin expression level by immunofluorescence indicated that such biomimetic architecture, especially COL I-grafted surface, plays a key role in cell adhesion and proliferation. The real-time polymerase chain reaction suggested that both surface topography and bioactive properties could facilitate the cell adhesion. The combined effect of biomimetic architecture with enhanced

  6. RENAL RETENTION OF LIPID MICROBUBBLES: A POTENTIAL MECHANISM FOR FLANK DISCOMFORT DURING ULTRASOUND CONTRAST ADMINISTRATION

    PubMed Central

    Liu, Ya Ni; Khangura, Jaspreet; Xie, Aris; Belcik, J. Todd; Qi, Yue; Davidson, Brian P.; Zhao, Yan; Kim, Sajeevani; Inaba, Yoichi; Lindner, Jonathan R.

    2013-01-01

    Background The etiology for flank pain sometimes experienced during administration of ultrasound contrast agents is unknown. We investigated whether microbubble ultrasound contrast agents are retained within the renal microcirculation which could lead to either flow disturbance or local release of vasoactive and pain mediators downstream from complement activation. Methods Retention of lipid-shelled microbubbles in the renal microcirculation of mice was assessed by confocal fluorescent microscopy and contrast-enhanced ultrasound (CEU) imaging with dose-escalating intravenous injection. Studies were performed with size-segregated microbubbles to investigate physical entrapment, after glycocalyx degradation, and in wild-type and C3-deficient mice to investigate complement-mediated retention. Urinary bradykinin was measured before and after microbubbles. Renal CEU in human subjects (n=13) was performed 7–10 min after completion of lipid microbubble administration. Results In both mice and humans, microbubble retention was detected in the renal cortex by persistent CEU signal enhancement. Microbubble retention in mice was linearly related to dose and occurred almost exclusively in cortical glomerular microvessels. Microbubble retention did not affect microsphere-derived renal blood flow. Microbubble retention was not influenced by glycocalyx degradation nor by microbubble size, thereby excluding lodging, but was reduced by 90% (p<0.01) in C3-deficient mice. Urinary bradykinin increased by 65% five minutes after microbubble injection. Conclusion Lipid-shelled microbubbles are retained in the renal cortex due to complement-mediated interactions with glomerular microvascular endothelium. Microbubble retention does not adversely affect renal perfusion but does generate complement-related intermediates that are known to mediate nociception and could be responsible for flank pain. PMID:24035699

  7. Microbubble Swarms in a Full-Scale Water Model Tundish

    NASA Astrophysics Data System (ADS)

    Chang, Sheng; Cao, Xiangkun; Zou, Zongshu; Isac, Mihaiela; Guthrie, Roderick I. L.

    2016-10-01

    Water modeling, using microbubble swarms, was performed in a full-scale, four-strand, delta-shaped tundish, located at the McGill Metals Processing Centre (MMPC). The objective of the study was to investigate the effectiveness of microbubbles in removing inclusions smaller than 50 μm, applying the principles and conditions previously researched using a smaller scale arrangement. Air was injected into a full-scale model of a ladle shroud (the connecting tube through which liquid steel flows into the tundish below). The model ladle shroud was fitted with twelve, laser-drilled orifices, so as to create microbubbles. The bubbles generated using different gas injection protocols were recorded using a high-speed camera, and the bubble images were postprocessed using the commercial software, ImageJ. With this newly designed ladle shroud, bubble sizes could be reduced dramatically, to as small as a 675 µm average diameter. A three-dimensional, CFD model simulation was developed, using parameters obtained from the corresponding water model experiments, in order to predict the behavior of these microbubbles within the tundish and their potential influence on flow patterns and inclusion float-out capability.

  8. Reparable Cell Sonoporation in Suspension: Theranostic Potential of Microbubble

    PubMed Central

    Nejad, S. Moosavi; Hosseini, Hamid; Akiyama, Hidenori; Tachibana, Katsuro

    2016-01-01

    The conjunction of low intensity ultrasound and encapsulated microbubbles can alter the permeability of cell membrane, offering a promising theranostic technique for non-invasive gene/drug delivery. Despite its great potential, the biophysical mechanisms of the delivery at the cellular level remains poorly understood. Here, the first direct high-speed micro-photographic images of human lymphoma cell and microbubble interaction dynamics are provided in a completely free suspension environment without any boundary parameter defect. Our real-time images and theoretical analyses prove that the negative divergence side of the microbubble's dipole microstreaming locally pulls the cell membrane, causing transient local protrusion of 2.5 µm in the cell membrane. The linear oscillation of microbubble caused microstreaming well below the inertial cavitation threshold, and imposed 35.3 Pa shear stress on the membrane, promoting an area strain of 0.12%, less than the membrane critical areal strain to cause cell rupture. Positive transfected cells with pEGFP-N1 confirm that the interaction causes membrane poration without cell disruption. The results show that the overstretched cell membrane causes reparable submicron pore formation, providing primary evidence of low amplitude (0.12 MPa at 0.834 MHz) ultrasound sonoporation mechanism. PMID:26941839

  9. On the Near Surface Population of Oceanic Microbubbles

    DTIC Science & Technology

    1989-06-01

    and J = 5. The slope of Monahan’s curves indic acs an r-4-3 dependance , approximately. During a number of the experimental runs of Walsh and...O’Muircheartaigh, I.G. Coverage Dependance on Wind-Speed". J. Phys. Oceanogr., 10, pp.2094-2099, 1980 8 Tate, P.M. "The Distribution of Ocean Microbubbles

  10. Laboratory comparisons of acoustic and optical sensors for microbubble measurement

    NASA Technical Reports Server (NTRS)

    Su, Ming Yang; Todoroff, Douglas; Cartmill, John

    1994-01-01

    This paper presents the results of a recent comparison between three microbubble size spectrum measurement systems. These systems are the light-scattering bubble counter, the photographic bubble-imaging system, and the acoustic resonator array. Good agreement was formed among these three systems over the bubble size range appropriate for each system.

  11. Cytotoxicity and intracellular fate of PLGA and chitosan-coated PLGA nanoparticles in Madin-Darby bovine kidney (MDBK) and human colorectal adenocarcinoma (Colo 205) cells.

    PubMed

    Trif, Mihaela; Florian, Paula E; Roseanu, Anca; Moisei, Magdalena; Craciunescu, Oana; Astete, Carlos E; Sabliov, Cristina M

    2015-11-01

    Polymeric nanoparticles (NPs) are known to facilitate intracellular uptake of drugs to improve their efficacy, with minimum bioreactivity. The goal of this study was to assess cellular uptake and trafficking of PLGA NPs and chitosan (Chi)-covered PLGA NPs in Madin-Darby bovine kidney (MDBK) and human colorectal adenocarcinoma (Colo 205) cells. Both PLGA and Chi-PLGA NPs were not cytotoxic to the studied cells at concentrations up to 2500 μg/mL. The positive charge conferred by the chitosan deposition on the PLGA NPs improved NPs uptake by MDBK cells. In this cell line, Chi-PLGA NPs colocalized partially with early endosomes compartment and showed a more consistent perinuclear localization than PLGA NPs. Kinetic uptake of PLGA NPs by Colo 205 was slower than that by MDBK cells, detected only at 24 h, exceeding that of Chi-PLGA NPs. This study offers new insights on NP interaction with target cells supporting the use of NPs as novel nutraceuticals/drug delivery systems in metabolic disorders or cancer therapy. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 3599-3611, 2015.

  12. Controlled release of drug and better bioavailability using poly(lactic acid-co-glycolic acid) nanoparticles.

    PubMed

    Pandey, Sanjeev K; Patel, Dinesh K; Maurya, Akhilendra K; Thakur, Ravi; Mishra, Durga P; Vinayak, Manjula; Haldar, Chandana; Maiti, Pralay

    2016-08-01

    Tamoxifen (Tmx) embedded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGA-Tmx) is prepared to evaluate its better DNA cleavage potential, cytotoxicity using Dalton's lymphoma ascite (DLA) cells and MDA-MB231 breast cancer cells. PLGA-Tmx nanoparticles are prepared through emulsified nanoprecipitation technique with varying dimension of 17-30nm by changing the concentrations of polymer, emulsifier and drug. Nanoparticles dimension are measured through electron and atomic force microscopy. Interactions between tamoxifen and PLGA are verified through spectroscopic and calorimetric methods. PLGA-Tmx shows excellent DNA cleavage potential as compared to pure Tmx raising better bioavailability. In vitro cytotoxicity studies indicate that PLGA-Tmx reduces DLA cells viability up to ∼38% against ∼15% in pure Tmx. Hoechst stain is used to detect apoptotic DLA cells through fluorescence imaging of nuclear fragmentation and condensation exhibiting significant increase of apoptosis (70%) in PLGA-Tmx vis-à-vis pure drug (58%). Enhanced DNA cleavage potential, nuclear fragmentation and condensation in apoptotic cells confirm greater bioavailability of PLGA-Tmx as compared to pure Tmx in terms of receptor mediated endocytosis. Hence, the sustained release kinetics of PLGA-Tmx nanoparticles shows much better anticancer efficacy through enhanced DNA cleavage potential and nuclear fragmentation and, thereby, reveal a novel vehicle for the treatment of cancer.

  13. Interactions of PLGA nanoparticles with blood components: protein adsorption, coagulation, activation of the complement system and hemolysis studies

    NASA Astrophysics Data System (ADS)

    Fornaguera, Cristina; Calderó, Gabriela; Mitjans, Montserrat; Vinardell, Maria Pilar; Solans, Conxita; Vauthier, Christine

    2015-03-01

    The intravenous administration of poly(lactic-co-glycolic) acid (PLGA) nanoparticles has been widely reported as a promising alternative for delivery of drugs to specific cells. However, studies on their interaction with diverse blood components using different techniques are still lacking. Therefore, in the present work, the interaction of PLGA nanoparticles with blood components was described using different complementary techniques. The influence of different encapsulated compounds/functionalizing agents on these interactions was also reported. It is worth noting that all these techniques can be simply performed, without the need for highly sophisticated apparatus or skills. Moreover, their transference to industries and application of quality control could be easily performed. Serum albumin was adsorbed onto all types of tested nanoparticles. The saturation concentration was dependent on the nanoparticle size. In contrast, fibrinogen aggregation was dependent on nanoparticle surface charge. The complement activation was also influenced by the nanoparticle functionalization; the presence of a functionalizing agent increased complement activation, while the addition of an encapsulated compound only caused a slight increase. None of the nanoparticles influenced the coagulation cascade at low concentrations. However, at high concentrations, cationized nanoparticles did activate the coagulation cascade. Interactions of nanoparticles with erythrocytes did not reveal any hemolysis. Interactions of PLGA nanoparticles with blood proteins depended both on the nanoparticle properties and the protein studied. Independent of their loading/surface functionalization, PLGA nanoparticles did not influence the coagulation cascade and did not induce hemolysis of erythrocytes; they could be defined as safe concerning induction of embolization and cell lysis.The intravenous administration of poly(lactic-co-glycolic) acid (PLGA) nanoparticles has been widely reported as a promising

  14. Porous silicon oxide-PLGA composite microspheres for sustained ocular delivery of daunorubicin.

    PubMed

    Nan, Kaihui; Ma, Feiyan; Hou, Huiyuan; Freeman, William R; Sailor, Michael J; Cheng, Lingyun

    2014-08-01

    A water-soluble anthracycline antibiotic drug (daunorubicin, DNR) was loaded into oxidized porous silicon (pSiO2) microparticles and then encapsulated with a layer of polymer (poly lactide-co-glycolide, PLGA) to investigate their synergistic effects in control of DNR release. Similarly fabricated PLGA-DNR microspheres without pSiO2, and pSiO2 microparticles without PLGA were used as control particles. The composite microparticles synthesized by a solid-in-oil-in-water emulsion method have mean diameters of 52.33±16.37μm for PLGA-pSiO2_21/40-DNR and the mean diameter of 49.31±8.87μm for PLGA-pSiO2_6/20-DNR. The mean size, 26.00±8μm, of PLGA-DNR was significantly smaller, compared with the other two (P<0.0001). Optical microscopy revealed that PLGA-pSiO2-DNR microspheres contained multiple pSiO2 particles. In vitro release experiments determined that control PLGA-DNR microspheres completely released DNR within 38days and control pSiO2-DNR microparticles (with no PLGA coating) released DNR within 14days, while the PLGA-pSiO2-DNR microspheres released DNR for 74days. Temporal release profiles of DNR from PLGA-pSiO2 composite particles indicated that both PLGA and pSiO2 contribute to the sustained release of the payload. The PLGA-pSiO2 composite displayed a more constant rate of DNR release than the pSiO2 control formulation, and displayed a significantly slower release of DNR than either the PLGA or pSiO2 formulations. We conclude that this system may be useful in managing unwanted ocular proliferation when formulated with antiproliferation compounds such as DNR.

  15. Sizing of microbubbles in blood stream based on ultrasound velocity

    NASA Astrophysics Data System (ADS)

    Kanani, Behrooz

    2005-05-01

    Microbubbles, are produced inside the human body by several mechanisms which may cause many serious health problems or even death. The ability of a gas bubble to scatter ultrasound waves has led to the testing of various ultrasonic devices to monitor microbubble formation in the blood stream. These have included pulsed echo, acoustic-optical imaging, Doppler technique and the through-transmission technique. In this work, a pulse through transmission method for measuring ultrasound velocity in bubbly gel phantoms was used. The bubble size has been assessed by measurement of the pulse-wave velocity. A specially designed pressure chamber ensured the measured velocity was directly related to the volume of microbubble by Boyle's law. This velocity is an average indicator of the bubble size between transmitting and receiving transducers. The average bubble radius was 0.1 mm. For best results the measurement were carried out around 1-3 MHz frequency range. It is shown that a large change in velocity of ultrasound occurs as a result of small changes in the volume of microbubble. When the fraction by volume of gas in gel is changed from 0.6 percent to 0.8 percent the velocity changed from 1500 to 500 m/s respectively. This large change in velocity should provide a good base for detecting and more importantly, sizing microbubbles in the blood stream. The measured results were compared with theoretical prediction with good agreement between theory and experiment. This technique can be used as a simple real time method to monitor and measure the volume of the microbubles in the blood stream. This technique has many application in medical field such as; open heart surgery, blood dialysis and deep sea diving (decompression sickness).

  16. A Study of Micro-bubble Enhanced Sonoporation

    NASA Astrophysics Data System (ADS)

    Okamoto, A.; Tachibana, R.; Yoshinaka, K.; Osada, K.; Takagi, S.; Kataoka, K.; Chung, U.; Matsumoto, Y.

    2011-09-01

    Sonoporation is a recently developed system for gene induction that uses ultrasound. Micro-bubbles are known to aid gene transfection through the introduction of genes into cells by the collapse of cavitation-bubbles (or micro-bubbles). However, the underlying mechanism and optimal introduction conditions have not been clarified in detail. In this research, we improved the gene introduction rate by forming DNA/Block copolymer micelles. Micelle formation compacts the DNA and enhances its stability, thereby facilitating the passage of greater amounts of DNA through holes in the cell surface and improving gene expression. Cells were exposed to ultrasonic plane waves from a piezoceramic transducer with a frequency of 2.0 MHz and a duty cycle of 10% (400/3600). Mouse fibroblast cells (NIH3T3) were cultured on the bottom of 24-well plates. Plasmid DNA and Sonazoid® (micro-bubbles) were added to the culture media and the cells were subsequently exposed to ultrasound. In the system described herein, micelles are formed by combining DNA and block copolymer. Block copolymer is composed of polyethyleneglycol-group and poly-lysine. Naked DNA and polymer micelles are added to culture media with micro-bubbles, and then exposed to ultrasound. The experimental conditions were as follows: plasmid density of 15 μg/ml, micro-bubble density of 1.7×105/mm3, ultrasound intensity of 5.08 W/cm2, ultrasound exposure time of 60 seconds, and a sample number of 12. Our results show that the gene induction ratio is doubled by the formation of polymer micelles (from ˜1% to ˜2%), thereby confirming that the system is capable of generating polymer micelles for introducing DNA into cells.

  17. Colonic gene silencing using siRNA-loaded calcium phosphate/PLGA nanoparticles ameliorates intestinal inflammation in vivo.

    PubMed

    Frede, Annika; Neuhaus, Bernhard; Klopfleisch, Robert; Walker, Catherine; Buer, Jan; Müller, Werner; Epple, Matthias; Westendorf, Astrid M

    2016-01-28

    Cytokines and chemokines are predominant players in the progression of inflammatory bowel diseases. While systemic neutralization of these players with antibodies works well in some patients, serious contraindications and side effects have been reported. Therefore, the local interference of cytokine signaling mediated by siRNA-loaded nanoparticles might be a promising new therapeutic approach. In this study, we produced multi-shell nanoparticles consisting of a calcium phosphate (CaP) core coated with siRNA directed against pro-inflammatory mediators, encapsulated into poly(d,l-lactide-co-glycolide acid) (PLGA), and coated with a final outer layer of polyethyleneimine (PEI), for the local therapeutic treatment of colonic inflammation. In cell culture, siRNA-loaded CaP/PLGA nanoparticles exhibited a rapid cellular uptake, almost no toxicity, and an excellent in vitro gene silencing efficiency. Importantly, intrarectal application of these nanoparticles loaded with siRNA directed against TNF-α, KC or IP-10 to mice suffering from dextran sulfate sodium (DSS)-induced colonic inflammation led to a significant decrease of the target genes in colonic biopsies and mesenteric lymph nodes which was accompanied with a distinct amelioration of intestinal inflammation. Thus, this study provides evidence that the specific and local modulation of the inflammatory response by CaP/PLGA nanoparticle-mediated siRNA delivery could be a promising approach for the treatment of intestinal inflammation.

  18. Orlistat and antisense-miRNA-loaded PLGA-PEG nanoparticles for enhanced triple negative breast cancer therapy

    PubMed Central

    Bhargava-Shah, Aarohi; Foygel, Kira; Devulapally, Rammohan; Paulmurugan, Ramasamy

    2016-01-01

    Background: This study explores the use of hydrophilic poly(ethylene glycol)-conjugated poly(lactic-co-glycolic acid) nanoparticles (PLGA-PEG-NPs) as delivery system to improve the antitumor effect of antiobesity drug orlistat for triple-negative breast cancer (TNBC) therapy by improving its bioavailability. Materials & methods: PLGA-PEG-NPs were synthesized by emulsion-diffusion-evaporation method, and the experiments were conducted in vitro in MDA-MB-231 and SKBr3 TNBC and normal breast fibroblast cells. Results: Delivery of orlistat via PLGA-PEG-NPs reduced its IC50 compared with free orlistat. Combined treatment of orlistat-loaded NPs and doxorubicin or antisense-miR-21-loaded NPs significantly enhanced apoptotic effect compared with independent doxorubicin, anti-miR-21-loaded NPs, orlistat-loaded NPs or free orlistat treatments. Conclusion: We demonstrate that orlistat in combination with antisense-miR-21 or current chemotherapy holds great promise as a novel and versatile treatment agent for TNBC. PMID:26787319

  19. Investigation and optimization of formulation parameters on preparation of targeted anti-CD205 tailored PLGA nanoparticles

    PubMed Central

    Jahan, Sheikh Tasnim; Haddadi, Azita

    2015-01-01

    The purpose of this study was to assess the effect of various formulation parameters on anti-CD205 antibody decorated poly(d, l-lactide co-glycolide) (PLGA) nanoparticles (NPs) in terms of their ability to target dendritic cells (DCs). In brief, emulsification solvent evaporation technique was adapted to design NP formulations using two different viscosity grades (low and high) of both ester and carboxylic acid terminated PLGA. Incorporation of ligand was achieved following physical adsorption or chemical conjugation processes. The physicochemical characterizations of formulations were executed to assess the effects of different solvents (chloroform and ethyl acetate), stabilizer percentage, polymer types, polymer viscosities, ligand-NP bonding types, cross-linkers, and cryoprotectants (sucrose and trehalose). Modification of any of these parameters shows significant improvement of physicochemical properties of NPs. Ethyl acetate was the solvent of choice for the formulations to ensure better emulsion formation. Infrared spectroscopy confirmed the presence of anti-CD205 antibody in the NP formulation. Finally, cytotoxicity assay confirmed the safety profile of the NPs for DCs. Thus, ligand modified structurally concealed PLGA NPs is a promising delivery tool for targeting DCs in vivo. PMID:26677326

  20. Immune responses to vaccines delivered by encapsulation into and/or adsorption onto cationic lipid-PLGA hybrid nanoparticles.

    PubMed

    Liu, Lanxia; Ma, Pingchuan; Wang, Hai; Zhang, Chao; Sun, Hongfan; Wang, Chun; Song, Cunxian; Leng, Xigang; Kong, Deling; Ma, Guilei

    2016-03-10

    In this study, we used cationic lipid-poly(lactide-co-glycolide) acid (PLGA) hybrid nanoparticles as antigen delivery carriers to investigate how antigen-loading methods affect antigen exposure to the immune system and evaluated the resulting antigen-specific immune responses. We formulated three classes of antigen adsorbed and/or encapsulated cationic lipid-PLGA hybrid nanoparticles; we designated antigen-adsorbed (out), antigen-encapsulated (in), and antigen-adsorbed/encapsulated (both) nanoparticles. Our results demonstrate significantly more efficient lysosomal escape and cross-presentation of antigen from dendritic cells (DCs) that were exposed to "both" and "in" nanoparticles. In vivo experiments further revealed that "both" nanoparticles significantly more effectively provided not only adequate initial antigen exposure but also long-term antigen persistence at the injection site. Data from flow cytometry and ELISA analyses demonstrated elevated in vivo immune responses from mice that were immunized with nanoparticles-delivered OVA when compared with free OVA. In addition, "in" and "both" nanoparticles elicited significantly higher antigen-specific immune response than "out" nanoparticles and free OVA. These results suggest that the location of antigen entrapment is an important factor in modulating the immune responses of antigens delivered by nanoparticles. Overall, we propose here a promising approach for the future design of vaccines using cationic lipid-PLGA nanoparticles.

  1. Curcumin Conjugated with PLGA Potentiates Sustainability, Anti-Proliferative Activity and Apoptosis in Human Colon Carcinoma Cells

    PubMed Central

    Waghela, Bhargav N.; Sharma, Anupama; Dhumale, Suhashini; Pandey, Shashibahl M.; Pathak, Chandramani

    2015-01-01

    Curcumin, an ingredient of turmeric, exhibits a variety of biological activities such as anti-inflammatory, anti-atherosclerotic, anti-proliferative, anti-oxidant, anti-cancer and anti-metastatic. It is a highly pleiotropic molecule that inhibits cell proliferation and induces apoptosis in cancer cells. Despite its imperative biological activities, chemical instability, photo-instability and poor bioavailability limits its utilization as an effective therapeutic agent. Therefore, enhancing the bioavailability of curcumin may improve its therapeutic index for clinical setting. In the present study, we have conjugated curcumin with a biodegradable polymer Poly (D, L-lactic-co-glycolic acid) and evaluated its apoptotic potential in human colon carcinoma cells (HCT 116). The results show that curcumin-PLGA conjugate efficiently inhibits cell proliferation and cell survival in human colon carcinoma cells as compared to native curcumin. Additionally, curcumin conjugated with PLGA shows improved cellular uptake and exhibits controlled release at physiological pH as compared to native curcumin. The curcumin-PLGA conjugate efficiently activates the cascade of caspases and promotes intrinsic apoptotic signaling. Thus, the results suggest that conjugation potentiates the sustainability, anti-proliferative and apoptotic activity of curcumin. This approach could be a promising strategy to improve the therapeutic index of cancer therapy. PMID:25692854

  2. Aqueous Two Phase System Assisted Self-Assembled PLGA Microparticles

    NASA Astrophysics Data System (ADS)

    Yeredla, Nitish; Kojima, Taisuke; Yang, Yi; Takayama, Shuichi; Kanapathipillai, Mathumai

    2016-06-01

    Here, we produce poly(lactide-co-glycolide) (PLGA) based microparticles with varying morphologies, and temperature responsive properties utilizing a Pluronic F127/dextran aqueous two-phase system (ATPS) assisted self-assembly. The PLGA polymer, when emulsified in Pluronic F127/dextran ATPS, forms unique microparticle structures due to ATPS guided-self assembly. Depending on the PLGA concentration, the particles either formed a core-shell or a composite microparticle structure. The microparticles facilitate the simultaneous incorporation of both hydrophobic and hydrophilic molecules, due to their amphiphilic macromolecule composition. Further, due to the lower critical solution temperature (LCST) properties of Pluronic F127, the particles exhibit temperature responsiveness. The ATPS based microparticle formation demonstrated in this study, serves as a novel platform for PLGA/polymer based tunable micro/nano particle and polymersome development. The unique properties may be useful in applications such as theranostics, synthesis of complex structure particles, bioreaction/mineralization at the two-phase interface, and bioseparations.

  3. Electrically stimulated osteogenesis on Ti-PPy/PLGA constructs prepared by laser-assisted processes.

    PubMed

    Paun, Irina Alexandra; Stokker-Cheregi, Flavian; Luculescu, Catalin Romeo; Acasandrei, Adriana Maria; Ion, Valentin; Zamfirescu, Marian; Mustaciosu, Cosmin Catalin; Mihailescu, Mona; Dinescu, Maria

    2015-10-01

    This work describes a versatile laser-based protocol for fabricating micro-patterned, electrically conductive titanium-polypyrrole/poly(lactic-co-glycolic)acid (Ti-PPy/PLGA) constructs for electrically stimulated (ES) osteogenesis. Ti supports were patterned using fs laser ablation in order to create high spatial resolution microstructures meant to provide mechanical resistance and physical cues for cell growth. Matrix Assisted Pulsed Laser Evaporation (MAPLE) was used to coat the patterned Ti supports with PPy/PLGA layers acting as biocompatible surfaces having chemical and electrical properties suitable for cell differentiation and mineralization. In vitro biological assays on osteoblast-like MG63 cells showed that the constructs maintained cell viability without cytotoxicity. At 24 h after cell seeding, electrical stimulation with currents of 200 μA was applied for 4 h. This treatment was shown to promote earlier onset of osteogenesis. More specifically, the alkaline phosphatase activity of the stimulated cultures reached the maximum before that of the non-stimulated ones, i.e. controls, indicating faster cell differentiation. Moreover, mineralization was found to occur at an earlier stage in the stimulated cultures, as compared to the controls, starting with Day 6 of cell culture. At later stages, calcium levels in the stimulated cultures were higher than those in control samples by about 70%, with Ca/P ratios similar to those of natural bone. In all, the laser-based protocol emerges as an efficient alternative to existing fabrication technologies.

  4. Nerve growth factor released from a novel PLGA nerve conduit can improve axon growth

    NASA Astrophysics Data System (ADS)

    Lin, Keng-Min; Shea, Jill; Gale, Bruce K.; Sant, Himanshu; Larrabee, Patti; Agarwal, Jay

    2016-04-01

    Nerve injury can occur due to penetrating wounds, compression, traumatic stretch, and cold exposure. Despite prompt repair, outcomes are dismal. In an attempt to help resolve this challenge, in this work, a poly-lactic-co-glycolic acid (PLGA) nerve conduit with associated biodegradable drug reservoir was designed, fabricated, and tested. Unlike current nerve conduits, this device is capable of fitting various clinical scenarios by delivering different drugs without reengineering the whole system. To demonstrate the potential of this device for nerve repair, a series of experiments were performed using nerve growth factor (NGF). First, an NGF dosage curve was developed to determine the minimum NGF concentration for optimal axonal outgrowth on chick dorsal root ganglia (DRG) cells. Next, PLGA devices loaded with NGF were evaluated for sustained drug release and axon growth enhancement with the released drug. A 20 d in vitro release test was conducted and the nerve conduit showed the ability to meet and maintain the minimum NGF requirement determined previously. Bioactivity assays of the released NGF showed that drug released from the device between the 15th and 20th day could still promote axon growth (76.6-95.7 μm) in chick DRG cells, which is in the range of maximum growth. These novel drug delivery conduits show the ability to deliver NGF at a dosage that efficiently promotes ex vivo axon growth and have the potential for in vivo application to help bridge peripheral nerve gaps.

  5. The biocompatibility of calcium phosphate cements containing alendronate-loaded PLGA microparticles in vitro

    PubMed Central

    Li, Yu-Hua; Wang, Zhen-Dong; Wang, Wei; Ding, Chang-Wei; Zhang, Hao-Xuan

    2015-01-01

    The composite of poly-lactic-co-glycolic acid (PLGA) and calcium phosphate cements (CPC) are currently widely used in bone tissue engineering. However, the properties and biocompatibility of the alendronate-loaded PLGA/CPC (APC) porous scaffolds have not been characterized. APC scaffolds were prepared by a solid/oil/water emulsion solvent evaporation method. The morphology, porosity, and mechanical strength of the scaffolds were characterized. Bone marrow mesenchymal stem cells (BMSCs) from rabbit were cultured, expanded and seeded on the scaffolds, and the cell morphology, adhesion, proliferation, cell cycle and osteogenic differentiation of BMSCs were determined. The results showed that the APC scaffolds had a porosity of 67.43 ± 4.2% and pore size of 213 ± 95 µm. The compressive strength for APC was 5.79 ± 1.21 MPa, which was close to human cancellous bone. The scanning electron microscopy, cell counting kit-8 assay, flow cytometry and ALP activity revealed that the APC scaffolds had osteogenic potential on the BMSCs in vitro and exhibited excellent biocompatibility with engineered bone tissue. APC scaffolds exhibited excellent biocompatibility and osteogenesis potential and can potentially be used for bone tissue engineering. PMID:25877763

  6. Optimization of Stability, Encapsulation, Release, and Cross-Priming of Tumor Antigen-Containing PLGA Nanoparticles

    PubMed Central

    Prasad, Shashi; Cody, Virginia; Saucier-Sawyer, Jennifer K.; Fadel, Tarek R.; Edelson, Richard L.; Birchall, Martin A.

    2014-01-01

    Purpose In order to investigate Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NP) as potential vehicles for efficient tumor antigen (TA) delivery to dendritic cells (DC), this study aimed to optimize encapsulation/release kinetics before determining immunogenicity of antigen-containing NP. Methods Various techniques were used to liberate TA from cell lines. Single (gp100) and multiple (B16-tumor lysate containing gp100) antigens were encapsulated within differing molecular weight PLGA co-polymers. Differences in morphology, encapsulation/release and biologic potency were studied. Findings were adopted to encapsulate fresh tumor lysate from patients with advanced tumors and compare stimulation of tumor infiltrating lymphocytes (TIL) against that achieved by soluble lysate. Results Four cycles of freeze-thaw + 15 s sonication resulted in antigen-rich lysates without the need for toxic detergents or protease inhibitors. The 80KDa polymer resulted in maximal release of payload and favorable production of immunostimulatory IL-2 and IFN-γ. NP-mediated antigen delivery led to increased IFN-γ and decreased immunoinhibitory IL-10 synthesis when compared to soluble lysate. Conclusions Four cycles of freeze-thaw followed by 15 s sonication is the ideal technique to obtain complex TA for encapsulation. The 80KDa polymer has the most promising combination of release kinetics and biologic potency. Encapsulated antigens are immunogenic and evoke favorable TIL-mediated anti-tumor responses. PMID:22798259

  7. Fe3O4-based PLGA nanoparticles as MR contrast agents for the detection of thrombosis

    PubMed Central

    Liu, Jia; Xu, Jie; Zhou, Jun; Zhang, Yu; Guo, Dajing; Wang, Zhigang

    2017-01-01

    Thrombotic disease is a great threat to human health, and early detection is particularly important. Magnetic resonance (MR) molecular imaging provides noninvasive imaging with the potential for early disease diagnosis. In this study, we developed Fe3O4-based poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) surface-modified with a cyclic Arg-Gly-Asp (cRGD) peptide as an MR contrast agent for the detection of thrombosis. The physical and chemical characteristics, biological toxicity, ability to target thrombi, and biodistribution of the NPs were studied. The Fe3O4-PLGA-cRGD NPs were constructed successfully, and hematologic and pathologic assays indicated no in vivo toxicity of the NPs. In a rat model of FeCl3-induced abdominal aorta thrombosis, the NPs readily and selectively accumulated on the surface of the thrombosis and under vascular endothelial cells ex vivo and in vivo. In the in vivo experiment, the biodistribution of the NPs suggested that the NPs might be internalized by the macrophages of the reticuloendothelial system in the liver and the spleen. The T2 signal decreased at the mural thrombus 10 min after injection and then gradually increased until 50 min. These results suggest that the NPs are suitable for in vivo molecular imaging of thrombosis under high shear stress conditions and represent a very promising MR contrast agent for sensitive and specific detection of thrombosis. PMID:28223802

  8. Passively Targeted Curcumin-Loaded PEGylated PLGA Nanocapsules for Colon Cancer Therapy In Vivo

    PubMed Central

    Klippstein, Rebecca; Wang, Julie Tzu-Wen; El-Gogary, Riham I; Bai, Jie; Mustafa, Falisa; Rubio, Noelia; Bansal, Sukhvinder; Al-Jamal, Wafa T; Al-Jamal, Khuloud T

    2015-01-01

    Clinical applications of curcumin for the treatment of cancer and other chronic diseases have been mainly hindered by its short biological half-life and poor water solubility. Nanotechnology-based drug delivery systems have the potential to enhance the efficacy of poorly soluble drugs for systemic delivery. This study proposes the use of poly(lactic-co-glycolic acid) (PLGA)-based polymeric oil-cored nanocapsules (NCs) for curcumin loading and delivery to colon cancer in mice after systemic injection. Formulations of different oil compositions are prepared and characterized for their curcumin loading, physico-chemical properties, and shelf-life stability. The results indicate that castor oil-cored PLGA-based NC achieves high drug loading efficiency (≈18% w(drug)/w(polymer)%) compared to previously reported NCs. Curcumin-loaded NCs internalize more efficiently in CT26 cells than the free drug, and exert therapeutic activity in vitro, leading to apoptosis and blocking the cell cycle. In addition, the formulated NC exhibits an extended blood circulation profile compared to the non-PEGylated NC, and accumulates in the subcutaneous CT26-tumors in mice, after systemic administration. The results are confirmed by optical and single photon emission computed tomography/computed tomography (SPECT/CT) imaging. In vivo growth delay studies are performed, and significantly smaller tumor volumes are achieved compared to empty NC injected animals. This study shows the great potential of the formulated NC for treating colon cancer. PMID:26140363

  9. The inclusion into PLGA nanoparticles enables α-bisabolol to efficiently inhibit the human dendritic cell pro-inflammatory activity

    NASA Astrophysics Data System (ADS)

    Marongiu, Laura; Donini, Marta; Bovi, Michele; Perduca, Massimiliano; Vivian, Federico; Romeo, Alessandro; Mariotto, Sofia; Monaco, Hugo L.; Dusi, Stefano

    2014-08-01

    α-bisabolol, a natural sesquiterpene alcohol, has generated considerable interest for its anti-inflammatory activity. Since the mechanisms of this anti-inflammatory action remain poorly understood, we investigated whether α-bisabolol affects the release of pro-inflammatory cytokines IL-12, IL-23, IL-6, and TNFα by human dendritic cells (DCs). We found that α-bisabolol did not induce the secretion of these cytokines and did not affect their release induced upon DC challenge with lipopolysaccharide (LPS), a well-known immune cell stimulator. As α-bisabolol is scarcely ingested by the cells, we wondered whether the inclusion of α-bisabolol into nanoparticles could favor its internalization by DCs and consequently its effects on cytokine secretion. We then prepared and characterized poly(lactic-co-glycolic acid) (PLGA) nanoparticles, with a dynamic light scattering peak centered at 154 nm and a half width at half maximum of about 48 nm. These particles were unable to affect per se cytokine secretion by both resting and LPS-stimulated DCs and were internalized by human DCs as demonstrated by confocal microscopy analysis. We then loaded PLGA nanoparticles with α-bisabolol and we observed that PLGA-associated α-bisabolol did not stimulate the cytokine release by resting DCs, but decreased IL-12, IL-23, IL-6, and TNFα secretion by LPS-stimulated DCs. Our results indicate that α-bisabolol inclusion into PLGA nanoparticles represents a very promising tool for designing new anti-inflammatory, anti-pyretic and, possibly, immunosuppressive therapeutic strategies.

  10. MAPs/bFGF-PLGA microsphere composite-coated titanium surfaces promote increased adhesion and proliferation of fibroblasts.

    PubMed

    Wang, Zhongshan; Wu, Guofeng; Bai, Shizhu; Feng, Zhihong; Dong, Yan; Zhou, Jian; Qin, Haiyan; Zhao, Yimin

    2014-06-01

    Infection and epithelial downgrowth are two major problems with maxillofacial transcutaneous implants, and both are mainly due to lack of stable closure of soft tissues at transcutaneous sites. Fibroblasts have been shown to play a key role in the formation of biological seals. In this work, titanium (Ti) model surfaces were coated with mussel adhesive proteins (MAPs) utilizing its unique adhesion ability on diverse inorganic and organic surfaces in wet environments. Prepared basic fibroblast growth factor (bFGF)-poly(lactic-co-glycolic acid) (PLGA) microspheres can be easily synthesized and combined onto MAPs-coated Ti surfaces, due to the negative surface charges of microspheres in aqueous solution, which is in contrast to the positive charges of MAPs. Titanium model surfaces were divided into three groups. Group A: MAPs/bFGF-PLGA microspheres composite-coated Ti surfaces. Group B: MAPs-coated Ti surfaces. Group C: uncoated Ti surfaces. The effects of coated Ti surfaces on adhesion of fibroblasts, cytoskeletal organization, proliferation, and extracellular matrix (ECM)-related gene expressions were examined. The results revealed increased adhesion (P < 0.05), enhanced actin cytoskeletal organization, and up-regulated ECM-related gene expressions in groups A and B compared with group C. Increased proliferation of fibroblasts during five days of incubation was observed in group A compared with groups B and C (P < 0.05). Collectively, the results from this in vitro study demonstrated that MAPs/bFGF-PLGA microspheres composite-coated Ti surfaces had the ability to increase fibroblast functionality. In addition, MAPs/bFGF-PLGA microsphere composite-coated Ti surfaces should be studied further as a method of promoting formation of stable biological seals around transcutaneous sites.

  11. Nerve guidance conduit with a hybrid structure of a PLGA microfibrous bundle wrapped in a micro/nanostructured membrane.

    PubMed

    Peng, Shih-Wen; Li, Ching-Wen; Chiu, Ing-Ming; Wang, Gou-Jen

    2017-01-01

    Nerve repair in tissue engineering involves the precise construction of a scaffold to guide nerve cell regeneration in the desired direction. However, improvements are needed to facilitate the cell migration/growth rate of nerves in the center of a nerve conduit. In this paper, we propose a nerve guidance conduit with a hybrid structure comprising a microfibrous poly(lactic-co-glycolic acid) (PLGA) bundle wrapped in a micro/nanostructured PLGA membrane. We applied sequential fabrication processes, including photolithography, nano-electroforming, and polydimethylsiloxane casting to manufacture master molds for the repeated production of the PLGA subelements. After demolding it from the master molds, we rolled the microfibrous membrane into a bundle and then wrapped it in the micro/nanostructured membrane to form a nerve-guiding conduit. We used KT98/F1B-GFP cells to estimate the migration rate and guidance ability of the fabricated nerve conduit and found that both elements increased the migration rate 1.6-fold compared with a flat PLGA membrane. We also found that 90% of the cells in the hybrid nano/microstructured membrane grew in the direction of the designed patterns. After 3 days of culturing, the interior of the nerve conduit was filled with cells, and the microfiber bundle was also surrounded by cells. Our conduit cell culture results also demonstrate that the proposed micro/nanohybrid and microfibrous structures can retain their shapes. The proposed hybrid-structured conduit demonstrates a high capability for guiding nerve cells and promoting cell migration, and, as such, is feasible for use in clinical applications.

  12. Nerve guidance conduit with a hybrid structure of a PLGA microfibrous bundle wrapped in a micro/nanostructured membrane

    PubMed Central

    Peng, Shih-Wen; Li, Ching-Wen; Chiu, Ing-Ming; Wang, Gou-Jen

    2017-01-01

    Nerve repair in tissue engineering involves the precise construction of a scaffold to guide nerve cell regeneration in the desired direction. However, improvements are needed to facilitate the cell migration/growth rate of nerves in the center of a nerve conduit. In this paper, we propose a nerve guidance conduit with a hybrid structure comprising a microfibrous poly(lactic-co-glycolic acid) (PLGA) bundle wrapped in a micro/nanostructured PLGA membrane. We applied sequential fabrication processes, including photolithography, nano-electroforming, and polydimethylsiloxane casting to manufacture master molds for the repeated production of the PLGA subelements. After demolding it from the master molds, we rolled the microfibrous membrane into a bundle and then wrapped it in the micro/nanostructured membrane to form a nerve-guiding conduit. We used KT98/F1B-GFP cells to estimate the migration rate and guidance ability of the fabricated nerve conduit and found that both elements increased the migration rate 1.6-fold compared with a flat PLGA membrane. We also found that 90% of the cells in the hybrid nano/microstructured membrane grew in the direction of the designed patterns. After 3 days of culturing, the interior of the nerve conduit was filled with cells, and the microfiber bundle was also surrounded by cells. Our conduit cell culture results also demonstrate that the proposed micro/nanohybrid and microfibrous structures can retain their shapes. The proposed hybrid-structured conduit demonstrates a high capability for guiding nerve cells and promoting cell migration, and, as such, is feasible for use in clinical applications. PMID:28138239

  13. Convection-Enhanced Delivery of Carboplatin PLGA Nanoparticles for the Treatment of Glioblastoma.

    PubMed

    Arshad, Azeem; Yang, Bin; Bienemann, Alison S; Barua, Neil U; Wyatt, Marcella J; Woolley, Max; Johnson, Dave E; Edler, Karen J; Gill, Steven S

    2015-01-01

    We currently use Convection-Enhanced Delivery (CED) of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioblastoma in adults and children. Although initial results show promise, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations in pre-clinical studies. Our treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. In this study, carboplatin was encapsulated in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system. Neuronal and tumour cytotoxicity were assessed in primary neuronal and glioblastoma cell cultures. Distribution, tissue clearance and toxicity of carboplatin nanoparticles following CED was assessed in rat and porcine models. Carboplatin nanoparticles conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life. In conclusion, this drug delivery system has the potential to improve the prognosis for patients with glioblastomas.

  14. Acoustic responses of monodisperse lipid-encapsulated microbubble contrast agents produced by flow focusing

    PubMed Central

    Kaya, Mehmet; Feingold, Steven; Hettiarachchi, Kanaka; Lee, Abraham P; Dayton, Paul A

    2010-01-01

    Lipid-encapsulated microbubbles are used as contrast agents in ultrasound imaging. Currently available commercially made contrast agents have a polydisperse size distribution. It has been hypothesised that improved imaging sensitivity could be achieved with a uniform microbubble radius. We have recently developed microfluidics technology to produce contrast agents with a nearly monodisperse distribution. In this manuscript, we analyze echo responses from individual microbubbles from monodisperse populations in order to establish the relationship between scattered echo, microbubble radius, and excitation frequency. Simulations of bubble response from a modified Rayleigh-Plesset type model corroborate experimental data. Results indicate that microbubble echo response can be greatly increased by optimal combinations of microbubble radius and acoustic excitation frequency. These results may have a significant impact in the formulation of contrast agents to improve ultrasonic sensitivity. PMID:21475641

  15. Technique for the Characterization of Phospholipid Microbubbles Coatings by Transmission Electron Microscopy.

    PubMed

    Owen, Joshua; Stride, Eleanor

    2015-12-01

    Gas microbubbles stabilized by a surfactant or polymer coating are of considerable clinical interest because of their imaging and drug delivery potential under ultrasound exposure. The utility of microbubbles for a given application is intrinsically linked to their structure and stability. These in turn are highly sensitive to coating composition and fabrication techniques. Various methods including fluorescence and atomic force microscopy have been applied to characterize microbubble properties, but direct observation of coating structure at the nanoscale still poses a considerable challenge. Here we describe a transmission electron microscopy (TEM) technique to observe the surface of microbubbles. Images from a series of phospholipid-coated microbubble systems, including those decorated with nanoparticles, are presented. They indicate that the technique enables visualization of the coating structure, in particular lipid discontinuities and nanoparticle distribution. This information can be used to better understand how microbubble surface structure relates to formulation and/or processing technique and ultimately to functionality.

  16. Comparison of intracellular accumulation and cytotoxicity of free mTHPC and mTHPC-loaded PLGA nanoparticles in human colon carcinoma cells

    NASA Astrophysics Data System (ADS)

    Löw, Karin; Knobloch, Thomas; Wagner, Sylvia; Wiehe, Arno; Engel, Andrea; Langer, Klaus; von Briesen, Hagen

    2011-06-01

    The second generation photosensitizer mTHPC was approved by the European Medicines Agency (EMA) for the palliative treatment of advanced head and neck cancer in October 2001. It is known that mTHPC possesses a significant phototoxicity against a variety of human cancer cells in vitro but also exhibits dark toxicity and can cause adverse effects (especially skin photosensitization). Due to its poor water solubility, the administration of hydrophobic photosensitizer still presents several difficulties. To overcome the administration problems, the use of nanoparticles as drug carrier systems is much investigated. Nanoparticles based on poly(lactic-co-glycolic acid) (PLGA) have been extensively studied as delivery systems into tumours due to their biocompatibility and biodegradability. The goal of this study was the comparison of free mTHPC and mTHPC-loaded PLGA nanoparticles concerning cytotoxicity and intracellular accumulation in human colon carcinoma cells (HT29). The nanoparticles delivered the photosensitizer to the colon carcinoma cells and enabled drug release without losing its activity. The cytotoxicity assays showed a time- and concentration-dependent decrease in cell proliferation and viability after illumination. However, first and foremost mTHPC lost its dark toxic effects using the PLGA nanoparticles as a drug carrier system. Therefore, PLGA nanoparticles are a promising drug carrier system for the hydrophobic photosensitizer mTHPC.

  17. Development of sulfadiazine-decorated PLGA nanoparticles loaded with 5-fluorouracil and cell viability.

    PubMed

    Guimarães, Pedro Pires Goulart; Oliveira, Sheila Rodrigues; de Castro Rodrigues, Gabrielle; Gontijo, Savio Morato Lacerda; Lula, Ivana Silva; Cortés, Maria Esperanza; Denadai, Ângelo Márcio Leite; Sinisterra, Rubén Dario

    2015-01-08

    The aim of this work was to synthesize sulfadiazine-poly(lactide-co-glycolide) (SUL-PLGA) nanoparticles (NPs) for the efficient delivery of 5-fluorouracil to cancer cells. The SUL-PLGA conjugation was assessed using FTIR, 1H-NMR, 13C-NMR, elemental analysis and TG and DTA analysis. The SUL-PLGA NPs were characterized using transmission and scanning electron microscopy and dynamic light scattering. Additionally, the zeta potential, drug content, and in vitro 5-FU release were evaluated. We found that for the SUL-PLGA NPs, Dh = 114.0 nm, ZP = -32.1 mV and the encapsulation efficiency was 49%. The 5-FU was released for up to 7 days from the NPs. Cytotoxicity evaluations of 5-FU-loaded NPs (5-FU-SUL-PLGA and 5-FU-PLGA) on two cancer cell lines (Caco-2, A431) and two normal cell lines (fibroblast, osteoblast) were compared. Higher cytotoxicity of 5-FU-SUL-PLGA NPs were found to both cancer cell lines when compared to normal cell lines, demonstrating that the presence of SUL could significantly enhance the cytotoxicity of the 5-FU-SUL-PLGA NPs when compared with 5-FU-PLGA NPs. Thus, the development of 5-FU-SUL-PLGA NPs to cancer cells is a promising strategy for the 5-FU antitumor formulation in the future.

  18. Effects of PLGA reinforcement methods on the mechanical property of carbonate apatite foam.

    PubMed

    Munar, Girlie M; Munar, Melvin L; Tsuru, Kanji; Ishikawa, Kunio

    2014-01-01

    The purpose of this study was to improve the mechanical property of brittle carbonate apatite (CO3Ap) foam aimed as bone substitute material by reinforcement with poly(DL-lactide-co-glycolide) (PLGA). The CO3Ap foam was reinforced with PLGA by immersion and vacuum infiltration methods. Compressive strength of CO3Ap foam (12.0±4.9 kPa) increased after PLGA reinforcement by immersion (187.6±57.6 kPa) or vacuum infiltration (407.0±111.4 kPa). Scanning electron microscopic (SEM) observation showed a gapless PLGA and CO3Ap foam interface and larger amount of PLGA inside the hollow space of the strut when vacuum infiltration method was employed. In contrast a gap was observed at the PLGA and CO3Ap foam interface and less amount of PLGA inside the hollow space of the strut when immersion method was employed. Strong PLGA-CO3Ap foam interface and larger amount of PLGA inside the hollow space of the strut is therefore the key to higher mechanical property obtained for CO3Ap foam when vacuum infiltration was employed for PLGA reinforcement.

  19. Preparation and properties of PLGA nanofiber membranes reinforced with cellulose nanocrystals.

    PubMed

    Mo, Yunfei; Guo, Rui; Liu, Jianghui; Lan, Yong; Zhang, Yi; Xue, Wei; Zhang, Yuanming

    2015-08-01

    Although extensively used in the fields of drug-carrier and tissue engineering, the biocompatibility and mechanical properties of polylactide-polyglycolide (PLGA) nanofiber membranes still limit their applications. The objective of this study was to improve their utility by introducing cellulose nanocrystals (CNCs) into PLGA nanofiber membranes. PLGA and PLGA/CNC composite nanofiber membranes were prepared via electrospinning, and the morphology and thermodynamic and mechanical properties of these nanofiber membranes were characterized by scanning electron microscopy (SEM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and dynamic mechanical analysis (DMA). The cytocompatibility and cellular responses of the nanofiber membranes were also studied by WST-1 assay, SEM, and confocal laser scanning microscopy (CLSM). Incorporation of CNCs (1, 3, 5, and 7 wt.%) increased the average fiber diameter of the prepared nanofiber membranes from 100 nm (neat PLGA) to ∼400 nm (PLGA/7 wt.% CNC) and improved the thermal stability of the nanofiber membranes. Among the PLGA/CNC composite nanofiber membranes, those loaded with 7 wt.% CNC nanofiber membranes had the best mechanical properties, which were similar to those of human skin. Cell culture results showed that the PLGA/CNC composite nanofiber membranes had better cytocompatibility and facilitated fibroblast adhesion, spreading, and proliferation compared with neat PLGA nanofiber membranes. These preliminary results suggest that PLGA/CNC composite nanofiber membranes are promising new materials for the field of skin tissue engineering.

  20. An experimental study on the stiffness of size-isolated microbubbles using atomic force microscopy

    NASA Astrophysics Data System (ADS)

    Chen, Cherry C.; Wu, Shih-Ying; Finan, John D.; Morrison, Barclay, III; Konofagou, Elisa E.

    2012-11-01

    In order to fully assess contrast-enhanced acoustic bioeffects in diagnostic and therapeutic ultrasound, the mechanical properties of microbubbles need to be taken into account. In the present study, direct measurements of the microbubble stiffness were performed using atomic force microscopy by applying nanoscale compressions (up to 25 nN/s) on size-isolated, phospholipid-coated microbubbles (diameters between 4-6 and 6-8 μm). The stiffness was found to lie between 4 and 22 mN/m and to decrease exponentially with microbubble size within the diameter range investigated. No cantilever spring constant effect was noted on the measured stiffness. The Young's modulus of the size-isolated microbubbles used in our study ranged between 0.4 and 2 MPa. Microstructures on the surface of the microbubbles were found to influence the overall microbubble elasticity. Our results indicated that more detailed theoretical models are needed to account for the size-dependent microbubble mechanical properties in order to accurately predict their acoustic behavior. The findings provided useful insights to control cavitation-induced drug and gene delivery and could be used as part of the framework in studies on the shear stresses induced on the blood vessel walls by the oscillating microbubbles.

  1. The momentum balance in upward turbulent channel flow laden with microbubbles

    NASA Astrophysics Data System (ADS)

    Mito, Yoichi; Ikeda, Shota

    2014-11-01

    The influence of the addition of microbubbles as dispersed gas phase on fully-developed turbulent flow in a vertical channel in which the liquid is flowing upward with a constant pressure gradient or a constant rate has been examined by using direct numerical simulation to calculate the liquid velocities seen by the microbubbles and the point force method to consider the influence of the microbubbles on the liquid. The microbubbles are represented by solid spheres and are released from uniformly distributed point sources. The streamwise momentum balance shows that the influence of the addition of the microbubbles on the drag of the liquid flow appears as a function of volume fraction, Froude number and friction velocity that results from distribution of the microbubbles. The experimental conditions are chosen such that zero to two hundred percent of the pressure gradient of the single-phase flow is added by the addition of the microbubbles. The drag decreases by the addition of the microbubbles, whereas the frictional drag increases with the increases in the accumulation of the microbubbles on walls, which attenuates the effect of reducing drag. Changes in the liquid turbulence are not clearly seen except for what are due to the changes in the bulk Reynolds number. This work was supported by JSPS KAKENHI Grant Number 26420097.

  2. Enhanced cytotoxic effect of cisplatin using diagnostic ultrasound and microbubbles in vitro

    NASA Astrophysics Data System (ADS)

    Sasaki, Noboru; Nakamura, Kensuke; Murakami, Masahiro; Lim, Sue Yee; Ohta, Hiroshi; Yamasaki, Masahiro; Takiguchi, Mitsuyoshi

    2012-10-01

    Diagnostic ultrasound has accomplished drug and gene delivery by ultrasound targeted microbubble destruction (UTMD). However, the efficacy of delivery is still relatively low. Therefore, we optimized conditions of UTMD using diagnostic ultrasound and ultrasound contrast agent microbubbles. Canine thyroid adenocarcinoma cells were cultured in a 96-well plate. After addition of cisplatin and Sonazoid®, the plate was inverted to raise microbubbles near cells and incubated. Cells were exposed to diagnostic ultrasound using a linear probe operated in the contrast harmonic imaging mode. The center frequency was 2.5 MHz with a mechanical index of 1.33 and a frame rate of 48 frames/sec. Cytotoxic effect of cisplatin was evaluated 24h after exposure using trypan blue dye exclusion test. We optimized incubation duration, cisplatin concentration, and the relationship between microbubble concentration and exposure duration. The optimum enhancement was observed at incubation duration of 5min, cisplatin concentration of 1 μg/ml, and microbubble concentration of 2.4 × 105 microbubbles/ml. Exposure duration did not influence the enhancement at the microbubble concentration of 2.4 × 105 microbubbles/ml. Our results suggest that relative low concentrations of drug and microbubbles with short exposure duration might be sufficient for drug delivery by UTMD using diagnostic ultrasound.

  3. Ultrasound modulated optical tomography contrast enhancement with non-linear oscillation of microbubbles

    PubMed Central

    Ruan, Haowen; Mather, Melissa L.

    2015-01-01

    Background Ultrasound modulated optical tomography (USMOT) is an imaging technique used to provide optical functional information inside highly scattering biological tissue. One of the challenges facing this technique is the low image contrast. Methods A contrast enhancement imaging technique based on the non-linear oscillation of microbubbles is demonstrated to improve image contrast. The ultrasound modulated signal was detected using a laser pulse based speckle contrast detection system. Better understanding of the effects of microbubbles on the optical signals was achieved through simultaneous measurement of the ultrasound scattered by the microbubbles. Results The length of the laser pulse was found to affect the system response of the speckle contrast method with shorter pulses suppressing the fundamental ultrasound modulated optical signal. Using this property, image contrast can be enhanced by detection of the higher harmonic ultrasound modulated optical signals due to nonlinear oscillation and destruction of the microbubbles. Experimental investigations were carried out to demonstrate a doubling in contrast by imaging a scattering phantom containing an embedded silicone tube with microbubbles flowing through it. Conclusions The contrast enhancement in USMOT resulting from the use of ultrasound microbubbles has been demonstrated. Destruction of the microbubbles was shown to be the dominant effect leading to contrast improvement as shown by simultaneously detecting the ultrasound and speckle contrast signals. Line scans of a microbubble filled silicone tube embedded in a scattering phantom demonstrated experimentally the significant image contrast improvement that can be achieved using microbubbles and demonstrates the potential as a future clinical imaging tool. PMID:25694948

  4. Binding Dynamics of Targeted Microbubbles in Response to Modulated Acoustic Radiation Force

    PubMed Central

    Wang, Shiying; Hossack, John A; Klibanov, Alexander L; Mauldin, F William

    2014-01-01

    Detection of molecular targeted microbubbles plays a foundational role in ultrasound-based molecular imaging and targeted gene or drug delivery. In this paper, an empirical model describing the binding dynamics of targeted microbubbles in response to modulated acoustic radiation forces in large vessels is presented and experimentally verified using tissue-mimicking flow phantoms. Higher flow velocity and microbubble concentration led to faster detaching rates for specifically bound microbubbles (p < 0.001). Higher time-averaged acoustic radiation force intensity led to faster attaching rates and a higher saturation level of specifically bound microbubbles (p < 0.05). The level of residual microbubble signal in targeted experiments after cessation of radiation forces was the only response parameter that was reliably different between targeted and control experiments (p < 0.05). A related parameter, the ratio of residual-to-saturated microbubble signal (Rresid), is proposed as a measurement that is independent of absolute acoustic signal magnitude and therefore able to reliably detect targeted adhesion independently of control measurements (p < 0.01). These findings suggest the possibility of enhanced detection of specifically bound microbubbles in real-time, using relatively short imaging protocols (approximately 3 min), without waiting for free microbubble clearance. PMID:24374866

  5. An Experimental Study on the Stiffness of Size-Isolated Microbubbles Using Atomic Force Microscopy

    PubMed Central

    Chen, Cherry C.; Wu, Shih-Ying; Finan, John D.; Morrison, Barclay; Konofagou, Elisa E.

    2014-01-01

    To fully assess contrast-enhanced acoustic bioeffects in diagnostic and therapeutic procedures, the mechanical properties of microbubbles need to be considered. In the present study, direct measurements of the microbubble stiffness were performed using atomic force microscopy by applying nanoscale compressions (up to 25 nN/s) on size-isolated, lipid-coated microbubbles (diameter ranges of 4 to 6 μm and 6 to 8 μm). The stiffness was found to lie between 4 and 22 mN/m and to decrease exponentially with the microbubble size within the diameter range investigated. No cantilever spring constant effect was found on the measured stiffness. The Young’s modulus of the size-isolated microbubbles used in our study ranged between 0.4 and 2 MPa. Microstructures on the surface of the microbubbles were found to influence the overall microbubble elasticity. Our results indicated that more detailed theoretical models are needed to account for the size-dependent microbubble mechanical properties to accurately predict their acoustic behavior. The findings provided useful insights into guidance of cavitation-induced drug and gene delivery and could be used as part of the framework in studies on the shear stresses induced on the blood vessel walls by oscillating microbubbles. PMID:23475918

  6. Ultrasound-mediated intracellular drug delivery using microbubbles and temperature-sensitive liposomes.

    PubMed

    Yudina, A; de Smet, M; Lepetit-Coiffé, M; Langereis, S; Van Ruijssevelt, L; Smirnov, P; Bouchaud, V; Voisin, P; Grüll, H; Moonen, C T W

    2011-11-07

    A novel two-step protocol for intracellular drug delivery has been evaluated in vitro. As a first step TO-PRO-3 (a cell-impermeable dye that displays a strong fluorescence enhancement upon binding to nucleic acids) encapsulated in thermosensitive liposomes was released after heating to 42°C. A second step consisted of ultrasound-mediated local permeabilization of cell membrane allowing TO-PRO-3 internalization observable as nuclear staining. Only the combination of two consecutive steps - heating and sonication in the presence of SonoVue microbubbles led to the model drug TO-PRO-3 release from the thermosensitive liposomes and its intracellular uptake. This protocol is potentially beneficial for the intracellular delivery of cell impermeable drugs that suffer from rapid clearance and/or degradation in blood and are not intrinsically taken up by cells.

  7. Nanostructured hydroxyapatite/poly(lactic-co-glycolic acid) composite coating for controlling magnesium degradation in simulated body fluid

    NASA Astrophysics Data System (ADS)

    Johnson, Ian; Akari, Khalid; Liu, Huinan

    2013-09-01

    Biodegradable magnesium (Mg) and its alloys have many attractive properties (e.g. comparable mechanical properties to cortical bone) for orthopedic implant applications, but they degrade too rapidly in the human body to meet clinical requirements. Nanostructured hydroxyapatite (nHA)/poly(lactic-co-glycolic acid) (PLGA) composite coatings provide synergistic properties for controlling degradation of Mg-based substrates and improving bone-implant integration. In this study, nHA/PLGA composites were spin coated onto Mg-based substrates and the results showed that the nHA/PLGA coatings retained nano-scale features with nHA dispersed in PLGA matrix. In comparison with non-coated Mg, the nHA/PLGA composite coated Mg increased the corrosion potential and decreased the corrosion current in revised simulated body fluid (rSBF). After 24 h of immersion in rSBF, increased calcium phosphate (CaP) deposition and formation of Mg-substituted CaP rosettes were observed on the surface of the nHA/PLGA coated Mg, indicating greater bioactivity. In contrast, no significant CaP was deposited on the PLGA coated Mg. Since both PLGA coating and nHA/PLGA coating showed some degree of delamination from Mg-based substrates during extended immersion in rSBF, the coating processing and properties should be further optimized in order to take full advantage of biodegradable Mg and nHA/PLGA nanocomposites for orthopedic applications.

  8. Nanostructured hydroxyapatite/poly(lactic-co-glycolic acid) composite coating for controlling magnesium degradation in simulated body fluid.

    PubMed

    Johnson, Ian; Akari, Khalid; Liu, Huinan

    2013-09-20

    Biodegradable magnesium (Mg) and its alloys have many attractive properties (e.g. comparable mechanical properties to cortical bone) for orthopedic implant applications, but they degrade too rapidly in the human body to meet clinical requirements. Nanostructured hydroxyapatite (nHA)/poly(lactic-co-glycolic acid) (PLGA) composite coatings provide synergistic properties for controlling degradation of Mg-based substrates and improving bone-implant integration. In this study, nHA/PLGA composites were spin coated onto Mg-based substrates and the results showed that the nHA/PLGA coatings retained nano-scale features with nHA dispersed in PLGA matrix. In comparison with non-coated Mg, the nHA/PLGA composite coated Mg increased the corrosion potential and decreased the corrosion current in revised simulated body fluid (rSBF). After 24 h of immersion in rSBF, increased calcium phosphate (CaP) deposition and formation of Mg-substituted CaP rosettes were observed on the surface of the nHA/PLGA coated Mg, indicating greater bioactivity. In contrast, no significant CaP was deposited on the PLGA coated Mg. Since both PLGA coating and nHA/PLGA coating showed some degree of delamination from Mg-based substrates during extended immersion in rSBF, the coating processing and properties should be further optimized in order to take full advantage of biodegradable Mg and nHA/PLGA nanocomposites for orthopedic applications.

  9. Fabrication of functional PLGA-based electrospun scaffolds and their applications in biomedical engineering.

    PubMed

    Zhao, Wen; Li, Jiaojiao; Jin, Kaixiang; Liu, Wenlong; Qiu, Xuefeng; Li, Chenrui

    2016-02-01

    Electrospun PLGA-based scaffolds have been applied extensively in biomedical engineering, such as tissue engineering and drug delivery system. Due to lack of the recognition sites on cells, hydropholicity and single-function, the applications of PLGA fibrous scaffolds are limited. In order to tackle these issues, many works have been done to obtain functional PLGA-based scaffolds, including surface modifications, the fabrication of PLGA-based composite scaffolds and drug-loaded scaffolds. The functional PLGA-based scaffolds have significantly improved cell adhesion, attachment and proliferation. Moreover, the current study has summarized the applications of functional PLGA-based scaffolds in wound dressing, vascular and bone tissue engineering area as well as drug delivery system.

  10. In-plant testing of microbubble column flotation

    SciTech Connect

    Yoon, R.H.; Luttrell, G.H.; Adel, G.T.

    1990-01-01

    During the past year, a joint project between the US Department of Energy (DOE), the Virginia Center for Coal and Minerals Processing (VCCMP) and the Shell Mining Corporation (SMC) was initiated to implement the testing of a full-scale microbubble flotation column. The work is being carried out at the Marrowbone Preparation Plant, located near Naugatuck in southwestern West Virginia. The primary objective of this effort was to determine the feasibility of using microbubble column flotation for the recovery of coal fines from a classifying cyclone overflow stream that is presently being discarded as refuse. During the past quarter, results obtained using a 30-inch diameter test unit were reviewed, flowsheet layouts and preliminary scale-up projections were generated and design, engineering, fabrication and installation of the full-scale test unit was completed. Preliminary results were also obtained with the full-scale test unit and are presented in this report. 5 figs., 7 tabs.

  11. In-plant testing of microbubble column flotation

    SciTech Connect

    Yoon, R.H.; Luttrell, G.H.; Adel, G.T.; Mankosa, M.J.

    1991-07-31

    Microbubble column flotation (MCF) was developed at the Virginia Center for Coal and Minerals Processing (VCCMP) for the selective recovery of fine particles. Bench-scale test work conducted at VCCMP, largely under the sponsorship of the U.S. Department of Energy (DOE), showed that the technology worked well for both coal and mineral applications. For the technology to be commercially successful, however, a full-scale demonstration of the MCF technology was deemed necessary. This report summarizes the results of work performed under the DOE project entitled In-plant Testing of Microbubble Column Flotation.'' The objectives of this research and development effort were to duplicate the bench-scale performance of the MCF process in a full-scale unit, to verify the scale-up procedure developed in an earlier project, and to demonstrate the applicability of the MCF technology to the coal industry.

  12. In-plant testing of microbubble column flotation. Final report

    SciTech Connect

    Yoon, R.H.; Luttrell, G.H.; Adel, G.T.; Mankosa, M.J.

    1991-07-31

    Microbubble column flotation (MCF) was developed at the Virginia Center for Coal and Minerals Processing (VCCMP) for the selective recovery of fine particles. Bench-scale test work conducted at VCCMP, largely under the sponsorship of the U.S. Department of Energy (DOE), showed that the technology worked well for both coal and mineral applications. For the technology to be commercially successful, however, a full-scale demonstration of the MCF technology was deemed necessary. This report summarizes the results of work performed under the DOE project entitled ``In-plant Testing of Microbubble Column Flotation.`` The objectives of this research and development effort were to duplicate the bench-scale performance of the MCF process in a full-scale unit, to verify the scale-up procedure developed in an earlier project, and to demonstrate the applicability of the MCF technology to the coal industry.

  13. Micro-Bubble Experiments at the Van de Graaff Accelerator

    SciTech Connect

    Sun, Z. J.; Wardle, Kent E.; Quigley, K. J.; Gromov, Roman; Youker, A. J.; Makarashvili, Vakhtang; Bailey, James; Stepinski, D. C.; Chemerisov, S. D.; Vandegrift, G. F.

    2015-02-01

    In order to test and verify the experimental designs at the linear accelerator (LINAC), several micro-scale bubble ("micro-bubble") experiments were conducted with the 3-MeV Van de Graaff (VDG) electron accelerator. The experimental setups included a square quartz tube, sodium bisulfate solution with different concentrations, cooling coils, gas chromatography (GC) system, raster magnets, and two high-resolution cameras that were controlled by a LabVIEW program. Different beam currents were applied in the VDG irradiation. Bubble generation (radiolysis), thermal expansion, thermal convection, and radiation damage were observed in the experiments. Photographs, videos, and gas formation (O2 + H2) data were collected. The micro-bubble experiments at VDG indicate that the design of the full-scale bubble experiments at the LINAC is reasonable.

  14. Investigating the nonlinear microbubble response to chirp encoded, multipulse sequences.

    PubMed

    Chetty, Kevin; Hajnal, Joseph V; Eckersley, Robert J

    2006-12-01

    A modified Rayleigh-Plesset model was used to investigate the nonlinear acoustic response of ultrasound contrast microbubbles to multipulse phase and amplitude modulated, chirp encoded sequences. Trade-offs between the signal-to-noise ratio (SNR) and axial resolution were quantified for differing chirp time-bandwidth products and methods for minimising the artifacts formed in the postprocessing stages were developed. It was found that the chirp length can be increased and bandwidth reduced to improve SNR, though resolution is sacrificed. Results from the simulated chirp, pulse inverted, amplitude modulated (chirp PIAM) sequences were also compared with equivalent short pulse PIAM sequences and it was found that the chirp sequences preserve their extra energy after scattering, which translates to an improved SNR after processing. Compression artifacts were reduced by using chirps with a centre frequency and bandwidth tuned to the frequency response of the microbubble and reversing the frequency sweep of one chirp in the sequence.

  15. Contact line pinning favors the mass production of monodisperse microbubbles.

    NASA Astrophysics Data System (ADS)

    Gordillo, Jose Manuel; Campo-Cortes, Francisco; Riboux, Guillaume

    2015-11-01

    A robust method for the generation of phospholipid covered monodisperse microbubbles of diameters ~10 microns at production rates exceeding 0.1 MHz, is presented here. We show that bubbles are periodically formed from the tip of a long and thin gas ligament stabilized thanks to both the strong favorable pressure gradient existing at the entrance region of a long rectangular PDMS-PDMS channel and to the pinning of the gas-liquid interface at a centered groove of several microns width placed on one of its walls. Moreover, the long exit channel incorporated in our design, favors the transport of phospholipid molecules towards the gas-liquid interface. Our experiments show that the resulting phospholipid shell inhibit both the diffusion of the gas in the surrounding liquid as well as the coalescence between contacting bubbles. These evidences indicate that the proposed method is suitable for the generation of monodisperse microbubbles for diagnosis or therapeutical applications.

  16. Nose-To-Brain Delivery of PLGA-Diazepam Nanoparticles.

    PubMed

    Sharma, Deepak; Sharma, Rakesh Kumar; Sharma, Navneet; Gabrani, Reema; Sharma, Sanjeev K; Ali, Javed; Dang, Shweta

    2015-10-01

    The objective of the present investigation was to optimize diazepam (Dzp)-loaded poly(lactic-co-glycolic acid) nanoparticles (NP) to achieve delivery in the brain through intranasal administration. Dzp nanoparticles (DNP) were formulated by nanoprecipitation and optimized using Box-Behnken design. The influence of various independent process variables (polymer, surfactant, aqueous to organic (w/o) phase ratio, and drug) on resulting properties of DNP (z-average and drug entrapment) was investigated. Developed DNP showed z-average 148-337 d.nm, polydispersity index 0.04-0.45, drug entrapment 69-92%, and zeta potential in the range of -15 to -29.24 mV. Optimized DNP were further analyzed by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), ex-vivo drug release, and in-vitro cytotoxicity. Ex-vivo drug release study via sheep nasal mucosa from DNP showed a controlled release of 64.4% for 24 h. 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay performed on Vero cell line showed less toxicity for DNP as compared to Dzp suspension (DS). Gamma scintigraphy and biodistribution study of DNP and DS was performed on Sprague-Dawley rats using technetium-99m-labeled ((99m)Tc) Dzp formulations to investigate the nose-to-brain drug delivery pathway. Brain/blood uptake ratios, drug targeting efficiency, and direct nose-to-brain transport were found to be 1.23-1.45, 258, and 61% for (99m)Tc-DNP (i.n) compared to (99m)Tc-DS (i.n) (0.38-1.06, 125, and 1%). Scintigraphy images showed uptake of Dzp from nose-to-brain, and this observation was in agreement with the biodistribution results. These results suggest that the developed poly(D,L-lactide-co-glycolide) (PLGA) NP could serve as a potential carrier of Dzp for nose-to-brain delivery in outpatient management of status epilepticus.

  17. Mechanistic analysis of triamcinolone acetonide release from PLGA microspheres as a function of varying in vitro release conditions.

    PubMed

    Doty, Amy C; Zhang, Ying; Weinstein, David G; Wang, Yan; Choi, Stephanie; Qu, Wen; Mittal, Sachin; Schwendeman, Steven P

    2017-04-01

    In vitro tests for controlled release PLGA microspheres in their current state often do not accurately predict in vivo performance of these products during formulation development. Here, we introduce a new mechanistic and multi-phase approach to more clearly understand in vitro-in vivo relationships, and describe the first "in vitro phase" with the model drug, triamcinolone acetonide (Tr-A). Two microsphere formulations encapsulating Tr-A were prepared from PLGAs of different molecular weights and end-capping (18kDa acid-capped and 54kDa ester-capped). In vitro release kinetics and the evidence for controlling mechanisms (i.e., erosion, diffusion, and water-mediated processes) were studied in four release media: PBST pH 7.4 (standard condition), PBST pH 6.5, PBS+1.0% triethyl citrate (TC), and HBST pH 7.4. The release mechanism in PBST was primarily polymer erosion-controlled as indicated by the similarity of release and mass loss kinetics. Release from the low MW PLGA was accelerated at low pH due to increased rate of hydrolysis and in the presence of the plasticizer TC due to slightly increased hydrolysis and much higher diffusion in the polymer matrix. TC also increased release from the high MW PLGA due to increased hydrolysis, erosion, and diffusion. This work demonstrates how in vitro conditions can be manipulated to change not only rates of drug release from PLGA microspheres but also the mechanism(s) by which release occurs. Follow-on studies in the next phases of this approach will utilize these results to compare the mechanistic data of the Tr-A/PLGA microsphere formulations developed here after recovery of microspheres in vivo. This new approach based on measuring mechanistic indicators of release in vitro and in vivo has the potential to design better, more predictive in vitro release tests for these formulations and potentially lead to mechanism-based in vitro-in vivo correlations.

  18. Noninvasive characterization of the effect of varying PLGA molecular weight blends on in situ forming implant behavior using ultrasound imaging.

    PubMed

    Solorio, Luis; Olear, Alexander M; Hamilton, Jesse I; Patel, Ravi B; Beiswenger, Ashlei C; Wallace, Jon E; Zhou, Haoyan; Exner, Agata A

    2012-01-01

    In situ forming implants (ISFIs) have shown promise in drug delivery applications due to their simple manufacturing and minimally invasive administration. Precise, reproducible control of drug release from ISFIs is essential to their successful clinical application. This study investigated the effect of varying the molar ratio of different molecular weight (Mw) poly(D,L-lactic-co-glycolic acid) (PLGA) polymers within a single implant on the release of a small Mw mock drug (sodium fluorescein) both in vitro and in vivo. Implants were formulated by dissolving three different PLGA Mw (15, 29, and 53 kDa), as well as three 1:1 molar ratio combinations of each PLGA Mw in 1-methyl-2-pyrrolidinone (NMP) with the mock drug fluorescein. Since implant morphology and microstructure during ISFI formation and degradation is a crucial determinant of implant performance, and the rate of phase inversion has been shown to have an effect on the implant microstructure, diagnostic ultrasound was used to noninvasively quantify the extent of phase inversion and swelling behavior in both environments. Implant erosion, degradation, as well as the in vitro and in vivo release profiles were also measured using standard techniques. A non-linear mathematical model was used to correlate the drug release behavior with polymer phase inversion, with all formulations yielding an R(2) value greater than 0.95. Ultrasound was also used to create a 3D image reconstruction of an implant over a 12 day span. In this study, swelling and phase inversion were shown to be inversely related to the polymer Mw with 53 kDa polymer implants increasing at an average rate of 9.4%/day compared with 18.6%/day in the case of the 15 kDa PLGA. Additionally the onset of erosion, complete phase inversion, and degradation facilitated release required 9 d for 53 kDa implants, while these same processes began 3 d after injection into PBS with the 15 kDa implants. It was also observed that PLGA blends generally had

  19. Magnetic resonance properties of Gd(III)-bound lipid-coated microbubbles and their cavitation fragments.

    PubMed

    Feshitan, Jameel A; Boss, Michael A; Borden, Mark A

    2012-10-30

    Gas-filled microbubbles are potentially useful theranostic agents for magnetic resonance imaging-guided focused ultrasound surgery (MRIgFUS). Previously, MRI at 9.4 T was used to measure the contrast properties of lipid-coated microbubbles with gadolinium (Gd(III)) bound to lipid headgroups, which revealed that the longitudinal molar relaxivity (r(1)) increased after microbubble fragmentation. This behavior was attributed to an increase in water proton exchange with the Gd(III)-bound lipid fragments caused by an increase in the lipid headgroup area that accompanied the lipid shell monolayer-to-bilayer transition. In this article, we explore this mechanism by comparing the changes in r(1) and its transverse counterpart, r(2)*, after the fragmentation of microbubbles consisting of Gd(III) bound to two different locations on the lipid monolayer shell: the phosphatidylethanolamine (PE) lipid headgroup region or the distal region of the poly(ethylene glycol) (PEG) brush. Nuclear magnetic resonance (NMR) at 1.5 T was used to measure the contrast properties of the various microbubble constructs because this is the most common field strength used in clinical MRI. Results for the lipid-headgroup-labeled Gd(III) microbubbles revealed that r(1) increased after microbubble fragmentation, whereas r(2)* was unchanged. An analysis of PEG-labeled Gd(III) microbubbles revealed that both r(1) and r(2)* decreased after microbubble fragmentation. Further analysis revealed that the microbubble gas core enhanced the transverse MR signal (T(2)*) in a concentration-dependent manner but minimally affected the longitudinal (T(1)) signal. These results illustrate a new method for the use of NMR to measure the biomembrane packing structure and suggest that two mechanisms, proton-exchange enhancement by lipid membrane relaxation and magnetic field inhomogeneity imposed by the gas/liquid interface, may be used to detect and differentiate Gd(III)-labeled microbubbles and their cavitation

  20. Influence of microbubble in physical cleaning of MF membrane process for wastewater reuse.

    PubMed

    Lee, Eui-Jong; Kim, Young-Hoon; Kim, Hyung-Soo; Jang, Am

    2015-06-01

    Currently, there is a growing emphasis on wastewater reclamation and reuse all over the world due to restricted water resources. Among a variety of wastewater reuse technologies, the use of microfiltration membranes (MF) is one of the popular processes because it has the ability to successfully eliminate particulates and colloidal matters. However, successful fouling control is not easy because effluents from the activated sludge process still contain small particulates and colloidal matters such as extracellular polymeric substance (EPS) and soluble microbial products (SMP). On the other hand, microbubbles have advantageous properties compared to common bubbles, but there hasn't been reporting of the use of microbubbles in physical cleaning instead of aeration. Encouraging results were obtained herein through the application of microbubbles for physical cleaning. In evaluation of the cleaning efficiency, the efficiency of microbubbles was observed to be twice as high as that of aeration, except during the course of the initial 30 min. Total organic carbon (TOC) concentration of the membrane tank after treatment with microbubbles was more than twice as high as that after aeration for physical cleaning. The membrane cleaned with microbubbles also had the smoothest surface, with a roughness of 42.5 nm. In addition, microbubbles were found to effectively remove EPS and make the structure of the gel layer loose. In particular, the microbubbles had the ability to remove proteins through the effect of pyrolytic decomposition. Therefore, in FT-IR spectra of the membrane surfaces taken before and after physical cleaning, while each treatment showed similar peak positions, the peak values of the membrane treated with microbubbles were the lowest. Through various analyses, it was confirmed that microbubbles can remove foulants on the gel layer in spite of their very low shear force. This means that microbubble cleaning has full potential for use as a physical cleaning

  1. Microbubbles as drug delivery systems in cerebrovascular diseases.

    PubMed

    Spinelli, Mariacarmela; Demitri, Christian; Sannino, Alessandro; Peruzzotti-Jametti, Luca; Bacigaluppi, Marco; Comi, Giancarlo; Corea, Francesco

    2009-11-01

    The field of neurovascular ultrasound is growing rapidly with new applications. While ultrasound contrast agents were initially used to overcome poor transcranial bone windows for identification of cerebral arteries, newgeneration microbubbles in combination with innovative contrast-specific ultrasound techniques now enable potential therapeutic procedures. This article will provide a review of recent and emerging developments along with patents in ultrasound technology and contrast-specific therapeutic techniques for cerebrovascular patients.

  2. Chitosan-PLGA polymer blends as coatings for hydroxyapatite nanoparticles and their effect on antimicrobial properties, osteoconductivity and regeneration of osseous tissues.

    PubMed

    Ignjatović, Nenad; Wu, Victoria; Ajduković, Zorica; Mihajilov-Krstev, Tatjana; Uskoković, Vuk; Uskoković, Dragan

    2016-03-01

    Composite biomaterials comprising nanostructured hydroxyapatite (HAp) have an enormous potential for natural bone tissue reparation, filling and augmentation. Chitosan (Ch) as a naturally derived polymer has many physicochemical and biological properties that make it an attractive material for use in bone tissue engineering. On the other hand, poly-D,L-lactide-co-glycolide (PLGA) is a synthetic polymer with a long history of use in sustained drug delivery and tissue engineering. However, while chitosan can disrupt the cell membrane integrity and may induce blood thrombosis, PLGA releases acidic byproducts that may cause tissue inflammation and interfere with the healing process. One of the strategies to improve the biocompatibility of Ch and PLGA is to combine them with compounds that exhibit complementary properties. In this study we present the synthesis and characterization, as well as in vitro and in vivo analyses of a nanoparticulate form of HAp coated with two different polymeric systems: (a) Ch and (b) a Ch-PLGA polymer blend. Solvent/non-solvent precipitation and freeze-drying were used for synthesis and processing, respectively, whereas thermogravimetry coupled with mass spectrometry was used for phase identification purposes in the coating process. HAp/Ch composite particles exhibited the highest antimicrobial activity against all four microbial strains tested in this work, but after the reconstruction of the bone defect they also caused inflammatory reactions in the newly formed tissue where the defect had lain. Coating HAp with a polymeric blend composed of Ch and PLGA led to a decrease in the reactivity and antimicrobial activity of the composite particles, but also to an increase in the quality of the newly formed bone tissue in the reconstructed defect area.

  3. Microvascular flow estimation by microbubble-assisted Nakagami imaging.

    PubMed

    Tsui, Po-Hsiang; Yeh, Chih-Kuang; Chang, Chien-Cheng

    2009-04-01

    The destruction and replenishment of microbubbles has been previously applied to estimating blood flow in the microcirculation. The rate of increase of the time-intensity curve (TIC) due to microbubbles flowing into the region-of-interest (ROI) as measured from the conventional B-mode images reflects the flow velocity. In this study, we monitored microbubble replenishment using a new proposed approach called the time-Nakagami-parameter curve (TNC) obtained from the parametric image based on the Nakagami statistical parameter for quantifying the microvascular flow velocity. The Nakagami parameter is estimated from signal envelope to reflect the backscattered statistics. The feasibility of using the TNC to estimate the microvascular flow was explored by carrying out phantom measurements and in vivo animal experiments. The rates of increase of the TIC and TNC were quantified as the rate constants beta(I) and beta(N) of monoexponential fitted curves, respectively. The experimental results showed that beta(N) behaves similarly to the conventional beta(I) in quantifying the flow velocity. Moreover, the tolerance to the effects of clutter is greater for the TNC than for the TIC, which makes it possible to use beta(N) to differentiate various flow velocities even when the ROI contains nonperfused areas. This finding suggests that the TNC-based technique can be used as a complementary tool for the conventional TIC to improve measurement of blood flow in the microcirculation.

  4. CAVITATION THRESHOLD OF MICROBUBBLES IN GEL TUNNELS BY FOCUSED ULTRASOUND

    PubMed Central

    Sassaroli, E.; Hynynen, K.

    2007-01-01

    The investigation of inertial cavitation in micro-tunnels has significant implications for the development of therapeutic applications of ultrasound such as ultrasound-mediated drug and gene delivery. The threshold for inertial cavitation was investigated using a passive cavitation detector with a center frequency of 1 MHz. Micro-tunnels of various diameters (90 to 800 μm) embedded in gel were fabricated and injected with a solution of Optison™ contrast agent of concentrations 1.2% and 0.2% diluted in water. An ultrasound pulse of duration 500 ms and center frequency 1.736 MHz was used to insonate the microbubbles. The acoustic pressure was increased at one second intervals until broadband noise emission was detected. The pressure threshold at which broadband noise emission was observed was found to be dependent on the diameter of the micro-tunnels, with an average increase of 1.2 to 1.5 between the smallest and the largest tunnels, depending on the microbubble concentration. The evaluation of inertial cavitation in gel tunnels rather than tubes provides a novel opportunity to investigate microbubble collapse in a situation that simulates in vivo blood vessels better than tubes with solid walls do. PMID:17590501

  5. Safety of Microbubbles and Transcranial Ultrasound in Rabbits

    NASA Astrophysics Data System (ADS)

    Culp, William C.; Brown, Aliza T.; Hennings, Leah; Lowery, John; Culp, Benjamin C.; Erdem, Eren; Roberson, Paula; Matsunaga, Terry O.

    2007-05-01

    The object of this study was to evaluate the safety of large doses of microbubbles and ultrasound administered to the head of rabbits as if they were receiving acute stroke therapy of a similar nature. Materials and Methods: Female New Zealand White rabbits were used, N=24, in three groups 1] n=4 control (no treatment), 2] n=10 bubble control (ultrasound plus aspirin), and 3] n=10 target group (ultrasound plus aspirin plus MRX-815 microbubbles). Group 3 was infused with IV bubbles over 1 hour at 0.16cc/kg. Ultrasound was delivered to the dehaired side of the head during bubble infusion and for 1 additional hour at 0.8 W/cm2 20% pulsed wave. Rabbits survived for 22 to 24 hours, were imaged with computerized tomography and 3 Tesla magnetic resonance imaging including contrast studies, and sacrificed. Tetrazolium (TTC) and Hematoxylin and Eosin (H&E) sections were made for pathological examination. Results: All 24 animals showed absence of bleeding, endothelial damage, EKG abnormalities, stroke, blood-brain-barrier breakdown, or other acute abnormalities. CT and MRI showed no bleeding or signs of stroke, but two animals had mild hydrocephalus. The EKGs showed normal variation in QTc. Rabbit behavior was normal in all. Minimal chronic inflammation unrelated to the study was seen in 5. Two animals were excluded because of protocol violations and replaced during the study. Conclusion: The administered dose of microbubbles and ultrasound demonstrated no detrimental effects on the healthy rabbit animal model.

  6. Cavitation microstreaming and stress fields created by microbubbles.

    PubMed

    Collis, James; Manasseh, Richard; Liovic, Petar; Tho, Paul; Ooi, Andrew; Petkovic-Duran, Karolina; Zhu, Yonggang

    2010-02-01

    Cavitation microstreaming plays a role in the therapeutic action of microbubbles driven by ultrasound, such as the sonoporative and sonothrombolytic phenomena. Microscopic particle-image velocimetry experiments are presented. Results show that many different microstreaming patterns are possible around a microbubble when it is on a surface, albeit for microbubbles much larger than used in clinical practice. Each pattern is associated with a particular oscillation mode of the bubble, and changing between patterns is achieved by changing the sound frequency. Each microstreaming pattern also generates different shear stress and stretch/compression distributions in the vicinity of a bubble on a wall. Analysis of the micro-PIV results also shows that ultrasound-driven microstreaming flows around bubbles are feasible mechanisms for mixing therapeutic agents into the surrounding blood, as well as assisting sonoporative delivery of molecules across cell membranes. Patterns show significant variations around the bubble, suggesting sonoporation may be either enhanced or inhibited in different zones across a cellular surface. Thus, alternating the patterns may result in improved sonoporation and sonothrombolysis. The clear and reproducible delineation of microstreaming patterns based on driving frequency makes frequency-based pattern alternation a feasible alternative to the clinically less desirable practice of increasing sound pressure for equivalent sonoporative or sonothrombolytic effect. Surface divergence is proposed as a measure relevant to sonoporation.

  7. Controlled and Sequential Delivery of Fluorophores from 3D Printed Alginate-PLGA Tubes.

    PubMed

    Do, Anh-Vu; Akkouch, Adil; Green, Brian; Ozbolat, Ibrahim; Debabneh, Amer; Geary, Sean; Salem, Aliasger K

    2017-01-01

    Controlled drug delivery systems, that include sequential and/or sustained drug delivery, have been utilized to enhance the therapeutic effects of many current drugs by effectively delivering drugs in a time-dependent and repeatable manner. In this study, with the aid of 3D printing technology, a novel drug delivery device was fabricated and tested to evaluate sequential delivery functionality. With an alginate shell and a poly(lactic-co-glycolic acid) (PLGA) core, the fabricated tubes displayed sequential release of distinct fluorescent dyes and showed no cytotoxicity when incubated with the human embryonic kidney (HEK293) cell line or bone marrow stromal stem cells (BMSC). The controlled differential release of drugs or proteins through such a delivery system has the potential to be used in a wide variety of biomedical applications from treating cancer to regenerative medicine.

  8. Apparatus and process for the separation of hydrophobic and hydrophilic particles using microbubble column flotation together with a process and apparatus for generation of microbubbles

    DOEpatents

    Yoon, R.H.; Adel, G.T.; Luttrell, G.H.

    1992-12-01

    A method and apparatus are disclosed for the microbubble flotation separation of very fine and coarse particles, especially coal and minerals, so as to produce high purity and high recovery efficiency. This is accomplished through the use of a flotation column, microbubbles, recycling of the flotation pulp, and countercurrent wash water to gently wash the froth. Also disclosed are unique processes and apparatus for generating microbubbles for flotation in a highly efficient and inexpensive manner using either a porous tube or in-line static generators. 14 figs.

  9. Apparatus and process for the separation of hydrophobic and hydrophilic particles using microbubble column flotation together with a process and apparatus for generation of microbubbles

    DOEpatents

    Yoon, R.H.; Adel, G.T.; Luttrell, G.H.

    1998-09-29

    A method and apparatus are disclosed for the microbubble flotation separation of very fine and coarse particles, especially coal and minerals, so as to produce high purity and high recovery efficiency. This is accomplished through the use of a flotation column, microbubbles, recycling of the flotation pulp, and countercurrent wash water to gently wash the froth. Also disclosed are unique processes and apparatus for generating microbubbles for flotation in a highly efficient and inexpensive manner using either a porous tube or in-line static generators. 14 figs.

  10. Apparatus for the separation of hydrophobic and hydrophilic particles using microbubble column flotation together with a process and apparatus for generation of microbubbles

    DOEpatents

    Yoon, Roe-Hoan; Adel, Gregory T.; Luttrell, Gerald H.

    1995-01-01

    An apparatus is disclosed for the microbubble flotation separation of very fine and coarse particles, especially coal, and minerals so as to produce high purity and high recovery efficiency. This is accomplished through the use of a flotation column, microbubbles, recycling of the flotation pulp, and countercurrent wash water to gently wash the froth. Also disclosed are unique processes and apparatus for generating microbubbles for flotation in a highly efficient and inexpensive manner using either a porous tube or in-line static generators.

  11. Apparatus and process for the separation of hydrophobic and hydrophilic particles using microbubble column flotation together with a process and apparatus for generation of microbubbles

    DOEpatents

    Yoon, Roe-Hoan; Adel, Gregory T.; Luttrell, Gerald H.

    1992-01-01

    A method and apparatus are disclosed for the microbubble flotation separation of very fine and coarse particles, especially coal and minerals, so as to produce high purity and high recovery efficiency. This is accomplished through the use of a flotation column, microbubbles, recycling of the flotation pulp, and countercurrent wash water to gently wash the froth. Also disclosed are unique processes and apparatus for generating microbubbles for flotation in a highly efficient and inexpensive manner using either a porous tube or in-line static generators.

  12. Apparatus for the separation of hydrophobic and hydrophilic particles using microbubble column flotation together with a process and apparatus for generation of microbubbles

    DOEpatents

    Yoon, R.H.; Adel, G.T.; Luttrell, G.H.

    1995-03-14

    An apparatus is disclosed for the microbubble flotation separation of very fine and coarse particles, especially coal, and minerals so as to produce high purity and high recovery efficiency. This is accomplished through the use of a flotation column, microbubbles, recycling of the flotation pulp, and countercurrent wash water to gently wash the froth. Also disclosed are unique processes and apparatus for generating microbubbles for flotation in a highly efficient and inexpensive manner using either a porous tube or in-line static generators. 14 figs.

  13. Apparatus and process for the separation of hydrophobic and hydrophilic particles using microbubble column flotation together with a process and apparatus for generation of microbubbles

    DOEpatents

    Yoon, Roe-Hoan; Adel, Gregory T.; Luttrell, Gerald H.

    1998-01-01

    A method and apparatus are disclosed for the microbubble flotation separation of very fine and coarse particles, especially coal and minerals, so as to produce high purity and high recovery efficiency. This is accomplished through the use of a flotation column, microbubbles, recycling of the flotation pulp, and countercurrent wash water to gently wash the froth. Also disclosed are unique processes and apparatus for generating microbubbles for flotation in a highly efficient and inexpensive manner using either a porous tube or in-line static generators.

  14. Synthesis and Characterization of PLGA Shell Microcapsules Containing Aqueous Cores Prepared by Internal Phase Separation.

    PubMed

    Abulateefeh, Samer R; Alkilany, Alaaldin M

    2016-08-01

    The preparation of microcapsules consisting of poly(D,L-lactide-co-glycolide) (PLGA) polymer shell and aqueous core is a clear challenge and hence has been rarely addressed in literature. Herein, aqueous core-PLGA shell microcapsules have been prepared by internal phase separation from acetone-water in oil emulsion. The resulting microcapsules exhibited mean particle size of 1.1 ± 0.39 μm (PDI = 0.35) with spherical surface morphology and internal poly-nuclear core morphology as indicated by scanning electron microscopy (SEM). The incorporation of water molecules into PLGA microcapsules was confirmed by differential scanning calorimetry (DSC). Aqueous core-PLGA shell microcapsules and the corresponding conventional PLGA microspheres were prepared and loaded with risedronate sodium as a model drug. Interestingly, aqueous core-PLGA shell microcapsules illustrated 2.5-fold increase in drug encapsulation in comparison to the classical PLGA microspheres (i.e., 31.6 vs. 12.7%), while exhibiting sustained release behavior following diffusion-controlled Higuchi model. The reported method could be extrapolated to encapsulate other water soluble drugs and hydrophilic macromolecules into PLGA microcapsules, which should overcome various drawbacks correlated with conventional PLGA microspheres in terms of drug loading and release.

  15. Surface modification of PLGA nanoparticles with biotinylated chitosan for the sustained in vitro release and the enhanced cytotoxicity of epirubicin.

    PubMed

    Chen, Hongli; Xie, Li Qin; Qin, Jingwen; Jia, Yajing; Cai, Xinhua; Nan, WenBin; Yang, Wancai; Lv, Feng; Zhang, Qi Qing

    2016-02-01

    In this study, poly(d,l-lactide-co-glycolide) nanoparticles (PLGA NPs) with biotinylated chitosan (Bio-CS)-surface modification were prepared to be usded as a tumor-targeted and prolonged delivery system for anticancer drugs. Epirubicin (EPB), as a model drug, was encapsulated into Bio-CS surface modified PLGA (Bio-CS-PLGA) NPs with a drug encapsulation efficiency of 84.1 ± 3.4%. EPB-loaded Bio-CS-PLGA NPs were spherical shaped, and had a larger size and higher positive zeta potential compared to the unmodfied EPB-loaded PLGA NPs. The in vitro drug releases showed that EPB-loaded Bio-CS-PLGA NPs exhibited relatively constant drug release kinetics during the first 48 h and the drug burst release significantly decreased in comparison to the unmodified PLGA NPs. The results of MTS assays showed that Bio-CS-PLGA NPs markedly increased the cytotoxicity of EPB, compared to both the unmodified PLGA NPs and the CS-PLGA NPs. The uptakes of NPs in human breast cancer MCF-7 cells were evaluated by the flow cytometry and the confocal microscope. The results revealed that Bio-CS-PLGA NPs exhibited a greater extent of cellular uptake than the unmodified PLGA NPs and CS-PLGA NPs. Moreover, the cellular uptake of Bio-CS-PLGA NPs was evidently inhibited by the endocytic inhibitors and the receptor ligand, indicating that biotin receptor-mediated endocytosis was perhaps involved in the cell entry of Bio-CS-PLGA NPs. In MCF-7 tumor-bearing nude mice, EPB-loaded Bio-CS-PLGA NPs were efficiently accumulated in the tumors. In summary, Bio-CS-PLGA NPs displayed great potential for application as the carriers of anticancer drugs.

  16. Study on the application of FCMC-1500 cyclonic microbubble flotation column for coal preparation

    SciTech Connect

    Xie Guangyuan; Ou Zeshen; Ge Mi; Wang Yongtian; Liu Jiongtian

    1997-12-31

    In this paper the cyclonic microbubble flotation column is introduced. Its structure and the principle of operation along with some results in a commercial plant are also presented. The test results have demonstrated the cyclonic microbubble flotation column to be highly selective and extremely efficient in ash rejection from fine coals, oil consumption, and energy conservation. It has a great future for commercialization.

  17. Theranostic mRNA-loaded Microbubbles in the Lymphatics of Dogs: Implications for Drug Delivery

    PubMed Central

    Dewitte, Heleen; Vanderperren, Katrien; Haers, Hendrik; Stock, Emmelie; Duchateau, Luc; Hesta, Myriam; Saunders, Jimmy H.; De Smedt, Stefaan C.; Lentacker, Ine

    2015-01-01

    Microbubbles have shown potential as intralymphatic ultrasound contrast agents while nanoparticle-loaded microbubbles are increasingly investigated for ultrasound-triggered drug and gene delivery. To explore whether mRNA-nanoparticle loaded microbubbles could serve as theranostics for detection of and mRNA transfer to the lymph nodes, we investigate the behavior of unloaded and mRNA-loaded microbubbles using contrast-enhanced ultrasound imaging after subcutaneous injection in dogs. Our results indicate that both types of microbubbles are equally capable of rapidly entering the lymph vessels and nodes upon injection, and novel, valuable and detailed information on the lymphatic structure in the animals could be obtained. Furthermore, additional observations were made regarding the dynamics of microbubble lymph node uptake. Importantly, neither the microbubble migration distance within the lymphatics, nor the observed contrast signal intensity was influenced by mRNA-loading. Although further optimization of acoustic parameters will be needed, this could represent a first step towards ultrasound-guided, ultrasound-triggered intranodal mRNA delivery using these theranostic microbubbles. PMID:25553101

  18. Sonothrombolysis with BR38 Microbubbles Improves Microvascular Patency in a Rat Model of Stroke

    PubMed Central

    Kampschulte, Marian; Hyvelin, Jean-Marc; Botteron, Catherine; Juenemann, Martin; Yeniguen, Mesut; Krombach, Gabriele A.; Kaps, Manfred; Spratt, Neil J.; Gerriets, Tibo; Nedelmann, Max

    2016-01-01

    Background Early recanalization of large cerebral vessels in ischemic stroke is associated with improved clinical outcome, however persisting hypoperfusion leads to poor clinical recovery despite large vessel recanalization. Limited experimental sonothrombolysis studies have shown that addition of microbubbles during treatment can improve microvascular patency. We aimed to determine the effect of two different microbubble formulations on microvascular patency in a rat stroke model. Methods We tested BR38 and SonoVue® microbubble-enhanced sonothrombolysis in Wistar rats submitted to 90-minute filament occlusion of the middle cerebral artery. Rats were randomized to treatment (n = 6/group): control, rt-PA, or rt-PA+3-MHz ultrasound insonation with BR38 or SonoVue® at full or 1/3 dose. Treatment duration was 60 minutes, beginning after withdrawal of the filament, and sacrifice was immediately after treatment. Vascular volumes were evaluated with microcomputed tomography. Results Total vascular volume of the ipsilateral hemisphere was reduced in control and rt-PA groups (p<0.05), but was not significantly different from the contralateral hemisphere in all microbubble-treated groups (p>0.1). Conclusions Microbubble-enhanced sonothrombolysis improves microvascular patency. This effect is not dose- or microbubble formulation-dependent suggesting a class effect of microbubbles promoting microvascular reopening. This study demonstrates that microbubble-enhanced sonothrombolysis may be a therapeutic strategy for patients with persistent hypoperfusion of the ischemic territory. PMID:27077372

  19. Factors that affect the efficiency of antisense oligodeoxyribonucleotide transfection by insonated gas-filled lipid microbubbles

    NASA Astrophysics Data System (ADS)

    Zhao, Ying-Zheng; Lu, Cui-Tao

    2008-03-01

    Objective: To investigate the factors that affect the efficiency of antisense oligodeoxyribonucleotide(AS-ODNs) transfection by insonated gas-filled lipid microbubbles. Methods: Lipid microbubbles filled with two types of gases-air and C3F8, were prepared respectively. An AS-ODNs sequence HA824 and a breast cancer cell line SK-BR-3 were used to define the various operating variables determining the transfection efficiency of insonated microbubbles. Two mixing methods, three levels of mixing speed, different mixing durations and various ultrasound initiation time after mixing were examined respectively. Transfection efficiency was detected by fluorescence microscopy. Results: C3F8 microbubbles gave higher levels of AS-ODNs transfection efficiency than air microbubbles in all test conditions. Transfection efficiency resulted from mixing method A (incubation of HA824 and microbubbles before mixing cells) did not show significant difference with that of mixing method B (without incubation of HA824 and microbubbles before mixing cells). Mixing speed, duration of mixing and ultrasound initiation time after mixing were central to determining HA824 transfection efficiency in vitro. The optimum parameters for SK-BR-3 cells were found at a mixing speed of 40-50 rpm for 30-60 s with less than 60 s delay before ultrasound. Conclusion: Ultrasound-mediated AS-ODNs transfection enhanced by C3F8-filled lipid microbubbles represents an effective avenue for AS-ODNs transfer.

  20. Analysis of polyvinyl alcohol microbubbles in human blood plasma using capillary electrophoresis.

    PubMed

    Josefsson, Leila; Larsson, Malin K; Bjällmark, Anna; Emmer, Åsa

    2016-04-01

    Recently, a new type of ultrasound contrast agent that consists of air-filled microbubbles stabilized with a shell of polyvinyl alcohol was developed. When superparamagnetic nanoparticles of iron oxide are incorporated in the polymer shell, a multimodal contrast agent can be obtained. The biodistribution and elimination pathways of the polyvinyl alcohol microbubbles are essential to investigate, which is limited with today's techniques. The aim of the present study was, therefore, to develop a method for qualitative and quantitative analysis of microbubbles in biological samples using capillary electrophoresis with ultraviolet detection. The analysis parameters were optimized to a wavelength at 260 nm and pH of the background electrolyte ranging between 11.9 and 12. Studies with high-intensity ultrasonication degraded microbubbles in water showed that degraded products and intact microbubbles could be distinguished, thus it was possible to quantify the intact microbubbles solely. Analysis of human blood plasma spiked with either plain microbubbles or microbubbles with nanoparticles demonstrated that it is possible to separate them from biological components like proteins in these kinds of samples.

  1. Understanding the Structure and Mechanism of Formation of a New Magnetic Microbubble Formulation

    PubMed Central

    Owen, Joshua; Zhou, Bin; Rademeyer, Paul; Tang, Meng-Xing; Pankhurst, Quentin; Eckersley, Robert; Stride, Eleanor

    2012-01-01

    Magnetic nanoparticles and ultrasound contrast agents have both been used as vehicles for therapeutic delivery. More recently, magnetic microbubbles have been developed as a new theranostic agent which combines the advantages of the individual carriers and overcomes many of their limitations. In a previous study of gene delivery using magnetic microbubbles, it was found that a combination of magnetic liquid droplets and non-magnetic phospholipid microbubbles produced higher transfection rates than magnetic microbubbles. The reasons for this were not fully understood, however. The aim of this study was to investigate the hypothesis that conjugation between the droplets and the microbubbles occurred. A combination of optical and fluorescence microscopy and ultrasound imaging studies in a flow phantom were performed. No interaction between magnetic droplets and microbubbles was observed under optical microscopy but the results from the fluorescence and acoustic imaging indicated that magnetic droplets and microbubbles do indeed combine to form a new magnetically and acoustically responsive particle. Theoretical calculations indicate that the driving force of the interaction is the relative surface energy and thus thermodynamic stability of the microbubbles and the droplets. The new particles were resistant to centrifugation, of comparable echogenicity to conventional ultrasound contrast agents and could be retained by a magnetic field (0.2T) in a flow phantom at centre line velocities of ~6 cm s-1 and shear rates of ~60 s -1. PMID:23382771

  2. Risk of decompression sickness in the presence of circulating microbubbles

    NASA Technical Reports Server (NTRS)

    Kumar, K. Vasantha; Powell, Michael R.

    1993-01-01

    In this study, we examined the association between microbubbles formed in the circulation from a free gas phase and symptoms of altitude decompression sickness (DCS). In a subgroup of 59 males of mean (S.D) age 31.2 (5.8) years who developed microbubbles during exposure to 26.59 kPa (4.3 psi) under simulated extravehicular activities (EVA), symptoms of DCS occurred in 24 (41 percent) individuals. Spencer grade 1 microbubbles occurred in 4 (7 percent), grade 2 in 9 (15 percent), grade 3 in 15 (25 percent), and grade 4 in 31 (53 percent) of subjects. Survival analysis using Cox proportional hazards regression showed that individuals with less than grade 3 CMB showed 2.46 times (95 percent confidence interval = 1.26 to 5.34) higher risk of symptoms. This information is crucial for defining the risk of DCS for inflight Doppler monitoring under space EVA. Altitude decompression sickness (DCS) occurs when there is acute reduction in ambient pressure. The symptoms of DCS are due to the formation of a free gas phase (in the form of gas microbubbles) in tissues during decompression. Musculo-skeletal pain of bends is the commonest form of DCS in altitude exposures. In the space flight environment, there is a risk of DCS when astronauts decompress from the normobaric shuttle pressure into the hypobaric space suit pressure (currently about 29.65 kPa (4.3 psi) for extra-vehicular activities (EVA). This risk is counterbalanced by a judicious combination of prior denitrogenation and staged decompression. Studies of DCS are limited by the duration of the test at reduced pressure. Since only a proportion of subjects tested develop symptoms, the information on DCS is generally incomplete or 'censored'. Many studies employ Doppler ultrasound monitoring of the precordial area for detecting circulating microbubbles (CMB). Although the association between CMB and bends pain is not causal, CMB are frequently monitored during decompression. In this paper, we examine the association

  3. Ultra-high Speed Optical Imaging of Ultrasound-activated Microbubbles in Mesenteric Microvessels

    NASA Astrophysics Data System (ADS)

    Chen, Hong

    Ultrasound contrast agent microbubbles have gained widespread applications in diagnostic and therapeutic ultrasound. Animal studies of bioeffects induced by ultrasound-activated microbubbles have demonstrated that microbubbles can cause microvessel damage. Much scientific attention has been attracted to such microvascular bioeffects, not only because of the related safety concerns, but also because of the potential useful applications of microbubbles in the intravascular delivery of drugs and genetic materials into target tissues. A significant challenge in using microbubbles in medical ultrasound is the lack of knowledge about how the microbubbles behave in blood vessels when exposed to ultrasound and how their interactions with ultrasound cause vascular damage. Although extensive studies were performed in the past to study the dynamics of microbubbles, most of those studies were performed in vitro and did not directly address the clinical environment in which microbubbles are injected into blood vessels. In this thesis work, a synchronized optical-acoustic system was set up for ultrahigh speed imaging of insonated microbubbles in microvessels. The recorded images revealed the formation of microjets penetrating the microbubbles, as well as vessel distention (motion outward against the surrounding tissue) and vessel invagination (motion inward toward the lumen) caused by the expansion and collapse of the microbubbles, respectively. Contrary to current paradigms which propose that microbubbles damage vessels either by distending them or by forming liquid jets impinging on them, microbubbles translation and jetting were in the direction away from the nearest vessel wall; furthermore, invagination typically exceeded distention in arterioles and venules. Vessel invagination was found to be associated with vascular damage. These studies suggest that vessel invagination may be a newly discovered potential mechanism for vascular damage by ultrasound-activated microbubbles

  4. Targeted gene transfection from microbubbles into vascular smooth muscle cells using focused, ultrasound-mediated delivery

    PubMed Central

    Phillips, Linsey C.; Klibanov, Alexander L.; Wamhoff, Brian R.; Hossack, John A.

    2010-01-01

    We investigate a method for gene delivery to vascular smooth muscle cells using ultrasound triggered delivery of plasmid DNA from electrostatically coupled cationic microbubbles. Microbubbles carrying reporter plasmid DNA were acoustically ruptured in the vicinity of smooth muscle cells in vitro under a range of acoustic pressures (0–950 kPa) and pulse durations (0–100 cycles). No effect on gene transfection or viability was observed from application of microbubbles, DNA, or ultrasound alone. Microbubbles in combination with ultrasound (500 kPa, 1MHz, 50 cycle bursts at a Pulse Repetition Frequency [PRF] of 100 Hz) significantly reduced viability both with DNA (53 +/− 27%) and without (19 +/− 8%). Maximal gene transfection (~1% of cells) occurred using 50 cycle, 1 MHz pulses at 300 kPa which resulted in 40% viability of cells. We demonstrated that we can locally deliver DNA to vascular smooth muscle cells in vitro using microbubble carriers and focused ultrasound. PMID:20800174

  5. Oil recovery in the presence of microbubbles in the filtration flow

    NASA Astrophysics Data System (ADS)

    Mikhailov, D. N.

    2012-05-01

    This paper presents mathematical models for oil-gas flow taking into account the various processes due to the formation of gas micronuclei (microbubbles) in oil: slip of oil relative to the walls of the pore channels (gas lubrication), changes in oil viscosity, and motion of microbubles with respect to oil. We consider examples of oil flow in the near-wellbore zone for the case where a reduction in pressure to the saturation pressure leads to the formation of gas microbubbles and micronuclei and examples of the action of a water-gas mixture in the case where oil foams in the contact area with the injected gas, i.e., a finely dispersed mixture of oil and microbubbles is formed. The behavior of indicator curves for an oil well with the formation of microbubbles is simulated, and the effect of microbubbles on the oil recovery factor in a water-alternating-gas injection process is studied.

  6. In situ conversion of porphyrin microbubbles to nanoparticles for multimodality imaging

    NASA Astrophysics Data System (ADS)

    Huynh, Elizabeth; Leung, Ben Y. C.; Helfield, Brandon L.; Shakiba, Mojdeh; Gandier, Julie-Anne; Jin, Cheng S.; Master, Emma R.; Wilson, Brian C.; Goertz, David E.; Zheng, Gang

    2015-05-01

    Converting nanoparticles or monomeric compounds into larger supramolecular structures by endogenous or external stimuli is increasingly popular because these materials are useful for imaging and treating diseases. However, conversion of microstructures to nanostructures is less common. Here, we show the conversion of microbubbles to nanoparticles using low-frequency ultrasound. The microbubble consists of a bacteriochlorophyll-lipid shell around a perfluoropropane gas. The encapsulated gas provides ultrasound imaging contrast and the porphyrins in the shell confer photoacoustic and fluorescent properties. On exposure to ultrasound, the microbubbles burst and form smaller nanoparticles that possess the same optical properties as the original microbubble. We show that this conversion is possible in tumour-bearing mice and could be validated using photoacoustic imaging. With this conversion, our microbubble can potentially be used to bypass the enhanced permeability and retention effect when delivering drugs to tumours.

  7. 3D printing PLGA: a quantitative examination of the effects of polymer composition and printing parameters on print resolution.

    PubMed

    Guo, Ting; Holzberg, Timothy R; Lim, Casey G; Gao, Feng; Gargava, Ankit; Trachtenberg, Jordan E; Mikos, Antonios G; Fisher, John P

    2017-04-12

    In the past few decades, 3D printing has played a significant role in fabricating scaffolds with consistent, complex structure that meet patient-specific needs in future clinical applications. Although many studies have contributed to this emerging field of additive manufacturing, which includes material development and computer-aided scaffold design, current quantitative analyses do not correlate material properties, printing parameters, and printing outcomes to a great extent. A model that correlates these properties has tremendous potential to standardize 3D printing for tissue engineering and biomaterial science. In this study, we printed poly(lactic-co-glycolic acid) (PLGA) utilizing a direct melt extrusion technique without additional ingredients. We investigated PLGA with various lactic acid:glycolic acid (LA:GA) molecular weight ratios and end caps to demonstrate the dependence of the extrusion process on the polymer composition. Micro-computed tomography was then used to evaluate printed scaffolds containing different LA:GA ratios, composed of different fiber patterns, and processed under different printing conditions. We built a statistical model to reveal the correlation and predominant factors that determine printing precision. Our model showed a strong linear relationship between the actual and predicted precision under different combinations of printing conditions and material compositions. This quantitative examination establishes a significant foreground to 3D print biomaterials following a systematic fabrication procedure. Additionally, our proposed statistical models can be applied to couple specific biomaterials and 3D printing applications for patient implants with particular requirements.

  8. Fabrication and evaluation of a sustained-release chitosan-based scaffold embedded with PLGA microspheres.

    PubMed

    Song, Kedong; Liu, Yingchao; Macedo, Hugo M; Jiang, Lili; Li, Chao; Mei, Guanyu; Liu, Tianqing

    2013-04-01

    Nutrient depletion within three-dimensional (3D) scaffolds is one of the major hurdles in the use of this technology to grow cells for applications in tissue engineering. In order to help in addressing it, we herein propose to use the controlled release of encapsulated nutrients within polymer microspheres into chitosan-based 3D scaffolds, wherein the microspheres are embedded. This method has allowed maintaining a stable concentration of nutrients within the scaffolds over the long term. The polymer microspheres were prepared using multiple emulsions (w/o/w), in which bovine serum albumin (BSA) and poly (lactic-co-glycolic) acid (PLGA) were regarded as the protein pattern and the exoperidium material, respectively. These were then mixed with a chitosan solution in order to form the scaffolds by cryo-desiccation. The release of BSA, entrapped within the embedded microspheres, was monitored with time using a BCA kit. The morphology and structure of the PLGA microspheres containing BSA before and after embedding within the scaffold were observed under a scanning electron microscope (SEM). These had a round shape with diameters in the range of 27-55 μm, whereas the chitosan-based scaffolds had a uniform porous structure with the microspheres uniformly dispersed within their 3D structure and without any morphological change. In addition, the porosity, water absorption and degradation rate at 37 °C in an aqueous environment of 1% chitosan-based scaffolds were (92.99±2.51) %, (89.66±0.66) % and (73.77±3.21) %, respectively. The studies of BSA release from the embedded microspheres have shown a sustained and cumulative tendency with little initial burst, with (20.24±0.83) % of the initial amount released after 168 h (an average rate of 0.12%/h). The protein concentration within the chitosan-based scaffolds after 168 h was found to be (11.44±1.81)×10(-2) mg/mL. This novel chitosan-based scaffold embedded with PLGA microspheres has proven to be a promising technique

  9. N-trimethyl chitosan chloride-coated PLGA nanoparticles overcoming multiple barriers to oral insulin absorption.

    PubMed

    Sheng, Jianyong; Han, Limei; Qin, Jing; Ru, Ge; Li, Ruixiang; Wu, Lihong; Cui, Dongqi; Yang, Pei; He, Yuwei; Wang, Jianxin

    2015-07-22

    Although several strategies have been applied for oral insulin delivery to improve insulin bioavailability, little success has been achieved. To overcome multiple barriers to oral insulin absorption simultaneously, insulin-loaded N-trimethyl chitosan chloride (TMC)-coated polylactide-co-glycoside (PLGA) nanoparticles (Ins TMC-PLGA NPs) were formulated in our study. The Ins TMC-PLGA NPs were prepared using the double-emulsion solvent evaporation method and were characterized to determine their size (247.6 ± 7.2 nm), ζ-potential (45.2 ± 4.6 mV), insulin-loading capacity (7.8 ± 0.5%) and encapsulation efficiency (47.0 ± 2.9%). The stability and insulin release of the nanoparticles in enzyme-containing simulated gastrointestinal fluids suggested that the TMC-PLGA NPs could partially protect insulin from enzymatic degradation. Compared with unmodified PLGA NPs, the positively charged TMC-PLGA NPs could improve the mucus penetration of insulin in mucus-secreting HT29-MTX cells, the cellular uptake of insulin via clathrin- or adsorption-mediated endocytosis in Caco-2 cells and the permeation of insulin across a Caco-2 cell monolayer through tight junction opening. After oral administration in mice, the TMC-PLGA NPs moved more slowly through the gastrointestinal tract compared with unmodified PLGA NPs, indicating the mucoadhesive property of the nanoparticles after TMC coating. Additionally, in pharmacological studies in diabetic rats, orally administered Ins TMC-PLGA NPs produced a stronger hypoglycemic effect, with 2-fold higher relative pharmacological availability compared with unmodified NPs. In conclusion, oral insulin absorption is improved by TMC-PLGA NPs with the multiple absorption barriers overcome simultaneously. TMC-PLGA NPs may be a promising drug delivery system for oral administration of macromolecular therapeutics.

  10. Polyplex-Microbubble Hybrids for Ultrasound-Guided Plasmid DNA Delivery to Solid Tumors

    PubMed Central

    Sirsi, Shashank; Hernandez, Sonia; Zielinski, Lukasz; Blomback, Henning; Koubaa, Adel; Synder, Milo; Homma, Shunichi; Kandel, Jessica J.; Yamashiro, Darrell J.; Borden, Mark A.

    2013-01-01

    Microbubble ultrasound contrast agents are being developed as image-guided gene carriers for targeted delivery in vivo. In this study, novel polyplex-microbubbles were synthesized, characterized and evaluated for systemic circulation and tumor transfection. Branched polyethylenimine (PEI; 25 kDa) was modified with polyethylene glycol (PEG; 5 kDa), thiolated and covalently attached to maleimide groups on lipid-coated microbubbles. The PEI-microbubbles demonstrated increasingly positive surface charge and DNA loading capacity with increasing maleimide content. The in vivo ultrasound contrast persistence of PEI-microbubbles was measured in the healthy mouse kidney, and a two-compartment pharmacokinetic model accounting for free and adherent microbubbles was developed to describe the anomalous time-intensity curves. The model suggested that PEI loading dramatically reduced free circulation and increased nonspecific adhesion to the vasculature. However, DNA loading to form polyplex-microbubbles increased circulation in the bloodstream and decreased nonspecific adhesion. PEI-microbubbles coupled to a luciferase bioluminescence reporter plasmid DNA were shown to transfect tumors implanted in the mouse kidney. Site-specific delivery was achieved using ultrasound applied over the tumor area following bolus injection of the DNA/PEI-microbubbles. In vivo imaging showed over 10-fold higher bioluminescence from the tumor region compared to untreated tissue. Ex vivo analysis of excised tumors showed greater than 40-fold higher expression in tumor tissue than non-sonicated control (heart) tissue. These results suggest that the polyplex-microbubble platform offers improved control of DNA loading and packaging suitable for ultrasound-guided tissue transfection. PMID:21945680

  11. Cardiac Gene Expression Knockdown Using Small Inhibitory RNA-Loaded Microbubbles and Ultrasound

    PubMed Central

    McTiernan, Charles F.; Chen, Xucai; Klein, Edwin C.; Villanueva, Flordeliza S.

    2016-01-01

    RNA interference has potential therapeutic value for cardiac disease, but targeted delivery of interfering RNA is a challenge. Custom designed microbubbles, in conjunction with ultrasound, can deliver small inhibitory RNA to target tissues in vivo. The efficacy of cardiac RNA interference using a microbubble-ultrasound theranostic platform has not been demonstrated in vivo. Therefore, our objective was to test the hypothesis that custom designed microbubbles and ultrasound can mediate effective delivery of small inhibitory RNA to the heart. Microbubble and ultrasound mediated cardiac RNA interference was tested in transgenic mice displaying cardiac-restricted luciferase expression. Luciferase expression was assayed in select tissues of untreated mice (n = 14). Mice received intravenous infusion of cationic microbubbles bearing small inhibitory RNA directed against luciferase (n = 9) or control RNA (n = 8) during intermittent cardiac-directed ultrasound at mechanical index of 1.6. Simultaneous echocardiography in a separate group of mice (n = 3) confirmed microbubble destruction and replenishment during treatment. Three days post treatment, cardiac luciferase messenger RNA and protein levels were significantly lower in ultrasound-treated mice receiving microbubbles loaded with small inhibitory RNA directed against luciferase compared to mice receiving microbubbles bearing control RNA (23±7% and 33±7% of control mice, p<0.01 and p = 0.03, respectively). Passive cavitation detection focused on the heart confirmed that insonification resulted in inertial cavitation. In conclusion, small inhibitory RNA-loaded microbubbles and ultrasound directed at the heart significantly reduced the expression of a reporter gene. Ultrasound-targeted destruction of RNA-loaded microbubbles may be an effective image-guided strategy for therapeutic RNA interference in cardiac disease. PMID:27471848

  12. Optical Verification of Microbubble Response to Acoustic Radiation Force in Large Vessels with In Vivo Results

    PubMed Central

    Wang, Shiying; Wang, Claudia Y.; Unnikrishnan, Sunil; Klibanov, Alexander L.; Hossack, John A.; Mauldin, F. William

    2015-01-01

    Objectives To optically verify the dynamic behaviors of adherent microbubbles in large blood vessel environments in response to a new ultrasound technique using modulated acoustic radiation force. Materials and Methods Polydimethylsiloxane (PDMS) flow channels coated with streptavidin were used in targeted groups to mimic large blood vessels. The custom modulated acoustic radiation force beam sequence was programmed on a Verasonics research scanner. In vitro experiments were performed by injecting a biotinylated lipid-perfluorobutane microbubble dispersion through flow channels. The dynamic response of adherent microbubbles was detected acoustically and simultaneously visualized using a video camera connected to a microscope. In vivo verification was performed in a large abdominal blood vessel of a murine model for inflammation with injection of biotinylated microbubbles conjugated with P-selectin antibody. Results Aggregates of adherent microbubbles were observed optically under the influence of acoustic radiation force. Large microbubble aggregates were observed solely in control groups without targeted adhesion. Additionally, the dispersion of microbubble aggregates were demonstrated to lead to a transient acoustic signal enhancement in control groups (a new phenomenon we refer to as “control peak”). In agreement with in vitro results, the “control peak” phenomenon was observed in vivo in a murine model. Conclusions This study provides the first optical observation of microbubble binding dynamics in large blood vessel environments with application of a modulated acoustic radiation force beam sequence. With targeted adhesion, secondary radiation forces were unable to produce large aggregates of adherent microbubbles. Additionally, the new phenomenon called “control peak” was observed both in vitro and in vivo in a murine model for the first time. The findings in this study provide us with a better understanding of microbubble behaviors in large blood

  13. Theranostic Gd(III)-lipid microbubbles for MRI-guided focused ultrasound surgery

    PubMed Central

    Feshitan, Jameel A.; Vlachos, Fotis; Sirsi, Shashank R.; Konofagou, Elisa E.; Borden, Mark A.

    2014-01-01

    We have synthesized a biomaterial consisting of Gd(III) ions chelated to lipid-coated, size-selected microbubbles for utility in both magnetic resonance and ultrasound imaging. The macrocyclic ligand DOTA-NHS was bound to PE headgroups on the lipid shell of pre-synthesized microbubbles. Gd(III) was then chelated to DOTA on the microbubble shell. The reaction temperature was optimized to increase the rate of Gd(III) chelation while maintaining microbubble stability. ICP-OES analysis of the microbubbles determined a surface density of 7.5 × 105 ± 3.0 × 105 Gd(III)/μm2 after chelation at 50 °C. The Gd(III)-bound microbubbles were found to be echogenic in vivo during high-frequency ultrasound imaging of the mouse kidney. The Gd(III)-bound microbubbles also were characterized by magnetic resonance imaging (MRI) at 9.4 T by a spin-echo technique and, surprisingly, both the longitudinal and transverse proton relaxation rates were found to be roughly equal to that of no-Gd(III) control microbubbles and saline. However, the relaxation rates increased significantly, and in a dose-dependent manner, after sonication was used to fragment the Gd(III)-bound microbubbles into non-gas-containing lipid bilayer remnants. The longitudinal (r1) and transverse (r2) molar relaxivities were 4.0 ± 0.4 and 120 ± 18 mM−1s−1, respectively, based on Gd(III) content. The Gd(III)-bound microbubbles may find application in the measurement of cavitation events during MRI-guided focused ultrasound therapy and to track the biodistribution of shell remnants. PMID:21993236

  14. Enhanced delivery of PEAL nanoparticles with ultrasound targeted microbubble destruction mediated siRNA transfection in human MCF-7/S and MCF-7/ADR cells in vitro

    PubMed Central

    Teng, Yanwei; Bai, Min; Sun, Ying; Wang, Qi; Li, Fan; Xing, Jinfang; Du, Lianfang; Gong, Tao; Duan, Yourong

    2015-01-01

    The gene knockdown activity of small interfering RNA (siRNA) has led to their use as potential therapeutics for a variety of diseases. However, successful gene therapy requires safe and efficient delivery systems. In this study, we choose mPEG-PLGA-PLL nanoparticles (PEAL NPs) with ultrasound targeted microbubble destruction (UTMD) to efficiently deliver siRNA into cells. An emulsification-solvent evaporation method was used to prepare siRNA-loaded PEAL NPs. The NPs possessed an average size of 132.6±10.3 nm (n=5), with a uniform spherical shape, and had an encapsulation efficiency (EE) of more than 98%. As demonstrated by MTT assay, neither PEAL NPs nor siRNA-loaded PEAL NPs showed cytotoxicity even at high concentrations. The results of cellular uptake showed, with the assistance of UTMD, the siRNA-loaded PEAL NPs can be effectively internalized and can subsequently release siRNA in cells. Taken together, PEAL NPs with UTMD may be highly promising for siRNA delivery, making it possible to fully exploit the potential of siRNA-based therapeutics. PMID:26346350

  15. Pulsatile drug release from PLGA hollow microspheres by controlling the permeability of their walls with a magnetic field.

    PubMed

    Chiang, Wei-Lun; Ke, Cherng-Jyh; Liao, Zi-Xian; Chen, San-Yuan; Chen, Fu-Rong; Tsai, Chun-Ying; Xia, Younan; Sung, Hsing-Wen

    2012-12-07

    Pulsatile release: When a high-frequency magnetic field is applied, heat will be generated by coupling to the iron oxide nanoparticles encapsulated in the shells of PLGA hollow microspheres. As the temperature approaches the T(g) of PLGA, the polymer chains become more mobile, subsequently increasing the free volume of PLGA matrix and significantly enhancing the diffusion of drug molecules.

  16. Poly(lactic-co-glycolic) acid-controlled-release systems: experimental and modeling insights.

    PubMed

    Hines, Daniel J; Kaplan, David L

    2013-01-01

    Poly(lactic-co-glycolic acid) (PLGA) has been the most successful polymeric biomaterial used in controlled drug delivery systems. There are several different chemical and physical properties of PLGA that impact the release behavior of drugs from PLGA delivery devices. These properties must be considered and optimized in the formulation of drug release devices. Mathematical modeling is a useful tool for identifying, characterizing, and predicting mechanisms of controlled release. The advantages and limitations of poly(lactic-co-glycolic acid) for controlled release are reviewed, followed by a review of current approaches in controlled-release technology that utilize PLGA. Mathematical modeling applied toward controlled-release rates from PLGA-based devices also will be discussed to provide a complete picture of a state-of-the-art understanding of the control that can be achieved with this polymeric system, as well as the limitations.

  17. Poly (lactic-co-glycolic acid) controlled release systems: experimental and modeling insights

    PubMed Central

    Hines, Daniel J.; Kaplan, David L.

    2013-01-01

    Poly-lactic-co-glycolic acid (PLGA) has been the most successful polymeric biomaterial for use in controlled drug delivery systems. There are several different chemical and physical properties of PLGA that impact the release behavior of drugs from PLGA delivery devices. These properties must be considered and optimized in drug release device formulation. Mathematical modeling is a useful tool for identifying, characterizing, and predicting the mechanisms of controlled release. The advantages and limitations of poly (lactic-co-glycolic acid) for controlled release are reviewed, followed by a review of current approaches in controlled release technology that utilize PLGA. Mathematical modeling applied towards controlled release rates from PLGA-based devices will also be discussed to provide a complete picture of state of the art understanding of the control achievable with this polymeric system, as well as the limitations. PMID:23614648

  18. Salivary gland cell differentiation and organization on micropatterned PLGA nanofiber craters

    PubMed Central

    Soscia, David A.; Sequeira, Sharon J.; Schramm, Robert A.; Jayarathanam, Kavitha; Cantara, Shraddha I.; Larsen, Melinda; Castracane, James

    2013-01-01

    There is a need for an artificial salivary gland as a long-term remedy for patients suffering from salivary hypofunction, a leading cause of chronic xerostomia (dry mouth). Current salivary gland tissue engineering approaches are limited in that they either lack sufficient physical cues and surface area needed to facilitate epithelial cell differentiation, or they fail to provide a mechanism for assembling an interconnected branched network of cells. We have developed highly-ordered arrays of curved hemispherical “craters” in polydimethylsiloxane (PDMS) using wafer-level integrated circuit (IC) fabrication processes, and lined them with electrospun poly-lactic-co-glycolic acid (PLGA) nanofibers, designed to mimic the three-dimensional (3-D) in vivo architecture of the basement membrane surrounding spherical acini of salivary gland epithelial cells. These micropatterned scaffolds provide a method for engineering increased surface area and were additionally investigated for their ability to promote cell polarization. Two immortalized salivary gland cell lines (SIMS, ductal and Par-C10, acinar) were cultured on fibrous crater arrays of various radii and compared with those grown on flat PLGA nanofiber substrates, and in 3-D Matrigel. It was found that by increasing crater curvature, the average height of the cell monolayer of SIMS cells and to a lesser extent, Par-C10 cells, increased to a maximum similar to that seen in cells grown in 3-D Matrigel. Increasing curvature resulted in higher expression levels of tight junction protein occludin in both cell lines, but did not induce a change in expression of adherens junction protein Ecadherin. Additionally, increasing curvature promoted polarity of both cell lines, as a greater apical localization of occludin was seen in cells on substrates of higher curvature. Lastly, substrate curvature increased expression of the water channel protein aquaporin-5 (Aqp-5) in Par-C10 cells, suggesting that curved nanofiber

  19. High-resolution direct 3D printed PLGA scaffolds: print and shrink.

    PubMed

    Chia, Helena N; Wu, Benjamin M

    2014-12-17

    Direct three-dimensional printing (3DP) produces the final part composed of the powder and binder used in fabrication. An advantage of direct 3DP is control over both the microarchitecture and macroarchitecture. Prints which use porogen incorporated in the powder result in high pore interconnectivity, uniform porosity, and defined pore size after leaching. The main limitations of direct 3DP for synthetic polymers are the use of organic solvents which can dissolve polymers used in most printheads and limited resolution due to unavoidable spreading of the binder droplet after contact with the powder. This study describes a materials processing strategy to eliminate the use of organic solvent during the printing process and to improve 3DP resolution by shrinking with a non-solvent plasticizer. Briefly, poly(lactic-co-glycolic acid) (PLGA) powder was prepared by emulsion solvent evaporation to form polymer microparticles. The printing powder was composed of polymer microparticles dry mixed with sucrose particles. After printing with a water-based liquid binder, the polymer microparticles were fused together to form a network by solvent vapor in an enclosed vessel. The sucrose is removed by leaching and the resulting scaffold is placed in a solution of methanol. The methanol acts as a non-solvent plasticizer and allows for polymer chain rearrangement and efficient packing of polymer chains. The resulting volumetric shrinkage is ∼80% at 90% methanol. A complex shape (honey-comb) was designed, printed, and shrunken to demonstrate isotropic shrinking with the ability to reach a final resolution of ∼400 μm. The effect of type of alcohol (i.e. methanol or ethanol), concentration of alcohol, and temperature on volumetric shrinking was studied. This study presents a novel materials processing strategy to overcome the main limitations of direct 3DP to produce high resolution PLGA scaffolds.

  20. Preparation, characterization and optimization of sildenafil citrate loaded PLGA nanoparticles by statistical factorial design

    PubMed Central

    2013-01-01

    Background and the aim of the study The objective of the present study was to formulate and optimize nanoparticles (NPs) of sildenafil-loaded poly (lactic-co-glycolic acid) (PLGA) by double emulsion solvent evaporation (DESE) method. The relationship between design factors and experimental data was evaluated using response surface methodology. Method A Box-Behnken design was made considering the mass ratio of drug to polymer (D/P), the volumetric proportion of the water to oil phase (W/O) and the concentration of polyvinyl alcohol (PVA) as the independent agents. PLGA-NPs were successfully prepared and the size (nm), entrapment efficiency (EE), drug loading (DL) and cumulative release of drug from NPs post 1 and 8 hrs were assessed as the responses. Results The NPs were prepared in a spherical shape and the sizes range of 240 to 316 nm. The polydispersity index of size was lower than 0.5 and the EE (%) and DL (%) varied between 14-62% and 2-6%, respectively. The optimized formulation with a desirability factor of 0.9 was selected and characterized. This formulation demonstrated the particle size of 270 nm, EE of 55%, DL of 3.9% and cumulative drug release of 79% after 12 hrs. In vitro release studies showed a burst release at the initial stage followed by a sustained release of sildenafil from NPs up to 12 hrs. The release kinetic of the optimized formulation was fitted to Higuchi model. Conclusions Sildenafil citrate NPs with small particle size, lipophilic feature, high entrapment efficiency and good loading capacity is produced by this method. Characterization of optimum formulation, provided by an evaluation of experimental data, showed no significant difference between calculated and measured data. PMID:24355133

  1. Release of insulin from PLGA-alginate dressing stimulates regenerative healing of burn wounds in rats.

    PubMed

    Dhall, Sandeep; Silva, João P; Liu, Yan; Hrynyk, Michael; Garcia, Monika; Chan, Alex; Lyubovitsky, Julia; Neufeld, Ronald J; Martins-Green, Manuela

    2015-12-01

    Burn wound healing involves a complex set of overlapping processes in an environment conducive to ischaemia, inflammation and infection costing $7.5 billion/year in the U.S.A. alone, in addition to the morbidity and mortality that occur when the burns are extensive. We previously showed that insulin, when topically applied to skin excision wounds, accelerates re-epithelialization and stimulates angiogenesis. More recently, we developed an alginate sponge dressing (ASD) containing insulin encapsulated in PLGA [poly(D,L-lactic-co-glycolic acid)] microparticles that provides a sustained release of bioactive insulin for >20 days in a moist and protective environment. We hypothesized that insulin-containing ASD accelerates burn healing and stimulates a more regenerative, less scarring healing. Using heat-induced burn injury in rats, we show that burns treated with dressings containing 0.04 mg insulin/cm(2) every 3 days for 9 days have faster closure, a higher rate of disintegration of dead tissue and decreased oxidative stress. In addition, in insulin-treated wounds, the pattern of neutrophil inflammatory response suggests faster clearing of the burned dead tissue. We also observe faster resolution of the pro-inflammatory macrophages. We also found that insulin stimulates collagen deposition and maturation with the fibres organized more like a basket weave (normal skin) than aligned and cross-linked (scar tissue). In summary, application of ASD-containing insulin-loaded PLGA particles on burns every 3 days stimulates faster and more regenerative healing. These results suggest insulin as a potential therapeutic agent in burn healing and, because of its long history of safe use in humans, insulin could become one of the treatments of choice when repair and regeneration are critical for proper tissue function.

  2. Optical barcoding of PLGA for multispectral analysis of nanoparticle fate in vivo.

    PubMed

    Medina, David X; Householder, Kyle T; Ceton, Ricki; Kovalik, Tina; Heffernan, John M; Shankar, Rohini V; Bowser, Robert P; Wechsler-Reya, Robert J; Sirianni, Rachael W

    2017-03-03

    Understanding of the mechanisms by which systemically administered nanoparticles achieve delivery across biological barriers remains incomplete, due in part to the challenge of tracking nanoparticle fate in the body. Here, we develop a new approach for "barcoding" nanoparticles composed of poly(lactic-co-glycolic acid) (PLGA) with bright, spectrally defined quantum dots (QDs) to enable direct, fluorescent detection of nanoparticle fate with subcellular resolution. We show that QD labeling does not affect major biophysical properties of n