Bovine serum albumin nanoparticles as controlled release carrier for local drug delivery to the inner ear

NASA Astrophysics Data System (ADS)

Yu, Zhan; Yu, Min; Zhang, Zhibao; Hong, Ge; Xiong, Qingqing

2014-07-01

Nanoparticles have attracted increasing attention for local drug delivery to the inner ear recently. Bovine serum albumin (BSA) nanoparticles were prepared by desolvation method followed by glutaraldehyde fixation or heat denaturation. The nanoparticles were spherical in shape with an average diameter of 492 nm. The heat-denatured nanoparticles had good cytocompatibility. The nanoparticles could adhere on and penetrate through the round window membrane of guinea pigs. The nanoparticles were analyzed as drug carriers to investigate the loading capacity and release behaviors. Rhodamine B was used as a model drug in this paper. Rhodamine B-loaded nanoparticles showed a controlled release profile and could be deposited on the osseous spiral lamina. We considered that the bovine serum albumin nanoparticles may have potential applications in the field of local drug delivery in the treatment of inner ear disorders.

Improving Service Delivery in a County Health Department WIC Clinic: An Application of Statistical Process Control Techniques

PubMed Central

Boe, Debra Thingstad; Parsons, Helen

2009-01-01

Local public health agencies are challenged to continually improve service delivery, yet they frequently operate with constrained resources. Quality improvement methods and techniques such as statistical process control are commonly used in other industries, and they have recently been proposed as a means of improving service delivery and performance in public health settings. We analyzed a quality improvement project undertaken at a local Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) clinic to reduce waiting times and improve client satisfaction with a walk-in nutrition education service. We used statistical process control techniques to evaluate initial process performance, implement an intervention, and assess process improvements. We found that implementation of these techniques significantly reduced waiting time and improved clients' satisfaction with the WIC service. PMID:19608964

Relief of Injection Pain During Delivery of Local Anesthesia by Computer-Controlled Anesthetic Delivery System for Periodontal Surgery: Randomized Clinical Controlled Trial.

PubMed

Chang, Hyeyoon; Noh, Jiyoung; Lee, Jungwon; Kim, Sungtae; Koo, Ki-Tae; Kim, Tae-Il; Seol, Yang-Jo; Lee, Yong-Moo; Ku, Young; Rhyu, In-Chul

2016-07-01

Pain from local anesthetic injection makes patients anxious when visiting a dental clinic. This study aims to determine differences in pain according to types of local anesthetizing methods and to identify the possible contributing factors (e.g., dental anxiety, stress, and sex). Thirty-one patients who underwent open-flap debridement in maxillary premolar and molar areas during treatment for chronic periodontitis were evaluated for this study. A randomized, split-mouth, single-masked clinical trial was implemented. The dental anxiety scale (DAS) and perceived stress scale (PSS) were administered before surgery. Two lidocaine ampules for each patient were used for local infiltration anesthesia (supraperiosteal injection). Injection pain was measured immediately after local infiltration anesthesia using the visual analog pain scale (VAS) questionnaire. Results from the questionnaire were used to assess degree of pain patients feel when a conventional local anesthetic technique (CNV) is used compared with a computer-controlled anesthetic delivery system (CNR). DAS and PSS did not correlate to injection pain. VAS scores were lower for CNR than for CNV regardless of the order in which anesthetic procedures were applied. VAS score did not differ significantly with sex. Pearson coefficient for correlation between VAS scores for the two procedures was 0.80, also indicating a strong correlation. Within the limitations of the present study, relief from injection pain is observed using CNR.

Clinical Considerations of Focal Drug Delivery in Cancer Treatment.

PubMed

Harris, Jamie; Klonoski, Samuel C; Chiu, Bill

2017-01-01

According to the US Center for Disease Control, cancer deaths are the second most common cause of mortality in both adults and children. Definitive treatment of solid tumors involves surgical resection with or without systemic chemotherapy and radiation. The advent of local drug delivery presents a unique treatment modality that can offer substantial benefits in cancer management. Three main phases in solid tumor management exist for the treating physician: initial diagnosis with tissue biopsy, surgical resection with or without chemotherapy, and management of metastatic disease. A literature review of both basic science as well as clinical trials using local drug delivery strategies in the management of solid tumors was done on PubMed. These were then further divided into the categories of initial tissue biopsy intervention, surgical resection, and management of metastatic disease. A total of 27 articles were review that included both pre-clinical as well as clinical investigation of local drug delivery therapies in the treatment of solid tumors. Treatments such as MRI guided therapies, FDA approved local therapies for intracranial gliomas as well as local therapy for single site metastatic disease were identified. This review focuses the current state of local drug delivery in the treatment of solid tumors in both the pre-clinical as well as clinical investigation settings. Local drug delivery therapy offers an exciting new treatment modality for solid malignancies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Hyperthermia in bone generated with MR imaging-controlled focused ultrasound: control strategies and drug delivery.

PubMed

Staruch, Robert; Chopra, Rajiv; Hynynen, Kullervo

2012-04-01

To evaluate the feasibility of achieving image-guided drug delivery in bone by using magnetic resonance (MR) imaging-controlled focused ultrasound hyperthermia and temperature-sensitive liposomes. Experiments were approved by the institutional animal care committee. Hyperthermia (43°C, 20 minutes) was generated in 10-mm-diameter regions at a muscle-bone interface in nine rabbit thighs by using focused ultrasound under closed-loop temperature control with MR thermometry. Thermosensitive liposomal doxorubicin was administered systemically during heating. Heating uniformity and drug delivery were evaluated for control strategies with the temperature control image centered 10 mm (four rabbits) or 0 mm (five rabbits) from the bone. Simulations estimated temperature elevations in bone. Drug delivery was quantified by using the fluorescence of doxorubicin extracted from bone marrow and muscle and was compared between treated and untreated thighs by using the one-sided Wilcoxon signed rank test. With ultrasound focus and MR temperature control plane 0 mm and 10 mm from the bone interface, average target region temperatures were 43.1°C and 43.3°C, respectively; numerically estimated bone temperatures were 46.8°C and 78.1°C. The 10-mm offset resulted in thermal ablation; numerically estimated muscle temperature was 66.1°C at the bone interface. Significant increases in doxorubicin concentration occurred in heated versus unheated marrow (8.2-fold, P = .002) and muscle (16.8-fold, P = .002). Enhancement occurred for 0- and 10-mm offsets, which suggests localized drug delivery in bone is possible with both hyperthermia and thermal ablation. MR imaging-controlled focused ultrasound can achieve localized hyperthermia in bone for image-guided drug delivery in bone with temperature-sensitive drug carriers. © RSNA, 2012.

A Micro-delivery Approach for Studying Microvascular Responses to Localized Oxygen Delivery

PubMed Central

Ghonaim, Nour W.; Lau, Leo W. M.; Goldman, Daniel; Ellis, Christopher G.; Yang, Jun

2011-01-01

In vivo video microscopy has been used to study blood flow regulation as a function of varying oxygen concentration in microcirculatory networks. However, previous studies have measured the collective response of stimulating large areas of the microvascular network at the tissue surface. Objective We aim to limit the area being stimulated by controlling oxygen availability to highly localized regions of the microvascular bed within intact muscle. Design and Method Gas of varying O2 levels was delivered to specific locations on the surface of the Extensor Digitorum Longus muscle of rat through a set of micro-outlets (100 μm diameter) patterned in ultrathin glass using state-of-the-art microfabrication techniques. O2 levels were oscillated and digitized video sequences were processed for changes in capillary hemodynamics and erythrocyte O2 saturation. Results and Conclusions Oxygen saturations in capillaries positioned directly above the micro-outlets were closely associated with the controlled local O2 oscillations. Radial diffusion from the micro-outlet is limited to ~75 μm from the center as predicted by computational modelling and as measured in vivo. These results delineate a key step in the design of a novel micro-delivery device for controlled oxygen delivery to the microvasculature to understand fundamental mechanisms of microvascular regulation of O2 supply. PMID:21914035

Sustained delivery of biomolecules from gelatin carriers for applications in bone regeneration.

PubMed

Song, Jiankang; Leeuwenburgh, Sander Cg

2014-08-01

Local delivery of therapeutic biomolecules to stimulate bone regeneration has matured considerably during the past decades, but control over the release of these biomolecules still remains a major challenge. To this end, suitable carriers that allow for tunable spatial and temporal delivery of biomolecules need to be developed. Gelatin is one of the most widely used natural polymers for the controlled and sustained delivery of biomolecules because of its biodegradability, biocompatibility, biosafety and cost-effectiveness. The current study reviews the applications of gelatin as carriers in form of bulk hydrogels, microspheres, nanospheres, colloidal gels and composites for the programmed delivery of commonly used biomolecules for applications in bone regeneration with a specific focus on the relationship between carrier properties and delivery characteristics.

Elution characteristics of teicoplanin-loaded biodegradable borate glass/chitosan composite.

PubMed

Jia, Wei-Tao; Zhang, Xin; Zhang, Chang-Qing; Liu, Xin; Huang, Wen-Hai; Rahaman, Mohamed N; Day, Delbert E

2010-03-15

Local antibiotic delivery system has an advantage over systemic antibiotic for osteomyelitis treatment due to the delivery of high local antibiotic concentration while avoiding potential systemic toxicity. Composite biomaterials with multifunctional roles, consisting of a controlled antibiotic release, a mechanical (load-bearing) function, and the ability to promote bone regeneration, gradually become the most active area of investigation and development of local antibiotic delivery vehicles. In the present study, a composite of borate glass and chitosan (designated BG/C) was developed as teicoplanin delivery vehicle. The in vitro elution kinetics and antibacterial activity of teicoplanin released from BG/C composite as a function of immersion time were determined. Moreover, the pH changes of eluents and the bioactivity of the composite were characterized using scanning electron microscopy coupled with energy-dispersive spectroscopy and X-ray diffraction analysis. 2009 Elsevier B.V. All rights reserved.

Local delivery of zoledronate from a poly (D,L-lactide)-Coating increases fixation of press-fit implants.

PubMed

Jakobsen, Thomas; Bechtold, Joan E; Søballe, Kjeld; Jensen, Thomas; Greiner, Stefan; Vestermark, Marianne T; Baas, Jørgen

2016-01-01

Early secure fixation of total joint replacements is crucial for long-term survival. Antiresorptive agents such as bisphosphonates have been shown to increase implant fixation. We investigated whether local delivery of zoledronate from poly-D, L-lactide (PDLLA)-coated implants could improve implant fixation and osseointegration. Experimental titanium implants were bilaterally inserted press-fit into the proximal tibiae of 10 dogs. On one side the implant was coated with PDLLA containing zoledronate. The contralateral implant was uncoated and used as control. Observation period was 12 weeks. Implant fixation was evaluated with histomorphometry and biomechanical push-out test. We found an approximately twofold increase in all biomechanical parameters when comparing data from the zoledronate group with their respective controls. Histomorphometry showed increased amount of preserved bone and increased bone formation around the zoledronate implants. This study indicates that local delivery of zoledronate from a PDDLA coating has the potential to increase implant fixation. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Recent advances of controlled drug delivery using microfluidic platforms.

PubMed

Sanjay, Sharma T; Zhou, Wan; Dou, Maowei; Tavakoli, Hamed; Ma, Lei; Xu, Feng; Li, XiuJun

2018-03-15

Conventional systematically-administered drugs distribute evenly throughout the body, get degraded and excreted rapidly while crossing many biological barriers, leaving minimum amounts of the drugs at pathological sites. Controlled drug delivery aims to deliver drugs to the target sites at desired rates and time, thus enhancing the drug efficacy, pharmacokinetics, and bioavailability while maintaining minimal side effects. Due to a number of unique advantages of the recent microfluidic lab-on-a-chip technology, microfluidic lab-on-a-chip has provided unprecedented opportunities for controlled drug delivery. Drugs can be efficiently delivered to the target sites at desired rates in a well-controlled manner by microfluidic platforms via integration, implantation, localization, automation, and precise control of various microdevice parameters. These features accordingly make reproducible, on-demand, and tunable drug delivery become feasible. On-demand self-tuning dynamic drug delivery systems have shown great potential for personalized drug delivery. This review presents an overview of recent advances in controlled drug delivery using microfluidic platforms. The review first briefly introduces microfabrication techniques of microfluidic platforms, followed by detailed descriptions of numerous microfluidic drug delivery systems that have significantly advanced the field of controlled drug delivery. Those microfluidic systems can be separated into four major categories, namely drug carrier-free micro-reservoir-based drug delivery systems, highly integrated carrier-free microfluidic lab-on-a-chip systems, drug carrier-integrated microfluidic systems, and microneedles. Microneedles can be further categorized into five different types, i.e. solid, porous, hollow, coated, and biodegradable microneedles, for controlled transdermal drug delivery. At the end, we discuss current limitations and future prospects of microfluidic platforms for controlled drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

Magnetic Nanomaterials for Hyperthermia-based Therapy and Controlled Drug Delivery

PubMed Central

Kumar, Challa S. S. R.; Mohammad, Faruq

2011-01-01

Previous attempts to review the literature on magnetic nanomaterials for hyperthermia-based therapy focused primarily on magnetic fluid hyperthermia (MFH) using mono metallic/metal oxide nanoparticles. The term “Hyperthermia” in the literature was also confined only to include use of heat for therapeutic applications. Recently, there have been a number of publications demonstrating magnetic nanoparticle-based hyperthermia to generate local heat resulting in the release of drugs either bound to the magnetic nanoparticle or encapsulated within polymeric matrices. In this review article, we present a case for broadening the meaning of the term “hyperthermia” by including thermotherapy as well as magnetically modulated controlled drug delivery. We provide a classification for controlled drug delivery using hyperthermia: Hyperthermia-based controlled Drug delivery through Bond Breaking (DBB) and Hyperthermia-based controlled Drug delivery through Enhanced Permeability (DEP). The review also covers, for the first time, core-shell type magnetic nanomaterials, especially nanoshells prepared using layer-by-layer self-assembly, for the application of hyperthermia-based therapy and controlled drug delivery. The highlight of the review article is to portray potential opportunities in the combination of hyperthermia-based therapy and controlled drug release paradigms for successful application in personalized medicine. PMID:21447363

Microencapsulation: A promising technique for controlled drug delivery.

PubMed

Singh, M N; Hemant, K S Y; Ram, M; Shivakumar, H G

2010-07-01

MICROPARTICLES OFFER VARIOUS SIGNIFICANT ADVANTAGES AS DRUG DELIVERY SYSTEMS, INCLUDING: (i) an effective protection of the encapsulated active agent against (e.g. enzymatic) degradation, (ii) the possibility to accurately control the release rate of the incorporated drug over periods of hours to months, (iii) an easy administration (compared to alternative parenteral controlled release dosage forms, such as macro-sized implants), and (iv) Desired, pre-programmed drug release profiles can be provided which match the therapeutic needs of the patient. This article gives an overview on the general aspects and recent advances in drug-loaded microparticles to improve the efficiency of various medical treatments. An appropriately designed controlled release drug delivery system can be a foot ahead towards solving problems concerning to the targeting of drug to a specific organ or tissue, and controlling the rate of drug delivery to the target site. The development of oral controlled release systems has been a challenge to formulation scientist due to their inability to restrain and localize the system at targeted areas of gastrointestinal tract. Microparticulate drug delivery systems are an interesting and promising option when developing an oral controlled release system. The objective of this paper is to take a closer look at microparticles as drug delivery devices for increasing efficiency of drug delivery, improving the release profile and drug targeting. In order to appreciate the application possibilities of microcapsules in drug delivery, some fundamental aspects are briefly reviewed.

Microencapsulation: A promising technique for controlled drug delivery

PubMed Central

Singh, M.N.; Hemant, K.S.Y.; Ram, M.; Shivakumar, H.G.

2010-01-01

Microparticles offer various significant advantages as drug delivery systems, including: (i) an effective protection of the encapsulated active agent against (e.g. enzymatic) degradation, (ii) the possibility to accurately control the release rate of the incorporated drug over periods of hours to months, (iii) an easy administration (compared to alternative parenteral controlled release dosage forms, such as macro-sized implants), and (iv) Desired, pre-programmed drug release profiles can be provided which match the therapeutic needs of the patient. This article gives an overview on the general aspects and recent advances in drug-loaded microparticles to improve the efficiency of various medical treatments. An appropriately designed controlled release drug delivery system can be a foot ahead towards solving problems concerning to the targeting of drug to a specific organ or tissue, and controlling the rate of drug delivery to the target site. The development of oral controlled release systems has been a challenge to formulation scientist due to their inability to restrain and localize the system at targeted areas of gastrointestinal tract. Microparticulate drug delivery systems are an interesting and promising option when developing an oral controlled release system. The objective of this paper is to take a closer look at microparticles as drug delivery devices for increasing efficiency of drug delivery, improving the release profile and drug targeting. In order to appreciate the application possibilities of microcapsules in drug delivery, some fundamental aspects are briefly reviewed. PMID:21589795

Nanostructured Platforms for the Sustained and Local Delivery of Antibiotics in the Treatment of Osteomyelitis

PubMed Central

Uskoković, Vuk

2015-01-01

This article provides a critical view of the current state of the development of nanoparticulate and other solid-state carriers for the local delivery of antibiotics in the treatment of osteomyelitis. Mentioned are the downsides of traditional means for treating bone infection, which involve systemic administration of antibiotics and surgical debridement, along with the rather imperfect local delivery options currently available in the clinic. Envisaged are more sophisticated carriers for the local and sustained delivery of antimicrobials, including bioresorbable polymeric, collagenous, liquid crystalline, and bioglass- and nanotube-based carriers, as well as those composed of calcium phosphate, the mineral component of bone and teeth. A special emphasis is placed on composite multifunctional antibiotic carriers of a nanoparticulate nature and on their ability to induce osteogenesis of hard tissues demineralized due to disease. An ideal carrier of this type would prevent the long-term, repetitive, and systemic administration of antibiotics and either minimize or completely eliminate the need for surgical debridement of necrotic tissue. Potential problems faced by even hypothetically “perfect” antibiotic delivery vehicles are mentioned too, including (i) intracellular bacterial colonies involved in recurrent, chronic osteomyelitis; (ii) the need for mechanical and release properties to be adjusted to the area of surgical placement; (iii) different environments in which in vitro and in vivo testings are carried out; (iv) unpredictable synergies between drug delivery system components; and (v) experimental sensitivity issues entailing the increasing subtlety of the design of nanoplatforms for the controlled delivery of therapeutics. PMID:25746204

Injectable nanoengineered stimuli-responsive hydrogels for on-demand and localized therapeutic delivery.

PubMed

Jalili, Nima A; Jaiswal, Manish K; Peak, Charles W; Cross, Lauren M; Gaharwar, Akhilesh K

2017-10-19

"Smart" hydrogels are an emerging class of biomaterials that respond to external stimuli and have been investigated for a range of biomedical applications, including therapeutic delivery and regenerative engineering. Stimuli-responsive nanogels constructed of thermoresponsive polymers such as poly(N-isopropylacrylamide-co-acrylamide) (poly(NIPAM-co-AM)) and magnetic nanoparticles (MNPs) have been developed as "smart carriers" for on-demand delivery of therapeutic biomolecules via magneto-thermal activation. However, due to their small size and systemic introduction, these poly(NIPAM-co-AM)/MNP nanogels result in limited control over long-term, localized therapeutic delivery. Here, we developed an injectable nanoengineered hydrogel loaded with poly(NIPAM-co-AM)/MNPs for localized, on-demand delivery of therapeutics (doxorubicin (DOX)). We have engineered shear-thinning and self-recoverable hydrogels by modulating the crosslinking density of a gelatin methacrylate (GelMA) network. Poly(NIPAM-co-AM)/MNP nanogels loaded with DOX were entrapped within a GelMA pre-polymer solution prior to crosslinking. The temperature and magnetic field dependent release of loaded DOX was observed from the nanoengineered hydrogels (GelMA/(poly(NIPAM-co-AM)/MNPs)). Finally, the in vitro efficacy of DOX released from injectable nanoengineered hydrogels was investigated using preosteoblast and osteosarcoma cells. Overall, these results demonstrated that the injectable nanoengineered hydrogels could be used for on-demand and localized therapeutic delivery for biomedical applications.

Labour analgesia: Recent advances

PubMed Central

Pandya, Sunil T

2010-01-01

Advances in the field of labour analgesia have tread a long journey from the days of ether and chloroform in 1847 to the present day practice of comprehensive programme of labour pain management using evidence-based medicine. Newer advances include introduction of newer techniques like combined spinal epidurals, low-dose epidurals facilitating ambulation, pharmacological advances like introduction of remifentanil for patient-controlled intravenous analgesia, introduction of newer local anaesthetics and adjuvants like ropivacaine, levobupivacaine, sufentanil, clonidine and neostigmine, use of inhalational agents like sevoflourane for patient-controlled inhalational analgesia using special vaporizers, all have revolutionized the practice of pain management in labouring parturients. Technological advances like use of ultrasound to localize epidural space in difficult cases minimizes failed epidurals and introduction of novel drug delivery modalities like patient-controlled epidural analgesia (PCEA) pumps and computer-integrated drug delivery pumps have improved the overall maternal satisfaction rate and have enabled us to customize a suitable analgesic regimen for each parturient. Recent randomized controlled trials and Cochrane studies have concluded that the association of epidurals with increased caesarean section and long-term backache remains only a myth. Studies have also shown that the newer, low-dose regimes do not have a statistically significant impact on the duration of labour and breast feeding and also that these reduce the instrumental delivery rates thus improving maternal and foetal safety. Advances in medical technology like use of ultrasound for localizing epidural space have helped the clinicians to minimize the failure rates, and many novel drug delivery modalities like PCEA and computer-integrated PCEA have contributed to the overall maternal satisfaction and safety. PMID:21189877

Spatiotemporal Quantification of Local Drug Delivery Using MRI

PubMed Central

Giers, Morgan B.; McLaren, Alex C.; Plasencia, Jonathan D.; McLemore, Ryan; Caplan, Michael R.

2013-01-01

Controlled release formulations for local, in vivo drug delivery are of growing interest to device manufacturers, research scientists, and clinicians; however, most research characterizing controlled release formulations occurs in vitro because the spatial and temporal distribution of drug delivery is difficult to measure in vivo. In this work, in vivo magnetic resonance imaging (MRI) of local drug delivery was performed to visualize and quantify the time resolved distribution of MRI contrast agents. Three-dimensional T 1 maps (generated from T 1-weighted images with varied T R) were processed using noise-reducing filtering. A segmented region of contrast, from a thresholded image, was converted to concentration maps using the equation 1/T 1 = 1/T 1,0 + R 1 C, where T 1,0 and T 1 are the precontrast and postcontrast T 1 map values, respectively. In this technique, a uniform estimated value for T 1,0 was used. Error estimations were performed for each step. The practical usefulness of this method was assessed using comparisons between devices located in different locations both with and without contrast. The method using a uniform T 1,0, requiring no registration of pre- and postcontrast image volumes, was compared to a method using either affine or deformation registrations. PMID:23710248

Calcium phosphate nanocoatings and nanocomposites, part 2: thin films for slow drug delivery and osteomyelitis.

PubMed

Ben-Nissan, Besim; Macha, Innocent; Cazalbou, Sophie; Choi, Andy H

2016-01-01

During the last two decades although many calcium phosphate based nanomaterials have been proposed for both drug delivery, and bone regeneration, their coating applications have been somehow slow due to the problems related to their complicated synthesis methods. In order to control the efficiency of local drug delivery of a biomaterial the critical pore sizes as well as good control of the chemical composition is pertinent. A variety of calcium phosphate based nanocoated composite drug delivery systems are currently being investigated. This review aims to give an update into the advancements of calcium phosphate nanocoatings and thin film nanolaminates. In particular recent research on PLA/hydroxyapatite composite thin films and coatings into the slow drug delivery for the possible treatment of osteomyelitis is covered.

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

PubMed

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

2018-06-06

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

Targeted delivery of growth factors in ischemic stroke animal models.

PubMed

Rhim, Taiyoun; Lee, Minhyung

2016-01-01

Ischemic stroke is caused by reduced blood supply and leads to loss of brain function. The reduced oxygen and nutrient supply stimulates various physiological responses, including induction of growth factors. Growth factors prevent neuronal cell death, promote neovascularization, and induce cell growth. However, the concentration of growth factors is not sufficient to recover brain function after the ischemic damage, suggesting that delivery of growth factors into the ischemic brain may be a useful treatment for ischemic stroke. In this review, various approaches for the delivery of growth factors to ischemic brain tissue are discussed, including local and targeting delivery systems. To develop growth factor therapy for ischemic stroke, important considerations should be taken into account. First, growth factors may have possible side effects. Thus, concentration of growth factors should be restricted to the ischemic tissues by local administration or targeted delivery. Second, the duration of growth factor therapy should be optimized. Growth factor proteins may be degraded too fast to have a high enough therapeutic effect. Therefore, delivery systems for controlled release or gene delivery may be useful. Third, the delivery systems to the brain should be optimized according to the delivery route.

Adjuncts to local anesthesia: separating fact from fiction.

PubMed

Wong, J K

2001-01-01

Adjunctive local anesthetic techniques and their armamentaria, such as intraosseous injection, computer-controlled delivery systems, periodontal ligament injection and needleless jet injection, have been proposed to hold particular advantages over conventional means of achieving local anesthesia. This article describes the use of each technique and proprietary armamentarium and reviews the literature appraising their use.

Nanolayered siRNA delivery platforms for local silencing of CTGF reduce cutaneous scar contraction in third-degree burns

PubMed Central

Castleberry, Steven A.; Golberg, Alexander; Sharkh, Malak Abu; Khan, Saiqa; Almquist, Benjamin D.; Austen, William G.; Yarmush, Martin L.; Hammond, Paula T.

2017-01-01

Wound healing is an incredibly complex biological process that often results in thickened collagen-enriched healed tissue called scar. Cutaneous scars lack many functional structures of the skin such as hair follicles, sweat glands, and papillae. The absence of these structures contributes to a number of the long-term morbidities of wound healing, including loss of function for tissues, increased risk of re-injury, and aesthetic complications. Scar formation is a pervasive factor in our daily lives; however, in the case of serious traumatic injury, scars can create long-lasting complications due to contraction and poor tissue remodeling. Within this report we target the expression of connective tissue growth factor (CTGF), a key mediator of TGFβ pro-fibrotic response in cutaneous wound healing, with controlled local delivery of RNA interference. Through this work we describe both a thorough in vitro analysis of nanolayer coated sutures for the controlled delivery of siRNA and its application to improve scar outcomes in a third-degree burn induced scar model in rats. We demonstrate that the knockdown of CTGF significantly altered the local expression of αSMA, TIMP1, and Col1a1, which are known to play roles in scar formation. The knockdown of CTGF within the healing burn wounds resulted in improved tissue remodeling, reduced scar contraction, and the regeneration of papillary structures within the healing tissue. This work adds support to a number of previous reports that indicate CTGF as a potential therapeutic target for fibrosis. Additionally, we believe that the controlled local delivery of siRNA from ultrathin polymer coatings described within this work is a promising approach in RNA interference that could be applied in developing improved cancer therapies, regenerative medicine, and fundamental scientific research. PMID:27108403

Wireless implantable chip with integrated nitinol-based pump for radio-controlled local drug delivery.

PubMed

Fong, Jeffrey; Xiao, Zhiming; Takahata, Kenichi

2015-02-21

We demonstrate an active, implantable drug delivery device embedded with a microfluidic pump that is driven by a radio-controlled actuator for temporal drug delivery. The polyimide-packaged 10 × 10 × 2 mm(3) chip contains a micromachined pump chamber and check valves of Parylene C to force the release of the drug from a 76 μL reservoir by wirelessly activating the actuator using external radio-frequency (RF) electromagnetic fields. The rectangular-shaped spiral-coil actuator based on nitinol, a biocompatible shape-memory alloy, is developed to perform cantilever-like actuation for pumping operation. The nitinol-coil actuator itself forms a passive 185 MHz resonant circuit that serves as a self-heat source activated via RF power transfer to enable frequency-selective actuation and pumping. Experimental wireless operation of fabricated prototypes shows successful release of test agents from the devices placed in liquid and excited by radiating tuned RF fields with an output power of 1.1 W. These tests reveal a single release volume of 219 nL, suggesting a device's capacity of ~350 individual ejections of drug from its reservoir. The thermal behavior of the activated device is also reported in detail. This proof-of-concept prototype validates the effectiveness of wireless RF pumping for fully controlled, long-lasting drug delivery, a key step towards enabling patient-tailored, targeted local drug delivery through highly miniaturized implants.

Development In Drug Targeting And Delivery In Cervical Cancer.

PubMed

Aggarwal, Urvashi; Goyal, Amit Kumar; Rath, Goutam

2017-10-09

Cervical cancer is the second most common cancer in women. Standard treatment options available for cervical cancer including chemotherapy, surgery and radiation therapy associated with their own side effects and toxicities. Tumor-targeted delivery of anticancer drugs is perhaps one of the most appropriate strategies to achieve optimal outcomes from treatment and improve quality of life. Recently nanocarriers based drug delivery systems owing to their unique properties have been extensively investigated for anticancer drug delivery. In addition to that addressing the anatomical significance of cervical cancer, various local drug delivery strategies for the cancer treatment are introduced like: gels, nanoparticles, polymeric films, rods and wafers, lipid based nanocarrier. Localized drug delivery systems allows passive drug targeting results in high drug concentration at the target site. Further they can be tailor made to achieve both sustained and controlled release behavior, substantially improving therapeutic outcomes and minimizing side effects. This review summarizes the meaningful advances in drug delivery strategies to treat cervical cancer. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

TiO2 nanotube platforms for smart drug delivery: a review

PubMed Central

Wang, Qun; Huang, Jian-Ying; Li, Hua-Qiong; Chen, Zhong; Zhao, Allan Zi-Jian; Wang, Yi; Zhang, Ke-Qin; Sun, Hong-Tao; Al-Deyab, Salem S; Lai, Yue-Kun

2016-01-01

Titania nanotube (TNT) arrays are recognized as promising materials for localized drug delivery implants because of their excellent properties and facile preparation process. This review highlights the concept of localized drug delivery systems based on TNTs, considering their outstanding biocompatibility in a series of ex vivo and in vivo studies. Considering the safety of TNT implants in the host body, studies of the biocompatibility present significant importance for the clinical application of TNT implants. Toward smart TNT platforms for sustainable drug delivery, several advanced approaches were presented in this review, including controlled release triggered by temperature, light, radiofrequency magnetism, and ultrasonic stimulation. Moreover, TNT implants used in medical therapy have been demonstrated by various examples including dentistry, orthopedic implants, cardiovascular stents, and so on. Finally, a future perspective of TNTs for clinical applications is provided. PMID:27703349

TiO2 nanotube platforms for smart drug delivery: a review.

PubMed

Wang, Qun; Huang, Jian-Ying; Li, Hua-Qiong; Chen, Zhong; Zhao, Allan Zi-Jian; Wang, Yi; Zhang, Ke-Qin; Sun, Hong-Tao; Al-Deyab, Salem S; Lai, Yue-Kun

Titania nanotube (TNT) arrays are recognized as promising materials for localized drug delivery implants because of their excellent properties and facile preparation process. This review highlights the concept of localized drug delivery systems based on TNTs, considering their outstanding biocompatibility in a series of ex vivo and in vivo studies. Considering the safety of TNT implants in the host body, studies of the biocompatibility present significant importance for the clinical application of TNT implants. Toward smart TNT platforms for sustainable drug delivery, several advanced approaches were presented in this review, including controlled release triggered by temperature, light, radiofrequency magnetism, and ultrasonic stimulation. Moreover, TNT implants used in medical therapy have been demonstrated by various examples including dentistry, orthopedic implants, cardiovascular stents, and so on. Finally, a future perspective of TNTs for clinical applications is provided.

Local drug delivery agents as adjuncts to endodontic and periodontal therapy

PubMed Central

Puri, K; Puri, N

2013-01-01

Abstract In the treatment of intracanal and periodontal infections, the local application of antibiotics and other therapeutic agents in the root canal or in periodontal pockets may be a promising approach to achieve sustained/controlled drug release, high antimicrobial activity and low systemic side effects. The conventional method for the elimination of subgingival microbial infection includes mechanical debridement, irrigation with antimicrobial agents or surgical access. But, the effectiveness of conventional nonsurgical treatment is limited by lack of accessibility to bacteria in deeper periodontal pockets, and/or does not completely eliminate intracanal microorganisms. Surgical intervention may be beneficial but cannot be done in all cases, medically compromised cases and also in patients not willing to be subjected to surgical therapy. Development of local drug delivery systems provides an answer to all such difficulties. This comprehensive review tries to cover the detailed information about the latest advances in the various local drug delivery systems, their indications, contraindications and their advantages over systemic drug therapy. PMID:24868252

Local anesthetic delivery via surgical drain provides improved pain control versus direct skin infiltration following axillary node dissection for breast cancer.

PubMed

Khpal, Muska; Miller, James R C; Petrovic, Zika; Hassanally, Delilah

2018-03-01

Axillary node dissection has a central role in the surgical management of breast cancer; however, it is associated with a significant risk of lymphoedema and chronic pain. Peri-operative administration of local anesthesia reduces acute and persistent post-surgical pain, but there is currently no consensus on the optimal method of local anesthetic delivery. Patients undergoing axillary dissection for breast cancer were randomly assigned to receive a one-off dose of levobupivacaine 0.5% (up to 2 mg/kg) following surgery, either via the surgical drain or by direct skin infiltration. Post-operative pain control at rest and on shoulder abduction was assessed using a numerical rating scale. Total analgesia consumption 48 h after surgery was also recorded. Pain scores were significantly lower when local anesthesia was administered via surgical drain at both 3 and 12 h after surgery; this trend extended to 24 h post-operatively. However, pain scores on shoulder abduction did not differ at the 12 or 24 h time points. No differences were found in the total analgesia consumption or length of hospital stay between treatment groups. This study demonstrates that local anesthetic delivery via a surgical drain provides improved pain control compared to direct skin infiltration following axillary node dissection. This is likely to be important for the management of acute pain in the immediate post-operative period; however, further studies may be required to validate this in specific patient subgroups, e.g., breast-conserving surgery versus mastectomy.

Magnetic forces enable controlled drug delivery by disrupting endothelial cell-cell junctions

NASA Astrophysics Data System (ADS)

Qiu, Yongzhi; Tong, Sheng; Zhang, Linlin; Sakurai, Yumiko; Myers, David R.; Hong, Lin; Lam, Wilbur A.; Bao, Gang

2017-06-01

The vascular endothelium presents a major transport barrier to drug delivery by only allowing selective extravasation of solutes and small molecules. Therefore, enhancing drug transport across the endothelial barrier has to rely on leaky vessels arising from disease states such as pathological angiogenesis and inflammatory response. Here we show that the permeability of vascular endothelium can be increased using an external magnetic field to temporarily disrupt endothelial adherens junctions through internalized iron oxide nanoparticles, activating the paracellular transport pathway and facilitating the local extravasation of circulating substances. This approach provides a physically controlled drug delivery method harnessing the biology of endothelial adherens junction and opens a new avenue for drug delivery in a broad range of biomedical research and therapeutic applications.

Sustained delivery of bioactive neurotrophin-3 to the injured spinal cord.

PubMed

Elliott Donaghue, Irja; Tator, Charles H; Shoichet, Molly S

2015-01-01

Spinal cord injury is a debilitating condition that currently lacks effective clinical treatment. Neurotrophin-3 (NT-3) has been demonstrated in experimental animal models to induce axonal regeneration and functional improvements, yet its local delivery remains challenging. For ultimate clinical translation, a drug delivery system is required for localized, sustained, and minimally invasive release. Here, an injectable composite drug delivery system (DDS) composed of biodegradable polymeric nanoparticles dispersed in a hyaluronan/methyl cellulose hydrogel was injected into the intrathecal space to achieve acute local delivery to the spinal cord after a thoracic clip compression injury. NT-3 was encapsulated in the DDS and released in vitro for up to 50 d. With a single injection of the DDS into the intrathecal space of the injured spinal cord, NT-3 diffused ventrally through the cord and was detectable in the spinal cord for at least 28 d therein. Delivery of NT-3 resulted in significant axon growth with no effect on the astroglial response to injury in comparison with vehicle and injury controls. NT-3 treatment promoted functional improvements at 21 d according to the Basso Beattie Bresnahan locomotor scale in comparison with the DDS alone. The sustained delivery of bioactive NT-3 to the injured spinal cord achieved in this study demonstrates the promise of this DDS for central nervous system repair.

Ultrasound-guided continuous interscalene block: the influence of local anesthetic background delivery method on postoperative analgesia after shoulder surgery: a randomized trial.

PubMed

Hamdani, Mehdi; Chassot, Olivier; Fournier, Roxane

2014-01-01

Automated bolus delivery has recently been shown to reduce local anesthetic consumption and improve analgesia, compared with continuous infusion, in continuous sciatic and epidural block. However, there are few data on the influence of local anesthetic delivery method on local anesthetic consumption following interscalene blockade. This randomized, double-blind trial was designed to determine whether hourly automated perineural boluses (4 mL) of local anesthesia delivered with patient-controlled pro re nata (PRN, on demand) boluses would result in a reduction in total local anesthesia consumption during continuous interscalene blockade after shoulder surgery compared with continuous perineural infusion (4 mL/h) plus patient-controlled PRN boluses. One hundred one patients undergoing major shoulder surgery under general anesthesia with ultrasound-guided continuous interscalene block were randomly assigned to receive 0.2% ropivacaine via interscalene end-hole catheter either by continuous infusion 4 mL/h (n = 50) or as automated bolus 4 mL/h (n = 51). Both delivery methods were combined with 5 mL PRN boluses of 0.2% ropivacaine with a lockout time of 30 minutes. Postoperative number of PRN boluses, 24- and 48-hour local anesthetic consumption, pain scores, rescue analgesia (morphine), and adverse events were recorded. There were no significant differences in either the number of PRN ropivacaine boluses or total 48 hour local anesthetic consumption between the groups (18.5 [11-25.2] PRN boluses in the continuous infusion group vs 17 [8.5-29] PRN boluses in the automated bolus group). Postoperative pain was similar in both groups; on day 2, the median average pain score was 4 (2-6) in the continuous infusion group versus 3 (2-5) in the automated bolus group (P = 0.54). Nor were any statistically significant intergroup differences observed with respect to morphine rescue, incidence of adverse events, or patient satisfaction. In continuous interscalene blockade under ultrasound guidance after shoulder surgery, automated boluses of local anesthetic combined with PRN boluses did not provide any reduction in local anesthetic consumption or rescue analgesia, compared with continuous infusion combined with PRN boluses.

Dental therapeutic systems.

PubMed

Iqbal, Zeenat; Jain, Nilu; Jain, Gaurav K; Talegaonkar, Sushama; Ahuja, Alka; Khar, Roop K; Ahmad, Farhan J

2008-01-01

The recognition of periodontal diseases as amenable to local antibiotherapy has resulted in a paradigmatic shift in treatment modalities of dental afflictions. Moreover the presence of antimicrobial resistance, surfacing of untoward reactions owing to systemic consumption of antibiotics has further advocated the use of local delivery of physiologically active substances into the periodontal pocket. While antimicrobials polymerized into acrylic strips, incorporated into biodegradable collagen and hollow permeable cellulose acetate fibers, multiparticulate systems, bio-absorbable dental materials, biodegradable gels/ointments, injectables, mucoadhesive microcapsules and nanospheres will be more amenable for direct placement into the periodontal pockets the lozenges, buccoadhesive tablets, discs or gels could be effectively used to mitigate the overall gingival inflammation. Whilst effecting controlled local delivery of a few milligram of an antibacterial agent within the gingival crevicular fluid for a longer period of time, maintaining therapeutic concentrations such delivery devices will circumvent all adverse effects to non- oral sites. Since the pioneering efforts of Goodson and Lindhe in 1989, delivery at gingival and subgingival sites has witnessed a considerable progress. The interest in locally active systems is evident from the patents being filed and granted. The present article shall dwell in reviewing the recent approaches being proffered in the field. Patents as by Shefer, et al. US patent, 6589562 dealing with multicomponent biodegradable bioadhesive controlled release system for oral care products, Lee, et al. 2001, US patent 6193994, encompassing a locally administrable, biodegradable and sustained-release pharmaceutical composition for periodontitis and process for preparation thereof and method of treating periodontal disease as suggested by Basara in 2004via US patent 6830757, shall be the types of intellectual property reviewed and presented in the current manuscript.

Therapeutic applications of hydrogels in oral drug delivery

PubMed Central

Sharpe, Lindsey A; Daily, Adam M; Horava, Sarena D; Peppas, Nicholas A

2015-01-01

Introduction Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications. Areas covered This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed. Expert opinion Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest. PMID:24848309

Buccoadhesive drug delivery systems--extensive review on recent patents.

PubMed

Pathan, Shadab A; Iqbal, Zeenat; Sahani, Jasjeet K; Talegaonkar, Sushma; Khar, Roop K; Ahmad, Farhan J

2008-01-01

Peroral administration of drugs, although most preferred by both clinicians and patients has several disadvantages such as hepatic first pass metabolism and enzymatic degradation within the GI tract, that prohibit oral administration of certain classes of drugs especially peptides and proteins. Consequently, other absorptive mucosae are considered as potential sites for administration of these drugs. Among the various transmucosal routes studied the buccal mucosa offers several advantages for controlled drug delivery for extended period of time. The mucosa is well supplied with both vascular and lymphatic drainage and first-pass metabolism in the liver and pre-systemic elimination in the gastrointestinal tract is avoided. The area is well suited for a retentive device and appears to be acceptable to the patient. With the right dosage form, design and formulation, the permeability and the local environment of the mucosa can be controlled and manipulated in order to accommodate drug permeation. Buccal drug delivery is thus a promising area for continued research with the aim of systemic and local delivery of orally inefficient drugs as well as feasible and attractive alternative for non-invasive delivery of potent protein and peptide drug molecules. Extensive review pertaining specifically to the patents relating to buccal drug delivery is currently available. However, many patents e.g. US patents 6, 585,997; US20030059376A1 etc. have been mentioned in few articles. It is the objective of this article to extensively review buccal drug delivery by discussing the recent patents available. Buccal dosage forms will also be reviewed with an emphasis on bioadhesive polymeric based delivery systems.

Additive manufacturing of hierarchical injectable scaffolds for tissue engineering.

PubMed

Béduer, A; Piacentini, N; Aeberli, L; Da Silva, A; Verheyen, C A; Bonini, F; Rochat, A; Filippova, A; Serex, L; Renaud, P; Braschler, T

2018-06-05

We present a 3D-printing technology allowing free-form fabrication of centimetre-scale injectable structures for minimally invasive delivery. They result from the combination of 3D printing onto a cryogenic substrate and optimisation of carboxymethylcellulose-based cryogel inks. The resulting highly porous and elastic cryogels are biocompatible, and allow for protection of cell viability during compression for injection. Implanted into the murine subcutaneous space, they are colonized with a loose fibrovascular tissue with minimal signs of inflammation and remain encapsulation-free at three months. Finally, we vary local pore size through control of the substrate temperature during cryogenic printing. This enables control over local cell seeding density in vitro and over vascularization density in cell-free scaffolds in vivo. In sum, we address the need for 3D-bioprinting of large, yet injectable and highly biocompatible scaffolds and show modulation of the local response through control over local pore size. This work combines the power of 3D additive manufacturing with clinically advantageous minimally invasive delivery. We obtain porous, highly compressible and mechanically rugged structures by optimizing a cryogenic 3D printing process. Only a basic commercial 3D printer and elementary control over reaction rate and freezing are required. The porous hydrogels obtained are capable of withstanding delivery through capillaries up to 50 times smaller than their largest linear dimension, an as yet unprecedented compression ratio. Cells seeded onto the hydrogels are protected during compression. The hydrogel structures further exhibit excellent biocompatibility 3 months after subcutaneous injection into mice. We finally demonstrate that local modulation of pore size grants control over vascularization density in vivo. This provides proof-of-principle that meaningful biological information can be encoded during the 3D printing process, deploying its effect after minimally invasive implantation. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Techniques to reduce perineal pain during spontaneous vaginal delivery and perineal suturing: a UK survey of midwifery practice.

PubMed

Sanders, Julia; Peters, Tim J; Campbell, Rona

2005-06-01

To investigate use of pharmacological and non-pharmacological methods of perineal analgesia used by midwives during the second stage of labour and perineal repair in the UK. Postal survey. Self-complete questionnaires were sent to Heads of Midwifery in all 219 maternity units in the UK. Information was requested on the number and type of deliveries undertaken in the previous year and on the midwifery procedures used to provide pain relief immediately before delivery and for perineal repair. Details were also sought on local anaesthetics given before episiotomy or perineal repair. 207 completed questionnaires were returned providing information on 210 maternity units. Midwives reported using a variety of non-pharmacological analgesic methods to control pain at the end of the second stage of labour. Hot packs were used in 70 (33%) maternity units, cold packs in 44 (21%) and perineal massage in 109 (52%). Midwives in 131 (62%) maternity units used injectable local anaesthetics to control perineal pain. All units advocated use of local anaesthetic before episiotomy or perineal repair, but the reported doses used varied widely. The literature on levels of pain experienced immediately before spontaneous vaginal delivery and during perineal repair is sparse, but what evidence exists suggests that, for some women, these occasions are accompanied by severe pain. Findings from this survey show that there is considerable variation in what midwives provide to control pain. Formal evaluation of the perineal analgesia offered to women during the second stage of labour is urgently required.

Silk-elastin-like protein biomaterials for the controlled delivery of therapeutics.

PubMed

Huang, Wenwen; Rollett, Alexandra; Kaplan, David L

2015-05-01

Genetically engineered biomaterials are useful for controlled delivery owing to their rational design, tunable structure-function, biocompatibility, degradability and target specificity. Silk-elastin-like proteins (SELPs), a family of genetically engineered recombinant protein polymers, possess these properties. Additionally, given the benefits of combining semi-crystalline silk-blocks and elastomeric elastin-blocks, SELPs possess multi-stimuli-responsive properties and tunability, thereby becoming promising candidates for targeted cancer therapeutics delivery and controlled gene release. An overview of SELP biomaterials for drug delivery and gene release is provided. Biosynthetic strategies used for SELP production, fundamental physicochemical properties and self-assembly mechanisms are discussed. The review focuses on sequence-structure-function relationships, stimuli-responsive features and current and potential drug delivery applications. The tunable material properties allow SELPs to be pursued as promising biomaterials for nanocarriers and injectable drug release systems. Current applications of SELPs have focused on thermally-triggered biomaterial formats for the delivery of therapeutics, based on local hyperthermia in tumors or infections. Other prominent controlled release applications of SELPs as injectable hydrogels for gene release have also been pursued. Further biomedical applications that utilize other stimuli to trigger the reversible material responses of SELPs for targeted delivery, including pH, ionic strength, redox, enzymatic stimuli and electric field, are in progress. Exploiting these additional stimuli-responsive features will provide a broader range of functional biomaterials for controlled therapeutics release and tissue regeneration.

Application of Chitosan and its Derivatives in Nanocarrier Based Pulmonary Drug Delivery Systems.

PubMed

Dua, Kamal; Bebawy, Mary; Awasthi, Rajendra; Tekade, Rakesh K; Tekade, Muktika; Gupta, Gaurav; De Jesus Andreoli Pinto, Terezinha; Hansbro, Philip M

2017-01-01

The respiratory tract as a non-invasive route of drug administration is gaining increasing attention in the present time on achieving both local and the systemic therapeutic effects. Success in achieving pulmonary delivery, requires overcoming barriers including mucociliary clearance and uptake by macrophages. An effective drug delivery system delivers the therapeutically active moieties at the right time and rate to target sites. A major limitation associated with most of the currently available conventional and controlled release drug delivery devices is that not all the drug candidates are well absorbed uniformly locally or systemically. We searched and reviewed the literature focusing on chitosan and chitosan derivative based nanocarrier systems used in pulmonary drug delivery. We focused on the applications of chitosan in the development of nanoparticles for this purpose. Chitosan, a natural linear bio-polyaminosaccharide is central in the development of novel drug delivery systems (NDDS) including nanoparticles for use in the treatment of various respiratory diseases. It achieves this through its unique properties of biodegradability, biocompatibility, mucoadhesivity and its ability to enhance macromolecule permeation across membranes. It also achieves sustained and targeted effects, primary requirements for an effective pulmonary drug delivery system. This review highlights the applications and importance of chitosan with special emphasis on nanotechnology, employed in the management of respiratory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD), lung cancer and pulmonary fibrosis. This review will be of interest to both the biological and formulation scientists as it provides a summary on the utility of chitosan in pulmonary drug delivery systems. At present, there are no patented chitosan based controlled release products available for pulmonary drug delivery and so this area has enormous potential in the field of respiratory science. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Near-infrared remotely triggered drug-release strategies for cancer treatment

NASA Astrophysics Data System (ADS)

Goodman, Amanda M.; Neumann, Oara; Nørregaard, Kamilla; Henderson, Luke; Choi, Mi-Ran; Clare, Susan E.; Halas, Naomi J.

2017-11-01

Remotely controlled, localized drug delivery is highly desirable for potentially minimizing the systemic toxicity induced by the administration of typically hydrophobic chemotherapy drugs by conventional means. Nanoparticle-based drug delivery systems provide a highly promising approach for localized drug delivery, and are an emerging field of interest in cancer treatment. Here, we demonstrate near-IR light-triggered release of two drug molecules from both DNA-based and protein-based hosts that have been conjugated to near-infrared-absorbing Au nanoshells (SiO2 core, Au shell), each forming a light-responsive drug delivery complex. We show that, depending upon the drug molecule, the type of host molecule, and the laser illumination method (continuous wave or pulsed laser), in vitro light-triggered release can be achieved with both types of nanoparticle-based complexes. Two breast cancer drugs, docetaxel and HER2-targeted lapatinib, were delivered to MDA-MB-231 and SKBR3 (overexpressing HER2) breast cancer cells and compared with release in noncancerous RAW 264.7 macrophage cells. Continuous wave laser-induced release of docetaxel from a nanoshell-based DNA host complex showed increased cell death, which also coincided with nonspecific cell death from photothermal heating. Using a femtosecond pulsed laser, lapatinib release from a nanoshell-based human serum albumin protein host complex resulted in increased cancerous cell death while noncancerous control cells were unaffected. Both methods provide spatially and temporally localized drug-release strategies that can facilitate high local concentrations of chemotherapy drugs deliverable at a specific treatment site over a specific time window, with the potential for greatly minimized side effects.

Local anaesthetic wound infiltration for postcaesarean section analgesia: A systematic review and meta-analysis.

PubMed

Adesope, Oluwaseyi; Ituk, Unyime; Habib, Ashraf S

2016-10-01

Wound infiltration with local anaesthetics has been investigated as a potentially useful method for providing analgesia after caesarean delivery, but the literature is inconclusive. The objective is to assess the efficacy of local anaesthetic wound infiltration in reducing pain scores and opioid consumption in women undergoing caesarean delivery. Systematic review of randomised controlled trials with meta-analyses. MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled trials (CENTRAL) until December 2015. Randomised controlled trials that assessed the efficacy of local anaesthetic wound infiltration using an infusion or single injection technique for postcaesarean section analgesia. A total of 21 studies were included in the final analysis (11 studies using an infusion technique and 10 studies using single infiltration). Local anaesthetic wound infiltration significantly decreased opioid consumption at 24 h [mean difference -9.69 mg morphine equivalents, 95% confidence interval (CI), -14.85 to -4.52] and pain scores after 24 h at rest (mean difference -0.36, 95% CI, -0.58 to -0.14) and on movement (mean difference -0.61, 95% CI, -1.19 to -0.03). Subgroup analysis did not suggest a difference in primary outcomes between infusions and single infiltration. Opioid consumption was reduced in patients who did not receive intrathecal morphine but not in those who received intrathecal morphine, although there were very little data in patients receiving intrathecal morphine. Pain scores at rest and on movement at 24 h were reduced with catheter placement below the fascia but not above the fascia. There were no statistically significant reductions in nausea, vomiting or pruritus with local anaesthetic infiltration. Local anaesthetic wound infiltration reduces postoperative opioid consumption but had minimal effect on pain scores and did not reduce opioid-related side-effects in women who had undergone delivery by caesarean section. The review is limited by a paucity of studies using intrathecal morphine and by the indirect comparisons performed for subgroup analyses.

Clinical evaluation of a confocal microendoscope system for imaging the ovary

NASA Astrophysics Data System (ADS)

Tanbakuchi, Anthony A.; Rouse, Andrew R.; Hatch, Kenneth D.; Sampliner, Richard E.; Udovich, Josh A.; Gmitro, Arthur F.

2008-02-01

We have developed a mobile confocal microendoscope system that provides live cellular imaging during surgery to aid in diagnosing microscopic abnormalities including cancer. We present initial clinical trial results using the device to image ovaries in-vivo using fluorescein and ex-vivo results using acridine orange. The imaging catheter has improved depth control and localized dye delivery mechanisms than previously presented. A manual control now provides a simple way for the surgeon to adjust and optimize imaging depth during the procedure while a tiny piezo valve in the imaging catheter controls the dye delivery.

Effect of local drug delivery in chronic periodontitis patients: A meta-analysis

PubMed Central

Kalsi, Rupali; Vandana, K. L.; Prakash, Shobha

2011-01-01

Periodontal diseases are multi-factorial in etiology, and bacteria are one among these etiologic agents. Thus, an essential component of therapy is to eliminate or control these pathogens. This has been traditionally accomplished through mechanical means (scaling and root planing (SRP)), which is time-consuming, difficult, and, sometimes, ineffective. From about the past 30 years, locally delivered, anti-infective pharmacological agents, most recently employing sustained-release vehicles, have been introduced to achieve this goal. This systematic review is an effort to determine the efficacy of the currently available anti-infective agents, with and without concurrent SRP, in controlling chronic periodontitis. Four studies were included, which were all randomized controlled trials, incorporating a total patient population of 80, with 97 control sites and 111 test sites. A meta-analysis completed on these four studies including SRP and local sustained-release agents compared with SRP alone indicated significant adjunctive probing depth (PD) reduction for 10% Doxycycline hycylate (ATRIDOX), minocycline hydrochloride (ARESTIN), tetracycline hydrochloride (PERIODONTAL PLUS AB), and chlorhexidine gluconate (PERIOCHIP). Essentially, all studies reported substantial reductions in gingival inflammation, plaque scores, and bleeding indices, which were similar in both the control and the experimental groups. Use of antimicrobial sustained-release systems as an adjunct to SRP does not result in significant patient-centered adverse events. Local drug delivery combined with SRP appears to provide additional benefits in PD reduction compared with SRP alone. PMID:22368351

A 3D-printed local drug delivery patch for pancreatic cancer growth suppression.

PubMed

Yi, Hee-Gyeong; Choi, Yeong-Jin; Kang, Kyung Shin; Hong, Jung Min; Pati, Ruby Gupta; Park, Moon Nyeo; Shim, In Kyong; Lee, Chan Mi; Kim, Song Cheol; Cho, Dong-Woo

2016-09-28

Since recurrence and metastasis of pancreatic cancer has a worse prognosis, chemotherapy has been typically performed to attack the remained malignant cells after resection. However, it is difficult to achieve the therapeutic concentration at the tumor site with systemic chemotherapy. Numerous local drug delivery systems have been studied to overcome the shortcomings of systemic delivery. However, because most systems involve dissolution of the drug within the carrier, the concentration of the drug is limited to the saturation solubility, and consequently cannot reach the sufficient drug dose. Therefore, we hypothesized that 3D printing of a biodegradable patch incorporated with a high drug concentration would provide a versatile shape to be administered at the exact tumor site as well as an appropriate therapeutic drug concentration with a controlled release. Here, we introduce the 3D-printed patches composed of a blend of poly(lactide-co-glycolide), polycaprolactone, and 5-fluorouracil for delivering the anti-cancer drug in a prolonged controlled manner and therapeutic dose. 3D printing technology can manipulate the geometry of the patch and the drug release kinetics. The patches were flexible, and released the drug over four weeks, and thereby suppressed growth of the subcutaneous pancreatic cancer xenografts in mice with minimized side effects. Our approach reveals that 3D printing of bioabsorbable implants containing anti-cancer drugs could be a powerful method for an effective local delivery of chemotherapeutic agents to treatment of cancers. Copyright © 2016 Elsevier B.V. All rights reserved.

Oromucosal multilayer films for tailor-made, controlled drug delivery.

PubMed

Lindert, Sandra; Breitkreutz, Jörg

2017-11-01

The oral mucosa has recently become increasingly important as an alternative administration route for tailor-made, controlled drug delivery. Oromucosal multilayer films, assigned to the monograph oromucosal preparations in the Ph.Eur. may be a promising dosage form to overcome the requirements related to this drug delivery site. Areas covered: We provide an overview of multilayer films as drug delivery tools, and discuss manufacturing processes and characterization methods. We focus on the suitability of characterization methods for particular requirements of multilayer films. A classification was performed covering indication areas and APIs incorporated in multilayer film systems for oromucosal use in order to provide a summary of data published in this field. Expert opinion: The shift in drug development to high molecular weight drugs will influence the field of pharmaceutical development and delivery technologies. For a high number of indication areas, such as hormonal disorders, cardiovascular diseases or local treatment of infections, the flexible layer design of oromucosal multilayer films provides a promising option for tailor-made, controlled delivery of APIs to or through defined surfaces in the oral cavity. However, there is a lack of discriminating or standardized testing methods to assess the quality of multilayer films in a reliable way.

Strategies for Controlled Delivery of Growth Factors and Cells for Bone Regeneration

PubMed Central

Vo, Tiffany N.; Kasper, F. Kurtis; Mikos, Antonios G.

2012-01-01

The controlled delivery of growth factors and cells within biomaterial carriers can enhance and accelerate functional bone formation. The carrier system can be designed with preprogrammed release kinetics to deliver bioactive molecules in a localized, spatiotemporal manner most similar to the natural wound healing process. The carrier can also act as an extracellular matrix-mimicking substrate for promoting osteoprogenitor cellular infiltration and proliferation for integrative tissue repair. This review discusses the role of various regenerative factors involved in bone healing and their appropriate combinations with different delivery systems for augmenting bone regeneration. The general requirements of protein, cell and gene therapy are described, with elaboration on how the selection of materials, configurations and processing affects growth factor and cell delivery and regenerative efficacy in both in vitro and in vivo applications for bone tissue engineering. PMID:22342771

In vivo performance of a microelectrode neural probe with integrated drug delivery

PubMed Central

Rohatgi, Pratik; Langhals, Nicholas B.; Kipke, Daryl R.; Patil, Parag G.

2014-01-01

Object The availability of sophisticated neural probes is a key prerequisite in the development of future brain machine interfaces (BMI). In this study, we developed and validated a neural probe design capable of simultaneous drug delivery and electrophysiology recordings in vivo. Focal drug delivery has promise to dramatically extend the recording lives of neural probes, a limiting factor to clinical adoption of BMI technology. Methods To form the multifunctional neural probe, we affixed a 16-channel microfabricated silicon electrode array to a fused silica catheter. Three experiments were conducted to characterize the performance of the device. Experiment 1 examines cellular damage from probe insertion and the drug distribution in tissue. Experiment 2 measures the effects of saline infusions delivered through the probe on concurrent electrophysiology. Experiment 3 demonstrates that a physiologically relevant amount of drug can be delivered in a controlled fashion. For these experiments, Hoechst and propidium iodide were used to assess insertion trauma and the tissue distribution of the infusate. Artificial cerebral spinal fluid and tetrodotoxin were injected to determine the efficacy of drug delivery. Results The newly developed multifunctional neural probes were successfully inserted into rat cortex and were able to deliver fluids and drugs that resulted in the expected electrophysiological and histological responses. The damage from insertion of the device into brain tissue was substantially less than the volume of drug dispersion in tissue. Electrophysiological activity, including both individual spikes as well as local field potentials, was successfully recorded with this device during real-time drug delivery. No significant changes were seen in response to delivery of artificial cerebral spinal fluid as a control experiment, whereas delivery of tetrodotoxin produced the expected result of suppressing all spiking activity in the vicinity of the catheter outlet. Conclusions Multifunctional neural probes such as the ones developed and validated within this study have great potential to help further understand the design space and criteria for the next generation of neural probe technology. By incorporating integrated drug delivery functionality into the probes, new treatment options for neurological disorders and regenerative neural interfaces utilizing localized and feedback controlled delivery of drugs can be realized in the near future. PMID:19569896

Short hospitalization after caesarean delivery: effects on maternal pain and stress at discharge.

PubMed

Zanardo, Vincenzo; Giliberti, Lara; Volpe, Francesca; Simbi, Alphonse; Guerrini, Pietro; Parotto, Matteo; Straface, Gianluca

2018-09-01

To characterize predischarge maternal pain and stress after caesarean delivery and short hospitalization. This is a descriptive study with 60 women in the postoperative period of caesarean section and 60 control women after vaginal delivery. Pain and stress were measured by McGill Pain Questionnaire (MGPQ) and by the Stress Measure (Psychological Stress Measure (PSM)), respectively, at mother-infant dyad discharge, scheduled at 36 hours after delivery. Caesarean section was the delivery modality with the highest MGPQ pain and sensorial, evaluative and mixed pain descriptive categories scores. The pain location involved lower abdomen, with associated localizations at back, breast and shoulders. Conversely, vaginal delivery was the delivery modality with the highest stress scores. This study provides important information on the quality of care implications of early discharge practices in puerperae after caesarean delivery, a critical time characterized by qualitatively and quantitatively high pain and stress.

Local convection-enhanced delivery of an anti-CD40 agonistic monoclonal antibody induces antitumor effects in mouse glioma models

PubMed Central

Shoji, Takuhiro; Saito, Ryuta; Chonan, Masashi; Shibahara, Ichiyo; Sato, Aya; Kanamori, Masayuki; Sonoda, Yukihiko; Kondo, Toru; Ishii, Naoto; Tominaga, Teiji

2016-01-01

Background Glioblastoma is one of the most malignant brain tumors in adults and has a dismal prognosis. In a previous report, we reported that CD40, a TNF-R-related cell surface receptor, and its ligand CD40L were associated with glioma outcomes. Here we attempted to activate CD40 signaling in the tumor and determine if it exerted therapeutic efficacy. Methods CD40 expression was examined in 3 mouse glioma cell lines (GL261, NSCL61, and bRiTs-G3) and 5 human glioma cell lines (U87, U251, U373, T98, and A172). NSCL61 and bRiTs-G3, as glioma stem cells, also expressed the glioma stem cell markers MELK and CD44. In vitro, we demonstrated direct antitumor effects of an anti-CD40 agonistic monoclonal antibody (FGK45) against the cell lines. The efficacy of FGK45 was examined by local convection-enhanced delivery of the monoclonal antibody against each glioma model. Results CD40 was expressed in all mouse and human cell lines tested and was found at the cell membrane of each of the 3 mouse cell lines. FGK45 administration induced significant, direct antitumor effects in vitro. The local delivery of FGK45 significantly prolonged survival compared with controls in the NSCL61 and bRiTs-G3 models, but the effect was not significant in the GL261 model. Increases in apoptosis and CD4+ and CD8+ T cell infiltration were observed in the bRiTs-G3 model after FGK45 treatment. Conclusions Local delivery of FGK45 significantly prolonged survival in glioma stem cell models. Thus, local delivery of this monoclonal antibody is promising for immunotherapy against gliomas. PMID:26917236

Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues

PubMed Central

Lai, Samuel K.; Wang, Ying-Ying; Hanes, Justin

2009-01-01

Mucus is a viscoelastic and adhesive gel that protects the lung airways, gastrointestinal (GI) tract, vagina, eye and other mucosal surfaces. Most foreign particulates, including conventional particle-based drug delivery systems, are efficiently trapped in human mucus layers by steric obstruction and/or adhesion. Trapped particles are typically removed from the mucosal tissue within seconds to a few hours depending on anatomical location, thereby strongly limiting the duration of sustained drug delivery locally. A number of debilitating diseases could be treated more effectively and with fewer side effects if drugs and genes could be more efficiently delivered to the underlying mucosal tissues in a controlled manner. This review first describes the tenacious mucus barrier properties that have precluded the efficient penetration of therapeutic particles. It then reviews the design and development of new mucus-penetrating particles that may avoid rapid mucus clearance mechanisms, and thereby provide targeted or sustained drug delivery for localized therapies in mucosal tissues. PMID:19133304

Localized Cell and Drug Delivery for Auditory Prostheses

PubMed Central

Hendricks, Jeffrey L.; Chikar, Jennifer A.; Crumling, Mark A.; Raphael, Yehoash; Martin, David C.

2011-01-01

Localized cell and drug delivery to the cochlea and central auditory pathway can improve the safety and performance of implanted auditory prostheses (APs). While generally successful, these devices have a number of limitations and adverse effects including limited tonal and dynamic ranges, channel interactions, unwanted stimulation of non-auditory nerves, immune rejection, and infections including meningitis. Many of these limitations are associated with the tissue reactions to implanted auditory prosthetic devices and the gradual degeneration of the auditory system following deafness. Strategies to reduce the insertion trauma, degeneration of target neurons, fibrous and bony tissue encapsulation, and immune activation can improve the viability of tissue required for AP function as well as improve the resolution of stimulation for reduced channel interaction and improved place-pitch and level discrimination. Many pharmaceutical compounds have been identified that promote the viability of auditory tissue and prevent inflammation and infection. Cell delivery and gene therapy have provided promising results for treating hearing loss and reversing degeneration. Currently, many clinical and experimental methods can produce extremely localized and sustained drug delivery to address AP limitations. These methods provide better control over drug concentrations while eliminating the adverse effects of systemic delivery. Many of these drug delivery techniques can be integrated into modern auditory prosthetic devices to optimize the tissue response to the implanted device and reduce the risk of infection or rejection. Together, these methods and pharmaceutical agents can be used to optimize the tissue-device interface for improved AP safety and effectiveness. PMID:18573323

The Effects of a Locally Developed mHealth Intervention on Delivery and Postnatal Care Utilization; A Prospective Controlled Evaluation among Health Centres in Ethiopia.

PubMed

Shiferaw, Solomon; Spigt, Mark; Tekie, Michael; Abdullah, Muna; Fantahun, Mesganaw; Dinant, Geert-Jan

2016-01-01

Although there are studies showing that mobile phone solutions can improve health service delivery outcomes in the developed world, there is little empirical evidence that demonstrates the impact of mHealth interventions on key maternal health outcomes in low income settings. A non-randomized controlled study was conducted in the Amhara region, Ethiopia in 10 health facilities (5 intervention, 5 control) together serving around 250,000 people. Health workers in the intervention group received an android phone (3 phones per facility) loaded with an application that sends reminders for scheduled visits during antenatal care (ANC), delivery and postnatal care (PNC), and educational messages on dangers signs and common complaints during pregnancy. The intervention was developed at Addis Ababa University in Ethiopia. Primary outcomes were the percentage of women who had at least 4 ANC visits, institutional delivery and PNC visits at the health center after 12 months of implementation of the intervention. Overall 933 and 1037 women were included in the cross-sectional surveys at baseline and at follow-up respectively. In addition, the medical records of 1224 women who had at least one antenatal care visit were followed in the longitudinal study. Women who had their ANC visit in the intervention health centers were significantly more likely to deliver their baby in the same health center compared to the control group (43.1% versus 28.4%; Adjusted Odds Ratio (AOR): 1.98 (95%CI 1.53-2.55)). A significantly higher percentage of women who had ANC in the intervention group had PNC in the same health center compared to the control health centers (41.2% versus 21.1%: AOR: 2.77 (95%CI 2.12-3.61)). Our findings demonstrated that a locally customized mHealth application during ANC can significantly improve delivery and postnatal care service utilization possibly through positively influencing the behavior of health workers and their clients.

Microchips and controlled-release drug reservoirs.

PubMed

Staples, Mark

2010-01-01

This review summarizes and updates the development of implantable microchip-containing devices that control dosing from drug reservoirs integrated with the devices. As the expense and risk of new drug development continues to increase, technologies that make the best use of existing therapeutics may add significant value. Trends of future medical care that may require advanced drug delivery systems include individualized therapy and the capability to automate drug delivery. Implantable drug delivery devices that promise to address these anticipated needs have been constructed in a variety of ways using micro- and nanoelectromechanical systems (MEMS or NEMS)-based technology. These devices expand treatment options for addressing unmet medical needs related to dosing. Within the last few years, advances in several technologies (MEMS or NEMS fabrication, materials science, polymer chemistry, and data management) have converged to enable the construction of miniaturized implantable devices for controlled delivery of therapeutic agents from one or more reservoirs. Suboptimal performance of conventional dosing methods in terms of safety, efficacy, pain, or convenience can be improved with advanced delivery devices. Microchip-based implantable drug delivery devices allow localized delivery by direct placement of the device at the treatment site, delivery on demand (emergency administration, pulsatile, or adjustable continuous dosing), programmable dosing cycles, automated delivery of multiple drugs, and dosing in response to physiological and diagnostic feedback. In addition, innovative drug-medical device combinations may protect labile active ingredients within hermetically sealed reservoirs. Copyright (c) 2010 John Wiley & Sons, Inc.

Advanced techniques and armamentarium for dental local anesthesia.

PubMed

Clark, Taylor M; Yagiela, John A

2010-10-01

Computer-controlled local anesthetic delivery (C-CLAD) devices and systems for intraosseous (IO) injection are important additions to the dental anesthesia armamentarium. C-CLAD using slow infusion rates can significantly reduce the discomfort of local anesthetic infusion, especially in palatal tissues, and facilitate palatal approaches to pulpal nerve block that find special use in cosmetic dentistry, periodontal therapy, and pediatric dentistry. Anesthesia of single teeth can be obtained using either C-CLAD intraligamentary injections or IO injections. Supplementary IO anesthesia is particularly suited for providing effective pain control of teeth diagnosed with irreversible pulpitis. Copyright © 2010 Elsevier Inc. All rights reserved.

Theranostic 3-Dimensional nano brain-implant for prolonged and localized treatment of recurrent glioma

NASA Astrophysics Data System (ADS)

Ramachandran, Ranjith; Junnuthula, Vijayabhaskar Reddy; Gowd, G. Siddaramana; Ashokan, Anusha; Thomas, John; Peethambaran, Reshmi; Thomas, Anoop; Unni, Ayalur Kodakara Kochugovindan; Panikar, Dilip; Nair, Shantikumar V.; Koyakutty, Manzoor

2017-03-01

Localized and controlled delivery of chemotherapeutics directly in brain-tumor for prolonged periods may radically improve the prognosis of recurrent glioblastoma. Here, we report a unique method of nanofiber by fiber controlled delivery of anti-cancer drug, Temozolomide, in orthotopic brain-tumor for one month using flexible polymeric nano-implant. A library of drug loaded (20 wt%) electrospun nanofiber of PLGA-PLA-PCL blends with distinct in vivo brain-release kinetics (hours to months) were numerically selected and a single nano-implant was formed by co-electrospinning of nano-fiber such that different set of fibres releases the drug for a specific periods from days to months by fiber-by-fiber switching. Orthotopic rat glioma implanted wafers showed constant drug release (116.6 μg/day) with negligible leakage into the peripheral blood (<100 ng) rendering ~1000 fold differential drug dosage in tumor versus peripheral blood. Most importantly, implant with one month release profile resulted in long-term (>4 month) survival of 85.7% animals whereas 07 day releasing implant showed tumor recurrence in 54.6% animals, rendering a median survival of only 74 days. In effect, we show that highly controlled drug delivery is possible for prolonged periods in orthotopic brain-tumor using combinatorial nanofibre libraries of bulk-eroding polymers, thereby controlling glioma recurrence.

Development of drug-loaded polymer microcapsules for treatment of epilepsy.

PubMed

Chen, Yu; Gu, Qi; Yue, Zhilian; Crook, Jeremy M; Moulton, Simon E; Cook, Mark J; Wallace, Gordon G

2017-09-26

Despite significant progress in developing new drugs for seizure control, epilepsy still affects 1% of the global population and is drug-resistant in more than 30% of cases. To improve the therapeutic efficacy of epilepsy medication, a promising approach is to deliver anti-epilepsy drugs directly to affected brain areas using local drug delivery systems. The drug delivery systems must meet a number of criteria, including high drug loading efficiency, biodegradability, neuro-cytocompatibility and predictable drug release profiles. Here we report the development of fibre- and sphere-based microcapsules that exhibit controllable uniform morphologies and drug release profiles as predicted by mathematical modelling. Importantly, both forms of fabricated microcapsules are compatible with human brain derived neural stem cells and differentiated neurons and neuroglia, indicating clinical compliance for neural implantation and therapeutic drug delivery.

The evaluation of doxycycline controlled release gel versus doxycycline controlled release implant in the management of periodontitis

PubMed Central

Chadha, Vandana Srikrishna; Bhat, Khandige Mahalinga

2012-01-01

Background: Investigators have sought different methods to deliver antimicrobials to periodontal pockets. This study was designed to assess the efficacy of locally made doxycycline gel versus locally made doxycycline implant as biodegradable controlled local delivery systems, by evaluating the pharmacological drug release and improvement in gingival status, gain in attachment, and reduction in pocket depth. Materials and Methods: Thirty patients with localized periodontal pockets ≥5 mm were randomly divided into three groups. The first group received the doxycycline gel, the second the doxycycline implant, and the third received only scaling and root planing (the control group). The patients in the first two groups were selected for the drug release. Clinical parameters such as gingival index, plaque index, probing depth, and attachment levels were recorded at baseline and the 90th day. Gingival crevicular fluid (GCF) and saliva samples were collected 1 hour following gel and implant placement and then on the 10th, 30th, and 60th days. Results: There was a statistically significant difference in the release of doxycycline from the gel when compared with the implant in the GCF and saliva on the 10th and 30th days. All the three groups showed improvement in clinical parameters. The improvements in both gel and implant groups were greater when compared with the control group with no statistically significant difference between the implant and gel systems. Conclusion: The use of local delivery of doxycycline through gel and Implant media further enhances the positive changes obtained following scaling and root planing. The release of doxycycline from the implant and the gel was comparable. PMID:23055585

Permeation enhancer strategies in transdermal drug delivery.

PubMed

Marwah, Harneet; Garg, Tarun; Goyal, Amit K; Rath, Goutam

2016-01-01

Today, ∼74% of drugs are taken orally and are not found to be as effective as desired. To improve such characteristics, transdermal drug delivery was brought to existence. This delivery system is capable of transporting the drug or macromolecules painlessly through skin into the blood circulation at fixed rate. Topical administration of therapeutic agents offers many advantages over conventional oral and invasive techniques of drug delivery. Several important advantages of transdermal drug delivery are prevention from hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. Human skin surface, as a site of drug application for both local and systemic effects, is the most eligible candidate available. New controlled transdermal drug delivery systems (TDDS) technologies (electrically-based, structure-based and velocity-based) have been developed and commercialized for the transdermal delivery of troublesome drugs. This review article covers most of the new active transport technologies involved in enhancing the transdermal permeation via effective drug delivery system.

Acoustic Characterization of a Vessel-on-a-Chip Microfluidic System for Ultrasound-Mediated Drug Delivery.

PubMed

Beekers, Ines; van Rooij, Tom; Verweij, Martin D; Versluis, Michel; de Jong, Nico; Trietsch, Sebastiaan J; Kooiman, Klazina

2018-04-01

Ultrasound in the presence of gas-filled microbubbles can be used to enhance local uptake of drugs and genes. To study the drug delivery potential and its underlying physical and biological mechanisms, an in vitro vessel model should ideally include 3-D cell culture, perfusion flow, and membrane-free soft boundaries. Here, we propose an organ-on-a-chip microfluidic platform to study ultrasound-mediated drug delivery: the OrganoPlate. The acoustic propagation into the OrganoPlate was determined to assess the feasibility of controlled microbubble actuation, which is required to study the microbubble-cell interaction for drug delivery. The pressure field in the OrganoPlate was characterized non-invasively by studying experimentally the well-known response of microbubbles and by simulating the acoustic wave propagation in the system. Microbubble dynamics in the OrganoPlate were recorded with the Brandaris 128 ultrahigh-speed camera (17 million frames/s) and a control experiment was performed in an OptiCell, an in vitro monolayer cell culture chamber that is conventionally used to study ultrasound-mediated drug delivery. When insonified at frequencies between 1 and 2 MHz, microbubbles in the OrganoPlate experienced larger oscillation amplitudes resulting from higher local pressures. Microbubbles responded similarly in both systems when insonified at frequencies between 2 and 4 MHz. Numerical simulations performed with a 3-D finite-element model of ultrasound propagation into the OrganoPlate and the OptiCell showed the same frequency-dependent behavior. The predictable and homogeneous pressure field in the OrganoPlate demonstrates its potential to develop an in vitro 3-D cell culture model, well suited to study ultrasound-mediated drug delivery.

Nanoparticulate delivery of agents for induced elastogenesis in three-dimensional collagenous matrices.

PubMed

Venkataraman, Lavanya; Sivaraman, Balakrishnan; Vaidya, Pratik; Ramamurthi, Anand

2016-12-01

The degradation of elastic matrix in the infrarenal aortic wall is a critical parameter underlying the formation and progression of abdominal aortic aneurysms. It is mediated by the chronic overexpression of matrix metalloprotease (MMP)-2 and MMP-9, leading to a progressive loss of elasticity and weakening of the aortic wall. Delivery of therapeutic agents to inhibit MMPs, while concurrently coaxing cell-based regenerative repair of the elastic matrix represents a potential strategy for slowing or arresting abdominal aortic aneurysm growth. Previous studies have demonstrated elastogenic induction of healthy and aneurysmal aortic smooth muscle cells and inhibition of MMPs, following exogenous delivery of elastogenic factors such as transforming growth factor (TGF)-β1, as well as MMP-inhibitors such as doxycycline (DOX) in two-dimensional culture. Based on these findings, and others that demonstrated elastogenic benefits of nanoparticulate delivery of these agents in two-dimensional culture, poly(lactide-co-glycolide) nanoparticles were developed for localized, controlled and sustained delivery of DOX and TGF-β1 to human aortic smooth muscle cells within a three-dimensional gels of type I collagen, which closely simulate the arterial tissue microenvironment. DOX and TGF-β1 released from these nanoparticles influenced elastogenic outcomes positively within the collagen constructs over 21 days of culture, which were comparable to that induced by exogenous supplementation of DOX and TGF-β1 within the culture medium. However, this was accomplished at doses ~20-fold lower than the exogenous dosages of the agents, illustrating that their localized, controlled and sustained delivery from nanoparticles embedded within a three-dimensional scaffold is an efficient strategy for directed elastogenesis. Copyright © 2014 John Wiley & Sons, Ltd. Copyright © 2014 John Wiley & Sons, Ltd.

Ultrasound-mediated gene delivery of naked plasmid DNA in skeletal muscles: a case for bolus injections.

PubMed

Sanches, Pedro Gomes; Mühlmeister, Mareike; Seip, Ralf; Kaijzel, Eric; Löwik, Clemens; Böhmer, Marcel; Tiemann, Klaus; Grüll, Holger

2014-12-10

Localized gene delivery has many potential clinical applications. However, the nucleic acids (e.g. pDNA and siRNA) are incapable of passively crossing the endothelium, cell membranes and other biological barriers which must be crossed to reach their intracellular targets. A possible solution is the use of ultrasound to burst circulating microbubbles inducing transient permeabilization of surrounding tissues which mediates nucleic acid extravasation and cellular uptake. In this study we report on an optimization of the ultrasound gene delivery technique. Naked pDNA (200 μg) encoding luciferase and SonoVue® microbubbles were co-injected intravenously in mice. The hindlimb skeletal muscles were exposed to ultrasound from a non-focused transducer (1 MHz, 1.25 MPa, PRI 30s) and injection protocols and total amounts as well as ultrasound parameters were systemically varied. Gene expression was quantified relative to a control using a bioluminescence camera system at day 7 after sonication. Bioluminescence ratios in sonicated/control muscles of up to 101× were obtained. In conclusion, we were able to specifically deliver genetic material to the selected skeletal muscles and overall, the use of bolus injections and high microbubble numbers resulted in increased gene expression reflected by stronger bioluminescence signals. Based on our data, bolus injections seem to be required in order to achieve transient highly concentrated levels of nucleic acids and microbubbles at the tissue of interest which upon ultrasound exposure should lead to increased levels of gene delivery. Thus, ultrasound mediated gene delivery is a promising technique for the clinical translation of localized drug delivery. Copyright © 2014 Elsevier B.V. All rights reserved.

Spatial analysis of instream nitrogen loads and factors controlling nitrogen delivery to streams in the southeastern United States using spatially referenced regression on watershed attributes (SPARROW) and regional classification frameworks

USGS Publications Warehouse

Hoos, A.B.; McMahon, G.

2009-01-01

Understanding how nitrogen transport across the landscape varies with landscape characteristics is important for developing sound nitrogen management policies. We used a spatially referenced regression analysis (SPARROW) to examine landscape characteristics influencing delivery of nitrogen from sources in a watershed to stream channels. Modelled landscape delivery ratio varies widely (by a factor of 4) among watersheds in the southeastern United States - higher in the western part (Tennessee, Alabama, and Mississippi) than in the eastern part, and the average value for the region is lower compared to other parts of the nation. When we model landscape delivery ratio as a continuous function of local-scale landscape characteristics, we estimate a spatial pattern that varies as a function of soil and climate characteristics but exhibits spatial structure in residuals (observed load minus predicted load). The spatial pattern of modelled landscape delivery ratio and the spatial pattern of residuals coincide spatially with Level III ecoregions and also with hydrologic landscape regions. Subsequent incorporation into the model of these frameworks as regional scale variables improves estimation of landscape delivery ratio, evidenced by reduced spatial bias in residuals, and suggests that cross-scale processes affect nitrogen attenuation on the landscape. The model-fitted coefficient values are logically consistent with the hypothesis that broad-scale classifications of hydrologic response help to explain differential rates of nitrogen attenuation, controlling for local-scale landscape characteristics. Negative model coefficients for hydrologic landscape regions where the primary flow path is shallow ground water suggest that a lower fraction of nitrogen mass will be delivered to streams; this relation is reversed for regions where the primary flow path is overland flow.

Spatial analysis of instream nitrogen loads and factors controlling nitrogen delivery to streams in the southeastern United States using spatially referenced regression on watershed attributes (SPARROW) and regional classification frameworks

USGS Publications Warehouse

Hoos, Anne B.; McMahon, Gerard

2009-01-01

Understanding how nitrogen transport across the landscape varies with landscape characteristics is important for developing sound nitrogen management policies. We used a spatially referenced regression analysis (SPARROW) to examine landscape characteristics influencing delivery of nitrogen from sources in a watershed to stream channels. Modelled landscape delivery ratio varies widely (by a factor of 4) among watersheds in the southeastern United States—higher in the western part (Tennessee, Alabama, and Mississippi) than in the eastern part, and the average value for the region is lower compared to other parts of the nation. When we model landscape delivery ratio as a continuous function of local-scale landscape characteristics, we estimate a spatial pattern that varies as a function of soil and climate characteristics but exhibits spatial structure in residuals (observed load minus predicted load). The spatial pattern of modelled landscape delivery ratio and the spatial pattern of residuals coincide spatially with Level III ecoregions and also with hydrologic landscape regions. Subsequent incorporation into the model of these frameworks as regional scale variables improves estimation of landscape delivery ratio, evidenced by reduced spatial bias in residuals, and suggests that cross-scale processes affect nitrogen attenuation on the landscape. The model-fitted coefficient values are logically consistent with the hypothesis that broad-scale classifications of hydrologic response help to explain differential rates of nitrogen attenuation, controlling for local-scale landscape characteristics. Negative model coefficients for hydrologic landscape regions where the primary flow path is shallow ground water suggest that a lower fraction of nitrogen mass will be delivered to streams; this relation is reversed for regions where the primary flow path is overland flow.

Local delivery of FTY720 in PCL membrane improves SCI functional recovery by reducing reactive astrogliosis.

PubMed

Wang, Junjuan; Wang, Jiaqiu; Lu, Ping; Cai, Youzhi; Wang, Yafei; Hong, Lan; Ren, Hao; Heng, Boon Chin; Liu, Hua; Zhou, Jing; Ouyang, Hongwei

2015-09-01

FTY720 has recently been approved as an oral drug for treating relapsing forms of multiple sclerosis, and exerts its therapeutic effect by acting as an immunological inhibitor targeting the sphingosine-1-phosphate (S1P) receptor subtype (S1P1) of T cells. Recently studies demonstrated positive efficacy of this drug on spinal cord injury (SCI) in animal models after systemic administration, albeit with significant adverse side effects. We hereby hypothesize that localized delivery of FTY720 can promote SCI recovery by reducing pathological astrogliosis. The mechanistic functions of FTY720 were investigated in vitro and in vivo utilizing immunofluorescence, histology, MRI and behavioral analysis. The in vitro study showed that FTY720 can reduce astrocyte migration and proliferation activated by S1P. FTY720 can prolong internalization of S1P1 and exert antagonistic effects on S1P1. In vivo study of SCI animal models demonstrated that local delivery of FTY720 with polycaprolactone (PCL) membrane significantly decreased S1P1 expression and glial scarring compared with the control group. Furthermore, FTY720-treated groups exhibited less cavitation volume and neuron loss, which significantly improved recovery of motor function. These findings demonstrated that localized delivery of FTY720 can promote SCI recovery by targeting the S1P1 receptor of astrocytes, provide a new therapeutic strategy for SCI treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Calcium Binding-Mediated Sustained Release of Minocycline from Hydrophilic Multilayer Coatings Targeting Infection and Inflammation

PubMed Central

Zhang, Zhiling; Nix, Camilla A.; Ercan, Utku K.; Gerstenhaber, Jonathan A.; Joshi, Suresh G.; Zhong, Yinghui

2014-01-01

Infection and inflammation are common complications that seriously affect the functionality and longevity of implanted medical implants. Systemic administration of antibiotics and anti-inflammatory drugs often cannot achieve sufficient local concentration to be effective, and elicits serious side effects. Local delivery of therapeutics from drug-eluting coatings presents a promising solution. However, hydrophobic and thick coatings are commonly used to ensure sufficient drug loading and sustained release, which may limit tissue integration and tissue device communications. A calcium-mediated drug delivery mechanism was developed and characterized in this study. This novel mechanism allows controlled, sustained release of minocycline, an effective antibiotic and anti-inflammatory drug, from nanoscale thin hydrophilic polyelectrolyte multilayers for over 35 days at physiologically relevant concentrations. pH-responsive minocycline release was observed as the chelation between minocycline and Ca2+ is less stable at acidic pH, enabling ‘smart’ drug delivery in response to infection and/or inflammation-induced tissue acidosis. The release kinetics of minocycline can be controlled by varying initial loading, Ca2+ concentration, and Ca2+ incorporation into different layers, enabling facile development of implant coatings with versatile release kinetics. This drug delivery platform can potentially be used for releasing any drug that has high Ca2+ binding affinity, enabling its use in a variety of biomedical applications. PMID:24409292

Gene Delivery Strategies to Promote Spinal Cord Repair

PubMed Central

Walthers, Christopher M; Seidlits, Stephanie K

2015-01-01

Gene therapies hold great promise for the treatment of many neurodegenerative disorders and traumatic injuries in the central nervous system. However, development of effective methods to deliver such therapies in a controlled manner to the spinal cord is a necessity for their translation to the clinic. Although essential progress has been made to improve efficiency of transgene delivery and reduce the immunogenicity of genetic vectors, there is still much work to be done to achieve clinical strategies capable of reversing neurodegeneration and mediating tissue regeneration. In particular, strategies to achieve localized, robust expression of therapeutic transgenes by target cell types, at controlled levels over defined time periods, will be necessary to fully regenerate functional spinal cord tissues. This review summarizes the progress over the last decade toward the development of effective gene therapies in the spinal cord, including identification of appropriate target genes, improvements to design of genetic vectors, advances in delivery methods, and strategies for delivery of multiple transgenes with synergistic actions. The potential of biomaterials to mediate gene delivery while simultaneously providing inductive scaffolding to facilitate tissue regeneration is also discussed. PMID:25922572

Inhaled nano- and microparticles for drug delivery

PubMed Central

El-Sherbiny, Ibrahim M.; El-Baz, Nancy M.; Yacoub, Magdi H.

2015-01-01

The 21st century has seen a paradigm shift to inhaled therapy, for both systemic and local drug delivery, due to the lung's favourable properties of a large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including non-invasive route of administration, low metabolic activity, control environment for systemic absorption and avoids first bypass metabolism. However, because the lung is one of the major ports of entry, it has multiple clearance mechanisms, which prevent foreign particles from entering the body. Although these clearance mechanisms maintain the sterility of the lung, clearance mechanisms can also act as barriers to the therapeutic effectiveness of inhaled drugs. This effectiveness is also influenced by the deposition site and delivered dose. Particulate-based drug delivery systems have emerged as an innovative and promising alternative to conventional inhaled drugs to circumvent pulmonary clearance mechanisms and provide enhanced therapeutic efficiency and controlled drug release. The principle of multiple pulmonary clearance mechanisms is reviewed, including mucociliary, alveolar macrophages, absorptive, and metabolic degradation. This review also discusses the current approaches and formulations developed to achieve optimal pulmonary drug delivery systems. PMID:26779496

EMERGING MICROTECHNOLOGIES FOR THE DEVELOPMENT OF ORAL DRUG DELIVERY DEVICES

PubMed Central

Chirra, Hariharasudhan D.; Desai, Tejal A.

2012-01-01

The development of oral drug delivery platforms for administering therapeutics in a safe and effective manner across the gastrointestinal epithelium is of much importance. A variety of delivery systems such as enterically coated tablets, capsules, particles, and liposomes have been developed to improve oral bioavailability of drugs. However, orally administered drugs suffer from poor localization and therapeutic efficacy due to various physiological conditions such as low pH, and high shear intestinal fluid flow. Novel platforms combining controlled release, improved adhesion, tissue penetration, and selective intestinal targeting may overcome these issues and potentially diminish the toxicity and high frequency of administration associated with conventional oral delivery. Microfabrication along with appropriate surface chemistry, provide a means to fabricate these platforms en masse with flexibility in tailoring the shape, size, reservoir volume, and surface characteristics of microdevices. Moreover, the same technology can be used to include integrated circuit technology and sensors for designing sophisticated autonomous drug delivery devices that promise to significantly improve point of care diagnostic and therapeutic medical applications. This review sheds light on some of the fabrication techniques and addresses a few of the microfabricated devices that can be effectively used for controlled oral drug delivery applications. PMID:22981755

Efficacy of local drug delivery of Achyranthes aspera gel in the management of chronic periodontitis: A clinical study.

PubMed

Boyapati, Ramanarayana; Gojja, Prathibha; Chintalapani, Srikanth; Nagubandi, Kirankumar; Ramisetti, Arpita; Salavadhi, Shyam Sunder

2017-01-01

Periodontitis is an inflammatory disease of microbial origin. Locally delivered antimicrobials reduce subgingival flora. Achyranthes aspera gel has antimicrobial, antioxidant, anti-inflammatory, and immunostimulant effects. To evaluate the efficacy of local drug delivery of A. aspera gel in the management of chronic periodontitis. Thirty patients with chronic periodontitis were considered in the study and categorized into two equal groups (Group A: scaling and root planing (SRP) with A. aspera gel, Group B: SRP with placebo gel). Patients were enlisted from the Department of Periodontics, Mamata Dental College and Hospital. The clinical parameters (gingival index, bleeding on probing, probing pocket depth, and clinical attachment level) were recorded at baseline and 3 months. All the obtained data were sent for statistical analyses using SPSS version 18. The periodontitis and the Achyranthes were statistically analyzed. A comparison of clinical parameters for test group and control group from baseline to 3 months was done using paired t -test. Intergroup comparison for both the groups was done using independent sample t -test. A. aspera gel when delivered locally along with SRP showed a beneficial effect. A. aspera gel as a non-surgical local drug delivery system proved to be without any side effects in the management of periodontitis. A. aspera gel has strong anti-inflammatory effects in addition to its antioxidant activity.

Efficacy of local drug delivery of Achyranthes aspera gel in the management of chronic periodontitis: A clinical study

PubMed Central

Boyapati, Ramanarayana; Gojja, Prathibha; Chintalapani, Srikanth; Nagubandi, Kirankumar; Ramisetti, Arpita; Salavadhi, Shyam Sunder

2017-01-01

Context: Periodontitis is an inflammatory disease of microbial origin. Locally delivered antimicrobials reduce subgingival flora. Achyranthes aspera gel has antimicrobial, antioxidant, anti-inflammatory, and immunostimulant effects. Aims: To evaluate the efficacy of local drug delivery of A. aspera gel in the management of chronic periodontitis. Materials and Methods: Thirty patients with chronic periodontitis were considered in the study and categorized into two equal groups (Group A: scaling and root planing (SRP) with A. aspera gel, Group B: SRP with placebo gel). Patients were enlisted from the Department of Periodontics, Mamata Dental College and Hospital. The clinical parameters (gingival index, bleeding on probing, probing pocket depth, and clinical attachment level) were recorded at baseline and 3 months. Statistical Analysis Used: All the obtained data were sent for statistical analyses using SPSS version 18. Results: The periodontitis and the Achyranthes were statistically analyzed. A comparison of clinical parameters for test group and control group from baseline to 3 months was done using paired t-test. Intergroup comparison for both the groups was done using independent sample t-test. Conclusions: A. aspera gel when delivered locally along with SRP showed a beneficial effect. A. aspera gel as a non-surgical local drug delivery system proved to be without any side effects in the management of periodontitis. A. aspera gel has strong anti-inflammatory effects in addition to its antioxidant activity. PMID:29386800

Local convection-enhanced delivery of an anti-CD40 agonistic monoclonal antibody induces antitumor effects in mouse glioma models.

PubMed

Shoji, Takuhiro; Saito, Ryuta; Chonan, Masashi; Shibahara, Ichiyo; Sato, Aya; Kanamori, Masayuki; Sonoda, Yukihiko; Kondo, Toru; Ishii, Naoto; Tominaga, Teiji

2016-08-01

Glioblastoma is one of the most malignant brain tumors in adults and has a dismal prognosis. In a previous report, we reported that CD40, a TNF-R-related cell surface receptor, and its ligand CD40L were associated with glioma outcomes. Here we attempted to activate CD40 signaling in the tumor and determine if it exerted therapeutic efficacy. CD40 expression was examined in 3 mouse glioma cell lines (GL261, NSCL61, and bRiTs-G3) and 5 human glioma cell lines (U87, U251, U373, T98, and A172). NSCL61 and bRiTs-G3, as glioma stem cells, also expressed the glioma stem cell markers MELK and CD44. In vitro, we demonstrated direct antitumor effects of an anti-CD40 agonistic monoclonal antibody (FGK45) against the cell lines. The efficacy of FGK45 was examined by local convection-enhanced delivery of the monoclonal antibody against each glioma model. CD40 was expressed in all mouse and human cell lines tested and was found at the cell membrane of each of the 3 mouse cell lines. FGK45 administration induced significant, direct antitumor effects in vitro. The local delivery of FGK45 significantly prolonged survival compared with controls in the NSCL61 and bRiTs-G3 models, but the effect was not significant in the GL261 model. Increases in apoptosis and CD4(+) and CD8(+) T cell infiltration were observed in the bRiTs-G3 model after FGK45 treatment. Local delivery of FGK45 significantly prolonged survival in glioma stem cell models. Thus, local delivery of this monoclonal antibody is promising for immunotherapy against gliomas. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Programmable release of multiple protein drugs from aptamer-functionalized hydrogels via nucleic acid hybridization.

PubMed

Battig, Mark R; Soontornworajit, Boonchoy; Wang, Yong

2012-08-01

Polymeric delivery systems have been extensively studied to achieve localized and controlled release of protein drugs. However, it is still challenging to control the release of multiple protein drugs in distinct stages according to the progress of disease or treatment. This study successfully demonstrates that multiple protein drugs can be released from aptamer-functionalized hydrogels with adjustable release rates at predetermined time points using complementary sequences (CSs) as biomolecular triggers. Because both aptamer-protein interactions and aptamer-CS hybridization are sequence-specific, aptamer-functionalized hydrogels constitute a promising polymeric delivery system for the programmable release of multiple protein drugs to treat complex human diseases.

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction.

PubMed

Zhang, Li; Sun, Zhenxing; Ren, Pingping; You, Manjie; Zhang, Jing; Fang, Lingyun; Wang, Jing; Chen, Yihan; Yan, Fei; Zheng, Hairong; Xie, Mingxing

2017-01-01

Hypoxia-inducible factor 1α (HIF-1α) plays a critical protective role in ischemic heart disease. Under normoxic conditions, HIF-1α was degraded by oxygen-dependent prolyl hydroxylase-2 (PHD2). Gene therapy has become a promising strategy to inhibit the degradation of HIF-1α and to improve cardiac function after ischemic injury. However, conventional gene delivery systems are difficult to achieve a targeted and localized gene delivery into the ischemic myocardia. Here, we report the localized myocardial delivery of shRNA against PHD2 through ultrasound-targeted microbubble destruction (UTMD) for protection the heart from acute myocardial infarction. In this study, a novel cationic microbubble was fabricated by using of the thin-film hydration and sonication method. The resulting microbubbles had a 28.2 ± 2.21 mV surface zeta potential and could greatly improve DNA binding performance, achieving 17.81 ± 1.46 μg of DNA loading capacity per 5 × 10 8 microbubbles. Combined with these cationic microbubbles, UTMD-mediated gene delivery was evaluated and the gene transfection efficiency was optimized in the H9C2 cardiac cells. Knockdown of PHD2 gene was successfully realized by UTMD-mediated shPHD2 transfection, resulting in HIF-1α-dependent protective effects on H9C2 cells through increasing the expression of HIF-1α, VEGF and bFGF. We further employed UTMD-mediated shPHD2 transfection into the localized ischemic myocardia in a rat ischemia model, demonstrating significantly reduced infarct size and greatly improved the heart function. The silencing of PHD2 and the up-regulation of its downstream genes in the treated myocardia were confirmed. Histological analysis further revealed numbers of HIF-1α- and VEGF-, and CD31-positive cells/mm 2 in the shPHD2-treated group were significantly greater than those in the sham or control vector groups (P < 0.05). In conclusion, our study provides a promising strategy to realize ultrasound-mediated localized myocardial shRNA delivery to protect the heart from acute myocardial infarction via cationic microbubbles.

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction

PubMed Central

Zhang, Li; Sun, Zhenxing; Ren, Pingping; You, Manjie; Zhang, Jing; Fang, Lingyun; Wang, Jing; Chen, Yihan; Yan, Fei; Zheng, Hairong; Xie, Mingxing

2017-01-01

Hypoxia-inducible factor 1α (HIF-1α) plays a critical protective role in ischemic heart disease. Under normoxic conditions, HIF-1α was degraded by oxygen-dependent prolyl hydroxylase-2 (PHD2). Gene therapy has become a promising strategy to inhibit the degradation of HIF-1α and to improve cardiac function after ischemic injury. However, conventional gene delivery systems are difficult to achieve a targeted and localized gene delivery into the ischemic myocardia. Here, we report the localized myocardial delivery of shRNA against PHD2 through ultrasound-targeted microbubble destruction (UTMD) for protection the heart from acute myocardial infarction. In this study, a novel cationic microbubble was fabricated by using of the thin-film hydration and sonication method. The resulting microbubbles had a 28.2 ± 2.21 mV surface zeta potential and could greatly improve DNA binding performance, achieving 17.81 ± 1.46 μg of DNA loading capacity per 5 × 108 microbubbles. Combined with these cationic microbubbles, UTMD-mediated gene delivery was evaluated and the gene transfection efficiency was optimized in the H9C2 cardiac cells. Knockdown of PHD2 gene was successfully realized by UTMD-mediated shPHD2 transfection, resulting in HIF-1α-dependent protective effects on H9C2 cells through increasing the expression of HIF-1α, VEGF and bFGF. We further employed UTMD-mediated shPHD2 transfection into the localized ischemic myocardia in a rat ischemia model, demonstrating significantly reduced infarct size and greatly improved the heart function. The silencing of PHD2 and the up-regulation of its downstream genes in the treated myocardia were confirmed. Histological analysis further revealed numbers of HIF-1α- and VEGF-, and CD31-positive cells/mm2 in the shPHD2-treated group were significantly greater than those in the sham or control vector groups (P < 0.05). In conclusion, our study provides a promising strategy to realize ultrasound-mediated localized myocardial shRNA delivery to protect the heart from acute myocardial infarction via cationic microbubbles. PMID:28042316

Concentration rather than dose defines the local brain toxicity of agents that are effectively distributed by convection-enhanced delivery.

PubMed

Zhang, Rong; Saito, Ryuta; Mano, Yui; Kanamori, Masayuki; Sonoda, Yukihiko; Kumabe, Toshihiro; Tominaga, Teiji

2014-01-30

Convection-enhanced delivery (CED) has been developed as a potentially effective drug-delivery strategy into the central nervous system. In contrast to systemic intravenous administration, local delivery achieves high concentration and prolonged retention in the local tissue, with increased chance of local toxicity, especially with toxic agents such as chemotherapeutic agents. Therefore, the factors that affect local toxicity should be extensively studied. With the assumption that concentration-oriented evaluation of toxicity is important for local CED, we evaluated the appearance of local toxicity among different agents after delivery with CED and studied if it is dose dependent or concentration dependent. Local toxicity profile of chemotherapeutic agents delivered via CED indicates BCNU was dose-dependent, whereas that of ACNU was concentration-dependent. On the other hand, local toxicity for doxorubicin, which is not distributed effectively by CED, was dose-dependent. Local toxicity for PLD, which is extensively distributed by CED, was concentration-dependent. Traditional evaluation of drug induced toxicity was dose-oriented. This is true for systemic intravascular delivery. However, with local CED, toxicity of several drugs exacerbated in concentration-dependent manner. From our study, local toxicity of drugs that are likely to distribute effectively tended to be concentration-dependent. Concentration rather than dose may be more important for the toxicity of agents that are effectively distributed by CED. Concentration-oriented evaluation of toxicity is more important for CED. Copyright © 2013 Elsevier B.V. All rights reserved.

Local vs. systemic administration of bisphosphonates in rat cleft bone graft: A comparative study

PubMed Central

Lin, Lawrence; Olson, Jeffrey; Kwon, Taewoo; Bezouglaia, Olga; Tran, Jaime; Hoang, Michael; Bui, Kimberly; Kim, Reuben H.; Tetradis, Sotirios

2018-01-01

A majority of patients with orofacial cleft deformity requires cleft repair through a bone graft. However, elevated amount of bone resorption and subsequent bone graft failure remains a significant clinical challenge. Bisphosphonates (BPs), a class of anti-resorptive drugs, may offer great promise in enhancing the clinical success of bone grafting. In this study, we compared the effects of systemic and local delivery of BPs in an intraoral bone graft model in rats. We randomly divided 34 female 20-week-old Fischer F344 Inbred rats into four groups to repair an intraoral critical-sized defect (CSD): (1) Control: CSD without graft (n = 4); (2) Graft/Saline: bone graft with systemic administration of saline 1 week post-operatively (n = 10); (3) Graft/Systemic: bone graft with systemic administration of zoledronic acid 1 week post-operatively (n = 10); and (4) Graft/Local: bone graft pre-treated with zoledronic acid (n = 10). At 6-weeks post-operatively, microCT volumetric analysis showed a significant increase in bone fraction volume (BV/TV) in the Graft/Systemic (62.99 ±14.31%) and Graft/Local (69.35 ±13.18%) groups compared to the Graft/Saline (39.18±10.18%). Similarly, histological analysis demonstrated a significant increase in bone volume in the Graft/Systemic (78.76 ±18.00%) and Graft/Local (89.95 ±4.93%) groups compared to the Graft/Saline (19.74±18.89%). The local delivery approach resulted in the clinical success of bone grafts, with reduced graft resorption and enhanced osteogenesis and bony integration with defect margins while avoiding the effects of BPs on peripheral osteoclastic function. In addition, local delivery of BPs may be superior to systemic delivery with its ease of procedure as it involves simple soaking of bone graft materials in BP solution prior to graft placement into the defect. This new approach may provide convenient and promising clinical applications towards effectively managing cleft patients. PMID:29304080

The Effects of a Locally Developed mHealth Intervention on Delivery and Postnatal Care Utilization; A Prospective Controlled Evaluation among Health Centres in Ethiopia

PubMed Central

Shiferaw, Solomon; Spigt, Mark; Tekie, Michael; Abdullah, Muna; Fantahun, Mesganaw; Dinant, Geert-Jan

2016-01-01

Background Although there are studies showing that mobile phone solutions can improve health service delivery outcomes in the developed world, there is little empirical evidence that demonstrates the impact of mHealth interventions on key maternal health outcomes in low income settings. Methods A non-randomized controlled study was conducted in the Amhara region, Ethiopia in 10 health facilities (5 intervention, 5 control) together serving around 250,000 people. Health workers in the intervention group received an android phone (3 phones per facility) loaded with an application that sends reminders for scheduled visits during antenatal care (ANC), delivery and postnatal care (PNC), and educational messages on dangers signs and common complaints during pregnancy. The intervention was developed at Addis Ababa University in Ethiopia. Primary outcomes were the percentage of women who had at least 4 ANC visits, institutional delivery and PNC visits at the health center after 12 months of implementation of the intervention. Findings Overall 933 and 1037 women were included in the cross-sectional surveys at baseline and at follow-up respectively. In addition, the medical records of 1224 women who had at least one antenatal care visit were followed in the longitudinal study. Women who had their ANC visit in the intervention health centers were significantly more likely to deliver their baby in the same health center compared to the control group (43.1% versus 28.4%; Adjusted Odds Ratio (AOR): 1.98 (95%CI 1.53–2.55)). A significantly higher percentage of women who had ANC in the intervention group had PNC in the same health center compared to the control health centers (41.2% versus 21.1%: AOR: 2.77 (95%CI 2.12–3.61)). Conclusions Our findings demonstrated that a locally customized mHealth application during ANC can significantly improve delivery and postnatal care service utilization possibly through positively influencing the behavior of health workers and their clients. PMID:27383186

High-dose versus low-dose local anaesthetic for transversus abdominis plane block post-Caesarean delivery analgesia: a meta-analysis.

PubMed

Ng, S C; Habib, A S; Sodha, S; Carvalho, B; Sultan, P

2018-02-01

The optimal local-anaesthetic (LA) dose for transversus-abdominis-plane (TAP) block is unclear. In this meta-analysis, we aimed to determine whether TAP blocks for Caesarean delivery (CD) with low-dose (LD) LA demonstrated non-inferiority in terms of analgesic efficacy, compared with high-dose (HD) LA. A literature search was performed for randomised controlled trials examining the analgesic efficacy of TAP blocks vs control after CD. The different dosing used in these studies was classified as HD or LD (bupivacaine equivalents >50 or ≤50 mg per block side, respectively). The pooled results of each dose group vs control were indirectly compared using the Q test. The primary outcome was 24 h opioid consumption. Secondary outcomes included 6 and 24 h postoperative pain scores, time to first analgesia, 6 h opioid consumption, opioid-related side-effects, and maternal satisfaction. Fourteen studies consisting of 770 women (389 TAP and 381 control) were included. Compared with controls, the 24 h opioid consumption (milligram morphine equivalents) was lower in HD [mean difference (MD) 95% confidence interval (CI) -22.41 (-38.56, -6.26); P=0.007; I 2 =93%] and LD [MD 95% CI -16.29 (-29.74, -2.84); P=0.02; I 2 =98%] TAP groups. However, no differences were demonstrated between the HD and LD groups (P=0.57). There were also no differences between the HD and LD groups for the 6 h opioid consumption, time to first analgesia, 6 and 24 h pain scores, postoperative nausea and vomiting, pruritus, and maternal satisfaction. Low-dose TAP blocks for Caesarean delivery provide analgesia and opioid-sparing effects comparable with the high-dose blocks. This suggests that lower doses can be used to reduce local anaesthetic toxicity risk without compromising the analgesic efficacy. Copyright © 2017 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Percutaneous dermal drug delivery for local pain control

PubMed Central

Tadicherla, Sujatha; Berman, Brian

2006-01-01

Topical anesthetics have evolved from a simple solution of cocaine to creams, ointments, gels, liposomal preparations, and to the latest sophisticated patches and peels. Topical anesthetics are essential for performing diagnostic, therapeutic, and cosmetic dermatology procedures. These anesthetics noninvasively deliver anesthesia in locally required areas. In this review, we present an overview on the mechanism of precutaneous absorption of skin and address the composition, duration of onset of anesthetic effect, uses, and side effects that are applicable for the products. Also discussed are the novel advances of using heat to enhance penetration of the anesthetic as seen in Synera™ patch and delivery of anesthesia using a peel method as seen in the yet to be US Food and Drug Administration-approved S-Caine peel. PMID:18360585

Delivery of S1P Receptor-Targeted Drugs via Biodegradable Polymer Scaffolds Enhances Bone Regeneration in a Critical Size Cranial Defect*

PubMed Central

Das, Anusuya; Tanner, Shaun; Barker, Daniel A.; Green, David; Botchwey, Edward A.

2014-01-01

Biodegradable polymer scaffolds can be used to deliver soluble factors to enhance osseous remodeling in bone defects. To this end, we designed a poly(lactic-co-glycolic acid) (PLAGA) microsphere scaffold to sustain the release of FTY720, a selective agonist for sphingosine 1-phosphate (S1P) receptors. The microsphere scaffolds were created from fast degrading 50:50 PLAGA and/or from slow-degrading 85:15 PLAGA. Temporal and spatial regulation of bone remodeling depended on the use of appropriate scaffolds for drug delivery. The release profiles from the scaffolds were used to design an optimal delivery system to treat critical size cranial defects in a rodent model. The ability of local FTY720 delivery to maximize bone regeneration was evaluated with microcomputed tomography (microCT) and histology. Following 4 weeks of defect healing, FTY720 delivery from 85:15 PLAGA scaffolds resulted in a significant increase in bone volumes in the defect region compared to the controls. 85:15 microsphere scaffolds maintain their structural integrity over a longer period of time, and cause an initial burst release of FTY720 due to surface localization of the drug. This encourages cellular in-growth and an increase in new bone formation. PMID:23640833

Delivery of S1P receptor-targeted drugs via biodegradable polymer scaffolds enhances bone regeneration in a critical size cranial defect.

PubMed

Das, Anusuya; Tanner, Shaun; Barker, Daniel A; Green, David; Botchwey, Edward A

2014-04-01

Biodegradable polymer scaffolds can be used to deliver soluble factors to enhance osseous remodeling in bone defects. To this end, we designed a poly(lactic-co-glycolic acid) (PLAGA) microsphere scaffold to sustain the release of FTY720, a selective agonist for sphingosine 1-phosphate (S1P) receptors. The microsphere scaffolds were created from fast degrading 50:50 PLAGA and/or from slow-degrading 85:15 PLAGA. Temporal and spatial regulation of bone remodeling depended on the use of appropriate scaffolds for drug delivery. The release profiles from the scaffolds were used to design an optimal delivery system to treat critical size cranial defects in a rodent model. The ability of local FTY720 delivery to maximize bone regeneration was evaluated with micro-computed tomography (microCT) and histology. Following 4 weeks of defect healing, FTY720 delivery from 85:15 PLAGA scaffolds resulted in a significant increase in bone volumes in the defect region compared to the controls. A 85:15 microsphere scaffolds maintain their structural integrity over a longer period of time, and cause an initial burst release of FTY720 due to surface localization of the drug. This encourages cellular in-growth and an increase in new bone formation. Copyright © 2013 Wiley Periodicals, Inc.

Non-ototoxic local delivery of bisphosphonate to the mammalian cochlea

PubMed Central

Kang, Woo Seok; Sun, Shuting; Nguyen, Kim; Kashemirov, Boris; McKenna, Charles E.; Hacking, S. Adam; Quesnel, Alicia M.; Sewell, William F.; McKenna, Michael J.; Jung, David H.

2015-01-01

Hypothesis Local delivery of bisphosphonates results in superior localization of these compounds for the treatment of cochlear otosclerosis, without ototoxicity. Background Otosclerosis is a common disorder of abnormal bone remodeling within the human otic capsule. It is a frequent cause of conductive hearing loss from stapes fixation. Large lesions that penetrate the cochlear endosteum and injure the spiral ligament result in sensorineural hearing loss. Nitrogen-containing bisphosphonates (e.g., zoledronate) are potent inhibitors of bone remodeling with proven efficacy in the treatment of metabolic bone diseases, including otosclerosis. Local delivery to the cochlea may allow for improved drug targeting, higher local concentrations, and the avoidance of systemic complications. In this study, we utilize a fluorescently labeled bisphosphonate compound (6-FAM-ZOL) to determine drug localization and concentration within the otic capsule. Various methods for delivery are compared. Ototoxicity is evaluated by ABR and DPOAEs. Methods 6-FAM-ZOL was administered to guinea pigs via intraperitoneal injection, placement of alginate beads onto the round window membrane (RWM), or microfluidic pump infusion via a cochleostomy. Hearing was evaluated. Specimens were embedded into resin blocks, ground to a mid-modiolar section, and quantitatively imaged using fluorescence microscopy. Results There was a dose-dependent increase in fluorescent signal following systemic 6-FAM-ZOL treatment. Local delivery via the RWM or a cochleostomy increased delivery efficiency. No significant ototoxicity was observed following either systemic or local 6-FAM-ZOL delivery. Conclusions These findings establish important pre-clinical parameters for the treatment of cochlear otosclerosis in humans. PMID:25996080

Modulation of release kinetics by plasma polymerization of ampicillin-loaded β-TCP ceramics

NASA Astrophysics Data System (ADS)

Labay, C.; Buxadera-Palomero, J.; Avilés, M.; Canal, C.; Ginebra, M. P.

2016-08-01

Beta-tricalcium phosphate (β-TCP) bioceramics are employed in bone repair surgery. Their local implantation in bone defects puts them in the limelight as potential materials for local drug delivery. However, obtaining suitable release patterns fitting the required therapeutics is a challenge. Here, plasma polymerization of ampicillin-loaded β-TCP is studied for the design of a novel antibiotic delivery system. Polyethylene glycol-like (PEG-like) coating of β-TCP by low pressure plasma polymerization was performed using diglyme as precursor, and nanometric PEG-like layers were obtained by simple and double plasma polymerization processes. A significant increase in hydrophobicity, and the presence of plasma polymer was visible on the surface by SEM and quantified by XPS. As a main consequence of the plasma polymerisation, the release kinetics were successfully modified, avoiding burst release, and slowing down the initial rate of release leading to a 4.5 h delay in reaching the same antibiotic release percentage, whilst conservation of the activity of the antibiotic was simultaneously maintained. Thus, plasma polymerisation on the surface of bioceramics may be a good strategy to design controlled drug delivery matrices for local bone therapies.

Silk constructs for delivery of muskuloskeletal therapeutics

PubMed Central

Meinel, Lorenz; Kaplan, David L.

2012-01-01

Silk fibroin (SF) is a biopolymer with distinguishing features from many other bio- as well as synthetic polymers. From a biomechanical and drug delivery perspective, SF combines remarkable versatility for scaffolding (solid implants, hydrogels, threads, solutions), with advanced mechanical properties and good stabilization and controlled delivery of entrapped protein and small molecule drugs, respectively. It is this combination of mechanical and pharmaceutical features which render SF so exciting for biomedical applications. his pattern along with the versatility of this biopolymer have been translated into progress for musculoskeletal applications. We review the use and potential of silk fibroin for systemic and localized delivery of therapeutics in diseases affecting the musculoskeletal system. We also present future directions for this biopolymer as well as the necessary research and development steps for their achievement. PMID:22522139

Photo-Modulated Therapeutic Protein Release from a Hydrogel Depot Using Visible Light.

PubMed

Basuki, Johan S; Qie, Fengxiang; Mulet, Xavier; Suryadinata, Randy; Vashi, Aditya V; Peng, Yong Y; Li, Lingli; Hao, Xiaojuan; Tan, Tianwei; Hughes, Timothy C

2017-01-19

The use of biomacromolecular therapeutics has revolutionized disease treatment, but frequent injections are required owing to their short half-life in vivo. Thus there is a need for a drug delivery system that acts as a reservoir and releases the drug remotely "on demand". Here we demonstrate a simple light-triggered local drug delivery system through photo-thermal interactions of polymer-coated gold nanoparticles (AuNPs) inside an agarose hydrogel as therapeutic depot. Localized temperature increase induced by the visible light exposure caused reversible softening of the hydrogel matrix to release the pre-loaded therapeutics. The release profile can be adjusted by AuNPs and agarose concentrations, light intensity and exposure time. Importantly, the biological activity of the released bevacizumab was highly retained. In this study we demonstrate the potential application of this facile AuNPs/hydrogel system for ocular therapeutics delivery through its versatility to release multiple biologics, compatibility to ocular cells and spatiotemporal control using visible light. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cholera toxin subunit B-mediated intracellular trafficking of mesoporous silica nanoparticles toward the endoplasmic reticulum

NASA Astrophysics Data System (ADS)

Walker, William Andrew

In recent decades, pharmaceutical research has led to the development of numerous treatments for human disease. Nanoscale delivery systems have the potential to maximize therapeutic outcomes by enabling target specific delivery of these therapeutics. The intracellular localization of many of these materials however, is poorly controlled, leading to sequestration in degradative cellular pathways and limiting the efficacy of their payloads. Numerous proteins, particularly bacterial toxins, have evolved mechanisms to subvert the degradative mechanisms of the cell. Here, we have investigated a possible strategy for shunting intracellular delivery of encapsulated cargoes from these pathways by modifying mesoporous silica nanoparticles (MSNs) with the well-characterized bacterial toxin Cholera toxin subunit B (CTxB). Using established optical imaging methods we investigated the internalization, trafficking, and subcellular localization of our modified MSNs in an in vitro animal cell model. We then attempted to demonstrate the practical utility of this approach by using CTxB-modified mesoporous silica nanoparticles to deliver propidium iodide, a membrane-impermeant fluorophore.

The role of intraoperative radiation therapy in patients with pancreatic cancer.

PubMed

Palta, Manisha; Willett, Christopher; Czito, Brian

2014-04-01

Intraoperative radiation therapy (IORT) techniques allow for the delivery of high doses of radiation therapy while excluding part or all of the nearby dose-limiting sensitive structures. Therefore, the effective radiation dose is increased and local tumor control potentially improved. This is pertinent in the case of pancreatic cancer because local failure rates are as high as 50%-80% in patients with resected and locally advanced disease. Available data in patients receiving IORT after pancreaticoduodenectomy reveal an improvement in local control, though overall survival benefit is unclear. Series of patients with locally advanced pancreatic cancer also suggest pain relief, and in select studies, improved survival associated with the inclusion of IORT. At present, no phase III data clearly supports the use of IORT in the management of pancreatic cancer. © 2013 Published by Elsevier Inc.

Photoacoustic microscopy imaging for microneedle drug delivery

NASA Astrophysics Data System (ADS)

Moothanchery, Mohesh; Seeni, Razina Z.; Xu, Chenjie; Pramanik, Manojit

2018-02-01

The recent development of novel transdermal drug delivery systems (TDDS) using microneedle technology allows micron-sized conduits to be formed within the outermost skin layers attracting keen interest in skin as an interface for localized and systemic delivery of therapeutics. In light of this, researchers are using microneedles as tools to deliver nanoparticle formulations to targeted sites for effective therapy. However, in such studies the use of traditional histological methods are employed for characterization and do not allow for the in vivo visualization of drug delivery mechanism. Hence, this study presents a novel imaging technology to characterize microneedle based nanoparticle delivery systems using optical resolution-photoacoustic microscopy (OR-PAM). In this study in vivo transdermal delivery of gold nanoparticles using microneedles in mice ear and the spatial distribution of the nanoparticles in the tissue was successfully illustrated. Characterization of parameters that are relevant in drug delivery studies such as penetration depth, efficiency of delivered gold nanoparticles were monitored using the system. Photoacoustic microscopy proves an ideal tool for the characterization studies of microneedle properties and the studies shows microneedles as an ideal tool for precise and controlled drug delivery.

Advances in radiotherapy techniques and delivery for non-small cell lung cancer: benefits of intensity-modulated radiation therapy, proton therapy, and stereotactic body radiation therapy

PubMed Central

Diwanji, Tejan P.; Mohindra, Pranshu; Vyfhuis, Melissa; Snider, James W.; Kalavagunta, Chaitanya; Mossahebi, Sina; Yu, Jen; Feigenberg, Steven

2017-01-01

The 21st century has seen several paradigm shifts in the treatment of non-small cell lung cancer (NSCLC) in early-stage inoperable disease, definitive locally advanced disease, and the postoperative setting. A key driver in improvement of local disease control has been the significant evolution of radiation therapy techniques in the last three decades, allowing for delivery of definitive radiation doses while limiting exposure of normal tissues. For patients with locally-advanced NSCLC, the advent of volumetric imaging techniques has allowed a shift from 2-dimensional approaches to 3-dimensional conformal radiation therapy (3DCRT). The next generation of 3DCRT, intensity-modulated radiation therapy and volumetric-modulated arc therapy (VMAT), have enabled even more conformal radiation delivery. Clinical evidence has shown that this can improve the quality of life for patients undergoing definitive management of lung cancer. In the early-stage setting, conventional fractionation led to poor outcomes. Evaluation of altered dose fractionation with the previously noted technology advances led to advent of stereotactic body radiation therapy (SBRT). This technique has dramatically improved local control and expanded treatment options for inoperable, early-stage patients. The recent development of proton therapy has opened new avenues for improving conformity and the therapeutic ratio. Evolution of newer proton therapy techniques, such as pencil-beam scanning (PBS), could improve tolerability and possibly allow reexamination of dose escalation. These new progresses, along with significant advances in systemic therapies, have improved survival for lung cancer patients across the spectrum of non-metastatic disease. They have also brought to light new challenges and avenues for further research and improvement. PMID:28529896

Local delivery of rapamycin: a toxicity and efficacy study in an experimental malignant glioma model in rats

PubMed Central

Tyler, Betty; Wadsworth, Scott; Recinos, Violette; Mehta, Vivek; Vellimana, Ananth; Li, Khan; Rosenblatt, Joel; Do, Hiep; Gallia, Gary L.; Siu, I-Mei; Wicks, Robert T.; Rudek, Michelle A.; Zhao, Ming; Brem, Henry

2011-01-01

Rapamycin, an anti-proliferative agent, is effective in the treatment of renal cell carcinoma and recurrent breast cancers. We proposed that this potent mammalian target of rapamycin inhibitor may be useful for the treatment of gliomas as well. We examined the cytotoxicity of rapamycin against a rodent glioma cell line, determined the toxicity of rapamycin when delivered intracranially, and investigated the efficacy of local delivery of rapamycin for the treatment of experimental malignant glioma in vivo. We also examined the dose-dependent efficacy of rapamycin and the effect when locally delivered rapamycin was combined with radiation therapy. Rapamycin was cytotoxic to 9L cells, causing 34% growth inhibition at a concentration of 0.01 µg/mL. No in vivo toxicity was observed when rapamycin was incorporated into biodegradable caprolactone-glycolide (35:65) polymer beads at 0.3%, 3%, and 30% loading doses and implanted intracranially. Three separate efficacy studies were performed to test the reproducibility of the effect of the rapamycin beads as well as the validity of this treatment approach. Animals treated with the highest dose of rapamycin beads tested (30%) consistently demonstrated significantly longer survival durations than the control and placebo groups. All dose-escalating rapamycin bead treatment groups (0.3%, 3% and 30%), treated both concurrently with tumor and in a delayed manner after tumor placement, experienced a significant increase in survival, compared with controls. Radiation therapy in addition to the simultaneous treatment with 30% rapamycin beads led to significantly longer survival duration than either therapy alone. These results suggest that the local delivery of rapamycin for the treatment of gliomas should be further investigated. PMID:21727209

Perivascular Delivery of Notch 1 siRNA Inhibits Injury-Induced Arterial Remodeling

PubMed Central

Redmond, Eileen M.; Liu, Weimin; Hamm, Katie; Hatch, Ekaterina; Cahill, Paul A.; Morrow, David

2014-01-01

Objectives To determine the efficacy of perivascular delivery of Notch 1 siRNA in preventing injury-induced arterial remodeling. Methods and Results Carotid artery ligation was performed to induce arterial remodeling. After 14 days, morphometric analysis confirmed increased vSMC growth and subsequent media thickening and neointimal formation. Laser capture microdissection, quantitative qRT-PCR and immunoblot analysis of medial tissue revealed a significant increase in Notch1 receptor and notch target gene, Hrt 1 and 2 expression in the injured vessels. Perivascular delivery of Notch 1 siRNA by pluronic gel inhibited the injury-induced increase in Notch 1 receptor and target gene expression when compared to scrambled siRNA controls while concomitantly reducing media thickening and neointimal formation to pre-injury, sham-operated levels. Selective Notch 1 knockdown also reversed the injury-induced inhibition of pro-apoptotic Bax expression while decreasing injury-induced anti-apoptotic Bcl-XL expression to sham-operated control levels. In parallel experiments, proliferative cyclin levels, as measured by PCNA expression, were reversed to sham-operated control levels following selective Notch 1 knockdown. Conclusion These results suggest that injury-induced arterial remodeling can be successfully inhibited by localized perivascular delivery of Notch 1 siRNA. PMID:24416200

Spatio-temporal control of gene expression and cancer treatment using magnetic resonance imaging-guided focused ultrasound.

PubMed

Moonen, Chrit T W

2007-06-15

Local temperature elevation may be used for tumor ablation, gene expression, drug activation, and gene and/or drug delivery. High-intensity focused ultrasound (HIFU) is the only clinically viable technology that can be used to achieve a local temperature increase deep inside the human body in a noninvasive way. Magnetic resonance imaging (MRI) guidance of the procedure allows in situ target definition and identification of nearby healthy tissue to be spared. In addition, MRI can be used to provide continuous temperature mapping during HIFU for spatial and temporal control of the heating procedure and prediction of the final lesion based on the received thermal dose. The primary purpose of the development of MRI-guided HIFU was to achieve safe noninvasive tissue ablation. The technique has been tested extensively in preclinical studies and is now accepted in the clinic for ablation of uterine fibroids. MRI-guided HIFU for ablation shows conceptual similarities with radiation therapy. However, thermal damage generally shows threshold-like behavior, with necrosis above the critical thermal dose and full recovery below. MRI-guided HIFU is being clinically evaluated in the cancer field. The technology also shows great promise for a variety of advanced therapeutic methods, such as gene therapy. MR-guided HIFU, together with the use of a temperature-sensitive promoter, provides local, physical, and spatio-temporal control of transgene expression. Specially designed contrast agents, together with the combined use of MRI and ultrasound, may be used for local gene and drug delivery.

Review paper: critical issues in tissue engineering: biomaterials, cell sources, angiogenesis, and drug delivery systems.

PubMed

Naderi, Hojjat; Matin, Maryam M; Bahrami, Ahmad Reza

2011-11-01

Tissue engineering is a newly emerging biomedical technology, which aids and increases the repair and regeneration of deficient and injured tissues. It employs the principles from the fields of materials science, cell biology, transplantation, and engineering in an effort to treat or replace damaged tissues. Tissue engineering and development of complex tissues or organs, such as heart, muscle, kidney, liver, and lung, are still a distant milestone in twenty-first century. Generally, there are four main challenges in tissue engineering which need optimization. These include biomaterials, cell sources, vascularization of engineered tissues, and design of drug delivery systems. Biomaterials and cell sources should be specific for the engineering of each tissue or organ. On the other hand, angiogenesis is required not only for the treatment of a variety of ischemic conditions, but it is also a critical component of virtually all tissue-engineering strategies. Therefore, controlling the dose, location, and duration of releasing angiogenic factors via polymeric delivery systems, in order to ultimately better mimic the stem cell niche through scaffolds, will dictate the utility of a variety of biomaterials in tissue regeneration. This review focuses on the use of polymeric vehicles that are made of synthetic and/or natural biomaterials as scaffolds for three-dimensional cell cultures and for locally delivering the inductive growth factors in various formats to provide a method of controlled, localized delivery for the desired time frame and for vascularized tissue-engineering therapies.

Clinical applications of image guided-intensity modulated radiation therapy (IG-IMRT) for conformal avoidance of normal tissue

NASA Astrophysics Data System (ADS)

Gutierrez, Alonso Navar

2007-12-01

Recent improvements in imaging technology and radiation delivery have led to the development of advanced treatment techniques in radiotherapy which have opened the door for novel therapeutic approaches to improve the efficacy of radiation cancer treatments. Among these advances is image-guided, intensity modulated radiation therapy (IG-IMRT), in which imaging is incorporated to aid in inter-/intra-fractional target localization and to ensure accurate delivery of precise and highly conformal dose distributions. In principle, clinical implementation of IG-IMRT should improve normal tissue sparing and permit effective biological dose escalation thus widening the radiation therapeutic window and lead to increases in survival through improved local control of primary neoplastic diseases. Details of the development of three clinical applications made possible solely with IG-IMRT radiation delivery techniques are presented: (1) Laparoscopically implanted tissue expander radiotherapy (LITE-RT) has been developed to enhance conformal avoidance of normal tissue during the treatment of intra-abdominopelvic cancers. LITE-RT functions by geometrically displacing surrounding normal tissue and isolating the target volume through the interfractional inflation of a custom-shaped tissue expander throughout the course of treatment. (2) The unique delivery geometry of helical tomotherapy, a novel form of IG-IMRT, enables the delivery of composite treatment plan m which whole brain radiotherapy (WBRT) with hippocampal avoidance, hypothesized to reduce the risk of memory function decline and improve the patient's quality of life, and simultaneously integrated boost to multiple brain metastases to improve intracranial tumor control is achieved. (3) Escalation of biological dose to targets through integrated, selective subvolume boosts have been shown to efficiently increase tumor dose without significantly increasing normal tissue dose. Helical tomotherapy was used to investigate the feasibility of delivering a simultaneously integrated subvolume boost to canine nasal tumors and was found to dramatically increase estimated 1-year tumor control probability (TCP) without increasing the dose to the eyes, so as to preserve vision, and to the brain, so as to prevent neuropathy.

Chlorhexidine controlled-release profile after EDTA root surface etching: an in vivo study.

PubMed

Gamal, Ahmed Y; Kumper, Radi M; Sadek, Hesham S; El Destawy, Mahmoud T

2011-05-01

The main objective of the present study was to quantify chlorhexidine (CHX) release after the use of CHX-EDTA root surface treatment as a local-delivery antimicrobial vehicle. Twenty non-smoking patients clinically diagnosed as having moderate-to-severe chronic periodontitis were selected to participate in this study. After cause-related therapy, one site in every patient received defect overfill with CHX gel 2% (20 sites). In addition, twenty contralateral sites received defect fill of CHX gel after 3 minutes of 24% EDTA gel root surface etching (20 sites). Gingival crevicular fluid samples were collected at 1, 3, 7, and 14 days post-therapy. The CHX-EDTA group showed statistically significantly higher levels of CHX than those of the control group at 1, 3, and 7 days. At 14 days, the CHX-EDTA group showed 0.8 mg/mL values. The use of CHX-EDTA root surface treatment as a local-delivery antimicrobial improves CHX substantivity.

Novel flower-shaped albumin particles as controlled-release carriers for drugs to penetrate the round-window membrane.

PubMed

Yu, Zhan; Yu, Min; Zhou, Zhimin; Zhang, Zhibao; Du, Bo; Xiong, Qingqing

2014-01-01

Controlled-release carriers for local drug delivery have attracted increasing attention for inner-ear treatment recently. In this paper, flower-shaped bovine serum albumin (FBSA) particles were prepared by a modified desolvation method followed by glutaraldehyde or heat denaturation. The size of the FBSA particles varied from 10 μm to 100 μm, and most were 50-80 μm. Heat-denatured FBSA particles have good cytocompatibility with a prolonged survival time for L929 cells. The FBSA particles were utilized as carriers to investigate the release behaviors of the model drug - rhodamine B. Rhodamine B showed a sustained-release effect and penetrated the round-window membrane of guinea pigs. We also confirmed the attachment of FBSA particles onto the round-window membrane by microscopy. The FBSA particles, with good biocompatibility, drug-loading capacity, adhesive capability, and biodegradability, may have potential applications in the field of local drug delivery for inner-ear disease treatment.

Thermosensitive liposomes for localized delivery and triggered release of chemotherapy

PubMed Central

Ta, Terence; Porter, Tyrone M.

2016-01-01

Liposomes are a promising class of nanomedicine with the potential to provide site-specific chemotherapy, thus improving the quality of cancer patient care. First-generation liposomes have emerged as one of the first nanomedicines used clinically for localized delivery of chemotherapy. Second-generation liposomes, i.e. stimuli-responsive liposomes, have the potential to not only provide site-specific chemotherapy, but also triggered drug release and thus greater spatial and temporal control of therapy. Temperature-sensitive liposomes are an especially attractive option, as tumors can be heated in a controlled and predictable manner with external energy sources. Traditional thermosensitive liposomes are composed of lipids that undergo a gel-to-liquid phase transition at several degrees above physiological temperature. More recently, temperature-sensitization of liposomes has been demonstrated with the use of lysolipids and synthetic temperature-sensitive polymers. The design, drug release behavior, and clinical potential of various temperature-sensitive liposomes, as well as the various heating modalities used to trigger release, are discussed in this review. PMID:23583706

Local delivery of nicotine does not mitigate fibrosis but may lead to angiogenesis.

PubMed

Ng, Kenneth K; Awad, Neven; Brook, Michael A; Holloway, Alison C; Sheardown, Heather

2011-09-01

As with most implanted biomaterials, the wound healing response following implantation of a silicone breast implant leads to the formation of a fibrotic capsule. This can result in capsular contracture, a painful complication that often necessitates the removal of implant. It is well established that nicotine and nicotinic agonists inhibit inflammatory signaling. Based on the link between the inflammatory response and capsule formation, we hypothesized that local delivery of nicotine from the implant may lead to the reduction in inflammation and capsule thickness, which may ultimately reduce the incidence of capsular contracture. Nicotine was loaded into PDMS membranes using a previously established method. The loaded materials were implanted into the submammary pockets between the third and fourth mammary glands of rats. To confirm that the nicotine was acting locally and not systemically, serum cotinine, the primary metabolite of nicotine, was measured by ELISA at 3 days. Thirty days post implantation, the animals were euthanized and the tissue samples were fixed for histological analysis. Blood vessel density was measured immunohistochemically, while the capsule thickness was evaluated microscopically. While the presence of the nicotine metabolite, cotinine, in the serum at the early time points demonstrated that the nicotine was released locally from the devices, there were no significant differences in the capsule thickness between the control and experimental implants. However, the results indicated that there were differences in angiogenesis with the local delivery of nicotine, which may have other implications for the development of biomaterials.

Controlled local drug delivery strategies from chitosan hydrogels for wound healing.

PubMed

Elviri, Lisa; Bianchera, Annalisa; Bergonzi, Carlo; Bettini, Ruggero

2017-07-01

The main target of tissue engineering is the preparation and application of adequate materials for the design and production of scaffolds, that possess properties promoting cell adhesion, proliferation and differentiation. The use of natural polysaccharides, such as chitosan, to prepare hydrogels for wound healing and controlled drug delivery is a research topic of wide and increasing interest. Areas covered: This review presents the latest results and challenges in the preparation of chitosan and chitosan-based scaffold/hydrogel for wound healing applications. A detailed overview of their behavior in terms of controlled drug delivery, divided by drug categories, and efficacy was provided and critically discussed. Expert opinion: The need to establish and exploit the advantages of natural biomaterials in combination with active compounds is playing a pivotal role in the regenerative medicine fields. The challenges posed by the many variables affecting tissue repair and regeneration need to be standardized and adhere to recognized guidelines to improve the quality of evidence in the wound healing process. Currently, different methodologies are followed to prepare innovative scaffold formulations and structures. Innovative technologies such as 3D printing or bio-electrospray are promising to create chitosan-based scaffolds with finely controlled structures with customizable shape porosity and thickness. Chitosan scaffolds could be designed in combination with a variety of polysaccharides or active compounds with selected and reproducible spacial distribution, providing active wound dressing with highly tunable controlled drug delivery.

Newly Engineered Magnetic Erythrocytes for Sustained and Targeted Delivery of Anti-Cancer Therapeutic Compounds

PubMed Central

Taranta, Monia; Naldi, Ilaria

2011-01-01

Cytotoxic chemotherapy of cancer is limited by serious, sometimes life-threatening, side effects that arise from toxicities to sensitive normal cells because the therapies are not selective for malignant cells. So how can they be selectively improved? Alternative pharmaceutical formulations of anti-cancer agents have been investigated in order to improve conventional chemotherapy treatment. These formulations are associated with problems like severe toxic side effects on healthy organs, drug resistance and limited access of the drug to the tumor sites suggested the need to focus on site-specific controlled drug delivery systems. In response to these concerns, we have developed a new drug delivery system based on magnetic erythrocytes engineered with a viral spike fusion protein. This new erythrocyte-based drug delivery system has the potential for magnetic-controlled site-specific localization and highly efficient fusion capability with the targeted cells. Here we show that the erythro-magneto-HA virosomes drug delivery system is able to attach and fuse with the target cells and to efficiently release therapeutic compounds inside the cells. The efficacy of the anti-cancer drug employed is increased and the dose required is 10 time less than that needed with conventional therapy. PMID:21373641

The Enhancement of Bone Allograft Incorporation by the Local Delivery of the Sphingosine 1-phosphate Receptor Targeted Drug FTY720

PubMed Central

Aronin, Caren E Petrie; Shin, Soo J; Naden, Kimberly B; Rios, Peter D; Sefcik, Lauren S; Zawodny, Sarah R; Bagayoko, Namory D; Cui, Quanjun; Khan, Yusuf

2010-01-01

Poor vascularization coupled with mechanical instability is the leading cause of post-operative complications and poor functional prognosis of massive bone allografts. To address this limitation, we designed a novel continuous polymer coating system to provide sustained localized delivery of pharmacological agent, FTY720, a selective agonist for sphingosine 1-phosphate receptors, within massive tibial defects. In vitro drug release studies validated 64% loading efficiency with complete release of compound following 14 days. Mechanical evaluation following six weeks of healing suggested significant enhancement of mechanical stability in FTY720 treatment groups compared with unloaded controls. Furthermore, superior osseous integration across the host-graft interface, significant enhancement in smooth muscle cell investment, and reduction in leukocyte recruitment was evident in FTY720 treated groups compared with untreated groups. Using this approach, we can capitalize on the existing mechanical and biomaterial properties of devitalized bone, add a controllable delivery system while maintaining overall porous structure, and deliver a small molecule compound to constitutively target vascular remodeling, osseous remodeling, and minimize fibrous encapsulation within the allograft-host bone interface. Such results support continued evaluation of drug-eluting allografts as a viable strategy to improve functional outcome and long-term success of massive cortical allograft implants. PMID:20621764

Review: emerging developments in the use of bioactive glasses for treating infected prosthetic joints.

PubMed

Rahaman, Mohamed N; Bal, B Sonny; Huang, Wenhai

2014-08-01

Bacterial contamination of implanted orthopedic prostheses is a serious complication that requires prolonged systemic antibiotic therapy, major surgery to remove infected implants, bone reconstruction, and considerable morbidity. Local delivery of high doses of antibiotics using poly(methyl methacrylate) (PMMA) cement as the carrier, along with systemic antibiotics, is the standard treatment. However, PMMA is not biodegradable, and it can present a surface on which secondary bacterial infection can occur. PMMA spacers used to treat deep implant infections must be removed after resolution of the infection. Alternative carrier materials for antibiotics that could also restore deficient bone are therefore of interest. In this article, the development of bioactive glass-based materials as a delivery system for antibiotics is reviewed. Bioactive glass is osteoconductive, converts to hydroxyapatite, and heals to hard and soft tissues in vivo. Consequently, bioactive glass-based carriers can provide the combined functions of controlled local antibiotic delivery and bone restoration. Recently-developed borate bioactive glasses are of particular interest since they have controllable degradation rates coupled with desirable properties related to osteogenesis and angiogenesis. Such glasses have the potential for providing a new class of biomaterials, as substitutes for PMMA, in the treatment of deep bone infections. Copyright © 2014 Elsevier B.V. All rights reserved.

Advances in dental local anesthesia techniques and devices: An update

PubMed Central

Saxena, Payal; Gupta, Saurabh K.; Newaskar, Vilas; Chandra, Anil

2013-01-01

Although local anesthesia remains the backbone of pain control in dentistry, researches are going to seek new and better means of managing the pain. Most of the researches are focused on improvement in the area of anesthetic agents, delivery devices and technique involved. Newer technologies have been developed that can assist the dentist in providing enhanced pain relief with reduced injection pain and fewer adverse effects. This overview will enlighten the practicing dentists regarding newer devices and methods of rendering pain control comparing these with the earlier used ones on the basis of research and clinical studies available. PMID:24163548

Gene delivery for periodontal tissue engineering: current knowledge - future possibilities.

PubMed

Chen, Fa-Ming; Ma, Zhi-Wei; Wang, Qin-Tao; Wu, Zhi-Fen

2009-08-01

The cellular and molecular events of periodontal healing are coordinated and regulated by an elaborate system of signaling molecules, pointing to a primary strategy for functional periodontal compartment regeneration to replicate components of the natural cellular microenvironment by providing an artificial extracellular matrix (ECM) and by delivering growth factors. However, even with optimal carriers, the localized delivery of growth factors often requires a large amount of protein to stimulate significant effects in vivo, which increases the risk and unwanted side effects. A simple and relatively new approach to bypassing this dilemma involves converting cells into protein producing factories. This is done by a so-called gene delivery method, where therapeutic agents to be delivered are DNA plasmids that include the gene encoding desired growth factors instead of recombinant proteins. As localized depots of genes, novel gene delivery systems have the potential to release their cargo in a sustained and controlled manner and finally provide time- and space- dependent levels of encoded proteins during all stages of tissue regrowth, offering great versatility in their application and prompting new tissue engineering strategy in periodontal regenerative medicine. However, gene therapy in Periodontology is clearly in its infancy. Significant efforts still need to be made in developing safe and effective delivery platforms and clarifying how gene delivery, in combination with tissue engineering, may mimic the critical aspects of natural biological processes occurring in periodontal development and repair. The aim of this review is to trace an outline of the state-of-the-art in the application of gene delivery and tissue engineering strategies for periodontal healing and regeneration.

In Vitro Investigation of the Individual Contributions of Ultrasound-Induced Stable and Inertial Cavitation in Targeted Drug Delivery.

PubMed

Gourevich, Dana; Volovick, Alexander; Dogadkin, Osnat; Wang, Lijun; Mulvana, Helen; Medan, Yoav; Melzer, Andreas; Cochran, Sandy

2015-07-01

Ultrasound-mediated targeted drug delivery is a therapeutic modality under development with the potential to treat cancer. Its ability to produce local hyperthermia and cell poration through cavitation non-invasively makes it a candidate to trigger drug delivery. Hyperthermia offers greater potential for control, particularly with magnetic resonance imaging temperature measurement. However, cavitation may offer reduced treatment times, with real-time measurement of ultrasonic spectra indicating drug dose and treatment success. Here, a clinical magnetic resonance imaging-guided focused ultrasound surgery system was used to study ultrasound-mediated targeted drug delivery in vitro. Drug uptake into breast cancer cells in the vicinity of ultrasound contrast agent was correlated with occurrence and quantity of stable and inertial cavitation, classified according to subharmonic spectra. During stable cavitation, intracellular drug uptake increased by a factor up to 3.2 compared with the control. Reported here are the value of cavitation monitoring with a clinical system and its subsequent employment for dose optimization. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Development and testing of gold nanoparticles for drug delivery and treatment of heart failure: a theranostic potential for PPP cardiology.

PubMed

Spivak, Mykola Ya; Bubnov, Rostyslav V; Yemets, Ilya M; Lazarenko, Liudmyla M; Tymoshok, Natalia O; Ulberg, Zoia R

2013-07-29

Nanoscale gold particles (AuNPs) have wide perspectives for biomedical applications because of their unique biological properties, as antioxidative activity and potentials for drug delivery. The aim was to test effects of AuNPs using suggested heart failure rat model to compare with proved medication Simdax, to test gold nanoparticle for drug delivery, and to test sonoporation effect to increase nanoparticles delivery into myocardial cells. We performed biosafety and biocompatibility tests for AuNPs and conjugate with Simdax. For in vivo tests, we included Wistar rats weighing 180-200 g (n = 54), received doxorubicin in cumulative dose of 12.0 mg/kg to model advance heart failure, registered by ultrasonography. We formed six groups: the first three groups of animals received, respectively, 0.06 ml Simdax, AuNPs, and conjugate (AuNPs-Simdax), intrapleurally, and the second three received them intravenously. The seventh group was control (saline). We performed dynamic assessment of heart failure regression in vivo measuring hydrothorax. Sonoporation of gold nanoparticles to cardiomyocytes was tested. We designed and constructed colloidal, spherical gold nanoparticles, AuNPs-Simdax conjugate, both founded biosafety (in cytotoxicity, genotoxicity, and immunoreactivity). In all animals of the six groups after the third day post-medication injection, no ascites and liver enlargement were registered (P < 0.001 vs controls). Conjugate injection showed significantly higher hydrothorax reduction than Simdax injection only (P < 0.01); gold nanoparticle injection showed significantly higher results than Simdax injection (P < 0.05). AuNPs and conjugate showed no significant difference for rat recovery. Difference in rat life continuity was significant between Simdax vs AuNPs (P < 0.05) and Simdax vs conjugate (P < 0.05). Sonoporation enhances AuNP transfer into the cell and mitochondria that were highly localized, superior to controls (P < 0.01 for both). Gold nanoparticles of 30 nm and its AuNPs-Simdax conjugate gave positive results in biosafety and biocompatibility in vitro and in vivo. AuNPs-Simdax and AuNPs have similar significant cardioprotective effects in rats with doxorubicin-induced heart failure, higher than that of Simdax. Intrapleural (local) delivery is preferred over intravenous (systemic) delivery according to all tested parameters. Sonoporation is able to enhance gold nanoparticle delivery to myocardial cells in vivo.

Pulmonary delivery of nanoparticle chemotherapy for the treatment of lung cancers: challenges and opportunities

PubMed Central

Mangal, Sharad; Gao, Wei; Li, Tonglei; Zhou, Qi (Tony)

2017-01-01

Lung cancer is the second most prevalent and the deadliest among all cancer types. Chemotherapy is recommended for lung cancers to control tumor growth and to prolong patient survival. Systemic chemotherapy typically has very limited efficacy as well as severe systemic adverse effects, which are often attributed to the distribution of anticancer drugs to non-targeted sites. In contrast, inhalation routes permit the delivery of drugs directly to the lungs providing high local concentrations that may enhance the anti-tumor effect while alleviating systemic adverse effects. Preliminary studies in animals and humans have suggested that most inhaled chemotherapies are tolerable with manageable pulmonary adverse effects, including cough and bronchospasm. Promoting the deposition of anticancer drugs in tumorous cells and minimizing access to healthy lung cells can further augment the efficacy and reduce the risk of local toxicities caused by inhaled chemotherapy. Sustained release and tumor localization characteristics make nanoparticle formulations a promising candidate for the inhaled delivery of chemotherapeutic agents against lung cancers. However, the physiology of respiratory tracts and lung clearance mechanisms present key barriers for the effective deposition and retention of inhaled nanoparticle formulations in the lungs. Recent research has focused on the development of novel formulations to maximize lung deposition and to minimize pulmonary clearance of inhaled nanoparticles. This article systematically reviews the challenges and opportunities for the pulmonary delivery of nanoparticle formulations for the treatment of lung cancers. PMID:28504252

Locally targeted delivery of a micron-size radiation therapy source using temperature-sensitive hydrogel.

PubMed

Kim, Yusung; Seol, Dong Rim; Mohapatra, Sucheta; Sunderland, John J; Schultz, Michael K; Domann, Frederick E; Lim, Tae-Hong

2014-04-01

To propose a novel radiation therapy (RT) delivery modality: locally targeted delivery of micron-size RT sources by using temperature-sensitive hydrogel (RT-GEL) as an injectable vehicle. Hydrogel is a water-like liquid at room temperature but gels at body temperature. Two US Food and Drug Administration-approved polymers were synthesized. Indium-111 (In-111) was used as the radioactive RT-GEL source. The release characteristics of In-111 from polymerized RT-GEL were evaluated. The injectability and efficacy of RT-GEL delivery to human breast tumor were tested using animal models with control datasets of RT-saline injection. As proof-of-concept studies, a total of 6 nude mice were tested by injecting 4 million tumor cells into their upper backs after a week of acclimatization. Three mice were injected with RT-GEL and 3 with RT-saline. Single-photon emission computed tomography (SPECT) and CT scans were performed on each mouse at 0, 24, and 48 h after injection. The efficacy of RT-GEL was determined by comparison with that of the control datasets by measuring kidney In-111 accumulation (mean nCi/cc), representing the distant diffusion of In-111. RT-GEL was successfully injected into the tumor by using a 30-gauge needle. No difficulties due to polymerization of hydrogel during injection and intratumoral pressure were observed during RT-GEL injection. No back flow occurred for either RT-GEL or RT-saline. The residual tumor activities of In-111 were 49% at 24 h (44% at 48 h, respectively) for RT-GEL and 29% (22%, respectively) for RT-saline. Fused SPECT-CT images of RT-saline showed considerable kidney accumulation of In-111 (2886%, 261%, and 262% of RT-GEL at 0, 24, and 48 h, respectively). RT-GEL was successfully injected and showed much higher residual tumor activity: 170% (200%, respectively), than that of RT-saline at 24 h (48 h, respectively) after injection with a minimal accumulation of In-111 to the kidneys. Preliminary data of RT-GEL as a delivery modality of a radiation source to a local tumor are promising. Published by Elsevier Inc.

The Effect of Short-term Intra-arterial Delivery of Paclitaxel on Neointimal Hyperplasia and the Local Thrombotic Environment after Angioplasty

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

Yajun, E, E-mail: eyj7681@yahoo.com.cn; He Nengshu, E-mail: eyajun@hotmail.com; Fan Hailun, E-mail: mydream510@yahoo.com.cn

2013-08-01

PurposeTo evaluate the effects of short-term intra-arterial delivery of paclitaxel on neointimal hyperplasia and the local thrombotic environment after angioplasty.MethodsAn experimental common carotid artery injury model was established in 60 rats, which were divided into experimental groups (40 rats) and controls (20 rats). Local intra-arterial administration of paclitaxel was applied at 2 doses (90 and 180 {mu}g/30 {mu}l), and the effects of short-term delivery of paclitaxel on neointimal hyperplasia and the expression of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated at days 15 and 30 by hematoxylin and eosin staining and immunohistochemistry.ResultsAt 15more » and 30 days after injury, neointimal thickness and area, the ratio of intimal area to medial area and the stenotic rate were all significantly decreased in the group provided the high concentrations (180 {mu}g/30 {mu}l) of paclitaxel for 2 min or 10 min and in the group provided the low concentration (90 {mu}g/30 {mu}l) of paclitaxel for 10 min (p < 0.05). At 30 days after injury, there were no significant changes in TF expression among all experimental groups. PAI-1 expression increased in the neointima of the high concentration 10 min group (p < 0.05), while t-PA expression decreased in the neointima of the high concentration 2 min group (p < 0.05).ConclusionIn the rat common carotid artery injury model, the short-term delivery of paclitaxel could effectively inhibit neointimal hyperplasia in the long term, with very little influence on the local expression of TF and PAI-1.« less

Photoactivatable Lipid-based Nanoparticles as a Vehicle for Dual Agent Delivery | NCI Technology Transfer Center | TTC

Cancer.gov

Researchers at the National Cancer Institute (NCI) RNA Biology Laboratory have developed nanoparticles that can deliver an agent (i.e., therapeutic or imaging) and release the agent upon targeted photoactivation allowing for controlled temporal and localized release of the agent.

Controlled release of celecoxib inhibits inflammation, bone cysts and osteophyte formation in a preclinical model of osteoarthritis.

PubMed

Tellegen, A R; Rudnik-Jansen, I; Pouran, B; de Visser, H M; Weinans, H H; Thomas, R E; Kik, M J L; Grinwis, G C M; Thies, J C; Woike, N; Mihov, G; Emans, P J; Meij, B P; Creemers, L B; Tryfonidou, M A

2018-11-01

Major hallmarks of osteoarthritis (OA) are cartilage degeneration, inflammation and osteophyte formation. COX-2 inhibitors counteract inflammation-related pain, but their prolonged oral use entails the risk for side effects. Local and prolonged administration in biocompatible and degradable drug delivery biomaterials could offer an efficient and safe treatment for the long-term management of OA symptoms. Therefore, we evaluated the disease-modifying effects and the optimal dose of polyesteramide microspheres delivering the COX-2 inhibitor celecoxib in a rat OA model. Four weeks after OA induction by anterior cruciate ligament transection and partial medial meniscectomy, 8-week-old female rats (n = 6/group) were injected intra-articular with celecoxib-loaded microspheres at three dosages (0.03, 0.23 or 0.39 mg). Unloaded microspheres served as control. During the 16-week follow-up, static weight bearing and plasma celecoxib concentrations were monitored. Post-mortem, micro-computed tomography and knee joint histology determined progression of synovitis, osteophyte formation, subchondral bone changes, and cartilage integrity. Systemic celecoxib levels were below the detection limit 6 days upon delivery. Systemic and local adverse effects were absent. Local delivery of celecoxib reduced the formation of osteophytes, subchondral sclerosis, bone cysts and calcified loose bodies, and reduced synovial inflammation, while cartilage histology was unaffected. Even though the effects on pain could not be evualated directly in the current model, our results suggest the application of celecoxib-loaded microspheres holds promise as novel, safe and effective treatment for inflammation and pain in OA.

Energy Deposition in the Body from External Sources to Chemically Trigger Cellular Responses in Desired Localized Regions

NASA Astrophysics Data System (ADS)

Ibsen, Stuart Duncan

One of the major challenges of modern chemotherapy is to deliver a therapeutic dose of active drug to the tumor tissue without causing systemic exposure. The realization of this goal could considerably reduce the negative side effects experienced by patients. The work conducted in this thesis looks at two different approaches to trigger drug activation with the use of external energy sources. This avoids the challenges of relying solely on biochemical and environmental differences as triggers. The two triggers used were low intensity focused ultrasound and 365 nm light delivered with a custom designed needle UV LED fiber optic system. Both can be localized within the body to spatially highlight just the tumor tissue creating a stark differentiation between it and the healthy tissue. The 365nm light based delivery scheme developed here was the first demonstration of a photoactivatable doxorubicin (DOX) prodrug called DOX-PCB. DOX-PCB was shown to be 200 times less toxic than DOX and could be activated to a fully therapeutic form upon exposure to 365nm light. The pharmacokinetics showed a circulation half life comparable to that of DOX and stability against in vivo metabolic degradation. The 365 nm light was shown to adequately irradiate a centimeter of tumor tissue and cause localized activation. In vivo tumors exposed to the light had significantly higher doses of DOX than unexposed control tumors in the same individual. The second delivery scheme made use of focused ultrasound to activate echogenic drug delivery vehicles. These vehicles were the first demonstration of encapsulating microbubbles within liposomes. Specially designed optical equipment documented that the microbubble was ultrasound responsive. The microbubble was shown to violently cavitate and rupture the outer liposome membrane releasing the payload contents. The three dimensional localization of activation was demonstrated in tissue phantoms. The strengths of these two delivery schemes could complement each other when used together. The delivery vehicle could achieve high doses of DOX-PCB within the tumor while the low toxicity prevents harm to the liver and spleen. The 365 nm light could then activate just the DOX-PCB found within the tumor itself causing localized cell death.

Effects of tissue impedance on heat generation during RF delivery with the Thermage system

NASA Astrophysics Data System (ADS)

Tomkoria, Sara; Pope, Karl

2005-04-01

The Thermage ThermaCool TC system is a non-ablative RF device designed to promote tissue tightening and contouring. The system delivers RF energy to a target area under the skin, with volumetric tissue heating in that area. While the amount of energy delivered to a patient can be controlled by ThermaCool system settings, the distribution of energy to the treatment area and underlying layers is variable from individual to individual due to differences in body composition. The present study investigated how local tissue impedance affects the amount of discomfort experienced by patients during RF energy delivery. Discomfort results from heat generation in the treatment area. By using features of the ThermaCool TC System, local impedance (impedance of the treatment area), bulk impedance (impedance of the underlying tissue layers), and total impedance (the sum of local and bulk impedance) were measured for 35 patients. For each patient, impedance measurements were compared to discomfort levels expressed during treatment. Analysis of whole body, local, and bulk impedance values indicate that the percent of total body impedance in the local treatment area contributes to discomfort levels expressed by patients during treatment.

Local application of an ibandronate/collagen sponge improves femoral fracture healing in ovariectomized rats

PubMed Central

Liu, Yansong; Hou, Zhiyong; Chen, Wei; Jin, Lin; Tian, Ye; Ju, Linlin; Liu, Bo; Dong, Tianhua; Zhang, Fei

2017-01-01

Non-union is a major clinical problem in the healing of fractures, especially in patients with osteoporosis. The systemic administration of drugs is time consuming and large doses are demanding and act slowly, whereas local release acts rapidly, increases the quality and quantity of the bone tissue. We hypothesize that local delivery demonstrates better therapeutic effects on an osteoporotic fracture. The aim of this paper is to investigate the effect of the local application of ibandronate loaded with a collagen sponge on regulating bone formation and remodeling in an osteoporotic rat model of fracture healing. We found that the local delivery of ibandronate exhibited excellent effects on improving the bone microarchitecture and suppressed effects on bone remodeling. At 4 weeks, more callus formation and improvement of mechanical character and microstructure were observed in a local delivery via μCT, mechanical test, histological research and serum analysis. The suppression of bone remodeling was compared with a systemic treatment at 12 weeks, and the structural mechanical properties and microarchitecture were also improved with local delivery. This research identifies an earlier, safer and integrated approach for local delivery of ibandronate with collagen and provides a better strategy for the treatment of osteoporotic fracture in rats. PMID:29108027

Local delivery of fluorescent dye for fiber-optics confocal microscopy of the living heart.

PubMed

Huang, Chao; Kaza, Aditya K; Hitchcock, Robert W; Sachse, Frank B

2014-01-01

Fiber-optics confocal microscopy (FCM) is an emerging imaging technology with various applications in basic research and clinical diagnosis. FCM allows for real-time in situ microscopy of tissue at sub-cellular scale. Recently FCM has been investigated for cardiac imaging, in particular, for discrimination of cardiac tissue during pediatric open-heart surgery. FCM relies on fluorescent dyes. The current clinical approach of dye delivery is based on systemic injection, which is associated with high dye consumption, and adverse clinical events. In this study, we investigated approaches for local dye delivery during FCM imaging based on dye carriers attached to the imaging probe. Using three-dimensional confocal microscopy, automated bench tests, and FCM imaging we quantitatively characterized dye release of carriers composed of open-pore foam only and foam loaded with agarose hydrogel. In addition, we compared local dye delivery with a model of systemic dye delivery in the isolated perfused rodent heart. We measured the signal-to-noise ratio (SNR) of images acquired in various regions of the heart. Our evaluations showed that foam-agarose dye carriers exhibited a prolonged dye release vs. foam-only carriers. Foam-agarose dye carriers allowed reliable imaging of 5-9 lines, which is comparable to 4-8 min of continuous dye release. Our study in the living heart revealed that the SNR of FCM images using local and systemic dye delivery is not different. However, we observed differences in the imaged tissue microstructure with the two approaches. Structural features characteristic of microvasculature were solely observed for systemic dye delivery. Our findings suggest that local dye delivery approach for FCM imaging constitutes an important alternative to systemic dye delivery. We suggest that the approach for local dye delivery will facilitate clinical translation of FCM, for instance, for FCM imaging during pediatric heart surgery.

The work of local healthcare innovation: a qualitative study of GP-led integrated diabetes care in primary health care.

PubMed

Foster, Michele; Burridge, Letitia; Donald, Maria; Zhang, Jianzhen; Jackson, Claire

2016-01-14

Service delivery innovation is at the heart of efforts to combat the growing burden of chronic disease and escalating healthcare expenditure. Small-scale, locally-led service delivery innovation is a valuable source of learning about the complexities of change and the actions of local change agents. This exploratory qualitative study captures the perspectives of clinicians and managers involved in a general practitioner-led integrated diabetes care innovation. Data on these change agents' perspectives on the local innovation and how it works in the local context were collected through focus groups and semi-structured interviews at two primary health care sites. Transcribed data were analysed thematically. Normalization Process Theory provided a framework to explore perspectives on the individual and collective work involved in putting the innovation into practice in local service delivery contexts. Twelve primary health care clinicians, hospital-based medical specialists and practice managers participated in the study, which represented the majority involved in the innovation at the two sites. The thematic analysis highlighted three main themes of local innovation work: 1) trusting and embedding new professional relationships; 2) synchronizing services and resources; and 3) reconciling realities of innovation work. As a whole, the findings show that while locally-led service delivery innovation is designed to respond to local problems, convincing others to trust change and managing the boundary tensions is core to local work, particularly when it challenges taken-for-granted practices and relationships. Despite this, the findings also show that local innovators can and do act in both discretionary and creative ways to progress the innovation. The use of Normalization Process Theory uncovered some critical professional, organizational and structural factors early in the progression of the innovation. The key to local service delivery innovation lies in building coalitions of trust at the point of service delivery and persuading organizational and institutional mindsets to consider the opportunities of locally-led innovation.

Pinpoint Delivery of Molecules by Using Electron Beam Addressing Virtual Cathode Display.

PubMed

Hoshino, Takayuki; Yoshioka, Moto; Wagatsuma, Akira; Miyazako, Hiroki; Mabuchi, Kunihiko

2018-03-01

Electroporation, a physical transfection method to introduce genomic molecules in selective living cells, could be implemented by microelectrode devices. A local electric field generated by a finer electrode can induces cytomembrane poration in the electrode vicinity. To employ fine, high-speed scanning electrodes, we developed a fine virtual cathode pattern, which was generated on a cell adhesive surface of 100-nm-thick SiN membrane by inverted-electron beam lithography. The SiN membrane works as both a vacuum barrier and the display screen of the virtual cathode. The kinetic energy of the incident primary electrons to the SiN membrane was completely blocked, whereas negative charges and leaking electric current appeared on the surface of the dielectric SiN membrane within a region of 100 nm. Locally controlled transmembrane molecular delivery was demonstrated on adhered C2C12 myoblast cells in a culturing medium with fluorescent dye propidium iodide (PI). Increasing fluorescence of pre-diluted PI indicated local poration and transmembrane inflow at the virtual cathode position, as well as intracellular diffusion. The transmembrane inflows depended on beam duration time and acceleration voltage. At the post-molecular delivery, a slight decrease in intracellular PI fluorescence intensity indicates membrane recovery from the poration. Cell viability was confirmed by time-lapse cell imaging of post-exposure cell migration.

Colon-specific delivery of 5-aminosalicylic acid from chitosan-Ca-alginate microparticles.

PubMed

Mladenovska, K; Raicki, R S; Janevik, E I; Ristoski, T; Pavlova, M J; Kavrakovski, Z; Dodov, M G; Goracinova, K

2007-09-05

Chitosan-Ca-alginate microparticles for colon-specific delivery and controlled release of 5-aminosalicylic acid after peroral administration were prepared using spray drying method followed by ionotropic gelation/polyelectrolyte complexation. Physicochemical characterization pointed to the negatively charged particles with spherical morphology having a mean diameter less than 9 microm. Chitosan was localized dominantly in the particle wall, while for alginate, a homogeneous distribution throughout the particles was observed. (1)H NMR, FTIR, X-ray and DSC studies indicated molecularly dispersed drug within the particles with preserved stability during microencapsulation and in simulated in vivo drug release conditions. In vitro drug release studies carried out in simulated in vivo conditions in respect to pH, enzymatic and salt content confirmed the potential of the particles to release the drug in a controlled manner. The diffusional exponents according to the general exponential release equation indicated anomalous (non-Fickian) transport in 5-ASA release controlled by a polymer relaxation, erosion and degradation. Biodistribution studies of [(131)I]-5-ASA loaded chitosan-Ca-alginate microparticles, carried out within 2 days after peroral administration to Wistar male rats in which TNBS colitis was induced, confirmed the dominant localization of 5-ASA in the colon with low systemic bioavailability.

Local delivery of sirolimus nanoparticles for the treatment of in-stent restenosis.

PubMed

Zago, Alexandre C; Raudales, José C; Attizzani, Guilherme; Matte, Bruno S; Yamamoto, German I; Balvedi, Julise A; Nascimento, Ludmila; Kosachenco, Beatriz G; Centeno, Paulo R; Zago, Alcides J

2013-02-01

To test the local delivery of sirolimus nanoparticles following percutaneous transluminal coronary angioplasty (PTCA) to treat in-stent restenosis (ISR) in a swine model. Coronary bare-metal stent (BMS) implantation reduces major adverse cardiac events when compared with PTCA; however, ISR rates remain high. Eighteen swine underwent BMS deployment guided by intravascular ultrasound (IVUS). Of these, 16 developed ISR (1 stent/swine) and underwent angioplasty with a noncompliant balloon (PTCA-NC). The animals were then randomized into four groups for local infusion of sirolimus nanoparticles through a porous balloon catheter, as follows: (1) PTCA-NC alone (control); (2) PTCA-NC + (polylactic acid)-based nanoparticle formulation (anionic 1); (3) PTCA-NC + (polylactic-co-glycolic acid)-based nanoparticle formulation (anionic 2); and (4) PTCA-NC + Eudragit RS nanoparticle formulation (cationic). Coronary angiography and IVUS follow-up were performed 28 days after ISR treatment. There was one episode of acute coronary occlusion with the cationic formulation. Late area loss was similar in all groups at 28 days according to IVUS. However, luminal volume loss (control = 20.7%, anionic 1 = 4.0%, anionic 2 = 6.7%, cationic = 9.6%; P = 0.01) and neointimal volume gain (control = 68.7%, anionic 1 = 17.4%, anionic 2 = 29.5%, cationic = 31.2%; P = 0.019) were significantly reduced in all treatment groups, especially in anionic 1. PTCA-NC followed by local infusion of sirolimus nanoparticles was safe and efficacious to reduce neointima in this model, and this strategy may be a promising treatment for BMS ISR. Further studies are required to validate this method in humans. Copyright © 2012 Wiley Periodicals, Inc.

Controlled release of GAG-binding enhanced transduction (GET) peptides for sustained and highly efficient intracellular delivery.

PubMed

Abu-Awwad, Hosam Al-Deen M; Thiagarajan, Lalitha; Dixon, James E

2017-07-15

Controlled release systems for therapeutic molecules are vital to allow the sustained local delivery of their activities which direct cell behaviour and enable novel regenerative strategies. Direct programming of cells using exogenously delivered transcription factors can by-pass growth factor signalling but there is still a requirement to deliver such activity spatio-temporally. We previously developed a technology termed GAG-binding enhanced transduction (GET) to efficiently deliver a variety of cargoes intracellularly, using GAG-binding domains which promote cell targeting, and cell penetrating peptides (CPPs) which allow cell entry. Herein we demonstrate that GET system can be used in controlled release systems to mediate sustained intracellular transduction over one week. We assessed the stability and activity of GET peptides in poly(dl-lactic acid-co-glycolic acid) (PLGA) microparticles (MPs) prepared using a S/O/W double emulsion method. Efficient encapsulation (∼65%) and tailored protein release profiles could be achieved, however intracellular transduction was significantly inhibited post-release. To retain GET peptide activity we optimized a strategy of co-encapsulation of l-Histidine, which may form a complex with the PLGA degradation products under acidic conditions. Simulations of the polymer microclimate showed that hydrolytic acidic PLGA degradation products directly inhibited GET peptide transduction activity, and use of l-Histidine significantly enhanced released protein delivery. The ability to control the intracellular transduction of functional proteins into cells will facilitate new localized delivery methods and allow approaches to direct cellular behaviour for many regenerative medicine applications. The goal for regenerative medicine is to restore functional biological tissue by controlling and augmenting cellular behaviour. Either Transcription (TFs) or growth factors (GFs) can be presented to cells in spatio-temporal gradients for programming cell fate and gene expression. Here, we have created a sustained and controlled release system for GET (Glycosaminoglycan-enhanced transducing)-tagged proteins using S/O/W PLGA microparticle fabrication. We demonstrated that PLGA and its acidic degradants inhibit GET-mediated transduction, which can be overcome by using pH-activated l-Histidine. l-Histidine inhibits the electrostatic interaction of GET/PLGA and allows enhanced intracellular transduction. GET could provide a powerful tool to program cell behaviour either in gradients or with sustained delivery. We believe that our controlled release systems will allow application of GET for tissue regeneration directly by TF cellular programming. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Gamma-index method sensitivity for gauging plan delivery accuracy of volumetric modulated arc therapy.

PubMed

Park, Jong In; Park, Jong Min; Kim, Jung-In; Park, So-Yeon; Ye, Sung-Joon

2015-12-01

The aim of this study was to investigate the sensitivity of the gamma-index method according to various gamma criteria for volumetric modulated arc therapy (VMAT). Twenty head and neck (HN) and twenty prostate VMAT plans were retrospectively selected for this study. Both global and local 2D gamma evaluations were performed with criteria of 3%/3 mm, 2%/2 mm, 1%/2 mm and 2%/1 mm. In this study, the global and local gamma-index calculated the differences in doses relative to the maximum dose and the dose at the current measurement point, respectively. Using log files acquired during delivery, the differences in parameters at every control point between the VMAT plans and the log files were acquired. The differences in dose-volumetric parameters between reconstructed VMAT plans using the log files and the original VMAT plans were calculated. The Spearman's rank correlation coefficients (rs) were calculated between the passing rates and those differences. Considerable correlations with statistical significances were observed between global 1%/2 mm, local 1%/2 mm and local 2%/1 mm and the MLC position differences (rs = -0.712, -0.628 and -0.581). The numbers of rs values with statistical significance between the passing rates and the changes in dose-volumetric parameters were largest in global 2%/2 mm (n = 16), global 2%/1 mm (n = 15) and local 2%/1 mm (n = 13) criteria. Local gamma-index method with 2%/1 mm generally showed higher sensitivity to detect deviations between a VMAT plan and the delivery of the VMAT plan. Copyright © 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Biodegradable Nanoneedles for Localized Delivery of Nanoparticles in Vivo: Exploring the Biointerface

PubMed Central

Chiappini, Ciro; Martinez, Jonathan O.; De Rosa, Enrica; Almeida, Carina S.

2016-01-01

Nanoneedles display potential in mediating the delivery of drugs and biologicals, as well as intracellular sensing and single cell stimulation through direct access to the cell cytoplasm. Nanoneedles enable cytosolic delivery, negotiating the cell membrane and the endolysosomal system, thus overcoming these major obstacles to the efficacy of nanotherapeutics. The low toxicity and minimal invasiveness of nanoneedles has a potential for the sustained non-immunogenic delivery of payloads in vivo, provided that the development of biocompatible nanoneedles with a simple deployment strategy is achieved. Here we present a mesoporous silicon nanoneedle array that achieves a tight interface with the cell, rapidly negotiating local biological barriers to grant temporary access to the cytosol with minimal impact on cell viability. The tightness of this interfacing enables both delivery of cell-impermeant quantum dots in vivo and live intracellular sensing of pH. Dissecting the biointerface over time elucidated the dynamics of cell association and nanoneedle biodegradation, showing rapid interfacing leading to cytosolic payload delivery within less than 30 minutes in vitro. The rapid and simple application of nanoneedles in vivo to the surface of tissues with different architectures invariably resulted in the localized delivery of quantum dots to the superficial cells and their prolonged retention. This investigation provides an understanding of the dynamics of nanoneedles’ biointerface and delivery outlining a strategy for highly local intracellular delivery of nanoparticles and cell-impermeant payloads within live tissues. PMID:25858596

Organic nanoparticle systems for spatiotemporal control of multimodal chemotherapy

PubMed Central

Meng, Fanfei; Han, Ning; Yeo, Yoon

2017-01-01

Introduction Chemotherapeutic drugs are used in combination to target multiple mechanisms involved in cancer cell survival and proliferation. Carriers are developed to deliver drug combinations to common target tissues in optimal ratios and desirable sequences. Nanoparticles (NP) have been a popular choice for this purpose due to their ability to increase the circulation half-life and tumor accumulation of a drug. Areas covered We review organic NP carriers based on polymers, proteins, peptides, and lipids for simultaneous delivery of multiple anticancer drugs, drug/sensitizer combinations, drug/photodynamic- or photothermal therapy combinations, and drug/gene therapeutics with examples in the past three years. Sequential delivery of drug combinations, based on either sequential administration or built-in release control, is introduced with an emphasis on the mechanistic understanding of such control. Expert opinion Recent studies demonstrate how a drug carrier can contribute to co-localizing drug combinations in optimal ratios and dosing sequences to maximize the synergistic effects. We identify several areas for improvement in future research, including the choice of drug combinations, circulation stability of carriers, spatiotemporal control of drug release, and the evaluation and clinical translation of combination delivery. PMID:27476442

Local delivery of molecules from a nanopipette for quantitative receptor mapping on live cells.

PubMed

Babakinejad, Babak; Jönsson, Peter; López Córdoba, Ainara; Actis, Paolo; Novak, Pavel; Takahashi, Yasufumi; Shevchuk, Andrew; Anand, Uma; Anand, Praveen; Drews, Anna; Ferrer-Montiel, Antonio; Klenerman, David; Korchev, Yuri E

2013-10-01

Using nanopipettes to locally deliver molecules to the surface of living cells could potentially open up studies of biological processes down to the level of single molecules. However, in order to achieve precise and quantitative local delivery it is essential to be able to determine the amount and distribution of the molecules being delivered. In this work, we investigate how the size of the nanopipette, the magnitude of the applied pressure or voltage, which drives the delivery, and the distance to the underlying surface influences the number and spatial distribution of the delivered molecules. Analytical expressions describing the delivery are derived and compared with the results from finite element simulations and experiments on delivery from a 100 nm nanopipette in bulk solution and to the surface of sensory neurons. We then developed a setup for rapid and quantitative delivery to multiple subcellular areas, delivering the molecule capsaicin to stimulate opening of Transient Receptor Potential Vanilloid subfamily member 1 (TRPV1) channels, membrane receptors involved in pain sensation. Overall, precise and quantitative delivery of molecules from nanopipettes has been demonstrated, opening up many applications in biology such as locally stimulating and mapping receptors on the surface of live cells.

Microsphere-Based Rapamycin Delivery, Systemic Versus Local Administration in a Rat Model of Renal Ischemia/Reperfusion Injury.

PubMed

Zandstra, Jurjen; van Beuge, Marike M; Zuidema, Johan; Petersen, Arjen H; Staal, Mark; Duque, Luisa F; Rodriguez, Sergio; Lathuile, Audrey A R; Veldhuis, Gert J; Steendam, Rob; Bank, Ruud A; Popa, Eliane R

2015-10-01

The increasing prevalence and treatment costs of kidney diseases call for innovative therapeutic strategies that prevent disease progression at an early stage. We studied a novel method of subcapsular injection of monodisperse microspheres, to use as a local delivery system of drugs to the kidney. We generated placebo- and rapamycin monodisperse microspheres to investigate subcapsular delivery of drugs. Using a rat model of acute kidney injury, subcapsular injection of placebo and rapamycin monodisperse microspheres (monospheres) was compared to subcutaneous injection, mimicking systemic administration. We did not find any adverse effects related to the delivery method. Irrespective of the injection site, a similar low dose of rapamycin was present in the circulation. However, only local intrarenal delivery of rapamycin from monospheres led to decreased macrophage infiltration and a significantly lower amount of myofibroblasts in the kidney, where systemic administration did not. Local delivery of rapamycin did cause a transient increase in the deposition of collagen I, but not of collagen III. We conclude that therapeutic effects can be increased when rapamycin is delivered subcapsularly by monospheres, which, combined with low systemic concentrations, may lead to an effective intrarenal delivery method.

New Updates Pertaining to Drug Delivery of Local Anesthetics in Particular Bupivacaine Using Lipid Nanoparticles

NASA Astrophysics Data System (ADS)

Beiranvand, Siavash; Eatemadi, Ali; Karimi, Arash

2016-06-01

Lipid nanoparticles (liposomes) were first described in 1965, and several work have led to development of important technical advances like triggered release liposomes and drug-loaded liposomes. These advances have led to numerous clinical trials in such diverse areas such as the delivery of anti-cancer, antifungal, and antibiotic drugs; the delivery of gene medicines; and most importantly the delivery of anesthesia drugs. Quite a number of liposomes are on the market, and many more are still in developmental stage. Lipid nanoparticles are the first nano-medicine delivery system to be advanced from laboratory concept to clinical application with high considerable clinical acceptance. Drug delivery systems for local anesthetics (LAs) have caught the interest of many researchers because there are many biomedical advantages connected to their application. There have been several formulation techniques to systemically deliver LA that include encapsulation in liposomes and complexation in cyclodextrins, nanoparticles, and to a little extent gold nanoparticles. The proposed formulations help to decrease the LA concentration utilized, increase its permeability, and most importantly increase the localization of the LA for a long period of time thereby leading to increase in the duration of the LA effect and finally to reduce any local and systemic toxicity. In this review, we will highlight on new updates pertaining to drug delivery of local anesthetics in particular bupivacaine using lipid nanoparticles.

New Updates Pertaining to Drug Delivery of Local Anesthetics in Particular Bupivacaine Using Lipid Nanoparticles.

PubMed

Beiranvand, Siavash; Eatemadi, Ali; Karimi, Arash

2016-12-01

Lipid nanoparticles (liposomes) were first described in 1965, and several work have led to development of important technical advances like triggered release liposomes and drug-loaded liposomes. These advances have led to numerous clinical trials in such diverse areas such as the delivery of anti-cancer, antifungal, and antibiotic drugs; the delivery of gene medicines; and most importantly the delivery of anesthesia drugs. Quite a number of liposomes are on the market, and many more are still in developmental stage. Lipid nanoparticles are the first nano-medicine delivery system to be advanced from laboratory concept to clinical application with high considerable clinical acceptance. Drug delivery systems for local anesthetics (LAs) have caught the interest of many researchers because there are many biomedical advantages connected to their application. There have been several formulation techniques to systemically deliver LA that include encapsulation in liposomes and complexation in cyclodextrins, nanoparticles, and to a little extent gold nanoparticles. The proposed formulations help to decrease the LA concentration utilized, increase its permeability, and most importantly increase the localization of the LA for a long period of time thereby leading to increase in the duration of the LA effect and finally to reduce any local and systemic toxicity. In this review, we will highlight on new updates pertaining to drug delivery of local anesthetics in particular bupivacaine using lipid nanoparticles.

Pain and efficacy rating of a microprocessor-controlled metered injection system for local anaesthesia in minor hand surgery.

PubMed

Nimigan, André S; Gan, Bing Siang

2011-01-01

Purpose. Little attention has been given to syringe design and local anaesthetic administration methods. A microprocessor-controlled anaesthetic delivery device has become available that may minimize discomfort during injection. The purpose of this study was to document the pain experience associated with the use of this system and to compare it with use of a conventional syringe. Methods. A prospective, randomized clinical trial was designed. 40 patients undergoing carpal tunnel release were block randomized according to sex into a two groups: a traditional syringe group and a microprocessor-controlled device group. The primary outcome measure was surgical pain and local anaesthetic administration pain. Secondary outcomes included volume of anaesthetic used and injection time. Results. Analysis showed that equivalent anaesthesia was achieved in the microprocessor-controlled group despite using a significantly lower volume of local anaesthetic (P = .0002). This same group, however, has significantly longer injection times (P < .0001). Pain during the injection process or during surgery was not different between the two groups. Conclusions. This RCT comparing traditional and microprocessor controlled methods of administering local anaesthetic showed similar levels of discomfort in both groups. While the microprocessor-controlled group used less volume, the total time for the administration was significantly greater.

Optically generated ultrasound for enhanced drug delivery

DOEpatents

Visuri, Steven R.; Campbell, Heather L.; Da Silva, Luiz

2002-01-01

High frequency acoustic waves, analogous to ultrasound, can enhance the delivery of therapeutic compounds into cells. The compounds delivered may be chemotherapeutic drugs, antibiotics, photodynamic drugs or gene therapies. The therapeutic compounds are administered systemically, or preferably locally to the targeted site. Local delivery can be accomplished through a needle, cannula, or through a variety of vascular catheters, depending on the location of routes of access. To enhance the systemic or local delivery of the therapeutic compounds, high frequency acoustic waves are generated locally near the target site, and preferably near the site of compound administration. The acoustic waves are produced via laser radiation interaction with an absorbing media and can be produced via thermoelastic expansion, thermodynamic vaporization, material ablation, or plasma formation. Acoustic waves have the effect of temporarily permeabilizing the membranes of local cells, increasing the diffusion of the therapeutic compound into the cells, allowing for decreased total body dosages, decreased side effects, and enabling new therapies.

Effect of green tea catechin, a local drug delivery system as an adjunct to scaling and root planing in chronic periodontitis patients: A clinicomicrobiological study

PubMed Central

Kudva, Praveen; Tabasum, Syeda Tawkhira; Shekhawat, Nirmal Kanwar

2011-01-01

Background: Evaluate the adjunctive use of locally delivered green tea catechin with scaling and root planing, as compared to scaling and root planing alone in the management of chronic periodontitis. Materials and Methods: Fourteen patients with two sites in the contralateral quadrants with probing pocket depth of 5–8mm were selected. Each of the sites was assessed for the plaque index, gingival index, and probing pocket depth at baseline and 21 days and for microbiological analysis at baseline, 1 week and 21 days. Test sites received scaling and root planing along with green tea catechin strips and control sites received scaling and root planning alone. Results: The result showed intercomparison of the plaque index and gingival index for test and control groups at 21 days was not significant with P>0.05, whereas the probing depth at 21 days was significant with P<0.001. Intercomparison between microbial results demonstrated a considerable reduction of occurrence of Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Fusobacterium species and Capnocytophaga in test. Conclusion: Green tea catechin local delivery along with scaling and root planing is more effective than scaling and root planing alone. PMID:21772720

Biomimetic Delivery of Keratinocyte Growth Factor upon Cellular Demand for Accelerated Wound Healing in Vitro and in Vivo

PubMed Central

Geer, David J.; Swartz, Daniel D.; Andreadis, Stelios T.

2005-01-01

Exogenous keratinocyte growth factor (KGF) significantly enhances wound healing, but its use is hampered by a short biological half-life and lack of tissue selectivity. We used a biomimetic approach to achieve cell-controlled delivery of KGF by covalently attaching a fluorescent matrix-binding peptide that contained two domains: one recognized by factor XIII and the other by plasmin. Modified KGF was incorporated into the fibrin matrix at high concentration in a factor XIII-dependent manner. Cell-mediated activation of plasminogen to plasmin degraded the fibrin matrix and cleaved the peptides, releasing active KGF to the local microenvironment and enhancing epithelial cell proliferation and migration. To demonstrate in vivo effectiveness, we used a hybrid model of wound healing that involved transplanting human bioengineered skin onto athymic mice. At 6 weeks after grafting, the transplanted tissues underwent full thickness wounding and treatment with fibrin gels containing bound KGF. In contrast to topical KGF, fibrin-bound KGF persisted in the wounds for several days and was released gradually, resulting in significantly enhanced wound closure. A fibrinolytic inhibitor prevented this healing, indicating the requirement for cell-mediated fibrin degradation to release KGF. In conclusion, this biomimetic approach of localized, cell-controlled delivery of growth factors may accelerate healing of large full-thickness wounds and chronic wounds that are notoriously difficult to heal. PMID:16314471

Biomaterials Transforming growth factor-beta 1 delivery from microporous scaffolds decreases inflammation post-implant and enhances function of transplanted islets

PubMed Central

Liu, JMH; Zhang, J; Zhang, X; Hlavaty, KA; Ricci, CF; Leonard, JN; Shea, LD; Gower, RM

2015-01-01

Biomaterial scaffolds are central to many regenerative strategies as they create a space for infiltration of host tissue and provide a platform to deliver growth factors and progenitor cells. However, biomaterial implantation results in an unavoidable inflammatory response, which can impair tissue regeneration and promote loss or dysfunction of transplanted cells. We investigated localized TGF-β1 delivery to modulate this immunological environment around scaffolds and transplanted cells. TGF-β1 was delivered from layered scaffolds, with protein entrapped within an inner layer and outer layers designed for cell seeding and host tissue integration. Scaffolds were implanted into the epididymal fat pad, a site frequently used for cell transplantation. Expression of cytokines TNF-a, IL-12, and MCP-1 were decreased by at least 40% for scaffolds releasing TGF-β1 relative to control scaffolds. This decrease in inflammatory cytokine production corresponded to a 60% decrease in leukocyte infiltration. Transplantation of islets into diabetic mice on TGF-β1 scaffolds significantly improved the ability of syngeneic islets to control blood glucose levels within the first week of transplant and delayed rejection of allogeneic islets. Together, these studies emphasize the ability of localized TGF-β1 delivery to modulate the immune response to biomaterial implants and enhance cell function in cell-based therapies. PMID:26701143

An industry update: the latest developments in therapeutic delivery.

PubMed

Steinbach, Oliver C

2018-02-01

The present industry update covers the period 1 October-31 October 2017, with information sourced from company press releases, regulatory and patent agencies as well as scientific literature. While the corporate news in October was traditionally dominated by the announcement of the third quarter results, with most of them showing market and revenue growth but also an increasing number of initial public offerings after years of slower financial development, we also saw trends continuing toward an increasing number of convergences of drugs with nanotechnology, devices and 21st century information technology. Whether it is using E Ink's 'Smart Patch', AstraZeneca's autoinjector, Elektrofi's Elektroject suspensions or NanOlogy's NanoPac, there is an ever increasing number of combinations dof devices, drugs and applications reaching, more and more the clinic and the market. Controlled release is another feature increasingly addressed by many of the above innovations. For example, the drug-loaded x-ray imageable microscopic beads that have been developed by researchers at UCL Cancer Institute (London, UK) take this one step further in order to pursue local, controlled and in situ validated local delivery.

Engineering tolerance using biomaterials to target and control antigen presenting cells.

PubMed

Tostanoski, Lisa H; Gosselin, Emily A; Jewell, Christopher M

2016-05-01

Autoimmune diseases occur when cells of the adaptive immune system incorrectly recognize and attack "self" tissues. Importantly, the proliferation and differentiation of these cells is triggered and controlled by interactions with antigen presenting cells (APCs), such as dendritic cells. Thus, modulating the signals transduced by APCs (e.g., cytokines, costimulatory surface proteins) has emerged as a promising strategy to promote tolerance for diseases such as multiple sclerosis, type 1 diabetes, and lupus. However, many approaches have been hindered by non-specific activity of immunosuppressive or immunoregulatory cues, following systemic administration of soluble factors via traditional injections routes (e.g., subcutaneous, intravenous). Biomaterials offer a unique opportunity to control the delivery of tolerogenic signals in vivo via properties such as controlled particle size, tunable release kinetics, and co-delivery of multiple classes of cargo. In this review, we highlight recent reports that exploit these properties of biomaterials to target APCs and promote tolerance via three strategies, i) passive or active targeting of particulate carriers to APCs, ii) biomaterial-mediated control over antigen localization and processing, and iii) targeted delivery of encapsulated or adsorbed immunomodulatory signals. These reports represent exciting advances toward the goal of more effective therapies for autoimmune diseases, without the broad suppressive effects associated with current clinically-approved therapies.

The Cost of Dengue Vector Control Activities in Malaysia by Different Service Providers.

PubMed

Packierisamy, P Raviwharmman; Ng, Chiu-Wan; Dahlui, Maznah; Venugopalan, B; Halasa, Yara A; Shepard, Donald S

2015-11-01

We examined variations in dengue vector control costs and resource consumption between the District Health Departments (DHDs) and Local Authorities (LAs) to assist informed decision making as to the future roles of these agencies in the delivery of dengue vector control services in Malaysia. Data were collected from the vector control units of DHDs and LAs in 8 selected districts. We captured costs and resource consumption in 2010 for premise inspection for mosquito breeding sites, fogging to destroy adult mosquitoes and larviciding of potential breeding sites. Overall, DHDs spent US$5.62 million or US$679 per case and LAs spent US$2.61 million or US$499 per case. The highest expenditure for both agencies was for fogging, 51.0% and 45.8% of costs for DHDs and LAs, respectively. The DHDs had higher resource costs for human personnel, vehicles, pesticides, and equipment. The findings provide some evidence to rationalize delivery of dengue vector control services in Malaysia. © 2015 APJPH.

Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer

PubMed Central

Papademetriou, Iason T; Porter, Tyrone

2015-01-01

Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood–brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers noninvasive delivery of small molecule and biological cancer therapeutics. Local delivery methods enable high dose delivery while avoiding systemic exposure. BBB disruption with focused ultrasound and microbubbles offers local and noninvasive treatment. Clinical trials show the prospects of these technologies and point to challenges for the future. PMID:26488496

Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer.

PubMed

Papademetriou, Iason T; Porter, Tyrone

2015-01-01

Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood-brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers noninvasive delivery of small molecule and biological cancer therapeutics. Local delivery methods enable high dose delivery while avoiding systemic exposure. BBB disruption with focused ultrasound and microbubbles offers local and noninvasive treatment. Clinical trials show the prospects of these technologies and point to challenges for the future.

Stimuli-Responsive Polymeric Systems for Controlled Protein and Peptide Delivery: Future Implications for Ocular Delivery.

PubMed

Mahlumba, Pakama; Choonara, Yahya E; Kumar, Pradeep; du Toit, Lisa C; Pillay, Viness

2016-07-30

Therapeutic proteins and peptides have become notable in the drug delivery arena for their compatibility with the human body as well as their high potency. However, their biocompatibility and high potency does not negate the existence of challenges resulting from physicochemical properties of proteins and peptides, including large size, short half-life, capability to provoke immune responses and susceptibility to degradation. Various delivery routes and delivery systems have been utilized to improve bioavailability, patient acceptability and reduce biodegradation. The ocular route remains of great interest, particularly for responsive delivery of macromolecules due to the anatomy and physiology of the eye that makes it a sensitive and complex environment. Research in this field is slowly gaining attention as this could be the breakthrough in ocular drug delivery of macromolecules. This work reviews stimuli-responsive polymeric delivery systems, their use in the delivery of therapeutic proteins and peptides as well as examples of proteins and peptides used in the treatment of ocular disorders. Stimuli reviewed include pH, temperature, enzymes, light, ultrasound and magnetic field. In addition, it discusses the current progress in responsive ocular drug delivery. Furthermore, it explores future prospects in the use of stimuli-responsive polymers for ocular delivery of proteins and peptides. Stimuli-responsive polymers offer great potential in improving the delivery of ocular therapeutics, therefore there is a need to consider them in order to guarantee a local, sustained and ideal delivery of ocular proteins and peptides, evading tissue invasion and systemic side-effects.

MRI-Guided Focused Ultrasound as a New Method of Drug Delivery

PubMed Central

Thanou, M.; Gedroyc, W.

2013-01-01

Ultrasound-mediated drug delivery under the guidance of an imaging modality can improve drug disposition and achieve site-specific drug delivery. The term focal drug delivery has been introduced to describe the focal targeting of drugs in tissues with the help of imaging and focused ultrasound. Focal drug delivery aims to improve the therapeutic profile of drugs by improving their specificity and their permeation in defined areas. Focused-ultrasound- (FUS-) mediated drug delivery has been applied with various molecules to improve their local distribution in tissues. FUS is applied with the aid of microbubbles to enhance the permeability of bioactive molecules across BBB and improve drug distribution in the brain. Recently, FUS has been utilised in combination with MRI-labelled liposomes that respond to temperature increase. This strategy aims to “activate” nanoparticles to release their cargo locally when triggered by hyperthermia induced by FUS. MRI-guided FUS drug delivery provides the opportunity to improve drug bioavailability locally and therefore improve the therapeutic profiles of drugs. This drug delivery strategy can be directly translated to clinic as MRg FUS is a promising clinically therapeutic approach. However, more basic research is required to understand the physiological mechanism of FUS-enhanced drug delivery. PMID:23738076

Evaluation of an injectable polymeric delivery system for controlled and localized release of biological factors to promote therapeutic angiogenesis

NASA Astrophysics Data System (ADS)

Rocker, Adam John

Cardiovascular disease remains as the leading cause of death worldwide and is frequently associated with partial or full occlusion of coronary arteries. Currently, angioplasty and bypass surgery are the standard approaches for treating patients with these ischemic heart conditions. However, a large number of patients cannot undergo these procedures. Therapeutic angiogenesis provides a minimally invasive tool for treating cardiovascular diseases by inducing new blood vessel growth from the existing vasculature. Angiogenic growth factors can be delivered locally through gene, cell, and protein therapy. Natural and synthetic polymer growth factor delivery systems are under extensive investigation due their widespread applications and promising therapeutic potential. Although biocompatible, natural polymers often suffer from batch-to-batch variability which can cause unpredictable growth factor release rates. Synthetic polymers offer advantages for growth factor delivery as they can be easily modified to control release kinetics. During the angiogenesis process, vascular endothelial growth factor (VEGF) is necessary to initiate neovessel formation while platelet-derived growth factor (PDGF) is needed later to help stabilize and mature new vessels. In the setting of myocardial infarction, additional anti-inflammatory cytokines like IL-10 are needed to help optimize cardiac repair and limit the damaging effects of inflammation following infarction. To meet these angiogenic and anti-inflammatory needs, an injectable polymer delivery system created from a sulfonated reverse thermal gel encapsulating micelle nanoparticles was designed and evaluated. The sulfonate groups on the thermal gel electrostatically bind to VEGF which controls its release rate, while the micelles are loaded with PDGF and are slowly released as the gel degrades. IL-10 was loaded into the system as well and diffused from the gel over time. An in vitro release study was performed which demonstrated the sequential release capabilities of the polymer system. The ability of the polymer system to induce new blood vessel formation was analyzed in vivo using a subcutaneous injection mouse model. Histological assessment was used to quantify blood vessel formation and an inflammatory response which showed that the polymer delivery system demonstrated a significant increase in functional and mature vessel formation while significantly reducing inflammation.

Right ventricular effects of intracoronary delivery of mesenchymal stem cells (MSC) in an animal model of pressure overload heart failure.

PubMed

Molina, Ezequiel J; Palma, Jon; Gupta, Dipin; Gaughan, John P; Houser, Steven; Macha, Mahender

2009-12-01

In a rat model of left ventricular pressure overload hypertrophy with biventricular failure, we studied the effects of intracoronary delivery of mesenchymal stem cells (MCS) upon right ventricular hemodynamic performance, profiles of local inflammation and apoptosis, and determinants of extracellular matrix remodeling. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography. After a decrease in left ventricular fractional shortening of 25% from the baseline (relative 50% reduction), animals were randomized to an intracoronary injection of MSC (n=28) or PBS (n=20). Right ventricular hemodynamic assessment and measurement of local inflammatory markers, proapoptotic factors, and determinants of extracellular matrix remodeling were performed on post-transplantation day 7, 14, 21 or 28. MSC injection improved right ventricular systolic function in the MSC group compared to the control group (mean+/-SD, max dP/dt 772+/-272 mm Hg/s vs. 392+/-132 at 28 days, P<0.01). Diastolic function was similarly improved (mean+/-SD, max -dP/dt -558+/-171 mm Hg/s vs. -327+/-131 at 28 days, P<0.05). Right ventricular levels of IL-1, IL-6, TNF-alpha, bax, bak and p38 were significantly decreased in the MSC treated animals. Expression of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3 declined in the MSC group compared with controls after 28 days. In this model of left ventricular pressure overload hypertrophy and biventricular failure, intracoronary delivery of MSC was associated with an improvement in the right ventricular hemodynamic performance, profiles of local inflammation and apoptosis, and determinants of extracellular matrix remodeling.

Nanosuspension improves tretinoin photostability and delivery to the skin.

PubMed

Lai, Francesco; Pireddu, Rosa; Corrias, Francesco; Fadda, Anna Maria; Valenti, Donatella; Pini, Elena; Sinico, Chiara

2013-12-15

The aims of this work were to improve cutaneous targeting and photostability of tretinoin by using nanosuspension formulation. Tretinoin is a drug widely used in the topical treatment of various dermatological diseases. The tretinoin nanosuspension was prepared by precipitation method and then characterized by photo correlation spectroscopy for mean size and size distribution, and by transmission electron microscopy for morphological studies. An oil in water tretinoin nanoemulsion was also prepared and used as a control. Dermal and transdermal delivery of both tretinoin nanosuspension and nanoemulsion were tested in vitro by using Franz diffusion cells and newborn pig skin. Photodegradation studies were carried out by UV irradiation (1h, λ=366 nm) of the tretinoin nanosuspension in comparison with the nanoemulsion and a methanolic solution of the drug. During 8h percutaneous experiments, the nanosuspesion was able to localize the drug into the pig skin with a very low transdermal drug delivery, whereas the nanoemulsion greatly improved drug permeation. UV irradiation of the nanosuspension showed a great improvement of tretinoin stability in comparison with both controls. Overall results show that nanosuspension might be a useful formulation for improving tretinoin dermal delivery and stability. Copyright © 2013 Elsevier B.V. All rights reserved.

A surface-mediated siRNA delivery system developed with chitosan/hyaluronic acid-siRNA multilayer films through layer-by-layer self-assembly

NASA Astrophysics Data System (ADS)

Wu, Lijuan; Wu, Changlin; Liu, Guangwan; Liao, Nannan; Zhao, Fang; Yang, Xuxia; Qu, Hongyuan; Peng, Bo; Chen, Li; Yang, Guang

2016-12-01

siRNA delivery remains highly challenging because of its hydrophilic and anionic nature and its sensitivity to nuclease degradation. Effective siRNA loading and improved transfection efficiency into cells represents a key problem. In our study, we prepared Chitosan/Hyaluronic acid-siRNA multilayer films through layer-by-layer self-assembly, in which siRNAs can be effectively loaded and protected. The construction process was characterized by FTIR, 13C NMR (CP/MAS), UV-vis spectroscopy, and atomic force microscopy (AFM). We presented the controlled-release performance of the films during incubation in 1 M NaCl solution for several days through UV-vis spectroscopy and polyacrylamide gel electrophoresis (PAGE). Additionally, we verified the stability and integrity of the siRNA loaded on multilayer films. Finally, the biological efficacy of the siRNA delivery system was evaluated via cells adhesion and gene silencing analyses in eGFP-HEK 293T cells. This new type of surface-mediated non-viral multilayer films may have considerable potential in the localized and controlled-release delivery of siRNA in mucosal tissues, and tissue engineering application.

A novel in situ permeation system and its utility in cancer tissue ablation

PubMed Central

WATANABE, MASAMI

2015-01-01

Focal ablation therapy is an emerging treatment modality for localized cancer lesions. It is an attractive strategy for inhibiting tumor progression and preventing morbidity associated with open surgery. As for intratissue drug delivery systems for use in local therapy, the convection-enhanced delivery (CED) of liquid drugs has been utilized, particularly for the treatment of malignant brain tumors. Although the conventional CED system is useful for providing drug/vehicle-based local therapy, there are several reported disadvantages in terms of the ability to control the extent of drug diffusion. We herein developed and validated a novel in situ permeation (ISP)-MW-1 system for achieving intratissue drug diffusion. The ISP system includes a perfusion catheter connected to an injector and aspirator, which enables intratissue perfusion of the solute diluted in the vehicle in the tip-inserted cavity. We subsequently evaluated the utility of the ISP-MW-1 system for in situ permeation in a subcutaneous tumor model in hamsters. Dehydrated ethanol, saline and 50% acetic acid were evaluated as the vehicle, and methylene blue was used as a dissolved substance for evaluating the diffusion of the agent. As a result, almost all of the tumor tissue within the capsule (tumor size: ~3 cm) was permeated with the dehydrated ethanol and 50% acetic acid and partially with the saline. We further demonstrated that ISP treatment with 50% acetic acid completely ablated the subcutaneous tumors in all of the treated hamsters (n=3). Therefore, the ISP-MW-1 system is a promising approach for controlling the intratissue diffusion of therapeutic agents and for providing local ablation therapy for cancer lesions. We believe that this system may be applicable to a broad range of medicinal and industrial fields, such as regenerative medicine, drug delivery systems, biochemistry and material technologies as well as cancer therapy. PMID:26134633

Local Delivery Is Critical for Monocyte Chemotactic Protein-1 Mediated Site-Specific Murine Aneurysm Healing.

PubMed

Hourani, Siham; Motwani, Kartik; Wajima, Daisuke; Fazal, Hanain; Jones, Chad H; Doré, Sylvain; Hosaka, Koji; Hoh, Brian L

2018-01-01

Local delivery of monocyte chemotactic protein-1 (MCP-1/CCL2) via our drug-eluting coil has been shown to promote intrasaccular aneurysm healing via an inflammatory pathway. In this study, we validate the importance of local MCP-1 in murine aneurysm healing. Whether systemic, rather than local, delivery of MCP-1 can direct site-specific aneurysm healing has significant translational implications. If systemic MCP-1 is effective, then MCP-1 could be administered as a pill rather than by endovascular procedure. Furthermore, we confirm that MCP-1 is the primary effector in our MCP-1 eluting coil-mediated murine aneurysm healing model. We compare aneurysm healing with repeated intraperitoneal MCP-1 versus vehicle injection, in animals with control poly(lactic-co-glycolic) acid (PLGA)-coated coils. We demonstrate elimination of the MCP-1-associated tissue-healing response by knockout of MCP-1 or CCR2 (MCP-1 receptor) and by selectively inhibiting MCP-1 or CCR2. Using immunofluorescent probing, we explore the cell populations found in healed aneurysm tissue following each intervention. Systemically administered MCP-1 with PLGA coil control does not produce comparable aneurysm healing, as seen with MCP-1 eluting coils. MCP-1-directed aneurysm healing is eliminated by selective inhibition of MCP-1 or CCR2 and in MCP-1-deficient or CCR2-deficient mice. No difference was detected in M2 macrophage and myofibroblast/smooth muscle cell staining with systemic MCP-1 versus vehicle in aneurysm wall, but a significant increase in these cell types was observed with MCP-1 eluting coil implant and attenuated by MCP-1/CCR2 blockade or deficiency. We show that systemic MCP-1 concurrent with PLGA-coated platinum coil implant is not sufficient to produce site-specific aneurysm healing. MCP-1 is a critical, not merely complementary, actor in the aneurysm healing pathway.

Rapid and efficient gene delivery into the adult mouse brain via focal electroporation

PubMed Central

Nomura, Tadashi; Nishimura, Yusuke; Gotoh, Hitoshi; Ono, Katsuhiko

2016-01-01

In vivo gene delivery is required for studying the cellular and molecular mechanisms of various biological events. Virus-mediated gene transfer or generation of transgenic animals is widely used; however, these methods are time-consuming and expensive. Here we show an improved electroporation technique for acute gene delivery into the adult mouse brain. Using a syringe-based microelectrode, local DNA injection and the application of electric current can be performed simultaneously; this allows rapid and efficient gene transduction of adult non-neuronal cells. Combining this technique with various expression vectors that carry specific promoters resulted in targeted gene expression in astrocytic cells. Our results constitute a powerful strategy for the genetic manipulation of adult brains in a spatio-temporally controlled manner. PMID:27430903

Macroscale delivery systems for molecular and cellular payloads

NASA Astrophysics Data System (ADS)

Kearney, Cathal J.; Mooney, David J.

2013-11-01

Macroscale drug delivery (MDD) devices are engineered to exert spatiotemporal control over the presentation of a wide range of bioactive agents, including small molecules, proteins and cells. In contrast to systemically delivered drugs, MDD systems act as a depot of drug localized to the treatment site, which can increase drug effectiveness while reducing side effects and confer protection to labile drugs. In this Review, we highlight the key advantages of MDD systems, describe their mechanisms of spatiotemporal control and provide guidelines for the selection of carrier materials. We also discuss the combination of MDD technologies with classic medical devices to create multifunctional MDD devices that improve integration with host tissue, and the use of MDD technology in tissue-engineering strategies to direct cell behaviour. As our ever-expanding knowledge of human biology and disease provides new therapeutic targets that require precise control over their application, the importance of MDD devices in medicine is expected to increase.

Chitosan-Based Multifunctional Platforms for Local Delivery of Therapeutics

PubMed Central

Hong, Seong-Chul; Yoo, Seung-Yup; Kim, Hyeongmin; Lee, Jaehwi

2017-01-01

Chitosan has been widely used as a key biomaterial for the development of drug delivery systems intended to be administered via oral and parenteral routes. In particular, chitosan-based microparticles are the most frequently employed delivery system, along with specialized systems such as hydrogels, nanoparticles and thin films. Based on the progress made in chitosan-based drug delivery systems, the usefulness of chitosan has further expanded to anti-cancer chemoembolization, tissue engineering, and stem cell research. For instance, chitosan has been used to develop embolic materials designed to efficiently occlude the blood vessels by which the oxygen and nutrients are supplied. Indeed, it has been reported to be a promising embolic material. For better anti-cancer effect, embolic materials that can locally release anti-cancer drugs were proposed. In addition, a complex of radioactive materials and chitosan to be locally injected into the liver has been investigated as an efficient therapeutic tool for hepatocellular carcinoma. In line with this, a number of attempts have been explored to use chitosan-based carriers for the delivery of various agents, especially to the site of interest. Thus, in this work, studies where chitosan-based drug delivery systems have successfully been used for local delivery will be presented along with future perspectives. PMID:28257059

Effects of Epidural Labor Analgesia With Low Concentrations of Local Anesthetics on Obstetric Outcomes: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

PubMed

Wang, Ting-Ting; Sun, Shen; Huang, Shao-Qiang

2017-05-01

Low concentrations of local anesthetics (LCLAs) are increasingly popular for epidural labor analgesia. The effects of epidural analgesia with low concentrations of anesthetics on the duration of the second stage of labor and the instrumental birth rate, however, remain controversial. A systematic review was conducted to compare the effects of epidural analgesia with LCLAs with those of nonepidural analgesia on obstetric outcomes. The databases of PubMed, Embase, and the Cochrane controlled trials register were independently searched by 2 researchers, and randomized controlled trials that compared epidural labor analgesia utilizing LCLAs with nonepidural analgesia were retrieved. The primary outcomes were the duration of the second stage of labor and the instrumental birth rate; secondary outcomes included the cesarean delivery rate, the spontaneous vaginal delivery rate, and the duration of the first stage of labor. Ten studies (1809 women) were included. There was no significant difference between groups in the duration of the second stage of labor (mean difference = 5.71 minutes, 95% confidence interval [CI], -6.14 to 17.83; P = .36) or the instrumental birth rate (risk ratio [RR] = 1.52, 95% CI, 0.97-2.4; P = .07). There was no significant difference between groups in the cesarean delivery rate (RR = 0.8, 95% CI, 0.6-1.05; P = .11), the spontaneous vaginal delivery rate (RR = 0.98, 95% CI, 0.91-1.06; P = .62), or the duration of the first stage of labor (mean difference = 17.34 minutes, 95% CI, -5.89 to 40.56; P = .14). Compared with nonepidural analgesia, epidural analgesia with LCLAs is not associated with a prolonged duration of the second stage of labor or an increased instrumental birth rate. The results of this meta-analysis are based on small trials of low quality. These conclusions require confirmation by large-sample and high-quality trials in the future.

Thermal Dose is Related to Duration of Local Control in Canine Sarcomas Undergoing Thermoradiotherapy

PubMed Central

Thrall, Donald E.; LaRue, Susan M.; Yu, Daohai; Samulski, Thaddeus; Sanders, Linda; Case, Beth; Rosner, Gary; Azuma, Chieko; Poulson, Jeannie; Pruitt, Amy F.; Stanley, Wilma; Hauck, Marlene L.; Williams, Laurel; Hess, Paul; Dewhirst, Mark W.

2009-01-01

Purpose To test that prospective delivery of higher thermal dose is associated with longer tumor control duration. Experimental Design 122 dogs with a heatable soft tissue sarcoma were randomized to receive a low (2–5 CEM43°CT90) or high (20–50 CEM43°CT90) thermal dose in combination with radiotherapy. Most dogs (90%) received 4–6 hyperthermia treatments over 5 weeks. Results In the primary analysis, median (95% CI) duration of local control in the low dose group was 1.2 (0.7–2.1) years versus 1.9 (1.4–3.2) years in the high dose group (logrank p=0.28). The probability (95% CI) of tumor control at one year in the low vs. high dose groups was 0.57 (0.43–0.70) vs. 0.74 (0.62–0.86), respectively. Using multivariable procedure, thermal dose group (p=0.023), total duration of heating (p=0.008), tumor volume (p=0.041) and tumor grade (p=0.027) were significantly related to duration of local tumor control. When correcting for volume, grade and duration of heating, dogs in the low dose group were 2.3 times as likely to experience local failure. Conclusions Thermal dose is directly related to local control duration in irradiated canine sarcomas. Longer heating being associated with shorter local tumor control was unexpected. However, the effect of thermal dose on tumor control was stronger than for heating duration. The heating duration effect is possibly mediated through deleterious effects on tumor oxygenation. These results are the first to show the value of prospectively controlled thermal dose in achieving local tumor control with thermoradiotherapy, and they establish a paradigm for prescribing thermoradiotherapy and writing a thermal prescription. PMID:16033838

Recent advances in radiation cancer therapy

NASA Astrophysics Data System (ADS)

Ma, C.-M. Charlie

2007-03-01

This paper presents the recent advances in radiation therapy techniques for the treatment of cancer. Significant improvement has been made in imaging techniques such as CT, MRI, MRS, PET, ultrasound, etc. that have brought marked advances in tumor target and critical structure delineation for treatment planning and patient setup and target localization for accurate dose delivery in radiation therapy of cancer. Recent developments of novel treatment modalities including intensity-modulated x-ray therapy (IMXT), energy- and intensity modulated electron therapy (MERT) and intensity modulated proton therapy (IMPT) together with the use of advanced image guidance have enabled precise dose delivery for dose escalation and hypofractionation studies that may result in better local control and quality of life. Particle acceleration using laser-induced plasmas has great potential for new cost-effective radiation sources that may have a great impact on the management of cancer using radiation therapy.

Novel drug delivery systems in pain therapy.

PubMed

Al Malyan, M; Becchi, C; Boncinelli, S; Ashammakhi, N

2007-03-01

Pain is an unpleasant sensory experience resulting from damage to bodily tissues. It is considered a significant public health problem because it affects 1/5 of the world population and causes loss of great amounts of money. Pain reflects a mixture of pathological, psychological and genetic conditions that need deep understanding to be efficiently treated. If under-treated, pain results in serious immune and metabolic problems. Pain management faces many problems that limit its control. For instance, efficiency of pain killers is limited, pain killers give rise to serious side effects and inability of drug administration methods to help in pain control. Technology can overcome some of these problems and the introduction of implantable controlled drug delivery systems (CDDS), manufactured from biodegradable materials, offers a solution. Implantable CDDS provide good level of pain control, as they continuously provide drug, reduce side effects and improve patients' compliance. Biodegradable type of implantable CDDS are polymer based devices that are fabricated to locally deliver drugs in a pre-designed manner. They are currently a focus of research in the field of pain therapy in order to explore their chance to offer an alternative to the conventional methods for drug delivery. This paper aims to highlight the dimensions of pain issue and to overview the basics of drug release from polymers used for CDDS in pain management. In addition, it discusses the recent advances in the technologically designed drug delivery systems in the field of pain medicine and their clinical applications. Future perspectives are also presented.

Engineering nanoparticles to overcome barriers to immunotherapy

PubMed Central

Toy, Randall

2016-01-01

Abstract Advances in immunotherapy have led to the development of a variety of promising therapeutics, including small molecules, proteins and peptides, monoclonal antibodies, and cellular therapies. Despite this wealth of new therapeutics, the efficacy of immunotherapy has been limited by challenges in targeted delivery and controlled release, that is, spatial and temporal control on delivery. Particulate carriers, especially nanoparticles have been widely studied in drug delivery and vaccine research and are being increasingly investigated as vehicles to deliver immunotherapies. Nanoparticle‐mediated drug delivery could provide several benefits, including control of biodistribution and transport kinetics, the potential for site‐specific targeting, immunogenicity, tracking capability using medical imaging, and multitherapeutic loading. There are also a unique set of challenges, which include nonspecific uptake by phagocytic cells, off‐target biodistribution, permeation through tissue (transport limitation), nonspecific immune‐activation, and poor control over intracellular localization. This review highlights the importance of understanding the relationship between a nanoparticle's size, shape, charge, ligand density and elasticity to its vascular transport, biodistribution, cellular internalization, and immunogenicity. For the design of an effective immunotherapy, we highlight the importance of selecting a nanoparticle's physical characteristics (e.g., size, shape, elasticity) and its surface functionalization (e.g., chemical or polymer modifications, targeting or tissue‐penetrating peptides) with consideration of its reactivity to the targeted microenvironment (e.g., targeted cell types, use of stimuli‐sensitive biomaterials, immunogenicity). Applications of this rational nanoparticle design process in vaccine development and cancer immunotherapy are discussed. PMID:29313006

Size and targeting to PECAM vs ICAM control endothelial delivery, internalization and protective effect of multimolecular SOD conjugates.

PubMed

Shuvaev, Vladimir V; Muro, Silvia; Arguiri, Evguenia; Khoshnejad, Makan; Tliba, Samira; Christofidou-Solomidou, Melpo; Muzykantov, Vladimir R

2016-07-28

Controlled endothelial delivery of SOD may alleviate abnormal local surplus of superoxide involved in ischemia-reperfusion, inflammation and other disease conditions. Targeting SOD to endothelial surface vs. intracellular compartments is desirable to prevent pathological effects of external vs. endogenous superoxide, respectively. Thus, SOD conjugated with antibodies to cell adhesion molecule PECAM (Ab/SOD) inhibits pro-inflammatory signaling mediated by endogenous superoxide produced in the endothelial endosomes in response to cytokines. Here we defined control of surface vs. endosomal delivery and effect of Ab/SOD, focusing on conjugate size and targeting to PECAM vs. ICAM. Ab/SOD enlargement from about 100 to 300nm enhanced amount of cell-bound SOD and protection against extracellular superoxide. In contrast, enlargement inhibited endocytosis of Ab/SOD and diminished mitigation of inflammatory signaling of endothelial superoxide. In addition to size, shape is important: endocytosis of antibody-coated spheres was more effective than that of polymorphous antibody conjugates. Further, targeting to ICAM provides higher endocytic efficacy than targeting to PECAM. ICAM-targeted Ab/SOD more effectively mitigated inflammatory signaling by intracellular superoxide in vitro and in animal models, although total uptake was inferior to that of PECAM-targeted Ab/SOD. Therefore, both geometry and targeting features of Ab/SOD conjugates control delivery to cell surface vs. endosomes for optimal protection against extracellular vs. endosomal oxidative stress, respectively. Copyright © 2016 Elsevier B.V. All rights reserved.

PROPEL: implementation of an evidence based pelvic floor muscle training intervention for women with pelvic organ prolapse: a realist evaluation and outcomes study protocol.

PubMed

Maxwell, Margaret; Semple, Karen; Wane, Sarah; Elders, Andrew; Duncan, Edward; Abhyankar, Purva; Wilkinson, Joyce; Tincello, Douglas; Calveley, Eileen; MacFarlane, Mary; McClurg, Doreen; Guerrero, Karen; Mason, Helen; Hagen, Suzanne

2017-12-22

Pelvic Organ Prolapse (POP) is estimated to affect 41%-50% of women aged over 40. Findings from the multi-centre randomised controlled "Pelvic Organ Prolapse PhysiotherapY" (POPPY) trial showed that individualised pelvic floor muscle training (PFMT) was effective in reducing symptoms of prolapse, improved quality of life and showed clear potential to be cost-effective. However, provision of PFMT for prolapse continues to vary across the UK, with limited numbers of women's health physiotherapists specialising in its delivery. Implementation of this robust evidence from the POPPY trial will require attention to different models of delivery (e.g. staff skill mix) to fit with differing care environments. A Realist Evaluation (RE) of implementation and outcomes of PFMT delivery in contrasting NHS settings will be conducted using multiple case study sites. Involving substantial local stakeholder engagement will permit a detailed exploration of how local sites make decisions on how to deliver PFMT and how these lead to service change. The RE will track how implementation is working; identify what influences outcomes; and, guided by the RE-AIM framework, will collect robust outcomes data. This will require mixed methods data collection and analysis. Qualitative data will be collected at four time-points across each site to understand local contexts and decisions regarding options for intervention delivery and to monitor implementation, uptake, adherence and outcomes. Patient outcome data will be collected at baseline, six months and one year follow-up for 120 women. Primary outcome will be the Pelvic Organ Prolapse Symptom Score (POP-SS). An economic evaluation will assess the costs and benefits associated with different delivery models taking account of further health care resource use by the women. Cost data will be combined with the primary outcome in a cost effectiveness analysis, and the EQ-5D-5L data in a cost utility analysis for each of the different models of delivery. Study of the implementation of varying models of service delivery of PFMT across contrasting sites combined with outcomes data and a cost effectiveness analysis will provide insight into the implementation and value of different models of PFMT service delivery and the cost benefits to the NHS in the longer term.

Multifunctional platinum-based nanoparticles for biomedical applications.

PubMed

Cheng, Qinqin; Liu, Yangzhong

2017-03-01

Platinum-based anticancer drugs play a central role in current cancer therapy. However, their applicability and efficacy are limited by drug resistance and adverse effects. Nanocarrier-based platinum drug delivery systems are promising alternatives to circumvent the disadvantages of bare platinum drugs. The various properties of nanoparticle chemistry allow for the trend toward multiple functionality. Nanoparticles preferentially accumulate at the tumor site through passive targeting, and the attachment of tumor targeting moieties further enhances their tumor-specific localization as well as tumor cell uptake. The introduction of stimuli-responsive groups into drug delivery systems can further achieve spatially and temporally controlled drug release in response to specific stimuli. Combination therapy strategies have been used to promote synergetic efficacy and overcome the resistance of platinum drugs. The tumor-localized drug delivery strategies exhibit benefits for preventing local tumor recurrence. In addition, the combination of platinum drugs and imaging agents in one unity allows the cancer diagnostics for real-time monitoring the distribution of drug-loaded nanoparticles inside the body and tumor. This review discusses recent scientific advances in multifunctional nanoparticle formulations of platinum drugs, and these designs exhibit new potential of multifunctional nanoparticles for delivering platinum-based anticancer drugs. WIREs Nanomed Nanobiotechnol 2017, 9:e1410. doi: 10.1002/wnan.1410 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.

Androgen actions in mouse wound healing: Minimal in vivo effects of local antiandrogen delivery.

PubMed

Wang, Yiwei; Simanainen, Ulla; Cheer, Kenny; Suarez, Francia G; Gao, Yan Ru; Li, Zhe; Handelsman, David; Maitz, Peter

2016-05-01

The aims of this work were to define the role of androgens in female wound healing and to develop and characterize a novel wound dressing with antiandrogens. Androgens retard wound healing in males, but their role in female wound healing has not been established. To understand androgen receptor (AR)-mediated androgen actions in male and female wound healing, we utilized the global AR knockout (ARKO) mouse model, with a mutated AR deleting the second zinc finger to disrupt DNA binding and transcriptional activation. AR inactivation enhanced wound healing rate in males by increasing re-epithelialization and collagen deposition even when wound contraction was eliminated. Cell proliferation and migration in ARKO male fibroblasts was significantly increased compared with wild-type (WT) fibroblasts. However, ARKO females showed a similar healing rate compared to WT females. To exploit local antiandrogen effects in wound healing, while minimizing off-target systemic effects, we developed a novel electrospun polycaprolactone (PCL) scaffold wound dressing material for sustained local antiandrogen delivery. Using the antiandrogen hydroxyl flutamide (HF) at 1, 5, and 10 mg/mL in PCL scaffolds, controlled HF delivery over 21 days significantly enhanced in vitro cell proliferation of human dermal fibroblasts and human keratinocytes. HF-PCL scaffolds also promoted in vivo wound healing in mice compared with open wounds but not to PCL scaffolds. © 2016 by the Wound Healing Society.

Development and Characterization of a Scalable Microperforated Device Capable of Long-Term Zero Order Drug Release

DTIC Science & Technology

2010-06-29

posterior segment of the eye and include posterior uveitis , age-related macular degeneration, and macular edema (Hsu 2007). Long term drug therapy may be...device for local and controlled delivery of drugs; as a protective carrier to transport labile drugs; and as an implant for treatment of various chronic

Periodontal therapy using local delivery of antimicrobial agents.

PubMed

Niederman, Richard; Abdelshehid, George; Goodson, J Max

2002-10-01

Antimicrobial agents, systemic and/or local, are thought by some to be effective agents for treating periodontal infections. Here the authors determine the costs and benefits of local delivery agents for treating periodontal disease. Applying this cost-benefit analysis to patient care, however, will depend upon a clinician's expertise and a patient's value system.

The efficacy of an intraosseous injection system of delivering local anesthetic.

PubMed

Leonard, M S

1995-01-01

This article describes the clinical testing of a new system for the intraosseous delivery of local anesthesia. The author concluded that the system delivered local anesthetic very effectively (in some situations more effectively than the traditional delivery method), thus offering a great potential advantage to both dentists and patients.

Designing and assessing a sustainable networked delivery (SND) system: hybrid business-to-consumer book delivery case study.

PubMed

Kim, Junbeum; Xu, Ming; Kahhat, Ramzy; Allenby, Braden; Williams, Eric

2009-01-01

We attempted to design and assess an example of a sustainable networked delivery (SND) system: a hybrid business-to-consumer book delivery system. This system is intended to reduce costs, achieve significant reductions in energy consumption, and reduce environmental emissions of critical local pollutants and greenhouse gases. The energy consumption and concomitant emissions of this delivery system compared with existing alternative delivery systems were estimated. We found that regarding energy consumption, an emerging hybrid delivery system which is a sustainable networked delivery system (SND) would consume 47 and 7 times less than the traditional networked delivery system (TND) and e-commerce networked delivery system (END). Regarding concomitant emissions, in the case of CO2, the SND system produced 32 and 7 times fewer emissions than the TND and END systems. Also the SND system offer meaningful economic benefit such as the costs of delivery and packaging, to the online retailer, grocery, and consumer. Our research results show that the SND system has a lot of possibilities to save local transportation energy consumption and delivery costs, and reduce environmental emissions in delivery system.

A novel local anti-colorectal cancer drug delivery system: negative lipidoid nanoparticles with a passive target via a size-dependent pattern

NASA Astrophysics Data System (ADS)

Ding, Weifeng; Wang, Feng; Zhang, Jianfeng; Guo, Yibing; Ju, Shaoqing; Wang, Huimin

2013-09-01

The nontoxic, targeted and effective delivery of nucleic acid drugs remains an important challenge for clinical development. Here, we describe a novel negative lipidoid nanoparticle delivery system, providing entrapment-based transfection agents for local delivery of siRNA to the colorectal cancer focus. The delivery system was synthesized with lipidoid material 98N12-5(1), mPEG2000-C12/C14 glyceride and cholesterol at a desired molar ratio to realize the anionic surface charge of particles, which could alleviate to a larger degree the inflammatory response and immune stimulation of the organism, embodying dramatic biocompatibility. In particular, mPEG2000-C12/C14 glyceride was selected to ameliorate the stability of the delivery system and protection of nucleic acids by extending the tail length of the carbons, crucial also to neutralize the positive charge of 98N12-5(1) to form a resultant anionic particle. In vivo experiments revealed that a particle size of 90 nm perfectly realized a passive target in a size-dependent manner and did not affect the function of the liver and kidneys by a local delivery method, enema. We clarified that the uptake of negative lipidoid nanoparticles internalized through a lipid raft endocytotic pathway with low cytotoxicity, strong biocompatibility and high efficacy. This study suggests that negative lipidoid nanoparticles with enema delivery costitute, uniquely and appropriately, a local anti-colorectal cancer nucleic acid drug delivery platform, and the application of similar modes may be feasible in other therapeutic settings.

Engineered Hydrogels for Local and Sustained Delivery of RNA-Interference Therapies.

PubMed

Wang, Leo L; Burdick, Jason A

2017-01-01

It has been nearly two decades since RNA-interference (RNAi) was first reported. While there are no approved clinical uses, several phase II and III clinical trials suggest the great promise of RNAi therapeutics. One challenge for RNAi therapies is the controlled localization and sustained presentation to target tissues, to both overcome systemic toxicity concerns and to enhance in vivo efficacy. One approach that is emerging to address these limitations is the entrapment of RNAi molecules within hydrogels for local and sustained release. In these systems, nucleic acids are either delivered as siRNA conjugates or within nanoparticles. A plethora of hydrogels has been implemented using these approaches, including both traditional hydrogels that have already been developed for other applications and new hydrogels developed specifically for RNAi delivery. These hydrogels have been applied to various applications in vivo, including cancer, bone regeneration, inflammation and cardiac repair. This review will examine the design and implementation of such hydrogel RNAi systems and will cover the most recent applications of these systems. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Controlled delivery of icariin on small intestine submucosa for bone tissue engineering.

PubMed

Li, Mei; Gu, Qiaoqiao; Chen, Mengjie; Zhang, Chi; Chen, Songdi; Zhao, Jiyuan

2017-02-01

Small intestine submucosa (SIS) has been reported as an excellent biomaterial for tissue engineering because of its naturally occurring collagenous extracellular matrix property with growth factors. However, SIS from submucosal layer of intestine provides different microenvironment from bone tissue, which limits its application to bone regeneration. The object of this study was to improve osteoinductivity of SIS by controlled local delivery of icariin (Ic), a potent osteogenic compound. Sustained release of icariin from SIS scaffold was achieved for >30days and the loading of icariin on SIS scaffold was uniform as scanned by SEM. In vitro experiments revealed that expression of osteogenic differentiation markers (Alp, Bsp and Ocn) was increased after treatment of Ic-SIS scaffold, without significant cytotoxicity. In an in vivo mouse calvarial defect model, bone regeneration was enhanced by SIS implantation at 8weeks, compared to control defect. New bone formation was further improved by implantation with Ic-SIS (low and high) at both 4 and 8weeks. The results of this study suggest that SIS scaffold has the potential as an icariin delivery carrier for enhancement of bone regeneration. Copyright © 2016 Elsevier B.V. All rights reserved.

Stereotactic Body Radiation Therapy Delivery in a Genetically Engineered Mouse Model of Lung Cancer.

PubMed

Du, Shisuo; Lockamy, Virginia; Zhou, Lin; Xue, Christine; LeBlanc, Justin; Glenn, Shonna; Shukla, Gaurav; Yu, Yan; Dicker, Adam P; Leeper, Dennis B; Lu, You; Lu, Bo

2016-11-01

To implement clinical stereotactic body radiation therapy (SBRT) using a small animal radiation research platform (SARRP) in a genetically engineered mouse model of lung cancer. A murine model of multinodular Kras-driven spontaneous lung tumors was used for this study. High-resolution cone beam computed tomography (CBCT) imaging was used to identify and target peripheral tumor nodules, whereas off-target lung nodules in the contralateral lung were used as a nonirradiated control. CBCT imaging helps localize tumors, facilitate high-precision irradiation, and monitor tumor growth. SBRT planning, prescription dose, and dose limits to normal tissue followed the guidelines set by RTOG protocols. Pathologic changes in the irradiated tumors were investigated using immunohistochemistry. The image guided radiation delivery using the SARRP system effectively localized and treated lung cancer with precision in a genetically engineered mouse model of lung cancer. Immunohistochemical data confirmed the precise delivery of SBRT to the targeted lung nodules. The 60 Gy delivered in 3 weekly fractions markedly reduced the proliferation index, Ki-67, and increased apoptosis per staining for cleaved caspase-3 in irradiated lung nodules. It is feasible to use the SARRP platform to perform dosimetric planning and delivery of SBRT in mice with lung cancer. This allows for preclinical studies that provide a rationale for clinical trials involving SBRT, especially when combined with immunotherapeutics. Copyright © 2016. Published by Elsevier Inc.

Bioactive factor delivery strategies from engineered polymer hydrogels for therapeutic medicine

PubMed Central

Nguyen, Minh Khanh; Alsberg, Eben

2014-01-01

Polymer hydrogels have been widely explored as therapeutic delivery matrices because of their ability to present sustained, localized and controlled release of bioactive factors. Bioactive factor delivery from injectable biopolymer hydrogels provides a versatile approach to treat a wide variety of diseases, to direct cell function and to enhance tissue regeneration. The innovative development and modification of both natural-(e.g., alginate (ALG), chitosan, hyaluronic acid (HA), gelatin, heparin (HEP), etc.) and synthetic-(e.g., polyesters, polyethyleneimine (PEI), etc.) based polymers has resulted in a variety of approaches to design drug delivery hydrogel systems from which loaded therapeutics are released. This review presents the state-of-the-art in a wide range of hydrogels that are formed though self-assembly of polymers and peptides, chemical crosslinking, ionic crosslinking and biomolecule recognition. Hydrogel design for bioactive factor delivery is the focus of the first section. The second section then thoroughly discusses release strategies of payloads from hydrogels for therapeutic medicine, such as physical incorporation, covalent tethering, affinity interactions, on demand release and/or use of hybrid polymer scaffolds, with an emphasis on the last 5 years. PMID:25242831

Tracking of Drug Release and Material Fate for Naturally Derived Omega-3 Fatty Acid Biomaterials.

PubMed

Faucher, Keith M; Artzi, Natalie; Beck, Moshe; Beckerman, Rita; Moodie, Geoff; Albergo, Theresa; Conroy, Suzanne; Dale, Alicia; Corbeil, Scott; Martakos, Paul; Edelman, Elazer R

2016-03-01

In vitro and in vivo studies were conducted on omega-3 fatty acid-derived biomaterials to determine their utility as an implantable material for adhesion prevention following soft tissue hernia repair and as a means to allow for the local delivery of antimicrobial or antibiofilm agents. Naturally derived biomaterials offer several advantages over synthetic materials in the field of medical device development. These advantages include enhanced biocompatibility, elimination of risks posed by the presence of toxic catalysts and chemical crosslinking agents, and derivation from renewable resources. Omega-3 fatty acids are readily available from fish and plant sources and can be used to create implantable biomaterials either as a stand-alone device or as a device coating that can be utilized in local drug delivery applications. In-depth characterization of material erosion degradation over time using non-destructive imaging and chemical characterization techniques provided mechanistic insight into material structure: function relationship. This in turn guided rational tailoring of the material based on varying fatty acid composition to control material residence time and hence drug release. These studies demonstrate the utility of omega-3 fatty acid derived biomaterials as an absorbable material for soft tissue hernia repair and drug delivery applications.

Development of a magnetic system for the treatment of Helicobacter pylori infections

NASA Astrophysics Data System (ADS)

Silva, Érica L.; Carvalho, Juliana F.; Pontes, Thales R. F.; Oliveira, Elquio E.; Francelino, Bárbara L.; Medeiros, Aldo C.; do Egito, E. Sócrates T.; Araujo, José H.; Carriço, Artur S.

2009-05-01

We report a study to develop a magnetic system for local delivery of amoxicillin. Magnetite microparticles produced by coprecipitation were coated with a solution of amoxicillin and Eudragit ®S100 by spray drying. Scanning electron microscopy, optical microscopy, X-ray powder diffraction and vibrating sample magnetometry revealed that the particles were superparamagnetic, with an average diameter of 17.2 μm, and an initial susceptibility controllable by the magnetite content in the suspension feeding the sprayer. Our results suggest a possible way to treat Helicobacter pylori infections, using an oral drug delivery system, and open prospects to coat magnetic microparticles by spray drying for biomedical applications.

Triage of oxidation-prone proteins by Sqstm1/p62 within the mitochondria

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

Lee, Minjung; Shin, Jaekyoon, E-mail: jkshin@med.skku.ac.kr

2011-09-16

Highlights: {yields} The mitochondrion contains its own protein quality control system. {yields} p62 localizes within the mitochondria and forms mega-dalton sized complexes. {yields} p62 interacts with oxidation-prone proteins and the proteins of quality control. {yields} In vitro delivery of p62 improves mitochondrial functions. {yields} p62 is implicated as a participant in mitochondrial protein quality control. -- Abstract: As the mitochondrion is vulnerable to oxidative stress, cells have evolved several strategies to maintain mitochondrial integrity, including mitochondrial protein quality control mechanisms and autophagic removal of damaged mitochondria. Involvement of an autophagy adaptor, Sqstm1/p62, in the latter process has been recently described.more » In the present study, we provide evidence that a portion of p62 directly localizes within the mitochondria and supports stable electron transport by forming heterogeneous protein complexes. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF) of mitochondrial proteins co-purified with p62 revealed that p62 interacts with several oxidation-prone proteins, including a few components of the electron transport chain complexes, as well as multiple chaperone molecules and redox regulatory enzymes. Accordingly, p62-deficient mitochondria exhibited compromised electron transport, and the compromised function was partially restored by in vitro delivery of p62. These results suggest that p62 plays an additional role in maintaining mitochondrial integrity at the vicinity of target machineries through its function in relation to protein quality control.« less

Cryotherapy for prostate cancer.

PubMed

Bermejo, Carlos E; Pisters, Louis L

2003-06-01

Cryotherapy, or the use of freezing, is a long-established method of tumor cell destruction. Although in the past cryotherapy was widely used as a local treatment for prostate cancer, this technique was abandoned not due to lack of efficacy but because the complication rate was unacceptably high. However, there has been a re-emergence in the popularity of cryotherapy for the treatment of localized prostate cancer due to improvements in instrumentation, tumor localization and treatment delivery. Using transrectal ultrasound imaging, prostate cryotherapy is currently delivered with multiple probes via a percutaneous transperineal approach. The extent of freezing can be precisely controlled and monitored with thermocouples and tissue destruction is monitored with real-time visualization of the prostate and surrounding structures. The role of cryotherapy in localized prostate cancer is reviewed.

Lipid Raft-Mediated Membrane Tethering and Delivery of Hydrophobic Cargos from Liquid Crystal-Based Nanocarriers.

PubMed

Nag, Okhil K; Naciri, Jawad; Oh, Eunkeu; Spillmann, Christopher M; Delehanty, James B

2016-04-20

A main goal of bionanotechnology and nanoparticle (NP)-mediated drug delivery (NMDD) continues to be the development of novel biomaterials that can controllably modulate the activity of the NP-associated therapeutic cargo. One of the desired subcellular locations for targeted delivery in NMDD is the plasma membrane. However, the controlled delivery of hydrophobic cargos to the membrane bilayer poses significant challenges including cargo precipitation and lack of specificity. Here, we employ a liquid crystal NP (LCNP)-based delivery system for the controlled partitioning of a model dye cargo from within the NP core into the plasma membrane bilayer. During synthesis of the NPs, the water-insoluble model dye cargo, 3,3'-dioctadecyloxacarbocyanine perchlorate (DiO), was efficiently incorporated into the hydrophobic LCNP core as confirmed by multiple spectroscopic analyses. Conjugation of a PEGylated cholesterol derivative to the NP surface (DiO-LCNP-PEG-Chol) facilitated the localization of the dye-loaded NPs to lipid raft microdomains in the plasma membrane in HEK 293T/17 cell. Analysis of DiO cellular internalization kinetics revealed that when delivered as a LCNP-PEG-Chol NP, the half-life of DiO membrane residence time (30 min) was twice that of free DiO (DiO(free)) (15 min) delivered from bulk solution. Time-resolved laser scanning confocal microscopy was employed to visualize the passive efflux of DiO from the LCNP core and its insertion into the plasma membrane bilayer as confirmed by Förster resonance energy transfer (FRET) imaging. Finally, the delivery of DiO as a LCNP-PEG-Chol complex resulted in the attenuation of its cytotoxicity; the NP form of DiO exhibited ∼30-40% less toxicity compared to DiO(free). Our data demonstrate the utility of the LCNP platform as an efficient vehicle for the combined membrane-targeted delivery and physicochemical modulation of molecular cargos using lipid raft-mediated tethering.

Changes in Local Public Health System Performance Before and After Attainment of National Accreditation Standards.

PubMed

Ingram, Richard C; Mays, Glen P; Kussainov, Nurlan

The aim of this study is to investigate the impact of Public Health Accreditation Board (PHAB) accreditation on the delivery of public health services and on participation from other sectors in the delivery of public health services in local public health systems. This study uses a longitudinal repeated measures design to identify differences between a cohort of public health systems containing PHAB-accredited local health departments and a cohort of public health systems containing unaccredited local health departments. It uses data spanning from 2006 to 2016. This study examines a cohort of local public health systems that serves large populations and contains unaccredited and PHAB-accredited local health departments. Data in this study were collected from the directors of health departments that include local public health systems followed in the National Longitudinal Study of Public Health Systems. The intervention examined is PHAB accreditation. The study focuses on 4 areas: the delivery of core public health services, local health department contribution toward these services, participation in the delivery of these services by other members of the public health system, and public health system makeup. Prior to the advent of accreditation, public health systems containing local health departments that were later accredited by PHAB appear quite similar to their unaccredited peers. Substantial differences between the 2 cohorts appear to manifest themselves after the advent of accreditation. Specifically, the accredited cohort seems to offer a broader array of public health services, involve more partners in the delivery of those services, and enjoy a higher percentage of comprehensive public health systems. The results of this study suggest that accreditation may yield significant benefits and may help public health systems develop the public health system capital necessary to protect and promote the public's health.

An overview of in vitro dissolution/release methods for novel mucosal drug delivery systems.

PubMed

Jug, Mario; Hafner, Anita; Lovrić, Jasmina; Kregar, Maja Lusina; Pepić, Ivan; Vanić, Željka; Cetina-Čižmek, Biserka; Filipović-Grčić, Jelena

2018-01-05

In vitro dissolution/release tests are an important tool in the drug product development phase as well as in its quality control and the regulatory approval process. Mucosal drug delivery systems are aimed to provide both local and systemic drug action via mucosal surfaces of the body and exhibit significant differences in formulation design, as well as in their physicochemical and release characteristics. Therefore it is not possible to devise a single test system which would be suitable for release testing of such complex dosage forms. This article is aimed to provide a comprehensive review of both compendial and noncompendial methods used for in vitro dissolution/release testing of novel mucosal drug delivery systems aimed for ocular, nasal, oromucosal, vaginal and rectal administration. Copyright © 2017 Elsevier B.V. All rights reserved.

'Smart' nanoparticles as drug delivery systems for applications in tumor therapy.

PubMed

Fang, Zhi; Wan, Lin-Yan; Chu, Liang-Yin; Zhang, Yan-Qiong; Wu, Jiang-Feng

2015-01-01

In the therapy of clinical diseases such as cancer, it is important to deliver drugs directly to tumor sites in order to maximize local drug concentration and reduce side effects. This objective may be realized by using 'smart' nanoparticles (NPs) as drug delivery systems, because they enable dramatic conformational changes in response to specific physical/chemical stimuli from the diseased cells for targeted and controlled drug release. In this review, we first briefly summarize the characteristics of 'smart' NPs as drug delivery systems in medical therapy, and then discuss their targeting transport, transmembrane and endosomal escape behaviors. Lastly, we focus on the applications of 'smart' NPs as drug delivery systems for tumor therapy. Biodegradable 'smart' NPs have the potential to achieve maximum efficacy and drug availability at the desired sites, and reduce the harmful side effects for healthy tissues in tumor therapy. It is necessary to select appropriate NPs and modify their characteristics according to treatment strategies of tumor therapy.

A model for food and stimulus changes that signal time-based contingency changes.

PubMed

Cowie, Sarah; Davison, Michael; Elliffe, Douglas

2014-11-01

When the availability of reinforcers depends on time since an event, time functions as a discriminative stimulus. Behavioral control by elapsed time is generally weak, but may be enhanced by added stimuli that act as additional time markers. The present paper assessed the effect of brief and continuous added stimuli on control by time-based changes in the reinforcer differential, using a procedure in which the local reinforcer ratio reversed at a fixed time after the most recent reinforcer delivery. Local choice was enhanced by the presentation of the brief stimuli, even when the stimulus change signalled only elapsed time, but not the local reinforcer ratio. The effect of the brief stimulus presentations on choice decreased as a function of time since the most recent stimulus change. We compared the ability of several versions of a model of local choice to describe these data. The data were best described by a model which assumed that error in discriminating the local reinforcer ratio arose from imprecise discrimination of reinforcers in both time and space, suggesting that timing behavior is controlled not only by discrimination elapsed time, but by discrimination of the reinforcer differential in time. © Society for the Experimental Analysis of Behavior.

Polymeric nanoparticles for the intracellular delivery of paclitaxel in lung and breast cancer

NASA Astrophysics Data System (ADS)

Zubris, Kimberly Ann Veronica

Nanoparticles are useful for addressing many of the difficulties encountered when administering therapeutic compounds. Nanoparticles are able to increase the solubility of hydrophobic drugs, improve pharmacokinetics through sustained release, alter biodistribution, protect sensitive drugs from low pH environments or enzymatic alteration, and, in some cases, provide targeting of the drug to the desired tissues. The use of functional nanocarriers can also provide controlled intracellular delivery of a drug. To this end, we have developed functional pH-responsive expansile nanoparticles for the intracellular delivery of paclitaxel. The pH-responsiveness of these nanoparticles occurs due to a hydrophobic to hydrophilic transition of the polymer occurring under mildly acidic conditions. These polymeric nanoparticles were systematically evaluated for the delivery of paclitaxel in vitro and in vivo to improve local therapy for lung and breast cancers. Nanoparticles were synthesized using a miniemulsion polymerization process and were subsequently characterized and found to swell when exposed to acidic environments. Paclitaxel was successfully encapsulated within the nanoparticles, and the particles exhibited drug release at pH 5 but not at pH 7.4. In addition, the uptake of nanoparticles was observed using flow cytometry, and the anticancer efficacy of the paclitaxel-loaded nanoparticles was measured using cancer cell lines in vitro. The potency of the paclitaxel-loaded nanoparticles was close to that of free drug, demonstrating that the drug was effectively delivered by the particles and that the particles could act as an intracellular drug depot. Following in vitro characterization, murine in vivo studies demonstrated the ability of the paclitaxel-loaded responsive nanoparticles to delay recurrence of lung cancer and to prevent establishment of breast cancer in the mammary fat pads with higher efficacy than paclitaxel alone. In addition, the ability of nanoparticles to migrate up to 40 cm through lymphatic channels to local lymph nodes was demonstrated using near infrared imaging in a large animal model. Continued investigation of functional nanoparticles, like the system described here for lung and breast cancer, will facilitate the development of new materials that meet the varied and demanding needs in chemotherapy, and may afford new treatment options for the local and metastatic control of many forms of cancer.

In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs.

PubMed

Bez, Maxim; Sheyn, Dmitriy; Tawackoli, Wafa; Avalos, Pablo; Shapiro, Galina; Giaconi, Joseph C; Da, Xiaoyu; David, Shiran Ben; Gavrity, Jayne; Awad, Hani A; Bae, Hyun W; Ley, Eric J; Kremen, Thomas J; Gazit, Zulma; Ferrara, Katherine W; Pelled, Gadi; Gazit, Dan

2017-05-17

More than 2 million bone-grafting procedures are performed each year using autografts or allografts. However, both options carry disadvantages, and there remains a clear medical need for the development of new therapies for massive bone loss and fracture nonunions. We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would induce efficient bone regeneration and fracture repair. To test this hypothesis, we surgically created a critical-sized bone fracture in the tibiae of Yucatán mini-pigs, a clinically relevant large animal model. A collagen scaffold was implanted in the fracture to facilitate recruitment of endogenous mesenchymal stem/progenitor cells (MSCs) into the fracture site. Two weeks later, transcutaneous ultrasound-mediated reporter gene delivery successfully transfected 40% of cells at the fracture site, and flow cytometry showed that 80% of the transfected cells expressed MSC markers. Human bone morphogenetic protein-6 ( BMP - 6 ) plasmid DNA was delivered using ultrasound in the same animal model, leading to transient expression and secretion of BMP-6 localized to the fracture area. Micro-computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to complete radiographic and functional fracture healing in all animals 6 weeks after treatment, whereas nonunion was evident in control animals. Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchymal progenitor cells can effectively treat nonhealing bone fractures in large animals, thereby addressing a major orthopedic unmet need and offering new possibilities for clinical translation. Copyright © 2017, American Association for the Advancement of Science.

Smart multifunctional drug delivery towards anticancer therapy harmonized in mesoporous nanoparticles.

PubMed

Baek, Seonmi; Singh, Rajendra K; Khanal, Dipesh; Patel, Kapil D; Lee, Eun-Jung; Leong, Kam W; Chrzanowski, Wojciech; Kim, Hae-Won

2015-09-14

Nanomedicine seeks to apply nanoscale materials for the therapy and diagnosis of diseased and damaged tissues. Recent advances in nanotechnology have made a major contribution to the development of multifunctional nanomaterials, which represents a paradigm shift from single purpose to multipurpose materials. Multifunctional nanomaterials have been proposed to enable simultaneous target imaging and on-demand delivery of therapeutic agents only to the specific site. Most advanced systems are also responsive to internal or external stimuli. This approach is particularly important for highly potent drugs (e.g. chemotherapeutics), which should be delivered in a discreet manner and interact with cells/tissues only locally. Both advances in imaging and precisely controlled and localized delivery are critically important in cancer treatment, and the use of such systems - theranostics - holds great promise to minimise side effects and boost therapeutic effectiveness of the treatment. Among others, mesoporous silica nanoparticles (MSNPs) are considered one of the most promising nanomaterials for drug delivery. Due to their unique intrinsic features, including tunable porosity and size, large surface area, structural diversity, easily modifiable chemistry and suitability for functionalization, and biocompatibility, MSNPs have been extensively utilized as multifunctional nanocarrier systems. The combination or hybridization with biomolecules, drugs, and other nanoparticles potentiated the ability of MSNPs towards multifunctionality, and even smart actions stimulated by specified signals, including pH, optical signal, redox reaction, electricity and magnetism. This paper provides a comprehensive review of the state-of-the-art of multifunctional, smart drug delivery systems centered on advanced MSNPs, with special emphasis on cancer related applications.

Smart multifunctional drug delivery towards anticancer therapy harmonized in mesoporous nanoparticles

NASA Astrophysics Data System (ADS)

Baek, Seonmi; Singh, Rajendra K.; Khanal, Dipesh; Patel, Kapil D.; Lee, Eun-Jung; Leong, Kam W.; Chrzanowski, Wojciech; Kim, Hae-Won

2015-08-01

Nanomedicine seeks to apply nanoscale materials for the therapy and diagnosis of diseased and damaged tissues. Recent advances in nanotechnology have made a major contribution to the development of multifunctional nanomaterials, which represents a paradigm shift from single purpose to multipurpose materials. Multifunctional nanomaterials have been proposed to enable simultaneous target imaging and on-demand delivery of therapeutic agents only to the specific site. Most advanced systems are also responsive to internal or external stimuli. This approach is particularly important for highly potent drugs (e.g. chemotherapeutics), which should be delivered in a discreet manner and interact with cells/tissues only locally. Both advances in imaging and precisely controlled and localized delivery are critically important in cancer treatment, and the use of such systems - theranostics - holds great promise to minimise side effects and boost therapeutic effectiveness of the treatment. Among others, mesoporous silica nanoparticles (MSNPs) are considered one of the most promising nanomaterials for drug delivery. Due to their unique intrinsic features, including tunable porosity and size, large surface area, structural diversity, easily modifiable chemistry and suitability for functionalization, and biocompatibility, MSNPs have been extensively utilized as multifunctional nanocarrier systems. The combination or hybridization with biomolecules, drugs, and other nanoparticles potentiated the ability of MSNPs towards multifunctionality, and even smart actions stimulated by specified signals, including pH, optical signal, redox reaction, electricity and magnetism. This paper provides a comprehensive review of the state-of-the-art of multifunctional, smart drug delivery systems centered on advanced MSNPs, with special emphasis on cancer related applications.

In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs

PubMed Central

Bez, Maxim; Sheyn, Dmitriy; Tawackoli, Wafa; Avalos, Pablo; Shapiro, Galina; Giaconi, Joseph C.; Da, Xiaoyu; Ben David, Shiran; Gavrity, Jayne; Awad, Hani A.; Bae, Hyun W.; Ley, Eric J.; Kremen, Thomas J.; Gazit, Zulma; Ferrara, Katherine W.; Pelled, Gadi; Gazit, Dan

2017-01-01

More than 2 million bone-grafting procedures are performed each year using autografts or allografts. However, both options carry disadvantages, and there remains a clear medical need for the development of new therapies for massive bone loss and fracture nonunions. We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would induce efficient bone regeneration and fracture repair. To test this hypothesis, we surgically created a critical-sized bone fracture in the tibiae of Yucatán mini-pigs, a clinically relevant large animal model. A collagen scaffold was implanted in the fracture to facilitate recruitment of endogenous mesenchymal stem/progenitor cells (MSCs) into the fracture site. Two weeks later, transcutaneous ultrasound-mediated reporter gene delivery successfully transfected 40% of cells at the fracture site, and flow cytometry showed that 80% of the transfected cells expressed MSC markers. Human bone morphogenetic protein-6 (BMP-6) plasmid DNA was delivered using ultrasound in the same animal model, leading to transient expression and secretion of BMP-6 localized to the fracture area. Micro–computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to complete radiographic and functional fracture healing in all animals 6 weeks after treatment, whereas nonunion was evident in control animals. Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchy-mal progenitor cells can effectively treat nonhealing bone fractures in large animals, thereby addressing a major orthopedic unmet need and offering new possibilities for clinical translation. PMID:28515335

Intracoronary and Retrograde Coronary Venous Myocardial Delivery of Adipose-Derived Stem Cells in Swine Infarction Lead to Transient Myocardial Trapping with Predominant Pulmonary Redistribution

PubMed Central

Hong, Soon Jun; Hou, Dongming; Brinton, Todd J.; Johnstone, Brian; Feng, Dongni; Rogers, Pamela; Fearon, William F.; Yock, Paul; March, Keith L.

2012-01-01

Objectives To examine the comparative fate of adipose-derived stem cells (ASCs) as well as their impact on coronary microcirculation following either retrograde coronary venous or arterial delivery. Background Local delivery of ASCs to the heart has been proposed as a practical approach to limiting the extent of myocardial infarction. Mouse models of mesenchymal stem cell effects on the heart have also demonstrated significant benefits from systemic (intravenous) delivery, prompting a question about the advantage of local delivery. There has been no study addressing the extent of myocardial vs. systemic disposition of ASCs in large animal models following local delivery to the myocardium. Methods In an initial experiment, dose-dependent effects of ASC delivery on coronary circulation in normal swine were evaluated to establish a tolerable ASC dosing range for intracoronary delivery. In a set of subsequent experiments, an anterior acute myocardial infarction (AMI) was created by balloon occlusion of the proximal left anterior descending (LAD) artery, followed by either intracoronary (IC) or retrograde coronary venous (RCV) infusion of 107 111Indium-labeled autologous ASCs 6 days following AMI. Indices of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured before sacrifices to collect tissues for analysis at 1 or 24 hours after cell delivery. Results IC delivery of porcine ASCs to normal myocardium was well-tolerated up to a cumulative dose of 14×106 cells (approximately 0.5×106 cells/kg). There was evidence suggesting microcirculatory trapping of ASC: at unit doses of 50×106 ASCs, IMR and CFR were found to be persistently altered in the target LAD distribution at 7 days following delivery, while at 10×106 ASCs, only CFR was altered. In the context of recent MI, a significantly higher percentage of ASCs was retained at 1 hour with IC delivery compared to RCV delivery (57.2 ± 12.7% vs. 17.9 ± 1.6%, p=0.037) but this initial difference was not apparent at 24 hours (22.6 ± 5.5% vs. 18.7 ± 8.6%; p= 0.722). In both approaches, most ASC redistributed to the pulmonary circulation by 24 hours post-delivery. There were no significant differences in CFR or IMR following ASC delivery to infarcted tissue by either route. Conclusions Selective intravascular delivery of ASC by coronary arterial and venous routes leads to similarly limited myocardial cell retention with predominant redistribution of cells to the lungs. Intracoronary arterial delivery of ASC leads to only transiently greater myocardial retention, which is accompanied by obstruction of normal regions of coronary microcirculation at higher doses. The predominant intrapulmonary localization of cells following local delivery via both methods prompts the notion that systemic delivery of ASC might provide similarly beneficial outcomes while avoiding risks of inadvertent microcirculatory compromise. PMID:22972685

Controlled propulsion of artificial magnetic nanostructured propellers.

PubMed

Ghosh, Ambarish; Fischer, Peer

2009-06-01

For biomedical applications, such as targeted drug delivery and microsurgery, it is essential to develop a system of swimmers that can be propelled wirelessly in fluidic environments with good control. Here, we report the construction and operation of chiral colloidal propellers that can be navigated in water with micrometer-level precision using homogeneous magnetic fields. The propellers are made via nanostructured surfaces and can be produced in large numbers. The nanopropellers can carry chemicals, push loads, and act as local probes in rheological measurements.

Responsive copolymer–graphene oxide hybrid microspheres with enhanced drug release properties

DOE PAGES

Dong, Fuping; Firkowska-Boden, Izabela; Arras, Matthias M. L.; ...

2017-01-13

Here, the ability to integrate both high encapsulation efficiency and controlled release in a drug delivery system (DDS) is a highly sought solution to cure major diseases. However, creation of such a system is challenging. This study was aimed at constructing a new delivery system based on thermoresponsive poly(N-isopropylacrylamide-co-styrene) (PNIPAAm-co-PS) hollow microspheres prepared via two-step precipitation polymerization. To control the diffusion-driven drug release, the PNIPAAm-co-PS spheres were electrostatically coated with graphene oxide (GO) nanosheets. As a result of the coating the permeability of such copolymer-GO hybrid microspheres was reduced to the extent that suppressed the initial burst release and enabledmore » sustained drug release in in vitro testing. The hybrid microspheres showed improved drug encapsulation by 46.4% which was attributed to the diffusion barrier properties and -conjugated structure of GO. The system presented here is promising to advance, e.g., the anticancer drug delivery technologies by enabling sustained drug release and thus minimizing local and systemic side effects.« less

Responsive copolymer–graphene oxide hybrid microspheres with enhanced drug release properties

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

Dong, Fuping; Firkowska-Boden, Izabela; Arras, Matthias M. L.

Here, the ability to integrate both high encapsulation efficiency and controlled release in a drug delivery system (DDS) is a highly sought solution to cure major diseases. However, creation of such a system is challenging. This study was aimed at constructing a new delivery system based on thermoresponsive poly(N-isopropylacrylamide-co-styrene) (PNIPAAm-co-PS) hollow microspheres prepared via two-step precipitation polymerization. To control the diffusion-driven drug release, the PNIPAAm-co-PS spheres were electrostatically coated with graphene oxide (GO) nanosheets. As a result of the coating the permeability of such copolymer-GO hybrid microspheres was reduced to the extent that suppressed the initial burst release and enabledmore » sustained drug release in in vitro testing. The hybrid microspheres showed improved drug encapsulation by 46.4% which was attributed to the diffusion barrier properties and -conjugated structure of GO. The system presented here is promising to advance, e.g., the anticancer drug delivery technologies by enabling sustained drug release and thus minimizing local and systemic side effects.« less

Watchdog Project

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

Smith, Rhett; Campbell, Jack; Hadley, Mark

The Watchdog Project completed 100% of the project Statement of Project Objective (SOPO). The Watchdog project was a very aggressive project looking to accomplish commercialization of technology that had never been commercialized, as a result it took six years to complete not the original three that were planned. No additional federal funds were requested from the original proposal and SEL contributed the additional cost share required to complete the project. The result of the Watchdog Project is the world’s first industrial rated Software Defined Network (SDN) switch commercially available. This technology achieved the SOPOO and DOE Roadmap goals to havemore » strong network access control, improve reliability and network performance, and give the asset owner the ability to minimize attack surface before and during an attack. The Watchdog project is an alliance between CenterPoint Energy Houston Electric, Pacific Northwest National Laboratories (PNNL), and Schweitzer Engineering Laboratories, Inc. (SEL). SEL is the world’s leader in microprocessor-based electronic equipment for protecting electric power systems. PNNL performs basic and applied research to deliver energy, environmental, and national security for our nation. CenterPoint Energy is the third largest publicly traded natural gas delivery company in the U.S and third largest combined electricity and natural gas delivery company. The Watchdog Project efforts were combined with the SDN Project efforts to produce the entire SDN system solution for the critical infrastructure. The Watchdog project addresses Topic Area of Interest 5: Secure Communications, for the DEFOA- 0000359 by protecting the control system local area network itself and the communications coming from and going to the electronic devices on the local network. Local area networks usually are not routed and have little or no filtering capabilities. Combine this with the fact control system protocols are designed with inherent trust the control system owners have very little choice on how to protect communications on the local network. The Watchdog project reduces security risks in electric sector control system local area networks (LANs) by providing: Network access control (NAC) Multi-Layer firewall (physical through transport layer) Containment of malware or unauthorized traffic spreading across the network White list protocols and application message types filtering Configurable, proactive traffic engineering The Watchdog project achieved all of the above by developing an SDN switch.« less

WE-FG-BRA-02: Docetaxel Eluting Brachytherapy Spacers for Local Chemo-Radiation Therapy in Prostate Cancer

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

Belz, J; Kumar, R; Sridhar, S

Purpose: We propose an innovative combinatorial treatment strategy of Local ChemoRadiation Therapy (LCRT) using a sustained drug delivery platform in the form of a spacer to locally radio-sensitize the prostate with Docetaxel (DTX) enabling a synergistic cure with the use of lower radiation doses. These biodegradable spacers are physically similar to the inert spacers routinely used in prostate brachytherapy but are now loaded with formulations of DTX. Methods: Spacers were loaded with ∼500µg Docetaxel (DTX) for prostate cancer studies. The implants were characterized in vitro using SEM and HPLC. The release kinetic studies were carried out in buffer (pH 6.0)more » at 37°C. Subcutaneous PC3 tumors were xenografted in nude mice. Prostate cancer studies were done with and without radiation using SARRP at 5Gy, 10Gy, and 15Gy. Drug-loaded implants were injected once intratumorally using an 18G brachytherapy needle. Results: The release study in vitro showed a highly sustained release for multiple weeks at therapeutically relevant doses. The monotherapy with local DTX spacer showed sustained tumor inhibition compared to empty implants and an equivalent DTX dose given systemically. At 40 days, 89% survival was observed for mice treated with DTX implants compared with 0% in all other treatment groups. The combined treatment with local DTX spacer and radiation (10Gy) showed the highest degree of tumor suppression (significant tumor growth inhibition by day 90). The control mice showed continuous tumor growth and were scarified by day 56. Groups of mice treated with DTX-spacer or radiation alone showed initial tumor suppression but growth continued after day 60. A larger experiment is ongoing. Conclusion: This approach provides localized delivery of the chemotherapeutic sensitizer directly to the tumor and avoids the toxicities associated with both brachytherapy and current systemic delivery of docetaxel. Sustained release of DTX is an effective chemotherapy option alone or in combination with radiation therapy.« less

A novel gene delivery composite system based on biodegradable folate-poly (ester amine) polymer and thermosensitive hydrogel for sustained gene release

PubMed Central

Yang, Yi; Zhao, Hang; Jia, YanPeng; Guo, QingFa; Qu, Ying; Su, Jing; Lu, XiaoLing; Zhao, YongXiang; Qian, ZhiYong

2016-01-01

Local anti-oncogene delivery providing high local concentration of gene, increasing antitumor effect and decreasing systemic side effects is currently attracting interest in cancer therapy. In this paper, a novel local sustained anti-oncogene delivery system, PECE thermoresponsive hydrogel containing folate-poly (ester amine) (FA-PEA) polymer/DNA (tumor suppressor) complexes, is demonstrated. First, a tumor-targeted biodegradable folate-poly (ester amine) (FA-PEA) polymer based on low-molecular-weight polyethyleneimine (PEI) was synthesized and characterized, and the application for targeted gene delivery was investigated. The polymer had slight cytotoxicity and high transfection efficiency in vitro compared with PEI 25k, which indicated that FA-PEA was a potential vector for targeted gene delivery. Meanwhile, we successfully prepared a thermoresponsive PECE hydrogel composite containing FA-PEA/DNA complexes which could contain the genes and slowly release the genes into cells. We concluded the folate-poly (ester amine) (FA-PEA) polymer would be useful for targeted gene delivery, and the novel gene delivery composite based on biodegradable folate-poly (ester amine) polymer and thermosensitive PECE hydrogel showed potential for sustained gene release. PMID:26883682

Systematizing the Delivery of Local Employment and Training Services. The Job Center Technical Assistance Guide.

ERIC Educational Resources Information Center

Wisconsin State Dept. of Industry, Labor and Human Relations, Madison.

This technical assistance guide was developed to consolidate a statewide understanding of the effort to systematize the delivery of employment and training programs through the local formation of job centers in Wisconsin, and to provide a compilation, drawn from 20 local models, that explains how the programs are delivered. The guide is organized…

Controlled power delivery for super-resolution imaging of biological samples using digital micromirror device

NASA Astrophysics Data System (ADS)

Valiya Peedikakkal, Liyana; Cadby, Ashley

2017-02-01

Localization based super resolution images of a biological sample is generally achieved by using high power laser illumination with long exposure time which unfortunately increases photo-toxicity of a sample, making super resolution microscopy, in general, incompatible with live cell imaging. Furthermore, the limitation of photobleaching reduces the ability to acquire time lapse images of live biological cells using fluorescence microscopy. Digital Light Processing (DLP) technology can deliver light at grey scale levels by flickering digital micromirrors at around 290 Hz enabling highly controlled power delivery to samples. In this work, Digital Micromirror Device (DMD) is implemented in an inverse Schiefspiegler telescope setup to control the power and pattern of illumination for super resolution microscopy. We can achieve spatial and temporal patterning of illumination by controlling the DMD pixel by pixel. The DMD allows us to control the power and spatial extent of the laser illumination. We have used this to show that we can reduce the power delivered to the sample to allow for longer time imaging in one area while achieving sub-diffraction STORM imaging in another using higher power densities.

Transdermal Drug Delivery: Opportunities and Challenges for Controlled Delivery of Therapeutic Agents Using Nanocarriers.

PubMed

Kurmi, Balak Das; Tekchandani, Pawan; Paliwal, Rishi; Paliwal, Shivani Rai

2017-01-01

Transdermal drug delivery represents an extremely attractive and innovative route across the skin owing to the possibility for achieving systemic effect of drugs. The present scenario demands a special focus on developing safe medicine with minimized toxic adverse effects related to most of the pharmacologically active agents. Transdermal drug delivery would be a focal paradigm which provides patient convenience, first-pass hepatic metabolism avoidance, local targeting and reduction in toxic effect related to various categories of drugs like, analgesics, antiinflammatory, antibiotics, antiviral, anaesthetic, anticancer etc. Even this route has challenges due to highly organized structure of skin which acts as a main barrier to penetration of drug via the skin. Several alternative possible strategies are available which overcome these barriers, including use of penetration enhancer, eletroporation, iontophoresis and various nanotechnologically developed nanocarrier systems. The latest one includes employing liposome, dendrimers, nanoparticles, ethosome, carbon nanotube and many more to avoid associated limitations of conventional formulations. Numerous transdermal products such as Estrasorb, Diractin, VivaGel®, Daytrana®, Aczone, Sileryst® are available in the market having a novel strategy to achieve higher penetration of drugs. This encourages formulation fraternity to develop structurally deformable and stable nanocarriers as an alternative approach for controlled and reliable drug delivery across the skin barrier. In this review, we will discuss nanocarriers mediated approaches that come-up with the solutions to the different challenges towards transdermal drug delivery, its clinical importance and latest insight to research in it. The reports presented in this review confirm the wide application of nanocarriers for transdermal delivery of drug/gene. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Controlled Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Closure with Decreased Scar Formation.

PubMed

Ma, Kun; Kwon, Sun Hyung; Padmanabhan, Jagannath; Duscher, Dominik; Trotsyuk, Artem A; Dong, Yixiao; Inayathullah, Mohammed; Rajadas, Jayakumar; Gurtner, Geoffrey C

2018-05-15

Formation of scars following wounding or trauma represents a significant healthcare burden costing the economy billions of dollars every year. Activation of focal adhesion kinase (FAK) has been shown to play a pivotal role in transducing mechanical signals to elicit fibrotic responses and scar formation during wound repair. We have previously shown that inhibition of FAK using local injections of a small molecule FAK inhibitor (FAKI) can attenuate scar development in a hypertrophic scar model. Clinical translation of FAKI therapy has been challenging, however, due to the lack of an effective drug delivery system for extensive burn injuries, blast injuries, and large excisional injuries. To address this issue, we have developed a pullulan collagen-based hydrogel to deliver FAKI to excisional and burn wounds in mice. Specifically, two distinct drug-laden hydrogels were developed for rapid or sustained release of FAKI for treatment of burn wounds and excisional wounds, respectively. Controlled delivery of FAKI via pullulan collagen hydrogels accelerated wound healing, reduced collagen deposition and activation of scar forming myofibroblasts in both wound healing models. Our study highlights a biomaterial-based drug delivery approach for wound and scar management that has significant translational implications. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Localised drug release using MRI-controlled focused ultrasound hyperthermia.

PubMed

Staruch, Robert; Chopra, Rajiv; Hynynen, Kullervo

2011-01-01

Thermosensitive liposomes provide a mechanism for triggering the local release of anticancer drugs, but this technology requires precise temperature control in targeted regions with minimal heating of surrounding tissue. The objective of this study was to evaluate the feasibility of using MRI-controlled focused ultrasound (FUS) and thermosensitive liposomes to achieve thermally mediated localised drug delivery in vivo. Results are reported from ten rabbits, where a FUS beam was scanned in a circular trajectory to heat 10-15 mm diameter regions in normal thigh to 43°C for 20-30 min. MRI thermometry was used for closed-loop feedback control to achieve temporally and spatially uniform heating. Lyso-thermosensitive liposomal doxorubicin was infused intravenously during hyperthermia. Unabsorbed liposomes were flushed from the vasculature by saline perfusion 2 h later, and tissue samples were harvested from heated and unheated thigh regions. The fluorescence intensity of the homogenised samples was used to calculate the concentration of doxorubicin in tissue. Closed-loop control of FUS heating using MRI thermometry achieved temperature distributions with mean, T90 and T10 of 42.9°C, 41.0°C and 44.8°C, respectively, over a period of 20 min. Doxorubicin concentrations were significantly higher in tissues sampled from heated than unheated regions of normal thigh muscle (8.3 versus 0.5 ng/mg, mean per-animal difference = 7.8 ng/mg, P < 0.05, Wilcoxon matched pairs signed rank test). The results show the potential of MRI-controlled focused ultrasound hyperthermia for enhanced local drug delivery with temperature-sensitive drug carriers.

Intracoronary and retrograde coronary venous myocardial delivery of adipose-derived stem cells in swine infarction lead to transient myocardial trapping with predominant pulmonary redistribution.

PubMed

Hong, Soon Jun; Hou, Dongming; Brinton, Todd J; Johnstone, Brian; Feng, Dongni; Rogers, Pamela; Fearon, William F; Yock, Paul; March, Keith L

2014-01-01

To examine the comparative fate of adipose-derived stem cells (ASCs) as well as their impact on coronary microcirculation following either retrograde coronary venous (RCV) or arterial delivery. Local delivery of ASCs to the heart has been proposed as a practical approach to limiting the extent of myocardial infarction. Mouse models of mesenchymal stem cell effects on the heart have also demonstrated significant benefits from systemic (intravenous) delivery, prompting a question about the advantage of local delivery. There has been no study addressing the extent of myocardial vs. systemic disposition of ASCs in large animal models following local delivery to the myocardium. In an initial experiment, dose-dependent effects of ASC delivery on coronary circulation in normal swine were evaluated to establish a tolerable ASC dosing range for intracoronary (IC) delivery. In a set of subsequent experiments, an anterior acute myocardial infarction (AMI) was created by balloon occlusion of the proximal left anterior descending (LAD) artery, followed by either IC or RCV infusion of 10(7) (111)Indium-labeled autologous ASCs 6 days following AMI. Indices of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured before sacrifices to collect tissues for analysis at 1 or 24 hr after cell delivery. IC delivery of porcine ASCs to normal myocardium was well tolerated up to a cumulative dose of 14 × 10(6) cells (approximately 0.5 × 10(6) cells/kg). There was evidence suggesting microcirculatory trapping of ASC: at unit doses of 50 × 10(6) ASCs, IMR and CFR were found to be persistently altered in the target LAD distribution at 7 days following delivery, whereas at 10 × 10(6) ASCs, only CFR was altered. In the context of recent MI, a significantly higher percentage of ASCs was retained at 1 hr with IC delivery compared with RCV delivery (57.2 ± 12.7% vs. 17.9 ± 1.6%, P = 0.037) but this initial difference was not apparent at 24 hr (22.6 ± 5.5% vs. 18.7 ± 8.6%; P = 0.722). In both approaches, most ASC redistributed to the pulmonary circulation by 24 hr postdelivery. There were no significant differences in CFR or IMR following ASC delivery to infarcted tissue by either route. Selective intravascular delivery of ASC by coronary arterial and venous routes leads to similarly limited myocardial cell retention with predominant redistribution of cells to the lungs. IC arterial delivery of ASC leads to only transiently greater myocardial retention, which is accompanied by obstruction of normal regions of coronary microcirculation at higher doses. The predominant intrapulmonary localization of cells following local delivery via both methods prompts the notion that systemic delivery of ASC might provide similarly beneficial outcomes while avoiding risks of inadvertent microcirculatory compromise. Copyright © 2012 Wiley Periodicals, Inc.

Learning effect of a conditional cash transfer programme on poor rural women's selection of delivery care in Mexico.

PubMed

Sosa-Rubí, Sandra G; Walker, Dilys; Serván, Edson; Bautista-Arredondo, Sergio

2011-11-01

BACKGROUND The Mexican programme Oportunidades/Progresa conditionally transfers money to beneficiary families. Over the past 10 years, poor rural women have been obliged to attend antenatal care (ANC) visits and reproductive health talks. We propose that the length of time in the programme influences women's preferences, thus increasing their use not only of services directly linked to the cash transfers, but also of other services, such as clinic-based delivery, whose utilization is not obligatory. OBJECTIVE To analyse the long-term effect of Oportunidades on women's use of antenatal and delivery care. METHODOLOGY 5051 women aged between 15 and 49 years old with at least one child aged less than 24 months living in rural localities were analysed. Multilevel probit and logit models were used to analyse ANC visits and physician/nurse attended delivery, respectively. Models were adjusted with individual and socio-economic variables and the locality's exposure time to Oportunidades. Findings On average women living in localities with longer exposure to Oportunidades report 2.1% more ANC visits than women living in localities with less exposure. Young women aged 15-19 and 20-24 years and living in localities with longer exposure to Oportunidades (since 1998) have 88% and 41% greater likelihood of choosing a physician/nurse vs. traditional midwife for childbirth, respectively. Women of indigenous origin are 68.9% less likely to choose a physician/nurse for delivery care than non-indigenous women. CONCLUSIONS An increase in the average number of ANC visits has been achieved among Oportunidades beneficiaries. An indirect effect is the increased selection of a physician/nurse for delivery care among young women living in localities with greater exposure time to Oportunidades. Disadvantaged women in Mexico (indigenous women) continue to have less access to skilled delivery care. Developing countries must develop strategies to increase access and use of skilled obstetric care for marginalized women.

Boron nitride nanotubes as vehicles for intracellular delivery of fluorescent drugs and probes.

PubMed

Niskanen, Jukka; Zhang, Issan; Xue, Yanming; Golberg, Dmitri; Maysinger, Dusica; Winnik, Françoise M

2016-01-01

To evaluate the response of cells to boron nitride nanotubes (BNNTs) carrying fluorescent probes or drugs in their inner channel by assessment of the cellular localization of the fluorescent cargo, evaluation of the in vitro release and biological activity of a drug (curcumin) loaded in BNNTs. Cells treated with curcumin-loaded BNNTs and stimulated with lipopolysaccharide were assessed for nitric oxide release and stimulation of IL-6 and TNF-α. The cellular trafficking of two cell-permeant dyes and a non-cell-permeant dye loaded within BNNTs was imaged. BNNTs loaded with up to 13 wt% fluorophores were internalized by cells and controlled release of curcumin triggered cellular pathways associated with the known anti-inflammatory effects of the drug. The overall findings indicate that BNNTs can function as nanocarriers of biologically relevant probes/drugs allowing one to examine/control their local intracellular localization and biochemical effects, leading the way to applications as intracellular nanosensors.

Formulation to target delivery to the ciliary body and choroid via the suprachoroidal space of the eye using microneedles.

PubMed

Kim, Yoo Chun; Oh, Kyung Hee; Edelhauser, Henry F; Prausnitz, Mark R

2015-09-01

In this work, we tested the hypothesis that particles injected into the suprachoroidal space can be localized at the site of injection or broadly distributed throughout the suprachoroidal space by controlling polymeric formulation properties. Single hollow microneedles were inserted into the sclera of New Zealand White rabbits and injected non-biodegradable fluorescently tagged nanoparticles and microparticles suspended in polymeric formulations into the suprachoroidal space of the eye. When formulated in saline, the particles were distributed over 29-42% of the suprachoroidal space immediately after injection. To spread particles over larger areas of the choroidal surface, addition of hyaluronic acid to make moderately non-Newtonian solutions increased particle spread to up to 100% of the suprachoroidal space. To localize particles at the site of injection adjacent to the ciliary body, strongly non-Newtonian polymer solutions localized particles to 8.3-20% of the suprachoroidal space, which exhibited a small increase in area over the course of two months. This study demonstrates targeted particle delivery within the suprachoroidal space using polymer formulations that spread particles over the whole choroidal surface or localized them adjacent to the ciliary body after injection. Copyright © 2015 Elsevier B.V. All rights reserved.

In vivo blockade of acetylcholinesterase increases intraovarian acetylcholine and enhances follicular development and fertility in the rat.

PubMed

Urra, Javier; Blohberger, Jan; Tiszavari, Michelle; Mayerhofer, Artur; Lara, Hernan E

2016-07-21

Growth and differentiation of ovarian follicles are regulated by systemic and local factors, which may include acetylcholine (ACh). Granulosa cells (GCs) of growing follicles and luteal cells produce ACh and in cultured GCs it exerts trophic actions via muscarinic receptors. However, such actions were not studied in vivo. After having established that rat ovarian GCs and luteal cells express the ACh-metabolizing enzyme ACh esterase (AChE), we examined the consequences of local application of an AChE inhibitor, huperzine A (HupA), by osmotic minipump delivery into the ovarian bursa of hemiovariectomized rats. Saline was used in the control group. Local delivery of HupA for 4 weeks increased ovarian ACh content. Estrus cyclicity was not changed indicating a locally restricted range of HupA action. The number of primordial and primary follicles was unaffected, but small secondary follicles significantly increased in the HupA group. Furthermore, a significant increase in the number of corpora lutea suggested increased ovulatory events. In support, as shown upon mating, HupA-treated females had significantly increased implantation sites and more pups. Thus the data are in support of a trophic role of ACh in follicular development and ovulation and point to an important role of ACh in female fertility.

In vivo blockade of acetylcholinesterase increases intraovarian acetylcholine and enhances follicular development and fertility in the rat

PubMed Central

Blohberger, Jan; Tiszavari, Michelle; Mayerhofer, Artur; Lara, Hernan E.

2016-01-01

Growth and differentiation of ovarian follicles are regulated by systemic and local factors, which may include acetylcholine (ACh). Granulosa cells (GCs) of growing follicles and luteal cells produce ACh and in cultured GCs it exerts trophic actions via muscarinic receptors. However, such actions were not studied in vivo. After having established that rat ovarian GCs and luteal cells express the ACh-metabolizing enzyme ACh esterase (AChE), we examined the consequences of local application of an AChE inhibitor, huperzine A (HupA), by osmotic minipump delivery into the ovarian bursa of hemiovariectomized rats. Saline was used in the control group. Local delivery of HupA for 4 weeks increased ovarian ACh content. Estrus cyclicity was not changed indicating a locally restricted range of HupA action. The number of primordial and primary follicles was unaffected, but small secondary follicles significantly increased in the HupA group. Furthermore, a significant increase in the number of corpora lutea suggested increased ovulatory events. In support, as shown upon mating, HupA-treated females had significantly increased implantation sites and more pups. Thus the data are in support of a trophic role of ACh in follicular development and ovulation and point to an important role of ACh in female fertility. PMID:27440195

Development and Characterization of Liquid Crystal-Gold Nanoparticle Hybrid Materials for Optical Applications

NASA Astrophysics Data System (ADS)

Quint, Makiko T.

Hybrid material, mixtures of two or more materials with new properties, represents an exciting class of new materials for a variety of potential applications such as displays, optoelectronics, and sensors due to their unique physical and optical properties. The scope of this dissertation is to produce two new plasmonic applications by combining liquid crystals with gold nanoparticles. The first application is gold nanoparticle coated liquid crystal thin film. Most liquid crystal (LC) thin films require external voltage to reorient LC molecules. Recent advances in optical controlling technology of LC molecule behavior, resulting in the reduction of energy consumption, have stimulated research and development of new LC thin films. In order to re-orient LC molecules by just using light, the common approach is to include either a photo-responsive LC host, one that require high power light and severely narrows the range of usable materials, or add photo-active dye or polymer layer, photodegradation over time. Our work designing an all-optical method for LC re-orientation that overcomes all the limitations mentioned above. We have successfully both in- and out-of-plane spatial orientation of nematic liquid crystal (LC) molecules by leveraging the highly localized electric fields produced in the near-field regime of a gold nanoparticle (AuNP) layer. This re-orientation of LC molecules in thin LC-AuNP film is all-optical, driven by a small resonance excitation power with the localized surface plasmon absorption of the AuNPs at room temperature. The second application is LC mediated nano-assembled gold microcapsules. This application has a potential in controlled-release cargo-style delivery system. Targeted delivery systems with controlled release mechanisms have been the subject of extensive research more than fifty years. One is to control the release process remotely by using optical excitation. Optical actuation of delivery capsules, which plasmonic nanoparticle such as gold, allows rapid release at specific locations and uses the photothermal effect to unload contents. Almost all gold-based delivery applications including Au coated nanocrystals or AuNPs with soft materials like gels and polymers are not suitable for control release applications in real life since these applications do not provide robust leakage-free containment lower than the American National Standards Institute (ANSI) maximum permissible light exposure limit. We have successfully managed the difficulties mentioned above and produced a new gold-based delivery application. The application is spherical capsules with a densely packed wall of AuNPs. The rigid capsule wall allows encapsulation of cargo that can be contained, virtually leakage-free, over several months. Further, by leveraging LSPR of AuNPs, we can rupture the microshells using optical excitation with ultralow power (< 2 mW), controllably and rapidly releasing the encapsulated contents in less than 5 seconds. Our results exhibiting the capture and optically regulated release of encapsulated substances are a novel platform that combines controlled-release cargo-style delivery and photothermal therapy in one versatile and multifunctional unit. Both our applications are overcoming current limitations and promising future research directions towards the next generation of LC-AuNPs hybrid material research and developments.

Drug delivery with microsecond laser pulses into gelatin

NASA Astrophysics Data System (ADS)

Shangguan, Hanqun; Casperson, Lee W.; Shearin, Alan; Gregory, Kenton W.; Prahl, Scott A.

1996-07-01

Photoacoustic drug delivery is a technique for localized drug delivery by laser-induced hydrodynamic pressure following cavitation bubble expansion and collapse. Photoacoustic drug delivery was investigated on gelatin-based thrombus models with planar and cylindrical geometries by use of one microsecond laser pulses. Solutions of a hydrophobic dye in mineral oil permitted monitoring of delivered colored oil into clear gelatin-based thrombus models. Cavitation bubble development and photoacoustic drug delivery were visualized with flash photography. This study demonstrated that cavitation is the governing mechanism for photoacoustic drug delivery, and the deepest penetration of colored oil in gels followed the bubble collapse. Spatial distribution measurements revealed that colored oil could be driven a few millimeters into the gels in both axial and radial directions, and the penetration was less than 500 mu m when the gelatin structure was not fractured. localized drug delivery, cavitation bubble, laser thrombolysis.

Biomaterials and Magnetic fields for Cancer Therapy

NASA Technical Reports Server (NTRS)

Ramachandran, Narayanan; Mazuruk, Konstanty

2003-01-01

The field of biomaterials has emerged as an important topic in the purview of NASA s new vision of research activities in the Microgravity Research Division. Although this area has an extensive track record in the medical field as borne out by the routine use of polymeric sutures, implant devices, and prosthetics, novel applications such as tissue engineering, artificial heart valves and controlled drug delivery are beginning to be developed. Besides the medical field, biomaterials and bio-inspired technologies are finding use in a host of emerging interdisciplinary fields such as self-healing and self-assembling structures, biosensors, fuel systems etc. The field of magnetic fluid technology has several potential applications in medicine. One of the emerging fields is the area of controlled drug delivery, which has seen its evolution from the basic oral delivery system to pulmonary to transdermal to direct inoculations. In cancer treatment by chemotherapy for example, targeted and controlled drug delivery has received vast scrutiny and substantial research and development effort, due to the high potency of the drugs involved and the resulting requirement to keep the exposure of the drugs to surrounding healthy tissue to a minimum. The use of magnetic particles in conjunction with a static magnetic field allows smart targeting and retention of the particles at a desired site within the body with the material transport provided by blood perfusion. Once so located, the therapeutical aspect (radiation, chemotherapy, hyperthermia, etc.) of the treatment, now highly localized, can be implemented.

Delivery of doxorubicin and paclitaxel from double-layered microparticles: The effects of layer thickness and dual-drug vs. single-drug loading.

PubMed

Lee, Wei Li; Guo, Wei Mei; Ho, Vincent H B; Saha, Amitaksha; Chong, Han Chung; Tan, Nguan Soon; Tan, Ern Yu; Loo, Say Chye Joachim

2015-11-01

Double-layered microparticles composed of poly(d,l-lactic-co-glycolic acid, 50:50) (PLGA) and poly(l-lactic acid) (PLLA) were loaded with doxorubicin HCl (DOX) and paclitaxel (PCTX) through a solvent evaporation technique. DOX was localized in the PLGA shell, while PCTX was localized in the PLLA core. The aim of this study was to investigate how altering layer thickness of dual-drug, double-layered microparticles can influence drug release kinetics and their antitumor capabilities, and against single-drug microparticles. PCTX-loaded double-layered microparticles with denser shells retarded the initial release of PCTX, as compared with dual-drug-loaded microparticles. The DOX release from both DOX-loaded and dual-drug-loaded microparticles were observed to be similar with an initial burst. Through specific tailoring of layer thicknesses, a suppressed initial burst of DOX and a sustained co-delivery of two drugs can be achieved over 2months. Viability studies using spheroids of MCF-7 cells showed that controlled co-delivery of PCTX and DOX from dual-drug-loaded double-layered microparticles were better in reducing spheroid growth rate. This study provides mechanistic insights into how by tuning the layer thickness of double-layered microparticles the release kinetics of two drugs can be controlled, and how co-delivery can potentially achieve better anticancer effects. While the release of multiple drugs has been reported to achieve successful apoptosis and minimize drug resistance, most conventional particulate systems can only deliver a single drug at a time. Recently, although a number of formulations (e.g. micellar nanoparticles, liposomes) have been successful in delivering two or more anticancer agents, sustained co-delivery of these agents remains inadequate due to the complex agent loading processes and rapid release of hydrophilic agents. Therefore, the present work reports the multilayered particulate system that simultaneously hosts different drugs, while being able to tune their individual release over months. We believe that our findings would be of interest to the readers of Acta Biomaterialia because the proposed system could open a new avenue on how two drugs can be released, through rate-controlling carriers, for combination chemotherapy. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Liposomal 64Cu-PET Imaging of Anti-VEGF Drug Effects on Liposomal Delivery to Colon Cancer Xenografts.

PubMed

Blocker, Stephanie J; Douglas, Kirk A; Polin, Lisa Anne; Lee, Helen; Hendriks, Bart S; Lalo, Enxhi; Chen, Wei; Shields, Anthony F

2017-01-01

Liposomes (LP) deliver drug to tumors due to enhanced permeability and retention (EPR). LP were labeled with 64 Cu for positron emission tomography (PET) to image tumor localization. Bevacizumab (bev), a VEGF targeted antibody, may modify LP delivery by altering tumor EPR and this change can also be imaged. Objective : Assess the utility of 64 Cu-labeled LP for PET in measuring altered LP delivery early after treatment with bev. Methods: HT-29 human colorectal adenocarcinoma tumors were grown subcutaneously in SCID mice. Empty LP MM-DX-929 (Merrimack Pharmaceuticals, Inc. Cambridge, MA) were labeled with 64 CuCl 2 chelated with 4-DEAP-ATSC. Tumor-bearing mice received ~200-300 μCi of 64 Cu-MM-DX-929 and imaged with microPET. All mice were scanned before and after the treatment period, in which half of the mice received bev for one week. Scans were compared for changes in LP accumulation during this time. Initially, tissues were collected after the second PET for biodistribution measurements and histological analysis. Subsequent groups were divided for further treatment. Tumor growth following bev treatment, with or without LP-I, was assessed compared to untreated controls. Results : PET scans of untreated mice showed increased uptake of 64 Cu-MM-DX-929, with a mean change in tumor SUV max of 43.9%±6.6% (n=10) after 7 days. Conversely, images of treated mice showed that liposome delivery did not increase, with changes in SUV max of 7.6%±4.8% (n=12). Changes in tumor SUV max were significantly different between both groups (p=0.0003). Histology of tumor tissues indicated that short-term bev was able to alter vessel size. Therapeutically, while bev monotherapy, LP-I monotherapy, and treatment with bev followed by LP-I all slowed HT-29 tumor growth compared to controls, combination provided no therapeutic benefit. Conclusions: PET with tracer LP 64 Cu-MM-DX-929 can detect significant differences in LP delivery to colon tumors treated with bev when compared to untreated controls. Imaging with 64 Cu-MM-DX-929 is sensitive enough to measure drug-induced changes in LP localization which can have an effect on outcomes of treatment with LP.

Site-specific gene delivery to stented arteries using magnetically guided zinc oleate-based nanoparticles loaded with adenoviral vectors

PubMed Central

Chorny, Michael; Fishbein, Ilia; Tengood, Jillian E.; Adamo, Richard F.; Alferiev, Ivan S.; Levy, Robert J.

2013-01-01

Gene therapeutic strategies have shown promise in treating vascular disease. However, their translation into clinical use requires pharmaceutical carriers enabling effective, site-specific delivery as well as providing sustained transgene expression in blood vessels. While replication-deficient adenovirus (Ad) offers several important advantages as a vector for vascular gene therapy, its clinical applicability is limited by rapid inactivation, suboptimal transduction efficiency in vascular cells, and serious systemic adverse effects. We hypothesized that novel zinc oleate-based magnetic nanoparticles (MNPs) loaded with Ad would enable effective arterial cell transduction by shifting vector processing to an alternative pathway, protect Ad from inactivation by neutralizing factors, and allow site-specific gene transfer to arteries treated with stent angioplasty using a 2-source magnetic guidance strategy. Ad-loaded MNPs effectively transduced cultured endothelial and smooth muscle cells under magnetic conditions compared to controls and retained capacity for gene transfer after exposure to neutralizing antibodies and lithium iodide, a lytic agent causing disruption of free Ad. Localized arterial gene expression significantly stronger than in control animal groups was demonstrated after magnetically guided MNP delivery in a rat stenting model 2 and 9 d post-treatment, confirming feasibility of using Ad-loaded MNPs to achieve site-specific transduction in stented blood vessels. In conclusion, Ad-loaded MNPs formed by controlled precipitation of zinc oleate represent a novel delivery system, well-suited for efficient, magnetically targeted vascular gene transfer.—Chorny, M., Fishbein, I., Tengood, J. E., Adamo, R. F., Alferiev, I. S., Levy, R. J. Site-specific gene delivery to stented arteries using magnetically guided zinc oleate-based nanoparticles loaded with adenoviral vectors. PMID:23407712

Nanodrug delivery systems in dentistry: a review on current status and future perspectives.

PubMed

Renugalakshmi, Apathsakayan; Vinothkumar, Thilla Sekar; Kandaswamy, Deivanayagam

2011-09-01

The present review provides an insight into various potential areas of dentistry that are being invaded by nanotechnology based drugs and drug delivery systems. Current treatments for diseases of dental and oral structures rely on the use of classical pharmacological agents which, in some cases are limited by low efficacy and lack of selectivity to target cells. However, various nanostructures in drug delivery and their challenges in the field of dentistry have not been reviewed so far in the literature. The different treatment opportunities of importance include caries control restorations, tooth remineralisation, management of dentinal hypersensitivity, dental caries vaccine, management of oral biofilm, root canal disinfection, local anaesthesia and periodontal infection. The authors have also identified few dental applications demanding extensive research to emerge as a promising therapeutic strategy. We conclude by claiming that dentistry should follow the trend of probing matter at nanoscale to achieve a predictable treatment outcome.

On the dynamics of StemBells: Microbubble-conjugated stem cells for ultrasound-controlled delivery

NASA Astrophysics Data System (ADS)

Kokhuis, Tom J. A.; Naaijkens, Benno A.; Juffermans, Lynda J. M.; Kamp, Otto; van der Steen, Antonius F. W.; Versluis, Michel; de Jong, Nico

2017-07-01

The use of stem cells for regenerative tissue repair is promising but hampered by the low number of cells delivered to the site of injury. To increase the delivery, we propose a technique in which stem cells are linked to functionalized microbubbles, creating echogenic complex dubbed StemBells. StemBells are highly susceptible to acoustic radiation force which can be employed after injection to push the StemBells locally to the treatment site. To optimally benefit from the delivery technique, a thorough characterization of the dynamics of StemBells during ultrasound exposure is needed. Using high-speed optical imaging, we study the dynamics of StemBells as a function of the applied frequency from which resonance curves were constructed. A theoretical model, based on a modified Rayleigh-Plesset type equation, captured the experimental resonance characteristics and radial dynamics in detail.

Controlled Bioactive Molecules Delivery Strategies for Tendon and Ligament Tissue Engineering using Polymeric Nanofibers.

PubMed

Hiong Teh, Thomas Kok; Hong Goh, James Cho; Toh, Siew Lok

2015-01-01

The interest in polymeric nanofibers has escalated over the past decade given its promise as tissue engineering scaffolds that can mimic the nanoscale structure of the native extracellular matrix. With functionalization of the polymeric nanofibers using bioactive molecules, localized signaling moieties can be established for the attached cells, to stimulate desired biological effects and direct cellular or tissue response. The inherently high surface area per unit mass of polymeric nanofibers can enhance cell adhesion, bioactive molecules loading and release efficiencies, and mass transfer properties. In this review article, the application of polymeric nanofibers for controlled bioactive molecules delivery will be discussed, with a focus on tendon and ligament tissue engineering. Various polymeric materials of different mechanical and degradation properties will be presented along with the nanofiber fabrication techniques explored. The bioactive molecules of interest for tendon and ligament tissue engineering, including growth factors and small molecules, will also be reviewed and compared in terms of their nanofiber incorporation strategies and release profiles. This article will also highlight and compare various innovative strategies to control the release of bioactive molecules spatiotemporally and explore an emerging tissue engineering strategy involving controlled multiple bioactive molecules sequential release. Finally, the review article concludes with challenges and future trends in the innovation and development of bioactive molecules delivery using polymeric nanofibers for tendon and ligament tissue engineering.

Enzyme-Controlled Nanodevice for Acetylcholine-Triggered Cargo Delivery Based on Janus Au-Mesoporous Silica Nanoparticles.

PubMed

Llopis-Lorente, Antoni; Díez, Paula; de la Torre, Cristina; Sánchez, Alfredo; Sancenón, Félix; Aznar, Elena; Marcos, María D; Martínez-Ruíz, Paloma; Martínez-Máñez, Ramón; Villalonga, Reynaldo

2017-03-28

This work reports a new gated nanodevice for acetylcholine-triggered cargo delivery. We prepared and characterized Janus Au-mesoporous silica nanoparticles functionalized with acetylcholinesterase on the Au face and with supramolecular β-cyclodextrin:benzimidazole inclusion complexes as caps on the mesoporous silica face. The nanodevice is able to selectively deliver the cargo in the presence of acetylcholine via enzyme-mediated acetylcholine hydrolysis, locally lowering the pH and opening the supramolecular gate. Given the key role played by ACh and its relation with Parkinson's disease and other nervous system diseases, we believe that these findings could help design new therapeutic strategies. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Diamond Nanogel-Embedded Contact Lenses Mediate Lysozyme-Dependent Therapeutic Release

PubMed Central

2015-01-01

Temporarily implanted devices, such as drug-loaded contact lenses, are emerging as the preferred treatment method for ocular diseases like glaucoma. Localizing the delivery of glaucoma drugs, such as timolol maleate (TM), can minimize adverse effects caused by systemic administration. Although eye drops and drug-soaked lenses allow for local treatment, their utility is limited by burst release and a lack of sustained therapeutic delivery. Additionally, wet transportation and storage of drug-soaked lenses result in drug loss due to elution from the lenses. Here we present a nanodiamond (ND)-embedded contact lens capable of lysozyme-triggered release of TM for sustained therapy. We find that ND-embedded lenses composed of enzyme-cleavable polymers allow for controlled and sustained release of TM in the presence of lysozyme. Retention of drug activity is verified in primary human trabecular meshwork cells. These results demonstrate the translational potential of an ND-embedded lens capable of drug sequestration and enzyme activation. PMID:24506583

Targeted gene delivery in the cricket brain, using in vivo electroporation.

PubMed

Matsumoto, Chihiro Sato; Shidara, Hisashi; Matsuda, Koji; Nakamura, Taro; Mito, Taro; Matsumoto, Yukihisa; Oka, Kotaro; Ogawa, Hiroto

2013-12-01

The cricket (Gryllus bimaculatus) is a hemimetabolous insect that is emerging as a model organism for the study of neural and molecular mechanisms of behavioral traits. However, research strategies have been limited by a lack of genetic manipulation techniques that target the nervous system of the cricket. The development of a new method for efficient gene delivery into cricket brains, using in vivo electroporation, is described here. Plasmid DNA, which contained an enhanced green fluorescent protein (eGFP) gene, under the control of a G. bimaculatus actin (Gb'-act) promoter, was injected into adult cricket brains. Injection was followed by electroporation at a sufficient voltage. Expression of eGFP was observed within the brain tissue. Localized gene expression, targeted to specific regions of the brain, was also achieved using a combination of local DNA injection and fine arrangement of the electroporation electrodes. Further studies using this technique will lead to a better understanding of the neural and molecular mechanisms that underlie cricket behaviors. Copyright © 2013 Elsevier Ltd. All rights reserved.

Strange Bedfellows: A Local Insurer/Physician Practice Partnership to Fund Innovation.

PubMed

Kraft, Sally; Strutz, Elizabeth; Kay, Lawrence; Welnick, Richard; Pandhi, Nancy

2015-01-01

Despite an unprecedented urgency to control healthcare costs while simultaneously improving quality, there are many barriers to investing in quality improvement. Traditional fee-for-service reimbursement models fail to reward providers whose improved processes lead to decreases in billable clinical activity. In addition, providers may lack the necessary skills for improvement, or the organizational infrastructure to conduct these activities. Insurance firms lack incentives to invest in healthcare delivery system improvements that lead to benefits for all patients, even those covered by competitors. In this article, we describe a novel program in its sixth year of existence that funds ambulatory care improvements through a collaborative partnership between a local academic healthcare delivery system and an insurance firm. The program is designed as a competitive grant program and the payer and healthcare organization jointly benefit from completed improvement projects. Factors contributing to the ongoing success of the program and lessons learned are discussed in order to inform the potential development of similar programs in other markets.

Thermo-responsive magnetic liposomes for hyperthermia-triggered local drug delivery.

PubMed

Dai, Min; Wu, Cong; Fang, Hong-Ming; Li, Li; Yan, Jia-Bao; Zeng, Dan-Lin; Zou, Tao

2017-06-01

We prepared and characterised thermo-responsive magnetic liposomes, which were designed to combine features of magnetic targeting and thermo-responsive control release for hyperthermia-triggered local drug delivery. The particle size and zeta-potential of the thermo-responsive magnetic ammonium bicarbonate (MagABC) liposomes were about 210 nm and -14 mV, respectively. The MagABC liposomes showed encapsulation efficiencies of about 15% and 82% for magnetic nanoparticles (mean crystallite size 12 nm) and doxorubicin (DOX), respectively. The morphology of the MagABC liposomes was visualised using transmission electron microscope (TEM). The MagABC liposomes showed desired thermo-responsive release. The MagABC liposomes, when physically targeted to tumour cells in culture by a permanent magnetic field yielded a substantial increase in intracellular accumulation of DOX as compared to non-magnetic ammonium bicarbonate (ABC) liposomes. This resulted in a parallel increase in cytotoxicity for DOX loaded MagABC liposomes over DOX loaded ABC liposomes in tumour cells.

Production and delivery of a fluid mixture to an annular volume of a wellbore

DOEpatents

Hermes, Robert E [Los Alamos, NM; Bland, Ronald Gene [Houston, TX; Foley, Ron Lee [Magnolia, TX; Bloys, James B [Katy, TX; Gonzalez, Manuel E [Kingwood, NM; Daniel, John M [Germantown, TN; Robinson, Ian M [Guisborough, GB; Carpenter, Robert B [Tomball, TX

2012-01-24

The methods described herein generally relate to preparing and delivering a fluid mixture to a confined volume, specifically an annular volume located between two concentrically oriented casing strings within a hydrocarbon fluid producing well. The fluid mixtures disclosed herein are useful in controlling pressure in localized volumes. The fluid mixtures comprise at least one polymerizable monomer and at least one inhibitor. The processes and methods disclosed herein allow the fluid mixture to be stored, shipped and/or injected into localized volumes, for example, an annular volume defined by concentric well casing strings.

Self-assembled polymeric nanocarriers for the targeted delivery of retinoic acid to the hair follicle

NASA Astrophysics Data System (ADS)

Lapteva, Maria; Möller, Michael; Gurny, Robert; Kalia, Yogeshvar N.

2015-11-01

Acne vulgaris is a highly prevalent dermatological disease of the pilosebaceous unit (PSU). An inability to target drug delivery to the PSU results in poor treatment efficacy and the incidence of local side-effects. Cutaneous application of nanoparticulate systems is reported to induce preferential accumulation in appendageal structures. The aim of this work was to prepare stable polymeric micelles containing retinoic acid (RA) using a biodegradable and biocompatible diblock methoxy-poly(ethylene glycol)-poly(hexylsubstituted lactic acid) copolymer (MPEG-dihexPLA) and to evaluate their ability to deliver RA to skin. An innovative punch biopsy sample preparation method was developed to selectively quantify follicular delivery; the amounts of RA present were compared to those in bulk skin, (i.e. without PSU), which served as the control. RA was successfully incorporated into micelle nanocarriers and protected from photoisomerization by inclusion of Quinoline Yellow. Incorporation into the spherical, homogeneous and nanometer-scale micelles (dn < 20 nm) increased the aqueous solubility of RA by >400-fold. Drug delivery experiments in vitro showed that micelles were able to deliver RA to porcine and human skins more efficiently than Retin-A® Micro (0.04%), a marketed gel containing RA loaded microspheres, (7.1 +/- 1.1% vs. 0.4 +/- 0.1% and 7.5 +/- 0.8% vs. 0.8 +/- 0.1% of the applied dose, respectively). In contrast to a non-colloidal RA solution, Effederm® (0.05%), both the RA loaded MPEG-dihexPLA polymeric micelles (0.005%) and Retin-A® Micro (0.04%) displayed selectivity for delivery to the PSU with 2-fold higher delivery to PSU containing samples than to control samples. Moreover, the micelle formulation outperformed Retin-A® Micro in terms of delivery efficiency to PSU presenting human skin (10.4 +/- 3.2% vs. 0.6 +/- 0.2%, respectively). The results indicate that the polymeric micelle formulation enabled an increased and targeted delivery of RA to the PSU, potentially translating to a safer and more efficient clinical management of acne.Acne vulgaris is a highly prevalent dermatological disease of the pilosebaceous unit (PSU). An inability to target drug delivery to the PSU results in poor treatment efficacy and the incidence of local side-effects. Cutaneous application of nanoparticulate systems is reported to induce preferential accumulation in appendageal structures. The aim of this work was to prepare stable polymeric micelles containing retinoic acid (RA) using a biodegradable and biocompatible diblock methoxy-poly(ethylene glycol)-poly(hexylsubstituted lactic acid) copolymer (MPEG-dihexPLA) and to evaluate their ability to deliver RA to skin. An innovative punch biopsy sample preparation method was developed to selectively quantify follicular delivery; the amounts of RA present were compared to those in bulk skin, (i.e. without PSU), which served as the control. RA was successfully incorporated into micelle nanocarriers and protected from photoisomerization by inclusion of Quinoline Yellow. Incorporation into the spherical, homogeneous and nanometer-scale micelles (dn < 20 nm) increased the aqueous solubility of RA by >400-fold. Drug delivery experiments in vitro showed that micelles were able to deliver RA to porcine and human skins more efficiently than Retin-A® Micro (0.04%), a marketed gel containing RA loaded microspheres, (7.1 +/- 1.1% vs. 0.4 +/- 0.1% and 7.5 +/- 0.8% vs. 0.8 +/- 0.1% of the applied dose, respectively). In contrast to a non-colloidal RA solution, Effederm® (0.05%), both the RA loaded MPEG-dihexPLA polymeric micelles (0.005%) and Retin-A® Micro (0.04%) displayed selectivity for delivery to the PSU with 2-fold higher delivery to PSU containing samples than to control samples. Moreover, the micelle formulation outperformed Retin-A® Micro in terms of delivery efficiency to PSU presenting human skin (10.4 +/- 3.2% vs. 0.6 +/- 0.2%, respectively). The results indicate that the polymeric micelle formulation enabled an increased and targeted delivery of RA to the PSU, potentially translating to a safer and more efficient clinical management of acne. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr04770f

Noninvasive remote-controlled release of drug molecules in vitro using magnetic actuation of mechanized nanoparticles.

PubMed

Thomas, Courtney R; Ferris, Daniel P; Lee, Jae-Hyun; Choi, Eunjoo; Cho, Mi Hyeon; Kim, Eun Sook; Stoddart, J Fraser; Shin, Jeon-Soo; Cheon, Jinwoo; Zink, Jeffrey I

2010-08-11

Mesoporous silica nanoparticles are useful nanomaterials that have demonstrated the ability to contain and release cargos with mediation by gatekeepers. Magnetic nanocrystals have the ability to exhibit hyperthermic effects when placed in an oscillating magnetic field. In a system combining these two materials and a thermally sensitive gatekeeper, a unique drug delivery system can be produced. A novel material that incorporates zinc-doped iron oxide nanocrystals within a mesoporous silica framework that has been surface-modified with pseudorotaxanes is described. Upon application of an AC magnetic field, the nanocrystals generate local internal heating, causing the molecular machines to disassemble and allowing the cargos (drugs) to be released. When breast cancer cells (MDA-MB-231) were treated with doxorubicin-loaded particles and exposed to an AC field, cell death occurred. This material promises to be a noninvasive, externally controlled drug delivery system with cancer-killing properties.

Fluvastatin as a micropore lifetime enhancer for sustained delivery across microneedle-treated skin.

PubMed

Ghosh, Priyanka; Brogden, Nicole K; Stinchcomb, Audra L

2014-02-01

Microneedles (MNs), a physical skin permeation enhancement technique, facilitate drug delivery across the skin, thus enhancing the number of drugs that can be delivered transdermally in therapeutically relevant concentrations. The micropores created in the skin by MNs reseal because of normal healing processes of the skin, thus limiting the duration of the drug delivery window. Pore lifetime enhancement strategies can increase the effectiveness of MNs as a drug delivery mechanism by prolonging the delivery window. Fluvastatin (FLU), a HMGCoA reductase inhibitor, was used in this study to enhance the pore lifetime by inhibiting the synthesis of cholesterol, a major component of the stratum corneum lipids. The study showed that using FLU as a pretreatment it is possible to enhance the pore lifetime of MN-treated skin and thus allow for sustained drug delivery. The skin recovered within a 30-45-min time period following the removal of occlusion, and there was no significant irritation observed due to the treatment compared to the control sites. Thus, it can be concluded that localized skin treatment with FLU can be used to extend micropore lifetime and deliver drugs for up to 7 days across MN-treated skin. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Gastroretentive drug delivery systems for the treatment of Helicobacter pylori

PubMed Central

Zhao, Shan; Lv, Yan; Zhang, Jian-Bin; Wang, Bing; Lv, Guo-Jun; Ma, Xiao-Jun

2014-01-01

Helicobacter pylori (H. pylori) is one of the most common pathogenic bacterial infections and is found in the stomachs of approximately half of the world’s population. It is the primary known cause of gastritis, gastroduodenal ulcer disease and gastric cancer. However, combined drug therapy as the general treatment in the clinic, the rise of antibiotic-resistant bacteria, adverse reactions and poor patient compliance are major obstacles to the eradication of H. pylori. Oral site-specific drug delivery systems that could increase the longevity of the treatment agent at the target site might improve the therapeutic effect and avoid side effects. Gastroretentive drug delivery systems potentially prolong the gastric retention time and controlled/sustained release of a drug, thereby increasing the concentration of the drug at the application site, potentially improving its bioavailability and reducing the necessary dosage. Recommended gastroretentive drug delivery systems for enhancing local drug delivery include floating systems, bioadhesive systems and expandable systems. In this review, we summarize the important physiological parameters of the gastrointestinal tract that affect the gastric residence time. We then focus on various aspects useful in the development of gastroretentive drug delivery systems, including current trends and the progress of novel forms, especially with respect to their application for the treatment of H. pylori infections. PMID:25071326

Local anesthetic lidocaine delivery system: chitosan and hyaluronic acid-modified layer-by-layer lipid nanoparticles.

PubMed

Zhang, Laizhu; Wang, Jianguo; Chi, Huimin; Wang, Shilei

2016-11-01

Transdermal local anesthesia is one of the most applied strategies to avoid systemic adverse effects; there is an appealing need for a prolonged local anesthetic that would provide better bioavailability and longer pain relief with a single administration. Layer-by-layer (LBL) technique was used in this study to explore a nanosized drug delivery system for local anesthetic therapy. LBL-coated lidocaine-loaded nanostructured lipid nanoparticles (LBL-LA/NLCs) were prepared and characterized in terms of particle size (PS), zeta potential, drug encapsulation efficiency (EE), in vitro skin permeation and in vivo local anesthetic studies. Evaluation of the in vitro skin permeation and in vivo anesthesia effect illustrated that LBL-LA/NLCs can enhance and prolong the anesthetic effect of LA. LBL-LA/NLCs could function as a promising drug delivery strategy for overcoming the barrier function of the skin and could deliver anesthetic through the skin with sustained release behavior for local anesthetic therapy.

Local delivery of FTY720 accelerates cranial allograft incorporation and bone formation

PubMed Central

Huang, Cynthia; Das, Anusuya; Barker, Daniel; Tholpady, Sunil; Wang, Tiffany; Cui, Quanjun; Ogle, Roy

2012-01-01

Endogenous stem cell recruitment to the site of skeletal injury is key to enhanced osseous remodeling and neovascularization. To this end, this study utilized a novel bone allograft coating of poly(lactic-co-glycolic acid) (PLAGA) to sustain the release of FTY720, a selective agonist for sphingosine 1-phosphate (S1P) receptors, from calvarial allografts. Uncoated allografts, vehicle-coated, low dose FTY720 in PLAGA (1:200 w:w) and high dose FTY720 in PLAGA (1:40) were implanted into critical size calvarial bone defects. The ability of local FTY720 delivery to promote angiogenesis, maximize osteoinductivity and improve allograft incorporation by recruitment of bone progenitor cells from surrounding soft tissues and microcirculation was evaluated. FTY720 bioactivity after encapsulation and release was confirmed with sphingosine kinase 2 assays. HPLC-MS quantified about 50% loaded FTY720 release of the total encapsulated drug (4.5 µg) after 5 days. Following 2 weeks of defect healing, FTY720 delivery led to statistically significant increases in bone volumes compared to controls, with total bone volume increases for uncoated, coated, low FTY720 and high FTY720 of 5.98, 3.38, 7.2 and 8.9 mm3, respectively. The rate and extent of enhanced bone growth persisted through week 4 but, by week 8, increases in bone formation in FTY720 groups were no longer statistically significant. However, micro-computed tomography (microCT) of contrast enhanced vascular ingrowth (MICROFIL®) and histological analysis showed enhanced integration as well as directed bone growth in both high and low dose FTY720 groups compared to controls. PMID:21863314

Broad control of disulfide stability through microenvironmental effects and analysis in complex redox environments.

PubMed

Wu, Chuanliu; Wang, Shuo; Brülisauer, Lorine; Leroux, Jean-Christophe; Gauthier, Marc A

2013-07-08

Disulfide bonds stabilize the tertiary- and quaternary structure of proteins. In addition, they can be used to engineer redox-sensitive (bio)materials and drug-delivery systems. Many of these applications require control of the stability of the disulfide bond. It has recently been shown that the charged microenvironment of the disulfide can be used to alter their stability by ∼3 orders of magnitude in a predictable and finely tunable manner at acidic pH. The aim of this work is to extend these findings to physiological pH and to demonstrate the validity of this approach in complex redox milieu. Disulfide microenvironments were manipulated synergistically with steric hindrance herein to control disulfide bond stability over ∼3 orders of magnitude at neutral pH. Control of disulfide stability through microenvironmental effects could also be observed in complex redox buffers (including serum) and in the presence of cells. Such fine and predictable control of disulfide properties is not achievable using other existing approaches. These findings provide easily implementable and general tools for controlling the responsiveness of biomaterials and drug delivery systems toward various local endogenous redox environments.

Design and Application of Multifunctional DNA Nanocarriers for Therapeutic Delivery

PubMed Central

Charoenphol, Phapanin; Bermudez, Harry

2013-01-01

The unique programmability of nucleic acids offers versatility and flexibility in the creation of self-assembled DNA nanostructures. To date, many three-dimensional DNA architectures have been precisely formed of varying sizes and shapes. Their biocompatibility, biodegradability, and high intrinsic stability in physiological environments emphasize their emerging use as carriers for drug and gene delivery. Furthermore, DNA nanocarriers have been shown to enter cells efficiently and without the aid of transfection reagents. A key strength of DNA nanocarriers over other delivery systems is their modularity and their ability to control the spatial distribution of cargoes and ligands. Optimizing DNA nanocarrier properties to dictate their localization, uptake, and intracellular trafficking is also possible. In this review, we present design considerations for DNA nanocarriers and examples of their use in the context of therapeutic delivery applications. The assembly of DNA nanocarriers and approaches for loading and releasing cargo are described. The stability and safety of DNA nanocarriers is also discussed, with particular attention to the in vivo physiological environment. Mechanisms of cellular uptake and intracellular trafficking are examined, and we conclude with strategies to enhance the delivery efficiency of DNA nanocarriers. PMID:23896566

Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia

PubMed Central

Bai, Hualong; Lee, Jung Seok; Chen, Elizabeth; Wang, Mo; Xing, Ying; Fahmy, Tarek M.; Dardik, Alan

2017-01-01

Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360 ng rapamycin per patch without detectable rapamycin in serum; nanoparticles were detectable in the liver, kidney and spleen but no other sites within 24 hours. In a rat venous patch angioplasty model, control patches developed robust neointimal hyperplasia on the patch luminal surface characterized by Eph-B4-positive endothelium and underlying SMC and infiltrating cells such as macrophages and leukocytes. Patches delivering rapamycin developed less neointimal hyperplasia, less smooth muscle cell proliferation, and had fewer infiltrating cells but retained endothelialization. NP covalently linked to pericardial patches are a novel composite delivery system that allows sustained site-specific delivery of therapeutics; NP delivering rapamycin inhibit patch neointimal hyperplasia. NP linked to patches may represent a next generation of tissue engineered cardiovascular implants. PMID:28071663

Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia

NASA Astrophysics Data System (ADS)

Bai, Hualong; Lee, Jung Seok; Chen, Elizabeth; Wang, Mo; Xing, Ying; Fahmy, Tarek M.; Dardik, Alan

2017-01-01

Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360 ng rapamycin per patch without detectable rapamycin in serum; nanoparticles were detectable in the liver, kidney and spleen but no other sites within 24 hours. In a rat venous patch angioplasty model, control patches developed robust neointimal hyperplasia on the patch luminal surface characterized by Eph-B4-positive endothelium and underlying SMC and infiltrating cells such as macrophages and leukocytes. Patches delivering rapamycin developed less neointimal hyperplasia, less smooth muscle cell proliferation, and had fewer infiltrating cells but retained endothelialization. NP covalently linked to pericardial patches are a novel composite delivery system that allows sustained site-specific delivery of therapeutics; NP delivering rapamycin inhibit patch neointimal hyperplasia. NP linked to patches may represent a next generation of tissue engineered cardiovascular implants.

Findings from case studies of state and local immunization programs.

PubMed

Fairbrother, G; Kuttner, H; Miller, W; Hogan, R; McPhillips, H; Johnson, K A; Alexander, E R

2000-10-01

As part of its examination of federal support for immunization services during the past decade, the Institute of Medicine (IOM) Committee on Immunization Finance Policies and Practices (IFPP) commissioned eight case studies of the states of Alabama, Maine, Michigan, New Jersey, North Carolina, Texas, and Washington; and a two-county study of Los Angeles and San Diego in California. Specifically, the IOM Committee and these studies reviewed the use of Section 317 grants by the states. Section 317 is a discretionary grant program that supports vaccine purchase and other immunization-related program activities. These studies afforded the Committee an in-depth look at local policy choices, the performance of immunization programs, and federal and state spending for immunization during the past decade. The case-study reports were developed through interviews with state and local health department officials, including immunization program directors, Medicaid agency staff, budget analysts, and Centers for Disease Control and Prevention public health advisors to the jurisdiction. Other sources included state and federal administrative records and secondary sources on background factors and state-level trends. The case studies were supplemented by site visits to Detroit, Houston, Los Angeles, Newark, and San Diego. The nature of immunization "infrastructure" supported by the Section 317 program is shifting from primarily service delivery to a broader set of roles that puts the public effort at the head of a broad immunization partnership among public health, health financing, and other entities in both the public and private sectors. The rate and intensity of transition vary across the case-study areas. In the emerging pattern, service delivery increasingly takes place in the private sector and is related to managed care. "Infrastructure" is moving beyond supporting a core state staff and local health department service delivery to include such activities as immunization registries, quality improvement, and coordination with programs outside public health agencies. At the same time, the recent decline in federal Section 317 support is forcing difficult choices between old and new activities at the state and local levels. Immunization programs function as an organic component of the local health care financing and delivery systems of which they are a part. Immunization efforts are organized and conducted within distinctive state and local fiscal, economic, and health care contexts. Section 317 Financial Assistance grants, while playing a vital role in supporting immunization "infrastructure," have been too unstable and unpredictable to elicit the strategic planning, programming, and own-source spending that would be optimal for state and local programs. The predominant immunization function of state and local public health agencies is becoming assurance of age-appropriate immunization throughout the lifespan. To be successful in this emerging role, the health agencies must be supported with appropriate staffing, interagency collaboration, and clearly articulated authority.

Variation in Delivery of the 10 Essential Public Health Services by Local Health Departments for Obesity Control in 2005 and 2008

PubMed Central

Luo, Huabin; Sotnikov, Sergey; Shah, Gulzar; Galuska, Deborah A.; Zhang, Xinzhi

2016-01-01

Objectives To describe and compare the capacity of local health departments (LHDs) to perform 10 essential public health services (EPHS) for obesity control in 2005 and 2008, and explore factors associated with provision of these services. Methods The data for this study were drawn from the 2005 and 2008 National Profile of Local Health Department surveys, conducted by the National Association of County and City Health Officials. Data were analyzed in SAS version 9.1 (SAS Institute Inc, Cary, North Carolina). Results The proportion of LHDs that reported that they do not provide any of the EPHS for obesity control decreased from 27.9% in 2005 to 17.0% in 2008. In both 2005 and 2008, the 2 most frequently provided EPHS for obesity control by LHDs were informing, educating, and empowering the people (EPHS 3) and linking people to needed personal health services (EPHS 7). The 2 least frequently provided services were enforcing laws and regulations (EPHS 6) and conducting research (EPHS 10). On average, LHDs provided 3.05 EPHS in 2005 and 3.69 EPHS in 2008. Multiple logistic regression results show that LHDs with larger jurisdiction population, with a local governance, and those that have completed a community health improvement plan were more likely to provide more of the EPHS for obesity (P < .05). Conclusions The provision of the 10 EPHS for obesity control by LHDs remains low. Local health departments need more assistance and resources to expand performance of EPHS for obesity control. Future studies are needed to evaluate and promote LHD capacity to deliver evidence-based strategies for obesity control in local communities. PMID:23169404

Hyperbaric versus plain bupivacaine for spinal anesthesia for cesarean delivery.

PubMed

Heng Sia, Alex Tiong; Tan, Kok Hian; Sng, Ban Leong; Lim, Yvonne; Chan, Edwin S Y; Siddiqui, Fahad Javaid

2015-01-01

Bupivacaine is an amide local anesthetic used in hyperbaric and plain forms administered as spinal anesthesia for cesarean delivery. In this systematic review, we summarized the effectiveness and safety of hyperbaric versus plain bupivacaine in providing anesthesia for cesarean delivery. We considered the adequacy of anesthesia for completion of cesarean delivery and the need for interventions to treat complications. We searched the CENTRAL, MEDLINE, and EMBASE databases. We imposed no language restriction. We included all randomized controlled trials involving patients undergoing spinal anesthesia for elective cesarean delivery that compared the use of hyperbaric bupivacaine with plain bupivacaine. We included 6 studies with a total of 394 patients in this review. These studies have small sample size, few observed events, differences in methodology, and insufficient information pertaining to assessment of risk of bias. This prevented us from calculating pooled estimates. Results show that there is no compelling evidence in favor of the use of intrathecal plain or hyperbaric bupivacaine for spinal anesthesia for cesarean delivery. There is a lack of clear evidence regarding the superiority of hyperbaric compared with plain bupivacaine for spinal anesthesia for cesarean delivery. The need for conversion to general anesthesia because of failed spinal anesthesia is an important clinical outcome, but current data are insufficient to compare spinal anesthesia induced with hyperbaric compared with plain bupivacaine for this outcome. Further research is required.

Impact of IGF-I release kinetics on bone healing: a preliminary study in sheep.

PubMed

Luginbuehl, Vera; Zoidis, Evangelos; Meinel, Lorenz; von Rechenberg, Brigitte; Gander, Bruno; Merkle, Hans P

2013-09-01

Spatiotemporal release of growth factors from a delivery device can profoundly affect the efficacy of bone growth induction. Here, we report on a delivery platform based on the encapsulation of insulin-like growth factor I (IGF-I) in different poly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA) microsphere (MS) formulations to control IGF-I release kinetics. In vitro IGF-I release profiles generally exhibited an initial burst (14-36% of total IGF-I content), which was followed by a more or less pronounced dormant phase with little release (2 to 34 days), and finally, a third phase of re-increased IGF-I release. The osteoinductive potential of these different IGF-I PL(G)A MS formulations was tested in studies using 8-mm metaphyseal drill hole bone defects in sheep. Histomorphometric analysis at 3 and 6 weeks after surgery showed that new bone formation was improved in the defects locally treated with IGF-I PL(G)A MS (n=5) as compared to defects filled with IGF-I-free PL(G)A MS (n=4). The extent of new bone formation was affected by the particular release kinetics, although a definitive relationship was not evident. Local administration of IGF-I resulted in down-regulation of inflammatory marker genes in all IGF-I treated defects. The over-expression of growth factor genes in response to IGF-I delivery was restricted to formulations that produced osteogenic responses. These experiments demonstrate the osteoinductive potential of sustained IGF-I delivery and show the importance of delivery kinetics for successful IGF-I-based therapies. Copyright © 2013 Elsevier B.V. All rights reserved.

Proconvulsant Actions of Intrahippocampal Botulinum Neurotoxin B in the Rat

PubMed Central

Bröer, Sonja; Zolkowska, Dorota; Gernert, Manuela; Rogawski, Michael A.

2013-01-01

Botulinum neurotoxins (BoNTs) may affect the excitability of brain circuits by inhibiting neurotransmitter release at central synapses. There is evidence that local delivery of BoNT serotypes A and E, which target SNAP-25, a component of the release machinery specific to excitatory synapses, can inhibit seizure generation. BoNT serotype B (BoNT/B) targets VAMP2, which is expressed in both excitatory and inhibitory terminals. Here we assessed the effects of unilateral intrahippocampal infusion of BoNT/B in the rat on intravenous pentylenetetrazol (PTZ) seizure thresholds, and on the expression of spontaneous behavioral and electrographic seizures. Infusion of BoNT/B (500 and 1000 unit) by convection-enhanced delivery caused a reduction in myoclonic twitch and clonic seizure thresholds in response to intravenous PTZ beginning about 6 days after the infusion. Handling-evoked and spontaneous convulsive seizures were observed in many BoNT/B-treated animals but not in vehicle-treated controls. Spontaneous electrographic seizure discharges were recorded in the dentate gyrus of animals that received local BoNT/B infusion. In addition, there was an increased frequency of interictal epileptiform spikes and sharp waves at the same recording site. BoNT/B treated animals also exhibited tactile hyperresponsivity in comparison with vehicle-treated controls. This is the first demonstration that BoNT/B causes a delayed proconvulsant action when infused into the hippocampus. Local infusion of BoNT/B could be useful as a focal epilepsy model. PMID:23906638

Folate receptor mediated in vivo targeted delivery of human serum albumin coated manganese ferrite magnetic nanoparticles to cancer cells

NASA Astrophysics Data System (ADS)

Zaidan, A.; Ilhami, F.; Fahmi, M. Z.; Purwanto, B.; Kharisma, R. Z.

2017-05-01

Manganese ferrite nanoparticles (MnFe2O4) have received increasing attention due to their remarkable magnetic properties and have been used for various biomedical applications. They have potential applications in magnetic resonance imaging and hyperthermia for cancer. Both novel applications require a delivery system that will allow nanoparticle to move easily and localization of nanoparticle to the target tissue. In our work, we developed human serum albumin coated manganese ferrite magnetic nanoparticles (HSA-MF NPs). The nanoparticles were prepared using solvothermal method and modified with folic acid for targeted delivery. Structure and morphology of manganese ferrite nanoparticle were characterized by X-ray diffraction (XRD) pattern and transmission electron microscopy (TEM). The size of folic acid conjugated HSA-MF NPs (HSA-MF-FA NPs) were studied by dynamic light scattering (DLS). In the in vivo study, we used benzopyrene-induced cancer in mice. We successfully delivered HSA-MF-FA NPs through intravenous tail injection after induction of the tumour. We found that 54% of initial HSA-MF-FA NPs which previously injected localize in the target tissue. While obtained p-value from independent T-test is 0.013 which shows that there is a difference between the control group (HSA-MF NPs) and the treated group (HSA-MF-FA NPs)

Polymeric microsphere-facilitated site-specific delivery of quercetin prevents senescence of pancreatic islets in vivo and improves transplantation outcomes in mouse model of diabetes.

PubMed

Pathak, Shiva; Regmi, Shobha; Nguyen, Tiep Tien; Gupta, Biki; Gautam, Milan; Yong, Chul Soon; Kim, Jong Oh; Son, Youlim; Kim, Jae-Ryong; Park, Min Hui; Bae, Young Kyung; Park, So Young; Jeong, Daewon; Yook, Simmyung; Jeong, Jee-Heon

2018-06-05

Attenuation of senescence progression may be attractive way to preserve the functionality of pancreatic islets (PI) after transplantation. In this study, we developed a model for in vitro induction of premature senescence in rat PI and showed the effectiveness of quercetin (QU) to prevent the senescence. To provide targeted-delivery of QU to the PI after transplantation, we prepared the hybrid clusters (HC) of islet single cells (ISC) and QU-loaded polymeric microspheres (QU; ∼7.55 ng HC -1 ). Long-term culture of the HC revealed reduced levels of reactive oxygen species and decreased expression of senescence-associated beta galactosidase, Rb, p53, p16, and p21 compared to that of the control islets. Transplantation of HC into subcutaneous space of the immune-deficient mice produced better glycemic control compared to the control islets or the ICC-transplanted mice. SA-β-Gal staining of the in vivo transplanted HC sample showed lower intensity compared to that of the control islets or the islet cell clusters. Thus, in situ delivery of therapeutic agent may be a promising approach to improve therapeutic outcomes in cell therapy. In this study, we aimed to improve outcomes in islet transplantation using in situ delivery of quercetin to pancreatic islets, using polymeric microspheres. We prepared prolonged release-type microspheres and constructed hybrid clusters of pancreatic islets and the microspheres using hanging drop method. The presence of quercetin in the cellular microenvironment attenuated the progression of senescence in the pancreatic islets in a long-term in vitro culture. Moreover, transplantation of the hybrid clusters in the diabetic mice produced better glycemic control compared to that of the control islets. In addition, quercetin delayed the progression of senescence in the pancreatic islets after in vivo transplantation. Thus, local delivery of antioxidants like quercetin may be an attractive way to improve outcomes in cell therapy. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Injectable visible light-cured glycol chitosan hydrogels with controlled release of anticancer drugs for local cancer therapy in vivo: a feasible study.

PubMed

Hyun, Hoon; Park, Min Ho; Lim, Wonbong; Kim, So Yeon; Jo, Danbi; Jung, Jin Seok; Jo, Gayoung; Um, Sewook; Lee, Deok-Won; Yang, Dae Hyeok

2018-05-11

Currently available chemotherapy is associated with serious side effects, and therefore novel drug delivery systems (DDSs) are required to specifically deliver anticancer drugs to targeted sites. In this study, we evaluated the feasibility of visible light-cured glycol chitosan (GC) hydrogels with controlled release of doxorubicin⋅hydrochloride (DOX⋅HCl) as local DDSs for effective cancer therapy in vivo. The storage modulus of the hydrogel precursor solutions was increased as a function of visible light irradiation time. In addition, the swelling ratio of the hydrogel irradiated for 10 s (GC 10 /DOX) was greater than in 60 s (GC 60 /DOX). In vitro release test showed that DOX was rapidly released in GC 10 /DOX compared with GC 60 /DOX due to the density of cross-linking. In vitro and in vivo tests including cell viability and measurement of tumor volume showed that the local treatment of GC 10 /DOX yielded substantially greater antitumor effect compared with that of GC 60 /DOX. Therefore, the visible light-cured GC hydrogel system may exhibit clinical potential as a local DDS of anticancer drugs with controlled release, by modulating cross-linking density.

Does the baricity of bupivacaine influence intrathecal spread in the prolonged sitting position before elective cesarean delivery? A prospective randomized controlled study.

PubMed

Loubert, Christian; Hallworth, Stephen; Fernando, Roshan; Columb, Malachy; Patel, Nisa; Sarang, Kavita; Sodhi, Vinnie

2011-10-01

Difficulties in inserting an epidural catheter while performing combined spinal-epidural anesthesia for cesarean delivery may lead to undue delays between the spinal injection of the local anesthetic mixture and the adoption of the supine position with lateral tilt. We hypothesized that this delay may affect the intrathecal distribution of local anesthetic of different baricities such that hypobaric local anesthetic would lead to a higher sensory block level. Healthy parturients with uncomplicated pregnancies undergoing elective cesarean delivery under combined spinal-epidural anesthesia were enrolled in this prospective double-blind randomized controlled trial. The subjects were allocated to receive hyperbaric (hyperbaric group), isobaric (isobaric group), or hypobaric (hypobaric group) spinal bupivacaine 10 mg. After the spinal injection, the subjects remained in the sitting position for 5 minutes (to simulate difficulty in inserting the epidural catheter) before being helped into the supine lateral tilt position. The primary outcome was the sensory block level during the 25 minutes after the spinal injection. Other end points included motor block score, maternal hypotension, and vasopressor requirements. Data from 89 patients were analyzed. Patient characteristics were similar in all groups. The median [interquartile range] (95% confidence interval) sensory levels after spinal injection were significantly higher with decreasing baricity: hyperbaric T10 [T11-8] (T10-9), isobaric T9 [T10-7] (T9-7), and hypobaric T6 [T8-4] (T8-5) (P < 0.001, Cuzick trend). All patients in the hypobaric group reached a sensory block level of T4 at 25 minutes after spinal injection compared with 80% of the patients in both the isobaric and hyperbaric groups (P = 0.04; difference 20%, 95% confidence interval of difference 4%-33%). Significantly more patients in the hypobaric group had complete lower limb motor block (Bromage score = 4) (hyperbaric 43%, isobaric 63%, and hypobaric 90%; P < 0.001). The incidences of maternal hypotension and nausea and vomiting were similar among groups, although the ephedrine requirements were significantly increased in the isobaric and hypobaric groups by factors of 1.83 and 3.0, respectively, compared with the hyperbaric group (P < 0.001, Cuzick trend). We demonstrated that when parturients undergoing cesarean delivery were maintained in the sitting position for 5 minutes after spinal injection of the local anesthetic, hypobaric bupivacaine resulted in sensory block levels that were higher compared with isobaric and hyperbaric bupivacaine, respectively, during the study period.

Thiol–ene click hydrogels for therapeutic delivery

PubMed Central

Kharkar, Prathamesh M.; Rehmann, Matthew S.; Skeens, Kelsi M.; Maverakis, Emanual; Kloxin, April M.

2016-01-01

Hydrogels are of growing interest for the delivery of therapeutics to specific sites in the body. For use as a delivery vehicle, hydrophilic precursors are usually laden with bioactive moieties and then directly injected to the site of interest for in situ gel formation and controlled release dictated by precursor design. Hydrogels formed by thiol–ene click reactions are attractive for local controlled release of therapeutics owing to their rapid reaction rate and efficiency under mild aqueous conditions, enabling in situ formation of gels with tunable properties often responsive to environmental cues. Herein, we will review the wide range of applications for thiol–ene hydrogels, from the prolonged release of anti-inflammatory drugs in the spine to the release of protein-based therapeutics in response to cell-secreted enzymes, with a focus on their clinical relevance. We will also provide a brief overview of thiol–ene click chemistry and discuss the available alkene chemistries pertinent to macromolecule functionalization and hydrogel formation. These chemistries include functional groups susceptible to Michael type reactions relevant for injection and radically-mediated reactions for greater temporal control of formation at sites of interest using light. Additionally, mechanisms for the encapsulation and controlled release of therapeutic cargoes are reviewed, including i) tuning the mesh size of the hydrogel initially and temporally for cargo entrapment and release and ii) covalent tethering of the cargo with degradable linkers or affinity binding sequences to mediate release. Finally, myriad thiol–ene hydrogels and their specific applications also are discussed to give a sampling of the current and future utilization of this chemistry for delivery of therapeutics, such as small molecule drugs, peptides, and biologics. PMID:28361125

Circulating Magnetic Microbubbles for Localized Real-Time Control of Drug Delivery by Ultrasonography-Guided Magnetic Targeting and Ultrasound

PubMed Central

Chertok, Beata; Langer, Robert

2018-01-01

Image-guided and target-selective modulation of drug delivery by external physical triggers at the site of pathology has the potential to enable tailored control of drug targeting. Magnetic microbubbles that are responsive to magnetic and acoustic modulation and visible to ultrasonography have been proposed as a means to realize this drug targeting strategy. To comply with this strategy in vivo, magnetic microbubbles must circulate systemically and evade deposition in pulmonary capillaries, while also preserving magnetic and acoustic activities in circulation over time. Unfortunately, challenges in fabricating magnetic microbubbles with such characteristics have limited progress in this field. In this report, we develop magnetic microbubbles (MagMB) that display strong magnetic and acoustic activities, while also preserving the ability to circulate systemically and evade pulmonary entrapment. Methods: We systematically evaluated the characteristics of MagMB including their pharmacokinetics, biodistribution, visibility to ultrasonography and amenability to magneto-acoustic modulation in tumor-bearing mice. We further assessed the applicability of MagMB for ultrasonography-guided control of drug targeting. Results: Following intravenous injection, MagMB exhibited a 17- to 90-fold lower pulmonary entrapment compared to previously reported magnetic microbubbles and mimicked circulation persistence of the clinically utilized Definity microbubbles (>10 min). In addition, MagMB could be accumulated in tumor vasculature by magnetic targeting, monitored by ultrasonography and collapsed by focused ultrasound on demand to activate drug deposition at the target. Furthermore, drug delivery to target tumors could be enhanced by adjusting the magneto-acoustic modulation based on ultrasonographic monitoring of MagMB in real-time. Conclusions: Circulating MagMB in conjunction with ultrasonography-guided magneto-acoustic modulation may provide a strategy for tailored minimally-invasive control over drug delivery to target tissues. PMID:29290812

Electroporation in veterinary oncology.

PubMed

Impellizeri, J; Aurisicchio, L; Forde, P; Soden, D M

2016-11-01

Cancer treatments in veterinary medicine continue to evolve beyond the established standard therapies of surgery, chemotherapy and radiation therapy. New technologies in cancer therapy include a targeted mechanism to open the cell membrane based on electroporation, driving therapeutic agents, such as chemotherapy (electro-chemotherapy), for local control of cancer, or delivery of gene-based products (electro-gene therapy), directly into the cancer cell to achieve systemic control. This review examines electrochemotherapy and electro-gene therapy in veterinary medicine and considers future directions and applications. Copyright © 2016 Elsevier Ltd. All rights reserved.

Opening the Black Box: Exploring the Effect of Transformation on Online Service Delivery in Local Governments

NASA Astrophysics Data System (ADS)

van Veenstra, Anne Fleur; Zuurmond, Arre

To enhance the quality of their online service delivery, many government organizations seek to transform their organization beyond merely setting up a front office. This transformation includes elements such as the formation of service delivery chains, the adoption of a management strategy supporting process orientation and the implementation of enterprise architecture. This paper explores whether undertaking this transformation has a positive effect on the quality of online service delivery, using data gathered from seventy local governments. We found that having an externally oriented management strategy in place, adopting enterprise architecture, aligning information systems to business and sharing activities between processes and departments are positively related to the quality of online service delivery. We recommend that further research should be carried out to find out whether dimensions of organizational development too have an effect on online service delivery in the long term.

Effects of local structural transformation of lipid-like compounds on delivery of messenger RNA

NASA Astrophysics Data System (ADS)

Li, Bin; Luo, Xiao; Deng, Binbin; Giancola, Jolynn B.; McComb, David W.; Schmittgen, Thomas D.; Dong, Yizhou

2016-02-01

Lipid-like nanoparticles (LLNs) have shown great potential for RNA delivery. Lipid-like compounds are key components in LLNs. In this study, we investigated the effects of local structural transformation of lipid-like compounds on delivery of messenger RNA. Our results showed that position change of functional groups on lipid-like compounds can dramatically improve delivery efficiency. We then optimized formulation ratios of TNT-b10 LLNs, a lead material, increasing delivery efficiency over 2-fold. More importantly, pegylated TNT-b10 LLNs is stable for over four weeks and is over 10-fold more efficient than that of its counterpart TNT-a10 LLNs. Additionally, the optimal formulation O-TNT-b10 LLNs is capable of delivering mRNA encoding luciferase in vivo. These results provide useful insights into the design of next generation LLNs for mRNA delivery.

Remote modulation of neural activities via near-infrared triggered release of biomolecules.

PubMed

Li, Wei; Luo, Rongcong; Lin, Xudong; Jadhav, Amol D; Zhang, Zicong; Yan, Li; Chan, Chung-Yuan; Chen, Xianfeng; He, Jufang; Chen, Chia-Hung; Shi, Peng

2015-10-01

The capability to remotely control the release of biomolecules provides an unique opportunity to monitor and regulate neural signaling, which spans extraordinary spatial and temporal scales. While various strategies, including local perfusion, molecular "uncaging", or photosensitive polymeric materials, have been applied to achieve controlled releasing of neuro-active substances, it is still challenging to adopt these technologies in many experimental contexts that require a straightforward but versatile loading-releasing mechanism. Here, we develop a synthetic strategy for remotely controllable releasing of neuro-modulating molecules. This platform is based on microscale composite hydrogels that incorporate polypyrrole (PPy) nanoparticles as photo-thermal transducers and is triggered by near-infrared-light (NIR) irradiation. Specifically, we first demonstrate the utility of our technology by recapitulating the "turning assay" and "collapse assay", which involve localized treatment of chemotactic factors (e.g. Netrin or Semaphorin 3A) to subcellular neural elements and have been extensively used in studying axonal pathfinding. On a network scale, the photo-sensitive microgels are also validated for light-controlled releasing of neurotransmitters (e.g. glutamate). A single NIR-triggered release is sufficient to change the dynamics of a cultured hippocampal neuron network. Taking the advantage of NIR's capability to penetrate deep into live tissue, this technology is further shown to work similarly well in vivo, which is evidenced by synchronized spiking activity in response to NIR-triggered delivery of glutamate in rat auditory cortex, demonstrating remote control of brain activity without any genetic modifications. Notably, our nano-composite microgels are capable of delivering various molecules, ranging from small chemicals to large proteins, without involving any crosslinking chemistry. Such great versatility and ease-of-use will likely make our optically-controlled delivery technology a general and important tool in cell biology research. Copyright © 2015 Elsevier Ltd. All rights reserved.

An implantable thermoresponsive drug delivery system based on Peltier device.

PubMed

Yang, Rongbing; Gorelov, Alexander V; Aldabbagh, Fawaz; Carroll, William M; Rochev, Yury

2013-04-15

Locally dropping the temperature in vivo is the main obstacle to the clinical use of a thermoresponsive drug delivery system. In this paper, a Peltier electronic element is incorporated with a thermoresponsive thin film based drug delivery system to form a new drug delivery device which can regulate the release of rhodamine B in a water environment at 37 °C. Various current signals are used to control the temperature of the cold side of the Peltier device and the volume of water on top of the Peltier device affects the change in temperature. The pulsatile on-demand release profile of the model drug is obtained by turning the current signal on and off. The work has shown that the 2600 mAh power source is enough to power this device for 1.3 h. Furthermore, the excessive heat will not cause thermal damage in the body as it will be dissipated by the thermoregulation of the human body. Therefore, this simple novel device can be implanted and should work well in vivo. Copyright © 2013 Elsevier B.V. All rights reserved.

Trojan particles: Large porous carriers of nanoparticles for drug delivery

PubMed Central

Tsapis, N.; Bennett, D.; Jackson, B.; Weitz, D. A.; Edwards, D. A.

2002-01-01

We have combined the drug release and delivery potential of nanoparticle (NP) systems with the ease of flow, processing, and aerosolization potential of large porous particle (LPP) systems by spray drying solutions of polymeric and nonpolymeric NPs into extremely thin-walled macroscale structures. These hybrid LPPs exhibit much better flow and aerosolization properties than the NPs; yet, unlike the LPPs, which dissolve in physiological conditions to produce molecular constituents, the hybrid LPPs dissolve to produce NPs, with the drug release and delivery advantages associated with NP delivery systems. Formation of the large porous NP (LPNP) aggregates occurs via a spray-drying process that ensures the drying time of the sprayed droplet is sufficiently shorter than the characteristic time for redistribution of NPs by diffusion within the drying droplet, implying a local Peclet number much greater than unity. Additional control over LPNPs physical characteristics is achieved by adding other components to the spray-dried solutions, including sugars, lipids, polymers, and proteins. The ability to produce LPNPs appears to be largely independent of molecular component type as well as the size or chemical nature of the NPs. PMID:12200546

Ultrasound-stimulated drug delivery for treatment of residual disease after incomplete resection of head and neck cancer.

PubMed

Sorace, Anna G; Korb, Melissa; Warram, Jason M; Umphrey, Heidi; Zinn, Kurt R; Rosenthal, Eben; Hoyt, Kenneth

2014-04-01

Microbubbles triggered with localized ultrasound (US) can improve tumor drug delivery and retention. Termed US-stimulated drug delivery, this strategy was applied to head and neck cancer (HNC) in a post-surgical tumor resection model. Luciferase-positive HNC squamous cell carcinoma (SCC) was implanted in the flanks of nude athymic mice (N = 24) that underwent various degrees of surgical tumor resection (0%, 50% or 100%). After surgery, animals received adjuvant therapy with cetuximab-IRDye alone, or cetuximab-IRDye in combination with US-stimulated drug delivery or saline injections (control) on days 4, 7 and 10. Tumor drug delivery was assessed on days 0, 4, 7, 10, 14 and 17 with an in vivo fluorescence imaging system, and tumor viability was evaluated at the same times with in vivo bioluminescence imaging. Tumor caliper measurements occurred two times per week for 24 d. Optical imaging revealed that in the 50% tumor resection group, US-stimulated drug delivery resulted in a significant increase in cetuximab delivery compared with administration of drug alone on day 10 (day of peak fluorescence) (p = 0.03). Tumor viability decreased in all groups that received cetuximab-IRDye in combination with US-stimulated drug delivery, compared with the group that received only the drug. After various degrees of surgical resection, this novel study reports positive improvements in drug uptake in the residual cancer cells when drug delivery is stimulated with US. Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Pulsed liquid microjet for intravascular injection

NASA Astrophysics Data System (ADS)

Palanker, Daniel V.; Fletcher, Daniel A.; Miller, Jason; Huie, Philip; Marmor, Michael; Blumenkranz, Mark S.

2002-06-01

Occlusions of the retinal veins and arteries are associated with common diseases such as hypertension and arteriosclerosis and usually cause severe and irreversible loss of vision. Treatments for these vascular diseases have been unsatisfactory to date in part because of the difficulty of delivering thrombolytic drugs locally within the eye. In this article we describe a pulsed liquid microjet for minimally invasive intra-vascular drug delivery. The microjet is driven by a vapor bubble following an explosive evaporation of saline, produced by a microsecond-long electric discharge in front of the 25 micrometers electrode inside the micronozzle. Expansion of the transient vapor bubble produces a water jet with a diameter equal to the diameter of the nozzle, and with a velocity and duration that are controlled by the pulse energy. We found that fluid could be injected through the wall of a 60-micrometers -diameter artery in choriallantoic membrane using a 15-micrometers diameter liquid jet traveling at more than 60 m/s. Histological analysis of these arteries showed that the width of the perforation is limited to the diameter of the micronozzle, and the penetration depth of the jet is controlled by the discharge energy. The pulsed liquid microjet offers a promising technique for precise and needle-free intravascular delivery of thrombolytic drugs for localized treatment of retinal vascular occlusions.

Tough Composite Hydrogels with High Loading and Local Release of Biological Drugs.

PubMed

Li, Jianyu; Weber, Eckhard; Guth-Gundel, Sabine; Schuleit, Michael; Kuttler, Andreas; Halleux, Christine; Accart, Nathalie; Doelemeyer, Arno; Basler, Anne; Tigani, Bruno; Wuersch, Kuno; Fornaro, Mara; Kneissel, Michaela; Stafford, Alexander; Freedman, Benjamin R; Mooney, David J

2018-05-01

Hydrogels are under active development for controlled drug delivery, but their clinical translation is limited by low drug loading capacity, deficiencies in mechanical toughness and storage stability, and poor control over the drug release that often results in burst release and short release duration. This work reports a design of composite clay hydrogels, which simultaneously achieve a spectrum of mechanical, storage, and drug loading/releasing properties to address the critical needs from translational perspectives. The clay nanoparticles provide large surface areas to adsorb biological drugs, and assemble into microparticles that are physically trapped within and toughen hydrogel networks. The composite hydrogels demonstrate feasibility of storage, and extended release of large quantities of an insulin-like growth factor-1 mimetic protein (8 mg mL -1 ) over four weeks. The release rate is primarily governed by ionic exchange and can be upregulated by low pH, which is typical for injured tissues. A rodent model of Achilles tendon injury is used to demonstrate that the composite hydrogels allow for highly extended and localized release of biological drugs in vivo, while demonstrating biodegradation and biocompatibility. These attributes make the composite hydrogel a promising system for drug delivery and regenerative medicine. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

PubMed Central

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

2011-01-01

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

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

PubMed Central

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

2012-01-01

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

Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor

NASA Astrophysics Data System (ADS)

Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan; Acosta, Camilo; Sierra Sánchez, Carlos; Konofagou, Elisa E.

2016-06-01

The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain.

A novel platelet lysate hydrogel for endothelial cell and mesenchymal stem cell-directed neovascularization.

PubMed

Robinson, Scott T; Douglas, Alison M; Chadid, Tatiana; Kuo, Katie; Rajabalan, Ajai; Li, Haiyan; Copland, Ian B; Barker, Thomas H; Galipeau, Jacques; Brewster, Luke P

2016-05-01

Mesenchymal stem cells (MSC) hold promise in promoting vascular regeneration of ischemic tissue in conditions like critical limb ischemia of the leg. However, this approach has been limited in part by poor cell retention and survival after delivery. New biomaterials offer an opportunity to localize cells to the desired tissue after delivery, but also to improve cell survival after delivery. Here we characterize the mechanical and microstructural properties of a novel hydrogel composed of pooled human platelet lysate (PL) and test its ability to promote MSC angiogenic activity using clinically relevant in vitro and in vivo models. This PL hydrogel had comparable storage and loss modulus and behaved as a viscoelastic solid similar to fibrin hydrogels despite having 1/4-1/10th the fibrin content of standard fibrin gels. Additionally, PL hydrogels enabled sustained release of endogenous PDGF-BB for up to 20days and were resistant to protease degradation. PL hydrogel stimulated pro-angiogenic activity by promoting human MSC growth and invasion in a 3D environment, and enhancing endothelial cell sprouting alone and in co-culture with MSCs. When delivered in vivo, the combination of PL and human MSCs improved local tissue perfusion after 8days compared to controls when assessed with laser Doppler perfusion imaging in a murine model of hind limb ischemia. These results support the use of a PL hydrogel as a scaffold for MSC delivery to promote vascular regeneration. Innovative strategies for improved retention and viability of mesenchymal stem cells (MSCs) are needed for cellular therapies. Human platelet lysate is a potent serum supplement that improves the expansion of MSCs. Here we characterize our novel PL hydrogel's desirable structural and biologic properties for human MSCs and endothelial cells. PL hydrogel can localize cells for retention in the desired tissue, improves cell viability, and augments MSCs' angiogenic activity. As a result of these unique traits, PL hydrogel is ideally suited to serve as a cell delivery vehicle for MSCs injected into ischemic tissues to promote vascular regeneration, as demonstrated here in a murine model of hindlimb ischemia. Published by Elsevier Ltd.

Localized increase of tissue oxygen tension by magnetic targeted drug delivery

NASA Astrophysics Data System (ADS)

Liong, Celine; Ortiz, Daniel; Ao-ieong, Eilleen; Navati, Mahantesh S.; Friedman, Joel M.; Cabrales, Pedro

2014-07-01

Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O2) tension (PO2) of tissue by delivering more O2 have been clinically disappointing, largely due to the way O2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O2 delivery to a target tissue by decreasing the Hb-O2 affinity of the blood circulating within the targeted tissue. As the Hb-O2 affinity decreases, the tissue PO2 to satisfy tissue O2 metabolic needs increases without increasing O2 delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxy-methylpropionic acid). L35 decreases Hb affinity for O2 and favors the release of O2. The L35-coated PMNPs (L35-PMNPs) were intravenously infused (10 mg kg-1) to hamsters instrumented with the dorsal window chamber model. A magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O2 transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO2 in untreated control animals was 25.2 mmHg. L35-PMNPs without magnetic field decreased tissue PO2 to 23.4 mmHg, increased blood pressure, and reduced blood flow, largely due to systemic modification of Hb-O2 affinity. L35-PMNPs with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O2 affinity can increase PO2 of target tissue without affecting systemic O2 delivery or triggering O2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to increase O2 in tumors, enhancing the efficacy of radiation therapies.

Understanding the organization of public health delivery systems: an empirical typology.

PubMed

Mays, Glen P; Scutchfield, F Douglas; Bhandari, Michelyn W; Smith, Sharla A

2010-03-01

Policy discussions about improving the U.S. health care system increasingly recognize the need to strengthen its capacities for delivering public health services. A better understanding of how public health delivery systems are organized across the United States is critical to improvement. To facilitate the development of such evidence, this article presents an empirical method of classifying and comparing public health delivery systems based on key elements of their organizational structure. This analysis uses data collected through a national longitudinal survey of local public health agencies serving communities with at least 100,000 residents. The survey measured the availability of twenty core public health activities in local communities and the types of organizations contributing to each activity. Cluster analysis differentiated local delivery systems based on the scope of activities delivered, the range of organizations contributing, and the distribution of effort within the system. Public health delivery systems varied widely in organizational structure, but the observed patterns of variation suggested that systems adhere to one of seven distinct configurations. Systems frequently migrated from one configuration to another over time, with an overall trend toward offering a broader scope of services and engaging a wider range of organizations. Public health delivery systems exhibit important structural differences that may influence their operations and outcomes. The typology developed through this analysis can facilitate comparative studies to identify which delivery system configurations perform best in which contexts.

Poly-cyclodextrin functionalized porous bioceramics for local chemotherapy and anticancer bone reconstruction.

PubMed

Chai, Feng; Abdelkarim, Mohamed; Laurent, Thomas; Tabary, Nicolas; Degoutin, Stephanie; Simon, Nicolas; Peters, Fabian; Blanchemain, Nicolas; Martel, Bernard; Hildebrand, Hartmut F

2014-08-01

The progress in bone cancer surgery and multimodal treatment concept achieve only modest improvement in the overall survival, due to failure in clearing out residual cancer cells at the surgical margin and extreme side-effects of adjuvant postoperative treatments. Our study aims to propose a new method based on cyclodextrin polymer (polyCD) functionalized hydroxyapatite (HA) for achieving a high local drug concentration with a sustained release profile and a better control of residual malignant cells via local drug delivery and promotion of the reconstruction of bone defects. PolyCD, a versatile carrier for therapeutic molecules, can be incorporated into HA (bone regeneration scaffold) through thermal treatment. The parameters of polyCD treatment on the macroporous HA (porosity 65%) were characterized via thermogravimetric analysis. Good cytocompatibility of polyCD functionalized bioceramics was demonstrated on osteoblast cells by cell vitality assay. An antibiotic (gentamicin) and an anticancer agent (cisplatin) were respectively loaded on polyCD functionalized bioceramics for drug release test. The results show that polyCD functionalization leads to significantly improved drug loading quantity (30% more concerning gentamicin and twice more for cisplatin) and drug release duration (7 days longer concerning gentamicin and 3 days longer for cisplatin). Conclusively, this study offers a safe and reliable drug delivery system for bioceramic matrices, which can load anticancer agents (or/and antibiotics) to reduce local recurrence (or/and infection). © 2014 Wiley Periodicals, Inc.

Folic acid-decorated polyamidoamine dendrimer exhibits high tumor uptake and sustained highly localized retention in solid tumors: Its utility for local siRNA delivery.

PubMed

Xu, Leyuan; Yeudall, W Andrew; Yang, Hu

2017-07-15

The utility of folic acid (FA)-decorated polyamidoamine dendrimer G4 (G4-FA) as a vector was investigated for local delivery of siRNA. In a xenograft HN12 (or HN12-YFP) tumor mouse model of head and neck squamous cell carcinomas (HNSCC), intratumorally (i.t.) injected G4-FA exhibited high tumor uptake and sustained highly localized retention in the tumors according to near infrared (NIR) imaging assessment. siRNA against vascular endothelial growth factor A (siVEGFA) was chosen as a therapeutic modality. Compared to the nontherapeutic treatment groups (PBS solution or dendrimer complexed with nontherapeutic siRNA against green fluorescent protein (siGFP)), G4-FA/siVEGFA showed tumor inhibition effects in single-dose and two-dose regimen studies. In particular, two doses of G4-FA/siVEGFA i.t. administered eight days apart resulted in a more profound inhibition of tumor growth, accompanied with significant reduction in angiogenesis, as judged by CD31 staining and microvessel counts. Tumor size reduction in the two-dose regimen study was ascertained semi-quantitatively by live fluorescence imaging of YFP tumors and independently supported antitumor effects of G4-FA/siVEGFA. Taken together, G4-FA shows high tumor uptake and sustained retention properties, making it a suitable platform for local delivery of siRNAs to treat cancers that are readily accessible such as HNSCC. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is difficult to transfect for gene therapy. We developed folate receptor (FR)-targeted polyamidoamine (PAMAM) dendrimer for enhanced delivery of genes to HNSCC and gained in-depth understanding of how gene delivery and transfection in head and neck squamous cancer cells can be enhanced via FR-targeted PAMAM dendrimers. The results we report here are encouraging and present latest advances in using dendrimers for cancer therapies, in particular for HNSCC. Our work has demonstrated that localized delivery of FR-targeted PAMAM dendrimer G4 complexed with siVEGFA resulted in pronounced tumor suppression in an HN12 xenograft tumor model. Tumor suppression was attributed to enhanced tumor uptake of siRNA and prolonged nanoparticle retention in the tumor. Taken together, G4-FA shows high tumor uptake and sustained highly localized retention properties, making it a suitable platform for local delivery of siRNAs to treat cancers that are readily accessible such as HNSCC. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

3D printed bioceramics for dual antibiotic delivery to treat implant-associated bone infection

PubMed Central

Inzana, Jason A.; Trombetta, Ryan P.; Schwarz, Edward M.; Kates, Stephen L.; Awad, Hani A.

2015-01-01

Surgical implant-associated bone infections (osteomyelitis) have severe clinical and socioeconomic consequences. Treatment of chronic bone infections often involves antibiotics given systemically and locally to the affected site via poly(methyl methacrylate) (PMMA) bone cement. Given the high antibiotic concentrations required to affect bacteria in biofilm, local delivery is important to achieve high doses at the infection site. PMMA is not suitable to locally deliver some biofilm-specific antibiotics, including rifampin, due to interference with PMMA polymerization. To examine the efficacy of localized, combinational antibiotic delivery compared to PMMA standards, we fabricated rifampin- and vancomycin-laden calcium phosphate scaffolds (CPS) by three-dimensional (3D) printing to treat an implant-associated Staphylococcus aureus bone infection in a murine model. All vancomycin- and rifampin-laden CPS treatments significantly reduced the bacterial burden compared with vancomycin-laden PMMA. The bones were bacteria culture negative in 50% of the mice that received sustained release vancomycin- and rifampin-laden CPS. In contrast, 100% of the bones treated with vancomycin monotherapy via PMMA or CPS were culture positive. Yet, the monotherapy CPS significantly reduced the bacterial metabolic load following revision compared to PMMA. Biofilm persisted on the fixation hardware, but the infection-induced bone destruction was significantly reduced by local rifampin delivery. These data demonstrate that, despite the challenging implant-retaining infection model, co-delivery of rifampin and vancomycin from 3D printed CPS, which is not possible with PMMA, significantly improved the outcomes of implant-associated osteomyelitis. However, biofilm persistence on the fixation hardware reaffirms the importance of implant exchange or other biofilm eradication strategies to complement local antibiotics. PMID:26535494

From home deliveries to health care facilities: establishing a traditional birth attendant referral program in Kenya.

PubMed

Tomedi, Angelo; Stroud, Sophia R; Maya, Tania Ruiz; Plaman, Christopher R; Mwanthi, Mutuku A

2015-07-16

To assess the effectiveness of a traditional birth attendant (TBA) referral program on increasing the number of deliveries overseen by skilled birth attendants (SBA) in rural Kenyan health facilities before and after the implementation of a free maternity care policy. In a rural region of Kenya, TBAs were recruited to educate pregnant women about the importance of delivering in healthcare facilities and were offered a stipend for every pregnant woman whom they brought to the healthcare facility. We evaluated the percentage of prenatal care (PNC) patients who delivered at the intervention site compared with the percentage of PNC patients who delivered at rural control facilities, before and after the referral program was implemented, and before and after the Kenya government implemented a policy of free maternity care. The window period of the study was from July of 2011 through September 2013, with a TBA referral intervention conducted from March to September 2013. The absolute increases from the pre-intervention period to the TBA referral intervention period in SBA deliveries were 5.7 and 24.0% in the control and intervention groups, respectively (p < 0.001). The absolute increases in SBA delivery rates from the pre-intervention period to the intervention period before the implementation of the free maternity care policy were 4.7 and 17.2% in the control and intervention groups, respectively (p < 0.001). After the policy implementation the absolute increases from pre-intervention to post-intervention were 1.8 and 11.6% in the control and intervention groups, respectively (p < 0.001). The percentage of SBA deliveries at the intervention health facility significantly increased compared to control health facilities when TBAs educated women about the need to deliver with a SBA and when TBAs received a stipend for bringing women to local health facilities to deliver. Furthermore, this TBA referral program proved to be far more effective in the target region of Kenya than a policy change to provide free obstetric care.

Transient and local increase in the permeability of the blood-brain barrier and the blood-retinal barrier by hyperthermia of magnetic nanoparticles in a rat model

NASA Astrophysics Data System (ADS)

Tabatabaei Shafie, Seyed Nasrollah

After successfully propelling therapeutic agents encapsulated in magnetic micro-carriers to a specific location inside an animal model by the gradient magnetic field of a modified clinical Magnetic Resonance (MR) scanner, we are now aiming to perform local drug delivery in the region of the central nervous system (CNS). To achieve localized drug delivery and increase efficacy, this project advances the theme that the therapeutic agents must be administered by means no more invasive than an intravenous injection followed by remote propulsion, controlled tracking, and on-command actuation in the CNS. The demanding function of the CNS requires an extremely stable environment. In fact, any small change in the composition of the interstitial fluid in the CNS plays a predominant role in regulating its microenvironment and neuronal activity. Therefore, the CNS is conceived to protect itself from frequent fluctuations of extracellular concentration of hormones, amino acids, and ion levels that occur after meals, exercise, or stress - as well as from toxic pathogens that may be circulating in the blood stream. This preventive barrier consists mainly of tightly interconnected endothelial cells that carpet the inner surface of most blood vessels in the CNS. While it provides a stable neuronal environment, more than 98% of all drug molecules are not able to cross this barrier and the extent to which a molecule enters is determined only by the permeability characteristics of the barrier. Therefore, while pharmaceutical research progresses for drug delivery to the CNS, it is limited by its pharmacokinetics through physiological barriers. Successful transient and local opening of the barrier for diffusion of therapeutics could strongly support the feasibility of treating a variety of neurological disorders. A recent effort presented in this dissertation provides evidence for the emergence of a novel approach to overcome this problem. This technique uses magnetic nanoparticles (MNPs) in conjunction with an alternating magnetic field to transiently increase barrier permeability for drug delivery. MNPs can act as miniaturized heat sources that, when under the influence of the alternating magnetic field, dissipate thermal energy directly and exclusively to the barrier (hyperthermia). In addition to its novelty, the findings confirm that the technique does not damage the neurovascular unit, i.e. neurons, astrocytes, etc. This in vivo investigation provides evidence that the proposed approach goes beyond former methods to access the CNS tissue with higher spatial precision, advanced control and apparent absence of immune reaction. Evidently, the ensemble of tracking and displacement abilities (MR technology), as well as hyperthermia, makes MNPs a principal component of the proposed non-invasive targeted drug delivery mechanism to the CNS. Because of its simplicity and specificity, this technique can introduce an enormous economical and social impact on quality of the life of patients diagnosed with CNS-related disorders.

Impact insertion of transfer-molded microneedle for localized and minimally invasive ocular drug delivery.

PubMed

Song, Hyun Beom; Lee, Kang Ju; Seo, Il Ho; Lee, Ji Yong; Lee, Sang-Mok; Kim, Jin Hyoung; Kim, Jeong Hun; Ryu, WonHyoung

2015-07-10

It has been challenging for microneedles to deliver drugs effectively to thin tissues with little background support such as the cornea. Herein, we designed a microneedle pen system, a single microneedle with a spring-loaded microneedle applicator to provide impact insertion. To firmly attach solid microneedles with 140 μm in height at the end of macro-scale applicators, a transfer molding process was employed. The fabricated microneedle pens were then applied to mouse corneas. The microneedle pens successfully delivered rhodamine dye deep enough to reach the stromal layer of the cornea with small entry only about 1000 μm(2). When compared with syringes or 30 G needle tips, microneedle pens could achieve more localized and minimally invasive delivery without any chances of perforation. To investigate the efficacy of microneedle pens as a way of drug delivery, sunitinib malate proven to inhibit in vitro angiogenesis, was delivered to suture-induced angiogenesis model. When compared with delivery by a 30 G needle tip dipped with sunitinib malate, only delivery by microneedle pens could effectively inhibit corneal neovascularization in vivo. Microneedle pens could effectively deliver drugs to thin tissues without impairing merits of using microneedles: localized and minimally invasive delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

Ultrasound mediated nanoparticle drug delivery

NASA Astrophysics Data System (ADS)

Mullin, Lee B.

Ultrasound is not only a powerful diagnostic tool, but also a promising therapeutic technology that can be used to improve localized drug delivery. Microbubble contrast agents are micron sized encapsulated gas filled bubbles that are administered intravenously. Originally developed to enhance ultrasound images, microbubbles are highly echogenic due to the gas core that provides a detectable impedance difference from the surrounding medium. The core also allows for controlled response of the microbubbles to ultrasound pulses. Microbubbles can be pushed using acoustic radiation force and ruptured using high pressures. Destruction of microbubbles can increase permeability at the cellular and vascular level, which can be advantageous for drug delivery. Advances in drug delivery methods have been seen with the introduction of nanoparticles, nanometer sized objects often carrying a drug payload. In chemotherapy, nanoparticles can deliver drugs to tumors while limiting systemic exposure due to abnormalities in tumor vasculature such large gaps between endothelial cells that allow nanoparticles to enter into the interstitial space; this is referred to as the enhanced permeability and retention (EPR) effect. However, this effect may be overestimated in many tumors. Additionally, only a small percentage of the injected dose accumulates in the tumor, which most the nanoparticles accumulating in the liver and spleen. It is hypothesized that combining the acoustic activity of an ultrasound contrast agent with the high payload and extravasation ability of a nanoparticle, localized delivery to the tumor with reduced systemic toxicity can be achieved. This method can be accomplished by either loading nanoparticles onto the shell of the microbubble or through a coadministration method of both nanoparticles and microbubbles. The work presented in this dissertation utilizes novel and commercial nanoparticle formulations, combined with microbubbles and a variety of ultrasound systems. Ultrasound parameters are optimized to achieve maximum cell internalization of molecules and increased nanoparticle delivery to a cell layer on a coverslip. In-vivo studies demonstrate the possibility of using a lower dose of paclitaxel to slow tumor growth rates, increase doxorubicin concentration in tumor tissue, and enhance tumor delivery of fluorescent molecules through treatments that combine nanoparticles with ultrasound and microbubbles.

MRI-Based Computational Model of Heterogeneous Tracer Transport following Local Infusion into a Mouse Hind Limb Tumor

PubMed Central

Magdoom, Kulam Najmudeen; Pishko, Gregory L.; Rice, Lori; Pampo, Chris; Siemann, Dietmar W.; Sarntinoranont, Malisa

2014-01-01

Systemic drug delivery to solid tumors involving macromolecular therapeutic agents is challenging for many reasons. Amongst them is their chaotic microvasculature which often leads to inadequate and uneven uptake of the drug. Localized drug delivery can circumvent such obstacles and convection-enhanced delivery (CED) - controlled infusion of the drug directly into the tissue - has emerged as a promising delivery method for distributing macromolecules over larger tissue volumes. In this study, a three-dimensional MR image-based computational porous media transport model accounting for realistic anatomical geometry and tumor leakiness was developed for predicting the interstitial flow field and distribution of albumin tracer following CED into the hind-limb tumor (KHT sarcoma) in a mouse. Sensitivity of the model to changes in infusion flow rate, catheter placement and tissue hydraulic conductivity were investigated. The model predictions suggest that 1) tracer distribution is asymmetric due to heterogeneous porosity; 2) tracer distribution volume varies linearly with infusion volume within the whole leg, and exponentially within the tumor reaching a maximum steady-state value; 3) infusion at the center of the tumor with high flow rates leads to maximum tracer coverage in the tumor with minimal leakage outside; and 4) increasing the tissue hydraulic conductivity lowers the tumor interstitial fluid pressure and decreases the tracer distribution volume within the whole leg and tumor. The model thus predicts that the interstitial fluid flow and drug transport is sensitive to porosity and changes in extracellular space. This image-based model thus serves as a potential tool for exploring the effects of transport heterogeneity in tumors. PMID:24619021

Toxicology study for magnetic injection of prednisolone into the rat cochlea.

PubMed

Shimoji, M; Ramaswamy, B; Shukoor, M I; Benhal, P; Broda, A; Kulkarni, S; Malik, P; McCaffrey, B; Lafond, J-F; Nacev, A; Weinberg, I N; Shapiro, B; Depireux, D A

2018-06-19

This paper investigates the safety of a novel 'magnetic injection' method of delivering therapy to the cochlea, in a rodent model. In this method of administration, a magnetic field is employed to actively transport drug-eluting iron oxide-core nanoparticles into the cochlea, where they then release their drug payload (we delivered the steroid prednisolone). Our study design and selection of control groups was based on published regulatory guidance for safety studies that involve local drug delivery. We tested for both single and multiple delivery doses to the cochlea, and found that magnetic delivery did not harm hearing. There was no statistical difference in hearing between magnetically treated ears versus ears that received intra-tympanic steroid (a mimic of a standard-of-care for sudden sensorineural hearing loss), both 2 and 30 days after treatment. Since our treatment is local to the ear, the levels of steroid and iron circulating systemically after our treatment were low, below mass-spectrometry detection limits for the steroid and no different from normal for iron. No adverse findings were observed in ear tissue histopathology or in animal gross behavior. At 2 and 30 days after treatment, inflammatory changes in the ear were limited to the middle ear, were very mild in severity, and by day 90 there was ongoing and almost complete reversibility of these changes. There were no ear tissue scarring or hemorrhage trends associated with magnetic delivery. In summary, after conducting a pre-clinical safety study based on FDA guidance documents, no adverse safety issues were observed. Copyright © 2017. Published by Elsevier B.V.

Drug delivery to the human and mouse uterus using immunoliposomes targeted to the oxytocin receptor.

PubMed

Paul, Jonathan W; Hua, Susan; Ilicic, Marina; Tolosa, Jorge M; Butler, Trent; Robertson, Sarah; Smith, Roger

2017-03-01

The ability to provide safe and effective pharmacotherapy during obstetric complications, such as preterm labor or postpartum hemorrhage, is hampered by the systemic toxicity of therapeutic agents leading to adverse side effects in the mother and fetus. Development of novel strategies to target tocolytic and uterotonic agents specifically to uterine myocytes would improve therapeutic efficacy while minimizing the risk of side effects. Ligand-targeted liposomes have emerged as a reliable and versatile platform for targeted drug delivery to specific cell types, tissues or organs. Our objective was to develop a targeted drug delivery system for the uterus utilizing an immunoliposome platform targeting the oxytocin receptor. We conjugated liposomes to an antibody that recognizes an extracellular domain of the oxytocin receptor. We then examined the ability of oxytocin receptor-targeted liposomes to deliver contraction-blocking (nifedipine, salbutamol and rolipram) or contraction-enhancing (dofetilide) agents to strips of spontaneously contracting myometrial tissue in vitro (human and mouse). We evaluated the ability of oxytocin receptor-targeted liposomes to localize to uterine tissue in vivo, and assessed if targeted liposomes loaded with indomethacin were capable of preventing lipopolysaccharide-induced preterm birth in mice. Oxytocin receptor-targeted liposomes loaded with nifedipine, salbutamol or rolipram consistently abolished human myometrial contractions in vitro, while oxytocin receptor-targeted liposomes loaded with dofetilide increased contraction duration. Nontargeted control liposomes loaded with these agents had no effect. Similar results were observed in mouse uterine strips. Following in vivo administration to pregnant mice, oxytocin receptor-targeted liposomes localized specifically to the uterine horns and mammary tissue. Targeting increased localization to the uterus 7-fold. Localization was not detected in the maternal brain or fetus. Targeted and nontargeted liposomes also localized to the liver. Oxytocin receptor-targeted liposomes loaded with indomethacin were effective in reducing rates of preterm birth in mice, whereas nontargeted liposomes loaded with indomethacin had no effect. Our results demonstrate that oxytocin receptor-targeted liposomes can be used to either inhibit or enhance human uterine contractions in vitro. In vivo, the liposomes localized to the uterine tissue of pregnant mice and were effective in delivering agents for the prevention of inflammation-induced preterm labor. The potential clinical advantage of targeted liposomal drug delivery to the myometrium is reduced dose and reduced toxicity to both mother and fetus. Copyright © 2016. Published by Elsevier Inc.

Improved wound healing of postischemic cutaneous flaps with the use of bone marrow-derived stem cells.

PubMed

Hu, Melissa; Ludlow, David; Alexander, J Steven; McLarty, Jerry; Lian, Timothy

2014-03-01

To determine if the intravascular delivery of mesenchymal stem cells improves wound healing and blood perfusion to postischemic cutaneous flap tissues. Randomized controlled study. A murine model of a cutaneous flap was created based on the inferior epigastric vessels. Mice (n = 14) underwent 3.5 hours of ischemia followed by reperfusion. Bone marrow stromal cells (BMSCs) 1 × 10(6) were injected intravenously. Wound healing was then assessed measuring percent flap necrosis, flap perfusion, and tensile strength of the flap after a period of 14 days. Localization of BMSCs was determined with radiolabeled and fluorescent labeled BMSCs. Postischemic cutaneous flap tissues treated with BMSCs demonstrated significantly less necrosis than control flaps (P <0.01). Beginning on postoperative day 5, BMSC-treated flaps demonstrated greater blood perfusion than untreated flaps (P <0.01). Tensile strength of BMSC-treated cutaneous flaps was significantly higher (P <0.01), with a mean strength of 283.4 ± 28.4 N/m than control flaps with a mean of 122.4 ± 23.5 N/m. Radiolabeled BMSCs localized to postischemic flaps compared to untreated tissues (P = 0.001). Fluorescent microscopy revealed incorporation of BMSCs into endothelial and epithelial tissues of postischemic flaps. This study demonstrates that the intravascular delivery of BMSCs increases wound healing and promotes flap survival following ischemia-reperfusion injury of cutaneous tissue flaps. © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

Sequential delivery of TAT-HSP27 and VEGF using microsphere/hydrogel hybrid systems for therapeutic angiogenesis.

PubMed

Shin, Seung-Hwa; Lee, Jangwook; Lim, Kwang Suk; Rhim, Taiyoun; Lee, Sang Kyung; Kim, Yong-Hee; Lee, Kuen Yong

2013-02-28

Ischemic disease is associated with high mortality and morbidity rates, and therapeutic angiogenesis via systemic or local delivery of protein drugs is one potential approach to treat the disease. In this study, we hypothesized that combined delivery of TAT-HSP27 (HSP27 fused with transcriptional activator) and VEGF could enhance the therapeutic efficacy in an ischemic mouse model, and that sequential release could be critical in therapeutic angiogenesis. Alginate hydrogels containing TAT-HSP27 as an anti-apoptotic agent were prepared, and porous PLGA microspheres loaded with VEGF as an angiogenic agent were incorporated into the hydrogels to prepare microsphere/hydrogel hybrid delivery systems. Sequential in vitro release of TAT-HSP27 and VEGF was achieved by the hybrid systems. TAT-HSP27 was depleted from alginate gels in 7 days, while VEGF was continually released for 28 days. The release rate of VEGF was attenuated by varying the porous structures of PLGA microspheres. Sequential delivery of TAT-HSP27 and VEGF was critical to protect against muscle degeneration and fibrosis, as well as to promote new blood vessel formation in the ischemic site of a mouse model. This approach to controlling the sequential release behaviors of multiple drugs could be useful in the design of novel drug delivery systems for therapeutic angiogenesis. Copyright © 2012 Elsevier B.V. All rights reserved.

Bio-inspired materials in drug delivery: Exploring the role of pulmonary surfactant in siRNA inhalation therapy.

PubMed

De Backer, Lynn; Cerrada, Alejandro; Pérez-Gil, Jesús; De Smedt, Stefaan C; Raemdonck, Koen

2015-12-28

Many pathologies of the respiratory tract are inadequately treated with existing small molecule-based therapies. The emergence of RNA interference (RNAi) enables the post-transcriptional silencing of key molecular disease factors that cannot readily be targeted with conventional small molecule drugs. Pulmonary administration of RNAi effectors, such as small interfering RNA (siRNA), allows direct delivery into the lung tissue, hence reducing systemic exposure. Unfortunately, the clinical translation of RNAi is severely hampered by inefficient delivery of siRNA therapeutics towards the cytoplasm of the target cells. In order to have a better control of the siRNA delivery process, both extra- and intracellular, siRNAs are typically formulated in nanosized delivery vehicles (nanoparticles, NPs). In the lower airways, which are the targeted sites of action for multiple pulmonary disorders, these siRNA-loaded NPs will encounter the pulmonary surfactant (PS) layer, covering the entire alveolar surface. The interaction between the instilled siRNA-loaded NPs and the PS at this nano-bio interface results in the adsorption of PS components onto the surface of the NPs. The formation of this so-called biomolecular corona conceals the original NP surface and will therefore profoundly determine the biological efficacy of the NP. Though this interplay has initially been regarded as a barrier towards efficient siRNA delivery to the respiratory target cell, recent reports have illustrated that the interaction with PS might also be beneficial for local pulmonary siRNA delivery.

Gold nanoparticles delivery in mammalian live cells: a critical review

PubMed Central

Lévy, Raphaël; Shaheen, Umbreen; Cesbron, Yann; Sée, Violaine

2010-01-01

Functional nanomaterials have recently attracted strong interest from the biology community, not only as potential drug delivery vehicles or diagnostic tools, but also as optical nanomaterials. This is illustrated by the explosion of publications in the field with more than 2,000 publications in the last 2 years (4,000 papers since 2000; from ISI Web of Knowledge, ‘nanoparticle and cell’ hit). Such a publication boom in this novel interdisciplinary field has resulted in papers of unequal standard, partly because it is challenging to assemble the required expertise in chemistry, physics, and biology in a single team. As an extreme example, several papers published in physical chemistry journals claim intracellular delivery of nanoparticles, but show pictures of cells that are, to the expert biologist, evidently dead (and therefore permeable). To attain proper cellular applications using nanomaterials, it is critical not only to achieve efficient delivery in healthy cells, but also to control the intracellular availability and the fate of the nanomaterial. This is still an open challenge that will only be met by innovative delivery methods combined with rigorous and quantitative characterization of the uptake and the fate of the nanoparticles. This review mainly focuses on gold nanoparticles and discusses the various approaches to nanoparticle delivery, including surface chemical modifications and several methods used to facilitate cellular uptake and endosomal escape. We will also review the main detection methods and how their optimum use can inform about intracellular localization, efficiency of delivery, and integrity of the surface capping. PMID:22110850

Differences in phosphorus and nitrogen delivery to the Gulf of Mexico from the Mississippi River Basin

USGS Publications Warehouse

Alexander, R.B.; Smith, R.A.; Schwarz, G.E.; Boyer, E.W.; Nolan, J.V.; Brakebill, J.W.

2008-01-01

Seasonal hypoxia in the northern Gulf of Mexico has been linked to increased nitrogen fluxes from the Mississippi and Atchafalaya River Basins, though recent evidence shows that phosphorus also influences productivity in the Gulf. We developed a spatially explicit and structurally detailed SPARROW water-quality model that reveals important differences in the sources and transport processes that control nitrogen (N) and phosphorus (P) delivery to the Gulf. Our model simulations indicate that agricultural sources in the watersheds contribute more than 70% of the delivered N and P. However, corn and soybean cultivation is the largest contributor of N (52%), followed by atmospheric deposition sources (16%); whereas P originates primarily from animal manure on pasture and rangelands (37%), followed by corn and soybeans (25%), other crops (18%), and urban sources (12%). The fraction of in-stream P and N load delivered to the Gulf increases with stream size, but reservoir trapping of P causes large local- and regional-scale differences in delivery. Our results indicate the diversity of management approaches required to achieve efficient control of nutrient loads to the Gulf. These include recognition of important differences in the agricultural sources of N and P, the role of atmospheric N, attention to P sources downstream from reservoirs, and better control of both N and P in close proximity to large rivers. ?? 2008 American Chemical Society.

In situ cross-linkable high molecular weight hyaluronan-bisphosphonate conjugate for localized delivery and cell-specific targeting: a hydrogel linked prodrug approach.

PubMed

Varghese, Oommen P; Sun, Weilun; Hilborn, Jöns; Ossipov, Dmitri A

2009-07-01

We present here a novel synthesis route to functionalize high molecular weight hyaluronan (HMW-HA) with a hydrazide group and a bioactive ligand, namely bisphosphonate (BP). For this purpose, a new symmetrical self-immolative biscarbazate linker has been devised. The hydrazide group was used to form hydrazone cross-linked hydrogel upon treating with previously described aldehyde modified hyaluronan. The 1:1 weight ratio of these two polymers gave hydrogel in less than 30 s. In this communication we present the first in vitro results showing that even though HA can target CD44 positive cancer cells (HCT-116), receptor mediated endocytosis could only occur by cleavage of high molecular weight HA with an ubiquitous enzyme, hyaluronidase (Hase). The cancer cells are known to overexpress CD44 receptors and also increase the hyaluronidase activity in vivo. Thus the pro-drug design, based on drug conjugation to HMW-HA, represents a new drug delivery platform where the drug potency is triggered by Hase mediated degradation of the HA-drug conjugate. We have successfully demonstrated that the cross-linkable HA-BP conjugate first undergoes Hase-mediated scission to the fragments of suitable sizes so as to be internalized by CD44 positive cells. The specificity of this targeting was proven by comparing the results with less CD44 positive HEK-293T cells. The localized delivery of such drugs at the surgical resection site opens up avenues to control tumor recurrence after removal of the tumor. In the form of hydrogel it would prevent systemic exposure of the drug and would allow its controlled release.

Local delivery of FTY720 accelerates cranial allograft incorporation and bone formation.

PubMed

Huang, Cynthia; Das, Anusuya; Barker, Daniel; Tholpady, Sunil; Wang, Tiffany; Cui, Quanjun; Ogle, Roy; Botchwey, Edward

2012-03-01

Endogenous stem cell recruitment to the site of skeletal injury is key to enhanced osseous remodeling and neovascularization. To this end, this study utilized a novel bone allograft coating of poly(lactic-co-glycolic acid) (PLAGA) to sustain the release of FTY720, a selective agonist for sphingosine 1-phosphate (S1P) receptors, from calvarial allografts. Uncoated allografts, vehicle-coated, low dose FTY720 in PLAGA (1:200 w:w) and high dose FTY720 in PLAGA (1:40) were implanted into critical size calvarial bone defects. The ability of local FTY720 delivery to promote angiogenesis, maximize osteoinductivity and improve allograft incorporation by recruitment of bone progenitor cells from surrounding soft tissues and microcirculation was evaluated. FTY720 bioactivity after encapsulation and release was confirmed with sphingosine kinase 2 assays. HPLC-MS quantified about 50% loaded FTY720 release of the total encapsulated drug (4.5 μg) after 5 days. Following 2 weeks of defect healing, FTY720 delivery led to statistically significant increases in bone volumes compared to controls, with total bone volume increases for uncoated, coated, low FTY720 and high FTY720 of 5.98, 3.38, 7.2 and 8.9 mm(3), respectively. The rate and extent of enhanced bone growth persisted through week 4 but, by week 8, increases in bone formation in FTY720 groups were no longer statistically significant. However, micro-computed tomography (microCT) of contrast enhanced vascular ingrowth (MICROFIL®) and histological analysis showed enhanced integration as well as directed bone growth in both high and low dose FTY720 groups compared to controls.

He Tamariki Kokoti Tau-Tackling Preterm: a data-linkage methodology to explore the clinical care pathway in preterm deliveries.

PubMed

Filoche, Sara; Cram, Fiona; Beard, Angela; Sim, Dalice; Geller, Stacie; Edmonds, Liza; Robson, Bridget; Lawton, Beverley

2018-05-21

Significant health inequities exist around maternal and infant health for Māori, the indigenous people of Aotearoa New Zealand - and in particular around a premature (preterm) delivery. Māori babies are more likely to be born preterm (8.1%, compared to an overall rate of 7.4%) and they are more likely to have a preterm death. An essential part of redressing these disparities is to examine the clinical care pathway and outcomes associated with preterm deliveries. This paper describes a protocol utilising national and local health collections to enable such a study. This is a retrospective cohort study comprising 5 years data pertaining to preterm deliveries from 2010 to 2014. These data are generated from linked national administrative and local health information collections to explore a range of neonatal outcomes and infant mortality in relation to the antenatal care pathway and known risk factors for preterm delivery. This study is being conducted within a Kaupapa Māori paradigm that dismisses victim blaming and seeks to intervene at structural levels to improve the health and wellbeing of Māori whānau (family). Our data-linkage methodology optimises the utility of New Zealand health collections to address a significant health issue. Our findings will fill the information gaps around the burden of preterm delivery by quantifying the incidence of preterm delivery and adverse neonatal and infant outcomes in Aotearoa New Zealand. It will explore access to evidenced based care including use of steroids before birth, and appropriate place of delivery. The results from this study will inform maternity care services to improve management of preterm deliveries - both locally and internationally. This in turn will improve the preterm sequela by reducing the long-term health burden and health inequities.

Transdermal delivery of scopolamine by natural submicron injectors: in-vivo study in pig.

PubMed

Shaoul, Esther; Ayalon, Ari; Tal, Yossi; Lotan, Tamar

2012-01-01

Transdermal drug delivery has made a notable contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. While transdermal delivery systems would appear to provide an attractive solution for local and systemic drug delivery, only a limited number of drugs can be delivered through the outer layer of the skin. The most difficult to deliver in this way are hydrophilic drugs. The aquatic phylum Cnidaria, which includes sea anemones, corals, jellyfish and hydra, is one of the most ancient multicellular phyla that possess stinging cells containing organelles (cnidocysts), comprising a sophisticated injection system. The apparatus is folded within collagenous microcapsules and upon activation injects a thin tubule that immediately penetrates the prey and delivers its contents. Here we show that this natural microscopic injection system can be adapted for systemic transdermal drug delivery once it is isolated from the cells and uploaded with the drug. Using a topically applied gel containing isolated natural sea anemone injectors and the muscarinic receptor antagonist scopolamine, we found that the formulated injectors could penetrate porcine skin and immediately deliver this hydrophilic drug. An in-vivo study in pigs demonstrated, for the first time, rapid systemic delivery of scopolamine, with T(max) of 30 minutes and C(max) 5 times higher than in controls treated topically with a scopolamine-containing gel without cnidocysts. The ability of the formulated natural injection system to penetrate a barrier as thick as the skin and systemically deliver an exogenous compound presents an intriguing and attractive alternative for hydrophilic transdermal drug delivery.

Transdermal Delivery of Scopolamine by Natural Submicron Injectors: In-Vivo Study in Pig

PubMed Central

Shaoul, Esther; Ayalon, Ari; Tal, Yossi; Lotan, Tamar

2012-01-01

Transdermal drug delivery has made a notable contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. While transdermal delivery systems would appear to provide an attractive solution for local and systemic drug delivery, only a limited number of drugs can be delivered through the outer layer of the skin. The most difficult to deliver in this way are hydrophilic drugs. The aquatic phylum Cnidaria, which includes sea anemones, corals, jellyfish and hydra, is one of the most ancient multicellular phyla that possess stinging cells containing organelles (cnidocysts), comprising a sophisticated injection system. The apparatus is folded within collagenous microcapsules and upon activation injects a thin tubule that immediately penetrates the prey and delivers its contents. Here we show that this natural microscopic injection system can be adapted for systemic transdermal drug delivery once it is isolated from the cells and uploaded with the drug. Using a topically applied gel containing isolated natural sea anemone injectors and the muscarinic receptor antagonist scopolamine, we found that the formulated injectors could penetrate porcine skin and immediately deliver this hydrophilic drug. An in-vivo study in pigs demonstrated, for the first time, rapid systemic delivery of scopolamine, with Tmax of 30 minutes and Cmax 5 times higher than in controls treated topically with a scopolamine-containing gel without cnidocysts. The ability of the formulated natural injection system to penetrate a barrier as thick as the skin and systemically deliver an exogenous compound presents an intriguing and attractive alternative for hydrophilic transdermal drug delivery. PMID:22363770

Polymeric drug delivery systems for intraoral site-specific chemoprevention of oral cancer.

PubMed

Desai, Kashappa Goud H

2018-04-01

Oral cancer is among the most prevalent cancers in the world. Moreover, it is one of the major health problems and causes of death in many regions of the world. The traditional treatment modalities include surgical removal, radiation therapy, systemic chemotherapy, or a combination of these methods. In recent decades, there has been significant interest in intraoral site-specific chemoprevention via local drug delivery using polymeric systems. Because of its easy accessibility and clear visibility, the oral mucosa is amenable for local drug delivery. A variety of polymeric systems-such as gels, tablets, films, patches, injectable systems (e.g., millicylindrical implants, microparticles, and in situ-forming depots), and nanosized carriers (e.g., polymeric nanoparticles, nanofibers, polymer-drug conjugates, polymeric micelles, nanoliposomes, nanoemulsions, and polymersomes)-have been developed and evaluated for the local delivery of natural and synthetic chemopreventive agents. The findings of in vitro, ex vivo, and in vivo studies and the positive outcome of clinical trials demonstrate that intraoral site-specific drug delivery is an attractive, highly effective and patient-friendly strategy for the management of oral cancer. Intraoral site-specific drug delivery provides unique therapeutic advantages when compared to systemic chemotherapy. Moreover, intraoral drug delivery systems are self-administrable and can be removed when needed, increasing patient compliance. This article covers important aspects and advances related to the design, development, and efficacy of polymeric systems for intraoral site-specific drug delivery. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1383-1413, 2018. © 2017 Wiley Periodicals, Inc.

Recent Advances in Drug Eluting Stents

PubMed Central

Puranik, Amey S.; Dawson, Eileen R.; Peppas, Nicholas A.

2013-01-01

One of the most common medical interventions to reopen an occluded vessel is the implantation of a coronary stent. While this method of treatment is effective initially, restenosis, or the re-narrowing of the artery frequently occurs largely due to neointimal hyperplasia of smooth muscle cells. Drug eluting stents were developed in order to provide local, site-specific, controlled release of drugs that can inhibit neointima formation. By implementing a controlled release delivery system it may be possible to control the time release of the pharmacological factors and thus be able to bypass some of the critical events associated with stent hyperplasia and prevent the need for subsequent intervention. However, since the advent of first-generation drug eluting stents, long-term adverse effects have raised concerns regarding their safety. These limitations in safety and efficacy have triggered considerable research in developing biodegradable stents and more potent drug delivery systems. In this review, we shed light on the current state-of-the-art in drug eluting stents, problems related to them and highlight some of the ongoing research in this area. PMID:23117022

3D printed bioceramics for dual antibiotic delivery to treat implant-associated bone infection.

PubMed

Inzana, J A; Trombetta, R P; Schwarz, E M; Kates, S L; Awad, H A

2015-11-04

Surgical implant-associated bone infections (osteomyelitis) have severe clinical and socioeconomic consequences. Treatment of chronic bone infections often involves antibiotics given systemically and locally to the affected site in poly (methyl methacrylate) (PMMA) bone cement. Given the high antibiotic concentrations required to affect bacteria in biofilm, local delivery is important to achieve high doses at the infection site. PMMA is not suitable to locally-deliver some biofilm-specific antibiotics, including rifampin, due to interference with PMMA polymerisation. To examine the efficacy of localised, combinational antibiotic delivery compared to PMMA standards, we fabricated rifampin- and vancomycin-laden calcium phosphate scaffolds (CPS) by three-dimensional (3D) printing to treat an implant-associated Staphylococcus aureus bone infection in a murine model. All vancomycin- and rifampin-laden CPS treatments significantly reduced the bacterial burden compared with vancomycin-laden PMMA. The bones were bacteria culture negative in 50 % of the mice that received sustained release vancomycin- and rifampin-laden CPS. In contrast, 100 % of the bones treated with vancomycin monotherapy using PMMA or CPS were culture positive. Yet, the monotherapy CPS significantly reduced the bacterial metabolic load following revision compared to PMMA. Biofilm persisted on the fixation hardware, but the infection-induced bone destruction was significantly reduced by local rifampin delivery. These data demonstrate that, despite the challenging implant-retaining infection model, co-delivery of rifampin and vancomycin from 3D printed CPS, which is not possible with PMMA, significantly improved the outcomes of implant-associated osteomyelitis. However, biofilm persistence on the fixation hardware reaffirms the importance of implant exchange or other biofilm eradication strategies to complement local antibiotics.

Enhancing topical analgesic administration: review and prospect for transdermal and transbuccal drug delivery systems.

PubMed

Sanz, Roser; Calpena, Ana C; Mallandrich, Mireia; Clares, Beatriz

2015-01-01

Topical administration is an appealing method for drug delivery due to its non-invasiveness, self-controlled application, avoidance of first-pass metabolism in the liver and reduction of systemic side effects compared to other conventional routes such as oral and parenteral. However, topical administration must overcome the permeable barriers that skin and mucosa represent for the drug to achieve its desired therapeutic effect. Penetration of drugs through human skin is mainly impaired by the stratum corneum- the uppermost keratinized skin layer. In contrast, the stratified squamous epithelium (a nonkeratinized tissue) represents the major physical barrier for transbuccal drug administration in humans. Different technologies have been studied to enhance the bioavailability or local effects of drugs administered through skin and buccal mucosa. Those technologies involve the use of physical or chemical enhancers and new dosage forms such as vesicles, cyclodextrins, nanoparticles and other complex systems. Combinations of these technologies may further increase drug delivery in some cases. As analgesia is one of the main therapeutic effects sought through topical administration, this paper focuses on the review of drug delivery systems to improve the topical and transdermal/transbuccal drug delivery of substances with known analgesic action. A discussion of their possibilities and limitations is also included.

Optimizing Implementation of Obesity Prevention Programs: A Qualitative Investigation Within a Large-Scale Randomized Controlled Trial.

PubMed

Kozica, Samantha L; Teede, Helena J; Harrison, Cheryce L; Klein, Ruth; Lombard, Catherine B

2016-01-01

The prevalence of obesity in rural and remote areas is elevated in comparison to urban populations, highlighting the need for interventions targeting obesity prevention in these settings. Implementing evidence-based obesity prevention programs is challenging. This study aimed to investigate factors influencing the implementation of obesity prevention programs, including adoption, program delivery, community uptake, and continuation, specifically within rural settings. Nested within a large-scale randomized controlled trial, a qualitative exploratory approach was adopted, with purposive sampling techniques utilized, to recruit stakeholders from 41 small rural towns in Australia. In-depth semistructured interviews were conducted with clinical health professionals, health service managers, and local government employees. Open coding was completed independently by 2 investigators and thematic analysis undertaken. In-depth interviews revealed that obesity prevention programs were valued by the rural workforce. Program implementation is influenced by interrelated factors across: (1) contextual factors and (2) organizational capacity. Key recommendations to manage the challenges of implementing evidence-based programs focused on reducing program delivery costs, aided by the provision of a suite of implementation and evaluation resources. Informing the scale-up of future prevention programs, stakeholders highlighted the need to build local rural capacity through developing supportive university partnerships, generating local program ownership and promoting active feedback to all program partners. We demonstrate that the rural workforce places a high value on obesity prevention programs. Our results inform the future scale-up of obesity prevention programs, providing an improved understanding of strategies to optimize implementation of evidence-based prevention programs. © 2015 National Rural Health Association.

Biodegradable polymers for targeted delivery of anti-cancer drugs.

PubMed

Doppalapudi, Sindhu; Jain, Anjali; Domb, Abraham J; Khan, Wahid

2016-06-01

Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy. This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered. Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity.

Topical drug delivery systems: a patent review.

PubMed

Singh Malik, Deepinder; Mital, Neeraj; Kaur, Gurpreet

2016-01-01

Topical administration is the favored route for local delivery of therapeutic agents due to its convenience and affordability. The specific challenge of designing a therapeutic system is to achieve an optimal concentration of a certain drug at its site of action for an appropriate duration. This review summarizes innovations from the past 3 years (2012-2015) in the field of topical drug delivery for the treatment of local infections of the vagina, nose, eye and skin. The review also throws some light on the anatomy and physiology of these organs and their various defensive barriers which affect the delivery of drugs administered topically. Topical administration has been gaining attention over the last few years. However, conventional topical drug delivery systems suffer from drawbacks such as poor retention and low bioavailability. The successful formulation of topical delivery products requires the careful manipulation of defensive barriers and selection of a soluble drug carrier. Extensive research is required to develop newer topical drug delivery systems aiming either to improve the efficacy or to reduce side effects compared to current patented systems.

pH-controlled drug loading and release from biodegradable microcapsules.

PubMed

Zhao, Qinghe; Li, Bingyun

2008-12-01

Microcapsules made of biopolymers are of both scientific and technological interest and have many potential applications in medicine, including their use as controlled drug delivery devices. The present study makes use of the electrostatic interaction between polycations and polyanions to form a multilayered microcapsule shell and also to control the loading and release of charged drug molecules inside the microcapsule. Micron-sized calcium carbonate (CaCO3) particles were synthesized and integrated with chondroitin sulfate (CS) through a reaction between sodium carbonate and calcium nitrate tetrahydrate solutions suspended with CS macromolecules. Oppositely charged biopolymers were alternately deposited onto the synthesized particles using electrostatic layer-by-layer self-assembly, and glutaraldehyde was introduced to cross-link the multilayered shell structure. Microcapsules integrated with CS inside the multilayered shells were obtained after decomposition of the CaCO3 templates. The integration of a matrix (i.e., CS) permitted the subsequent selective control of drug loading and release. The CS-integrated microcapsules were loaded with a model drug, bovine serum albumin labeled with fluorescein isothiocyanate (FITC-BSA), and it was shown that pH was an effective means of controlling the loading and release of FITC-BSA. Such CS-integrated microcapsules may be used for controlled localized drug delivery as biodegradable devices, which have advantages in reducing systemic side effects and increasing drug efficacy.

Antimicrobial delivery systems for local infection prophylaxis in orthopedic- and trauma surgery.

PubMed

ter Boo, Gert-Jan A; Grijpma, Dirk W; Moriarty, Thomas F; Richards, Robert G; Eglin, David

2015-06-01

Infectious complications occur in a minor but significant portion of the patients undergoing joint replacement surgery or fracture fixation, particularly those with severe open fractures, those undergoing revision arthroplasty or those at elevated risk because of poor health status. Once established, infections are difficult to eradicate, especially in the case of bacterial biofilm formation on implanted hardware. Local antibiotic carriers offer the prospect of controlled delivery of antibiotics directly in target tissues and implant, without inducing toxicity in non-target organs. Polymeric carriers have been developed to optimize the release and targeting of antibiotics. Passive polymeric carriers release antibiotics by diffusion and/or upon degradation, while active polymeric carriers release their antibiotics upon stimuli provided by bacterial pathogens. Additionally, some polymeric carriers gelate in-situ in response to physiological stimuli to form a depot for antibiotic release. As antibiotic resistance has become a major issue, also other anti-infectives such as silver and antimicrobial peptides have been incorporated in research. Currently, several antibiotic loaded biomaterials for local infection prophylaxis are available for use in the clinic. Here we review their advantages and limitations and provide an overview of new materials emerging that may overcome these limitations. Copyright © 2015 Elsevier Ltd. All rights reserved.

Technique for Periarticular Local Infiltrative Anesthesia Delivery Using Liposomal Bupivacaine in Total Knee Arthroplasty.

PubMed

Connelly, Jacob O; Edwards, Paul K; Mears, Simon C; Barnes, C Lowry

2015-01-01

Postoperative pain control after total knee arthroplasty is a major contributing factor to patient satisfaction, rehabilitation, and length of stay. Current clinical practice guidelines recommend a multimodal pain management protocol, including the use of regional anesthesia. Periarticular injection (PAI) has been shown to provide excellent pain relief after total knee arthroplasty. Recently, liposomal bupivacaine has been introduced as a long-acting alternative to traditional local anesthetics, such as bupivacaine or ropivacaine. Liposomal bupivacaine is a sustained-release preparation designed to provide local analgesia up to 72 hours after initial application. The efficacy of PAI relies significantly on a meticulous, systematic injection technique. This article details recommendations for solution preparation and injection during total knee arthroplasty on the basis of the experience of a high-volume orthopaedic reconstruction service.

Nanotechnology in diagnosis and treatment of coronary artery disease.

PubMed

Karimi, Mahdi; Zare, Hossein; Bakhshian Nik, Amirala; Yazdani, Narges; Hamrang, Mohammad; Mohamed, Elmira; Sahandi Zangabad, Parham; Moosavi Basri, Seyed Masoud; Bakhtiari, Leila; Hamblin, Michael R

2016-01-01

Nanotechnology could provide a new complementary approach to treat coronary artery disease (CAD) which is now one of the biggest killers in the Western world. The course of events, which leads to atherosclerosis and CAD, involves many biological factors and cellular disease processes which may be mitigated by therapeutic methods enhanced by nanotechnology. Nanoparticles can provide a variety of delivery systems for cargoes such as drugs and genes that can address many problems within the arteries. In order to improve the performance of current stents, nanotechnology provides different nanomaterial coatings, in addition to controlled-release nanocarriers, to prevent in-stent restenosis. Nanotechnology can increase the efficiency of drugs, improve local and systematic delivery to atherosclerotic plaques and reduce the inflammatory or angiogenic response after intravascular intervention. Nanocarriers have potential for delivery of imaging and diagnostic agents to precisely targeted destinations. This review paper will cover the current applications and future outlook of nanotechnology, as well as the main diagnostic methods, in the treatment of CAD.

Nanotechnology in diagnosis and treatment of coronary artery disease

PubMed Central

Karimi, Mahdi; Zare, Hossein; Bakhshian Nik, Amirala; Yazdani, Narges; Hamrang, Mohammad; Mohamed, Elmira; Sahandi Zangabad, Parham; Moosavi Basri, Seyed Masoud; Bakhtiari, Leila; Hamblin, Michael R

2016-01-01

Nanotechnology could provide a new complementary approach to treat coronary artery disease (CAD) which is now one of the biggest killers in the Western world. The course of events, which leads to atherosclerosis and CAD, involves many biological factors and cellular disease processes which may be mitigated by therapeutic methods enhanced by nanotechnology. Nanoparticles can provide a variety of delivery systems for cargoes such as drugs and genes that can address many problems within the arteries. In order to improve the performance of current stents, nanotechnology provides different nanomaterial coatings, in addition to controlled-release nanocarriers, to prevent in-stent restenosis. Nanotechnology can increase the efficiency of drugs, improve local and systematic delivery to atherosclerotic plaques and reduce the inflammatory or angiogenic response after intravascular intervention. Nanocarriers have potential for delivery of imaging and diagnostic agents to precisely targeted destinations. This review paper will cover the current applications and future outlook of nanotechnology, as well as the main diagnostic methods, in the treatment of CAD. PMID:26906471

Plasminogen Activators and Ischemic Stroke: Conditions for Acute Delivery

PubMed Central

del Zoppo, Gregory J

2013-01-01

Appropriate acute treatment with plasminogen activators (PAs) can significantly increase the probability of minimal or no disability in selected ischemic stroke patients. There is a great deal of evidence showing that intravenous recombinant tissue PAs (rt-PA) infusion accomplishes this goal, recanalization with other PAs has also been demonstrated in the development of this treatment. Recanalization of symptomatic, documented carotid or vertebrobasilar arterial territory occlusions have also been achieved by local intra-arterial PA delivery, although only a single prospective double-blinded randomized placebo-controlled study has been reported. The increase in intracerebral hemorrhage with these agents by either delivery approach underscores the need for careful patient selection, dose-appropriate safety and efficacy, proper clinical trial design, and an understanding of the evolution of cerebral tissue injury due to focal ischemia. Principles underlying the evolution of focal ischemia have been expanded by experience with acute PA intervention. Several questions remain open that concern the manner in which PAs can be applied acutely in ischemic stroke and how injury development can be limited. PMID:23539414

Porous Hydroxyapatite Bioceramic Scaffolds for Drug Delivery and Bone Regeneration

NASA Astrophysics Data System (ADS)

Loca, Dagnija; Locs, Janis; Salma, Kristine; Gulbis, Juris; Salma, Ilze; Berzina-Cimdina, Liga

2011-10-01

The conventional methods of supplying a patient with pharmacologic active substances suffer from being very poorly selective, so that damage can occurs to the healthy tissues and organs, different from the intended target. In addition, high drug doses can be required to achieve the desired effect. An alternative approach is based on the use of implantable delivery tools, able to release the active substance in a controlled way. In the current research local drug delivery devices containing 8mg of gentamicin sulphate were prepared using custom developed vacuum impregnation technique. In vitro dissolution tests showed that gentamicin release was sustained for 12h. In order to decrease gentamicin release rate, biopolymer coatings were applied and coating structure investigated. The results showed that gentamicin release can be sustained for more than 70h for poly(epsilon-caprolactone) coated calcium phosphate scaffolds. From poly lactic acid and polyvinyl alcohol coated scaffolds gentamicin was released within 20h and 50h, respectively.

Biocompatibility and safety of a hybrid core-shell nanoparticulate OP-1 delivery system intramuscularly administered in rats.

PubMed

Haidar, Ziyad S; Hamdy, Reggie C; Tabrizian, Maryam

2010-04-01

A hybrid, localized and release-controlled delivery system for bone growth factors consisting of a liposomal core incorporated into a shell of alternating layer-by-layer self-assembled natural polyelectrolytes has been formulated. Hydrophilic, monodisperse, spherical and stable cationic nanoparticles (< or =350 nm) with an extended shelf-life resulted. Cytocompatibility was previously assayed with MC3T3-E1.4 mouse preosteoblasts showing no adverse effects on cell viability. In this study, the in vivo biocompatibility of unloaded and loaded nanoparticles with osteogenic protein-1 or OP-1 was investigated. Young male Wistar rats were injected intramuscularly and monitored over a period of 10 weeks for signs of inflammation and/or adverse reactions. Blood samples (600 microL/collection) were withdrawn followed by hematological and biochemical analysis. Body weight changes over the treatment period were noted. Major organs were harvested, weighed and examined histologically for any pathological changes. Finally, the injection site was identified and examined immunohistochemically. Overall, all animals showed no obvious toxic health effects, immune responses and/or change in organ functions. This hybrid core-shell nanoparticulate delivery system localizes the effect of the released bioactive load within the site of injection in muscle with no significant tissue distress. Hence, a safe and promising carrier for therapeutic growth factors and possibly other biomolecules is presented. 2009 Elsevier Ltd. All rights reserved.

mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation.

PubMed

Levy, Oren; Zhao, Weian; Mortensen, Luke J; Leblanc, Sarah; Tsang, Kyle; Fu, Moyu; Phillips, Joseph A; Sagar, Vinay; Anandakumaran, Priya; Ngai, Jessica; Cui, Cheryl H; Eimon, Peter; Angel, Matthew; Lin, Charles P; Yanik, Mehmet Fatih; Karp, Jeffrey M

2013-10-03

Mesenchymal stem cells (MSCs) are promising candidates for cell-based therapy to treat several diseases and are compelling to consider as vehicles for delivery of biological agents. However, MSCs appear to act through a seemingly limited "hit-and-run" mode to quickly exert their therapeutic impact, mediated by several mechanisms, including a potent immunomodulatory secretome. Furthermore, MSC immunomodulatory properties are highly variable and the secretome composition following infusion is uncertain. To determine whether a transiently controlled antiinflammatory MSC secretome could be achieved at target sites of inflammation, we harnessed mRNA transfection to generate MSCs that simultaneously express functional rolling machinery (P-selectin glycoprotein ligand-1 [PSGL-1] and Sialyl-Lewis(x) [SLeX]) to rapidly target inflamed tissues and that express the potent immunosuppressive cytokine interleukin-10 (IL-10), which is not inherently produced by MSCs. Indeed, triple-transfected PSGL-1/SLeX/IL-10 MSCs transiently increased levels of IL-10 in the inflamed ear and showed a superior antiinflammatory effect in vivo, significantly reducing local inflammation following systemic administration. This was dependent on rapid localization of MSCs to the inflamed site. Overall, this study demonstrates that despite the rapid clearance of MSCs in vivo, engineered MSCs can be harnessed via a "hit-and-run" action for the targeted delivery of potent immunomodulatory factors to treat distant sites of inflammation.

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

Du, Shisuo; Lockamy, Virginia; Zhou, Lin

Purpose: To implement clinical stereotactic body radiation therapy (SBRT) using a small animal radiation research platform (SARRP) in a genetically engineered mouse model of lung cancer. Methods and Materials: A murine model of multinodular Kras-driven spontaneous lung tumors was used for this study. High-resolution cone beam computed tomography (CBCT) imaging was used to identify and target peripheral tumor nodules, whereas off-target lung nodules in the contralateral lung were used as a nonirradiated control. CBCT imaging helps localize tumors, facilitate high-precision irradiation, and monitor tumor growth. SBRT planning, prescription dose, and dose limits to normal tissue followed the guidelines set by RTOGmore » protocols. Pathologic changes in the irradiated tumors were investigated using immunohistochemistry. Results: The image guided radiation delivery using the SARRP system effectively localized and treated lung cancer with precision in a genetically engineered mouse model of lung cancer. Immunohistochemical data confirmed the precise delivery of SBRT to the targeted lung nodules. The 60 Gy delivered in 3 weekly fractions markedly reduced the proliferation index, Ki-67, and increased apoptosis per staining for cleaved caspase-3 in irradiated lung nodules. Conclusions: It is feasible to use the SARRP platform to perform dosimetric planning and delivery of SBRT in mice with lung cancer. This allows for preclinical studies that provide a rationale for clinical trials involving SBRT, especially when combined with immunotherapeutics.« less

Kinetics of reciprocating drug delivery to the inner ear.

PubMed

Pararas, Erin E Leary; Chen, Zhiqiang; Fiering, Jason; Mescher, Mark J; Kim, Ernest S; McKenna, Michael J; Kujawa, Sharon G; Borenstein, Jeffrey T; Sewell, William F

2011-06-10

Reciprocating drug delivery is a means of delivering soluble drugs directly to closed fluid spaces in the body via a single cannula without an accompanying fluid volume change. It is ideally suited for drug delivery into small, sensitive and unique fluid spaces such as the cochlea. We characterized the pharmacokinetics of reciprocating drug delivery to the scala tympani within the cochlea by measuring the effects of changes in flow parameters on the distribution of drug throughout the length of the cochlea. Distribution was assessed by monitoring the effects of DNQX, a reversible glutamate receptor blocker, delivered directly to the inner ear of guinea pigs using reciprocating flow profiles. We then modeled the effects of those parameters on distribution using both an iterative curve-fitting approach and a computational fluid dynamic model. Our findings are consistent with the hypothesis that reciprocating delivery distributes the drug into a volume in the base of the cochlea, and suggest that the primary determinant of distribution throughout more distal regions of the cochlea is diffusion. Increases in flow rate distributed the drug into a larger volume that extended more apically. Over short time courses (less than 2h), the apical extension, though small, significantly enhanced apically directed delivery of drug. Over longer time courses (>5h) or greater distances (>3mm), maintenance of drug concentration in the basal scala tympani may prove more advantageous for extending apical delivery than increases in flow rate. These observations demonstrate that this reciprocating technology is capable of providing controlled delivery kinetics to the closed fluid space in the cochlea, and may be suitable for other applications such as localized brain and retinal delivery. Copyright © 2011 Elsevier B.V. All rights reserved.

Kinetics of Reciprocating Drug Delivery to the Inner Ear

PubMed Central

Leary Pararas, Erin E.; Chen, Zhiqiang; Fiering, Jason; Mescher, Mark J.; Kim, Ernest S.; McKenna, Michael J.; Kujawa, Sharon G.; Borenstein, Jeffrey T.; Sewell, William F.

2011-01-01

Reciprocating drug delivery is a means of delivering soluble drugs directly to closed fluid spaces in the body via a single cannula without an accompanying fluid volume change. It is ideally suited for drug delivery into small, sensitive and unique fluid spaces such as the cochlea. We characterized the pharmacokinetics of reciprocating drug delivery to the scala tympani within the cochlea by measuring the effects of changes in flow parameters on the distribution of drug throughout the length of the cochlea. Distribution was assessed by monitoring the effects of DNQX, a reversible glutamate receptor blocker, delivered directly to the inner ear of guinea pigs using reciprocating flow profiles. We then modeled the effects of those parameters on distribution using both an iterative curve-fitting approach and a computational fluid dynamic model. Our findings are consistent with the hypothesis that reciprocating delivery distributes the drug into a volume in the base of the cochlea, and suggest that the primary determinant of distribution throughout more distal regions of the cochlea is diffusion. Increases in flow rate distributed the drug into a larger volume that extended more apically. Over short time courses (less than 2 h), the apical extension, though small, significantly enhanced apically directed delivery of drug. Over longer time courses (>5 h) or greater distances (>3 mm), maintenance of drug concentration in the basal scala tympani may prove more advantageous for extending apical delivery than increases in flow rate. These observations demonstrate that this reciprocating technology is capable of providing controlled delivery kinetics to the closed fluid space in the cochlea, and may be suitable for other applications such as localized brain and retinal delivery. PMID:21385596

Insights on Localized and Systemic Delivery of Redox-Based Therapeutics

PubMed Central

Batrakova, Elena V.; Mota, Roberto

2018-01-01

Reactive oxygen and nitrogen species are indispensable in cellular physiology and signaling. Overproduction of these reactive species or failure to maintain their levels within the physiological range results in cellular redox dysfunction, often termed cellular oxidative stress. Redox dysfunction in turn is at the molecular basis of disease etiology and progression. Accordingly, antioxidant intervention to restore redox homeostasis has been pursued as a therapeutic strategy for cardiovascular disease, cancer, and neurodegenerative disorders among many others. Despite preliminary success in cellular and animal models, redox-based interventions have virtually been ineffective in clinical trials. We propose the fundamental reason for their failure is a flawed delivery approach. Namely, systemic delivery for a geographically local disease limits the effectiveness of the antioxidant. We take a critical look at the literature and evaluate successful and unsuccessful approaches to translation of redox intervention to the clinical arena, including dose, patient selection, and delivery approach. We argue that when interpreting a failed antioxidant-based clinical trial, it is crucial to take into account these variables and importantly, whether the drug had an effect on the redox status. Finally, we propose that local and targeted delivery hold promise to translate redox-based therapies from the bench to the bedside. PMID:29636836

Bubble-generating nano-lipid carriers for ultrasound/CT imaging-guided efficient tumor therapy.

PubMed

Zhang, Nan; Li, Jia; Hou, Ruirui; Zhang, Jiangnan; Wang, Pei; Liu, Xinyang; Zhang, Zhenzhong

2017-12-20

Ideal therapeutic effectiveness of chemotherapy is obtained only when tumor cells are exposed to a maximal drug concentration, which is often hindered by dose-limiting toxicity. We designed a bubble-generating liposomal delivery system by introducing ammonium bicarbonate and gold nanorods into folic acid-conjugated liposomes to allow both multimodal imaging and the local release of drug (doxorubicin) with hyperthermia. The key component, ammonium bicarbonate, allows a controlled, rapid release of doxorubicin to provide an effective drug concentration in the tumor microenvironment. An in vitro temperature-triggered drug release study showed that cumulative release improved more than two-fold. In addition, in vitro and in vivo studies indicated that local heat treatment or ultrasonic cavitation enhanced the therapeutic efficiency greatly. The delivery system could also serve as an excellent contrast agent to allow ultrasonic imaging and computerized tomography imaging simultaneously to further achieve the aim of accurate diagnostics. Results of this study showed that this versatile bubble-generating liposome is a promising system to provide optimal therapeutic effects that are guided by multimodal imaging. Copyright © 2017 Elsevier B.V. All rights reserved.

Biodegradable Scaffolds for Bone Regeneration Combined with Drug-Delivery Systems in Osteomyelitis Therapy

PubMed Central

Dorati, Rossella; DeTrizio, Antonella; Modena, Tiziana; Conti, Bice; Benazzo, Francesco; Gastaldi, Giulia; Genta, Ida

2017-01-01

A great deal of research is ongoing in the area of tissue engineering (TE) for bone regeneration. A possible improvement in restoring damaged tissues involves the loading of drugs such as proteins, genes, growth factors, antibiotics, and anti-inflammatory drugs into scaffolds for tissue regeneration. This mini-review is focused on the combination of the local delivery of antibiotic agents with bone regenerative therapy for the treatment of a severe bone infection such as osteomyelitis. The review includes a brief explanation of scaffolds for bone regeneration including scaffolds characteristics and types, a focus on severe bone infections (especially osteomyelitis and its treatment), and a literature review of local antibiotic delivery by the combination of scaffolds and drug-delivery systems. Some examples related to published studies on gentamicin sulfate-loaded drug-delivery systems combined with scaffolds are discussed, and future perspectives are highlighted. PMID:29231857

A phase 1, randomized, controlled dose-escalation study of EP-1300 polyepitope DNA vaccine against Plasmodium falciparum malaria administered via electroporation.

PubMed

Spearman, Paul; Mulligan, Mark; Anderson, Evan J; Shane, Andi L; Stephens, Kathy; Gibson, Theda; Hartwell, Brooke; Hannaman, Drew; Watson, Nora L; Singh, Karnail

2016-11-04

Plasmodium falciparum malaria is one of the leading infectious causes of childhood mortality in Africa. EP-1300 is a polyepitope plasmid DNA vaccine expressing 38 cytotoxic T cell epitopes and 16 helper T cell epitopes derived from P. falciparum antigens expressed predominantly in the liver phase of the parasite's life cycle. We performed a phase 1 randomized, placebo-controlled, dose escalation clinical trial of the EP-1300 DNA vaccine administered via electroporation using the TriGrid Delivery System device (Ichor Medical Systems). Although the delivery of the EP-1300 DNA vaccine via electroporation was safe, tolerability was less than that usually observed with standard needle and syringe intramuscular administration. This was primarily due to acute local discomfort at the administration site during electroporation. Despite the use of electroporation, the vaccine was poorly immunogenic. The reasons for the poor immunogenicity of this polyepitope DNA vaccine remain uncertain. ClinicalTrials.gov NCT01169077. Copyright © 2016 Elsevier Ltd. All rights reserved.

Magneto-electric Nanoparticles to Enable Field-controlled High-Specificity Drug Delivery to Eradicate Ovarian Cancer Cells

PubMed Central

Guduru, Rakesh; Liang, Ping; Runowicz, Carolyn; Nair, Madhavan; Atluri, Venkata; Khizroev, Sakhrat

2013-01-01

The nanotechnology capable of high-specificity targeted delivery of anti-neoplastic drugs would be a significant breakthrough in Cancer in general and Ovarian Cancer in particular. We addressed this challenge through a new physical concept that exploited (i) the difference in the membrane electric properties between the tumor and healthy cells and (ii) the capability of magneto-electric nanoparticles (MENs) to serve as nanosized converters of remote magnetic field energy into the MENs' intrinsic electric field energy. This capability allows to remotely control the membrane electric fields and consequently trigger high-specificity drug uptake through creation of localized nano-electroporation sites. In in-vitro studies on human ovarian carcinoma cell (SKOV-3) and healthy cell (HOMEC) lines, we applied a 30-Oe d.c. field to trigger high-specificity uptake of paclitaxel loaded on 30-nm CoFe2O4@BaTiO3 MENs. The drug penetrated through the membrane and completely eradicated the tumor within 24 hours without affecting the normal cells. PMID:24129652

Magneto-electric nanoparticles to enable field-controlled high-specificity drug delivery to eradicate ovarian cancer cells.

PubMed

Guduru, Rakesh; Liang, Ping; Runowicz, Carolyn; Nair, Madhavan; Atluri, Venkata; Khizroev, Sakhrat

2013-10-16

The nanotechnology capable of high-specificity targeted delivery of anti-neoplastic drugs would be a significant breakthrough in Cancer in general and Ovarian Cancer in particular. We addressed this challenge through a new physical concept that exploited (i) the difference in the membrane electric properties between the tumor and healthy cells and (ii) the capability of magneto-electric nanoparticles (MENs) to serve as nanosized converters of remote magnetic field energy into the MENs' intrinsic electric field energy. This capability allows to remotely control the membrane electric fields and consequently trigger high-specificity drug uptake through creation of localized nano-electroporation sites. In in-vitro studies on human ovarian carcinoma cell (SKOV-3) and healthy cell (HOMEC) lines, we applied a 30-Oe d.c. field to trigger high-specificity uptake of paclitaxel loaded on 30-nm CoFe₂O₄ @BaTiO₃ MENs. The drug penetrated through the membrane and completely eradicated the tumor within 24 hours without affecting the normal cells.

Chitosan Nanoparticles for Nuclear Targeting: The Effect of Nanoparticle Size and Nuclear Localization Sequence Density.

PubMed

Tammam, Salma N; Azzazy, Hassan M E; Breitinger, Hans G; Lamprecht, Alf

2015-12-07

Many recently discovered therapeutic proteins exert their main function in the nucleus, thus requiring both efficient uptake and correct intracellular targeting. Chitosan nanoparticles (NPs) have attracted interest as protein delivery vehicles due to their biocompatibility and ability to escape the endosomes offering high potential for nuclear delivery. Molecular entry into the nucleus occurs through the nuclear pore complexes, the efficiency of which is dependent on NP size and the presence of nuclear localization sequence (NLS). Chitosan nanoparticles of different sizes (S-NPs ≈ 25 nm; L-NP ≈ 150 nm) were formulated, and they were modified with different densities of the octapeptide NLS CPKKKRKV (S-NPs, 0.25, 0.5, 2.0 NLS/nm(2); L-NPs, 0.6, 0.9, 2 NLS/nm(2)). Unmodified and NLS-tagged NPs were evaluated for their protein loading capacity, extent of cell association, cell uptake, cell surface binding, and finally nuclear delivery efficiency in L929 fibroblasts. To avoid errors generated with cell fractionation and nuclear isolation protocols, nuclear delivery was assessed in intact cells utilizing Förster resonance energy transfer (FRET) fluorometry and microscopy. Although L-NPs showed ≈10-fold increase in protein loading per NP when compared to S-NPs, due to higher cell association and uptake S-NPs showed superior protein delivery. NLS exerts a size and density dependent effect on nanoparticle uptake and surface binding, with a general reduction in NP cell surface binding and an increase in cell uptake with the increase in NLS density (up to 8.4-fold increase in uptake of High-NLS-L-NPs (2 NLS/nm(2)) compared to unmodified L-NPs). However, for nuclear delivery, unmodified S-NPs show higher nuclear localization rates when compared to NLS modified NPs (up to 5-fold by FRET microscopy). For L-NPs an intermediate NLS density (0.9 NLS/nm(2)) seems to provide highest nuclear localization (3.7-fold increase in nuclear delivery compared to High-NLS-L-NPs). Results indicate that a higher NLS density does not result in maximum protein nuclear localization and that a universal optimal density for NPs of different sizes does not exist.

Optimising postoperative pain management in the ambulatory patient.

PubMed

Shang, Allan B; Gan, Tong J

2003-01-01

Over 60% of surgery is now performed in an ambulatory setting. Despite improved analgesics and sophisticated drug delivery systems, surveys indicate that over 80% of patients experience moderate to severe pain postoperatively. Inadequate postoperative pain relief can prolong recovery, precipitate or increase the duration of hospital stay, increase healthcare costs, and reduce patient satisfaction. Effective postoperative pain management involves a multimodal approach and the use of various drugs with different mechanisms of action. Local anaesthetics are widely administered in the ambulatory setting using techniques such as local injection, field block, regional nerve block or neuraxial block. Continuous wound infusion pumps may have great potential in an ambulatory setting. Regional anaesthesia (involving anaesthetising regional areas of the body, including single extremities, multiple extremities, the torso, and the face or jaw) allows surgery to be performed in a specific location, usually an extremity, without the use of general anaesthesia, and potentially with little or no sedation. Opioids remain an important component of any analgesic regimen in treating moderate to severe acute postoperative pain. However, the incorporation of non-opioids, local anaesthetics and regional techniques will enhance current postoperative analgesic regimens. The development of new modalities of treatment, such as patient controlled analgesia, and newer drugs, such as cyclo-oxygenase-2 inhibitors, provide additional choices for the practitioner. While there are different routes of administration for analgesics (e.g. oral, parenteral, intramuscular, transmucosal, transdermal and sublingual), oral delivery of medications has remained the mainstay for postoperative pain control. The oral route is effective, the simplest to use and typically the least expensive. The intravenous route has the advantages of a rapid onset of action and easier titratibility, and so is recommended for the treatment of acute pain.Non-pharmacological methods for the management of postoperative pain include acupuncture, electromagnetic millimetre waves, hypnosis and the use of music during surgery. However, further research of these techniques is warranted to elucidate their effectiveness in this indication. Pain is a multifactorial experience, not just a sensation. Emotion, perception and past experience all affect an individual's response to noxious stimuli. Improved postoperative pain control through innovation and creativity may improve compliance, ease of delivery, reduce length of hospital stay and improve patient satisfaction. Patient education, early diagnosis of symptoms and aggressive treatment of pain using an integrative approach, combining pharmacotherapy as well as complementary technique, should serve us well in dealing with this complex problem.

Efficacy of Local Molsidomine Delivery from a Hydrogel-Coated Angioplasty Balloon Catheter in the Atherosclerotic Porcine Model

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

Rolland, Pierre H.; Mekkaoui, Choukri; Palassi, Maria

2003-02-15

Purpose: To evaluate the therapeutic effects of local molsidomine delivery via a hydrogel-coated angioplasty balloon catheter during overstretch angioplasty in atheroscleroticswine iliac vessels. Molsidomine is retained in the arterial wall after local delivery for more than 72 hr and is slowly metabolized intolinsidomine, releasing nitric oxide (NO). Methods: A hydrogel-coated angioplasty balloon catheter was used to both deliver drug locally (150 mg molsidomine or placebo in the contralateral vessel) and dilate iliac vessels in nine Pietrin pigs that had been on an atherogenic diet for 5 months. Animals were killed at 3 hr(n = 2), 24 hr (n = 3)more » and 3 months(n = 3) after treatment. Iliac arteries were examined for wall pulsatility, histomorphometry, cell proliferation and platelet aggregation. Results: No significant therapeutic effects were detected 3 hr after treatment. At 24 hr, wall pulsatility,thrombo resistance and vascular cell homeostasis were significantly restored in the molsidomine-treated versus placebo group. At 3 months,molsidomine inhibited restenotic lesion development, except in scarred areas of histologically detectable adventitial/medial dissection. Conclusion: Local delivery of concentrated molsidomine from a hydrogel-coated angioplasty balloon catheter resulted in early NO-dependent vasodilation/stress normalization and antithrombotic and antiproliferative effects. In the medium term, molsidomine inhibited restenosis in the absence of vessel dissection.« less

Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.

PubMed

Yang, Fan; Ma, Hongwei; Belcher, Joshua; Butler, Michael R; Redmond, T Michael; Boye, Sanford L; Hauswirth, William W; Ding, Xi-Qin

2016-12-01

Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations. Subretinal delivery of AAV5-IRBP/GNAT2-DIO3, which directs expression of human DIO3 specifically in cones, increased cone density by 30-40% in a Rpe65 -/- mouse model of Lebers congenital amaurosis (LCA) and in a Cpfl1 mouse with Pde6c defect model of achromatopsia, compared with their respective untreated controls. Intravitreal and topical delivery of the DIO2 inhibitor iopanoic acid also significantly improved cone survival in the LCA model mice. Moreover, the expression levels of DIO2 and Slc16a2 were significantly higher in the diseased retinas, suggesting locally elevated TH signaling. We show that targeting DIOs protects cones, and intracellular inhibition of TH components locally in the retina may represent a novel strategy for retinal degeneration management.-Yang, F., Ma, H., Belcher, J., Butler, M. R., Redmond, T. M., Boye, S. L., Hauswirth, W. W., Ding, X.-Q. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration. © FASEB.

Ultrasound Targeted Microbubble Destruction-Mediated Delivery of a Transcription Factor Decoy Inhibits STAT3 Signaling and Tumor Growth

PubMed Central

Kopechek, Jonathan A.; Carson, Andrew R.; McTiernan, Charles F.; Chen, Xucai; Hasjim, Bima; Lavery, Linda; Sen, Malabika; Grandis, Jennifer R.; Villanueva, Flordeliza S.

2015-01-01

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many cancers where it acts to promote tumor progression. A STAT3-specific transcription factor decoy has been developed to suppress STAT3 downstream signaling, but a delivery strategy is needed to improve clinical translation. Ultrasound-targeted microbubble destruction (UTMD) has been shown to enhance image-guided local delivery of molecular therapeutics to a target site. The objective of this study was to deliver STAT3 decoy to squamous cell carcinoma (SCC) tumors using UTMD to disrupt STAT3 signaling and inhibit tumor growth. Studies performed demonstrated that UTMD treatment with STAT3 decoy-loaded microbubbles inhibited STAT3 signaling in SCC cells in vitro. Studies performed in vivo demonstrated that UTMD treatment with STAT3 decoy-loaded microbubbles induced significant tumor growth inhibition (31-51% reduced tumor volume vs. controls, p < 0.05) in mice bearing SCC tumors. Furthermore, expression of STAT3 downstream target genes (Bcl-xL and cyclin D1) was significantly reduced (34-39%, p < 0.05) in tumors receiving UTMD treatment with STAT3 decoy-loaded microbubbles compared to controls. In addition, the quantity of radiolabeled STAT3 decoy detected in tumors eight hours after treatment was significantly higher with UTMD treatment compared to controls (70-150%, p < 0.05). This study demonstrates that UTMD can increase delivery of a transcription factor decoy to tumors in vivo and that the decoy can inhibit STAT3 signaling and tumor growth. These results suggest that UTMD treatment holds potential for clinical use to increase the concentration of a transcription factor signaling inhibitor in the tumor. PMID:26681983

TU-AB-201-03: A Robot for the Automated Delivery of An Electromagnetic Tracking Sensor for the Localization of Brachytherapy Catheters

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

Don, S; Cormack, R; Viswanathan, A

Purpose: To present a programmable robotic system for the accurate and fast deployment of an electromagnetic (EM) sensor for brachytherapy catheter localization. Methods: A robotic system for deployment of an EM sensor was designed and built. The system was programmed to increment the sensor position at specified time and space intervals. Sensor delivery accuracy was measured in a phantom using the localization of the EM sensor and tested in different environmental conditions. Accuracy was tested by measuring the distance between the physical locations reached by the sensor (measured by the EM tracker) and the intended programmed locations. Results: The systemmore » consisted of a stepper motor connected to drive wheels (that grip the cable to move the sensor) and a series of guides to connect to a brachytherapy transfer tube, all controlled by a programmable Arduino microprocessor. The total cost for parts was <$300. The positional accuracy of the sensor location was within 1 mm of the expected position provided by the motorized guide system. Acquisition speed to localize a brachytherapy catheter with 20 cm of active length was 10 seconds. The current design showed some cable slip and warping depending on environment temperature. Conclusion: The use of EM tracking for the localization of brachytherapy catheters has been previously demonstrated. Efficient data acquisition and artifact reduction requires fast and accurate deployment of an EM sensor in consistent, repeatable patterns, which cannot practically be achieved manually. The design of an inexpensive, programmable robot allowing for the precise deployment of stepping patterns was presented, and a prototype was built. Further engineering is necessary to ensure that the device provides efficient independent localization of brachytherapy catheters. This research was funded by the Kaye Family Award.« less

Transverse occiput position: Using manual Rotation to aid Normal birth and improve delivery OUTcomes (TURN-OUT): A study protocol for a randomised controlled trial.

PubMed

de Vries, Bradley; Phipps, Hala; Kuah, Sabrina; Pardey, John; Ludlow, Joanne; Bisits, Andrew; Park, Felicity; Kowalski, David; Hyett, Jon A

2015-08-18

Fetal occiput transverse position in the form of deep transverse arrest has long been associated with caesarean section and instrumental vaginal delivery. Occiput transverse position incidentally found in the second stage of labour is also associated with operative delivery in high risk cohorts. There is evidence from cohort studies that prophylactic manual rotation reduces the caesarean section rate. This is a protocol for a double blind, multicentre, randomised, controlled clinical trial to define whether this intervention decreases the operative delivery (caesarean section, forceps or vacuum delivery) rate. Eligible participants will be ≥37 weeks pregnant, with a singleton pregnancy, and a cephalic presentation in the occiput transverse position on transabdominal ultrasound early in the second stage of labour. Based on a background risk of operative delivery of 49%, for a reduction to 35%, an alpha value of 0.05 and a beta value of 0.2, 416 participants will need to be enrolled. Participants will be randomised to either prophylactic manual rotation or a sham procedure. The primary outcome will be operative delivery. Secondary outcomes will be caesarean section, significant maternal mortality and morbidity, and significant perinatal mortality and morbidity. Analysis will be on an intention-to-treat basis. Primary and secondary outcomes will be compared using a chi-squared test. A logistic regression for the primary outcome will be undertaken to account for potential confounders. This study has been approved by the Ethics Review Committee (RPAH Zone) of the Sydney Local Health District, Sydney, Australia, (protocol number: X110410). This trial addresses an important clinical question concerning a commonly used procedure which has the potential to reduce operative delivery and its associated complications. Some issues discussed in the protocol include methods of assessing risk of bias due to inadequate masking of a procedural interventions, variations in intervention efficacy due to operator experience and the recruitment difficulties associated with intrapartum studies. This trial was registered with the Australian New Zealand Clinical Trials Registry (identifier: ACTRN12613000005752 ) on 4 January 2013.

The Whole PIC Catalog: Organization, Planning and Service Delivery Options under JTPA.

ERIC Educational Resources Information Center

National Alliance of Business, Inc., Washington, DC.

This handbook illustrates and discusses organizational options for the delivery of employment and training services within service delivery areas (SDAs) mandated by the Job Training Partnership Act (JTPA) of 1982. Addressed primarily to members of private industry councils (PICs), representatives of local governments, and employment and training…

29 CFR 551.8 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... as picking up and returning the delivery vehicle at the beginning and end of the workday, cleaning... in loading or unloading the goods, and picking up empty containers or other goods from customers for... local deliveries. (f) A plan of compensation on the basis of trip rates or other delivery payment plan...

Status of Statewide Career Information Delivery Systems.

ERIC Educational Resources Information Center

Dunn, Wynonia L.

Intended as a resource document as well as a status report on all the statewide career information delivery systems (CIDS) in operation, this report examines the status of 39 statewide information systems. (Career information delivery systems are computer-based systems that provide national, state, and local information to individuals who are in…

Sustained Release Talazoparib Implants for Localized Treatment of BRCA1-deficient Breast Cancer

PubMed Central

Belz, Jodi E.; Kumar, Rajiv; Baldwin, Paige; Ojo, Noelle Castilla; Leal, Ana S.; Royce, Darlene B.; Zhang, Di; van de Ven, Anne L.; Liby, Karen T.; Sridhar, Srinivas

2017-01-01

Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre-clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1-deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0.8 mm diameter) loaded with subclinical dose (25 or 50 µg) Talazoparib were fabricated and characterized. In vitro studies with Brca1-deficient W780 and W0069 breast cancer cells were conducted to test sensitivity to PARP inhibition. The in vivo therapeutic efficacy of Talazoparib implants was assessed following a one-time intratumoral injection in Brca1Co/Co;MMTV-Cre;p53+/- mice and compared to drug-free implants and oral gavage. Immunohistochemistry studies were performed on tumor sections using PCNA and γ-H2AX staining. Sustained release of Talazoparib was observed over 28 days in vitro. Mice treated with Talazoparib implants showed statistically significant tumor growth inhibition compared to those receiving drug-free implants or free Talazoparib orally. Talazoparib implants were well-tolerated at both drug doses and resulted in less weight loss than oral gavage. PARP inhibition in mice treated with Talazoparib implants significantly increased double-stranded DNA damage and decreased tumor cell proliferation as shown by PCNA and γ-H2AX staining as compared to controls. These results demonstrate that localized and sustained delivery of Talazoparib via implants has potential to provide superior treatment outcomes at sub-clinical doses with minimal toxicity in patients with BRCA1 deficient tumors. PMID:29158830

Sustained Release Talazoparib Implants for Localized Treatment of BRCA1-deficient Breast Cancer.

PubMed

Belz, Jodi E; Kumar, Rajiv; Baldwin, Paige; Ojo, Noelle Castilla; Leal, Ana S; Royce, Darlene B; Zhang, Di; van de Ven, Anne L; Liby, Karen T; Sridhar, Srinivas

2017-01-01

Talazoparib, a potent PARP inhibitor, has shown promising clinical and pre-clinical activity by inducing synthetic lethality in cancers with germline Brca1/2 mutations. Conventional oral delivery of Talazoparib is associated with significant off-target effects, therefore we sought to develop new delivery systems in the form of an implant loaded with Talazoparib for localized, slow and sustained release of the drug at the tumor site in Brca1 -deficient breast cancer. Poly(lactic-co-glycolic acid) (PLGA) implants (0.8 mm diameter) loaded with subclinical dose (25 or 50 µg) Talazoparib were fabricated and characterized. In vitro studies with Brca1 -deficient W780 and W0069 breast cancer cells were conducted to test sensitivity to PARP inhibition. The in vivo therapeutic efficacy of Talazoparib implants was assessed following a one-time intratumoral injection in Brca1 Co/Co ;MMTV-Cre;p53 +/- mice and compared to drug-free implants and oral gavage. Immunohistochemistry studies were performed on tumor sections using PCNA and γ-H2AX staining. Sustained release of Talazoparib was observed over 28 days in vitro . Mice treated with Talazoparib implants showed statistically significant tumor growth inhibition compared to those receiving drug-free implants or free Talazoparib orally. Talazoparib implants were well-tolerated at both drug doses and resulted in less weight loss than oral gavage. PARP inhibition in mice treated with Talazoparib implants significantly increased double-stranded DNA damage and decreased tumor cell proliferation as shown by PCNA and γ-H2AX staining as compared to controls. These results demonstrate that localized and sustained delivery of Talazoparib via implants has potential to provide superior treatment outcomes at sub-clinical doses with minimal toxicity in patients with BRCA1 deficient tumors.

Antibiotic-containing polymers for localized, sustained drug delivery

PubMed Central

Stebbins, Nicholas D.; Ouimet, Michelle A.; Uhrich, Kathryn E.

2014-01-01

Many currently used antibiotics suffer from issues such as systemic toxicity, short half-life, and increased susceptibility to bacterial resistance. Although most antibiotic classes are administered systemically through oral or intravenous routes, a more efficient delivery system is needed. This review discusses the chemical conjugation of antibiotics to polymers, achieved by forming covalent bonds between antibiotics and a pre-existing polymer or by developing novel antibiotic-containing polymers. Through conjugating antibiotics to polymers, unique polymer properties can be taken advantage of. These polymeric antibiotics display controlled, sustained drug release and vary in antibiotic class type, synthetic method, polymer composition, bond lability, and antibacterial activity. The polymer synthesis, characterization, drug release, and antibacterial activities, if applicable, will be presented to offer a detailed overview of each system. PMID:24751888

Nanotechnology: A New Opportunity in Plant Sciences.

PubMed

Wang, Peng; Lombi, Enzo; Zhao, Fang-Jie; Kopittke, Peter M

2016-08-01

The agronomic application of nanotechnology in plants (phytonanotechnology) has the potential to alter conventional plant production systems, allowing for the controlled release of agrochemicals (e.g., fertilizers, pesticides, and herbicides) and target-specific delivery of biomolecules (e.g., nucleotides, proteins, and activators). An improved understanding of the interactions between nanoparticles (NPs) and plant responses, including their uptake, localization, and activity, could revolutionize crop production through increased disease resistance, nutrient utilization, and crop yield. Herewith, we review potential applications of phytonanotechnology and the key processes involved in the delivery of NPs to plants. To ensure both the safe use and social acceptance of phytonanotechnology, the adverse effects, including the risks associated with the transfer of NPs through the food chain, are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

PLGA particulate subunit tuberculosis vaccines promote humoral and Th17 responses but do not enhance control of Mycobacterium tuberculosis infection

PubMed Central

Parumasivam, Thaigarajan; Chan, John Gar Yan; Lin, Leon C. W.; Flórido, Manuela; West, Nicholas P.; Chan, Hak-Kim; Britton, Warwick J.

2018-01-01

Tuberculosis places a staggering burden on human health globally. The new World Health Organisation End-TB Strategy has highlighted the urgent need for more effective TB vaccines to improve control of the disease. Protein-based subunit vaccines offer potential as safe and effective generators of protective immunity, and the use of particulate vaccine formulation and delivery by the pulmonary route may enhance local immunogenicity. In this study, novel particulate subunit vaccines were developed utilising biodegradable poly(lactic-co-glycolic acid) (PLGA) slow-release particles as carriers for the Mycobacterium tuberculosis lipoprotein MPT83, together with the adjuvants trehalose-dibehenate (TDB) or Monophosphoryl lipid A (MPL). Following delivery by the pulmonary or subcutaneous routes, the immunogenicity and protective efficacy of these vaccines were assessed in a murine model of M. tuberculosis infection. When delivered peripherally, these vaccines induced modest, antigen-specific Th1 and Th17 responses, but strong anti-MPT83 antibody responses. Mucosal delivery of the PLGA(MPT83) vaccine, with or without TDB, increased antigen-specific Th17 responses in the lungs, however, PLGA-encapsulated vaccines did not provide protection against M. tuberculosis challenge. By contrast, peripheral delivery of DDA liposomes containing MPT83 and TDB or MPL, stimulated both Th1 and Th17 responses and generated protection against M. tuberculosis challenge. Therefore, PLGA-formulated vaccines primarily stimulate strong humoral immunity, or Th17 responses if used mucosally, and may be a suitable carrier for vaccines against extracellular pathogens. This study emphasises the critical nature of the vaccine carrier, adjuvant and route of delivery for optimising vaccine efficacy against TB. PMID:29554138

Exploiting for medical and biological applications

NASA Astrophysics Data System (ADS)

Giano, Michael C.

Biotherapeutics are an emerging class of drug composed of molecules ranging in sizes from peptides to large proteins. Due to their poor stability and mucosal membrane permeability, biotherapeutics are administered by a parenteral method (i.e., syringe, intravenous or intramuscular). Therapeutics delivered systemically often experience short half-lives. While, local administration may involve invasive surgical procedures and suffer from poor retention at the site of application. To compensate, the patient receives frequent doses of highly concentrated therapeutic. Unfortunately, the off-target side effects and discomfort associated with multiple injections results in poor patient compliance. Therefore, new delivery methods which can improve therapeutic retention, reduce the frequency of administration and may aid in decreasing the off-target side effects is a necessity. Hydrogels are a class of biomaterials that are gaining interests for tissue engineering and drug delivery applications. Hydrogel materials are defined as porous, 3-dimensional networks that are primarily composed of water. Generally, they are mechanically rigid, cytocompatible and easily chemically functionalized. Collectively, these properties make hydrogels fantastic candidates to perform as drug delivery depots. Current hydrogel delivery systems physically entrap the target therapeutic which is then subsequently released over time at the site of administration. The swelling and degradation of the material effect the diffusion of the therapy from the hydrogel, and therefore should be controlled. Although these strategies provide some regulation over therapeutic release, full control of the delivery is not achieved. Newer approaches are focused on designing hydrogels that exploit known interactions, covalently attach the therapy or respond to an external stimulus in an effort to gain improved control over the therapy's release. Unfortunately, the biotherapeutic is typically required to be chemically functionalized which can lead to loss in function. Additionally, cytotoxic crosslinkers are employed to formulate hydrogels, providing another obstacle for their application. Therefore, newer materials that can provide various delivery profiles, remain cytocompatible with little or no loss in therapeutic activity are required. This thesis is focused on controlling material degradation and protein loading to modulate the release and activity of therapeutic proteins. In the first part of this thesis a series of five hydrogels prepared from self-assembling beta-hairpin peptides were designed to be enzymatically degraded by matrix metalloproteinase-13 (MMP-13) at controllable rates with the potential to effect on demand release of biotherapies. Hydrogel degradation products were characterized by high performance liquid chromatography and identified by mass spectrometry. Oscillatory rheology showed that various degradation profiles can be achieved by changing the primary amino acid sequence. An in vitro migration study showed that a model cell line was capable of degrading, invading and migrating through select hydrogels is possible. For applications that require steady delivery of a therapeutic, an alternative approach to controlling hydrogel degradation is to design a material whose degradation is dictated by hydrolysis. In the second part of the dissertation, the design and study of a novel bioadhesive hydrogel formed by mixing solutions of dextran-aldehyde and target protein(s) was studied for its potential use as a localized steady delivery system. The effect of changing the dextran chain length, dextran percent oxidiation, dextran concentration and crosslinking protein concentration on the mechanical and bioadhesive properties was explored with dynamic oscillatory rheology and lap-shear uniaxial tension measurements, respectively. Model degradation and release studies were performed in vitro and in vivo with a model fluorescent protein (eGFP). In addition, a therapeutically relevant recombinant interleukin-2 (rIL-2) was co-crosslinked with BSA and biologic function was assessed upon its release from the hydrogel network to gain insight into the hydrogels ability to delivery biotherapeutics. Lastly, the utility of the dextran-aldehyde crosslinked with polyethylenimine (PEI) bioadhesive hydrogel to prevent surgical site infections was explored. Surgical site infections that occur during the implantation of wound fillers can delay wound healing, resulting in increased antibiotic administration, longer hospital stays and, in the most severe cases, sepsis. To prevent bacterial infection during wound filling a new injectable bioadhesive antibacterial hydrogel was designed exploiting dextran-aldehyde crosslinked networks. Mechanical analysis, mammalian cytocompatibility and antibacterial properties of the material will be discussed.

Iontophoretic transport kinetics of ketorolac in vitro and in vivo: demonstrating local enhanced topical drug delivery to muscle.

PubMed

Gratieri, Taís; Pujol-Bello, Ester; Gelfuso, Guilherme M; de Souza, Joel G; Lopez, Renata F V; Kalia, Yogeshvar N

2014-02-01

The objective of the study was to investigate the iontophoretic delivery kinetics of ketorolac (KT), a highly potent NSAID and peripherally-acting analgesic that is currently indicated to treat moderate to severe acute pain. It was envisaged that, depending on the amounts delivered, transdermal iontophoretic administration might have two distinct therapeutic applications: (i) more effective and faster local therapy with shorter onset times (e.g. to treat trauma-related pain/inflammation in muscle) or (ii) a non-parenteral, gastrointestinal tract sparing approach for systemic pain relief. The first part of the study investigated the effect of experimental conditions on KT iontophoresis using porcine and human skin in vitro. These results demonstrated that KT electrotransport was linearly dependent on current density - from 0.1875 to 0.5mA/cm(2) - (r(2)>0.99) and drug concentration - from 5 to 20mg/ml (r(2)>0.99). Iontophoretic permeation of KT from a 2% hydroxymethyl cellulose gel was comparable to that from an aqueous solution with equivalent drug loading (584.59±114.67 and 462.05±66.56μg/cm(2), respectively). Cumulative permeation (462.05±66.56 and 416.28±95.71μg/cm(2)) and steady state flux (106.72±11.70 and 94.28±15.47μg/cm(2)h), across porcine and human skin, were statistically equivalent confirming the validity of the model. Based on the results in vitro, it was decided to focus on topical rather than systemic applications of KT iontophoresis in vivo. Subsequent experiments, in male Wistar rats, investigated the local enhancement of KT delivery to muscle by iontophoresis. Drug biodistribution was assessed in skin, in the biceps femoris muscle beneath the site of iontophoresis ('treated muscle'; TM), in the contralateral muscle ('non-treated muscle'; NTM) and in plasma (P). Passive topical delivery and oral administration served as negative and positive controls, respectively. Iontophoretic administration for 30min was superior to passive topical delivery for 1h and resulted in statistically significant increases in KT levels in the skin (91.04±15.48 vs. 20.16±8.58μg/cm(2)), in the biceps femoris at the treatment site (TM; 6.74±3.80 vs.

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

PubMed

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

2014-03-01

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

Interventional MRI-guided catheter placement and real time drug delivery to the central nervous system.

PubMed

Han, Seunggu J; Bankiewicz, Krystof; Butowski, Nicholas A; Larson, Paul S; Aghi, Manish K

2016-06-01

Local delivery of therapeutic agents into the brain has many advantages; however, the inability to predict, visualize and confirm the infusion into the intended target has been a major hurdle in its clinical development. Here, we describe the current workflow and application of the interventional MRI (iMRI) system for catheter placement and real time visualization of infusion. We have applied real time convection-enhanced delivery (CED) of therapeutic agents with iMRI across a number of different clinical trials settings in neuro-oncology and movement disorders. Ongoing developments and accumulating experience with the technique and technology of drug formulations, CED platforms, and iMRI systems will continue to make local therapeutic delivery into the brain more accurate, efficient, effective and safer.

A novel local anesthetic system: transcriptional transactivator peptide-decorated nanocarriers for skin delivery of ropivacaine.

PubMed

Chen, Chuanyu; You, Peijun

2017-01-01

Barrier properties of the skin and physicochemical properties of drugs are the main factors for the delivery of local anesthetic molecules. The present work evaluates the anesthetic efficacy of drug-loaded nanocarrier (NC) systems for the delivery of local anesthetic drug, ropivacaine (RVC). In this study, transcriptional transactivator peptide (TAT)-decorated RVC-loaded NCs (TAT-RVC/NCs) were successfully fabricated. Physicochemical properties of NCs were determined in terms of particle size, zeta potential, drug encapsulation efficiency, drug-loading capacity, stability, and in vitro drug release. The skin permeation of NCs was examined using a Franz diffusion cell mounted with depilated mouse skin in vitro, and in vivo anesthetic effect was evaluated in mice. The results showed that TAT-RVC/NCs have a mean diameter of 133.2 nm and high drug-loading capacity of 81.7%. From the in vitro skin permeation results, it was observed that transdermal flux of TAT-RVC/NCs was higher than that of RVC-loaded NCs (RVC/NCs) and RVC injection. The evaluation of in vivo anesthetic effect illustrated that TAT-RVC/NCs can enhance the transdermal delivery of RVC by reducing the pain threshold in mice. These results indicate that TAT-decorated NCs systems are useful for overcoming the barrier function of the skin, decreasing the dosage of RVC and enhancing the anesthetic effect. Therefore, TAT-decorated NCs can be used as an effective transdermal delivery system for local anesthesia.

Three-dimensional printing of strontium-containing mesoporous bioactive glass scaffolds for bone regeneration.

PubMed

Zhang, Jianhua; Zhao, Shichang; Zhu, Yufang; Huang, Yinjun; Zhu, Min; Tao, Cuilian; Zhang, Changqing

2014-05-01

In this study, we fabricated strontium-containing mesoporous bioactive glass (Sr-MBG) scaffolds with controlled architecture and enhanced mechanical strength using a three-dimensional (3-D) printing technique. The study showed that Sr-MBG scaffolds had uniform interconnected macropores and high porosity, and their compressive strength was ∼170 times that of polyurethane foam templated MBG scaffolds. The physicochemical and biological properties of Sr-MBG scaffolds were evaluated by ion dissolution, apatite-forming ability and proliferation, alkaline phosphatase activity, osteogenic expression and extracelluar matrix mineralization of osteoblast-like cells MC3T3-E1. The results showed that Sr-MBG scaffolds exhibited a slower ion dissolution rate and more significant potential to stabilize the pH environment with increasing Sr substitution. Importantly, Sr-MBG scaffolds possessed good apatite-forming ability, and stimulated osteoblast cells' proliferation and differentiation. Using dexamethasone as a model drug, Sr-MBG scaffolds also showed a sustained drug delivery property for use in local drug delivery therapy, due to their mesoporous structure. Therefore, the 3-D printed Sr-MBG scaffolds combined the advantages of Sr-MBG such as good bone-forming bioactivity, controlled ion release and drug delivery and enhanced mechanical strength, and had potential application in bone regeneration. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Microemulsion-Based Mucoadhesive Buccal Wafers: Wafer Formation, In Vitro Release, and Ex Vivo Evaluation.

PubMed

Pham, Minh Nguyet; Van Vo, Toi; Tran, Van-Thanh; Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh

2017-10-01

Microemulsion has the potentials to enhance dissolution as well as facilitate absorption and permeation of poorly water-soluble drugs through biological membranes. However, its application to govern a controlled release buccal delivery for local treatment has not been discovered. The aim of this study is to develop microemulsion-based mucoadhesive wafers for buccal delivery based on an incorporation of the microemulsion with mucoadhesive agents and mannitol. Ratio of oil to surfactant to water in the microemulsion significantly impacted quality of the wafers. Furthermore, the combination of carbopol and mannitol played a key role in forming the desired buccal wafers. The addition of an extra 50% of water to the formulation was suitable for wafer formation by freeze-drying, which affected the appearance and distribution of carbopol in the wafers. The amount of carbopol was critical for the enhancement of mucoadhesive properties and the sustained drug release patterns. Release study presented a significant improvement of the drug release profile following sustained release for 6 h. Ex vivo mucoadhesive studies provided decisive evidence to the increased retention time of wafers along with the increased carbopol content. The success of this study indicates an encouraging strategy to formulate a controlled drug delivery system by incorporating microemulsions into mucoadhesive wafers.

Controlled release of bupivacaine using hybrid thermoresponsive nanoparticles activated via photothermal heating.

PubMed

Alejo, Teresa; Andreu, Vanesa; Mendoza, Gracia; Sebastian, Victor; Arruebo, Manuel

2018-08-01

Near-infrared (NIR) responsive nanoparticles are of great interest in the biomedical field as antennas for photothermal therapy and also as triggers for on-demand drug delivery. The present work reports the preparation of hollow gold nanoparticles (HGNPs) with plasmonic absorption in the NIR region covalently bound to a thermoresponsive polymeric shell that can be used as an on-demand drug delivery system for the release of analgesic drugs. The photothermal heating induced by the nanoparticles is able to produce the collapse of the polymeric shell thus generating the release of the local anesthetic bupivacaine in a spatiotemporally controlled way. Those HGNPs contain a 10 wt.% of polymer and present excellent reversible heating under NIR light excitation. Bupivacaine released at physiological temperature (37 °C) showed a pseudo-zero order release that could be spatiotemporally modified on-demand after applying several pulses of light/temperature above and below the lower critical solution temperature (LCST) of the polymeric shell. Furthermore, the nanomaterials obtained did not displayed detrimental effects on four mammalian cell lines at doses up to 0.2 mg/mL. From the results obtained it can be concluded than this type of hybrid thermoresponsive nanoparticle can be used as an externally activated on-demand drug delivery system. Copyright © 2018 Elsevier Inc. All rights reserved.

A minocycline-releasing PMMA system as a space maintainer for staged bone reconstructions-in vitro antibacterial, cytocompatibility and anti-inflammatory characterization.

PubMed

Silva, Tiago; Grenho, Liliana; Barros, Joana; Silva, José Carlos; Pinto, Rosana V; Matos, Ana; Colaço, Bruno; Fernandes, Maria Helena; Bettencourt, Ana; Gomes, Pedro S

2017-06-06

In the present work, we study the development and biological characterization of a polymethyl methacrylate (PMMA)-based minocycline delivery system, to be used as a space maintainer within craniofacial staged regenerative interventions. The developed delivery systems were characterized regarding solid state characteristics and assayed in vitro for antibacterial and anti-inflammatory activity, and cytocompatibility with human bone cells. A drug release profile allowed for an initial burst release and a more sustained and controlled release over time, with minimum inhibitory concentrations for the assayed and relevant pathogenic bacteria (i.e., Staphylococcus aureus, slime-producer Staphylococcus epidermidis and Escherichia coli) being easily attained in the early time points, and sustained up to 72 h. Furthermore, an improved osteoblastic cell response-with enhancement of cell adhesion and cell proliferation-and increased anti-inflammatory activity were verified in developed systems, compared to a control (non minocycline-loaded PMMA cement). The obtained results converge to support the possible efficacy of the developed PMMA-based minocycline delivery systems for the clinical management of complex craniofacial trauma. Here, biomaterials with space maintenance properties are necessary for the management of staged reconstructive approaches, thus minimizing the risk of peri-operative infections and enhancing the local tissue healing and early stages of regeneration.

Controlled extended octenidine release from a bacterial nanocellulose/Poloxamer hybrid system.

PubMed

Alkhatib, Y; Dewaldt, M; Moritz, S; Nitzsche, R; Kralisch, D; Fischer, D

2017-03-01

Although bacterial nanocellulose (BNC) has been widely investigated in the last 10years as drug delivery system, up to now no long-term controlled release of drugs could be realized. Therefore, the aim of the present work was the development of a BNC-based drug delivery system that provides prolonged retention time for the antiseptic octenidine up to one week with improved mechanical and antimicrobial properties as well as a high biocompatibility. BNC was modified by incorporation of differently concentrated Poloxamers 338 and 407 as micelles and gels that were extensively investigated regarding size, surface charge, and dynamic viscosity. Depending on type and concentration of the Poloxamer, a retarded octenidine release up to one week could be accomplished. Additionally, superior material properties such as high compression stability and water binding could be achieved. The antimicrobial activity of octenidine against Staphylococcus aureus and Pseudomonas aeruginosa was not changed by the use of Poloxamers. Excellent biocompatibility of the Poloxamer loaded BNC could be demonstrated after local administration in a shell-less hen's egg model. In conclusion, a long-term delivery system consisting of BNC and Poloxamer could be developed for octenidine as a ready-to-use system e.g. for long-term dermal wound treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Ionic Driven Embedment of Hyaluronic Acid Coated Liposomes in Polyelectrolyte Multilayer Films for Local Therapeutic Delivery

NASA Astrophysics Data System (ADS)

Hayward, Stephen L.; Francis, David M.; Sis, Matthew J.; Kidambi, Srivatsan

2015-10-01

The ability to control the spatial distribution and temporal release of a therapeutic remains a central challenge for biomedical research. Here, we report the development and optimization of a novel substrate mediated therapeutic delivery system comprising of hyaluronic acid covalently functionalized liposomes (HALNPs) embedded into polyelectrolyte multilayer (PEM) platform via ionic stabilization. The PEM platform was constructed from sequential deposition of Poly-L-Lysine (PLL) and Poly(Sodium styrene sulfonate) (SPS) “(PLL/SPS)4.5” followed by adsorption of anionic HALNPs. An adsorption affinity assay and saturation curve illustrated the preferential HALNP deposition density for precise therapeutic loading. (PLL/SPS)2.5 capping layer on top of the deposited HALNP monolayer further facilitated complete nanoparticle immobilization, cell adhesion, and provided nanoparticle confinement for controlled linear release profiles of the nanocarrier and encapsulated cargo. To our knowledge, this is the first study to demonstrate the successful embedment of a translatable lipid based nanocarrier into a substrate that allows for temporal and spatial release of both hydrophobic and hydrophilic drugs. Specifically, we have utilized our platform to deliver chemotherapeutic drug Doxorubicin from PEM confined HALNPs. Overall, we believe the development of our HALNP embedded PEM system is significant and will catalyze the usage of substrate mediated delivery platforms in biomedical applications.

Development of nanovesicular systems for dermal imiquimod delivery: physicochemical characterization and in vitro/in vivo evaluation.

PubMed

Ma, Man; Wang, Jinping; Guo, Fang; Lei, Mingzhu; Tan, Fengping; Li, Nan

2015-06-01

The aim of the current investigation was to develop and statistically evaluate nanovesicular systems for dermal imiquimod delivery. To this purpose, transethosomes were prepared with phospholipid, ethanol and different permeation enhancers. Conventional ethosomes, with soy phospholipid and ethanol, were used as control. The prepared vesicles were characterized for size, zeta potential, stability and entrapment efficiency. The optimal transethosomal formulation with mean particle size of 82.3 ± 9.5 nm showed the higher entrapment efficiency (68.69 ± 1.7%). In vitro studies, permeation results of accumulated drug and local accumulation efficiency were significantly higher for transethosomes (24.64 µg/cm(2) and 6.70, respectively) than control (14.45 µg/cm(2) and 3.93, respectively). Confocal laser scanning microscopy of rhodamine 6G-loaded transethosomes revealed an enhanced retention into the deeper skin layers as compared to conventional ethosomes. Besides, Fourier-transform infra-red spectroscopy studies were also performed to understand the mechanism of interaction between skin and carriers. What's more, results of in vivo studies indicated the transethosomes of imiquimod providing the most effectiveness for dermal delivery among all of the formulations. These results suggested that transethosomes would be a promising dermal carrier for imiquimod in actinic keratose treatment.

How complexity science can inform scale-up and spread in health care: understanding the role of self-organization in variation across local contexts.

PubMed

Lanham, Holly Jordan; Leykum, Luci K; Taylor, Barbara S; McCannon, C Joseph; Lindberg, Curt; Lester, Richard T

2013-09-01

Health care systems struggle to scale-up and spread effective practices across diverse settings. Failures in scale-up and spread (SUS) are often attributed to a lack of consideration for variation in local contexts among different health care delivery settings. We argue that SUS occurs within complex systems and that self-organization plays an important role in the success, or failure, of SUS. Self-organization is a process whereby local interactions give rise to patterns of organizing. These patterns may be stable or unstable, and they evolve over time. Self-organization is a major contributor to local variations across health care delivery settings. Thus, better understanding of self-organization in the context of SUS is needed. We re-examine two cases of successful SUS: 1) the application of a mobile phone short message service intervention to improve adherence to medications during HIV treatment scale up in resource-limited settings, and 2) MRSA prevention in hospital inpatient settings in the United States. Based on insights from these cases, we discuss the role of interdependencies and sensemaking in leveraging self-organization in SUS initiatives. We argue that self-organization, while not completely controllable, can be influenced, and that improving interdependencies and sensemaking among SUS stakeholders is a strategy for facilitating self-organization processes that increase the probability of spreading effective practices across diverse settings. Published by Elsevier Ltd.

Local sustained delivery of acetylsalicylic acid via hybrid stent with biodegradable nanofibers reduces adhesion of blood cells and promotes reendothelialization of the denuded artery

PubMed Central

Lee, Cheng-Hung; Lin, Yu-Huang; Chang, Shang-Hung; Tai, Chun-Der; Liu, Shih-Jung; Chu, Yen; Wang, Chao-Jan; Hsu, Ming-Yi; Chang, Hung; Chang, Gwo-Jyh; Hung, Kuo-Chun; Hsieh, Ming-Jer; Lin, Fen-Chiung; Hsieh, I-Chang; Wen, Ming-Shien; Huang, Yenlin

2014-01-01

Incomplete endothelialization, blood cell adhesion to vascular stents, and inflammation of arteries can result in acute stent thromboses. The systemic administration of acetylsalicylic acid decreases endothelial dysfunction, potentially reducing thrombus, enhancing vasodilatation, and inhibiting the progression of atherosclerosis; but, this is weakened by upper gastrointestinal bleeding. This study proposes a hybrid stent with biodegradable nanofibers, for the local, sustained delivery of acetylsalicylic acid to injured artery walls. Biodegradable nanofibers are prepared by first dissolving poly(D,L)-lactide-co-glycolide and acetylsalicylic acid in 1,1,1,3,3,3-hexafluoro-2-propanol. The solution is then electrospun into nanofibrous tubes, which are then mounted onto commercially available bare-metal stents. In vitro release rates of pharmaceuticals from nanofibers are characterized using an elution method, and a highperformance liquid chromatography assay. The experimental results suggest that biodegradable nanofibers release high concentrations of acetylsalicylic acid for three weeks. The in vivo efficacy of local delivery of acetylsalicylic acid in reducing platelet and monocyte adhesion, and the minimum tissue inflammatory reaction caused by the hybrid stents in treating denuded rabbit arteries, are documented. The proposed hybrid stent, with biodegradable acetylsalicylic acid-loaded nanofibers, substantially contributed to local, sustained delivery of drugs to promote re-endothelialization and reduce thrombogenicity in the injured artery. The stents may have potential applications in the local delivery of cardiovascular drugs. Furthermore, the use of hybrid stents with acetylsalicylic acid-loaded nanofibers that have high drug loadings may provide insight into the treatment of patients with high risk of acute stent thromboses. PMID:24421640

Microprocessor-controlled iontophoretic drug delivery of 5-fluorouracil: pharmacodynamic and pharmacokinetic study.

PubMed

Chandrashekar, N S; Shobha Rani, R H

2007-01-01

The purpose of this study was to fabricate monolithic 5-fluorouracil (5-FU) transdermal patch with microprocessor- controlled iontophoretic delivery, to evaluate the pharmacodynamic effects on Dalton's lymphoma ascites (DLA) induced in Balb/c mice, and to study pharmacokinetics in rabbits. The transdermal patches were prepared by solvent casting method; a reprogrammable microprocessor was developed and connected to the patches. DLA cells were injected to the hind limb of Balb/c mice (10 animals/group). In the first group of mice 5-FU was administered i.v. (12 mg/kg). In the second group of mice, transdermal patches (20 mg/patch/animal) were installed and kept for 10 consecutive days, while the third (control) group was kept without any treatment. The tumor diameter was measured every 5th day for 30 days, and the animal survival time and death pattern were studied. The electric current density protocol of 0.5 mA/cm(2) for 30 min was used in the pharmacokinetic study in rabbits. There was a significant reduction in tumor volume in the animals treated with monolithic matrix 5-FU transdermal patch compared to untreated controls and i.v. therapy. Tumor volume of the control animals was 5.8 cm(3) on the 30th day, while in 5-FU with transdermal patch delivery animals it was only 0.23 cm(3) (p <0.05). DLA cells tumor-bearing mice treated with 5-FU with transdermal patch had significantly increased lifespan (ILS). Control animals survived only 21+/-1 days after the tumor inoculation, while i.v. 5-FU and 5-FU patches animals survived 24+/-2.7 days and 39.5+/-1.87 days with ILS of 25.58% and 88.09%, respectively (p <0.01). There was significant sustained release of 5-FU through microprocessor-controlled patches and half-life was significantly higher (p <0.05) compared to the i.v. route. Cytotoxic concentration of 5-FU can be achieved through the transdermal drug delivery and effective therapeutic drug concentration can be maintained up to 24 h, with less toxicity. A new generation of transdermal drug delivery systems based on microprocessor-controlled iontophoresis is in the late stages of development and promises to enhance the treatment of local and systemic medical conditions. The incorporation of microprocessor into these systems has been an important advancement to ensure safe and efficient administration of a wide variety of drugs.

Evaluation of a mucoadhesive fenretinide patch for local intraoral delivery: a strategy to reintroduce fenretinide for oral cancer chemoprevention

PubMed Central

Holpuch, Andrew S.; Phelps, Maynard P.; Desai, Kashappa-Goud H.; Chen, Wei; Koutras, George M.; Han, Byungdo B.; Warner, Blake M.; Pei, Ping; Seghi, Garrett A.; Tong, Meng; Border, Michael B.; Fields, Henry W.; Stoner, Gary D.; Larsen, Peter E.; Liu, Zhongfa; Schwendeman, Steven P.; Mallery, Susan R.

2012-01-01

Systemic delivery of fenretinide in oral cancer chemoprevention trials has been largely unsuccessful due to dose-limiting toxicities and subtherapeutic intraoral drug levels. Local drug delivery, however, provides site-specific therapeutically relevant levels while minimizing systemic exposure. These studies evaluated the pharmacokinetic and growth-modulatory parameters of fenretinide mucoadhesive patch application on rabbit buccal mucosa. Fenretinide and blank-control patches were placed on right/left buccal mucosa, respectively, in eight rabbits (30 min, q.d., 10 days). No clinical or histological deleterious effects occurred. LC-MS/MS analyses of post-treatment samples revealed a delivery gradient with highest fenretinide levels achieved at the patch-mucosal interface (no metabolites), pharmacologically active levels in fenretinide-treated oral mucosa (mean: 5.65 μM; trace amounts of 4-oxo-4-HPR) and undetectable sera levels. Epithelial markers for cell proliferation (Ki-67), terminal differentiation (transglutaminase 1—TGase1) and glucuronidation (UDP-glucuronosyltransferase1A1—UGT1A1) exhibited fenretinide concentration-specific relationships (elevated TGase1 and UGT1A1 levels <5 μM, reduced Ki-67 indices >5μM) relative to blank-treated epithelium. All fenretinide-treated tissues showed significantly increased intraepithelial apoptosis (TUNEL) positivity, implying activation of intersecting apoptotic and differentiation pathways. Human oral mucosal correlative studies showed substantial interdonor variations in levels of the enzyme (cytochrome P450 3A4—CYP3A4) responsible for conversion of fenretinide to its highly active metabolite, 4-oxo-4-HPR. Complementary in vitro assays in human oral keratinocytes revealed fenretinide and 4-oxo-4-HPR’s preferential suppression of DNA synthesis in dysplastic as opposed to normal oral keratinocytes. Collectively, these data showed that mucoadhesive patch-mediated fenretinide delivery is a viable strategy to reintroduce a compound known to induce keratinocyte differentiation to human oral cancer chemoprevention trials. PMID:22427354

Evaluation of a mucoadhesive fenretinide patch for local intraoral delivery: a strategy to reintroduce fenretinide for oral cancer chemoprevention.

PubMed

Holpuch, Andrew S; Phelps, Maynard P; Desai, Kashappa-Goud H; Chen, Wei; Koutras, George M; Han, Byungdo B; Warner, Blake M; Pei, Ping; Seghi, Garrett A; Tong, Meng; Border, Michael B; Fields, Henry W; Stoner, Gary D; Larsen, Peter E; Liu, Zhongfa; Schwendeman, Steven P; Mallery, Susan R

2012-05-01

Systemic delivery of fenretinide in oral cancer chemoprevention trials has been largely unsuccessful due to dose-limiting toxicities and subtherapeutic intraoral drug levels. Local drug delivery, however, provides site-specific therapeutically relevant levels while minimizing systemic exposure. These studies evaluated the pharmacokinetic and growth-modulatory parameters of fenretinide mucoadhesive patch application on rabbit buccal mucosa. Fenretinide and blank-control patches were placed on right/left buccal mucosa, respectively, in eight rabbits (30 min, q.d., 10 days). No clinical or histological deleterious effects occurred. LC-MS/MS analyses of post-treatment samples revealed a delivery gradient with highest fenretinide levels achieved at the patch-mucosal interface (no metabolites), pharmacologically active levels in fenretinide-treated oral mucosa (mean: 5.65 μM; trace amounts of 4-oxo-4-HPR) and undetectable sera levels. Epithelial markers for cell proliferation (Ki-67), terminal differentiation (transglutaminase 1-TGase1) and glucuronidation (UDP-glucuronosyltransferase1A1-UGT1A1) exhibited fenretinide concentration-specific relationships (elevated TGase1 and UGT1A1 levels <5 μM, reduced Ki-67 indices >5 μM) relative to blank-treated epithelium. All fenretinide-treated tissues showed significantly increased intraepithelial apoptosis (TUNEL) positivity, implying activation of intersecting apoptotic and differentiation pathways. Human oral mucosal correlative studies showed substantial interdonor variations in levels of the enzyme (cytochrome P450 3A4-CYP3A4) responsible for conversion of fenretinide to its highly active metabolite, 4-oxo-4-HPR. Complementary in vitro assays in human oral keratinocytes revealed fenretinide and 4-oxo-4-HPR's preferential suppression of DNA synthesis in dysplastic as opposed to normal oral keratinocytes. Collectively, these data showed that mucoadhesive patch-mediated fenretinide delivery is a viable strategy to reintroduce a compound known to induce keratinocyte differentiation to human oral cancer chemoprevention trials.

Impact of Refugees on Local Health Systems: A Difference-in-Differences Analysis in Cameroon.

PubMed

Tatah, Lambed; Delbiso, Tefera Darge; Rodriguez-Llanes, Jose Manuel; Gil Cuesta, Julita; Guha-Sapir, Debarati

2016-01-01

Hosting refugees may represent a drain on local resources, particularly since external aid is frequently insufficient. Between 2004 and 2011, over 100,000 refugees settled in the eastern border of Cameroon. With little known on how refugee influx affects health services of the hosting community, we investigated the impact of refugees on mother and child health (MCH) services in the host community in Cameroon. We used Cameroon's 2004 and 2011 Demographic and Health Surveys to evaluate changes in MCH indicators in the refugee hosting community. Our outcome variables were antenatal care (ANC) coverage, caesarean delivery rate, place of delivery and child vaccination coverage; whereas the exposure variable was residence in the refugee hosting community. We used a difference-in-differences analysis to compare indicators of the refugee hosting community to a control group selected through propensity score matching from the rest of the country. A total of 10,656 women were included in our 2004 analysis and 7.6% (n = 826) of them resided in the refugee hosting community. For 2011, 15,426 women were included and 5.8% (n = 902) of them resided in the hosting community. Between 2004 and 2011, both the proportion of women delivering outside health facilities and children not completing DPT3 vaccination in the refugee hosting community decreased by 9.0% (95% Confidence Interval (CI): 3.9-14.1%) and 9.6% (95% CI: 7.9-11.3%) respectively. However, ANC attendance and caesarean delivery did not show any significant change. Our findings demonstrate that none of the evaluated MCH service indicators deteriorated (in fact, two of them improved: delivery in health facilities and completing DPT3 vaccine) with the presence of refugees. This suggests evidence disproving the common belief that refugees always have a negative impact on their hosting community.

Walnut kernel-like mesoporous silica nanoparticles as effective drug carrier for cancer therapy in vitro

NASA Astrophysics Data System (ADS)

Ge, Kun; Ren, Huihui; Sun, Wentong; Zhao, Qi; Jia, Guang; Zang, Aimin; Zhang, Cuimiao; Zhang, Jinchao

2016-03-01

In drug delivery systems, nanocarriers could reduce the degradation and renal clearance of drugs, increase the half-life in the bloodstream and payload of drugs, control the release patterns, and improve the solubility of some insoluble drugs. In particular, mesoporous silica nanoparticles (MSNs) are considered to be attractive nanocarriers for application of delivery systems because of their large surface areas, large pore volume, tunable pore sizes, good biocompatibility, and the ease of surface functionalization. However, the large-scale synthesis of monodisperse MSNs that are smaller than 200 nm remains a challenge. In this study, monodisperse walnut kernel-like MSNs with diameters of approximately 100 nm were synthesized by a sol-gel route on a large scale. The morphology and structure of MSNs were characterized by scanning electron microscope, and transmission electron microscopy, N2 adsorption-desorption isotherms, Zeta potentials, and dynamic light scattering. Drug loading and release profile, cellular uptake, subcellular localization, and anticancer effect in vitro were further investigated. The results indicated that the loading efficiency of doxorubicinhydrochloride (DOX) into the MSNs was 57 %. The MSNs-DOX delivery system exhibited a drug-pronounced initial burst release within 12 h, followed by the slow sustained release of DOX molecules; moreover, MSNs could improve DOX release efficiency in acidic medium. Most free DOX was localized in the cytoplasm, whereas the MSNs-DOX was primarily distributed in lysosome. MSNs-DOX exhibited a potential anticancer effect against MCF-7, HeLa, and A549 cells in dose- and time-dependent manners. In summary, the as-synthesized MSNs may have well function as a promising drug carrier in drug delivery fields.

Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain.

PubMed

Upadhyay, Urvashi M; Tyler, Betty; Patta, Yoda; Wicks, Robert; Spencer, Kevin; Scott, Alexander; Masi, Byron; Hwang, Lee; Grossman, Rachel; Cima, Michael; Brem, Henry; Langer, Robert

2014-11-11

Metastases represent the most common brain tumors in adults. Surgical resection alone results in 45% recurrence and is usually accompanied by radiation and chemotherapy. Adequate chemotherapy delivery to the CNS is hindered by the blood-brain barrier. Efforts at delivering chemotherapy locally to gliomas have shown modest increases in survival, likely limited by the infiltrative nature of the tumor. Temozolomide (TMZ) is first-line treatment for gliomas and recurrent brain metastases. Doxorubicin (DOX) is used in treating many types of breast cancer, although its use is limited by severe cardiac toxicity. Intracranially implanted DOX and TMZ microcapsules are compared with systemic administration of the same treatments in a rodent model of breast adenocarcinoma brain metastases. Outcomes were animal survival, quantified drug exposure, and distribution of cleaved caspase 3. Intracranial delivery of TMZ and systemic DOX administration prolong survival more than intracranial DOX or systemic TMZ. Intracranial TMZ generates the more robust induction of apoptotic pathways. We postulate that these differences may be explained by distribution profiles of each drug when administered intracranially: TMZ displays a broader distribution profile than DOX. These microcapsule devices provide a safe, reliable vehicle for intracranial chemotherapy delivery and have the capacity to be efficacious and superior to systemic delivery of chemotherapy. Future work should include strategies to improve the distribution profile. These findings also have broader implications in localized drug delivery to all tissue, because the efficacy of a drug will always be limited by its ability to diffuse into surrounding tissue past its delivery source.

Multifunctional magnetic nanostructured hardystonite scaffold for hyperthermia, drug delivery and tissue engineering applications.

PubMed

Farzin, Ali; Fathi, Mohammadhossein; Emadi, Rahmatollah

2017-01-01

Hyperthermia and local drug delivery have been proposed as potential therapeutic approaches for killing cancer cells. The development of bioactive materials such as Hardystonite (HT) with magnetic and drug delivery properties can potentially meet this target. This new class of magnetic bioceramic can replace the widely used magnetic iron oxide nanoparticles, whose long-term biocompatibility is not clear. Magnetic HT can be potentially employed to develop new ceramic scaffolds for bone surgery and anticancer therapies. With this in mind, a synthesis procedure was developed to prepare multifunctional bioactive scaffold for tissue engineering, hyperthermia and drug delivery applications. To this end, iron (Fe 3+ )-containing HT scaffolds were prepared. The effect of Fe on biological, magnetic and drug delivery properties of HT scaffolds were investigated. The results showed that obtained Fe-HT is bioactive and magnetic with no magnetite or maghemite as secondary phases. The Fe-HT scaffolds obtained also possessed high specific surface areas and demonstrated sustained drug delivery. These results potentially open new aspects for biomaterials aimed at regeneration of large-bone defects caused by malignant bone tumors through a combination of hyperthermia, local drug delivery and osteoconductivity. Copyright © 2016 Elsevier B.V. All rights reserved.

Vaginal delivery of carboplatin-loaded thermosensitive hydrogel to prevent local cervical cancer recurrence in mice.

PubMed

Wang, Xue; Wang, Jin; Wu, Wenbin; Li, Hongjun

2016-11-01

Local tumor recurrence after cervical cancer surgery remains a clinical problem. Vaginal delivery of thermosensitive hydrogel may be suited to reduce tumor relapse rate with more efficacy and safety. A pilot study was carried out to evaluate the efficacy of carboplatin-loaded poloxamer hydrogel to prevent local recurrence of cervical cancer after surgery. In vivo vaginal retention evaluation of 27% poloxamer hydrogel in mice was proven to be a suitable vaginal drug delivery formulation due to its low gelation temperature. A mimic orthotopic cervical/vaginal cancer recurrence model after surgery was established by injecting murine cervical cancer cell line U14 into the vaginal submucosa to simulate the residual tumor cells infiltrated in the surgical site, followed by drug administration 24 h later to interfere with the formation/recurrence of the tumor. By infusing fluorescein sodium-loaded hydrogel into the vagina of mice, a maximized accumulation of fluorescein sodium (Flu) in the vagina was achieved and few signals were observed in other organs. When used in the prevention of the cervical cancer formation/recurrence in mice, the carboplatin-loaded poloxamer hydrogel exhibited great efficacy and systemic safety. In conclusion, thermosensitive hydrogel presents a simple, practical approach for the local drug delivery via vagina against cervical cancer recurrence.

Immunization Route Dictates Cross-Priming Efficiency and Impacts the Optimal Timing of Adjuvant Delivery

PubMed Central

Bouvier, Isabelle; Jusforgues-Saklani, Hélène; Lim, Annick; Lemaître, Fabrice; Lemercier, Brigitte; Auriau, Charlotte; Nicola, Marie-Anne; Leroy, Sandrine; Law, Helen K.; Bandeira, Antonio; Moon, James J.; Bousso, Philippe; Albert, Matthew L.

2011-01-01

Delivery of cell-associated antigen represents an important strategy for vaccination. While many experimental models have been developed in order to define the critical parameters for efficient cross-priming, few have utilized quantitative methods that permit the study of the endogenous repertoire. Comparing different strategies of immunization, we report that local delivery of cell-associated antigen results in delayed T cell cross-priming due to the increased time required for antigen capture and presentation. In comparison, delivery of disseminated antigen resulted in rapid T cell priming. Surprisingly, local injection of cell-associated antigen, while slower, resulted in the differentiation of a more robust, polyfunctional, effector response. We also evaluated the combination of cell-associated antigen with poly I:C delivery and observed an immunization route-specific effect regarding the optimal timing of innate immune stimulation. These studies highlight the importance of considering the timing and persistence of antigen presentation, and suggest that intradermal injection with delayed adjuvant delivery is the optimal strategy for achieving CD8+ T cell cross-priming. PMID:22566860

Evaluation of Calendula mucilage as a mucoadhesive and controlled release component in buccal tablets.

PubMed

Sabale, V; Patel, V; Paranjape, A

2014-01-01

Mucoadhesive drug delivery systems were developed to sustain drug delivery via various mucus membranes for either local or systemic delivery of poorly absorbed drugs such as peptides and proteins as well as drugs that are subjected to high first-pass metabolism. The present study was undertaken to use isolated Calendula mucilage as a mucoadhesive agent and to formulate controlled release buccoadhesive tablets with an intention to avoid hepatic first-pass metabolism as well as to enhance residence time of drug in the buccal cavity. The mucilage was isolated from the Calendula petals by aqueous extraction method and characterized for various physiochemical parameters as well as for its adhesive properties. By using direct compression technique, tablets were prepared containing dried mucilage and chlorpheniramine maleate (CPM) as a model drug. Three batches of tablets were prepared and evaluated containing three mucoadhesive components namely Methocel K4M, Carbopol 974P and isolated Calendula mucilage in 16.66%, 33.33 % and 50 % (1:2:3 ratio) resulting in 9 different formulations. FTIR studies between mucilage and CPM suggested the absence of a chemical interaction between CPM and Calendula mucilage. The results of the study showed that the isolated mucilage had good physicochemical and morphological characteristics and tablets conformed to the pharmacopoeial specifications. Also in vitro release studies showed controlled action of drug with increasing the concentration of the isolated Calendula mucilage as a mucoadhesive agent in the formulations. Permeability studies indicated that permeability behavior was not statistically different (P>0.05) by changing the mucoadhesive component. The formulated mucoadhesive tablets for buccal administration containing 75 mg Calendula mucilage showed controlled drug release. Thus, mucoadhesive natural Calendula mucilage based buccal tablets for controlled release were successfully formulated.

Evaluation of Calendula mucilage as a mucoadhesive and controlled release component in buccal tablets

PubMed Central

Sabale, V.; Patel, V.; Paranjape, A.

2014-01-01

Mucoadhesive drug delivery systems were developed to sustain drug delivery via various mucus membranes for either local or systemic delivery of poorly absorbed drugs such as peptides and proteins as well as drugs that are subjected to high first-pass metabolism. The present study was undertaken to use isolated Calendula mucilage as a mucoadhesive agent and to formulate controlled release buccoadhesive tablets with an intention to avoid hepatic first-pass metabolism as well as to enhance residence time of drug in the buccal cavity. The mucilage was isolated from the Calendula petals by aqueous extraction method and characterized for various physiochemical parameters as well as for its adhesive properties. By using direct compression technique, tablets were prepared containing dried mucilage and chlorpheniramine maleate (CPM) as a model drug. Three batches of tablets were prepared and evaluated containing three mucoadhesive components namely Methocel K4M, Carbopol 974P and isolated Calendula mucilage in 16.66%, 33.33 % and 50 % (1:2:3 ratio) resulting in 9 different formulations. FTIR studies between mucilage and CPM suggested the absence of a chemical interaction between CPM and Calendula mucilage. The results of the study showed that the isolated mucilage had good physicochemical and morphological characteristics and tablets conformed to the pharmacopoeial specifications. Also in vitro release studies showed controlled action of drug with increasing the concentration of the isolated Calendula mucilage as a mucoadhesive agent in the formulations. Permeability studies indicated that permeability behavior was not statistically different (P>0.05) by changing the mucoadhesive component. The formulated mucoadhesive tablets for buccal administration containing 75 mg Calendula mucilage showed controlled drug release. Thus, mucoadhesive natural Calendula mucilage based buccal tablets for controlled release were successfully formulated. PMID:25598798

Continuous subcutaneous delivery of medications for home care palliative patients-using an infusion set or a pump?

PubMed

Menahem, Sasson; Shvartzman, Pesach

2010-09-01

The purpose of this study was to evaluate safety, feasibility, and efficacy of continuous drug delivery by the subcutaneous route through a solution bag connected to an infusion set compared with an infusion pump in a home palliative care setting. Patients in need of continuous subcutaneous medication delivery for pain control, nausea, and/or vomiting were recruited. The study was designed as a double-blind, crossover study. The patient was connected to two parallel subcutaneous lines running simultaneously, connected together to a line entering the subcutaneous tissue. One line is connected to an infusion set and the other to a pump. The infusion set included a 500-cc solution bag connected to a 1.5-m plastic tube containing a drip chamber controlled by a roller clamp that is gravity driven without hyaluronidase. Active medications were randomly assigned to start in either administration method and switched after 24 h. An independent research assistant evaluated symptom control and side effects at baseline and every 24 h for 2 days using a structured questionnaire. Another independent research assistant connected the lines after adding medications and evaluated technical and clinical failures. Twenty-seven patients were recruited, and of them, 18 completed the study. Incidents in fluid administration were more common through the infusion set (18 times) compared to the pump (only twice). On the other hand, no clinical significant change was noted in the average symptom levels and side effects when medications were given through the infusion set versus the pump. No local edema or irritation was observed in either way of administration. In a home palliative care setting with a medical staff on call for 24 h, using medications for symptom control can be considered to be infused to a fluid solution bag through an infusion set instead of using a syringe driver or a pump when there is a responsible caregiver to follow up on the fluid. Subcutaneous constant drug delivery through a pump is more accurate.

Population-centered Risk- and Evidence-based Dental Interprofessional Care Team (PREDICT): study protocol for a randomized controlled trial.

PubMed

Cunha-Cruz, Joana; Milgrom, Peter; Shirtcliff, R Michael; Bailit, Howard L; Huebner, Colleen E; Conrad, Douglas; Ludwig, Sharity; Mitchell, Melissa; Dysert, Jeanne; Allen, Gary; Scott, JoAnna; Mancl, Lloyd

2015-06-20

To improve the oral health of low-income children, innovations in dental delivery systems are needed, including community-based care, the use of expanded duty auxiliary dental personnel, capitation payments, and global budgets. This paper describes the protocol for PREDICT (Population-centered Risk- and Evidence-based Dental Interprofessional Care Team), an evaluation project to test the effectiveness of new delivery and payment systems for improving dental care and oral health. This is a parallel-group cluster randomized controlled trial. Fourteen rural Oregon counties with a publicly insured (Medicaid) population of 82,000 children (0 to 21 years old) and pregnant women served by a managed dental care organization are randomized into test and control counties. In the test intervention (PREDICT), allied dental personnel provide screening and preventive services in community settings and case managers serve as patient navigators to arrange referrals of children who need dentist services. The delivery system intervention is paired with a compensation system for high performance (pay-for-performance) with efficient performance monitoring. PREDICT focuses on the following: 1) identifying eligible children and gaining caregiver consent for services in community settings (for example, schools); 2) providing risk-based preventive and caries stabilization services efficiently at these settings; 3) providing curative care in dental clinics; and 4) incentivizing local delivery teams to meet performance benchmarks. In the control intervention, care is delivered in dental offices without performance incentives. The primary outcome is the prevalence of untreated dental caries. Other outcomes are related to process, structure and cost. Data are collected through patient and staff surveys, clinical examinations, and the review of health and administrative records. If effective, PREDICT is expected to substantially reduce disparities in dental care and oral health. PREDICT can be disseminated to other care organizations as publicly insured clients are increasingly served by large practice organizations. ClinicalTrials.gov NCT02312921 6 December 2014. The Robert Wood Johnson Foundation and Advantage Dental Services, LLC, are supporting the evaluation.

Enzymatic- and temperature-sensitive controlled release of ultrasmall superparamagnetic iron oxides (USPIOs).

PubMed

Yu, Shann S; Scherer, Randy L; Ortega, Ryan A; Bell, Charleson S; O'Neil, Conlin P; Hubbell, Jeffrey A; Giorgio, Todd D

2011-02-27

Drug and contrast agent delivery systems that achieve controlled release in the presence of enzymatic activity are becoming increasingly important, as enzymatic activity is a hallmark of a wide array of diseases, including cancer and atherosclerosis. Here, we have synthesized clusters of ultrasmall superparamagnetic iron oxides (USPIOs) that sense enzymatic activity for applications in magnetic resonance imaging (MRI). To achieve this goal, we utilize amphiphilic poly(propylene sulfide)-bl-poly(ethylene glycol) (PPS-b-PEG) copolymers, which are known to have excellent properties for smart delivery of drug and siRNA. Monodisperse PPS polymers were synthesized by anionic ring opening polymerization of propylene sulfide, and were sequentially reacted with commercially available heterobifunctional PEG reagents and then ssDNA sequences to fashion biofunctional PPS-bl-PEG copolymers. They were then combined with hydrophobic 12 nm USPIO cores in the thin-film hydration method to produce ssDNA-displaying USPIO micelles. Micelle populations displaying complementary ssDNA sequences were mixed to induce crosslinking of the USPIO micelles. By design, these crosslinking sequences contained an EcoRV cleavage site. Treatment of the clusters with EcoRV results in a loss of R2 negative contrast in the system. Further, the USPIO clusters demonstrate temperature sensitivity as evidenced by their reversible dispersion at ~75°C and re-clustering following return to room temperature. This work demonstrates proof of concept of an enzymatically-actuatable and thermoresponsive system for dynamic biosensing applications. The platform exhibits controlled release of nanoparticles leading to changes in magnetic relaxation, enabling detection of enzymatic activity. Further, the presented functionalization scheme extends the scope of potential applications for PPS-b-PEG. Combined with previous findings using this polymer platform that demonstrate controlled drug release in oxidative environments, smart theranostic applications combining drug delivery with imaging of platform localization are within reach. The modular design of these USPIO nanoclusters enables future development of platforms for imaging and drug delivery targeted towards proteolytic activity in tumors and in advanced atherosclerotic plaques.

Supplementary routes to local anaesthesia.

PubMed

Meechan, J G

2002-11-01

The satisfactory provision of many dental treatments, particularly endodontics, relies on achieving excellent pain control. Unfortunately, the administration of a local anaesthetic solution does not always produce satisfactory anaesthesia of the dental pulp. This may be distressing for both patient and operator. Fortunately, failure of local anaesthetic injections can be overcome. This is often achieved by using alternative routes of approach for subsequent injections. Nerves such as the inferior alveolar nerve can be anaesthetized by a variety of block methods. However, techniques of anaesthesia other than the standard infiltration and regional block injections may be employed successfully when these former methods have failed to produce adequate pain control. This paper describes some supplementary local anaesthetic techniques that may be used to achieve pulpal anaesthesia for endodontic procedures when conventional approaches have failed. Although some of these techniques can be used as the primary form of anaesthesia, these are normally employed as 'back-up'. The methods described are intraligamentary (periodontal ligament) injections, intraosseous anaesthesia and the intrapulpal approach. The factors that influence the success of these methods and the advantages and disadvantages of each technique are discussed. The advent of new instrumentation, which permits the slow delivery of local anaesthetic solution has led to the development of novel methods of anaesthesia in dentistry. These new approaches are discussed.

A global health delivery framework approach to epilepsy care in resource-limited settings.

PubMed

Cochran, Maggie F; Berkowitz, Aaron L

2015-11-15

The Global Health Delivery (GHD) framework (Farmer, Kim, and Porter, Lancet 2013;382:1060-69) allows for the analysis of health care delivery systems along four axes: a care delivery value chain that incorporates prevention, diagnosis, and treatment of a medical condition; shared delivery infrastructure that integrates care within existing healthcare delivery systems; alignment of care delivery with local context; and generation of economic growth and social development through the health care delivery system. Here, we apply the GHD framework to epilepsy care in rural regions of low- and middle-income countries (LMIC) where there are few or no neurologists. Copyright © 2015 Elsevier B.V. All rights reserved.

Localization of magnetic pills

PubMed Central

Laulicht, Bryan; Gidmark, Nicholas J.; Tripathi, Anubhav; Mathiowitz, Edith

2011-01-01

Numerous therapeutics demonstrate optimal absorption or activity at specific sites in the gastrointestinal (GI) tract. Yet, safe, effective pill retention within a desired region of the GI remains an elusive goal. We report a safe, effective method for localizing magnetic pills. To ensure safety and efficacy, we monitor and regulate attractive forces between a magnetic pill and an external magnet, while visualizing internal dose motion in real time using biplanar videofluoroscopy. Real-time monitoring yields direct visual confirmation of localization completely noninvasively, providing a platform for investigating the therapeutic benefits imparted by localized oral delivery of new and existing drugs. Additionally, we report the in vitro measurements and calculations that enabled prediction of successful magnetic localization in the rat small intestines for 12 h. The designed system for predicting and achieving successful magnetic localization can readily be applied to any area of the GI tract within any species, including humans. The described system represents a significant step forward in the ability to localize magnetic pills safely and effectively anywhere within the GI tract. What our magnetic pill localization strategy adds to the state of the art, if used as an oral drug delivery system, is the ability to monitor the force exerted by the pill on the tissue and to locate the magnetic pill within the test subject all in real time. This advance ensures both safety and efficacy of magnetic localization during the potential oral administration of any magnetic pill-based delivery system. PMID:21257903

'Boomerang' technique: an improved method for conformal treatment of locally advanced nasopharyngeal cancer.

PubMed

Corry, June; Hornby, Colin; Fisher, Richard; D'Costa, Ieta; Porceddu, Sandro; Rischin, Danny; Peters, Lester J

2004-06-01

The primary aim of the present study was to assess radiation dosimetry and subsequent clinical outcomes in patients with locally advanced nasopharyngeal cancer using a novel radiation technique termed the 'Boomerang'. Dosimetric comparisons were made with both conventional and intensity modulated radiation therapy (IMRT) techniques. This is a study of 22 patients treated with this technique from June 1995 to October 1998. The technique used entailed delivery of 36 Gy in 18 fractions via parallel opposed fields, then 24 Gy in 12 fractions via asymmetric rotating arc fields for a total of 60 Gy in 30 fractions. Patients also received induction and concurrent chemotherapy. The radiation dosimetry was excellent. Dose-volume histograms showed that with the arc fields, 90% of the planning target volume received 94% of the prescribed dose. Relative to other conventional radiation therapy off-cord techniques, the Boomerang technique results in a 27% greater proportion of the prescribed dose being received by 90% of the planning target volume. This translates into an overall 10% greater dose received for the same prescribed dose. At 3 years, the actuarial loco-regional control rate, the failure-free survival rate and the overall survival rate were 91, 75 and 91%, respectively. At 5 years, the actuarial loco-regional control rate, the failure-free survival rate and the overall survival rate were 74, 62 and 71%, respectively. The Boomerang technique provided excellent radiation dosimetry with correspondingly good loco-regional control rates (in conjunction with chemotherapy) and very acceptable acute and late toxicity profiles. Because treatment can be delivered with conventional standard treatment planning and delivery systems, it is a validated treatment option for centres that do not have the capability or capacity for IMRT. A derivative of the Boomerang technique, excluding the parallel opposed component, is now our standard for patients with locally advanced nasopharyngeal cancer when IMRT is not available.

Optical microscopy of targeted drug delivery and local distribution in skin of a topical minocycline: implications in translational research and guidance for therapeutic dose selection (Conference Presentation)

NASA Astrophysics Data System (ADS)

Hermsmeier, Maiko; Sawant, Tanvee; Lac, Diana; Yamamoto, Akira; Chen, Xin; Huang, Susan Y.; Nagavarapu, Usha; Evans, Conor L.; Chan, Kin Foong; Daniels, AnnaMarie

2017-02-01

Acne vulgaris is a chronic inflammatory skin condition commonly resulting in negative aesthetic and social impacts on those affected. Minocycline, currently available as an oral antibiotic for moderate to severe acne, has a known minimum inhibitory concentration (MIC) for the acne-causing bacterium Propionibacterium acnes (P. acnes) in vitro, with its anti-inflammatory properties also eliciting inhibitory effects on pro-inflammatory molecules. A novel topical gel composition containing solubilized minocycline (BPX-01) has been developed to directly deliver the drug to the skin. Because minocycline is a known fluorophore, fluorescence microscopy and concurrent quantitative measurements were performed on excised human facial skin dosed with different concentrations, in order to determine the spatial distribution of the drug and quantification of its local concentration in the epidermis and the pilosebaceous unit where P. acnes generally reside. Local minocycline delivery confirmed achievement of an adequate therapeutic dose to support clinical studies. Subsequently, a 4-week double-blind, randomized, vehicle controlled clinical study was performed to assess the safety and efficacy of 1% minocycline BPX-01 applied daily. No instances of cutaneous toxicity were reported, and a greater than 1 log reduction of P. acnes count was observed at week 4 with statistical significance from baseline and vehicle control. In addition, no detectable amounts of minocycline in the plasma were reported, suggesting the potential of this new formulation to diminish the known systemic adverse effects associated with oral minocycline. Follow-on clinical plans are underway to further establish the safety of BPX-01 and to evaluate its efficacy against inflammatory acne lesions in a 225 patient multi-center dose-finding study.

Oral and transdermal drug delivery systems: role of lipid-based lyotropic liquid crystals.

PubMed

Rajabalaya, Rajan; Musa, Muhammad Nuh; Kifli, Nurolaini; David, Sheba R

2017-01-01

Liquid crystal (LC) dosage forms, particularly those using lipid-based lyotropic LCs (LLCs), have generated considerable interest as potential drug delivery systems. LCs have the physical properties of liquids but retain some of the structural characteristics of crystalline solids. They are compatible with hydrophobic and hydrophilic compounds of many different classes and can protect even biologicals and nucleic acids from degradation. This review, focused on research conducted over the past 5 years, discusses the structural evaluation of LCs and their effects in drug formulations. The structural classification of LLCs into lamellar, hexagonal and micellar cubic phases is described. The structures of these phases are influenced by the addition of surfactants, which include a variety of nontoxic, biodegradable lipids; these also enhance drug solubility. LLC structure influences drug localization, particle size and viscosity, which, in turn, determine drug delivery properties. Through several specific examples, we describe the applications of LLCs in oral and topical drug formulations, the latter including transdermal and ocular delivery. In oral LLC formulations, micelle compositions and the resulting LLC structures can determine drug solubilization and stability as well as intestinal transport and absorption. Similarly, in topical LLC formulations, composition can influence whether the drug is retained in the skin or delivered transdermally. Owing to their enhancement of drug stability and promotion of controlled drug delivery, LLCs are becoming increasingly popular in pharmaceutical formulations.

Oral and transdermal drug delivery systems: role of lipid-based lyotropic liquid crystals

PubMed Central

Rajabalaya, Rajan; Musa, Muhammad Nuh; Kifli, Nurolaini; David, Sheba R

2017-01-01

Liquid crystal (LC) dosage forms, particularly those using lipid-based lyotropic LCs (LLCs), have generated considerable interest as potential drug delivery systems. LCs have the physical properties of liquids but retain some of the structural characteristics of crystalline solids. They are compatible with hydrophobic and hydrophilic compounds of many different classes and can protect even biologicals and nucleic acids from degradation. This review, focused on research conducted over the past 5 years, discusses the structural evaluation of LCs and their effects in drug formulations. The structural classification of LLCs into lamellar, hexagonal and micellar cubic phases is described. The structures of these phases are influenced by the addition of surfactants, which include a variety of nontoxic, biodegradable lipids; these also enhance drug solubility. LLC structure influences drug localization, particle size and viscosity, which, in turn, determine drug delivery properties. Through several specific examples, we describe the applications of LLCs in oral and topical drug formulations, the latter including transdermal and ocular delivery. In oral LLC formulations, micelle compositions and the resulting LLC structures can determine drug solubilization and stability as well as intestinal transport and absorption. Similarly, in topical LLC formulations, composition can influence whether the drug is retained in the skin or delivered transdermally. Owing to their enhancement of drug stability and promotion of controlled drug delivery, LLCs are becoming increasingly popular in pharmaceutical formulations. PMID:28243062

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

PubMed Central

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

2014-01-01

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

Magnetically-actuated drug delivery device (MADDD) for minimally invasive treatment of prostate cancer: An in vivo animal pilot study.

PubMed

Struss, Werner J; Tan, Zheng; Zachkani, Payam; Moskalev, Igor; Jackson, John K; Shademani, Ali; D'Costa, Ninadh M; Raven, Peter A; Frees, Sebastian; Chavez-Munoz, Claudia; Chiao, Mu; So, Alan I

2017-05-01

The vast majority of prostate cancer presents clinically localized to the prostate without evidence of metastasis. Currently, there are several modalities available to treat this particular disease. Despite radical prostatectomy demonstrating a modest prostate cancer specific mortality benefit in the PIVOT trial, several novel modalities have emerged to treat localized prostate cancer in patients that are either not eligible for surgery or that prefer an alternative approach. Athymic nude mice were subcutaneously inoculated with prostate cancer cells. The mice were divided into four cohorts, one cohort untreated, two cohorts received docetaxel (10 mg/kg) either subcutaneously (SC) or intravenously (IV) and the fourth cohort was treated using the magnetically-actuated docetaxel delivery device (MADDD), dispensing 1.5 μg of docetaxel per 30 min treatment session. Treatment in all three therapeutic arms (SC, IV, and MADDD) was administered once weekly for 6 weeks. Treatment efficacy was measured once a week according to tumor volume using ultrasound. In addition, calipers were used to assess tumor volume. Animals implanted with the device demonstrated no signs of distress or discomfort, neither local nor systemic symptoms of inflammation and infection. Using an independent sample t-test, the tumor growth rate of the treated tumors was significant when compared to the control. Post hoc Tukey HSD test results showed that the mean tumor growth rate of our device cohort was significantly lower than SC and control cohorts. Moreover, IV cohort showed slight reduction in mean tumor growth rates than the ones from the device cohort, however, there was no statistical significance in tumor growth rate between these two cohorts. Furthermore, immunohistochemistry demonstrated an increased cellular apoptosis in the MADDD treated tumors and a decreased proliferation when compared to the other cohorts. In addition, IV cohort showed increased treatment side effects (weight loss) when compared to the device cohort. Finally, MADDD showed minimal expression of CD45 comparable to the control cohort, suggesting no signs of chronic inflammation. In conclusion, this study showed for the first time that MADDD, clearly suppressed tumor growth in local prostate cancer tumors. This could potentially be a novel clinical treatment approach for localized prostate cancer. © 2017 Wiley Periodicals, Inc.

Effectiveness of new vibration delivery system on pain associated with injection of local anesthesia in children.

PubMed

Shilpapriya, Mangalampally; Jayanthi, Mungara; Reddy, Venumbaka Nilaya; Sakthivel, Rajendran; Selvaraju, Girija; Vijayakumar, Poornima

2015-01-01

Pain is highly subjective and it is neurologically proven that stimulation of larger diameter fibers - e.g., using appropriate coldness, warmth, rubbing, pressure or vibration - can close the neural "gate" so that the central perception of itch and pain is reduced. This fact is based upon "gate control" theory of Melzack and Wall. The present study was carried out to investigate the effects of vibration stimuli on pain experienced during local anesthetic injections. Thirty patients aged 6-12 years old of both the genders with Frankel's behavior rating scale as positive and definitely positive requiring bilateral local anesthesia injections for dental treatment were included in the split-mouth cross over design. Universal pain assessment tool was used to assess the pain with and without vibration during the administration of local anesthesia and the results obtained were tabulated and statistically analyzed. Local anesthetic administration with vibration resulted in significantly less pain (P = 0.001) compared to the injections without the use of vibe. The results suggest that vibration can be used as an effective method to decrease pain during dental local anesthetic administration.

The effect of the PROSPER partnership model on cultivating local stakeholder knowledge of evidence-based programs: a five-year longitudinal study of 28 communities.

PubMed

Crowley, D Max; Greenberg, Mark T; Feinberg, Mark E; Spoth, Richard L; Redmond, Cleve R

2012-02-01

A substantial challenge in improving public health is how to facilitate the local adoption of evidence-based interventions (EBIs). To do so, an important step is to build local stakeholders' knowledge and decision-making skills regarding the adoption and implementation of EBIs. One EBI delivery system, called PROSPER (PROmoting School-community-university Partnerships to Enhance Resilience), has effectively mobilized community prevention efforts, implemented prevention programming with quality, and consequently decreased youth substance abuse. While these results are encouraging, another objective is to increase local stakeholder knowledge of best practices for adoption, implementation and evaluation of EBIs. Using a mixed methods approach, we assessed local stakeholder knowledge of these best practices over 5 years, in 28 intervention and control communities. Results indicated that the PROSPER partnership model led to significant increases in expert knowledge regarding the selection, implementation, and evaluation of evidence-based interventions. Findings illustrate the limited programming knowledge possessed by members of local prevention efforts, the difficulty of complete knowledge transfer, and highlight one method for cultivating that knowledge.

Ultrasound-Stimulated Drug Delivery Using Therapeutic Reconstituted High-Density Lipoprotein Nanoparticles.

PubMed

Xiong, Fangyuan; Nirupama, Sabnis; Sirsi, Shashank R; Lacko, Andras; Hoyt, Kenneth

2017-01-01

The abnormal tumor vasculature and the resulting abnormal microenvironment are major barriers to optimal chemotherapeutic drug delivery. It is well known that ultrasound (US) can increase the permeability of the tumor vessel walls and enhance the accumulation of anticancer agents. Reconstituted high-density lipoproteins (rHDL) nanoparticles (NPs) allow selective delivery of anticancer agents to tumor cells via their overexpressed scavenger receptor type B1 (SR-B1) receptor. The goal of this study is to investigate the potential of noninvasive US therapy to further improve delivery and tumor uptake of the payload from rHDL NPs, preloaded with an infrared dye (IR-780), aimed to establish a surrogate chemotherapeutic model with optical localization. Athymic nude mice were implanted orthotopically with one million breast cancer cells (MDA-MB-231/Luc). Three weeks later, animals were divided into seven groups with comparable mean tumor size: control, low, moderate, and high concentration of rHDL NPs alone groups, as well as these three levels of rHDL NPs plus US therapy groups ( N = 7 to 12 animals per group), where low, moderate and high denote 5, 10, and 50 µg of the IR-780 dye payload per rHDL NP injection, respectively. The US therapy system included a single element focused transducer connected in series with a function generator and power amplifier. A custom 3D printed cone with an acoustically transparent aperture and filled with degassed water allowed delivery of focused US energy to the tumor tissue. US exposure involved a pulsed sequence applied for a duration of 5 min. Each animal in the US therapy groups received a slow bolus co-injection of MB contrast agent and rHDL NPs. Animals were imaged using a whole-body optical system to quantify intratumoral rHDL NP accumulation at baseline and again at 1 min, 30 min, 24 h, and 48 h. At 48 h, all animals were euthanized and tumors were excised for ex vivo analysis. We investigated a noninvasive optical imaging method for monitoring the effects of US-stimulated drug delivery of IR-780 dye-loaded rHDL NPs in living animals. No change in optical imaging data was found in the control animals. However, there was considerable dye accumulation (surrogate drug) within 48 h in the low (5 µg), moderate (10 µg), and high (50 µg) rHDL NP concentration-dosed group animals ( p < 0.09). With US therapy added to the experimental protocol, there was an additional and significant increase in local tumor drug uptake at 48 h ( p < 0.02). Optical image data collected from ex vivo tumor samples confirmed tumor retention of the IR-780 dye-loaded rHDL NPs and correlated positively with in vivo optical imaging results ( R 2 > 0.69, p < 0.003). IR-780 dye extraction from the tumor tissue samples confirmed the in vivo and ex vivo US therapy findings. Overall, the addition of US therapy considerably improved local rHDL NP accumulation in tumor tissue. This study concludes that US-mediated drug delivery can facilitate tumor uptake of rHDL NPs and more research is warranted to optimize the drug dosing schedule and the respective therapeutic protocols.

pH-controlled drug loading and release from biodegradable microcapsules

PubMed Central

Zhao, Qinghe; Li, Bingyun

2013-01-01

Microcapsules made of biopolymers are of both scientific and technological interest and have many potential applications in medicine including their use as controlled drug delivery devices. The present study employs the electrostatic interaction between polycations and polyanions to form a multilayered microcapsule shell and also to control the loading and release of charged drug molecules inside the microcapsule. Micron-sized CaCO3 particles were synthesized and integrated with chondroitin sulfate (CS) through a reaction between Na2CO3 and Ca(NO3)2 solutions suspended with CS macromolecules. Oppositely-charged biopolymers were alternately deposited onto the synthesized particles using electrostatic layer-by-layer self-assembly, and glutaraldehyde was introduced to crosslink the multilayered shell structure. Microcapsules integrated with CS inside the multilayered shells were obtained after decomposition of the CaCO3 templates. The integration of a matrix, i.e. CS, enabled the subsequent selective control of drug loading and release. The CS integrated microcapsules were loaded with a model drug, i.e. bovine serum albumin labeled with fluorescein isothiocyanate (FITC-BSA), and it was shown that pH was an effective means of controlling the loading and release of FITC-BSA. Such CS integrated microcapsules may be used for controlled localized drug delivery as biodegradable devices, which have advantages in reducing systemic side effects and increasing drug efficacy. PMID:18657478

Pain associated with local anesthetic injection in eyelid procedures: Comparison of microprocessor-controlled versus traditional syringe techniques.

PubMed

Lee, Edward W; Tucker, Nancy A

2007-01-01

To evaluate the pain associated with local infiltration of the eyelid, using a microprocessor-controlled delivery system (CompuMed, using the Wand), as compared with traditional manual syringe infiltration technique. A randomized clinical trial of 30 patients undergoing minor eyelid surgical procedures was performed. Fifteen patients were injected by use of the CompuMed system and 15 patients were injected by the traditional manual syringe technique. The severity of pain was recorded from each patient by using a visual analog scale (0 to 10). The duration of pain experienced by the patient was also recorded. The mean pain level reported was 1.5 in the Wand group and 3.2 in the syringe group (p < 0.01). The mean duration of pain experienced was 1.5 seconds in the Wand group and 34 seconds in the syringe group (p < 0.01). The Wand was effective at significantly reducing the pain associated with local anesthetic infiltration in minor eyelid surgical procedures. Patients appear to feel pain from the initial needle stick but not during the actual injection.

Synthesis and Characterization of Poly(lactic-co-glycolic) Acid Nanoparticles-Loaded Chitosan/Bioactive Glass Scaffolds as a Localized Delivery System in the Bone Defects

PubMed Central

Nazemi, K.; Moztarzadeh, F.; Jalali, N.; Asgari, S.; Mozafari, M.

2014-01-01

The functionality of tissue engineering scaffolds can be enhanced by localized delivery of appropriate biological macromolecules incorporated within biodegradable nanoparticles. In this research, chitosan/58S-bioactive glass (58S-BG) containing poly(lactic-co-glycolic) acid (PLGA) nanoparticles has been prepared and then characterized. The effects of further addition of 58S-BG on the structure of scaffolds have been investigated to optimize the characteristics of the scaffolds for bone tissue engineering applications. The results showed that the scaffolds had high porosity with open pores. It was also shown that the porosity decreased with increasing 58S-BG content. Furthermore, the PLGA nanoparticles were homogenously distributed within the scaffolds. According to the obtained results, the nanocomposites could be considered as highly bioactive bone tissue engineering scaffolds with the potential of localized delivery of biological macromolecules. PMID:24949477

49 CFR 174.20 - Local or carrier restrictions.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 2 2011-10-01 2011-10-01 false Local or carrier restrictions. 174.20 Section 174... General Requirements § 174.20 Local or carrier restrictions. (a) When local conditions make the acceptance, transportation, or delivery of hazardous materials unusually hazardous, local restrictions may be imposed by the...

49 CFR 174.20 - Local or carrier restrictions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 2 2010-10-01 2010-10-01 false Local or carrier restrictions. 174.20 Section 174... General Requirements § 174.20 Local or carrier restrictions. (a) When local conditions make the acceptance, transportation, or delivery of hazardous materials unusually hazardous, local restrictions may be imposed by the...

Pain Experience and Behavior Management in Pediatric Dentistry: A Comparison between Traditional Local Anesthesia and the Wand Computerized Delivery System.

PubMed

Garret-Bernardin, Annelyse; Cantile, Tiziana; D'Antò, Vincenzo; Galanakis, Alexandros; Fauxpoint, Gabriel; Ferrazzano, Gianmaria Fabrizio; De Rosa, Sara; Vallogini, Giulia; Romeo, Umberto; Galeotti, Angela

2017-01-01

Aim. To evaluate the pain experience and behavior during dental injection, using the Wand computerized delivery system versus conventional local anesthesia in children and adolescents. Methods. An observational crossover split mouth study was performed on 67 patients (aged 7 to 15 years), requiring local anesthesia for dental treatments in both sides of the dental arch. Patients received both types of injections in two separate appointments, one with the use of a Computer Delivery System (the Wand STA system) and one with the traditional syringe. The following data were recorded: pain rating; changes in heart rate; level of collaboration; patient satisfaction. The data were analyzed using ANOVA for quantitative outcomes and nonparametric analysis (Kruskal-Wallis) for qualitative parameters. Results. The use of the Wand system determined significantly lower pain ratings and lower increase of heart rate than the traditional syringe. During injection, the number of patients showing a relaxed behavior was higher with the Wand than with the traditional local anesthesia. The patient level of satisfaction was higher with the Wand compared to the conventional local anesthesia. Conclusions. The Wand system may provide a less painful injection when compared to the conventional local anesthesia and it seemed to be better tolerated with respect to a traditional syringe.

Pain Experience and Behavior Management in Pediatric Dentistry: A Comparison between Traditional Local Anesthesia and the Wand Computerized Delivery System

PubMed Central

D'Antò, Vincenzo; Fauxpoint, Gabriel; De Rosa, Sara; Vallogini, Giulia

2017-01-01

Aim. To evaluate the pain experience and behavior during dental injection, using the Wand computerized delivery system versus conventional local anesthesia in children and adolescents. Methods. An observational crossover split mouth study was performed on 67 patients (aged 7 to 15 years), requiring local anesthesia for dental treatments in both sides of the dental arch. Patients received both types of injections in two separate appointments, one with the use of a Computer Delivery System (the Wand STA system) and one with the traditional syringe. The following data were recorded: pain rating; changes in heart rate; level of collaboration; patient satisfaction. The data were analyzed using ANOVA for quantitative outcomes and nonparametric analysis (Kruskal–Wallis) for qualitative parameters. Results. The use of the Wand system determined significantly lower pain ratings and lower increase of heart rate than the traditional syringe. During injection, the number of patients showing a relaxed behavior was higher with the Wand than with the traditional local anesthesia. The patient level of satisfaction was higher with the Wand compared to the conventional local anesthesia. Conclusions. The Wand system may provide a less painful injection when compared to the conventional local anesthesia and it seemed to be better tolerated with respect to a traditional syringe. PMID:28293129

Vascularization and Cellular Isolation Potential of a Novel Electrospun Cell Delivery Vehicle

PubMed Central

Krishnan, Laxminarayanan; Touroo, Jeremy; Reed, Robert; Boland, Eugene; Hoying, James B.; Williams, Stuart K.

2014-01-01

A clinical need exists for a cell delivery device that supports long term cell viability, cell retention within the device and retrieval of delivered cells if necessary. Previously, cell isolation devices have been based on hollow fiber membranes, porous polymer scaffolds, alginate systems, or micro-machined membranes. We present the development and characterization of a novel dual porosity electrospun membrane based device, which supports cellular infiltration and vascularization of its outer porous layer and maintains cellular isolation within a lumen bounded by an inner low porosity layer. Electrospinning conditions were initially established to support electrospun fiber deposition onto nonconductive silicone surfaces. With these parameters established, devices for in vivo evaluations were produced using nylon as a nonconductive scaffold for deposition of dual porosity electrospun fibers. The outer porous layer supported the development of a penetrating microcirculation and the membrane supported the transfer of insulin from encapsulated sustained release pellets for four weeks. Viable cells implanted within the device could be identified after two weeks of implantation. Through the successful demonstration of survival and cellular isolation of human epithelial cells within the implanted devices and the ability to use the device to deliver insulin, we have established the utility of this device toward localized cell transplantation. The Cell Delivery Device establishes a platform to test the feasibility of approaches to cell dose control and cell localization at the site of implantation in the clinical use of modified autologous or allogeneic cells. PMID:23913805

The acceptability to Aboriginal Australians of a family-based intervention to reduce alcohol-related harms.

PubMed

Calabria, Bianca; Clifford, Anton; Shakeshaft, Anthony; Allan, Julaine; Bliss, Donna; Doran, Christopher

2013-05-01

Cognitive-behavioural interventions that use familial and community reinforcers in an individual's environment are effective for reducing alcohol-related harms. Such interventions have considerable potential to reduce the disproportionately high burden of alcohol-related harm among Aboriginal Australians if they can be successfully tailored to their specific needs and circumstances. The overall aim of this paper is to describe the perceived acceptability of two cognitive-behavioural interventions, the Community Reinforcement Approach (CRA) and Community Reinforcement and Family Training (CRAFT), to a sample of Aboriginal people. Descriptive survey was administered to 116 Aboriginal people recruited through an Aboriginal Community Controlled Health Service and a community-based drug and alcohol treatment agency in rural New South Wales, Australia. Participants perceived CRA and CRAFT to be highly acceptable for delivery in their local Aboriginal community. Women were more likely than men to perceive CRAFT as highly acceptable. Participants expressed a preference for counsellors to be someone they knew and trusted, and who has experience working in their local community. CRA was deemed most acceptable for delivery to individuals after alcohol withdrawal and CRAFT for people who want to help a relative/friend start alcohol treatment. There was a preference for five or more detailed sessions. Findings of this study suggest that CRA and CRAFT are likely to be acceptable for delivery to some rural Aboriginal Australians, and that there is potential to tailor these interventions to specific communities. © 2012 Australasian Professional Society on Alcohol and other Drugs.

Interval From Imaging to Treatment Delivery in the Radiation Surgery Age: How Long Is Too Long?

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

Seymour, Zachary A., E-mail: seymourz@radonc.ucsf.edu; Fogh, Shannon E.; Westcott, Sarah K.

Purpose: The purpose of this study was to evaluate workflow and patient outcomes related to frameless stereotactic radiation surgery (SRS) for brain metastases. Methods and Materials: We reviewed all treatment demographics, clinical outcomes, and workflow timing, including time from magnetic resonance imaging (MRI), computed tomography (CT) simulation, insurance authorization, and consultation to the start of SRS for brain metastases. Results: A total of 82 patients with 151 brain metastases treated with SRS were evaluated. The median times from consultation, insurance authorization, CT simulation, and MRI for treatment planning were 15, 7, 6, and 11 days to SRS. Local freedom from progressionmore » (LFFP) was lower in metastases with MRI ≥14 days before treatment (P=.0003, log rank). The 6- and 12-month LFFP rate were 95% and 75% for metastasis with interval of <14 days from MRI to treatment compared to 56% and 34% for metastases with MRI ≥14 days before treatment. On multivariate analysis, LFFP remained significantly lower for lesions with MRI ≥14 days at SRS (P=.002, Cox proportional hazards; hazard ratio: 3.4, 95% confidence interval: 1.6-7.3). Conclusions: Delay from MRI to SRS treatment delivery for brain metastases appears to reduce local control. Future studies should monitor the timing from imaging acquisition to treatment delivery. Our experience suggests that the time from MRI to treatment should be <14 days.« less

Localized delivery of chemotherapy to the cervix for radiosensitization.

PubMed

Hodge, Lucy S; Downs, Levi S; Chura, Justin C; Thomas, Sajeena G; Callery, Patrick S; Soisson, A Patrick; Kramer, Paul; Wolfe, Stephen S; Tracy, Timothy S

2012-10-01

Chemoradiation is the mainstay of therapy for advanced cervical cancer, with the most effective treatment regimens involving combinations of radiosensitizing agents. However, administration of radiosensitizing chemotherapeutics concurrently with pelvic radiation is not without side effects. The aim of this study was to examine the utility of localized drug delivery as a means of improving drug targeting of radiosensitizing chemotherapeutics to the cervix while limiting systemic toxicities. An initial proof-of-concept study was performed in 14 healthy women following local administration of diazepam utilizing a novel cervical delivery device (CerviPrep™). Uterine vein and peripheral blood samples were collected and diazepam was measured using a GC-MS method. In the follow-up study, gemcitabine was applied to the cervix in 17 women undergoing hysterectomy for various gynecological malignancies. Cervical tissue, uterine vein blood samples, and peripheral plasma were collected, and gemcitabine and its deaminated metabolite 2',2'-difluorodeoxyuridine (dFdU) were measured using HPLC-UV and LC/MS methods. Targeted delivery of diazepam to the cervix was consistent with parent drug detectable in the uterine vein of 13 of 14 women. In the second study, pharmacologically relevant concentrations of gemcitabine (0.01-6.6 nmol/g tissue) were detected in the cervical tissue of 11 of 16 available specimens with dFdU measureable in 15 samples (0.04-8.8 nmol/g tissue). Neither gemcitabine nor its metabolites were detected in the peripheral plasma of any subject. Localized drug delivery to the cervix is possible and may be useful in limiting toxicity associated with intravenous administration of chemotherapeutics for radiosensitization. Copyright © 2012 Elsevier Inc. All rights reserved.

Physical property control in core/shell inorganic nanostructures for fluorescence and magnetic targeting applications

NASA Astrophysics Data System (ADS)

Roberts, Stephen K.

Nanomaterials show immense promise for the future in numerous areas of application. Properties that are unique from the bulk material and are tunable allow for innovation in material design. This thesis will focus on controlling the physical properties of core/shell nanostructures to enhance the utility of the materials. The first focus is on the impact of different solvent mixtures during the shell growth phase of SILAR based core/shell quantum dot synthesis is studied. Gaining insight into the mechanism for SILAR growth of core/shell nanoparticles allows improved synthetic yields and precursor binding, providing enhanced control to synthesis of core/shell nanoparticles. The second focus of this thesis is exploring the use of magnetic nanoparticles for magnetic drug targeting for cardiovascular conditions. Magnetic targeting for drug delivery enables increased local drug concentration, while minimizing non-specific interactions. In order to be effective for magnetic targeting, it must be shown that low magnetic strength is sufficient to capture flowing nanoparticles. By demonstrating the binding of a therapeutic agent to the surface at medicinal levels, the viability for use as a nanoparticle drug delivery system is improved.

Size-dependent control of colloid transport via solute gradients in dead-end channels

PubMed Central

Shin, Sangwoo; Um, Eujin; Sabass, Benedikt; Ault, Jesse T.; Rahimi, Mohammad; Warren, Patrick B.; Stone, Howard A.

2016-01-01

Transport of colloids in dead-end channels is involved in widespread applications including drug delivery and underground oil and gas recovery. In such geometries, Brownian motion may be considered as the sole mechanism that enables transport of colloidal particles into or out of the channels, but it is, unfortunately, an extremely inefficient transport mechanism for microscale particles. Here, we explore the possibility of diffusiophoresis as a means to control the colloid transport in dead-end channels by introducing a solute gradient. We demonstrate that the transport of colloidal particles into the dead-end channels can be either enhanced or completely prevented via diffusiophoresis. In addition, we show that size-dependent diffusiophoretic transport of particles can be achieved by considering a finite Debye layer thickness effect, which is commonly ignored. A combination of diffusiophoresis and Brownian motion leads to a strong size-dependent focusing effect such that the larger particles tend to concentrate more and reside deeper in the channel. Our findings have implications for all manners of controlled release processes, especially for site-specific delivery systems where localized targeting of particles with minimal dispersion to the nontarget area is essential. PMID:26715753

A Fully Implanted Drug Delivery System for Peripheral Nerve Blocks in Behaving Animals

PubMed Central

Pohlmeyer, Eric A.; Jordon, Luke R.; Kim, Peter; Miller, Lee E.

2009-01-01

Inhibiting peripheral nerve function can be useful for many studies of the nervous system or motor control. Accomplishing this in a temporary fashion in animal models by using peripheral nerve blocks permits studies of the immediate effects of the loss, and/or any resulting short-term changes and adaptations in behavior or motor control, while avoiding the complications commonly associated with permanent lesions, such as sores or self-mutilation. We have developed a method of quickly and repeatedly inducing temporary, controlled motor deficits in rhesus macaque monkeys via a chronically implanted drug delivery system. This assembly consists of a nerve cuff and a subdermal injection dome, and has proved effective for delivering local anesthetics directly to peripheral nerves for many months. Using this assembly for median and ulnar nerve blocks routinely resulted in over 80% losses in hand and wrist strength for rhesus monkeys. The assembly was also effective for inducing ambulatory motor deficits in rabbits through blocks of the sciatic nerve. Interestingly, while standard anesthetics were sufficient for the rabbit nerve blocks, the inclusion of epinephrine was essential for achieving significant motor blockade in the monkeys. PMID:19524613

A micropatterning approach for imaging Cx43 dynamic trafficking to cell-cell borders

PubMed Central

Zhang, Shan-Shan; Hong, SoonGweon; Kléber, André G.; Lee, Luke P.; Shaw, Robin M.

2014-01-01

The precise expression and timely delivery of connexin 43 (Cx43) proteins to form gap junctions are essential for electrical coupling of cardiomyocytes. Growing evidence supports a cytoskeletal-based trafficking paradigm for Cx43 delivery directly to adherens junctions at the intercalated disc. A limitation of Cx43 localization assays in cultured cells, in which cell-cell contacts are essential, is the inability to control for cell geometry or reproducibly generate contact points. Here we present a micropatterned cell pairing system well suited for live microscopy to examine how the microtubule and actin cytoskeleton confer specificity to Cx43 trafficking to precisely defined cell-cell junctions. This system can also be adapted for other cell types and used to study dynamic intracellular movements of other proteins important for cell-cell communication‥ PMID:24444605

Local Drug Delivery to Prevent Restenosis

PubMed Central

Seedial, Stephen M.; Ghosh, Soumojit; Saunders, R. Scott; Suwanabol, Pasithorn A.; Shi, Xudong; Liu, Bo; Kent, K. Craig

2013-01-01

Introduction Despite significant advances in vascular biology, bioengineering and pharmacology, restenosis remains a limitation to the overall efficacy of vascular reconstructions, both percutaneous and open. Although the pathophysiology of intimal hyperplasia is complex, a number of drugs and/or molecular tools have been identified that can prevent restenosis. Moreover, the focal nature of this process lends itself to treatment with local drug administration. In this article we provide a broad overview of current and future techniques for local drug delivery that have been developed to prevent restenosis following vascular intervention. Methods A systematic electronic literature search using PubMed was performed for all accessible published articles through September 2012. In an effort to remain current, additional searches were performed for abstracts presented at relevant societal meetings, filed patents, clinical trials and funded NIH awards. Results The efficacy of local drug delivery has been demonstrated in the coronary circulation with the current clinical use of drug-eluting stents (DES). Until recently, however, DES were not found to be efficacious in the peripheral circulation. Further pursuit of intraluminal devices has led to the development of balloon-based technologies with a recent surge in trials involving drug-eluting balloons. Early data appears encouraging, particularly for treatment of lesions in the superficial femoral artery, with several devices having recently received the CE mark in Europe. Investigators have also explored periadventitial application of biomaterials containing anti-restenotic drugs, an approach that could be particularly useful for surgical bypass or endarterectomy. In the past systemic drug delivery has been unsuccessful, however, there has been recent exploration of intravenous delivery of drugs designed specifically to target injured or reconstructed arteries. Our review revealed a multitude of additional interesting strategies including more than 65 new patents issued over the past two years for approaches to local drug delivery focused on preventing restenosis. Conclusion Restenosis following intraluminal or open vascular reconstruction remains an important clinical problem. Success in the coronary circulation has not translated into solutions for the peripheral arteries. However, our review of the literature reveals a number of promising approaches including drug-eluting balloons, periadventitial drug delivery as well as targeted systemic therapies. These innovations as well as others suggest that the future is bright and a solution for preventing restenosis in peripheral vessels will soon be at hand. PMID:23601595

Convection-enhanced delivery of SN-38-loaded polymeric micelles (NK012) enables consistent distribution of SN-38 and is effective against rodent intracranial brain tumor models.

PubMed

Zhang, Rong; Saito, Ryuta; Mano, Yui; Sumiyoshi, Akira; Kanamori, Masayuki; Sonoda, Yukihiko; Kawashima, Ryuta; Tominaga, Teiji

2016-10-01

Convection-enhanced delivery (CED) of therapeutic agents is a promising local delivery technique that has been extensively studied as a treatment for CNS diseases over the last two decades. One continuing challenge of CED is accurate and consistent delivery of the agents to the target. The present study focused on a new type of therapeutic agent, NK012, a novel SN-38-loaded polymeric micelle. Local delivery profiles of NK012 and SN-38 were studied using rodent brain and intracranial rodent brain tumor models. First, the cytotoxicity of NK012 against glioma cell lines was determined in vitro. Proliferations of glioma cells were significantly reduced after exposure to NK012. Then, the distribution and local toxicity after CED delivery of NK012 and SN-38 were evaluated in vivo. Volume of distribution of NK012 after CED was much larger than that of SN-38. Histological examination revealed minimum brain tissue damage in rat brains after delivery of 40 µg NK012 but severe damage with SN-38 at the same dose. Subsequently, the efficacy of NK012 delivered via CED was tested in 9L and U87MG rodent orthotopic brain tumor models. CED of NK012 displayed excellent efficacy in the 9L and U87MG orthotopic brain tumor models. Furthermore, NK012 and gadolinium diamide were co-delivered via CED to monitor the NK012 distribution using MRI. Volume of NK012 distribution evaluated by histology and MRI showed excellent agreement. CED of NK012 represents an effective treatment option for malignant gliomas. MRI-guided CED of NK012 has potential for clinical application.

Nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) in pediatric and young adult patients: Results from a prospective study using limited-margin radiotherapy.

PubMed

Tinkle, Christopher L; Fernandez-Pineda, Israel; Sykes, April; Lu, Zhaohua; Hua, Chia-Ho; Neel, Michael D; Bahrami, Armita; Shulkin, Barry L; Kaste, Sue C; Pappo, Alberto; Spunt, Sheri L; Krasin, Matthew J

2017-11-15

Indications for and delivery of adjuvant therapies for pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) have been derived largely from adult studies; therefore, significant concern remains regarding radiation exposure to normal tissue. The authors report long-term treatment outcomes and toxicities for pediatric and young adult patients with high-grade NRSTS who were treated on a prospective trial using limited-margin radiotherapy. Sixty-two patients (ages 3-22 years) with predominantly high-grade NRSTS requiring radiation were treated on a phase 2 institutional study of conformal external-beam radiotherapy and/or brachytherapy using a 1.5-cm to 2-cm anatomically constrained margin. The estimated cumulative incidence of local failure, Gray's method estimated cumulative incidence of local failure, Kaplan-Meier method estimated survival, competing-risk regression model determined predictors of disease outcome, and toxicity was reported according to CTCAE v2.0. At a median follow-up of 5.1 years (range, 0.2-10.9 years), 9 patients had experienced local failure. The 5-year overall cumulative incidence of local failure was 14.8% (95% confidence interval [CI], 7.2%-25%), and all but 1 local failure occurred outside the highest-dose irradiation volume. The 5-year Kaplan-Meier estimates for event-free and overall survival were 49.3% (95% CI, 36.3%-61.1%) and 67.9% (95% CI, 54.2%-78.3%), respectively. Multivariable analysis indicated that younger age was the only independent predictor of local recurrence (P = .004). The 5-year cumulative incidence of grade 3 or 4 late toxicity was 15% (95% CI, 7.2%-25.3%). The delivery of limited-margin radiotherapy using conformal external-beam radiotherapy or brachytherapy provides a high rate of local tumor control without an increase in marginal failures and with acceptable treatment-related morbidity. Cancer 2017;123:4419-29. © 2017 American Cancer Society. © 2017 American Cancer Society.

Myocardial Drug Distribution Generated from Local Epicardial Application: Potential Impact of Cardiac Capillary Perfusion in a Swine Model Using Epinephrine

PubMed Central

Maslov, Mikhail Y.; Edelman, Elazer R.; Pezone, Matthew J.; Wei, Abraham E.; Wakim, Matthew G.; Murray, Michael R.; Tsukada, Hisashi; Gerogiannis, Iraklis S.; Groothuis, Adam; Lovich, Mark A.

2014-01-01

Prior studies in small mammals have shown that local epicardial application of inotropic compounds drives myocardial contractility without systemic side effects. Myocardial capillary blood flow, however, may be more significant in larger species than in small animals. We hypothesized that bulk perfusion in capillary beds of the large mammalian heart enhances drug distribution after local release, but also clears more drug from the tissue target than in small animals. Epicardial (EC) drug releasing systems were used to apply epinephrine to the anterior surface of the left heart of swine in either point-sourced or distributed configurations. Following local application or intravenous (IV) infusion at the same dose rates, hemodynamic responses, epinephrine levels in the coronary sinus and systemic circulation, and drug deposition across the ventricular wall, around the circumference and down the axis, were measured. EC delivery via point-source release generated transmural epinephrine gradients directly beneath the site of application extending into the middle third of the myocardial thickness. Gradients in drug deposition were also observed down the length of the heart and around the circumference toward the lateral wall, but not the interventricular septum. These gradients extended further than might be predicted from simple diffusion. The circumferential distribution following local epinephrine delivery from a distributed source to the entire anterior wall drove drug toward the inferior wall, further than with point-source release, but again, not to the septum. This augmented drug distribution away from the release source, down the axis of the left ventricle, and selectively towards the left heart follows the direction of capillary perfusion away from the anterior descending and circumflex arteries, suggesting a role for the coronary circulation in determining local drug deposition and clearance. The dominant role of the coronary vasculature is further suggested by the elevated drug levels in the coronary sinus effluent. Indeed, plasma levels, hemodynamic responses, and myocardial deposition remote from the point of release were similar following local EC or IV delivery. Therefore, the coronary vasculature shapes the pharmacokinetics of local myocardial delivery of small catecholamine drugs in large animal models. Optimal design of epicardial drug delivery systems must consider the underlying bulk capillary perfusion currents within the tissue to deliver drug to tissue targets and may favor therapeutic molecules with better potential retention in myocardial tissue. PMID:25234821

Design of calcium phosphate ceramics for drug delivery applications in bone diseases: A review of the parameters affecting the loading and release of the therapeutic substance.

PubMed

Parent, Marianne; Baradari, Hiva; Champion, Eric; Damia, Chantal; Viana-Trecant, Marylène

2017-04-28

Effective treatment of critical-size defects is a key challenge in restorative surgery of bone. The strategy covers the implantation of biocompatible, osteoconductive, bioactive and biodegradable devices which (1) well interact with native tissue, mimic multi-dimensional and hierarchical structure of bone and (2) are able to enhance bone repair, treating post implantation pathologies or bone diseases by local delivery of therapeutic agents. Among different options, calcium phosphate biomaterials are found to be attractive choices, due to their excellent biocompatibility, customisable bioactivity and biodegradability. Several approaches have been established to enhance this material ability to be loaded with a therapeutic agent, in order to obtain an in situ controlled release that meets the clinical needs. This article reviews the most important factors influencing on both drug loading and release capacity of porous calcium phosphate bone substitutes. Characteristics of the carrier, drug/carrier interactions, experimental conditions of drug loading and evaluation of drug delivery are considered successively. Copyright © 2017 Elsevier B.V. All rights reserved.

Nuclear and cytoplasmic delivery of lactoferrin in glioma using chitosan nanoparticles: Cellular location dependent-action of lactoferrin.

PubMed

Tammam, Salma N; Azzazy, Hassan M E; Lamprecht, Alf

2018-08-01

Lactoferrin (Lf) exerts anti-cancer effects on glioma, however, the exact mechanism remains unclear. Despite possessing a nuclear localization sequence (NLS), Lf was found to allocate only in the cytoplasm of glioma 261. Lf was therefore loaded into nuclear and cytoplasmic targeted nanoparticles (NPs) to determine whether nuclear delivery of Lf would enhance its anti-cancer effect. Upon treatment with 300 and 800 µg/mL Lf loaded chitosan NPs, nuclear targeted Lf-NPs showed 1.3 and 2.7 folds increase in cell viability, whereas cytoplasmic targeted Lf-NPs at 300 µg/mL decreased cell viability by 0.8 folds in comparison to free Lf and controls. Results suggest that the cytotoxicity of Lf on glioma is attributable to its cytoplasmic allocation. Nuclear delivery of Lf induced cell proliferation rather than cytotoxicity, indicating that the mode of action of Lf in glioma is cell location dependent. This calls for caution about the general use of Lf as an anti-cancer protein. Copyright © 2018. Published by Elsevier B.V.

Photo-crosslinked Biodegradable Elastomers for Controlled Nitric Oxide Delivery

PubMed Central

Wang, Ying; Kibbe, Melina R.; Ameer, Guillermo A.

2013-01-01

The delivery of nitric oxide (NO) has important applications in medicine, especially for procedures that involve the vasculature. We report photo-curable biodegradable poly(diol citrate) elastomers capable of slow release of NO. A methacrylated poly(diol citrate) macromonomer was prepared by polycondensation of citric acid with 1, 8-octanediol or 1, 12-dodecanediol followed by functionalization with 2-aminoethyl methacrylate. A miscible NO donor, diazeniumdiolated N, N-diethyldiethylenetriamine, was synthesized and incorporated into the polymer matrix. An elastomeric network was obtained via photo-polymerization of macromonomers upon UV irradiation within three minutes. Films and tubes of the NO-releasing crosslinked macromonomers exhibited strong tensile strength and radial compressive strength, respectively. They also exhibited cell compatibility and biodegradability in vitro. Sustained NO release under physiological conditions was achieved for at least one week. NO release enhanced the proliferation of human umbilical vein endothelial cells but inhibited the proliferation of human aortic smooth muscle cells. Photo-polymerizable NO-releasing materials provide a new approach for the localized and sustained delivery of NO to treat thrombosis and restenosis in the vasculature. PMID:24707352

Magnetic Nano- and Micro- Particles in Living Cells: Kinetics and Fluctuations

NASA Astrophysics Data System (ADS)

Pease, C.; Chiang, N.; Pierce, C.; Muthusamy, N.; Sooryakumar, R.

2015-03-01

Functional nano and micro materials have recently been used not only as diagnostic tools for extracellular studies but also as intracellular drug delivery vehicles and as internal probes of the cell. To realize proper cellular applications, it is important not only to achieve efficient delivery of these materials to targeted cells, but also to control their movement and activity within the confines of the cell. In this presentation, superparamagnetic nano and micro particles are utilized as probes, with their responses to weak external magnetic fields enabling them to be maneuvered within a cell. In order to generate the required local magnetic fields needed for manipulation, the fields emanating from microscopic domain walls stabilized on patterned surface profiles are used in conjunction with weak external magnetic fields to create mobile traps that can localize and transport the internalized particle. Preliminary findings on creating the mobile traps suitable for applications to probe the interior of cells, and the responses, both Brownian fluctuations and directed motion, of particles ranging in size from 200 nm to 1 micron within HS-5 cells will be presented. Future applications to probe cellular behavior within the framework of emerging biomaterials will be discussed.

Urushiol Patch Test Using the T.R.U.E. TEST System.

PubMed

Kim, Yesul; Longenecker, Amy; ElSohly, Mahmoud A; Gul, Waseem; Hage, Raymond J; Hamann, Curtis P; Marks, James G

Poison ivy, poison oak, and poison sumac are the most common causes of allergic contact dermatitis in North America. Although extensive efforts have been made to develop therapies that prevent and treat allergic contact dermatitis to these plants, there lacks an entirely effective method, besides complete avoidance. Efforts to develop a more effective preventive therapy, such as a vaccine, are ongoing. To accurately evaluate the efficacy of these new therapies, an appropriate assessment tool is needed. The aim of this study was to evaluate the safety and appropriate doses of urushiol required for a patch test based on the hydrogel delivery system of the Thin-Layer Rapid Use Epicutaneous Patch Test. Nine subjects were patch tested with various doses of urushiol and a negative control on day 0. Patch test sites were inspected for any local reaction on days 2, 4, 7, 14, and 21 after the initial exposure and graded by standard morphology. All 9 subjects did not have any significant adverse effects. The urushiol patch test using the hydrogel delivery method demonstrated urushiol sensitivity. All doses of urushiol resulted in a local reaction, and severity of reactions was correlated with dosage of urushiol used in the patch test.

Aloe vera: Nature's soothing healer to periodontal disease

PubMed Central

Bhat, Geetha; Kudva, Praveen; Dodwad, Vidya

2011-01-01

Background: Recent interest and advances in the field of alternative medicine has promoted the use of various herbal and natural products for multiple uses in the field of medicine. Aloe vera is one such product exhibiting multiple benefits and has gained considerable importance in clinical research. This clinical study focuses on Aloe vera and highlights its property when used as a medicament in the periodontal pocket. Materials and Methods: A total number of 15 subjects were evaluated for clinical parameters like plaque index, gingival index, probing pocket depth at baseline, followed by scaling and root planing (SRP). Test site comprised of SRP followed by intra-pocket placement of Aloe vera gel, which was compared with the control site in which only SRP was done, and clinical parameters were compared between the two sites at one month and three months from baseline. Results: Results exhibited encouraging findings in clinical parameters of the role of Aloe vera gel as a drug for local delivery. Conclusion: We conclude that subgingival administration of Aloe vera gel results in improvement of periodontal condition. Aloe vera gel can be used as a local drug delivery system in periodontal pockets. PMID:22028505

Alginate hydrogel improves anti-angiogenic bevacizumab activity in cancer therapy.

PubMed

Ferreira, Natália N; M B Ferreira, Leonardo; Miranda-Gonçalves, Vera; Reis, Rui M; Seraphim, Thiago V; Borges, Júlio César; Baltazar, Fátima; Gremião, Maria Palmira D

2017-10-01

Anti-vascular endothelial growth factor (anti-VEGF) therapy applied to solid tumors is a promising strategy, yet, the challenge to deliver these agents at high drug concentrations together with the maintenance of therapeutic doses locally, at the tumor site, minimizes its benefits. To overcome these obstacles, we propose the development of a bevacizumab-loaded alginate hydrogel by electrostatic interactions to design a delivery system for controlled and anti-angiogenic therapy under tumor microenvironmental conditions. The tridimensional hydrogel structure produced provides drug stability and a system able to be introduced as a flowable solution, stablishing a depot after local administration. Biological performance by the chick embryo chorioallantoic membrane (CAM) assay indicated a pH-independent improved anti-angiogenic activity (∼50%) compared to commercial available anti-VEGF drug. Moreover, there was a considerable regression in tumor size when treated with this system. Immunohistochemistry highlighted a reduced number and disorganization of microscopic blood vessels resulting from applied therapy. These results suggest that the developed hydrogel is a promising approach to create an innovative delivery system that offers the possibility to treat different solid tumors by intratumoral administration. Copyright © 2017 Elsevier B.V. All rights reserved.

Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: selective targeting to diseased versus healthy tissue.

PubMed

Hua, Susan; Marks, Ellen; Schneider, Jennifer J; Keely, Simon

2015-07-01

Colon targeted drug delivery is an active area of research for local diseases affecting the colon, as it improves the efficacy of therapeutics and enables localized treatment, which reduces systemic toxicity. Targeted delivery of therapeutics to the colon is particularly advantageous for the treatment of inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease. Advances in oral drug delivery design have significantly improved the bioavailability of drugs to the colon; however in order for a drug to have therapeutic efficacy during disease, considerations must be made for the altered physiology of the gastrointestinal (GI) tract that is associated with GI inflammation. Nanotechnology has been used in oral dosage formulation design as strategies to further enhance uptake into diseased tissue within the colon. This review will describe some of the physiological challenges faced by orally administered delivery systems in IBD, the important developments in orally administered nano-delivery systems for colon targeting, and the future advances of this research. Inflammatory Bowel Disease (IBD) poses a significant problem for a large number of patients worldwide. Current medical therapy mostly aims at suppressing the active inflammatory episodes. In this review article, the authors described and discussed the various approaches current nano-delivery systems can offer in overcoming the limitations of conventional drug formulations. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

UV-crosslinkable and thermo-responsive chitosan hybrid hydrogel for NIR-triggered localized on-demand drug delivery.

PubMed

Wang, Lei; Li, Baoqiang; Xu, Feng; Xu, Zheheng; Wei, Daqing; Feng, Yujie; Wang, Yaming; Jia, Dechang; Zhou, Yu

2017-10-15

Innovative drug delivery technologies based on smart hydrogels for localized on-demand drug delivery had aroused great interest. To acquire smart UV-crosslinkable chitosan hydrogel for NIR-triggered localized on-demanded drug release, a novel UV-crosslinkable and thermo-responsive chitosan was first designed and synthesized by grafting with poly N-isopropylacrylamide, acetylation of methacryloyl groups and embedding with photothermal carbon. The UV-crosslinkable unit (methacryloyl groups) endowed chitosan with gelation via UV irradiation. The thermo-responsive unit (poly N-isopropylacrylamide) endowed chitosan hydrogel with temperature-triggered volume shrinkage and reversible swelling/de-swelling behavior. The chitosan hybrid hydrogel embedded with photothermal carbon exhibited distinct NIR-triggered volume shrinkage (∼42% shrinkage) in response to temperature elevation as induced by NIR laser irradiation. As a demonstration, doxorubicin release rate was accelerated and approximately 40 times higher than that from non-irradiated hydrogels. The UV-crosslinkable and thermal-responsive hybrid hydrogel served as in situ forming hydrogel-based drug depot is developed for NIR-triggered localized on-demand release. Copyright © 2017 Elsevier Ltd. All rights reserved.

Measuring public health practice and outcomes in chronic disease: a call for coordination.

PubMed

Porterfield, Deborah S; Rogers, Todd; Glasgow, LaShawn M; Beitsch, Leslie M

2015-04-01

A strategic opportunity exists to coordinate public health systems and services researchers' efforts to develop local health department service delivery measures and the efforts of divisions within the Centers for Disease Control and Prevention's National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP) to establish outcome indicators for public health practice in chronic disease. Several sets of outcome indicators developed by divisions within NCCDPHP and intended for use by state programs can be tailored to assess outcomes of interventions within smaller geographic areas or intervention settings. Coordination of measurement efforts could potentially allow information to flow from the local to the state to the federal level, enhancing program planning, accountability, and even subsequent funding for public health practice.

Enhancing palliative care delivery in a regional community in Australia.

PubMed

Phillips, Jane L; Davidson, Patricia M; Jackson, Debra; Kristjanson, Linda; Bennett, Margaret L; Daly, John

2006-08-01

Although access to palliative care is a fundamental right for people in Australia and is endorsed by government policy, there is often limited access to specialist palliative care services in regional, rural and remote areas. This article appraises the evidence pertaining to palliative care service delivery to inform a sustainable model of palliative care that meets the needs of a regional population on the mid-north coast of New South Wales. Expert consultation and an eclectic literature review were undertaken to develop a model of palliative care service delivery appropriate to the needs of the target population and resources of the local community. On the basis of this review, a local palliative care system that is based on a population-based approach to service planning and delivery, with formalized integrated network agreements and role delineation between specialist and generalist providers, has the greatest potential to meet the palliative care needs of this regional coastal community.

Fiberoptic microneedles: novel optical diffusers for interstitial delivery of therapeutic light.

PubMed

Kosoglu, Mehmet A; Hood, Robert L; Rossmeisl, John H; Grant, David C; Xu, Yong; Robertson, John L; Rylander, Marissa Nichole; Rylander, Christopher G

2011-11-01

Photothermal therapies have limited efficacy and application due to the poor penetration depth of light inside tissue. In earlier work, we described the development of novel fiberoptic microneedles to provide a means to mechanically penetrate dermal tissue and deliver light directly into a localized target area.This paper presents an alternate fiberoptic microneedle design with the capability of delivering more diffuse, but therapeutically useful photothermal energy. Laser lipolysis is envisioned as a future clinical application for this design. A novel fiberoptic microneedle was developed using hydrofluoric acid etching of optical fiber to permit diffuse optical delivery. Microneedles etched for 10, 30, and 50 minutes, and an optical fiber control were compared with three techniques. First, red light delivery from the microneedles was evaluated by imaging the reflectance of the light from a white paper.Second, spatial temperature distribution of the paper in response to near-IR light (1,064 nm, 1 W CW) was recorded using infrared thermography. Third, ex vivo adipose tissue response during 1,064 nm, (5 W CW)irradiation was recorded with bright field microscopy. Acid etching exposed a 3 mm length of the fiber core, allowing circumferential delivery of light along this length. Increasing etching time decreased microneedle diameter, resulting in increased uniformity of red and 1,064 nm light delivery along the microneedle axis. For equivalent total energy delivery, thinner microneedles reduced carbonization in the adipose tissue experiments. We developed novel microscale optical diffusers that provided a more homogeneous light distribution from their surfaces, and compared performance to a flat-cleaved fiber, a device currently utilized in clinical practice. These fiberoptic microneedles can potentially enhance clinical laser procedures by providing direct delivery of diffuse light to target chromophores, while minimizing undesirable photothermal damage in adjacent, non-target tissue. Copyright © 2011 Wiley Periodicals, Inc.

Fabrication, Characterization, and Biological Activity of Avermectin Nano-delivery Systems with Different Particle Sizes

NASA Astrophysics Data System (ADS)

Wang, Anqi; Wang, Yan; Sun, Changjiao; Wang, Chunxin; Cui, Bo; Zhao, Xiang; Zeng, Zhanghua; Yao, Junwei; Yang, Dongsheng; Liu, Guoqiang; Cui, Haixin

2018-01-01

Nano-delivery systems for the active ingredients of pesticides can improve the utilization rates of pesticides and prolong their control effects. This is due to the nanocarrier envelope and controlled release function. However, particles containing active ingredients in controlled release pesticide formulations are generally large and have wide size distributions. There have been limited studies about the effect of particle size on the controlled release properties and biological activities of pesticide delivery systems. In the current study, avermectin (Av) nano-delivery systems were constructed with different particle sizes and their performances were evaluated. The Av release rate in the nano-delivery system could be effectively controlled by changing the particle size. The biological activity increased with decreasing particle size. These results suggest that Av nano-delivery systems can significantly improve the controllable release, photostability, and biological activity, which will improve efficiency and reduce pesticide residues.

The application of nanomaterials in controlled drug delivery for bone regeneration.

PubMed

Shi, Shuo; Jiang, Wenbao; Zhao, Tianxiao; Aifantis, Katerina E; Wang, Hui; Lin, Lei; Fan, Yubo; Feng, Qingling; Cui, Fu-zhai; Li, Xiaoming

2015-12-01

Bone regeneration is a complicated process that involves a series of biological events, such as cellular recruitment, proliferation and differentiation, and so forth, which have been found to be significantly affected by controlled drug delivery. Recently, a lot of research studies have been launched on the application of nanomaterials in controlled drug delivery for bone regeneration. In this article, the latest research progress in this area regarding the use of bioceramics-based, polymer-based, metallic oxide-based and other types of nanomaterials in controlled drug delivery for bone regeneration are reviewed and discussed, which indicates that the controlling drug delivery with nanomaterials should be a very promising treatment in orthopedics. Furthermore, some new challenges about the future research on the application of nanomaterials in controlled drug delivery for bone regeneration are described in the conclusion and perspectives part. Copyright © 2015 Wiley Periodicals, Inc.

Polymer-iron oxide composite nanoparticles for EPR-independent drug delivery.

PubMed

Park, Jinho; Kadasala, Naveen Reddy; Abouelmagd, Sara A; Castanares, Mark A; Collins, David S; Wei, Alexander; Yeo, Yoon

2016-09-01

Nanoparticle (NP)-based approaches to cancer drug delivery are challenged by the heterogeneity of the enhanced permeability and retention (EPR) effect in tumors and the premature attrition of payload from drug carriers during circulation. Here we show that such challenges can be overcome by a magnetophoretic approach to accelerate NP delivery to tumors. Payload-bearing poly(lactic-co-glycolic acid) NPs were converted into polymer-iron-oxide nanocomposites (PINCs) by attaching colloidal Fe3O4 onto the surface, via a simple surface modification method using dopamine polymerization. PINCs formed stable dispersions in serum-supplemented medium and responded quickly to magnetic field gradients above 1 kG/cm. Under the field gradients, PINCs were rapidly transported across physical barriers and into cells and captured under flow conditions similar to those encountered in postcapillary venules, increasing the local concentration by nearly three orders of magnitude. In vivo magnetophoretic delivery enabled PINCs to accumulate in poorly vascularized subcutaneous SKOV3 xenografts that did not support the EPR effect. In vivo magnetic resonance imaging, ex vivo fluorescence imaging, and tissue histology all confirmed that the uptake of PINCs was higher in tumors exposed to magnetic field gradients, relative to negative controls. Copyright © 2016 Elsevier Ltd. All rights reserved.

Alternating-pulse iontophoresis for targeted cutaneous anesthesia

NASA Technical Reports Server (NTRS)

Meyer, Peter F.; Oddsson, Lars I E.

2003-01-01

In studies of sensory contributions to motor control, it may be advantageous to temporarily reduce the sensitivity of specific sensory systems. This article details a method for non-invasively inducing cutaneous anesthesia, leaving proprioceptive and motor functions intact. This method, called alternating-pulse iontophoresis, differs from conventional direct-current (DC) iontophoretic drug delivery in that adjacent drug delivery electrodes are stimulated out-of-phase. The total current delivered at any instant is then less than that produced during a comparable DC application, while the uniformity of drug delivery is expected to improve. Effective delivery of local anesthetics to the cutaneous foot soles by alternating-pulse iontophoresis was demonstrated using cutaneous pressure sensory threshold levels (STL's) assessed with Semmes-Weinstein monofilaments (arbitrary units of perceived force, or a.u.). Thirteen of 16 healthy subjects achieved a level of anesthesia greater than or equal to that normally associated with clinical peripheral sensory neuropathy. Average STL's measured prior to the anesthesia procedure were 4.00 a.u. ( approximately 10 mN). Immediately following the procedure, STL's were elevated to an average of 5.40 a.u. ( approximately 246 mN) and averaged 4.97 a.u. ( approximately 92 mN) after 50 min of standing. A number of research and clinical applications for this technique are suggested.

Drug delivery system and breast cancer cells

NASA Astrophysics Data System (ADS)

Colone, Marisa; Kaliappan, Subramanian; Calcabrini, Annarica; Tortora, Mariarosaria; Cavalieri, Francesca; Stringaro, Annarita

2016-06-01

Recently, nanomedicine has received increasing attention for its ability to improve the efficacy of cancer therapeutics. Nanosized polymer therapeutic agents offer the advantage of prolonged circulation in the blood stream, targeting to specific sites, improved efficacy and reduced side effects. In this way, local, controlled delivery of the drug will be achieved with the advantage of a high concentration of drug release at the target site while keeping the systemic concentration of the drug low, thus reducing side effects due to bioaccumulation. Various drug delivery systems such as nanoparticles, liposomes, microparticles and implants have been demonstrated to significantly enhance the preventive/therapeutic efficacy of many drugs by increasing their bioavailability and targetability. As these carriers significantly increase the therapeutic effect of drugs, their administration would become less cost effective in the near future. The purpose of our research work is to develop a delivery system for breast cancer cells using a microvector of drugs. These results highlight the potential uses of these responsive platforms suited for biomedical and pharmaceutical applications. At the request of all authors of the paper an updated version was published on 12 July 2016. The manuscript was prepared and submitted without Dr. Francesca Cavalieri's contribution and her name was added without her consent. Her name has been removed in the updated and re-published article.

Novel freeze-dried DDA and TPGS liposomes are suitable for nasal delivery of vaccine.

PubMed

Yusuf, Helmy; Ali, Ahlam A; Orr, Natalie; Tunney, Michael M; McCarthy, Helen O; Kett, Vicky L

2017-11-25

There is a pressing need for effective needle-free vaccines that are stable enough for use in the developing world and stockpiling. The inclusion of the cationic lipid DDA and the PEG-containing moiety TPGS into liposomes has the potential to improve mucosal delivery. The aim of this study was to develop stable lyophilized cationic liposomes based on these materials suitable for nasal antigen delivery. Liposomes containing DDA and TPGS were developed. Size and zeta potential measurements, ex vivo, CLSM cell penetration study and cell viability investigations were made. Preliminary immunisation and stability studies using ovalbumin were performed. The liposomes exhibited suitable size and charge for permeation across nasal mucosa. DDA and TPGS increased tissue permeation in ex vivo studies and cell uptake with good cell viability. The liposomes improved immune response both locally and vaginally when compared to i.m administration or control liposomes delivered nasally. Additionally, the lyophilized products demonstrated good stability in terms of Tg, size and antigen retention. This study has shown that the novel liposomes have potential for development as a mucosal vaccine delivery system. Furthermore, the stability of the lyophilized liposomes offers potential additional benefits in terms of thermal stability over liquid formats. Copyright © 2017 Elsevier B.V. All rights reserved.

Local transdermal delivery of phenylephrine to the anal sphincter muscle using microneedles

PubMed Central

Baek, Changyoon; Han, MeeRee; Min, Junghong; Prausnitz, Mark R.; Park, Jung-Hwan; Park, Jungho

2014-01-01

We propose pretreatment using microneedles to increase perianal skin permeability for locally targeted delivery of phenylephrine (PE), a drug that increases resting anal sphincter pressure to treat fecal incontinence. Microneedle patches were fabricated by micromolding poly-lactic-acid. Pre-treatment of human cadaver skin with microneedles increased PE delivery across the skin by up to 10-fold in vitro. In vivo delivery was assessed in rats receiving treatment with or without use of microneedles and with or without PE. Resting anal sphincter pressure was then measured over time using water-perfused anorectal manometry. For rats pretreated with microneedles, topical application of 30% PE gel rapidly increased the mean resting anal sphincter pressure from 7 ± 2 cm H2O to a peak value of 43 ± 17 cm H2O after 1 h, which was significantly greater than rats receiving PE gel without microneedle pretreatment. Additional safety studies showed that topically applied green fluorescent protein–expressing E. coli penetrated skin pierced with 23- and 26-gauge hypodermic needles, but E. coli was not detected in skin pretreated with microneedles, which suggests that microneedle-treated skin may not be especially susceptible to infection. In conclusion, this study demonstrates local transdermal delivery of PE to the anal sphincter muscle using microneedles, which may provide a novel treatment for fecal incontinence. PMID:21586307

Bioelectronic neural pixel: Chemical stimulation and electrical sensing at the same site

PubMed Central

Jonsson, Amanda; Inal, Sahika; Uguz, Ilke; Williamson, Adam J.; Kergoat, Loïg; Rivnay, Jonathan; Khodagholy, Dion; Berggren, Magnus; Bernard, Christophe; Malliaras, George G.

2016-01-01

Local control of neuronal activity is central to many therapeutic strategies aiming to treat neurological disorders. Arguably, the best solution would make use of endogenous highly localized and specialized regulatory mechanisms of neuronal activity, and an ideal therapeutic technology should sense activity and deliver endogenous molecules at the same site for the most efficient feedback regulation. Here, we address this challenge with an organic electronic multifunctional device that is capable of chemical stimulation and electrical sensing at the same site, at the single-cell scale. Conducting polymer electrodes recorded epileptiform discharges induced in mouse hippocampal preparation. The inhibitory neurotransmitter, γ-aminobutyric acid (GABA), was then actively delivered through the recording electrodes via organic electronic ion pump technology. GABA delivery stopped epileptiform activity, recorded simultaneously and colocally. This multifunctional “neural pixel” creates a range of opportunities, including implantable therapeutic devices with automated feedback, where locally recorded signals regulate local release of specific therapeutic agents. PMID:27506784

Intracochlear administration of steroids with a catheter during human cochlear implantation: a safety and feasibility study.

PubMed

Prenzler, Nils K; Salcher, Rolf; Timm, Max; Gaertner, Lutz; Lenarz, Thomas; Warnecke, Athanasia

2018-05-14

Suppression of foreign body reaction, improvement of electrode-nerve interaction, and preservation of residual hearing are essential research topics in cochlear implantation. Intracochlear pharmaco- or cell-based therapies can open new horizons in this field. Local drug delivery strategies are desirable as higher local concentrations of agents can be realized and side effects can be minimized compared to systemic administrations. When administered locally at accessible, basal parts of the cochlea, drugs reach apical regions later and in much lower concentrations due to poor diffusion patterns in cochlear fluids. Therefore, new devices are needed to warrant rapid distribution of agents into all parts of the cochlea. Five patients received a deep intracochlear injection of triamcinolone with a specifically designed cochlear catheter during cochlear implantation right before inserting a cochlear implant electrode. As a measure for formation of fibrous tissue around the electrode, electrical impedances were measured in the operation room and over 4 months thereafter. No adverse events were observed peri- and postoperatively. The handling of the device was easy. Severe damage to the microstructure of the cochlea was excluded as far as possible by cone beam computed tomography and vestibular testing. A delayed rise of the impedances was seen in the catheter group compared to controls over all regions of the cochlea. A statistical significance, however, was only obtained at the midregion of the cochlea. Consequently, the cochlear catheter is a safe and feasible device for local drug delivery of pharmaceutical agents into deeper regions of the cochlea.

Rectal cancer delivery of radiotherapy in adequate time and with adequate dose is influenced by treatment center, treatment schedule, and gender and is prognostic parameter for local control: Results of study CAO/ARO/AIO-94

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

Fietkau, Rainer; Roedel, Claus; Hohenberger, Werner

2007-03-15

Purpose: The impact of the delivery of radiotherapy (RT) on treatment results in rectal cancer patients is unknown. Methods and Materials: The data from 788 patients with rectal cancer treated within the German CAO/AIO/ARO-94 phase III trial were analyzed concerning the impact of the delivery of RT (adequate RT: minimal radiation RT dose delivered, 4300 cGy for neoadjuvant RT or 4700 cGy for adjuvant RT; completion of RT in <44 days for neoadjuvant RT or <49 days for adjuvant RT) in different centers on the locoregional recurrence rate (LRR) and disease-free survival (DFS) at 5 years. The LRR, DFS, andmore » delivery of RT were analyzed as endpoints in multivariate analysis. Results: A significant difference was found between the centers and the delivery of RT. The overall delivery of RT was a prognostic factor for the LRR (no RT, 29.6% {+-} 7.8%; inadequate RT, 21.2% {+-} 5.6%; adequate RT, 6.8% {+-} 1.4%; p = 0.0001) and DFS (no RT, 55.1% {+-} 9.1%; inadequate RT, 57.4% {+-} 6.3%; adequate RT, 69.1% {+-} 2.3%; p = 0.02). Postoperatively, delivery of RT was a prognostic factor for LRR on multivariate analysis (together with pathologic stage) but not for DFS (independent parameters, pathologic stage and age). Preoperatively, on multivariate analysis, pathologic stage, but not delivery of RT, was an independent prognostic parameter for LRR and DFS (together with adequate chemotherapy). On multivariate analysis, the treatment center, treatment schedule (neoadjuvant vs. adjuvant RT), and gender were prognostic parameters for adequate RT. Conclusion: Delivery of RT should be regarded as a prognostic factor for LRR in rectal cancer and is influenced by the treatment center, treatment schedule, and patient gender.« less

Chemoprevention of Breast Cancer by Transdermal Delivery of α-Santalol through Breast Skin and Mammary Papilla (Nipple).

PubMed

Dave, Kaushalkumar; Alsharif, Fahd M; Islam, Saiful; Dwivedi, Chandradhar; Perumal, Omathanu

2017-09-01

Almost all breast cancers originate from epithelial cells lining the milk ducts in the breast. To this end, the study investigated the feasibility of localized transdermal delivery of α-santalol, a natural chemopreventive agent to the breast. Different α-santalol formulations (cream, solution and microemulsion) were developed and the in vitro permeability was studied using excised animal (porcine and rat) and human breast skin/mammary papilla (nipple). The in vivo biodistribution and efficacy studies were conducted in female rats. A chemical carcinogenesis model of breast cancer was used for the efficacy studies. Phospholipid based α-santalol microemulsion showed the highest penetration through the nipple and breast skin. Delivery of α-santalol through the entire breast (breast skin and nipple) in vivo in rats resulted in significantly higher concentration in the mammary gland compared to transdermal delivery through the breast skin or nipple. There was no measurable α-santalol concentration in the blood. Transdermal delivery of α-santalol reduced the tumor incidence and tumor multiplicity. Furthermore, the tumor size was significantly reduced with α-santalol treatment. The findings from this study demonstrate the feasibility of localized transdermal delivery of α-santalol for chemoprevention of breast cancer.

Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy

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

Blanchard, Miran; Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota; Shim, Kevin G.

Purpose: The oligometastatic state is an intermediate state between a malignancy that can be completely eradicated with conventional modalities and one in which a palliative approach is undertaken. Clinically, high rates of local tumor control are possible with stereotactic ablative radiation therapy (SABR), using precisely targeted, high-dose, low-fraction radiation therapy. However, in oligometastatic melanoma, virtually all patients develop progression systemically at sites not initially treated with ablative radiation therapy that cannot be managed with conventional chemotherapy and immunotherapy. We have demonstrated in mice that intravenous administration of vesicular stomatitis virus (VSV) expressing defined tumor-associated antigens (TAAs) generates systemic immune responsesmore » capable of clearing established tumors. Therefore, in the present preclinical study, we tested whether the combination of systemic VSV-mediated antigen delivery and SABR would be effective against oligometastatic disease. Methods and Materials: We generated a model of oligometastatic melanoma in C57BL/6 immunocompetent mice and then used a combination of SABR and systemically administered VSV-TAA viral immunotherapy to treat both local and systemic disease. Results: Our data showed that SABR generates excellent control or cure of local, clinically detectable, and accessible tumor through direct cell ablation. Also, the immunotherapeutic activity of systemically administered VSV-TAA generated T-cell responses that cleared subclinical metastatic tumors. We also showed that SABR induced weak T-cell-mediated tumor responses, which, particularly if boosted by VSV-TAA, might contribute to control of local and systemic disease. In addition, VSV-TAA therapy alone had significant effects on control of both local and metastatic tumors. Conclusions: We have shown in the present preliminary murine study using a single tumor model that this approach represents an effective, complementary combination therapy model that addresses the need for both systemic and local control in oligometastatic melanoma.« less

Regionalization and Local Hospital Closure in Norwegian Maternity Care—The Effect on Neonatal and Infant Mortality

PubMed Central

Grytten, Jostein; Monkerud, Lars; Skau, Irene; Sørensen, Rune

2014-01-01

Objective To study whether neonatal and infant mortality, after adjustments for differences in case mix, were independent of the type of hospital in which the delivery was carried out. Data The Medical Birth Registry of Norway provided detailed medical information for all births in Norway. Study Design Hospitals were classified into two groups: local hospitals/maternity clinics versus central/regional hospitals. Outcomes were neonatal and infant mortality. The data were analyzed using propensity score weighting to make adjustments for differences in case mix between the two groups of hospitals. This analysis was supplemented with analyses of 13 local hospitals that were closed. Using a difference-in-difference approach, the effects that these closures had on neonatal and infant mortality were estimated. Principal Finding Neonatal and infant mortality were not affected by the type of hospital where the delivery took place. Conclusion A regionalized maternity service does not lead to increased neonatal and infant mortality. This is mainly because high-risk deliveries were identified well in advance of the birth, and referred to a larger hospital with sufficient perinatal resources to deal with these deliveries. PMID:24476021

Delivery after external cephalic version, is there an increased rate of cesarian section?

PubMed

Lago Leal, Victor; Pradillo Aramendi, Tamara; Nicolas Montero, Estefania; Ocaña Martínez, Vanesa; Del Barrio Fernández, Pablo; Martínez-Cortés, Luis

2016-04-01

The aim of this study was to compare the obstetric outcomes after successful external cephalic version (cases) with a group of pregnant women with a spontaneous cephalic fetal position at delivery (controls). Retrospective review of the cohort of study was performed at the University Hospital of Getafe (Madrid, Spain) between January 2012 and January 2013. 1516 patients (48 cases; 1468 controls). We compared the type of delivery in pregnant women after ECV performed successfully (cases) with spontaneous cephalic presentations (controls). Pregnancies with vaginal delivery contraindicated, elective cesarean section (CS) justified by maternal disease, multiple pregnancies, or pregnancies below 37 weeks were excluded. Maternal age, BMI, parity, gestational age at delivery, and onset of labor (spontaneous or induced) were controlled. Prevalence of CS and operative delivery in both groups. Women who underwent a successful ECV had a significantly higher CS rate compared with the women of the control group (12/48 [25%] vs. 202/1468 [13.76%]; P=0.028). There was no difference in the rate of operative delivery (6/48 [12.5%] vs. 177/1468 [12.05%] P=0.92). Deliveries following a successful ECV are associated with an increased CS rate compared with deliveries of fetuses with spontaneous cephalic presentations.

A Review of the Development of a Vehicle for Localized and Controlled Drug Delivery for Implantable Biosensors

PubMed Central

Bhardwaj, Upkar; Papadimitrakopoulos, Fotios; Burgess, Diane J.

2008-01-01

A major obstacle to the development of implantable biosensors is the foreign body response (FBR) that results from tissue trauma during implantation and the continuous presence of the implant in the body. The in vivo stability and functionality of biosensors are compromised by damage to sensor components and decreased analyte transport to the sensor. This paper summarizes research undertaken by our group since 2001 to control the FBR toward implanted sensors. Localized and sustained delivery of the anti-inflammatory drug, dexamethasone, and the angiogenic growth factor, vascular endothelial growth factor (VEGF), was utilized to inhibit inflammation as well as fibrosis and provide a stable tissue–device interface without producing systemic adverse effects. The drug-loaded polylactic-co-glycolic acid (PLGA) microspheres were embedded in a polyvinyl alcohol (PVA) hydrogel composite to fabricate a drug-eluting, permeable external coating for implantable devices. The composites were fabricated using the freeze–thaw cycle method and had mechanical properties similar to soft body tissue. Dexamethasone-loaded microsphere/hydrogel composites were able to provide anti-inflammatory protection, preventing the FBR. Moreover, concurrent release of dexamethasone with VEGF induced neoangiogenesis in addition to providing anti-inflammatory protection. Sustained release of dexamethasone is required for the entire sensor lifetime, as a delayed inflammatory response developed after depletion of the drug from the composites. These studies have shown the potential of PLGA microsphere/PVA hydrogel-based composites as drug-eluting external coatings for implantable biosensors. PMID:19885291

Microparticles, microcapsules and microspheres: A review of recent developments and prospects for oral delivery of insulin.

PubMed

Wong, Chun Y; Al-Salami, Hani; Dass, Crispin R

2018-02-15

Diabetes mellitus is a chronic metabolic health disease affecting the homeostasis of blood sugar levels. However, subcutaneous injection of insulin can lead to patient non-compliance, discomfort, pain and local infection. Sub-micron sized drug delivery systems have gained attention in oral delivery of insulin for diabetes treatment. In most of the recent literature, the terms "microparticles" and "nanoparticle" refer to particles where the dimensions of the particle are measured in micrometers and nanometers respectively. For instance, insulin-loaded particles are defined as microparticles with size larger than 1 μm by most of the research groups. The size difference between nanoparticles and microparticles proffers numerous effects on the drug loading efficiency, aggregation, permeability across the biological membranes, cell entry and tissue retention. For instance, microparticulate drug delivery systems have demonstrated a number of advantages including protective effect against enzymatic degradation, enhancement of peptide stability, site-specific and controlled drug release. Compared to nanoparticulate drug delivery systems, microparticulate formulations can facilitate oral absorption of insulin by paracellular, transcellular and lymphatic routes. In this article, we review the current status of microparticles, microcapsules and microspheres for oral administration of insulin. A number of novel techniques including layer-by-layer coating, self-polymerisation of shell, nanocomposite microparticulate drug delivery system seem to be promising for enhancing the oral bioavailability of insulin. This review draws several conclusions for future directions and challenges to be addressed for optimising the properties of microparticulate drug formulations and enhancing their hypoglycaemic effects. Copyright © 2017 Elsevier B.V. All rights reserved.

A Disposable Microfluidic Device for Controlled Drug Release from Thermal-Sensitive Liposomes by High Intensity Focused Ultrasound.

PubMed

Meng, Long; Deng, Zhiting; Niu, Lili; Li, Fei; Yan, Fei; Wu, Junru; Cai, Feiyan; Zheng, Hairong

2015-01-01

The drug release triggered thermally by high intensity focused ultrasound (HIFU) has been considered a promising drug delivery strategy due to its localized energy and non-invasive characters. However, the mechanism underlying the HIFU-mediated drug delivery remains unclear due to its complexity at the cellular level. In this paper, micro-HIFU (MHIFU) generated by a microfluidic device is introduced which is able to control the drug release from temperature-sensitive liposomes (TSL) and evaluate the thermal and mechanical effects of ultrasound on the cellular drug uptake and apoptosis. By simply adjusting the input electrical signal to the device, the temperature of sample can be maintained at 37 °C, 42 °C and 50 °C with the deviation of ± 0.3 °C as desired. The flow cytometry results show that the drug delivery under MHIFU sonication leads to a significant increase in apoptosis compared to the drug release by incubation alone at elevated temperature of 42 °C. Furthermore, increased squamous and protruding structures on the surface membrane of cells were detected by atomic force microscopy (AFM) after MHIFU irradiation of TSL. We demonstrate that compared to the routine HIFU treatment, MHIFU enables monitoring of in situ interactions between the ultrasound and cell in real time. Furthermore, it can quantitatively analyze and characterize the alterations of the cell membrane as a function of the treatment time.

Nanoparticles for controlled delivery and sustained release of chlorhexidine in the oral environment.

PubMed

Garner, S; Barbour, M E

2015-07-01

Chlorhexidine (CHX) is in widespread use as a topical antimicrobial agent. Within the field of oral medicine, it is used in the prevention of ventilator-associated pneumonia as well as in the treatment of oral candidosis and microbial-associated lichenoid reactions. The objective of this study was to develop a strategy for controlled, sustained topical delivery of CHX using nanoparticle technology. Chlorhexidine was applied to hydroxyapatite, selected as a tooth analogue, as conventional CHX digluconate solutions and as aqueous suspensions of CHX hexametaphosphate nanoparticles with total CHX concentrations of 1, 2.2 and 5 mM. Soluble CHX release from the treated hydroxyapatite was monitored over a period of 7 days. A repeated-measures ANOVA with post hoc LSD test indicated that CHX release was 2-3× greater, and sustained for longer, when CHX was delivered as CHX hexametaphosphate nanoparticles than in aqueous solution with 2.2 and 5 mM CHX (P = 0.020 and 0.013, respectively), but there was no statistically significant difference at 1 mM CHX (P = 0.172). Chlorhexidine hexametaphosphate nanoparticles increased both the local dose and duration of soluble CHX delivery when applied to hydroxyapatite surfaces. This may provide a means to deliver a sustained dose of CHX with less frequent interventions. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Molecularly Engineered Polymer-Based Systems in Drug Delivery and Regenerative Medicine.

PubMed

Piluso, Susanna; Soultan, Al Halifa; Patterson, Jennifer

2017-01-01

Polymer-based systems are attractive in drug delivery and regenerative medicine due to the possibility of tailoring their properties and functions to a specific application. The present review provides several examples of molecularly engineered polymer systems, including stimuli responsive polymers and supramolecular polymers. The advent of controlled polymerization techniques has enabled the preparation of polymers with controlled molecular weight and well-defined architecture. By using these techniques coupled to orthogonal chemical modification reactions, polymers can be molecularly engineered to incorporate functional groups able to respond to small changes in the local environment or to a specific biological signal. This review highlights the properties and applications of stimuli-responsive systems and polymer therapeutics, such as polymer-drug conjugates, polymer-protein conjugates, polymersomes, and hyperbranched systems. The applications of polymeric membranes in regenerative medicine are also discussed. The examples presented in this review suggest that the combination of membranes with polymers that are molecularly engineered to respond to specific biological functions could be relevant in the field of regenerative medicine. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A ferromagnetic compound with anti-cancer proeprties for controlled drug delivery and imaging

DOE PAGES

Eguchi, Haruki; Hirata, Kunio; Kurotani, Reiko; ...

2015-03-17

New anticancer agents and modalities for their use are of great interest. Recent studies have demonstrated the presence of anti-cancer properties in salen derivatives. We found that an iron salen derivative, i.e., [Fe(salen)] 2O, displays ferromagnetic order above room temperature and shows spontaneous field-dependent magnetization and hysteresis. Understanding of this magnetic property is provided by first-principles calculations based on structures obtained by X-ray crystallography. [Fe(salen)] 2O exhibited potent anti-cancer properties against various cancer cell types and was readily attracted by even moderate-strength permanent magnets in vitro. We demonstrated that the delivery of [Fe(salen)] 2O to melanoma tissues transplanted into themore » tails of mice using a permanent magnet leads to a robust decrease in tumor size. The local accumulation of [Fe(salen)] 2O was visualized by MRI. Thus, [Fe(salen)] 2O acted as an anti-cancer and MRI contrast compound that has a pharmacological effect that is delivered in a controlled manner, suggesting new strategies for anti-cancer drug development.« less

A ferromagnetic compound with anti-cancer proeprties for controlled drug delivery and imaging

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

Eguchi, Haruki; Hirata, Kunio; Kurotani, Reiko

New anticancer agents and modalities for their use are of great interest. Recent studies have demonstrated the presence of anti-cancer properties in salen derivatives. We found that an iron salen derivative, i.e., [Fe(salen)] 2O, displays ferromagnetic order above room temperature and shows spontaneous field-dependent magnetization and hysteresis. Understanding of this magnetic property is provided by first-principles calculations based on structures obtained by X-ray crystallography. [Fe(salen)] 2O exhibited potent anti-cancer properties against various cancer cell types and was readily attracted by even moderate-strength permanent magnets in vitro. We demonstrated that the delivery of [Fe(salen)] 2O to melanoma tissues transplanted into themore » tails of mice using a permanent magnet leads to a robust decrease in tumor size. The local accumulation of [Fe(salen)] 2O was visualized by MRI. Thus, [Fe(salen)] 2O acted as an anti-cancer and MRI contrast compound that has a pharmacological effect that is delivered in a controlled manner, suggesting new strategies for anti-cancer drug development.« less

Can Glucose Be Monitored Accurately at the Site of Subcutaneous Insulin Delivery?

PubMed Central

Castle, Jessica R.; Jacobs, Peter G.; Cargill, Robert S.

2014-01-01

Because insulin promotes glucose uptake into adipocytes, it has been assumed that during measurement of glucose at the site of insulin delivery, the local glucose level would be much lower than systemic glucose. However, recent investigations challenge this notion. What explanations could account for a reduced local effect of insulin in the subcutaneous space? One explanation is that, in humans, the effect of insulin on adipocytes appears to be small. Another is that insulin monomers and dimers (from hexamer disassociation) might be absorbed into the circulation before they can increase glucose uptake locally. In addition, negative cooperativity of insulin action (a lower than expected effect of very high insulin concentrations)may play a contributing role. Other factors to be considered include dilution of interstitial fluid by the insulin vehicle and the possibility that some of the local decline in glucose might be due to the systemic effect of insulin. With regard to future research, redundant sensing units might be able to quantify the effects of proximity, leading to a compensatory algorithm. In summary, when measured at the site of insulin delivery, the decline in subcutaneous glucose level appears to be minimal, though the literature base is not large. Findings thus far support (1) the development of integrated devices that monitor glucose and deliver insulin and (2) the use of such devices to investigate the relationship between subcutaneous delivery of insulin and its local effects on glucose. A reduction in the number of percutaneous devices needed to manage diabetes would be welcome. PMID:24876621

A Novel Methodology for Applying Multivoxel MR Spectroscopy to Evaluate Convection-Enhanced Drug Delivery in Diffuse Intrinsic Pontine Gliomas.

PubMed

Guisado, D I; Singh, R; Minkowitz, S; Zhou, Z; Haque, S; Peck, K K; Young, R J; Tsiouris, A J; Souweidane, M M; Thakur, S B

2016-07-01

Diffuse intrinsic pontine gliomas are inoperable high-grade gliomas with a median survival of less than 1 year. Convection-enhanced delivery is a promising local drug-delivery technique that can bypass the BBB in diffuse intrinsic pontine glioma treatment. Evaluating tumor response is critical in the assessment of convection-enhanced delivery of treatment. We proposed to determine the potential of 3D multivoxel (1)H-MR spectroscopy to evaluate convection-enhanced delivery treatment effect in these tumors. We prospectively analyzed 3D multivoxel (1)H-MR spectroscopy data for 6 patients with nonprogressive diffuse intrinsic pontine gliomas who received convection-enhanced delivery treatment of a therapeutic antibody (Phase I clinical trial NCT01502917). To compare changes in the metabolite ratios with time, we tracked the metabolite ratios Cho/Cr and Cho/NAA at several ROIs: normal white matter, tumor within the convection-enhanced delivery infusion site, tumor outside of the infused area, and the tumor average. There was a comparative decrease in both Cho/Cr and Cho/NAA metabolite ratios at the tumor convection-enhanced delivery site versus tumor outside the infused area. We used MR spectroscopy voxels with dominant white matter as a reference. The difference between changes in metabolite ratios became more prominent with increasing time after convection-enhanced delivery treatment. The comparative change in metabolite ratios between the convection-enhanced delivery site and the tumor site outside the infused area suggests that multivoxel (1)H-MR spectroscopy, in combination with other imaging modalities, may provide a clinical tool to accurately evaluate local tumor response after convection-enhanced delivery treatment. © 2016 by American Journal of Neuroradiology.

Controlled release of metronidazole from composite poly-ε-caprolactone/alginate (PCL/alginate) rings for dental implants.

PubMed

Lan, Shih-Feng; Kehinde, Timilehin; Zhang, Xiangming; Khajotia, Sharukh; Schmidtke, David W; Starly, Binil

2013-06-01

Dental implants provide support for dental crowns and bridges by serving as abutments for the replacement of missing teeth. To prevent bacterial accumulation and growth at the site of implantation, solutions such as systemic antibiotics and localized delivery of bactericidal agents are often employed. The objective of this study was to demonstrate a novel method of controlled localized delivery of antibacterial agents to an implant site using a biodegradable custom fabricated ring. The study involved incorporating a model antibacterial agent (metronidazole) into custom designed poly-ε-caprolactone/alginate (PCL/alginate) composite rings to produce the intended controlled release profile. The rings can be designed to fit around the body of any root form dental implants of various diameters, shapes and sizes. In vitro release studies indicate that pure (100%) alginate rings exhibited an expected burst release of metronidazole in the first few hours, whereas Alginate/PCL composite rings produced a medium burst release followed by a sustained release for a period greater than 4 weeks. By varying the PCL/alginate weight ratios, we have shown that we can control the amount of antibacterial agents released to provide the minimal inhibitory concentration (MIC) needed for adequate protection. The fabricated composite rings have achieved a 50% antibacterial agent release profile over the first 48 h and the remaining amount slowly released over the remainder of the study period. The PCL/alginate agent release characteristic fits the Ritger-Peppas model indicating a diffusion-based mechanism during the 30-day study period. The developed system demonstrates a controllable drug release profile and the potential for the ring to inhibit bacterial biofilm growth for the prevention of diseases such as peri-implantitis resulting from bacterial infection at the implant site. Copyright © 2013 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Intra- versus retroplacental hematomas: a retrospective case-control study on pregnancy outcomes.

PubMed

Ott, Johannes; Pecnik, Philipp; Promberger, Regina; Pils, Sophie; Binder, Julia; Chalubinski, Kinga M

2017-10-26

Intrauterine hematomas are a common pregnancy complication. The literature lacks studies about outcomes based on hematoma localization. Thus, we aimed to compare pregnancies complicated by an intraplacental hematoma to cases with a retroplacental hematoma and to a control group. In a retrospective case-control study, 32 women with an intraplacental hematoma, 199 women with a retroplacental hematoma, and a control group consisting of 113 age-matched women with no signs of placental abnormalities were included. Main outcome measures were pregnancy complications. Second-trimester miscarriage was most common in the intraplacental hematoma group (9.4%), followed by women with a retroplacental hematoma (4.2%), and controls (0%; p = 0.007). The intraplacental hematoma group revealed the highest rates for placental insufficiency, intrauterine growth retardation, premature preterm rupture of membranes, preterm labor, preterm delivery <37 weeks, and early preterm delivery <34 weeks (p < 0.05), followed by the retroplacental hematoma group. When tested in multivariate models, intraplacental hematomas were independent predictors for placental insufficiency (ß = 4.19, p < 0.001) and intrauterine growth restriction (ß = 1.44, p = 0.035). Intrauterine fetal deaths occurred only in women with a retroplacental hematoma (p = 0.042). Intra- and retroplacental hematomas have different risk profiles for the affected pregnancy and act as independent risk factors.

Rab11-FIP3 Regulation of Lck Endosomal Traffic Controls TCR Signal Transduction.

PubMed

Bouchet, Jérôme; Del Río-Iñiguez, Iratxe; Vázquez-Chávez, Elena; Lasserre, Rémi; Agüera-González, Sonia; Cuche, Céline; McCaffrey, Mary W; Di Bartolo, Vincenzo; Alcover, Andrés

2017-04-01

The role of endosomes in receptor signal transduction is a long-standing question, which remains largely unanswered. The T cell Ag receptor and various components of its proximal signaling machinery are associated with distinct endosomal compartments, but how endosomal traffic affects T cell signaling remains ill-defined. In this article, we demonstrate in human T cells that the subcellular localization and function of the protein tyrosine kinase Lck depends on the Rab11 effector FIP3 (Rab11 family interacting protein-3). FIP3 overexpression or silencing and its ability to interact with Rab11 modify Lck subcellular localization and its delivery to the immunological synapse. Importantly, FIP3-dependent Lck localization controls early TCR signaling events, such as tyrosine phosphorylation of TCRζ, ZAP70, and LAT and intracellular calcium concentration, as well as IL-2 gene expression. Interestingly, FIP3 controls both steady-state and poststimulation phosphotyrosine and calcium levels. Finally, our findings indicate that FIP3 modulates TCR-CD3 cell surface expression via the regulation of steady-state Lck-mediated TCRζ phosphorylation, which in turn controls TCRζ protein levels. This may influence long-term T cell activation in response to TCR-CD3 stimulation. Therefore, our data underscore the importance of finely regulated endosomal traffic in TCR signal transduction and T cell activation leading to IL-2 production. Copyright © 2017 by The American Association of Immunologists, Inc.

Controlled Drug Release and Chemotherapy Response in a Novel Acoustofluidic 3D Tumor Platform.

PubMed

Zervantonakis, Ioannis K; Arvanitis, Costas D

2016-05-01

Overcoming transport barriers to delivery of therapeutic agents in tumors remains a major challenge. Focused ultrasound (FUS), in combination with modern nanomedicine drug formulations, offers the ability to maximize drug transport to tumor tissue while minimizing toxicity to normal tissue. This potential remains unfulfilled due to the limitations of current approaches in accurately assessing and quantifying how FUS modulates drug transport in solid tumors. A novel acoustofluidic platform is developed by integrating a physiologically relevant 3D microfluidic device and a FUS system with a closed-loop controller to study drug transport and assess the response of cancer cells to chemotherapy in real time using live cell microscopy. FUS-induced heating triggers local release of the chemotherapeutic agent doxorubicin from a liposomal carrier and results in higher cellular drug uptake in the FUS focal region. This differential drug uptake induces locally confined DNA damage and glioblastoma cell death in the 3D environment. The capabilities of acoustofluidics for accurate control of drug release and monitoring of localized cell response are demonstrated in a 3D in vitro tumor mode. This has important implications for developing novel strategies to deliver therapeutic agents directly to the tumor tissue while sparing healthy tissue. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Local capillary supply in muscle is not determined by local oxidative capacity.

PubMed

Bosutti, Alessandra; Egginton, Stuart; Barnouin, Yoann; Ganse, Bergita; Rittweger, Jörn; Degens, Hans

2015-11-01

It is thought that the prime determinant of global muscle capillary density is the mean oxidative capacity. However, feedback control during maturational growth or adaptive remodelling of local muscle capillarisation is likely to be more complex than simply matching O2 supply and demand in response to integrated tissue function. We tested the hypothesis that the maximal oxygen consumption (MO2,max) supported by a capillary is relatively constant, and independent of the volume of tissue supplied (capillary domain). We demonstrate that local MO2,max assessed by succinate dehydrogenase histochemistry: (1) varied more than 100-fold between individual capillaries and (2) was positively correlated to capillary domain area in both human vastus lateralis (R=0.750, P<0.001) and soleus (R=0.697, P<0.001) muscles. This suggests that, in contrast to common assumptions, capillarisation is not primarily dictated by local oxidative capacity, but rather by factors such as fibre size, or consequences of differences in fibre size such as substrate delivery and metabolite removal. © 2015. Published by The Company of Biologists Ltd.

Convection-enhanced Delivery of Therapeutics for Malignant Gliomas.

PubMed

Saito, Ryuta; Tominaga, Teiji

2017-01-15

Convection-enhanced delivery (CED) circumvents the blood-brain barrier by delivering agents directly into the tumor and surrounding parenchyma. CED can achieve large volumes of distribution by continuous positive-pressure infusion. Although promising as an effective drug delivery method in concept, the administration of therapeutic agents via CED is not without challenges. Limitations of distribution remain a problem in large brains, such as those of humans. Accurate and consistent delivery of an agent is another challenge associated with CED. Similar to the difficulties caused by immunosuppressive environments associated with gliomas, there are several mechanisms that make effective local drug distribution difficult in malignant gliomas. In this review, methods for local drug application targeting gliomas are discussed with special emphasis on CED. Although early clinical trials have failed to demonstrate the efficacy of CED against gliomas, CED potentially can be a platform for translating the molecular understanding of glioblastomas achieved in the laboratory into effective clinical treatments. Several clinical studies using CED of chemotherapeutic agents are ongoing. Successful delivery of effective agents should prove the efficacy of CED in the near future.

Convection-enhanced Delivery of Therapeutics for Malignant Gliomas

PubMed Central

SAITO, Ryuta; TOMINAGA, Teiji

2017-01-01

Convection-enhanced delivery (CED) circumvents the blood–brain barrier by delivering agents directly into the tumor and surrounding parenchyma. CED can achieve large volumes of distribution by continuous positive-pressure infusion. Although promising as an effective drug delivery method in concept, the administration of therapeutic agents via CED is not without challenges. Limitations of distribution remain a problem in large brains, such as those of humans. Accurate and consistent delivery of an agent is another challenge associated with CED. Similar to the difficulties caused by immunosuppressive environments associated with gliomas, there are several mechanisms that make effective local drug distribution difficult in malignant gliomas. In this review, methods for local drug application targeting gliomas are discussed with special emphasis on CED. Although early clinical trials have failed to demonstrate the efficacy of CED against gliomas, CED potentially can be a platform for translating the molecular understanding of glioblastomas achieved in the laboratory into effective clinical treatments. Several clinical studies using CED of chemotherapeutic agents are ongoing. Successful delivery of effective agents should prove the efficacy of CED in the near future. PMID:27980285

Ultrasound-Mediated Local Drug and Gene Delivery Using Nanocarriers

PubMed Central

Zhou, Qiu-Lan; Chen, Zhi-Yi; Yang, Feng

2014-01-01

With the development of nanotechnology, nanocarriers have been increasingly used for curative drug/gene delivery. Various nanocarriers are being introduced and assessed, such as polymer nanoparticles, liposomes, and micelles. As a novel theranostic system, nanocarriers hold great promise for ultrasound molecular imaging, targeted drug/gene delivery, and therapy. Nanocarriers, with the properties of smaller particle size, and long circulation time, would be advantageous in diagnostic and therapeutic applications. Nanocarriers can pass through blood capillary walls and cell membrane walls to deliver drugs. The mechanisms of interaction between ultrasound and nanocarriers are not clearly understood, which may be related to cavitation, mechanical effects, thermal effects, and so forth. These effects may induce transient membrane permeabilization (sonoporation) on a single cell level, cell death, and disruption of tissue structure, ensuring noninvasive, targeted, and efficient drug/gene delivery and therapy. The system has been used in various tissues and organs (in vitro or in vivo), including tumor tissues, kidney, cardiac, skeletal muscle, and vascular smooth muscle. In this review, we explore the research progress and application of ultrasound-mediated local drug/gene delivery with nanocarriers. PMID:25202710

Focal macromolecule delivery in neuronal tissue using simultaneous pressure ejection and local electroporation

PubMed Central

Barker, Matthew; Billups, Brian; Hamann, Martine

2009-01-01

Electroporation creates transient pores in the plasma membrane to introduce macromolecules within a cell or cell population. Generally, electrical pulses are delivered between two electrodes separated from each other, making electroporation less likely to be localised. We have developed a new device combining local pressure ejection with local electroporation through a double-barrelled glass micropipette to transfer impermeable macromolecules in brain slices or in cultured HEK293 cells. The design achieves better targeting of the site of pressure ejection with that of electroporation. With this technique, we have been able to limit the delivery of propidium iodide or dextran amine within areas of 100–200 μm diameter. We confirm that local electroporation is transient and show that when combined with pressure ejection, it allows local transfection of EGFP plasmids within HEK293 cells or within cerebellar and hippocampal slice cultures. We further show that local electroporation is less damaging when compared to global electroporation using two separate electrodes. Focal delivery of dextran amine dyes within trapezoid body fibres allowed tracing axonal tracts within brainstem slices, enabling the study of identified calyx of Held presynaptic terminals in living brain tissue. This labelling method can be used to target small nuclei in neuronal tissue and is generally applicable to the study of functional synaptic connectivity, or live axonal tracing in a variety of brain areas. PMID:19014970

Multifunctional particles for melanoma-targeted drug delivery.

PubMed

Wadajkar, Aniket S; Bhavsar, Zarna; Ko, Cheng-Yu; Koppolu, Bhanuprasanth; Cui, Weina; Tang, Liping; Nguyen, Kytai T

2012-08-01

New magnetic-based core-shell particles (MBCSPs) were developed to target skin cancer cells while delivering chemotherapeutic drugs in a controlled fashion. MBCSPs consist of a thermo-responsive shell of poly(N-isopropylacrylamide-acrylamide-allylamine) and a core of poly(lactic-co-glycolic acid) (PLGA) embedded with magnetite nanoparticles. To target melanoma cancer cells, MBCSPs were conjugated with Gly-Arg-Gly-Asp-Ser (GRGDS) peptides that specifically bind to the α(5)β(3) receptors of melanoma cells. MBCSPs consist of unique multifunctional and controlled drug delivery characteristics. Specially, they can provide dual drug release mechanisms (a sustained release of drugs through degradation of PLGA core and a controlled release in response to changes in temperature via thermo-responsive polymer shell), and dual targeting mechanisms (magnetic localization and receptor-mediated targeting). Results from in vitro studies indicate that GRGDS-conjugated MBCSPs have an average diameter of 296 nm and exhibit no cytotoxicity towards human dermal fibroblasts up to 500 μg ml(-1). Further, a sustained release of curcumin from the core and a temperature-dependent release of doxorubicin from the shell of MBCSPs were observed. The particles also produced a dark contrast signal in magnetic resonance imaging. Finally, the particles were accumulated at the tumor site in a B16F10 melanoma orthotopic mouse model, especially in the presence of a magnet. Results indicate great potential of MBCSPs as a platform technology to target, treat and monitor melanoma for targeted drug delivery to reduce side effects of chemotherapeutic reagents. Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Comparison of computer-integrated patient-controlled epidural analgesia with no initial basal infusion versus moderate basal infusion for labor and delivery: A randomized controlled trial

PubMed Central

Sng, Ban Leong; Woo, David; Leong, Wan Ling; Wang, Hao; Assam, Pryseley Nkouibert; Sia, Alex TH

2014-01-01

Background and Aims: Computer-integrated patient-controlled epidural analgesia (CIPCEA) is a novel epidural drug delivery system. It automatically adjusts the basal infusion based on the individual's need for analgesia as labor progresses. Materials and Methods: This study compared the time-weighted local anesthetic (LA) consumption by comparing parturients using CIPCEA with no initial basal infusion (CIPCEA0) with CIPCEA with initial moderate basal infusion of 5 ml/H (CIPCEA5). We recruited 76 subjects after ethics approval. The computer integration of CIPCEA titrate the basal infusion to 5, 10, 15, or 20 ml/H if the parturient required respectively, one, two, three, or four patient demands in the previous hour. The basal infusion reduced by 5 ml/H if there was no demand in the previous hour. The sample size was calculated to show equivalence in LA consumption. Results: The time-weighted LA consumption between both groups were similar with CIPCEA0 group (mean [standard deviation (SD)] 8.9 [3.5] mg/H) compared to the CIPCEA5 group (mean [SD] 9.9 [3.5] mg/H), P = 0.080. Both groups had a similar incidence of breakthrough pain, duration of the second stage, mode of delivery, and patient satisfaction. However, more subjects in the CIPCEA0 group required patient self-bolus. There were no differences in fetal outcomes. Discussion: Both CIPCEA regimens had similar time-weighted LA consumption and initial moderate basal infusion with CIPCEA may not be required. PMID:25425774

Cellulose based polymeric systems in drug delivery

USDA-ARS?s Scientific Manuscript database

The pharmaceutical industry requires the development of biodegradable, biocompatible, non toxic, site specific drug delivery polymers, which can be easily coupled with drugs to be delivered orally, topically, locally, or parenterally. The use of the most abundant biopolymer, cellulose along with its...

Human papillomavirus infects placental trophoblast and Hofbauer cells, but appears not to play a causal role in miscarriage and preterm labor.

PubMed

Ambühl, Lea M M; Leonhard, Anne K; Widen Zakhary, Carina; Jørgensen, Annemette; Blaakaer, Jan; Dybkaer, Karen; Baandrup, Ulrik; Uldbjerg, Niels; Sørensen, Suzette

2017-10-01

Recently, an association between human papillomavirus infection and both spontaneous abortion and spontaneous preterm delivery was suggested. However, the reported human papillomavirus prevalence in pregnant women varies considerably and reliable conclusions are difficult. We aimed to investigate human papillomavirus infection in placental tissue of a Danish study cohort. Furthermore, we studied the cellular localization of human papillomavirus. In this prospective case-control study, placental tissue was analyzed for human papillomavirus infection by nested PCR in the following four study groups: full-term delivery (n = 103), spontaneous preterm delivery (n = 69), elective abortion (n = 54), and spontaneous abortion (n = 44). Moreover, human papillomavirus cellular target was identified using in situ hybridization. Human papillomavirus prevalence in placental tissue was 8.7% in full-term deliveries, 8.8% in spontaneous preterm deliveries, 10.9% in spontaneous abortions, and 20.4% in elective abortions. Twelve different human papillomavirus types were detected, and placental human papillomavirus infection was associated to a disease history of cervical cancer. Human papillomavirus DNA was identified in trophoblast cells, cells of the placental villi mesenchyme including Hofbauer cells, and in parts of the encasing endometrium. Placental human papillomavirus infections are not likely to constitute a risk factor for spontaneous preterm labor or spontaneous abortions in the Danish population, although an effect of human papillomavirus DNA in placental cells cannot be excluded. © 2017 Nordic Federation of Societies of Obstetrics and Gynecology.

Textural feature calculated from segmental fluences as a modulation index for VMAT.

PubMed

Park, So-Yeon; Park, Jong Min; Kim, Jung-In; Kim, Hyoungnyoun; Kim, Il Han; Ye, Sung-Joon

2015-12-01

Textural features calculated from various segmental fluences of volumetric modulated arc therapy (VMAT) plans were optimized to enhance its performance to predict plan delivery accuracy. Twenty prostate and twenty head and neck VMAT plans were selected retrospectively. Fluences were generated for each VMAT plan by summations of segments at sequential groups of control points. The numbers of summed segments were 5, 10, 20, 45, 90, 178 and 356. For each fluence, we investigated 6 textural features: angular second moment, inverse difference moment, contrast, variance, correlation and entropy (particular displacement distances, d = 1, 5 and 10). Spearman's rank correlation coefficients (rs) were calculated between each textural feature and several different measures of VMAT delivery accuracy. The values of rs of contrast (d = 10) with 10 segments to both global and local gamma passing rates with 2%/2 mm were 0.666 (p <0.001) and 0.573 (p <0.001), respectively. It showed rs values of -0.895 (p <0.001) and 0.727 (p <0.001) to multi-leaf collimator positional errors and gantry angle errors during delivery, respectively. The number of statistically significant rs values (p <0.05) to the changes in dose-volumetric parameters during delivery was 14 among a total of 35 tested parameters. Contrast (d = 10) with 10 segments showed higher correlations to the VMAT delivery accuracy than did the conventional modulation indices. Copyright © 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Experimental investigation of a general real-time 3D target localization method using sequential kV imaging combined with respiratory monitoring.

PubMed

Cho, Byungchul; Poulsen, Per; Ruan, Dan; Sawant, Amit; Keall, Paul J

2012-11-21

The goal of this work was to experimentally quantify the geometric accuracy of a novel real-time 3D target localization method using sequential kV imaging combined with respiratory monitoring for clinically realistic arc and static field treatment delivery and target motion conditions. A general method for real-time target localization using kV imaging and respiratory monitoring was developed. Each dimension of internal target motion T(x, y, z; t) was estimated from the external respiratory signal R(t) through the correlation between R(t(i)) and the projected marker positions p(x(p), y(p); t(i)) on kV images by a state-augmented linear model: T(x, y, z; t) = aR(t) + bR(t - τ) + c. The model parameters, a, b, c, were determined by minimizing the squared fitting error ∑‖p(x(p), y(p); t(i)) - P(θ(i)) · (aR(t(i)) + bR(t(i) - τ) + c)‖(2) with the projection operator P(θ(i)). The model parameters were first initialized based on acquired kV arc images prior to MV beam delivery. This method was implemented on a trilogy linear accelerator consisting of an OBI x-ray imager (operating at 1 Hz) and real-time position monitoring (RPM) system (30 Hz). Arc and static field plans were delivered to a moving phantom programmed with measured lung tumour motion from ten patients. During delivery, the localization method determined the target position and the beam was adjusted in real time via dynamic multileaf collimator (DMLC) adaptation. The beam-target alignment error was quantified by segmenting the beam aperture and a phantom-embedded fiducial marker on MV images and analysing their relative position. With the localization method, the root-mean-squared errors of the ten lung tumour traces ranged from 0.7-1.3 mm and 0.8-1.4 mm during the single arc and five-field static beam delivery, respectively. Without the localization method, these errors ranged from 3.1-7.3 mm. In summary, a general method for real-time target localization using kV imaging and respiratory monitoring has been experimentally investigated for arc and static field delivery. The average beam-target error was 1 mm.

Experimental investigation of a general real-time 3D target localization method using sequential kV imaging combined with respiratory monitoring

NASA Astrophysics Data System (ADS)

Cho, Byungchul; Poulsen, Per; Ruan, Dan; Sawant, Amit; Keall, Paul J.

2012-11-01

The goal of this work was to experimentally quantify the geometric accuracy of a novel real-time 3D target localization method using sequential kV imaging combined with respiratory monitoring for clinically realistic arc and static field treatment delivery and target motion conditions. A general method for real-time target localization using kV imaging and respiratory monitoring was developed. Each dimension of internal target motion T(x, y, z; t) was estimated from the external respiratory signal R(t) through the correlation between R(ti) and the projected marker positions p(xp, yp; ti) on kV images by a state-augmented linear model: T(x, y, z; t) = aR(t) + bR(t - τ) + c. The model parameters, a, b, c, were determined by minimizing the squared fitting error ∑‖p(xp, yp; ti) - P(θi) · (aR(ti) + bR(ti - τ) + c)‖2 with the projection operator P(θi). The model parameters were first initialized based on acquired kV arc images prior to MV beam delivery. This method was implemented on a trilogy linear accelerator consisting of an OBI x-ray imager (operating at 1 Hz) and real-time position monitoring (RPM) system (30 Hz). Arc and static field plans were delivered to a moving phantom programmed with measured lung tumour motion from ten patients. During delivery, the localization method determined the target position and the beam was adjusted in real time via dynamic multileaf collimator (DMLC) adaptation. The beam-target alignment error was quantified by segmenting the beam aperture and a phantom-embedded fiducial marker on MV images and analysing their relative position. With the localization method, the root-mean-squared errors of the ten lung tumour traces ranged from 0.7-1.3 mm and 0.8-1.4 mm during the single arc and five-field static beam delivery, respectively. Without the localization method, these errors ranged from 3.1-7.3 mm. In summary, a general method for real-time target localization using kV imaging and respiratory monitoring has been experimentally investigated for arc and static field delivery. The average beam-target error was 1 mm.

Comprehensive review on additives of topical dosage forms for drug delivery.

PubMed

Garg, Tarun; Rath, Goutam; Goyal, Amit K

2015-12-01

Skin is the largest organ of the human body and plays the most important role in protecting against pathogen and foreign matter. Three important modes such as topical, regional and transdermal are widely used for delivery of various dosage forms. Among these modes, the topical dosage forms are preferred because it provides local therapeutic activity when applied to the skin or mucous membranes. Additives or pharmaceutical excipients (non-drug component of dosage form) are used as inactive ingredients in dosage form or tools for structuring dosage forms. The main use of topical dosage form additives are controling the extent of absorption, maintaining the viscosity, improving the stability as well as organoleptic property and increasing the bulk of the formulation. The overall goal of this article is to provide the clinician with information related to the topical dosage form additives and their current major applications against various diseases.

From Kilimanjaro to the Himalayas: studies of health determinants in Third World communities.

PubMed

Cockroft, A

1998-01-01

Studies in communities in developing countries may seem far from occupational medicine in the UK, but there is much in common. Poverty and inequality, and the lack of control and choices that follow, are important causes of ill health. The methodology described in this paper is based on the concept that measurement should itself contribute to development and empower people. It combines quantitative data from large scale household surveys with qualitative data from focus groups, key informants and institutional reviews. In Nepal, malnutrition in children is seen to be related not only to feeding practices but also to the status of women. In Uganda, highlighting areas of poor service delivery in health and agriculture has initiated dialogue about improving local delivery of these services. In Tanzania, corruption in public services adversely affects everyday life; the survey results are part of an integrated strategy to tackle the problem.

Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications

PubMed Central

Labiris, N R; Dolovich, M B

2003-01-01

As the end organ for the treatment of local diseases or as the route of administration for systemic therapies, the lung is a very attractive target for drug delivery. It provides direct access to disease in the treatment of respiratory diseases, while providing an enormous surface area and a relatively low enzymatic, controlled environment for systemic absorption of medications. As a major port of entry, the lung has evolved to prevent the invasion of unwanted airborne particles from entering into the body. Airway geometry, humidity, mucociliary clearance and alveolar macrophages play a vital role in maintaining the sterility of the lung and consequently are barriers to the therapeutic effectiveness of inhaled medications. In addition, a drug's efficacy may be affected by where in the respiratory tract it is deposited, its delivered dose and the disease it may be trying to treat. PMID:14616418

Golgi bypass for local delivery of axonal proteins, fact or fiction?

PubMed

González, Carolina; Cornejo, Víctor Hugo; Couve, Andrés

2018-04-06

Although translation of cytosolic proteins is well described in axons, much less is known about the synthesis, processing and trafficking of transmembrane and secreted proteins. A canonical rough endoplasmic reticulum or a stacked Golgi apparatus has not been detected in axons, generating doubts about the functionality of a local route. However, axons contain mRNAs for membrane and secreted proteins, translation factors, ribosomal components, smooth endoplasmic reticulum and post-endoplasmic reticulum elements that may contribute to local biosynthesis and plasma membrane delivery. Here we consider the evidence supporting a local secretory system in axons. We discuss exocytic elements and examples of autonomous axonal trafficking that impact development and maintenance. We also examine whether unconventional post-endoplasmic reticulum pathways may replace the canonical Golgi apparatus. Copyright © 2018. Published by Elsevier Ltd.

Reconciling IWRM and water delivery in Ghana - The potential and the challenges

NASA Astrophysics Data System (ADS)

Anokye, Nana Amma; Gupta, Joyeeta

The key elements of integrated water resources management include a holistic integrated approach and the main principles of public participation, the role of gender and the notion of recognising the economic value of water. This paper investigates how these notions play out in the context of providing water to the rural communities in the Densu basin in Ghana. This investigation is based on a content analysis of the relevant policy documents and interviews with state agencies and local stakeholders. The paper concludes that there is a conflict between the IWRM goal of integrating all water uses and sectors in the management of water resources and focusing on the prioritisation of water delivery services. However, three of the IWRM principles can be used in implementing water delivery. While Ghana has adopted IWRM, it clearly prioritises water delivery. At basin level, the IWRM planning process does not take water delivery into account and water delivery is conducted independent of the IWRM process. Although the participatory and gender approaches are being implemented relatively successfully, if slowly, the ‘water as an economic good’ principle is given less priority than the notion of the human right to water as local communities pay only 5% of the capital costs of water delivery services. The impact of the rural water delivery services has been positive in the Densu basin in seven different ways; and if this helps the rural community out of the poverty trap, it may lead to economically viable water facilities in the long-term.

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions

PubMed Central

Zeng, Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A.; Trofimov, Alexei

2013-01-01

Purpose: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. Methods: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery. Results: IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE. Conclusions: In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled. PMID:23635256

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions.

PubMed

Zeng, Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A; Trofimov, Alexei

2013-05-01

Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery. IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE. In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled.

The retrograde delivery of adenovirus vector carrying the gene for brain-derived neurotrophic factor protects neurons and oligodendrocytes from apoptosis in the chronically compressed spinal cord of twy/twy mice.

PubMed

Uchida, Kenzo; Nakajima, Hideaki; Hirai, Takayuki; Yayama, Takafumi; Chen, Kebing; Guerrero, Alexander Rodriguez; Johnson, William Eustace; Baba, Hisatoshi

2012-12-15

The twy/twy mouse undergoes spontaneous chronic mechanical compression of the spinal cord; this in vivo model system was used to examine the effects of retrograde adenovirus (adenoviral vector [AdV])-mediated brain-derived neurotrophic factor (BDNF) gene delivery to spinal neural cells. To investigate the targeting and potential neuroprotective effect of retrograde AdV-mediated BDNF gene transfection in the chronically compressed spinal cord in terms of prevention of apoptosis of neurons and oligodendrocytes. Several studies have investigated the neuroprotective effects of neurotrophins, including BDNF, in spinal cord injury. However, no report has described the effects of retrograde neurotrophic factor gene delivery in compressed spinal cords, including gene targeting and the potential to prevent neural cell apoptosis. AdV-BDNF or AdV-LacZ (as a control gene) was injected into the bilateral sternomastoid muscles of 18-week old twy/twy mice for retrograde gene delivery via the spinal accessory motor neurons. Heterozygous Institute of Cancer Research mice (+/twy), which do not undergo spontaneous spinal compression, were used as a control for the effects of such compression on gene delivery. The localization and cell specificity of β-galactosidase expression (produced by LacZ gene transfection) and BDNF expression in the spinal cord were examined by coimmunofluorescence staining for neural cell markers (NeuN, neurons; reactive immunology protein, oligodendrocytes; glial fibrillary acidic protein, astrocytes; OX-42, microglia) 4 weeks after gene injection. The possible neuroprotection afforded by retrograde AdV-BDNF gene delivery versus AdV-LacZ-transfected control mice was assessed by scoring the prevalence of apoptotic cells (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells) and immunoreactivity to active caspases -3, -8, and -9, p75, neurofilament 200 kD (NF), and for the oligodendroglial progenitor marker, NG2. RESULTS.: Four weeks after injection, the retrograde delivery of the LacZ marker gene was identified in cervical spinal neurons and some glial cells, including oligodendrocytes in the white matter of the spinal cord, in both the twy/twy mouse and the heterozygous Institute of Cancer Research mouse (+/twy). In the compressed spinal cord of twy/twy mouse, AdV-BDNF gene transfection resulted in a significant decrease in the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells present in the spinal cord and a downregulation in the caspase apoptotic pathway compared with AdV-LacZ (control) gene transfection. There was a marked and significant increase in the areas of the spinal cord of AdV-BDNF-injected mice that were NF- and NG2-immunopositive compared with AdV-LacZ-injected mice, indicating the increased presence of neurons and oligodendrocytes in response to BDNF transfection. Our results demonstrate that targeted retrograde BDNF gene delivery suppresses apoptosis in neurons and oligodendrocytes in the chronically compressed spinal cord of twy/twy mouse. Further work is required to establish whether this method of gene delivery may provide neuroprotective effects in other situations of compressive spinal cord injury.

Controlled delivery of SDF-1α and IGF-1: CXCR4(+) cell recruitment and functional skeletal muscle recovery.

PubMed

Rybalko, Viktoriya Y; Pham, Chantal B; Hsieh, Pei-Ling; Hammers, David W; Merscham-Banda, Melissa; Suggs, Laura J; Farrar, Roger P

2015-11-01

Therapeutic delivery of regeneration-promoting biological factors directly to the site of injury has demonstrated its efficacy in various injury models. Several reports describe improved tissue regeneration following local injection of tissue specific growth factors, cytokines and chemokines. Evidence exists that combined cytokine/growth factor treatment is superior for optimizing tissue repair by targeting different aspects of the regeneration response. The purpose of this study was to evaluate the therapeutic potential of the controlled delivery of stromal cell-derived factor-1alpha (SDF-1α) alone or in combination with insulin-like growth factor-I (SDF-1α/IGF-I) for the treatment of tourniquet-induced ischemia/reperfusion injury (TK-I/R) of skeletal muscle. We hypothesized that SDF-1α will promote sustained stem cell recruitment to the site of muscle injury, while IGF-I will induce progenitor cell differentiation to effectively restore muscle contractile function after TK-I/R injury while concurrently reducing apoptosis. Utilizing a novel poly-ethylene glycol PEGylated fibrin gel matrix (PEG-Fib), we incorporated SDF-1α alone (PEG-Fib/SDF-1α) or in combination with IGF-I (PEG-Fib/SDF-1α/IGF-I) for controlled release at the site of acute muscle injury. Despite enhanced cell recruitment and revascularization of the regenerating muscle after SDF-1α treatment, functional analysis showed no benefit from PEG-Fib/SDF-1α therapy, while dual delivery of PEG-Fib/SDF-1α/IGF-I resulted in IGF-I-mediated improvement of maximal force recovery and SDF-1α-driven in vivo neovasculogenesis. Histological data supported functional data, as well as highlighted the important differences in the regeneration process among treatment groups. This study provides evidence that while revascularization may be necessary for maximizing muscle force recovery, without modulation of other effects of inflammation it is insufficient.

Injectable nanocomposite cryogels for versatile protein drug delivery.

PubMed

Koshy, Sandeep T; Zhang, David K Y; Grolman, Joshua M; Stafford, Alexander G; Mooney, David J

2018-01-01

Sustained, localized protein delivery can enhance the safety and activity of protein drugs in diverse disease settings. While hydrogel systems are widely studied as vehicles for protein delivery, they often suffer from rapid release of encapsulated cargo, leading to a narrow duration of therapy, and protein cargo can be denatured by incompatibility with the hydrogel crosslinking chemistry. In this work, we describe injectable nanocomposite hydrogels that are capable of sustained, bioactive, release of a variety of encapsulated proteins. Injectable and porous cryogels were formed by bio-orthogonal crosslinking of alginate using tetrazine-norbornene coupling. To provide sustained release from these hydrogels, protein cargo was pre-adsorbed to charged Laponite nanoparticles that were incorporated within the walls of the cryogels. The presence of Laponite particles substantially hindered the release of a number of proteins that otherwise showed burst release from these hydrogels. By modifying the Laponite content within the hydrogels, the kinetics of protein release could be precisely tuned. This versatile strategy to control protein release simplifies the design of hydrogel drug delivery systems. Here we present an injectable nanocomposite hydrogel for simple and versatile controlled release of therapeutic proteins. Protein release from hydrogels often requires first entrapping the protein in particles and embedding these particles within the hydrogel to allow controlled protein release. This pre-encapsulation process can be cumbersome, can damage the protein's activity, and must be optimized for each protein of interest. The strategy presented in this work simply premixes the protein with charged nanoparticles that bind strongly with the protein. These protein-laden particles are then placed within a hydrogel and slowly release the protein into the surrounding environment. Using this method, tunable release from an injectable hydrogel can be achieved for a variety of proteins. This strategy greatly simplifies the design of hydrogel systems for therapeutic protein release applications. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Controlled delivery of SDF-1α and IGF-1: CXCR4+ cell recruitment and functional skeletal muscle recovery

PubMed Central

Rybalko, Viktoriya Y.; Pham, Chantal B.; Hsieh, Pei-Ling; Hammers, David W.; Merscham-Banda, Melissa; Suggs, Laura J.; Farrar, Roger P.

2017-01-01

Therapeutic delivery of regeneration-promoting biological factors directly to the site of injury has demonstrated its efficacy in various injury models. Several reports describe improved tissue regeneration following local injection of tissue specific growth factors, cytokines and chemokines. Evidence exists that combined cytokine/growth factor treatment is superior for optimizing tissue repair by targeting different aspects of the regeneration response. The purpose of this study was to evaluate the therapeutic potential of the controlled delivery of stromal cell-derived factor-1alpha (SDF-1α) alone or in combination with insulin-like growth factor-I (SDF-1α/IGF-I) for the treatment of tourniquet-induced ischemia/reperfusion injury (TK-I/R) of skeletal muscle. We hypothesized that SDF-1α will promote sustained stem cell recruitment to the site of muscle injury, while IGF-I will induce progenitor cell differentiation to effectively restore muscle contractile function after TK-I/R injury while concurrently reducing apoptosis. Utilizing a novel poly-ethylene glycol PEGylated fibrin gel matrix (PEG-Fib), we incorporated SDF-1α alone (PEG-Fib/SDF-1α) or in combination with IGF-I (PEG-Fib/SDF-1α/IGF-I) for controlled release at the site of acute muscle injury. Despite enhanced cell recruitment and revascularization of the regenerating muscle after SDF-1α treatment, functional analysis showed no benefit from PEG-Fib/SDF-1α therapy, while dual delivery of PEG-Fib/SDF-1α/IGF-I resulted in IGF-I-mediated improvement of maximal force recovery and SDF-1α-driven in vivo neovasculogenesis. Histological data supported functional data, as well as highlighted the important differences in the regeneration process among treatment groups. This study provides evidence that while revascularization may be necessary for maximizing muscle force recovery, without modulation of other effects of inflammation it is insufficient. PMID:26247892

The macrophage as a Trojan horse for antisense oligonucleotide delivery.

PubMed

Novak, James S; Jaiswal, Jyoti K; Partridge, Terence A

2018-06-04

The gateway to the promised land of gene therapy has been obstructed by the problem of accurate and efficient delivery of therapeutic agents to their target sites. This is true both of constructs designed to directly express proteins of interest, and of constructs or agents aimed at modifying the expression of endogenous genes. It is recognized as a major impediment to the effective application of genetic therapies currently or incipiently in clinical trial. Our recent study has examined the mechanism underlying delivery of therapeutic antisense oligonucleotides (ASO) for treating the devastating muscle disease Duchenne muscular dystrophy [1]. Working to understand the mode of ASO delivery in DMD, we discovered that inflammatory cells act as a depot that locally stores the intravenously administered ASO. This local depot of ASO then becomes available to the muscle fibres by way of satellite cells that deliver their cargo by fusion with damaged fibres during muscle repair. This finding points to a potentially novel strategy for systemic ASO delivery, involving the use of the inflammatory cell as a Trojan horse. Such an approach would have the benefit not only of enhancing tissue-specific delivery of ASO, but also of reducing the impact of their rapid clearance from the circulation. Here, we discuss the issues surrounding ASO-mediated exon skipping efficacy for DMD, and outline research aimed at improving targeted ASO delivery.

Pharmacodynamic and Therapeutic Investigation of Focused Ultrasound-Induced Blood-Brain Barrier Opening for Enhanced Temozolomide Delivery in Glioma Treatment

PubMed Central

Liu, Hao-Li; Huang, Chiung-Yin; Chen, Ju-Yu; Wang, Hay-Yan Jack; Chen, Pin-Yuan; Wei, Kuo-Chen

2014-01-01

Focused ultrasound (FUS) exposure with the presence of microbubbles has been shown to transiently open the blood-brain barrier (BBB), and thus has potential to enhance the delivery of various kinds of therapeutic agents into brain tumors. The purpose of this study was to assess the preclinical therapeutic efficacy of FUS-BBB opening for enhanced temozolomide (TMZ) delivery in glioma treatment. FUS exposure with microbubbles was delivered to open the BBB of nude mice that were either normal or implanted with U87 human glioma cells. Different TMZ dose regimens were tested, ranging from 2.5 to 25 mg/kg. Plasma and brain samples were obtained at different time-points ranging from 0.5 to 4 hours, and the TMZ concentration within samples was quantitated via a developed LC-MS/MS procedure. Tumor progression was followed with T2-MRI, and animal survival and brain tissue histology were conducted. Results demonstrated that FUS-BBB opening caused the local TMZ accumulation in the brain to increase from 6.98 to 19 ng/mg. TMZ degradation time in the tumor core was found to increase from 1.02 to 1.56 hours. Improved tumor progression and animal survival were found at different TMZ doses (up to 15% and 30%, respectively). In conclusion, this study provides preclinical evidence that FUS-BBB opening increases the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting the potential for clinical application to improve current brain tumor treatment. PMID:25490097

Biomimetic transport and rational drug delivery.

PubMed

Ranney, D F

2000-01-15

Medicine and pharmaceutics are encountering critical needs and opportunities for transvascular drug delivery that improves site targeting and tissue permeation by mimicking natural tissue addressing and transport mechanisms. This is driven by the accelerated development of genomic agents requiring targeted controlled release. Although rationally designed for in vitro activity, such agents are not highly effective in vivo, due to opsonization and degradation by plasma constituents, and failure to transport across the local vascular endothelium and tissue matrix. A growing knowledge of the addresses of the body can be applied to engineer "Bio-Logically" staged delivery systems with sequential bioaddressins complementary to the discontinuous compartments encountered--termed discontinuum pharmaceutics. Effective tissue targeting is accomplished by leukocytes, bacteria, and viruses. We are increasingly able to mimic their bioaddressins by genomic means. Approaches described in this commentary include: (a) endothelial-directed adhesion mediated by oligosaccharides and carbohydrates (e.g. dermatan sulfate as a mimic of sulfated CD44) and peptidomimetics interacting with adhesins, selectins, integrins, hyaluronans, and locally induced growth factors (e.g. vascular endothelial growth factor, VEGF) and coagulation factors (e.g. factor VIII antigen); (b) improved tissue permeation conferred by hydrophilically "cloaked" carrier systems; (c) "uncloaking" by matrix dilution or selective triggering near the target cells; and (d) target binding-internalization by terminally exposed hydrophobic moieties, cationic polymers, and receptor-binding lectins, peptides, or carbohydrates. This commentary also describes intermediate technology solutions (e.g. "hybrid drugs"), and highlights the high-resolution, dynamic magnetic resonance imaging and radiopharmaceutical imaging technologies plus the groups and organizations capable of accelerating these important initiatives.

The Effect of the Local Delivery of Platelet-derived Growth Factor from Reactive Two-Component Polyurethane Scaffolds on the Healing in Rat Skin Excisional Wounds

PubMed Central

Li, Bing; Davidson, Jeffrey M.; Guelcher, Scott A.

2009-01-01

A key tenet of tissue engineering is the principle that the scaffold can perform the dual roles of biomechanical and biochemical support through presentation of the appropriate mediators to surrounding tissue. While growth factors have been incorporated into scaffolds to achieve sustained release, there are a limited number of studies investigating release of biologically active molecules from reactive two-component polymers, which have potential application as injectable delivery systems. In this study, we report the sustained release of platelet-derived growth factor (PDGF) from a reactive two-component polyurethane. The release of PDGF was bi-phasic, characterized by an initial burst followed by a period of sustained release for up to 21 days. Despite the potential for amine and hydroxyl groups in the protein to react with the isocyanate groups in the reactive polyurethane, the in vitro bioactivity of the released PDGF was largely preserved when added as a lyophilized powder. PUR/PDGF scaffolds implanted in rat skin excisional wounds accelerated wound healing relative to the blank PUR control, resulting in almost complete healing with reepithelization at day 14. The presence of PDGF attracted both fibroblasts and mononuclear cells, significantly accelerating degradation of the polymer and enhancing formation of new granulation tissue as early as day 3. The ability of reactive two-component PUR scaffolds to promote new tissue formation in vivo through local delivery of PDGF may present compelling opportunities for the development of novel injectable therapeutics. PMID:19328544

Use of a nanoporous biodegradable miniature device to regulate cytokine release for cancer treatment

PubMed Central

He, Hongyan; Grignol, Valerie; Karpa, Volodymyr; Yen, Chi; LaPerle, Krista; Zhang, Xiaoli; Jones, Natalie B.; Liang, Margaret I.; Lesinski, Gregory B.; Ho, W.S. Winston; Carson, William E.; Lee, L. James

2014-01-01

The clinical management of locally recurrent or unresectable malignant melanoma continues to pose a significant challenge. These lesions are typically painful and currently available treatments, such as repeated intratumoral injections of interferon-alpha (IFN-α), are costly and inconvenient. Nanotechnology offers promise as a novel means of drug delivery. A capsule-like nanoporous miniature device (NMD) based on a biodegradable polymer, poly(polycaprolactone) (PCL) was developed for controlling the local delivery of immunological agents to the tumor microenvironment. The device consists of a nanoporous release gate, a fabricated drug reservoir loaded with IFN-α and a protective layer. To improve the biocompatibility of the device, a hydrophilic poly(ethylene glycol) monoacrylate was applied to the outside wall of the device via covalent bonding techniques. Microscopic visualization of the nanoporous gate from in vitro experiments exhibited good pore stability over a two-month period. In vitro experiments demonstrated a constant release rate of IFN-α from the NMD and showed that the release rate could be regulated by the gate area. The released IFN-α was biologically functional. Cytokine-containing supernatants from release experiments phosphorylated signal transducer and activator of transcription (STAT1) in peripheral blood mononuclear cells. Subcutaneous implantation of the NMDs was well tolerated and associated with an anti-tumor effect in a human xenograft model of melanoma. There was no evidence of a significant inflammatory response to the NMD or encapsulation of the NMD by fibrosis. These experiments show that the NMD can be fabricated and employed in vivo as a versatile drug delivery platform. PMID:21362447

50 CFR 27.82 - Possession and delivery of controlled substances.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 50 Wildlife and Fisheries 9 2014-10-01 2014-10-01 false Possession and delivery of controlled... THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM PROHIBITED ACTS Disturbing Violations: Personal Conduct § 27.82 Possession and delivery of controlled substances. (a) Definitions for the purpose...

50 CFR 27.82 - Possession and delivery of controlled substances.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 50 Wildlife and Fisheries 6 2010-10-01 2010-10-01 false Possession and delivery of controlled... THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM PROHIBITED ACTS Disturbing Violations: Personal Conduct § 27.82 Possession and delivery of controlled substances. (a) Definitions for the purpose...

50 CFR 27.82 - Possession and delivery of controlled substances.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 50 Wildlife and Fisheries 8 2011-10-01 2011-10-01 false Possession and delivery of controlled... THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM PROHIBITED ACTS Disturbing Violations: Personal Conduct § 27.82 Possession and delivery of controlled substances. (a) Definitions for the purpose...

50 CFR 27.82 - Possession and delivery of controlled substances.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 50 Wildlife and Fisheries 9 2012-10-01 2012-10-01 false Possession and delivery of controlled... THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM PROHIBITED ACTS Disturbing Violations: Personal Conduct § 27.82 Possession and delivery of controlled substances. (a) Definitions for the purpose...

50 CFR 27.82 - Possession and delivery of controlled substances.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 50 Wildlife and Fisheries 9 2013-10-01 2013-10-01 false Possession and delivery of controlled... THE INTERIOR (CONTINUED) THE NATIONAL WILDLIFE REFUGE SYSTEM PROHIBITED ACTS Disturbing Violations: Personal Conduct § 27.82 Possession and delivery of controlled substances. (a) Definitions for the purpose...

Irreversible electroporation therapy in the management of locally advanced pancreatic adenocarcinoma.

PubMed

Martin, Robert C G; McFarland, Kelli; Ellis, Susan; Velanovich, Vic

2012-09-01

Locally advanced pancreatic cancer patients have limited options for disease control. Local ablation technologies based on thermal damage have been used but are associated with major complications in this region of the pancreas. Irreversible electroporation (IRE) is a nonthermal ablation technology that we have shown is safe near vital vascular and ductal structures. The aim of this study was to evaluate the safety and efficacy of IRE as a therapy in the treatment of locally advanced pancreatic cancer. We performed a prospective multi-institutional pilot evaluation of patients undergoing IRE for locally advanced pancreatic cancer from December 2009 to March 2011. These patients were evaluated for 90-day morbidity, mortality, and local disease control. Twenty-seven patients (13 women and 14 men) underwent IRE, with median age of 61 years (range 45 to 80 years). Eight patients underwent margin accentuation with IRE in combination with left-sided resection (n = 4) or pancreatic head resection (n = 4). Nineteen patients had in situ IRE. All patients underwent successful IRE, with intraoperative imaging confirming effective delivery of therapy. All 27 patients demonstrated nonclinically relevant elevation of their amylase and lipase, which peaked at 48 hours and returned to normal at 72 hour postprocedure. There has been one 90-day mortality. No patient has shown evidence of clinical pancreatitis or fistula formation. After all patients have completed 90-day follow-up, there has been 100% ablation success. IRE ablation of locally advanced pancreatic cancer tumors is a safe and feasible primary local treatment in unresectable, locally advanced disease. Confirming these early results must occur in a planned phase II investigational device exemption (IDE) study to be initiated in 2012. Copyright © 2012 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Schistosomiasis and soil-transmitted helminth control in Niger: cost effectiveness of school based and community distributed mass drug administration [corrected].

PubMed

Leslie, Jacqueline; Garba, Amadou; Oliva, Elisa Bosque; Barkire, Arouna; Tinni, Amadou Aboubacar; Djibo, Ali; Mounkaila, Idrissa; Fenwick, Alan

2011-10-01

In 2004 Niger established a large scale schistosomiasis and soil-transmitted helminths control programme targeting children aged 5-14 years and adults. In two years 4.3 million treatments were delivered in 40 districts using school based and community distribution. Four districts were surveyed in 2006 to estimate the economic cost per district, per treatment and per schistosomiasis infection averted. The study compares the costs of treatment at start up and in a subsequent year, identifies the allocation of costs by activity, input and organisation, and assesses the cost of treatment. The cost of delivery provided by teachers is compared to cost of delivery by community distributers (CDD). The total economic cost of the programme including programmatic, national and local government costs and international support in four study districts, over two years, was US$ 456,718; an economic cost/treatment of $0.58. The full economic delivery cost of school based treatment in 2005/06 was $0.76, and for community distribution was $0.46. Including only the programme costs the figures are $0.47 and $0.41 respectively. Differences at sub-district are more marked. This is partly explained by the fact that a CDD treats 5.8 people for every one treated in school. The range in cost effectiveness for both direct and direct and indirect treatments is quantified and the need to develop and refine such estimates is emphasised. The relative cost effectiveness of school and community delivery differs by country according to the composition of the population treated, the numbers targeted and treated at school and in the community, the cost and frequency of training teachers and CDDs. Options analysis of technical and implementation alternatives including a financial analysis should form part of the programme design process.

Antibiotic-loaded plaster of Paris implants coated with poly lactide-co-glycolide as a controlled release delivery system for the treatment of bone infections.

PubMed

Benoit, M A; Mousset, B; Delloye, C; Bouillet, R; Gillard, J

1997-01-01

Plaster of Paris implants containing vancomycin (60 mg/g of carrier) were prepared in order to be used as local delivery system for the treatment of bone infections. The regulation of the release rate was performed by coating the carrier with a polylactide-co-glycolide polymer composed by 10% (w/w) polyglycolic acid and 90% (w/w) racemic poly (D,L-lactic acid). The release of the antibiotic from the biodegradable matrix was evaluated in vitro. From this investigation, it is clear that the drug elution depends on the coating depth. After a burst effect occurring on the first day of the experiment, therapeutic concentrations were measured during one week when uncoated implants were used. The coating allowed decrease of the burst effect and extended efficient release to more than five weeks when the implants were embedded with six layers (162 microns) of PLA45GA10. This delivery system was implanted into the femoral condyle of rabbits. It was shown that the in vivo release was also closely regulated by the coating depth. In all bone tissues (bone marrow and cortical bone) surrounding the pellets, the drug concentration exceeded the Minimum Inhibitory Concentration for the common causative organisms of bone infections (Staphylococcus aureus) for at least four weeks without inducing serum toxic levels. Due to its cheapness, facility of use and sterilization, biocompatibility and biodegradability, plaster of Paris coated with PLA45GA10 polymer giving a controlled release of vancomycin appears to be a promising sustained release delivery system of antibiotics for the treatment of bone and joint infections.

Skin Electroporation: Effects on Transgene Expression, DNA Persistence and Local Tissue Environment

PubMed Central

Roos, Anna-Karin; Eriksson, Fredrik; Timmons, James A.; Gerhardt, Josefine; Nyman, Ulrika; Gudmundsdotter, Lindvi; Bråve, Andreas; Wahren, Britta; Pisa, Pavel

2009-01-01

Background Electrical pulses have been used to enhance uptake of molecules into living cells for decades. This technique, often referred to as electroporation, has become an increasingly popular method to enhance in vivo DNA delivery for both gene therapy applications as well as for delivery of vaccines against both infectious diseases and cancer. In vivo electrovaccination (gene delivery followed by electroporation) is currently being investigated in several clinical trials, including DNA delivery to healthy volunteers. However, the mode of action at molecular level is not yet fully understood. Methodology/Principal Findings This study investigates intradermal DNA electrovaccination in detail and describes the effects on expression of the vaccine antigen, plasmid persistence and the local tissue environment. Gene profiling of the vaccination site showed that the combination of DNA and electroporation induced a significant up-regulation of pro-inflammatory genes. In vivo imaging of luciferase activity after electrovaccination demonstrated a rapid onset (minutes) and a long duration (months) of transgene expression. However, when the more immunogenic prostate specific antigen (PSA) was co-administered, PSA-specific T cells were induced and concurrently the luciferase expression became undetectable. Electroporation did not affect the long-term persistence of the PSA-expressing plasmid. Conclusions/Significance This study provides important insights to how DNA delivery by intradermal electrovaccination affects the local immunological responses of the skin, transgene expression and clearance of the plasmid. As the described vaccination approach is currently being evaluated in clinical trials, the data provided will be of high significance. PMID:19789652

Cerebellar medulloblastoma: the importance of posterior fossa dose to survival and patterns of failure

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

Silverman, C.L.; Simpson, J.R.

1982-11-01

Fifty patients with biopsy-proven cerebellar medulloblastoma were retrospectively analyzed for prognostic factors, survival and patterns of failure. Five- and ten-year actuarial survivals for the entire group were 51% and 42%. Survival and local control were significantly better for the 21 patients who received doses greater than 5000 rad to the posterior fossa (85% and 80% respectively) than for the remaining patients (38% and 38%, respectively). Significant prognostic factors included achievement of local control in the posterior fossa (p = .0001) and dose to the posterior fossa (p = .0005). Sex, age, duration of symptoms, extent of surgery and initial T-stagemore » of disease were not significant. Posterior fossa was the predominant site of failure (71% of failures), but 10% of patients failed in the cerebrum and 12% outside the CNS. This experience confirms that survival rates of 70-80% are achievable with current treatment policies but accurate and consistent dose delivery to the posterior fossa is essential.« less

Cerebellar medulloblastoma: the importance of posterior fossa dose to survival and patterns of failure

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

Silverman, C.L.; Simpson, J.R.

1982-11-01

Fifty patients with biopsy-proven cerebellar medulloblastoma were retrospectively analyzed for prognostic factors, survival and patterns of failure. Five- and ten-year actuarial survivals for the entire group were 51% and 42%. Survival and local control were significantly better for the 21 patients who received doses greater that 5000 rad to the posterior fossa (85% and 80% respectively) than for the remaining patients (38% and 38%, respectively). Significant prognostic factors included achievement of local control in the posterior fossa (p = .0001) and dose to the posterior fossa (p = .0005). Sex, age, duration of symptoms, extent of surgery and initial T-stagemore » of disease were not significant. Posterior fossa was the predominant site of failure (71% of failures), but 10% of patients failed in the cerebrum and 12% outside the CNS. This experience confirms that survival rates of 70-80% are achievable with current treatment policies but accurate and consistent dose delivery to the posterior fossa is essential.« less

Plant nutrition: root transporters on the move.

PubMed

Zelazny, Enric; Vert, Grégory

2014-10-01

Nutrient and water uptake from the soil is essential for plant growth and development. In the root, absorption and radial transport of nutrients and water toward the vascular tissues is achieved by a battery of specialized transporters and channels. Modulating the amount and the localization of these membrane transport proteins appears as a way to drive their activity and is essential to maintain nutrient homeostasis in plants. This control first involves the delivery of newly synthesized proteins to the plasma membrane by establishing check points along the secretory pathway, especially during the export from the endoplasmic reticulum. Plasma membrane-localized transport proteins are internalized through endocytosis followed by recycling to the cell surface or targeting to the vacuole for degradation, hence constituting another layer of control. These intricate mechanisms are often regulated by nutrient availability, stresses, and endogenous cues, allowing plants to rapidly adjust to their environment and adapt their development. © 2014 American Society of Plant Biologists. All Rights Reserved.

Effect of Hypnosis During Administration of Local Anesthesia in Six- to 16-year-old Children.

PubMed

Oberoi, Jyoti; Panda, Anup; Garg, Iti

2016-01-01

Hypnosis is a tool that can help pediatric dentists allay fear or increase patient cooperation while administering local anesthesia. The purpose of this study was to determine whether hypnosis altered a patient's physical and/or verbal resistance and oxygen saturation or heart rate during administration of local anesthesia. Two hundred six- to 16-year-olds were randomly allocated to either a control group or an experimental group that received hypnotic induction prior to the delivery of local anesthesia. Subjects were monitored for signs of physical or verbal resistance and changes in pulse rate and oxygen saturation at baseline and upon administration of local anesthetic. Children under hypnosis exhibited significantly less resistance to administration of local anesthesia (P<0.05). A bi-serial correlation for age and resistance showed a significant positive correlation (0.337) in the experimental group, indicating that resistance in children increases with age, but none was shown between gender and hypnotic suggestibility. There was a significant difference in pulse rate, attributable to the hypnotic condition (P=.000), but not in oxygen saturation level. Using hypnosis may increase patient cooperation, decrease resistance during painful procedures, and lead to a lower heart rate.

The economic, institutional, and political determinants of public health delivery system structures.

PubMed

Ingram, Richard C; Scutchfield, F Douglas; Mays, Glen P; Bhandari, Michelyn W

2012-01-01

A typology of local public health systems was recently introduced, and a large degree of structural transformation over time was discovered in the systems analyzed. We present a qualitative exploration of the factors that determine variation and change in the seven structural configurations that comprise the local public health delivery system typology. We applied a 10-item semistructured telephone interview protocol to representatives from the local health agency in two randomly selected systems from each configuration--one that had maintained configuration over time and one that had changed configuration over time. We assessed the interviews for patterns of variation between the configurations. Four key determinants of structural change emerged: availability of financial resources, interorganizational relationships, public health agency organization, and political relationships. Systems that had changed were more likely to experience strengthened partnerships between public health agencies and other community organizations and enjoy support from policy makers, while stable systems were more likely to be characterized by strong partnerships between public health agencies and other governmental bodies and less supportive relationships with policy makers. This research provides information regarding the determinants of system change, and may help public health leaders to better prepare for the impacts of change in the areas discussed. It may also help those who are seeking to implement change to determine the contextual factors that need to be in place before change can happen, or how best to implement change in the face of contextual factors that are beyond their control.

Regulation of skeletal muscle blood flow during exercise in ageing humans

PubMed Central

Hearon, Christopher M.

2015-01-01

Abstract The regulation of skeletal muscle blood flow and oxygen delivery to contracting skeletal muscle is complex and involves the mechanical effects of muscle contraction; local metabolic, red blood cell and endothelium‐derived substances; and the sympathetic nervous system (SNS). With advancing age in humans, skeletal muscle blood flow is typically reduced during dynamic exercise and this is due to a lower vascular conductance, which could ultimately contribute to age‐associated reductions in aerobic exercise capacity, a primary predictor of mortality in both healthy and diseased ageing populations. Recent findings have highlighted the contribution of endothelium‐derived substances to blood flow control in contracting muscle of older adults. With advancing age, impaired nitric oxide availability due to scavenging by reactive oxygen species, in conjunction with elevated vasoconstrictor signalling via endothelin‐1, reduces the local vasodilatory response to muscle contraction. Additionally, ageing impairs the ability of contracting skeletal muscle to blunt sympathetic vasoconstriction (i.e. ‘functional sympatholysis’), which is critical for the proper regulation of tissue blood flow distribution and oxygen delivery, and could further reduce skeletal muscle perfusion during high intensity and/or large muscle mass exercise in older adults. We propose that initiation of endothelium‐dependent hyperpolarization is the underlying signalling event necessary to properly modulate sympathetic vasoconstriction in contracting muscle, and that age‐associated impairments in red blood cell adenosine triphosphate release and stimulation of endothelium‐dependent vasodilatation may explain impairments in both local vasodilatation and functional sympatholysis with advancing age in humans. PMID:26332887

An in vivo study on the metabolism and osteogenic activity of bioabsorbable Mg-1Sr alloy.

PubMed

Tie, Di; Guan, Renguo; Liu, Huinan; Cipriano, Aaron; Liu, Yili; Wang, Qiang; Huang, Yuanding; Hort, Norbert

2016-01-01

Previous studies indicated that local delivery of strontium effectively increased bone quality and formation around osseointegrating implants. Therefore, implant materials with long-lasting and controllable strontium release are avidly pursued. The central objective of the present study was to investigate the in vivo biocompatibility, metabolism and osteogenic activity of the bioabsorbable Mg-1Sr (wt.%, nominal composition) alloy for bone regeneration. The general corrosion rate of the alloy implant as a femoral fracture fixation device was 0.55±0.03mm·y(-1) (mean value±standard deviation) in New Zealand White rabbits which meet the bone implantation requirements and can be adjusted by material processing methods. All rabbits survived and the histological evaluation showed no abnormal physiology or diseases 16 weeks post-implantation. The degradation process of the alloy did not significantly alter 16 primary indexes of hematology, cardiac damage, inflammation, hepatic functions and metabolic process. Significant increases in peri-implant bone volume and direct bone-to-implant contact (48.3%±15.3% and 15.9%±5.6%, respectively) as well as the expressions of four osteogenesis related genes (runt-related transcription factor 2, alkaline phosphatase, osteocalcin, and collagen, type I, alpha 1) were observed after 16 weeks implantation for the Mg-1Sr group when compared to the pure Mg group. The sound osteogenic properties of the Mg-1Sr alloy by long-lasting and controllable Sr release suggesting a very attractive clinical potential. Sr (strontium) has exhibited pronounced effects to reduce the bone fracture risk in osteoporotic patients. Nonetheless, long-lasting local Sr release is hardly achieved by traditional methods like surface treatment. Therefore, a more efficient Sr local delivery platform is in high clinical demand. The stable and adjustable degradation process of Mg alloy makes it an ideal Sr delivery platform. We combine the well-known osteogenic properties of strontium with magnesium to manufacture bioabsorbable Mg-1Sr alloy with stable Sr release based on our previous studies. The in vitro and in vivo results both showed the alloy's suitable degradation rate and biocompatibility, and the sound osteogenic properties and stimulation effect on bone formation suggest its very attractive clinical potential. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Route of delivery following successful external cephalic version.

PubMed

Policiano, Catarina; Costa, Ana; Valentim-Lourenço, Alexandre; Clode, Nuno; Graça, Luís M

2014-09-01

To evaluate the delivery route and the indications for cesarean delivery after successful external cephalic version (ECV). A retrospective matched case-control study was conducted at a hospital in Lisbon, Portugal, between 2002 and 2012. Each woman who underwent successful ECV (n = 44) was compared with the previous and next women who presented for labor management and who had the same parity and a singleton vertex pregnancy at term (n = 88). The outcome measures were route of delivery, indications for cesarean delivery, and incidence of nonreassuring fetal status. Attempts at ECV were successful in 62 (46%) of 134 women, and 44 women whose fetuses remained in a cephalic presentation until delivery were included in the study. The rates of intrapartum cesarean delivery and operative vaginal delivery did not differ significantly between cases and controls (intrapartum cesarean delivery, 9 [20%] vs 16 [18%], P = 0.75; operative vaginal delivery, 14 [32%] vs 19 [22%], P = 0.20). The indications for cesarean delivery after successful ECV did not differ; in both groups, cesarean delivery was mainly performed for labor arrest disorders (cases, 6 [67%] vs controls, 13 [81%]; P = 0.63). Successful ECV was not associated with increased rates of intrapartum cesarean delivery or operative vaginal delivery. Copyright © 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

It takes a village: Exploring the impact of social determinants on delivery system outcomes for heart failure patients.

PubMed

Knighton, Andrew J; Savitz, Lucy A; Benuzillo, Jose; VanDerslice, James A

2017-06-24

Local social determinants may act as effect modifiers for the impact of neighborhood material deprivation on patient-level healthcare outcomes. The objective of this study was to understand the mediating effect of local social determinants on neighborhood material deprivation and delivery outcomes in heart failure (HF) patients. A retrospective cohort study was conducted using 4737 HF patients receiving inpatient care (n=6065 encounters) from an integrated healthcare delivery system from 2010 to 2014. Outcomes included post-discharge mortality, readmission risk and length of stay. Deprivation was measured using an area deprivation index by address of residence. Effect modifications measured included urban-rural residency and faith identification using generalized linear regression models. Patient-level data was drawn from the delivery system data warehouse. Faith identification had a significant protective effect on HF patients from deprived areas, lowering 30-day mortality odds by one-third over patients who did not identify with a faith (OR 0.35 95%CI:0.12-0.98;p=0.05). Significant effects persisted at the 90 and 180-day timeframes. In rural areas, lack of faith identification had a multiplicative effect on 30-day mortality for deprived patients (OR 14.0 95%CI:1.47-132.7;p=0.02). No significant effects were noted for other healthcare outcomes. The lack of expected association between area deprivation and healthcare outcomes in some communities may be explained by the presence of effect modifiers. Understanding existing effect modifiers for area deprivation in local communities that delivery systems serve can inform targeted quality improvement. These factors should also be considered when comparing delivery system performance for reimbursement and in population health management. Copyright © 2017 Elsevier Inc. All rights reserved.

Residents' choice of and control over food in care homes.

PubMed

Winterburn, Susan

2009-04-01

This study aimed to map food pathways in care homes to identify how residents exercised choice and control over their food intake and any associated or influencing factors. Four homes were visited, interviews were conducted with chefs and nursing staff and the dining facilities were noted. It was found that residents were dependent on the care home for the provision of food. There was almost no direct contact between residents and external food retailers. A food map was constructed, which identified three routes for potential improvements in practice: supply and delivery of food; serving of food; and consumption of food. Residents' choice and control over food could be improved through the design of new products for serving and consumption of food and eating aids, access to local food retailers and nutritional training.

Titanium wire implants with nanotube arrays: A study model for localized cancer treatment.

PubMed

Kaur, Gagandeep; Willsmore, Tamsyn; Gulati, Karan; Zinonos, Irene; Wang, Ye; Kurian, Mima; Hay, Shelley; Losic, Dusan; Evdokiou, Andreas

2016-09-01

Adverse complications associated with systemic administration of anti-cancer drugs are a major problem in cancer therapy in current clinical practice. To increase effectiveness and reduce side effects, localized drug delivery to tumour sites requiring therapy is essential. Direct delivery of potent anti-cancer drugs locally to the cancer site based on nanotechnology has been recognised as a promising alternative approach. Previously, we reported the design and fabrication of nano-engineered 3D titanium wire based implants with titania (TiO2) nanotube arrays (Ti-TNTs) for applications such as bone integration by using in-vitro culture systems. The aim of present study is to demonstrate the feasibility of using such Ti-TNTs loaded with anti-cancer agent for localized cancer therapy using pre-clinical cancer models and to test local drug delivery efficiency and anti-tumour efficacy within the tumour environment. TNF-related apoptosis-inducing ligand (TRAIL) which has proven anti-cancer properties was selected as the model drug for therapeutic delivery by Ti-TNTs. Our in-vitro 2D and 3D cell culture studies demonstrated a significant decrease in breast cancer cell viability upon incubation with TRAIL loaded Ti-TNT implants (TRAIL-TNTs). Subcutaneous tumour xenografts were established to test TRAIL-TNTs implant performance in the tumour environment by monitoring the changes in tumour burden over a selected time course. TRAIL-TNTs showed a significant regression in tumour burden within the first three days of implant insertion at the tumour site. Based on current experimental findings these Ti-TNTs wire implants have shown promising capacity to load and deliver anti-cancer agents maintaining their efficacy for cancer treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Gold nanoparticle-DNA aptamer composites as a universal carrier for in vivo delivery of biologically functional proteins.

PubMed

Ryou, Sang-Mi; Yeom, Ji-Hyun; Kang, Hyo Jung; Won, Miae; Kim, Jin-Sik; Lee, Boeun; Seong, Maeng-Je; Ha, Nam-Chul; Bae, Jeehyeon; Lee, Kangseok

2014-12-28

Although the delivery of biologically functional protein(s) into mammalian cells could be of tremendous value to biomedical research, the development of such technology has been hindered by the lack of a safe and effective delivery method. Here, we present a simple, efficient, and versatile gold nanoparticle-DNA aptamer conjugate (AuNP-Apt)-based system, with nanoblock-like properties, that allows any recombinant protein to be loaded without additional modifications and delivered into mammalian living systems. AuNP-Apt-based protein delivery system was able to deliver various proteins into variety of cell types in vitro without showing cytotoxicity. This AuNP-Apt system was also effective for the local and systemic targeted delivery of proteins in vivo. A local injection of the AuNP-Apt loaded with the apoptosis-inducing BIM protein efficiently inhibited the growth of xenograft tumors in mice. Furthermore, an intravenous injection of AuNP-Apt loaded with both epidermal growth factor (EGF) and BIM resulted in the targeted delivery of BIM into a xenograft tumor derived from EGF receptor-overexpressing cancer cells with no detectable systemic toxicity. Our findings show that this system can serve as an innovative platform for the development of protein-based biomedical applications. Copyright © 2014 Elsevier B.V. All rights reserved.

Clinical Case Registries: Simultaneous Local and National Disease Registries for Population Quality Management

PubMed Central

Backus, Lisa I.; Gavrilov, Sergey; Loomis, Timothy P.; Halloran, James P.; Phillips, Barbara R.; Belperio, Pamela S.; Mole, Larry A.

2009-01-01

The Department of Veterans Affairs (VA) has a system-wide, patient-centric electronic medical record system (EMR) within which the authors developed the Clinical Case Registries (CCR) to support population-centric delivery and evaluation of VA medical care. To date, the authors have applied the CCR to populations with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Local components use diagnosis codes and laboratory test results to identify patients who may have HIV or HCV and support queries on local care delivery with customizable reports. For each patient in a local registry, key EMR data are transferred via HL7 messaging to a single national registry. From 128 local registry systems, over 60,000 and 320,000 veterans in VA care have been identified as having HIV and HCV, respectively, and entered in the national database. Local and national reports covering demographics, resource usage, quality of care metrics and medication safety issues have been generated. PMID:19717794

Bespoke program design for school-aged therapy disability service delivery.

PubMed

Weatherill, Pamela; Bahn, Susanne; Cooper, Trudi

2012-01-01

This article uses the evaluation of a school-aged therapy service for children with disabilities in Western Australia to investigate models of service delivery. The current literature on family-centered practice, multidisciplinary and transdisciplinary approaches, and 4 models of service are reviewed. The models include the life needs model, the relational goal-orientated model of optimal service delivery to children and families, the quality of life model, and the collaborative model of service delivery. Analysis of the data is presented together with a bespoke model of service delivery for children with disabilities, arguing that local contexts benefit from custom-made service design.

Controlled drug delivery systems: past forward and future back.

PubMed

Park, Kinam

2014-09-28

Controlled drug delivery technology has progressed over the last six decades. This progression began in 1952 with the introduction of the first sustained release formulation. The 1st generation of drug delivery (1950-1980) focused on developing oral and transdermal sustained release systems and establishing controlled drug release mechanisms. The 2nd generation (1980-2010) was dedicated to the development of zero-order release systems, self-regulated drug delivery systems, long-term depot formulations, and nanotechnology-based delivery systems. The latter part of the 2nd generation was largely focused on studying nanoparticle formulations. The Journal of Controlled Release (JCR) has played a pivotal role in the 2nd generation of drug delivery technologies, and it will continue playing a leading role in the next generation. The best path towards a productive 3rd generation of drug delivery technology requires an honest, open dialog without any preconceived ideas of the past. The drug delivery field needs to take a bold approach to designing future drug delivery formulations primarily based on today's necessities, to produce the necessary innovations. The JCR provides a forum for sharing the new ideas that will shape the 3rd generation of drug delivery technology. Copyright © 2014 Elsevier B.V. All rights reserved.

Delivery of drugs, growth factors, genes and stem cells via intrapericardial, epicardial and intramyocardial routes for sustained local targeted therapy of myocardial disease.

PubMed

Maslov, Mikhail; Foianini, Stephan; Lovich, Mark

2017-10-01

Local myocardial delivery (LMD) of therapeutic agents is a promising strategy that aims to treat various myocardial pathologies. It is designed to deliver agents directly to the myocardium and minimize their extracardiac concentrations and side effects. LMD aims to enhance outcomes of existing therapies by broadening their therapeutic window and to utilize new agents that could not be otherwise be implemented systemically. Areas covered: This article provides a historical overview of six decades LMD evolution in terms of the approaches, including intrapericardial, epicardial, and intramyocardial delivery, and the wide array of classes of agents used to treat myocardial pathologies. We examines delivery of pharmaceutical compounds, targeted gene transfection and cell implantation techniques to produce therapeutic effects locally. We outline therapeutic indications, successes and failures as well as technical approaches for LMD. Expert opinion: While LMD is more complicated than conventional oral or intravenous administration, given recent advances in interventional cardiology, it is safe and may provide better therapeutic outcomes. LMD is complex as many factors impact pharmacokinetics and biologic result. The choice between routes of LMD is largely driven not only by the myocardial pathology but also by the nature and physicochemical properties of the therapeutic agents.

Effect of sodium nitrite on local control of contracting skeletal muscle microvascular oxygen pressure in healthy rats.

PubMed

Colburn, Trenton D; Ferguson, Scott K; Holdsworth, Clark T; Craig, Jesse C; Musch, Timothy I; Poole, David C

2017-01-01

Exercise intolerance characteristic of diseases such as chronic heart failure (CHF) and diabetes is associated with reduced nitric oxide (NO) bioavailability from nitric oxide synthase (NOS), resulting in an impaired microvascular O 2 driving pressure (Po 2 mv; O 2 delivery/O 2 utilization) and metabolic control. Infusions of the potent NO donor sodium nitroprusside augment NO bioavailability yet decrease mean arterial pressure (MAP) thereby reducing its potential efficacy for patient populations. To eliminate or reduce hypotensive sequelae, [Formula: see text] was superfused onto the spinotrapezius muscle. It was hypothesized that local [Formula: see text] administration would elevate resting Po 2 mv and slow Po 2 mv kinetics [increased time constant (τ) and mean response time (MRT)] following the onset of muscle contractions without decreasing MAP. In 12 anesthetized male Sprague-Dawley rats, Po 2 mv of the circulation-intact spinotrapezius muscle was measured by phosphorescence quenching during 180 s of electrically induced twitch contractions (1 Hz) before and after superfusion of sodium nitrite (NaNO 2 30 mM). [Formula: see text] superfusion elevated resting Po 2 mv (control: 28.4 ± 1.1 vs. [Formula: see text]: 31.6 ± 1.2 mmHg; P ≤ 0.05), τ (control: 12.3 ± 1.2 vs. [Formula: see text]: 19.7 ± 2.2 s; P ≤ 0.05), and MRT (control: 19.3 ± 1.9 vs. [Formula: see text]: 25.6 ± 3.3 s; P ≤ 0.05). Importantly, these effects occurred in the absence of any reduction in MAP (103 ± 4 vs. 105 ± 4 mmHg, pre- and postsuperfusion respectively; P > 0.05). These results indicate that [Formula: see text] supplementation delivered to the muscle directly through [Formula: see text] superfusion enhances the blood-myocyte oxygen driving pressure without compromising MAP at rest and following the onset of muscle contraction. This strategy has substantial clinical utility for a range of ischemic conditions. Ischemic conditions as diverse as chronic heart failure (CHF) and frostbite inflict tissue damage via inadequate O 2 delivery. Herein we demonstrate that direct application of sodium nitrite enhances the O 2 supply-O 2 demand relationship, raising microvascular O 2 pressure in healthy skeletal muscle. This therapeutic action of nitrite-derived nitric oxide occurred without inducing systemic hypotension and has the potential to relieve focal ischemia and preserve tissue vitality by enhancing O 2 delivery. Copyright © 2017 the American Physiological Society.

Career Information Delivery Systems: A Summary Status Report. NOICC Occasional Paper.

ERIC Educational Resources Information Center

Hopkins, Valorie; Kinnison, Joyce; Morgenthau, Eleanor; Ollis, Harvey

The National Occupational Information Coordinating Committee/State Occupational Information Coordinating Committees (NOICC/SOICC) Network sponsors numerous occupational information programs and systems, including career information delivery systems (CIDS). CIDS provide useful national, state, and local information for people who are exploring,…

7 CFR 246.12 - Food delivery systems.

Code of Federal Regulations, 2010 CFR

2010-01-01

... being modified. (1) Management. The State agency is responsible for the fiscal management of, and... State or local agency for the management or operation of food delivery systems must conform to the... effective State agency management, oversight, and review of its authorized vendors. (2) Vendor limiting...

Enzymatic- and temperature-sensitive controlled release of ultrasmall superparamagnetic iron oxides (USPIOs)

PubMed Central

2011-01-01

Background Drug and contrast agent delivery systems that achieve controlled release in the presence of enzymatic activity are becoming increasingly important, as enzymatic activity is a hallmark of a wide array of diseases, including cancer and atherosclerosis. Here, we have synthesized clusters of ultrasmall superparamagnetic iron oxides (USPIOs) that sense enzymatic activity for applications in magnetic resonance imaging (MRI). To achieve this goal, we utilize amphiphilic poly(propylene sulfide)-bl-poly(ethylene glycol) (PPS-b-PEG) copolymers, which are known to have excellent properties for smart delivery of drug and siRNA. Results Monodisperse PPS polymers were synthesized by anionic ring opening polymerization of propylene sulfide, and were sequentially reacted with commercially available heterobifunctional PEG reagents and then ssDNA sequences to fashion biofunctional PPS-bl-PEG copolymers. They were then combined with hydrophobic 12 nm USPIO cores in the thin-film hydration method to produce ssDNA-displaying USPIO micelles. Micelle populations displaying complementary ssDNA sequences were mixed to induce crosslinking of the USPIO micelles. By design, these crosslinking sequences contained an EcoRV cleavage site. Treatment of the clusters with EcoRV results in a loss of R2 negative contrast in the system. Further, the USPIO clusters demonstrate temperature sensitivity as evidenced by their reversible dispersion at ~75°C and re-clustering following return to room temperature. Conclusions This work demonstrates proof of concept of an enzymatically-actuatable and thermoresponsive system for dynamic biosensing applications. The platform exhibits controlled release of nanoparticles leading to changes in magnetic relaxation, enabling detection of enzymatic activity. Further, the presented functionalization scheme extends the scope of potential applications for PPS-b-PEG. Combined with previous findings using this polymer platform that demonstrate controlled drug release in oxidative environments, smart theranostic applications combining drug delivery with imaging of platform localization are within reach. The modular design of these USPIO nanoclusters enables future development of platforms for imaging and drug delivery targeted towards proteolytic activity in tumors and in advanced atherosclerotic plaques. PMID:21352596

Electrospun poly-l-lactide scaffold for the controlled and targeted delivery of a synthetically obtained Diclofenac prodrug to treat actinic keratosis.

PubMed

Piccirillo, Germano; Bochicchio, Brigida; Pepe, Antonietta; Schenke-Layland, Katja; Hinderer, Svenja

2017-04-01

Actinic Keratosis' (AKs) are small skin lesions that are related to a prolonged sun-damage, which can develop into invasive squamous cell carcinoma (SCC) when left untreated. Effective, specific and well tolerable therapies to cure AKs are still of great interest. Diclofenac (DCF) is the current gold standard for the local treatment of AKs in terms of costs, effectiveness, side effects and tolerability. In this work, an electrospun polylactic acid (PLA) scaffold loaded with a synthetic DCF prodrug was developed and characterized. Specifically, the prodrug was successfully synthetized by binding DCF to a glycine residue via solid phase peptide synthesis (SPPS) and then incorporated in an electrospun PLA scaffold. The drug encapsulation was verified using multiphoton microscopy (MPM) and its scaffold release was spectrophotometrically monitored and confirmed with MPM. The scaffold was further characterized with scanning electron microscopy (SEM), tensile testing and contact angle measurements. Its biocompatibility was verified by performing a cell proliferation assay and compared to PLA scaffolds containing the same amount of DCF sodium salt (DCFONa). Finally, the effect of the electrospun scaffolds on human dermal fibroblasts (HDFs) morphology and metabolism was investigated by combining MPM with fluorescence lifetime imaging microscopy (FLIM). The obtained results suggest that the obtained scaffold could be suitable for the controlled and targeted delivery of the synthesized prodrug for the treatment of AKs. Electrospun scaffolds are of growing interest as materials for a controlled drug delivery. In this work, an electrospun polylactic acid scaffold containing a synthetically obtained Diclofenac prodrug is proposed as a novel substrate for the topical treatment of actinic keratosis. A controlled drug delivery targeted to the area of interest could enhance the efficacy of the therapy and favor the healing process. The prodrug was synthesized via solid phase, employing a clean and versatile approach to obtain Diclofenac derivatives. Here, we used multiphoton microscopy to image drug encapsulation within the fibrous scaffold and fluorescence lifetime imaging microscopy to investigate Diclofenac effects and potential mechanisms of action. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Lymphatic delivery of etanercept via nanotopography improves response to collagen-induced arthritis.

PubMed

Aldrich, Melissa B; Velasquez, Fred C; Kwon, Sunkuk; Azhdarinia, Ali; Pinkston, Kenneth; Harvey, Barrett R; Chan, Wenyaw; Rasmussen, John C; Ross, Russell F; Fife, Caroline E; Sevick-Muraca, E M

2017-05-31

Evidence suggests lymphatic function mediates local rheumatoid arthritis (RA) flares. Yet biologics that target the immune system are dosed systemically via the subcutaneous (SC) administration route, thereby inefficiently reaching local lymphatic compartments. Nanotopography has previously been shown to disrupt tight cellular junctions, potentially enhancing local lymphatic delivery and potentially improving overall therapeutic efficacy. We first characterized nanotopography (SOFUSA™) delivery of an anti-TNF drug, etanercept, by comparing pharmacokinetic profiles to those obtained by conventional SC, intravenous (IV), and intradermal (ID) routes of administration, and assessed uptake of radiolabeled etanercept in draining lymph nodes (LNs) in single dosing studies. We then compared etanercept efficacy in a progressive rat model of collagen-induced arthritis (CIA), administered systemically via SC route of administration; via the regional lymphatics through ID delivery; or through a nanotopography (SOFUSA™) device at 10, 12, and 14 days post CIA induction. Measurements of hind limb swelling and near-infrared fluorescence (NIRF) imaging of afferent lymph pumping function and reflux were conducted on days 11, 13, and 18 post CIA induction and compared to untreated CIA animals. Univariate and multivariate analysis of variance were used to compare the group differences for percentage swelling and lymphatic contractile activity. Even though all three modes of administration delivered an equal amount of etanercept, SOFUSA™ delivery resulted in increased lymphatic pumping and significantly reduced swelling as compared to untreated, ID, and SC groups. Pharmacokinetic profiles in serum and LN uptake studies showed that using the nanotopography device resulted in the greatest uptake and retention in draining LNs. Locoregional lymphatic delivery of biologics that target the immune system may have more favorable pharmacodynamics than SC or IV administration. Nanotopography may provide a more efficient method for delivery of anti-TNF drugs to reverse impairment of lymphatic function and reduce swelling associated with RA flares.

En Route Use of Analgesics in Nonintubated, Critically Ill Patients Transported by U.S. Air Force Critical Care Air Transport Teams.

PubMed

Mora, Alejandra G; Ganem, Victoria J; Ervin, Alicia T; Maddry, Joseph K; Bebarta, Vikhyat S

2016-05-01

U.S. Critical Care Air Transport Teams (CCATTs) evacuate critically ill patients with acute pain in the combat setting. Limited data have been reported on analgesic administration en route, and no study has reported analgesic use by CCATTs. Our objective was to describe analgesics used by CCATTs for nonintubated, critically ill patients during evacuation from a combat setting. We conducted an institutional review board-approved, retrospective review of CCATT records. We included nonintubated, critically ill patients who were administered analgesics in flight and were evacuated out of theater (2007-2012). Demographics, injury description, analgesics and anesthetics, and predefined clinical adverse events were recorded. Data were presented as mean ± standard deviation or percentage (%). Of 1,128 records, we analyzed 381 subjects with the following characteristics: age 26 ± 7.0 years; 98% male; and 97% trauma (70% blast, 17% penetrating, 11% blunt, and 3% burn). The injury severity score was 19 ± 9. Fifty-one percent received morphine, 39% hydromorphone, 15% fentanyl, and 5% ketamine. Routes of delivery were 63% patient-controlled analgesia (PCA), 32% bolus intravenous (IV) administration, 24% epidural delivery, 21% continuous IV infusions, and 9% oral opioids. Patients that were administered local anesthetics (nerve block or epidural delivery) with IV opioids received a lower total dose of opioids than those who received opioids alone. No differences were associated between analgesics and frequency of complications in flight or postflight. About half of nonintubated, critically ill subjects evacuated out of combat by CCATT received morphine and more than half had a PCA. In our study, ketamine was not frequently used and pain scores were rarely recorded. However, we detected an opioid-sparing effect associated with local anesthetics (regional nerve blocks and epidural delivery). Reprint & Copyright © 2016 Association of Military Surgeons of the U.S.

Sulfonate-modified phenylboronic acid-rich nanoparticles as a novel mucoadhesive drug delivery system for vaginal administration of protein therapeutics: improved stability, mucin-dependent release and effective intravaginal placement.

PubMed

Li, ChunYan; Huang, ZhiGang; Liu, ZheShuo; Ci, LiQian; Liu, ZhePeng; Liu, Yu; Yan, XueYing; Lu, WeiYue

Effective interaction between mucoadhesive drug delivery systems and mucin is the basis of effective local placement of drugs to play its therapeutic role after mucosal administration including vaginal use, which especially requires prolonged drug presence for the treatment of gynecological infectious diseases. Our previous report on phenylboronic acid-rich nanoparticles (PBNPs) demonstrated their strong interaction with mucin and mucin-sensitive release profiles of the model protein therapeutics interferon (IFN) in vitro, but their poor stability and obvious tendency to aggregate over time severely limited future application. In this study, sulfonate-modified PBNPs (PBNP-S) were designed as a stable mucoadhesive drug delivery system where the negative charges conferred by sulfonate groups prevented aggregation of nanoparticles and the phenylboronic acid groups ensured effective interaction with mucin over a wide pH range. Results suggested that PBNP-S were of spherical morphology with narrow size distribution (123.5 nm, polydispersity index 0.050), good stability over a wide pH range and 3-month storage and considerable in vitro mucoadhesion capability at vaginal pH as shown by mucin adsorption determination. IFN could be loaded to PBNP-S by physical adsorption with high encapsulation efficiency and released in a mucin-dependent manner in vitro. In vivo near-infrared fluorescent whole animal imaging and quantitative vaginal lavage followed by enzyme-linked immunosorbent assay (ELISA) assay of IFN demonstrated that PBNP-S could stay in the vagina and maintain intravaginal IFN level for much longer time than IFN solution (24 hours vs several hours) without obvious histological irritation to vaginal mucosa after vaginal administration to mice. In summary, good stability, easy loading and controllable release of protein therapeutics, in vitro and in vivo mucoadhesive properties and local safety of PBNP-S suggested it as a promising nanoscale mucoadhesive drug delivery system for vaginal administration of protein therapeutics.

A novel approach to scavenging anesthetic gases in rodent surgery.

PubMed

Nesbitt, Jeffrey C; Krageschmidt, Dale A; Blanco, Michael C

2013-01-01

Laboratory animal procedures using gas anesthetics may amass elevated waste gas concentrations in operating rooms if controls are not implemented for capturing and removing the vapors. Area sampling using an infrared analyzer indicated isoflurane concentrations likely to exceed occupational exposure guidelines. Our study showed environmental concentrations of oxygen as high as 40% and isoflurane concentrations >100 ppm when no controls or merely passive controls were utilized. These extraneous isoflurane emissions were determined to be originating from the pre-procedural induction process as well as the gas delivery nose cone. A novel waste gas collection cylinder was designed to enclose the gas delivery nose cone and animal head during the administration of anesthetic gases. The vented cylinder utilized a house vacuum to remove the waste anesthetic gases from the surgical field. A commercially available induction chamber designed to be actively and externally exhausted was used to lower concentrations during the induction process. With implementation of local exhaust ventilation controls, waste anesthetic gas concentrations decreased to below recommended occupational exposure levels. In vitro (sham) testing compared favorably to in vivo measurements validating the reduction capability of active ventilation during rodent anesthetic administration. In vivo isoflurane reductions for the induction chamber emissions, the operating room, and the surgeon's breathing zone were 95%, 60%, and 53%, respectively. The same measurements for an in vitro procedure were 98%, 84%, and 87%, respectively.

Endocervical ultrasound applicator for integrated hyperthermia and HDR brachytherapy in the treatment of locally advanced cervical carcinoma.

PubMed

Wootton, Jeffery H; Hsu, I-Chow Joe; Diederich, Chris J

2011-02-01

The clinical success of hyperthermia adjunct to radiotherapy depends on adequate temperature elevation in the tumor with minimal temperature rise in organs at risk. Existing technologies for thermal treatment of the cervix have limited spatial control or rapid energy falloff. The objective of this work is to develop an endocervical applicator using a linear array of multisectored tubular ultrasound transducers to provide 3-D conformal, locally targeted hyperthermia concomitant to radiotherapy in the uterine cervix. The catheter-based device is integrated within a HDR brachytherapy applicator to facilitate sequential and potentially simultaneous heat and radiation delivery. Treatment planning images from 35 patients who underwent HDR brachytherapy for locally advanced cervical cancer were inspected to assess the dimensions of radiation clinical target volumes (CTVs) and gross tumor volumes (GTVs) surrounding the cervix and the proximity of organs at risk. Biothermal simulation was used to identify applicator and catheter material parameters to adequately heat the cervix with minimal thermal dose accumulation in nontargeted structures. A family of ultrasound applicators was fabricated with two to three tubular transducers operating at 6.6-7.4 MHz that are unsectored (360 degrees), bisectored (2 x 180 degrees), or trisectored (3 x 120 degrees) for control of energy deposition in angle and along the device length in order to satisfy anatomical constraints. The device is housed in a 6 mm diameter PET catheter with cooling water flow for endocervical implantation. Devices were characterized by measuring acoustic efficiencies, rotational acoustic intensity distributions, and rotational temperature distributions in phantom. The CTV in HDR brachytherapy plans extends 20.5 +/- 5.0 mm from the endocervical tandem with the rectum and bladder typically <8 mm from the target boundary. The GTV extends 19.4 +/- 7.3 mm from the tandem. Simulations indicate that for 60 min treatments the applicator can heat to 41 degrees C and deliver > 5EM(43 degrees C) over 4-5 cm diameter with Tmax < 45 degrees C and 1 kg m(-3) s(-1) blood perfusion. The 41 degrees C contour diameter is reduced to 3-4 cm at 3 kg m(-3) s(-1) perfusion. Differential power control to transducer elements and sectors demonstrates tailoring of heating along the device length and in angle. Sector cuts are associated with a 14-47 degrees acoustic dead zone, depending on cut width, resulting in a approximately 2-4 degrees C temperature reduction within the dead zone below Tmax. Dead zones can be oriented for thermal protection of the rectum and bladder. Fabricated devices have acoustic efficiencies of 33.4%-51.8% with acoustic output that is well collimated in length, reflects the sectoring strategy, and is strongly correlated with temperature distributions. A catheter-based ultrasound applicator was developed for endocervical implantation with locally targeted, 3-D conformal thermal delivery to the uterine cervix. Feasibility of heating clinically relevant target volumes was demonstrated with power control along the device length and in angle to treat the cervix with minimal thermal dose delivery to the rectum and bladder.

Laser-assisted delivery of synergistic combination chemotherapy in in vivo skin.

PubMed

Wenande, Emily; Tam, Joshua; Bhayana, Brijesh; Schlosser, Steven Kyle; Ishak, Emily; Farinelli, William A; Chlopik, Agata; Hoang, Mai P; Pinkhasov, Omar R; Caravan, Peter; Rox Anderson, R; Haedersdal, Merete

2018-04-10

The effectiveness of topical drugs for treatment of non-melanoma skin cancer is greatly reduced by insufficient penetration to deep skin layers. Ablative fractional lasers (AFLs) are known to enhance topical drug uptake by generating narrow microchannels through the skin, but information on AFL-drug delivery in in vivo conditions is limited. In this study, we examined pharmacokinetics, biodistribution and toxicity of two synergistic chemotherapy agents, cisplatin and 5-fluorouracil (5-FU), following AFL-assisted delivery alone or in combination in in vivo porcine skin. Detected at 0-120 h using mass spectrometry techniques, we demonstrated that fractional CO 2 laser pretreatment (196 microchannels/cm 2 , 852 μm ablation depth) leads to rapid drug uptake in 1500 μm deep skin layers, with a sixfold enhancement in peak cisplatin concentrations versus non-laser-treated controls (5 h, P = 0.005). Similarly, maximum 5-FU deposition was measured within an hour of AFL-delivery, and exceeded peak deposition in non-laser-exposed skin that had undergone topical drug exposure for 5 days. Overall, this accelerated and deeper cutaneous drug uptake resulted in significantly increased inflammatory and histopathological effects. Based on clinical scores and transepidermal water loss measurement, AFL intensified local toxic responses to drugs delivered alone and in combination, while systemic drug exposure remained undetectable. Quantitative histopathologic analyses correspondingly revealed significantly reduced epidermal proliferation and greater cellular apoptosis after AFL-drug delivery; particularly after combined cisplatin + 5-FU exposure. In sum, by overcoming the primary limitation of topical drug penetration and providing accelerated, enhanced and deeper delivery, AFL-assisted combination chemotherapy may represent a promising treatment strategy for non-melanoma skin cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

Light-switchable systems for remotely controlled drug delivery.

PubMed

Shim, Gayong; Ko, Seungbeom; Kim, Dongyoon; Le, Quoc-Viet; Park, Gyu Thae; Lee, Jaiwoo; Kwon, Taekhyun; Choi, Han-Gon; Kim, Young Bong; Oh, Yu-Kyoung

2017-12-10

Light-switchable systems have recently received attention as a new mode of remotely controlled drug delivery. In the past, a multitude of nanomedicine studies have sought to enhance the specificity of drug delivery to target sites by focusing on receptors overexpressed on malignant cells or environmental features of diseases sites. Despite these immense efforts, however, there are few clinically available nanomedicines. We need a paradigm shift in drug delivery. One strategy that may overcome the limitations of pathophysiology-based drug delivery is the use of remotely controlled delivery technology. Unlike pathophysiology-based active drug targeting strategies, light-switchable systems are not affected by the heterogeneity of cells, tissue types, and/or microenvironments. Instead, they are triggered by remote light (i.e., near-infrared) stimuli, which are absorbed by photoresponsive molecules or three-dimensional nanostructures. The sequential conversion of light to heat or reactive oxygen species can activate drug release and allow it to be spatio-temporally controlled. Light-switchable systems have been used to activate endosomal drug escape, modulate the release of chemical and biological drugs, and alter nanoparticle structures to control the release rates of drugs. This review will address the limitations of pathophysiology-based drug delivery systems, the current status of light-based remote-switch systems, and future directions in the application of light-switchable systems for remotely controlled drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

Developmental Regulation of p66Shc Is Altered by Bronchopulmonary Dysplasia in Baboons and Humans

PubMed Central

Lee, Matt K.; Pryhuber, Gloria S.; Schwarz, Margaret A.; Smith, Susan M.; Pavlova, Zdena; Sunday, Mary E.

2005-01-01

Rationale: The p66Shc adapter protein antagonizes mitogen-activated protein, or MAP, kinase, mediates oxidative stress, and is developmentally regulated in fetal mouse lungs. Objectives: To determine if p66Shc is similarly regulated in primates and in bronchopulmonary dysplasia (BPD), which results from oxidative injury to immature lungs. Methods: Normal and injured lungs from humans and baboons were evaluated by Western analysis and immunohistochemistry. Measurements and Main Results: In baboons, p66Shc decreased 80% between 125 and 175 days' gestation (p = 0.025), then doubled after term delivery at 185 days (p = 0.0013). In the hyperoxic 140-day fetal baboon BPD model, p66Shc expression persisted, and its localization shifted from the epithelium of gestational controls to the mesenchyme of diseased lungs, coincident with expression of proliferating cell nuclear antigen and cleaved poly(adenyl ribose) polymerase, a marker of apoptosis. Treatment with the antibombesin antibody 2A11 attenuated BPD, reduced cell proliferation, increased p66Shc expression 10.5-fold, and preserved epithelial p66Shc localization. p66Shc also decreased during normal human lung development, falling 87% between 18 and 24 weeks' gestation (p = 0.02). p66Shc was expressed throughout 18-week human lungs, became restricted to scattered epithelial cells by 24 weeks, and localized to isolated mesenchymal cells after term delivery. In contrast, p66Shc remained prominent in the epithelium of lungs with acute injury or mild BPD, and in the mesenchyme of lungs with severe disease. p66Shc localized to tissues expressing proliferating cell nuclear antigen and cleaved poly(adenyl ribose) polymerase. Conclusions: p66Shc expression, cell proliferation, and apoptosis are concomitantly altered during lung development and in BPD. PMID:15778491

Caesarean delivery and risk of childhood leukaemia: a pooled analysis from the Childhood Leukemia International Consortium (CLIC)

PubMed Central

Marcotte, Erin L; Thomopoulos, Thomas P; Infante-Rivard, Claire; Clavel, Jacqueline; Petridou, Eleni Th; Schüz, Joachim; Ezzat, Sameera; Dockerty, John D; Metayer, Catherine; Magnani, Corrado; Scheurer, Michael E; Mueller, Beth A; Mora, Ana M; Wesseling, Catharina; Skalkidou, Alkistis; Rashed, Wafaa M; Francis, Stephen S; Ajrouche, Roula; Erdmann, Friederike; Orsi, Laurent; Spector, Logan G

2017-01-01

Summary Background Results from case-control studies have shown an increased risk of acute lymphoblastic leukaemia (ALL) in young children born by caesarean delivery, and prelabour caesarean delivery in particular; however, an association of method of delivery with childhood leukaemia subtypes has yet to be established. We therefore did a pooled analysis of data to investigate the association between childhood leukaemia and caesarean delivery. Methods We pooled data from 13 case-control studies from the Childhood Leukemia International Consortium done in nine countries (Canada, Costa Rica, Egypt, France, Germany, Greece, Italy, New Zealand, and the USA) for births from 1970-2013. We analysed caesarean delivery overall and by indications that probably resulted in prelabour caesarean delivery or emergency caesarean delivery. We used multivariable logistic regression models, adjusted for child's birthweight, sex, age, ethnic origin, parental education, maternal age, and study, to estimate odds ratios (ORs) and 95% CIs for the risk of ALL and acute myeloid leukaemia (AML) in children aged 0-14 years at diagnosis. Findings The studies provided data for 8780 ALL cases, 1332 AML cases, and 23 459 controls, of which the birth delivery method was known for 8655 (99%) ALL cases, 1292 (97%) AML cases, and 23 351 (>99%) controls. Indications for caesarean delivery were available in four studies (there were caesarean deliveries for 1061 of 4313 ALL cases, 138 of 664 AML cases, and 1401 of 5884 controls). The OR for all indications of caesarean delivery and ALL was 1.06 (95% CI 0.99–1.13), and was significant for prelabour caesarean delivery and ALL (1.23 [1.04-1.47]; p=0.018). Emergency caesarean delivery was not associated with ALL (OR 1.02 [95% CI 0.81-1.30]). AML was not associated with caesarean delivery (all indications OR 0.99 [95% CI 0.84-1.17]; prelabour caesarean delivery 0.83 [0.54-1.26]; and emergency caesarean delivery 1.05 [0.63-1.77]). Interpretation Our results suggest an increased risk of childhood ALL after prelabour caesarean delivery. If this association is causal, maladaptive immune activation due to an absence of stress response before birth in children born by prelabour caesarean delivery could be considered as a potential mechanism. PMID:27063976

Building tobacco control research in Thailand: meeting the need for innovative change in Asia.

PubMed

Hamann, Stephen L; Mock, Jeremiah; Hense, Sibasis; Charoenca, Naowarut; Kungskulniti, Nipapun

2012-01-28

In low- and middle-income countries (LMICs) over the past two decades locally relevant tobacco control research has been scant. Experience shows that tobacco control measures should be based on sound research findings to ensure that measures are appropriate for local conditions and that they are likely to have an impact. Research should also be integrated within tobacco control measures to ensure ongoing learning and the production of knowledge. Thailand, a middle-income country, has a public health community with a record of successful tobacco control and a longstanding commitment to research. Thailand's comprehensive approach includes taxation; bans on tobacco advertising, sponsorship and promotion; smoke-free areas; graphic cigarette pack warnings; social marketing campaigns; cessation counseling; and an established tobacco control research program. The purpose of this study was to document and analyze the development of tobacco control research capacity in Thailand and the impact of research on Thai tobacco control measures. We used mixed methods including review of historical documentation and policy reports, qualitative interviews with key members of Thailand's tobacco control community, and an analysis of research productivity. In Thailand, tobacco control research has evolved through three phases: (1) discovery of the value of research in the policymaking arena, (2) development of a structure to support research capacity building through international collaborations supported by foreign funding agencies, and (3) delivery of locally relevant research made possible largely through substantial stable funding from a domestic health promotion foundation. Over two decades, Thai tobacco control advocates have constructed five steppingstones to success: (1) adapting foreign research to inform policymaking and lobbying for more support for domestic research; (2) attracting foreign funding agencies to support small-scale research and capacity building; (3) participating in multi-country research and capacity building programs; (4) using collaborative experiences to demonstrate the need for domestic support of locally relevant research; and (5) maintaining an unwavering commitment to research while being vigilant to ensure continued research support. The evolution of tobacco control research in Thailand provides examples of steppingstones that LMICs may be able to use to construct their own tobacco control research pathways.

Building tobacco control research in Thailand: meeting the need for innovative change in Asia

PubMed Central

2012-01-01

Introduction In low- and middle-income countries (LMICs) over the past two decades locally relevant tobacco control research has been scant. Experience shows that tobacco control measures should be based on sound research findings to ensure that measures are appropriate for local conditions and that they are likely to have an impact. Research should also be integrated within tobacco control measures to ensure ongoing learning and the production of knowledge. Thailand, a middle-income country, has a public health community with a record of successful tobacco control and a longstanding commitment to research. Thailand's comprehensive approach includes taxation; bans on tobacco advertising, sponsorship and promotion; smoke-free areas; graphic cigarette pack warnings; social marketing campaigns; cessation counseling; and an established tobacco control research program. The purpose of this study was to document and analyze the development of tobacco control research capacity in Thailand and the impact of research on Thai tobacco control measures. Method We used mixed methods including review of historical documentation and policy reports, qualitative interviews with key members of Thailand's tobacco control community, and an analysis of research productivity. Findings In Thailand, tobacco control research has evolved through three phases: (1) discovery of the value of research in the policymaking arena, (2) development of a structure to support research capacity building through international collaborations supported by foreign funding agencies, and (3) delivery of locally relevant research made possible largely through substantial stable funding from a domestic health promotion foundation. Over two decades, Thai tobacco control advocates have constructed five steppingstones to success: (1) adapting foreign research to inform policymaking and lobbying for more support for domestic research; (2) attracting foreign funding agencies to support small-scale research and capacity building; (3) participating in multi-country research and capacity building programs; (4) using collaborative experiences to demonstrate the need for domestic support of locally relevant research; and (5) maintaining an unwavering commitment to research while being vigilant to ensure continued research support. Conclusion The evolution of tobacco control research in Thailand provides examples of steppingstones that LMICs may be able to use to construct their own tobacco control research pathways. PMID:22284811

Effect of periodontal therapy on pregnancy outcome in women affected by periodontitis.

PubMed

Tarannum, Fouzia; Faizuddin, Mohamed

2007-11-01

There is convincing evidence to suggest that infections affecting the mother during pregnancy may produce alterations in the normal cytokine- and hormone-regulated gestation, which could result in preterm labor, premature rupture of membranes, and preterm birth (PTB). Studies in the late 1990s associated periodontitis with preterm low birth weight (PLBW) deliveries, and this may have similar pathogenic mechanisms as other maternal infections. This study determined the effect of non-surgical periodontal therapy on pregnancy outcome. A total of 200 pregnant women with periodontitis were randomly assigned to treatment and control groups. Detailed data about previous and current pregnancies were obtained. All women received a full-mouth periodontal examination, including oral hygiene index-simplified, bleeding index, and clinical attachment level. The women in the treatment group received non-surgical periodontal therapy during the gestational period, and those in the control group received periodontal treatment after delivery. Periodontal therapy included plaque control instructions and scaling and root planing performed under local anesthesia. The outcome measures assessed were gestational age and birth weight of the infant. PTB was recorded when delivery occurred at <37 weeks of gestation, and low birth weight (LBW) was recorded when the infant weighed<2,500 g. There were 53 PTBs in the treatment group and 68 PTBs in the control group. Twenty-six LBW infants were recorded in the treatment group, and 48 LBW infants were noted in the control group. The mean gestational ages were 33.8+/-2.8 weeks and 32.7+/-2.8 weeks in the treatment and control groups, respectively. The difference was statistically significant at P<0.006. The mean birth weight was 2,565.3+/-331.2 g in the treatment group and 2,459.6+/-380.7 g in the control group, with the difference being statistically significant at P<0.044. A multiple regression model showed a significant effect of periodontal treatment on birth outcomes. Non-surgical periodontal therapy can reduce the risk for preterm births in mothers who are affected by periodontitis. Additional multicentered, randomized, controlled clinical trials are required to confirm this link between periodontitis and PLBW.

Ocular delivery of macromolecules

PubMed Central

Kim, Yoo-Chun; Chiang, Bryce; Wu, Xianggen; Prausnitz, Mark R.

2014-01-01

Biopharmaceuticals are making increasing impact on medicine, including treatment of indications in the eye. Macromolecular drugs are typically given by physician-administered invasive delivery methods, because non--invasive ocular delivery methods, such as eye drops, and systemic delivery, have low bioavailability and/or poor ocular targeting. There is a need to improve delivery of biopharmaceuticals to enable less-invasive delivery routes, less-frequent dosing through controlled-release drug delivery and improved drug targeting within the eye to increase efficacy and reduce side effects. This review discusses the barriers to drug delivery via various ophthalmic routes of administration in the context of macromolecule delivery and discusses efforts to develop controlled-release systems for delivery of biopharmaceuticals to the eye. The growing number of macromolecular therapies in the eye needs improved drug delivery methods that increase drug efficacy, safety and patient compliance. PMID:24998941

Training the Trainers of Tomorrow Today - driving excellence in medical education.

PubMed

Fellow-Smith, Elizabeth; Beveridge, Ed; Hogben, Katy; Wilson, Graeme; Lowe, John; Abraham, Rachel; Ingle, Digby; Bennett, Danielle; Hernandez, Carol

2013-01-01

Training the Trainers of Tomorrow Today (T4) is a new way to deliver "Training for Trainers". Responding to local dissatisfaction with existing arrangements, T4 builds on 3 essential requirements for a future shape of training: 1. Clinical Leadership and a Collaborative Approach 2. Cross-Specialty Design and Participation 3. Local Delivery and Governance Networks Design principles also included: 3 levels of training to reflect differing needs of clinical supervisors, educational supervisors and medical education leader, mapping to GMC requirements and the London Deanery's Professional Development Framework; alignment of service, educational theory and research; recognition of challenges in delivering and ensuring attendance in busy acute and mental health settings, and the development of a faculty network. The delivery plan took into account census of professional development uptake and GMC Trainee Surveys. Strong engagement and uptake from the 11 Trusts in NW London has been achieved, with powerful penetration into all specialties. Attendance has exceeded expectations. Against an initial 12 month target of 350 attendances, 693 were achieved in the first 8 months. Evaluation of content demonstrates modules are pitched appropriately to attendees needs, with positive feedback from trainers new to the role. Delivery style has attracted high ratings of satisfaction: 87% attendees rating delivery as "good\\excellent". External evaluation of impact demonstrated improved training experiences through changes in supervision, the learning environment and understanding of learning styles. We have addressed sustainability of the programme by advertising and recruiting Local Faculty Development Trainers. Volunteer consultants and higher trainees are trained to deliver the programme on a cascade model, supported by the Specialty Tutors, individual coaching and educational bursaries. The Trainers are local champions for excellence in training, provide a communication between the programme and local providers, are a repository of expertise in their service, and trouble shoot local barriers to engagement.

SU-E-T-268: Proton Radiosurgery End-To-End Testing Using Lucy 3D QA Phantom

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

Choi, D; Gordon, I; Ghebremedhin, A

2014-06-01

Purpose: To check the overall accuracy of proton radiosurgery treatment delivery using ready-made circular collimator inserts and fixed thickness compensating boluses. Methods: Lucy 3D QA phantom (Standard Imaging Inc. WI, USA) inserted with GaFchromicTM film was irradiated with laterally scattered and longitudinally spread-out 126.8 MeV proton beams. The tests followed every step in the proton radiosurgery treatment delivery process: CT scan (GE Lightspeed VCT), target contouring, treatment planning (Odyssey 5.0, Optivus, CA), portal calibration, target localization using robotic couch with image guidance and dose delivery at planned gantry angles. A 2 cm diameter collimator insert in a 4 cm diametermore » radiosurgery cone and a 1.2 cm thick compensating flat bolus were used for all beams. Film dosimetry (RIT114 v5.0, Radiological Imaging Technology, CO, USA) was used to evaluate the accuracy of target localization and relative dose distributions compared to those calculated by the treatment planning system. Results: The localization accuracy was estimated by analyzing the GaFchromic films irradiated at gantry 0, 90 and 270 degrees. We observed 0.5 mm shift in lateral direction (patient left), ±0.9 mm shift in AP direction and ±1.0 mm shift in vertical direction (gantry dependent). The isodose overlays showed good agreement (<2mm, 50% isodose lines) between measured and calculated doses. Conclusion: Localization accuracy depends on gantry sag, CT resolution and distortion, DRRs from treatment planning computer, localization accuracy of image guidance system, fabrication of ready-made aperture and cone housing. The total deviation from the isocenter was 1.4 mm. Dose distribution uncertainty comes from distal end error due to bolus and CT density, in addition to localization error. The planned dose distribution was well matched (>90%) to the measured values 2%/2mm criteria. Our test showed the robustness of our proton radiosurgery treatment delivery system using ready-made collimator inserts and fixed thickness compensating boluses.« less

Clean delivery practices in rural northern Ghana: a qualitative study of community and provider knowledge, attitudes, and beliefs

PubMed Central

2012-01-01

Background Knowledge, attitudes and practices of community members and healthcare providers in rural northern Ghana regarding clean delivery are not well understood. This study explores hand washing/use of gloves during delivery, delivering on a clean surface, sterile cord cutting, appropriate cord tying, proper cord care following delivery, and infant bathing and cleanliness. Methods In-depth interviews and focus group discussions were audiotaped, transcribed, and analyzed using NVivo 9.0. Results 253 respondents participated, including women with newborn infants, grandmothers, household and compound heads, community leaders, traditional birth attendants, and formally trained health care providers. There is widespread understanding of the need for clean delivery to reduce the risk of infection to both mothers and their babies during and shortly after delivery. Despite this understanding, the use of gloves during delivery and hand washing during and after delivery were mentioned infrequently. The need for a clean delivery surface was raised repeatedly, including explicit discussion of avoiding delivering in the dirt. Many activities to do with cord care involved non-sterile materials and practices: 1) Cord cutting was done with a variety of tools, and the most commonly used were razor blades or scissors; 2) Cord tying utilized a variety of materials, including string, rope, thread, twigs, and clamps; and 3) Cord care often involved applying traditional salves to the cord - including shea butter, ground shea nuts, local herbs, local oil, or “red earth sand.” Keeping babies and their surroundings clean was mentioned repeatedly as an important way to keep babies from falling ill. Conclusions This study suggests a widespread understanding in rural northern Ghana of the need for clean delivery. Nonetheless, many recommended clean delivery practices are ignored. Overarching themes emerging from this study included the increasing use of facility-based delivery, the disconnect between healthcare providers and the community, and the critical role grandmothers play in ensuring clean delivery practices. Future interventions to address clean delivery and prevention of neonatal infections include educating healthcare providers about harmful traditional practices so they are specifically addressed, strengthening facilities, and incorporating influential community members such as grandmothers to ensure success. PMID:22703032