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1.  Enhanced function of immuno-isolated islets in diabetes therapy by co-encapsulation with an anti-inflammatory drug 
Biomaterials  2013;34(23):5792-5801.
Immuno-isolation of islets has the potential to enable the replacement of pancreatic function in diabetic patients. However, host response to the encapsulated islets frequently leads to fibrotic overgrowth with subsequent impairment of the transplanted grafts. Here, we identified and incorporated anti-inflammatory agents into islet-containing microcapsules to address this challenge. In vivo subcutaneous screening of 16 small molecule anti-inflammatory drugs was performed to identify promising compounds that could minimize the formation of fibrotic cell layers. Using parallel non-invasive fluorescent and bioluminescent imaging, we identified dexamethasone and curcumin as the most effective drugs in inhibiting the activities of inflammatory proteases and reactive oxygen species in the host response to subcutaneously injected biomaterials. Next, we demonstrated that co-encapsulating curcumin with pancreatic rat islets in alginate microcapsules reduced fibrotic overgrowth and improved glycemic control in a mouse model of chemically-induced type I diabetes. These results showed that localized administration of anti-inflammatory drug can improve the longevity of encapsulated islets and may facilitate the translation of this technology towards a long-term cure for type I diabetes.
PMCID: PMC3901568  PMID: 23660251
Anti-inflammatory drugs; curcumin; encapsulated islets; diabetes; fibrotic overgrowth; host response
2.  Blockade of peroxynitrite-induced neural stem cell death in the acutely injured spinal cord by drug-releasing polymer 
Stem cells (Dayton, Ohio)  2009;27(5):1212-1222.
Therapeutic impact of neural stem cells (NSCs) for acute spinal cord injury (SCI) has been limited by the rapid loss of donor cells. Neuroinflammation is likely the cause. Since there are close temporal-spatial correlations between the inducible nitric oxide (NO) synthase expression and the donor NSC death after neurotrauma, we reasoned that NO-associated radical species might be the inflammatory effectors which eliminate NSC grafts and kill host neurons. To test this hypothesis, human NSCs (hNSCs: 5×104-2×106/ml) were treated in vitro with “plain” medium, 20 μM glutamate, or donors of NO and peroxynitrite (ONOO-; 100 and 400 μM of spermine or DETA NONOate, and SIN-1, respectively). hNSC apoptosis primarily resulted from SIN-1 treatment, showing ONOO--triggered protein nitration and the activation of p38 MAPK, cytochrome c release, and caspases. Therefore, cell death following post-SCI (p.i.) NO serge may be mediated through conversion of NO into ONOO-. We subsequently examined such causal relationship in a rat model of dual penetrating SCI using a retrievable design of poly-lactic-co-glycolic acid (PLGA) scaffold seeded with hNSCs that was shielded by drug-releasing polymer. Besides confirming the ONOO--induced cell death signaling, we demonstrated that co-transplantation of PLGA film embedded with ONOO- scavenger, manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) or uric acid (1 μmol/film), markedly protected hNSCs 24 h p.i. (total: n = 10). Our findings may provide a bioengineering approach for investigating mechanisms underlying the host microenvironment and donor NSC interaction and help formulate strategies for enhancing graft and host cell survival after SCI.
PMCID: PMC4070520  PMID: 19418456
spinal cord injury; neural stem cell; nitric oxide; peroxynitrite; PLGA scaffold; neuroinflammation
3.  Injectable Hyaluronic Acid-Dextran Hydrogels and Effects of Implantation in Ferret Vocal Fold 
Injectable hydrogels may potentially be used for augmentation/regeneration of the lamina propria of vocal fold tissue. In this study, hyaluronic acid (HA) and dextran were chemically modified and subsequently crosslinked via formation of hydrazone bonds in phosphate buffer. Swelling ratios, degradation, and compressive moduli of the resulting hydrogels were investigated. It was found that the properties of HA-dextran hydrogels were variable and the trend of variation could be correlated with the hydrogel composition. The biocompatibility of three injectable HA-dextran hydrogels with different crosslinking density was assessed in the vocal fold region using a ferret model. It was found that HA-dextran hydrogels implanted for three weeks stimulated mild foreign-body reactions. Distinct tissue-material interactions were also observed for hydrogels made from different formulations: the hydrogel 7with the lowest crosslinking density was completely degraded in vivo; while material residues were visible for other types of hydrogel injections, with or without cell penetration into the implantation depending on the hydrogel composition. The in vivo results suggest that the HA-dextran hydrogel matrices can be further developed for applications of vocal fold tissue restoration.
PMCID: PMC4070526  PMID: 20151459
hydrogel; vocal fold; hyaluronic acid; dextran; tissue restoration
4.  An injectable thiol-acrylate poly(ethylene glycol) hydrogel for sustained release of methylprednisolone sodium succinate 
Biomaterials  2010;32(2):587-597.
Clinically available injectable hydrogels face technical challenges associated with swelling after injection and toxicity from unreacted constituents that impede their performance as surgical biomaterials. To overcome these challenges, we developed a system where chemical gelation was controlled by a conjugate Michael addition between thiol and acrylate in aqueous media, with 97% monomer conversion and 6 wt.% sol fraction. The hydrogel exhibited syneresis on equilibration, reducing to 59.7% of its initial volume. It had mechanical properties similar to soft human tissue with an elastic modulus of 189.8 kPa. Furthermore, a mesh size of 6.9 nm resulted in sustained release of methylprednisolone sodium succinate with a loading efficiency of 2 mg/mL. Functionalization with 50 µg/mL of an oligolysine peptide resulted in attachment of freshly isolated murine mesenchymal stem cells. The rational design of the physical, chemical and biological properties of the hydrogel makes it a potentially promising candidate for injectable applications.
PMCID: PMC4070531  PMID: 20880573
Cell adhesion; Controlled drug release; Hydrogel; Peptide; Polyethylene oxide; Spinal surgery
5.  Facile Synthetic Route for Surface-Functionalized Magnetic Nanoparticles: Cell Labeling and Magnetic Resonance Imaging Studies 
ACS nano  2011;5(6):4329-4336.
Currently available methods to stably disperse iron oxide nanoparticles (IONPs) in aqueous solution need to be improved due to potential aggregation, reduction of superparamagnetism, and the use of toxic reagents. Herein, we present a facile strategy for aqueous transfer and dispersion of organic-synthesized IONPs using only polyethylene glycol (PEG), a biocompatible polymer. A library of PEG derivatives was screened, and it was determined that amine-functionalized six-armed PEG, 6(PEG-NH2), was the most effective dispersion agent. The 6(PEG-NH2)-modified IONPs (IONP-6PEG) were stable after extensive washing, exhibited high superparamagnetism, and could be used as a platform material for secondary surface functionalization with bioactive polymers. IONP-6PEG biofunctionalized with hyaluronic acid (IONP-6PEG-HA) was shown to specifically label mesenchymal stem cells and demonstrate MR contrast potential with high r2 relaxivity (442.7 s−1mM−1) compared to the commercially available Feridex (182.1 s−1mM−1).
PMCID: PMC4060805  PMID: 21619063
iron oxide nanoparticles; dispersion; PEG; surface functionalization; MRI
6.  Retinal transplantation using surface modified poly(glycerol-co-sebacic acid) membranes 
Biomaterials  2010;31(31):7978-7984.
In retinal transplantation experiments it is hypothesized that remaining diseased photoreceptor cells in the host retina and inner retinal cells in transplants physically obstruct the development of graft-host neuronal contacts which are required for vision. Recently, we developed methods for the isolation of donor photoreceptor layers in vitro, and the selective removal of host photoreceptors in vivo using biodegradable elastomeric membranes composed of poly(glycerol-co-sebacic acid) (PGS). We also coated PGS membranes with electrospun nanofibers, composed of laminin and poly(epsilon-caprolactone) (PCL), to promote attachment of embryonic retinal explants, allowing the resulting composites to be handled surgically as a single entity. Here, we report subretinal transplantation of these composites into adult porcine eyes. In hematoxylin and eosin stained sections of composite explants after 5–7 days in vitro, excellent fusion of retinas and biomaterial membranes was noted, with the immature retinal components showing laminated as well as folded and rosetted areas. The composite grafts could be transplanted in all cases and, 3 months after surgery, eyes displayed clear media, attached retinas and the grafts located subretinally. Histological examination revealed that the biomaterial membrane had degraded without any signs of inflammation. Transplanted retinas displayed areas of rosettes as well as normal lamination. In most cases inner retinal layers were present in the grafts. Laminated areas displayed well-developed photoreceptors adjacent to an intact host retinal pigment epithelium and degeneration of the host outer nuclear layer (ONL) was often observed together with occasional fusion of graft and host inner layers.
PMCID: PMC4059040  PMID: 20656341
Cell adhesion; Elastomer; Nanotopography; Polycaprolactone; Retina; Transplantation
7.  Superstructure based on β-CD self-assembly induced by a small guest molecule† 
The size, shape and surface chemistry of nanoparticles play an important role in cellular interaction. Thus, the main objective of the present study was the determination of the β-cyclodextrin (β-CD) self-assembly thermodynamic parameters and its structure, aiming to use these assemblies as a possible controlled drug release system. Light scattering measurements led us to obtain the β-CD’s critical aggregation concentration (cac) values, and consequently the thermodynamic parameters of the β-CD spontaneous self-assembly in aqueous solution: ΔaggGo = − 16.31 kJ mol−1, ΔaggHo = − 26.48 kJ mol−1 and TΔaggSo = − 10.53 kJ mol−1 at 298.15 K. Size distribution of the self-assembled nanoparticles below and above cac was 1.5 nm and 60–120 nm, respectively. The number of β-CD molecules per cluster and the second virial coefficient were identified through Debye’s plot and molecular dynamic simulations proposed the three-fold assembly for this system below cac. Ampicillin (AMP) was used as a drug model in order to investigate the key role of the guest molecule in the self-assembly process and the β-CD:AMP supramolecular system was studied in solution, aiming to determine the structure of the supramolecular aggregate. Results obtained in solution indicated that the β-CD’s cac was not affected by adding AMP. Moreover, different complex stoichiometries were identified by nuclear magnetic resonance and isothermal titration calorimetry experiments.
PMCID: PMC4059046  PMID: 22234498
8.  Poly (β-amino esters): Procedures for Synthesis and Gene Delivery 
Non-viral gene delivery systems are promising as they avoid many problems of viral gene therapy by having increased design flexibility, high safety, large DNA cargo capacity, and ease of manufacture. Here, we describe the use of polymeric vectors, in particular biodegradable poly(β-amino esters) (PBAEs), for non-viral gene delivery. These polymers are able to self-assemble with DNA and form positively charged gene delivery nanoparticles. Methods for synthesis of these polymers, particle self-assembly, and transfection using these particles are delineated. A standard protocol is presented as well as a high-throughput screening technique that can be used to more quickly optimize transfection parameters for efficient delivery.
PMCID: PMC4059050  PMID: 19085119
Gene therapy; Drug delivery; Polymers; Transfection; High-throughput screening
9.  Formulation/Preparation of Functionalized Nanoparticles for In Vivo Targeted Drug Delivery 
Targeted cancer therapy allows the delivery of therapeutic agents to cancer cells without incurring undesirable side effects on the neighboring healthy tissues. Over the past decade, there has been an increasing interest in the development of advanced cancer therapeutics using targeted nanoparticles. Here we describe the preparation of drug-encapsulated nanoparticles formulated with biocompatible and biodegradable poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) copolymer and surface functionalized with the A10 2-fluoropyrimidine ribonucleic acid aptamers that recognize the extracellular domain of prostate-specific membrane antigen (PSMA), a well-characterized antigen expressed on the surface of prostate cancer cells. We show that the self-assembled nanoparticles can selectively bind to PSMA-targeted prostate cancer cells in vitro and in vivo. This formulation method may contribute to the development of highly selective and effective cancer therapeutic and diagnostic devices.
PMCID: PMC4059054  PMID: 19488725
Aptamers; Nanoparticles; Chemotherapy; Targeted drug delivery; Bioconjugated chemistry
10.  Biocompatibility of biodegradable semiconducting melanin films for nerve tissue engineering 
Biomaterials  2009;30(17):3050-3057.
The advancement of tissue engineering is contingent upon the development and implementation of advanced biomaterials. Conductive polymers have demonstrated potential for use as a medium for electrical stimulation, which has shown to be beneficial in many regenerative medicine strategies including neural and cardiac tissue engineering. Melanins are naturally occurring pigments that have previously been shown to exhibit unique electrical properties. This study evaluates the potential use of melanin films as a semiconducting material for tissue engineering applications. Melanin thin films were produced by solution processing and the physical properties were characterized. Films were molecularly smooth with a roughness (Rms) of 0.341 nm and a conductivity of 7.00 ± 1.10 × 10−5 S cm−1 in the hydrated state. In vitro biocompatibility was evaluated by Schwann cell attachment and growth as well as neurite extension in PC12 cells. In vivo histology was evaluated by examining the biomaterial–tissue response of melanin implants placed in close proximity to peripheral nerve tissue. Melanin thin films enhanced Schwann cell growth and neurite extension compared to collagen films in vitro. Melanin films induced an inflammation response that was comparable to silicone implants in vivo. Furthermore, melanin implants were significantly resorbed after 8 weeks. These results suggest that solution-processed melanin thin films have the potential for use as a biodegradable semiconducting biomaterial for use in tissue engineering applications.
PMCID: PMC4059055  PMID: 19286252
Electroactive polymer; Biocompatibility; Nerve tissue engineering
11.  Nanotechnological strategies for engineering complex tissues 
Nature nanotechnology  2010;6(1):13-22.
Tissue engineering aims at developing functional substitutes for damaged tissues and organs. Before transplantation, cells are generally seeded on biomaterial scaffolds that recapitulate the extracellular matrix and provide cells with information that is important for tissue development. Here we review the nanocomposite nature of the extracellular matrix, describe the design considerations for different tissues and discuss the impact of nanostructures on the properties of scaffolds and their uses in monitoring the behaviour of engineered tissues. We also examine the different nanodevices used to trigger certain processes for tissue development, and offer our view on the principal challenges and prospects of applying nanotechnology in tissue engineering.
PMCID: PMC4059057  PMID: 21151110
12.  Elasticity and safety of alkoxyethyl cyanoacrylate tissue adhesives 
Acta biomaterialia  2011;7(8):3150-3157.
Cyanoacrylate glues are easily applied to wounds with good cosmetic results. However, they tend to be brittle and can induce local tissue toxicity. A series of cyanoacrylate monomers with a flexible ether linkage and varying side-chain lengths was synthesized and characterized for potential use as tissue adhesives. The effect of side-chain length on synthesis yield, physical and mechanical properties, formaldehyde generation, cytotoxicity in vitro and biocompatibility in vivo were examined. The incorporation of etheric oxygen allowed the production of flexible monomers with good adhesive strength. Monomers with longer side-chains were found to have less toxicity both in vitro and in vivo. Polymerized hexoxyethyl cyanoacrylate was more elastic than its commercially available and widely used alkyl analog 2-octyl cyanoacrylate, without compromising biocompatibility.
PMCID: PMC4059060  PMID: 21569875
Cyanoacrylates; Tissue adhesives; Surgical glue; Biocompatibility; Mechanical properties
13.  Isolation, differentiation and characterization of vascular cells derived from human embryonic stem cells 
Nature protocols  2010;5(6):1115-1126.
Herein, we describe a protocol for the isolation of human embryonic stem cells (hESCs)-derived vascular cells at various stages of development. The cells are isolated from 10 to 15-d-old human embryoid bodies (EBs) cultured in suspension. After dissociation, cells are labeled with anti-CD34 or anti-CD31 (PECAM1) antibody and separated from the cell mixture by magnetic-activated cell separation (MACS) or fluorescent-activated cell sorting (FACS). Isolated vascular cells are then cultured in media conditions that support specific differentiation and expansion pathways. The resulting vascular cell populations contain > 80% endothelial-like or smooth muscle-like cells. Assuming typical initial cell adhesion and proliferation rates, the entire procedure can be completed within 1.5 months. Vascular cells isolated and differentiated under the described conditions may constitute a potential cell source for therapeutic application toward repair of ischemic tissues, preparation of tissue-engineered vascular grafts and design of cellular kits for drug screening applications.
PMCID: PMC4059065  PMID: 20539287
14.  Evaluation of viscoelastic poly(ethylene glycol) sols as vitreous substitutes in an experimental vitrectomy model in rabbits 
Acta biomaterialia  2010;7(3):936-943.
The aim of this study was to employ an experimental protocol for in vivo evaluation of sols of 5 wt.% poly(ethylene glycol) (PEG) in phosphate-buffered saline as artificial vitreous substitutes. A 20 gauge pars plana vitrectomy and posterior vitreous detachment were performed in the right eye of eight pigmented rabbits. Approximately 1 ml of the viscoelastic PEG sols was then injected into the vitreous space of six eyes. PEG with an average molecular weight of 300,000 and 400,000 g mol−1 was used in two and four eyes, respectively. Two eyes received balanced salt solution and served as controls. Full-field electroretinography was carried out and intra-ocular pressure (IOP, palpation) measured pre- and post-operatively at regular intervals up to 41 days. The rabbits were killed and the eyes examined by retinal photography, gross macroscopic examination and histology. The viscoelastic sols were successfully injected and remained translucent throughout the post-operative period, with some inferior formation of precipitates. None of the eyes displayed IOP elevation post-operatively, but in three of the PEG sol injected eyes transient hypotony was noted. One eye sustained retinal detachment during surgery and another two in the post-operative period. ERG recordings confirmed preservation of retinal function in three out of four eyes injected with 400,000 g mol−1 PEG. Histological examination revealed up-regulation of glial acidic fibrillary protein in Müller cells in PEG sol injected eyes, but normal overall morphology in eyes with attached retinas. The viscosity of the sol was not retained throughout the post-operative period, indicating the demand for polymer cross-linking to increase residence time. The results provide promising preliminary results on the use of PEG hydrogels as a vitreous substitute.
PMCID: PMC4059419  PMID: 21081184
Electrophysiology; Polyethylene oxide; Ophthalmology; Hydrogel; Vitreous
15.  Synergistic Cytotoxicity of Irinotecan and Cisplatin in Dual-Drug PSMA-Targeted Polymeric Nanoparticles 
Nanomedicine (London, England)  2012;8(5):687-698.
Two unexplored aspects for irinotecan and cisplatin (I&C) combination chemotherapy are (1) actively targeting both drugs to a specific diseased cell type and (2) delivering both drugs on the same vehicle to ensure their synchronized entry into the cell at a well-defined ratio. In this work we report the use of targeted polymeric nanoparticles (NPs) to co-encapsulate and deliver I&C to cancer cells expressing the Prostate Specific Membrane Antigen (PSMA).
We prepared targeted NPs in a single-step by mixing four different precursors inside microfluidic devices.
I&C were encapsulated in 55-nm NPs and showed an 8-fold increase in internalization by PSMA-expressing LNCaP cells compared to non-targeted NPs. NPs co-encapsulating both drugs exhibited strong synergism in LNCaP cells with a combination index of 0.2.
The strategy of co-encapsulating both irinotecan and cisplatin in a single NP targeted to a specific cell type could potentially be used to treat different types of cancer.
PMCID: PMC3694785  PMID: 23075285
Nanoparticles; Combination Chemotherapy; Cisplatin; Irinotecan; PSMA
16.  Lipidoid-coated Iron Oxide Nanoparticles for Efficient DNA and siRNA delivery 
Nano letters  2013;13(3):1059-1064.
The safe, targeted and effective delivery of gene therapeutics remains a significant barrier to their broad clinical application. Here we develop a magnetic nucleic acid delivery system composed of iron oxide nanoparticles and cationic lipid-like materials termed lipidoids. Coated nanoparticles are capable of delivering DNA and siRNA to cells in culture. The mean hydrodynamic size of these nanoparticles was systematically varied and optimized for delivery. While nanoparticles of different sizes showed similar siRNA delivery efficiency, nanoparticles of 50–100 nm displayed optimal DNA delivery activity. The application of an external magnetic field significantly enhanced the efficiency of nucleic acid delivery, with performance exceeding that of the commercially available lipid-based reagent, Lipofectamine 2000. The iron oxide nanoparticle delivery platform developed here offers the potential for magnetically guided targeting, as well as an opportunity to combine gene therapy with MRI imaging and magnetic hyperthermia.
PMCID: PMC3992974  PMID: 23394319
siRNA delivery; DNA delivery; iron oxide nanoparticle; magnetofection; gene therapy
17.  Crosslinked Linear Polyethyleneimine Enhances Delivery of DNA to the Cytoplasm 
Crosslinked polyethylenimines (PEIs) have been frequently examined over the past decade since they can maintain the transfection efficiency of commercially available, 25k branched PEI, but exhibit less cytotoxicity. The argument is often made that the degradability of such polymers, generally synthesized with either disulfide or hydrolytically degradable crosslinkers, is critical to the high efficiency and low toxicity of the system. In this work, we present a crosslinked linear PEI (xLPEI) system in which either disulfide-responsive or non-degradable linkages are incorporated. As with previous systems, strong transfection efficiency in comparison with commercial standards was achieved with low cytotoxicity. However, these properties were shown to be present when either the degradable or non-degradable crosslinker was used. Uncomplexed polymer was demonstrated to be the critical factor determining transfection efficiency for these polymers, mediating efficient endosomal escape without signs of cell membrane damage. While several crosslinked PEI systems in the literature have demonstrated the effect of the disulfide moiety, this work demonstrates that disulfide-mediated unpackaging may not be as important as conventionally thought for some PEI systems.
PMCID: PMC3914540  PMID: 22995755
Gene Delivery; Polyethylenimine; Bioresponsive; Reducible; Endosomal Escape
18.  Skin Permeabilization for Transdermal Drug Delivery: Recent Advances and Future Prospects 
Expert opinion on drug delivery  2014;11(3):393-407.
Transdermal delivery has potential advantages over other routes of administration. It could reduce first-pass metabolism associated with oral delivery and is less painful than injections. However, the outermost layer of the skin, the stratum corneum (SC), limits passive diffusion to small lipophilic molecules. Therefore, methods are needed to safely permeabilize the SC so that ionic and larger molecules may be delivered transdermally.
Areas Covered
This review focuses on low-frequency sonophoresis, microneedles, electroporation and iontophoresis, and combinations of these methods to permeabilize the SC. The mechanisms of enhancement and developments in the last five years are discussed. Potentially high-impact applications, including protein delivery, vaccination, and sensing, are presented. Finally, commercial interest and clinical trials are discussed.
Expert Opinion
Not all permeabilization methods are appropriate for all applications. Focused studies into applications utilizing the advantages of each method are needed. The total dose and kinetics of delivery must be considered. Vaccination is one application where permeabilization methods could make an impact. Protein delivery and analyte sensing are also areas of potential impact, although the amount of material that can be delivered (or extracted) is of critical importance. Additional work on the miniaturization of these technologies will help to increase commercial interest.
PMCID: PMC3980659  PMID: 24392787
Cavitation; Drug Delivery; Electroporation; Immunization; Iontophoresis; Microneedles; Microprojections; Penetration Enhancers; Permeabilization; Sonophoresis; Transcutaneous Immunization; Transdermal; Ultrasound; Vaccination
19.  A Stiff Injectable Biodegradable Elastomer 
Advanced functional materials  2012;23(12):1527-1533.
Injectable materials often have shortcomings in mechanical and drug-eluting properties that are attributable to their high water contents. A water-free, liquid four-armed PEG modified with dopamine end groups is described which changed from liquid to elastic solid by reaction with a small volume of Fe3+ solution. The elastic modulus and degradation times increased with increasing Fe3+ concentrations. Both the free base and the water-soluble form of lidocaine could be dissolved in the PEG4-dopamine and released in a sustained manner from the cross-linked matrix. PEG4-dopamine was retained in the subcutaneous space in vivo for up to 3 weeks with minimal inflammation. This material’s tailorable mechanical properties, biocompatibility, ability to incorporate hydrophilic and hydrophobic drugs and release them slowly are desirable traits for drug delivery and other biomedical applications.
PMCID: PMC3646576  PMID: 23667350
Biomedical Applications; Biomimetics; Drug Delivery; Hydrogels; Polymeric Materials
20.  Delivery of Small Interfering RNA for Inhibition of Endothelial Cell Apoptosis by Hypoxia and Serum Deprivation 
RNA interference (RNAi) for anti-angiogenic or pro-apoptotic factors in endothelial cells (ECs) has great potential for the treatment of ischemic diseases by promoting angiogenesis or inhibiting apoptosis. Here, we report the utility of small interfering RNA (siRNA) in inhibiting EC apoptosis induced by tumor necrosis factor-α (TNF-α). siRNA was designed and synthesized targeting tumor necrosis factor-α receptor-1 (TNFR-1) and Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1). Human umbilical vein endothelial cells (HUVECs) were cultured under in vitro hypoxic and serum-deprived conditions to simulate in vivo ischemic conditions. Two days after liposomal delivery of siRNA targeting TNFR-1 and SHP-1, significant silencing of each target (TNFR-1; 76.5 % and SHP-1; 97.2 %) was detected. Under serum-deprived hypoxic (1% oxygen) conditions, TNF-α expression in HUVECs increased relative to normoxic (20% oxygen) and serum-containing conditions. Despite enhanced TNF-α expression, suppression of TNFR-1 or SHP-1 by siRNA delivery not only enhanced expression of angiogenic factors (KDR/Flk-1 and eNOS) and anti-apoptotic factor (Bcl-xL) but also reduced expression of a pro-apoptotic factor (Bax). Transfection of TNFR-1 or SHP-1 siRNA significantly decreased the HUVEC apoptosis while significantly enhancing HUVEC proliferation and capillary formation. The present study demonstrates that TNFR-1 and SHP-1 may be useful targets for the treatment of myocardial or hindlimb ischemia.
PMCID: PMC3957099  PMID: 18765230
RNA interference; Endothelial cell; Hypoxia; Serum Deprivation; Apoptosis
21.  Modular ‘Click-in-Emulsion’ Bone-Targeted Nanogels 
Advanced materials (Deerfield Beach, Fla.)  2012;25(10):10.1002/adma.201202881.
A new class of nanogel demonstrates modular biodistribution and affinity for bone. Nanogels, 67 nm in diameter and synthesized via an astoichiometric click-chemistry-inemulsion method, controllably display residual, free click-able functional groups. Functionalization with a bisphosphonate ligand results in significant binding to bone on the inner walls of marrow cavities, liver avoidance, and anti-osteoporotic effects.
PMCID: PMC3815631  PMID: 23280931
Nanotechnology; Drug delivery; Polymers; Nanogel; Bone
22.  Degradable terpolymers with alkyl side chains demonstrate enhanced gene delivery potency and nanoparticle stability 
Advanced materials (Deerfield Beach, Fla.)  2013;25(10):10.1002/adma.201204346.
PMCID: PMC3824380  PMID: 23293063
Polymer; Lipid; DNA; Nanoparticle; Gene therapy
23.  Three-Dimensional Elastomeric Scaffolds Designed with Cardiac-Mimetic Structural and Mechanical Features 
Tissue Engineering. Part A  2012;19(5-6):793-807.
Tissue-engineered constructs, at the interface of material science, biology, engineering, and medicine, have the capacity to improve outcomes for cardiac patients by providing living cells and degradable biomaterials that can regenerate the native myocardium. With an ultimate goal of both delivering cells and providing mechanical support to the healing heart, we designed three-dimensional (3D) elastomeric scaffolds with (1) stiffnesses and anisotropy mimicking explanted myocardial specimens as predicted by finite-element (FE) modeling, (2) systematically varied combinations of rectangular pore pattern, pore aspect ratio, and strut width, and (3) structural features approaching tissue scale. Based on predicted mechanical properties, three scaffold designs were selected from eight candidates for fabrication from poly(glycerol sebacate) by micromolding from silicon wafers. Large 20×20 mm scaffolds with high aspect ratio features (5:1 strut height:strut width) were reproducibly cast, cured, and demolded at a relatively high throughput. Empirically measured mechanical properties demonstrated that scaffolds were cardiac mimetic and validated FE model predictions. Two-layered scaffolds providing fully interconnected pore networks were fabricated by layer-by-layer assembly. C2C12 myoblasts cultured on one-layered scaffolds exhibited specific patterns of cell elongation and interconnectivity that appeared to be guided by the scaffold pore pattern. Neonatal rat heart cells cultured on two-layered scaffolds for 1 week were contractile, both spontaneously and in response to electrical stimulation, and expressed sarcomeric α-actinin, a cardiac biomarker. This work not only demonstrated several scaffold designs that promoted functional assembly of rat heart cells, but also provided the foundation for further computational and empirical investigations of 3D elastomeric scaffolds for cardiac tissue engineering.
PMCID: PMC3566675  PMID: 23190320
24.  A highly tunable biocompatible and multifunctional biodegradable elastomer 
PMCID: PMC3905612  PMID: 23239051
elastomer; biodegradable polymer; biocompatible; drug delivery; biomacromolecules
25.  Materials for Diabetes Therapeutics 
Advanced healthcare materials  2012;1(3):267-284.
This review is focused on the materials and methods used to fabricate closed-loop systems for type 1 diabetes therapy. Herein, we give a brief overview of current methods used for patient care and discuss two types of possible treatments and the materials used for these therapies–(i) artificial pancreases, comprised of insulin producing cells embedded in a polymeric biomaterial, and (ii) totally synthetic pancreases formulated by integrating continuous glucose monitors with controlled insulin release through degradable polymers and glucose-responsive polymer systems. Both the artificial and the completely synthetic pancreas have two major design requirements: the device must be both biocompatible and be permeable to small molecules and proteins, such as insulin. Several polymers and fabrication methods of artificial pancreases are discussed: microencapsulation, conformal coatings, and planar sheets. We also review the two components of a completely synthetic pancreas. Several types of glucose sensing systems (including materials used for electrochemical, optical, and chemical sensing platforms) are discussed, in addition to various polymer-based release systems (including ethylene-vinyl acetate, polyanhydrides, and phenylboronic acid containing hydrogels).
PMCID: PMC3899887  PMID: 23184741
artificial pancreases; islet encapsulations; alginate hydrogels; glucose responsive polymers; electrochemical and optical glucose sensors

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