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Purpose: Hydrogel composites of oligo(poly(ethylene glycol) fumarate) (OPF) and gelatin microparticles (GMs) were investigated as carriers of bone morphogenetic protein-2 (BMP-2) for bone tissue engineering applications. Methods: Hydrogel composites with different physical characteristics were prepared by changing the amount and type (acidic vs. basic) of gelatin incorporated in the OPF bulk phase. Composites with differing physical properties (degradation, swelling, and mechanical properties) and differing BMP-2 loading phase were investigated to determine the effect of these factors on BMP-2 release profiles over 28 days. Results: Overall, higher gelatin amount increased the degradation and swelling of composites, and acidic GMs further increased the degradation and swelling and reduced the compressive modulus of the composites. The most significant factor affecting the release of BMP-2 from composites was the loading phase of the growth factor: GM loading reduced the burst release, increased BMP-2 release during the later phases of the experiment, and increased the cumulative release in faster degrading samples. Conclusions: The results indicate that the physical properties and the BMP-2 release kinetics of hydrogel composites can be controlled by adjusting multiple parameters at the time of the hydrogel composite fabrication. [ABSTRACT FROM AUTHOR]

Purpose: Formulate phospho-sulindac (P-S, OXT-328) in a Pluronic hydrogel to be used as a topical anti-inflammatory agent and study its efficacy, safety and pharmacokinetics in an arthritis model. Methods: LEW/crlBR rats with Freund's adjuvant-induced arthritis were treated with P-S formulated in Pluronic hydrogel (PSH). We determined the clinical manifestations of arthritis including the locomotor activity of the rats; evaluated joints for inflammation, bone resorption, cartilage damage, COX-2 expression and NF-κB activation; assayed plasma IL-6 and IL-10 levels; and studied the pharmacokinetics of P-S in rats after topical or oral administration. Results: PSH applied at the onset of arthritis or when arthritis was fully developed, suppressed it by 56-82%, improved the locomotor activity of the rats 2.1-4.4 fold, suppressed synovial inflammation, bone resorption, cartilage damage, NF-κB activation and COX-2 expression but not plasma IL-6 and IL-10 levels. There were no side effects. PSH produced rapidly high local levels of P-S with <14% of P-S reaching the circulation, while orally administered P-S was rapidly metabolized generating much lower joint levels of P-S. Conclusions: Topical application of PSH is efficacious and safe in the treatment of Freund's adjuvant-induced arthritis; has a favorable pharmacokinetic profile; and likely acts by suppressing key pro-inflammatory signaling pathways. [ABSTRACT FROM AUTHOR]

Purpose: β-chitin hydrogel/nZnO composite bandage was fabricated and evaluated in detail as an alternative to existing bandages. Methods: β-chitin hydrogel was synthesized by dissolving β-chitin powder in Methanol/CaCl solvent, followed by the addition of distilled water. ZnO nanoparticles were added to the β-chitin hydrogel and stirred for homogenized distribution. The resultant slurry was frozen at 0°C for 12 h. The frozen samples were lyophilized for 24 h to obtain porous composite bandages. Results: The bandages showed controlled swelling and degradation. The composite bandages showed blood clotting ability as well as platelet activation, which was higher when compared to the control. The antibacterial activity of the bandages were proven against Staphylococcus aureus (S. aureus) and Escherichia coli (E.coli). Cytocompatibility of the composite bandages were assessed using human dermal fibroblast cells (HDF) and these cells on the composite bandages were viable similar to the Kaltostat control bandages and bare β-chitin hydrogel based bandages. The viability was reduced to 50-60% in bandages with higher concentration of zinc oxide nanoparticles (nZnO) and showed 80-90% viability with lower concentration of nZnO. In vivo evaluation in Sprague Dawley rats (S.D. rats) showed faster healing and higher collagen deposition ability of composite bandages when compared to the control. Conclusions: The prepared bandages can be used on various types of infected wounds with large volume of exudates. [ABSTRACT FROM AUTHOR]

During the last decades, great efforts have been devoted to design polymers for reducing the toxicity, increasing the absorption, and improving the release profile of drugs. Advantage has been also taken from the inherent multivalency of polymers and dendrimers for the incorporation of diverse functional molecules of interest in targeting and diagnosis. In addition, polymeric hydrogels with the ability to encapsulate drugs and cells have been developed for drug delivery and tissue engineering applications. In the long road to this successful story, pharmaceutical sciences have been accompanied by parallel advances in synthetic methodologies allowing the preparation of precise polymeric materials with enhanced properties. In this context, the introduction of the click concept by Sharpless and coworkers in 2001 focusing the attention on modularity and orthogonality has greatly benefited polymer synthesis, an area where reaction efficiency and product purity are significantly challenged. The purpose of this Expert Review is to discuss the impact of click chemistry in the preparation and functionalization of polymers, dendrimers, and hydrogels of interest in drug delivery. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to deliver both transforming growth factor β3 (TGF-β3) and shRNA targeting type I collagen (Col I) by optimal construction and application of various dual-functioning lentiviral vectors to induce Col I-suppressed chondrogenesis in synovium-derived mesenchymal stem cells (SMSCs). Methods: We constructed four lentiviral vectors (LV-1, LV-2, LV-3 and LV-4) with various arrangements of the two expression cassettes in different positions and orientations. Col I inhibition efficiency and chondrogenic markers were assessed with qPCR, ELISA and staining techniques. Among the four vectors, LV-1 has two distant and reversely oriented cassettes, LV-2 has two distant and same-oriented cassettes, LV-3 has two proximal and reversely oriented cassettes, and LV-4 has two proximal and same-oriented cassettes. Col I and chondrogenic markers, including type II collagen (Col II), aggrecan and glycosaminoglycan (GAG), were examined in SMSCs cultured in 3-D alginate hydrogel. Results: All of the four vectors showed distinct effects in Col I level as well as diverse inductive efficiencies in upregulation of the cartilaginous markers. Based on real-time PCR results, LV-1 was optimal towards Col I-suppressed chondrogenesis. Conclusion: LV-1 vector is competent to promote Col I-suppressed chondrogenesis in SMSCs. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the possibility of using localized nucleic drug delivery methods for the treatment of osteolysis-related bone disease. Methods: A bio-degradable cationic hydrogel composed of gelatin and chitosan was used to deliver an antisense oligonucleotide (ASO) targeting murine TNF-α for the treatment of endotoxin-induced osteolysis. Results: ASO combined with this hydrogel was released when it was digested by adhering cells. The released ASO was efficiently delivered into contacted cells and tissues in vitro and in vivo. When tested in animal models of edotoxin-induced bone resorption, ASO delivered by such means effectively suppressed the expression of TNF-α and subsequently the osteoclastogenesis in vivo. Osteolysis in the edotoxin-induced bone resorption animal models was blocked by the treatment. Conclusion: This is a successful attempt to apply localized gene delivery method to treat inflammatory diseases in vivo. [ABSTRACT FROM AUTHOR]

Purpose: To develop a biomaterial composite for promoting proliferation and migration of neural stem cells (NSCs), as well as angiogenesis on the materials, to rescue central nervous system (CNS) injuries. Methods: A delivery system was constructed based on cross-linked hyaluronic acid (HA) hydrogels, containing embedded BDNF and VEGF-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres for controlled delivery and support for NSCs in the CNS. The surface morphologies were evaluated by SEM and AFM, mechanical property was investigated by rheological tests, and release kinetics were performed by ELISA. Bioactivity of released BDNF and VEGF was assessed by neuron and endothelial cell culture, respectively. Compatibility with NSCs was studied by immunofluorescent staining. Results: Release kinetics showed the delivery of BDNF and VEGF from PLGA microspheres and HA hydrogel composite were sustainable and stable, releasing ~20-30% within 150 h. The bioactivities preserved well to promote survival and growth of the cells. Evaluation of structure and mechanical properties showed the hydrogel composite possessed an elastic scaffold structure. Biocompatibility assay showed NSCs adhered and proliferated well on the hydrogel. Conclusions: Our created HA hydrogel/PLGA microsphere systems have a good potential for controlled delivery of varied biofactors and supporting NSCs for brain repair and implantation. [ABSTRACT FROM AUTHOR]

Purpose: In this study, we evaluated the effect of hydrogel structural properties on proliferation and biosynthesis activity of encapsulated chondrocytes. Methods: Hydrogels with varying structural and mechanical properties were prepared by photopolymerizing PEGDA precursors having MWs of 3.4 kDa, 6 kDa, 10 kDa, and 20 kDa and were characterized for their swelling ratio, network structure, morphology, and mechanical properties. The effect of hydrogel structural properties on the cellular activity of encapsulated chondrocytes was studied over four weeks. Results: Varying the molecular weight of PEGDA precursors exhibited a significant effect on the structural and mechanical properties of the hydrogels. Large mesh size was found to support cell proliferation. However, extracellular matrix (ECM) accumulation varied with the precursor molecular weight. Both PEGDA 6 kDa and 10 kDa hydrogels supported GAG accumulation, while PEGDA 10 kDa and 20KDa hydrogels supported collagen accumulation. Chondrocytes cultured in PEGDA 10 kDa hydrogels expressed a relative increase in collagen type II and aggrecan expression while maintaining low collagen type I expression. Conclusions: Increasing mesh size of the hydrogels resulted in an increase in cellular proliferation exhibiting the strong correlation between mesh size and cell growth, while mesh size had a differential effect on ECM accumulation and expression of cartilage specific markers. [ABSTRACT FROM AUTHOR]

Purpose: To implement a bioinspired methodology using superhydrophobic surfaces suitable for producing smart hydrogel beads in which the bioactive substance is introduced in the particles during their formation. Methods: Several superhydrophobic surfaces, including polystyrene, aluminum and copper, were prepared. Polymeric solutions composed by photo-crosslinked dextran-methacrylated and thermal responsive poly( N-isopropylacrylamide) mixed with a protein (insulin or albumin) were dropped on the superhydrophobic surfaces, and the obtained millimetric spheres were hardened in a dry environment under UV light. Results: Spherical and non-sticky hydrogels particles were formed in few minutes on the superhydrophobic surfaces. The proteins included in the liquid formulation were homogeneously distributed in the particle network. The particles exhibited temperature-sensitive swelling, porosity and protein release rate, with the responsiveness tunable by the dextran-MA/PNIPAAm weight ratio. Conclusions: The proposed method permitted the preparation of smart hydrogel particles in one step with almost 100% encapsulation yield. The temperature-sensitive release profiles suggest that the obtained spherical-shaped biomaterials are suitable as protein carriers. These stimuli-responsive beads could have potential to be used in pharmaceutical or other biomedical applications, including tissue engineering and regenerative medicine. [ABSTRACT FROM AUTHOR]

Purpose: A challenge in the field of nanobubbles, including lipobubbles and polymeric nanobubbles, is identification of formulation approaches to enhance circulation time or 'bubble life' in the specific organ to allow for organ visualization. The aim of this study was to investigate the potential of two specific preparation approaches, polymeric surface modification to lipobubbles and a one-step approach for the preparation of ionotropically originated polymeric hydrogel nanobubbles for the production of biocompatible, biodegradable, and sufficiently echogenic ('flexible') bubbles, preferably within the nanometer range, that possess an enhanced in vivo lifetime compared to an unmodified lipobubble to allow visualization of the lymph node vasculature. Methods: In the first approach, formed liposomes (basic and polymerically enhanced) were sequentially layered with appropriate cationic and anionic polyelectrolytes followed by transformation into polymer-coated nanobubbles. In addition, a one-step approach was employed for the fabrication of ionotropically originated polymeric hydrogel bubbles. Results: Bubble lifetime was marginally enhanced by self-deposition of polyelectrolytes onto the normal lipobubble, however, not significantly ( P = 0.0634). In general, formulations possessing a higher ratio of anionic:cationic coats and highly anionic overall surface charge (−20.62 mV to −17.54 mV) possessed an enhanced lifetime. The improvement in bubble lifetime was significant when a purely polymeric polyionic hydrogel bubble shell was instituted compared to a normal unmodified lipobubble ( P = 0.004). There was enhanced persistence of these systems compared to lipobubbles, attributed to the highly flexible, interconnected hydrogel shell which minimized gas leakage. The prolonged contrast signal may also be attributed to a degree of polymeric deposition/endothelial attachment. Conclusions: This study identified the relevance of polymeric modifications to nanobubbles for an improved circulating lifetime, which would be essential for application of these systems in passive drug or gene targeting via the enhanced permeability and retention effect. [ABSTRACT FROM AUTHOR]

Purpose: In vitro and in vivo permeation studies were conducted to evaluate the characteristic of percutaneous administration of high hydrophilic drug L-carnitine (LC) by Functional MicroArray (FMA) painless intradermal delivery system. Methods: In vitro study was designed to assess the effects of various skins, donor concentration and hydrogels from different carbomer derivatives on the release of LC in a Franz-type diffusion cell. The LC gel patches with carbomer 980 P were prepared and successfully applied to pharmacokinetic study of SD rats with and without FMA. Intravenous injection and oral administration were performed to support pharmacokinetic calculations and comparison of bioavailability. Results: Enhanced delivery of LC using FMA was achieved in skin of different species in vitro studies. The 750 mg LC gel patches were applied to rats over 6 h, and approximately 27% of loaded dose was transported into rat. A 2.8-fold enhancement of absolute bioavailability for LC with FMA intradermal delivery system was observed compared with oral LC administration in vivo study. Conclusions: Both in vitro and in vivo studies demonstrated that the FMA intradermal delivery system can enhance the delivery and bioavailability of LC. [ABSTRACT FROM AUTHOR]

Abstract Purpose  To elucidate the key parameters affecting solute transport from semi-interpenetrating networks (sIPNs) comprised of poly(ethylene glycol) diacrylate (PEGdA) and gelatin that are partially crosslinked, water-swellable and biodegradable. Effects of material compositions, solute size, solubility, and loading density have been investigated. Materials and Methods  sIPNs of following gelatin/PEGdA weight-to-weight ratios were prepared: 10:15, 10:20, 10:30, 15:15, 20:15. Five model solutes of different physicochemical properties were selected, i.e. silver sulfadiazine (AgSD), bupivacaine hydrochloride (Bup), sulfadiazine sodium (NaSD), keratinocyte growth factor (KGF), and bovine serum albumin conjugated with fluorescein isothiocyanate (BSA-FITC). Release studies were performed and the results were analyzed using three hydrogel based common theories (free volume, hydrodynamic and obstruction). Results  The release kinetics of model solutes was influenced by each factor under investigation. Specifically, the initial release rates and intra-gel diffusivity decreased with increasing PEGdA content or increasing solute molecular weight. However, the initial release rate and intra-gel diffusivity increased with increasing gelatin content or increasing solute water solubility, which contradicted with the classical hydrogel based solute transport theories, i.e. increasing polymer volume leads to decreased solute diffusivity within the gel. Conclusion  This analysis provides structure-functional information of the sIPN as a potential therapeutic delivery matrix. [ABSTRACT FROM AUTHOR]

Abstract Purpose  To develop paclitaxel-delivering PLGA microspheres entrapped in a gel matrix with sustained drug release properties and implantability advantages for local glioma chemotherapy. Methods  Paclitaxel-loaded PLGA microspheres were fabricated using electrohydrodynamic atomization and entrapped by electrospray and gelation. The physicochemical characterizations were performed using scanning electron microscopy and differential scanning calorimetry. The influence of various parameters on the disintegration time was investigated. In vitro release of paclitaxel was quantified using high performance liquid chromatography. Cytotoxicity of the formulations was assessed by the quantification of IC50 and caspase-3 activity against C6 glioma cells in vitro. The formulations were tested against a subcutaneous C6 glioma tumour in mice. Results  Highly monodisperse gel beads containing a uniform microsphere distribution were obtained. Gelation using Ca2 ions ensured entrapment of microspheres with high loading efficiency. With an increase in the gelation time, gelling bath concentration and decrease in microsphere loading, it was more difficult to disintegrate the beads and release the microspheres. The formulations demonstrated sustained drug release for more than 60 days at a near-constant rate and a low initial burst. Cell culture studies proved the cytotoxicity against C6 glioma and improved performance in comparison to Taxol®. The formulations could reduce subcutaneous tumour volume to a greater extent compared to Taxol® and the control. Conclusions  Paclitaxel-loaded PLGA microspheres entrapped in an alginate gel matrix could be potential local chemotherapy implants to treat malignant glioma with critical advantages of implantability and sustained drug release with low initial burst. [ABSTRACT FROM AUTHOR]

Abstract  Anatomy and physiology of the eye makes it a highly protected organ. Designing an effective therapy for ocular diseases, especially for the posterior segment, has been considered as a formidable task. Limitations of topical and intravitreal route of administration have challenged scientists to find alternative mode of administration like periocular routes. Transporter targeted drug delivery has generated a great deal of interest in the field because of its potential to overcome many barriers associated with current therapy. Application of nanotechnology has been very promising in the treatment of a gamut of diseases. In this review, we have briefly discussed several ocular drug delivery systems such as microemulsions, nanosuspensions, nanoparticles, liposomes, niosomes, dendrimers, implants, and hydrogels. Potential for ocular gene therapy has also been described in this article. In near future, a great deal of attention will be paid to develop non-invasive sustained drug release for both anterior and posterior segment eye disorders. A better understanding of nature of ocular diseases, barriers and factors affecting in vivo performance, would greatly drive the development of new delivery systems. Current momentum in the invention of new drug delivery systems hold a promise towards much improved therapies for the treatment of vision threatening disorders. [ABSTRACT FROM AUTHOR]

Abstract Purpose  Current dry eye treatment includes delivering comfort agents to the eye via drops, but low bioavailability and multiple administration continues to be a barrier to effective treatment. There exists a significant unmet need for devices to treat dry eye and for more comfortable contact lenses. Methods  Using molecular imprinting strategies with an analysis of biology, we have rationally designed and synthesized hydrogel contact lenses that can release hyaluronic acid (HA) at a controlled rate. Results  Delayed release characteristics were significantly improved through biomimetic imprinting, as multiple functional monomers provided non-covalent complexation points within nelfilcon A gels without altering structural, mechanical, or optical properties. The diffusion coefficient of 1.2 million Dalton HA was controlled by varying the number and variety of functional monomers (increasing the variety lowered the HA diffusion coefficient 1.5 times more than single functional monomers, and 1.6 times more than nelfilcon A alone). Conclusions  HA can be delivered from a daily disposable lens at a therapeutic rate of approximately 6 μg/h for 24 h. This is the first demonstration of imprinting a large molecular weight polymer within a hydrogel and the effect of imprinting on the reptation of the long chain macromolecule from the structure. [ABSTRACT FROM AUTHOR]

Abstract Purpose  This work evaluated the feasibility of combining insulin PEGylation with pH responsive hydrogels for oral insulin delivery. Methods  A mono-substituted PEG–insulin conjugate was synthesized and purified. The site of conjugation was determined by MALDI-TOF MS. Uptake and release of PEGylated insulin was performed in complexation hydrogels to simulate oral dosing. The bioactivity of the conjugate and PK/PD profile was measured in vivo in rats. Results  PEGylation was confirmed to be specifically located at the amino terminus of the B-chain of insulin. Higher loading efficiency was achieved with PEGylated insulin than regular human insulin in pH responsive hydrogels. The release of PEGylated insulin was lower than that of human insulin at all pH levels considered. Full retention of bioactivity of the PEG–insulin conjugate was confirmed by intravenous dosing while subcutaneous dosing exhibited a relative hypoglycemic effect 127.8% that of human insulin. Conclusions  Polyethylene glycol conjugated specifically to the amino terminus of the B-chain of insulin maintained the bioactivity of the protein and significantly extended the duration of the hypoglycemic effect. Used in combination with pH responsive hydrogels, PEGylated insulin has significant potential for oral delivery. [ABSTRACT FROM AUTHOR]

Abstract  Polyethylene glycol (PEG) hydrogels are widely used in a variety of biomedical applications, including matrices for controlled release of biomolecules and scaffolds for regenerative medicine. The design, fabrication, and characterization of PEG hydrogels rely on the understanding of fundamental gelation kinetics as well as the purpose of the application. This review article will focus on different polymerization mechanisms of PEG-based hydrogels and the importance of these biocompatible hydrogels in regenerative medicine applications. Furthermore, the design criteria that are important in maintaining the availability and stability of the biomolecules as well as the mechanisms for loading of biomolecules within PEG hydrogels will also be discussed. Finally, we overview and provide a perspective on some of the emerging novel design and applications of PEG hydrogel systems, including the spatiotemporal-controlled delivery of biomolecules, hybrid hydrogels, and PEG hydrogels designed for controlled stem cell differentiation. [ABSTRACT FROM AUTHOR]

Abstract Purpose  To demonstrate remote controlled degradation of degradable nanocomposite hydrogels by application of an alternating magnetic field (AMF). Further, it was desired to study the AMF effect on the drug release properties of these systems. Methods  Degradable nanocomposite hydrogels were synthesized by incorporating iron oxide nanoparticles into a degradable hydrogel that exhibited temperature dependent degradation. Heating, degradation, and drug release studies were conducted by application of an AMF to determine if modulation of degradation and drug release could be attained. Results  Hydrogels were successfully prepared, shown to have temperature dependent degradation, and shown to heat when exposed to the AMF. The degradation rate of the exposed samples was demonstrated to be higher than control samples, thus modulation of degradation was obtained. The release of a model drug from the system was modulated by exposure to the AMF. Conclusions  This is the first demonstration of remote controlled degradation using an AMF stimulus. Here, the proof of the concept has been presented, and there is great potential to enhance this effect through various methods. The ability to remotely control degradation of an implanted device opens a new area of improved medical devices. [ABSTRACT FROM AUTHOR]

Abstract Purpose  To study the ultrastructure of biorelevant media and digestion products of self-nanoemulsifying drug delivery system (SNEDDS) at high level BS/PL conditions. Methods  Cryogenic transmission electron microscopy (Cryo-TEM) was employed to visualize the colloid structures in the biorelevant media and lipolytic products generated during hydrolysis of a SNEDDS formulation. Their electrical properties were investigated by measuring their ζ-potential values. Results  In the biorelevant media, vesicles (either unilamellar or multilamellar) and bilayer fragments are visualized. Occasionally, vesicles with an internal deformed structure are recognized, suggesting surface tension or uneven lateral stress. Visualization studies of the intermediate colloidal phases produced during digestion of a SNEDDS using the in vitro lipolysis model revealed the formation of similar structures as previously reported. The ζ-potential of the media was negatively charged and decreased from −23 to −35 mV with increasing surfactant/lipid load. Lower ζ-potential values (−16 mV) obtained for the structures formed during the lipid hydrolysis of the SNEDDS were probably due to the presence of calcium, which shields the surface, thereby reducing the charge. Conclusions  The diversity of these vesicles in terms of size, lamellarity, and internal organization advocate their important role during lipid digestion in the gastrointestinal milieu. [ABSTRACT FROM AUTHOR]

Abstract Purpose  Synthetic hydrogels fabricated from photopolymerization are attractive for tissue engineering for their controlled macroscopic properties, the ability to incorporate biological functionalities, and cell encapsulation. The goal of the present study was to exploit the attractive features of synthetic hydrogels to elucidate the role of gel structure and chemistry in regulating biomechanical cues. Methods  Cartilage cells were encapsulated in poly(ethylene glycol) (PEG) hydrogels with different crosslinking densities. Cellular deformation was examined as a function of gel crosslinking. The effects of continuous versus intermittent dynamic loading regimens were examined. RGD, a cell adhesion peptide, was incorporated into PEG gels and subjected to mechanical loading. Chondrocyte morphology and activity was assessed by anabolic and catabolic ECM gene expression and matrix production by collagen and glycosaminoglycan production. Results  Cell deformation was mediated by gel crosslinking. In the absence of loading, anabolic activity was moderately upregulated while catabolic activity was significantly inhibited regardless of gel crosslinking. Dynamic loading enhanced anabolic activities, but continuous loading inhibited catabolic activity, while intermittent loading stimulated catabolic activity. RGD acted as a mechanoreceptor to influence tissue deposition. Conclusions  We demonstrate the ability to regulate biomechanical cues through manipulations in the gel structure and chemistry and cartilage tissue engineering. [ABSTRACT FROM AUTHOR]