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Abstract: The anticancer drug cisplatin was encapsulated within the cucurbit[7]uril macrocycle to form the host-guest complex: cisplatin@CB[7]. This was then incorporated into gelatin and 0–4% w/v polyvinyl alcohol (PVA)-based hydrogels as slow release drug delivery vehicles. The hydrogels demonstrated predicable swelling and disintegration dependent on the PVA concentration. The hydrogel with the highest PVA content was slower to swell and release drug compared with lower concentrations of PVA. The effect of the hydrogel PVA concentration on in vitro cytotoxicity was examined using A2780/CP70 ovarian cancer cells. Over the 24h drug exposure time used, hydrogels containing 4% PVA showed a 20% decrease in viable cells compared to the control, whereas hydrogels containing 0% and 2% PVA induced an 80% and 45% inhibition of cell growth, respectively. There was no measurable difference in the in vitro cytotoxicity of free cisplatin and cisplatin@CB[7] containing hydrogels. Finally, the in vivo effectiveness of a 2%-PVA hydrogel implanted under the skin of nude mice bearing A2780/CP70 xenografts showed that low dose hydrogels containing cisplatin@CB[7] (30μg equivalent of drug) was just as effective as an intraperitoneal high dose administration of free cisplatin (150μg) at inhibiting tumour growth. [Copyright &y& Elsevier]

Abstract: The development of high-resolution neuroprosthetics has driven the need for better electrode materials. Approaches to achieve both electrical and mechanical improvements have included the development of hydrogel and conducting polymer composites. However, these composites have limited biological interaction, as they are often composed of synthetic polymers or non-ideal biological polymers, which lack the required elements for biorecognition. This study explores the covalent incorporation of bioactive molecules within a conducting hydrogel (CH). The CH was formed from the biosynthetic co-hydrogel poly(vinyl alcohol)–heparin and the conductive polymer (CP), poly(3,4-ethylene dioxythiophene). Adhesive biomolecules sericin and gelatin were covalently incorporated via methacrylate crosslinking within the CH. Electrical properties of the bioactive CH were assessed, and it was shown that the polar biomolecules improved charge transfer. The bioactivity of heparin within the hybrid assessed by examining stimulation of B-lymphocyte (BaF3) proliferation showed that bioactivity was retained after electropolymerization of the CP through the hydrogel. Similarly, incorporation of sericin and gelatin in the CH promoted neural cell adhesion and proliferation, with only small percentages (⩽2wt.%) required to achieve optimal results. Sericin provided the best support for the outgrowth of neural processes, and 1wt.% was sufficient to facilitate adhesion and differentiation of neurons. The drug delivery capability of CH was shown through incorporation of nerve growth factor during polymer fabrication. NGF was delivered to the target cells, resulting in outgrowth of neural processes. The CH system is a flexible technology platform, which can be tailored to covalently incorporate bioactive protein sequences and deliver mobile water-soluble drug molecules. [Copyright &y& Elsevier]

Abstract: A novel degradable microsphere (MS) for intra-articular drug delivery, composed of a polyethylene glycol (PEG) core containing degradable regions made of short poly-(lactic-co-glycolic acid) (PLGA) sequences – named PEG-hydrogel MS – was injected into the cavity of sheep shoulder joint, and compared to non-degradable MS devoid of hydrolysable crosslinker in terms of location, degradation and inflammation. One week after intra-articular injection both groups of MS were localized beneath the synovial lining of the synovial fringes located at bottom of the shoulder joint, while a fraction of particles remained in synovial fluid. Histological analyses made one and 4 weeks after intra-articular injection showed cell proliferation around the non-degradable MS entrapped within the synovium. By contrast, degradable PEG-hydrogel MS were surrounded by few cells. The degradation of degradable PEG-hydrogel MS within the synovium was slow and was not fully complete after four weeks. Our findings indicate that the tissue entrapment of MS below the synovial lining was independent of the material degradability, while degradable PEG-hydrogel MS are less inflammatory than the non-degradable one. Degradable PEG-hydrogel MS offer several advantages over the non-degradable MS as carriers for a sustained drug delivery in synovial tissue according to the low intensity of inflammatory reaction triggered in synovium. [Copyright &y& Elsevier]

Highlights: [•] PMMA NPs were prepared by emulsion free radical polymerization. [•] NPs were loaded in chemical cross-linked hydrogels to guarantee suitable drug release profiles. [•] Different sized NPs were loaded in different entangled hydrogels to create a tunable material library. [•] Mathematical model provides a complete understanding of material library behavior. [•] In vivo studies were performed to confirm in vitro release kinetics. [Copyright &y& Elsevier]

Abstract: Objective: We have recently developed a novel inner ear drug delivery system using chitosan glycerophosphate (CGP) hydrogel loaded with drugs commonly used for treatment of inner ear diseases, significantly improving the drugs'' sustained delivery. The goal of this study is to evaluate the effectiveness of chitosanase as a “switch off” mechanism for this drug delivery system when side effects and potential ototoxicities appear during treatment. To evaluate this effect, we tested gentamicin (GENT) in the inner ear following CGP delivery with/without regulation. Methods: Purified chitosanase was obtained and used for regulating the CGP delivery system. In vitro studies were performed to evaluate the effect of the interaction between chitosanase and CGP-hydrogel loaded with GENT or Texas Red-labeled GENT (GTTR). In vivo studies were performed using our mouse model to investigate the regulatory effect of chitosanase application on the delivery of GENT to the inner ear. To assess the potential drug rerouting regulatory effect of chitosanase the GTTR fluorescence intensity was evaluated at the round window niche (RWN) and the Eustachian tube (ET). To further characterize this regulatory effect, GENT concentration in the perilymph of the inner ear was analyzed by chromatographic tandem mass spectrometry (LC–MS/MS), and the uptake in the inner ear cells was measured using fluorescence microscopy following CGP delivery with/without chitosanase application. Results: The chitosanase effectively digested the CGP-hydrogel, quickly releasing GENT and GTTR from the system in vitro. When reacted with GENT alone chitosanase did not produce any reducing sugars and did not affect GENT''s antimicrobial activity. In vivo GTTR was effectively rerouted from the RWN to the ET, limiting its uptake in inner ear hair cells. Concurrent with these findings, GENT concentration in the inner ear perilymph was significantly decreased after chitosanase application. Conclusion: Our study findings suggest that, for the first time, sustained and controlled inner ear drug delivery can be successfully regulated enhancing its translation potential for clinical application. The use of chitosanase to digest the CGP-hydrogel results in the rerouting of the loaded drug away from the RWN, effectively downregulating its delivery to the inner ear. This important modification to our drug delivery system has the ability to deliver therapy to the inner ear until desired effect is achieved and to stop this process when side effects or treatment-related ototoxicities start to occur, providing a novel and salient approach for safe and effective delivery to the inner ear. [Copyright &y& Elsevier]

Abstract: The aim of this work was to develop mucoadhesive hydrogels with variable drug delivery properties by crosslinking poly(acrylic acid) (PAA) with cyclodextrins (CDs). CD-PAA polymers with high CD content and good inter-batch reproducibility were synthesized by activating PAA with SOCl2, then reacting PAA chloride with CD in the presence of 4-dimethylaminopyridine at 50°C. Manipulation of the synthesis conditions affected the physicochemical character of the CD-PAA polymers and hydrogels in terms of CD content, the average number of ester bonds to an individual CD, viscosity, and the association and release of model drugs. Inclusion complexation of diflunisal (DIF) and fluconazole (FLZ) with CD-PAA hydrogels was assessed by 19F NMR spectroscopy and association constants (K a s) for DIF were in the range 220–486M−1 with βCD-PAA and 1327–6055M−1 with hydroxypropyl-βCD-PAA. For FLZ the K a range was 34–171M−1 with hydroxypropyl-βCD-PAA. The hydrogels were found to release both drugs by means of Fickian diffusion as the predominant mechanism. A slight trend toward negative correlation was found between the K a and Higuchi k H values for DIF. These results highlight the potential of CD-PAA hydrogels to control the release of model drugs through inclusion complexation. [Copyright &y& Elsevier]

Abstract: There is a clear need for methods to provide a safe controlled release of therapeutic proteins, either to achieve and maintain high local protein concentrations, or for sustained systemic delivery. We have developed a protein delivery system that combines in situ cross-linkable polysaccharide hydrogels with gelatin. This formulation is injectable, easy to apply, and obviates the need for organic solvents or potentially toxic cross-linking agents in the formulation process. The cross-linked polysaccharides themselves (comprising hyaluronic acid, dextran and/or carboxymethylcellulose) provided prolonged release of fluorescently labeled albumin (FITC-albumin). The duration of release was markedly extended by the incorporation of gelatin into the formulation: FITC-albumin and interleukin-2 (IL-2) were released over the course of more than 3weeks. The IL-2 maintained >70% activity throughout that time. Gelatin also accelerated the gelation time of the hydrogels, and reduced their swelling in phosphate-buffered saline. The composite hydrogel (dextran–carboxymethylcellulose–gelatin) showed minimal cytotoxicity in vitro, and benign tissue reaction after subcutaneous injection in rats. [Copyright &y& Elsevier]

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]

Abstract: Intraperitoneal (IP) chemotherapy is an effective way of treating local and regional malignancies confined in the peritoneal cavity such as ovarian cancer. However, a persistent major challenge in IP chemotherapy is the need to provide effective drug concentrations in the peritoneal cavity for an extended period of time. We hypothesized that hyaluronic acid (HA)-based in-situ crosslinkable hydrogel would serve as a carrier of paclitaxel (PTX) particles to improve their IP retention and therapeutic effects. In-vitro gel degradation and release kinetics studies demonstrated that HA gels could entrap microparticulate PTX (>100μm) and release the drug over 10days, gradually degraded by hyaluronidase, but had limited effect on retention of Taxol, a 14-nm micelle form of PTX. When administered IP to tumor-bearing nude mice, PTX was best retained in the peritoneal cavity as PTX-gel (microparticulate PTX entrapped in the HA gel), whereas Taxol-gel and other Taxol-based formulations left negligible amount of PTX in the cavity after 14days. Despite the increase in IP retention of PTX, PTX-gel did not further decrease the tumor burdens than Taxol-based formulations, presumably due to the limited dissolution of PTX. This result indicates that spatial availability of a drug does not necessarily translate to the enhanced anti-tumor effect unless it is accompanied by the temporal availability. [Copyright &y& Elsevier]

Abstract: Biomaterials for the precise control of protein release are important to the development of new strategies for treating human diseases. This study aimed to fundamentally understand aptamer–protein dissociation triggered by complementary oligonucleotides, and to apply this understanding to develop affinity hydrogels for controlled protein release. The results showed that the oligonucleotide tails of the aptamers played a critical role in inducing intermolecular hybridization and triggering aptamer–protein dissociation. In addition, the attachment of the oligonucleotide tails to the aptamers and the increase of hybridizing length could produce a synergistic effect on the dissociation of bound proteins from their aptamers. More importantly, pegylated complementary oligonucleotides could successfully trigger protein release from the aptamer-functionalized hydrogels at multiple time points. Based on these results, it is believed that aptamer-functionalized hydrogels and complementary oligonucleotides hold great potential of controlling the release of protein drugs to treat human diseases. [Copyright &y& Elsevier]

Abstract: One of the challenges in treating central nervous system (CNS) disorders with biomolecules is achieving local delivery while minimizing invasiveness. For the treatment of stroke, stimulation of endogenous neural stem/progenitor cells (NSPCs) by growth factors is a promising strategy for tissue regeneration. Epidermal growth factor (EGF) enhances proliferation of endogenous NSPCs in the subventricular zone (SVZ) when delivered directly to the ventricles of the brain; however, this strategy is highly invasive. We designed a biomaterials-based strategy to deliver molecules directly to the brain without tissue damage. EGF or poly(ethylene glycol)-modified EGF (PEG-EGF) was dispersed in a hyaluronan and methylcellulose (HAMC) hydrogel and placed epi-cortically on both uninjured and stroke-injured mouse brains. PEG-modification decreased the rate of EGF degradation by proteases, leading to a significant increase in protein accumulation at greater tissue depths than previously shown. Consequently, EGF and PEG-EGF increased NSPC proliferation in uninjured and stroke-injured brains; and in stroke-injured brains, PEG-EGF significantly increased NSPC stimulation. Our epi-cortical delivery system is a minimally-invasive method for local delivery to the brain, providing a new paradigm for local delivery to the brain. [Copyright &y& Elsevier]

Abstract: Using vitamin C as a model drug we focus our attention to the experimental and theoretical investigation of swelling equilibria of ternary system made from water, cross-linked poly (N-isopropylacrylamide) and vitamin C. This contribution aims to the prediction of the amount of drug uptake by the hydrogel using a thermodynamic model and independent experimental information, like the demixing behavior of linear polymer in water and in aqueous vitamin C solutions as well as the solubility of vitamin C in water. As theoretical approach a combination of the Koningsveld–Kleintjens model for the Gibbs energy of mixing and the affine network theory for the elasticity of the gel is applied. The model shows an excellent performance in the prediction of the degree of swelling as function of vitamin C concentration and in the amount of drug in the hydrogel. Only for the calculation of the temperature dependency two parameters must be refitted slightly in order to achieve quantitative agreement with the experimental data. From the experimental point of view some hysteresis effects, growing with increasing vitamin C concentration are found, especially in the transformation range. [Copyright &y& Elsevier]

Abstract: The goal of this study was to develop a polymeric carrier for delivery of anti-tumor drugs and sustained release of these agents in order to optimize anti-tumor activity while minimizing systemic effects. We used oligo(poly(ethylene glycol) fumarate) (OPF) hydrogels modified with small negatively charged molecules, sodium methacrylate (SMA), for delivery of doxorubicin (DOX). SMA at different concentrations was incorporated into the OPF hydrogel with a photo-crosslinking method. The resulting hydrogels exhibited sensitivity to the pH and ionic strength of the surrounding environment. Our results revealed that DOX was bound to the negatively charged hydrogel through electrostatic interaction and was released in a timely fashion with an ion-exchange mechanism. Release kinetics of DOX was directly correlated to the concentration of SMA in the hydrogel formulations. Anti-tumor activity of the released DOX was assessed using a human osteosarcoma cell line. Our data revealed that DOX released from the modified, charged hydrogels remained biologically active and had the capability to kill cancer cells. In contrast, control groups of unmodified OPF hydrogels with or without DOX did not exhibit any cytotoxicity. This study demonstrates the feasibility of using SMA-modified OPF hydrogels as a potential carrier for chemotherapeutic drugs for cancer treatments. [ABSTRACT FROM AUTHOR]

Abstract: Major traumatic spinal cord injury (SCI) results in permanent paralysis below the site of injury. The effectiveness of systemically delivered pharmacological therapies against SCI can be limited by the blood–spinal cord barrier and side effects. Local drug delivery to the injured spinal cord can be achieved using a minimally invasive biopolymer matrix of hyaluronan and methylcellulose injected into the intrathecal space, bypassing the blood–spinal cord barrier and overcoming limitations of existing strategies. Composite hydrogels of drug-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles dispersed in this biopolymer matrix meet the in vitro design criteria for prolonged local release. Using a blank (without drug) composite designed for 28-day sustained release, we presently explore the mechanism of particle-mediated hydrogel stabilization in vitro and aspects of biocompatibility and safety in vivo. The composite hydrogel is well tolerated in the intrathecal space of spinal cord injured rats, showing no increase in inflammation, scarring, or cavity volume relative to controls, and no significant effect on locomotor function up to 28 days. Furthermore, there was no effect on locomotor function in healthy animals which received the composite hydrogel, although a qualitative increase in ED-1 staining was apparent. These data support the further development of composite hydrogels of hyaluronan and methylcellulose containing PLGA nanoparticles for sustained local delivery to the injured spinal cord, an application for which there are no approved alternatives. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, a novel class of microspheric hydrogels was synthesized by grafting of N-isopropyacrylamide (NIPAAm) with gelatin. The possibility of inserting commercial gelatin in a crosslinked structure bearing thermo-sensitive moieties, by radical process, represents an interesting innovation that significantly improves the device performance, opening new applications in biomedical and pharmaceutical fields. This synthetic approach allows a modification of the polymeric network composition, producing hydrogels with suitable physico-chemical properties and a transition temperature higher than NIPAAm homopolymers. The incorporation of monomers into the network was confirmed by infrared spectroscopy, and the composition of the polymerization feed was found to strictly influence the network density and the shape of hydrogels. Thermal analyses showed negative thermo-responsive behaviour with shrinking/swelling transition values in the temperature range 34.6–34.8°C, according to the amount of the hydrophilic portions in the network. In order to test the preformed materials as drug carriers, diclofenac sodium salt was loaded into the spherical microparticles. After the determination of the drug entrapment percent, drug release profiles in media at different temperature were analysed. By using semi-empirical equations, the release mechanism was extensively studied and the diffusional contribution was evaluated. [ABSTRACT FROM AUTHOR]

Abstract: Osteomyelitis characterized by an inflammatory response often leads to bone loss and the spread of bacterial infection to surrounding soft tissues. To overcome the side effects induced by the systemic antibiotic treatment for osteomyelitis, recent investigations have explored the use of antibiotic-loaded undegradable or biodegradable delivery implants at the infected bone. Here, we show a novel biodegradable thermosensitive implant composed of poly(ethylene glycol) monomethyl ether (mPEG) and poly(lactic-co-glycolic acid) (PLGA) copolymer as a sol–gel drug delivery system for treating bone infection. The physical properties of a series of mPEG–PLGA nanocomposites, including the critical micelle concentration (CMC), particle size, polyindex (PI), sol–gel transition, viscosity and degradation rate, have been characterized in vitro. This sol-to-gel drug delivery system could provide several advantages in treating osteomyelitis, including easy preparation, 100% encapsulated rate, near-linear sustained release of drugs, injectable design and in situ gelling at the target tissue. Similar to the undegradable teicoplanin-impregnated polymethylmethacylate (PMMA) bone cements, we showed that implantation of the mPEG–PLGA hydrogel containing teicoplanin was effective for treating osteomyelitis in rabbits as detected by the histological staining and immunoblotting analyses. The use of the mPEG–PLGA-based biodegradable hydrogels may hold great promise as a therapeutic strategy for other infected diseases. [Copyright &y& Elsevier]

Abstract: Serum albumin acts as a physiological carrier for various compounds including drugs. A hydrogel consisting of recombinant human serum albumin (rHSA) was prepared to take advantage of drug binding ability of albumin for a sustained drug release carrier. The hydrogel was prepared by mixing rHSA and dithiothreitol and casted to a polystyrene mold. Hydrogel formation was thought to occur through the intermolecular interaction of the hydrophobic groups by protein denaturation. The release of sodium benzoate and salicylic acid from the hydrogel completed in 2h, while warfarin release continued for 24h. The total amounts of the drugs released from 100mg of 15 and 5% rHSA hydrogel were 2.3 and 1.4μmol for warfarin, 1.4 and 1.1μmol for salicylic acid and 0.9 and 0.9μmol for sodium benzoate. These results reflected the order of the binding ability of drugs for intact albumin indicating that the drug binding ability of HSA still remained after the hydrogel formation. However, fibroblast cells attached and proliferated well on the hydrogel, indicating that denaturation of rHSA proceeded to the extent to allow the cell attachment. The present rHSA hydrogel might be suitable for a sustained release carrier of drugs having affinity for albumin. [Copyright &y& Elsevier]

Abstract: Cyclodextrin-based hydrogels were synthesized to create robust networks with tunable mechanical properties capable of serving as device coatings. The CD networks were able to swell and load drug in aqueous and organic solvents. The rheological properties of the swollen gels were investigated using stress and frequency sweeps, with both demonstrating high storage modulus, indicating strong elastic gels. The ability of the gels to swell in numerous solvents allowed for the separate loading and release of different antibiotic drug molecules with varying hydrophilicities. Based on FTIR and TGA studies, each drug was found to form an inclusion complex with CD. For comparison, dextran gels were prepared similarly. As expected for affinity-based mechanisms, the release of drugs from the CD-based gels was slower than diffusion-based release from the dextran gels, and could be sustained for more than 200h. Coating potential was tested by coating two different medical devices: metal screws and polymer meshes. The meshes were characterized by SEM, revealing that CD-based coatings resulted in a uniform thin film, whereas the dextran gels only partly coated the device and showed delamination. Considerably longer bactericidal activity against Staphylococcus aureus was observed for both the CD hydrogels and coatings, as compared to dextran-based ones. The slow, sustained, affinity-based release of antibiotics from the CD-based networks reflects their potential as a delivery platform. [Copyright &y& Elsevier]

Abstract: Hyaluronic acid (HA) is a biodegradable, biocompatible, non-toxic, non-immunogenic and non-inflammatory linear polysaccharide, which has been used for various medical applications such as arthritis treatment, ocular surgery, tissue augmentation, and so on. In this review, the effect of chemical modification of HA on its distribution throughout the body was reported for target specific and long-acting delivery applications of protein, peptide, and nucleotide therapeutics. According to the real-time bio-imaging of HA derivatives using quantum dots (QDot), HA–QDot conjugates with 35mol% HA modification maintaining enough binding sites for HA receptors were mainly accumulated in the liver, while those with 68mol% HA modification losing much of HA characteristics were evenly distributed to the tissues in the body. The results are well matched with the fact that HA receptors are abundantly present in the liver with a high specificity to HA molecules. Accordingly, slightly modified HA derivatives were used for target specific intracellular delivery of nucleotide therapeutics and highly modified HA derivatives were used for long-acting conjugation of peptide and protein therapeutics. HA has been also used as a novel depot system in the forms of physically and chemically crosslinked hydrogels for various protein drug delivery. This review will give you a peer overview on novel HA derivatives and the latest advances in HA-based drug delivery systems of various biopharmaceuticals for further clinical development. [Copyright &y& Elsevier]

Abstract: Degradable hydrogels have been extensively used in biomedical applications such as drug delivery, and recent interest has grown in hydrogels that degrade in recognition of a cellular response. This contribution describes a poly(ethylene glycol) (PEG) hydrogel platform with human neutrophil elastase (HNE) sensitive peptide cross-links formed using thiol-ene photopolymerization rendering the gel degradable at sites of inflammation. Further, protein therapeutics can be physically entrapped within the network and selectively released upon exposure to HNE. HNE-responsive hydrogels exhibited surface erosion where the degradation kinetics was influenced by changes in peptide k cat, concentration of HNE, and concentration of peptide within the gel. Using this platform, we were able to achieve controlled, zero-order release of bovine serum albumin (BSA) in the presence of HNE, and release was arrested in the absence of HNE. To further exploit the advantages of surface eroding delivery systems, a smaller protein (carbonic anhydrase) was delivered at the same rate as BSA and only dependent on gel formulation and environmental conditions. Also, protein release was predicted from a 3-layered hydrogel device using mass loss data. Lastly, the bioactivity of lysozyme was maintained above 90% following the exposure to thiol-ene photopolymerization conditions. [Copyright &y& Elsevier]

Abstract: Osteosarcoma (OS) is the most common type of malignant bone cancer, and the sixth most common type of cancer in children and young adults. Currently, gene therapy is being evaluated as a novel method for OS treatment. Here we report on an in situ gelling chitosan-based hydrogel system that sustains the release of a potential anti-cancer gene (pigment epithelium-derived factor) to the tumor site. A significant reduction of the primary OS in a clinically relevant orthotopic model was measured. The combination of plasmid treatment and chemotherapy together with the use of this delivery system led to the highest suppression of tumor growth without side effects. The results obtained from this study demonstrate the potential application of a biodegradable hydrogel technology as an anti-cancer drug delivery system for successful chemo-gene therapy. [Copyright &y& Elsevier]

Abstract: We report the development of a series of physical hydrogel blends composed of hyaluronan (HA) and methyl cellulose (MC) designed for independent delivery of one or more drugs, from 1 to 28 days, for ultimate application in spinal cord injury repair strategies. To achieve a diversity of release profiles we exploit the combination of fast diffusion-controlled release of dissolved solutes from the HAMC itself and slow drug release from poly(lactide-co-glycolide) particles dispersed within the gel. Delivery from the composite hydrogels was demonstrated using the neuroprotective molecules NBQX and FGF-2, which were released for 1 and 4 days, respectively; the neuroregenerative molecules dbcAMP and EGF, and proteins α-chymotrypsin and IgG, which were released for 28 days. α-chymotrypsin and IgG were selected as model proteins for the clinically relevant neurotrophin-3 and anti-NogoA. Particle loaded hydrogels were significantly more stable than HAMC alone and drug release was longer and more linear than from particles alone. The composite hydrogels are minimally swelling and injectable through a 30 gauge/200 µm inner diameter needle at particle loads up to 15 wt.% and particle diameters up to 15 µm. [Copyright &y& Elsevier]

In our quest to develop new drug delivery systems, we designed and synthesized PEG-conjugates and PEG-hydrogels with a degradable linkage to the drug. Specifically, methoxyPEG-doxorubicin (MPEG-CH=N-Doxo) and doxorubicin-PEG aldehyde (OHC-PEG-CH=N-Doxo) conjugates, plus poly (vinyl amine)-PEG-doxorubicin (PVAm-PEG-Doxo) hydrogels were prepared. The hydrogels were crosslinked by PEG-Schiff base linkages, and the Doxo was conjugated to the gel by pendant Schiff base bonds (PVAm-N=CH-PEG-CH=N- Doxo). The release profile of Doxo from the hydrogels was dependent on pH and on the ratio of PVAm to the PEG-dialdehyde crosslinker. These degradable PEG hydrogels could be good candidates for slow release of Doxo from subcutaneous or IM implants. [ABSTRACT FROM AUTHOR]