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Highlights: [•] The work is development of delivery system using biocompatible porcine articular cartilage (PCP). [•] BSA-loaded PCP suspension become gel upon s.c. injection into rats. [•] PCP hydrogels exhibit sustained release of BSA over extended experimental periods. [•] PCP hydrogel may provide numerous benefits as a minimally invasive therapeutics depot. [ABSTRACT FROM AUTHOR]

Purpose: Vesicoureteral reflux is frequently diagnosed in the pediatric population. Endoscopic treatment has become a popular form of first-line therapy. Available products offer good short-term success rates. However, the cost of these injected implants is an issue. We evaluated the success of endoscopic treatment for vesicoureteral reflux using polyacrylamide hydrogel. Materials and Methods: We performed a single center, single surgeon, prospective, off-label study using polyacrylamide hydrogel to treat vesicoureteral reflux. All patients underwent endoscopic subureteral double hydrodistention implantation technique injection followed by renal ultrasound and voiding cystourethrogram at 3 months postoperatively to confirm the absence of de novo hydronephrosis and correction of vesicoureteral reflux (grade 0). Results: A total of 40 patients (69 refluxing ureters) underwent polyacrylamide hydrogel injection. Median age at surgery was 50 months. Bilateral reflux was identified in 29 patients (73%). Nine patients had duplex systems, 2 with reflux into both moieties. Reflux was graded using the International Reflux Study in Children grading system, with grade I seen in 9 ureters, II in 17, III in 20, IV in 18 and V in 5. Mean volume injected was 1.1 ml. Success rate for grade I to III vesicoureteral reflux at 3 months after a single treatment was 87%, and the overall success for all grades was 81.2%. Conclusions: Off-label use of polyacrylamide hydrogel injection therapy for primarily low grade vesicoureteral reflux demonstrates that the technique and short-term success rates are comparable to the most popular bulking agent, dextranomer/hyaluronic acid. These results suggest that further trials comparing polyacrylamide hydrogel and dextranomer/hyaluronic acid would be worthwhile. [ABSTRACT FROM AUTHOR]

Abstract: Peripheral nerve injuries requiring surgery can be repaired by autograft, the clinical “gold standard”, allograft, or nerve conduits. Most published clinical studies show the effectiveness of nerve conduits in small size defects in sensory nerves. Many preclinical studies suggest that peripheral nerve regeneration through conduits can be enhanced and repair lengths increased with the use of a biomaterial filler in the conduit lumen. We have previously shown that a luminal hydrogel filler derived from human hair keratin (HHK) can improve electrophysiological and histological outcomes in mouse, rabbit, and non-human primate nerve injury models, but insight into potential mechanisms has been lacking. Based on the premise that a keratin biomaterial (KOS) hydrogel provides an instantaneous structural matrix within the lumen, the current study compares the cellular behavior elicited by KOS hydrogel to Matrigel (MAT) and saline (SAL) conduit fillers in a 1 cm rat sciatic nerve injury model at early stages of regeneration. While there was little difference in initial cellular influx, the KOS group showed earlier migration of dedifferentiated Schwann cells (SC) from the proximal nerve end compared to the other groups. The KOS group also showed faster SC dedifferentiation and myelin debris clearance, and decreased macrophage infiltration during Wallerian degeneration of the distal nerve tissue. [Copyright &y& Elsevier]

Highlights: [•] Peptide hydrogel. [•] Biocompatible trigger to form hydrogels. [•] 3D cell culture. [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: Wound dressings of chitosan are biocompatible, biodegradable, antibacterial and hemostatic biomaterials. However, applications for chitosan are limited due to its poor mechanical properties. Here, we conducted an in vivo mouse angiogenesis study on reinforced poly(ethylene glycol) (PEG)-chitosan (RPC) hydrogels. RPC hydrogels were formed by cross-linking chitosan with PEGs of different molecular weights at various PEG to chitosan ratios in our previous paper. These dressings can keep the wound moist, had good gas exchange capacity, and was capable of absorbing or removing the wound exudate. We examined the ability of these RPC hydrogels and neat chitosan to heal small cuts and full-thickness skin defects on the backs of male Balb/c mice. Histological examination revealed that chitosan suppressed the infiltration of inflammatory cells and accelerated fibroblast proliferation, while PEG enhanced epithelial migration. The RPC hydrogels promoted wound healing in the small cuts and full layer wounds. The optimal RPC hydrogel had a swelling ratio of 100% and a water vapor transmission rate (WVTR) of about 2000g/m2/day. In addition, they possess good mechanical property and appropriate degradation rates. Thus, the optimal RPC hydrogel formulation functioned effectively as a wound dressing and promoted wound healing. [Copyright &y& Elsevier]

Abstract: Biodegradable oligo(poly(ethylene glycol) fumarate) (OPF) composite hydrogels have been investigated for the delivery of growth factors (GFs) with the aid of gelatin microparticles (GMPs) and stem cell populations for osteochondral tissue regeneration. In this study, a bilayered OPF composite hydrogel that mimics the distinctive hierarchical structure of native osteochondral tissue was utilized to investigate the effect of transforming growth factor-β3 (TGF-β3) with varying release kinetics and/or insulin-like growth factor-1 (IGF-1) on osteochondral tissue regeneration in a rabbit full-thickness osteochondral defect model. The four groups investigated included (i) a blank control (no GFs), (ii) GMP-loaded IGF-1 alone, (iii) GMP-loaded IGF-1 and gel-loaded TGF-β3, and (iv) GMP-loaded IGF-1 and GMP-loaded TGF-β3 in OPF composite hydrogels. The results of an in vitro release study demonstrated that TGF-β3 release kinetics could be modulated by the GF incorporation method. At 12weeks post-implantation, the quality of tissue repair in both chondral and subchondral layers was analyzed based on quantitative histological scoring. All groups incorporating GFs resulted in a significant improvement in cartilage morphology compared to the control. Single delivery of IGF-1 showed higher scores in subchondral bone morphology as well as chondrocyte and glycosaminoglycan amount in adjacent cartilage tissue when compared to a dual delivery of IGF-1 and TGF-β3, independent of the TGF-β3 release kinetics. The results suggest that although the dual delivery of TGF-β3 and IGF-1 may not synergistically enhance the quality of engineered tissue, the delivery of IGF-1 alone from bilayered composite hydrogels positively affects osteochondral tissue repair and holds promise for osteochondral tissue engineering applications. [Copyright &y& Elsevier]

Abstract: Physical hydrogels have been obtained from hyaluronic acid derivatized with polylactic acid in the presence or in the absence of polyethylene glycol chains. They have been extemporarily loaded with antibacterial agents, such as vancomycin and tobramycin. These medicated hydrogels have been used to coat titanium disks (chosen as simple model of orthopedic prosthesis) and in vitro studies in simulated physiological fluid have been performed as a function of time and for different drug loading and polymer concentration values. Sterilization process performed on the hydrogels does not change their rheological behavior and release properties as well as the chemical structure of starting copolymers. A preliminary test has been performed by coating with the hydrogel a prosthesis that has been inserted in a seat of a lyophilized human femur, to confirm the ability of the hydrogel to adhere to the prosthesis surface also after its insertion in the implant seat. Cell compatibility of obtained hydrogels has been confirmed in vitro by using human dermal fibroblasts chosen as a model cell line. Obtained results suggest the potential use of these hydrogels in the orthopedic field, in particular for the production of antibacterial coatings of prostheses for implant in the human or animal body in the prevention and/or treatment of post surgical infections. [Copyright &y& Elsevier]

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]

Abstract: In this work, we developed a biodegradable and injectable composite drug delivery system (DDS), camptothecine (CPT) loaded polymeric microsphere in thermosensitive hydrogel, for colorectal peritoneal carcinomatosis (CRPC) therapy. In our previous studies, we found that poly(ɛ-caprolactone)–poly(ethylene glycol)–poly(ɛ-caprolactone) (PCL–PEG–PCL, PCEC) copolymers with different molecular weight and PEG/PCL ratio could be administrated to form microsphere or thermosensitive hydrogel, respectively. Therefore, the composite DDS was composed of CPT loaded microsphere (CPT-MS) and thermosensitive hydrogel. CPT-MS was prepared by CPT and PCEC copolymer (M n =31,600) using an oil-in-water emulsion solvent evaporation method. Besides, biodegradable and injectable thermosensitive PCEC hydrogel (M n =3150) with lower sol–gel transition temperature at around body temperature was also prepared. The CPT-MS in thermosensitive hydrogel (CPT-MS/hydrogel) composite is a free-flowing sol at ambient temperature and instantly converts into a non-flowing gel at body temperature. Furthermore, cytotoxicity assay indicated that both microsphere and hydrogel were biocompatible with very low cytotoxicity. In vitro release profile demonstrated a significant difference between rapid release of free CPT and much slower and sustained release of CPT-MS/hydrogel. In addition, intraperitoneal administration of CPT-MS/hydrogel could effectively suppress growth and metastasis of CT26 peritoneal carcinomatosis in vivo, and prolonged the survival of tumor bearing mice. Compared with CPT-MS or free CPT, CPT-MS/hydrogel induced a stronger anti-tumor effect by increasing apoptosis of tumor cells and inhibiting microvessel density of tumor tissue. Besides, side effects of CPT were also alleviated in CPT-MS/hydrogel-treated mice. Thus, our results suggested that CPT-MS/hydrogel may have great potential applications in clinic. [Copyright &y& Elsevier]

Abstract: Islet transplantation offers a promising treatment for type 1 diabetes (T1D). However, a major hurdle in this treatment is the rapid loss of functional islets during culture and after transplantation. The liver site, currently utilized for transplantation, is suboptimal for achieving long-term insulin independence due to a rapid islet loss followed by a chronic decline in islet function after transplantation. Herein, we report a synthetic saccharide–peptide (SP) hydrogel that allows suspending islets in liquid and injecting for in situ polymerization without forming islet clumps, indicating its potential in extrahepatic islet transplantation. In vitro, rat islets in SP hydrogel maintained a 3D structure and high glucose-stimulated insulin release similar to that observed in freshly isolated islets for 4 weeks, while control islets cultured in suspension lost their 3D structure and insulin release responses by 2 weeks. Biocompatibility of SP hydrogel was shown by the absence of cytokine mRNA activation in peripheral blood mononuclear cells (PBMCs) exposed to hydrogel in vitro and by the absence of cellular infiltrates in and around the hydrogel implanted subcutaneously. Syngeneic Lewis rat islets transplanted in SP hydrogel in various extrahepatic sites stained strongly for insulin, and more effectively reversed diabetes than unencapsulated islets when transplanted in an omental pocket. In conclusion, the SP hydrogel is non-cytotoxic and supports normal islet structure and function both in vitro and in vivo. Specifically, the ability of the hydrogel to separate individual islets after transplantation is important for maintaining their function in vivo. This important property, combined with the versatility and biocompatibility, makes our SP hydrogel a promising synthetic scaffold that can facilitate transplantation of organized heterogeneous cells to preserve their micro-structure and function. [Copyright &y& Elsevier]

Abstract: This work reports the self-assembly of a sparingly soluble antibiotic (ciprofloxacin) and a hydrophobic tripeptide (DLeu–Phe–Phe) into supramolecular nanostructures that yield a macroscopic hydrogel at physiological pH. Drug incorporation results in modified morphology and rheological properties of the self-assembled hydrogel. These changes can be correlated with intermolecular interactions between the drug and the peptide, as confirmed by spectroscopic analysis (fluorescence, circular dichroism, IR). The drug appears bound within the hydrogel by non-covalent interactions, and retains its activity over a prolonged release timescale. Antimicrobial activity of the ciprofloxacin-peptide self-assembled hydrogel was evaluated against Staphylococcus aureus, Escherichia coli, and a clinical strain of Klebsiella pneumoniae. Interestingly, the peptide hydrogel alone exhibited a mild anti-bacterial activity against Gram-negative bacteria. While toxic to bacteria, no major cytotoxicity was seen in haemolysis assays of human red blood cells or in mouse fibroblast cell cultures. This new approach of drug incorporation into the nanostructure of a simple tripeptide hydrogel by self-assembly may have important applications for cost-effective wound dressings and novel antimicrobial formulations. [Copyright &y& Elsevier]

Abstract: Introduction: A potent mesenchymal stem cell (MSC) population was recently isolated from the Wharton''s jelly of human umbilical cord (UC). The aim of the current experiments was to determine the potential of human UC-derived MSC (UC-MSC) in cartilage healing. Materials and methods: Chondrogenic differentiation of collagen hydrogel-embedded cells was induced in standard chondrocyte conditioning medium and further detected by real-time PCR, histochemistry and immunohistochemistry analyses. Cell viability and apoptosis of the MSCs in the collagen I hydrogels were monitored using apoptosis detection kit. Results: Cells isolated from UC were positive for MSC biomarkers and negative for haematopoietic lineage and endothelial biomarkers and possess the capacity to differentiate along osteogenic lineage. UC-MSCs embedded in collagen hydrogel can undergo chondrogenesis characterised by significantly increased expressions of collagen II, aggrecan, COMP (cartilage oligomeric matrix protein) and sox9 after exposed cells-embedded hydrogels to chondrogenic factors. The most of cells remained viable throughout the hydrogels after 3weeks of cultivation in chondrogenic differentiation medium. Conclusions: Collagen hydrogel can provide an appropriate 3-D environment for the chondrogenesis of UC-MSCs. UC-MSCs embedded in biocompatible scaffold may have great potential for cartilage engineering. [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: We report an injectable hydrogel system that incorporates interferon-α2a (IFN-α2a) for liver cancer therapy. IFN-α2a was incorporated in hydrogels composed of hyaluronic acid-tyramine (HA-Tyr) conjugates through the oxidative coupling of Tyr moieties with hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). IFN-α2a-incorporated HA-Tyr hydrogels of varying stiffness were formed by changing the H2O2 concentration. The incorporation of IFN-α2a did not affect the rheological properties of the hydrogels. The activity of IFN-α2a was furthermore well-maintained in the hydrogels with lower stiffness. Through the caspase-3/7 pathway in vitro, IFN-α2a released from HA-Tyr hydrogels inhibited the proliferation of liver cancer cells and induced apoptosis. In the study of the pharmacokinetics, a higher concentration of IFN-α2a was shown in the plasma of mice treated with IFN-α2a-incorporated hydrogels after 4h post injection, with a much higher amount of IFN-α2a delivered at the tumor tissue comparing to that of injecting an IFN-α2a solution. The tumor regression study revealed that IFN-α2a-incorporated HA-Tyr hydrogels effectively inhibited tumor growth, while the injection of an IFN-α2a solution did not demonstrate antitumor efficacy. Histological studies confirmed that tumor tissues in mice treated with IFN-α2a-incorporated HA-Tyr hydrogels showed lower cell density, with more apoptotic and less proliferating cells compared with tissues treated with an IFN-α2a solution. In addition, the IFN-α2a-incorporated hydrogel treatment greatly inhibited the angiogenesis of tumor tissues. [Copyright &y& Elsevier]

Pluronic® F127 is a biocompatible, injectable, and thermoresponsive polymer with promising biomedical applications. In this study, a chemically modified form, i.e., Pluronic ALA-L with tailored degradation rate, was tested as an encapsulation vehicle for osteoblastic cells. UV cross-linking of the modified polymer results in a stable hydrogel with a slower degradation rate. Toxicological screening showed no adverse effects of the modified Pluronic ALA-L on the cell viability. Moreover, high viability of embedded cells in the cross-linked Pluronic ALA-L was observed with life/death fluorescent staining during a 7-day-culture period. Cells were also cultured on macroporous, cross-linked gelatin microbeads, called CultiSpher-S® carriers, and encapsulated into the modified cross-linked hydrogel. Also, in this situation, good cell proliferation and migration could be observed in vitro. Preliminary in vivo tests have shown the formation of new bone starting from the injected pre-loaded CultiSpher-S® carriers. [ABSTRACT FROM AUTHOR]

Calcium cross-linked alginate hydrogel has shown positive results for the treatment of myocardial infarction in both acute and chronic rat models. However, cross-linked alginate hydrogels possess poor mechanical properties, uncontrollable degradation, and poor cell adhesion and infiltration. In this study, covalent cross-linking of partially oxidized alginate and gelatin hydrogel was developed for myocardial infarction treatment, as compared to cross-linked alginate hydrogel and saline. Specifically, the gelation process, mechanical properties, and biodegradation of both cross-linked alginate hydrogel and oxidized alginate and gelatin hydrogel were examined in vitro and in vivo; and a rat myocardial infarction model was developed by injecting hydrogel into hearts, and postinjection, echocardiography was performed at 2, 4, and 6 weeks, respectively. Matrix metalloprotease-2/9 activity was also examined by in situ zymography on frozen slices of the treated hearts. Based on the results, that both hydrogels enhanced scar thickness and attenuated heart remodeling compared with the saline control group and that, compared to cross-linked alginate hydrogel, oxidized alginate and gelatin hydrogel exhibited the increased mechanical strength, enhanced angiogenesis, and stronger cell-recruiting capacity. It has also been illustrated that oxidized alginate and gelatin hydrogel–treated hearts have much weaker cardiac remodeling, enhanced extracellular matrix accumulation, and reduced matrix metalloprotease activity than cross-linked alginate hydrogel–treated ones. All results suggest oxidized alginate and gelatin hydrogel may be more suitable for the myocardial infarction treatment. [ABSTRACT FROM AUTHOR]

Medtronic's INFUSE Bone Graft provides surgeons with a potent tool for stimulating bone formation. Current delivery vehicles that rely on Absorbable Collagen Sponges (ACS) require excessive quantities of the active ingredient in INFUSE, recombinant human Bone Morphogenic Protein-2 (rhBMP2), to achieve physiologically relevant concentrations of the growth factor, driving up the cost of the product and increasing the likelihood of undesirable side effects in neighboring tissues. We demonstrate that a simple light-mediated, thiol-ene chemistry can be used to create an effective polymer delivery vehicle for rhBMP2, eliminating the use of xenographic materials and reducing the dose of rhBMP2 required to achieve therapeutic effects. Comprised entirely of synthetic components, this system entraps rhBMP2 within a biocompatible hydrogel scaffold that is degraded by naturally occurring remodeling enzymes, clearing the way for new tissue formation. When tested side-by-side with ACS in a critical-sized bone defect model in rats, this polymeric delivery system significantly increased bone formation over ACS controls. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 401-406, 2013 [ABSTRACT FROM AUTHOR]

Abstract: Damage to cartilage caused by injury or disease can lead to pain and loss of mobility, diminishing one''s quality of life. Because cartilage has a limited capacity for self-repair, tissue engineering strategies, such as cells encapsulated in synthetic hydrogels, are being investigated as a means to restore the damaged cartilage. However, strategies to date are suboptimal in part because designing degradable hydrogels is complicated by structural and temporal complexities of the gel and evolving tissue along multiple length scales. To address this problem, this study proposes a multi-scale mechanical model using a triphasic formulation (solid, fluid, unbound matrix molecules) based on a single chondrocyte releasing extracellular matrix molecules within a degrading hydrogel. This model describes the key players (cells, proteoglycans, collagen) of the biological system within the hydrogel encompassing different length scales. Two mechanisms are included: temporal changes of bulk properties due to hydrogel degradation, and matrix transport. Numerical results demonstrate that the temporal change of bulk properties is a decisive factor in the diffusion of unbound matrix molecules through the hydrogel. Transport of matrix molecules in the hydrogel contributes both to the development of the pericellular matrix and the extracellular matrix and is dependent on the relative size of matrix molecules and the hydrogel mesh. The numerical results also demonstrate that osmotic pressure, which leads to changes in mesh size, is a key parameter for achieving a larger diffusivity for matrix molecules in the hydrogel. The numerical model is confirmed with experimental results of matrix synthesis by chondrocytes in biodegradable poly(ethylene glycol)-based hydrogels. This model may ultimately be used to predict key hydrogel design parameters towards achieving optimal cartilage growth. [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: Ischemic disease is associated with high mortality and morbidity rates, and therapeutic angiogenesis via systemic or local delivery of protein drugs is one potential approach to treat the disease. In this study, we hypothesized that combined delivery of TAT-HSP27 (HSP27 fused with transcriptional activator) and VEGF could enhance the therapeutic efficacy in an ischemic mouse model, and that sequential release could be critical in therapeutic angiogenesis. Alginate hydrogels containing TAT-HSP27 as an anti-apoptotic agent were prepared, and porous PLGA microspheres loaded with VEGF as an angiogenic agent were incorporated into the hydrogels to prepare microsphere/hydrogel hybrid delivery systems. Sequential in vitro release of TAT-HSP27 and VEGF was achieved by the hybrid systems. TAT-HSP27 was depleted from alginate gels in 7days, while VEGF was continually released for 28days. The release rate of VEGF was attenuated by varying the porous structures of PLGA microspheres. Sequential delivery of TAT-HSP27 and VEGF was critical to protect against muscle degeneration and fibrosis, as well as to promote new blood vessel formation in the ischemic site of a mouse model. This approach to controlling the sequential release behaviors of multiple drugs could be useful in the design of novel drug delivery systems for therapeutic angiogenesis. [Copyright &y& Elsevier]

Abstract: Objectives: The clinical translation of stem cell-based Regenerative Endodontics demands further development of suitable injectable scaffolds. Puramatrix™ is a defined, self-assembling peptide hydrogel which instantaneously polymerizes under normal physiological conditions. Here, we assessed the compatibility of Puramatrix™ with dental pulp stem cell (DPSC) growth and differentiation. Methods: DPSC cells were grown in 0.05–0.25% Puramatrix™. Cell viability was measured colorimetrically using the WST-1 assay. Cell morphology was observed in 3D modeling using confocal microscopy. In addition, we used the human tooth slice model with Puramatrix™ to verify DPSC differentiation into odontoblast-like cells, as measured by expression of DSPP and DMP-1. Results: DPSC survived and proliferated in Puramatrix™ for at least three weeks in culture. Confocal microscopy revealed that cells seeded in Puramatrix™ presented morphological features of healthy cells, and some cells exhibited cytoplasmic elongations. Notably, after 21 days in tooth slices containing Puramatrix™, DPSC cells expressed DMP-1 and DSPP, putative markers of odontoblastic differentiation. Significance: Collectively, these data suggest that self-assembling peptide hydrogels might be useful injectable scaffolds for stem cell-based Regenerative Endodontics. [Copyright &y& Elsevier]

Abstract: Hydrogels are presently under investigation as matrices for the controlled release of bioactive molecules, in particular pharmaceutical proteins, and for the encapsulation of living cells. For these applications, it is often required that the gels degrade under physiological conditions. This means that the originally three-dimensional structure has to disintegrate preferably in harmless products to ensure a good biocompatibility of the hydrogel. In this overview, different chemical and physical crosslinking methods used for the design of biodegradable hydrogels are summarized and discussed. Chemical crosslinking is a highly versatile method to create hydrogels with good mechanical stability. However, the crosslinking agents used are often toxic compounds, which have been extracted from the gels before they can be applied. Moreover, crosslinking agents can give unwanted reactions with the bioactive substances present in the hydrogel matrix. Such adverse effects are avoided with the use of physically crosslinked gels. [Copyright &y& Elsevier]

Abstract: Inorganic–organic hydrogels based on methacrylated star polydimethylsiloxane (PDMSstar-MA) and diacrylated poly(ethylene glycol) (PEG-DA) macromers were prepared via solvent-induced phase separation (SIPS). The macromers were combined in a dichloromethane precursor solution and sequentially photopolymerized, dried and hydrated. The chemical and physical properties of the hydrogels were further tailored by varying the number average molecular weight (Mn) of PEG-DA (Mn =3.4k and 6k gmol−1) as well as the weight percent ratio of PDMSstar-MA (Mn =7k gmol−1) to PEG-DA from 0:100 to 20:80. Compared to analogous hydrogels fabricated from aqueous precursor solutions, SIPS produced hydrogels with a macroporous morphology, a more even distribution of PDMSstar-MA, increased modulus and enhanced degradation rates. The morphology, swelling ratio, mechanical properties, bioactivity, non-specific protein adhesion, controlled introduction of cell adhesion, and cytocompatibility of the hydrogels were characterized. As a result of their tunable properties, this library of hydrogels is useful to study material-guided cell behavior and ultimate tissue regeneration. [Copyright &y& Elsevier]

Abstract: Induced pluripotent stem cells (iPSCs) have promising potential in regenerative medicine, but whether iPSCs can promote corneal reconstruction remains undetermined. In this study, we successfully reprogrammed human corneal keratocytes into iPSCs. To prevent feeder cell contamination, these iPSCs were cultured onto a serum- and feeder-free system in which they remained stable through 30 passages and showed ESC-like pluripotent property. To investigate the availability of iPSCs as bioengineered substitutes in corneal repair, we developed a thermo-gelling injectable amphiphatic carboxymethyl-hexanoyl chitosan (CHC) nanoscale hydrogel and found that such gel increased the viability and CD44 + proportion of iPSCs, and maintained their stem-cell like gene expression, in the presence of culture media. Combined treatment of iPSC with CHC hydrogel (iPSC/CHC hydrogel) facilitated wound healing in surgical abrasion-injured corneas. In severe corneal damage induced by alkaline, iPSC/CHC hydrogel enhanced corneal reconstruction by downregulating oxidative stress and recruiting endogenous epithelial cells to restore corneal epithelial thickness. Therefore, we demonstrated that these human keratocyte-reprogrammed iPSCs, when combined with CHC hydrogel, can be used as a rapid delivery system to efficiently enhance corneal wound healing. In addition, iPSCs reprogrammed from corneal surgical residues may serve as an alternative cell source for personalized therapies for human corneal damage. [Copyright &y& Elsevier]

Abstract: Cells have been extensively studied for their uses in various therapies because of their capacities to produce therapeutic proteins and recreate new tissues. It has often been suggested that the efficacy of cell therapies can greatly be improved through the ability to localize and regulate cellular activities at a transplantation site; however, the technologies for this control are lacking. Therefore, this study reports a cell-Laden hydrogel patch engineered to support the proliferation and angiogenic growth factor expression of cells adhered to their surfaces, and to further promote neovascularization. Hydrogels consisting of alginate chemically linked with pyrrole units, termed alginate-g-pyrrole, were prepared through an oxidative cross-linking reaction between pyrrole units. Fibroblasts adhered to the alginate-g-pyrrole hydrogels, and exhibited increased proliferation and overall vascular endothelial growth factor (VEGF) expression, compared to those on pyrrole-free hydrogels. Furthermore, the alginate-g-pyrrole hydrogel surfaces were modified to present microposts, subsequently increasing the amount of pyrrole units on their surfaces. Cells adhered to the microfabricated gel surfaces exhibited increased proliferation and overall VEGF expression proportional to the density of the microposts. The resulting micropatterned alginate-g-pyrrole hydrogels exhibited increases in the size and density of mature blood vessels when implanted on chick chorioallantoic membranes (CAMs). The hydrogel system developed in this study will be broadly useful for improving the efficacy of a wide array of cell-based wound healing and tissue regenerative therapies. [Copyright &y& Elsevier]

Abstract: Characterizing the wear behavior of hydrogel articulations is problematic and a standardized method has not yet been developed. The aims of this study were to evaluate the wear resistance of hydrogel-on-hydrogel articulations and to assess the suitability of a submerged measurement technique as a practical and non-destructive method in quantifying their wear rates. Five hydrogel bearings were tested for 5 million cycles using a pin-on-disk tester. As the test progressed, the coefficient of friction increased (Spearman’s rho=0.76; p<0.001) while the surfaces of the pins were burnished (Spearman’s rho=−0.31; p<0.001) and those of the disks got rougher (Spearman’s rho=0.19; p<0.01). Environmental scanning electron microscopy analysis showed no evidence of gross wear and revealed similar surface morphology between contacting and non-contacting regions of specimens. These results support the finding of low wear, which were −1.4±8.3 and 6.6±35.3mm3/MC based on submerged and wet weights, respectively. Pins displayed higher wear than disks based on submerged weights. This was anticipated since surfaces of pins were constantly under load and cross-shear while only a portion of the disk in contact with the pin was loaded at a given time. Wet weights, on the other hand, indicated higher wear for disks than pins. In addition, submerged weights yielded a lower standard error of the mean in wear rates than wet weights, 3.7 and 14.6mm3/MC, respectively. These results indicated that submerged weights were more suitable than wet weights in quantifying wear of hydrogels in spite of unwanted effects of swelling. [Copyright &y& Elsevier]

Abstract: It is well appreciated that delivery of therapeutic agents through the pulmonary route could provide significant improvement in patient compliance and reduce systemic toxicity for a variety of diseases. Many inhalable drug formulations suffer from low respirable fractions, rapid clearance by alveolar macrophages, target non-specificity, and difficulty in combining aerodynamic properties with efficient cellular uptake. To overcome these challenges, we developed an enzyme-responsive, nanoparticle-in-microgel delivery system. This system is designed to provide optimal aerodynamic carrier size for deep lung delivery, improved residence time of carriers in the lungs by avoiding rapid clearance by macrophages, and reduction of side effects and toxicity by releasing encapsulated therapeutics in response to disease-specific stimuli. This unique carrier system is fabricated using a new Michael addition during (water-in-oil) emulsion (MADE) method, especially suitable for biologic drugs due to its gentle fabrication conditions. The resulting microgels have a highly porous internal structure and an optimal aerodynamic diameter for effective deep lung delivery. They also exhibit triggered release of various nanoparticles and biologics in the presence of physiological levels of enzyme. In addition, the nanoparticle-carrying microgels showed little uptake by macrophages, indicating potential for increased lung residence time and minimal clearance by alveolar macrophages. Collectively, this system introduces a rationally designed, disease-specific, multi-tiered delivery system for use as an improved pulmonary carrier for biologic drugs. [Copyright &y& Elsevier]

Abstract: Chitosan–poly(ethylene glycol)–tyramine (CPT) hydrogels were rapidly formed in situ using horseradish peroxidase and hydrogen peroxide to explore their performance as efficient tissue adhesives. A poly(ethylene glycol) modified with tyramine was grafted onto a chitosan backbone to enhance the solubility of the chitosan and to crosslink into three-dimensional networks. The elastic modulus of the hydrogels could be controlled by changing the crosslinking conditions, and the mechanical strength influenced the tissue adhesiveness of the hydrogels. The hydrogels showed the adhesiveness ranging from 3- to 20-fold that of fibrin glue (Greenplast®). The hemostatic ability of the hydrogels was evaluated on the basis that bleeding from liver defects was significantly arrested by the combined effect of the adhesiveness of the hydrogels and the hemostatic property of the chitosan materials. The enzymatic crosslinking method enabled the water-soluble chitosan to rapidly form hydrogels within 5s of an incision into the skin of rats. Histological results demonstrated that the CPT hydrogels showed superior healing effects in the skin incision when compared to suture, fibrin glue and cyanoacrylate. By 2weeks post-implantation, the wound was completely recovered, with a newly formed dermis, due to the presence of the CPT hydrogels in the incision. These results suggest that the in situ curable chitosan hydrogels are very interesting and promising tissue adhesive devices for biomedical applications. [Copyright &y& Elsevier]

Abstract: Injectable biomaterials alone may alter local tissue responses, including inflammatory cascades and matrix production (e.g. stimulatory dermal fillers are used as volumizing agents that induce collagen production). To expand upon the available material compositions and timing of presentation, a tunable hyaluronic acid (HA) and poly(lactide-co-glycolide) (PLGA) microsphere composite system was formulated and assessed in subcutaneous and cardiac tissues. HA functionalized with hydroxyethyl methacrylate (HeMA) was used as a precursor to injectable and degradable hydrogels that carry PLGA microspheres (∼50μm diameter) to tissues, where the HA hydrogel degradation (∼20 or 70days) and quantity of PLGA microspheres (0–300mgml−1) are readily varied. When implanted subcutaneously, faster hydrogel degradation and more microspheres (e.g. 75mgml−1) generally induced more rapid tissue and cellular interactions and a greater macrophage response. In cardiac applications, tissue bulking may be useful to alter stress profiles and to stabilize the tissue after infarction, limiting left ventricular (LV) remodeling. When fast degrading HeMA–HA hydrogels containing 75mgml−1 microspheres were injected into infarcted tissue in sheep, LV dilation was limited and the thickness of the myocardial wall and the presence of vessels in the apical infarct region were increased ∼35 and ∼60%, respectively, compared to empty hydrogels. Both groups decreased volume changes and infarct areas at 8weeks, compared to untreated controls. This work illustrates the importance of material design in expanding the application of tissue bulking composites to a range of biomedical applications. [Copyright &y& Elsevier]

In this study, to clarify the utility of polypseudorotaxane (PPRX) hydrogels composed of poly(ethylene glycol) (PEG) and α- or γ-cyclodextrin (α- or γ-CyD) as a sustained-release system for protein drugs, we prepared CyD PPRX hydrogels including lysozyme, and then the release profiles of lysozyme from these hydrogels and the release mechanisms were investigated. The α- and γ-CyD formed PPRX hydrogels by threading onto one PEG chain and two PEG chains, respectively. The formation of α- and γ-CyD PPRX hydrogels including lysozyme was based on physical cross-linking arisen from their columnar structures. The in vitro release rates of lysozyme were markedly decreased by the encapsulation into CyD PPRX hydrogels. In addition, when release data were plotted according to Korsmeyer-Peppas model, the exponent values ( n) in the α- and γ-CyD systems had no statistically significant difference, suggesting that these release mechanisms were almost same. In conclusion, these results suggest that α- and γ-CyD PPRX hydrogels possess the potential as a sustained-release system for lysozyme. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2891-2899, 2012 [ABSTRACT FROM AUTHOR]

Abstract: Injuries and disease to the central nervous system (CNS) are accompanied by severe consequences, as the adult CNS has very limited capacity to replace the lost neural cells. Different sources of neural stem cells for CNS tissue regeneration exist, including embryonic stem cells (ESCs), fetal stem cells, adult stem cells, and induced pluripotent stem cells (iPSCs), and so on. However, before stem cell therapy can be a viable option for treatments, many issues still need to be resolved, including low viability, lack of control of stem cell fate, and low cell engraftment after transplantation. Though controlling these parameters is extremely challenging, engineering structures that create permissive niches for the transplanted cells, such as the use of biocompatible hydrogels, is a promising approach. This review will focus on highlighting existing hydrogel systems currently being investigated for CNS tissue regeneration, as well as discuss design criteria for hydrogels and methods for manipulating stem cells within hydrogels systems. Finally, the use of these hydrogel systems as carriers for stem cell transplantation in CNS injury and disease models will be discussed. [Copyright &y& Elsevier]

Abstract: The need to enhance the immunogenicity of tumor-associated antigens and modulate the resulting immune responses has prompted the development of new adjuvants. We prepared a novel adjuvant, lipopolysaccharides (LPS) loaded thermosensitive hydrogel (LPS-Hydrogel), for truncated basic fibroblast growth factor (tbFGF) peptide to enhance immunological responses and improve therapeutic effects in cancer. When co-formulated with tbFGF, LPS-Hydrogel formed antigen-adjuvant complexes, which enhanced antibody and cell-mediated responses in mice, thus promoting a more balanced antibody-mediated and cytotoxic T lymphocyte (CTL)-mediated immune response to inhibit tumor growth and metastases in vivo. Furthermore, the secretion of IFN-γ and IL-4 was detected, confirming activation of the two immune responses in vivo. There were no significant systemic toxicities observed with tbFGF-LPS-Hydrogel treatment. These results suggested that the thermosensitive and biodegradable LPS-Hydrogel was a novel adjuvant and carrier for peptide vaccines in cancer immunotherapy. [Copyright &y& Elsevier]

Abstract: The extracellular matrix is continually remodelled by the action of various enzymes such as heparanase, which specifically targets heparan sulfate (HS) and is found in human platelets at high levels. The activity of heparin-containing hydrogels following incubation with platelet extract (PE) was investigated in order to simulate the responses that might occur when the hydrogels, as tissue engineered scaffolds, come in contact with blood products at the site of an injury. The heparanase activity of PE on heparin, used as a model of HS, was confirmed by the decrease in molecular weight. PE treatment diminished heparin''s anticoagulation property but increased its FGF-2 signalling activity, suggesting that the PE''s heparanase activity cleaves at the 3-O-sulfated glucosamine to produce large fragments that can signal cell receptors. The dual effect observed when poly(vinyl alcohol)/heparin co-hydrogels were incubated with PE supports the hypothesis of platelets having the capacity to limit anticoagulation and thus promote blood clot formation, which may be critical in the process of tissue repair. [Copyright &y& Elsevier]

Abstract: Dendrimer hydrogel (DH), made from ultraviolet-cured polyamidoamine dendrimer G3.0 tethered with three polyethylene glycol (PEG, 12,000 Da)–acrylate chains (8.1% w/v) in pH 7.4 phosphate buffered saline (PBS), was studied for the delivery of brimonidine (0.1% w/v) and timolol maleate (0.5% w/v), two antiglaucoma drugs. DH was found to be mucoadhesive to mucin particles and nontoxic to human corneal epithelial cells. DH increased the PBS solubility of brimonidine by 77.6% and sustained the in vitro release of both drugs over 56–72 hours. As compared to eye drop formulations (PBS-drug solutions), DH brought about substantially higher human corneal epithelial cells uptake and significantly increased bovine corneal transport for both drugs. DH increased timolol maleate uptake in bovine corneal epithelium, stroma, and endothelium by 0.4- to 4.6-fold. This work demonstrated that DH can enhance the delivery of antiglaucoma drugs in multiple aspects and represents a novel platform for ocular drug delivery. From the Clinical Editor: Dendrimer hydrogel was studied as agent for simultaneous delivery of two anti-glaucoma drugs, one hydrophobic and one hydrophilic. Superiority over standard PBS-based formulation was clearly demonstrated for both drugs. The work may be a novel platform for ocular drug delivery. [Copyright &y& Elsevier]

Abstract: Poly(β-amino ester) (PBAE) biodegradable hydrogels were investigated for potential combined chemotherapeutic and heat delivery in the synergistic treatment of cancer. Hyperthermia, the heating of cancerous tissue from 41 to 45°C, increases the efficacy of conventional cancer therapies such as irradiation and chemotherapy. The hydrogel nanocomposites in this work provide a drug delivery vehicle (via the biodegradable PBAE polymer network) and the ability to be heated remotely upon exposure to an alternating magnetic field (via iron oxide nanoparticles incorporated into the hydrogel matrix). PBAE macromers composed of poly(ethylene glycol) (N =400) diacrylate (PEG400DA) or diethylene glycol diacrylate (DEGDA) with isobutylamine (IBA) were synthesized. Hydrogel nanocomposites were fabricated via free-radical polymerization to form a bulk hydrogel matrix entrapping both iron oxide nanoparticles and paclitaxel. The 2EG–IBA hydrogel exhibited complete degradation after approximately 7 weeks whereas the 9EG–IBA hydrogel degraded completely in 11h. The hydrogels heated upon exposure to an alternating magnetic field throughout the degradation process. Additionally, the cytotoxicity of the degradation products was evaluated. Paclitaxel release was controlled via bulk degradation of the hydrogels. The tailorability of these nanocomposites makes them solid candidates for the synergistic treatment of cancer. [Copyright &y& Elsevier]

Abstract: Three-dimensional scaffolds like hydrogels can be used for cell and drug delivery and have become a major research focus in tissue engineering. Presently, we investigated the regenerative potency of platelet-rich plasma (PRP) combined with a chondrocyte/hydrogel composite scaffold in the repair of articular cartilage defects using a rabbit model. Primary isolated joint chondrocytes from the trachlear groove of rabbit were cultured in hydrogels as follows; hydrogel (2900Pa or 5900Pa)+chondrocytes and hydrogel+chondrocytes+PRP for in vitro analysis and in vivo implantation. The 5900Pa hydrogel markedly increased cellular viability and development in a time-dependent manner. Furthermore, the hydrogels attenuated the expression of SOX-9, aggrecan, and type II collagen. PRP-containing hydrogels produced an immediate increase in mRNA levels of cannabinoid receptor (CB)1 and CB2, compared with control and PRP-free hydrogels. Osteochondral defects were enhanced recovery with formation of cartilage and perichondrium in the 5900Pa hydrogel+chondrocytes+PRP. Hydrogel may provide a suitable environment for proliferation and maturation of joint chondrocytes in relation to the gelation density and bioactive sources like PRP resulting in improvement for cartilage regeneration. [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]

Abstract: The multifactorial pathological progress of spinal cord injury (SCI) is probably the main reason behind the absence of efficient therapeutic approaches. Hence, very recent highlights suggest the use of new multidrug delivery systems capable of local controlled release of therapeutic agents. In this work, a biocompatible hydrogel-based system was developed as multiple drug delivery tool, specifically designed for SCI repair strategies. Multiple release profiles were achieved by loading gel with a combination of low and high steric hindrance molecules. In vitro, in vivo and ex vivo release studies showed an independent combination of fast diffusion-controlled kinetics for smaller molecules together with slow diffusion-controlled kinetics for bigger ones. A preserved functionality of loaded substances was always achieved, confirming the absence of any chemical stable interactions between gel matrix and loaded molecules. Moreover, the relevant effect of the cerebrospinal fluid flux dynamics on the drug diffusion in the spinal cord tissue was here revealed for the first time: an oriented delivery of the released molecules in the spinal cord tract caudally to the gel site is demonstrated, thus suggesting a more efficient gel positioning rostrally to the lesion. [Copyright &y& Elsevier]

Abstract: Small cartilage defects are frequently treated with debridement or left untreated, predisposing to early onset osteoarthritis. We propose to fill these defects with a cell-free injectable hydrogel comprising dextran-tyramine conjugates (Dex-TA) that can be applied during arthroscopic procedures. In this study, we report on the adhesion mechanism between cartilage and Dex-TA hydrogels and enhancement of cell ingrowth by incorporation of Heparin-tyramine (Hep-TA) conjugates. The enzyme-catalyzed crosslinking reaction of Dex-TA and Hep-TA hydrogels is based on covalent bonding of hydroxyphenyl residues. We hypothesized that this reaction results in covalent bonding of the hydroxyphenyl residues in Dex-TA and Hep-TA to tyrosine residues in cartilage matrix proteins. The involvement of TA residues was confirmed by modelling the enzymatic reaction occurring during gelation. The mechanical analysis indicated that higher tyramine content led to stronger binding. Interfacial cartilage-hydrogel morphology and Raman spectroscopy demonstrated collagens’ reorganization and evidenced the coupling of TA to tyrosine residues in collagen. Moreover, the addition of Hep-TA induced cell recruitment. Collectively, in vitro and ex vivo functional studies evidenced the covalent bonding of TA-containing hydrogels to tyrosine residues in cartilaginous matrix proteins. Moreover, the cell-attracting ability of these hydrogels could be explored to guide tissue repair in focal cartilage defects, preventing or delaying the onset osteoarthritis. [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: Chitosan hydrogels (CHs) have been considered as a potential implant material for replacement and repair of the Nucleus Pulposus (NP) within the intervertebral disk. The nonlinear mechanical behavior of a CH material is investigated experimentally and computationally in this study. A series of confined and unconfined compression tests are designed and conducted for this hydrogel. Hyperelastic strain energy density functions (SEDFs) are calibrated using the experimental data. A hyperelastic constitutive model is selected to best fit the multi-axial behavior of the hydrogel. Its general prediction ability is verified using finite element (FE) simulations of hydrogel indentation experiments conducted using a spherical tip indentor. In addition, digital image correlation (DIC) technique is also used in the indentation test in order to process the full-field surface strains where the indentor contacts the hydrogel. The DIC test results in the form of top-surface strains compared well with those predicted by the FE model. Results show repeatability for the examined specimens under the applied tests. Confined and unconfined test results are found to be sufficient to calibrate the SEDFs. The Ogden model was selected to represent the nonlinear behavior of the CH material which can be used in future biomechanical simulations of the spine. [Copyright &y& Elsevier]

Abstract: In this work, we have investigated the development of a synthetic hydrogel that contains a negatively charged phosphate group for use as a substrate for bone cell attachment and differentiation in culture. The photoreactive, phosphate-containing molecule, bis(2-(methacryloyloxy)ethyl)phosphate (BP), was incorporated into oligo(polyethylene glycol) fumarate hydrogel and the mechanical, rheological and thermal properties of the resulting hydrogels were characterized. Our results showed changes in hydrogel compression and storage moduli with incorporation of BP. The modification also resulted in decreased crystallinity as recorded by differential scanning calorimetry. Our data revealed that incorporation of BP improved attachment and differentiation of human fetal osteoblast (hFOB) cells in a dose-dependent manner. A change in surface chemistry and mineralization of the phosphate-containing surfaces verified by scanning electron microscopy and energy dispersive X-ray analysis was found to be important for hFOB cell attachment and differentiation. We also demonstrated that phosphate-containing hydrogels support attachment and differentiation of primary bone marrow stromal cells. These findings suggest that BP-modified hydrogels are capable of sustaining attachment and differentiation of both bone marrow stromal cells and osteoblasts that are critical for bone regeneration. [Copyright &y& Elsevier]

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 are increasingly being investigated as a means of reducing stress within the ventricular wall of infarcted hearts and thus attenuating pathological remodelling and loss of function. In this context, we have examined the influence of timing of delivery on the efficacy of a polyethylene glycol hydrogel polymerised with an enzymatically degradable peptide sequence. Delivery of the hydrogel immediately after infarct induction resulted in no observable improvements, but a delay of one week in delivery resulted in significant increases in scar thickness and fractional shortening, as well as reduction in end-systolic diameter against saline controls and immediately injected hydrogel at both 2 and 4 weeks post-infarction (p < 0.05). Hydrogels injected at one week were degraded significantly slower than those injected immediately and this may have played a role in the differing outcomes. The hydrogel assumed markedly different morphologies at the two time points having either a fibrillar or bulky appearance after injection immediately or one week post-infarction respectively. We argue that the different morphologies result from infarction induced changes in the cardiac structure and influence the degradability of the injectates. The results indicate that timing of delivery is important and that very early time points may not be beneficial. [Copyright &y& Elsevier]

Abstract: Low melting-point poly(1,3-trimethylene carbonate-co-ε-caprolactone)-b-poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate-co-ε-caprolactone), P(TMC-CL)2-PEG, was employed to fabricate microspheres for sustained growth factor delivery in a photocrosslinked N-methacrylate glycol chitosan hydrogel matrix. The P(TMC-CL)2-PEG had a melting range such that it was solid at 10°C, yet liquid with a low degree of crystallinity at 37°C. The in vitro degradation of P(TMC-CL)2-PEG microspheres was slow, regardless of the triblock copolymer molecular weight and so did not influence protein release. The size of protein loaded P(TMC-CL)2-PEG microspheres manufactured using a low-temperature electrospray technique was between 65 and 85μm. Initial formulation work was done with the model protein lysozyme, co-lyophilized with trehalose and encapsulated as approximately 2μm particles within P(TMC-CL)2-PEG microspheres. This work indicated a sustained release could be achieved with high trehalose content (90% w/w) in the particles. Under these conditions, the release rate of bone morphogenetic protein-6 was more sustained than that of the excipient bovine serum albumin (BSA) and closely followed that of lysozyme. On the other hand, transforming growth factor-β3 and the stabilizing agent BSA generated similar release profiles. This difference in release was proposed to be linked to the protein isoelectric point, with positively charged proteins possibly being more strongly adsorbed to the P(TMC-CL)2-PEG. Both growth factors were released in highly bioactive form, indicating the potential of the release approach. [Copyright &y& Elsevier]

Abstract: The interactions of a number of commercially available dextran preparations with the lectin Concanavalin A (ConA) have been investigated. Dextrans over the molecular mass range 6×103–2×106 gmol−1 were initially characterised in terms of their branching and hence terminal ligand density, using NMR. This showed a range of branching ratios between 3% and 5%, but no clear correlation with molecular mass. The bio-specific interaction of these materials with ConA was investigated using microcalorimetry. The data obtained were interpreted using a number of possible binding models reflecting the known structure of both dextran and the lectin. The results of this analysis suggest that the interaction is most appropriately described in terms of a two-site model. This offers the best compromise for the observed relationship between data and model predictions and the number of parameters used based on the chi-squared values obtained from a nonlinear least-squares fitting procedure. A two-site model is also supported by analysis of the respective sizes of the dextrans and the ConA tetramer. Using this model, the relationship between association constants, binding energy and molecular mass was determined. [Copyright &y& Elsevier]

Abstract: Recent advances in pluripotent stem cell research have provided investigators with potent sources of cardiogenic cells. However, tissue engineering methodologies to assemble cardiac progenitors into aligned, 3-dimensional (3D) myocardial tissues capable of physiologically relevant electrical conduction and force generation are lacking. In this study, we introduced 3D cell alignment cues in a fibrin-based hydrogel matrix to engineer highly functional cardiac tissues from genetically purified mouse embryonic stem cell-derived cardiomyocytes (CMs) and cardiovascular progenitors (CVPs). Procedures for CM and CVP derivation, purification, and functional differentiation in monolayer cultures were first optimized to yield robust intercellular coupling and maximize velocity of action potential propagation. A versatile soft-lithography technique was then applied to reproducibly fabricate engineered cardiac tissues with controllable size and 3D architecture. While purified CMs assembled into a functional 3D syncytium only when supplemented with supporting non-myocytes, purified CVPs differentiated into cardiomyocytes, smooth muscle, and endothelial cells, and autonomously supported the formation of functional cardiac tissues. After a total culture time similar to period of mouse embryonic development (21 days), the engineered cardiac tissues exhibited unprecedented levels of 3D organization and functional differentiation characteristic of native neonatal myocardium, including: 1) dense, uniformly aligned, highly differentiated and electromechanically coupled cardiomyocytes, 2) rapid action potential conduction with velocities between 22 and 25cm/s, and 3) significant contractile forces of up to 2mN. These results represent an important advancement in stem cell-based cardiac tissue engineering and provide the foundation for exploiting the exciting progress in pluripotent stem cell research in the future tissue engineering therapies for heart disease. [Copyright &y& Elsevier]

In controlled drug delivery, the drug diffusion coefficient in a given matrix is a key factor for predicting its release rate. In this work, we compare 31P nuclear magnetic resonance (NMR) profiling for obtaining the mutual-diffusion coefficient () of a drug in hydrogel with results obtained from conventional source/sink experiments. Despite the fact that NMR profiling is a powerful approach for measuring transport properties, it is rarely used for characterizing drug diffusion in gel matrices in pharmaceutical sciences. This work provides an illustration of the applicability of this technique and highlights its advantages for studying drug release systems. The comparison with results obtained from the source/sink experiment clearly establishes the validity of the NMR profiling approach. Alendronate was used as a model drug while curdlan, a gel-forming bacterial polysaccharide, served as a model biomaterial. The determined value (5.6 ± 0.3 × 10−10 m2/s) agrees with the one obtained from a conventional source/sink experiment (5.4 ± 0.5 × 10−10 m2/s). In addition, the alendronate self-diffusion coefficients in solution () and in the hydrogel () were measured on the same system using pulse-field gradient (PFG) 31P NMR. These supplementary parameters provided a more detailed characterization of the drug transport properties in the gel matrix. [ABSTRACT FROM AUTHOR]

Abstract: This research focused on developing a modular poly(ethylene glycol) (PEG) scaffold, assembled from PEG microgels and collagen I, to provide an environment to decouple the chemical and mechanical cues within a three-dimensional scaffold. We first characterized the microgel fabrication process, examining the size, polydispersity, swelling ratio, mesh size and storage modulus of the polymer particles. The resulting microgels had a low polydispersity index, PDI=1.08, and a diameter of ∼1.6μm. The mesh size of the microgels, calculated from the swelling ratio, was 47.53Å. Modular hydrogels (modugels) were then formed by compacting N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride/N-hydroxysuccinimidyl group-activated microgels with PEG–4arm-amine and 0, 1, 10, or 100μgml−1 collagen. The stiffness (G ∗) of the modugels was not significantly altered with the addition of collagen, allowing for modification of the chemical environment independent from the mechanical properties of the scaffold. PC12 cell aggregation increased in modugels as collagen concentrations increased and cell viability in modugels was improved over bulk PEG hydrogels. Overall, these results indicate that further exploration of modular scaffolds formed from microgels could allow for a better understanding of the relationship between the chemical and mechanical properties and cellular behavior. [Copyright &y& Elsevier]