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Silver nanoparticles (AgNPs) have attracted intensive research interest and have been recently incorporated in polymers, medical devices, hydrogels and burn dressings to control the proliferation of microorganisms. In this study a novel silver antibacterial coating was deposited for the first time on hydrogel fibers through an in-situ photo-chemical reaction. Hydrogel blends obtained by mixing different percentages of silver-treated and untreated fibers were characterized by thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). Four different fluids, such as phosphate buffered saline (PBS), simulated body fluid (SBF), chemical simulated wound fluid (cSWF), and deionized water (DI water), were used for evaluating the swelling properties. The results obtained confirmed that the presence of silver did not affect the properties of the hydrogel. Moreover, the results obtained through inductively coupled plasma mass spectrometry (ICP-MS) demonstrated very low silver release values, thus indicating the perfect adhesion of the silver coating to the substrate. Good antibacterial capabilities were demonstrated by any hydrogel blend on Escherichia coli ( E. coli ) and Staphylococcus aureus ( S. aureus ) through agar diffusion tests and optical density readings. [ABSTRACT FROM AUTHOR]

An in situ-formed hydrogel was synthesized by enzymatic cross-linking of poly(γ-glutamic acid)–tyramine conjugates (PGA–Tyr) using horseradish peroxidase (HRP) and hydrogen peroxide (H2O2). The gelation time ranged from 25 s to 5 min was accomplished by tuning the concentration of HRP, H2O2/Tyr molar ratio and the degree of substitution (DS) of Tyr groups. The storage modulus (G′), cross-link density, and mesh size can be tailored by controlling the H2O2/Tyr ratio and DS. The rheological analysis indicated that the storage modulus (G′) can be tailored from approximately 40 to over 1100 Pa with the increasing H2O2/Tyr ratio and DS. The bovine serum albumin (BSA) was used as model protein and encapsulated into the hydrogel during the enzyme-mediated cross-linking reaction. Controlled release of BSA in vitrofrom the PGA–Tyr hydrogel was obtained. The release rate and cumulative release amount of encapsulated BSA were manipulated by controlling the H2O2/Tyr ratio and DS. More than 90% of encapsulated BSA was released from the hydrogel with low cross-link density and lager mesh size in 60 h, while only 68% of BSA was released from the hydrogel with high cross-link density and small mesh size. The results indicated that the PGA–Tyr hydrogel is a promising material for the controlled release of therapeutic protein or peptides. [ABSTRACT FROM AUTHOR]

Cartilage tissue lacks an intrinsic capacity for self-regeneration due to slow matrix turnover, a limited supply of mature chondrocytes and insufficient vasculature. Although cartilage tissue engineering has achieved some success using agarose as a scaffolding material, major challenges of agarose-based cartilage repair, including non-degradability, poor tissue–scaffold integration and limited processing capability, have prompted the search for an alternative biomaterial. In this study, silk fiber–hydrogel composites (SF–silk hydrogels) made from silk microfibers and silk hydrogels were investigated for their potential use as a support material for engineered cartilage. We demonstrated the use of 100% silk-based fiber–hydrogel composite scaffolds for the development of cartilage constructs with properties comparable to those made with agarose. Cartilage constructs with an equilibrium modulus in the native tissue range were fabricated by mimicking the collagen fiber and proteoglycan composite architecture of native cartilage using biocompatible, biodegradable silk fibroin from Bombyx mori . Excellent chondrocyte response was observed on SF–silk hydrogels, and fiber reinforcement resulted in the development of more mechanically robust constructs after 42 days in culture compared to silk hydrogels alone. Thus, we demonstrate the versatility of silk fibroin as a composite scaffolding material for use in cartilage tissue repair to create functional cartilage constructs that overcome the limitations of agarose biomaterials, and provide a much-needed alternative to the agarose standard. [ABSTRACT FROM AUTHOR]

The formation and assembly of diverse tissue building blocks is considered a promising bottom-up approach for the construction of complex three-dimensional tissues. Patterned shape-changing materials were investigated as an innovative method to form and harvest free-standing tissue modules with preserved spatial organization and cell–cell connections. Arrays of micro-scale surface-attached hydrogels made of a thermoresponsive polymer were used as cell culture supports to fabricate tissue modules of defined geometric shape. Upon stimulation, these hydrogels swelled anisotropically, resulting in significant expansion of the culture surface and subsequent expulsion of the intact tissue modules. By varying the network crosslink density, the surface strain was modulated and a strain threshold for tissue module release was identified. This mechanical mechanism for rapid tissue module harvest was found to require inter- and intra-cellular tension. These results suggest that the cell–matrix adhesions are disrupted by the incompatibility of surface expansion with tissue module cohesion and stiffness, thus providing a novel method of forming and harvesting tissue building blocks by a mechanism independent of the thermal stimulus that induces the biomaterial shape change. [ABSTRACT FROM AUTHOR]

Hydrogels designed to sustainably release bioactive molecules are extensively used to enhance tissue repair and regenerative therapies. Along this line, numerous efforts are made to control the molecular release rate and amount. In contrast, few efforts are made to control the molecular release pattern, and, subsequently, modulate the spatial organization of newly forming tissues, including blood vessels. Therefore, using a hydrogel printed to release vascular endothelial growth factor (VEGF) into a pre-defined pattern, this study demonstrates that spatial distribution of VEGF is important in guiding growth direction of new blood vessels, and also in retaining the structural integrity of pre-existing vasculature. Guided by a computational model, we fabricated a patch composed of micro-sized VEGF-releasing poly(ethylene glycol) diacrylate (PEGDA) hydrogel cylinders using an ink-jet printer. Interestingly, hydrogel printed with computationally optimized spacing created anisotropically aligned vasculature exclusively when the printed gel pattern was placed parallel to pre-existing blood vessels. In contrast, vascular sprouting from placing the printed gel pattern perpendicular to pre-existing vessels resulted in deformation and structural disintegration of the original vasculature. We envision that this study will be useful to better understand angiogenesis-modulated neovascularization and further improve the treatment quality for various wounds and tissue defects. [ABSTRACT FROM AUTHOR]

Craniosynostosis is the premature fusion of cranial sutures, which can result in progressive cranial deformations, increased intracranial pressure, and restricted brain growth. Most cases of craniosynostosis require surgical reconstruction of the cranial vault with the goal of increasing the intracranial volume and correcting the craniofacial deformities. However, patients often experience rapid post-operative bone regrowth, known as re-synostosis, which necessitates additional surgical intervention. Bone morphogenetic protein (BMP) inhibitors have tremendous potential to treat re-synostosis, but the realization of a clinically viable inhibitor-based therapeutic requires the development of a delivery vehicle that can localize the release to the site of administration. Here, we present an in situ rapidly crosslinking injectable hydrogel that has the properties necessary to encapsulate co-administered proteins and demonstrate that the delivery of rmGremlin1 via our hydrogel system delays bone regrowth in a weanling mouse model of re-synostosis. Our hydrogel is composed of two mutually reactive poly(ethylene glycol) macromolecules, which when mixed crosslink via a bio-orthogonal Cu free click reaction. Hydrogels containing Gremlin caused a dose dependent inhibition of bone regrowth. In addition to craniofacial applications, our injectable click hydrogel has the potential to provide customizable protein, small molecule, and cell delivery to any site accessible via needle or catheter. [ABSTRACT FROM AUTHOR]

The development of pancreatic ductal adenocarcinoma (PDAC) is heavily influenced by local stromal tissues, or desmoplasia. Biomimetic hydrogels capable of mimicking tumor niches are particularly useful for discovering the role of independent matrix cues on cancer cell development. Here, we report a photo-curable and bio-orthogonal thiol-ene (i.e., cross-linked by mutually reactive norbornene and thiol groups via photoinitiation) hydrogel platform for studying the growth, morphogenesis, drug resistance, and cancer stem cell marker expression in PDAC cells cultured in 3D. The hydrogels were prepared from multi-arm poly(ethylene glycol)-norbornene cross-linked with protease-sensitive peptide to permit cell-mediated matrix remodeling. Collagen 1 fibrils were incorporated into the covalent network while cytokines (e.g., EGF and TGF-β1) were supplemented in the culture media for controlling cell fate. We found that the presence of collagen 1 enhanced cell proliferation and Yes-associated protein (YAP) translocation to cell nuclei. Cytokines and collagen 1 synergistically up-regulated MT1-MMP expression and induced cell spreading, suggestive of epithelial-mesenchymal transition (EMT) in the encapsulated cells. Furthermore, PDAC cells cultured in 3D developed chemo-resistance even in the absence of collagen 1 and cytokines. This phenotype is likely a consequence of the enrichment of pancreatic cancer stem cells that expressed high levels of CD24, sonic hedgehog (SHH), and vascular endothelial growth factor (VEGF). [ABSTRACT FROM AUTHOR]

Despite the recent expansion of peptide drugs, delivery remains a challenge due to poor localization and rapid clearance. Therefore, a hydrogel-based platform technology was developed to control and sustain peptide drug release via matrix metalloproteinase (MMP) activity. Specifically, hydrogels were composed of poly(ethylene glycol) and peptide drugs flanked by MMP substrates and terminal cysteine residues as crosslinkers. First, peptide drug bioactivity was investigated in expected released forms (e.g., with MMP substrate residues) in vitro prior to incorporation into hydrogels. Three peptides (Qk (from Vascular Endothelial Growth Factor), SPARC 113 , and SPARC 118 (from Secreted Protein Acidic and Rich in Cysteine)) retained bioactivity and were used as hydrogel crosslinkers in full MMP degradable forms. Upon treatment with MMP2, hydrogels containing Qk, SPARC 113 , and SPARC 118 degraded in 6.7, 6, and 1 days, and released 5, 8, and, 19% of peptide, respectively. Further investigation revealed peptide drug size controlled hydrogel swelling and degradation rate, while hydrophobicity impacted peptide release. Additionally, Qk, SPARC 113 , and SPARC 118 releasing hydrogels increased endothelial cell tube formation 3.1, 1.7, and 2.8-fold, respectively. While pro-angiogenic peptides were the focus of this study, the design parameters detailed allow for adaptation of hydrogels to control peptide release for a variety of therapeutic applications. [ABSTRACT FROM AUTHOR]

Hydrogels closely resemble the extracellular matrix (ECM) and can support cell proliferation while new tissue is formed, making them materials of choice as tissue engineering scaffolds. However, their sometimes-poor mechanical properties can hinder their application. The addition of meshes of nanofibers embedded in their matrix forms a composite that draws from the advantages of both components. Given that these materials are still in the early stages of development, there is a lack of uniformity across methods for characterizing their mechanical properties. Here, we propose a simple metric to enable comparisons between materials. The fibrous constituent improves the mechanical properties of the hydrogel, while the biocompatibility and functionality of the gels are maintained or even improved. [ABSTRACT FROM AUTHOR]

The similarity between the extracellular matrix of soft tissue and hydrogels, characterized by high-water-content viscoelastic polymeric networks, has been sustaining the advancement of hydrogels for tissue engineering and regenerative medicine (TERM) purposes. Current research on hydrogels has focused on introducing cell-adhesive peptides to promote cell adhesion and spreading, a critical applicability limitation. Here we report the development of gellan gum (GG) spongy-like hydrogels with ameliorated mechanical performance and flexibility in relation to hydrogels, using a simple and cost-effective method. Most importantly, these materials allow the entrapment of different cell types representing mesenchymal, epidermal and osteoblastic phenotypes that spread within the three-dimensional microstructure. This effect was associated with microstructural rearrangements characterized by pore wall thickening and pore size augmentation, and lower water content than precursor hydrogels. These properties significantly affected protein adsorption once cell adhesion was inhibited in the absence of serum. Spongy-like hydrogels are not adhesive for endothelial cells; however, this issue was surpassed by a pre-incubation with a cell-adhesive protein, as demonstrated for other substrates but not for traditional hydrogels. The proposed cell-compatible GG-based structures avoid time-consuming and expensive strategies that have been used to include cell-adhesive features in traditional hydrogels. This, associated with their off-the-shelf availability in an intermediary dried state, represents unique and highly relevant features for diverse TERM applications. [ABSTRACT FROM AUTHOR]

Development of a xenogeneic biological liver support is important in providing a bridge to transplantation or liver regeneration, thus helping to overcome the chronic shortage of liver donors. Among the critical factors in developing biological liver support are the creation of in vivo mimetic micro liver tissue (mLT), especially mLTs containing liver-specific ultrastructure, and an encapsulation method that can package massive numbers of cells while providing immune-protection from the host immune system. We describe here the development of mLTs that include liver microarchitecture and their in situ encapsulation in hydrogel composites. Concave microwells and the tri-culture of three types of primary liver cells were applied for the construction of mLTs showing excellent liver functions and long-term (>1 month) viability in vitro. Large quantities of rat mLTs were encapsulated in collagen-alginate composites, implanted into hepatic failure mice and sustained their survival during regeneration of the remaining liver. The proposed liver support system offers xenogeneic hepatic assistance by mimicking native liver microarchitecture and providing immune-protection without the need for complicated devices or processes, and as such represents a promising system for recovery of organ function. [ABSTRACT FROM AUTHOR]

Chitosan (CS)-based thermosensitive solutions that turn into semi-solid hydrogels upon injection at body temperature have increasingly drawn attention over the last decades as an attractive new type of in situ forming depot (ISFD) drug delivery system. Despite the great potential of the standard CS/β-glycerophosphate (β-GP) thermogelling solutions, their lack of stability over time at room temperature as well as at refrigerated conditions renders them unsuitable as ready-to-use drug product. In the present study, we investigated Glucose-1-Phosphate (G1-P) as an alternative gelling agent for improving the stability of CS-based ISFD solutions. The in vitro release performance of CS/G1-P formulations was assessed using several model compounds. Furthermore, the local tolerance of subcutaneously implanted CS/G1-P hydrogels was investigated by histological examination over three weeks. The thermogelling potential of CS/G1-P solutions, determined by rheology, is dependent on the polymer molecular weight (Mw) and concentration as well as on the G1-P concentration. Differential scanning calorimetry (DSC) measurements confirmed that sol/gel transition takes place at around body temperature and is not fully thermo-reversible. The long term storage stability was evaluated through the appearance, pH, viscosity and gelation time at 37 °C of the solution. The results emphasized an enhanced stability of the CS/G1-P system compared to the standard CS/β-GP. CS solution with 0.40 mmol/g G1-P is stable for at least 9 months at 2–8 °C, versus less than 1 month when using β-GP as gelling agent. Furthermore, the solution is easy to inject, as evidenced from injectability evaluation using 23–30 G needles. In vitro release experiments showed a sustained release over days to weeks for hydrophilic model compounds, demonstrating thereby that CS/G1-P may be suitable for the prolonged delivery of drugs. The inflammatory reaction observed in the tissue surrounding the hydrogel in rats was a typical foreign body reaction, similar to the one observed for CS/β-GP hydrogels. These features confirm the potential of CS/G1-P solutions as an injectable ready-to-use in situ forming hydrogel. [ABSTRACT FROM AUTHOR]

By providing a three-dimensional (3D) support to cells, hydrogels offer a more relevant in vivo tissue-like environment as compared to two-dimensional cell cultures. Hydrogels can be applied as screening platforms to investigate in 3D the role of biochemical and biophysical cues on cell behaviour using bioluminescent reporter cells. Gradients in oxygen concentration that result from the interplay between molecular transport and cell metabolism can however cause substantial variability in the observed bioluminescent reporter cell activity. To assess the influence of these oxygen gradients on the emitted bioluminescence for various hydrogel geometries, a combined experimental and modelling approach was implemented. We show that the applied model is able to predict oxygen gradient independent bioluminescent intensities which correlate better to the experimentally determined viable cell numbers, as compared to the experimentally measured bioluminescent intensities. By analysis of the bioluminescence reaction dynamics we obtained a quantitative description of cellular oxygen metabolism within the hydrogel, which was validated by direct measurements of oxygen concentration within the hydrogel. Bioluminescence peak intensities can therefore be used as a quantitative measurement of reporter cell activity within a hydrogel, but an unambiguous interpretation of these intensities requires a compensation for the influence of cell-induced oxygen gradients on the luciferase activity. [ABSTRACT FROM AUTHOR]

Abstract: Cancer stem-like cells (CSCs) are rare subpopulations of cancer cells that are reported to be responsible for cancer resistance and metastasis associated with conventional cancer therapies. Therefore, effective enrichment/culture of CSCs is of importance to both the understanding and treatment of cancer. However, it usually takes approximately 10 days for the widely used conventional approach to enrich CSCs through the formation of CSC-containing aggregates. Here we report the time can be shortened to 2 days while obtaining prostate CSC-containing aggregates with better quality based on the expression of surface receptor markers, dye exclusion, gene and protein expression, and in vivo tumorigenicity. This is achieved by encapsulating and culturing human prostate cancer cells in the miniaturized 3D liquid core of microcapsules with an alginate hydrogel shell. The miniaturized 3D culture in core–shell microcapsules is an effective strategy for enriching/culturing CSCs in vitro to facilitate cancer research and therapy development. [Copyright &y& Elsevier]

Purpose Bulkamid® is a new polyacrylamide hydrogel bulking agent for stress urinary incontinence that is injected in the urethral submucosa using a specifically designed device. We evaluated the safety and efficacy of Bulkamid vs Contigen® collagen gel for stress urinary incontinence or stress predominant mixed urinary incontinence. Materials and Methods This was a single-blind, randomized, prospective, 33-center, 2-arm parallel study of hydrogel vs collagen gel with followup to 1 year. At baseline patients underwent physical examination and bladder testing, and completed quality of life questionnaires and bladder diaries. After randomization patients could receive up to 3 injections at 1-month intervals. Patients were assessed 3, 6, 9 and 12 months after bulking. They completed bladder diaries and quality of life questionnaires, and pad weight was tested. At the last visit Valsalva leak point pressure was measured. Subjective and objective incontinence outcomes and adverse events were compared. Results Of the 345 women 229 were randomized to hydrogel and 116 were randomized to collagen gel. At 12 months a 50% or greater decrease in leakage and incontinence episodes was seen in 53.2% and 55.4% of patients who received hydrogel and collagen gel, respectively. At 12 months 47.2% of patients with hydrogel and 50% with collagen gel reported zero stress incontinence episodes, and 77.1% and 70%, respectively, considered themselves cured or improved. Major adverse events were rare in each group. Conclusions Bulkamid is not inferior to Contigen. It has a favorable, persistent effect on stress urinary incontinence with a low risk of serious adverse events. Bulkamid is a new, simple, office based bulking system that shows promise as a treatment in women with stress urinary incontinence, particularly since Contigen is no longer commercially available. r [ABSTRACT FROM AUTHOR]

Temperature-sensitive hydrogels were designed using a series of A-B-A triblock copolymers consisting of poly (ethylene glycol) (PEG) with different molecular weights as the hydrophilic block B and poly (β-butyrolactone-co-lactic acid)(PBLA) with varying block lengths and composition as the hydrophobic block A. The triblock copolymers were synthesized by ring-opening polymerization (ROP) of β-BL and LA in bulk using PEG as an initiator and Sn(Oct)2 as the catalyst. Their chemical structure and molecular characteristics were determined by NMR, GPC and DSC, and the relationship between structure and phase behaviors in aqueous solutions was investigated as well. It was found that the phase behaviors in aqueous solutions including critical micelle concentration (CMC), sol-gel-sedimentation phase transition temperature, gel window width and critical gelation concentration (CGC) are largely dependent on the molecular weight and block length ratio of PEG/PBLA. Most importantly, they show a very low CGC ranging from 4 to 8 wt% because of the introduction of β-BL. Furthermore, the biodegradability and biocompatibility of the hydrogels were evaluated. Finally, lysozyme as a model protein was used to evaluate the ability to deliver protein drugs in a sustained release manner and biologically active form. All results demonstrated that the temperature-sensitive in situ forming hydrogel has a promising potential as sustained delivery system for protein drugs. [ABSTRACT FROM AUTHOR]

Physical injuries of the central nervous system (CNS) are prevalent and very severe because the CNS has limited capacity to replace neuronal loss from the injury. A growing body of evidence has suggested that exogenous cell transplantation is one promising strategy to promote CNS regeneration. Direct injection of neural stem cells (NSCs) to the lesion site, however, may not be an optimal therapeutic strategy because of poor viability and functionality of transplanted cells resulting from the local hostile tissue environment. The overall objective of this study is to engineer an injectable and biocompatible hydrogel system as a supportive niche to provide a regeneration permissive microenvironment for transplanted NSCs to survive, functionally differentiate, and integrate with host tissues for CNS regeneration. A highly biocompatible hydrogel, based on thiol functionalized hyaluronic acid and thiol functionalized gelatin (Gtn-SH), which can be cross-linked by poly(ethylene glycol) diacrylate (PEGDA), was used. By controlling the cross-linking density via varying the amount of cross-linker (PEGDA) and the concentration of the adhesive component gelatin, an optimal microenvironment for the survival, proliferation, and neuronal differentiation of NSCs was created in vitro. The soft hydrogel of less than 10 Pa with Gtn-SH content (50%) is one of the optimal conditions to support NSCs growth and neuronal differentiation in vitro. The optimized hydrogel holds great potential as a carrier of stem cells to treat CNS injuries and diseases in which cell therapies may be essential. [ABSTRACT FROM AUTHOR]

Abstract: Alginate hydrogels are commonly used in biomedical applications such as scaffolds for tissue engineering, drug delivery, and as a medium for cell immobilisation. Multivalent cations are often employed to create physical crosslinks between carboxyl and hydroxyl moieties on neighbouring polysaccharide chains, creating hydrogels with a range of mechanical properties. This work describes the manufacture and characterisation of sodium alginate hydrogels using the divalent cations Mg2+, Ca2+ and Sr2+ to promote gelation via non-covalent crosslinks. Gelation time and Young׳s modulus are characterised as a function of cation and alginate concentrations. The implications of this work towards the use of environmental elasticity to control stem cell differentiation are discussed. [Copyright &y& Elsevier]

Meniscal tears are the most common orthopedic injuries to the human body, yet the current treatment of choice is a partial meniscectomy, which is known to lead to joint degeneration and osteoarthritis. As a result, there is a significant clinical need to develop materials capable of restoring function to the meniscus following an injury. Fiber-reinforced hydrogel composites are particularly suited for replicating the mechanical function of native fibrous tissues due to their ability to mimic the native anisotropic property distribution present. A critical issue with these materials, however, is the potential for the fiber-matrix interfacial properties to severely limit composite performance. In this work, the interfacial properties of an ultra-high-molecular-weight polyethylene (UHMWPE) fiber-reinforced poly(vinyl alcohol) (PVA) hydrogel are studied. A novel chemical grafting technique, confirmed using X-ray photoelectron spectroscopy, is used to improve UHMWPE-PVA interfacial adhesion. Interfacial shear strength is quantified using fiber pull-out tests. Results indicate significantly improved fiber-hydrogel interfacial adhesion after chemical grafting, where chemically grafted samples have an interfacial shear strength of 256.4±64.3kPa compared to 11.5±2.9kPa for untreated samples. Additionally, scanning electron microscopy of fiber surfaces after fiber pull-out reveal cohesive failure within the hydrogel matrix for treated fiber samples, indicating that the UHMWPE-PVA interface has been successfully optimized. Lastly, inter-fiber spacing is observed to have a significant effect on interfacial adhesion. Fibers spaced further apart have significantly higher interfacial shear strengths, which is critical to consider when optimizing composite design. The results in this study are applicable in developing similar chemical grafting techniques and optimizing fiber-matrix interfacial properties for other hydrogel-based composite systems. [ABSTRACT FROM AUTHOR]

The reversible attachment of proteins to polymers is one potential strategy to control protein release from hydrogels. In this study, we report the reversible attachment of lysozyme to poly(ethylene glycol) (PEG) by degradable carbamate linkers. Phenyl groups with different substituents were used to control the rate of carbamate hydrolysis and the resulting protein release. Sodium dodecyl sulfate polyacrylamide gel electrophoresis showed modification with 1–3 PEG chains per lysozyme molecule. Protein PEGylation and PEG chain elimination occurred without changes in secondary protein structure, as demonstrated by circular dichroism spectroscopy. The lytic activity of lysozyme was restored to 73.4±1.7%–92.5±1.2% during PEG chain elimination. Attached PEG chains were eliminated within 24h to 28days, depending on the used linker molecule. When formulated into hydrogels, a maximum of about 60% of the initial dose was released within 7days to 21days. Linker elimination occurs ‘traceless’, so that the protein is released in its native, unmodified form. Altogether, we believe that tethering proteins by degradable carbamate linkers is a promising strategy to control their release from hydrogels. [ABSTRACT FROM AUTHOR]

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: Metastatic melanoma is highly resistant to drug treatment, and the underlying mechanisms of this resistance remain unclear. Increased tissue stiffness is correlated with tumor progression, but whether increased tissue stiffness contributes to treatment resistance in melanoma is not known. To investigate the effect of substrate stiffness on melanoma cell treatment responsiveness, PEG hydrogels were utilized as a cell culture system to precisely vary matrix elasticity and investigate melanoma cell responses to a commercially available pharmacological inhibitor (PLX4032). The tensile moduli were varied between 0.6 and 13.1 kPa (E) and the effects of PLX4032 on metabolic activity, apoptosis, and proliferation were evaluated on human cell lines derived from radial growth phase (WM35) and metastatic melanoma (A375). The A375 cells were found to be stiffness-independent; matrix elasticity did not alter cell morphology or apoptosis with PLX4032 treatment. The WM35 cells, however, were more dependent on substrate modulus, displaying increased apoptosis and smaller focal adhesions on compliant substrates. Culturing melanoma cells on PEG hydrogels revealed stage-dependent responses to PLX4032 that would have otherwise been masked if cultured strictly on TCPS. These findings demonstrate the utility of PEG hydrogels as a versatile in vitro culture platform with which to investigate the molecular mechanisms of melanoma biology and treatment responsiveness. [Copyright &y& Elsevier]

Abstract: Three-dimensional (3D) tissue-engineered tumor models have the potential to bridge the gap between monolayer cultures and patient-derived xenografts for the testing of nanoparticle (NP)-based cancer therapeutics. In this study, a hydrogel-derived prostate cancer (PCa) model was developed for the in vitro evaluation of doxorubicin (Dox)-loaded polymer NPs (Dox-NPs). The hydrogels were synthesized using chemically modified hyaluronic acid (HA) carrying acrylate groups (HA-AC) or reactive thiols (HA-SH). The crosslinked hydrogel networks exhibited an estimated pore size of 70–100 nm, similar to the spacing of the extracellular matrices (ECM) surrounding tumor tissues. LNCaP PCa cells entrapped in the HA matrices formed distinct tumor-like multicellular aggregates with an average diameter of 50 μm after 7 days of culture. Compared to cells grown on two-dimensional (2D) tissue culture plates, cells from the engineered tumoroids expressed significantly higher levels of multidrug resistance (MDR) proteins, including multidrug resistance protein 1 (MRP1) and lung resistance-related protein (LRP), both at the mRNA and the protein levels. Separately, Dox-NPs with an average diameter of 54 ± 1 nm were prepared from amphiphilic block copolymers based on poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) bearing pendant cyclic ketals. Dox-NPs were able to diffuse through the hydrogel matrices, penetrate into the tumoroid and be internalized by LNCaP PCa cells through caveolae-mediated endocytosis and macropinocytosis pathways. Compared to 2D cultures, LNCaP PCa cells cultured as multicellular aggregates in HA hydrogel were more resistant to Dox and Dox-NPs treatments. Moreover, the NP-based Dox formulation could bypass the drug efflux function of MRP1, thereby partially reversing the resistance to free Dox in 3D cultures. Overall, the engineered tumor model has the potential to provide predictable results on the efficacy of NP-based cancer therapeutics. [Copyright &y& Elsevier]

Abstract: Hydrogels have been widely used for 3-dimensional (3D) cell culture and tissue regeneration due to their tunable biochemical and physicochemical properties as well as their high water content, which resembles the aqueous microenvironment of the natural extracellular matrix. While many properties of natural hydrogel matrices are modifiable, their intrinsic isotropic structure limits the control over cellular organization, which is critical to restore tissue function. Here we report a generic approach to incorporate alignment topography inside the hydrogel matrix using a combination of electrical and mechanical stretching. Hydrogel fibres with uniaxial alignment were prepared from aqueous solutions of natural polymers such as alginate, fibrin, gelatin, and hyaluronic acid under ambient conditions. The unique internal alignment feature drastically enhances the mechanical properties of the hydrogel microfibres. Furthermore, the facile, organic solvent-free processing conditions are amenable to the incorporation of live cells within the hydrogel fibre or on the fibre surface; both approaches effectively induce cellular alignment. This work demonstrates a versatile and scalable strategy to create aligned hydrogel microfibres from various natural polymers. [Copyright &y& Elsevier]

Abstract: Regeneration of chronic myocardial infarction (CMI) is one of the challenging issues due to its limited regeneration activity compared to acute or sub-acute stage. In this study, we examined whether combination of stem cell homing factor (SDF-1) and angiogenic peptides (Ac-SDKP) injected with biomimetic hydrogels promote regeneration of cardiac function in a CMI model. We evaluated the regeneration of chronically infarcted myocardium using injectable biomimetic hydrogels containing two therapeutic factors; stromal-derived factor-1 (SDF-1) and Ac-SDKP for stem cell homing and angiogenesis, respectively. Injection of the two therapeutic factors into the infarct region of the left ventricle showed that the biomimetic hydrogels containing two therapeutic factor exhibited significantly improved left ventricle function, increased angiogenesis, decreased infarct size and greatest wall thickness within the infarct region at 4 weeks post-treatment. From these results, it is clear that hydrogels containing two therapeutic factors showed synergistic effects on regeneration in the chronic heart failure model. In conclusion, these results suggest that combination of stem cell homing factor with angiogenic peptides recruit stem cells to the microenvironments, increase the expression of angiogenic genes, enhance the matured vessel formation and improve the cardiac function in chronic MI. [Copyright &y& Elsevier]

Abstract: Photocrosslinked hyaluronic acid (HA) hydrogels provide a conducive 3-D environment that supports the chondrogenesis of human mesenchymal stem cells (hMSCs). The HA macromer concentration in the hydrogels has a significant impact on the chondrogenesis of the encapsulated MSCs due to changes in the physical properties of the hydrogels. Meanwhile, hypoxia has been shown to promote MSC chondrogenesis and suppress subsequent hypertrophy. This study investigates the combinatorial effect of tuning HA macromer concentration (1.5–5%w/v) and hypoxia on MSC chondrogenesis and hypertrophy. To decouple the effect of HA concentration from that of crosslinking density, the HA hydrogel crosslinking density was adjusted by varying the extent of the reaction through the light exposure time while keeping the HA concentration constant (5%w/v at 5 or 15min). It was found that hypoxia had no significant effect on the chondrogenesis and cartilaginous matrix synthesis of hMSCs under all hydrogel conditions. In contrast, the hypoxia-mediated positive or negative regulation of hMSC hypertrophy in HA hydrogels is dependent on the HA concentration but independent of the crosslinking density. Specifically, hypoxia significantly suppressed hMSC hypertrophy and neocartilage calcification in low HA concentration hydrogels, whereas hypoxia substantially enhanced hMSC hypertrophy, leading to elevated tissue calcification in high HA concentration hydrogels irrespective of their crosslinking density. In addition, at a constant high HA concentration, increasing hydrogel crosslinking density promoted hMSC hypertrophy and matrix calcification. To conclude, the findings from this study demonstrate that the effect of hypoxia on hMSC chondrogenesis and hypertrophy is differentially influenced by the encapsulating HA hydrogel properties. [Copyright &y& Elsevier]

Abstract: The load-bearing biomechanical role of the intervertebral disc is governed by the composition and organization of its major macromolecular components, collagen and aggrecan. The major function of aggrecan is to maintain tissue hydration, and hence disc height, under the high loads imposed by muscle activity and body weight. Key to this role is the high negative fixed charge of its glycosaminoglycan side chains, which impart a high osmotic pressure to the tissue, thus regulating and maintaining tissue hydration and hence disc height under load. In degenerate discs, aggrecan degrades and is lost from the disc, particularly centrally from the nucleus pulposus. This loss of fixed charge results in reduced hydration and loss of disc height; such changes are closely associated with low back pain. The present authors developed biomimetic glycosaminoglycan analogues based on sulphonate-containing polymers. These biomimetics are deliverable via injection into the disc where they polymerize in situ, forming a non-degradable, nuclear “implant” aimed at restoring disc height to degenerate discs, thereby relieving back pain. In vitro, these glycosaminoglycan analogues possess appropriate fixed charge density, hydration and osmotic responsiveness, thereby displaying the capacity to restore disc height and function. Preliminary biomechanical tests using a degenerate explant model showed that the implant adapts to the space into which it is injected and restores stiffness. These hydrogels mimic the role taken by glycosaminoglycans in vivo and, unlike other hydrogels, provide an intrinsic swelling pressure, which can maintain disc hydration and height under the high and variable compressive loads encountered in vivo. [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 series of high refractive index (RI) ZnS/PVP/PDMAA hydrogel nanocomposites containing ZnS nanoparticles (NPs) were successfully synthesized via a simple ultraviolet-light-initiated free radical co-polymerization method. The average diameter of the ZnS NPs is ∼3nm and the NPs are well dispersed and stabilized in the PVP/PDMAA hydrogel matrix up to a high content of 60wt.% in the hydrogel nanocomposites. The equilibrium water content of ZnS/PVP/PDMAA hydrogel nanocomposites varied from 82.0 to 66.8wt.%, while the content of mercaptoethanol-capped ZnS NPs correspondingly varied from 30 to 60wt.%. The resulting nanocomposites are clear and transparent and their RIs were measured to be as high as 1.58–1.70 and 1.38–1.46 in the dry and hydrated states, respectively, which can be tuned by varying the ZnS NPs content. In vitro cytotoxicity assays suggested that the introduction of ZnS NPs added little cytotoxicity to the PVP/PDMAA hydrogel and all the hydrogel nanocomposites exhibited minimal cytotoxicity towards common cells. The hydrogel nanocomposites implanted in rabbit eyes can be well tolerated over 3weeks. Hence, the high RI ZnS/PVP/PDMAA hydrogel nanocomposites with adjustable RIs developed in this work might potentially be a candidate material for artificial corneal implants. [Copyright &y& Elsevier]

Temperature-sensitive hydrogels hold great promise in biological applications as they can respond to changes in physiological temperature to produce a desired effect like controlled drug delivery. In this study, a series of poly(N-isopropylacrylamide-co-N-vinyl-2-pyrrolidinone) thermosensitive hydrogels were synthesized by radical copolymerization of NIPAm with 1-vinyl-2-pyrrolidinone (NVP). By altering the initial NIPAm/NVP mole ratios, copolymers were synthesized to have their own distinctive lower critical solution temperature which was established using differential scanning calorimetry. The swelling behavior of the hydrogel was analyzed gravimetrically and it was observed that reswelling rate increases with increasing NVP mole ratio. Further characterizations of the hydrogels were per-formed using Fourier transform infrared spectroscopy and scanning electron microscopy. Release kinetics with respect to temperature was studied using methy-lene blue dye solution and vitamin B12. Kinetic modeling of the release profile revealed that the release mechanism is a non-Fickian diffusion mechanism. These results suggested that this material has potential application as intelligent drug carri-ers. The quantities of residual monomers in the PIV4 hydrogel were determined by HPLC method, and the results show almost complete conversion. [ABSTRACT FROM AUTHOR]

Abstract: Cell-based drug delivery systems (DDSs) have been increasingly exploited because cells can be utilized as a continuous drug delivering system to produce therapeutic molecules over a more extended period compared to the simple drug carriers. Although hydrogels have many advantages for this application, their mechanical properties are generally not desirable to structurally protect implanted cells. Here, we present a three-dimensional (3D) hybrid scaffold with a combination of a 3D framework and a hydrogel to enhance the mechanical properties without chemically altering the transport properties of the hydrogel. Based on the 3D Ormocomp scaffold (framework) fabricated by projection-based microstereolithography with defined parameters, we developed a 3D hybrid scaffold by injection of the mixture of cells and the alginate gel into the internal space of the framework. This hybrid scaffold showed the improved mechanical strength and the framework in the scaffold played the role of an adhesion site for the encapsulated cells during the culture period. Additionally, we confirmed its protection of exogenous human cells from acute immune rejection in a mouse model. Eventually, we demonstrated the feasibility of applying this hybrid scaffold to the treatment of Parkinson's disease as a cell-based DDS. Dopamine released from the 3D hybrid scaffolds encapsulating dopamine-secreting cells for 8weeks suggested its clinical applicability. Further study on its long-term efficacy is necessary for the clinical applicability of this 3D hybrid scaffold for the treatment of Parkinson's disease. [Copyright &y& Elsevier]

Abstract: We developed an injectable hydrogel system to evaluate the effect of hydrogel stiffness on chondrocyte cellular functions in a three-dimensional (3D) environment and its subsequent influence on ectopic cartilage formation and early-stage osteochondral defect repair in a rabbit model. The hydrogels, composed of gelatin-hydroxyphenylpropionic acid (Gtn-HPA) conjugate, were formed using oxidative coupling of HPA moieties catalyzed by hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). The storage modulus (G′) of the hydrogels, which was tunable by changing the H2O2 and Gtn-HPA concentrations, ranged from 570 Pa to 2750 Pa. It was found that the cellular functions of chondrocytes encapsulated in hydrogels, including cell proliferation, biosynthesis of collagen and sulfated glycosaminoglycans (sGAG), as well as gene expression of type I (Col-I) and type II collagen (Col-II), were strongly affected by the stiffness of the hydrogels. Of note, chondrocytes cultured within the Gtn-HPA hydrogel of medium stiffness (G′ = 1000 Pa) produced highest level of sGAG production, as well as highest ratio of Col-II to Col-I gene expression among the Gtn-HPA hydrogels of different stiffness. Consistent with the results from in vitro and in vivo ectopic cartilage formation, osteochondral defect repair in a rabbit model showed stiffness-dependent tissue repair, with defects implanted with chondrocytes in hydrogels of medium stiffness having markedly more hyaline cartilage formation, smoother surface and better integration with adjacent cartilage, compared to defects treated with hydrogels of low or high stiffness. These results suggest that the tunable stiffness of Gtn-HPA hydrogels modulates chondrocyte cellular functions, and has a dramatic impact on cartilage tissue histogenesis and repair. [Copyright &y& Elsevier]

The article focuses on researches based on hydrogel materials. Topics discussed include methods of preparing hydrogel materials, their chemical properties and applications of hydrogel materials in medical device coating, tissue engineering and drug delivery. The mechanical characterization techniques for hydrogel materials including universal test frame, indentation and frequency based testing have also been discussed.

Abstract: Temperature has been extensively explored as a trigger to control the delivery of a payload from environment-sensitive polymers. The need for an external heat source only allows limited spatiotemporal control over the delivery process. We propose a new approach by using the dissipative properties of a hydrogel matrix as an internal heat source when the material is mechanically loaded. The system is comprised of a highly dissipative hydrogel matrix and thermo-sensitive nanoparticles that shrink upon an increase in temperature. Exposing the hydrogel to a cyclic mechanical loading for a period of 5 min leads to an increase of temperature of the nanoparticles. The concomitant decrease in the volume of the nanoparticles increases the permeability of the hydrogel network facilitating the release of its payload. As a proof-of-concept, we showed that the payload of the hydrogel is released after 5–8 min following the initiation of the mechanical loading. This delivery method would be particularly suited for the release of growth factor as it has been shown that cell receptor to growth factor is activated 5–20 min following a mechanical loading. [Copyright &y& Elsevier]

Abstract: Phenol derivative-containing adhesive hydrogels has been widely recognized as having potential for biomedical applications, but their conventional production methods, utilizing a moderate/strong base, alkaline buffers, the addition of oxidizing agents or the use of enzymes, require alternative approaches to improve their biocompatibility. In this study, we report a polymeric, enzyme-mimetic biocatalyst, hematin-grafted chitosan (chitosan-g-hem), which results in effective gelation without the use of alkaline buffers or enzymes. Furthermore, gelation occurs under mild physiological conditions. Chitosan-g-hem biocatalyst (0.01%, w/v) has excellent catalytic properties, forming chitosan–catechol hydrogels rapidly (within 5min). In vivo adhesive force measurement demonstrated that the hydrogel formed by the chitosan-g-hem activity showed an increase in adhesion force (33.6±5.9kPa) compared with the same hydrogel formed by pH-induced catechol oxidation (20.6±5.5kPa) in mouse subcutaneous tissue. Using the chitosan-g-hem biocatalyst, other catechol-functionalized polymers (hyaluronic acid–catechol and poly(vinyl alcohol)–catechol) also formed hydrogels, indicating that chitosan-g-hem can be used as a general polymeric catalyst for preparing catechol-containing hydrogels. [Copyright &y& Elsevier]

Abstract: Stimuli triggered polymers provide a variety of applications related with the biomedical fields. Among various stimuli triggered mechanisms, thermoresponsive mechanisms have been extensively investigated, as they are relatively more convenient and effective stimuli for biomedical applications. In a contemporary approach for achieving the sustained action of proteins, peptides and bioactives, injectable depots and implants have always remained the thrust areas of research. In the same series, Poloxamer based thermogelling copolymers have their own limitations regarding biodegradability. Thus, there is a need to have an alternative biomaterial for the formulation of injectable hydrogel, which must remain biocompatible along with safety and efficacy. In the same context, poly(ethylene glycol) (PEG) based copolymers play a crucial role as a biomedical material for biomedical applications, because of their biocompatibility, biodegradability, thermosensitivity and easy controlled characters. This review stresses on the physicochemical property, stability and composition prospects of smart PEG/poly(lactic-co-glycolic acid) (PLGA) based thermoresponsive injectable hydrogels, recently utilized for biomedical applications. The manuscript also highlights the synthesis scheme and stability characteristics of these copolymers, which will surely help the researchers working in the same area. We have also emphasized the applied use of these smart copolymers along with their formulation problems, which could help in understanding the possible modifications related with these, to overcome their inherent associated limitations. [Copyright &y& Elsevier]

Abstract: Current antimicrobial strategies have mostly been developed to manage infections due to planktonic cells. However, microbes in their nature state will tend to exist by attaching to and growing on living and inanimate surfaces that result in the formation of biofilms. Conventional therapies for treating biofilm-related infections are likely to be insufficient due to the lower susceptibility of microbes that are embedded in the biofilm matrix. In this study, we report the development of biodegradable hydrogels from vitamin E-functionalized polycarbonates for antimicrobial applications. These hydrogels were formed by incorporating positively-charged polycarbonates containing propyl and benzyl side chains with vitamin E moiety into physically cross-linked networks of “ABA”-type polycarbonate and poly(ethylene glycol) triblock copolymers. Investigations of the mechanical properties of the hydrogels showed that the G′ values ranged from 1400 to 1600 Pa and the presence of cationic polycarbonate did not affect the stiffness of the hydrogels. Shear-thinning behavior was observed as the hydrogels displayed high viscosity at low shear rates that dramatically decreased as the shear rate increased. In vitro antimicrobial studies revealed that the more hydrophobic VE/BnCl(1:30)-loaded hydrogels generally exhibited better antimicrobial/antifungal effects compared to the VE/PrBr(1:30) counterpart as lower minimum biocidal concentrations (MBC) were observed in Staphylococcus aureus (Gram-positive), Escherichia coli (Gram-negative) and Candida albicans (fungus) (156.2, 312.5, 312.5 mg/L for VE/BnCl(1:30) and 312.5, 2500 and 625 mg/L for VE/PrBr(1:30) respectively). Similar trends were observed for the treatment of biofilms where VE/BnCl(1:30)-loaded hydrogels displayed better efficiency with regards to eradication of biomass and reduction of microbe viability of the biofilms. Furthermore, a high degree of synergistic antimicrobial effects was also observed through the co-delivery of antimicrobial polycarbonates with a conventionally-used antifungal agent, fluconazole. These hydrogels also displayed excellent compatibility with human dermal fibroblasts with cell viability >80% after treatment with hydrogels loaded with cationic polymers and/or fluconazole at minimum biocidal concentrations (MBC). [Copyright &y& Elsevier]

Abstract: Non-viral gene delivery holds great promise for promoting tissue regeneration, and offers a potentially safer alternative than viral vectors. Great progress has been made to develop biodegradable polymeric vectors for non-viral gene delivery in 2D culture, which generally involves isolating and modifying cells in vitro, followed by subsequent transplantation in vivo. Scaffold-mediated gene delivery may eliminate the need for the multiple-step process in vitro, and allows sustained release of nucleic acids in situ. Hydrogels are widely used tissue engineering scaffolds given their tissue-like water content, injectability and tunable biochemical and biophysical properties. However, previous attempts on developing hydrogel-mediated non-viral gene delivery have generally resulted in low levels of transgene expression inside 3D hydrogels, and increasing hydrogel stiffness further decreased such transfection efficiency. Here we report the development of biodegradable polymeric vectors that led to efficient gene delivery inside poly(ethylene glycol) (PEG)-based hydrogels with tunable matrix stiffness. Photocrosslinkable gelatin was maintained constant in the hydrogel network to allow cell adhesion. We identified a lead biodegradable polymeric vector, E6, which resulted in increased polyplex stability, DNA protection and achieved sustained high levels of transgene expression inside 3D PEG-DMA hydrogels for at least 12 days. Furthermore, we demonstrated that E6-based polyplexes allowed efficient gene delivery inside hydrogels with tunable stiffness ranging from 2 to 175 kPa, with the peak transfection efficiency observed in hydrogels with intermediate stiffness (28 kPa). The reported hydrogel-mediated gene delivery platform using biodegradable polyplexes may serve as a local depot for sustained transgene expression in situ to enhance tissue engineering across broad tissue types. [Copyright &y& Elsevier]

Abstract: Intervertebral disc (IVD) degeneration is one of the leading causes of lower back pain and a major health problem worldwide. Current surgical treatments include excision or immobilisation, with neither approach resulting in the repair of the degenerative disc. As such, a tissue engineering-based approach in which stem cells, coupled with an advanced delivery system, could overcome this deficiency and lead to a therapy that encourages functional fibrocartilage generation in the IVD. In this study, we have developed an injectable hydrogel system based on enzymatically-crosslinked polyethylene glycol and hyaluronic acid. We examined the effects of adding pentosan polysulphate (PPS), a synthetic glycosaminoglycan-like factor that has previously been shown (in vitro and in vivo) to this gel system in order to induce chondrogenesis in mesnchymal precursor cells (MPCs) when added as a soluble factor, even in the absence of additional growth factors such as TGF-β. We show that both the gelation rate and mechanical strength of the resulting hydrogels can be tuned in order to optimise the conditions required to produce gels with the desired combination of properties for an IVD scaffold. Human immunoselected STRO-1+ MPCs were then incorporated into the hydrogels. They were shown to retain good viability after both the initial formation of the gel and for longer-term culture periods in vitro. Furthermore, MPC/hydrogel composites formed cartilage-like tissue which was significantly enhanced by the incorporation of PPS into the hydrogels, particularly with respect to the deposition of type-II-collagen. Finally, using a wild-type rat subcutaneous implantation model, we examined the extent of any immune reaction and confirmed that this matrix is well tolerated by the host. Together these data provide evidence that such a system has significant potential as both a delivery vehicle for MPCs and as a matrix for fibrocartilage tissue engineering applications. [Copyright &y& Elsevier]

Abstract: A wide variety of hydrogels have been explored as 3D culture platforms and for applications in tissue engineering. Hydrogels formed from natural extracellular matrix (ECM) proteins readily support the formation of vasculature in vitro, but only a handful of hydrogels composed of synthetic materials have shown anything comparable. This relative lack of synthetic material options has hindered efforts to better understand how ECM cues direct vascularization. We developed a biosynthetic hydrogel consisting of polyethylene glycol diacrylamide conjugated to macromolecular type-I collagen. Through their acrylamide-based crosslinks, these materials allow for independent control of physical properties and bulk ligand concentration. These hydrogels exhibited hydrolytic stability, but the collagen component retained its susceptibility to enzymatic remodeling. Photoencapsulation of endothelial cells and fibroblasts within this hydrogel material and their subsequent co-culture led to the formation of capillary vessel-like networks with well-defined hollow lumens. Capillary formation was prevented by inhibiting matrix metalloproteinase (MMP) activity, recapitulating the MMP-dependence of vascularization observed in natural hydrogels. These findings validate the utility of this material platform to decipher how the ECM regulates capillary morphogenesis and to support the formation of vascularized tissue constructs for potential applications in regenerative medicine. [Copyright &y& Elsevier]

A series of biodegradable hydrogels based on dextran and poly(L-glutamic acid) were fabricated for effective vancomycin loading and release. The preparation of hydrogels was simply achieved by photo cross-linking of methacrylated dextran and poly(L-glutamic acid)- g-hydroxyethyl methacrylate (PGH) in the presence of photoinitiator I2959. The structures of hydrogels were characterized by FTIR and SEM. The swelling and enzymatic degradation behaviors of hydrogels were examined to be dependent on the poly(L-glutamic acid) content in the hydrogels. The higher content of poly(L-glutamic acid) in the gel, the higher swelling ratio and quicker degradation were observed. More interestingly, the hydrogel with higher PGH ratio showed higher vancomycin (VCM) loading content, which might be due to the electrostatic interaction between carboxylate groups in hydrogel and ammonium group of VCM. In vitro drug release from the VCM-loaded hydrogels in aqueous solution exhibited sustained release of VCM up to 72 h, while the in vitro antibacterial test based on the VCM-loaded hydrogel showed an efficient Methicillin-Resistant S. aureus (MRSA) inhibition extending out to 7 days. These results demonstrated that the biodegradable hydrogels which formed by in situ photo-cross linking would be promising as scaffolds or coatings for local antibacterial drug release in tissue engineering. [ABSTRACT FROM AUTHOR]

Abstract: Microparticles capable of releasing protein drugs are often incorporated into injectable hydrogels to minimize their displacement at an implantation site, reduce initial drug burst, and further control drug release rates over a broader range. However, there is still a need to develop methods for releasing drug molecules over extended periods of time, in order to sustain the bioactivity of drug molecules at an implantation site. In this study, we hypothesized that a hydrogel formed through the cross-linking of pyrrole units linked to a hydrophilic polymer would release protein drugs in a more sustained manner, because of an enhanced association between cross-linked pyrrole groups and the drug molecules. To examine this hypothesis, we prepared hydrogels of alginate substituted with pyrrole groups, alginate-g-pyrrole, through a horse-radish peroxidase (HRP)-activated cross-linking of the pyrrole groups. The hydrogels were encapsulated with poly(lactic-co-glycolic acid) (PLGA) microparticles loaded with vascular endothelial growth factor (VEGF). The resulting hydrogel system released VEGF in a more sustained manner than Ca2+ alginate or Ca2+ alginate-g-pyrrole gel systems. Finally, implantations of the VEGF-releasing HRP-activated alginate-g-pyrrole hydrogel system on chicken chorioallantoic membranes resulted in the formation of blood vessels in higher densities and with larger diameters, compared to other control conditions. Overall, the drug releasing system developed in this study will be broadly useful for regulating release rates of a wide array of protein drugs, and further enhance the quality of protein drug-based therapies. [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]

Abstract: In this study, an injectable calcium silicate (CS)/sodium alginate (SA) hybrid hydrogel was prepared using a novel material composition design. CS was incorporated into an alginate solution and internal in situ gelling was induced by the calcium ions directly released from CS with the addition of d-gluconic acid δ-lactone (GDL). The gelling time could be controlled, from about 30s to 10min, by varying the amounts of CS and GDL added. The mechanical properties of the hydrogels with different amounts of CS and GDL were systematically analyzed. The compressive strength of 5% CS/SA hydrogels was higher than that of 10% CS/SA for the same amount of GDL. The swelling behaviors of 5% CS/SA hydrogels with different contents of GDL were therefore investigated. The swelling ratios of the hydrogels decreased with increasing GDL, and 5% CS/SA hydrogel with 1% GDL swelled by only less than 5%. Scanning electron microscopy (SEM) observation of the scaffolds showed an optimal interconnected porous structure, with the pore size ranging between 50 and 200μm. Fourier transform infrared spectroscopy and SEM showed that the CS/SA composite hydrogel induced the formation of hydroxyapatite on the surface of the materials in simulated body fluid. In addition, rat bone mesenchymal stem cells (rtBMSCs) cultured in the presence of hydrogels and their ionic extracts were able to maintain the viability and proliferation. Furthermore, the CS/SA composite hydrogel and its ionic extracts stimulated rtBMSCs to produce alkaline phosphatase, and its ionic extracts could also promote angiogenesis of human umbilical vein endothelial cells. Overall, all these results indicate that the CS/SA composite hydrogel efficiently supported the adhesion, proliferation and differentiation of osteogenic and angiogenic cells. Together with its porous three-dimensional structure and injectable properties, CS/SA composite hydrogel possesses great potential for bone regeneration and tissue engineering applications. [Copyright &y& Elsevier]

Abstract: Hydrogels are finding increased clinical utility as advances continue to exploit their favorable material properties. Hydrogels can be adapted for many applications, including surface coatings and drug delivery. Anti-infectious surfaces and delivery systems that actively destroy invading organisms are alternative ways to exploit the favorable material properties offered by hydrogels. Sterilization techniques are commonly employed to ensure the materials are non-infectious upon placement, but sterilization is not absolute and infections are still expected. Natural, anti-bacterial proteins have been discovered which have the potential to act as anti-infectious agents; however, the proteins are toxic and need localized release to have therapeutic efficacy without toxicity. In these studies, we explore the use of the glutathione s-transferase (GST) to anchor the bactericidal peptide, melittin, to the surface of poly(ethylene glycol) diacrylate (PEGDA) hydrogel microspheres. We show that therapeutic levels of protein can be anchored to the surface of the microspheres using the GST anchor. We compared the therapeutic efficacy of recombinant melittin released from PEGDA microspheres to melittin. We found that, when released by an activating enzyme, thrombin, recombinant melittin efficiently inhibits growth of the pathogenic bacterium Streptococcus pyogenes as effectively as melittin created by solid phase peptide synthesis. We conclude that a GST protein anchor can be used to immobilize functional protein to PEGDA microspheres and the protein will remain immobilized under physiological conditions until the protein is enzymatically released. [Copyright &y& Elsevier]

The objective of this study was to develop a novel antimicrobial seaweed wound dressing. The seaweed extract was active against nine clinically-relevant wound pathogens. A hydrogel formulation was prepared using polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP), followed by addition of 1% seaweed extract. The antimicrobial properties of the novel dressing were tested using agar diffusion assays, with release-profiles examined using gel leaching and gel transfer assays. The dressing was found to be effective against the same microbial strains as the seaweed extract, with similar efficacy to the commonly used silver-based dressing, Acticoat®. Antimicrobial release-profile assays revealed that the dressing was effective in inhibiting 70–90% of the bacterial population within the first 30min, followed by a long, sustained released up to 97h, without leaving a residue following five subsequent transfers of the dressing. Antimicrobial activity was stable for up to 6 months of storage at 4°C, but activity was reduced slightly after 15 weeks. Following autoclave sterilization, the dressing displayed a slower release profile compared to a non-autoclaved counterpart. Hence, the seaweed dressing may have commercial applications, potentially competing with silver-based dressings at a lower cost per-application. This is the first report of development of a seaweed-based antimicrobial dressing. [ABSTRACT FROM AUTHOR]

Abstract: Our objective was to characterize the elasticity of hydrogel formulations intended to mimic physical properties that cells and tissues experience in vivo. Using atomic force microscopy (AFM), we tested a variety of concentrations in a variety of biomaterials, including agarose, alginate, the collagens, fibrin, hyaluronic acid, kerateine, laminin, Matrigel, polyacrylamide, polyethylene glycol diacrylate (PEGDA) and silicone elastomer (polydimethylsiloxane). Manipulations of the concentration of biomaterials were detectable in AFM measurements of elasticity (Young′s modulus, E), and E tended to increase with increased concentration. Depending on the biomaterials chosen, and their concentrations, generation of tunable biocompatible hydrogels in the physiologic range is possible. [Copyright &y& Elsevier]

In vitro and in vivo experimentation of various synthetic polymer hydrogels was conducted to establish some of the integral material properties that influence hemostasis. In vitro swelling experiments suggested that positive electrostatic charge was a key determinant of the ability of a polymer hydrogel to absorb physiological fluids, e.g. human plasma and blood. In vitro testing using unadulterated sheep blood suggested positive electrostatic charge and crosslink density were key determinants of the ability of a material to induce or enhance clot formation. Hydrogel formulations composed of higher amounts of positive electrostatic charge and lower crosslink density were able to effectively induce and enhance clot formation in the presence of a coagulation cascade activator. In vivo experimentation confirmed that hydrogels containing higher electrostatic charge and low crosslink density are more effective at fostering the formation of a robust hemostatic plug to control blood loss. [ABSTRACT FROM AUTHOR]

The synergy between nanostructured lipid carriers (NLC) and chemical penetration enhancers provides the basis for a promising strategy to effectively deliver drugs through the skin. In the present work, focus is given to the study of the interaction of limonene, ethanol, and Carbopol Ultrez 10NF, as the gelling agent, with a co-encapsulating NLC dispersion, containing both olanzapine and simvastatin. The analysis is based on rheological, mechanical, and physicochemical properties. The nanoparticle size ranged from 130 to 400 nm, depending on the system considered. The inclusion of carbopol resulted in a considerable increase in the NLC particle size, which was attributed to carbomer bridging nanoparticles, resulting in some particle aggregation. Rheological measurements indicated that the viscosity of the neat carbopol hydrogel was reduced by the enhancers and to a higher extent by the presence of NLC. A more apolar medium can be pointed out as a general explanation, while a polymer/nanoparticle hydrophobic interaction coupled with surfactant/polymer H-bonding provides the rationale for the NLC effect. The inclusion of enhancers and a carbomer largely contributed to the physicochemical stability of the NLC formulation, as revealed by the low transmission profiles and more negative zeta potential values. [ABSTRACT FROM AUTHOR]

Highlights: [•] Physical and chemical basis for collagen triple helix stabilization. [•] Higher-order assembly of collagen like peptides. [•] Self-assembly of CLP–polymer conjugates for drug delivery. [•] CLP containing hydrogels for tissue engineering. [ABSTRACT FROM AUTHOR]