Poly(2‐oxazoline) hydrogels crosslinked with aliphatic bis(2‐oxazoline)s: Properties,cytotoxicity, and cell cultivation

A series of hydrogels from 2‐ethyl‐2‐oxazoline and three bis(2‐oxazoline) crosslinkers—1,4‐butylene‐2,2′‐bis(2‐oxazoline), 1,6‐hexamethylene‐2,2′‐bis(2‐oxazoline), and 1,8‐octamethylene‐2,2′‐bis(2‐oxazoline)—are prepared. The hydrogels differ by the length of aliphatic chain of crosslinker and by the percentage of crosslinker (2–10%). The influence of the type and the percentage of the crosslinker on swelling properties, mechanical properties, and state of water is studied. The equilibrium swelling degree in water ranges from 2 to 20. With a proper selection of the crosslinker, Young's modulus can be varied from 10 kPa to almost 100 kPa. To evaluate the potential for medical applications, the cytotoxicity of extracts and the contact toxicity toward murine fibroblasts are measured. The hydrogels with the crosslinker containing a shorter aliphatic exhibit low toxicity toward fibroblast cells. Moreover, the viability and the proliferation of pancreatic β‐cells incubated inside hydrogels for 12 days are analyzed. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1548–1559     

Electrochemical characterization of hydrogels for biomimetic applications

Hydrogels are increasingly being recognized as having potential in bio‐compatible applications. In previous work, we investigated the feasibility of poly(ethylene glycol)‐dimethacrylate (PEG‐1000‐DMA) and poly(ethylene glycol)‐diacrylate (PEG‐400‐DA) polymerized using either a chemical initiator (C) or a photoinitiator (P) to encapsulate and stabilize biomimetic membranes for novel separation technologies or biosensor applications. In this paper, we have investigated the electrochemical properties of the hydrogels used for membrane encapsulation. Specifically, we studied the crosslinked hydrogels by using electrochemical impedance spectroscopy (EIS), and we demonstrated that chemically crosslinked hydrogels had lower values for the effective electrical resistance and higher values for the electrical capacitance compared with hydrogels with photoinitiated crosslinking. Transport numbers were obtained using electromotive force measurements and demonstrated that at low salt concentrations, both PEG‐400‐DA‐C and PEG‐400‐DA‐P hydrogels presented an electropositive character whereas PEG‐1000‐DMA‐P was approximately neutral and PEG‐1000‐DMA‐C showed electronegative character. Sodium transport numbers approached the bulk NaCl electrolyte value at high salt concentrations for all hydrogels, indicating screening of fixed charges in the hydrogels. The average salt diffusional permeability 〈P_s〉 and water permeability 〈P_w〉 were found to correlate with EIS results. Both PEG‐1000‐DMA‐C and PEG‐400‐DA‐C had higher 〈P_s〉 and 〈P_w〉 values than PEG‐1000‐DMA‐P and PEG‐400‐DA‐P hydrogels. In conclusion, our results show that hydrogel electrochemical properties can be controlled by the choice of polymer and type of crosslinking used and that their water and salt permeability properties are congruent with the use of hydrogels for biomimetic membrane encapsulation. Copyright © 2011 John Wiley & Sons, Ltd.     

Rational Design and Development of Anisotropic and Mechanically Strong Gelatin‐Based Stress Relaxing Hydrogels for Osteogenic/Chondrogenic Differentiation

Rational design and development of tailorable simple synthesis process remains a centerpiece of investigational efforts toward engineering advanced hydrogels. In this study, a green and scalable synthesis approach is developed to formulate a set of gelatin‐based macroporous hybrid hydrogels. This approach consists of four sequential steps starting from liquid‐phase pre‐crosslinking/grafting, unidirectional freezing, freeze‐drying, and finally post‐curing process. The chemical crosslinking mainly involves between epoxy groups of functionalized polyethylene glycol and functional groups of gelatin both in liquid and solid state. Importantly, this approach allows to accommodate different polymers, chitosan or hydroxyethyl cellulose, under identical benign condition. Structural and mechanical anisotropy can be tuned by the selection of polymer constituents. Overall, all hydrogels show suitable structural stability, good swellability, high porosity and pore interconnectivity, and maintenance of mechanical integrity during 3‐week‐long hydrolytic degradation. Under compression, hydrogels exhibit robust mechanical properties with nonlinear elasticity and stress‐relaxation behavior and show no sign of mechanical failure under repeated compression at 50% deformation. Biological experiment with human bone marrow mesenchymal stromal cells (hMSCs) reveals that hydrogels are biocompatible, and their physicomechanical properties are suitable to support cells growth, and osteogenic/chondrogenic differentiation, demonstrating their potential application for bone and cartilage regenerative medicine toward clinically relevant endpoints.     

Stimuli Responsive Scaffolds Based on Carboxymethyl Starch and Poly(2‐Dimethylaminoethyl Methacrylate) for Anti‐Inflammatory Drug Delivery

The purpose of the study is to obtain multicomponent polyelectrolyte hydrogels with optimal synergistic properties by combining a modified starch with a synthetic one. Thus, new low‐cost and biocompatible semi‐interpenetrating polymer network (semi‐IPN) hydrogels of carboxymethyl starch and poly(2‐dimethylaminoethyl methacrylate) are prepared and investigated. The synthesized hydrogels are studied with respect to the specific characteristics of the gels: swelling kinetics, thermal analysis, viscoelastic characteristics, and their ability to be used as a matrix in drug delivery systems. Therefore, the semi‐IPN gels are loaded with ibuprofen, followed by additional tests to assess the in vitro drug release. The cytocompatibility of the hydrogels with respect to their composition is evaluated in vitro on fibroblast cell culture. The investigations confirm the obtainment of new semi‐IPN hydrogels with pH and temperature responsiveness, good mechanical strength, and potential for use as drug delivery systems or transdermal patches.     

A Bi‐Layer PVA/CMC/PEG Hydrogel with Gradually Changing Pore Sizes for Wound Dressing

Wound dressings are vital for cutaneous wound healing. In this study, a bi‐layer dressing composed of polyvinyl alcohol/carboxymethyl cellulose/polyethylene glycol (PVA/CMC/PEG) hydrogels is produced through a thawing–freezing method based on the study of the pore size of single‐layer hydrogels. Then the physical properties and healing of full‐thickness skin defects treated with hydrogels are inspected. The results show that the pore size of the single‐layer PVA/CMC/PEG hyrogel can be controlled. The obtained non‐adhesive bi‐layer hydrogels show gradually increasing pore sizes from the upper to the lower layer and two layers are well bonded. In addition, bi‐layer dressings with good mechanical properties can effectively prevent bacterial penetration and control the moisture loss of wounds to maintain a humid environment for wounds. A full‐thickness skin defect test shows that bi‐layer hydrogels can significantly accelerate wound closure. The experiment indicates that the bi‐layer PVA/CMC/PEG hydrogels can be used as potential wound dressings.     

Thermally exfoliated graphene oxide reinforced stress responsive conductive nanocomposite hydrogel

Lightweight and flexible biosensors that can sustain mechanical deformation and can be adhered to human skin is an interesting field of study. In the current article, a systematic study on development of thermally exfoliated graphene oxide (TEGO)–reinforced poly(vinyl alcohol) (PVA)–based conductive hydrogel nanocomposites has been reported. The free‐standing hydrogels were synthesized using controlled and repetitive freeze‐thaw cycles. The samples were then studied for their mechanical as well as electrical properties. The hydrogels were characterized for their microstructural, chemical, and rheological properties to understand the observed macroscopic properties. Additionally, a study on the behavior of hydrogels immersed in phosphate‐buffered saline (PBS) was carried out to investigate their hydrolytic stability within simulated biological environment. Overall, the nanocomposite hydrogels demonstrated excellent static and dynamic mechanical performance, stability in PBS, considerable electrical conductivity, and significant electrical response to applied external stress, establishing their potential for use as flexible biosensors.     

Effect of Sodium Alginate on the Properties of Thermosensitive Hydrogels

Sodium alginate (SA ) was combined with poly(N ‐isopropylacrylamide) (PNIPAAm ) to prepare thermosensitive hydrogels through semi‐interpenetrating polymer network (semi‐IPN ) and fully interpenetrating polymer network (full‐IPN ). The thermosensitive, swelling, mechanical, and thermal properties of pure PNIPAAm , SA /PNIPAAm semi‐IPN , and Ca‐alginate/PNIPAAm full‐IPN hydrogels were investigated. The formation of semi‐IPN and full‐IPN significantly improved the hydrogels’ swelling capability and mechanical properties without altering their thermosensitivity. 5‐Fluorouracil (5‐Fu) was selected as a model drug to study the release behaviors of the hydrogels. It was found that in vitro controlled drug release from semi‐IPN hydrogels showed an initial release burst, followed by a slower and sustained release, before reaching equilibrium. Full‐IPN hydrogels showed slow and sustained release during the whole process. Temperature and pH were found to affect the rate of drug release. Ca‐alginate/PNIPAAm full‐IPN hydrogels have potential application as drug delivery matrices in controlled drug release.     

pH‐Sensitive Mechanical Properties of Elastin‐Based Hydrogels

Ionizable amino acids in protein‐based hydrogels can confer pH‐responsive behavior. Because elastin‐like polypeptides (ELPs) have an established sequence and can crosslink to form hydrogels, they are an ideal system for creating pH‐sensitive materials. This study examines different parameters that might affect pH‐sensitive behavior and characterizes the mechanical and physical properties between pH 3 and 11 of three ELP‐based crosslinked hydrogels. The first finding is that varying the amount of crosslinker affects the overall stiffness and resilience of the hydrogels but does not strongly affect water content, swelling ratio, or pH sensitivity. Second, the choice of two popular tag sequences, which vary in histidine and aspartic acid content, does not have a strong effect on pH‐sensitive properties. Last, selectively blocking lysine and tyrosine residues through acetylation significantly decreases the pH‐sensitive zeta potential. Acetylated hydrogels also demonstrate different behavior at low pH values with reduced swelling, reduced water content, and higher stiffness. Overall, this work demonstrates that ELP hydrogels with ionizable groups are promising materials for environmentally‐responsive applications such as drug delivery, tissue engineering, and microfluidics.     

Smart DNA Hydrogel Integrated Nanochannels with High Ion Flux and Adjustable Selective Ionic Transport

Nanochannels based on smart DNA hydrogels as stimulus‐responsive architecture are presented for the first time. In contrast to other responsive molecules existing in the nanochannel in monolayer configurations, the DNA hydrogels are three‐dimensional networks with space negative charges, the ion flux and rectification ratio are significantly enhanced. Upon cyclic treatment with K⁺ ions and crown ether, the DNA hydrogel states could be reversibly switched between less stiff and stiff networks, providing the gating mechanism of the nanochannel. Based on the architecture of DNA hydrogels and pH stimulus, cation or anion transport direction could be precisely controlled and multiple gating features are achieved. Meanwhile, G‐quadruplex DNA in the hydrogels might be replaced by other stimulus‐responsive DNA molecules, peptides, or proteins, and thus this work opens a new route for improving the functionalities of nanochannel by intelligent hydrogels.     

Rational Fabrication of Anti‐Freezing,Non‐Drying Tough Organohydrogels by One‐Pot Solvent Displacement

Tough hydrogels, polymeric network structures with excellent mechanical properties (such as high stretchability and toughness), are emerging soft materials. Despite their remarkably mechanical features, tough hydrogels exhibit two flaws (freezing around the icing temperatures of water and drying under arid conditions). Inspired by cryoprotectants (CPAs) used in the inhibition of the icing of water in biological samples, a versatile and straightforward method is reported to fabricate extreme anti‐freezing, non‐drying CPA‐based organohydrogels with long‐term stability by partially displacing water molecules within the pre‐fabricated hydrogels. CPA‐based Ca‐alginate/polyacrylamide (PAAm) tough hydrogels were successfully fabricated with glycerol, glycol, and sorbitol. The CPA‐based organohydrogels remain unfrozen and mechanically flexible even up to −70 °C and are stable under ambient conditions or even vacuum.     

Rational Fabrication of Anti‐Freezing,Non‐Drying Tough Organohydrogels by One‐Pot Solvent Displacement

Tough hydrogels, polymeric network structures with excellent mechanical properties (such as high stretchability and toughness), are emerging soft materials. Despite their remarkably mechanical features, tough hydrogels exhibit two flaws (freezing around the icing temperatures of water and drying under arid conditions). Inspired by cryoprotectants (CPAs) used in the inhibition of the icing of water in biological samples, a versatile and straightforward method is reported to fabricate extreme anti‐freezing, non‐drying CPA‐based organohydrogels with long‐term stability by partially displacing water molecules within the pre‐fabricated hydrogels. CPA‐based Ca‐alginate/polyacrylamide (PAAm) tough hydrogels were successfully fabricated with glycerol, glycol, and sorbitol. The CPA‐based organohydrogels remain unfrozen and mechanically flexible even up to ?70 °C and are stable under ambient conditions or even vacuum.     

Reinforced Supramolecular Hydrogels from Attapulgite and Cyclodextrin Pseudopolyrotaxane for Sustained Intra‐Articular Drug Delivery

Injectable hydrogels for nonsteroidal anti‐inflammatory drugs’ (NSAIDs) delivery to minimize the side effects of NSAIDs and achieve long‐term sustained release at the targeted site of synovial joint are attractive for osteoarthritis therapy, but how to improve its mechanical strength remains a challenge. In this work, a kind of 1D natural clay mineral material, attapulgite (ATP), is introduced to a classical cyclodextrin pseudopolyrotaxane (PPR) system to form a reinforced supramolecular hydrogel for sustained release of diclofenac sodium (DS) due to its rigid, rod‐like morphology, and unique structure, which has great potential in tissue regeneration, repair, and engineering. Investigation on the interior morphology and rheological property of the obtained hydrogel points out that the ATP distributed in PPR hydrogel plays a role similar to the “reinforcement in concrete” and exhibits a positive effect on improving the mechanical properties of PPR hydrogel by regulating their interior morphology from a randomly distributed style to the well‐ordered porous frame structure. The hybrid hydrogels demonstrate good shear‐thinning and thixotropic properties, excellent biocompability, and sustained release behavior both in vitro and in vivo. Furthermore, preliminary in vivo treatment in an acute inflammatory rat model reveals that the ATP hybrid hydrogels present sustained anti‐inflammatory effect.     

Robust and smart hydrogels based on natural polymers

This review summarizes recent progress of the robust and smart hydrogels prepared from natural polymers including polysaccharides,proteins,etc.These hydrogels exhibit outstanding mechanical properties due to their nanofibrous aggregated microstructures and special crosslinking networks.Furthermore,these hydrogels show some smart stimuliresponsive behaviors triggered by pH,temperature,light,electricity and magnetism.Hopefully,these hydrogels derived from natural polymers with inherent biodegradation and biocompatibility have great application potential in the fields of biomedicine,tissue engineering,soft robots and bio-machine.     

A Hydrogel Vitreous Substitute that Releases Antioxidant

Current experimental vitreous substitutes only replace the physical functions of the natural vitreous humor. Removal of the native vitreous disrupts oxygen homeostasis in the eye, causing oxidative damage to the lens that likely results in cataract formation. Neither current clinical treatments nor other experimental vitreous substitutes consider the problem of oxidative stress after vitrectomy. To address this problem, biomimetic hydrogels are prepared by free radical polymerization of poly(ethylene glycol) methacrylate and poly(ethylene glycol) diacrylate. These hydrogels have similar mechanical and optical properties to the vitreous. The hydrogels are injectable through small‐gauge needles and demonstrate in vitro biocompatibility with human retinal and lens epithelial cells. The hydrogels and added vitamin C, an antioxidant, show a synergistic effect in protecting ocular cells against reactive oxygen species, which fulfills a chemical function of the natural vitreous. These hydrogels have the potential to prevent post‐vitrectomy cataract formation and reduce the cost of additional surgeries.     

Injectable poloxamer/graphene oxide hydrogels with well‐controlled mechanical and rheological properties

Although significant progress has been made in the design and application of injectable hydrogels for biomedical applications, concurrent control of rheological and mechanical properties of injectable hydrogels has remained as an open challenge to the researchers. In this work, we introduce and put into practice a photo‐curable poloxamer (also known as Pluronic)/graphene oxide (Plu/GO) injectable hydrogel with well‐controlled rheological and mechanical properties. Acrylate group was anchored to hydrogel structure to endow photo‐crosslinking ability through decelerating degradation rate of poloxamer hydrogels after injection. It was found that the modified Plu remains stable in biological media for a long‐term period without significant weight loss. Rheological properties of hydrogels were also carried out as essential prerequisite for an ideal injectability via frequency sweep, flow curve, recovery, and yield stress before and after modification, signifying shear‐thinning behavior of Plu/GO hydrogels with high recoverability. The viscosity of shear‐thinning‐like hydrogels dropped at higher shear stress, which facilitated injection process. Moreover, mechanical behavior of Plu was optimized by manipulating the content of Plu, degree of modification with reactive precursor, curing, and particularly incorporation of GO without deteriorating effects on rheological behavior of Plu.     

PEG‐dialdehyde–the new cross‐linking agent for collagen/elastin hydrogels

Collagen and elastin are the major proteins of an extracellular matrix. They possess attractive, complementary mechanical properties in their native state, but during isolation, its unique structure is destroyed, which affects the parameters of the materials. However, they still have excellent biological properties. The cross‐linking process improves the physicochemical properties of protein materials. The ideal cross‐linking agent should be effective and does not impair the biological properties of the material. Therefore, poly(ethylene) glycol‐dialdehyde was used in the study. The results show that the addition of poly(ethylene) glycol‐dialdehyde in combination with the neutralization of a collagen/elastin solution is a useful method for preparation of protein hydrogels. The gels are transparent and relatively stiff. They exhibit good mechanical properties, surface properties and are attractive for 3 T3 cells. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis and characterization of acrylamide/acrylic acid hydrogels crosslinked using a novel diacrylate of glycerol to produce multistructured materials

In this work we propose a new crosslinking agent and the method to use it for the synthesis of acrylate based hydrogels. The use of this diacrylate of glycerol, synthesized in our laboratory, allows the generation of materials with well defined micro‐structures in the dry state, unique meso‐ and macro‐structures during swelling, and enhanced mechanical properties and swelling capacity in water. These properties depend on the crosslinking agent concentration, as well as synthesis thermal history. Poly(acrylamide‐co‐acrylic acid) hydrogels are commonly crosslinked with N, N′‐methylenebisacrylamide or N‐isopropylacrylamide. Here we obtain and use a new crosslinking agent, obtained from the reaction between glycerol and acrylic acid to produce a Diacrylate of glycerol (DAG). Two synthesis methods at equivalent molar ratio of acrylamide/acrylic acid (AM/AA) were analyzed. The mechanical properties, the swelling capacity, and the morphology at microscale of these hydrogels showed a well defined transition at a critical concentration of crosslinking agent. DAG induces the generation of hydrogels with hierarchichal structure. The micro‐structure surface morphology was investigated by scanning electron microscopy, the meso‐structure by polarized light microscopy and the macro‐structure by CCD imaging. The hydrogels with hierarchical structures showed improved mechanical properties when compared with structureless hydrogels. Control of the microstructure allows the generation of materials for different applications, i.e. templates or smart materials that interact with electromagnetic radiation. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 2667–2679, 2008     

Graphene Oxide/Polyacrylamide/Aluminum Ion Cross‐Linked Carboxymethyl Hemicellulose Nanocomposite Hydrogels with Very Tough and Elastic Properties

Development of high‐strength hydrogels has recently attracted ever‐increasing attention. In this work, a new design strategy has been proposed to prepare graphene oxide (GO)/polyacrylamide (PAM)/aluminum ion (Al³⁺)‐cross‐linked carboxymethyl hemicellulose (Al‐CMH) nanocomposite hydrogels with very tough and elastic properties. GO/PAM/Al‐CMH hydrogels were synthesized by introducing graphene oxide (GO) into PAM/CMH hydrogel, followed by ionic cross‐linking of Al³⁺. The nanocomposite hydrogels were characterized by means of FTIR, X‐ray diffraction (XRD), and scanning electron microscopy/energy‐dispersive X‐ray analysis (SEM‐EDX) along with their swelling and mechanical properties. The maximum compressive strength and the Young's modulus of GO_3.5/PAM/Al‐CMH_0.45 hydrogel achieved values of up to 1.12 and 13.27 MPa, increased by approximately 6488 and 18330 % relative to the PAM hydrogel (0.017 and 0.072 MPa). The as‐prepared GO/PAM/Al‐CMH nanocomposite hydrogels possess high strength and great elasticity giving them potential in bioengineering and drug‐delivery system applications.     

Micromechanical Properties of Microstructured Elastomeric Hydrogels

Local, micromechanical environment is known to influence cellular function in heterogeneous hydrogels, and knowledge gained in micromechanics will facilitate the improved design of biomaterials for tissue regeneration. In this study, a system comprising microstructured resilin‐like polypeptide (RLP)–poly(ethylene glycol) (PEG) hydrogels is utilized. The micromechanical properties of RLP‐PEG hydrogels are evaluated with oscillatory shear rheometry, compression dynamic mechanic analysis, small‐strain microindentation, and large‐strain indentation and puncture over a range of different deformation length scales. The measured elastic moduli are consistent with volume averaging models, indicating that volume fraction, not domain size, plays a dominant role in determining the low strain mechanical response. Large‐strain indentation under a confocal microscope enables the visualization of the microstructured hydrogel micromechanical deformation, emphasizing the translation, rotation, and deformation of RLP‐rich domains. The fracture initiation energy results demonstrate that failure of the composite hydrogels is controlled by the RLP‐rich phase, and their independence with domain size suggested that failure initiation is controlled by multiple domains within the strained volume. This approach and findings provide new quantitative insight into the micromechanical response of soft hydrogel composites and highlight the opportunities in employing these methods to understand the physical origins of mechanical properties of soft synthetic and biological materials.     

Mineralization of synthetic polymer scaffolds: a bottom-up approach for the development of artificial bone

The controlled integration of organic and inorganic components confers natural bone with superior mechanical properties. Bone biogenesis is thought to occur by templated mineralization of hard apatite crystals by an elastic protein scaffold, a process we sought to emulate with synthetic biomimetic hydrogel polymers. Cross-linked polymethacrylamide and polymethacrylate hydrogels were functionalized with mineral-binding ligands and used to template the formation of hydroxyapatite. Strong adhesion between the organic and inorganic materials was achieved for hydrogels functionalized with either carboxylate or hydroxy ligands. The mineral-nucleating potential of hydroxyl groups identified here broadens the design parameters for synthetic bonelike composites and suggests a potential role for hydroxylated collagen proteins in bone mineralization.