Preparation and Characterization of Attractive Poly(amino acid)Hydrogels Based on 2-Ureido-4[1H]-pyrimidinone

Self-healing hydrogels with the shear-thinning property are novel injectable materials and are superior to traditional injectable hydrogels.The self-healing hydrogels based on 2-ureido-4[1 H]-pyrimidinone(UPy)have recently received extensive attention due to their dynamic reversibility of UPy dimerization.However,generally,UPy-based self-healing hydrogels exhibit poor stability,cannot degrade in vivo and can hardly be excreted from the body,which considerably limit their bio-application.Here,using poly(l-glutamic acid)(PLGA)as biodegradable matrix,branchingα-hydroxy-ω-amino poly(ethylene oxide)(HAPEO)as bridging molecule to introduce UPy,and ethyl acrylate polyethylene glycol(MAPEG)to introduce double bond,the hydrogel precursors(PMHU)are prepared.A library of the self-healing hydrogels has been achieved with well self-healable and shear-thinning properties.With the increase of MAPEG grafting ratio,the storage modulus of the self-healing hydrogels decreases.The self-healing hydrogels are stable in solution only for 6 h,hard to meet the requirements of tissue regeneration.Consequently,ultraviolet(UV)photo-crosslinking is involved to obtain the dual crosslinking hydrogels with enhanced mechanical properties and stability.When MAPEG grafting ratio is 35.5%,the dual crosslinking hydrogels can maintain the shape in phosphate-buffered saline solution(PBS)for at least 8 days.Loading with adipose-derived stem cell spheroids,the self-healing hydrogels are injected and self-heal to a whole,and then they are crosslinked in situ via UV-irradiation,obtaining the dual crosslinking hydrogels/cell spheroids complex with cell viability of 86.7%±6.0%,which demonstrates excellent injectability,subcutaneous gelatinization,and biocompatibility of hydrogels as cell carriers.The novel PMHU hydrogels crosslinked by quadruple hydrogen bonding and then dual photo-crosslinking of double bond are expected to be applied for minimal invasive surgery or therapies in tissue engineering.     

Rhodamine Mechanophore Functionalized Mechanochromic Double Network Hydrogels with High Sensitivity to Stress

Mechanochromic hydrogels, a new class of stimuli-responsive soft materials, have potential applications in a number of fields such as damage reporting and stress/strain sensing. We prepared a novel mechanochromic hydrogel using a strategy that has been developed to prepare dual-network(DN) hydrogels. A hydrophobic rhodamine derivative(Rh mechanophore) was covalently incorporated into a first network as a cross-linker. This first network embedded with Rh mechanophore within the DN hydrogel was pre-stretched. This guaranteed that the stress could be transferred extensively to the Rh-crosslinked first network once the hydrogel was under an applied force. Interestingly, we found that the threshold stress required to activate the mechanochromism of the hydrogel was less than 200 kPa, and much less than those in previous reports. Moreover, because of the excellent sensitivity of the hydrogel to stress, the DN hydrogel exhibited reversible freezing-induced mechanochromism. Benefiting from the sensitivity of Rh mechanophore to both p H and force, the DN hydrogel showed p H-regulated mechanochromic behavior. Our experimental results indicate that the preparation strategy we used introduces sensitive mechanochromism into the hydrogel and preserves the advantageous mechanical properties of the DN hydrogel. These results will be beneficial to the design and preparation of mechanochromic hydrogels with high stress sensitivity, and foster their practical applications in a number of fields such as damage reporting and stress/strain sensing.     

Promotion of microvasculature formation in alginate composite hydrogels by an immobilized peptide GYIGSRG

The ability to create artificial thick tissues is a major tissue engineering problem,requiring the formation of a suitable vascular supply.In this work we examined the ability of inducing angiogenesis in a bioactive hydrogel.GYIGSRG(NH 2-Gly-Tyr-IleGly-Ser-Arg-Gly-COOH,GG) has been conjugated to sodium alginate(ALG) to synthesize a biological active biomaterial ALG-GG.The product was characterized by 1 H NMR,FT-IR and elemental analysis.A series of CaCO 3 /ALG-GG composite hydrogels were prepared by crosslinking ALG-GG with D-glucono-lactone/calcium carbonate(GDL/CaCO 3) in different molar ratios.The mechanical strength and swelling ratio of the composite hydrogels were studied.The results revealed that both of them can be regulated under different preparation conditions.Then,CaCO 3 /ALG-GG composite hydrogel was implanted in vivo to study the ability to induce angiogenesis.The results demonstrated that ALG-GG composited hydrogel can induce angiogenesis significantly compared with non-modified ALG group,and it may be valuable in the development of thick tissue engineering scaffold.     

Enhancing hydrophilicity and protein resistance of silicone hydrogels by plasma induced grafting with hydrophilic polymers

<正>The hydrophilicity of silicone hydrogels used as soft corneal contact lens plays an important role in wearing comfort.In order to enhance hydrophilicity and protein resistance,silicone hydrogel membranes were modified by atmospheric pressure glow discharge plasma(APGDP) induced surface graft polymerization of N-vinyl pyrrolidone(NVP) and poly(oligoethylene glycol methyl ether methacrylate)(PEGMA) in this paper.XPS analysis demonstrated the success of graft polymerization of NVP and PEGMA onto the surface of silicone hydrogel membranes.The hydrophilicity of silicone hydrogels was characterized by the measurement of water contact angle(WCA).The result showed that NVP grafted silicone hydrogel has the WCA of about 68°and PEGMA grafted silicone hydrogel has the lowest WCA of about 62°,while the pristine silicone hydrogel is hydrophobic with the WCA of about 103°.Protein resistance of silicone hydrogels was investigated by the method of bicinchoninic acid assay using bovine serum albumin(BSA) as a model.It's found that the grafted silicone hydrogel has a significant improvement of protein resistance,and PEGMA grafting is more efficient for the reduction of protein adsorption than NVP grafting.The silicone hydrogel membranes grafted with NVP and PEGMA are good candidates of soft corneal contact lenses.     

Hydrogels with Dynamically Controllable Mechanics and Biochemistry for 3D Cell Culture Platforms

Many cell-matrix interaction studies have proved that dynamic changes in the extracellular matrix(ECM)are crucial to maintain cellular properties and behaviors.Thus,developing materials that can recapitulate the dynamic attributes of the ECM is highly desired for threedimensional(3 D)cell culture platforms.To this end,we sought to develop a hydrogel system that would enable dynamic and reversible turning of its mechanical and biochemical properties,thus facilitating the control of cell culture to imitate the natural ECM.Herein,a hydrogel with dynamic mechanics and a biochemistry based on an addition-fragmentation chain transfer(AFCT)reaction was constructed.Thiol-modified hyaluronic acid(HA)and allyl sulfide-modifiedε-poly-L-lysine(EPL)were synthesized to form hydrogels,which were non-swellable and biocompatible.The reversible modulus of the hydrogel was first achieved through the AFCT reaction;the modulus can also be regulated stepwise by changing the dose of UVA irradiation.Dynamic patterning of fluorescent markers in the hydrogel was also realized.Therefore,this dynamically controllable hydrogel has great potential as a 3 D cell culture platform for tissue engineering applications.     

ε-Poly(L-lysine)-based Hydrogels with Fast-acting and Prolonged Antibacterial Activities

Bacterial infections and the associated morbidity and mortality due to bacterial pathogens in wounds and medical implants have been increasing as most of current coatings cannot fulfill all the requirements including excellent intrinsically antibacterial activity,low cytotoxicity, and favorable physical properties. Herein, we present a kind of antibacterial hydrogel based on ε-poly(L-lysine)(EPL)grafted carboxymethyl chitosan(CMC-g-EPL) as the inherently antibacterial matrix and the surplus EPL as highly efficient antimicrobial agent. Such hydrogels possess tunable swelling abilities with water absorption percentages of 800%–2000% and modulus varying from10 kPa to 100 kPa, and exhibit two-stage excellent antibacterial behavior. First, the free EPL can be released from the hydrogel network for quick and highly efficient bacteria killing with 99.99% of efficacy; second, the grafted EPL endows hydrogel matrix with prolonged intrinsically antibacterial activity, especially when most of free EPL is released from the hydrogel. Overall, we provide a new insight for preparing highly effective antibacterial hydrogels.     

Hydrogels of chemically cross-linked and organ-metallic complexed interpenetrating PEG networks

The aim of the present work was to prepare a well-defined hydrogel of chemically cross-linked and organ-metallic complexed interpenetrating PEG networks. The hydrogel was synthesized via the reaction of copper(I)- catalyzed 1,3-dipolar azide-alkyne cycloaddition(CuA AC) with poly(ethylene glycol)-dopamine(PEG-DA)("Click Chemistry") followed by complexation with Fe~(3+) ions to crosslink the polymeric network. The chemical composition and morphology of the resulting hydrogels were characterized by Fourier transform infrared spectroscopy(FTIR), ~1H-NMR and scanning electron microscopy(SEM). Swelling ratio, mechanical strength, conductivity, and degradation behaviors of the hydrogels were also studied. The effect of the polymer chain length on properties of hydrogels was explored. The compressive strength of hydrogels could reach as high as 13.1 MPa with a conductivity of 2.2 × 10~(-5) S·cm~(-1). The hydrogels also exhibited excellent thermal stability even at a temperature of 300 °C, whereas degradation of the hydrogel after 7 weeks was observed under a physiological condition. In addition, the hydrogel exhibited a good biocompatibility based on its in vivo performance through an in vivo subcutaneous implantation model. No inflammation and no obvious abnormality of the surrounding tissue were observed when the hydrogel was subcutaneously implanted for 2 weeks. This work is a step towards creating a new pathway to synthesize hydrogels of interpenetrating networks which could be of important applications in the future research.     

TEMPERATURE AND pH RESPONSE, AND SWELLING BEHAVIOR OF POROUS ACRYLONITRILE-ACRYLIC ACID COPOLYMER HYDROGELS

Macroporous acrylonitrile-acrylic acid （AN-AA） copolymer hydrogels were synthesized by flee-radical solution polymerizations, using ammonium persulfate （APS）/N,N,N＇,N＇-tetramethylethylenediamine （TEMED） redox initiator system and alcohols porogens. The morphology, temperature and pH sensitive swelling behavior, and swelling kinetics of the resulting hydrogels were investigated. It was found that alcohol type and concentration had great influences on the pore structure and porosity of hydrogels. The pore size of hydrogel increases with the moderate increase of the length of alcohol alkyl chain. However, a further increase of alkyl length would result in the formation of cauliflower-like structure and the decrease of pore size. The porosity of hydrogels increases with the increase of porogen concentration in the polymerization medium. The hydrogels with macroporous structure swell or shrink much faster in response to the change of pH in comparison with the conventional hydrogel without macroporous structure. Furthermore, the response rate is closely related to the porosity of the hydrogels, which could be easily controlled by modulating the concentration of the porogen in the medium. The circular swelling behavior of hydrogels indicated the formation of a relaxing three-dimensional network.     

Controlled cross-linking strategy for formation of hydrogels,microgels and nanogels

Hydrogels are a kind of unique cross-linking polymeric materials with three-dimensional networks.Various efforts have been devoted to manipulate the formation of functional hydrogels in situ and enrich the production of hydrogels,microgels and nanogels with improved modulation capacity.However,these methods always fail to tune the gel properties because of the difficulty in achieving the precise control of cross-linking extents once the gel formation is initiated.Therefore,the preparation of tailor-made hydrogels remains a great challenge.Herein,we summarize a controlled cross-linking strategy towards not only fabrication of hydrogels at nano-,micro-and macro-scales,but also achievement of controlled assembly of nanoparticles into multifunctional materials in macroscopic and microscopic scales.The strategy is conducted by controllably activating and terminating the disulfide reshuffling reactions of disulfide-linked core/shell materials with selective core/shell separation using system pH or UV triggers.So it provides a facile approach to producing hydrogels,hydrogel particles and nanoparticle aggregates with tunable structures and properties,opening up the design possibility,flexibility and complexity of hydrogels,microgels/nanogels and nanoparticle aggregates from nanoscopic components to macroscopic objects.     

Construction of pH-Triggered DNA Hydrogels Based on Hybridization Chain Reactions

As a novel type of bio-functional material,DNA hydrogels have attracted more and more attention due to their successful applications in 3D cell culturing and tissue engineering for the designable and programmable responsiveness.Herein,we have developed a pH-triggered DNA hydrogel based on a clamped hybridization chain reaction(C-HCR).In this system,a DNA switch was designed,which can release the initiator strand in a controllable way via the formation of the C-G-C4 triplex under the pH stimuli.While the pre-gelation solution is stable in neutral environment,the C-HCR will trigger the sol-gel transition as the pH decreased to 5.0.This strategy has endowed the DNA hydrogel with good controllability for triggering,which also shows potential in intellectual responsiveness to certain stimuli.     

Biodegradable thermogel as culture matrix of bone marrow mesenchymal stem cells for potential cartilage tissue engineering

Poly（lactide-co-glycolide）-poly（ethylene glycol）-poly（lactide-co-glycolide）（PLGA-PEG-PLGA） triblock copolymer was synthesized through the ring-opening polymerization of LA and GA with PEG as macroinitiator and stannous octoate as catalyst. The amphiphilic copolymer self-assembled into micelles in aqueous solutions, and formed hydrogels as the increase of temperature at relatively high concentrations（〉 15 wt%）. The favorable degradability of the hydrogel was confirmed by in vitro and in vivo degradation experiments. The good cellular and tissular compatibilities of the thermogel were demonstrated. The excellent adhesion and proliferation of bone marrow mesenchymal stem cells endowed PLGA-PEGPLGA thermogelling hydrogel with fascinating prospect for cartilage tissue engineering.     

Photo cross-linked biodegradable hydrogels for enhanced vancomycin loading and sustained release

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 12959. 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.     

SWELLING BEHAVIOR OF ACRYLAMIDE HYDROGEL IN DIFFERENT SOLVENTS AND pHs

Swelling property of acrylamide hydrogels, prepared from aqueous solutions of acrylamide monomer having concentrations in the range of 10-60 wt% by γ-ray irradiation method using a Co-60 gamma radiation source at doses ranging 1-30.0 kGy, has been investigated under various swelling media. These swelling media were basically solvents (solutions), produced by dissolving methanol, ethanol, glucose, sucrose, sodium chloride and sodium persulfate individually with distilled water, and solutions prepared with pHs = 3, 7 and 10. The investigation was performed in order to observe the effect of these solvents and pHs as well as the influence of monomer concentrations, radiation doses and times on swelling behavior of hydrogels. Swelling values were found higher for hydrogels prepared with lower monomer concentrations (ca.20 wt%) and radiation doses (ca. 5 kGy) and showed a leveling off tendency within 24 h. The glucose solvent and the buffer solution of pH = 10 revealed significant increase of swelling of hydrogels as compared to other solutions. Results are explained based on crosslinking density in hydrogel, polymer-solvent/polymer-polymer interactions in solutions,permeability of molecules in solutions and ionization capacity of hydrogel in pH.     

SHAPE MEMORY EFFECT OF SLIGHTLY-CROSSLINKED POLYETHYLENE

A series of slightly crosslinked polyethylenes (SXLPE) was prepared by aone-step method using dicumyl peroxide as crosslinking agent in a Haake Mixer. The gelcontents G (Soxhlet extracted) of the samples are in the range from 5% to 20% by weight.Their shear viscosity, crystallization and melting behavior, dynamic mechanical propertiesand shape recovery effect were systematically investigated in terms of the content of thecrosslinking agent. It shows that under certain experimental conditions the SXLPE's mayexhibit good shape fixation ability and shape memory properties, which are similar to thoseof the commercially available shape memory polyethylenes prepared by gamma-irradiationtechnique. However the shape memory behavior of these samples is not very stable due totheir low crosslinking degree, or gel content. Thus their application is limited in specialcases with fast strain fixing procedures.     

Synthetic hydrogels as scaffolds for manipulating endothelium cell behaviors

Synthetic hydrogels can be used as scaffolds that not only favor endothelial cells（ECs） proliferation but also manipulate the behaviors and functions of the ECs.In this review paper,the effect of chemical structure,Young’s modulus （E） and zeta potential（ξ） of synthetic hydrogel scaffolds on static cell behaviors,including cell morphology,proliferation, cytoskeleton structure and focal adhesion,and on dynamic cell behaviors,including migration velocity and morphology oscillation,as well as on EC function such as anti-platelet adhesion,are reported.It was found that negatively charged hydrogels,poly（2-acrylamido-2-methylpropanesulfonic sodium）（PNaAMPS） and poly（sodium p-styrene sulphonate） （PNaSS）,can directly promote cell proliferation,with no need of surface modification by any cell-adhesive proteins or peptides at the environment of serum-containing medium.In addition,the Young’s modulus（E） and zeta potential（ξ） of hydrogel scaffolds are quantitatively tuned by copolymer hydrogels,poly（NaAMPS-co-DMAAm） and poly（NaSS-co-DMAAm）, in which the two kinds of negatively charged monomers NaAMPS and NaSS are copolymerized with neutral monomer,N,N-dimethylacrylamide（DMAAm）.It was found that the critical zeta potential of hydrogels manipulating EC morphology,proliferation,and motility isξ_critical= -20.83 mV andξ_critical= -14.0 mV for poly（NaAMPS-co-DMAAm） and poly（NaSS-co-DMAAm）,respectively.The above mentioned EC behaviors well correlate with the adsorption of fibronectin, a kind of cell-adhesive protein,on the hydrogel surfaces.Furthermore,adhered platelets on the EC monolayers cultured on the hydrogel scaffolds obviously decreases with an increase of the Young’s modulus（E） of the hydrogels,especially when E>60 kPa.Glycocalyx assay and gene expression of ECs demonstrate that the anti-platelet adhesion well correlates with the EC-specific glycocalyx.The above investigation suggests that understanding the relationship between physic-chemical properties of synthetic hydrogels and cell responses is essential to design optimal soft and wet scaffolds for tissue engineering.     

Bioinspired Adaptive Gel Materials with Synergistic Heterostructures

In nature,many biological soft tissues with synergistic heterostructures,such as sea cucumbers,skeletal muscles and cartilages,exhibit high functionality to adapt to complex environments.In artificial soft materials,hydrogels are similar to biological soft tissues due to the unique integration of"soft and wet" properties and elastic characteristics.However,currently hydrogel materials lack theft necessary adaptability,including narrow working temperature windows and uncontrollable mechanics,thus restrict their engineering application in complex environments.Inspired by abovementioned biological soft tissues,researchers have increasingly developed heterostructural gel materials as functional soft materials with high adaptability to various mechanical and environmental conditions.This article summarizes our recent work on high-performance adaptive gel materials with synergistic heterostructures,including the critical design criteria and the state-of-the-art fabrication strategies of our gel materials.The functional adaptation properties of these heterostructural gel materials are also presented in details,including temperature,wettability,mechanical and shape adaption.     

A Polysaccharide-based Hydrogel and PLGA Microspheres for Sustained P24 Peptide Delivery: An In vitro and In vivo Study Based on Osteogenic Capability

A bone morphogenetic protein-2(BMP-2) derived synthetic oligopeptide, S [PO4]KIPKASSVPTELSAISTLYLDDD(P24), has shown great potential for facilitating bone regeneration. However, P24 cannot be directly used onto bone defects, while a continuous sustained delivery of P24 may lead to a better formation of bone tissue. Based on this issue, we have developed a sustained delivery system incorporating P24-loaded poly(lactide-co-glycolide)(PLGA) microspheres and nano-hydroxyapatite(n-HA) into the composite hydrogel. The P24-contained compound material was characterized with NMR, FTIR and SEM to demonstrate the fomiation of compound structure containing P24, PLGA and n-HA. A continuous drug release of P24 was observed for over 60 d that evidently enhanced the efficiency in promoting the proliferation of MC3T3-E1 cells and the secrete of alkaline phosphatase(ALP) in vitro. Moreover, the osteoinduction eflect of the hydrogel system with P24 peptide niicrospheres was demonstrated in vivo and manifested by the result of immunohistochemistry. This novel injectable composite hydrogel is expected to be applied to improving the bone defect treatment in bone tissue engineering.     

Poly(maleic anhydride-co-acrylic acid)/poly(ethylene glycol) hydrogels with pH- and ionic-strength-responses

<正>Poly(maleic anhydride-coacrylic acid),P(MA-AA),was synthesized by the free-radical copolymerization of maleic anhydride with acrylic acid,and fast responsive pH-sensitive poly(maleic anhydride-co-acrylic acid)/polyethylene glycol,P(MA-AA)/PEG,hydrogels were prepared using PEG as macromolecular cross-linking agent.FT-IR and ~1H-NMR spectrometry were applied to characterize the structure of P(MA-AA).The influences of pH and ionic strength on the swelling behavior of P(MA-AA)/PEG hydrogels and the swelling-deswelling changes along with the repeated changes between acid and alkali conditions were studied.The results showed that there was a hundredfold difference in the swelling ratios between the conditions of acid and alkali,and the swelling capability could not be weakened after multiple swelling-deswelling cycles.The results of swelling kinetics demonstrated that the response rate of P(MA-AA)/PEG hydrogels was very fast,because the swelling transition points always occurred at 10 min.The pH-responsive hydrogels reported here might be a smart material for potentially applications in many areas,including biosensors,drug-delivery devices and tissue engineering.     

OPTIMIZATION OF THE SYNTHESIS OF ACRYLAMIDE HYDROGEL BY γ-RAY IRRADIATION

Hydrogels have been synthesized from 10%, 20%, 30%, 40%, 50% and 60% aqueous solutions of acrylamide monomer by gamma radiation employing doses in the range of 0.2-30 kGy from a Co-60 source. The effect of solution concentration, y-ray dose, pH and time was studied in order to observe the optimizing conditions in the characterization of hydrogels. Gel fraction increases with dose for all concentrations indicating hundred-percentage conversion of gel at doses ≥5 kGy for homogenous solutions in the range of 20%-50% concentration. On the other hand, 10% solution provides conversion less than 86% even at 30 kGy, whereas 60% monomer makes an inhomogeneous solution which stile gives about 100% gel fraction. Swelling of hydrogels under water with respect to time varies with both the doses and concentrations due to the change of crosslinking density in the gels. The maximum volume change of hydrogels during swelling and water desorption mainly occurs within 24 h. Swelling is also enhanced with the rise of pH due to change of ionic content of the solvent. Considering the amount of gel fraction and the properties of hydrogel, the samples prepared from 20% solution at 5 kGy show better results. Moreover, the effect of bacteria on hydrogel was found to be nil, suggesting a prohibition of growth of microorganism in it.     

An injectable mPEG-PDLLA microsphere/PDLLA-PEG-PDLLA hydrogel composite for soft tissue augmentation

Injectable filling material is a simple and efficient method for soft tissues reconstruction and is extremely popular in not only plastic surgery but also cosmetic industry. However, there is a lack of soft tissue fillers with perfect performance on the market currently. Here, we constructed a new microsphere/hydrogel composite and evaluated its potential as a candidate for soft tissue augmentation. mPEG-PDLLA microspheres were prepared by utilizing a SPG membrane emulsifier which endowed micros...