Mussel-inspired chemistry in producing mechanically robust and bioactive hydrogels as skin dressings

The development of hydrogels as skin dressings demonstrates a great potential in real life applications. To achieve this, the hydrogel has to conquer its natural poor mechanical strength, and to prolong its lifetime, antifatigue and self-healing properties originating from dynamic interactions are also required. As skin dressings, the hydrogel needs to maintain its ductility while pursuing the above mentioned properties. In this work, poly(ethylene glycol) diacrylate is used to produce skin dressings by reinforcing poly(ethylene glycol) diacrylate/alginate double network hydrogels with a crosslinker from mussel-inspired chemistry, which is 3,4-dihydroxy-l-phenylalanine. This crosslinking methodology significantly improved mechanical strength of the hydrogel, with 11,200% increase in compressive failure strength; it endowed the hydrogel with outstanding antifatigue and training strengthening properties that makes its mechanical strength increasing in a 50 cycles compressive test; the hydrogel showed excellent self-healing properties that in rheological characterization; it also displayed enhanced storage modulus after withstanding a shear strain up to 1100%; meanwhile, the hydrogel exhibited extreme ductility with an elastic modulus of only 10.90–16.53 kPa. 3,4-dihydroxy-l-phenylalanine also renders the hydrogel its inherent antioxidant activity, conductivity, and bioadhesiveness. Together with the highly transparent appearance, the hydrogels possess a great potential and practibility in the fields of skin dressings.     

强韧型自愈合水凝胶的研究进展

水凝胶作为一种由大量水和与众不同的三维网状结构构成的智能软材料,已经广泛应用于许多领域,如药物输送、软骨修复、废物处理及电子设备等。然而,水凝胶不良的机械性能及自愈合性极大地限制了它们的潜在应用。目前已报道的韧性水凝胶通常不具有或只有很弱的自修复性,而自修复水凝胶通常机械性能非常弱。因此,研发具有高效自修复性能和优异机械性能的水凝胶材料,无论是从学术角度还是工业角度都是非常重要的。本文总结了近些年来强韧型自愈合水凝胶的最新研究进展,从其制备方法、性能等方面进行了简要介绍,并对未来的发展前景进行了展望。     

Cell-Encapsulating Hydrogel Puzzle: Polyrotaxane-Based Self-Healing Hydrogels

Slide-ring hydrogels using polyrotaxanes have been developed as highly tough soft materials. However, they have never been used as biomaterials because of the lack of biocompatibility. Meanwhile, self-healing hydrogels are expected to improve fatigue resistance and extend the period of use. However, owing to the lack of high mechanical strength, they are limited in their use as biomaterials. Here we first developed a biocompatible self-healing/slide-ring hydrogel using glycol chitosan and a water-soluble polyrotaxane. We obtained excellent mechanical toughness and biocompatibility to promote the proliferation of human umbilical vein endothelial cells (HUVECs) encapsulated in the hydrogel. Owing to the rapid self-healing property, the cell-encapsulating gels adjusted arbitrarily, maintaining good cell proliferation function. Therefore, slide-ring hydrogels enable the use of biomaterials for soft-tissue engineering.     

A fast on-demand preparation of injectable self-healing nanocomposite hydrogels for efficient osteoinduction

Injectable hydrogels have been considered as promising materials for bone regeneration,but their osteoinduction and mechanical performance are yet to be improved.In this study,a novel biocompatible injectable and self-healing nano hybrid hydrogel was on-demand prepared via a fast(within 30 s) and easy gelation approach by reversible Schiff base formed between-CH=O of oxidized sodium alginate(OSA) and-NH_2 of glycol chitosan(GCS) mixed with calcium phosphate nanoparticles(CaP NPs).Its raw materials can be ready in large quantities by a simple synthesis process.The mechanical strength,degradation and swelling behavior of the hydrogel can be readily controlled by simply controlling the molar ratio of-CH=O and-NH_2.This hydrogel exhibits pH responsiveness,good degradability and biocompatibility.The hydrogel used as the matrix for mesenchymal stem cells can significantly induce the proliferation,differentiation and osteoinduction in vitro.These results showed this novel hydrogel is an ideal candidate for applications in bone tissue regeneration and drug delivery.     

氧化石墨烯/聚合物复合水凝胶的研究进展

氧化石墨烯是一种具有单原子厚度的二维材料, 具有优异的力学性能和良好的水分散性, 其表面有大量的含氧官能团. 将氧化石墨烯引入水凝胶体系中可以提高水凝胶的机械性能, 丰富其刺激响应的类型. 目前, 氧化石墨烯水凝胶在高强度、 吸附、 自愈合及智能材料等很多领域均有出色的表现. 氧化石墨烯水凝胶的研究已有10年的历史. 本文总结了氧化石墨烯水凝胶的制备方法, 归纳了智能氧化石墨烯水凝胶在光热响应、 pH响应和自愈合3个方面的响应机理和研究进展, 并综合评述了其在高强度水凝胶、 生物医学、 智能材料和污水处理等方面的应用前景.     

A Shear-Thinning,Self-Healing,Dual-Cross Linked Hydrogel Based on Gelatin/Vanillin/Fe3+/AGP-AgNPs: Synthesis,Antibacterial, and Wound-Healing Assessment

A shear-thinning and self-healing hydrogel based on a gelatin biopolymer is synthesized using vanillin and Fe³⁺ as dual crosslinking agents. Rheological studies indicate the formation of a strong gel found to be injectable and exhibit rapid self-healing (within 10 min). The hydrogels also exhibited a high degree of swelling, suggesting potential as wound dressings since the absorption of large amounts of wound exudate, and optimum moisture levels, lead to accelerated wound healing. Andrographolide, an anti-inflammatory natural product is used to fabricate silver nanoparticles, which are characterized and composited with the fabricated hydrogels to imbue them with anti-microbial activity. The nanoparticle/hydrogel composites exhibit activity against Escherichia coli, Staphylococcus aureus, and Burkholderia pseudomallei, the pathogen that causes melioidosis, a serious but neglected disease affecting southeast Asia and northern Australia. Finally, the nanoparticle/hydrogel composites are shown to enhance wound closure in animal models compared to the hydrogel alone, confirming that these hydrogel composites hold great potential in the biomedical field.     

Self-healing mineralized hydrogel scaffolds for stretch-triggered dye release

Hydrogels, with self-healing properties that can self-repair spontaneously when subjected to mechanical stress, are gaining popularity in the biomedical field. Numerous attempts have been made to create distinctive hydrogels with self-healing properties, along with stimuli-responsiveness and biocompatibility. Several techniques exist for fabricating hydrogels, including physical and chemical crosslinking via the creation of covalent bonds, and so on. Here, we prepared self-healing, stimuli-responsive, mineralized hydrogel by simply dissolving Kollidon 90-F, sodium chloride (NaCl), and potassium carbonate (K₂CO₃) in an aqueous solution. The dissociated CO₃²⁻ replaces the water molecules from the Kollidon 90-F polymer backbone and facilitates the cross-linking of the polymer chain, resulting in hydrogel formation. In addition, the in-situ produced sodium carbonate (Na₂CO₃) strengthens the hydrogel network. We optimized the mineralized hydrogels by taking various metal salts and different concentrations of K₂CO₃. The optimized hydrogel showed good stability over a period of time, was able to maintain viscoelastic properties, possessed good self-healing ability, and showed a shape retention ability. The shear-thinning property demonstrated by the optimized hydrogel could open a ray of hope in the bioprinting or 3D printing industry. Further, the stretch-responsive release of dye from the Self-healing mineralized hydrogel (SHMH) matrix confirms the mechanoresponsive behavior of the hydrogel. Overall, the findings could be utilized in the future to fabricate a stable drug delivery system that can autonomously release the drug molecules when stretched by daily processes such as joint movements.     

基于动态共价键的自愈性水凝胶及其在医学领域的应用

自愈性水凝胶作为一种新型仿生智能材料受到了科研人员的广泛关注.近年来,人们利用动态共价键、超分子作用,发展了一系列自愈性水凝胶,并将其应用于药物控释、细胞三维培养、组织工程等生物医用领域.本文总结和评述了基于动态共价键的自愈性水凝胶及这些水凝胶作为药物载体的相关研究,并展望了基于动态化学的自愈性水凝胶的未来发展.     

One-step synthesis of self-healable hydrogels by the spontaneous phase separation of linear multi-block copolymers during the emulsion copolymerization

Self-healable polyacrylamide-based hydrogels were prepared at room temperature via a one-step emulsion copolymerization of acrylamide(AM),dodecyl 2-methacryIate(DM),and 5-acetylaminopentyl acrylate(AAPA) using sodium dodecyl sulfonate(SDS) as the emulsifier and ammonium persulfate(APS)as the initiator.The produced linear multi-block copolymer chains are composed of randomly-linked hydrophilic polyacrylamide segments(PAM) and hydrophobic segments constituted by DM and AAPA units(P(DM-co-AAPA)).The P(DM-co-AAPA) segments will self-aggregate into hydrophobic microdomains during the polymerization process driven by the hydrophobic interactions,and finally separate from water phase,acting as the crosslinks and leading to the formation of strong hydrogels with a storage modulus as high as 400 Pa.These hydrophobic microdomains will be dissolved in water when the temperature increases to 70℃,resulting in a temperature-responsive reversible sol-gel transition of the prepared hydrogels.Furthermore,the prepared hydrogels have excellent self-healing ability.The broken hydrogels can be automatically healed into a body with a same strength within 2-min's contact.This work provides a new simple way to prepare reversible physical crosslinked hydrogel with high strength and self-healing efficiency.     

基于Pickering乳液的磁性高强水凝胶的制备及性能表征

合成了一种磁性Fe3O4纳米颗粒稳定的水包油(O/W)Pickering乳液并以其作为交联剂,在适宜条件下引发单体丙烯酰胺聚合来制备了一种新型的磁性高强复合水凝胶.采用X射线衍射(XRD)及场发射扫描电子显微镜(SEM)分别对磁性Fe3O4纳米颗粒和复合水凝胶的结构进行了表征,结果表明Pickering乳胶粒子较均匀地分布在复合凝胶网络中.溶胀性能测试及溶胀动力学分析表明复合水凝胶具有良好的溶胀性能,能够吸收自身干重100倍左右的水,其溶胀过程不遵循Fickian扩散模型;拉伸测试表明该水凝胶具有优异的力学性能,其拉伸强度能够达到150 kPa左右,断裂伸长率能够达到300%左右,并且当其承受的应力释放后能快速地恢复到初始形态.磁性能测试的结果显示该水凝胶具有良好的磁性.     

Injectable and self-healing hydrogels with tissue adhesiveness and antibacterial activity as wound dressings for infected wound healing

The design of wound dressings with excellent self-healing ability, adequate adhesion, good biocompatibility, and potential antibacterial ability is of great significance for the healing of infected wounds arising from human activities. Herein, a series of multi-functional hydrogel dressings, poly(ionized isocyanoethyl methacrylate-glutamine)/poly(hexamethylene guanidine) (iG_x/PHMG_y) hydrogels, were obtained through homopolymerization of fully ionized isocyanoethyl methacrylate-glutamine (iIEM-Gln) in the presence of poly(hexamethylene guanidine) (PHMG), in which strong hydrogen bonds were formed among urea groups in the P (iIEM-Gln) chain to form a stable hydrogel network. The prepared iG_x/PHMG_y hydrogels exhibited adequate self-healing ability and tissue adhesion, which could be firmly adhered to the wound surface and remained intact during application. In addition, the presence of PHMG imparted good antibacterial activity to the hydrogels for the effective promotion of the wound healing in S. aureus infected skin wound on mice. Overall, this multi-functional hydrogel provides a facile and effective strategy for the design of infected wound dressings, and may show great potential in clinical applications.     

Bioinspired dual dynamic network hydrogels promote cartilage regeneration through regulating BMSC chondrogenic differentiation

How to improve the therapeutic efficacy of cell delivery during mechanical injection has been a great challenge for tissue engineering. Here, we present a facile strategy based on dynamic chemistry to prepare injectable hydrogels for efficient stem cell delivery using hyaluronic acid (HA) and poly(γ-glutamic acid) (γ-PGA). The combination of the guest–host (GH) complexation and dynamic hydrazone bonds enable the HA/γ-PGA hydrogels with physical and chemical dual dynamic network and endow hydrogels a stable structure, rapid self-healing ability, and injectability. The mechanical properties, self-healing ability, and adaptability can be programmed by changing the ratio of GH network to hydrazine bond cross-linked network. Benefitting from the dynamic cross-linking networks, mild preparation process, and cytocompatibility of HA/γ-PGA hydrogels, bone marrow mesenchymal stem cells (BMSCs) show high cell viability in this system following mechanical injection. Moreover, HA/γ-PGA hydrogels can promote BMSC proliferation and upregulate the expression of cartilage-critical genes. Notably, in a rabbit auricular cartilage defect model, BMSC-laden HA/γ-PGA hydrogels can effectively promote cartilage regeneration. Together, we propose a general strategy to develop injectable self-healing HA/γ-PGA hydrogels for effective stem cell delivery in cartilage tissue engineering.     

Multi-bond network hydrogels with robust mechanical and self-healable properties

Multi-bond network(MBN) which contains a single network with hierarchical cross-links is a suggested way to fabricate robust hydrogels. In order to reveal the roles of different cross-links with hierarchical bond energy in the MBN, here we fabricate poly(acrylic acid) physical hydrogels with dual bond network composed of ionic cross-links between carboxylFe3+ interactions and hydrogen bonds, and compare these dually cross-linked hydrogels with singly and ternarily cross-linked hydrogels. Simple models are employed to predict the tensile property, and the results confirm that the multi-bond network with hierarchical distribution in the bond energy of cross-links endows hydrogel with effective energy-dissipating mechanism. Moreover, the dually cross-linked MBN gels exhibit excellent mechanical properties(tensile strength up to 500 k Pa, elongation at break ~ 2400%) and complete self-healing after being kept at 50 °C for 48 h. The factors on promoting self-healing are deeply explored and the dynamic multi-bonds are regarded to trigger the self-healing along with the mutual diffusion of long polymer chains and ferric ions.     

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.     

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.     

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.     

Highly stretchable and self-healing hydrogels based on poly(acrylic acid) and functional POSS

Herein, we present a novel way for the production of self-healing hydrogels with stretch beyond 4200% than their initial length and relatively high tensile strength(0.1?0.25 MPa). Furthermore, the hydrogel was insensitive to notch. Even for the samples containing V-notches, a stretch of 2300% was demonstrated. The hydrogels were developed by in situ crosslinking of the self-assembled colloidal poly(acrylic acid)(PAA)/functionalized polyhedral oligomeric silsesquioxane(POSS) micelles. This was achieved by the addition of functionalized polyhedral oligomeric silsesquioxane with tertiary amines and hydroxyls(POSS-AH) into the PAA reaction solution. The POSS-AH led to micellar growth, then the dualcrosslinked network was constructed. One type of crosslink was formed by hydrogen-bonding and ionic interactions between PAA chains and POSS-AH, the other type of crosslink was formed by covalent bonds between PAA and bis(N,N'-methylenebis-acrylamide).     

Natural polymers-enhanced double-network hydrogel as wearable flexible sensor with high mechanical strength and strain sensitivity

Conductive hydrogels have shown great prospects as wearable flexible sensors. Nevertheless, it is still a challenge to construct hydrogel-based sensor with great mechanical strength and high strain sensitivity. Herein, an ion-conducting hydrogel was fabricated by introducing gelatin-dialdehyde β-cyclodextrin (Gel-DACD) into polyvinyl alcohol-borax (PVA-borax) hydrogel network. Natural Gel-DACD network acted as mechanical deformation force through non-covalent cross-linking to endow the polyvinyl alcohol-borax/gelatin-dialdehyde β-cyclodextrin hydrogel (PGBCDH) with excellent mechanical stress (1.35 MPa), stretchability (400%), toughness (1.84 MJ/m³) and great fatigue resistance (200% strain for 100 cycles). Surprisingly, PGBCDH displayed good conductivity of 0.31 S/m after adding DACD to hydrogel network. As sensor, it showed rapid response (168 ms), high strain sensitivity (gage factor (GF) = 8.57 in the strain range of 200%-250%) and reliable sensing stability (100% strain for 200 cycles). Importantly, PGBCDH-based sensor can accurately monitor complex body movements (knee, elbow, wrist and finger joints) and large-scale subtle movements (speech, swallow, breath and facial expressions). Thus, PGBCDH shows great potential for human monitoring with high precision.     

Tunable biohybrid hydrogels from coacervation of hyaluronic acid and PEO-based block copolymers

Accurately tuning the macroscopic properties of biopolymer-based hydrogels remains challenging due to the ill-defined molecular architecture of the natural building blocks. Here, we report a biohybrid coacervate hydrogel, combining the biocompatibility and biodegradability of naturally occurring hyaluronic acid (HA) with the tunability of a synthetic polyethylene oxide (PEO) -based ABA-triblock copolymer. Coacervation of the cationic ammonium or guanidinium-functionalized copolymer A-blocks with the anionic HA leads to hydrogel formation. Both mechanical properties and water content of the self-healing hydrogels can be controlled independently by altering the copolymer structure. By controlling the strength of the interaction between the polymer network and small-molecule cargo, both release rate and maximum release are controlled. Finally, we show that coacervation of HA and the triblock copolymer leads to increased biostability upon exposure to hyaluronidase. We envision that noncovalent crosslinking of HA hydrogels through coacervation is an attractive strategy for the facile synthesis of tunable hydrogels for biomedical applications.