The design,mechanism and biomedical application of self-healing hydrogels

Current advances made in self-healing hydrogels relating to the design strategies, self-healing mechanism, testing methods and biomedical application in vivo were extensively reviewed in this article.     

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.     

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.     

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。     

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.     

Self‐Healing Supramolecular Hydrogels for Tissue Engineering Applications

Self‐healing supramolecular hydrogels have emerged as a novel class of biomaterials that combine hydrogels with supramolecular chemistry to develop highly functional biomaterials with advantages including native tissue mimicry, biocompatibility, and injectability. These properties are endowed by the reversibly cross‐linked polymer network of the hydrogel. These hydrogels have great potential for realizing yet to be clinically translated tissue engineering therapies. This review presents methods of self‐healing supramolecular hydrogel formation and their uses in tissue engineering as well as future perspectives.     

Human Albumin-Based Hydrogels for Their Potential Xeno-Free Microneedle Applications

Nowadays, hydrogels-based microneedles (MNs) have attracted a great interest owing to their outstanding qualities for biomedical applications. For the fabrication of hydrogels-based microneedles as tissue engineering scaffolds and drug delivery carriers, various biomaterials have been tested. They are required to feature tunable physiochemical properties, biodegradability, biocompatibility, nonimmunogenicity, high drug loading capacity, and sustained drug release. Among biomaterials, human proteins are the most ideal biomaterials for fabrication of hydrogels-based MNs; however, they are mechanically weak and poorly processible. To the best of the knowledge, there are no reports of xeno-free human protein-based MNs so far. Here, human albumin-based hydrogels and microneedles for tissue engineering and drug delivery by using relatively new processible human serum albumin methacryloyl (HSAMA) are engineered. The resultant HSAMA hydrogels display tunable mechanical properties, biodegradability, and good biocompatibility. Moreover, the xeno-free HSAMA microneedles display a sustained drug release profile and significant mechanical strength to penetrate the model skin. In vitro, they also show good biocompatibility and anticancer efficacy. Sustainable processible human albumin-based biomaterials may be employed as a xeno-free platform in vivo for tissue engineering and drug delivery in clinical trials in the future.     

Self-healing Hydrogels and Underlying Reversible Intermolecular Interactions

Self-healing hydrogels have attracted growing attention over the past decade due to their biomimetic structure, biocompatibility, as well as enhanced lifespan and reliability, thereby have been widely used in various biomedical, electrical and environmental engineering applications. This feature article has reviewed our recent progress in self-healing hydrogels derived from mussel-inspired interactions, multiple hydrogen-bonding functional groups such as 2-ureido-4[1 H]-pyrimidinone(UPy), dynami...     

Oxidized Xanthan Gum Crosslinked NOCC: Hydrogel System and Their Biological Stability from Oxidation Levels of the Polymer

Dynamic hydrogel systems from N,O-carboxymethyl chitosan (NOCC) are investigated in the past years, which has facilitated their widespread use in many biomedical engineering applications. However, the influence of the polymer's oxidation levels on the hydrogel biological properties is not fully investigated. In this study, chitosan is converted into NOCC and introduced to react spontaneously with oxidized xanthan gum (OXG) to form several injectable hydrogels with controlled degradability. Different oxidation levels of xanthan gum, as well as NOCC/OXG volume ratios, are trialed. The infrared spectroscopy spectra verify chemical modification on OXG and successful crosslinking. With increasing oxidation levels, more dialdehyde groups are introduced into the OXG, resulting in changes in physical properties including gelation, swelling, and self-healing efficiency. Under different volume ratios, the hydrogel shows a stable structure and rigidity with higher mechanical properties, and a slower degradation rate. The shear-thinning and self-healing properties of the hydrogels are confirmed. In vitro assays with L929 cells show the biocompatibility of all formulations although the use of a high amount of OXG15 and OXG25 limited the cell proliferation capacity. Findings in this study suggested a suitable amount of OXG at different oxidation levels in NOCC hydrogel systems for tissue engineering applications.     

Incorporation of Cell-Adhesive Proteins in 3D-Printed Lipoic Acid-Maleic Acid-Poly(Propylene Glycol)-Based Tough Gel Ink for Cell-Supportive Microenvironment

In extrusion-based 3D printing, the use of synthetic polymeric hydrogels can facilitate fabrication of cellularized and implanted scaffolds with sufficient mechanical properties to maintain the structural integrity and physical stress within the in vivo conditions. However, synthetic hydrogels face challenges due to their poor properties of cellular adhesion, bioactivity, and biofunctionality. New compositions of hydrogel inks have been designed to address this limitation. A viscous poly(maleate-propylene oxide)-lipoate-poly(ethylene oxide) (MPLE) hydrogel is recently developed that shows high-resolution printability, drug-controlled release, excellent mechanical properties with adhesiveness, and biocompatibility. In this study, the authors demonstrate that the incorporation of cell-adhesive proteins like gelatin and albumin within the MPLE gel allows printing of biologically functional 3D scaffolds with rapid cell spreading (within 7 days) and high cell proliferation (twofold increase) as compared with MPLE gel only. Addition of proteins (10% w/v) supports the formation of interconnected cell clusters (≈1.6-fold increase in cell areas after 7-day) and spreading of cells in the printed scaffolds without additional growth factors. In in vivo studies, the protein-loaded scaffolds showed excellent biocompatibility and increased angiogenesis without inflammatory response after 4-week implantation in mice, thus demonstrating the promise to contribute to the printable tough hydrogel inks for tissue engineering.     

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.     

Antibacterial Hybrid Hydrogels

Bacterial infectious diseases and bacterial‐infected environments have been threatening the health of human beings all over the world. In view of the increased bacteria resistance caused by overuse or improper use of antibiotics, antibacterial biomaterials are developed as the substitutes for antibiotics in some cases. Among them, antibacterial hydrogels are attracting more and more attention due to easy preparation process and diversity of structures by changing their chemical cross‐linkers via covalent bonds or noncovalent physical interactions, which can endow them with various specific functions such as high toughness and stretchability, injectability, self‐healing, tissue adhesiveness and rapid hemostasis, easy loading and controlled drug release, superior biocompatibility and antioxidation as well as good conductivity. In this review, the recent progress of antibacterial hydrogel including the fabrication methodologies, interior structures, performances, antibacterial mechanisms, and applications of various antibacterial hydrogels is summarized. According to the bacteria‐killing modes of hydrogels, several representative hydrogels such as silver nanoparticles‐based hydrogel, photoresponsive hydrogel including photothermal and photocatalytic, self‐bacteria‐killing hydrogel such as inherent antibacterial peptides and cationic polymers, and antibiotics‐loading hydrogel are focused on. Furthermore, current challenges of antibacterial hydrogels are discussed and future perspectives in this field are also proposed.     

Injectable Hyaluronic Acid/Poly(γ-glutamic acid) Hydrogel with Step-by-step Tunable Properties for Soft Tissue Engineering

Injectable hydrogels as an important class of biomaterials have gained much attention in tissue engineering. However, their crosslinking degree is difficult to be controlled after being injected into body. As we all know, the crosslinking degree strongly influences the physicochemical properties of hydrogels. Therefore, developing an injectable hydrogel with tunable crosslinking degree in vivo is important for tissue engineering. Herein, we present a dual crosslinking strategy to prepare injectable hydrogels with step-by-step tunable crosslinking degree using Schiff base reaction and photopolymerization. The developed hyaluronic acid/poly(γ-glutamic acid)(HA/γ-PGA) hydrogels exhibit step-bystep tunable swelling behavior, enzymatic degradation behavior and mechanical properties. Mechanical performance tests show that the storage moduli of HA/γ-PGA hydrogels are all less than 2000 Pa and the compressive moduli are in kilopascal, which have a good match with soft tissue. In addition, NIH 3 T3 cells encapsulated in HA/γ-PGA hydrogel exhibit a high cell viability, indicating a good cytocompatibility of HA/γ-PGA hydrogel.Therefore, the developed HA/γ-PGA hydrogel as an injectable biomaterial has a good potential in soft tissue engineering.     

Characterization and Optimization of Injectable In Situ Crosslinked Chitosan-Genipin Hydrogels

In recent years, there has been an increased interest in injectable, in situ crosslinking hydrogels due to their minimally invasive application and ability to conform to their environment. Current in situ crosslinking chitosan hydrogels are either mechanically robust with poor biocompatibility and limited biodegradation due to toxic crosslinking agents or the hydrogels are mechanically weak and undergo biodegradation too rapidly due to insufficient crosslinking. Herein, the authors developed and characterized a thermally-driven, injectable chitosan-genipin hydrogel capable of in situ crosslinking at 37 °C that is mechanically robust, biodegradable, and maintain high biocompatibility. The natural crosslinker genipin is utilized as a thermally-driven, non-toxic crosslinking agent. The chitosan-genipin hydrogel's crosslinking kinetics, injectability, viscoelasticity, swelling and pH response, and biocompatibility against human keratinocyte cells are characterized. The developed chitosan-genipin hydrogels are successfully crosslinked at 37 °C, demonstrating temperature sensitivity. The hydrogels maintained a high percentage of swelling over several weeks before degrading in biologically relevant environments, demonstrating mechanical stability while remaining biodegradable. Long-term cell viability studies demonstrated that chitosan-genipin hydrogels have excellent biocompatibility over 7 days, including during the hydrogel crosslinking phase. Overall, these findings support the development of an injectable, in situ crosslinking chitosan-genipin hydrogel for minimally invasive biomedical applications.     

A Rapidly and Highly Self-Healing Poly(Sulfobetaine Methacrylate) Hydrogel with Stretching Properties,Adhesive Properties,and Biocompatibility

This study focuses on the preparation of stretchable zwitterionic poly(sulfobetaine methacrylate) (PSBMA) hydrogels. To address the weak mechanical properties of chemically crosslinked PSBMA hydrogels, a physical crosslinking method utilizing hydrophobic interactions to crosslink hydrogels to approach tough properties is developed. Here, sodium dodecyl sulfate (SDS)-based micelle is used as a physical crosslinker to prepare physically crosslinked PSBMA (PSBMA_phy) hydrogels, and ethylene glycol dimethylacrylate (EGDMA) is used to prepare a control group of chemically crosslinked PSBMA (PSBMA_chem) hydrogels. The mechanical properties of the two hydrogels are compared, and PSBMA_phy hydrogels exhibit greater flexibility than the PSBMA_chem hydrogels. When the PSBMA_phy hydrogels are subjected to external forces, the micelles act as dynamic crosslinking sites, allowing the stress to disperse and prevent the hydrogel from breaking. In addition, the PSBMA_phy hydrogels have nearly 100% self-healing properties within 2.5 min. The PSBMA_phy hydrogels exhibit usable adhesive properties to porcine skin and subcutis. MTT and hemolysis tests show that the PSBMA_phy hydrogels have excellent biocompatibility and hemocompatibility. This study proposes that the multifunctional PSBMA_phy hydrogels with micelles will be potential to carry drugs for use in drug delivery systems in the future.     

双重响应性生物基自修复凝胶的制备及其性能

为拓宽多重响应性凝胶在生物医学领域中的应用,本文基于生物大分子构筑具有pH响应、糖响应性的可自修复性水凝胶。 本文选用3-氨基苯硼酸(APBA)和2,3-环氧丙基三甲基氯化铵(CHGTA)分别对聚谷氨酸(γ-PGA)和瓜尔胶(GG)进行改性制备了聚谷氨酸-g-氨基苯硼酸(γ-PGA-g-APBA)和阳离子瓜尔胶,在此基础上,对γ-PGA-g-APBA和阳离子瓜尔胶进行物理共混制备生物基凝胶。 通过傅里叶变换红外光谱仪(FTIR)、核磁共振波谱仪(¹H NMR)和流变仪对聚合物化学结构、接枝率、流变性能和力学性能进行表征,并考察了凝胶在不同pH值及糖浓度下刺激响应性。 结果表明,凝胶具有自修复性,修复效率可达100%;具有pH响应性,在环境pH值较高时更易形成凝胶,且凝胶强度随pH值升高而增大;同时所制凝胶具有糖响应性,在4 g/L的葡萄糖溶液中浸泡后即可导致凝胶解体。 这些结果说明功能基团APBA的引入可赋予凝胶多重响应性。 所制的双重响应性生物基凝胶具有良好的生物相容性,有望应用于生物医学、功能器件、传感等领域。     

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.     

Surfactant-induced healing of tough hydrogels formed via hydrophobic interactions

Different reversible molecular interactions have been used in the past few years to generate self-healing in synthetic hydrogels. However, self-healing hydrogels synthesized so far suffer from low mechanical strength which may limit their use in any stress-bearing applications. Here, we present a simple technique to heal mechanically strong polyacrylamide hydrogels formed via hydrophobic interactions between stearyl groups. A complete healing in the hydrogels was achieved by the treatment of the damaged areas with an aqueous solution of wormlike sodium dodecyl sulfate micelles. The micelles in the healing agent solubilize the hydrophobes in the cut surfaces, so that they easily find their partners in the other cut surface due to the hydrophobic interactions. Surfactant-induced healing produces high toughness (～1 MPa) gels withstanding 150 kPa of stress at a deformation ratio of 1,100 %. The healing technique developed here is generally applicable to the physical gels formed by hydrophobic associations.     

Build in seconds: Small-molecule hydrogels of self-assembled tryptophan derivatives

Small-molecule hydrogels based on amino acid derivatives have promising applications in many biological fields, including cell culture, drug delivery, and tissue engineering. Although these hydrogels have been widely reported to have low cytotoxicity, biocompatibility, and tunable bioactivity, problems such as harsh preparation conditions and complex material design hinder their application. Herein, by adjusting pH to induce non-covalent interactions between small-molecule tryptophan derivatives (N-[(phenylmethoxy)carbonyl]-l-tryptophan, Mw: 338.35), we developed a self-assembled three-dimensional network hydrogel that can be rapidly formed in seconds. And the supramolecular self-assembly mechanism of the hydrogels was also investigated in detail through experimental characterizations and density functional theory calculation. As-prepared hydrogels also exhibit reversible pH-stimulated response and self-healing properties. This study details a research process for the simple and rapid preparation of tryptophan derivative-based hydrogels, which provides more reference ideas for the future development of materials based on other amino acid derivatives.     

水凝胶仿生柔性电子学

水凝胶力学性质与生物组织相似,生物相容性好,在生物电子学领域具有独特的优势.受生物组织——如皮肤、神经、肌肉等启发,发展了具有仿生结构和功能的水凝胶材料.以这种水凝胶材料制作而成的柔性电子器件具有感知温度、压力、应变、电场等外界刺激的功能,可模拟生物组织的传感能力,在仿生电子皮肤,人工肌肉,人工神经等领域具有重要的应用...