Injectable hydrogels

Hydrogels are promising for a variety of medical applications due to their high water content and mechanical similarity to natural tissues. When made injectable, hydrogels can reduce the invasiveness of application, which in turn reduces surgical and recovery costs. Key schemes used to make hydrogels injectable include in situ formation due to physical and/or chemical cross‐linking. Advances in polymer science have provided new injectable hydrogels for applications in drug delivery and tissue engineering. A number of these injectable hydrogel systems have reached the clinic and impact the health care of many patients. However, a significant remaining challenge is translating the ever‐growing family of injectable hydrogels developed in laboratories around the world to the clinic. © 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2012     

可注射水凝胶的制备与应用

可注射水凝胶在再生医学和药物控释等方面有着广泛的用途,是近年来生物医用材料领域新的研究方向.本文综述了近年来人们在可注射水凝胶制备和应用方面的研究进展,最后展望了其发展前景.     

可注射水凝胶及其在再生医学领域的应用

近年来,由工程生物材料制成的可注射治疗剂正变得越来越流行,并推动传统的临床实践走向微创化.可注射水凝胶由于其可调控的物理及化学特性、可控的降解性能、高含水量以及在微创方式下实现递送的能力,在组织工程和药物递送领域中变得越来越重要.研究者们已开发出例如原位交联水凝胶、大孔水凝胶、水凝胶微粒、动态交联水凝胶等一系列性能独特的可注射水凝胶.通过调控水凝胶的固含量和交联密度,并引入适当的共价或非共价相互作用,例如静电相互作用、疏水相互作用等,这些水凝胶可在注射过程中实现生物活性分子的递送.同时,可注射水凝胶亦可用于细胞的递送,提供细胞培养所需的三维环境,并通过调控力学性能、化学修饰、生物功能化修饰等手段调控细胞黏附、增殖、分化等行为.本文旨在回顾近年来可注射水凝胶的设计和制备的相关进展,以及其在再生医学中的应用,并对该领域存在的挑战和潜力进行了展望.     

Strong and Injectable Hydrogels Based on Multivalent Metal Ion-Peptide Cross-linking

Injectable hydrogels are ideal biomaterials for delivering cells, growth factors and drugs specifically to localized lesions and subsequent controlled release. Many factors can affect the efficacy of injectable hydrogels. To avoid potential damage to encapsulated cells or drugs, injectable hydrogels should be highly dynamic so that they can undergo shear-thinning at low strain rates and rapidly reform after injection. However, dynamic hydrogels are often mechanically weak, leading to the leakage of encapsulated cells or drugs. Here we demonstrated a convenient method to improve the mechanical strength without jeopardizing the dynamic properties of hydrogels by using metal ion-peptide crosslinkers containing multiple metal ion-ligand bonds. We showed that the dynamic properties of the hydrogels correlated with the intrinsic dynamics of the metal-ligand bonds and were not affected by the formation of multivalent binding. Yet, the mechanical stability of the hydrogels was significantly improved due to the increased thermodynamic stability of the crosslinkers. We further showed that the drug release rates were slowed down by the formation of multivalent crosslinkers. Our results highlight the importance of ligand valency to the mechanical response of hydrogels and provide a universal route to rationally tune the dynamic and mechanical properties of injectable hydrogels.     

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.     

Current Intelligent Injectable Hydrogels for In Situ Articular Cartilage Regeneration

Abstract

A high number of sport injuries result in damage to articular cartilage, a tissue type with poor self-healing capacity. Articular cartilage tissue is a sophisticated hydrogel, which contains 80% water and possesses strong mechanical properties. For this reason, synthetic hydrogels are thought to be an optimal material for cartilage regeneration. In the last decade, more than 2,000 research papers pertaining to “hydrogel and cartilage” have been published. Due to its biomimetic properties and user-friendly nature, especially in the field of minimal invasive surgery, intelligent injectable hydrogel have gradually become a focal point in cartilage research in recent years. In this review, we systematically summarize current “state-of-the-art” manufacture technologies of injectable hydrogels including ion-induced, thermo-induced, non-induced chemical, and light-induced crosslinking. We also review current strategies for designing intelligent injectable hydrogels, such as component-based, mechanical property-based and structure-based intelligent design to simulate the natural articular cartilage. Lastly, the applications of intelligent injectable hydrogels for cartilage regeneration are presented, and their outlooks for future clinical translation is dicussed.     

聚L-谷氨酸可注射水凝胶的制备及性能

通过活化改性聚L-谷氨酸（PLGA）制备酰肼化PLGA（PLGA-ADH）和3-氨基-1,2-丙二醇改性的PLGA（PLGA-OH）,PLGA-OH经高碘酸钠氧化制得醛基化PLGA（PLGA-CHO）,以PLGA-ADH和PLGA-CHO为前驱体,通过席夫碱交联反应构建了PLGA可注射水凝胶.研究了酰肼化和醛基化改性前后PLGA的结构变化,考察了固含量对水凝胶成胶时间、溶胀行为、机械性能、体外降解性能、药物释放行为及微观形貌等的影响,并进行了初步的细胞培养实验及裸鼠皮下注射成胶实验.结果表明,该PLGA可注射水凝胶在组织工程领域具有良好的应用前景.     

可注射水凝胶在伤口敷料中的研究进展

目前,在伤口治疗中对伤口敷料的选择越来越严格。传统的伤口敷料如纱布、绷带、海绵等在伤口愈合过程中容易诱发细菌感染,延缓伤口愈合,甚至引发慢性并发症。可注射水凝胶具备良好的生物相容性,能够适应伤口的形状以填充伤口,且具备一定的抗菌活性,从而避免伤口感染,相比传统的水凝胶伤口敷料更具备医疗优势,因此在生物医药领域得到广泛关注。本文对天然型可注射水凝胶和复合型可注射水凝胶在伤口愈合中的研究进展进行了综述;也对可注射水凝胶的未来发展趋势进行了展望。     

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.     

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.     

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.     

Injectable Supramolecular Hydrogel/Microgel Composites for Therapeutic Delivery

Shear‐thinning hydrogels are useful for biomedical applications, from 3D bioprinting to injectable biomaterials. Although they have the appropriate properties for injection, it may be advantageous to decouple injectability from the controlled release of encapsulated therapeutics. Toward this, composites of hydrogels and encapsulated microgels are introduced with microgels that are fabricated via microfluidics. The microgel cross‐linker controls degradation and entrapped molecule release, and the concentration of microgels alters composite hydrogel rheological properties. For the treatment of myocardial infarction (MI), interleukin‐10 (IL‐10) is encapsulated in microgels and released from composites. In a rat model of MI, composites with IL‐10 reduce macrophage density after 1 week and improve scar thickness, ejection fraction, cardiac output, and the size of vascular structures after 4 weeks when compared to saline injection. Improvements are also observed with the composite without IL‐10 over saline, emphasizing the role of injectable hydrogels alone on tissue repair.     

Injectable Hydrogels for Cardiac Tissue Engineering

In light of the limited efficacy of current treatments for cardiac regeneration, tissue engineering approaches have been explored for their potential to provide mechanical support to injured cardiac tissues, deliver cardio‐protective molecules, and improve cell‐based therapeutic techniques. Injectable hydrogels are a particularly appealing system as they hold promise as a minimally invasive therapeutic approach. Moreover, injectable acellular alginate‐based hydrogels have been tested clinically in patients with myocardial infarction (MI) and show preservation of the left ventricular (LV) indices and left ventricular ejection fraction (LVEF). This review provides an overview of recent developments that have occurred in the design and engineering of various injectable hydrogel systems for cardiac tissue engineering efforts, including a comparison of natural versus synthetic systems with emphasis on the ideal characteristics for biomimetic cardiac materials.     

Thermosensitive Injectable Gradient Hydrogel-Induced Bidirectional Differentiation of BMSCs

Osteochondral defects threaten the quality of life of patients to a great extent. To simulate gradient changes in osteochondral tissue, a gradient-mixing injection device consisting of a controller and injection pumps is design. Bioactive glass (BG) and gellan gum (GG) are used to prepare thermosensitive injectable gradient hydrogels (B_0.5G, B₁G) with an upper critical solution temperature (UCST) range of 37.7–40.2 °C using this device for the first time. The mechanical properties of gradient hydrogels are significantly better than those of pure GG hydrogels. The gradients in the composition, structure, and morphology of gradient hydrogels are confirmed via physicochemical characterization. Cytocompatibility tests show that hydrogels, especially B_0.5G gradient hydrogels, promote the proliferation of bone marrow mesenchymal stem cells (BMSCs). Most importantly, qRT-PCR shows that the different components in B_0.5G gradient hydrogels simultaneously induce the osteogenic and chondrogenic differentiation of BMSCs. Experimental injection in porcine osteochondral defects indicates that the B_0.5G gradient hydrogel seamlessly fills irregular osteochondral defects in a less invasive manner by controlling the temperature to avoid cellular and tissue damage arising from crosslinkers or other conditions. These results show that thermosensitive injectable B_0.5G gradient hydrogels have the potential for less invasive integrated osteochondral repair.     

DNA-based supramolecular hydrogels: From construction strategies to biomedical applications

DNA-based supramolecular hydrogels are important and promising biomaterials for various applications due to their inherent biocompatibility and tunable physicochemical properties. The three-dimensional supramolecular matrix of DNA formed by non-covalently dynamic cross-linking provides exceptional adaptability, self-healing, injectable and responsive properties for hydrogels. In addition, DNA hydrogels are also ideal bio-scaffold materials owing to their tissue-like mechanics and intrinsic biological functions. Technically, DNA can assemble into supramolecular networks by pure complementary base pairing; it can also be combined with other building blocks to construct hybrid hydrogels. This review focuses on the development and construction strategies of DNA hydrogels. Assembly and synthesis methods, diverse responsiveness and biomedical applications are summarized. Finally, the challenges and prospects of DNA-based supramolecular hydrogels are discussed.     

光聚合水凝胶及其在组织工程中的应用

水凝胶是一种亲水性聚合物网络,可以溶胀大量水,其物理性质接近软组织.光聚合与传统的聚合方法相比,具有反应速率快、反应条件缓和、反应放热低等特点.因此,光聚合水凝胶广泛应用于生物医学领域.本文介绍了光聚合水凝胶材料,并详细论述了光聚合水凝胶在药物释放体系、组织工程支架材料、细胞受控生长、细胞微囊化和可注射水凝胶等方面的应用.可以预见光聚合水凝胶作为生物材料在组织工程及再生医学领域中具有良好的应用前景.     

Injectable solid peptide hydrogel as a cell carrier: effects of shear flow on hydrogels and cell payload

β-hairpin peptide-based hydrogels are a class of injectable solid hydrogels that can deliver encapsulated cells or molecular therapies to a target site via syringe or catheter injection as a carrier material. These physical hydrogels can shear-thin and consequently flow as a low-viscosity material under a sufficient shear stress but immediately recover back into a solid upon removal of the stress, allowing them to be injected as preformed gel solids. Hydrogel behavior during flow was studied in a cylindrical capillary geometry that mimicked the actual situation of injection through a syringe needle in order to quantify effects of shear-thin injection delivery on hydrogel flow behavior and encapsulated cell payloads. It was observed that all β-hairpin peptide hydrogels investigated displayed a promising flow profile for injectable cell delivery: a central wide plug flow region where gel material and cell payloads experienced little or no shear rate, and a narrow shear zone close to the capillary wall where gel and cells were subject to shear deformation. The width of the plug flow region was found to be weakly dependent on hydrogel rigidity and flow rate. Live-dead assays were performed on encapsulated MG63 cells 3 h after injection flow and revealed that shear-thin delivery through the capillary had little impact on cell viability and the spatial distribution of encapsulated cell payloads. These observations help us to fundamentally understand how the gels flow during injection through a thin catheter and how they immediately restore mechanically and morphologically relative to preflow, static gels.     

聚N-异丙基丙烯酰胺/类水滑石复合水凝胶的制备及温敏性

以类水滑石(LDHs)和N-异丙基丙烯酰胺(NIPA)为原材料,采用自由基引发聚合制得了有机无机PNIPA/LDHs温度敏感复合水凝胶。 通过热重分析仪(TGA)、示差扫描量热仪(DSC)和扫描电子显微镜(SEM)等技术手段表征了材料的结构和性能。 结果表明,PNIPA/LDHs复合水凝胶在33 ℃左右可实现溶胶-凝胶的可逆性变化,LDHs质量分数基本不影响复合水凝胶的胶凝化温度和胶凝时间。 LDHs添加可使PNIPA/LDHs复合水凝胶的热稳定性较NIPA有大幅度提升。 随LDHs质量分数及n(Mg):n(Al)的增加,复合凝胶的吸热峰值稍有增加。 所合成PNIPA/LDHs复合水凝胶表面粗糙不平,具有一定的孔洞结构。     

Modified silicon carbide NPs reinforced nanocomposite hydrogels based on alginate-gelatin by with high mechanical properties for tissue engineering

Hydrogels are encouraging for different clinical purposes because of their high water absorption and mechanical relation to native tissues. Injectable hydrogels can modify the invasiveness of utilization, which decreases recovery and surgical costs. Principal designs applied to create injectable hydrogels incorporate in situ formation owing to chemical or/and physical crosslinking. Here, we report nontoxic, thermosensitive, injectable hydrogels composed of gelatin (GEL) and oxidized alginate (OA) reinforced by silicon carbide nanoparticles (SiC NPs) and crosslinked with N-hydroxysuccinimide (NHS) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). The mechanical characteristics of the hydrogels were examined via rheological analysis. The outcomes reveal that extending the SiC NPs contents enhances the mechanical properties around five times. The cross-sectional microstructure of the scaffolds comprising 0.25, 1.0, and 1.5% SiC NPs was scrutinized by FESEM, verifying porous structure with interconnected pores. Because of the smaller pore sizes in the hydrogels, the swelling rate has reduced at the higher content of SiC, which diminishes the water uptake. Additionally, the biodegradation study unveils that the hydrogels with SiC are more long-lasting than the hydrogel without SiC. By adding SiC NPs, a decrease is observed in the biodegradation and swelling ratio. The scaffold with a higher SiC NPs content (1.5%) manifested better cell attachment and was less cytotoxic than hydrogel without SiC. OA/GEL composites embedded SiC NPs have manifested excellent physical properties for tissue engineering in comparison with hydrogel without nanoparticles.