Ultrasound augmenting injectable chemotaxis hydrogel for articular cartilage repair in osteoarthritis

The increasing incidence of osteoarthritis (OA) seriously affects life quality, posing a huge socioeconomic burden. Tissue engineering technology has become a hot topic in articular cartilage repair as one of the key treatment methods to alleviate OA. Hydrogel, one of the most commonly used scaffold materials, can provide a good extracellular matrix microenvironment for seed cells such as bone marrow mesenchymal stem cells (BMSCs), which can promote cartilage regeneration. However, the low homing rate of stem cells severely limits their role in promoting articular cartilage regeneration. Stromal cell-derived factor-1α (SDF-1α) plays a crucial role in the activation, mobilization, homing, and migration of MSCs. Herein, a novel injectable chemotaxis hydrogel, composed of chitosan-based injectable hydrogel and embedding SDF-1α-loaded nanodroplets (PFP@NDs-PEG-SDF-1α) was designed and fabricated. The ultrasound was then used to augment the injectable chemotaxis hydrogel and promote the homing migration of BMSCs for OA cartilage repair. The effect of ultrasound augmenting injectable PFP@NDs-PEG-SDF-1α/hydrogel on the migration of BMSCs was verified in vitro and in vivo, which remarkably promotes stem cell homing and the repair of cartilage in the OA model. Therefore, the treatment strategy of ultrasound augmenting injectable chemotaxis hydrogel has a bright potential for OA articular cartilage repair.     

A Stereolithography‐Based 3D Printed Hybrid Scaffold for In Situ Cartilage Defect Repair

Damage to articular cartilage can over time cause degeneration to the tissue surrounding the injury. To address this problem, scaffolds that prevent degeneration and promote neotissue growth are needed. A new hybrid scaffold that combines a stereolithography‐based 3D printed support structure with an injectable and photopolymerizable hydrogel for delivering cells to treat focal chondral defects is introduced. In this proof of concept study, the ability to a) infill the support structure with an injectable hydrogel precursor solution, b) incorporate cartilage cells during infilling using a degradable hydrogel that promotes neotissue deposition, and c) minimize damage to the surrounding cartilage when the hybrid scaffold is placed in situ in a focal chondral defect in an osteochondral plug that is cultured under mechanical loading is demonstrated. With the ability to independently control the properties of the structure and the injectable hydrogel, this hybrid scaffold approach holds promise for treating chondral defects.     

Development of injectable high molecular weight hyaluronic acid hydrogels for cartilage regeneration

The study focuses on developing hyaluronic acid (1200 kilo Dalton) hydrogels for cartilage regeneration. In spite of being highly biocompatible; a large amount of water absorption and easily degrading nature restricts the use of hyaluronic acid in the field of tissue regeneration. This can be rectified by crosslinking hyaluronic acid with a crosslinking agent such as divinyl sulfone; which results in a biocompatible hydrogel with superior rheological properties. Different amounts of divinyl sulfone have been used for crosslinking hyaluronic acid to get three types of hydrogels with differing properties. Swelling studies, rheology analysis, enzymatic degradation and scanning electron microscopic analysis were conducted on all the different types of hydrogels prepared. Viscoelastic properties of the hydrogel were analyzed so that a hydrogel with better elastic property and stability is obtained. Scanning electron microscopy was used to study the morphology of the HA hydrogels. The cytotoxicity testing was conducted to prove the non-toxic nature of the hydrogels and cell culture studies using adipose mesenchymal stem cells showed better adhesion and proliferation properties in all the three hydrogels. Thus hyaluronic acid hydrogel makes a promising material for cartilage regeneration.     

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.     

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.     

结冷胶与聚乙二醇丙烯酸酯双网络凝胶的制备及生物相容性评价

针对结冷胶脆性较大的问题,将聚乙二醇丙烯酸酯(PEGDA)引入结冷胶,通过紫外交联制备了结冷胶/PEGDA双网络凝胶,并对单组分凝胶和双网络凝胶的溶胀性能、微观形貌、拉伸力学性能、动态压缩性能和流变性能等进行比较.结果表明,双网络凝胶在类生理环境中具有较小的溶胀率和较好的尺寸稳定性,PEGDA的引入能够大幅度提高结冷胶的韧性,双网络凝胶的拉断伸长率可达340%,断裂能达1.01×103J/m2,与天然关节软骨相当.将成纤维细胞种植在凝胶内部进行体外三维立体培养,结果显示,细胞在凝胶内部生存状态良好,双网络凝胶的细胞负载率高于单网络结冷胶,说明该体系在生物医用领域具有良好的应用前景.     

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.     

可拉伸超韧水凝胶的制备和应用

综述了可拉伸超韧水凝胶的设计原理及其在组织工程和柔性电子器件领域的应用. 通过将网络结构层次、 化学结构、 增韧机制与宏观力学性能相结合, 重点讨论了单网络水凝胶、 双网络水凝胶、 纳米复合水凝胶及其它水凝胶等可拉伸超韧水凝胶的研究进展, 并总结和展望了新思路和新方向.     

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

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

Advances in Mechanical Properties of Hydrogels for Cartilage Tissue Defect Repair

Numerous factors, such as degeneration and accidents, frequently cause cartilage deterioration. Owing to the absence of blood vessels and nerves in cartilage tissue, the ability of cartilage tissue to heal itself after an injury is relatively low. Hydrogels are beneficial for cartilage tissue engineering owing to their cartilage-like structure and advantageous properties. Due to the disruption of its mechanical structure, the bearing capacity and shock absorption of cartilage are diminished. The tissue should possess excellent mechanical properties to ensure the efficacy of cartilage tissue repair. This paper discusses the application of hydrogels in the fields of cartilage repair, the mechanical properties of hydrogels used for cartilage repair, and the materials used for hydrogels in cartilage tissue engineering. In addition, the challenges faced by hydrogels and future research directions are discussed.     

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.     

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.     

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.     

Cationic Modified PVA Hydrogels Provide Low Friction and Excellent Mechanical Properties for Potential Cartilage and Orthopedic Applications

Poly(vinyl alcohol) (PVA) hydrogel is a promising candidate for articular cartilage repair yet restrained by its mechanical strength and tribological property. Current work reports a newly designed PVA-based hydrogel modified by glycerol (g), bacterial cellulose (BC), and a cationic polymer poly (diallyl dimethylammonium chloride) (PDMDAAC), which is a novel cationic strengthening choice. The resultant PVA-g-BC-PDMDAAC hydrogel proves the effectiveness of this modification scheme, with a confined compressive modulus of 19.56 MPa and a friction coefficient of 0.057 at a joint-equivalent load and low sliding speed. The water content, swelling property, and creep behavior of this hydrogel are also within a cartilage-mimetic range. The properties of PVA-based hydrogels before PDMDAAC addition are likewise studied as a cross-reference. Besides, PDMDAAC-modified PVA hydrogel realizes ideal mechanical and lubrication properties with a relatively low PVA concentration (10 wt.%) and facile fabrication process, which lays a foundation for mass production and marketization in the future.     

Xylan hemicellulose improves chitosan hydrogel for bone tissue regeneration

The hemicellulose xylan, which has immunomodulatory effects, has been combined with chitosan to form a composite hydrogel to improve the healing of bone fractures. This thermally responsive and injectable hydrogel, which is liquid at room temperature and gels at physiological temperature, improves the response of animal host tissue compared with similar pure chitosan hydrogels in tissue engineering models. The composite hydrogel was placed in a subcutaneous model where the composite hydrogel is replaced by host tissue within 1 week, much earlier than chitosan hydrogels. A tibia fracture model in mice showed that the composite encourages major remodeling of the fracture callus in less than 4 weeks. A non‐union fracture model in rat femurs was used to demonstrate that the composite hydrogel allows bone regeneration and healing of defects that with no treatment are unhealed after 6 weeks. These results suggest that the xylan/chitosan composite hydrogel is a suitable bone graft substitute able to aid in the repair of large bone defects. Copyright © 2016 John Wiley & Sons, Ltd.     

Tetronic-oligolactide-heparin hydrogel as a multi-functional scaffold for tissue regeneration

A novel cell-supporting scaffold, Tetronic-oligolactide-heparin (TLH) hydrogel, was prepared by coupling heparin to polymerized Tetronic-oligolactide for use in improving tissue regeneration. Aqueous TLH solutions showed thermosensitive behavior, demonstrating potential for use as injectable hydrogels. The content and activity of conjugated heparin were determined to be 61 wt.-% of total polymer and 67.2% of intact heparin activity, respectively. The basic fibroblast growth factor (bFGF) binding assay showed TLH hydrogel had a relatively high bFGF affinity, which indicates applicability for growth factor delivery. Chondrocyte culture on hydrogels revealed that the cell viability and the amount of synthesized glycosaminoglycan for TLH hydrogel were higher than those for alginate gel.     

Overview of Polyvinyl Alcohol Nanocomposite Hydrogels for Electro‐Skin,Actuator, Supercapacitor and Fuel Cell

The properties of polyvinyl alcohol (PVA) nanocomposite hydrogels influenced by nanoparticles are reviewed. Various kinds of nanoparticles with excellent mechanical and electrical properties have been introduced into PVA hydrogel to produce stretchable and conductive PVA nanocomposite hydrogel. Understanding the mechanism between the matrix of PVA hydrogel and nanoparticles is therefore critical for the development of PVA nanocomposite hydrogels. This review focuses on the nanoparticles include carbon nanotubes, graphene oxide and metal nanoparticles, and describes the effects of nanoparticles on the mechanical and conductive properties of PVA nanocomposite hydrogels. A new promising area of soft stretchable PVA nanocomposite hydrogel is highlighted for possible applications. Finally, a brief outlook for future research is presented.     

Viscoelasticity,mechanical properties,and in vivo biocompatibility of injectable polyvinyl alcohol/bioactive glass composite hydrogels as potential bone tissue scaffolds

Abstract

An injectable composite hydrogel composed of polyvinyl alcohol (PVA) and bioactive glass (BG) particles were synthesized by a physical crosslinking approach. The morphology, mechanical properties, and viscoelasticity of the PVA/BG composite hydrogel were characterized. Scanning electronic microscopy (SEM) showed uniform and homogeneous distribution of BG particles throughout the composite hydrogel. The incorporation of 2.5?wt% of BG particles in the composite hydrogel formulations, enhanced the static compressive strength and static elastic modulus by 325% and 150%, respectively. The storage molds (G′) was greater than the loss modules (G′′) at all the frequency range studied, which revealed a self-standing elastic composite hydrogel with a smooth injectability. The PVA/BG composite hydrogel was also implanted subcutaneously in the dorsal region of adult male rats. After 4?weeks of implantation, no inflammatory cells were seen within and around the implant, which indicated that the composite hydrogel was biocompatible. The properties of the synthesized injectable PVA/BG composite hydrogel demonstrate its capability toward bone regeneration.     

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.     

Recent advances of injectable hydrogels for drug delivery and tissue engineering applications

Injectable hydrogel is a kind of in situ gelling system but has its specificity on the process procedure, which requires a better control of gelation kinetics. Hydrogels with injectability under mild condition are preferred in the field of biomedicine, especially for drug delivery and tissue engineering, because of the favorable carrier property in three-dimension, biocompatibility, low invasive and adaptable shape for administration. Despite the advantages, the development of injectable hydrogels may also face some challenges to meet the various clinical requirements. In this review, we provide a brief summary on the recent progresses on the design, synthesis and evaluation of injectable hydrogels towards biomedical applications.