Alginate: properties and biomedical applications

Alginate is a biomaterial that has found numerous applications in biomedical science and engineering due to its favorable properties, including biocompatibility and ease of gelation. Alginate hydrogels have been particularly attractive in wound healing, drug delivery, and tissue engineering applications to date, as these gels retain structural similarity to the extracellular matrices in tissues and can be manipulated to play several critical roles. This review will provide a comprehensive overview of general properties of alginate and its hydrogels, their biomedical applications, and suggest new perspectives for future studies with these polymers.     

Chitosan‐based hydrogels: recent design concepts to tailor properties and functions

Chitosan (CS) has received much attention as a functional biopolymer for designing various hydrogels for biomedical applications. This review provides an overview of the different types of CS‐based hydrogels, the approaches that can be used to fabricate hydrogel matrices with specific features and their applications in controlled drug delivery and tissue engineering. Emphasis is laid on the recent design concepts of hybrid hydrogels based on mixtures of CS and natural or synthetic polymers, interpenetrating polymer networks as well as composite hydrogels prepared by embedding nanoparticles into CS matrices. © 2017 Society of Chemical Industry     

Thiol–norbornene photoclick hydrogels for tissue engineering applications

Thiol–norbornene (thiol–ene) photoclick hydrogels have emerged as a diverse material system for tissue engineering applications. These hydrogels are crosslinked through light‐mediated orthogonal reactions between multifunctional norbornene‐modified macromers [e.g., poly(ethylene glycol) (PEG), hyaluronic acid, gelatin] and sulfhydryl‐containing linkers (e.g., dithiothreitol, PEG–dithiol, biscysteine peptides) with a low concentration of photoinitiator. The gelation of thiol–norbornene hydrogels can be initiated by long‐wave UV light or visible light without an additional coinitiator or comonomer. The crosslinking and degradation behaviors of thiol–norbornene hydrogels are controlled through material selections, whereas the biophysical and biochemical properties of the gels are easily and independently tuned because of the orthogonal reactivity between norbornene and the thiol moieties. Uniquely, the crosslinking of step‐growth thiol–norbornene hydrogels is not oxygen‐inhibited; therefore, gelation is much faster and highly cytocompatible compared with chain‐growth polymerized hydrogels with similar gelation conditions. These hydrogels have been prepared as tunable substrates for two‐dimensional cell cultures as microgels and bulk gels for affinity‐based or protease‐sensitive drug delivery, and as scaffolds for three‐dimensional cell encapsulation. Reports from different laboratories have demonstrated the broad utility of thiol–norbornene hydrogels in tissue engineering and regenerative medicine applications, including valvular and vascular tissue engineering, liver and pancreas‐related tissue engineering, neural regeneration, musculoskeletal (bone and cartilage) tissue regeneration, stem cell culture and differentiation, and cancer cell biology. This article provides an up‐to‐date overview on thiol–norbornene hydrogel crosslinking and degradation mechanisms, tunable material properties, and the use of thiol–norbornene hydrogels in drug‐delivery and tissue engineering applications. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41563.     

Synthesis,characterization, and cytotoxicity of PCL–PEG–PCL diacrylate and agarose interpenetrating network hydrogels for cartilage tissue engineering

Hydrogels are suitable biomaterials for cartilage tissue engineering due to the excellent ability to retain water to provide suitable environment for the tissue, however, the insufficient mechanical properties often prevent their wider applications. The objective of this study was to fabricate biocompatible hydrogels with good mechanical performance, high-water content, and porous microstructure for cartilage regeneration. Photocrosslinked hydrogels are one of the most widely used systems in tissue engineering due to the superior mechanical properties. In this study, block copolymer, poly(ε -caprolactone)-poly(ethylene)-poly(ε -caprolactone) diacrylate (PCL–PEG–PCL; PEC), was prepared by ring-opening polymerization, and PEC hydrogels were made through free radical crosslinking mechanism. Agarose network is chosen as another component of the hydrogels, because of the high-swelling behavior and cartilage-like microstructure, which is helpful for chondrocytes growth. Interpenetrating networks (IPN) were fabricated by diffusing PEC into agarose network followed by photo-crosslinking process. It was noted that incorporating PEC into the agarose network increased the elastic modulus and the compressive failure properties of individual component networks. In addition, high-swelling ratio and uniform porosity microstructures were found in the IPN hydrogels. IPN and PEC showed low cytotoxicity and good biocompatibility in elution test method. The results suggest promising characteristics of IPN hydrogels as a potential biomaterial for cartilage tissue engineering.     

Biodegradable polymers exhibiting temperature-responsive sol–gel transition as injectable biomedical materials

Injectable biodegradable copolymer hydrogels, which exhibit temperature-responsive sol-to-gel transition, have recently drawn much attention as promising biomedical materials such as drug delivery, cell implantation, and tissue engineering. These injectable hydrogels can be implanted in the human body with minimal surgical invasion. Temperature-responsive gelling copolymers usually possess block- and/or branched architectures and amphiphilicity with a delicate hydrophobic/hydrophilic balance. Poly(ethylene glycol) (PEG) has typically been used as hydrophilic segments due to its biocompatibility and temperature-dependent dehydration nature. Aliphatic polyesters such as polylactide, poly(lactide-co-glycolide), poly(ε-caprolactone), and their modified copolymers have been used as hydrophobic segments based on their biodegradability and biocompatibility. Copolymers of PEG with other hydrophobic polymers such as polypeptides, polydepsipeptides have also been recently reported as injectable hydrogels. In this review, brief history and recent advances in injectable biodegradable polymer hydrogels are summarized especially focusing on the relationship between polymer architecture and their gelation properties. Moreover, the applications of these injectable polymer gels for biomedical use such as drug delivery and tissue engineering are also described.     

可注射水凝胶在组织工程中应用进展

组织工程采用可注射原位形成水凝胶,与预成型支架相比具有特定的优势：能填充任意形状的缺损,并在很大程度上降低植入对机体组织的侵入性,且能与各种治疗药物混合。本文介绍了可注射凝胶形成过程及几种水凝胶系统．并以实例说明可注射水凝胶在组织工程中的应用。     

Advanced Hydrogels as Exosome Delivery Systems for Osteogenic Differentiation of MSCs: Application in Bone Regeneration

Hydrogels are known as water-swollen networks formed from naturally derived or synthetic polymers. They have a high potential for medical applications and play a crucial role in tissue repair and remodeling. MSC-derived exosomes are considered to be new entities for cell-free treatment in different human diseases. Recent progress in cell-free bone tissue engineering via combining exosomes obtained from human mesenchymal stem cells (MSCs) with hydrogel scaffolds has resulted in improvement of the methodologies in bone tissue engineering. Our research has been actively focused on application of biotechnological methods for improving osteogenesis and bone healing. The following text presents a concise review of the methodologies of fabrication and preparation of hydrogels that includes the exosome loading properties of hydrogels for bone regenerative applications.     

Effect of different bases and neutralization steps on porosity and properties of collagen‐based hydrogels

The aim of the work reported was to investigate the effect of bases and neutralization steps on hydrogel microstructures. A series of porous hydrogels with various pore sizes were prepared by neutralizing a conventional hydrogel after gel formation. Scanning electron microscopy was used to characterize the microstructure of the porous hydrogels. The morphology of the samples showed the pores were induced into the hydrogels by water evaporation and gas release resulting from the neutralization process. Experimental results indicated that the hydrogels had an absorbency of 200–220 and 48–50 g g^?1 for distilled water and sodium chloride solutions, respectively. A simple method was used to prepare porous hydrogels. The prepared hydrogels are suitable for horticulture and tissue engineering applications due to their superior salt‐resisting properties. Copyright © 2009 Society of Chemical Industry     

A Review: Tailor-made Hydrogel Structures (Classifications and Synthesis Parameters)

Hydrogels are being prepared for use in a wide variety of applications ranging from medicines, tissue engineering, superabsorbents, controlled release of drugs & fertilizers, and oil absorbers etc. This review highlights hydrogel structure and their different classifications under various heads. It also discusses various routes to obtain tailormade hydrogels by polymerizing a combination of two or more monomers with proper type of crosslinks in order to obtain desired properties in the resulting hydrogel. Novel hydrogel configurations like microgels and nanogels, slide ring gels, double network hydrogels and nanocomposite gels have also been reviewed.     

Degradable natural polymer hydrogels for articular cartilage tissue engineering

Articular cartilage has poor ability to heal once damaged. Tissue engineering with scaffolds of polymer hydrogels is promising for cartilage regeneration and repair. Polymer hydrogels composed of highly hydrated crosslinked networks mimic the collagen networks of the cartilage extracellular matrix and thus are employed as inserts at cartilage defects not only to temporarily relieve the pain but also to support chondrocyte proliferation and neocartilage regeneration. The biocompatibility, biofunctionality, mechanical properties, and degradation of the polymer hydrogels are the most important parameters for hydrogel‐based cartilage tissue engineering. Degradable biopolymers with natural origin have been widely used as biomaterials for tissue engineering because of their outstanding biocompatibility, low immunological response, low cytotoxicity, and excellent capability to promote cell adhesion, proliferation, and regeneration of new tissues. This review covers several important natural proteins (collagen, gelatin, fibroin, and fibrin) and polysaccharides (chitosan, hyaluronan, alginate and agarose) widely used as hydrogels for articular cartilage tissue engineering. The mechanical properties, structures, modification, and structure–performance relationship of these hydrogels are discussed since the chemical structures and physical properties dictate the in vivo performance and applications of polymer hydrogels for articular cartilage regeneration and repair. © 2012 Society of Chemical Industry     

Application of minimally invasive injectable conductive hydrogels as stimulating scaffolds for myocardial tissue engineering

So far, several methods for myocardial tissue engineering have been developed to regenerate myocardium and even create contractile heart muscles. Among these approaches, hydrogel based methods have attracted much attention due to their ability to mimic the architecture of native extracellular matrix. Injectable hydrogels are a specific class of hydrogels which can be formed in situ by physical and/or chemical crosslinking. Generally, using these hydrogels is more advantageous because they are minimally (less) invasive in comparison with open surgery. Moreover, with respect to the fact that ‘myocardium is a conductive tissue’, utilization of conductive polymers for myocardial tissue engineering has demonstrated promising results. Both the injectable hydrogels and conductive polymers have some merits and demerits, but studies show that using a combination of them has prominently enhanced regeneration of the myocardium. In this review, the focus is on injectable hydrogels, conductive polymers and injectable conductive hydrogels for myocardial tissue engineering. © 2018 Society of Chemical Industry     

环境刺激响应型高强度智能水凝胶研究进展

环境刺激响应型智能水凝胶能够对外界环境因素的变化产生显著的体积或其他特性的变化,且其性质和结构与生物组织类似,有望应用于人工软骨、人造肌肉、组织工程等领域,引起了广泛的关注。提高环境刺激响应型智能水凝胶的力学性能是智能水凝胶应用研究的重要方向之一。本文综述了近年来环境刺激响应型高强度智能水凝胶的研究进展,简述了高强度智能水凝胶的网络结构的构建策略与方法,分析了其具备高力学性能的机理,重点介绍了4类不同结构的高强度智能水凝胶,即超低交联结构水凝胶、纳米颗粒复合水凝胶、拓扑结构水凝胶以及双网络结构水凝胶,最后讨论了环境刺激响应型高强度智能水凝胶在面向应用的研究过程中仍然需要解决的关键科学问题,如智能水凝胶的环境刺激与力学性能的博弈效应以及响应环境刺激前后的力学性能差异等。     

The synthesis,mechanisms, and additives for bio-compatible polyvinyl alcohol hydrogels: A review on current advances,trends, and future outlook

Vinyl polymers are widely used in biological, textile and industrial applications and are currently attracting research attention for specialized bio-based applications. Polyvinyl alcohol (PVA) hydrogels show great advantages as a material with high biocompatibility, permeability, hydrophilicity, and low-friction coefficient, allowing applications as smart materials, wound dressings, and flexible sensors. However, the poor mechanical properties of PVA hydrogels and biocompatibility less than natural polymers make them unsuitable in practical applications. Additives are often added to PVA hydrogels to enhance mechanical properties, endow more compatibility, functionality and expand their application range. Among them, bio-additives such as nanocellulose, natural polysaccharides and proteins are biodegradable, biocompatible, and inexpensive, broadening their applications in the biomedical and tissue engineering fields. This work reviews the synthesis of PVA hydrogels, methods to enhance their mechanical properties, types of bio-additives incorporated for biocompatibility, their mechanism of interaction with PVA and future prospects of PVA composite bio-hydrogels for application in various fields. Representative cases are carefully selected and discussed with regard to their composition and pros and cons are discussed. Finally, future requirements, as well as the opportunities and challenges of these bio-additives for improving the multifunctionality of PVA hydrogels are also presented.     

A Novel Polyvinyl Alcohol-Based Hydrogel with Ultra-Fast Self-Healing Ability and Excellent Stretchability Based on Multi Dynamic Covalent Bond Cross-Linking

A novel self-healing poly(vinyl alcohol) (PVA)-based hydrogel is developed by cross-linking PVA chains through multi dynamic covalent bonds by use of a small cross-linker composed by 4-formylphenylboric acid (FPBA) and lysine (Lys). The dynamic borate-imine-imine-borate bond structure between PVA chains endows the hydrogel excellent stretchability and ultra-fast self-healing ability without external stimulation. The self-healing efficiency can attain 94% and the elongation at break can reach up to near 1000% after only 3 min healing. Moreover, the self-healing of the hydrogel through the contact of two faces from both the same cut position and different cut positions has similar excellent efficiency. The hydrogel with the unusual self-healing performance and stretchability is used as an ideal material in strain sensors monitoring human movement and tiny vibrations caused by human voice. Interestingly, the sensor can continue to function normally after self-healing for only ≈3 s. It is expected that this simple strategy of fabricating self-healing hydrogels with multi dynamic bonds will provide new opportunities in the design and preparation of PVA-based hydrogels to expand their potential applications in sensors and other various fields.     

温敏型分子印迹水凝胶的研究进展

近年来分子印迹技术发展迅速,以其高选择性、预定识别性等优点,在分离工程、化学传感器及模拟酶催化等领域均得到了广泛应用,但是其在水凝胶方面的研究却较少。将温敏水凝胶引入分子印迹技术制备温敏印迹水凝胶不仅能保持其特异识别性能,还赋予其对环境温度变化的响应性,使其对模板分子的识别具有温度可控性。本文简单介绍了温敏型分子印迹水凝胶的基本原理和制备方法,基于模板分子种类的不同,着重综述了温敏印迹凝胶在金属离子、有机小分子及生物蛋白方面的应用。同时对温敏印迹水凝胶的发展方向进行了展望,指出温敏印迹水凝胶将在物料分离、药物控释等领域表现出较好的应用前景。     

Short-peptide-based molecular hydrogels: novel gelation strategies and applications for tissue engineering and drug delivery

Molecular hydrogels hold big potential for tissue engineering and controlled drug delivery. Our lab focuses on short-peptide-based molecular hydrogels formed by biocompatible methods and their applications in tissue engineering (especially, 3D cell culture) and controlled drug delivery. This feature article firstly describes our recent progresses of the development of novel methods to form hydrogels, including the strategy of disulfide bond reduction and assistance with specific protein-peptide interactions. We then introduce the applications of our hydrogels in fields of controlled stem cell differentiation, cell culture, surface modifications of polyester materials by molecular self-assembly, and anti-degradation of recombinant complex proteins. A novel molecular hydrogel system of hydrophobic compounds that are only formed by hydrolysis processes was also included in this article. The hydrogels of hydrophobic compounds, especially those of hydrophobic therapeutic agents, may be developed into a carrier-free delivery system for long term delivery of therapeutic agents. With the efforts in this field, we believe that molecular hydrogels formed by short peptides and hydrophobic therapeutic agents can be practically applied for 3D cell culture and long term drug delivery in near future, respectively.     

Fabrication of alginate/sericin/cellulose nanocrystals interpenetrating network composite hydrogels with enhanced physicochemical properties and biological activity

Sodium alginate (SA) possesses good biocompatibility and can form hydrogel materials under certain conditions, which has been widely used in tissue engineering. However, the absence of cellular recognition sites and low mechanical strength for single-component alginate (ALG) hydrogels limit their practical applications. Therefore, enhancing the shortcomings of ALG hydrogels and augmenting their characteristics hold immense importance for their medical uses. In this study, comprehensively considering the excellent properties of cellulose nanocrystals (CNCs) and sericin (SS), the alginate/sericin/cellulose nanocrystalline (ALG/SS/CNCS) composite hydrogels were constructed by interpenetrating network (IPN) technique using hydroxyapatite/D-glucono-δ-lactone (HAP/GDL) as the endogenous ionic cross-linking agent of SA, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS) as the chemical covalent cross-linking agent of SS and CNCS as the reinforcing agent. The effects of SS and CNCs additions on the comprehensive properties of ALG/SS/CNCs composite hydrogels, such as their morphologies, structure, mechanical properties, swelling, degradability, and cytocompatibility were investigated. The findings indicated that the ALG/SS/CNCS IPN composite hydrogels which were created through the physical blending of SA and SS, displayed a consistent three-dimensional form and a porous configuration. The weak mechanical strength of pure ALG hydrogels can be effectively improved and the swelling stability and mechanical properties of the composite hydrogels can be enhanced through the construction of IPN network and the incorporation of CNCs, thanks to the presence of intermolecular hydrogen bonding. The biodegradability of ALG/SS/CNCS composite hydrogels increased as the SS content increased, indicating that SS facilitated their biomineralization due to its inherent susceptibility to degradation. The results of the cell compatibility test conducted in a laboratory setting showed that SS and CNCS had the ability to enhance the attachment, proliferation, and differentiation of MC3T3-E1 cells on the ALG/SS/CNCS composite hydrogels. Hence, incorporating SS and CNCS into the alginate matrix to create IPN composite hydrogels could significantly enhance the physicochemical and biological characteristics of ALG hydrogels, thus rendering them appropriate for tissue engineering purposes.     

Mechanical reinforcement of hydrogels by nanofiber network undergoing biaxial deformation

Hydrogels can encapsulate large quantities of water within a three‐dimensional crosslinked polymer network. Polyvinyl alcohol (PVA) hydrogels have been widely used in tissue engineering, wound dressing, and drug delivery. However, the inferior mechanical properties of PVA hydrogels limit their utility in load‐bearing applications. To alleviate this deficiency, we used a hybrid electrospinning/solution casting continuous process to reinforce PVA hydrogels using polyurethane nanofibers. In this process, the nanofibers were electrospun into the wet solution cast film prior to solidification. The reinforcement of PVA hydrogels at a series of extent of water swelling was determined using a custom built bubble biaxial stretching device. The results showed that nanofibers have substantial enhancement effect on mechanical properties particularly in thin hydrogel films at high water concentrations. Reduction of nanofiber diameter was also found to increase this reinforcement due to increased interfacial area between nanofibers and hydrogels. POLYM. COMPOS., 37:709–717, 2016. © 2014 Society of Plastics Engineers     

BIOMIMETIC GRADIENT HYDROGELS FOR TISSUE ENGINEERING

During tissue morphogenesis and homeostasis, cells experience various signals in their environments, including gradients of physical and chemical cues. Spatial and temporal gradients regulate various cell behaviours such as proliferation, migration, and differentiation during development, inflammation, wound healing, and cancer. One of the goals of functional tissue engineering is to create microenvironments that mimic the cellular and tissue complexity found in vivo by incorporating physical, chemical, temporal, and spatial gradients within engineered three-dimensional (3D) scaffolds. Hydrogels are ideal materials for 3D tissue scaffolds that mimic the extracellular matrix (ECM). Various techniques from material science, microscale engineering, and microfluidics are used to synthesise biomimetic hydrogels with encapsulated cells and tailored microenvironments. In particular, a host of methods exist to incorporate micrometer to centimetre scale chemical and physical gradients within hydrogels to mimic the cellular cues found in vivo. In this review, we draw on specific biological examples to motivate hydrogel gradients as tools for studying cell-material interactions. We provide a brief overview of techniques to generate gradient hydrogels and showcase their use to study particular cell behaviours in two-dimensional (2D) and 3D environments. We conclude by summarizing the current and future trends in gradient hydrogels and cell-material interactions in context with the long-term goals of tissue engineering.     

Synthesis and Evaluation of AlgNa-g-Poly(QCL-co-HEMA) Hydrogels as Platform for Chondrocyte Proliferation and Controlled Release of Betamethasone

Hydrogels obtained from combining different polymers are an interesting strategy for developing controlled release system platforms and tissue engineering scaffolds. In this study, the applicability of sodium alginate-g-(QCL-co-HEMA) hydrogels for these biomedical applications was evaluated. Hydrogels were synthesized by free-radical polymerization using a different concentration of the components. The hydrogels were characterized by Fourier transform-infrared spectroscopy, scanning electron microscopy, and a swelling degree. Betamethasone release as well as the in vitro cytocompatibility with chondrocytes and fibroblast cells were also evaluated. Scanning electron microscopy confirmed the porous surface morphology of the hydrogels in all cases. The swelling percent was determined at a different pH and was observed to be pH-sensitive. The controlled release behavior of betamethasone from the matrices was investigated in PBS media (pH = 7.4) and the drug was released in a controlled manner for up to 8 h. Human chondrocytes and fibroblasts were cultured on the hydrogels. The MTS assay showed that almost all hydrogels are cytocompatibles and an increase of proliferation in both cell types after one week of incubation was observed by the Live/Dead^® assay. These results demonstrate that these hydrogels are attractive materials for pharmaceutical and biomedical applications due to their characteristics, their release kinetics, and biocompatibility.