组织工程用水凝胶制备方法研究进展

高分子水凝胶作为-类重要的生物材料被广泛应用于生物医药和组织工程领域.本文综述了基于化学交联和物理交联的有关组织工程用水凝胶的设计方法,重点介绍了通过自由基共聚、结构互补基团间的化学反应、高能辐射和酶交联的化学交联型水凝胶以及通过离子间的相互作用,结晶作用、氢键及疏水性相互作用形成的物理交联型水凝胶的研究进展,对比了各种交联机制的优缺点,并对水凝胶在组织工程领域中的进-步应用进行了展望.     

Extracellular matrix regenerated: tissue engineering via electrospun biomimetic nanofibers

While electrospinning had seen intermittent use in the textile industry from the early twentieth century, it took the explosion of the field of tissue engineering, and its pursuit of biomimetic extracellular matrix (ECM) structures, to create an electrospinning renaissance. Over the past decade, a growing number of researchers in the tissue engineering community have embraced electrospinning as a polymer processing technique that effectively and routinely produces non‐woven structures of nanoscale fibers (sizes of 80 nm to 1.5 µm). These nanofibers are of physiological significance as they closely resemble the structure and size scale of the native ECM (fiber diameters of 50 to 500 nm). Attempts to replicate the many roles of native ECM have led to the electrospinning of a wide array of polymers, both synthetic (poly(glycolic acid), poly(lactic acid), polydioxanone, polycaprolactone, etc.) and natural (collagen, fibrinogen, elastin, etc.) in origin, for a multitude of different tissue applications. With various compositions, fiber dimensions and fiber orientations, the biological, chemical and mechanical properties of the electrospun materials can be tailored. In this review we highlight the role of electrospinning in the engineering of different tissues and applications (skin/wound healing, cartilage, bone, vascular tissue, urological tissues, nerve, and ligament), and discuss its potential role in future work. Copyright © 2007 Society of Chemical Industry     

Interpenetrating networks hydrogels based on hyaluronic acid for drug delivery and tissue engineering

There are several techniques for preparing hydrogel biomaterials. Among these techniques, preparation of interpenetrating polymer networks hydrogel (IPNs) has been more interested during last years. IPNs are fabricated by the incorporation of monomers or polymeric chains in hydrogel network. Natural polymers such as hyaluronic acids have some advantages such as biocompatibility, biodegradability and non-toxicity. In this review, we would have a brief view to the interpenetrating polymer networks hydrogel based on hyaluronic acids and its applications as a drug delivery system and tissue engineering applications.     

Design of artificial extracellular matrices for tissue engineering

The design of artificial extracellular matrix (ECM) is important in tissue engineering because artificial ECM regulates cellular behaviors, including proliferation, survival, migration, and differentiation. Artificial ECMs have several functions in tissue engineering, including provision of cell-adhesive substrate, control of three-dimensional tissue structure, and presentation of growth factors, cell-adhesion signals, and mechanical signals. Design criteria for artificial ECMs vary considerably depending on the type of the engineered tissue. This article reviews the materials and methods that have been used in fabrication of artificial ECMs for engineering of specific tissues, including liver, cartilage, bone, and skin. This article also reviews artificial ECMs used for modulation of stem cell behaviors for tissue engineering applications.     

PVA-based hydrogels for tissue engineering: A review

Poly (vinyl alcohol) (PVA) is a hydrophilic polymer with excellent biocompatibility and has been applied in various biomedical areas due to its favorable properties. PVA-based hydrogels have been recognized as promising biomaterials and suitable candidates for tissue engineering applications and can be manipulated to act various critical roles. However, due to some disadvantages (i.e., lack of cell-adhesive property), they needs further modification for desired and targeted applications. This review highlights recent progress in the design and fabrication of PVA-based hydrogels, including crosslinking and processing techniques. Finally, major challenges and future perspectives in tissue engineering are briefly discussed.     

Swelling behavior of polyelectrolyte complex hydrogels composed of chitosan and hyaluronic acid

Polyelectrolyte complex (PEC) hydrogels composed of various weight ratios of chitosan and hyaluronic acid were prepared. The PEC hydrogels were formed by the reaction of the oppositely charged chitosan polymers. The PEC films swelled in water rapidly, reaching equilibrium within 30 min, and exhibited relatively high swelling ratios, 243–322%, at 25°C. The swelling ratio increased with increasing temperature. The transport phenomena of all PEC samples were non‐Fickian and diffusion and relaxation controlled. The diffusion coefficients of the PEC films ranged from 2.22 × 10^?6 to 10.05 × 10^?6 cm²/s. The activation energy of the polyelectrolyte complexes ranged from 37.14 to 54.58 kJ/mol and proved to be hydrophilic. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 1097–1101, 2004     

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     

In situ-forming injectable hydrogels for regenerative medicine

Regenerative medicine involves interdisciplinary biomimetic approaches for cell therapy and tissue regeneration, employing the triad of cells, signals, and/or scaffolds. Remarkably, the field of therapeutic cells has evolved from the use of embryonic and adult stem cells to the use of induced pluripotent stem cells. For application of these cells in regenerative medicine, cell fate needs to be carefully controlled via external signals, such as the physical properties of an artificial extracellular matrix (ECM) and biologically active molecules in the form of small molecules, peptides, and proteins. It is therefore crucial to develop biomimetic scaffolds, reflecting the nanoenvironment of three-dimensional (3D) ECM in the body. Here, we describe in situ-forming injectable hydrogel systems, prepared using a variety of chemical crosslinkers and/or physical interactions, for application in regenerative medicine. Selective and fast chemical reactions under physiological conditions are prerequisites for in situ formation of injectable hydrogels. These hydrogels are attractive for regenerative medicine because of their ease of administration, facile encapsulation of cells and biomolecules without severe toxic effects, minimally invasive treatment, and possibly enhanced patient compliance. Recently, the Michael addition reaction between thiol and vinyl groups, the click reaction between bis(yne) molecules and multiarm azides, and the Schiff base reaction have been investigated for generation of injectable hydrogels, due to the high selectivity and biocompatibility of these reactions. Noncovalent physical interactions have also been proposed as crosslinking mechanisms for in situ forming injectable hydrogels. Hydrophobic interactions, ionic interactions, stereocomplex formation, complementary pair formation, and host–guest interactions drive the formation of 3D polymeric networks. In particular, supramolecular hydrogels have been developed using the host–guest chemistry of cyclodextrin (CD) and cucurbituril (CB), which allows highly selective, simple, and biocompatible crosslinking. Molecular recognition and complex formation of supramolecules, without the need for additional additives, have been successfully applied to the 3D network formation of polymer chains. Finally, we review the current state of the art of injectable hydrogel systems for application in regenerative medicine, including cell therapy and tissue regeneration.     

纤维素基水凝胶的研究进展

纤维素是世界上最丰富的天然、可再生以及可生物降解的高分子材料,在化工、材料等领域有广泛的应用。本文主要对近几年来纤维素基水凝胶的研究进展进行了归纳总结。首先,介绍了纤维素基水凝胶的研究背景。其次,列举了纤维素水基凝胶的交联方法,主要有物理交联与化学交联。其中物理交联有氢键交联、疏水性交联、离子交联等,化学交联则是酯化交联、迈克尔加成、自由基共聚合、动态共价键交联等。最后,重点介绍了纤维素基水凝胶在可降解性、生物医学性、亲水性、吸附性、导电性等领域方面的应用。此外,对于纤维素基水凝胶材料在高机械性和产业化制备等方面的发展进行了展望。     

聚天冬氨酸水凝胶合成及其应用于药物控释的研究进展

聚天冬氨酸是一种新型的聚合氨基酸材料,具有很好的生物相容性、生物降解性。本文综述了聚天冬氨酸及其衍生物水凝胶的研究现状,介绍了化学交联、光交联、γ射线交联3种交联方法合成的聚天冬氨酸及其衍生物水凝胶,以及近年来聚天冬氨酸基凝胶对大分子蛋白药物、小分子抗炎性药物、抗癌和基因药物控释的研究进展,并对该凝胶在药物控释领域的发展方向进行了预测。     

Synthesis and characterization of dextran hydrogels prepared with chlor‐ and nitrogen‐containing crosslinkers

In this study, we have synthesized dextran hydrogels by the crosslinking reactions of dextran with some selective Cl‐, and N‐containing functional monomers, such as epichlorohydrin (ECH), N,N′‐methylenebisacrylamide (MBAm), and glutaraldehyde (GA). Crosslinking reactions were carried out in the basic aqueous solutions (2.8NNaOH) at 25–50°C. The optimum conditions for effective crosslinking, i.e., temperature, crosslinking time, and amount of crosslinker, were determined for each system. The hydrogel discs of 3 mm diameter and 1.5 mm thickness were subjected to a number of Tris‐buffer solutions of desired pH (2.0–9.0) at 37°C. Swelling kinetics of the hydrogels were evaluated with second–order swelling model. The pH‐dependent swelling of hydrogels was strongly influenced by the functional group of crosslinker and crosslinker content. While the hydrogels prepared with ECH and MBAm shows higher swelling ability at basic medium than that of acidic medium, GA‐containing hydrogels exhibited just the opposite behavior. Mesh sizes (ξ) and average molecular weights between crosslinks (M_c) were estimated from swelling data using the Flory‐Rehner theory. Characterization studies were completed by Fourier transform infrared spectroscopy and thermal gravimetric analysis. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102:4213–4221, 2006     

Electrical/pH responsive properties of poly(2‐acrylamido‐2‐methylpropane sulfonic acid)/hyaluronic acid hydrogels

Poly(2‐acrylamido‐2‐methylpropane sulfonic acid) (PAMPS)/hyaluronic acid (HA) interpenetrating polymer network (IPN) hydrogels have been prepared by using the sequential‐IPN method. The IPN hydrogels exhibited swelling behavior in solutions at various pHs, in NaCl solutions, and under electrical DC stimulation. The IPN hydrogels were highly swollen in water, but lost much of their water capacity when transferred to solutions having a high ionic strength. The IPN hydrogels showed a significant responsive deswelling in an applied electric field. This behavior indicates the potential application of IPN hydrogels as biomaterials. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 1731–1736, 2004     

Bioadhesive Hyaluronic Acid/Dopamine Hydrogels for Vascular Applications Prepared by Initiator-Free Crosslinking

Intimal hyperplasia, a vascular pathology characterized by vessel wall thickening, is implicated in vein graft failures. For efficient prevention, a biodegradable drug delivery system should be applied externally to the graft for an extended time. Finding a gel suitable for such a system is challenging. We have synthesized HA-Dopamine conjugates (HA-Dop) with several degrees of substitution (DS) and used two crosslinking methods: initiator-free crosslinking by basic pH shift or commonly used crosslinking by a strong oxidizer, sodium periodate. The rheological properties, bioadhesion to vascular tissue, cytocompatibility with fibroblasts have been compared for both methods. Our results suggest that initiator-free crosslinking provides HA-Dop gels with more adequate properties with regards to vascular application than crosslinking by strong oxidizer. We have also established the cytocompatibility of the initiator-free crosslinked HA-Dop gels and the cytotoxicity of dopamine-sodium periodate combinations. Furthermore, we have incorporated a drug with anti-restenotic effect in perivascular application, atorvastatin, into the gel, which showed adequate release profile for intimal hyperplasia prevention. The oxidizer-free formulation with improved bioadhesion holds promise as an efficient and safe drug delivery system for vascular applications.     

Synthetic polymeric absorbent for dye based on chemically crosslinked acrylamide/mesaconic acid hydrogels

Adsorption properties of copolymers of acrylamide and mesaconic acid (CAME) in aqueous Basic Blue 12 (Nile blue chloride) solution have been investigated. Chemically crosslinked CAME hydrogels with various compositions were prepared from ternary mixtures of acrylamide (A), mesaconic(ME) acid, and water by free radical polymerization in aqueous solution, using a multifunctional crosslinker such as ethylene glycol dimethacrylate (EGDMA). Dynamic swelling tests in water was applied to the hydrogels. Weight swelling ratio (S) values have been calculated. Sorption of Basic Blue 12 (BB 12) onto CAME hydrogels was studied by batch sorption technique at 25°C. In the experiments of the sorption, L type sorption in the Giles classification system was found. Some binding parameters such as initial binding constant (K_i), equilibrium constant (K), monolayer coverage (n), site‐size (u), and maximum fractional occupancy (Ô) for CAME hydrogels‐BB 12 binding system were calculated by using Klotz, Scatchard, and Langmuir linearization methods. Finally, the amount of sorbed BB 12 per gram of dry hydrogel (q) was calculated to be 2.28 × 10^?6–7.91× 10^?6 mol BB 12 per gram for hydrogels. Sorption % was changed range 16.09–58.86%. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 405–413, 2006     

Preparation and properties of high performance gelatin-based hydrogels with chitosan or hydroxyethyl cellulose for tissue engineering applications

High performance gelatin-based biocompatible hybrid hydrogels are developed using functionalized polyethylene glycol as a cross-linker in presence of chitosan or hydroxyethyl cellulose. Tensile test shows robust and tunable mechanical properties and reveals non-linear and J-shaped stress-strain curves similar to those found for native extracellular matrix. Degradation study demonstrates that the mass loss and change in mechanical properties are dependent on hydrogel composition and cross-linking density. Structural features of the hydrogels are confirmed by infrared spectroscopy. A preliminary biological evaluation is carried out using rat myoblasts and human fibroblasts cell lines. The results show that all hydrogels allow cell adhesion and proliferation during four days culture, hence, they might have a great potential for use in the biomedical applications.     

Matricryptic peptide-inspired hydrogels for promoting osteogenic differentiation

In the natural process of bone repair, matricryptic peptides were activated by up-regulated ECM-degrading enzymes and properly released at bone injury sites, which plays critical roles in bone self-healing. Inspired by this natural process, here, matricryptic peptide-inspired (MPI) hydrogels were designed to promote osteogenic differentiation. MPI hydrogels can be degraded by enzymes and during this time, the masked bioactive components were released to promote osteogenic differentiation. These MPI hydrogels which normally serve as structural support for cell proliferation while promote osteogenic differentiation using embedded osteogenic BFP-1 peptides after degradation may provide a novel design for bone regeneration materials.     

表面强化交联聚(N-异丙基丙烯酰胺) 水凝胶的温敏和浓缩分离性能

为了提高聚(N-异丙基丙烯酰胺)(PNIPA)凝胶粒子的浓缩分离效果,以过硫酸铵/N,N,N,N,-四甲基乙二胺为引发体系,N,N′-亚甲基双丙烯酰胺(BIS)和二乙烯苯(DVB)为复合交联剂,通过反相悬浮聚合合成了表面强化交联的PNIPA凝胶粒子.考察了凝胶颗粒形态、温敏特性及其浓缩分离聚乙二醇/水性能.发现得到的凝胶为紧密珠状粒子,低临界溶解温度为32℃;随着溶质聚乙二醇相对分子质量增大或浓度减小,凝胶对聚乙二醇/水的分离效率提高;增加合成PNIPA凝胶时的BIS用量,可提高凝胶对聚乙二醇/水的分离效率,但溶胀率显著下降;增加DVB用量,分离效率大幅提高,而凝胶溶胀率基本不变.     

Novel physically crosslinked hydrogels of carboxymethyl chitosan and cellulose ethers: Structure and controlled drug release behavior

Novel hydrogels, physically crosslinked by hydrogen bonding of component polymers, were obtained by mixing aqueous solutions of carboxymethylchitosan (CMCS) with cellulose ethers including hydroxyethylcellulose (HEC) and methylcellulose (MC). The hydrogels were characterized by IR, XPS, WAXD, and SEM. The swelling and controlled drug release behaviors of hydrogels were also studied. The results indicate that intermacromolecular hydrogen bonding in CMCS/HEC is stronger than that in CMCS/MC. The swelling and drug release rate of hydrogels decrease as the interaction of component polymers increases. Both the swelling and drug release from hydrogels can be controlled by component polymer ratio. The hydrogels may be potential candidates for biomedical applications. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

One‐shot radical polymerization of vinyl monomers with different reactivity accompanying spontaneous delay of polymerization for the synthesis of double‐network hydrogels

Double‐network hydrogels were conveniently synthesized by the one‐shot radical polymerization of an ionic monomer for the first network and a non‐ionic monomer for the second network in the presence of crosslinkers by simultaneous addition of the monomers, that is, one‐shot and spontaneous two‐step polymerization accompanying the delay of polymerization of a second network monomer. We analyzed the polymerization process based on the conversion of each monomer during the reaction in the absence of crosslinkers. Then we fabricated the double‐network hydrogels using several polymerization systems consisting of a conjugated monomer and a non‐conjugated monomer in the presence of the dual crosslinkers. We analyzed the swelling, mechanical and viscoelastic properties of hydrogels synthesized by one‐shot radical polymerization to confirm the production mechanism and the network structure of the hydrogels. © 2020 Society of Chemical Industry     

Fabrication and characterization of novel macroporous cellulose–alginate hydrogels

Novel macroporous hydrogels were prepared by blending of cellulose and sodium alginate (SA) solution, and then cross-linking with epichlorohydrin. The resulting cellulose/SA hydrogels were characterized by solid-state ¹³C NMR, wide-angle X-ray diffraction (WXRD), thermo-gravimetric analysis (TGA), scanning electron microscopy (SEM), rheological measurement, dynamic mechanical analysis (DMA) and swelling test to evaluate their structure, interior morphology, gelation time, compressive modulus, and equilibrium swelling ratio. Our findings revealed that the cellulose acted as backbone in the hydrogels, whereas SA contributed to the higher equilibrium swelling ratio. The combination of cellulose having semi-stiff chains and SA containing –COOH groups in the cross-linking hydrogel created the macroporous structure. This work provided a new pathway for preparation of hydrogel with large porous structure through incorporation of stiff polymer as support of pore wall and acidic polysaccharide as expander of pore size because of high water-absorbency.