高强度水凝胶作为结构生物医用材料的基础研究

Recently，researchers have developed a variety of approaches to fabricate high strength hydrogels. However, they are almost confined to chemical crosslinking and synthetic polymer species; while most of supramolecular hydrogels reported thus far are poor in mechanical properties. In addition, most high strength hydrogels become unstable when exposed in physiological water milieu. All these drawbacks have severely restrained their reliable application as structural biomedical materials. Inspired by the specific effect of multiple hydrogen bonding microdomains from polypeptides in proteins on stabilization of the conformations, we propose to construct novel high strength supramolecular polymer hydrogels based on the multiple hydrogen bonding physical crosslinkage of peptide bonds in the present project. We will investigate the influence of peptide hydrogen bonding on the gelation and physicochemical properties of the hydrogels obtained. The tailored vinyl peptide monomers will be copolymerized with various conventional vinyl monomers to prepare a series of supramolecular copolymer hydrogels, and the feasibility of peptide monomers as a universal mechanical enhancer is explored；we will develop a series of multifunctional bioinks for 3D printing. Last but not least, we will expand the peptide hydrogen bonging reinforcement to natural biopolymers to fabricate high strength natural macromolecular hydrogels. Their mechanical features, biodegradability and biocompatibility will be examined. The high strength hydrogel scaffolds tailored by 3D printing technique are primarily tested for the substitute and reconstruction of the load-bearing menisci and articular cartilages. This project offers a unique concept to design and construct high strength hydrogels, thus pointing out a novel strategy to treat the degenerated load-bearing menisci and cartilages.

近年来，研究者提出了众多制备高强度水凝胶的方法，但基本是限于化学交联和合成高分子，而现有的超分子水凝胶大多数力学性能较弱。此外，大多数高强度水凝胶在生理水环境会进一步溶胀，致使性能变得不稳定。这些缺点极大地限制了高强度水凝胶作为结构生物医用材料的应用。受蛋白质中的多肽氢键微区对构象稳定作用的启发，本项目拟创建基于肽键间多重氢键物理交联的高强度超分子聚合物水凝胶，探索肽键氢键对凝胶物化性能的影响规律；将乙烯基肽键单体与一系列单体共聚，探究肽键单体作为力学增强因子的普适性,发展一系列具有多种功能的生物墨水；将肽键氢键作用拓展至天然高分子中，研制高强度天然高分子水凝胶，考察高强度天然高分子凝胶的力学特征、降解性和生物相容性；重点探讨以3D打印技术定制的高强度水凝胶支架用于半月板和关节软骨承载组织的替代和修复。本课题将为创制高强度水凝胶提供独特的设计理念，为受损的承载软支撑组织提供新的策略。

本课题针对传统水凝胶力学性能差，已报道高强凝胶体系在水环境中不稳定，无法用于受损承载组织替代/修复的问题，研制了一系列氢键增强型高强度生物医用高分子水凝胶，取得了如下成果：（1）构建了一系列多重氢键增强超分子聚合物高强度水凝胶，考察了“超支化结构”以及“改变侧基结构”对超分子聚合物水凝胶力学性能的影响；提出了以氢键单体—N-丙烯酰基脲胺（NASC）和N-丙烯酰基甘氨酰胺（NAGA）作为“力学增强因子”，通过与其他单体进行共聚，通用便捷地构建高强度水凝胶的新方法，并基于此方法，构建了多种高强度超分子聚合物水凝胶；值得一提的是，PNASC水凝胶杨氏模量达100 MPa,可媲美半月板环向模量（2）通过天然高分子及其衍生物增稠以及利用超分子共聚物水凝胶温度响应性等方法，发展了可用于挤出打印高强度水凝胶的墨水体系；提出自增稠自增强策略以及凝胶微颗粒自增稠策略，设计合成了可用于挤出打印耐溶胀高强度PNAGA水凝胶和生理环境稳定高模量PNASC水凝胶的墨水体系；（3）借助于3D打印技术，构建出一系列几何形状与半月板匹配的PNAGA和PNASC高强度水凝胶基半月板支架，并验证其作为半月板替代物保护关节软骨的作用；（4）借助于3D打印技术，构建了梯度杂化高强度水凝胶双层支架，并验证其在促进骨-软骨一体化修复方面的功能；构建了仿生双层人工骨膜，并验证其在促进颅骨修复方面的适用性；（5）提出了一种通过浸泡茶多酚溶液，改善天然高分子基水凝胶力学性能的普适方法。除高强度水凝胶体系外，本课题还构建了具有不同侧基结构的氢键交联水凝胶体系，并探索了其在黏合剂以及术后防黏连方面的应用。