聚氨基酸基自愈合水凝胶构建及关节骨软骨复合组织重建

Articular osteochondral regeneration is a clinical challenge. It is important to construct a scaffold, which can bind cartilage and subchondral bone tightly, and promote the integration of neo-cartilage and normal tissue. In the present subject, the polyamino acid based self-healing hydrogels with biodegradability, proper mechanical strength, erosion resistance and shear thinning properties were created. Cartilage hydrogels and subchondral hydrogels were fabricated from poly(L-glutamic acid) (PLGA) with high molecular weight and hydroxyapatite-g-PLGA, respectively. The combination of cartilage and subchondral bone was achieved through the self-healing ability of hydrogels. The hydrogels were functionalized to exhibit tissue adhesion property. Besides, the second network was created by UV light to effectively improve the mechanical strength and gel stability in vivo. Adipose derived stem cell (ASC) spheroids were packed in gel densely, depositing abundant extracellular matrix. With the assistance of bonding action of materials, cartilage integration was enhanced. Due to the shear thinning property, cells were protected during the injection process. Osteochondral tissue was regenerated without fibrosis and obscission, possessing significant hyaline-like cartilage features. The present subject could provide scientific basis for the clinical application of polyamino acid in tissue engineering.

关节骨软骨缺损共修复是临床具有挑战性课题。构建既能牢固结合软骨和下骨，又能促进再生软骨与正常软骨整合的材料，是解决骨软骨缺损共修复的关键问题。本项目提出基于动态键构建生物可降解性、一定力学强度、抗溶蚀性和剪切变稀特性的聚氨基酸自愈合水凝胶，软骨和下骨层分别由高分子量聚L-谷氨酸（PLGA）和纳米羟基磷灰石接枝的PLGA组成。利用材料的自愈合性能，使软骨和骨界面牢固结合。通过PLGA侧链功能化，赋予凝胶良好的组织黏附性，体外光照可实现双重网络结构，有效提高凝胶在体内的力学强度和胶体稳定性。脂肪干细胞微团密堆积于凝胶体系，使其稳定高效地在软骨界面分泌细胞外基质，再借助材料和正常组织的键合作用，实现组织工程软骨和正常软骨的整合。凝胶具有剪切变稀特性，避免包裹的细胞在注射时受到损伤，微创下可实现骨软骨组织重建，再生组织接近透明软骨，避免再生软骨纤维化和脱落，为聚氨基酸材料临床应用提供科学依据。

日常运动损伤或是人类老龄退行性病变等会引起骨软骨损伤，组织工程技术的出现为骨软骨损伤修复提供了新的治疗策略，其中支架材料是实现骨软骨组织损伤共修复的关键因素之一。构建既能牢固结合软骨和下骨，又能促进再生软骨与正常软骨整合的水凝胶，是解决骨软骨缺损共修复的关键问题。.本项目提出基于动态键构建具有生物可降解性、一定力学强度、抗溶蚀性和剪切变稀特性的聚氨基酸自愈合水凝胶和微凝胶或微载体，软骨和下骨层分别由高分子量聚L-谷氨酸（PLGA）和无机粒子（如羟基磷灰石、锶取代羟基磷灰石等）接枝的PLGA组成。通过PLGA侧链功能化，赋予水凝胶或微凝胶或微载体良好的组织黏附性。负载脂肪干细胞（rASCs）体外诱导分化，期望实现组织工程软骨和软骨下骨再生。在上述工作基础上，构建基于PLGA的具有诱导活性一体化水凝胶支架，进一步构筑炎症响应释药的原位软骨水凝胶支架，并开展软骨再生修复研究。.首先合成基于PLGA 的一系列改性原料，并探索其在软骨和骨组织修复中的可行性。进一步优化后，获得具有良好生物相容性、一定力学性能和可注射性的自愈合水凝胶，将其植入兔关节软骨缺损处，三个月实现兔关节软骨组织修复。其次，构建基于PLGA的微凝胶，软骨层和骨层微凝胶基于迈克尔加成反应形成界面牢固的一体化支架，负载rASCs并分别进行软骨和成骨诱导后实现了兔骨软骨组织共修复，再生组织和正常软骨整合性良好。.在上述工作基础上，以PCL对聚L-谷氨酸改性并引入小分子KGN，构建基于PLGA的具有诱导活性水凝胶一体化支架，两层支架微区密度不同，从而调控干细胞分别向纤维软骨和透明软骨分化，最终实现山羊髁突骨再生。进一步构建炎症响应释药的原位软骨水凝胶支架，炎症环境释放的高浓度药物促进内源性干细胞募集，而基于酯键水解缓释的低浓度药物促进干细胞软骨向分化，最终实现大鼠关节软骨再生。

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