脂肪干细胞外泌体复合梯度矿化水凝胶支架促进肩袖腱骨愈合的作用及分子机制

肩袖修补术是治疗肩袖损伤的常用方法，但术后腱骨愈合困难一直是困扰骨科医生的一大难题，促进腱骨止点区域的梯度矿化软骨再生是解决该难题的关键。本项目组发现脂肪干细胞外泌体（ASCs-Exos）具有诱导BMSCs成软骨分化及调控巨噬细胞（MØ）极化的双重生物学作用。在初步明确miR-10a为其活性分子的基础上，本课题拟进一步研究ASCs-Exos通过miR-10a靶向KLF4基因促进BMSCs成软骨分化，探讨其向MØ递送miR-10a经IRAK4/TAK1/NF-κB通路抑制经典活化型MØ极化，阐明其促进腱骨间软骨再生的双重生物学作用及分子机制。研制具有连续梯度矿化结构的新型腱骨仿生支架，分析其搭载并缓释ASCs-Exos的规律，体内验证ASCs-Exos与该材料复合后促进腱骨止点再生软骨形成具有优良力学性能的梯度矿化软骨结构的性能，为解决肩袖腱骨愈合的临床难题提供新方法新思路。

Rotator cuff repair is a common method for treating rotator cuff tears, but the difficulty of tendon-bone healing after surgery has always been a great challenge for orthopedists. Promoting the regeneration of gradient mineralized cartilage in the region of tendon-bone enthesis is the key factor to solve this problem. In our previous study, we found that adipose stem cells derived exosomes (ASCs-Exos) showed the dual biological effects on inducing chondrogenic differentiation of BMSCs and regulating macrophage polarization. Based on the identification of miR-10a as an active molecule of ASCs-Exos, this project intends to further study the role of ASCs-Exos in targeting KLF4 gene to promote chondrogenesis of BMSCs and its regulation on macrophage polarization via targeting the IRAK4 / TAK1 / NF-κB pathway, aiming to clarify the molecular mechanism of ASCs-Exos in promoting cartilage regeneration of tendon-bone enthesis. By developing a new biomimetic scaffold with a continuous gradient mineralization structure to mimic tendon-bone enthesis, analyzing the release behaviors of ASCs-Exos from this scaffold, and verifying the in vivo promotion effects of the ASCs-Exos/scaffolds complex on the formation of gradient mineralized cartilage with excellent mechanical properties, this project will provide a new method and idea for solving the clinical problems of rotator cuff tendon-bone healing.