负载炎性诱导干细胞源性外泌体的复合支架促进糖尿病牙槽骨再生的作用及机制研究

Diabetes causes changes in the function of BMSCs, which leads to decreased osteogenic capacity, imbalance of bone metabolism, and severely affects alveolar bone regeneration. Studies have shown that inflammatory induced stem cell-derived exosomes have stronger abilities of immunomodulation and promoting tissue regeneration than non-inflammatory induced exosomes. However, their effects on diabetic bone regeneration and its mechanism are still unclear, and the efficiency of direct use is low. This study aims to construct a 3D printed SF/COL/nHA composite scaffold with inflammatory induced ASCs-derived exosomes. We study the effect of exosomes on regulating the migration, proliferation and osteogenic differentiation of diabetic BMSCs. We suppose PI3K/AKT signaling pathway mediates the mechanism of exosomes on promoting osteogenic differentiation of diabetic BMSCs. We also establish a model of skull defect in diabetic mice, and study the effect of exosomes on the repair of critical bone defects in diabetic mice, and explore the mechanism of exosomes on promoting bone regeneration in diabetes. This study is expected to use exosomes to reverse the changes of cell function caused by diabetes, promote bone regeneration in diabetic patients, and provide new ideas for the application of exosomes in the field of alveolar bone repair in diabetic patients.

糖尿病引起BMSCs功能改变，从而导致成骨能力下降、骨代谢失衡，严重影响牙槽骨再生。研究表明，炎性诱导干细胞源性外泌体较非炎性诱导外泌体具有更强的免疫调节和促进组织再生的能力，但其对糖尿病骨组织再生的作用和机制尚不清楚，且存在直接使用效率低等问题。本课题拟构建负载炎性诱导ASCs源性外泌体的3D打印SF/COL/nHA复合支架，研究该支架释放外泌体调控糖尿病BMSCs迁移、增殖和成骨分化的作用，并明确PI3K/AKT信号通路介导外泌体促进糖尿病BMSCs成骨分化的作用机制；建立糖尿病小鼠颅骨缺损模型，深入研究该支架释放外泌体对糖尿病小鼠临界骨缺损的修复效果，并探讨外泌体调控BMSCs功能促进糖尿病骨再生的作用机制。本课题有望利用外泌体逆转糖尿病引起的细胞功能改变，促进糖尿病患者骨再生，为外泌体在糖尿病患者牙槽骨修复领域的应用提供新的思路。

糖尿病引起骨髓间充质干细胞(BMSCs)功能改变，从而导致成骨能力下降、骨代谢失衡，严重影响牙槽骨再生。无细胞组织工程研究表明，干细胞源性外泌体具有较强的促进骨组织再生潜力，但直接使用易流失、效率低，且促进糖尿病环境下骨组织再生的作用和机制尚不清楚。本课题利用明胶(Gel)、透明质酸(HA)和纳米羟基磷灰石(nHAP)，模拟天然骨的有机和无机成分，通过3D打印技术制备出复合支架，并构建了缓释BMSCs来源外泌体的复合支架。该支架具有释放外泌体调控糖尿病BMSCs迁移、增殖和成骨分化的作用。通过建立糖尿病鼠骨缺损模型，研究了该支架释放外泌体对糖尿病鼠骨缺损的修复效果，并探讨了外泌体调控BMSCs功能促进糖尿病骨再生的作用机制。本项目共发表论文6篇，其中SCI检索期刊论文5篇，核心期刊论文1篇，授权实用新型专利1项，培养了1位博士研究生和2位硕士研究生。项目执行顺利，完成了既定的研究目标。相关研究成果可以为无细胞组织工程骨修复提供新策略，同时为外泌体在糖尿病患者牙槽骨再生性治疗的临床转化提供基础。