免疫调节性生物材料诱导心脏瓣膜原位再生的机制研究

生物材料调节免疫反应诱导组织修复再生是研究热点。本项目对具自主知识产权的去细胞瓣膜，应用酶敏感型聚乙二醇（PEG）水凝胶和负载miRNA的聚己内酯（PCL）纳米颗粒进行功能化修饰。旨在：1）PEG水凝胶改变材料表面特征，影响中性粒细胞、单核细胞黏附，减轻继发性损伤，揭示Mac-1/SLAM7对蛋白吸附调控免疫反应机制；2）免疫细胞分泌基质金属蛋白酶降解PEG水凝胶，所释放PCL纳米颗粒借助叶酸识别靶向作用于巨噬细胞，miR-223诱导巨噬细胞向M2型极化，加速炎症消退；3）植入体内诱导内皮祖细胞等迁移、增殖与分化，促进瓣膜材料细胞化，探讨HMGB1/CXCR4在免疫反应影响修复再生的作用。本项目构建免疫调节性生物材料，调控组织工程心脏瓣膜免疫微环境，阐明瓣膜材料影响蛋白吸附、关键免疫细胞表型转化及干细胞修复等方面机制，为实现心脏瓣膜原位再生提供坚实基础。

It is a research hotspot that biomaterials induce tissue repair and regeneration by regulating immune response. This project is to functionalize the decellularized valve with the independent intellectual property rights by using enzyme-sensitive polyethylene glycol (PEG) hydrogel and miRNA-loaded polycaprolactone (PCL) nanoparticles. The aims are the following: 1) PEG Hydrogel changes the surface characteristics of the material, affects the adhesion of neutrophils and monocytes, and reduces secondary damage, which may reveal the mechanism of Mac-1/SLAM7 absorbing protein to regulate immune response; 2) matrix metalloproteinase secreted by immune cells degrade PEG hydrogel, and the released PCL nanoparticles target the macrophages with folate. miR-223 induces the transformation of macrophage to M2 type, accelerating inflammation subsides; 3) The biomaterial implanted in vivo induce migration, proliferation and differentiation of endothelial progenitor cells, promoting the cellularization of decellularized valves. And the role of HMGB1/CXCR4 in the immune response which influences repair and regeneration is explored. This project fabricates immunomodulatory biomaterials that regulate the immune microenvironment of tissue engineering heart valve, and clarifies the mechanisms of valve material affecting protein adsorption, key immune cell phenotype transformation and stem cell repair, which provides a solid foundation for regeneration of heart valves in situ.