有机锶修饰脱细胞骨基质促进骨再生的作用与机制研究

由于具有天然的三维孔隙结构和与正常骨组织相似的组份，脱细胞骨基质已成为优良的骨修复材料，并应用于临床。但由于材料制备过程中的脱细胞和消除抗原等处理，使得其骨诱导性显著降低或缺失，因此，脱细胞骨基质的骨诱导性和骨再生潜能有待改善。鉴于微量元素锶特有的骨诱导性及与羧基的螯合特性，本项目提出将锶元素与羧基及金属基质蛋白酶底物片段结合，在脱细胞骨基质表面形成可酶解的有机锶诱导层。本项目将优化有机锶的化学结构与复合工艺，研究材料的降解特性及锶离子释放行为；以干细胞为研究对象评价复合材料的细胞相容性，利用裸鼠皮下移植和山羊大段骨缺损模型评价其生物相容性及诱导骨再生的潜能；并针对与成骨密切相关的Hedgehog-Wnt/β-catenin 信号通路，探讨该新型复合材料促进骨再生的可能分子机制。

Acellular bone matrix (ACBM) has been commercialized as one of the best bone grafts because of its sophisticated porous structure with interconnectivity and similar components to natural bone. However, the osteoinductivity of ACBM was reduced or lost during the process of removing cells and eliminating antigens. It is necessary to improve the osteoinductivity and bone regeneration ability of ACBM. Trace element of Strontium (Sr) has unique properties in inducing bone formation and chelating with carboxyl groups. This project aimsto synthesize novel organic compounds with matrix metalloproteinases (MMPs) sensitive substrate and carboxyl groups, which is the binding site for Sr ion. Sr ions will be mediated by carboxyl groups and decorated on the ACBM surface to improve its osteoinductivity. In this project, the methods for synthesizing organic Sr compounds and fabricating osteoinductive ACBM-Sr will be optimized. The degradation ability and Sr ion release profile will be studied. The cytotoxicity of ACBM-Sr will be evaluated with mesenchymal stem cells (MSCs). The biocompatibility and efficacy of Sr compounds for promoting bone formation will be evaluated with dude mice and goats. Furthermore, the effects of ACBM-Sr on regulating Hedgehog-Wnt/β-catenin signaling pathway in MSCs will be investigated and possible mechanism of Sr compound for inducing bone regeneration will be explored at both cellular and molecular levels. Hopefully, upon completion of this project, we expect to have developed an optimized, controlled release Sr composite biomaterial for bone grafting.