激活内源性干细胞的骨修复材料构建及其原位诱导骨再生机制研究

The excellent osteoinduction property of the bone grafts is the key bottleneck for their clinical applications which needs to be urgently solved, especially in the regeneration of bone defects with critical size and difficult-healed capacity. Simulating the “self-healing mechanism of human bone tissue” and applying the principle of “human body bioreactor”, the present project intends to design and synthesize the bioceramics and their composites with the activation of endogenous bone mesenchymal stem cells (BMSCs) responses, and induction the bone regenerations in situ through tailoring the micro-/nano-structured surfaces, bioactive components and the functions of the materials. After optimization and designing, the micro-/nano-structured surfaces of the fabricated materials will promote the recruitment of endogenous active factors, mediate the chemotaxis and homing of endogenous BMSCs and regulate their proliferation and osteogenic differentiation. In addition, the microenvironments generated by the releasing of bioactive ions from the degradation of the implants may also continuously activate endogenous BMSCs and accelerate bone formation. Furthermore, the micro-/nano-structures and the bioactive components stimulate bone formation synergistically. The closely combination between the material constructions and cell/tissue evaluation will reveal the laws and biological mechanisms among the material structures, bioactive components and their synthetic effects on cell response and in situ induction osteogenesis. The implementation of this project will establish foundation for the development and property modulation of the bioactive bone regeneration materials, and also provide implications for the research and development of other kinds of inductive tissue regeneration materials. The present project plays an important theoretic and clinical application role in the designing and development of bioactive bone grafts.

材料良好的诱导成骨活性是突破其临床应用瓶颈的关键，尤其在大尺寸和难愈合骨缺损修复领域。本项目模拟“人体骨组织自愈合”机制、利用“人体自身生物反应器”原理，从材料微纳结构、活性组成及功能三个角度设计、合成具有主动激活内源性骨髓间充质干细胞(BMSCs)响应，并原位诱导骨再生功能的生物陶瓷及复合材料。通过优化设计，实现材料自身微纳结构促进内源性活性因子募集，介导内源性BMSCs的募集和趋化、并调控其增殖与成骨分化；同时，通过材料降解释放的活性离子形成持续激活内源性BMSCs响应和诱导成骨的微环境，并实现微纳结构和活性组成协同成骨功能。将材料构建与细胞/组织评价紧密结合，揭示材料结构、活性组成及其之间的协同细胞响应和原位成骨的规律与生物学机制。该项目的实施将为生物活性骨修复材料的设计和性能调控奠定基础、也为其他组织诱导再生材料的研发提供借鉴，具有重要科学意义和临床应用价值。

材料良好的诱导成骨活性是突破其临床应用瓶颈的关键，尤其在大尺寸和难愈合骨缺损修复领域。基于“人体骨组织自愈合”机制和“人体自身生物反应器”原理，从材料微纳结构、活性组成及功能三个角度出发，有望设计、合成具有主动激活内源性骨髓间充质干细胞(BMSCs)响应，并原位诱导骨再生功能的生物材料。项目较系统开展了相关Ca-P和Ca-Si基生物陶瓷、生物玻璃粉体、功能元素掺杂生物陶瓷及其与聚酯类生物高分子、水凝胶复合材料的制备与性能研究。采用3D打印、静电纺丝技术实现多孔支架材料和个性化钛合金植入体的制备与结构调控；利用水热转化与原位重结晶技术、碱热-水热两步法、酸蚀与阳极氧化法等，在生物陶瓷、陶瓷涂层和钛合金表面实现纳米结构、微米-亚微米-纳米多级仿生结构的构筑；开展了无定型C磁控溅射涂层修饰方法、原位聚多巴胺（PDA）化学涂层修饰调控多类型骨修复材料的表面活性化改性方法研究。研究表明特定微纳结构改性、无定型C涂层、PDA化学修饰能够良好地促进功能蛋白的募集，促进BMSCs和内皮细胞的迁移、粘附和成骨/成血管分化，进而促进成骨。基于同轴静电纺丝技术构建成血管、成骨小分子药物程序性释放系统，实现血管化骨修复的动物实验验证。项目基于功能元素掺杂思路，发现Li、Sr离子掺杂能够良好介导内源性BMSCs的归巢，促进细胞成骨分化，并良好地调控临界尺寸骨缺损修复，以及在糖尿病、骨质疏松性骨缺损修复领域中有良好的应用潜力。此外，基于人体骨骼压电效应调控骨骼发育与重塑的特性，实现了基于内源性电刺激响应促成骨材料设计与成骨性能验证，证实内源性生物力引发的摩擦发电电刺激激活钙离子通道促成骨的生物学机制。项目组还开展了成骨与抗肿瘤双功能型生物陶瓷表面功能化与性能研究。研究成果为生物活性骨修复材料的设计奠定了良好的基础，具有重要的理论意义和实际应用价值。