仿生矿化高生物活性纳米材料调控病理性骨折再生修复的机制研究

There is a significant increase in the case of osteoporosis in recent years. Because of its high disability and mortality, osteoporotic bone fracture is considered as one of the key global public health problems. The basic way to treat this kind of bone defect is to explore the new material for promoting osteoporotic fracture repair as soon as possible.Trace element silicon, strontium, zinc have already been found that not only can promote bone regeneration, but also have anti-inflammatory property. However, it is still challenge to fabricate the trace elements-co-doped calcium phosphate (TEs-CaP) biomimetic nanomaterials with controllable release hehavior to synergistically enhancing the repair of osteoportic fracture. This proposal is motivated by previous research from our lab to optimize the TEs-CaP nanomaterials to meet the special requirement in osteoporotic fracture repair. The first work is to prepare CaP nanoparticles in modified simulated body fluids (SBFs) complemented with silicon, strontium, and/or zinc ions via a biomimetic mineralization pathway under mild conditions. The techniques will be optimized according to the comparameters involving in chemical composition, particle size and morphology of the nanomaterials. The second is to evaluate the effects of different trace elements-doped nanomaterials on the osteogenic differentiation of OVX rat-derived marrow mesenchymal stem cells(OMSCs) and anti-inflammatory property in vitro and explore their mechanisms. The third is to validate the biological effect of TE-CaP on improving the osteoporotic bone defect healing and anti-inflammatory in vivo. The advantages of these studies will include: (1) to provide a more reliable technology platform for combining the tarce elements with the biodegradable CaP mineralization products; (2) to develop a simple method to prepare highly bioactive and biodegradable nanomaterials to meet the special requirement for enahncing bone regeneration and anti-inflammatory of osteoporotic bone defects; and (3)to set up a comprehensive underatanding of the biological performances and mechanism of trace elements on osteoporotic bone defect treatment. It is also helpful to develop the trace element-based nutrition and provide knowledge of osteoporotic prevention.

骨质疏松症发病率逐年快速增长，其伴发骨折因其高致残、致死率已成为全球性公共健康问题。加快探索促进骨质疏松性骨折修复的新材料技术，是解决这类骨损伤治疗难题的根本途径。现有研究表明，微量矿物元素在促进骨再生、抗炎性反应方面具有其独特的生物学效应，但是在病理性骨损伤再生修复中的协同性生物效应尚不明确。本项目立足于团队的前期研究基础，利用模拟生理液为仿生矿化体系构建微量矿物元素硅、锶、锌协同掺杂的可降解型高生物活性类骨矿物磷酸钙纳米材料，拟进一步开展该类纳米材料协同促进成骨(从细胞生物学和促进骨折愈合修复角度)、改善骨代谢(微创注入骨髓腔考察其骨代谢改善效果)以及抗炎效应(对病理性条件下关键炎性细胞以及炎性细胞因子表达的调节作用规律和水平)研究，探索和发现其内在作用机制，为骨质疏松性骨损伤再生修复人工骨材料的优化设计奠定理论基础，并对微量矿物元素营养学、骨质疏松用药的研究和发展提供有益的知识。

骨质疏松的发病率逐年快速增长，其伴发骨折因其高致残、致死性已成为重大公共健康问题。加快探索促进该类病理性骨损伤修复的材料，是解决该类问题的有效途径。某些人体必需的微量元素被证实在促进新骨组织再生、抗炎症反应方面显示出一定生物学效应，但是在骨质疏松等病理性骨损伤修复中的（协同性）生物效应值得探索。本项目运用仿生矿化的原理，成功制备出一系列多元微量元素共掺杂磷酸钙（TE-CaPs）的超细微粒材料；从细胞分子学实验结果发现，TE-CaPs纳米材料比临床用高生物活性玻璃具有更为优良的改善病理条件与否的骨髓间充质干细胞(MSCs、OMSCs)的活性效应，并在RNA水平、蛋白水平均能有效调控成骨相关的关键基因、蛋白的表达，有效促进钙质沉积；对MSCs、OMSCs分化成骨显示出极为优良的促进作用。其次，通过微创注入股骨髓腔进而干预骨质疏松发展的动物模型研究，结果表明，仿生矿化TE-CaPs能显著提升骨质疏松性动物股骨各部位矿物微结构致密性以及骨密度、骨强度。此外，本项目针对不同类型高生物活性仿生纳米材料的制备及其生物性能进行了骨损伤再生修复模型研究。相关表征分析发现，微量元素锶掺杂半水硫酸钙（Sr-CS）及微量元素锶掺杂硅酸钙（Sr-CSi）作为人工骨填充材料，均具有高度的组织相容性和骨再生活性；同时，该类生物活性陶瓷微粒与丝素蛋白纤维薄膜材料对薄壁型颅骨类缺损的再生修复也具有显著的促进效果。本项目的一系列研究结果为骨质疏松性骨损伤再生修复人工材料的优化设计奠定理论基础，明确了微量元素作为介导成骨的关键 “因子”在新一代生物材料构筑中的突出地位，并对病理性骨损伤微创治疗、微量元素营养学、骨质疏松用药的研究和发展提供有益的知识。本项目研究成果已发表SCI论文8篇（即将被接受发表2篇），获得授权专利1项，培养青年人才2名，并对本项目主持人在本领域的学术提升和相关交叉科学研究提供及宝贵的支持。