具有快-慢交替降解特征的高生物响应性多壳层化复相陶瓷微球构建及原位骨再生研究

It is still a great challenge to treat the osteoporosis-derived pathological bone defect which is usually delayed healing. Nowadays the design of artifical implants cannot attention simultaneously the bioactivity and biodegradability of bioceramics, and such implants are hardly to quickly trigger new bone regeneration in osteoporosis. This proposal is motivated by previous work from our lab on the bioactive microsphere implants for enhancing the early-stage repair of the pathological bone defect. This work aims to design multi-shell calcium silicate(CS)-β-tricalium phosphate(β-TCP) composite ceramics microspheres for treatment of osteoporotic bone defect. This study is based on the optimization of component choice that CS is biodegradable faster than bone regeneration but β-TCP is slowly biodegradable so that the multi-layered CS-TCP spheres possess a novel "fast-slow-fast" biodegradation characteristic. The first work is to dilutely dop the CS or β-TCP shell layers with trace element such as strontium and zinc to modulate its biodegradation rate and improve the bioactivity, and evaluate the relationship between porous newtwork evolution and shell size. The second is to explore the biologically active ion dissolution products and surface properties of the CS-TCP microspheres on inflammatory cell responses and differentiation potential of osteogenous stem cells in vitro. The multi-shell microspheres developed in our lab will be dispersed into the cell culture medium (CCM), on the basis on their compositions and structure. The research approach will be guided by inorganic ion dissolution in CCM, and their effects such as the viability, proliferation, and differentiation and the dynamic metabolic behavior of stem cells in CCM will be determined and evaluated in detail. The third is to validate the bone defect repair rate regulated by the microspheres fillers in vivo. The influence of microspheres with different shell components (CS or β-TCP) on the inflammation response and new trabeculae regeneration will be monitored to determine the inorganic ion combination effects from the microspheres. The advantages of these studies will include: 1) to validate the tailorable bioactivity and biodegradation rates of composite bioceramics with novel multi-layered microstructures; 2) to get a better understanding on the porous network evolution of implants on the in situ bone regeneration in the early and later stage of pathological bone defect; and 3) clearly to elucidate the mechanism of synergistically bioactive effects of bioactive inrganic ions combination at molecule and cell levels on positvely mediating inflammatory cell and osteogenous stem cell responses,and improving bone regeneration in osteoporosis. These studies will help to develop new tailorable biodegradable bioceramics to combat the pathological bone defects. Also,this revelation greatly widens the basis of new design concept for next generation of biomaterials.

骨质疏松等病理性骨损伤愈合迟缓、修复缓慢是骨修复医学的难题。目前的人工骨陶瓷设计难以兼顾其降解性、生物活性按骨修复进程实现自我动态调节，因而难以达到快速启动骨再生修复、避免其它并发症发生的需求。本项目优选降解速率快于和慢于骨再生的硅酸钙和β-磷酸三钙两种物质，设计并构建由二者交替组装的多壳层复相陶瓷微球，并通过锶/锌微掺杂精细调控各个壳层的降解速率和生物活性，明确各壳层的尺度对微球降解进程和微球堆砌体多孔网络动态演化的基本关系，分析微球对骨质疏松病源炎性细胞、成骨相关干细胞活性的介导作用规律，以及微球堆砌体对病理性骨缺损再生修复效率的研究，揭示这一新颖微结构构造陶瓷微球的组成、释放离子组合物、孔道网络演化特征对病理骨缺损内宿主细胞、组织的刺激-响应机制，这些诸多问题的研究和解决，对指导临床紧迫需求新型人工骨开发具有重要的现实意义，并将丰富和发展降解速率可动态剪裁的高生物响应性材料的设计理论

本项目从生物材料组分优化制备及颗粒型生物陶瓷复合材料构筑工艺技术创新设计两方面出发，围绕生物活性复合陶瓷微球的核-壳结构构造及理化与生物学性能展开了深入系统研究，完成了研究内容并取得一系列重要成果。首先发现，海藻微球模板在钙-磷酸盐、钙-硅酸盐溶液交替浸泡置换并烧结后处理能制备钙-硅、钙-磷陶瓷组分交替包裹型中空微球。据此，团队自主设计多个系列同轴多喷头陶瓷微球制备技术平台，成功实现对二元到多元（如硅灰石、磷酸三钙、生物玻璃等）生物(玻璃)陶瓷交替分层组装微球颗粒的优化制备，并通过向浆料选择性添加有机微粒实现特定陶瓷组分多孔微结构可控剪裁，解决了长期以来制约复合生物陶瓷各组分活性、降解及离子释放剂量精准剪裁的重大难题。其次，通过低剂量异质离子掺杂硅灰石，解决了硅灰石陶瓷的烧结性能、降解性调控，并成功构建出以锶、镁分别掺杂核、壳层硅灰石组分的非计量比硅灰石陶瓷，发展了单相陶瓷微球内部不同区域性能的精确调控、剪裁新理论和关键技术。再次，运用大白兔、比格犬承重骨(股骨)、薄壁骨(颅骨、颌骨)等多个骨缺损模型，论证了二、三元复合生物陶瓷核-壳结构及内部微孔道结构等对介导骨再生和材料同步降解行为，获得组成分布和微结构最优化参数，为不同临床骨缺损适应症条件对材料各性能理想需求建立了新材料体系，相关复合陶瓷微球材料达到可临床转化应用水平。本项目成果全面阐明了生物活性复合陶瓷“劣势性能转化为优势性能”的科学设计思路和可靠性，项目成果不仅回答了项目提出的主要科学问题，并系统阐释了过快、过慢降解性陶瓷分层组装复合对调控骨再生、改建的材料化学机制，为高效再生修复新型材料开发开拓了全新的材料设计方案。本项目研究期间在ACS Mater Interf、JMC-B、J Am Ceram Soc、J Euro Ceram Soc等发表SCI收录学术论文13篇，即将(待)发表论文4篇，参与学术会议10余人次，做全国生物材料大会邀请报告1次，获授权专利2项，培养青年人才10余人。