钛基生物功能化界面的构建及其成骨协同效应的研究

The poor osseointegration between titanium implant and tissue will make insufficient fixation of implant, and lead to plant loosning and osteolysis. The basic research related to titanium based medical devices is a urgent requirement for clinical application due to the weak basic research level in our country. In this project, multi-modality biological signals nano-reserviors (biomacromolecule complexed with functional gene or cytokine or drug-loaded mesoporous silca nanoparticles) were assembled onto titanium surface via combined techniques of LBL and drug release or gene therapy to form a "sanwhich-like" structure. This approach employed here is expected to raise the loading capacity of drugs (β-estrodial, alendronate) or biomacromolecules (cytokine and functional gene) and maintain their bioactivities, improving the osseointegration between titanium implant and tissue. We will focus on the studies of behavior of "biological cues communication" between cells and the functional titanium surface. Meanwhile, we will investigate osteoinductive potential and anti-osteoporosis effect on such functional titanium surface in situ and its regulation mechanism from the cellular and molecular level. The study will lay basis for developing novel drug-medicine titanium/alloy-based implants with independent intellectual property rights.

钛材植入体与组织间不良骨整合易导致植入体固定强度不足，造成植入体的松动并引发骨溶症。我国钛基骨植入医疗器械的基础研究相对薄弱，相关研究具有重大的国家战略和临床需求。本项目拟结合层层组装技术、药物释放及基因治疗技术，将多模态生物信号分子纳米储存器（功能基因/生物大分子纳米复合颗粒、细胞因子/生物大分子纳米复合颗粒、介孔硅-药物/生物大分子纳米复合颗粒等）等组装到钛材表面，构建类"三明治"结构的钛基生物活性界面；从而实现钛材界面功能药物（阿伦磷酸钠等）与生物活性分子（细胞因子，功能基因等）的高负载率并维持其长期生物活性，提高钛材植入体与骨组织的整合性。本项目拟重点考察钛基生物活性界面与细胞动态生物学信号交流行为，探索活性界面原位诱导骨形成及抗骨质疏松症的协同效应，并从细胞、分子水平探讨、阐释其界面原位调控机理；为开发具有自主知识产权的新型医用钛/钛合金骨修复植入体奠定理论和应用基础。

钛材植入体与组织间不良骨整合导致植入体固定强度不足，造成植入体的松动并引发骨溶症。对于骨疾病患者，如患有骨质疏松症，骨移植手术面临更大挑战。为了提高钛基植入体在骨疾病（如骨质疏松症）患者中的长期稳定性，本研究利用层层组装技术，将生长因子（BMP2）及功能药物（阿伦磷酸钠、降钙素）或功能基因组装到钛基材表面，构建活性纳米存储器细胞外微环境界面。通过体外及体内实验考察了钛基植入体表面功能分子与骨组织的相互作用。结果发现：(1)钛材表面多层膜可以有效控制生物分子或功能药物的释放行为并保持其活性。（2）钛基材表面释放的生长因子(如BMP2)纳米复合颗粒激活smad信号通路，调控下游成骨相关基因（如ALP、OCN、OPN、OPG等）的表达，进而促进钛基界面骨生成。（3）钛基材表面释放的功能分子（如阿伦磷酸钠、降钙素等）有效抑制破骨细胞的分化及形成，调节骨质疏松性环境中骨的代谢平衡，提高了钛基植入体在骨疾病患者中的长期稳定性。（4）钛基界面纳米颗粒杂化膜促进功能基因的转染，实现材料界面与细胞的双向交流。这些研究结果提示，钛基活性纳米存储器仿生界面通过多层膜的降解调控生物大分子或多重活性纳米颗粒的释放，实现了生物/化学信号对成骨效应的协同调控。该研究为开发新型医用钛/钛合金骨修复植入体奠定理论和应用基础。