骨靶向纳米缓释系统在牙种植中的应用研究

Long process of dental implant osseointegration , long growth cycle of the bone substitutes and osseointegration problem for some patients with poor bone metabolism, are three hot topics in the field of oral implantology. Enhance the biological activities of the implant surfaces and the bone substitutes in order to accelerate local formation of new bone are effective ways to solve the three subjects. Construction of local bone targeting nano-drug delivery system of simvastatin (SV) as the representative of the bone bioactive substances can provide a stable, high-performance biological activity to dental implants or bone augmentation materials. This project will combine the bone targeting tetracycline (TC) molecules with SV-loaded polymer to self-assemble into micelles, and load the micelles in titania nanotubes to construct the local bone targeting nano-drug delivery system on an implant, and then test the release effects through in vitro drug release. Bone targeting experiments, cytological experiments and zoology experiments will be designed to verify the bone biological effects of SV-loaded polymer micelles-nanotubes modified with TC molecules, and explore their mechanisms. The bone targeting nano-drug delivery system, which not only can be applied topically to the bone augmentation materials, but also as a choice of medication improving systemic bone metabolism, has a broader prospect of research and clinical application.

牙种植体骨结合进程过长、骨代用品生长周期过长以及骨代谢较差患者的骨结合问题是目前口腔种植领域的三大热点课题。增强种植体表面和骨代用品的生物活性，以加速局部新骨形成是解决三大课题的有效途径。本课题构建以辛伐他汀（simvastatin，SV）为代表的骨生物活性物质的局部骨靶向纳米缓释系统，可为牙种植体或骨增量材料提供稳定高效能的生物活性。课题设计将骨靶向四环素(tetracycline, TC)分子结合于载SV 聚合物上并自组装成胶束，再将其载入二氧化钛纳米管中,构建种植体局部骨靶向纳米缓释系统，通过体外药物释放实验检验其缓释效应；通过骨靶向实验、细胞学实验和动物学实验验证TC分子修饰的载SV聚合物胶束-纳米管的骨生物学效应并在分子学水平探究其产生骨效应的机制。其中骨靶向纳米缓释系统既可局部应用于各种骨增量材料中，又可作为改善全身骨代谢用药的选择，有着更广阔的科研和临床应用前景。

牙种植体骨结合进程过长以及骨代谢较差患者的骨结合问题是目前口腔种植领域的热点课题。增强种植体表面的生物活性，以加速局部新骨形成是解决这些课题的有效途径。因此本课题通过构建以辛伐他汀为代表的骨生物活性物质的局部骨靶向纳米缓释系统，希望赋予钛种植体 - 骨界面以骨靶向功能和生物活性，从而增强种植体的骨整合效能和种植体周围的骨再生功能，这对于骨质疏松症者尤其重要。将骨靶向四环素分子结合于载辛伐他汀 聚合物上并自组装成胶束，再将其载入二氧化钛纳米管中,成功构建一种新型的双重控制的种植体局部骨靶向纳米递送系统，并将此系统植入大鼠体内成功构建了骨靶向钛种植体-骨界面。通过体外和体内实验共同评价递送系统的生物学效应。体外实验结果表明修饰了二氧化钛纳米管-骨靶向胶束的钛表面可以促进大鼠成骨细胞的细胞骨架的伸展、早期粘附、碱性磷酸酶活性和胞外骨钙素浓度，并且能增强的骨形态发生蛋白-2的蛋白表达。体内试验在正常大鼠和卵巢切除后大鼠（绝经后骨质疏松动物模型）体内进行，建立单壁骨缺损种植模型。通过微-CT成像以及骨形态发生蛋白-2的体内表达检测体内台种植体的骨结合情况。结果证明具有二氧化钛纳米管-靶向胶束表面的钛种植体在正常大鼠模型和绝经后骨质疏松动物模型体内均能够促进种植体周的骨再生和种植体骨结合。其中单独的载辛伐他汀的骨靶向胶束既可局部应用于各种骨增量材料中，又可作为改善全身骨代谢用药的选择，有着更广阔的科研和临床应用前景。