掺杂晶须原位增强BCP孔定向仿松质骨抗菌骨诱导材料研究

In vivo biological performance and bone regeneration behavior of bone tissue engineering scaffolds are generally determined by their chemical composition and pore-structural characteristics. Unfortunately, conventional CaPs materials hardly satisfy the requirements for their tissue engineering application. Metal ions doping could enhance the interaction of biphasic calcium phosphate (BCP) scaffold with natural bone tissue, improve their osteoinductive potential, angiogenesis and antibacterial performance. It was shown that calcium deficient hydroxyapatite whiskers with various Ca/P ratios have been successfully prepared in our previous studies; BCP materials with various HA/TCP ratio and well whisker-like morphology have been obtained after heat-treated such whiskers at high temperatures. Based on these research findings, novel bioinductive and antibacterial BCP cancellous bone-like scaffolds will be in-situ reinforced and prepared innovatively using metal ions doped Ca-deficient apatite whiskers in the present proposal. The green body with orientated pores and micro-pores interconnected porous structure will be formed by unidirectional freeze drying technique using ions doped apatite whiskers as resource materials. Novel BCP scaffolds obtained after heat-treated at high temperature are expected to be an ideal osteoinductive & antibacterial scaffold whose mechanical properties and biological performances match with natural cancellous bone. The present research work will focus on the following studies: formation process of pore structure of the scaffolds and their reinforcing mechanism, interaction behaviors of the scaffolds with bone tissue, and their effects on blood vessel formation and new bone tissue remodeling. The effect mechanisms of the doped metal ions and orientated pore structure on the bone formation and the osteoinductive & antibacterial performances of the scaffolds are also analysed here. The research results of the present proposal would be expect to not only provide a new preparation technique for designing and fabricating novel osteoinductive and antibacterial BCP scaffolds with cancellous bone characteristics, but also offer a theoretical basis of pore structure control, which will lay a theoretical foundation for the tissue engineered research of calcium phosphate materials.

组织工程支架材料的化学组成和孔结构决定其在体内的生物学特性和骨再生行为，常用的CaPs材料很难满足其性能要求。金属离子掺杂可增强BCP材料与骨组织的相互作用，提高骨诱导潜力、血管再生和抗菌效能。申请人前期制备出不同Ca/P比的钙缺陷HA晶须，高温处理后获得具有完好晶须形貌特征的BCP材料。为此，本项目创新性地利用掺杂钙缺陷HA晶须原位增强仿松质骨BCP骨诱导抗菌材料。以掺杂钙缺陷HA晶须为原料，定向冷冻干燥成型获得定向孔和微孔互连互通结构，高温下原位增强和制备新型BCP材料，以期得到力学性能和生物学性能与松质骨相似的骨诱导抗菌材料。研究材料孔结构形成及增强机理、材料与组织的相互作用及其对血管形成和新骨组织重塑的影响。探明金属离子和定向孔结构对材料骨诱导抗菌的影响机理。本课题成果为仿松质骨BCP支架材料的设计与制备提供新的技术和孔结构控制理论依据，并为掺杂BCP材料的组织工程化奠定理论基础。

制备具有高孔隙率、高孔相互连通性和适宜力学性能的骨组织工程支架材料是目前获得理想磷酸钙基支架材料面临的一个问题。项目利用金属离子掺杂HA晶须原位制备HA和TCP双相磷酸钙支架材料，使获得具有纤维状类松质骨结构的支架材料成为现实，它不仅有利于提高支架材料的骨诱导能力，而且可通过调整金属离子掺杂种类还可起到长期抗菌作用。项目首先对利用水热合成技术制备HA晶须的条件进行优化，制备出表面光滑、长和高长径比、形貌均一、结晶度较高、且易于分散、物相单一的Zn、Sr、Mg和Cu离子掺杂HA晶须，并对其形貌、相组成、结晶度、晶体结构、晶体生长特性的影响因素和规律进行研究，并开展了高温热稳定性能及其原位形成HA/TCP双相磷酸钙的过程和机理以及组成控制技术进行研究。利用注模成型和冷冻干燥获得具有定向孔结构特征的支架材料，支架材料的定向孔径为122～211μm，孔隙率83%，抗压强度～0.96 MPa的高孔隙、高连通的HA/TCP支架材料，基本符合项目预期。与利用单一HA纳米粉料相比，所得支架材料的抗压强度提高3-5倍。掺杂晶须及其支架材料的体外溶解性能和生物学研究表明，金属离子掺杂和添加生物玻璃可提高支架材料的溶解性能。通过改变存在离子的种类和掺杂量，可以获得具有长期稳定的抗菌效果和骨诱导能力的支架材料。Cu和Zn掺杂HA晶须具有明显的长效抗菌效果、细胞毒性较低和较好的组织相容性；掺镁、锶和锌的掺杂支架材料比单纯HA支架材料更易于促进成骨细胞产生和分化，该材料有望成为一种良好的骨折内固定和骨填充修复材料，具有广阔的临床应用前景。.项目资助发表共发表SCI论文7篇，SCI源期刊接受1篇，Ei或CPCI收录3篇；另外投寄论文2篇；获国家发明专利4项。培养硕士研究生6名。其中4位获得硕士学位、在读2名。项目投入经费80万元，支出经费约66.5万元。各项支出与预算基本符合，剩余将用于本项目后续研究。