基于3D打印多孔生物陶瓷的孔道特性对病理性骨再生修复效率的基础研究

Additive manufacturing technologies, especially the ceramic ink writing (CIW) technique, have been well recongnized as an effective approach to fabricate the highly porous bioceramic constructs with fully interconnective pore structures. However, the layer-by-layer filament overlying and post-trement of high temperature sintering result in the potential issues involving side-wall pore size adjustment and biological responses in the pore strut wall. This is thus still a challenge to use such porous bioceramic scaffolds to treat the pathological bone defects. This proposal is based the researches regarding Ca-Si- based bioceramics in our team in recently years to fabricate the porous calcium-magensium-silicate-based bioceramics with adjustable porous morphology, pore size, pore wall chemistry to treat the osteoporotic bone defect, and meet the specific requirement in innovative therapy for enhancing bone regeneration and repair, to avoid secondary bone damages. The first work is to prepare the porous bioactive glass(BG)-reinforced calcium magensium silicate bioceramic by CIW technique, and to explore the relationship between the mechanical strength/osteogenic capacity and the pore morphology. The techniques will be optimized according to the parameters involving in pore shape (e.g. sqaure, honeycomb, archimedean cords), pore size, as well as internal wall microstucture of nozzle. The second is to systematically evaluate the potential biological effects derived from the surface chemical composition and microscale to nanoscopic structures of coating layers in pore strut walls on mediating imflammantory reaction, osteogenic cell viability, and especially to evaluate the osteoproduction in osteoporotic animal models according to the biomimetic mineralized trace element-doped Ca-phosphate coating or highly bioactive mesoporous bioactive glass coating in the scaffolds. The third is to validate the biological performances of the very thin, 3D printed, side-pore-tailorable bioceramic plates on improving the bone regeneration and bone remodeling progress in skull defects for a long time stage in vivo. The advantages of these studies will include: (1) to provide a more reliable 3D printing technology for fabricating bioactive ceramic scaffolds with pore morphology/size tailorability, highly bioactivity, and mechanical stability, and (2) to set up a comprehensive underatanding of the biological performances of 3D printed biomaterials with improved pore constructs and mechanism of composition and microstructures in pore strut wall on improving pathological bone repair. Also, it is helpful to develop the tissue-engineering combination therapy for osteoporosis-derived bone damages, and provide knowledge of regenerative medicine.

自动注浆成型3D打印是解决生物活性陶瓷类材料“高度贯通性孔道构造”较为理想的技术，但是借助逐层叠加打印的多孔陶瓷支架中孔道壁的表面特性、叠加面的孔维度是影响骨再生修复效率的重大制约因素。本项目拟运用注浆成型打印工艺，优化构建一类由低熔点生物玻璃助烧结钙镁硅酸盐多孔生物活性陶瓷，从打印喷头内孔形态（如圆形、椭圆形、内壁微凸螺纹）、支架孔道形态（如方形、蜂窝形、阿基米德弧形）以及支架内孔道壁表面二次修饰改性（如仿生矿化、介孔生物玻璃改性）等角度，系统性分析生物活性陶瓷孔道形态特性、表面化学与结构特性对材料综合力学性能的影响关系和基本规律，并重点分析这些微结构特征介导骨质疏松性成骨相关（干）细胞的粘附、生长及成骨矿化规律，明确孔道壁表面微纳结构、化学组成所示特异性生物学讯号，介导病理环境下骨再生修复的效率和效果及内在关系。本项目的研究旨在推动病理性骨再生修复医学及3D打印技术的完善和发展。

3D打印生物材料的孔道微结构特征及孔道壁表面化学组成特性，直接决定着骨生成效率及修复可靠性，但仍缺乏对该类关键问题的系统性研究。本项目重点围绕生物活性材料的孔道微结构及化学组成对材料-骨损伤接触表/界面新骨再生效率的影响关系，着力分析孔道壁化学组成及微结构对调控新骨再生及血管化效率的基本规律开展了系统研究，完成了项目中的研究内容并取得系列学术成果。首先，项目团队利用注浆打印平台，突破性设计核-壳结构“间断打印”模式，成功实现了使用低剂量异质离子掺杂、有机微颗粒多孔网络裁剪等技术对“核-壳”两相组分生物陶瓷材料内部特定组分分布和微结构调控，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要难题。其次，基于数字光学加工（DLP）的光固化三维打印平台，结合计算机辅助设计方法，实现了对孔道特征更精准、更多元的调控，成功设计出一系列参数可控的孔尺度系列、三周期极小化曲面结构系列、常规柱形结构系列支架结构，系统性考察了孔尺度、孔形态及异质离子掺杂对钙-硅基生物陶瓷支架体内外性能的影响规律，获得了优化后的3D打印高生物活性多孔陶瓷材料满足病理性骨损伤修复所涉及的组成分布和微结构最佳参数，为解决病理性骨损伤再生修复用材料的优化设计提供技术和理论支撑，进一步发展骨损伤再生修复生物材料制备科学，并最终实现临床转化和应用。本项目研究期间在Bioactive Mater、Regen Biomater、J Europ Ceram Soc、J Biolog Eng等发表SCI收录论文12篇，部分实验数据仍在论文撰写中。在本项目执行期间，新冠疫情一定程度影响到学术交流，不过采用线上和线下等形式参与学术会议10余人次，培养骨科学、生物材料学方向的青年人才6人。