三维打印多级微纳结构生物陶瓷调控成骨/成血管机制及其促颌骨节段性缺损修复研究

The quality and efficiency of the vascularization play critical role on the regeneration and the functional reconstruction of segmental mandibular bone defects. The excellent vascularization property of the bone grafts is the key bottleneck for their clinical applications which needs to be urgently solved, especially in the regeneration of bone defects with critical size and difficult-healed capacity. Designing the grafts with rapid regulation ability of osteogenesis and angiogenesis is the pivotal strategy to break through the bottleneck in their clinical applications. Previously, we have developed the bioceramics with hierarchical micro-/nano-topographical surfaces, which show enhanced effects on the osteogenic differentiation of osteoblasts and mesenchymal stem cells (MSCs). Recently, our preliminary studies indicate that the similar hierarchical micro-/nano-topographies can also stimulate the expression of angiogenic factors of osteoblasts and MSCs, and promote the formation of vascular tissue in vivo. However, the exact effects of the topographies on osteogenesis and angiogenesis, the underlying mechanisms and the influence of the related processes on bone regeneration are still unclear. The present project aims to investigate the effects of surface micro-/nano-topographies on osteogenesis and angiogenesis, to illuminate the related mechanisms and rules regulated by the surface micro-/nano-topographies, and finally to develop the controllable methods to fabricate the 3D-printed bioceramic scaffolds with optimized micro-/nano-structured topography surfaces, and then were used in repairing the segmental mandibular bone defects. The present project plays an important theoretic and applied role in the surface designing and development of the bone grafts, especially for the grafts in the regeneration of bone defects with critical size and difficult-healed capacity.

血管化的质量和效率直接决定了颌面部骨组织再生和后续功能重建的效果。植骨材料的良好血管化性能是其临床应用中亟待解决的“关键瓶颈”，尤其在大尺寸骨和难愈合骨缺损修复领域。设计具有“快速调控成骨/成血管响应”特性的骨修复材料是突破其临床应用瓶颈的关键。我们前期预实验发现可促进成骨细胞和间充质干细胞成骨分化的微纳结构生物陶瓷具有显著促进细胞分泌成血管相关因子/蛋白、并促进体内血管组织形成的现象。然而，生物陶瓷微纳结构调控成骨/成血管的规律、机制及其该过程对骨修复的影响仍然未知。本项目旨在研究材料表面微纳结构的成骨/成血管效应，揭示微纳结构调控血管化的生物学机制与规律，实现具有良好调控成骨/成血管功能的三维打印多级微纳结构生物陶瓷支架的可控制备与结构优化，并应用于动物颌骨节段性缺损的修复。该项目的实施将为发展适合大尺寸骨、难愈合骨缺损修复用材料的设计奠定基础，具有重要的科学意义和临床应用价值。

生物陶瓷被广泛应用于骨缺损修复领域。然而，对于大尺寸和难愈合颌骨缺损修复，目前还有许多难点需要解决。在这些领域，常出现延迟愈合甚至不愈合后果。其中的关键性瓶颈——“骨组织内部的再血管化问题”一直未得到有效的解决。血管化的质量和效率直接决定了颌面部骨组织再生和后续功能重建的效果。设计具有“快速调控成骨/成血管响应”特性的骨修复材料是突破其临床应用瓶颈的关键。本项目系统开展了多孔生物陶瓷材料的3D打印和表面微纳结构构筑、以及功能元素掺杂微纳结构修饰的制备工艺与结构/组成调控技术研究。在材料制备基础上，较深入地研究了材料表面微纳结构及功能元素掺杂调控BMSCs生物学响应和相关机制研究。研究表明：通过3D打印设计实现了三维孔道贯通的个性化多孔支架制备，这种贯通孔道结构可以促进宿主细胞和组织长入支架内部、促进植入体附近血液和营养成分渗透并灌注至支架中心部位，进而促进新陈代谢和组织的再生；而在多孔支架表面实施的特异微纳结构设计可以显著促进材料对功能蛋白的募集，介导间充质干细胞在材料表面的粘附和增殖，激活相关成骨和成血管基因的表达，将最终促进缺损部位骨组织的修复；实现了表面微纳结构3D打印多孔羟基磷灰石生物陶瓷在节段性骨缺损修复中的实验应用，并证实了这类材料具有良好血管化骨再生能力；并发现人体必需微量功能元素的掺杂能够有效协同微纳结构促成骨的功能。同时，采用本项目研究发展的水热转化和原位重结晶技术成功用于承重型钛合金植入器械的表面微纳结构羟基磷灰石生物陶瓷涂层修饰，获得的植入器械具有优异的成骨活性，在承重型骨缺损修复领域有良好的应用潜力。相关研究成果为新型生物活性骨修复材料的结构和化学组成的设计奠定了良好基础，具有重要的理论意义和实际应用价值。