可控释CGRP的硼硅酸盐生物活性支架促进骨缺损修复的作用机制研究

Bone defect after trauma is a common disease even for today, and the repair and reconstruction of the injury site still be a great challenge for clinical treatment. Using artificial biomaterials to regenerate bone tissue presents the popular and important direction. However, there are some outstanding problems for biomaterials using for bone repair currently, such as poor vascularization ability, lack of bioactivity, slow bone regeneration rate, poor repair outcome and so on. Based on the previous research, multilevel structure of bone tissue, we proposed that, the synergistic effect of sufficient blood supply and highly stimulation on osteogenesis, is the essential requirements for bone tissue engineering. Hence，in this study, a borosilicate bioactive scaffold loading with CGRP was fabricated under bio-mimic design. The borosilicate bioactive glass in scaffold would release Si, B, Ca into the surround environment, and mediate the osteogenic differentiation of stem cells to stimulate osteogenesis. The sustainable release of CGRP can promote the local vascularization and strengthen the blood supply. Therefore, research the bone regeneration of the borosilicate bioactive scaffold with controllable CGRP release, and the mechanism of the synergistic effect of sufficient blood supply and highly stimulation on osteogenesis osteogenesis, have a great theoretical significance for clinic bone repair.

创伤后骨缺损与损伤是一类常见疾病，实现其损伤部位的修复重建是现代医学力求解决的重大难题，采用人工骨移植材料对其进行修复是其中重要的研究方向。然而目前临床用骨修复材料普遍存在着血管化能力差、生物活性低、降解速度与骨再生不匹配、骨不连发生率高等突出问题。在前期研究基础上，团队提出在模拟天然骨组织结构基础上，促进骨折部位成骨和加强局部血供的协同作用是实现骨缺损修复重建的必要条件。本研究通过构建固载降钙素基因相关肽（CGRP）的硼硅酸盐生物活性支架，用于骨缺损的修复重建。生物活性支架中的硼硅酸盐生物活性玻璃具有优异的生物活性和降解性，能够释放出骨代谢元素硅、钙、硼等，介导细胞定向成骨分化，促进新骨生成。CGRP的可控释放能有效地诱导局部微血管形成、加强骨折处血供。因此，探讨可控释CGRP的硼硅酸盐生物活性支架重构新骨形成和局部血供这一协同作用修复重建骨缺损的机制，具有重大的骨缺损临床修复理论意义。

本项目针对现有骨科植入材料生物活性低、与骨折环境不匹配、骨再生速度慢等临床问题，将降钙素基因相关肽（CGRP）和硼硅酸盐生物活性玻璃（BSG）支架结合，通过海藻酸钠（SA）水凝胶与钙离子温性化学胶联作用物理性诱捕CGRP于BSG支架的有序三维多孔结构中，保护蛋白活性的同时实现其可控释放，以期促进局部免疫调控、微血管重构与成骨代谢活性，加速新骨形成，从而实现大段骨缺损修复重建这一最终目标。项目成功构建的可控释放CGRP的BSG复合支架BSG-SA/CGRP具有良好的抗压强度、体外生物活性和体内外生物相容性，可通过直接激活Wnt/β-catenin信号通路促进骨髓基质干细胞（BMSCs）增殖、成骨分化及矿化，同时间接调控炎症和血管因子加强其对BMSCs的成骨生物学行为调控，动物体内实验表明BSG-SA/CGRP可促进异位成骨区的前成骨反应和原位成骨的新骨生成，促进新西兰大白兔颅骨和胫骨大段骨缺损修复与重建。本项目的完成，为研发的新型骨科生物活性支架材料提供坚实的理论依据。