HIF-1α信号通路调控下预血管化骨组织的构建及促进长段骨再生的作用和机制

With high disability rate, large bone defects still lack of satisfactory treatment. The traditional artificial bone fails to induce sufficient angiogenesis in vivo to survive and function in large bone defects. Therefore, construction of bioactive artificial bone possesses a vast application prospect. In our previous study, an artificial bone with short-term prevascularization was constructed in vivo, and proved to promote angiogenesis and bone regeneration in small bone defects, which may be mediated through up-regulation of HIF-1α pathway. Therefore, whether fully prevascularized artificial bone could achieve satisfactory results in repairing large bone defects deserves further research. To clarify this hypothesis, a novel artificial bone containing Co2+ inducing chemical hypoxia will be constructed to study its effect on HIF-1α pathway in osteoblasts in vitro. Then, the constructed artificial bone seeded with osteoblasts will be prevascularized in vivo. The optimal conditions for angiogenesis will also be defined. Further, the effect and related mechanism of prevascularized artificial bone combined with distraction osteogenesis, which provides stable environment for bone regeneration, on large bone regeneration is to be investigated. This project will help to provide experimental basis for the clinical application of prevascularized artificial bone in large bone defects.

大段骨缺损致残率高，缺乏满意的治疗方案。传统人工骨因不能诱导体内足量血管长入而难以在大段骨缺损区存活并发挥作用。因此，构建生物活性的人工骨组织拥有广阔的应用前景。课题组前期在动物体内成功构建了短期预血管化的骨组织，证实能促进小范围骨缺损区血管形成及新骨再生，并发现与低氧诱导因子1α（HIF-1α）通路信号上调有关。基于此，构建充分预血管化的人工骨组织修复大段骨缺损，是否也能取得满意疗效值得深入研究。为此，本项目拟（1）运用能诱导化学性低氧的钴离子（Co2+），构建新型含Co2+的人工骨，体外研究对成骨细胞HIF-1α通路的影响；（2）将成骨细胞种植于新型含Co2+的人工骨组织内，进行在体预血管化构建，明确血管生成的最佳条件；（3）将充分预血管化的骨组织与能提供稳定成骨环境的牵张技术联合，探讨对长段骨再生的促进作用及可能机制。本课题为预血管化骨组织在大段骨缺损中的临床应用提供重要实验依据。

大段骨缺损致残率高，缺乏满意的治疗方案。传统人工骨因不能诱导体内足量血管长入而难以在大段骨缺损区存活并发挥作用。因此，构建生物活性的人工骨组织拥有广阔的应用前景。课题组前期在动物体内成功构建了短期预血管化的骨组织，证实能促进小范围骨缺损区血管形成及新骨再生，并发现与低氧诱导因子1α（HIF-1α）通路信号上调有关。基于此，构建充分预血管化的人工骨组织修复大段骨缺损，是否也能取得满意疗效值得深入研究。本项目已完成了预血管化人工骨材料促进骨缺损修复的研究，人工骨的预血管化处理显著增加了大鼠骨缺损的愈合速度。在此基础上，本项目充分评估了钴离子缓释材料促进成骨、成血管的功能，我们构建了可调性钴离子缓释复合水凝胶，证实其显著促进大鼠骨缺损处的血管新生及骨再生。本项目的研究成果为实现充分预血管化骨组织的构建及在大段骨缺损中的运用提供重要的理论依据和实验基础。目前发表受本项目资助的 SCI论文共 15 篇，成功培养博士研究生4名，硕士研究生1名，参加国内学术会议 6 人次，获省部级奖励1项，获得授权专利2项，完成预期目标。