基于仿生矿化胶原的内源性骨再生与骨免疫调控机制的研究

Traditional bone tissue regeneration strategies usually require the simultaneous provision of scaffold materials, growth factors, or stem cells. The shortcomings of these strategies include the high cost of exogenous cells and growth factors, the formation of heterotopic bone, and even increased cancer risk. Therefore, the synthesis of an intelligent biomaterial that can recruit endogenous cells to restore the structure and function of bone is more significant. The biomaterials-mediated bone regeneration process involves the interactions among scaffolds, immune cells, and bone marrow mesenchymal stem cells (BMSCs). In the previous studies, we prepared biomimetic mineralized collagen mimicking bone hierarchical nanostructure, and found that macrophage polarization was involved in the bone regeneration process mediated by mineralized collagen. T cells are the important effector cells of the adaptive immune system and play an important role in the process of bone remodeling. However, the involvement of T cells and the synergistic regulation of mineralized collagen-mediated bone regeneration with macrophages are unknown. This project aims to investigate the interactions among biomimetic mineralized collagen, BMSCs, immune cells (T cells and macrophages) during endogenous bone regeneration, especially about T cell activation and differentiation. We could promote the bone regeneration effect of biomaterials by regulating T cells subsets and related cytokines. This project is expected to discover a new mechanism of endogenous bone regeneration mediated by biomaterials and to promote the clinical translation of biomimetic mineralized collagen.

传统骨再生策略需同时提供支架材料、生长因子或干细胞，后者可导致异位骨形成，增加癌症风险等。因此，仅由骨仿生材料招募宿主细胞形成的内源性骨再生更具临床意义。仿生材料介导的骨再生过程涉及材料、免疫细胞和宿主骨髓间充质干细胞（BMSCs）之间相互作用。课题组在前期研究中成功制备具骨样多级结构的仿生矿化胶原，并发现巨噬细胞极化参与材料介导的骨再生过程。T细胞是适应性免疫系统的重要效应细胞，在骨改建过程中发挥重要作用。然而，T细胞是否参与、并与巨噬细胞协同调节仿生矿化胶原介导的骨再生过程尚未知。本项目拟以仿生矿化胶原、免疫细胞（T细胞及巨噬细胞）和BMSCs之间相互作用为切入点，探讨仿生矿化胶原介导的内源性骨再生的骨免疫机制，尤其是对T细胞的激活和分化，并通过调节T细胞亚群及相关细胞因子促进仿生材料对骨缺损的再生效果。本项目有望发现一种新的材料介导的内源性骨再生机制，推动仿生矿化胶原的临床转化。

传统骨再生策略需同时提供支架材料、生长因子或干细胞，后者可导致异位骨形成，增加癌症风险等。因此，仅由骨仿生材料招募宿主细胞形成的内源性骨再生更具临床意义。仿生材料介导的骨再生过程涉及材料、免疫细胞和宿主骨髓间充质干细胞(BMSCs)之间相互作用。本项目以仿生矿化胶原、免疫细胞(T细胞及巨噬细胞)和BMSCs之间相互作用为切入点，发现仿生矿化胶原可激活T细胞，增加CD4+IL4+Th2细胞数量并减少CD4+IFN-γ+Th1细胞数量，从而促进内源性骨再生；同时，仿生矿化胶原促进CD90+CD146+MSCs 和 M2巨噬细胞的招募，M2巨噬细胞通过分泌的外泌体促进BMSCs成骨分化，且BMP2/Smad5通路被激活；当阻断M2巨噬细胞外囊泡分泌时，BMSCs的增殖、免疫调节及成骨分化能力减弱。本项目有望发现一种新的材料介导的内源性骨再生机制，推动仿生矿化胶原的临床转化。