载药介孔生物玻璃通过诱导巨噬细胞的自噬作用调节骨免疫及成骨效应

Accumulating evidence indicates that the immune and skeletal systems interact with each other through various regulators, especially the macrophage-osteoblast interaction is considered to play a vital role in regulating the osteogenic process. Osteoimmunomodulation, a concept arising from the convergence of osteoimmunology and immunomodulation, has informed the importance of modulating a favorable osteo-immune environment for the successful materials-mediated bone regeneration, which is considered to be a vital biological property of bone biomaterials for mediating osteogenic outcomes. It has recently reported that autophagy, an indispensable process in maintaining cell metabolism, plays a vital role not only in osteogenesis, but also in mediating macrophage activity and function, and therefore should be proposed to be a key regulator in osteoimmunomodulation. Hence, the current study aims to utilize a novel scaffold with the autophagy-inducing property to study the role of autophagy in bone repair. Firstly, regulations on autophagy will be performed on the cross-interacted immune cells and osteoblasts by gene modification; and dynamics of autophagy expression during bone healing will be investigated in an animal model of induced bone defect, which will be compared with the macrophage phenotypes variation to find the role of autophagy in the regulation of osteoimmunology in vitro and in vivo; based on this, the novel scaffold with autophagy-inducing property will be designed and manufactured; and the modulation of this scaffold on osteoimmunology will be studied in vitro and in vivo; the effect of the scaffold on in vitro osteogenesis and in vivo bone healing will also be studied. Taken together, this study will systemically illustrate the ultimate mechanism of autophagy-driven osteoimmunomodulation, which will also provide a novel strategy for bone biomaterials development.

现代骨免疫学认为，巨噬细胞-成骨细胞之间的相互作用是调控骨再生的关键。如何合理调节局部免疫反应，从而形成一个有益于成骨的微环境，是骨修复生物材料的研究新热点。最新研究发现，细胞代谢活动的重要环节-自噬不仅参与细胞成骨，还影响巨噬细胞的极化，从而为调节骨免疫反应的重要靶点。因此，本项目拟研究靶向自噬诱导性骨修复材料在骨缺损中的治疗作用和机制：通过构建自噬缺陷/过表达型体外免疫成骨细胞交互作用模型，研究自噬在骨免疫调控中的作用机制，并通过骨缺损动物模型，检测骨修复过程中自噬水平变化及与局部巨噬细胞功能的关系；，在此基础上，研制携带靶向自噬诱导剂的生物支架调控局部免疫微环境内巨噬细胞和成骨细胞的自噬水平，并通过体外实验研究巨噬细胞的相应功能变化，以及其对成骨细胞分化和矿化的作用；通过体内实验观察对骨再生的影响，从而阐明自噬在生物材料对骨免疫的调节过程中的重要作用，并为骨组织再生研究提供理论依据。

自噬在免疫细胞、成骨细胞的交互作用中的调控机制尚不清楚，而自噬在骨缺损修复过程中的表达及作用仍不明确。本课题通过研究自噬激活/抑制状态下巨噬-成骨细胞交互作用体系，从而系统性研究自噬在骨免疫中的调节机制；以此为基础研制自噬诱导性生物活性材料，用于骨缺损再生修复。研究结果表明，在一定水平上，自噬激活能够指导免疫反应，抑制过度的炎症反应导致的骨破坏，转变巨噬细胞极性，诱导形成有利于成骨的微环境，从而促进骨再生修复。研制的自噬诱导生物材料R@HSNs能够通过自噬途径调节骨免疫，促进巨噬细胞分泌抑炎细胞因子IL-10, TGF-β，促进干细胞成骨分化，促进骨缺损再生修复。项目完成总共发表学术论文15篇，获得授权发明专利1项。为明确自噬在骨免疫以及骨再生中的调节机制提供了理论依据。为新型骨再生材料设计提供了新的思路。