基于“炎症微环境调节”的镁-卷曲石墨烯促进骨再生及机制探讨

Bone substitute is a promising alternative for the treatment of bone defect. However, one of the biggest challenges to clinical success is the poor osteointegration after the in vivo transplantation, due to the adverse inflammation reaction, which leads to the compromised defect regeneration efficacy. Based on our preliminary study showing that the timely and accurate modulation of macrophage M2 polarization can help to modulate the inflammatory response and enhance the osteogenesis. Thus, we propose a novel magnesium wrapped graphene nanoscroll (Mg@GNS) nanoplatform, where the pro-inflammatory pattern of graphene oxide and can interact with immunoregulatory magnesium ions to create a desired pro-healing microenvironment at the biomaterial-host interface for downstream bone regeneration. In this study, we will develop and optimize the “inflammation modulation” based Mg@GNS nanoplatform to enhance downstream osteogenesis and investigate its underlying mechanism at the tissue, cell and molecular levels: (1) to optimize the construction of Mg@GNS nanoplatform, which can accurately modulate the inflammation microenvironment; (2) using prime polycaprolactone (PCL) scaffold as a model material, to explore whether the Mg@GNS coating could create a desired pro-healing microenvironment at the biomaterial-host interface for downstream osteointegration and osteogenesis; and (3) to investigate which factor plays an important role in Mg@GNS promoting bone regeneration in vitro by downstream. The systematically investigation of “inflammation modulation” based bone substitute technique will help to boost up the healing efficacy of bone substitute, minimize the individual variation and promote its clinical translation. On the other hand, it can serve as a useful reference for developing tissue regeneration strategies for other tissue defect treatment.

骨替代材料有望满足我国骨缺损治疗的巨大临床需求，但其临床转化瓶颈在于植入后由于局部不利炎症反应、新生组织难以长入，纤维愈合，功能性再生疗效有限。基于前期实验发现巨噬细胞介导的适时、适度炎症调节可促进骨缺损修复，我们构建了镁-卷曲石墨烯（Mg@GNS）纳米递释系统：借助独特的卷曲结构，“促炎”石墨烯和“抑炎”镁离子得以协同作用实现巨噬细胞精确时序性极化，构建适宜骨再生的微环境。我们拟建立“炎症微环境调节”Mg@GNS纳米递释系统以促进骨再生并从组织、细胞、分子水平研究其机理：①优化Mg@GNS实现精确炎症微环境调节；②与单纯聚己内酯支架对比，探索“炎症微环境调节”Mg@GNS涂层能否促进骨整合及功能性骨再生；③Mg@GNS是通过下游哪些因子促进骨再生。基于“炎症微环境调节”骨替代材料构建策略可提高疗效，减少个体差异，加速临床转化；也是现有骨功能性再生理论的重要补充，对其他组织修复有借鉴意义。

骨替代材料有望满足我国骨缺损治疗的巨大临床需求，但其临床转化瓶颈在于植入后由于局部不利炎症反应、新生组织难以长入，纤维愈合，功能性再生疗效有限。基于前期实验发现巨噬细胞介导的适时、适度炎症调节可促进骨缺损修复，我们通过精确调控巨噬细胞的极化状态来模拟生理状态的炎症过程，来提高人工骨的修复和骨整合效果。我们构建了镁-卷曲石墨烯（MgNPs@GNS）纳米递释系统。通过与巨噬细胞培养证实氧化石墨烯和缓释的活性金属离子Mg2+实现对巨噬细胞M0-M1-M2的时序性调节，优化局部炎症微环境。体内大鼠颅骨缺损模型证实炎症调节 MgNPs@GNS可以通过调节支架-组织界面炎症水平，促进支架材料植入后的骨再生和功能性整合效果；进一步机理研究表明巨噬细胞M1型极化有利细胞迁移，M2型极化有利于细胞增殖和分化，证实巨噬细胞时序性极化有利于骨再生，并初步表明TGF-β/SMAD在炎症微环境调控促进成骨分化中起调控作用。基于“炎症微环境调节”骨替代材料构建策略可进一步提高现有生物材料的骨修复疗效，减少个体差异，加速生物材料临床转化；也是现有骨功能性再生理论的重要补充，对其他组织修复也有这重要的借鉴意义。