激发巨噬细胞免疫应答的骨修复材料构建及其促进骨组织再生的机制研究

Given the initiative interactions between bone substitutes and immunocyte after implantation, macrophages play important roles in mediating the bone regeneration process besides the foreign body reactions, which can determine the in vivo fate of bone repairing. Therefore, in this project, we focus on the designing criteria of stimulating immune response of macrophages and the promotion role for bone repairing. Biodegradable polyester is selected as model scaffold for its commonly used in bone regeneration. The research will systematically investigate the influence of both hierarchical microstructure and polysaccharide modification on the polarization of macrophages, as well as its secretion spectrum of cytokines. Further exploration will applied to illuminate the promoting mechanism of recruitment and differentiation of bone-related stem cells and angiogenesis capacity which were mediated by the immune response of macrophages. The research will raise a novel thought of promoting bone regeneration through stimulating the host immune response via interactions between biomaterials and macrophages, followed by triggering the succedent cascade response. These hypotheses will be validate through in vivo animal test by implanting the optimal scaffolds. The work will explore a breakthrough of promoting both bone forming and angiogenesis during bone repairing, as well as provide a fresh thought designing of novel immunoregulation materials. Furthermore, the research will supply experimental basis and theoretic reference on how to take advantage of both endogenous and exogenous growth factors.

骨修复材料植入体内后首先发生的是与免疫细胞的相互作用。巨噬细胞产生的免疫应答不仅对植入体产生异物反应，而且介导了骨修复过程，是影响材料修复成败的关键因素。本项目围绕构建激发巨噬细胞免疫应答材料这一目标，以骨修复中常用的可降解聚酯基支架为模型，从细胞和分子水平深入研究支架的多级微观孔道结构和支架表面多糖修饰对巨噬细胞极化方向及细胞因子分泌的影响规律，并进一步从骨组织再生的角度阐明巨噬细胞的免疫应答对干细胞募集、成骨分化和血管化能力的促进机制，提出通过材料-巨噬细胞的相互作用来激发宿主内在的免疫应答，进而启动和调控级联反应，促进骨组织修复的学术思想，并通过优化材料参数在动物体内进行实验验证，为加快成骨和促进血管化寻找一个新的突破口，为构建新型免疫调控材料提供新思路，同时也为骨修复中更合理地利用内源性和外源性生长因子提供实验依据和理论借鉴。

材料植入后产生的免疫响应对组织再生过程有重要影响。本研究围绕材料的免疫调控效应为中心，研究了材料中的不同离子组成、支架材料的微观孔道结构、材料的特定分子链和官能基团激发产生的免疫响应，以及由此导致的骨修复中各个序列过程的影响。研究发现，无机中引入低浓度的镁离子可降低钙磷基材料产生的巨噬细胞的炎性响应，并且上调成骨和成血管基因的表达，对骨组织修复产生积极作用；大孔-微孔-介孔多级微纳结构的支架结构支架有利于细胞快速募集和BMSCs成骨分化；磺化壳聚糖具有植入初期快速激发巨噬细胞响应、后期介导巨噬细胞向M2极化，降低炎性因子分泌的免疫调控效应，产生的免疫微环境有利于干细胞快速募集、增强BMP-2成骨分化活性，并且协同巨噬细胞促血管发生，在体内缺血性模型以及联合生长因子的异位成骨实验中均证实了磺化壳聚糖的促血管发生和促成骨作用。本研究证实材料的组成、结构等参数所产生的巨噬细胞免疫响应对骨修复序列过程的作用具有十分重要的作用，揭示材料参数对于宿主的免疫应答和再生修复的激发和调控机制，为利用材料的生物学效应促进骨组织修复提供新思路，也为构建新型组织再生生物材料提供了理论和实验依据。