响应性调控巨噬细胞表型的动态图案化材料研究

Immune response is a necessary and important stage of tissue repair and regeneration. Proactive and precise regulations of immune response are at the leading edge in the design of tissue regeneration materials. Macrophages have been regarded as a primary target in regulating immune response because of their critical roles in regulating multiple phases of tissue repair through their unique ability to rapidly shift phenotypes. Aiming at the problem of immune regulation in tissue regeneration, the study of designing a thermo- or light- responsive patterned surface with the property to topographical control the phenotypes of macrophage dynamically is proposed. And further explore the influence of transformed phenotypes of macrophage on the tissue repair-related cells. The immune regulation material is designed based on the explored relationship between material surface patterns and macrophage phenotypes. The shape memory poly-caprolactone (PCL) that functions near physiological temperature was synthesized, and combined with gold nano-rods which own excellent photo-thermal conversion effect to fabricate a near-infrared-responsive patterned PCL substrate, endowing with the properties of topographical transformation and macrophage phenotypes regulation. The macrophage phenotypes and the fate of tissue repair- related cells can be dynamically regulated by the switch of high spatial selective light. The influences of the surface pattern on the macrophage phenotypes will be elucidated, and the interactions among the dynamic surface pattern, the macrophage phenotypes and the behaviors of tissue repair-related cells will be revealed, providing theoretical support for the further understanding of material-cell interactions and the development of tissue regeneration materials with proactive immune regulation properties.

免疫反应是组织再生修复的重要阶段，主动和精确调控免疫反应是组织再生材料研究的前沿课题。本项目针对组织再生过程免疫调控难题，以巨噬细胞表型及其动态转变对组织再生的重要作用为启示，结合材料表面图案对巨噬细胞表型的调控规律，构建一种具有热、光响应的动态图案化基底，实现巨噬细胞表型动态调控，探索表型动态转变对组织修复相关细胞行为的影响。合成可在生理温度范围变形的形状记忆聚己内酯（PCL），结合金纳米棒的优异光热转化效应和近红外光的高度空间选择性，构建近红外光响应的金纳米棒/形状记忆PCL动态图案化基底。以光为开关，实现动态图案化基底对巨噬细胞表型和组织修复相关细胞行为的调控。阐明基底表面图案特征及其动态转变对巨噬细胞表型的调控规律，揭示基底动态表界面特征—巨噬细胞表型—组织修复相关细胞行为间的相互影响机制。为深入理解材料-细胞相互作用，发展具有主动免疫调控性能的新型组织再生材料提供理论依据。

近年来，免疫反应被认为是组织再生修复的必经和重要阶段，通过合理利用和精准调控免疫反应可以取得更积极的组织再生修复效果。巨噬细胞作为一种在免疫反应初期大量存在的免疫细胞，其具有多种表型，且具有独特的可快速转换表型的特性，对决定创面环境类型及最终修复效果有着不可或缺的作用。在正常的组织修复过程中，由M1促炎表型巨噬细胞主导的炎症创面会逐渐转变为由M2抗炎表型主导的促修复创面。由此可见，不同表型的巨噬细胞对组织再生修复发挥不同的调控机制和作用。因此，为匹配再生修复不同阶段的免疫需要，设计具有顺序的、精准的动态调控巨噬细胞表型的新型生物材料具有重要意义。. 结合前期研究基础，本项目针对组织再生修复过程中的免疫调控难题，以匹配组织再生过程巨噬细胞表型的动态转变需求为核心理念，提出通过材料表面图案的动态转变实现主动和精确地调控巨噬细胞表型的有效策略。本项目构建了3种不同刺激诱导的动态图案化材料，包括近红外光（NIR）响应的聚己内酯（PCL）形状记忆膜、紫外光（UV）响应的聚乙二醇（PEG）水凝胶和活性氧（ROS）响应的透明质酸（HA）水凝胶。系统性地研究了材料表面图案在刺激响应下的动态转变，从而实现了在特定时间下有效诱导巨噬细胞形态由圆形向长梭形的转变及相关促炎因子的高表达到上调相关抗炎因子的转变。采用大鼠皮下埋植模型，准备了动态图案化材料，有效、原位、无创地实现了对巨噬细胞表型地顺序调控，匹配了组织再生过程的需求，有利于深入理解材料-细胞相互作用，为发展高性能组织再生材料提供了理论支撑。