仿生生物材料重建再生微环境调控免疫反应实现内源性组织再生

In situ tissue regeneration via instructive biomaterials has a great potential for population-wide applications, which would only require off the shelf standardized biomaterials without the need of ex vivo cultured cells. In this regard, biomaterials should mimic the microenvironment of regenerating tissues and have potential to augment the endogenous tissue regeneration capacities. Functionally, the chemotaxis of regenerative cells, their amplification as a transient amplifying pool and their concerted differentiation and remodeling should be addressed. Besides, it is especially important for the materials to positively influence the host immune system bacause negative foreign body responses would interfere with regeneration and healing. The role of the innate immune system, especially the role of macrophages, in the host response to implanted materials has recently received considerable attention. The constructive and regulatory, and in fact essential, role of macrophages in positive outcomes represents a significant departure from the classical paradigms of host–biomaterial interactions, which typically consider activation of the host immune system as a detrimental event. It appears desirable that emerging regenerative approaches should not only accommodate but also promote the involvement of the immune system to facilitate positive outcomes. Previously, we have developed an in vitro cell culture system with hierarchical micro/nanotopogrpahies by mimicking the natural cell environment, termed Dex-GMA/Gtn macrocapsule system, which show an enhanced effect on cell homing and indeed, the biological performance of residing cells. Recently, our study indicates that such material devices also influence the behavior of macrophages, depending upon the design parameters. Nonetheless, the exact effects of the chemistry, strucutre and functionality of the biomaterials on macrophage function, particularly the underlying mechanism as well as the influence of immunomodulation on endogenous cell recruitment and homing remain largely unexplored. Our present project aims to investigate the basic molecular and cellular immunology principles governing immunomodulation with our material system and the correlation of macrophage to materials design in vitro and in vivo, specifically, we observe the regulation of M1/M2-polarization and funtion via biomimetic design, thus to uncover the molecular mechanism underlying the regulatory effect of the system on the functions of macrophages and the recruited stem cells. Finally, we study the impacts of the macrophage secretions, either alone or combined with the physical cues, on the cell behaviour toward tissue regeneration and integration. Our project will advance the current understanding of macrophage-centered approached in regenerative medicine and expand new insights into context-dependent macrophage polarization that leads to concurrent improvement in clinical outcomes of in situ tissue engineering.

通过仿生生物材料募集宿主干细胞实现内源性再生是原位组织工程设计的的主要策略。现已证实，植入材料模拟再生微环境、通过对巨噬细胞表型与功能的调控是启动机体自修复机制的关键。由于缺乏体外模型真实模拟体内三维细胞生长微环境，材料与巨噬细胞相互作用及其机理不清。本项目拟优化项目组前期设计合成的Dex-GMA/Gtn舱腔囊球，体外构建三维细胞培养体系，建立相关参数标准；探索材料物理、化学、生物信号联合、协同与巨噬细胞相互作用及其影响规律，揭示再生微环境参与正向免疫调控的关键因子和分子机制；巨噬细胞受控动物模型体内观察舱腔囊球系统对巨噬细胞M1/M2极化和细胞因子分泌的影响，重现体外研究结果，并进一步通过牙槽骨巨型缺损动物模型，阐明功能材料调控机体免疫反应对细胞归巢和组织再生的的影响，为建立内源性再生微环境、优化原位组织工程设计提供新思路，为生物材料的仿生设计、临床转化和产品开发提供实验数据支撑。

通过仿生生物材料募集宿主干细胞实现内源性再生是原位组织工程设计的的主要策略。现已证实，植入材料模拟再生微环境、通过对巨噬细胞表型与功能的调控是启动机体自修复机制的关键。本项目旨在通过仿生生物材料设计，募集宿主干细胞实现内源性组织再生。重点探索了植入材料如何模拟再生微环境、通过对巨噬细胞表型与功能的调控，促进机体内源性再生修复的机制。本项目在前期基础上，实现了Dex-GMA/Gtn舱腔囊球系统的设计和优化，建立三维细胞培养体系及其参数标准；系统探索了材料物化和生物学性能参与巨噬细胞调控的一般规律，揭示了仿生生物材料参与正向免疫调控的关键因子和分子机制；进一步在巨噬细胞受控动物模型和牙槽骨巨型缺损动物模型中，观察了功能材料对巨噬细胞极化的动态影响，阐明了其调控机体免疫反应促进牙周组织再生的机制。本项目为建立内源性再生微环境、优化原位组织工程设计提供新思路，为生物材料的仿生设计、临床转化和产品开发提供实验数据支撑。本项目共发表基金标注论文37篇，其中第一标注35篇。部分研究成果参与获得陕西省科学技术一等奖1项。项目负责人获批2016教育部长江学者特娉教授，入选2017科技部中青年科技创新领军人才、2019国家万人计划，连续3年进入中国高被引学者医学榜单。所在“牙周组织工程与再生”团队获批2016陕西省重点科技创新团队。