IL-4与间充质干细胞在纳米纤维支架异物反应中的免疫调节研究

The process of foreign body reactions lead to contribute the formation of fibrosis collagen capsules and block signal transmission between biomaterials and tissue, which resulting in biomaterials reduce or even completely loss biological functions. Recently, nanofibrous scaffolds have enormous potential for tissue engineering and drug delivery applications since they can mimic the structure and function of native extracellular matrix. However, the large surface area give nanofibrous scaffolds high non-specific protein adsorption, resulting in the enhancement of foreign body reaction. This study aims to use biological tools to regulate pro-inflammatory M1 and pro-wound healing M2 type functional plasticity of macrophage to ease the foreign body reaction of nanofibrous scaffold-tissue interface. Through the use of immunomodulatory cytokines interleukin-4 (IL-4) and pro-immunosuppressive mesenchymal stem cells (MSCs), or combination of above-mentioned two factors, the applicants want to employ layer-by-layer self-assembly and click chemistry techniques to fabricate surface functional three-dimensional nanofibrous scaffold, exploring their effects or synergistic effects on macrophage functional plasticity, further suppressing the foreign body reaction of biomaterial-tissue interface and promoting tissue regeneration. This project will combine biology, chemistry and materials science for the design of new functional immunosuppressive nanofibrous scaffold, which will provide new experimental and theoretical basis to improve and solve the foreign body reactions of biomaterials.

生物材料异物反应所形成的纤维化胶原囊能够影响甚至阻断材料与组织间的信号传递，导致材料生物学功能的降低甚至完全丧失。目前，纳米纤维支架材料由于能够模拟细胞外基质的结构与功能，在组织工程与药物递送领域中具有良好的应用前景。然而，其超高的比表面积能够明显增加材料与组织界面的非特异性蛋白吸附进而导致异物反应的加强。本研究旨在利用生物学手段调控巨噬细胞的促炎症M1与促愈合M2型功能可塑性来降低纳米纤维与组织界面的异物反应。申请者拟采用免疫调节因子白介素-4(IL-4)，或促免疫抑制型间充质干细胞,或将以上两者相结合,通过自组装与点击化学等技术构建表面功能化纳米纤维支架，探索其调节巨噬细胞功能可塑性转化的效应与协同效应，进而抑制材料与组织界面的异物反应并促进组织再生。本项目将结合生物学、化学与材料学因素构建新颖的功能性免疫抑制型纳米纤维支架，为改善与解决生物材料的异物反应提供新的实验与理论依据。

生物材料体内植入引起的异物反应是其功能失效与临床并发症主要因素。静电纺丝纳米纤维支架能够模拟细胞外基质结构与成分，在组织工程与再生医学领域中具有广泛的应用前景。然而由于其高比表面积，能够产生大量的非特异性蛋白吸附，从而引起严重的异物反应。本项目系统研究了免疫调节因子白介素-4（IL-4）与间充质干细胞（MSCs）胞外基质两种生物化学因素对可降解高分子聚己内酯（Polycaprolactone）静电纺丝纤维支架植入体内后所产生的炎症与异物反应的积极影响，揭示生化因素调控高比表面积支架材料生物相容性响应的机理。通过项目研究主要发现以下2点：①通过生化因素调节前期的巨噬细胞M1型向M2型转化，能够有效降低后期的胶原纤维囊与异物巨细胞的产生；② 降低软组织例如跟腱修复材料本身的异物反应可以有效改善软组织创伤修复过程中组织黏连情况。此外，本项目中使用了丝素蛋白层层自组装与点击化学技术进行电纺纤维表面功能化，可以提高生物化学因素IL-4的长期固定并提高其体内半衰期。本项目研究结果体现了较为新颖的化学与材料学的技术优势，着重突出生物因素调节体内巨噬细胞极化进而降低异物反应的机制，为植介入组织工程修复材料的临床应用提供了一定的理论支撑与实践经验。