PDLLA/PRGD/β-TCP神经修复材料抑制神经瘤形成的作用机制

Peripheral nerve injury is the common cause that leads to disability. Large nerve defect and traumatic neuroma are two main bottleneck problems during repairing after peripheral nerve injury. So far, the mechanism of neuroma development and progression are still unclear, and there is very limited research on neuroma inhibition with nerve conduit. Our group previously found that a PDLLA/PRGD/β-TCP composite conduit had beneficial effect on nerve regeneration, and no obvious neuroma formation was found in around 300 experimental animals. The main mechanism of neuroma formation is based on excessively sedimentary collagen proliferation. This project intends to investigate the effects of PDLLA/PRGD/β-TCP composite on the neural scar formation-related cytokines such as NGF, IFN-γ etc., matrix metallo-proteinases, gene expression and protein level of collagen, as well as the signal of NF-κB, TGFβ1-Smads. The effect of the conduit on neural scar distribution and scar ratio, nerve function recovery, structure of regenerated myelin sheath will be studied. This project will discover the signal transduction pathway from composite signal to cytokines and enzymatic response to determine the fate of cells and nerves. This project will also reveal mechanism underlying material promoting nerve regeneration and inhibition neuroma formation. It is going to provide experimental basis for future studies in nerve conduits for inhibition of neuroma formation and promoting long-distance nerve regeneration as well as the clinical therapy for neuroma.

周围神经损伤是常见的致残性创伤，长段神经缺损和神经瘤形成是神经修复的两大瓶颈。目前关于神经瘤的发生、发展和抑制机理尚未明了，抑制神经瘤的材料研究非常匮乏。前期本课题组研制的PDLLA/PRGD/β-TCP导管促神经再生效果良好，近300例动物实验未见神经瘤形成。本项目以胶原过度增生沉积致神经瘢痕形成是神经瘤的主要成因为契机，通过体内、体外实验，探讨PDLLA/PRGD/β-TCP复合材料对神经瘢痕形成相关细胞因子NGF、IFN-γ等、基质酶MMPs等的变化规律及对胶原蛋白和基因表达、NF-κB、TGFβ1-Smads信号通路的影响；探讨神经导管对神经瘢痕分布、比率和含量、神经功能恢复和髓鞘结构等的影响；系统揭示材料信号-细胞因子及酶学响应信号-细胞及组织效应信号的影响规律，初步阐明材料抑制神经瘤形成的机制，为构建抑制神经瘤形成并促神经再生的神经导管及神经瘤的临床治疗提供实验依据。

周围神经损伤导致的创伤性神经瘤易引起顽固性疼痛，临床常用的两种方法是将神经瘤截断／将神经断端埋入周围组织，但易复发且需要进行二次或多次手术再切除或者套入套管，因此临床上迫切需要研制开发出抑制神经瘤的材料。本课题在前期研究的基础上，通过仿生设计优化制备了PRGD/PDLLA/TCP复合神经修复材料，构建了神经缺损、神经瘤动物模型。通过体内外实验，对PRGD/PDLLA/TCP 复合材料降解产物和病灶局部炎性因子进行实时检测，探讨了神经导管对神经瘢痕分布、比率和含量、神经功能恢复和髓鞘结构等的影响，系统揭示了材料信号-细胞因子-细胞及组织效应信号的影响规律，初步阐明PRGD/PDLLA/TCP复合材料抑制神经瘤形成的机制。该项目为构建抑制神经瘤形成并促神经再生的神经修复材料研制及神经瘤的临床治疗提供了实验依据和临床指导。