寻找自体神经替代物修复周围神经缺损，一直是周围神经再生研究热点。申请者前一个国家自然科学基金项目发现，再生的时间窗口是决定再生结果的关键。鉴于此申请者开始关注从损伤早期以及周围神经再生机制上，寻求周围神经损伤修复研究的新突破。大鼠全基因组芯片检测结果发现，多个调控生长与凋亡相关的差异表达基因均与TNF-α受体1有关。ELISA检测坐骨神经离断后，TNF-α蛋白表达量逐渐增加。并且TNF-α在不同剂量下对体外培养施万细胞，呈现双向调控作用，即低浓度有促施万细胞增殖作用；而高浓度则抑制施万细胞增殖迁移，并最终引发凋亡。本研究申请者拟运用组织工程研究手段，构建含TNF-α抑制剂缓释系统的神经移植物，并将其用于修复大鼠坐骨神经10mm缺损。通过调控周围神经损伤后局部TNF-α浓度，以期改善局部免疫微环境，抑制施万细胞凋亡，加快神经生长速度，促进神经功能良好恢复，为周围神经损伤修复提供新思路新方法。

Tissue engineered nerve grafts (TENGs) represent a promising alternative to autologous nerve grafts used for peripheral nerve repair, and have become a focus in research of peripheral nerve regeneration. The results of my project that has been previously sponsored by National Natural Science Foundation (grant No. 81000678) showed that the time window of nerve regeneration is a key point for the regeneration outcome. Therefore, we concern about on molecular events occurring at an early stage following peripheral nerve injury and their correlation with regeneration mechanisms, and attempt to develop new breakthrough in research of peripheral nerve regeneration. In preliminary experiments, whole rat genome microarray has indicated that a number of survival/ apoptosis genes are related to tumor necrosis factor receptor1 (TNFR1), and ELISA assay found that tumor necrosis factor-α (TNF-α) protein level increased after nerve injury. These findings collectively suggested the dose-dependent dual effects of TNF-α on primary cultured Schwann cells, i.e., an increase and decreased cell proliferation and migration or reduced and enhanced cell apoptosis induced by lower and higher dosages of TNF-α, respectively. Based on this premise, this project aims to construct a novel TENG that is featured by a controlled release drug delivery system through immobilizing a TNF-α inhibitor to a silk fibroin-based nerve conduit by using genipin as a crosslinking agent, and to use the TENG for repairing a 10 mm long sciatic nerve defect in rats. Our design is hoped to optimize an immune microenvironment by controlling the dosages of TNF-α used, and thus to inhibit apoptosis of Schwann cells and accelerate nerve growth, thus leading to the better outcome of nerve regeneration and function restoration.