Sericin Nerve Guidance Conduit Delivering Therapeutically Repurposed Clobetasol for Functional and Structural Regeneration of Transected Peripheral Nerves
Sericin Nerve Guidance Conduit Delivering Therapeutically Repurposed Clobetasol for Functional and Structural Regeneration of Transected Peripheral Nerves
复制标题
丝胶神经引导导管提供治疗用途的氯倍他索，用于横断周围神经的功能和结构再生
DOI：
10.1021/acsbiomaterials.8b01297
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Zhang L;Yang W;Xie HJ;Wang H;Wang J;Su QF;Li XL;Song Y;Wang GB;Wang L;Wang Z
周围神经损伤常常导致显着的功能丧失。自体神经移植作为治疗此类损伤的金标准修复策略受到供体神经供应的限制。组织工程神经引导导管（TENGC）作为自体移植的一种有前途的替代方案，但面临着大神经间隙的挑战。在此，我们制造了一种与糖皮质激素受体激动剂氯倍他索结合的戊二醛交联丝胶神经导管（GSC），用于修复大鼠模型中10毫米长的坐骨神经间隙。 GSC 表现出生物相容性和有利于再生的理化特性。 GSC的降解产物促进雪旺细胞分泌神经营养因子。通过重新利用氯倍他索用于周围神经再生，我们的工作揭示了氯倍他索以前未知的促进雪旺细胞增殖和上调髓磷脂相关基因表达的功能。重要的是，将这种负载氯倍他索的 GSC 植入体内可导致横断的坐骨神经成功再生。引人注目的是，再生结果在功能上与自体神经移植相当（通过三个参数证明）。具体而言，第12周时，氯倍他索/GSC组的静态坐骨指数（SSI）、相对反应时间（RRT）和神经传导速度（NCV）分别为-74.55、1.30和46.4 mm/s，而自体移植组的这些参数分别为-64.53、1.23和49.8 mm/s。因此，这项工作代表了第一份揭示氯倍他索在周围神经再生中的潜力的报告，揭示了应用丝胶导管修复大神经缺损的可行性，并证明了基于负载氯倍他索的 GSC 策略在横断神经再生中的有效性。
Peripheral nerve injury often causes significant function loss. Autologous nerve grafting as a gold-standard repair strategy for treating such an injury is limited by donor nerve supply. Tissue-engineered nerve guidance conduits (TENGCs) as a promising alternative for autografting are challenged by large nerve gaps. Herein, we fabricate a glutaraldehyde-cross-linked sericin nerve guidance conduit (GSC) incorporated with clobetasol, a glucocorticoid receptor agonist, for repairing a 10 mm long sciatic nerve gap in a rat model. The GSC exhibits biocompatibility and regeneration-favorable physicochemical properties. GSC’s degradation products promote the secretion of neurotrophic factors in Schwann cells. By repurposing clobetasol for peripheral nerve regeneration, our work uncovers clobetasol’s previously unknown functions in promoting Schwann cell proliferation and upregulating the expression of myelin-related genes. Importantly, the implantation of this clobetasol-loaded GSC in vivo leads to successful regeneration of the transected sciatic nerve. Strikingly, the regeneration outcome is functionally comparable to that of autologous nerve grafting (evidenced by three parameters). Specifically, the static sciatic index (SSI), relative reaction time (RRT) and nerve conduction velocity (NCV) in Clobetasol/GSC group are −74.55, 1.30, and 46.4 mm/s at Week 12, respectively, while these parameters are −64.53, 1.23, and 49.8 mm/s in Autograft group. Thus, this work represents the first report unveiling clobetasol’s potential in peripheral nerve regeneration, reveals the feasibility of applying a sericin conduit for repairing a large nerve defect, and demonstrates the effectiveness of the clobetasol-loaded-GSC based strategy in transected nerves’ regeneration.