mRNA-containing fibrous conduits for repair of long-gap peripheral nerve injury

项目摘要/摘要 周围神经损伤在美国和退伍军人中仍然是一个严重的问题。 即使经过几十年的研究，临床上也很少有治疗长间隙周围神经的方法。 受伤。通常，长间隙周围神经的修复是通过采集和放置腓肠神经来实现的。 自体骨移植到损伤部位。腓肠神经隔离导致供区病变，部分患者不能 因其他并发症(如糖尿病)而捐献神经组织。作为自体移植的替代品，神经 同种异体移植物和生物材料支架已成为替代自体移植物的可能方法。然而， 同种异体移植物需要广泛的脱细胞过程，而且很难找到尺寸匹配的同种异体移植物 病人。生物材料管道可以被塑造成合适的尺寸。许多生物材料管道缺乏足够的 细胞外基质促进轴突的广泛再生。总的来说，自体移植、同种异体移植和生物材料 策略通常不能完全挽救丧失的功能。因此，需要新的战略来推动 菲尔德。由排列的电纺纤维组成的生物材料导管有力地促进了轴突的再生 周围神经损伤的临床前模型。纤维材料是用合成的、可降解的 不含细胞外基质的聚合物。雪旺细胞迁移到损伤部位是导致 产生足够的ECM以促进强劲的再生。不幸的是，雪旺细胞紧接着 周围神经损伤减少了神经营养因子-3(NT-3)等关键生长因子的产生。因此， 雪旺细胞不能产生足够的因子来产生细胞外基质和生长因子来强劲地诱导 再生。包括释放再生因子的外源干细胞和雪旺细胞或使用 释放生长因子的生物材料改善了临床前模型的再生。然而，细胞外植体 来自供体组织的蛋白质需要免疫抑制，而且很难从可降解的聚合物中释放蛋白质 (通常需要苛刻的化学品才能合成聚合物)。用于制造生物材料的苛刻化学品 支架可变性生长因子，需要研究替代方法。在这个尖顶应用程序中， 我们建议开发释放信使核糖核酸的纤维支架，并评估其释放信使核糖核酸的能力。 在临床前损伤模型中促进外周再生的支架。总体而言，新的发展 治疗周围神经损伤的生物材料方法可能导致能够促进健壮的新工具 退伍军人的周围神经再生。

Project Summary/Abstract Peripheral nerve injury remains a significant problem in the United States and among the Veteran population. Even after decades of research, there are few clinically available approaches to treat long-gap peripheral nerve injury. Often, long-gap peripheral nerve repair is facilitated through harvest and placement of sural nerve autografts into the injury site. Sural nerve isolation induces donor site morbidity, and some patients are unable to donate neural tissue due to other co-morbidities (such as diabetes). As alternatives to the autografts, nerve allografts and biomaterial scaffolds have emerged as possible approaches to supplant the autograft. However, allografts require extensive decellularization processes, and it is challenging to find size-matched allografts for patients. Biomaterial conduits can be shaped into appropriate sizes. Many biomaterial conduits lack sufficient extracellular matrix to promote extensive regeneration of axons. In total, autograft, allograft, and biomaterial strategies routinely fail to completely rescue lost function. Thus, new strategies are needed to advance the field. Biomaterial conduits that consist of aligned, electrospun fibers robustly promote axonal regeneration in preclinical models of peripheral nerve injury. Fibrous materials are produced using synthetic, degradable polymers that contain no extracellular matrix. Schwann cells migrating into the injury site are responsible for producing sufficient ECM to foster robust regeneration. Unfortunately, Schwann cells immediately after peripheral nerve injury reduce their production of key growth factors, such as neurotrophin-3 (NT-3). Therefore, Schwann cells are unable to produce sufficient factors to create ECM and growth factors to robustly induce regeneration. Inclusion of exogenous stem cells and Schwann cells that release regenerative factors or use of biomaterials that release growth factors improve regeneration in preclinical models. However, cellular explants from donor tissue require immunosuppression, and it is difficult to release proteins from degradable polymers (which typically require harsh chemicals for polymer synthesis). Harsh chemicals used to fabricate biomaterial scaffolds denature growth factors, requiring investigation of alternative approaches. In this SPiRE application, we propose to develop mRNA-releasing fibrous scaffolds and assess the ability of the mRNA-releasing scaffolds to promote peripheral regeneration in a pre-clinical injury model. In total, the development of new biomaterial approaches to treat peripheral nerve injury may lead to new tools capable of promoting robust peripheral nerve regeneration for the Veteran population.