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

项目总结/摘要 周围神经损伤在美国和退伍军人群体中仍然是一个重要的问题。 即使经过几十年的研究，也很少有临床可用的方法来治疗长间隙周围神经 损伤通常，长间隙周围神经的修复是通过腓肠神经的收获和安置来促进的 自体移植到损伤部位腓肠神经隔离会导致供区发病，一些患者无法 由于其他合并症（如糖尿病）而捐赠神经组织。作为自体移植物的替代品，神经 同种异体移植物和生物材料支架已经成为替代自体移植物的可能方法。然而，在这方面， 同种异体移植物需要广泛的去细胞化过程，并且寻找大小匹配的同种异体移植物用于移植是具有挑战性的。 患者生物材料导管可以成形为适当的尺寸。许多生物材料导管缺乏足够的 细胞外基质促进轴突的广泛再生。总的来说，自体移植物，同种异体移植物和生物材料 策略通常无法完全挽救失去的功能。因此，需要采取新的战略， 领域由对齐的静电纺丝纤维组成的生物材料导管强烈促进轴突再生， 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。迁移到损伤部位的雪旺细胞负责 产生足够的ECM以促进稳健的再生。不幸的是，雪旺细胞在 周围神经损伤减少了它们的关键生长因子如神经营养素-3（NT-3）的产生。因此，我们认为， 雪旺细胞不能产生足够的因子来产生ECM和生长因子，以稳健地诱导 再生包括释放再生因子的外源性干细胞和许旺细胞或使用 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，并且难以从可降解聚合物中释放蛋白质 （其通常需要苛刻的化学品用于聚合物合成）。用于制造生物材料的苛刻化学品 支架使生长因子变性，需要研究替代方法。在此SPiRE应用程序中， 我们建议开发释放mRNA的纤维支架，并评估mRNA释放的能力。 支架以促进临床前损伤模型中的外周再生。总的来说，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鲁棒性的新工具， 为退伍军人提供外周神经再生服务

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.