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

含有 mRNA 的纤维导管用于修复长间隙周围神经损伤

• 批准号: 10588480
• 负责人: Ryan J. Gilbert
• 金额: --
• 依托单位: STRATTON VETERANS ADMIN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10588480
• 关键词: Allografting; Autologous; Autologous Transplantation; Biocompatible Materials; Cells; Chemicals; Chicago; Clinical; Clinical Medicine; Collaborations; Complications of Diabetes Mellitus; DNA; Defect; Development; Diabetes Mellitus; Diabetic Neuropathies; Disease; Distal; Drug Delivery Systems; Extracellular Matrix; Fiber; Fostering; Growth Factor; Harvest; Health; Immunosuppression; Infiltration; Injury; Interdisciplinary Study; Investigation; Lesion; Macrophage; Messenger RNA; Military Personnel; Modeling; Morbidity - disease rate; Natural regeneration; Nerve; Nerve Regeneration; Nerve Tissue; Neurites; Neurotrophin 3; Outcome; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Peripheral nerve injury; Pharmaceutical Preparations; Polymers; Pre-Clinical Model; Preparation; Procedures; Process; Production; Proteins; Publications; Rattus; Recovery; Recovery of Function; Regenerative response; Research; Research Institute; Schwann Cells; Science; Shapes; Site; Spinal Ganglia; Surface; Surgical sutures; Testing; Tissue Donors; Tissue Engineering; Tissues; United States; Veterans; Work; axon growth; axon regeneration; biodegradable polymer; bioscaffold; cell growth; cell motility; comorbidity; design; disability; effectiveness evaluation; experimental study; implantation; improved; in vivo Model; injured; innovation; mRNA delivery; military health system; military veteran; nerve autograft; nerve gap; nerve injury; nerve repair; neural; novel; novel strategies; performance site; peripheral nerve regeneration; peripheral nerve repair; poly-L-lactic acid; pre-clinical; protein expression; prototype; regenerative; repaired; response; scaffold; sciatic nerve; small molecule; stem cells; sural nerve; tool; tumor

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.

项目概要/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大问题。 即使经过数十年的研究，临床上可用于治疗长间隙周围神经的方法仍然很少 受伤。通常，通过收获和放置腓肠神经来促进长间隙周围神经修复 将自体移植物植入损伤部位。腓肠神经隔离会导致供体部位发病，一些患者无法进行 由于其他合并症（例如糖尿病）而捐献神经组织。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成为替代自体移植物的可能方法。然而， 同种异体移植需要广泛的脱细胞过程，并且很难找到尺寸匹配的同种异体移植物 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。总共有自体移植物、同种异体移植物和生物材料移植物 策略通常无法完全挽救丧失的功能。因此，需要新的战略来推进 场地。由排列整齐的电纺纤维组成的生物材料导管可强有力地促进轴突再生 周围神经损伤的临床前模型。纤维材料是使用合成的、可降解的材料生产的 不含细胞外基质的聚合物。雪旺细胞迁移到损伤部位负责 产生足够的 ECM 以促进强劲的再生。不幸的是，施万细胞立即 周围神经损伤会减少关键生长因子的产生，例如神经营养蛋白-3 (NT-3)。所以， 雪旺细胞无法产生足够的因子来产生 ECM 和生长因子来强力诱导 再生。包含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可改善临床前模型的再生。然而，细胞外植体 来自供体组织的蛋白质需要免疫抑制，并且很难从可降解聚合物中释放蛋白质 （通常需要刺激性化学品来进行聚合物合成）。用于制造生物材料的刺激性化学品 支架会使生长因子变性，需要研究替代方法。在此 SPiRE 应用程序中， 我们建议开发mRNA释放纤维支架并评估mRNA释放的能力 在临床前损伤模型中促进外周再生的支架。总体而言，新开发 治疗周围神经损伤的生物材料方法可能会产生能够促进强健的新工具 退伍军人周围神经再生。