Restoration of Muscular Function Following Direct Muscle Neurotization

摘要/摘要 在美国，每年有50多万例外科手术治疗周围神经损伤 (PNI)，成本超过11亿美元。PNI及其后遗症影响了2000多万美国人， 每年产生的经济影响超过1500亿美元。尽管显微外科技术的进步和固有的 周围神经系统再生的能力，只有不到50%的患者感到满意 功能恢复。在显著的神经肌肉组织丢失后成功复苏可引起临床 由于远端神经肌蒂的缺失而引起的挑战。在这些情况下，诸如免费- 可能需要有功能的肌肉转移来恢复功能。这些程序既复杂又费时 消耗，导致捐献部位的功能丧失，并可能构成重大风险。另一种方法是 神经再支配是一种直接的肌肉神经化(DMN)，神经被直接转移到目标肌肉上 而不依赖于先前存在的神经肌肉桥。DMN的成功依赖于 神经与现有的或新形成的神经肌肉接头(NMJ)建立新的连接 失去神经的肌肉。这一过程明显受阻于引导神经结构和 再生提示，并进一步受到修复前失神经时间的影响。 为了满足这一需求，Renerva寻求进一步开发用于临床的外周神经基质(PNM) DNM的使用，并确定终端灭菌的临床级PNM产品的能力，以促进功能 在即时和延迟DMN模型中随时间恢复。PNM含有天然存在的结构和 为神经修复和再生提供理想环境的功能蛋白质。在之前的工作中，PNM已经 已被证明能促进与神经挤压、神经切断和神经损伤相关的结果的改善 缝隙损伤。在这个第一阶段的项目中，Renerva寻求进一步开发用于临床DNM的PNM，以及 确定终末灭菌的临床级PNM产品促进功能恢复的能力 在立即DMN模型和延迟DMN模型中的时间。本项目的具体目标如下：1)优化 制备临床分级的PNM，为DMN提供理想的体外支持；2)测定PNM的能力 目的：加速和增强啮齿动物DMN模型的功能恢复。 拟议的工作将加快DMN应用产品的开发。这样的产品具有 有可能为挑战临床应用提供新的选择，包括髋部严重的坐骨神经损伤， 近端神经损伤和广泛的肌肉组织丢失，通常与延迟修复和 糟糕的结果。它还将为新出现的程序提供支持，如有针对性的肌肉神经再支配 和再生的周围神经接口。这项提案目标的实现将支持额外的 第二阶段临床相关大动物模型的研究。

Summary/Abstract More than 500,000 surgical procedures are performed annually in the US to address peripheral nerve injury (PNI), at a cost of more than $1.1B. PNI and their sequelae affect more than 20 million Americans, with total economic impacts in excess of $150B annually. Despite advances in microsurgical techniques and the inherent ability of the peripheral nervous system to regenerate, fewer than 50% of patients experience satisfactory functional recovery. Successful reanimation following significant neuromuscular tissue loss can pose a clinical challenge due to the absence of the distal nerve-muscle pedicle. In these cases, approaches such as free- functioning muscle transfer may be required to restore function. These procedures are complex and time consuming, cause loss of function at the donor site, and can pose substantial risks. Another approach to reinnervation is direct muscle neurotization (DMN), in which a nerve is transferred directly to a targeted muscle without relying on previously existing neuro-muscular bridges. The success of DMN relies on the ability of the nerve to establish new connections to existing or newly formed neuromuscular junctions (NMJ) within the denervated muscle. This process is significantly hindered by the loss of guiding nerve structures and regenerative cues and is further affected by the time of denervation before repair. To address this need, Renerva seeks to further the development of Peripheral Nerve Matrix (PNM) for clinical DNM use, and determine the ability of a terminally sterilized, clinical grade PNM product to facilitate functional recovery over time in both immediate and delayed DMN models. PNM contains naturally occurring structural and functional proteins that provide an ideal environment for nerve repair and regeneration. In prior work, PNM has been shown to promote improvements in outcomes associated with nerve crush, nerve transection and nerve gap injuries. In this Phase I project, Renerva seeks to further the development of PNM for clinical DNM use, and determine the ability of a terminally sterilized, clinical grade PNM product to facilitate functional recovery over time in both immediate and delayed DMN models. Specific Aims of this project are as follows: 1) Optimize the formulation of clinical grade PNM to provide ideal support for DMN in vitro; and 2) Determine the ability of PNM to accelerate and enhance functional recovery in a rodent DMN model. The proposed work will accelerate the development of a product for DMN applications. Such a product has the potential to provide new options for challenging clinical applications including severe sciatic injury at the hip, proximal nerve injuries, and extensive muscle tissue loss, which are often associated with delayed repair and poor outcomes. It would also provide support for emerging procedures such as targeted muscle reinnervation and regenerative peripheral nerve interfaces. The achievement of the aims of this proposal will support additional investigations in clinically relevant large animal models in Phase II.