Restoration of Muscular Function Following Direct Muscle Neurotization

直接肌肉神经化后肌肉功能的恢复

• 批准号: 10699345
• 负责人: Lorenzo Soletti
• 金额: $ 49.5万
• 依托单位: RENERVA, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10699345
• 关键词: Acceleration; Achievement; Acute; Address; Affect; American; Angiogenic Factor; Animal Model; Animals; Axon; Behavior assessment; Biological; Clinical; Complex; Consumption; Cues; Denervation; Development; Diameter; Distal; Environment; Exhibits; Family suidae; Fiber; Formulation; Gastrocnemius Muscle; Gel; Goals; Growth; Hip region structure; Histologic; In Situ; In Vitro; Inflammatory; Injury; Investigation; Macrophage; Methods; Microsurgery; Modeling; Modulus; Motor; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Natural regeneration; Nature; Nerve; Nerve Crush; Nerve Regeneration; Nerve Tissue; Nerve Transfer; Neuromuscular Junction; Operative Surgical Procedures; Outcome; Patients; Performance; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Phase; Phenotype; Procedures; Process; Proteins; Quality Control; Quality of life; Recovery; Recovery of Function; Research; Risk; Rodent; Rodent Model; Schwann Cells; Site; Sterilization; Structure; Techniques; Time; Tissues; Work; animation; clinical application; clinically relevant; cost; economic impact; effective therapy; experience; experimental study; functional restoration; healing; improved; loss of function; manufacture; mechanical properties; migration; motor function recovery; muscle reinnervation; nerve gap; nerve injury; nerve repair; nerve transection; neuromuscular; peroneal nerve; prevent; recruit; regenerative; reinnervation; repaired; response; restoration; standard of care; success; supply chain

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.

摘要/摘要 美国每年进行超过 500,000 例外科手术来解决周围神经损伤 (PNI)，成本超过 $1.1B。 PNI 及其后遗症影响了超过 2000 万美国人，总计 每年的经济影响超过 $150B。尽管显微外科技术和固有的进步 周围神经系统的再生能力，不到 50% 的患者体验满意 功能恢复。神经肌肉组织明显丧失后的成功复活可能会带来临床影响 由于缺乏远端神经肌肉蒂而面临挑战。在这些情况下，诸如免费的方法 可能需要进行功能性肌肉移植才能恢复功能。这些程序复杂且耗时 消耗，导致供体部位功能丧失，并可能造成重大风险。另一种方法 神经再支配是直接肌肉神经化 (DMN)，其中神经直接转移到目标肌肉 无需依赖先前存在的神经肌肉桥。 DMN 的成功依赖于 神经与现有或新形成的神经肌肉接头（NMJ）建立新的连接 去神经支配的肌肉。这一过程因引导神经结构的丧失而受到严重阻碍 再生信号，并进一步受到修复前去神经支配时间的影响。 为了满足这一需求，Renerva 寻求进一步开发用于临床的周围神经矩阵 (PNM) DNM 使用，并确定最终灭菌的临床级 PNM 产品促进功能性的能力 在即时和延迟 DMN 模型中随着时间的推移恢复。 PNM 包含天然存在的结构和 功能蛋白为神经修复和再生提供理想的环境。在之前的工作中，PNM 已被证明可以促进与神经挤压、神经横断和神经相关的结果的改善 间隙损伤。在这个第一阶段项目中，Renerva 寻求进一步开发 PNM 以供临床 DNM 使用，并且 确定最终灭菌的临床级 PNM 产品促进功能恢复的能力 即时和延迟 DMN 模型中的时间。本项目的具体目标如下： 1）优化 制定临床级PNM，为体外DMN提供理想支持； 2）确定PNM的能力 加速和增强啮齿动物 DMN 模型的功能恢复。 拟议的工作将加速 DMN 应用产品的开发。这样的产品具有 有可能为具有挑战性的临床应用提供新的选择，包括髋部的严重坐骨神经损伤， 近端神经损伤和广泛的肌肉组织损失，这通常与修复和延迟延迟有关 结果不佳。它还将为新兴手术提供支持，例如有针对性的肌肉神经支配 和再生周围神经接口。实现本提案的目标将支持更多 II 期临床相关大型动物模型的研究。