Reinnervation of Paralyzed Muscle by Nerve-Muscle-Endplate Band Grafting

通过神经-肌肉-终板带移植术恢复瘫痪肌肉的神经

• 批准号: 7740156
• 负责人: LIANCAI MU
• 金额: $ 33万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740156
• 关键词: Anastomosis - action; Animals; Automobile Driving; Axon; Biochemical; Cervical; Clinical; Contralateral; Control Groups; Critiques; Data; Denervation; Documentation; Epidemiology; Evaluation; Feasibility Studies; Fiber; Future; Glycogen; Grouping; Harvest; Head and neck structure; Healthcare; Horseradish Peroxidase; Label; Measurement; Medical; Methods; Minor; Modeling; Motor Endplate; Motor Neurons; Movement; Muscle; Muscle Fibers; Muscle denervation procedure; Muscle rehabilitation; Muscular Atrophy; Myosin Heavy Chains; Natural regeneration; Nerve; Neuromuscular Diseases; Operative Surgical Procedures; Outcome; Paralysed; Patients; Peripheral nerve injury; Pilot Projects; Postoperative Period; Procedures; Protocols documentation; Published Comment; Rattus; Recovery of Function; Rehabilitation therapy; Relative (related person); Research; Research Design; Science; Skeletal Muscle; Solutions; Source; Sternocleidomastoid Muscle; Techniques; Testing; Time; Transplantation; Work; Writing; base; chromosome 1 loss; chromosome 3 loss; clinical application; clinically relevant; demographics; functional restoration; improved; muscle form; nervous system disorder; neuromuscular; novel strategies; reinnervation; relating to nervous system; repaired; restoration

DESCRIPTION (provided by applicant): Neuromuscular denervation is a common consequence of peripheral nerve injuries and neurological diseases. There is a pressing need to seek novel approaches of reinnervation for restoration of paralyzed muscles as the presently used methods generally result in poor functional recovery. The global hypothesis driving this project is that better outcomes could be achieved by reinnervating a paralyzed muscle with an abundant source of intact nerve terminals and motor endplates. This idea promoted us to develop a nerve- muscle-endplate band grafting (NMEG) method to reinnervate paralyzed muscles. Cervical strap muscles were selected to perform feasibility studies in a rat model. The NMEG was harvested from the omohyoid (OH) muscle and then transplanted to the experimentally paralyzed sternomastoid (SM) muscle. Meanwhile, nerve- muscle pedicle (NMP) and end-to-end anastomosis (EEA) reinnervation procedures were also carried out for comparison. Our pilot studies using immediate reinnervation model showed that NMEG resulted in successful neuroregeneration and better functional recovery than the NMP and EEA. This research is to determine the efficacy of the NMEG for the immediate and delayed reinnervation of paralyzed cervical strap muscles as compared with the classic EEA technique. Studies designed in this proposal will document the fundamental neural basis of the functional recovery and other major factors influencing outcomes. We hypothesized that the extent of functional recovery of a reinnervated muscle is largely dependent on both the quantity of the reestablished nerve-muscle contacts and the denervation induced muscular alterations and that the NMEG would be a better option for muscle reinnervation than the commonly used EEA and other methods. These hypotheses will be tested with the following 3 specific aims. Specific Aim 1 is to evaluate functional recovery of the reinnervated muscles by analyzing electromyographic (EMG) recordings, muscle force and movement measurements, and distribution of the glycogen depleted muscle fibers. Specific Aim 2 is to demonstrate the neural basis of the functional restoration of the reinnervated muscles by quantifying the retrograde horseradish peroxidase (HRP) labeled motoneurons, regenerating axons and sprouts, and newly formed motor endplates. Specific Aim 3 is to explore procedure-related and time-dependent morphological, immunocytochemical, and biochemical changes in the reinnervated muscles by analyzing muscle mass, fiber size, fiber type grouping, and fiber type and myosin heavy chain (MHC) composition. The results will allow the reliable documentation of the efficacy of the NMEG in rehabilitation of muscle paralysis. The significance of the proposed work extends far beyond what is currently understood. Once the advantages of the NMEG are fully documented by extensive animal studies, the impact of this research on science and health care could be substantial as the data obtained from this research are useful for ultimate clinical application in the near future to the treatment of patients with paralytic neuromuscular disorders. As an entirely satisfactory solution to restoration of the paralyzed skeletal muscles has not yet been found, we developed a new technique (nerve-muscle-endplate band grafting) to reinnervate paralyzed cervical strap muscles in a rat model. Our preliminary work showed that this technique results in better outcomes than currently used methods. The data obtained from this research is useful for future clinical application to treat muscle paralysis.

描述（由申请人提供）：神经肌肉去神经支配是周围神经损伤和神经系统疾病的常见后果。由于目前使用的方法通常导致功能恢复差，因此迫切需要寻求用于恢复瘫痪肌肉的神经再支配的新方法。推动这一项目的总体假设是，通过重新神经支配具有丰富来源的完整神经末梢和运动终板的瘫痪肌肉可以实现更好的结果。这一想法促使我们发展了一种神经-肌肉-终板带移植（NMEG）方法来重新支配瘫痪的肌肉。选择颈带肌在大鼠模型中进行可行性研究。从肩胛舌骨（OH）肌中获取NMEG，然后将其移植到实验性麻痹的胸锁乳突肌（SM）。同时进行神经-肌肉蒂（NMP）和端端吻合（EEA）两种神经再支配方法的比较。我们使用即时神经再支配模型的初步研究表明，NMEG导致成功的神经再生和更好的功能恢复比NMP和EEA。本研究旨在确定与经典的EEA技术相比，NMEG对瘫痪颈带肌的即时和延迟神经再支配的有效性。本提案中设计的研究将记录功能恢复的基本神经基础和影响结果的其他主要因素。我们假设，神经再支配肌肉的功能恢复程度在很大程度上取决于重新建立的神经-肌肉接触的数量和去神经诱导的肌肉变化，并且NMEG将是比常用的EEA和其他方法更好的肌肉神经再支配选择。这些假设将通过以下3个具体目标进行检验。具体目标1是通过分析肌电图（EMG）记录、肌肉力量和运动测量以及糖原耗尽肌纤维的分布来评估神经再支配肌肉的功能恢复。具体目标2是通过定量逆行辣根过氧化物酶（HRP）标记的运动神经元，再生轴突和芽，以及新形成的运动终板来证明神经支配肌肉功能恢复的神经基础。具体目标3是通过分析肌肉质量、纤维大小、纤维类型分组、纤维类型和肌球蛋白重链（MHC）组成，探索手术相关和时间依赖性的形态学、免疫细胞化学和生物化学变化。这些结果将允许可靠的记录NMEG在肌肉麻痹康复中的疗效。拟议工作的重要性远远超出目前的理解。一旦广泛的动物研究充分证明了NMEG的优势，这项研究对科学和医疗保健的影响可能是巨大的，因为从这项研究中获得的数据对于在不久的将来治疗麻痹性神经肌肉疾病患者的最终临床应用是有用的。作为一个完全令人满意的解决方案，恢复瘫痪的骨骼肌尚未找到，我们开发了一种新的技术（神经肌肉终板带移植），以再神经支配瘫痪的颈带肌在大鼠模型。我们的初步工作表明，这种技术的结果比目前使用的方法更好。从这项研究中获得的数据是有用的，为未来的临床应用，以治疗肌肉麻痹。