Low-Voltage Nerve Electrophoresis In Vivo: Role in Peripheral Nerve Regeneration

体内低压神经电泳：在周围神经再生中的作用

• 批准号: 8050343
• 负责人: Roger D. Madison
• 金额: $ 22.49万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050343
• 关键词: Accounting; Adult; Animals; Arts; Attention; Axon; Back; Behavior; Biological; Bite; Cells; Charge; Chronic; Clinical Research; Complex; Control Groups; Cutaneous; Data; Development; Distal; Electrophoresis; Environment; Event; Future; Healthcare Systems; Injury; Intervention; Laboratories; Lesion; Limb structure; Mechanics; Metric; Microscope; Modeling; Modern Medicine; Molecular; Motor; Motor Neurons; Movement; Mus; Muscle; Natural regeneration; Needles; Nerve; Nerve Regeneration; Neurosciences; Operative Surgical Procedures; Organ; Paralysed; Pathway interactions; Patients; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Physiological; Population; Procedures; Process; Proteins; Recovery; Recovery of Function; Rehabilitation therapy; Role; Schwann Cells; Site; Suggestion; Surgical sutures; Techniques; Therapeutic Intervention; Transfection; Translating; Tube; United States; Walking; Work; axon growth; axon regeneration; clinical practice; femoral nerve; hybrid protein; in vivo; indexing; injury and repair; innovation; nerve injury; peroneal nerve; public health relevance; quadriceps muscle; reinnervation; repaired; research study; response; trauma centers; uptake; voltage

DESCRIPTION (provided by applicant): Despite regeneration, extensive peripheral nerve injuries can result in the effective paralysis of the entire limb or distal portions of the limb. Refinement of microsurgical techniques involving the introduction of the surgical microscope and microsutures has increased the accuracy of this mechanical process, however only 10% of adults will recover normal nerve function using state-of-the-art techniques. The major key to recovery of function following nerve lesions in the peripheral nervous system is the accurate regeneration of axons to their original target end-organs. Unfortunately, when a mixed peripheral nerve is repaired, regenerating motor axons are often misrouted to a non-muscle target which leads to poor functional recovery and rehabilitation. During the course of our recent studies we have made an unexpected discovery; information from a denervated muscle is apparently rapidly conveyed to the proximal nerve lesion site and influences the subsequent accuracy of motor neuron regeneration. We have also made the surprising observation that the application of a low voltage direct current field in vivo enhances the uptake of compounds injected into distal peripheral nerve, and that such stimulation also results in the accumulation of the applied compounds at a more proximal nerve repair site (a phenomenon that we have termed Whole-Nerve Electrophoresis) In response to suggestions from the initial review of this application, we have examined the possibility of using the distal denervated muscle itself as a delivery vehicle, and we now show that this is possible. The preliminary data in this revised application clearly show the feasibility of using the distal denervated muscle and/or nerve to effectively deliver exogenous compounds to an anatomically discrete set of Schwann cell tubes at a more proximal nerve repair site. Since the accuracy of motor neuron axon regeneration is largely determined by the Schwann cell tubes that an axon enters at the initial repair site, such anatomical targeting of specific exogenously applied compounds could have a significant impact on eventual regeneration accuracy. This innovative approach is a significant addition to current interventions that directly target the motor neuron cell body itself. We are seeking to shift clinical and research attention by highlighting the distal denervated muscle and nerve pathway as a selective delivery mechanism; if successful this technique could be rapidly translated into standard clinical practice. PUBLIC HEALTH RELEVANCE: In the general US population peripheral nerve injuries are common, accounting for approximately 5% of all patients admitted to Level I trauma centers. Since only 10% of adults will recover normal nerve function using state-of-the-art current techniques a better understanding of the underlying mechanisms that limit the accuracy of peripheral nerve regeneration could, in the long-term, reduce the overall financial burden on the US health care system associated with extensive nerve injuries.

描述（由申请人提供）：尽管再生，广泛的周围神经损伤可导致整个肢体或肢体远端部分的有效瘫痪。显微外科技术的改进，包括手术显微镜和显微缝合的引入，提高了这种机械过程的准确性，但只有10%的成年人将使用最先进的技术恢复正常的神经功能。周围神经系统神经损伤后功能恢复的主要关键是轴突准确再生到其原始靶终末器官。不幸的是，当修复混合周围神经时，再生的运动轴突通常被错误地路由到非肌肉目标，这导致功能恢复和康复不良。在我们最近的研究过程中，我们有了一个意想不到的发现;来自失神经肌肉的信息显然迅速传递到近端神经损伤部位，并影响随后的运动神经元再生的准确性。 我们还进行了令人惊讶的观察，即在体内施加低压直流电场增强了注射到远端外周神经中的化合物的摄取，并且这种刺激还导致所施加的化合物在更近端的神经修复部位处的积累（我们称之为全神经电泳的现象）响应于来自本申请的初始审查的建议，我们已经研究了使用远端失神经肌肉本身作为递送载体的可能性，现在我们证明这是可能的。 该修订申请中的初步数据清楚地显示了使用远端去神经肌肉和/或神经将外源性化合物有效递送至更近端神经修复部位处的解剖学上离散的一组许旺细胞管的可行性。由于运动神经元轴突再生的准确性在很大程度上取决于轴突在初始修复位点进入的许旺细胞管，因此特定外源性应用化合物的这种解剖靶向可能对最终的再生准确性产生显著影响。这种创新的方法是对目前直接针对运动神经元细胞体本身的干预措施的重要补充。我们正在寻求通过强调远端失神经肌肉和神经通路作为选择性递送机制来转移临床和研究注意力;如果成功，这种技术可以迅速转化为标准临床实践。 公共卫生关系：在一般美国人群中，周围神经损伤很常见，约占I级创伤中心收治的所有患者的5%。由于只有10%的成年人将恢复正常的神经功能，使用最先进的技术，更好地了解限制周围神经再生准确性的潜在机制，从长远来看，可以减少与广泛神经损伤相关的美国医疗保健系统的整体经济负担。