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

描述(申请人提供)：尽管再生，但广泛的周围神经损伤可导致整个肢体或肢体远端的有效瘫痪。显微外科技术的改进包括引入手术显微镜和微缝线，提高了这种机械过程的准确性，然而只有10%的成年人可以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地再生到其原始的靶终末器官。不幸的是，当修复混合周围神经时，再生的运动轴突常被错误地投向非肌肉靶点，导致功能恢复和康复较差。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会迅速传递到近端神经损伤部位，并影响随后运动神经元再生的准确性。我们还做了令人惊讶的观察到，在体内应用低电压直流电场增强了注射到远端周围神经的化合物的摄取，并且这种刺激还导致应用的化合物在更近的神经修复部位积累(我们称之为全神经电泳)。在对这一应用的初步审查中提出的建议，我们研究了使用远端失神经肌肉本身作为输送工具的可能性，我们现在表明这是可能的。这一修订后的应用中的初步数据清楚地表明，使用远端失神经肌肉和/或神经有效地将外源性化合物输送到位于更近端神经修复部位的一组解剖上不连续的雪旺细胞管。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最初修复部位进入的雪旺细胞管，这种针对特定外源化合物的解剖靶向可能对最终的再生准确性产生重大影响。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的重大补充。我们正试图通过强调远端失神经肌肉和神经通路作为一种选择性递送机制来转移临床和研究的注意力；如果成功，这项技术可能会迅速转化为标准的临床实践。 公共卫生相关性：在普通美国人中，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%的成年人可以使用最先进的当前技术恢复正常的神经功能，因此，从长远来看，更好地了解限制周围神经再生准确性的潜在机制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。

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.