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

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，包括手术显微镜和微缝合线的引入，提高了这一机械过程的准确性，但只有10%的成年人使用最先进的技术恢复正常的神经功能。周围神经系统损伤后功能恢复的关键是轴突向原目标终器官的准确再生。不幸的是，当修复混合周围神经时，再生的运动轴突经常被错误地定向到非肌肉目标，导致功能恢复和康复不良。在我们最近的研究过程中，我们有一个意想不到的发现；来自失神经支配肌肉的信息显然能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。我们也得到了令人惊讶的观察结果，即在体内应用低电压直流电场可以增强注入远端周围神经的化合物的吸收，并且这种刺激也会导致所应用的化合物在更近端的神经修复部位积累（我们称之为全神经电泳的现象）。我们已经研究了使用远端去神经支配肌肉作为运载工具的可能性，我们现在证明这是可能的。本修订申请的初步数据清楚地表明，在更近端的神经修复部位，使用远端去神经支配肌肉和/或神经有效地将外源性化合物输送到解剖学上离散的一组雪旺细胞管中是可行的。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，因此特定外源应用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。这种创新的方法是当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，这项技术可以迅速转化为标准的临床实践。

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.