Novel Modular Nerve Lengthening Device for Peripheral Nerve Regeneration

 描述(由申请人提供)： 周围神经损伤是士兵四肢爆炸伤的结果，也是颈髓损伤后的次要结果。周围神经损伤后的功能恢复通常很差，导致运动功能受损、感觉丧失和疼痛。退伍军人的临床复杂性和康复预后进一步复杂化，他们的受伤在与武装部队分离后通过手术修复或修正。这一时间线导致慢性神经损伤，这导致了与急性损伤完全不同的临床情景，而且缺乏治疗和康复策略。退伍军人群体增强慢性失神经功能的策略的重要性被VA RR&D脊髓损伤和再生医学计划优先考虑的神经再生和脊髓康复所突显。我们开发了一种创新的神经再生策略，该策略利用了完整的近端神经残端在拉伸变形(拉伸)时生长的固有能力。我们的新型模块化内固定装置以可控的方式将近端残端延长到远端残端，并将比其他方法更快地促进神经残端的重新连接，包括黄金标准的自体移植。重要的是，这种神经再生的加速也将使更多的远端连接成为可能，这尤其是 对于绕过慢性损伤神经远端的大片残端至关重要，因为这会严重抑制再生。我们假设，更快、更远端的重新连接将反过来， 促进运动和感觉功能的恢复。为了实现这些目标，我们将采用综合、跨学科的方法来解决两个具体目标。在目标1中，我们将研究中等水平的拉伸负荷对急性损伤和慢性失神经损伤后的中等10 mm大鼠坐骨神经损伤后神经再生和功能恢复的影响。在这个动物模型中，我们可以有效和实际地检验我们提出的概念，我们假设在急性和慢性损伤组中，与自体移植物相比，对近端神经残端施加适度水平的持续神经张力将加速神经再生以及感觉和运动功能的恢复。疗效将通过比较生物、结构和功能结果的综合组合进行统计评估。在目标2中，我们将研究中等水平的拉伸负荷对慢性失神经后20 mm兔坐骨神经大段缺损区神经再生和功能恢复的影响。在兔模型中，较长的鳞片产生了更具临床相关性的再生挑战，也使直接测量损伤部位的神经传导速度成为可能。根据生物学、结构和功能结果的比较，我们预测，与自体移植物修复的缺损区相比，延长的神经在慢性失神经后的20 mm缺损区将显示出显著的促进再生和功能恢复的作用。我们建议的目标的成功完成将证明神经延长作为一种新的策略用于先前不可修复的周围神经再生的可行性和有效性。我们预计，这些努力将有助于改善受伤退伍军人的运动和感觉恢复。

 DESCRIPTION (provided by applicant): Peripheral nerve damage is a consequence of blast injury to the extremities of soldiers and a secondary outcome following cervical spinal cord injury. Functional recovery from peripheral nerve damage is often poor, resulting in impaired motor function, sensory loss, and pain. Clinical complexity and prognosis for recovery is further compounded for Veterans, whose injuries are surgically repaired or revised following separation from the armed forces. This timeline results in a chronic nerve injury, which results in a fundamentally different clinical scenario from acute injury, and one for which therapeutic and rehabilitative strategies are lacking. The significance of strategies for enhancing function of chronically denervated nerves for a Veteran's population is highlighted by the prioritization of nerve regeneration and spinal cord rehabilitation by the VA RR&D Spinal Cord Injury and Regenerative Medicine Program. We have developed an innovative strategy for nerve regeneration that takes advantage of the inherent capacity of intact proximal nerve stumps to grow in response to tensile deformation (stretch). Our novel, modular internal-fixator device lengthens the proximal stump towards the distal stump in a controlled manner, and will facilitate reconnectivity of nerve stumps more rapidly than other strategies, including gold- standard autologous grafts. Importantly, this acceleration of nerve regeneration will also enable more distal connectivity, which is particularly crucial to bypass large swaths of the distal stump of chronically injured nerves, which severely inhibits regeneration. We hypothesize that more rapid and more distal reconnectivity will, in turn, enhance motor and sensory functional recovery. Towards these goals, we will use an integrative, cross-disciplinary approach to address two specific aims. In Aim 1, we will examine the impact of moderate levels of tensile loading on nerve regeneration and functional recovery in moderate 10mm rat sciatic defects, following acute injury and chronic denervation. In this animal model, which allows us to efficiently and practically test our proposed concept, we hypothesize that in both acute and chronic injury groups, moderate levels of continuous nerve strain imposed on the proximal nerve stump will accelerate nerve regeneration as well as sensory and motor functional recovery compared to autologous grafts. Efficacy will be evaluated statistically by comparing a comprehensive battery of biological, structural, and functional outcomes. In Aim 2, we will examine the impact of moderate levels of tensile loading on nerve regeneration and functional recovery in massive 20mm rabbit sciatic nerve defects, following chronic denervation. The longer length scale in a rabbit model creates a more clinically relevant regenerative challenge, and also enables direct measurement of nerve conduction velocity across the injury site. Based on comparison of biological, structural, and functional outcomes, we predict that lengthened nerves will display dramatically enhanced regeneration and functional recovery across a 20mm gap following chronic denervation, compared to gaps repaired with autologous grafts. Successful completion of our proposed aims will demonstrate the feasibility and efficacy of nerve lengthening as a novel strategy for regeneration of previously irreparable injured peripheral nerves. We anticipate that these efforts will contribute to improved motor and sensory recovery for injured Veterans.