Novel Modular Nerve Lengthening Device for Peripheral Nerve Regeneration

用于周围神经再生的新型模块化神经延长装置

• 批准号: 9172207
• 负责人: Sameer B. Shah
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9172207
• 关键词: Acceleration; Acute; Address; Afferent Neurons; Animal Model; Autologous; Autologous Transplantation; Biological; Biomedical Engineering; Blast Injuries; Bypass; Cellular biology; Cervical spinal cord injury; Chronic; Clinical; Defect; Denervation; Device Designs; Devices; Distal; Environment; Goals; Gold; Growth; Hybrids; Implant; In Vitro; Injury; Internal Fixators; Isogeneic graft; Length; Limb structure; Measurement; Modeling; Morbidity - disease rate; Motor; Motor Neurons; Natural regeneration; Nerve; Nerve Regeneration; Neural Conduction; Neuronal Plasticity; Neurons; Oryctolagus cuniculus; Pain; Peripheral Nerves; Peripheral nerve injury; Physiology; Population; Pre-Clinical Model; Rattus; Recovery; Recovery of Function; Regenerative Medicine; Rehabilitation therapy; Research; Second Look Surgery; Sensory; Site; Soldier; Source; Spinal Cord; Spinal cord injury; Stretching; Structure; Testing; Therapeutic; TimeLine; Tissues; Translations; Traumatic injury; Veterans; arm; base; chronic pain; clinical application; clinically relevant; functional outcomes; improved; in vivo; injured; innovation; motor recovery; nerve gap; nerve injury; neuronal growth; novel; novel strategies; outcome forecast; peripheral nerve regeneration; programs; public health relevance; regenerative; repaired; response; scaffold; sciatic nerve; secondary outcome

 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.

 描述（由申请人提供）： 周围神经损伤是士兵肢体爆炸损伤的结果，而宫颈脊髓损伤后的次要结果。从周围神经损伤中恢复功能通常很差，导致运动功能受损，感觉丧失和疼痛。退伍军人进一步使恢复的临床复杂性和预后更加复杂，退伍军人在与武装部队分离后对其受伤进行了手术修复或修订。该时间表导致慢性神经损伤，这与急性损伤产生了根本不同的临床情况，并且缺乏治疗和康复策略。通过VA RR＆D脊髓损伤和再生医学计划的优先考虑，神经再生和脊髓康复的优先次序，强调了退伍军人人口的慢性神经功能的重要性。我们已经为神经再生开发了一种创新的策略，该策略利用了固有的神经残势的继承能力，以响应拉伸变形（拉伸）。我们的新型模块化内部固定装置以受控的方式延长了向远端树桩的近端树桩，并且将比其他策略（包括金标准的自体移植物）更快地促进神经残端的重新连接。重要的是，这种神经再生的加速也将使更多的盘式连接性，这尤其是 绕过慢性损伤神经的远端树桩的大刀至关重要，这严重抑制了再生。我们假设，更快，更刻板的重新联系将反过来 增强电机和感觉功能恢复。为了实现这些目标，我们将使用一种集成的跨学科方法来解决两个具体目标。在AIM 1中，我们将在急性损伤和慢性神经膜上检查中等水平的拉伸负荷对中等10mm大鼠坐骨神经缺损的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，实际地测试提出的概念，我们假设在急性和慢性损伤组中，与自动图相比，在近端神经损伤上施加的中等水平的连续神经菌株将加速神经再生以及感觉和运动功能恢复。通过比较一系列的生物，结构和功能结果，将通过统计评估功效。在AIM 2中，我们将检查中等水平的拉伸负荷对神经再生和功能恢复的影响，在慢性神经疗法后，大量20mm兔子坐骨神经缺陷。兔模型中的较长长度尺度会引起更临床相关的再生挑战，并且还可以直接测量整个损伤部位的神经传导速度。基于对生物，结构和功能结果的比较，我们预测，与自体移植物修复的间隙相比，延长的神经将在20mm间隙中显示出大幅增强的再生和功能恢复。成功完成我们提出的目标将证明神经延长的可行性和效率，作为先前无法弥补的受伤外周神经的新策略。我们预计这些努力将有助于改善受伤的退伍军人的运动和感觉恢复。