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四肢爆炸伤的后果，也是颈脊髓损伤的继发结果。周围神经损伤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，他们的受伤在脱离武装部队后进行手术修复或翻修。该时间轴导致慢性神经损伤，这导致与急性损伤根本不同的临床情况，并且缺乏治疗和康复策略。VA RR&D脊髓损伤和再生医学计划优先考虑神经再生和脊髓康复，突出了退伍军人群体增强慢性失神经支配神经功能的策略的重要性。 我们开发了一种神经再生的创新策略，该策略利用了完整的近端神经残端的固有能力，以响应拉伸变形（拉伸）而生长。我们的新型模块化内固定器装置以受控的方式将近端残端向远端残端延长，并且将比其他策略（包括金标准自体移植物）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远端连接成为可能，这是特别重要的。 对于绕过严重抑制再生的慢性损伤神经远端残端的大片区域至关重要。我们假设，更快和更远的重新连接，反过来， 促进运动和感觉功能恢复。 为了实现这些目标，我们将使用综合的，跨学科的方法来解决两个具体目标。在目标1中，我们将研究在急性损伤和慢性去神经后，中等水平的拉伸负荷对中度10 mm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，这使我们能够有效地和实际地测试我们提出的概念，我们假设在急性和慢性损伤组中，施加在近端神经残端上的中等水平的连续神经应变将加速神经再生以及与自体移植物相比的感觉和运动功能恢复。将通过比较生物学、结构和功能结局的综合组合，对疗效进行统计学评价。在目标2中，我们将研究中等水平的拉伸负荷对大面积20 mm兔坐骨神经缺损的神经再生和功能恢复的影响。兔模型中较长的长度尺度产生了更临床相关的再生挑战，并且还能够直接测量整个损伤部位的神经传导速度。基于生物学、结构和功能结局的比较，我们预测，与自体移植物修复的间隙相比，在慢性去神经支配后，延长的神经将在20 mm间隙内显示出显著增强的再生和功能恢复。 我们提出的目标的成功完成将证明神经延长作为一种新的策略，以前无法修复的损伤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。