Microscopic Robot-Assisted Axon Regrowth for Rapid Repair of Peripheral Nerve Injuries

显微机器人辅助轴突再生快速修复周围神经损伤

• 批准号: 10453290
• 负责人: Marc Miskin
• 金额: $ 23.72万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453290
• 关键词: 3-Dimensional; Address; Adopted; Architecture; Axon; Biomimetics; Bioreactors; Cell Culture Techniques; Cells; Characteristics; Chemicals; Clinical; Complex; Defect; Development; Distal; Electrophysiology (science); Environment; Europe; Eye; Future; Gait; Generations; Goals; Growth; Health; Hydrogels; Implant; In Vitro; Injury; Leg; Length; Locomotion; Measures; Mechanics; Medical; Medicine; Microfabrication; Microscopic; Modeling; Morphology; Motion; Muscle; Muscle function; Natural regeneration; Nerve; Nerve Fibers; Nerve Tissue; Neurites; Neuromuscular Junction; Neurons; Operative Surgical Procedures; Optic Nerve; Outcome; Patient-Focused Outcomes; Patients; Pattern; Peripheral Nervous System; Peripheral nerve injury; Physiologic pulse; Positioning Attribute; Protocols documentation; Race; Recovery of Function; Research; Robot; Robotics; Role; Series; Shapes; Shoulder; Side; Site; Solid Neoplasm; Somatotype; Speed; Stretching; Surface; Synapses; Technology; Testing; Time; Tissue Model; Tissues; United States; Walking; arm; axon growth; axon injury; axon regeneration; clinical application; design; functional outcomes; functional restoration; healing; implantation; improved; in vivo; injury and repair; microrobot; nanofabrication; nerve damage; nerve injury; nerve repair; neuromuscular; neurosurgery; new technology; novel strategies; peripheral nerve repair; reconstruction; regenerative; reinnervation; relating to nervous system; repair strategy; repaired; robot assistance; stem; success

PROJECT SUMMARY Functional recovery following peripheral nerve injury (PNI) only occurs in about half of all cases, even after state of the art surgical reconstruction. Generally, poor functional outcomes stem from the inability of current repair strategies to overcome lengthy regenerative distances. When damaged, axons attempt to reform lost connections by growing from the proximal side of the injury towards the distal nerve target. Under natural regenerative conditions, axons grow at a rate of roughly 1 mm/day, which is often too slow to reach distal targets before regenerative conditions degrade. However, when pulled, axons can grow at least 10x faster. Indeed, stretch growth is a mechanism both naturally used during development and routinely exploited by macroscale mechanobioreactors to produce elongated axon tracks for surgical implantation. These characteristics show that if stretch growth can be adequately controlled, it could enable rapid repair of extremely long neural defects that would otherwise be impossible to heal. The result would be a paradigm shifting technology for PNI that dramatically improves patient outcomes. While the feasibility of stretch growth is well established, the key challenge for adopting it as a clinical solution to PNI is implementing tension on an axon at the injury site in a way that can tow the neurite to its distal target. Remarkably, recent advances in microfabrication have produced a new technology capable of performing this difficult task: microscopic robots. These machines can operate fully autonomously, supply force, take discrete steps and are small enough to directly apply tension to an axon from within a nerve fiber. Thus, microscopic robots provide a remarkable opportunity to reimagine PNI repair: if appropriately developed, they could be implanted, attach to axons, and pull them to the distal target, rewiring the lost connection by application of force. Here we propose developing a new breed of microrobots that can heal damaged axons by literally pulling them where they need to go. As the first steps towards this goal, we will systematically accomplish two key objectives: (1) We will fabricate a new generation of microrobots with body types and locomotion strategies optimized for navigating in tissue. We will study the role of shape, leg position, gait pattern, and chemical functionalization of the robot's surface to optimize machines for reliable motion in the body at sufficient rates to support stretch growth. (2) We will apply these optimized robots to “stretch-grow” axons ex vivo, within biomimetic hydrogels and then within excised nerve segments. We will demonstrate that the robot can supply sufficient tension to trigger axon stretch growth, that they speed up axon growth enough to have major clinical impact, and that the resulting axons are healthy, capable of transmitting electrical pulses, and capable of forming neuromuscular junctions. Combined, these results will provide proof of concept for a radically new approach to PNI repair, and an outstanding “first indication” of microrobot technology in a clinical application.

项目概要 即使在状态恢复后，周围神经损伤 (PNI) 后的功能恢复也仅发生在大约一半的病例中 一般来说，不良的功能结果源于当前修复的无力。 克服长再生距离的策略当受损时，轴突会尝试重新恢复丢失。 在自然状态下从损伤的近侧向远端神经目标生长连接。 再生条件下，轴突以大约 1 毫米/天的速度生长，通常太慢而无法到达远端目标 然而，在再生条件退化之前，轴突的生长速度至少可以快 10 倍。 拉伸生长是一种在开发过程中自然使用的机制，并且通常被宏观尺度利用 机械生物反应器可产生用于手术植入的细长轴突轨迹。 如果拉伸生长能够得到充分控制，它可以快速修复极长的神经缺陷 否则将无法治愈，其结果将是 PNI 的范式转变技术。 虽然拉伸生长的可行性已得到充分证实，但关键是可以显着改善患者的治疗效果。 采用它作为 PNI 的临床解决方案的挑战是在损伤部位的轴突上施加张力 值得注意的是，微加工的最新进展已经产生了可以将神经突拖到其远端目标的方法。 能够执行这项艰巨任务的新技术：这些机器可以完全运行。 自主地提供力，采取离散步骤，并且足够小，可以直接向轴突施加张力 因此，微型机器人为重新构想 PNI 修复提供了绝佳的机会： 如果开发得当，它们可以被植入，附着在轴突上，并将它们拉到远端目标，重新布线 在这里，我们建议开发一种可以治愈的新型微型机器人。 通过将轴突拉到需要去的地方来损坏轴突作为实现这一目标的第一步，我们将 （1）我们将制造新一代具有本体的微型机器人 为在组织中导航而优化的类型和运动策略我们将研究形状、腿部位置、 步态模式和机器人表面的化学功能化，以优化机器以实现可靠的运动 （2）我们将应用这些优化的机器人来“拉伸生长”轴突 我们将在离体、仿生水凝胶内以及切除的神经段内演示该机器人。 可以提供足够的张力来触发轴突拉伸生长，它们加速轴突生长足以 主要的临床影响，并且由此产生的轴突是健康的，能够传输电脉冲，并且 结合起来，这些结果将为从根本上形成神经肌肉接头提供概念证明。 PNI 修复的新方法，以及微型机器人技术在临床应用中的杰出“首次适应症”。