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

项目摘要 周围神经损伤（PNI）后的功能恢复仅发生在约一半的病例中，即使在状态 外科重建的最高水平一般来说，不良的功能结果源于目前的修复能力不足 克服再生距离过长的策略。当受损时，轴突试图改革的努力失败了 通过从损伤的近端侧向远端神经靶生长来形成连接。在自然 在再生条件下，轴突以大约1 mm/天的速率生长，这通常太慢而不能到达远端目标 在再生条件恶化之前。然而，当被拉动时，轴突的生长速度至少可以快10倍。的确， 拉伸生长是一种在发育过程中自然使用的机制， 机械生物反应器以产生用于外科植入的细长轴突轨迹。这些特征表明， 如果能够充分控制拉伸生长，就能够快速修复极长神经缺损， 否则是不可能治愈的其结果将是PNI的范式转变技术， 极大地改善了患者的治疗效果。虽然拉伸增长的可行性已经很好地建立，但关键是 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， 将神经突拖向远端目标值得注意的是，最近在微细加工方面的进展已经产生了 一项新技术能够完成这项艰巨的任务：微型机器人。这些机器可以充分运转 自主地，供应力，采取离散的步骤，并且小到足以直接向轴突施加张力 在神经纤维中。因此，微型机器人提供了一个重新设想PNI修复的绝佳机会：如果 适当地开发，它们可以被植入，附着在轴突上，并将它们拉到远端目标，重新连接 因用力而失去联系。在这里，我们建议开发一种新的微型机器人， 破坏轴突，把它们拉到需要去的地方作为实现这一目标的第一步，我们将 系统地完成了两个关键目标：（1）我们将制造新一代的微型机器人与身体 类型和运动策略优化在组织中导航。我们将研究形状，腿的位置， 步态模式和机器人表面的化学功能化，以优化机器， 身体以足够的速率支持拉伸生长。(2)我们将把这些优化的机器人应用于“拉伸生长”轴突 离体，在仿生水凝胶内，然后在切除的神经节段内。我们将证明机器人 可以提供足够的张力来触发轴突的伸展生长，它们可以加速轴突的生长， 主要的临床影响，并且所产生的轴突是健康的，能够传输电脉冲， 能够形成神经肌肉接头。结合起来，这些结果将提供一个从根本上证明概念 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“第一适应症”。

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.