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

项目总结 周围神经损伤(PNI)后的功能恢复只有大约一半的病例发生，即使在状态 艺术外科重建术。一般来说，不良的功能结果源于无法进行当前的修复。 克服漫长的再生距离的策略。当轴突受损时，轴突试图重塑丢失的 通过从损伤的近端向远端神经靶点生长而形成连接。在自然状态下 在再生条件下，轴突以大约1毫米/天的速度生长，通常太慢，无法到达远端靶点 在再生条件退化之前。然而，当被拉出时，轴突的生长速度至少会快10倍。的确， 伸展生长是一种既在发育过程中自然使用的机制，也是宏观尺度上常规利用的机制 机械生物反应器产生用于外科植入的细长轴突轨迹。这些特点表明， 如果伸展生长能够得到充分的控制，它可以使极长的神经缺陷得到快速修复 否则是无法治愈的。其结果将是PNI的范式转换技术， 显著改善了患者的预后。虽然拉伸生长的可行性已经确立，但关键是 将其作为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 可以将轴突拖到远端目标的方法。值得注意的是，最近在微制造方面的进步已经产生了 一种能够完成这项艰巨任务的新技术：微型机器人。这些机器可以完全运转。 自主地提供力量，采取离散的步骤，并且足够小，可以直接对轴突施加张力 在神经纤维内。因此，微型机器人提供了一个重新想象PNI修复的绝佳机会：如果 经过适当的开发，它们可以被植入，附着在轴突上，并将它们拉到远端靶点，重新连接 由于使用武力而失去了联系。在这里，我们建议开发一种新型的微型机器人，它可以治愈 通过将轴突拉到需要去的地方而损坏轴突。作为迈向这一目标的第一步，我们将 系统地完成了两个关键目标：(1)制造新一代带身体的微型机器人 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，以及机器人表面的化学功能化，以优化机器在 身体以足够的速度支持伸展生长。(2)我们将应用这些经过优化的机器人来“拉伸生长”轴突 在体外，在仿生水凝胶内，然后在切除的神经节段内。我们将演示该机器人 可以提供足够的张力来触发轴突伸展生长，从而加速轴突生长 主要的临床影响，以及由此产生的轴突是健康的，能够传输电脉冲，以及 能够形成神经肌肉连接的。综合起来，这些结果将为从根本上证明 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“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.