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.

项目摘要 外周神经损伤后的功能恢复（PNI）仅发生在所有情况的一半，即使在状态之后 通常，由于目前的维修无法进行功能不佳的结果 克服冗长再生距离的策略。当损坏时，轴突试图丢失 通过从损伤的近端向远端神经靶标生长来连接。在自然之下 再生条件，轴突以大约1毫米/天的速度生长，这通常太慢，无法达到不同的目标 在再生条件下降之前。但是，当拉动时，轴突至少可以更快地生长10倍。的确， 伸展生长是一种在开发过程中自然使用的机制，并且经常被宏观探索 机器人反应器产生细长的轴突轨道进行手术植入。这些特征表明 如果可以充分控制拉伸生长，则可以快速修复极长的神经缺陷 否则将无法治愈。结果将是PNI的范式转移技术 动态改善患者的预后。虽然伸展增长的可行性已经很好，但关键 采用它作为PNI的临床解决方案的挑战是在伤害部位的轴突上实现张力 可以将神经蛋白拖到不同目标的方式。值得注意的是，微加工的最新进展已产生 一种能够执行这项艰巨任务的新技术：微观机器人。这些机器可以完全运行 自主，供应力，采取离散步骤并且足够小，可以直接在轴突上施加张力 在神经纤维中。这是微观机器人为重新想象PNI维修提供了一个了不起的机会：如果 适当地开发，可以植入它们，附着在轴突上，并将其拉到不同的目标，重新布线 通过施加武力而失去连接。在这里，我们建议开发一种可以治愈的新型微型机器人 从字面上将它们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 系统地实现了两个关键目标：（1）我们将与身体造成新一代的微型机器人 针对组织导航优化的类型和运动策略。我们将研究形状，腿部位置的作用， 步态模式和机器人表面的化学功能化，以优化机器以在 身体以足够的速度支持扩展生长。 （2）我们将将这些优化的机器人应用于“拉伸”轴突 离体，在仿生水凝胶中，然后在极好的神经段内。我们将证明机器人 可以提供足够的张力来触发轴突拉伸生长，使它们加快轴突的生长足以具有 主要的临床影响，所产生的轴突健康，能够传输电脉冲，并且 能够形成神经肌肉连接。结合在一起，这些结果将为彻底提供概念证明 PNI维修的新方法，以及临床应用中微型机器人技术的出色“第一指示”。