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

项目总结

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.