Polyethylene glycol fusion repair of peripheral nerve injuries

Peripheral nerve injury results in debilitating physical impairments, including loss of motor, sensory, and autonomic functions, which are often permanent. The greatest advancement to clinical repair of traumatic peripheral nerve injury came in the 19th century with the implementation of microsurgical suturing to re-approximate severed nerve ends. However, even upon surgical repair, the distal nerve segment undergoes degeneration and therefore requires the slow regeneration of proximal axons (at a rate of 1-2mm per day) for restoration of functions. This results in slow and often unsatisfactory recovery. To overcome these obstacles, we have developed a method of nerve repair utilizing the fusogen polyethylene glycol (PEG) to fuse severed axons and rapidly restore lost functions. The work within this dissertation characterizes the mechanisms underlying PEG-fusion restoration of function for injuries to peripheral nerves. Chapter 1 provides background on the events that occur after nerve injury, current clinical strategies aimed at improving nerve function after injury, and the development of the PEG-fusion procedure from previously published work. Chapter 2 examines the functional and morphological changes that occur after PEG-fusion of transected peripheral nerves, extending our mechanistic understanding of PEG-fusion mediated repair. Here, we found PEG-fusion restores axonal continuity across the lesion site, Wallerian degeneration is prevented for many distal axons, and muscle innervation is maintained. Chapter 3 examines alterations in motoneuron morphology and circuity after PEG-fusion repair of peripheral nerves. PEG-fusion repair results in no changes to motoneuron soma size or number but does alter dendritic arborizations. Surprisingly, PEG-fusion results in the mismatch of proximal axons and distal muscle and sensory targets yet results in significant functional recovery. Chapter 4 highlights studies to translate our findings to the clinical setting. Here we have optimized the PEG-fusion procedure using a series of FDA approved solutions and precise surgical resection of axons after initial severance, leading to increased functional recovery and easy adaptation of methods for clinical trials. Chapter 5 provides a summary of the dissertation and future directions of the research, including the adaptation of PEG-fusion technology for vascularized composite allotransplantation and spinal cord injury.