UC San Diego

Peripheral nerve injuries, particularly transection injuries, are difficult to repair and treatment strategy is decided on a case-by-case basis. When there is a large gap between the proximal and distal stumps of the nerve, the use of a graft to bridge the distance between the stumps is the current clinical gold standard of treatment. However, grafts are often either expensive (allografts) or necessitate loss of function (autografts). Axons must also grow from the proximal stump, through the graft, to the distal stump, and so outcomes are often poor. Correspondingly, substantial clinical and pre-clinical evidence demonstrates that graft-free end-to-end repair of nerve endings would be preferable when possible. In this dissertation, I examine lengthening of injured peripheral nerves followed by end-to-end repair as a new method to bridge large nerve gaps, using a novel device to directionally stretch the proximal nerve stump. Though tension is often considered to be damaging to the nerve, studies have shown that axons can in fact grow more quickly when under modest tension. We first showed that for moderate gaps, an end-to-end nerve repair under tension had equivalent functional and growth outcomes when compared to tension-free repairs. Following an acute large-gap injury, nerves that were lengthened had equal or better outcomes when compared to a graft. Following a chronic large-gap injury, nerves that were lengthened had equivalent outcomes when compared to a graft, but, consistent with prior literature, outcomes as a whole were inferior to those following acute injury. Finally, we used proteomic profiling to probe biological pathways upregulated during tension-based regeneration. Cumulatively, we found that nerve lengthening followed by end-to-end repair is a new and potentially efficacious approach for nerve regeneration. Future work will examine the possibility of lengthening the nerve over very large gaps as well as new strategies for regeneration following chronic injury.