Grants We Funded

Abstract
Peripheral nerve injury (PNI) is a common and challenging problem with many patients experiencing persistent deficits despite optimal intervention. Poor outcomes result primarily from prolonged periods of latency prior to reinnervation. Over time, the absence of target muscle innervation causes irreversible atrophy that limits functional motor recovery. Further hindering outcomes, chronically denervated Schwann cells (SC) within the distal nerve stump senesce and lose their capacity to support regenerating axons.
Augmentation of the growth hormone (GH) axis has emerged as a promising therapeutic approach, the effects of which are primarily mediated by Insulin-like Growth Factor 1 (IGF-1). IGF-1 acts on neurons to speed axonal regeneration, and importantly, also acts independently on denervated muscle and SCs to limit denervation induced atrophy and senescence, respectively.

Despite promising experimental results, these therapies have not reached clinical practice. This is largely due to the multitude of side effects caused by systemic administration, in addition to the need for daily re-dosing injections.

To overcome these obstacles, we developed biodegradable nanoparticles (NPs) to encapsulate and slowly release small amounts of IGF-1 over a prolonged period of time. These can be administered locally to desired tissues in a depot-like fashion to mitigate systemic effects and eliminate the need for frequent re-dosing.

The first aim of this project is to mechanistically evaluate the effects of locally delivered IGF-1 NPs on denervated muscle and nerve, and to determine optimal dosing. IGF-1 NPs will be administered in a depot-like fashion to denervated muscle groups and along the distal nerve stump. Histologic analysis will assess the degree of muscle atrophy and SC senescence.

The second aim of this study will evaluate the effects of IGF-1 NPs on functional recovery after a period of denervation. We will use a forearm chronic denervation model in which the median nerve is transected and left in discontinuity for a period of time, followed by a proximal ulnar nerve to distal median nerve transfer. The experimental group will receive IGF-1 NP therapy, administered at the site of nerve transection, around the exposed distal nerve stump, and injected into the denervated forearm muscle group. The results from this study will provide important information on the efficacy of local, sustained release IGF-1 and its ability to offset the effects of dene

Biography
Dr. Philip Hanwright is an integrated resident in the Department of Plastic and Reconstructive Surgery at Johns Hopkins. He studied biochemistry at Miami University before obtaining his medical degree from Northwestern University’s Feinberg School of Medicine. Upon completion, he began his plastic surgery training at Johns Hopkins in 2015, and is currently in his second year of training. Philip has a broad research background and has previously investigated tumor pathogenesis and early biomarker identification at the Lerner Research Institute and Miami University, respectively. More recently, he has been investigating clinical outcomes and building prediction models in plastic surgery. In July 2017, he will begin a dedicated year completing his research fellowship at the Johns Hopkins Peripheral Nerve Lab.