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An Interim Analysis of Outcomes following 5-cm Median Nerve Defect Repair in Non-Human Primates
Jacqueline M. Bliley, MSc, Wes Sivak, MD PhD, Donald Crammond, MD, Danielle Minteer, BS, Meghan McLaughlin, BA BS, Rich Liberatore, BS, Ryan Schroth, BS, Han Tsung Liao, MD PhD, Tyler Simpson, MSc, Jim Hokanson, BS, Greg Williamson, BS, Casey Tompkins-Rhoades, BS, Kia Washington, MD, Alex Spiess, MD, Douglas Weber, PhD, Kacey G. Marra, PhD.
University of Pittsburgh, Pittsburgh, PA, USA.
Nerve injuries may occur due to trauma, tumor removal, and accidental surgical resection. Rodents are the most common pre-clinical nerve defect models; however, accelerated regeneration of the damaged peripheral nerves in rodents and inability to investigate large gaps are major limitations for the rodent model, making large animal models necessary. The purpose of this project is to identify key considerations in developing a non-human primate (NHP) large-gap peripheral nerve model, as well as to provide an interim analysis of our first set of NHPs.
5-cm median nerve defects were created and repaired by either autograft, decellularized nerve allograft, a poly(caprolactone) conduit, or a poly(caprolactone) conduit with embedded glial cell line-derived neurotrophic factor (GDNF)-containing polymeric microspheres.
Function: Rhesus macaques were trained to retrieve treats from a modified Klüver board utilizing a pinch between their thumb and forefinger. Functional assessments were performed starting at POD 13 and percentage of successful retrieval attempts (defined as a pinch between the thumb and forefinger) were recorded. Treat retrieval time was also quantified.
Electrophysiology: Non-invasive electrophysiology assessments, including somatosensory evoked potentials (SSEPs) and transcranial motor evoked potentials (Tc-MEPs), were used to determine the time course of regeneration. Baseline and post-operative (day 14, 28, 37 and 79) electrophysiological tests were performed. Nerve conduction velocity was obtained prior to and after nerve transection and at the time of explant.
Histology: Explants occurred at POD 43, 90, and 180 to establish a time course for regeneration and to correlate histological and electrophysiological results. Histological analysis of nerve architecture, Schwann cells (S-100), and nerve fiber density (PGP 9.5) was performed. Histomorphometry was performed on nerve sections to determine myelination, axon area, and g-ratio.
Function: Pinch percentage steadily increased following nerve repair. Prior to operation, NHPs utilized a thumb and forefinger pinch 70-80% of time. After surgery, thumb usage was diminished with near-baseline functional values observed at POD 60. A significant increase in retrieval time, after surgery (p<.05) was observed with near-baseline retrieval times at POD 86-105.
Electrophysiology: SSEP negative peak amplitudes were significantly decreased (p<.05) at POD 14, 28, 37, and 79 when compared to baseline with significant recovery at POD 79.
SSEP stimulation thresholds were significantly increased (p<.05) at POD 37 and 79 with significant recovery occurring at POD 79. Abductor pollicis brevis thresholds obtained from Tc-MEP stimulation were significantly increased at POD 37 and 79. CNAPs were first measured at POD 42 and confirmed with stimulation-response curve. Nerve conduction velocity was 40% baseline at POD 90 with significantly increased CNAP stimulation thresholds (p<.05).
Histology: Preliminary S-100 and PGP 9.5 data indicate no notable difference between decellularized nerve allograft and autograft. Histomorphometry data indicate larger numbers of smaller fibers present in regenerated nerve through decellularized nerve allograft with normal bimodal frequency being approached.
Peripheral nerve regeneration proceeded at a rate of 1.35 mm/day, comparable to the rate commonly observed in humans (1-2 mm/day).
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