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Controlling Axonal Regeneration Following Rat Sciatic Nerve Transection Reduces Neuroma Formation
Miles Bichanich, BS1; Thomas Hong, MS1; Daniel Hunter, RA1; Lauren Schellhardt, BA1; Ying Yan, MD, PhD1; Susan Mackinnon, MD1, Thomas Davis, PhD2,3; Scott Tintle, MD2,3; Matthew Wood, PhD1; Amy Moore, MD1
1Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, Saint Louis, MO, 2Naval Medical Research Center, Regenerative Medicine Department, Silver Spring, MD; 3USU Walter Reed Department of Surgery, Uniformed Services University, Bethesda, MD
Introduction: The treatment of neuroma is a challenging clinical problem despite existing management approaches. Investigation of acellular nerve allografts (ANAs) as a tool to bridge nerve gaps has shown an unintentional, controlled termination of axonal regrowth within long (>3cm) ANAs. We hypothesized that long ANAs can be beneficially utilized to "cap" injured nerve and guide regenerating axons to a gradual termination effectively minimizing neuroma formation.
Materials & Methods: Thy1-GFP and Lewis rats were randomized to eight groups which received: 1) nerve transection alone, 2) traction neurectomy, 3) transection and 0.5 cm closed end silicone conduit, 4) transection and 0.5 cm ANA, 5) transection and 2.5 cm ANA, 6) transection and 5.0 cm ANA, 7) transection and proximal nerve crush, or 8) transection, proximal nerve crush and 5.0 cm ANA. In all groups, the distal nerve stump was ligated and the distal nerve turned from the proximal end to remove any trophic influence. The Thy1-GFP rat nerves were serially imaged for 20 weeks to provide a visual history of regeneration. Lewis rats were sacrificed at 5 and 20 weeks for quantitative nerve histology and IHC. ANOVA with post hoc analysis were performed to evaluate significance (p<0.05).
Results: GFP animals that received transection alone, traction neurectomy, or transection and crush showed signs of neuroma with chaotic nerve regeneration (multidirectional axonal regrowth) extending from the proximal stump as early as 4 weeks confirmed with histology. At 5 weeks, axons grew through the entirety of the 0.5 cm ANAs, with neuroma formation extending beyond the grafts. In the 2.5 and 5.0 cm ANAs, robust axonal regeneration was demonstrated in the proximal portions of the grafts with a gradual tapering of regeneration as it moved distally, and axons failed to grow beyond the grafts. At 20 weeks, gross visualization of Thy1-GFP labeled axons demonstrates that regeneration dwindles and terminates within 5.0 cm ANAs by 5 months without neuroma formation. Further histological analysis is ongoing, as are additional 20 week experiments to evaluate controlled termination.
Conclusions: Following nerve transection, long ANA "caps" can be used to control aberrant axonal growth, the hallmark of neuroma formation. Therefore, the "capping" of a transected nerve with a long ANA is a potential surgical tool in the future of neuroma management.
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