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Axons Preferentially Regenerate Across the Most Proximal Nerve Bridge in a Model of Side-to-Side Bridging for Protection of Denervated Nerves
Alison Snyder-Warwick, MD1, Tessa Gordon2, Edward H. Liu2, Tanya Cellucci2, Cameron D. Chiang2, Christine Lafontaine2, Stephen W. P. Kemp2 and Gregory H. Borschel3
1Division of Plastic and Reconstructive Surgery, Washington University in St. Louis, St. Louis, MO, 2Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada, 3Division of Plastic and Reconstructive Surgery, Hospital for Sick Children, Toronto, ON, Canada
PURPOSE: Muscle denervation remains a challenge for the reconstructive peripheral nerve surgeon, particularly when nerve injury occurs distant from the target muscle. Prolonged denervation periods result in poor, if any, functional recovery. Recent studies have suggested Schwann cell denervation accounts for poor axonal regeneration after chronic nerve injury. We hypothesize that a denervated nerve stump can be protected via side-to-side nerve bridges to an uninjured adjacent nerve with healthy Schwann cells. In this study we demonstrate axonal regeneration through side-to-side nerve bridges, with axonal fibers preferentially regenerating through the most proximal nerve bridge when three bridges are utilized. METHODOLOGY: The common peroneal (CP) and tibial (TIB) nerves were exposed in adult transgenic Thy1-GFP Sprague Dawley rats. The CP nerve was transected proximally, and the transected ends were sutured to surrounding muscle to prevent regeneration. A period of 2-3 weeks of denervation followed before the CP and TIB nerves were bridged with three 4mm segments of reversed CP nerve grafts from the contralateral limb. Bridges were placed end-to-side to both the CP and TIB nerves via corresponding epineurial windows to create side-to-side bridges positioned perpendicularly at 3-4mm intervals between the two nerves. Coaptations were performed with Tisseel glue consisting of equal volumes of thrombin and fibrinogen. Nerve bridges were then harvested at 1, 2, 4, 8, and 12 week time points, with a minimum of four animals evaluated at each time point. Nerves were analyzed via fluorescent microscopy and histomorphometry to determine myelinated axonal counts. RESULTS: The presence of Wallerian degeneration decreased in bridges over time, while regenerating axon numbers and myelin thickness increased over time. Greater numbers of axons were present in the proximal nerve bridges compared to the middle and distal nerve bridges. At 4 weeks, an average of 101 myelinated fibers were present in the proximal bridge compared to 30 fibers in the middle bridge (p<0.068) and 12 fibers in the distal bridge (p<0.021). Gross fluorescence was qualitatively most intense in the proximal nerve bridge at time of harvest. Current histomorphometric analysis of later time points is underway. CONCLUSIONS: Axonal regeneration occurs across side-to-side nerve bridges with preferential regeneration through the proximal nerve bridge. This model provides initial data to confirm the feasibility of this technique in protection of chronically denervated nerve stumps. Additional investigations regarding Schwann cell activity in this model are ongoing.
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