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Evaluating the Mechanisms of the Supercharged End-to-Side (SETS) Nerve Transfer in a More Accurate Rodent Chronic Denervation Model
Zachary Zamore
*, Kitae E. Park, Jeffrey Khong, Rachana Suresh, John Nguyen, Jared Zhang, Christopher Erb, Keith Kuo, Sami Tuffaha
Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
Background:The supercharged end-to-side (SETS) nerve transfer may enhance functional by introducing donor axons that "babysit" target muscles until recipient axons arrive and prevent chronic denervation. We used fluorescent-protein-encoding AAVs to label donor and recipient axons and assess their contributions to reinnervation.
Methods:A rat model was developed to simulate clinical chronic denervation. In the experimental group, the right median nerve was transected at mid-brachium and coapted to a reversed 2 cm contralateral sciatic nerve graft, with its distal end implanted into the pectoralis major to prevent regeneration. A SETS transfer from ulnar to median nerve was performed via an epineurial window. Ten weeks later, the graft was repaired to the distal median nerve.
Controls included a negative control (no SETS transfer), a SETS-only control (no graft repair), and a positive control (immediate repair with graft). At eight weeks, intra-neural injections of AAV.Php.EB.Tdtomato (ulnar) and AAV.Php.EB.EGFP (median) were performed. At 22 weeks, nerves were stimulated at 100 Hz and grip strength was measured. Statistical analysis was conducted using Kruskal-Wallis with Dunn's post-hoc test (α=0.05).
Results:Grip strength from median nerve stimulation was significantly greater in the experimental group than in the negative control (1.89 N vs. 1.31 N, p<0.05), supporting a SETS-mediated "babysitting" effect. Robust AAV expression enabled visualization of motor endplate innervation from donor and recipient axons.
Conclusion:This model overcomes size limitations in rodents and accurately reflects clinical timing of donor vs. recipient reinnervation. SETS transfer enhanced strength recovery after delayed repair, providing the first functional evidence of a babysitting effect. Ongoing histology will confirm neuromuscular junction reinnervation from both axon sources.
