Neural Regeneration After Supercharged End-to-Side Nerve Transfer: Which Way to Go?

BACKGROUND AND OBJECTIVE: The exact regeneration pattern and directional fiber distribution of donor axons within the recipient nerve after supercharged end-to-side nerve transfer (SETS NT) over time still remains elusive. This study aimed to investigate whether axons preferably regenerate toward an end organ and how the regenerative condition of the recipient nerve influences axonal ingrowth and directional preference. METHODS: SETS NTs were performed in an upper-limb rat model divided into 3 groups: musculocutaneous nerve (MCN) transection and repair (Group A), SETS NT to intact MCN (Group B), and SETS NT to regenerating MCN (Group C), using the ulnar nerve as a donor. Retrograde labeling was conducted 3 and 12 weeks postoperatively to assess direction of donor axon regeneration within the recipient nerve and further validated via histological analyses of nerve samples proximal and distal to the SETS coaptation. RESULTS: Donor axon ingrowth was observed after transfer to intact and regenerating MCNs. At 3 weeks, motor axon distribution was balanced proximally and distally across both groups. By 12 weeks, retrograde labeling exhibited significantly enhanced distal regeneration in Group C, whereas Group B showed decreased total motor neuron counts and no directional preference. Immunohistochemical analysis corroborated these findings for motor fibers, additionally revealing distal preference for afferent fibers in Group C and, unexpectedly, likewise in Group B. CONCLUSION: These results represent the stages of donor axon regeneration after SETS NT. Although early regeneration extended bidirectionally in intact and regenerating nerves, long-term outcomes favored regeneration directionally toward an end organ in the latter by reduction of proximal projections. In addition to robust axonal ingrowth, SETS NT exhibited a nonsignificant reduced distal regeneration capacity compared with end-to-end coaptation. Consequently, it might represent a considerable alternative while simultaneously preserving native nerve regeneration capacities, warranting further investigation to validate these findings in a clinical context.