Nerve Regeneration And Functional Recovery Following Delayed Application Of Regenerative Peripheral Nerve Interface (RPNI)

PURPOSE: Approximately 2 million people in the United States are affected by limb loss, many of whom have physical impairments and activity limitations. The Regenerative Peripheral Nerve Interface (RPNI) is a novel surgical technique that allows individuals to restore extremity function by real-time control of myoelectric prosthetic devices. Following amputation, successful regeneration of axons across an injury site is critical, yet prolonged denervation from an appropriate distal target can severely compromise the functional outcomes. Therefore, substantial delays prior to implantation of RPNI may result in progressive decline in the regenerative ability and meaningful functional recovery of chronically axotomized neurons. This study aimed to determine regenerative capacity and signal amplification ability of 3- and 6-month delayed RPNI following chronic axotomy in a rat model. METHODS: Eighteen Lewis rats were randomly assigned to one of three groups (n=6/group): (1) Prophylactic RPNI, (2) chronic axotomy with 3-month delayed RPNI, or (3) chronic axotomy with 6-month delayed RPNI. After a three-month maturation period, electrophysiologic analyses were conducted to record compound muscle action potentials (CMAPs). RPNIs were then harvested for immunohistochemistry and gene analysis to evaluate muscle reinnervation, the extent of axonal regeneration, and inflammatory markers and cellular senescence in the graft microenvironment. RESULTS: All RPNIs remained viable over the maturation period and the wet RPNI muscle weight did not differ between the groups (p=0.8174). Electrophysiological testing of RPNI recorded amplified CMAP amplitudes (Figure 1). No significant difference was observed in peak-to-peak CMAP amplitudes between prophylactic RPNI (14.071.67 mV), 3-month delayed RPNI (14.102.98 mV), and 6-month delayed RPNI groups (10.591.33 mV) (p=0.478). RNA sequencing identified 1,433 differentially expressed genes shared across neuroma, prophylactic RPNI, and delayed RPNI samples. Genes associated with inflammation, disorganized nerve growth, and pain( S100B, S100A, Mal, Nfasc, SOX10, SCN9a, TRP ) were consistently upregulated in neuroma compared to RPNI at all time points (p<0.001). Vascularization genes (VEGFA, VEGFB) were significantly downregulated in neuroma compared to RPNI at all time points (p<0.001). CONCLUSION: RPNIs can mitigate the adverse impact of chronic axotomy and elicit biologically amplified signals to restore extremity function in the setting of chronic axotomy and delayed treatment. *Source: https://ps-rc.org/meeting/Program/2026/51.cgi*