Translating Novel Peripheral Nerve Allograft Technologies Toward Clinical Use

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PROJECT SUMMARY/ABSTRACT Peripheral nerve injuries (PNIs) that result in nerve gap (segmental-loss, ablation) defects are the most common and costly cause of temporary and permanent nervous system dysfunction. The current best clinical practice to repair ablation PNIs is to suture to host nerves bridging devices such as autografts, acellular nerve allografts or synthetic conduits. Outcomes are poor because the return of any sensation or behavioral recovery depends upon slow and imprecise axonal outgrowths, often taking months to years to re-innervate targets. Viable peripheral nerve allografts (PNAs) are rarely used experimentally or clinically due to the risks of immunosuppressive therapy and graft rejection. To greatly improve current treatments for segmental-loss PNIs, our team will translate our synergistic technologies of localized immunosuppression and polyethylene -induced axon fusion (PEG-fusion) of viable PNAs. PEG-fusion of PNAs rapidly (within minutes) restores cytoplasmic/electrical continuity and prevents Wallerian Degeneration to 40-60% of axons, immediately re-innervates denervated tissues and reliably promotes a highly accelerated return of voluntary behaviors within weeks. PEG-fused chimeric axonal segments within PNAs are not rejected by the host even without immune suppression (ISN) and tissue matching. Localized ISN further reduces the immune response. Translation of PEG-fused PNAs with localized ISN technologies would produce a paradigm shift from current clinical practice of waiting days to months to repair ablation PNIs with autografts, acellular nerve allografts or conduits, where the patient outcome is solely dependent upon axon regeneration. In contrast, repairing ablation PNIs by PEG-fusion/localized ISN of donor allografts applied within three days of injury would generate significantly improved functional outcomes (weeks instead of months/years) produced by PEG- fusion axons and robust regeneration of non-fused axons through the viable PNA enhanced by localized ISN. .