Advancing Peripheral Nerve Regeneration (Nerve SPACE 2025).

Peripheral nerve injuries remain a major clinical challenge due to slow axonal regeneration, rapid Wallerian degeneration (WD), and degeneration of target organs prior to reinnervation. Where are we now?: Strategies to enhance regeneration can be broadly divided into three categories: preventing or delaying WD, speeding up axonal regeneration, and improving the molecular environment at the injury site. Approaches to delay WD include polyethylene glycol-mediated axonal fusion, which may restore early axonal continuity and conduction, and inhibition of sterile alpha and TIR motif-containing 1, the central executioner of WD, with small-molecule inhibitors now in clinical trials. Methods to accelerate axon regrowth include brief intraoperative electrical stimulation, which activates regeneration-associated gene programs and improves motor and sensory recovery in both preclinical and early clinical studies, and pharmacologic augmentation with 4-aminopyridine, which enhances conduction across demyelinated fibers and promotes remyelination. Where do we need to go?: Optimizing the local microenvironment through cellular and molecular adjuncts, including mesenchymal stem cells, Schwann cells, exosomes, surgical angiogenesis, and local delivery of neuroregenerative drugs such as FK506, has also shown promise in experimental models. Across all approaches, progress is hindered by heterogeneous outcome measures, a lack of standardized protocols, and barriers to multicenter collaboration. How do we get there?: Coordinated efforts among academia, industry, and regulatory agencies are needed to standardize methodologies, develop objective outcome measures, and enable well-structured multicenter clinical trials to achieve meaningful clinical translation. Ultimately, meaningful functional recovery will depend on integrating complementary approaches and bridging gaps in mechanistic understanding, delivery systems, and trial design, creating the synergy needed to translate promising therapies from bench to bedside.