Peripheral nerve repair: innovations and future directions

Peripheral nerve injuries (PNIs) remain a major clinical and socioeconomic challenge, frequently resulting in motor weakness, sensory loss, and chronic neuropathic pain that cause long-term disability and restrict daily function. Functional recovery is limited by slow axonal regrowth, Wallerian degeneration, interstitial fibrosis, and progressive denervation-induced muscle atrophy. Although microsurgical epineurial repair and autologous nerve grafting are standard treatments, clinical outcomes remain inconsistent, especially in long-gap or delayed repairs. These limitations underscore the need for more effective regenerative strategies that address both the structural and biological barriers to nerve recovery.

Contemporary research on PNIs focuses on four interconnected domains: structural reconstruction, biological acceleration, functional remodelling, and anatomical restoration. Advanced nerve-guidance conduits offer biomimetic, aligned pathways that reduce axonal misdirection and complement microsuture or autograft repair. Biological approaches, including localized delivery of neurotrophic factors, mesenchymal stem cells, induced-pluripotent stem cell derivatives, and their exosomes, enhance Schwann cell reprogramming, angiogenesis, and pro-regenerative immune polarization while reducing risks associated with live cell transplantation. Non-invasive biophysical stimulation modalities, such as electrical stimulation, magnetic fields, photobiomodulation, low-intensity pulsed ultrasound, and piezoelectric scaffolds, further promote axonal growth and neurotrophic signaling. Emerging integrated strategies that combine stem cell-derived exosomes with physical cues demonstrate synergistic regeneration in preclinical models, representing promising avenues for treating critical-sized nerve gaps. Multi-omics technologies, including transcriptomics, proteomics, metabolomics, and spatial profiling, have deepened mechanistic understanding of Schwann cell plasticity, axon-glia communication, and injury-induced inflammatory dynamics. However, clinical translation remains constrained by heterogeneity in study design, biomaterial manufacturing, regulatory requirements, and the lack of validated biomarkers for monitoring nerve regeneration. Overcoming these obstacles will require coordinated efforts across surgery, biomaterials engineering, stem cell biology, pharmacology, neuromodulation, and rehabilitation medicine.

Recent progress in biomaterial conduits, cell-free biologics, and biophysical stimulation is transforming PNI treatment and providing options that surpass conventional microsurgical repair. Continued advancement will require reliable biomarkers, standardized production and evaluation methods, and well-designed randomized controlled trials. Coordinated collaboration across research, clinical practice, industry, and regulatory agencies is essential to develop safe, effective, and widely applicable neuroregenerative therapies that restore meaningful function after peripheral nerve injury.