Mechanistic Advancements and Translational Progress in Hyaluronic Acid-Based Scaffolds and Conduits for Peripheral Nerve Regeneration

Peripheral nerve injuries often recover poorly. Hyaluronic acid (HA) biomaterials, with regenerative and anti-fibrotic properties, may augment repair. We performed a PRISMA-guided systematic review of PubMed, Scopus, Web of Science, and Embase (January 2000-August 2024), capturing in vitro, in vivo, and clinical investigations of HA in peripheral nerve repair; data on study context, interventions, and outcomes were extracted. Screening and extraction were performed in duplicate. Forty-eight studies met inclusion criteria. Across in vitro and in vivo models, HA-based biomaterials consistently reduced perineural fibrosis, enhanced axonal regeneration, and improved SFI, CMAP, and NCV compared with conventional repair. Several HA hydrogels and composite conduits achieved functional outcomes approaching autografts, particularly when combined with exosomes, neurotrophic factors, or mechanobiologically tuned scaffolds. Early clinical studies demonstrated safety but remain limited by size and short follow-up. Overall, HA-containing biomaterials appear anti-fibrotic, neuroprotective, and pro-regenerative, supporting their promise as adjuncts for peripheral nerve reconstruction. For this to translate into clinical practice, future work should standardize formulations and dosing, employ rigorous, clinically relevant animal models with long-term endpoints, and advance well-powered, controlled trials to test effectiveness and durability in patients. Clinically, HA platforms show promise as anti-adhesion barriers after neurolysis and as biofunctional fillers/coatings for nerve conduits, but standardized formulations and adequately powered trials are needed to define indications and dosing.