Dual-Modality Bioactive Repair of Facial Nerve Injury Using PEG-Mediated Axonal Fusion and Extracellular Vesicles-Enriched Human GMSC Secretome

Abstract Facial nerve injuries may cause severe functional deficits with limited recovery after standard neurorrhaphy. Polyethylene glycol (PEG)–mediated axonal fusion enables immediate structural reconnection and prevents Wallerian degeneration, while gingiva-derived mesenchymal stem cell (GMSC) secretome provides a potent, acellular trophic stimulus that supports neuronal survival and remyelination. We report a dual-modality bioactive repair interface integrating PEG fusion with human GMSC secretome to accelerate neural repair. Fluorescently labeled secretome components were rapidly internalized by neurons in vitro within 24 hours. Also, GMSC secretome preserved axonal structure in a dose-depedent manner in a rat sciatic nerves ex vivo . In a rat facial nerve transection model, PEG fusion restored immediate compound muscle action potentials (CMAPs) and, at 7 days post-repair, PEG fusion and GMSC secretome preserved large-caliber myelinated axons. In particular, secretome treatment increased axon density and myelination, while the combined PEG + secretome approach produced the highest axon density and axonal area. By 42 days, combined treatment yielded the greatest total axon and myelinated axon densities, organized myelin architecture, and superior functional recovery, reflected by increased CMAP amplitudes. These findings define a clinically translatable, cell-free repair platform that couples immediate axonal fusion with trophic signaling to promote rapid and durable recovery after cranial and peripheral nerve injury.