Cod-derived collagen peptides with nerve-regeneration function enable sustained release through 4-Arm PEG hydrogel for peripheral nerve repair

• A method for the efficient extraction and characterization of collagen peptides from cod skin was provided. • Collagen peptides were encapsulated in the 4-arm PEG hydrogel to achieve the adjustable sustained release. • Evidence of enhanced Schwann cell proliferation, neurite outgrowth, and myelination through NFκB signaling pathways. • In situ implantation effectively repaired 12-mm rat sciatic nerve defects. Peripheral nerve injuries involving large gaps remain a significant clinical challenge due to the disrupted native microenvironment and the limited regenerative capacity of nerve tissues. In this study, we demonstrated that collagen peptides (CPs) derived from Alaskan cod skin effectively promote nerve cell proliferation and can be covalently immobilized within a 4-arm polyethylene glycol (PEG) hydrogel for simulating the extracellular matrix (ECM). The crosslinking of CPs with hydrogel precursors enhances the network density and increases porosity, resulting in sustained release properties. We systematically optimized the CP concentration and characterized its release kinetics. Our in vitro study confirmed that the CP/PEG hydrogel significantly promotes the proliferation of Schwann cells and PC12 cells through NFκB signaling pathways. To enable in situ delivery, CP/PEG hydrogel was encapsulated within electrospun nerve guidance conduits (NGCs), providing a structurally supportive and biomimetic microenvironment. In a 12-mm rat sciatic nerve defect model, the CP/PEG hydrogel facilitated extensive axonal regeneration and remyelination, comparable to the outcomes of autografts. These findings highlight the potential of this fish-derived peptide-loaded hydrogel system as a sustainable, biocompatible, and effective strategy for the functional repair of long-gap peripheral nerve injuries.