Flexible and immunomodulatory milk-derived protein hydrogels as transient interfacing scaffolds for peripheral nerve integration

Abstract

Next-generation implantable neural interfaces require highly flexible, biocompatible, and transient material platforms to minimize mechanical mismatch with neural tissues and avoid secondary retrieval surgeries. This study developed a soft and biodegradable neural interfacing platform fabricated from milk-derived protein (MDP) and polyvinyl alcohol functionalized with 3,4-dihydroxyphenylalanine (DOPA) as an immunomodulatory nerve guidance conduit. The fabricated MDP-DOPA hydrogel conduits exhibited favorable protein-release kinetics, compliant mechanical stability that matched native neural tissues, and controlled biodegradation profiles. In vitro, the MDP-DOPA substrate significantly attenuated pro-inflammatory M1 macrophage polarization while selectively promoting the pro-regenerative M2 phenotype in RAW 264.7 cells, subsequently enhancing PC12 neuritogenesis through the bioactivity of released cascade peptides. In vivo, a rat 10-mm sciatic nerve defect model demonstrated that the implantation of soft MDP-DOPA conduits drastically improved structural and functional neural integration. This was evidenced by an enhanced sciatic functional index, elevated nerve conduction velocity, and robust axonal remyelination in the distal segments, closely approaching the recovery level of clinical gold-standard autografts. Furthermore, early-stage in vivo analysis verified that the platform successfully orchestrated a pro-regenerative immunomodulatory microenvironment at the interface site within 1 week. These findings highlight the potential of MDP-DOPA hydrogels as bioinstructive, soft, and stable electronic encapsulation or scaffolding platforms for next-generation implantable neural technologies for clinical translation.

Keywords

Bioabsorbable materials / immunomodulatory biomaterials / implantable hydrogel / peripheral nerve repair / soft neural interface / transient platform

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