Electrowritten topographical conduit integrated with 4-octyl itaconate for peripheral nerve immunomodulation and regeneration.

Abstract

Peripheral nerve injury (PNI) affects over one million individuals each year, resulting in persistent motor and sensory deficits and imposing substantial socioeconomic costs. Although autologous nerve grafting remains the gold standard, it is limited by donor site morbidity and incomplete functional recovery, and existing nerve conduits do not effectively modulate the early inflammatory response that impedes regeneration. Itaconic acid, a macrophage-specific metabolite, exhibits potent anti-inflammatory properties and therefore represents a promising candidate for promoting peripheral nerve repair. In this study, we fabricated a dual-layer nerve conduit (PCL+GelMA/4OI) by melt electrowriting (MEW) of polycaprolactone (PCL) microfibrous grids rolled into tubular scaffolds, followed by intraluminal injection of gelatin methacryloyl (GelMA) hydrogel encapsulating 4-octyl itaconate (4OI). In vitro assays demonstrated that 4OI inhibited TNF-α-induced activation of the NF-κB pathway in Schwann cells. The aligned MEW microfibers promoted neurite alignment along PCL fibers, while interfilamentous pores facilitated efficient mass transfer essential for nerve regeneration. In a rat sciatic nerve defect model, implantation of the PCL+GelMA/4OI conduit significantly reduced pro-inflammatory cytokine levels and improved electrophysiological recovery; histological analysis confirmed enhanced myelination and reduced muscle atrophy. Overall, this work presents a bifunctional strategy that combines topographical guidance with targeted immunomodulation, demonstrating that localized 4OI delivery synergistically accelerates nerve regeneration by attenuating inflammation and directing axonal growth. STATEMENT OF SIGNIFICANCE: : Peripheral nerve injury (PNI) affects over one million individuals annually, often leading to lasting motor and sensory disabilities. While autologous nerve grafting is the standard treatment, it is limited by donor site morbidity and incomplete functional recovery. Current synthetic conduits fail to address the early inflammatory response, which hampers regeneration. To overcome these challenges, we developed a bifunctional nerve conduit that combines polycaprolactone (PCL) microfibers for topographical guidance with 4-octyl itaconate (4OI) for macrophage-specific immunomodulation. In vitro, 4OI inhibited TNF-α-induced NF-κB activation in Schwann cells, while in vivo, it reduced pro-inflammatory cytokines and improved electrophysiological recovery. The conduit promoted neurite alignment and enhanced myelination, demonstrating that targeted immunomodulation accelerates nerve regeneration through inflammation modulation and axonal guidance.