Hydrogen-releasing electroactive nerve guidance conduits promote peripheral nerve regeneration by remodeling the microenvironment

Abstract

Following peripheral nerve injury (PNI), the early inflammatory response induces excessive production of reactive oxygen species (ROS), resulting in severe damage to the regenerative microenvironment, which poses a huge challenge to the autonomous regeneration of nerves. Exogenous nerve grafts are often needed to assist and guide nerve regeneration. In recent years, nerve conduits (NGCs) with directional structures and favorable bioactivity have made significant progress, but single-function scaffolds still cannot meet the multiple needs of reconstructing an ideal regenerative microenvironment. In this study, a construction strategy for hydrogen-releasing electroactive nerve conduit scaffolds was proposed. The system uses poly(3S-methylmorpholine-2,5-dione-co-ε-caprolactone) [P(MMD-CL)] conduits coated with helically wound metal magnesium wires as a source of gaseous transmitters that continuously release hydrogen. Under the action of an external alternating magnetic field, the magnesium wire coil can form a closed loop and generate weak electrical stimulation (ES). The conduit is further filled with photo-crosslinked lipoic acid-gelatin (Gel-LA) microgels to synergistically regulate cell behavior and assist tissue regeneration. In vitro studies have shown that the system exhibits multiple biological effects, including reducing ROS levels, regulating inflammatory responses, promoting angiogenesis, and maintaining mitochondrial function, reflecting the potential roles of H₂, ES, and Mg²⁺ in regulating the regenerative microenvironment. In vivo, the establishment of a 15 mm sciatic nerve defect model further verified the significant efficacy of the H₂ delivery system in promoting nerve morphology and functional recovery. In summary, this study constructed a multifunctional nerve conduit scaffold with gaseous transmitter delivery, electrical activity regulation, and injectable microgel filling, which provides a new therapeutic idea for improving the post-injury microenvironment and promoting peripheral nerve regeneration, and provides an experimental basis for gas molecule-guided nerve repair strategies.

Keywords: Electrical stimulation; H(2); Injectable microgel; Peripheral nerve treatment; Regenerative microenvironment.