ROS-scavenging lipoic acid-modified chitosan hydrogels with rapid photocrosslinked ability accelerates peripheral nerve regeneration

Abstract Peripheral nerve injury (PNI) triggers excessive oxidative stress and inflammation that impede nerve regeneration, leading to target organ atrophy and incomplete functional recovery. Conventional drug-loaded nerve conduits release anti-inflammatory drugs sustainably via filled hydrogels, requiring a precisely engineered hydrogel system to match drug release kinetics without impeding regenerating nerve tissue growth. Meanwhile, constructing complex conduit systems may introduce potential cytotoxic factors and induce aseptic inflammation via acidic degradation products. Herein, we fabricated a ROS-scavenging CS-LA/P(MMD-CL) composite nerve conduit with rapid photo-crosslinking (365 nm UV irradiation, photoinitiator-free) via integrating lipoic acid-modified chitosan (CS-LA) hydrogel into an oriented P(MMD-CL) conduit. Disulfide bonds in CS-LA scavenged ROS to alleviate oxidative stress, modulate inflammatory factor expression and resolve excessive inflammation, while the oriented P(MMD-CL) provided physical support and directional guidance for axon growth. In vivo studies on SD rats revealed that CS-LA/P(MMD-CL) promoted nerve regeneration through enhancing cell proliferation and angiogenesis, improving the maturity of regenerative peripheral nerve, mitigating gastrocnemius atrophy and promoting nerve function recovery (SFI: −77.51 ± 1.51), and exhibited great biosafety—no organ damage from degradation byproducts. This simple, multifunctional composite conduit effectively modulates the PNI microenvironment and promotes peripheral nerve regeneration, offering a promising strategy for PNI repair.