An Injectable and Modular NO-Adaptive Delivery System for Modulating Regenerative Microenvironment in Long-Segment Nerve Injury.

Abstract

Repairing long-segment peripheral nerve injuries remains a significant clinical challenge, hindered by oxidative stress, inflammation, insufficient revascularization, and limited axonal regeneration speeds. This study addresses these barriers by reconstructing the nerve regeneration microenvironment, enhancing cell migration, and accelerating axonal growth. An integrated regenerative microenvironment combining chemical signals, micro/nano structures, and electrical stimulation is developed. Specifically, nitric oxide (NO), a versatile signaling molecule, is dynamically released using sustained and responsive-release strategies to regulate oxidative stress and inflammation effectively. Furthermore, a gelatin-lipoic acid-seleno-lipoic acid (Gel-LA-SA) microgel-based hydrogel is designed, forming interconnected macroporous scaffolds that significantly enhance cell infiltration and growth compared to traditional hydrogels. Additionally, a non-invasive electroactive conduit is constructed to provide external electrical stimulation, promoting nerve cell migration and nerve growth factor secretion. Together, these elements guide axonal regeneration, support rapid revascularization, and enhance nutrient supply. By integrating NO signaling, advanced hydrogel scaffolds, and electrical stimulation, this multifunctional conduit effectively addresses the critical barriers to regenerating nerves across extensive defect sites, offering a promising approach for repairing long-segment peripheral nerve injuries and providing insights into broader applications for neurological disease treatment and tissue regeneration.