Dynamic adaptive hydrogel facilitates neuroregeneration in segmental nerve deficits via immunomodulation and mitochondrial homeostasis

Abstract

The clinical management of segmental nerve deficits faces significant challenges, particularly in achieving substantial neural structural reconstruction and functional recovery. Dynamic, adaptive smart hydrogels hold great promise for restoring tissue function by mimicking regenerative microenvironments and cytokine secretion. However, the influence of hydrogel structure on drug release behavior and its role in maintaining nerve bridging during repair remains underexplored and warrants attention. Here, we present a sequentially gel-forming nerve-guiding conduit (NC/DS@HPBGP) composed of bisphosphonates-modified hyaluronic acid (HA-PBA-BP) and Tannic acid-modified GelMA (GelMA-TA), which contains borate ester bonds and metal coordination bonds, allowing for a dual response to ROS and Ca2+ at nerve injury sites. After implantation, the conduit undergoes dynamic gel-sol–gel transitions, including ROS-responsive release of narciclasine (NC) and 5-iodoisoquinoline (DS) and Ca2+ cross-linking-induced 3D structural reorganization, resulting in enhancing nerve regeneration proximally through immunomodulation and ensuring structural integrity distally via mitochondrial autophagy. This multifaceted integration facilitates dynamic remodeling of the nerve regeneration microenvironment, markedly augmenting nerve regeneration and repair efficacy.