Hyaluronic Acid-Based Injectable Dual-Network Hydrogel for 6'-Sialyllactose Mimetic Peptide Delivery and Microenvironment Reconstruction in Brachial Plexus Root Avulsion.

Brachial plexus root avulsion (BPRA) results in extensive motor neurons (MNs) loss, muscle atrophy, and irreversible motor dysfunction. Current surgical strategies with reimplantation fail to promote the motor recovery often leading to poor clinical outcomes, because of the too slow re-growth of the axons of MNs to re-innervate the target muscles before atrophy happens. To reconstruct the neuroprotective microenvironment to reduce the MNs death following BPRA, we developed an injectable dual-network HGα composite hydrogel encapsulating a 6'-sialyllactose (6'-SL) mimetic peptide. The HGα hydrogel was formed via Zn2+-induced self-assembly of glycyrrhizic acid (GA) to establish a primary physical network, combined with photocrosslinking of methacryloyl hyaluronic acid (HAMA) and 6'-SL mimetic peptide to form a secondary covalent network. In vitro studies demonstrated that HGα exhibits favorable injectability and tissue adhesiveness. HGα showed potent antioxidant capacity. In a rat BPRA model, at week 8, 50% of rats in the HGα-treated group achieved a Terzis Grooming Test score of 5, HGα hydrogel significantly improved in forelimb motor function, modulated the local inflammatory microenvironment to preserve the spinal MNs, promoted remyelination of musculocutaneous nerve, attenuated muscle atrophy, offering a promising strategy to restore motor function.