Blood-Coagulation-Inspired Dual-Network Hydrogel with Delayed In Situ Gelation for Enhancing Intradiscal Diffusion and Promoting Intervertebral Disc Degeneration Repair.

Abstract

Injectable hydrogels offer a promising strategy for treating intervertebral disc degeneration (IVDD), a leading cause of chronic low back pain. However, effective intradiscal diffusion and timely in situ gelation remain challenging within the confined high-pressure nucleus pulposus. Inspired by the temporal regulation of blood coagulation, we developed a biomimetic dual-network hydrogel (named HAD-HPTC) that achieves time-programmed diffusion and delayed solidification to enhance delivery and retention. Upon injection, an initial physical network, formed through dynamic hydrogen bonding and coordination between hyaluronic acid-phenylboronic acid (HA-PBA) and tannic acid-cerium metal polyphenol networks (TA-Ce MPNs), enables fluid-like diffusion and conformal defect filling, analogous to initial blood infiltration in wounds. Subsequently, a second chemical network gradually forms via thiol-Michael addition between hyaluronic acid acrylate (HA-AA) and dithiothreitol (DTT) under physiological conditions, achieving stable in situ gelation reminiscent of fibrin formation. This temporally programmed structure provides delayed gelation and improved diffusion, while integrated TA-Ce MPNs confer antioxidant, anti-inflammatory, and anti-senescence functions. Furthermore, in vivo studies in rat and rabbit models demonstrated superior disc height preservation, extracellular matrix restoration, and inflammation suppression compared to conventional preformed hydrogels. These findings establish blood-coagulation-inspired, time-programmed hydrogels as a promising platform for minimally invasive intervertebral disc regeneration.