A One-Stone-Two-Birds Strategy for Intervertebral Disc Repair: Constructing a Reductive Chelation Hydrogel to Mitigate Oxidative Stress and Promote Disc Matrix Reconstruction

Intervertebral disc degeneration (IVDD) is characterized by fibrosis of nucleus pulposus (NP) cells and accelerated surrounding extracellular matrix catabolism. Bioactive hydrogels have shown significant potential in regulating cellular functions and tissue homeostasis. In this work, a dynamic hydrogel (HA-NCSN/Cu) is designed via the reductive chelation of hyaluronic acid grafted with thiourea (HA-NCSN) and Cu²⁺. The reductivity of the grafted thiourea groups of HA-NCSN can quickly reduce part of the chelated Cu²⁺ to Cu⁺. Therefore, during the gelation process, the color of hydrogel become dark immediately, which endowed hydrogel with remarkable photothermal effect. The abundant thiourea groups inside hydrogel can effectively scavenge reactive oxygen species to mitigate the inflammatory stress of NP cells. RNA sequencing analysis further reveals that glutathione signaling pathway is significantly altered. Meanwhile, mild photothermal therapy could activate the TGF-β/Smad pathway in NP cells, promoting the expression and secretion of Aggrecan and Collagen II. Ultimately, the combined modulation of inflammation alleviation and matrix regeneration achieves the restoration of the structure and function of the damaged intervertebral disc, which is also strongly demonstrated by the in vivo animal experiments. All of these results demonstrate the great potential of the dynamic HA-NCSN/Cu hydrogel in IVDD treatment.