An ECM-mimetic hydrogel for disc repair: reconstituting hypoxia and alleviating NPC senescence to halt intervertebral disc degeneration

Abstract

Intervertebral disc degeneration, the leading cause of chronic low back pain, remains incurable with traditional conservative therapies limited to symptomatic alleviation. We present an ECM-mimetic injectable hydrogel (HPTC) synthesized via dynamic crosslinking of hyaluronic acid-phenylboronic acid (HA-PBA) and tannic acid-cerium(III) metal-polyphenol networks (TA-Ce³⁺ MPNs), which faithfully recapitulates native nucleus pulposus ECM to enable functional tissue regeneration. In vitro, HPTC presented broad-spectrum reactive oxygen species scavenging and downregulated pro-inflammatory cytokine expression (TNF-α, IL-1β, IL-6), while upregulating anti-inflammatory markers (IL-4, IL-10). Crucially, Ce³⁺ effectively reduced dissolved oxygen levels (to 105% vs. 115% in control at 15 min), thereby promoting HIF-1α signal expression and mitigating nucleus pulposus cells senescence under H₂O₂-induced oxidative stress. In rat and rabbit intervertebral disc degeneration models, a single, minimally invasive injection of the ECM-mimetic HPTC hydrogel preserved the disc height index and magnetic resonance imaging signal intensity, enhanced aggrecan and collagen II deposition, suppressed inflammatory mediators, and elevated HIF-1α while reducing p21 expression in situ. Transcriptomic analysis further implicated HIF-1α pathways in ECM regeneration. All these findings demonstrate that the HPTC hydrogel leverages metal-polyphenol chemistry within an ECM-inspired framework to synergistically modulate oxygen homeostasis, oxidative stress, and inflammation, offering a bifunctional and biomimetic platform for disc regeneration.