Melatonin rhythm-mimicking smart hydrogel for circadian clock regulation and promotion of intervertebral disc regeneration

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, with growing evidence suggesting a connection between its pathogenesis and circadian rhythm disruption. This study investigated the link between circadian regulation and IVDD by integrating epidemiological evidence from the UK Biobank cohort (n = 287,150), Mendelian randomization analysis, and multi-species validation using Bmal1 knockout mice and human and rat disc samples. Core circadian clock proteins were significantly downregulated in degenerated intervertebral disc tissues across species. To counteract this, a composite hydrogel was developed for the cyclic delivery of melatonin, which effectively upregulated BMAL1 and CLOCK protein expression, restored circadian rhythm, and enhanced extracellular matrix (ECM) synthesis. When implanted into degenerated rat discs, the hydrogel alleviated IVDD by reestablishing circadian homeostasis. These findings highlight cyclic melatonin delivery as a promising therapeutic approach for IVDD.