Bioengineered inflammation-sensitive supramolecular β–cyclodextrin–complex embedded in collagen/hyaluronic acid injectable hydrogel for nucleus pulposus regeneration in an intervertebral disc degeneration rat model

Intervertebral disc degeneration (IVDD) is a primary contributor to chronic low back pain, affecting over 500 million people globally. In this study, we engineered an injectable collagen-hyaluronic acid (Col-HA) hydrogel incorporating a β-cyclodextrin-resveratrol (β-CD-RES) supramolecular complex, designed to exhibit inflammation-sensitive drug release and promote nucleus pulposus (NP) regeneration. The hydrogel exhibited rapid gelation (within ∼3 min at 37 °C), high compressive strength (35 kPa), and an extended water retention time of 7 h. Drug release analysis showed a sustained resveratrol release, with 60 % released from β-CD-RES and 40 % from β-CD-RES/Col-HA over 96 h. In vitro, the hydrogel supported enhanced NPC proliferation, maintained >90 % cell viability, and significantly reduced ROS levels and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), indicating effective inflammation-facilitated drug delivery. In vivo, rats treated with β-CD-RES/Col-HA showed a marked improvement in disc height index (DHI%), as well as higher expression of COL-II and aggrecan mRNA after 8 weeks. These findings demonstrate the hydrogel's dual role as a supportive scaffold and targeted therapeutic platform for minimally invasive intervertebral disc regeneration.