Synergistic reversal of inflammation-mediated degeneration in intervertebral discs: Phenylboric acid-grafted hyaluronic acid hydrogel as an anti-oxidative vehicle for Timp-3 delivery and promotion of extracellular matrix synthesis.

Abstract

Background: Intervertebral disc degeneration (IDD) is intricately linked to the aging process, wherein reactive oxygen species (ROS) and inflammatory responses markedly contribute to matrix degradation and hyperplasia. Injectable antioxidant hydrogels loaded with pharmacological agents hold immense promise for clinical translation in early intervention of IDD. Our previous study revealed that the tissue inhibitor of metalloproteinase-3 (TIMP3) is a pivotal regulator of matrix remodeling and inflammation.

Results: We developed a biodegradable ROS-responsive hydrogel functionalized with phenylboronic acid (R-gel) as a controlled release carrier of TIMP3 (R-gel-TIMP3). R-gel-TIMP3 effectively scavenged ROS and provided sustained TIMP3 delivery, thereby attenuating inflammation-driven disc degeneration. In vitro, R-gel-TIMP3 exhibited negligible cytotoxicity, reduced ROS levels in the nucleus pulposus cells, and alleviated cellular senescence and apoptosis. In vivo, it decreased ROS accumulation, inflammatory M1 macrophages, matrix degradation, and neovascularization, significantly ameliorating IDD pathology.

Conclusion: The synergistic action of ROS-responsive TIMP3 delivery markedly amplified the therapeutic efficacy against IDD, underscoring the therapeutic potential of R-gel-TIMP3 in IDD management.

Statement of significance: 1 We synthesized an injectable bioactive ROS-responsive hydrogel as an anti-oxidative vehicle for TIMP3 protein delivery. 2 The hydrogel enabled sustained release of TIMP-3 in situ and acted as an efficient ROS scavenger to protect NPs against oxidative stress. 3 This treatment could effectively intervene in the progression of IDD from early stage, promote extracellular matrix synthesis, and ultimately reduce IDD in a rat model.