Oxygen metabolism-balanced engineered hydrogel microspheres promote the regeneration of the nucleus pulposus by inhibiting acid-sensitive complexes

Intervertebral disc degeneration (IVDD) is commonly caused by imbalanced oxygen metabolism-triggered inflammation. Overcoming the shortcomings of antioxidants in IVDD treatment, including instability and the lack of targeting, remains challenging. Microfluidic and surface modification technologies were combined to graft chitosan nanoparticles encapsulated with strong reductive black phosphorus quantum dots (BPQDs) onto GelMA microspheres via amide bonds to construct oxygen metabolism-balanced engineered hydrogel microspheres (GM@CS-BP), which attenuate extracellular acidosis in nucleus pulposus (NP), block the inflammatory cascade, reduce matrix metalloproteinase expression (MMP), and remodel the extracellular matrix (ECM) in intervertebral discs (IVDs). The GM@CS-BP microspheres reduce H2O2 intensity by 229%. Chemical grafting and electrostatic attraction increase the encapsulation rate of BPQDs by 167% and maintain stable release for 21 days, demonstrating the antioxidant properties and sustained modulation of the BPQDs. After the GM@CS-BP treatment, western blotting revealed decreased acid-sensitive ion channel-3 and inflammatory factors. Histological staining in an 8-week IVDD model confirmed the regeneration of NP. GM@CS-BP microspheres therefore maintain a balance between ECM synthesis and degradation by regulating the positive feedback between imbalanced oxygen metabolism in IVDs and inflammation. This study provides an in-depth interpretation of the mechanisms underlying the antioxidation of BPQDs and a new approach for IVDD treatment.