A 3D-printed chitosan-based pH-responsive dual functional scaffold for osteomyelitis: synergistic antibacterial and osteogenic treatment.

Despite advances in osteomyelitis treatment, achieving spatiotemporal coordination of infection control and bone regeneration remains challenging due to bacterial-induced acidic microenvironments and toxin-mediated osteoblast dysfunction. Herein, a novel 3D-printed chitosan-based composite scaffold (VM@n-HA/CS/DM) was developed. The scaffold strategically integrates two functional components: (1) Vancomycin-loaded chitosan microspheres (VM) conjugated with scaffold via pH-sensitive Schiff base bonds formed between aldehyde and amine groups, selectively breaking down in the acidic microenvironment of bacterial infections, thereby enabling on-demand release of vancomycin (Van) to target and eliminate Staphylococcus aureus (S. aureus). (2) Diflunisal-loaded chitosan microspheres (DM) dispersed within the scaffold matrix, providing sustained release to suppress alpha-type phenol-soluble modulins (PSMs) expression and shield osteoblasts from bacterial toxins. The scaffold employs pH-responsive and diffusion-mediated mechanisms to match the timing of infection control and bone regeneration. Furthermore, the 3D-printed hierarchical porous structure, with spatially optimized microsphere/matrix distribution, ensures dual functionality: multiscale porosity facilitates nutrient transport and cell infiltration while maintaining mechanical integrity, and compartmentalized drug delivery achieves precise therapeutic control. This dual therapeutic modality advances osteomyelitis treatment by providing a clinically viable strategy to address persistent challenges.