Mild photothermal-responsive hydrogel with H2Se delivery for anti-infection and microenvironment remodeling to bone regeneration in diabetic osteomyelitis.

Diabetic osteomyelitis, exacerbated by a hyperglycemic microenvironment, leads to increased bacterial infections and bone tissue destruction, raising the risk of amputation. Current antibiotic therapies are limited in effectiveness due to rising antibiotic resistance and biofilm barrier. In response, we developed a microgel-based hydrogel system that delivers H2Se gas combined with mild photothermal therapy (MPTT) to achieve integrated treatment for infection control, anti-inflammation, and osteogenesis. This system utilizes Fe3O4 nanoparticles as photothermal-responsive carriers to encapsulate the H2Se donor TDN1042, which is constructed into lipoic acid-modified gelatin (Gel-LA) microgels using microfluidic technology. Upon in situ injection, photocrosslink forms the TF@GL hydrogel that enables triple modulation under 808 nm NIR. First, MPTT promotes H2Se release, disrupting bacterial metabolic homeostasis and lysing biofilms. Second, H2Se scavenges excess reactive oxygen species (ROS) to alleviate cell death, simultaneously inhibiting inflammation pathways (NF-κB and NLR). Lastly, the TF@GL hydrogel promotes osteogenic differentiation by activating the TGF-β/BMP osteogenic pathway, and the porous structure enhances cell migration and nutrient diffusion, accelerating bone repair. This design provides a comprehensive therapeutic strategy for diabetic osteomyelitis through the spatiotemporal synergy of gas delivery and controlled photothermal effects, offering effective antibacterial activity, oxidative stress alleviation, and bone regeneration induction.