Injectable Photoacoustic‐Traceable Prussian Blue Nano‐hybridized Hydrogel Microspheres Loaded with Stem Cells for Promoting Diabetic Bone Regeneration

Diabetic patients frequently experience impaired healing of tooth extraction wounds, likely due to excessive reactive oxygen species (ROS) in the diabetic bone microenvironment, which compromises bone marrow mesenchymal stem cells (BMSCs). While Prussian blue nanoparticles (PBNPs) show promise as ROS scavengers, their clinical application remains limited due to the lack of stable, targeted and minimally invasive delivery systems. To address this, we developed an injectable microsphere system encapsulating PBNPs through microfluidic technology (GelMA/PEGDA/PBNPs). These microspheres exhibited excellent mechanical properties, controlled biodegradability, a pro-proliferative microenvironment, and photoacoustic imaging (PAI) tracking capabilities. In vitro, they significantly enhanced stem cell expansion, reversed oxidative stress in BMSCs, and enhanced osteogenesis. In vivo, these microspheres, through surface-loaded stem cell delivery, accelerated regeneration of irregular bone defects in tooth extraction sockets in diabetic rat. Transcriptomic sequencing analysis indicated that the antioxidant effects of the microspheres were closely associated with activation of the PI3K/AKT/mTOR signaling pathway. The optimized system enhanced local retention, achieved sustained and stable release of PBNPs, improved bioavailability of PBNPs, and enabled real-time tracking of the implants. This nano-hybrid microsphere system provides a novel minimally invasive therapeutic strategy for bone tissue defects in diabetic patients, demonstrating significant potential for clinical translation.