Bioadhesive Microcryogels Synergize with Therapeutic Ions to Enhance BMSC‐Exosomes Function for Vascularized Bone Regeneration

ABSTRACT Bone marrow stromal cells‐derived exosomes (BMSC‐Exo) have emerged as promising cell‐free therapeutic agents for bone tissue engineering due to their regenerative potential. However, their clinical translation is hindered by limitations in production yield and biofunctional efficacy. To overcome these challenges, this study develops a novel approach using bioadhesive porous microcryogels (BM) fabricated from methacrylated gelatin (GelMA) and oxidized hyaluronic acid methacrylate (OHAMA) for 3D cell culture, significantly enhancing exosome production. Therapeutic ions, magnesium (Mg) and silicon (Si), play crucial roles in modulating neo‐bone growth and maturation, are added into culture medium to coordinate the angiogenic and osteogenic responses of BMSC for the collection of exosomes (3D‐Mg/Si‐Exo) with enhanced bone tissue‐specific bioactivity. The exosomes are re‐encapsulated within BM (3D‐Mg/Si‐Exo BM ) to achieve sustained exosome release. The 3D‐Mg/Si‐Exo BM is injected into rat calvarial defects to its therapeutic efficacy on bone repair. The outcomes demonstrate that the combination of 3D aggregate culture and therapeutic ion modulation is greatly helpful in harvesting BMSC‐Exo to promote the regeneration of vascularized bone, with BM serving as a cell culture substrate, exosome delivery carrier, and injectable microscaffold. Overall, this platform provides a versatile strategy for advanced tissue engineering applications, addressing critical challenges in exosome‐based regenerative medicine.