Curcumin-loaded strontium-based metal-organic framework hydrogel microspheres for bone regeneration: Combined effects of curcumin-mediated immunomodulation and Sr2+-induced osteogenesis

A multifunctional hydrogel microsphere system with antioxidant, immunomodulatory, and osteogenic functions was developed. • The Sr-MOF enabled efficient curcumin loading for ROS scavenging and macrophage polarization regulation. • Microfluidics encapsulated Cur-loaded Sr-MOF into GelMA microspheres for sustained release of Cur and Sr 2+ . • Cur@Sr-MOF@GelMA microspheres promoted osteogenesis by establishing a favorable immune microenvironment. Bone regeneration in large bone defects is often impeded by an unfavorable microenvironment characterized by excessive reactive oxygen species (ROS), dysregulated macrophage polarization, and poor osteogenic capacity. Therefore, it was hypothesized that a bioactive material targeting these disadvantages is promising in bone defect repair. In the study, we synthesized a hydrogel microsphere system (Cur@Sr-MOF@GelMA), in which the polyphenolic compound curcumin (Cur) was adsorbed onto a strontium-based metal - organic framework (Sr-MOF) and subsequently encapsulated within gelatin methacryloyl (GelMA) microspheres. The Cur@Sr-MOF@GelMA microspheres enabled the sustained release of Cur and Sr 2+ . Cur effectively scavenged ROS and induced M2 polarization of macrophages (RAW264.7 cells), establishing a favorable microenvironment for bone regeneration. Furthermore, Cur@Sr-MOF@GelMA microspheres demonstrated a dual osteogenic effect on MC3T3-E1 cells, directly via Sr 2+ and indirectly through Cur-mediated immunomodulation of RAW264.7 cells. Transcriptomic sequencing analysis indicated that Cur@Sr-MOF@GelMA microspheres might enhance M2 polarization of RAW264.7 cells through suppression of pro-inflammatory pathways (NLR, TLR and TNF signaling), and promote osteogenic differentiation of MC3T3-E1 cells via upregulation of the Wnt signaling pathway. In vivo experiments in rats demonstrated that Cur@Sr-MOF@GelMA microspheres established an M2 macrophage-dominant microenvironment at early stages, accelerated bone formation and eventually resulted in the highest bone volume fraction (BV/TV) in critical-sized calvarial defects at 12 weeks. In conclusion, the Cur@Sr-MOF@GelMA microsphere system possesses antioxidant, immunomodulatory, and osteoinductive properties, and represents a promising material for bone defect repair.