Embryonic-Like Mineralized Extracellular Matrix/Stem Cell Microspheroids as a Bone Graft Substitute.

Native bone extracellular matrix (ECM) secreted by mesenchymal precursors provides an optimal biological framework, comprising structural collagen proteins and a microenvironment niche, which supports cell attachment and differentiation, and bone growth. Inspired by nature, the embryonic-like mineralized ECM/stem cell microspheroids (MECS) are developed, in which self-assembly of the stem cell microspheroids (CS) and mineralization of the self-produced ECM occur simultaneously. The uniform-sized MECS exhibit a solid spherical appearance with stem cells embedded inside, recapitulating the early stage of intramembranous ossification. Compared with pure CS, MECS show enhanced Young's modulus, cell viability, intercellular communication, and osteogenic differentiation. Additionally, the capability of MECS is explored without the use of exogenous scaffolds to substitute and repair lost bone in rat critical-sized defects. It is found that the MECS can achieve excellent bone regeneration outcomes with 97.99 ± 2.28% of the defect area filled with new bony structures and blood vessels, while nearly half or one-third of the defect area is repaired by CS (52.79 ± 4.63%) or β-tricalcium phosphate (38.09 ± 7.79%), respectively. The study demonstrates that embryonic-like MECS is a novel effective bone graft substitute for bone tissue regeneration.