Abstract

The regeneration of large bone defects remains a major clinical challenge due to the lack of stable and effective osteoinductive signals. Although extracellular vesicles have shown promising potential for cell-free bone regeneration, their application is largely constrained by complex purification and embedding into scaffolds. Migrasomes, newly identified organelles with the extracellular matrix affinity, represent a promising yet underexplored avenue for cell-free tissue engineering. Here, we report a migrasome-enriched bioactive layer as a functional osteoinductive interface for cell-free bone regeneration. We demonstrated that osteoprogenitor stem cells (OPSCs) derived from human cortical bone exhibit robust osteogenic capacity and, upon osteogenic induction, promote the release and deposition of migrasomes together with calcium on culture surfaces. Utilizing these characteristics, we developed an in situ deposition strategy where OPSCs are preseeded on biphasic calcium phosphate (BCP) scaffolds, induced to mineralize, followed by decellularization. This process robustly preserves a native, osteogenic migrasome layer on the scaffold without the need for vesicle isolation or chemical conjugation. The resulting migrasome-functionalized scaffolds markedly up-regulated osteogenic gene expression and promoted bone regeneration in a murine calvarial defect model. Altogether, these findings validate migrasomes as a potent, endogenous signaling platform for bone tissue engineering. Moreover, our new paradigm for cell-free biomaterials employing cellular secretomes opens a new frontier in regenerative medicine, where the transient activity of cells is permanently captured to direct tissue repair.