Three-dimensional printing of bioceramic-induced macrophage exosomes: immunomodulation and osteogenesis/angiogenesis

Exosomes have attracted increasing attention in tissue regeneration and repair due to their roles in intercellular communication. Developing a customized delivery system is key to exosome-based regenerative therapeutics. Bioceramics play an important role in the immunomodulation of macrophages. Here, three-dimensional (3D) printing was applied to construct porous scaffolds with β-tricalcium phosphate (β-TCP) bioceramic-induced macrophage exosomes (BC-Exos). The three-dimensional-printed BC-Exo scaffolds, exhibiting a predefined structure and persistent release of exosomes, displayed distinct immunomodulatory effects and improved osteogenesis/angiogenesis. The BC-Exos in the printed scaffolds modulated macrophage polarization and the expression of chemokines for the recruitment of bone marrow mesenchymal stem cells (BMSCs) and endothelial cells. Scaffolds with BC-Exos from macrophages with a mixed phenotype significantly enhanced the osteogenic differentiation and immunosuppression of BMSCs and improved the angiogenic activity of human umbilical vein endothelial cells in vitro. For the potential mechanism, β-TCP bioceramics have an important effect on the immunomodulation of macrophages by regulating gene expression, increasing exosome production, and altering exosomal miRNA cargos, thereby affecting the paracrine effects of BC-Exos on immunomodulation and osteogenesis/angiogenesis. This study suggests that 3D printing of bioceramic-induced macrophage exosomes may be a useful strategy for tissue engineering and regenerative medicine. 3D printing of bioceramic-induced macrophage exosomes (BC-Exos) displayed stimulatory effects on immunomodulation, osteogenesis, and angiogenesis of macrophage (MΦs), mesenchymal stem cells (MSCs) and endothelial cells (ECs), respectively. BC-Exos enhanced the expression of chemotaxis, osteogenic and angiogenic genes by altering their miRNAs profile. 3D printing of BC-Exos offers a new cell-free strategy for tissue regeneration.