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

Yuhua Sun,Dong Zhai,Bingjun Zhang,Chengtie Wu

doi:10.1038/s41427-021-00340-w

Abstract

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.

Highlights

In the past few decades, tissue engineering technology has become an effective strategy for repairing lost or damaged tissue
The results showed that the bioceramic-induced macrophage exosomes (BC-Exos) were positive for characteristic exosomal surface marker proteins, including CD9, CD81, and TSG101
Comparing the effect of β-tricalcium phosphate (β-TCP) stimulation on BC-Exo functionality, we demonstrated that bone marrow mesenchymal stem cells (BMSCs) proliferation and osteogenic differentiation were significantly increased in the SE-25T2D group compared to the SE-0T-2D and SE-100T-2D groups

Summary

Introduction

In the past few decades, tissue engineering technology has become an effective strategy for repairing lost or damaged tissue. Hydrogels for exosome delivery are mainly prepared via freeze-drying, injection molding, bulk crosslinking, or self-assembly technologies These materials display common drawbacks, such as an uncontrollable structure and lack of macropores, which are not conducive to the continuous growth of tissue. Three-dimensional (3D) printing, known as additive manufacturing, enables the precise control of manufacturing processes and fabrication of tissue constructs of predefined architecture and shapes This method has been widely used in the preparation of porous scaffolds for bone tissue engineering.[6] Three-dimensional printing of hydrogels can combine the advantages of both additive manufacturing and hydrogel materials. In this work, 3D printing was proposed to construct a biocompatible porous hydrogel scaffold for the long-term release of nanosized exosomes and exosome-mediated paracrine effects

Methods

Results

Conclusion