Biomineralization empowers bone organoids.

Abstract

Bone organoids (BOs) are self-organizing, three-dimensional (3D) in vitro models that offer a promising platform for recapitulating the intricate components, architecture and functionality of native bone. However, accurately mimicking the hierarchical structure and mineralized extracellular matrix of mature bone remains challenging. Biomineralization is the biologically orchestrated process governing bone development, architecture, and mechanical integrity. It plays a critical role in guiding the structural and functional maturation of BOs. This review provides a comprehensive overview of BOs, emphasizing the importance of biomineralization in BO engineering. We thoroughly review of the key mechanisms of biomineralization, including cell-controlled, extracellular vesicle-mediated, and cell-independent pathways, as well as the biochemical and physical factors within the microenvironment. We also discuss strategies that enable biomimetic mineralization, which is the process of replicating the properties of native bone in BOs. Furthermore, we explore integrating 3D cell-matrix assembly strategies with bioengineering technologies such as 3D bioprinting, dynamic culture systems, and organ-on-a-chip platforms, which enhance BO structural fidelity and functional maturation. Finally, we highlight the biomedical potential of biomineralization-guided BOs for bone regeneration, disease modeling, and drug screening, while addressing current challenges and future directions toward scalable and clinically relevant BOs.