Abstract
Bone organoids, as three-dimensional (3D) biomimetic constructs, have emerged as a promising platform for studying bone development, disease modeling, drug screening, and regenerative medicine. This review comprehensively explores innovative strategies driving bone organoid advancements, emphasizing the integration of cutting-edge technologies such as bioprinting, artificial intelligence, assembloids, and gene editing. While 3D bioprinting enhances spatial precision and structural complexity, artificial intelligence accelerates organoid optimization through data-driven approaches. Assembloids enable the assembly of multicellular systems to better replicate bone tissue microenvironments, whereas gene editing refines disease modeling and functional modifications. Despite these advancements, challenges remain, including the lack of vascularization, insufficient mechanical stimulation, and standardization issues across different models. Also, the clinical translation of bone organoids necessitates the establishment of rigorous evaluation frameworks, ethical guidelines, and regulatory policies to ensure their reproducibility and safety. Looking ahead, interdisciplinary convergence will be critical for constructing physiologically relevant "ex vivo skeletal systems", advancing bone biology, precision medicine, and biomaterial testing. This review highlights the transformative potential of bone organoid technology and its future applications in personalized orthopedics and bone disease intervention. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This review provides a comprehensive overview of cutting-edge strategies for constructing bone organoids, emphasizing their integration with advanced technologies such as bioprinting, artificial intelligence, assembloids, and gene editing. By systematically discussing their applications in bone development, disease modeling, drug screening, and regenerative medicine, this article bridges the gap between experimental models and clinical translation. The insights into vascularization, skeletal patterning, and high-throughput screening platforms offer a foundation for developing physiologically relevant bone organoids with enhanced fidelity and functionality. These advancements hold significant potential for accelerating personalized medicine, facilitating preclinical evaluation of therapeutics, and ultimately improving treatment outcomes for skeletal diseases.