Advances in Bone-on-a-Chips for In Vitro Modeling of Bone Physiology and Pathology.

Bone is a dynamic and multifunctional tissue that provides mechanical support, regulates mineral homeostasis, supports hematopoiesis, and relies on complex interactions among multiple cell types. The increasing incidence of bone-related diseases, such as osteoporosis, osteoarthritis, fracture non-union, and bone cancer, highlights the need for in vitro models that better reflect human bone physiology. Bone-on-a-chip technology, developed through advances in microfluidics, biomaterials, and tissue engineering, offers a promising approach to recreate key features of the bone microenvironment in vitro. By incorporating bone-mimicking materials, relevant bone cells, vascular components, fluid perfusion, and mechanical stimulation, these platforms allow more realistic investigation of bone remodeling, regeneration, disease mechanisms, and drug responses. In parallel, bone organoids and their integration with microfluidic chips have further expanded the capabilities of in vitro bone models by enabling the formation of self-organized, human-relevant bone tissues with increased cellular complexity. This review summarizes recent progress in bone-on-a-chip systems, including models for osteogenesis and bone regeneration, vascularized bone, bone marrow and hematopoietic niches, cancer bone metastasis, and mechanobiological studies. Key design principles, materials, cellular components, and applications in disease modeling, drug screening, toxicity assessment, and personalized medicine are discussed. Current challenges and future directions are also discussed to support the continued development of more physiologically relevant in vitro bone models.