In Vitro Platforms in Bone Tissue Engineering: From Biological Foundations to Advanced Models.

Large bone defects and related diseases affect millions worldwide, while conventional treatments such as autologous grafting remain limited by donor supply and high complication rates. Bone tissue engineering (BTE) has therefore emerged as a potential strategy to complement existing therapies. Over the past four decades, BTE has progressed from simple scaffold-based methods toward advanced bone-on-a-chip (BOC) systems. Despite substantial advances, current in vitro models still fail to fully capture the complexity of the bone microenvironment, hindering preclinical future translation. This study traces the evolution of BTE (1980-present) across four phases (foundational, expansion, foundation refinement, and advanced regeneration phase), highlighting innovations in biomaterials, cellular strategies, signaling factors, and culture platforms, which integrate multicellular cocultures, real-time biosensing, and physiologically relevant mechanical cues. BOC not only represents a major step forward for regenerative medicine but also provides versatile applications in disease modeling and drug screening. Nonetheless, three critical challenges remain: standardized design, complete vascularization, and scalable manufacturing. With such advances, BOC may reduce reliance on animal testing, accelerate drug discovery, and enable bone therapies within the near future. The integration of advanced BTE platforms could significantly expand the impact of regenerative medicine worldwide. Interestingly, integration of biosensors with BOC and BTE platforms holds the potential to advance real-time monitoring, increase translational relevance, and assist the development of personalized regenerative strategies in future clinical applications.