Bone microphysiological models for biomedical research

Bone related disorders are highly prevalent, and many of these pathologies still do not have curative and definitive treatment methods. This is due to a complex interplay of multiple factors, such as the crosstalk between different tissues and cellular components, all of which are affected by microenvironmental factors. Moreover, these bone pathologies are specific, and current treatment results vary from patient to patient owing to their intrinsic biological variability. Current approaches in drug development to deliver new drug candidates against common bone disorders, such as standard two-dimensional (2D) cell culture and animal-based studies, are now being replaced by more relevant diseases modelling, such as three-dimension (3D) cell culture and primary cells under human-focused microphysiological systems (MPS) that can resemble human physiology by mimicking 3D tissue organization and cell microenvironmental cues. In this review, various technological advancements for in vitro bone modeling are discussed, highlighting the progress in biomaterials used as extracellular matrices, stem cell biology, and primary cell culture techniques. With emphasis on examples of modeling healthy and disease-associated bone tissues, this tutorial review aims to survey current approaches of up-to-date bone-on-chips through MPS technology, with special emphasis on the scaffold and chip capabilities for mimicking the bone extracellular matrix as this is the key environment generated for cell crosstalk and interaction. The relevant bone models are studied with critical analysis of the methods employed, aiming to serve as a tool for designing new and translational approaches. Additionally, the features reported in these state-of-the-art studies will be useful for modeling bone pathophysiology, guiding future improvements in personalized bone models that can accelerate drug discovery and clinical translation.