Translating Structural Hierarchy and Mechanobiology of Bone in Microphysiological Systems

ABSTRACT The bone exhibits a complex scale‐spanning hierarchical structure with integrated mechanical cues that provide structural integrity, regulate cellular signaling, and maintain tissue homeostasis, thereby preserving the overall form and function of the human body. The structured arrangement of multiple cellular and acellular components enables the mechanobiological regulation of various osteologic processes. At the nanoscale, collagen fibrils and crystalline hydroxyapatite (HA) govern force propagation necessary for high mechanical stiffness and toughness. At the microscale, the pericellular matrix acts as a mechanosensitive force transducer that influences interstitial fluid flow, pressure gradients, matrix deformation, and response to external physical loads. Concurrently, shear‐sensitive endothelial and neural cells in the neurovascular microenvironment also adapt to mechanical loading. In cancer, homeostasis is disrupted by altered matrix stiffness, elevated interstitial pressures, and tumor‐associated biochemical gradients, leading to impaired mechanotransduction, aberrant remodeling, and invasive growth. This review provides a perspective on spatially and mechanically distinct but connected interfaces involved in mechanobiological crosstalk. Recapitulation of in vivo mechanical stimuli, microenvironmental cues, and disease‐specific mechanobiological signaling in microfluidics‐based bone‐on‐chip platforms is described, along with opportunities for pharmacological intervention. These platforms will have wider applications in drug screening and complement animal models by providing predictive pre‐clinical information related to cancer and other bone pathologies.