Microphysiological Systems for Musculoskeletal Research: Current Advances in Organ-on-Chip Platforms

Organ-on-chip (OoC) technology has emerged as a powerful class of microphysiological systems capable of recapitulating human tissue architecture, biochemical gradients, and dynamic cellular interactions with high fidelity. While OoC platforms have advanced rapidly in organs such as liver, heart, and lung, their application to the musculoskeletal system remains comparatively underdeveloped despite the central role of biomechanics in tissue function and disease. Musculoskeletal tissues, including skeletal muscle, bone, cartilage, and tendon, present unique challenges due to their hierarchical structure, anisotropic mechanical properties, and tightly coupled immune, vascular, and stromal interactions that govern repair and degeneration. In this review, we critically evaluate recent advances in musculoskeletal OoC platforms, including muscle, bone, cartilage, and tendon-on-chip systems, with emphasis on structural design, biomaterial composition, and integration of mechanical cues. We highlight how these systems enable precise control of microenvironmental conditions and support human-relevant disease modeling and drug testing. However, we identify key limitations that constrain their translational potential, including inadequate representation of physiologically relevant mechanical loading, incomplete vascular and immune integration, lack of standardization, and limited modeling of inter-tissue interfaces. Importantly, we propose a unifying framework for next-generation musculoskeletal OoC systems centered on three principles: mechanobiological fidelity, multicellular integration, and interface-level modeling of the muscle–tendon–bone axis. We further discuss emerging strategies, including advanced biomaterials, 3D bioprinting, multi-tissue integration, and artificial-intelligence-driven analysis that can address current limitations and enable scalable, predictive platforms. By bridging reductionist in vitro systems and complex in vivo physiology, musculoskeletal OoC technologies have the potential to transform mechanobiology research, accelerate drug discovery, and enable precision regenerative therapies. Realizing this potential will require coordinated advances in engineering, biology, and standardization to establish OoC platforms as robust, clinically relevant tools for musculoskeletal medicine.