Organ-on-a-chip systems for osteochondral units: unveiling biomechanical and pathological mechanisms

With the establishment of key principles governing osteochondral structure, function, and reconstruction, researchers have gained an expanded toolkit for the precise<i>in-vitro</i>reconstruction of osteochondral tissues. As a convergence of tissue engineering and microphysiological modeling, the biomechanical heterogeneity of the osteochondral layers, which is critical to joint function, can be precisely engineered within osteochondral unit-on-a-chip (OC-OoCs), making them ideal tools for studying physiological activities. Specifically speaking, OC-OoCs are regarded as a promising platform for investigating the complex physiology of the osteochondral unit and its pathophysiology in disorders such as osteoarthritis (OA) and osteochondritis dissecans (OCDs). In OA, multiple forms of endochondral ossification, including chondrocalcinosis and osteophyte formation, disrupt the normal tissue relationship of cartilage, subchondral bone plate, and subchondral trabecular bone. Additionally, cellular and molecular communication networks between cartilage and subchondral bone are altered due to increased vascularization, porosity, microcracks, and fissures. Recapitulating these key physiological factors is therefore a critical objective in OC-OoC design. However, incorporation of increasing numbers of physiological parameters inevitably elevates system complexity, posing challenges to chip-to-chip reproducibility and batch-to-batch consistency. Robust quality control (QC) and standardization are thus essential to enhance the reliability and translational value of OC-OoC-derived data. This review summarizes the current advancements in OC-OoCs technology for osteochondral research and, from both diseases oriented as well as translational and clinical perspectives, highlights OC-OoCs' potential to advance our understanding of OA and facilitate the development of novel therapeutic strategies.