Abstract: The global increase in chronic diseases and comorbidities due to aging populations is placing significant strain on healthcare systems. Chronic kidney disease (CKD) and osteoarthritis (OA) are among the most prevalent conditions in the elderly, with complex interconnections driven by shared risk factors such as systemic inflammation and metabolic dysregulation. Despite the critical need to understand these interactions, traditional animal models often fail to adequately capture the multidirectional crosstalk between human comorbid conditions, limiting insights into their mechanisms and complicating translational research. Advancements in microphysiological systems (MPS), which also known as organ‐on‐a‐chip (OoC) technologies, offer a promising alternative for studying comorbidities, such as CKD‐OA. MPS, which integrate human cells within biomimetic, bioengineered platforms, replicate the structural and functional properties of human tissues with unparalleled physiological relevance. This review explores the transformative potential of MPS technology in comorbidity research, focusing on CKD‐OA as a case study. Kidney‐on‐a‐chip and joint‐on‐a‐chip models and their applications in CKD and OA modeling are summarized and discussed. Furthermore, multi‐organ‐on‐a‐chip systems are = discussed for their potential to model comorbidities = and support the development of safer and more effective disease treatment strategies. This review underscores the potential of MPS to revolutionize comorbidity research and pave the way for personalized therapies.
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