Kidney-on-Chip and Organoid Models: Harnessing Mechanical Forces for Translational Kidney Biology

The FDA Modernization Act and the subsequent federal policy changes in 2025 have signaled a shift towards the use of non-animal, human-centered models for preclinical drug development and toxicity screening, emphasizing 3D cell-based, organ-on-chip, and organoid platforms as alternatives to animal models. While animal models have been instrumental in improving our understanding of disease mechanisms, they do not allow decoupling of biomechanical and biochemical effects during pathogenesis. Standard in vitro systems offer improved accessibility but often lack physiologically relevant microenvironments. In this review, we discuss how kidney-on-chip and iPSC-derived kidney organoid models serve as physiologically relevant platforms for modeling nephrotoxicity, kidney development, and pathophysiology. Kidney-on-chip models can recapitulate in vivo mechanical forces, such as fluid shear stress and mechanical strain, experienced by cells, enabling real-time functional readouts of glomerular filtration, tubular reabsorption, and potential nephrotoxic response. Integrating on-chip platforms with patient-derived iPSCs and differentiated kidney cell types allows human-relevant responses unavailable in static culture. iPSC-derived kidney organoids recapitulate the 3D architecture of nephron segments and ureteric bud branching patterns, demonstrating selective transport, toxicity responses, and structural stability over months in culture. We detail how bioengineering approaches, including organoid-on-chip models, bioprinting, and multi-organ-on-chip integration, could address the current limitations of these systems, like maturity, scalability and vascularization. We further discuss how integrating publicly available clinical databases and machine learning approaches with on-chip validation can improve translational relevance. We conclude that interdisciplinary collaboration between engineers, biologists, and physician scientists will be essential to translate bioengineered kidney models into clinical and therapeutic applications.