MRC DiMeN Doctoral Training Partnership: Developing Microfluidic Devices for Cellular Modelling of Inherited Kidney Disorders

Polycystic kidney disease (PKD) and related renal cystic dysplasias arise from defects in cilia-associated proteins such as polycystin-1/2 and fibrocystin, yet their molecular mechanisms remain poorly understood. Current in vitro kidney models incompletely recapitulate human nephrogenesis and often lack physiological cues such as fluid flow. Here, we developed a three-channel microfluidic organ-on-a-chip system to improve differentiation and maturation of human induced pluripotent stem cell (hiPSC), derived kidney organoids, including lines harbouring a predicted biallelic pathogenic PKD2 variant and isogenic controls. The device supported long-term hiPSC culture and differentiation with minimal maintenance, maintained pluripotency under perfusion, and incorporated SU-8 microstructures to enhance early cell adhesion. Kidney organoids generated on-chip formed nephron-like structures expressing markers of the glomerulus, proximal tubule, and collecting duct. Differentiation was accelerated relative to static cultures, with tubular structures appearing 2–3 days earlier and mature organoids achieved by day 18 versus ≥25 days in traditional systems. On-chip organoids exhibited larger and more patent tubules, increased intercalated and principal cell populations, and elevated expression of maturation markers. These findings demonstrate that a simple perfused microfluidic platform can enhance nephron differentiation and complexity, offering an improved model for studying PKD pathogenesis and enabling future applications in live imaging, drug screening, and precision disease modelling.