Translating microvascularised chips of a nephrotoxicity model

Nephrotoxicity is an important side-effect of many drugs and metabolites, and considerably limits the design of novel therapeutics (e.g. used in chemotherapy and as antibiotics). The kidney vasculature is not only essential for the proper functioning of the kidney, but is also a major mediator of nephrotoxicity and contributes to exacerbate its effects. Drugs used in chemotherapies (e.g. cisplatin) or as antibiotics (e.g. polymyxin) are known to induce nephrotoxicity, which considerably limits their dosage. The correct prediction and understanding of nephrotoxicity is therefore essential to the development of new drugs.

For such predictions, animal models remain the primary models, despite a poor reliability and poor predictive potential of kidney toxicity in patients. Overall, animal models contribute to over 30,000 mice being tested worldwide in the last five years (estimates based on number of articles focused on nephrotoxicity). However, an induced pluripotent stem cell-derived multicellular in vitro model of the kidney (kidney organoid) was recently developed, offering unique opportunities for the modelling of kidney diseases and nephrotoxicity and for personalised medicine. However, these organoids lack the integration of a microvasculature to better mimic key processes associated with kidney diseases and toxicity.

Microfluidic chips, such as those developed in the Gautrot lab (including 3D printed), have proven very successful for the study of angiogenesis, vascularisation and tissue-vasculature interactions in vitro. These platforms allow the control of the microscale geometry and organisation of a vascular network and imaging at high resolution. This project will allow to integrate a microvascularised network within kidney organoids.