Human Kidney Proximal Tubule-Microvascular Model Facilitates High-Throughput Analyses of Structural and Functional Effects of Ischemia-Reperfusion Injury.

Kidney ischemia reperfusion injury (IRI) poses a major global healthcare burden, but effective treatments remain elusive. IRI involves a complex interplay of tissue-level structural and functional changes caused by interruptions in blood and filtrate flow and reduced oxygenation. Existing in vitro models poorly replicate the in vivo injury environment and lack means of monitoring tissue function during the injury process.

Steady-state monitoring of oxygen in a high-throughput organ-on-chip platform enables rapid and non-invasive assessment of drug-induced nephrotoxicity.

High-throughput, rapid and non-invasive readouts of tissue health in microfluidic kidney co-culture models would expand their capabilities for pre-clinical assessment of drug-induced nephrotoxicity. Here, we demonstrate a technique for monitoring steady state oxygen levels in PREDICT96-O, a high-throughput organ-on-chip platform with integrated optical-based oxygen sensors, for evaluation of drug-induced nephrotoxicity in a human microfluidic co-culture model of the kidney proximal tubule (PT). Oxygen consumption measurements in PREDICT96-O detected dose and time-dependent injury responses of human PT cells to cisplatin, a drug with known toxic effects in the PT.

Measurement of oxygen consumption rates of human renal proximal tubule cells in an array of organ-on-chip devices to monitor drug-induced metabolic shifts.

Measurement of cell metabolism in moderate-throughput to high-throughput organ-on-chip (OOC) systems would expand the range of data collected for studying drug effects or disease in physiologically relevant tissue models. However, current measurement approaches rely on fluorescent imaging or colorimetric assays that are focused on endpoints, require labels or added substrates, and lack real-time data. Here, we integrated optical-based oxygen sensors in a high-throughput OOC platform and developed an approach for monitoring cell metabolic activity in an array of membrane bilayer devices.

Evaluation of rapid transepithelial electrical resistance (TEER) measurement as a metric of kidney toxicity in a high-throughput microfluidic culture system.

Rapid non-invasive kidney-specific readouts are essential to maximizing the potential of microfluidic tissue culture platforms for drug-induced nephrotoxicity screening. Transepithelial electrical resistance (TEER) is a well-established technique, but it has yet to be evaluated as a metric of toxicity in a kidney proximal tubule (PT) model that recapitulates the high permeability of the native tissue and is also suitable for high-throughput screening. We utilized the PREDICT96 high-throughput microfluidic platform, which has rapid TEER measurement capability and multi-flow control, to evaluate the utility of TEER sensing for detecting cisplatin-induced toxicity in a human primary PT model under both mono- and co-culture conditions as well as two levels of fluid shear stress (FSS).