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

Samuel H Kann; Erin M Shaughnessey; Jonathan R Coppeta; Hesham Azizgolshani; Brett C Isenberg; Else M Vedula; Xin Zhang; Joseph L Charest

doi:10.1038/s41378-022-00442-7

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

Microsyst Nanoeng. 2022 Sep 29:8:109. doi: 10.1038/s41378-022-00442-7. eCollection 2022.

Authors

Samuel H Kann^{1

2}, Erin M Shaughnessey^{1

3}, Jonathan R Coppeta⁴, Hesham Azizgolshani⁴, Brett C Isenberg⁴, Else M Vedula⁴, Xin Zhang², Joseph L Charest^{4

5}

Affiliations

¹ Draper Scholar, 555 Technology Square, Cambridge, MA 02139 USA.
² Department of Mechanical Engineering, Boston University, 110 Cummington Mall, Boston, MA 02215 USA.
³ Department of Biomedical Engineering, Tufts University, 4 Colby Street, Medford, MA 02155 USA.
⁴ Draper, 555 Technology Square, Cambridge, MA 02139 USA.
⁵ Present Address: Biogen, 225 Binney Street, Cambridge, MA 02142 USA.

Abstract

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. Each membrane bilayer device supported a culture of human renal proximal tubule epithelial cells on a porous membrane suspended between two microchannels and exposed to controlled, unidirectional perfusion and physiologically relevant shear stress for several days. For the first time, we measured changes in oxygen in a membrane bilayer format and used a finite element analysis model to estimate cell oxygen consumption rates (OCRs), allowing comparison with OCRs from other cell culture systems. Finally, we demonstrated label-free detection of metabolic shifts in human renal proximal tubule cells following exposure to FCCP, a drug known for increasing cell oxygen consumption, as well as oligomycin and antimycin A, drugs known for decreasing cell oxygen consumption. The capability to measure cell OCRs and detect metabolic shifts in an array of membrane bilayer devices contained within an industry standard microtiter plate format will be valuable for analyzing flow-responsive and physiologically complex tissues during drug development and disease research.

Keywords: Chemistry; Engineering.