A high throughput blood–brain barrier model incorporating shear stress with improved predictive power for drug discovery

Abstract

The blood–brain barrier is a key structure regulating the health of the brain and access of drugs and pathogens to neural tissue. Shear stress is a key regulator of the blood–brain barrier; however, the commonly used multi-well vitro models of the blood–brain barrier do not incorporate shear stress. In this work, we designed and validated a high-throughput system for simulating the blood–brain barrier that incorporates physiological flow and incorporates an optimized cellular model of the blood–brain barrier. This system can perform assays of blood–brain barrier function with shear stress, with 48 independent assays simultaneously. Using the high throughput assay, we conducted drug screening assays to explore the effects of compounds for opening or closing blood–brain barrier. Our studies revealed that assays with shear stress were more predictive and were able to identify compounds known to modify the blood–brain barrier function while static assays were not. Overall, we demonstrate an optimized, high throughput assay for simulating the blood–brain barrier that incorporates shear stress and is practical for use in drug screening and other high throughput studies of toxicology.