4.8 Article

3D In Vitro Blood-Brain-Barrier Model for Investigating Barrier Insults

Journal

ADVANCED SCIENCE
Volume 10, Issue 11, Pages -

Publisher

WILEY
DOI: 10.1002/advs.202205752

Keywords

3D models; blood-brain-barrier; cerebral ischemia; microfluidics; transendothelial electrical resistance (TEER)

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This study presents a human-cell-based platform for monitoring the tightness of the blood-brain barrier in real time. The results demonstrate that oxygen-glucose deprivation induces cellular actin remodeling and morphological changes in endothelial cells, leading to barrier breakage. The platform recapitulates the main barrier functions and can be used to investigate the reorganization of the blood-brain barrier.
Blood-brain-barrier (BBB) disruption has been associated with a variety of central-nervous-system diseases. In vitro BBB models enable to investigate how the barrier reacts to external injury events, commonly referred to as insults. Here, a human-cell-based BBB platform with integrated, transparent electrodes to monitor barrier tightness in real time at high resolution is presented. The BBB model includes human cerebral endothelial cells and primary pericytes and astrocytes in a 3D arrangement within a pump-free, open-microfluidic platform. With this platform, this study demonstrates that oxygen-glucose deprivation (OGD), which mimics the characteristics of an ischemic insult, induces a rapid remodeling of the cellular actin structures and subsequent morphological changes in the endothelial cells. High-resolution live imaging shows the formation of large actin stress-fiber bundles in the endothelial layer during OGD application, which ultimately leads to cell shrinkage and barrier breakage. Simultaneous electrical measurements evidence a rapid decrease of the barrier electrical resistance before the appearance of stress fibers, which indicates that the barrier function is compromised already before the appearance of drastic morphological changes. The results demonstrate that the BBB platform recapitulates the main barrier functions in vitro and can be used to investigate rapid reorganization of the BBB upon application of external stimuli.

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