Abstract
Neurology has always been one of the therapeutic areas with higher attrition rates. One of the main difficulties is the presence of the blood–brain barrier (BBB) that restricts access to the brain for major drugs. This low success rate has led to an increasing demand for in vitro tools. The shear stress, which positively affects endothelial cell differentiation by mimicking blood flow, is required for a more physiological in vitro BBB model. We created an innovative device specifically designed for cell culture under shear stress to investigate drug permeability. Our dynamic device encompasses two compartments communicating together via a semi-permeable membrane, on which human cerebral microvascular endothelial (hCMEC/D3) cells were seeded. The fluidic controlled environment ensures a laminar and homogenous flow to culture cells for at least seven days. Cell differentiation was characterized by immunodetection of inter-endothelial junctions directly in the device by confocal microscopy. Finally, we performed permeability assay with lucifer yellow in both static and dynamic conditions in parallel. Our dynamic device is suited to the evaluation of barrier function and the study of drug transport across the BBB, but it could also be used with other human cell types to reproduce intestinal or kidney barriers.
Highlights
While neurological disorders continue to be the world’s leading cause of disability and death, their associated costs are expected to exponentially increase in the coming years [1,2].Neurology has always been one of the therapeutic areas with the highest attrition rates [3,4,5].Effective brain targeting is a prerequisite for the treatment of neurological disorders [6]
The blood–brain barrier (BBB) is primarily composed of brain microvascular endothelial cells (BMEC), forming the wall of cerebral capillaries
Invitrogen, Corning, and Gibco products were purchased from ThermoFisher Scientific (Rockford, IL, USA). hCMEC/D3 cells were kindly provided by Dr Pierre-Olivier Couraud (Inserm U1016, Cochin Institute, Paris, France)
Summary
While neurological disorders continue to be the world’s leading cause of disability and death, their associated costs are expected to exponentially increase in the coming years [1,2]. Effective brain targeting is a prerequisite for the treatment of neurological disorders [6]. One of the main difficulties is the presence of the blood–brain barrier (BBB), which restricts access to the brain for more than 98% of drugs [2]. This structural and functional barrier separates the vasculature from the central nervous system (CNS). The BBB is primarily composed of brain microvascular endothelial cells (BMEC), forming the wall of cerebral capillaries
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