Abstract
The blood-brain barrier (BBB) is a critical structure that serves as the gatekeeper between the central nervous system and the rest of the body. It is the responsibility of the BBB to facilitate the entry of required nutrients into the brain and to exclude potentially harmful compounds; however, this complex structure has remained difficult to model faithfully in vitro. Accurate in vitro models are necessary for understanding how the BBB forms and functions, as well as for evaluating drug and toxin penetration across the barrier. Many previous models have failed to support all the cell types involved in the BBB formation and/or lacked the flow-created shear forces needed for mature tight junction formation. To address these issues and to help establish a more faithful in vitro model of the BBB, we have designed and fabricated a microfluidic device that is comprised of both a vascular chamber and a brain chamber separated by a porous membrane. This design allows for cell-to-cell communication between endothelial cells, astrocytes, and pericytes and independent perfusion of both compartments separated by the membrane. This NeuroVascular Unit (NVU) represents approximately one-millionth of the human brain, and hence, has sufficient cell mass to support a breadth of analytical measurements. The NVU has been validated with both fluorescein isothiocyanate (FITC)-dextran diffusion and transendothelial electrical resistance. The NVU has enabled in vitro modeling of the BBB using all human cell types and sampling effluent from both sides of the barrier.
Highlights
The blood-brain barrier (BBB) is a critical structure acting as the gatekeeper between the central nervous system (CNS) and the rest of the body
Many previous models have failed to support all the cell types involved in the BBB formation and/or lacked the flowcreated shear forces needed for mature tight junction formation
Current in vitro BBB models, such as the popular transwell-based cell culture method,56 are predominantly static, i.e., they lack flow and the shear forces needed for mature barrier formation
Summary
The blood-brain barrier (BBB) is a critical structure acting as the gatekeeper between the central nervous system (CNS) and the rest of the body. Traffic of small molecules, hormones, and nutrients between the body and the brain but it is the principal means of regulating drug and toxin access into the brain Because of these features, the ability to model the BBB is essential to testing the delivery and safety of drugs designed to act in the CNS. In addition to multiple cell types, true formation of a BBB requires shear forces experienced by endothelial cells from blood circulation, as well as the differential serum concentration across the BBB.. In addition to multiple cell types, true formation of a BBB requires shear forces experienced by endothelial cells from blood circulation, as well as the differential serum concentration across the BBB.3,4 Recapitulation of this complicated and dynamic barrier of the BBB requires innovation for high fidelity modeling It has been shown that both cell-to-cell interactions and diffusible cues from the CNS, primarily originating from pericytes and astrocytes, are necessary for cell polarity and the proper formation of tight junctions. In addition to multiple cell types, true formation of a BBB requires shear forces experienced by endothelial cells from blood circulation, as well as the differential serum concentration across the BBB. recapitulation of this complicated and dynamic barrier of the BBB requires innovation for high fidelity modeling
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