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Review
. 2012 Apr;101(4):1337-54.
doi: 10.1002/jps.23022. Epub 2011 Dec 27.

In vitro blood-brain barrier models: current and perspective technologies

Pooja Naik  1 , Luca Cucullo
Affiliations
Review

In vitro blood-brain barrier models: current and perspective technologies

Pooja Naik et al. J Pharm Sci. 2012 Apr.

Abstract

Even in the 21st century, studies aimed at characterizing the pathological paradigms associated with the development and progression of central nervous system diseases are primarily performed in laboratory animals. However, limited translational significance, high cost, and labor to develop the appropriate model (e.g., transgenic or inbred strains) have favored parallel in vitro approaches. In vitro models are of particular interest for cerebrovascular studies of the blood-brain barrier (BBB), which plays a critical role in maintaining the brain homeostasis and neuronal functions. Because the BBB dynamically responds to many events associated with rheological and systemic impairments (e.g., hypoperfusion), including the exposure of potentially harmful xenobiotics, the development of more sophisticated artificial systems capable of replicating the vascular properties of the brain microcapillaries are becoming a major focus in basic, translational, and pharmaceutical research. In vitro BBB models are valuable and easy to use supporting tools that can precede and complement animal and human studies. In this article, we provide a detailed review and analysis of currently available in vitro BBB models ranging from static culture systems to the most advanced flow-based and three-dimensional coculture apparatus. We also discuss recent and perspective developments in this ever expanding research field.

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Conflict of interest statement

Disclosure/conflict of interest: Dr. Luca Cucullo owns stocks in Flocel Inc.

Figures

Figure 1
Figure 1. Schematic representation of a typical brain microcapillary
Note that the passage of substances across the BBB endothelium is controlled by a multimodal barrier system: (1) gating barrier (tight junctions), which prevent paracellular diffusion of polar molecules; (2) transport barrier, which includes number of active efflux systems (P-gp, MRPs, etc.) with affinity for lipophilic substances; (3) metabolic/enzymatic barrier (cytochrome P450 enzymes, MAO, etc.), which catalyze the oxidation/metabolism of organic substrates including xenobiotic substances such as drugs and other potentially toxic chemicals.
Figure 2
Figure 2. Effect of shear stress forces on BBB endothelial cells
Shear stress (SS) is a major pleiotropic modulator of the endothelial cell physiology by controlling gene involved in the regulation of cell division, differentiation, migration, and apoptosis. For example, the exposure to physiological SS promoted mitotic arrest by contact and the endothelium assumed the typical monolayer appearance observed in vivo.
Figure 3
Figure 3. Schematic representation of a Transwell apparatus
The Transwell (e.g., Corning) is a vertical side by side diffusion system across a semipermeable microporous membrane, which allows for free passage of nutrients and diffusible factors between the luminal and abluminal compartments. Depending on the pore size of the membrane, cell trafficking across the compartments (generally lumen to albumen) can be enabled. Note the cellular layout in monoculture (endothelial cells only) and coculture (luminal endothelial cells, which juxtapose perivascular/abluminal astrocytes) in vitro BBB configurations.
Figure 4
Figure 4. Schematic representation of a cone and plate viscometer
The endothelial monolayer can be exposed to a quasi/uniform laminar or pulsatile shear stress (SS) by the use of a purpose-built cone and plate viscometer. Note that μ is the viscosity, ν is kinematic viscosity, ω is angular velocity, and &agr; is the cone angle. The cone angle and the angular velocity determine the level of SS to which the endothelium is exposed.
Figure 5
Figure 5. Dynamic in vitro BBB model (DIV-BBB)
The top panel shows a schematic representation of a DIV-BBB module. In this system, cerebral endothelial cells are cultured in the lumen of fibronectin-coated polypropylene microporous hollow fibers, in the presence of astrocytes cultured on poly-D-lysine-coated outer surface of the same. The bundle of hollow fibers is suspended inside a sealed chamber. The artificial capillaries are in continuity with a medium source through a flow path consisting of gas-permeable silicon tubing. Ports positioned on either side of the module allow access to the luminal and abluminal compartments. The capillaries are exposed to luminal pulsatile flow generated by a pumping mechanism. Note the pressure waveforms changes (pre-versus postcapillaries) mimicking the rheological changes observed in vivo.
Figure 6
Figure 6. Schematic representation of a 3D ECM-based in vitro BBB model
Note the assembly of a microcapillary-like structure.
See this image and copyright information in PMC

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