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Review
. 2017 Jan;12(1):89-103.
doi: 10.1080/17460441.2017.1253676. Epub 2016 Nov 7.

New experimental models of the blood-brain barrier for CNS drug discovery

Mohammad A Kaisar  1 , Ravi K Sajja  1 , Shikha Prasad  1 , Vinay V Abhyankar  2 , Taylor Liles  1 , Luca Cucullo  1   3
Affiliations
Review

New experimental models of the blood-brain barrier for CNS drug discovery

Mohammad A Kaisar et al. Expert Opin Drug Discov. 2017 Jan.

Abstract

The blood-brain barrier (BBB) is a dynamic biological interface which actively controls the passage of substances between the blood and the central nervous system (CNS). From a biological and functional standpoint, the BBB plays a crucial role in maintaining brain homeostasis inasmuch that deterioration of BBB functions are prodromal to many CNS disorders. Conversely, the BBB hinders the delivery of drugs targeting the brain to treat a variety of neurological diseases. Area covered: This article reviews recent technological improvements and innovation in the field of BBB modeling including static and dynamic cell-based platforms, microfluidic systems and the use of stem cells and 3D printing technologies. Additionally, the authors laid out a roadmap for the integration of microfluidics and stem cell biology as a holistic approach for the development of novel in vitro BBB platforms. Expert opinion: Development of effective CNS drugs has been hindered by the lack of reliable strategies to mimic the BBB and cerebrovascular impairments in vitro. Technological advancements in BBB modeling have fostered the development of highly integrative and quasi- physiological in vitro platforms to support the process of drug discovery. These advanced in vitro tools are likely to further current understanding of the cerebrovascular modulatory mechanisms.

Keywords: In vitro; alternative; brain; brain disorders; cell culture; cerebrovascular; drug testing; permeability; technology.

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Figures

Figure 1
Figure 1. Schematic illustration of BBB anatomy
A cross-section of brain microcapillary representing luminal compartment composed of basal lamina, endothelial cells and pericytes tightly ensheathed by the astrocytic end-feet. Tight junctions (TJs), present between the cerebral endothelial cells selectively excludes paracellular trafficking of substances from entering into brain.
Figure 2
Figure 2. Schematic diagram of currently available in vitro BBB models simulating in vivo NVU milieu based on two distinct principles- static vs dynamic culture
Static models include transwell and 3D ECM platform while dynamic models utilize hollow fiber based apparatus or micro fluidic devices.
Figure 3
Figure 3. In vitro BBB models on transwell platform using co (left panel) or triple (right panel) culture
BMECs are cultured on top of semipermeable microporous inserts while astrocytes or pericytes are seeded at the bottom (a & b) of the insert or bottom of the wells (c & d) in co-culture conditions. Triple cultures using three different cells pericytes, astrocytes, and/or neurons in different arrangements (e,f,g,h) have also been investigated. Key: a-[129, 130]; b-[129]; c-[14]; d-[13]; e-[21]; f-[9]; g- [131]; h- [10]
Figure 4
Figure 4
Left panel A) Schematic representation of three compartments NVU. B) Microfluidic design layouts with details of each layer C) assembled device with top (blue) and bottom (red) channels. D) Experimental setup with microengineered NVU within environmental chamber for long term imaging. Reproduced from [62] with permission of AIP publishing. Right panel- Confocal imaging of various cell population within the cylindrical collagen lumen. Endothelial cells alone (A–C), with pre-added pericytes (D–F), or astrocytes in the bulk gel (G–I). Magenta is VE-Cadherin, green is F-actin, blue are nuclei. Arrows indicate contact points between cell populations. Reproduced from [63] with permission of PLOS.
Figure 5
Figure 5
Schematic representation of a 3D ECM BBB model. This platform allows the cells to co-exist with other cell populations embedded in environment that contains multiple ECM components, and nurtured by a variety of cell-secreted factors necessary for vasculogenesis/angiogenesis and/or cell migration. Thus microcapillary like structures forms within the 3D matrix.
See this image and copyright information in PMC

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