Review of Design Considerations for Brain-on-a-Chip Models

Abstract

In recent years, the need for sophisticated human in vitro models for integrative biology has motivated the development of organ-on-a-chip platforms. Organ-on-a-chip devices are engineered to mimic the mechanical, biochemical and physiological properties of human organs; however, there are many important considerations when selecting or designing an appropriate device for investigating a specific scientific question. Building microfluidic Brain-on-a-Chip (BoC) models from the ground-up will allow for research questions to be answered more thoroughly in the brain research field, but the design of these devices requires several choices to be made throughout the design development phase. These considerations include the cell types, extracellular matrix (ECM) material(s), and perfusion/flow considerations. Choices made early in the design cycle will dictate the limitations of the device and influence the end-point results such as the permeability of the endothelial cell monolayer, and the expression of cell type-specific markers. To better understand why the engineering aspects of a microfluidic BoC need to be influenced by the desired biological environment, recent progress in microfluidic BoC technology is compared. This review focuses on perfusable blood–brain barrier (BBB) and neurovascular unit (NVU) models with discussions about the chip architecture, the ECM used, and how they relate to the in vivo human brain. With increased knowledge on how to make informed choices when selecting or designing BoC models, the scientific community will benefit from shorter development phases and platforms curated for their application.

Vascularizing the brain in vitro

“…When tested with 20-kDa and 70-kDa fluorescein isothiocyanate (FITC)-dextran, the model had low permeability coefficients that were consistent with the results in vivo ( Yuan et al., 2009 ). Yet, the culture model suffered from two major inconveniences, including its use of umbilical cord ECs rather than brain-derived ECs, and non-employment of PCs whereas they have shown their essential role in the formation of the BBB in other studies ( Abbott et al., 2010 ; Cameron et al., 2021 ; Wilhelm and Krizbai, 2014 ).…”

Modeling the blood-brain barrier for treatment of central nervous system (CNS) diseases

“… 140 In recent years, tissue chips have become extremely popular in BBB modeling not only for patient specific cultures, but to hopefully eradicate the need for animal studies in drug discovery, especially in industrial settings where high throughput manufacturing, analysis, and implementation are required. 141 One shortcoming of current studies focusing on microfluidics is that the complexity of the BBB is still not being matched. In addition to microfluidics, newer models, specifically organoids, are being used to mimic the BBB.…”

Brain-on-a-Chip: Characterizing the next generation of advanced in vitro platforms for modeling the central nervous system

“… 8–12 , 42 , and 75 for reviews of advanced in vitro models of the CNS, in general; and see Refs. 17–35 and 76 for specific reviews of the Brain-on-a-Chip). Accordingly, in what follows, I will provide only a brief overview of these technologies.…”