The Use of Sensors in Blood-Brain Barrier-on-a-Chip Devices: Current Practice and Future Directions

Abstract

The application of lab-on-a-chip technologies in in vitro cell culturing swiftly resulted in improved models of human organs compared to static culture insert-based ones. These chip devices provide controlled cell culture environments to mimic physiological functions and properties. Models of the blood-brain barrier (BBB) especially profited from this advanced technological approach. The BBB represents the tightest endothelial barrier within the vasculature with high electric resistance and low passive permeability, providing a controlled interface between the circulation and the brain. The multi-cell type dynamic BBB-on-chip models are in demand in several fields as alternatives to expensive animal studies or static culture inserts methods. Their combination with integrated biosensors provides real-time and noninvasive monitoring of the integrity of the BBB and of the presence and concentration of agents contributing to the physiological and metabolic functions and pathologies. In this review, we describe built-in sensors to characterize BBB models via quasi-direct current and electrical impedance measurements, as well as the different types of biosensors for the detection of metabolites, drugs, or toxic agents. We also give an outlook on the future of the field, with potential combinations of existing methods and possible improvements of current techniques.

Keywords: biosensor; blood-brain barrier; cell surface charge; chemosensor; electrical impedance spectroscopy; optical sensor; organ-on-a-chip; streaming potential; transendothelial electrical resistance.

Figure 1

Blood-brain barrier-on-a-chip models. (a) The cellular composition of the blood-brain barrier (BBB). Endothelial cells (EC), which are the functional basis of the BBB, are surrounded by pericytes (PC) and the astrocytes’ endfeet (AC). (b) Schematic representation of a BBB-on-a-chip design with two compartments separated by a porous membrane and the co-culture of three cell types. ‘Blood’ represents the compartment with fluid flow in contact with the luminal plasma membrane of ECs. ‘Brain’ indicates the abluminal compartment in which the PCs and ACs are cultured. (c) Different designs of BBB-on-a-chip models. Created with BioRender.com.

Figure 2

Schematic illustration of BBB-on-a-chip devices with widely used or promising integrated and/or modular (bio)sensors. For electric signal measurements, chip-integrated sensors are used to measure transendothelial electrical resistance (TEER) and electrical impedance spectroscopy, while electrochemical biosensors can be designed as modular sensing techniques. Regarding optical sensing and monitoring, microscopic observation provides a direct and practical chip-integrated approach. Evanescent-field sensing methods, such as surface plasmon resonance or integrated optical (IO) interferometry—e.g., Mach-Zehnder interferometer (MZI)—can be used as modules attached to chips to detect bioparticles, e.g., proteins, pathogens, of interest. The figure was created with Biorender.com.

Figure 3

Current and potential sensing technologies that can be integrated with blood-brain barrier-on-a-chip devices. Abbreviations: TEER, transendothelial electrical resistance; EIS, electrical impedance spectroscopy. Created with BioRender.com.