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.

Lab-on-a-chip models of the blood–brain barrier: evolution, problems, perspectives

“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] The channels and sensors provide better opportunities to model the physiological conditions in vitro. 20 The small size of LOC tools makes it easy to transport them between the CO 2 incubator and the measurement devices, or even enables to perform the measurements inside the incubator. BBB studies especially profited from the breakthrough of the LOC techniques, since the dynamic LOC devices have several advantages compared to static culture inserts, e.g.…”

“…9 To address these issues, it appears necessary to physically separate different monitoring functions. 20 For real-time assessment of crucial physical parameters, however, direct access to the BBB model is essential. It is achieved using electrical sensors that measure TEER and/or zeta-potential to gauge transmembrane conductivity and surface electric charge (Fig.…”

“…It will be essential to integrate biosensors in the chip systems to measure multiple physiological BBB parameters including barrier integrity and secretion of biomolecules, but except for TEER measurement, this area is still in its infancy. 20 We anticipate that complex BBB-on-chip co-culture systems will be key to deepen our understanding of cell-cell interactions at the neurovascular unit in the upcoming years.…”

“…9 To address these issues, it appears necessary to physically separate different monitoring functions. 20…”

Experimental Models to Study the Functions of the Blood–Brain Barrier

“…Originally, this model's limitation was the employment of EC monoculture, which restricted its use by omitting the influence of EC interactions with astrocytes and pericytes. However, since the first chip, an increasing number of advanced chips have been developed, e.g., based on multicultures, where ECs are cultured on the top side of the membrane while cocultures of astrocytes and pericytes are placed on the bottom side [128,129]. For the time being, it seems that these models will play crucial roles in HTS testing.…”