Barriers-on-chips: Measurement of barrier function of tissues in organs-on-chips

Abstract

Disruption of tissue barriers formed by cells is an integral part of the pathophysiology of many diseases. Therefore, a thorough understanding of tissue barrier function is essential when studying the causes and mechanisms of disease as well as when developing novel treatments. In vitro methods play an integral role in understanding tissue barrier function, and several techniques have been developed in order to evaluate barrier integrity of cultured cell layers, from microscopy imaging of cell-cell adhesion proteins to measuring ionic currents, to flux of water or transport of molecules across cellular barriers. Unfortunately, many of the current in vitro methods suffer from not fully recapitulating the microenvironment of tissues and organs. Recently, organ-on-chip devices have emerged to overcome this challenge. Organs-on-chips are microfluidic cell culture devices with continuously perfused microchannels inhabited by living cells. Freedom of changing the design of device architecture offers the opportunity of recapitulating the in vivo physiological environment while measuring barrier function. Assessment of barriers in organs-on-chips can be challenging as they may require dedicated setups and have smaller volumes that are more sensitive to environmental conditions. But they do provide the option of continuous, non-invasive sensing of barrier quality, which enables better investigation of important aspects of pathophysiology, biological processes, and development of therapies that target barrier tissues. Here, we discuss several techniques to assess barrier function of tissues in organs-on-chips, highlighting advantages and technical challenges.

Microengineered human blood–brain barrier platform for understanding nanoparticle transport mechanisms

“…In addition to our evaluation of the barrier function with molecular permeability (permeability coefficient analysis), we measured the TEER values from the electrode wires inserted in the end of the inlet and outlet of the channels, as shown in previous studies [51][52][53] , in order to cross-validate the barrier function difference between our models in the same device (not comparing them with Transwell or other models). We note that 3D astrocyte-laden hydrogel in the lower channel prevents electrodes from being coated along the bottom hydrogel channel as reported in recent studies 22,54 . We also note that the TEER values measured in our current study can be affected by the uneven distribution of the potential across the membrane and may not indicate the accurate values of the cell layer resistance as reported in recent studies [55][56][57] .…”

Multiplexed blood–brain barrier organ-on-chip

“…10 The integrity of the barrier created inside the microfluidic device is usually confirmed by fluorescent imaging, permeability studies, or by means of trans endothelial electrical resistance (TEER) measurements. [24][25][26] Geometry, design and functionality vary for the different in vitro models of the BBB. 18,27 Depending on the research question the most appropriate design can be selected.…”

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

“…[ 398,399 ] Development of new platforms or extension of existing ones is expected to provide insights into molecular mechanisms underlying pathogenesis of neurodegenerative diseases and facilitate drug delivery through the BBB. [ 155,395,400–402 ] However, mechanisms of structural and functional degeneration of the NVU and BBB due to fluctuations in shear stress, cyclic stretch, or pressure and associated changes in strain induced in the vascular wall and adjacent tissue warrant further investigation within these microengineered systems, owing to their important role preceding multiple neural pathologies. In addition, the potential role of the gut microbiota in driving neuronal disorders through changes in vascular permeability and systemic inflammation could also be recapitulated in microphysiological systems.…”