Non-invasive sensing of transepithelial barrier function and tissue differentiation in organs-on-chips using impedance spectroscopy

Helm, Marinke W. van der; Henry, Olivier; Bein, Amir; Hamkins-Indik, Tiama; Cronce, Michael J.; Leineweber, William D.; Odijk, Mathieu; Meer, Andries D. van der; Eijkel, Jan C. T.; Ingber, Donald E.; Berg, Albert van den; Segerink, Loes

doi:10.1039/c8lc00129d

Cited by 130 publications

(132 citation statements)

References 29 publications

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“…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] . The TEER values measured in this study thus were simply used to compare the barrier integrity between the EC only and the BBB models in the same device for the purpose of cross-validation of permeability coefficient analysis.…”

Section: Discussioncontrasting

confidence: 72%

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

et al. 2020

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Challenges in drug development of neurological diseases remain mainly ascribed to the blood-brain barrier (BBB). Despite the valuable contribution of animal models to drug discovery, it remains difficult to conduct mechanistic studies on the barrier function and interactions with drugs at molecular and cellular levels. Here we present a microphysiological platform that recapitulates the key structure and function of the human BBB and enables 3D mapping of nanoparticle distributions in the vascular and perivascular regions. We demonstrate on-chip mimicry of the BBB structure and function by cellular interactions, key gene expressions, low permeability, and 3D astrocytic network with reduced reactive gliosis and polarized aquaporin-4 (AQP4) distribution. Moreover, our model precisely captures 3D nanoparticle distributions at cellular levels and demonstrates the distinct cellular uptakes and BBB penetrations through receptor-mediated transcytosis. Our BBB platform may present a complementary in vitro model to animal models for prescreening drug candidates for the treatment of neurological diseases.

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Section: Discussioncontrasting

confidence: 72%

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

et al. 2020

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“…These include models such as immortalized 2D cell lines, 3D spheroids, and tissue-on-a-chip for the reconstructed human epidermis and intestine. Future work will include investigation and optimization of fluidic cycles (e.g., by increasing the stabilization time before the test substance is added) and the electrode geometry, and collection of spectrometric information (Gilbert et al, 2019;van der Helm et al, 2019), to create a versatile tissue-on-a-chip tool that can also be applied to lung or other mucous cell models.…”

Section: Resultsmentioning

confidence: 99%

Tissue-on-a-Chip: Microphysiometry With Human 3D Models on Transwell Inserts

Schmidt¹,

Markus

Kanďárová

et al. 2020

Front. Bioeng. Biotechnol.

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Microphysiometry has proved to be a useful tool for monitoring the energy metabolism of living cells and their interactions with other cells. The technique has mainly been used for monitoring two-dimensional (2D) monolayers of cells. Recently, our group showed that it is also possible to monitor the extracellular acidification rate and transepithelial electrical resistance (TEER) of 3D skin constructs in an automated assay maintaining an air-liquid interface (ALI) with a BioChip extended by 3D-printed encapsulation. In this work, we present an optimized multichannel intestine-on-a-chip for monitoring the TEER of the commercially available 3D small intestinal tissue model (EpiIntestinal TM from MatTek). Experiments are performed for 1 day, during which a 60 min cycle is repeated periodically. Each cycle consists of three parts: (1) maintain ALI; (2) application of the measurement medium or test substance; and (3) the rinse cycle. A cytotoxic and barrierdisrupting benchmark chemical (0.2% sodium dodecyl sulfate) was applied after 8 h of initial equilibration. This caused time-dependent reduction of the TEER, which could not be observed with typical cytotoxicity measurement methods. This work represents a proof-of-principle of multichannel time-resolved TEER monitoring of a 3D intestine model using an automated ALI. Reconstructed human tissue combined with the Intelligent Mobile Lab for In vitro Diagnostic technology represents a promising research tool for use in toxicology, cellular metabolism studies, and drug absorption research.

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“…During the last decade, these findings have led to the massive efforts regarding the development of microfluidic organs-on-a-chip mimicking the entire human body [148,149]; in fact, at least one microfluidic-based model has been made to reproduce lung [147,[150][151][152], gut [153][154][155][156][157], brain [158][159][160], eye [161,162], skin [163,164], liver [165][166][167][168], kidney [169,170], pancreas [171,172], adipose tissue [173,174], and heart [175][176][177] (Figure 5). An overview of all these organs-on-a-chip is beyond the scope of the present review, but we want to focus on some examples related to their application to toxicology.…”

Section: Organs- Organoids-on-a-chip and 3d Printingmentioning

confidence: 99%

Microfluidics as a Novel Tool for Biological and Toxicological Assays in Drug Discovery Processes: Focus on Microchip Electrophoresis

et al. 2020

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The last decades of biological, toxicological, and pharmacological research have deeply changed the way researchers select the most appropriate ‘pre-clinical model’. The absence of relevant animal models for many human diseases, as well as the inaccurate prognosis coming from ‘conventional’ pre-clinical models, are among the major reasons of the failures observed in clinical trials. This evidence has pushed several research groups to move more often from a classic cellular or animal modeling approach to an alternative and broader vision that includes the involvement of microfluidic-based technologies. The use of microfluidic devices offers several benefits including fast analysis times, high sensitivity and reproducibility, the ability to quantitate multiple chemical species, and the simulation of cellular response mimicking the closest human in vivo milieu. Therefore, they represent a useful way to study drug–organ interactions and related safety and toxicity, and to model organ development and various pathologies ‘in a dish’. The present review will address the applicability of microfluidic-based technologies in different systems (2D and 3D). We will focus our attention on applications of microchip electrophoresis (ME) to biological and toxicological studies as well as in drug discovery and development processes. These include high-throughput single-cell gene expression profiling, simultaneous determination of antioxidants and reactive oxygen and nitrogen species, DNA analysis, and sensitive determination of neurotransmitters in biological fluids. We will discuss new data obtained by ME coupled to laser-induced fluorescence (ME-LIF) and electrochemical detection (ME-EC) regarding the production and degradation of nitric oxide, a fundamental signaling molecule regulating virtually every critical cellular function. Finally, the integration of microfluidics with recent innovative technologies—such as organoids, organ-on-chip, and 3D printing—for the design of new in vitro experimental devices will be presented with a specific attention to drug development applications. This ‘composite’ review highlights the potential impact of 2D and 3D microfluidic systems as a fast, inexpensive, and highly sensitive tool for high-throughput drug screening and preclinical toxicological studies.

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Non-invasive sensing of transepithelial barrier function and tissue differentiation in organs-on-chips using impedance spectroscopy

Abstract: Combining impedance spectroscopy with electrical simulation to reveal transepithelial barrier function and tissue structure of human intestinal epithelium cultured in an organ-on-chip.

Cited by 130 publications

References 29 publications

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

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

Tissue-on-a-Chip: Microphysiometry With Human 3D Models on Transwell Inserts

Microfluidics as a Novel Tool for Biological and Toxicological Assays in Drug Discovery Processes: Focus on Microchip Electrophoresis

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