Introducing an automated high content confocal imaging approach for Organs-on-Chips

Peel, Samantha; Corrigan, Adam; Ehrhardt, Beate; Jang, Kyung Jin; Caetano-Pinto, Pedro; Boeckeler, Matthew; Rubins, Jonathan E.; Kodella, Konstantia; Petropolis, Debora B.; Ronxhi, Janey; Kulkarni, Gauri; Foster, Alison J.; Williams, Dominic P.; Ewart, Lorna

doi:10.1039/c8lc00829a

Cited by 78 publications

(54 citation statements)

References 20 publications

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“…Liver-Chips, fabricated from polydimethylsiloxane (PDMS), contain two microchannels separated by a submillimeter-sized flexible, porous, PDMS membrane. A detailed description of the Liver-Chip can be found in Peel et al (Peel et al 2019).…”

Section: Liver-chip Preparation and Cell Seedingmentioning

confidence: 99%

Integrated in vitro models for hepatic safety and metabolism: evaluation of a human Liver-Chip and liver spheroid

et al. 2019

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Drug-induced liver injury remains a frequent reason for drug withdrawal. Accordingly, more predictive and translational models are required to assess human hepatotoxicity risk. This study presents a comprehensive evaluation of two promising models to assess mechanistic hepatotoxicity, microengineered Organ-Chips and 3D hepatic spheroids, which have enhanced liver phenotype, metabolic activity and stability in culture not attainable with conventional 2D models. Sensitivity of the models to two hepatotoxins, acetaminophen (APAP) and fialuridine (FIAU), was assessed across a range of cytotoxicity biomarkers (ATP, albumin, miR-122, α-GST) as well as their metabolic functionality by quantifying APAP, FIAU and CYP probe substrate metabolites. APAP and FIAU produced dose-and time-dependent increases in miR-122 and α-GST release as well as decreases in albumin secretion in both Liver-Chips and hepatic spheroids. Metabolic turnover of CYP probe substrates, APAP and FIAU, was maintained over the 10-day exposure period at concentrations where no cytotoxicity was detected and APAP turnover decreased at concentrations where cytotoxicity was detected. With APAP, the most sensitive biomarkers were albumin in the Liver-Chips (EC 50 5.6 mM, day 1) and miR-122 and ATP in the liver spheroids (14-fold and EC 50 2.9 mM, respectively, day 3). With FIAU, the most sensitive biomarkers were albumin in the Liver-Chip (EC 50 126 µM) and miR-122 (15-fold) in the liver spheroids, both on day 7. In conclusion, both models exhibited integrated toxicity and metabolism, and broadly similar sensitivity to the hepatotoxicants at relevant clinical concentrations, demonstrating the utility of these models for improved hepatotoxicity risk assessment.

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Section: Liver-chip Preparation and Cell Seedingmentioning

confidence: 99%

Integrated in vitro models for hepatic safety and metabolism: evaluation of a human Liver-Chip and liver spheroid

et al. 2019

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“…In one study, researchers applied a liver‐on‐a‐chip model to evaluate the hepatotoxic effects of both benzbromarone and AstraZeneca drug candidates, illustrating its applicability in drug safety assessment. [ 39 ] Griffith et al have developed a liver‐on‐a‐chip device to distinguish several hepatotoxins (fialuridine acetaminophen and clozapine) from nontoxins (olanzapine and entecavir). [ 40 ]…”

Section: Evolution Of In Vitro Methods For Drug Screeningmentioning

confidence: 99%

Grafting of 3D Bioprinting to In Vitro Drug Screening: A Review

Nie

Gao

et al. 2020

Adv Healthcare Materials

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The inadequacy of conventional cell‐monolayer planar cultures and animal experiments in predicting the toxicity and clinical efficacy of drug candidates has led to an imminent need for in vitro methods with the ability to better represent in vivo conditions and facilitate the systematic investigation of drug candidates. Recent advances in 3D bioprinting have prompted the precise manipulation of cells and biomaterials, rendering it a promising technology for the construction of in vitro tissue/organ models and drug screening devices. This review presents state‐of‐the‐art in vitro methods used for preclinical drug screening and discusses the limitations of these methods. In particular, the significance of constructing 3D in vitro tissue/organ models and microfluidic analysis devices for drug screening is emphasized, and a focus is placed on the grafting process of 3D bioprinting technology to the construction of such models and devices. The in vitro methods for drug screening are generalized into three types: mini‐tissue, organ‐on‐a‐chip, and tissue/organ construct. The revolutionary process of the in vitro methods is demonstrated in detail, and relevant studies are listed as examples. Specifically, the tumor model is adopted as a precedent to illustrate the possible grafting of 3D bioprinting to antitumor drug screening.

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“…The sensing component for detecting and compiling data can be an embedded sensing output component or a transparent chip based visual function evaluation system. Peel et al [48] used automated systems to image multicellular OOACs, producing detailed cell phenotypes and statistical models for measurements. Kane et al [49] developed a cell system to monitor cells in a 3D microfluidic setting.…”

Section: Key Componentsmentioning

confidence: 99%

Organ-on-a-chip: recent breakthroughs and future prospects

et al. 2020

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BackgroundMicrofluidics is a science and technology that precisely manipulates and processes microscale fluids. It is commonly used to precisely control microfluidic (10 −9 to 10 −18 L) fluids using channels that range in size from tens to hundreds of microns and is known as a "lab-on-a-chip" [1][2][3][4]. The microchannel is small, but has a large surface area and high mass transfer, favoring its use in microfluidic technology applications including low regent usage, controllable volumes, fast mixing speeds, rapid responses, and precision control of physical and chemical properties [1,5,6]. Microfluidics integrate sample preparation, reactions, separation, detection, and basic operating units such as cell culture, sorting and cell lysis [7]. For these reasons, interest in OOAC has intensified [8]. OOAC combines a range of chemical, biological and material science disciplines [9] and was selected as one of the "Top Ten Emerging Technologies" in the World Economic Forum [10].OOAC is a biomimetic system that can mimic the environment of a physiological organ, with the ability to regulate key parameters including AbstractThe organ-on-a-chip (OOAC) is in the list of top 10 emerging technologies and refers to a physiological organ biomimetic system built on a microfluidic chip. Through a combination of cell biology, engineering, and biomaterial technology, the microenvironment of the chip simulates that of the organ in terms of tissue interfaces and mechanical stimulation. This reflects the structural and functional characteristics of human tissue and can predict response to an array of stimuli including drug responses and environmental effects. OOAC has broad applications in precision medicine and biological defense strategies. Here, we introduce the concepts of OOAC and review its application to the construction of physiological models, drug development, and toxicology from the perspective of different organs. We further discuss existing challenges and provide future perspectives for its application.

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Introducing an automated high content confocal imaging approach for Organs-on-Chips

Abstract: A novel, automated workflow to capture and analyse confocal images of Organ-Chips allowing detailed assessment of cellular phenotype in situ.

Cited by 78 publications

References 20 publications

Integrated in vitro models for hepatic safety and metabolism: evaluation of a human Liver-Chip and liver spheroid

Integrated in vitro models for hepatic safety and metabolism: evaluation of a human Liver-Chip and liver spheroid

Grafting of 3D Bioprinting to In Vitro Drug Screening: A Review

Organ-on-a-chip: recent breakthroughs and future prospects

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