High Content Analysis of an In Vitro Model for Metabolic Toxicity: Results with the Model Toxicants 4-Aminophenol and Cyclophosphamide

Cole, Stephanie D.; Madren-Whalley, Janna S.; Li, Albert P.; Dorsey, Russell; Salem, Harry

doi:10.1177/1087057114550399

Cited by 10 publications

(5 citation statements)

References 11 publications

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“…A liver-lung µCCA developed by Viravaidya et al demonstrated liver metabolism dependent naphthalene toxicity towards lung epithelial cells. [44] A liver-fibroblast model built on the IdMOC platform showed that the presence of hepatocytes modified the viability of fibroblasts in response to 4-aminophenol and cyclophosphamide treatment through diffusible metabolites after liver detoxification or activation of the drugs, [149] while the cytotoxic effects of aflatoxin B1 were only limited to the liver compartment after the metabolic activation with no toxicant diffused to outside of the liver cells. [150] Liver-skin models using HepaRG hepatocyte spheroids and skin biopsies were built on the transwell compatible, pneumatic micropump-driven recirculating MOM platform, and used to study chronic toxicity of repeated dosing of troglitazone for up to 9 days.…”

Section: Applications For Multi-organ Microphysiological Systemsmentioning

confidence: 99%

Multiorgan Microphysiological Systems for Drug Development: Strategies, Advances, and Challenges

Wang

Carmona

Hickman

et al. 2017

Adv Healthcare Materials

113

105

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Traditional cell culture and animal models utilized for preclinical drug screening have led to high attrition rates of drug candidates in clinical trials due to their low predictive power for human response. Alternative models using human cells to build in vitro biomimetics of the human body with physiologically relevant organ-organ interactions hold great potential to act as "human surrogates" and provide more accurate prediction of drug effects in humans. This review is a comprehensive investigation into the development of tissue-engineered human cell-based microscale multiorgan models, or multiorgan microphysiological systems for drug testing. The evolution from traditional models to macro- and microscale multiorgan systems is discussed in regards to the rationale for recent global efforts in multiorgan microphysiological systems. Current advances in integrating cell culture and on-chip analytical technologies, as well as proof-of-concept applications for these multiorgan microsystems are discussed. Major challenges for the field, such as reproducibility and physiological relevance, are discussed with comparisons of the strengths and weaknesses of various systems to solve these challenges. Conclusions focus on the current development stage of multiorgan microphysiological systems and new trends in the field.

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Section: Applications For Multi-organ Microphysiological Systemsmentioning

confidence: 99%

Multiorgan Microphysiological Systems for Drug Development: Strategies, Advances, and Challenges

Wang

Carmona

Hickman

et al. 2017

Adv Healthcare Materials

113

105

View full text Add to dashboard Cite

show abstract

“…HCS has also been applied to cocultures of PHHs and stromal cells by developing computational algorithms that can separate out the fluorescent intensities from multiple cell types based on nuclear size/shape or other cell type-specific signals [ 91 ]. The “Integrated Discrete Multiple Organ Coculture” (IdMOC) system was used to coculture PHHs and 3T3-L1 cells in separate wells that share culture media for the assessment of multiple endpoints after 4-aminophenol and cyclophosphamide exposure [ 92 ]. HCS has recently been adapted to monolayers of iPSC-HHs [ 93 , 94 ].…”

Section: High Content Readoutsmentioning

confidence: 99%

Advances in Engineered Liver Models for Investigating Drug-Induced Liver Injury

Lin

Khetani

2016

BioMed Research International

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Drug-induced liver injury (DILI) is a major cause of drug attrition. Testing drugs on human liver models is essential to mitigate the risk of clinical DILI since animal studies do not always suffice due to species-specific differences in liver pathways. While primary human hepatocytes (PHHs) can be cultured on extracellular matrix proteins, a rapid decline in functions leads to low sensitivity (<50%) in DILI prediction. Semiconductor-driven engineering tools now allow precise control over the hepatocyte microenvironment to enhance and stabilize phenotypic functions. The latest platforms coculture PHHs with stromal cells to achieve hepatic stability and enable crosstalk between the various liver cell types towards capturing complex cellular mechanisms in DILI. The recent introduction of induced pluripotent stem cell-derived human hepatocyte-like cells can potentially allow a better understanding of interindividual differences in idiosyncratic DILI. Liver models are also being coupled to other tissue models via microfluidic perfusion to study the intertissue crosstalk upon drug exposure as in a live organism. Here, we review the major advances being made in the engineering of liver models and readouts as they pertain to DILI investigations. We anticipate that engineered human liver models will reduce drug attrition, animal usage, and cases of DILI in humans.

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“…Advancement of 3Rs research is one of the objectives of Mahatma Gandhi-Doerenkamp Center (MGDC). [ 38 39 40 41 ] This objective was realized when MGDC and Dr. Albert Li, CEO, AP Sciences, USA, entered into an understanding to distribute IdMOC plates, free of cost, to deserving researchers. Through this arrangement, Dr. Li, the inventor of this technology, provides a gift of a substantial number of IdMOC plates to MGDC for distribution to qualified and competent Indian scientists interested in in vitro toxicology/pharmacology for their research endeavors.…”

Section: Popularization Of Idmoc Technologymentioning

confidence: 99%

“…Thus, the conjunction of high content analysis with the IdMOC technology provides quick and high-quality screening of multiple compounds for hepatotoxicity and the effects of hepatic metabolism on non-liver cell types. [39] POPULARIZATION OF IdMOC TECHNOLOGY…”

Section: Metabolic Toxicitymentioning

confidence: 99%

Scientific concepts and applications of integrated discrete multiple organ co-culture technology

Gayathri

Dhanasekaran

Akbarsha

2015

Journal of Pharmacology and Pharmacotherapeutics

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Over several decades, animals have been used as models to investigate the human-specific drug toxicity, but the outcomes are not always reliably extrapolated to the humans in vivo. Appropriate in vitro human-based experimental system that includes in vivo parameters is required for the evaluation of multiple organ interaction, multiple organ/organ-specific toxicity, and metabolism of xenobiotic compounds to avoid the use of animals for toxicity testing. One such versatile in vitro technology in which human primary cells could be used is integrated discrete multiple organ co-culture (IdMOC). IdMOC system adopts wells-within-well concept that facilitates co-culture of cells from different organs in a discrete manner, separately in the respective media in the smaller inner wells which are then interconnected by an overlay of a universal medium in the large containing well. This novel in vitro approach mimics the in vivo situation to a great extent, and employs cells from multiple organs that are physically separated but interconnected by a medium that mimics the systemic circulation and provides for multiple organ interaction. Applications of IdMOC include assessment of multiple organ toxicity, drug distribution, organ-specific toxicity, screening of anticancer drugs, metabolic cytotoxicity, etc.

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High Content Analysis of an In Vitro Model for Metabolic Toxicity: Results with the Model Toxicants 4-Aminophenol and Cyclophosphamide

Cited by 10 publications

References 11 publications

Multiorgan Microphysiological Systems for Drug Development: Strategies, Advances, and Challenges

Multiorgan Microphysiological Systems for Drug Development: Strategies, Advances, and Challenges

Advances in Engineered Liver Models for Investigating Drug-Induced Liver Injury

Scientific concepts and applications of integrated discrete multiple organ co-culture technology

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