Organ Model: Liver

Organ Model: Liver

Application: Toxicology

Highlights

Researchers from AbbVie built rat and dog quad-culture Liver-Chips (hepatocytes + sinusoidal endothelial, Kupffer, and stellate cells) under physiological flow, validated one week of experimental window stability (monitoring albumin, LDH/AST, CYPs/FMO), and then dosed ABT-288. The chips reproduced in vivo, species-specific metabolism: dog chips showed much higher FMO-mediated N-oxide formation and modestly greater toxicity signals (↓albumin, ↑ALT/AST/LDH) than rat—differences that were not seen in liver microsomes or 2D hepatocytes.

Significance: animal-cell MPS models can capture species differences in metabolism-driven hepatotoxicity that conventional in vitro systems miss, providing a translational bridge that both builds confidence in human MPS readouts and can help interpret preclinical safety signals (potentially reducing animal use and de-risking First in Human decisions).

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Organ Model: Liver

Application: Toxicology

Highlights

In this study, researchers used the Emulate Quad-Culture Liver-Chip to evaluate the hepatotoxicity of four phytocannabinoids—CBD, CBN, CBC, and CBG—by continuously dosing chips for 7 days and assessing markers of liver injury. The Liver-Chip revealed compound-specific toxicity profiles, with CBC showing the most pronounced hepatotoxic effects, and provided mechanistic insights into oxidative stress and mitochondrial dysfunction in both hepatocytes and non-parenchymal cells. These findings highlight the Liver-Chip as a human-relevant alternative for liver toxicity screening of cannabinoids.

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Originally presented at the MPS World Summit 2025 Annual Meeting in Brussels, Belgium.

Authors

Randy S. Daughters¹*, Anthony R. Heng¹, Adriana Cespedes¹, Max Winkelman¹, Sushma Jadalannagari¹, Taehee Lee¹, Gabrielle Fortes¹, Jake Chaff¹, Josiah Sliz¹, Lorna Ewart¹

¹ Emulate, Inc., 27 Drydock Avenue, Boston, MA, 02210, USA

Abstract

Emulate’s new Chip-R1™ Rigid Chip is a minimally drug-absorbing Organ-Chip consumable designed for improved in vitro toxicology. It incorporates minimally drug absorbing thermoplastics along with a new porous, cell culture-treated membrane that reduce small lipophilic drug absorption. Validated with a quad culture liver model consisting of human primary hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and stellate cells, Chip-R1 supports physiological features of the liver, including albumin production and small molecule metabolism. Its reduced drug absorption enhances reproducibility and sensitivity in detecting toxicity versus PDMS-based chips. This significant improvement enables more accurate prediction of small molecule toxicity and metabolism in a human-relevant liver model, advancing drug development workflows.

Organ Model: Liver

Application: Toxicology

Highlights

Researchers used the Emulate Liver-Chip S1 Quad-Culture BioKit containing primary human hepatocytes, endothelial cells, stellate cells, and Kupffer cells to model radiation-induced liver disease (RILD). Radiation exposure on the chip reproduced key features of RILD—including DNA damage, cellular senescence, metabolic and endothelial dysfunction, inflammation, and stellate cell activation—and enabled discovery of molecular pathways involved. The chip was further used to test N-acetylcysteine amide (NACA), which reduced radiation-associated damage and supported identification of potential biomarkers for radiation response and treatment efficacy.

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Article Type: Perspective

Organ Models: Liver

Application: Toxicology

Abstract: Predicting which drugs might have the potential to cause drug-induced liver injury (DILI) is highly complex and the current methods, 2D cell-based models and animal tests, are not sensitive enough to prevent some costly failures in clinical trials or to avoid all patient safety concerns for DILI post-market. Animal-based methods are hampered by important species differences in metabolism and adaptive immunity compared to humans and the standard 2D in vitro approaches have limited metabolic functionality and complexity. On 24 April 2023 the Alliance for Human Relevant Science hosted a workshop at the Royal Society, London entitled Drug-Induced Liver Injury (DILI): Can Human-Focused Testing Improve Clinical Translation? The conclusion was that complex in vitro models (CIVMs) provide a significant step forward in the safety testing paradigm. This perspective article, written by the participants, builds on those discussions to provide a ‘state of play’ on liver CIVMs with recommendations for how to encourage their greater uptake by the pharmaceutical industry.

Organ Model: Liver

Application: Inflammation & Disease Modeling

How Organ-Chips Were Used: The Liver-Chip S1 Quad Culture was used to model hepatic steatosis and validate proteomic and transcriptomic targets identified in human cohorts.

Key highlights:

• Early stage MASLD was mimicked on Liver-Chips by treating both channels with a combination of fatty acids (oleic acid and palmitic acid) for 5 consecutive days.
• The Liver-Chip recapitulated key features of hepatic steatosis, including lipid accumulation and transcriptional changes in response to fatty acid treatment.
• The protein secretion patterns from hepatocytes and non-parenchymal cells in the Liver-Chips were consistent with the proteomic findings in human populations.
• The model demonstrated its utility for studying dynamic cellular responses to steatosis and identifying cell-specific biomarkers relevant for MASLD.

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Discover a new standard in Organ-on-a-Chip technology with the Emulate Chip-R1™ Rigid Chip. This new Organ-Chip consumable is designed to minimize drug absorption for enhanced precision in drug toxicology, ADME, and efficacy studies. The Chip-R1 maintains the two-channel architecture of the Chip-S1^® Stretchable Chip while incorporating several enhancements, including low-absorbing rigid materials, increased maximum shear stress in the vascular channel, a tissue-culture treated membrane for streamlined workflows, and a reduced chip membrane pore diameter. 

Watch our expert speakers as they dive into the advanced features of the Chip-R1 and share data from our Liver-Chip R1 Application Note, demonstrating how this consumable can be used to model the liver sinusoid and improve prediction of drug-induced liver injury (DILI). 

In this webinar, you will: 

• Discover the advanced features of the Chip-R1, including its low-absorbing materials, pre-activated tissue culture membrane, and increased maximum vascular channel shear force. 
• See how low-drug-absorbing materials reduce compound loss, enabling more precise toxicity and efficacy assessments for lipophilic small molecules. 
• Explore the Liver-Chip R1’s robust liver functionality, including albumin production, metabolic activity, and immunofluorescence imaging of the four primary cell types of the human liver sinusoid. 
• Learn how to leverage the Liver-Chip R1 for improved DILI detection, with comparative data highlighting the advantages of Liver-Chip R1 over Liver-Chip S1.

Discover how the Liver-Chip S1 is transforming drug development and toxicology prediction. This white paper highlights key findings from our 2022 Communications Medicine study, where the Liver-Chip achieved 87% sensitivity and 100% specificity in detecting drug-induced liver injury across 870 chips.

What’s inside:

• How the Liver-Chip S1 outperforms traditional models by delivering human-relevant insights into drug safety.
• The potential $3B+ annual productivity impact of integrating the Liver-Chip S1 into R&D workflows.
• Regulatory milestones, including Liver-Chip S1 acceptance into the FDA ISTAND program.
• Advancing drug testing precision with the Liver-Chip R1, which addresses non-specific binding.

Explore the next generation of preclinical safety testing. Download the white paper now to see how Emulate Organ-on-a-Chip technology is reshaping toxicology prediction and accelerating safer therapeutics to market.

The Chip-R1 Rigid Chip minimizes drug absorption while maintaining the essential architecture of Chip-S1. This enables researchers to build biologically complex Organ-Chip models for tissues that do not require stretch (e.g., liver, kidney, brain, and lung airway).

Here, we describe the development of the Chip-R1 Rigid Chip and the Liver-Chip R1 organ model, including data from an equivalency study that demonstrates its utility in modeling the liver and predicting drug hepatotoxicity.

• The Chip-R1™ Rigid Chip has the same two-channel configuration as the Chip-S1® Stretchable Chip, with several updates, including reduced drug absorption.
• The Liver-Chip R1 demonstrates robust liver functionality, as indicated by morphology, marker expression, albumin production, and drug metabolism.
• The Liver-Chip R1 displays increased sensitivity to detecting the drug-induced liver injury risk of small-molecule drugs with absorption liability in PDMS.
• The Chip-R1 exhibits reduced absorption of a range of small molecules with diverse physicochemical properties.

The Liver-Chip R1 BioKit contains all the components needed to build a Liver-Chip R1 using the Chip-R1^® Rigid Chip. Designed to minimize drug absorption and enhance biological modeling by using low-drug-absorbing materials, this model is particularly well-suited for applications in which drug absorption is a concern, including human-relevant assessments of drug toxicology, efficacy, and ADME profiles​​.