‘A leading-edge preclinical testing method’

Intestine-on-a-Chip promises better personalized medicine

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BOSTON—Emulate Inc. has expanded its Organs-on-Chip library to include an initially successful Duodenum Intestine-Chip, which appears to recreate true-to-life functions of the small intestine and colon. The chip is created using endoscopic biopsies of healthy adult human donors coupled with primary human intestinal microvascular endothelial cells derived from human small intestine. When populated with organoids, these chips appear to outperform organoids alone as a mechanism to predict human response to various drugs.
As with each of Emulate’s Organ-Chips—for organs including the lung, liver, brain or kidney—the Intestine-Chip is lined with tens of thousands of living human cells and tissue, and then integrated within the instrumentation of their Human Emulation System to recreate the true-to-life physiology that cells experience within the human body. While Emulate’s chip design is universal, the cells within each Organ-Chip and the tuning of the surrounding instrumentation are customized to reflect the distinct biology of each human organ, allowing a more reliable platform through which to study disease and pharmacological interventions.
In a study conducted in partnership with Johns Hopkins School of Medicine and published in the journal eLife, researchers found two essential elements of the Intestine-Chip’s functionality. First, the Intestine-Chip produced a nearly identical genetic signature at the transcriptomic level compared to human intestine duodenum tissue, showing its ability to emulate the human intestine tissue for highly predictive drug assessment. Second, it showed that the biology of important drug transporters and drug metabolizing enzymes of the intestine remained intact in the Intestine-Chip, which opens up new testing capabilities beyond current animal testing because of the unique human species-specific nature of these drug transporters and enzymes.
Together, these findings show that the Intestine-Chip offers a technology for more human-relevant and robust system to better predict pharmacokinetics and drug-drug interaction.
“One of the most compelling findings from this published research is the demonstration that intestinal organoids function extremely well in the Intestine-Chip,” according to Geraldine A. Hamilton, president and chief scientific officer of Emulate. “Emulate’s Intestine-Chip recreates the biology of the human intestine by taking advantage of intestinal organoids, which are generated from biopsies and contain multiple cell types, immune cells, microbiota and intricate tissue structures. The Intestine-Chip provides the microenvironment in which these organoids maintain their 3D structure and immune cell function. We see the value of using our Intestine-Chip product with organoids as a leading-edge preclinical testing method.”
Efforts to imitate the intestinal biome for research purposes are not new. A variety of approaches have yielded useful models, but none of them have successfully accounted for the vast differentials in the dynamic and complex intestinal microenvironment. Emulate’s Duodenum Intestine-Chip, currently under development with a rollout planned this year, is demonstrating a robust ability to accurately recreate human intestine tissues for highly predictive and human-relevant preclinical drug assessment.
“Using our Intestine-Chip, we are able to accurately recreate key functions of the human duodenum. These findings show a path forward to using a more human-relevant and robust system to better predict pharmacokinetics and drug-drug interaction,” said Hamilton. “Today, we see the value of using our Intestine-Chip product with organoids as a leading-edge preclinical testing method. Further in the future, we envision exciting potential applications for our Intestine-Chip to utilize cells isolated from individual patients to be used for personalized medicine.”
According to the eLife paper, the Chip appears to succeed where other models have failed in a variety of areas. Emulate successfully applied mechanical forces to recapitulate the blood flow and shear stress which improved the formation of polarized cytoarchitecture and the appearance of intestinal microvilli on the apical cell surface. The Chip also supported successful maturation of all major intestinal epithelial cell types in the physiologically relevant ratios and demonstrated low paracellular permeability.
Importantly for its use in pharmacokinetic studies, it more closely mimics in-vivo expression of drug uptake and efflux transporters and exhibits the correct luminal localization and functional activity observed in the human duodenal tissue. Researchers also found that the organoid-derived intestinal cells can be combined with Organs-on-Chips technology to provide a robust and human-relevant system for preclinical assessment of CYP450-mediated metabolism, activity of drug transporters, and the potential risk of drug-drug interactions.
The study authors are very hopeful about the future utility of the Duodenum Intestine-Chip in personalized medicine, as noted in the conclusion of the paper: “As [the Chip] is composed of cells isolated from individual patients, it could be personalized as needed, in order to assess interindividual differences in drug disposition and responses, study the effect of genetic polymorphisms on pharmacokinetics and pharmacodynamics, as well as decoupling the effect of various factors such as age, sex, disease state, and diet on metabolism, clearance, and bioavailability of xenobiotics. This system could also help us to better understand the basic biology of human intestinal tissue in healthy and disease states and potentially enable novel therapeutic development as we further our understanding of the mechanisms driving key disease phenotypes.”

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