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Organoid in Chip Device Better Simulates Gut Functions

Tissue on intestine chip

Folds in tissue lining an earlier version of the Emulate Inc. intestine chip (Cedars-Sinai Medical Center and Emulate Inc.)

15 Jan. 2020. A chip device simulating intestinal functions, bolstered by a gut tissue organoid, behaves more like a human intestine in lab tests than the gut organoid alone. Researchers from the company Emulate Inc. in Boston that develops organ chip devices, with academic scientists, describe the device and findings in yesterday’s issue of the journal eLife.

The team led by Emulate’s associate research director Magdalena Kasendra is seeking better tools to evaluate the metabolism of drugs in the gut, a key factor in determining toxicity of new drugs, and the interactions of different drugs in the body. Tests with lab animals do not always return reliable results, and raise ethical concerns in many people. As a result, chip devices — blocks of clear plastic the size of microscope slides, with wells and fine channels etched in the surface, lined with human cells — that simulate the functions of organs are being assessed as alternatives to animals.

Another option for lab testing drug candidates without animals is organoids, small three-dimensional samples of organ tissue derived from stem cells. As the stem cells differentiate into mature tissue, they organize and form tiny structures that function in some ways like larger organs. Various labs developed organoids that so far simulate functions of the brain, kidney, lung, intestine, stomach, and liver. In February 2019, Science & Enterprise described development of an organoid with ovarian tumor cells for faster drug testing and precision medicine.

The Emulate team, with colleagues from Johns Hopkins University in Baltimore, tested a chip device simulating the human gut that includes an intestinal tissue organoid as part of the chip. Tests of the company’s duodenum intestine-chip show the device contains specialized cells found in the gut, arrayed in the appropriate architecture. In addition, the chip demonstrates the expression of genes and functioning of efflux pump drug transporters, enzymes that move toxic substances out of gut cells as part of the metabolic process.

One of those enzymes is cytochrome P3A4, or CYP3A4, believed to metabolize about half of all drugs on the market. Tests of the duodenum intestine-chip show the device expressed more of the gene and produced more of the CYP3A4 enzyme than intestinal cell organoids alone, reaching levels similar to those found in the human gut.

The organoids tested in the study were derived from stem cells donated by individual volunteers. As a result, says the team, the research indicates duodenum intestine-chip devices can be created with a patient’s own cells that encourage more use of precision medicine, tailoring treatments that match the patient’s molecular profile. That molecular composition can affect an individual’s response to different drugs, including adverse effects from the interaction of multiple drugs in the gut.

“Using our intestine-chip, we are able to accurately recreate key functions of the human duodenum,” says Emulate’s president Geraldine Hamilton in a company statement. “These findings show a path forward to using a more human-relevant and robust system to better predict pharmacokinetics and drug-drug interaction.”

Emulate Inc. is a spin-off enterprise from the Wyss Institute for Biologically Inspired Engineering at Harvard University. The institute studies and designs human organs on chips.

Intestine chip image

Scanning electron microscope image of cells on an intestine chip showing a well-developed continuous brush border consisting of densely packed microvilli, as well as mature specialized cell types, such as mucus producing goblet cells. (Emulate Inc.)

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