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Organ Chip Systems Simulate Full Body Drug Responses

Liver chip device

Liver chip device (Wyss Institute, Harvard University)

27 Jan. 2020. A robotic system that ties together multiple chip devices representing different human organs can test for drug effects on patients without affecting the individuals. Researchers from the Wyss Institute for Biologically Inspired Engineering at Harvard University and associated academic and industry labs describe the organ chip system and their results in three separate articles in today’s issue of the journal Nature Biomedical Engineering (paid subscription required on all articles).

One of the Wyss Institute’s main areas of study is chip devices that simulate human organs, to provide safer and more reliable techniques to test effects of drug candidates than lab animals. Testing drugs on animals raises ethical concerns in many individuals, and lab animals with simpler organ systems are not always reliable indicators of a drug’s activity in humans. In addition, early-stage clinical trials, often designed to test for safety and tolerability of drug candidates, enroll human volunteers in many instances, again raising ethical concerns and safety issues for volunteers.

Wyss Institute researchers designed chip devices to simulate several human organs built with small blocks of clear plastic or silicone about the size of a flash memory drive. In the plastic chips are etched fine channels and wells lined with human cells, through which fluids flow, while connected to measuring units. Wyss teams developed chips to simulate intestine, liver, kidney, heart, lung, skin, and the brain, as well as the blood-brain barrier and bone marrow. These organ chips can also be fabricated with cells from specific persons, making it possible to test effects of drugs on individual patients.

The Interrogator

All eight of these chips are linked together in a system simulating interactions of these organs to generate responses near those of the human body to prospective drugs. The platform, called Interrogator, is described in the first Nature Biomedical Engineering article as a robotic-controlled network with a capacity of 10 organ chips that simulates flow of blood and fluids through channels lined with endothelium cells, like those found in blood vessels and other organs.

In lab tests, Interrogator kept cells and tissue on the chips viable for three weeks, while allowing for automated sampling and replacement of cells. An integrated mobile microscope captures images from the chips. In the paper, Wyss Institute researchers and colleagues use Interrogator to predict distribution of an insulin tracer throughout the multiple organs represented in the system. This video shows Interrogator in action.

In the second paper, another Wyss team and colleagues employed a system of three chips on the Interrogator to simulate activity of these organs when encountering two different substances. The researchers first tested an array of intestine, liver, and kidney chips to simulate effects of nicotine, inserting nicotine into the intestine chip to simulate oral ingestion of nicotine, such as with chewing gum to stop smoking, and absorption of the substance.

The test followed the nicotine from the intestine into the liver chip where it’s metabolized, then on to the kidney chip for excretion, tracking the nicotine with mass spectrometry, which also quantified levels of the substance through the system. In addition, the team devised a computational model that converts spectrometry readings from the chips to a full-scale human body. The researchers applied these tools to a simulation of the cancer chemotherapy drug cisplatin, through organ chips representing, kidney, liver, and bone marrow. Cisplatin levels predicted from the organ chip system and computational model matched results from patients in a clinical trial.

Donald Ingber, director of the Wyss Institute, was senior author on all three papers. He notes in an institute statement that “we hope our demonstration that this level of biomimicry is possible using organ chip technology will garner even greater interest from the pharmaceutical industry so that animal testing can be progressively reduced over time.”

Bone marrow chip

A third Nature Biomedical Engineering paper again used the Wyss Institute bone marrow chip, in this case to simulate injury to bone marrow from chemotherapy drugs or radiation. Testing these effects in human bone marrow is difficult, often requiring biopsies, and animals are not reliable substitutes. The chip contains two parallel channels, separated by a permeable membrane. One channel contains bone marrow progenitor cells, similar to stem cells, and the second channel contains a gel material similar to bone marrow with simulated blood vessels lined with endothelium cells.

After verifying the bone marrow chips’ functions, the researchers tested the chip with cancer drugs and radiation similar to cancer therapy. The results show the current chemotherapy drug fluorouracil, known for adverse effects on bone marrow, causes damage to bone marrow in the chip similar to patient experiences, while conventional lab cultures require higher doses of the drug to show damage. A similar test with ionizing gamma-radiation used in radiation therapy also shows toxicity to bone marrow like that experienced by cancer patients.

Another test with an experimental cancer drug in clinical trials shows loss of red and white blood cells using comparable doses as those used in the clinical studies, but lower doses — which can be more readily tested with the chip — show less blood cell damage. The researchers also cultured bone marrow cells from patients with Shwachman-Diamond syndrome, a rare inherited disorder, where bone marrow does not produce all types of white blood cells. With the chip, the team revealed bone marrow with Shwachman-Diamond syndrome produces less of a protein called CD-13 or aminopeptidase, that contributes to few neutrophils, a common white blood cell.

“With this model in hand that can also replicate patient-specific marrow responses,” says Ingber in a separate Wyss Institute statement, “we are in a position to assist in the design of human clinical trials for rare genetic disorders and advance personalized medicine in ways not possible before.”

Among the authors of the first paper is Geraldine Hamilton, president and chief scientist of Emulate Inc., a company spun-off from Wyss Institute to develop and commercialize its organ chip technology. Ingber is the company’s scientific founder.

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