Organ-on-a-chip for diabetes drug discovery

Burcak Yesildag from InSphero and Patrick Misun from the Bio Engineering Laboratory of ETH Zürich in Basel talk about a new testing platform that will help diabetes researchers to find new drugs and to get deeper insights into underlying biological mechanisms.

02.07.2020 by Melanie Johnson

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Illustration of the organ-on-chip platform with a hanging drop — Fig. 1 Mock-up illustration of the organ-on-chip platform – the chip enables researchers to maintain sample tissues in hanging drops.

You are using human cells on your chip?

Patrick: That is correct. We build platforms for testing drugs outside the body under conditions that resemble those in the living organ as closely as possible. Our goal is to obtain physiologically meaningful and reproducible data. In this particular case, we studied the insulin secretion of pancreatic microtissues over time.

Your chip has an unusual design. It is open at the bottom. Drops are dangling from it. Why should researchers do secretion studies in hanging drops instead of properly enclosed chambers? The set-up looks a bit shaky ….

Patrick: The hanging drops have proven to provide an absolutely reliable and reproducible environment for drug testing on microtissues. We place single microtissues in individual drops, where they settle at the water-air-interface at the bottom of the drop (see fig. 2). We perfuse small volumes of liquid directly through these hanging drops to provide the tissue with nutrients and to expose them to drugs. Flowing liquids inside hanging drops feature a unique flow pattern compared to flows in closed chambers. We take advantage of this specific flow pattern to obtain secretion profiles at high temporal resolution.

sample human islet tissue and tissue inside a hanging drop — Fig. 2 (left) Sample human islet tissue. (right) Tissue inside a hanging drop. Nutrients as well as drugs flow smoothly through the hanging drop.

Where does the sample tissue come from?

Patrick: This is a question for my colleague Burcak from InSphero. For this project, we have an excellent collaboration, in which ETH Zürich covers the engineering part for the organ-on-chip tests and InSphero prepares the microtissues.

Burcak: Indeed, our complementary skills come in handy. At InSphero, we prepare the pancreatic microtissues from donor organs. We obtain isolated human-donor islets, which are the microorgans in the pancreas secreting hormones such as insulin, which regulates the blood-sugar level in our body. We disassemble the islets, which come in different sizes and compositions, and reassemble them into standardised three-dimensional microtissues. The more regular the sample tissue is, the more reproducible will be the outcome of experiments with these tissues.

Are these fabricated microtissue still natural?

Burcak: Our pancreatic microtissues closely mimic the structure of the original human islets and preserve their natural response to various stimuli. When exposed to a high concentration of glucose, they display a first instantaneous burst of insulin secretion. Several minutes later, a somewhat less intense, but well-sustained oscillatory release of insulin follows (see fig. 3). In case of diabetes, these responses are impaired, and there are multiple strategies aiming at restoring healthy insulin secretion. Researchers want to observe these details at high temporal resolution so that they can better understand the mechanisms underlying diabetes and develop compounds for its treatment. The combination of robustly functioning islet microtissues with Patrick’s hanging-drop platform provides unprecedented temporal resolution as far as we know.

graph showing insulin secretion over time and corresponding glucose levels — Fig. 3 Microtissues secrete insulin upon exposure to elevated levels of blood sugar. Insulin secretion follows a very typical pattern: a first burst, followed by a pulsatile second phase.

Last question: Is the organ-on-a-chip platform commercially available?

Burcak: The microtissues are readily available for collaborative projects with InSphero.

Patrick: Currently we have working platform prototypes, and we are open to collaborations with academic and industrial partners for optimizing our platform. Our prototypes enable us to perform very sensitive measurements of single islets. We hope this technological advancement will help diabetes researchers to find new drugs and to get deeper insights into islet biology. In a next step, we would like to increase the experimental throughput, as this is one of the key requirements for compound testing. Also, we are further decreasing the operational complexity with the goal to make the system available for researchers across different laboratories.