Microtissues in hanging drops mimic organ system

The drops are continuously supplied with nutrient solution, which is pumped into the channels. A rim structure around the edge of the channel prevents liquid from escaping and the platform from being flooded. The nutrient solution is supplied in a way that the drop size remains the same. If too much solution were to be pumped in, the drops would drip off. Frey designed the system without an airtight lid, which makes the new platform much easier to fabricate and operate. However, the cell cultures still need to be stored in an incubator at controlled temperature and high humidity levels.

Body-on-a-chip vision realised

The researchers can also feed active substances to be tested into the system in defined concentrations via supply lines. Thanks to the arrangement of these feed lines, channels, and drops, different substance concentrations can be produced from one microtissue series to the next so that a concentration gradient develops across the entire platform.

This “hanging” microfluidic system, which has just been presented in Nature Communications, enables the BSSE researchers to organise several spheroids of different cell types in the orders in which they are found in the body and expose them to different concentrations of a substance. The system enables the scientists to simulate a multi-organ system realistically on a single platform. “We realised a body-on-a-chip system relatively easily,” says a delighted Frey, who has been working on the test platform for two years.

Liver cells connected to cancer cells

The initial tests on liver and cancer cell spheroids were promising. In one series, Frey and his team inserted liver cells into the first three drops and cancer cells into the fourth. After the cells had organised themselves into spheroids, he fed a cytostatic agent, i.e., a substance that inhibits cell growth, into the test setup in different concentrations for each set of microtissues.

The agent only kills off cancer cells if liver cells activate it beforehand – an effect the researchers were able to recreate. At the same time, they could observe the concentration at which the toxin affects the cancer cells and the point, at which the liver also begins to suffer. As expected, if there were no liver cells in the microfluidic system, the drug did not affect the cancer cell growth at the respective concentration.

Patent pending for the system

Frey and his team have applied for a patent for their new test platform, which can be produced relatively easily and at low cost by using a replication method. The fabrication requires a negative master form, made of silicon, which is produced in a cleanroom. Multiple casts of it can then be made with a polymer. For large quantities, an injection moulding technique can also be used, where the pieces only cost a few cents. The Basel-based researchers developed the production of the microtissues for the platform in collaboration with InSphero, a D-BSSE spin-off.

Pharmaceutical companies that are looking to test new substances for efficacy and undesired side-effects may be particularly interested in the new system, as it enables to conduct such testing in a quick, flexible and straightforward way. “Our system is attractive for pharmaceutical companies, because it gives them a realistic idea of whether a new substance might be harmful already at an early stage in the drug development process,” stresses Frey. How and whether a new heart drug affects the liver, for instance, can be tested in an early phase.

The researchers are now looking to equip their hanging drop platform with sensors that can measure metabolic products in the drops and that should enable a continuous data read out. The sensors are intended to measure lactate or glucose, for instance. “The chip production might well be a little bit more costly through sensor integration, but this kind of platform will provide us with a lot more information,” says Andreas Hierlemann.