Organs-On-Chips Go Electric

Organs-on-chips is a new tool that allows researchers to study human organs and tissues in a new and groundbreaking way. The chips mimic normal blood flow, mechanical microenvironment and how tissues interface with one another in living organs. This new technology allows researchers to test drugs and in vitro methods more systematically than before. Organs-on-chips could eventually replace animal testing.

The only problem with this new technology is time. It can take weeks to grow human cells into intact differentiated and functional tissues, like the lung and intestine. A team of researchers at the Wyss Institute for Biologically Inspired Engineering, led by Donald Ingber, set out to find new ways to monitor the health and maturity of the cells cultured with the microfluidic devices over time in a non-invasive way. It has been difficult for researchers to track electrical functions in cells grown on organ chips that are normally electrically active, like beating heart cells, during differentiation and in response to drugs.

Lung on a Chip sitting on a microscope connected to vaccum and flow channels. (Wyss Institute)

Ingber and his team collaborated with Wyss Core Faculty member Kit Parker and his team of researchers to bring solutions to those problems by fitting the organ chips with embedded electrodes. This enables accurate and continuous monitoring of trans-epithelial electrical resistance (TERR). TERR is a broadly used measure of tissue health and differentiation and real-time assessment of electrical activity on living cells. This is demonstrated in a heart chip model.

"These electrically active organ chips help to open a window into how living human cells and tissues function within an organ context, without having to enter the human body or even remove the cells from our chips," said Ingber. "We can now start to study how different tissue barriers are wounded in real time by infection, radiation, drug exposure or even malnutrition, and how and when they heal in response to new regenerative therapeutics."

TEER is used to quantify the flow of ions between electrodes and across tissue-tissue interface made of organ-specific epithelium and endothelium. Those two products are core components of the many human organ chips. Epithelial cells form the tissue layers that cover out skin and surface of most of our internal organs. Endothelial cells line the blood-transporting vessels and capillaries that support the vessel’s functions. Both of the cell layers act as a barrier to small molecules and ions and protect the organs and enable specialized functions.

Drug toxicities, infections, inflammation and other injurious stimuli can disrupt the barriers. TEER can be used to access the baseline functional integrity of the cell layers and damage responses triggered by drugs and toxic agents.

"Using a new layer-by-layer fabrication process, we created a microfluidic environment in which TEER-measuring electrodes are integral components of the chip architecture and are positioned as close as possible to the tissues grown in one or both of two parallel running channels," said Olivier Henry, Ph.D., a Wyss Institute Staff Engineer behind the new organ chip designs. "In contrast to past electrode designs, this fixed geometry allows accurate measurements that are fully comparable within and between experiments, and that tell us exactly how tissues like that of lung or gut mature within a channel, keep in shape and break down under the influence of drugs or other manipulations."

The Ingber-Henry team collaborated with Kit Parker to further enhance the functionality of TEER chips. They integrated multi-electrode arrays (MEAs) into the chips. MEAs can measure the behavior of electrically active cells, like beating heart muscle cells.

Researchers used TEER-MEA chips to build a beating vascularized heart chip that has human cardiomyocytes cultured in one microfluidic channel that is separated by a semi-permeable membrane from a second endothelium-lined vascular channel. The team treated the vascularized heart chip with an inflammatory stimulant that disrupts endothelial barriers or heart stimulant that acts on cardiomyocytes to test the new chip’s abilities.

"The future of organs-on-chips is instrumented chips: the idea that the experimenter is taken out of the loop during data collection. Continuous data collection off of organ mimics is what we need to measure efficacy and safety of drugs during long-duration experiments. These kinds of technologies offer us a granularity we have not had before," said Kit Parker.

The studies on this research were published in the journal Lab on a Chip. To read more about this, click here.