‘Heart-on-a-chip’ successfully predicts cardiotoxicity of cancer therapies
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A miniature, three-dimensional heart model, called the “heart-on-a-chip,” successfully used reprogrammed stem cells to determine cardiotoxicity of cancer drugs on the human heart, according to a study published in Lab on a Chip.
Additionally, the heart-on-a-chip matured the stem cells, making them more accurate representations of heart cells for testing.
“It can predict the cardiotoxicity associated with certain cancer drugs in a way that hasn’t really been described to this level,” Arun Sharma, PhD, research scientist at Cedars-Sinai Cancer, told Healio.
How does the heart-on-a-chip work?
Researchers first develop the stem cells, which takes about 3 weeks.
In the first study, they reprogrammed induced pluripotent stem cells into both heart muscle cells and blood vessel cells. They flowed those into the microfluidic chip, which is about 2 inches by an inch in size.
The chip features two tubes crossed like an ‘X.’
“The heart muscle cells are on one side and the blood vessel cells on the other side, but between those two channels are some ports that allow the two different types of cells to talk to each other, which is something that is traditionally not done in a standard two-dimensional plate system,” Sharma said.
The chip stretches the cells back and forth, like a heart would do. The “workout” strengthens the cells.
“We weren’t expecting that per se, and the rapidity at which it happened — that was really exciting because the No. 1 limitation of all of these cells that are created from stem cells is that they are not mature,” Sharma said.
“They’re not perfect replicates of what you would find in adult[s], but just by putting these cells on the chip ... [made] the cells more mature and closer to what you would find in the adult human body,” he added. “That, to me, was the thing that excited me the most and was the foundation for everything else that we use the chip for.”
Researchers tested VEGFR2/PDGFR-inhibiting tyrosine kinase inhibitors (VPTKIs), chemotherapy drugs that have long-established cardiotoxicities.
They found that both the heart muscle and blood vessel cells sustained damage.
Heart-on-a-chip’s benefits
Traditionally, testing the cardiotoxicity of drugs occurred in culture plates.
“It’s really easy to make and grow stuff in those multi-well plates,” Sharma said. “For a lot of situations, that two-dimensional, high-tubal system has been pretty good if you’re just looking at the toxicity of certain cancer drugs that do damage to the heart or the blood vessel cells.”
However, the “immature” cells produce a limited amount of data.
“There’s electrophysiology,” Sharma said. “Certain components of that process are immature in a two-dimensional system, but when you move these things into a chip, it gets better. The drugs that impact the beating rates or rhythm, EKG of the cells, you may not be able to see those drug-induced changes in a two-dimensional system.”
The chip allows different cell types to interact, expounding the effect the drugs have on the heart.
“We’re showing that there is a difference in the toxicity of that same drug on the two different populations of cells,” Sharma said.
He said they can test multiple cell types as well.
“There’s other cell types in the heart that we haven’t put on these chips,” Sharma said. “There’s smooth muscle cells, fibroblasts — there is a lot we can do to improve this first version of the chip.”
Future applications
The heart-on-a-chip is not ready for “commercial prime time,” Sharma said.
The chip’s lifespan is an area that needs development.
“We can get them to [function] for a few months but, ideally, we want them to go even longer — for years,” he said.
“We want them to go as long as we possibly can — indefinitely is the dream,” Sharma added. “Right now, there is an upper limit in terms of how long we can grow the cells on these chips.”
The two channels of the heart-on-a-chip are also a consideration, although how many should be included is debatable.
“The heart is way more complicated than that,” Sharma said. “It has a much more intricate vasculature. There are other folks around the world who have their own versions of these chips that are much more intricate and complex, but it’s a tradeoff. The more complicated you make these systems, the less scalable they can be. That’s perhaps one advantage of a simplified system like this.”
Looking forward, Sharma has big ideas ready for when those determinations are made.
The first test of the heart-on-a-chip confirmed the cardiotoxicity of VPTKIs. Sharma eventually wants to use it to screen newer classes of drugs, such as immune-checkpoint inhibitors.
He also would like to test the pharmacogenomics of cancer drugs.
“We can make personalized heart chips, flow drugs through them — toxic drugs — and use this as an ‘avatar-on-a-chip,’ being able to predict on a personalized level who’s going to respond badly to a drug vs. someone who may not,” Sharma said. “That’s the real dream.”
Cedars-Sinai has also worked on other organs on chips, including brain and liver chips. Eventually, Sharma would like to connect them all and have a “body-on-a-chip.”
“Ultimately, that connected system would be a more accurate one because certain drugs out there may not just cause damage to the heart, they could also cause damage to the liver, other cell types, the brain as well,” Sharma said. “Neurotoxicity, hepatotoxicity and cardiotoxicity are three of the biggest areas of study when it comes to unintended drug toxicity.”
For more information:
Arun Sharma, PhD, can be reached at arun.sharma@cshs.org.
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