Each approach has its flaws: revived hearts can only beat for a few hours; springs cannot reproduce the force acting on the real muscle. But a better understanding of this vital organ is urgently needed: in the US, one person dies from heart disease every 36 seconds, according to the Centers for Disease Control and Prevention.
Now, an interdisciplinary team of engineers, biologists and geneticists have developed a new way to study the heart: they have created a miniature replica of a heart chamber from a combination of nanofabricated organs and human heart tissue. No springs or external power source — like the real thing, it just beats on its own, controlled by living heart tissue grown from stem cells.
The device could give researchers a more precise view of how the organ works, allowing them to monitor how the heart develops in an embryo, study the effects of disease and test its effectiveness. potential outcomes and side effects of new treatments — all without patient risk and without leaving the lab.
The Boston University-led team behind the device — nicknamed the miniPUMP, and officially known as the Miniature Precision Activated One-Way Microfluidic Pump for the Heart — says the technology also works. could pave the way for building lab-based versions of other organs, from the lungs to the kidneys. Their findings have been published in the journal Science Advances.
“We can study disease progression in a way that hasn’t been possible before,” said Alice White, professor at BU College of Engineering and chair of the department of mechanical engineering. “We chose to work on heart tissue because of its exceptionally complex mechanics, but we’ve shown that, when you take nanotechnology and combine it with tissue engineering, there’s the potential to regenerate it for many agencies.”
The device could eventually speed up drug development, making it faster and cheaper, according to the researchers. Instead of spending millions – and possibly decades – moving a drug through the development pipeline only to see it hit the final hurdle in human testing, researchers can use miniPUMP right away. from scratch to better predict success or failure.
The project is part of CELL-MET, a multi-institutional National Science Foundation Engineering Research Center for Mobile Metamaterials led by BU. The center’s goals are to regenerate diseased human heart tissue, build a community of scientists and industry experts to test new drugs, and create implantable artificial patches for damaged hearts. damage from a heart attack or illness.
“Heart disease is the number one cause of death in the United States, which is emotional for all of us,” said White, who was chief scientist at Alcatel-Lucent Bell Labs before joining BU in 2013. . attack. CELL-MET’s vision is to change this. “
There are many things that can happen to your heart. When it’s working properly on all four cylinders, the top two chambers and the bottom two chambers of your heart keep your blood circulating so that oxygen-rich blood circulates and feeds your body. But when disease strikes, the arteries that carry blood away from your heart can narrow or become blocked, valves can leak or malfunction, heart muscle can thin or thicken, or electrical signals can be damaged. short, causing too many – or too few – beats. If left unchecked, heart disease can lead to discomfort — like shortness of breath, fatigue, swelling, and chest pain — and, for many people, death.
“The heart is subjected to complex forces as it pumps blood through our bodies,” says Christopher Chen, BU’s William F. Warren Distinguished Professor of Biomedical Engineering. “And while we know that the heart muscle changes for the worse in response to abnormal forces – for example, due to high blood pressure or valve disease – it is difficult to mimic and study these disease processes. This is why we wanted to build miniature heart chambers.”
At just 3 square centimeters, the miniPUMP isn’t much bigger than a postage stamp. Built to function like a human ventricle — or submuscular cavity — its custom-built components are attached to a thin 3D-printed piece of plastic. There are miniature acrylic valves that open and close to control the flow of fluid — in this case, water, not blood — and tiny tubes, which connect that fluid like an artery and a vein. And beating away at an angle, the muscle cells that make the heart tissue contract, the cardiomyocytes, created with stem cell technology.
“They were created using stem cells,” says Christos Michas (ENG’21), a postdoctoral researcher who designed and led the development of miniPUMP in his doctoral thesis. multi-touch.
To create heart muscle cells, the researchers take a cell from an adult — it can be a skin cell, a blood cell, or any other cell — and reprogram it to become an embryo-like stem cell fetus, which then transforms into cardiac cells. In addition to giving the device a literal heart, Michas says the cardiomyocytes also give the system huge potential in supporting pioneering personalized medicines. For example, researchers can put a diseased tissue in the device, then test a drug on that tissue and monitor to see how its pumping ability is affected.
“With this system, if I take cells from you, I can see how the drug will react in you, because these are your cells,” says Michas. “This system better reproduces some heart functions, but at the same time, gives us the flexibility to have different people it’s replicating. It’s a better predictive model to see what to see. would happen in humans – without actually entering humans.”
That could allow scientists to assess a new heart drug’s chances of success long before clinical trials begin, says Michas. Many drug candidates fail because of their adverse side effects.
“From the very beginning, while we were still playing with cells, we could introduce these devices and have more accurate predictions of what would happen in clinical trials,” says Michas. “It also means that the drug can have fewer side effects.”
Thinner than human hair
One of the key components of the miniPUMP is an acrylic stand that supports and moves the heart tissue as it contracts. A series of superfine concentric spirals – thinner than a human hair – connected by horizontal rings, the scaffolding looks like an art piston. That’s an important part of the puzzle, giving structure to the heart cells — which would be just an invisible blob without it — but without exerting any force on them.
“We don’t think that previous methods of studying heart tissue capture how muscle would react in your body,” said Chen, who is also director of BU’s Center for Bioengineering and an associate professor in the Department of Bioengineering. from Harvard University’s Institute of Biologically Inspired Engineering. “This gives us the first opportunity to build something that’s mechanically similar to what we think the heart is actually experiencing — it’s a huge step forward.”
To print each small component, the team used a process called two-photon direct laser recording — a more precise version of 3D printing. When light hits a liquid plastic, the areas it comes in contact with turn solid; because light can be aimed with such precision — focused to a small spot — many components in miniPUMP are measured in micrometers, smaller than a speck of dust.
The decision to make the pump so small, rather than life size or larger, was intentional and very important to its operation.
“The structural elements are so fine that things that would normally stiffen can be flexible,” says White. “Similarly, think of fiber optics: a glass window is very stiff, but you can wrap a glass fiber optic around your finger. Acrylic can be very stiff, but at the scale of miniPUMP, acrylic scaffolds can be compressed by beating cardiac muscle cells.”
Chen says that the scale of the pump shows that “with better printing architectures, you can create more complex cellular organizations than we previously thought.” Now, when researchers try to make cells, he says, heart cells or liver cells, they’re disorganized — “to get structure, you have to get through fingers and hopefully the cells make something.” That means the tissue scaffold pioneered in miniPUMP has great potential beyond the heart, laying the groundwork for other organs on a chip, from the kidneys to the lungs.
According to White, this breakthrough was made possible because there are many experts on CELL-MET’s research team, not just mechanical, biomedical, and materials engineers like herself, Chen, and Arvind. Agarwal of Florida International University, but also geneticist Jonathan G Seidman of Harvard Medical School and cardiovascular medicine expert Christine E. Seidman of Harvard Medical School and Brigham and Women’s Hospital.
It’s a wealth of experience that not only benefits the project but also Michas. As an electrical and computer engineering student while a college student, he said he had “never seen cells in my life before starting this project.”
Now, he’s preparing to start a new position with Seattle-based biotech company Curi Bio, a company that combines stem cell technology, tissue biology systems, and artificial intelligence. to promote the development of drugs and therapy.
“Christos is someone who understands biology, can do cell differentiation and tissue manipulation, but also understands nanotechnology and what is needed, in a technical way, to create structures,” says White. bamboo”.
The next immediate goal for the miniPUMP team? To improve technology. They also plan to test ways of manufacturing the device without compromising its reliability.
“There are a lot of research applications,” says Chen. “In addition to giving us access to human heart muscle to study disease, this work also paves the way to create heart patches that could eventually be available to people with existing heart defects. their.”