New miniature heart can help speed up the heartbeat

Photo: A miniature version of the heart’s chamber made of engineered parts and tissue from stem cells — all on a slide not much larger than a postage stamp — could help researchers study diseases and test new treatments.
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Credit: Jackie Ricciardi Photography by Boston University

There’s no safe way to get an up-close view of the human heart in action: you can’t just take it out, look, and then put it back in again. Scientists have tried different ways to get around this basic problem: They attached cadaver hearts to machines to get them to pump again, and they attached lab-grown heart tissue to springs to watch them expand and contract. Each approach has its drawbacks: revived hearts can only beat for a few hours; Springs cannot multiply the forces acting on a real muscle. But getting a better understanding of this vital organ is urgent: In America, a person dies of heart disease every 36 seconds, according to the Centers for Disease Control and Prevention.

Now, an interdisciplinary team of engineers, biologists and geneticists has developed a new way to study the heart: They’ve built a miniature version of the heart’s chamber from a mixture of nano-engineered parts and human heart tissue. There are no springs or external energy sources – like the real thing, it beats on its own, propelled by living heart tissue growing from stem cells. The device could give researchers a more precise view of how the organ is functioning, allowing them to track how the heart is developing in a fetus, study the impact of disease, and test the potential efficacy and side effects of new treatments — all without patient risks and without leaving the lab.

The Boston University-led team behind the tool — dubbed miniPUMP, formally known as a single-way micro-precision heart pump — says the technology could also pave the way for building lab copies of other organs, from the lungs to the kidneys. Their findings were published in science progress.

“We can study disease progression in a way that was not possible before,” says Alice White, professor of engineering at Britain’s Boston University and chair of the Department of Mechanical Engineering. “We chose to work on heart tissue because of its particularly complex mechanisms, but we’ve shown that when you take nanotechnology and marry it with tissue engineering, there is potential to replicate this for multiple organs.”

According to the researchers, the device could eventually speed up drug development, making it faster and cheaper. Rather than spending millions — and possibly decades — moving a medical drug through the development pipeline only to notice it hit the last hurdle when testing it on people, researchers can use miniPUMP initially to better predict success or failure.

The project is part of CELL-MET, a multi-institutional National Science Foundation engineering research center in meta-cellular materials led by BU. The center’s goal is to regenerate diseased human heart tissue, build a community of scientists and industry experts to test new drugs and create implantable artificial patches for hearts affected by heart attacks or disease.

“Heart disease is the number one cause of death in the United States, and it affects us all,” says White, who was chief scientist at Alcatel-Lucent Bell Labs before joining BU in 2013. “Today, there is no cure for a heart attack. CELL-MET’s vision is to change this.”

personal medicine

There are many things that can go wrong in your heart. When all four cylinders are firing properly, the heart’s two upper chambers and two lower chambers maintain blood flow so that oxygen-rich blood circulates and nourishes your body. But when disease strikes, the arteries that carry blood away from your heart can narrow or block, valves can leak or malfunction, heart muscle can weaken or thicken, or electrical signals can shorten, causing too many — or too few beats. -. Heart disease, if left unchecked, can lead to discomfort — such as shortness of breath, fatigue, swelling, and chest pain — and can be fatal for many.

Christopher Chen, professor of biomedical engineering and William F. “While we know that heart muscle changes for the worse in response to abnormal forces – for example, due to high blood pressure or valve disease – these pathological processes have been difficult to mimic and study. That is why we wanted to build a small chamber for the heart.”

At just 3 square centimeters, a miniPUMP isn’t much larger than a postage stamp. Designed to function like the human heart’s ventricle – or muscular bottom chamber – its specially designed components are mounted on a thin, 3D-printed piece of plastic. There are miniature acrylic valves, which open and close to control the flow of fluid – water, in this case, not blood – and tiny tubes, which pass this fluid just like arteries and veins. And beating in one corner, the muscle cells that make heart tissue contract, cardiomyocytes, are made using stem cell technology.

“They are created using induced pluripotent stem cells,” says Christos Michas (ENG’21), the postdoctoral researcher who designed and led the development of the miniPUMP as part of his doctoral thesis.

To make the heart muscle cell, researchers take a cell from an adult — which could be a skin cell, blood cell, or almost any other cell — reprogram it into an embryonic stem cell, then turn it into a heart cell. In addition to giving the device a real heart, Michas says, the heart muscle cells also give the system tremendous potential in assisting groundbreaking personalized medications. Researchers could put diseased tissue into the device, for example, then test a drug on that tissue and watch how its pumping ability is affected.

“With this system, if I take cells from you, I can see how the drug will interact with you you, because these are your cells,” Michas says. “This system replicates some of the heart’s functions better, but at the same time, it gives us the flexibility to have different humans replicate it. It’s a more predictive model for figuring out what’s going to happen to humans — without actually getting into humans.”

According to Michas, this could allow scientists to assess the chances of a new heart disease drug being successful long before heading into clinical trials. Many drug candidates fail due to their adverse side effects.

“Initially, when we’re still playing with cells, we can insert these devices and get more accurate predictions of what’s going to happen in clinical trials,” Michas says. “It would also mean that the drugs could have fewer side effects.”

Thinner than a human hair

One of the key parts of the miniPUMP is an acrylic scaffold that supports the heart tissue and moves with it as it contracts. A series of ultra-fine concentric spirals – thinner than a human hair – connected by horizontal loops, the scaffold looks like an art piston. It’s a key piece of the puzzle, giving structure to the heart’s cells – which would just be a shapeless bubble without it – but not exerting any active force on them.

“We don’t think previous approaches to studying heart tissue capture the way the muscles in your body respond,” says Chen, who is also director of the Harvard Center for Biological Design and an associate faculty member at Harvard University’s Wyss Institute for Biologically Inspired Engineering. “This gives us the first opportunity to build something that is mechanically very similar to what we think the core is actually experiencing – it’s a huge step forward.”

To print each of the tiny components, the team used a process called two-photon direct laser writing, which is a more precise version of 3D printing. When light is emitted into a resinous liquid, the areas it touches become solid; Because light can be directed with such precision – by focusing on a tiny spot – many components in the miniPUMP are measured in microns, smaller than a dust particle.

The decision to make the pump very small, rather than a normal size or larger, was intentional and is crucial to its operation.

“The structural elements are so good that things that would normally be rigid are flexible,” White says. By analogy, think of fiber optics: A glass window is very stiff, but you can wrap the fiberglass around your finger. Acrylic can be very rigid, but to the scale included in the miniPUMP, the acrylic scaffold can be compressed by beating cardiomyocytes. “

Chen says the pump scale shows “that with microprinting architectures, you may be able to create more complex cell organizations than we previously thought possible.” Right now, when researchers try to make cells, he says, whether they’re heart cells or liver cells, they’re all disorganized — “to get structure, you have to cross your fingers and hope the cells create something.” This means that miniPUMP’s pioneering tissue scaffolding has significant potential effects beyond the heart, laying the foundation for other organs on a chip, from the kidneys to the lungs.

technology refinement

According to White, the breakthrough is possible due to the group of experts on the CELL-MET research team, which included not only mechanical, biomedical and materials engineers like her, Chen and Arvind Agarwal from Florida International University, but also geneticist Jonathan J. Seidman of Harvard Medical School and cardiovascular medicine specialist Christine E. Seidman of Harvard Medical School and Brigham and Women’s Hospital. He has benefited from a wide range of experiences not only the project, but Michas. An electrical and computer engineering student when he was an undergraduate, he says he had “never seen cells in my life before starting this project”. Now, he’s preparing to start a new position at Seattle-based biotech company Curi Bio, a company that combines stem cell technology, tissue biosystems and artificial intelligence to advance drug and therapeutic development.

“Christos is someone who understands biology, who can do cell differentiation and tissue processing, but also understands nanotechnology and what is required, in an engineering way, to fabricate the structure,” White says.

The next immediate target for the miniPUMP team? to refine technology. They also plan to test manufacturing methods for the device without compromising its reliability.

“There are a lot of applications for research,” says Chen. “In addition to giving us access to human heart muscle to study disease and pathology, this work paves the way for making heart spots that could eventually be for someone with their existing heart defect.”

Other researchers on this project include Camille Ekinci, professor of mechanical engineering and materials science and engineering at Boston University, and Jeroen Ekmans, assistant professor of biomedical engineering, M. Pranjal Nutial, a postdoctoral researcher at the University of Pennsylvania who recently completed his Ph.D. at Florida International University.


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