New miniature heart could help speed recovery from heart disease

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There’s no sure way to get a close-up view of the human heart as it does its job: you can’t just take it out, peek inside, then put it back in. Scientists have tried different ways to circumvent this problem. fundamental problem: they hooked up cadaver hearts to machines to make them pump again, attached lab-grown heart tissue to springs to watch them expand and contract. Each approach has its flaws: revived hearts can only beat for a few hours; the springs cannot reproduce the forces acting on the real muscle. But better understanding 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 have developed a new way to study the heart: They’ve built a miniature replica of a heart chamber from a combination of nanotech parts and tissue. human heart. There are no springs or external power sources – like the real thing, it just beats on its own, driven by living stem cell-derived heart tissue. The device could give researchers a more accurate view of the functioning of the organ, allowing them to follow the growth of the heart in the embryo, study the impact of the disease and test the potential effectiveness and effects side effects of new treatments, all without risk. to patients and without leaving a laboratory.

The Boston University-led team behind the gadget – dubbed miniPUMP and officially known as the Miniaturized Cardiac-Precision One-Way Microfluidic Pump – says the technology could also pave the way for building versions in the lab. other organs, from the lungs to the kidneys. Their findings were published in Scientists progress.

“We can study disease progression in a way that wasn’t possible before,” says Alice White, a professor at the BU College of Engineering and holder of the chair of mechanical engineering. “We chose to work on heart tissue because of its uniquely complicated mechanics, but we’ve shown that when you take nanotechnology and combine it with tissue engineering, there is potential for multiple organs to reproduce.”

The device could potentially speed up the drug development process, making it faster and cheaper, the researchers say. Instead of spending millions – and possibly decades – pushing a drug through the development pipeline only to see it fall at the final hurdle when tested on people, researchers could use the miniPUMP from the start to better predict success or failure.

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

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

Personalized medicine

There are many things that can go wrong with your heart. When working properly on all four cylinders, the upper and lower two chambers of the heart keep your blood flowing so that oxygen-rich blood flows and fuels your body. But when illness strikes, the arteries that carry blood to your heart can become narrowed or blocked, valves can leak or malfunction, heart muscle can thin or thicken, or electrical signals can short- circuit, causing too many or too few Beats. If left unchecked, heart disease can lead to discomfort – such as shortness of breath, fatigue, swelling and chest pain – and, for many, death.

“The heart experiences complex forces as it pumps blood through our body,” says Christopher Chen, BU William F. Warren Professor Emeritus of Biomedical Engineering. “And although we know that heart muscle worsens in response to abnormal forces – for example, due to high blood pressure or valve disease – it has been difficult to mimic and study these processes. pathological. That’s why we wanted to build a miniaturized heart chamber.”

With only 3 square centimeters, the miniPUMP is not much larger than a postage stamp. Designed to act like a human heart ventricle – or muscular lower chamber – its custom components are mounted on a thin piece of 3D-printed plastic. There are miniature acrylic valves, which open and close to control the flow of liquid – water, in this case, rather than blood – and small tubes, channeling this liquid like arteries and veins. And beating in one corner are muscle cells that contract heart tissue, cardiomyocytes, made using stem cell technology.

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

To make the cardiomyocyte, researchers take a cell from an adult — it could be a skin cell, a blood cell, or just about any other cell — reprogram it into a type stem cell. embryo, then transform it into a heart cell. In addition to giving the device a literal heart, Michas says the cardiomyocytes also give the system huge potential to help launch personalized drugs. For example, researchers could place diseased tissue in the device, then test a drug on that tissue and observe the impact on its pumping ability.

“With this system, if I take cells from you, I can see how the drug would react in you, because these are your cells,” says Michas. “This system better replicates some of the function of the heart, but at the same time gives us the flexibility to have different humans that it replicates. It’s a more predictive model to see what would happen in humans – without actually going into humans.”

According to Michas, this could allow scientists to assess the chances of success of a new heart disease drug long before it enters clinical trials. Many drug candidates fail due to their undesirable side effects.

“At the very beginning, when we’re still playing with the cells, we can introduce these devices and have more accurate predictions of what will happen in clinical trials,” says Michas. “It will also mean that the drugs could have fewer side effects.”

Thinner than a human hair

One of the key components of the miniPUMP is an acrylic scaffold that supports and moves with heart tissue as it contracts. A series of wafer-thin concentric spirals – thinner than a human hair – connected by horizontal rings, the scaffold resembles an artistic piston. It is an essential piece of the puzzle, giving structure to heart cells – which would be just a shapeless blob – but exerting no active force on them.

“We don’t think previous methods of studying heart tissue capture how muscle would react in your body,” says Chen, who is also director of BU’s Biological Design Center and an associate faculty member at the Wyss Institute for Biologically Inspired Engineering from Harvard University. “It gives us the first opportunity to build something that mechanically looks more like what we think the heart actually lives in – it’s a big step forward.”

To print each of the tiny components, the team used a process called direct two-photon laser writing, a more precise version of 3D printing. When light is projected into a liquid resin, the areas it hits become solid; because light can be directed with such precision – focused on a tiny point – many components of the miniPUMP are measured in microns, smaller than a particle of dust.

The decision to make the pump so small, rather than life-size or larger, was deliberate and is crucial to its operation.

“Structural elements are so thin that things that would normally be rigid are flexible,” says White. “By analogy, 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 involved in the miniPUMP, the acrylic scaffold can be compressed by beating cardiomyocytes.

Chen says the pump scale shows “that with finer print architectures, you might be able to create more complex cell organizations than we previously thought.” Right now when researchers try to create cells, he says, whether they’re heart cells or liver cells, they’re all disorganized – “to get a structure, you have to cross your fingers and hope the cells create something”. This means that the tissue scaffold engineered in the miniPUMP has great potential implications beyond the heart, laying the foundation for other on-chip organs, from kidneys to lungs.

Refine Technology

According to White, the breakthrough is possible thanks to the range of experts on the CELL-MET research team, which included not only mechanical, biomedical and materials engineers like her, Chen and Arvind Agarwal of the International University of Florida, but also geneticist Jonathan G. Seidman of Harvard Medical School and cardiovascular medicine specialist Christine E. Seidman of Harvard Medical School and Brigham and Women’s Hospital. It’s a vast experience that has benefited not only the project, but Michas. An undergraduate electrical and computer engineering student, he says he had “never seen a cell in my life before I started this project.” Now he’s gearing up for a new role at Seattle-based biotech Curi Bio, a company that combines stem cell technology, tissue biosystems and artificial intelligence to power the development of drugs and therapies.

“Christos is someone who understands biology,” says White, “can do cell differentiation and tissue manipulation, but also understands nanotechnology and what is required, from a technical standpoint, to make the structure .”

The next immediate goal for the miniPUMP team? To refine the technology. They also plan to test ways to make the device without compromising its reliability.

“There are so many search apps out there,” Chen says. “As well as giving us access to human heart muscle to study disease and pathology, this work paves the way for making heart patches that could ultimately be made for someone who had a defect in their current heart.”

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