Cardiovascular disease accounts for nearly a third of deaths worldwide according to the World Health Organization. Scientists need to understand how the human heart works to develop new and improved therapeutics, but getting up close and personal with a beating human heart is tricky. Now, there may be a way to do so without ever leaving the lab. Researchers from Boston University spearheaded the development of a stamp-sized heart chamber composed of unique nanoengineered materials and cardiomyocytes that beat on their own (1).
The heart has an important job: keep oxygen-rich blood flowing through the body. It does this by moving oxygenated blood from the lung to the body and sending oxygen depleted blood back to the lung to start the cycle over again. Arteries and veins move the blood into and out of the heart, and gate-like valves between the chambers ensure that blood flows to the right place at the right time.
The new device, officially known as the cardiac miniaturized Precision-enabled Unidirectional Microfluidic Pump or miniPUMP, recapitulates this process better than its predecessors, including an artificially powered heart from a human cadaver.
The entire nanoengineered heart chamber, dubbed the miniPUMP, is about the size of a stamp.
Credit: Jackie Ricciardi, Boston University Photography
The device looks like a piston-shaped tube covered in beating cardiomyocytes that were differentiated from patient-derived induced pluripotent stem cells (iPSCs). The iPSC-derived cardiomyocytes compress the tube, mimicking a beating heart. A complex set of tiny tubes like the veins and arteries moves water in and out, and tiny plastic valves control the flow.
Researchers plan to use this miniPUMP to better understand how the heart develops and to screen new therapeutics.
“It's a way to make miniaturized heart tissues with valves. I think the main contributions are actually the valves that generate a kind of natural pattern of mechanical loading for this heart tissue,” said Nenad Bursac, a biomedical engineer from Duke University who was not involved in this study. “It's really preliminary though. They haven't found any application, so they haven't tested any drugs.”
According to Bursac, the miniPUMP is one step closer to drug testing than artificial hearts created by other teams. Previous iterations were much larger, and the pumping was powered by an outside force rather than by the cells.
Alice White, a mechanical engineer from Boston University who specializes in nanofabrication coauthored the new study in Science Advances with Christopher Chen, a biomedical engineer from Boston University. The pair hatched the idea to develop the miniPUMP and recruited Christos Michas, a post-doctoral fellow in Chen’s lab, to take on the project.
Boston University researchers Christopher Chen (left), Christos Michas (middle), and Alice White (right) led a team of engineers in developing the miniPUMP.
Credit: Jackie Ricciardi, Boston University Photography
“[Michas] got interested in making a little heart tube — just a miniature heart using some of that tissue — and quickly realized that a hard tube, which is kind of a linear configuration, was really not going to recapitulate the function that he wanted to demonstrate. And because he had expertise in nanofabrication, he realized that he could make a scaffold to create a chamber,” said White.
Michas opted to use a precise form of 3D printing called two-photon direct laser writing that allows him to produce smaller, more detailed structures. He printed a piston-like scaffold to hold the small components, including tiny valves and tubes that would contract in response to beating cardiomyocytes. His first attempt failed when the cardiomyocytes crushed the tube. He defeatedly showed the video that captured the destructive cardiomyocytes in action. But his mentors weren’t discouraged; in fact, they were excited.
“At that point, I thought, ‘he's onto something! We just have to solve this crushing problem.’ But of course, as a scientist, you look at things that sort of work but sort of fail. It takes a little bit of optimism and elbow grease and tenacity to get to the point of saying, 'oh, yeah, it really is working,'" said Chen.
“When I saw that first video, I thought, ‘now it’s just an engineering problem.’ He could see fluid moving in and out [of the scaffold],” added White.
The 3D printing process is fast, so Michas quickly printed multiple new designs until he found one that could withstand the force exerted by the cardiomyocytes. He then used mathematical modeling to design the pressure responsive valves that allow liquid to flow in and out of the miniPUMP.
Michas tested the functionality of the device four weeks after seeding the cardiomyocytes on the scaffold. The device pumped liquid in and out, and due to a pressure gradient, the liquid moved across the acrylic valves just like in a real heart. Modeling this function allows researchers to explore how the heart functions differently when pressure is disrupted in disease, such as in patients with high blood pressure.
The researchers are still fine-tuning the miniPUMP and looking for easier ways to make it.
“It would be great if they were able to somehow simplify the design because it's still kind of a complex design. If you would like multiple labs to be able to reproduce this — it's hard, right? It's a state-of-the-art, cutting-edge technology that not everyone can just readily adopt,” said Bursac.
Michas’ team used a stereoscope to take images of the miniPUMP at different stages of the assembly process. From above, the researchers captured a cardiac chamber containing cardiomyocytes submerged in media (A). A close up of the cardiac chamber clearly
CREDIT: CHRISTOS MICHAS, Science Translational Medicine (see ref 1)
The team also uses the device to answer biological questions about cardiomyocyte development. Currently, iPSC-derived cardiomyocytes are akin to fetal heart cells, but researchers want to produce more mature heart cells to answer questions about the aging heart.
“One of the things that we are really interested in is whether the mechanical conditioning — how the cells are beating and contracting — might contribute to how the cells mature. When a fetus is born, there are major shifts in the mechanical forces that the cells experience and have to generate in order to function. One of our hypotheses is that maybe they're experiencing the same kinds of forces that they would in vivo, and that might further differentiate [them],” said Chen.
The researchers are currently testing how long the miniPUMP can last to determine how the device influences cardiomyocyte maturation. There is still a lot of work to be done before anyone will be screening drugs using the miniPUMP, but Chen, White, and Bursac think the future is bright.
“I'm really excited about being able to continuously improve this scaffolding structure and design and to keep building progressively better chambers,” said Chen. “The physician side of me is really interested in the idea of being able to actually take these out longer and study the effects of high blood pressure, for example, on these kinds of chambers, both in a normal heart setting and in a disease heart setting. I really do think that that gives us some more insights into what happens in people.”
Reference
- Michas, C. et al. Engineering a living cardiac pump on a chip using high-precision fabrication. Sci Adv 8, eabm3791 (2022).
