Getting to the heart of the problem

If you look at the wall of a heart muscle through a microscope, you will see that the tissue, called the myocardium, is composed of parallel, aligned fibers that enable regular heartbeats.

Veldhuizen and Nikkhah mimic this structure on a chip platform with elliptical microposts — a unique design for organ-on-a-chip platforms.

“The importance of these posts is their ability to affect the surrounding 3D tissue, causing it to align around the posts,” Veldhuizen said. “We found that these posts can align heart tissue in a similar fashion (to natural myocardial tissue), which not only enhances the structure of the tissue, but also its function, making it a better heart-on-a-chip model.”

Another way to better represent a real heart is to use more than just muscle cells. Cardiomyocytes enable the heart muscle to beat throughout a person’s life, but they need their support structures, the fibroblast connective cells, to reliably function.

Creating these cells is a challenging task for researchers — and Veldhuizen had to do it three times with different stem cell types. In the final stage of the research, Veldhuizen used human pluripotent stem cells to create cardiomyocytes. Pluripotent stem cells are expensive and hard-to-produce, but they are very beneficial as they can turn into any type of organ cell. But turning them into the right type of organ cell is a researcher's biggest challenge.

Typically, researchers use specific stimuli or reagents to make human pluripotent stem cells “differentiate” themselves into the type of cells they want. But sometimes the stem cells spontaneously start on their journey to become something the researchers don’t want, like kidney cells. In Veldhuizen’s work, she’d sometimes see spontaneous differentiation of the stem cells, where they'd become some mixture of cells instead of the heart cells they needed to use in their model.

Even when Veldhuizen got the cardiomyocyte cells she wanted, another obstacle she encountered was their immaturity. When first differentiated, stem cells reflect tissue cells in an embryonic or fetal state, not how typical adult cells look and behave.

“The ability to mature human pluripotent stem cell cardiomyocytes is a major obstacle in the field of heart tissue modeling,” Veldhuizen said. “The differences between the fetal and the mature or adult types span cell size, shape, metabolism, gene expression, calcium handling and contractile patterns. Therefore it is important to mature these cells to model the adult human heart in a lab, and to translate any biological or pharmaceutical findings into clinical relevance.”

Veldhuizen found that by both co-culturing the muscle cells with supporting fibroblast cells among a 3D hydrogel and causing them to align with the microposts, her research team’s heart-on-a-chip model enhances the maturity level of these heart cells, so they’re more suitable for in vitro heart studies.

A multidisciplinary team tackles a complex organ

Just as the human body uses a team of specialized organs to function, complex health technology requires an interdisciplinary group of researchers to get results.

Veldhuizen and Nikkhah worked with stem cell biology expert David Brafman, an assistant professor of biomedical engineering and faculty member of the ASU-Banner Neurodegenerative Disease Research Center, as well as recent bioengineering and biomedical engineering doctoral degree graduate Joshua Cutts.

Brafman and Cutts provided guidance on the foundations of differentiating commercial stem cell lines into heart tissue, and access to a quantitative polymerase chain reaction machine in their lab, which is used for gene expression analysis.

To ensure their work is clinically relevant, the team consulted with Dr. Raymond Migrino, a cardiologist and cardiovascular biology expert from the Phoenix Veterans Affairs Health Care System and the University of Arizona.

Working together with experts in these areas allowed Veldhuizen and other members of the Nikkhah Lab to design a chip that resulted in the best functional model of a heart for a range of important uses.

A new way to study heart diseases, treatments and drug effects

Now that Veldhuizen and Nikkhah have validated the technology, it can be used as a platform to model the progression and treatment of cardiovascular diseases.

This is an important platform for testing pharmaceutical effects on the heart. Many drug discovery approaches fail in preclinical and clinical trials because the conventional assays used in earlier tests do not sufficiently mimic the human heart. As well, researchers can bypass animal models that do not accurately reflect human physiology.

By introducing drugs to tissue on the chip, researchers can observe toxicity and side effects that would negatively affect the heart. For example, chemotherapy often leads to cardiac toxicity, but no one knows why. Researchers can study this phenomenon with Veldhuizen and Nikkhah’s new platform.

In addition to drug experiments, researchers can introduce “insults” such as oxygen deprivation for a heart attack or high glucose to simulate diabetes-related heart disease as a means to study common ailments, or to discover causes of diseases that are currently unknown.

Finally, since it has been validated for use with stem cells from adult humans — the pluripotent stem cells — the platform can use a particular individual’s cells to study their own genetic diseases. In the future, the individual’s care team can safely find the most effective treatments by experimenting on the chip and not the person’s heart.

“We can study disease manifestations, mechanisms for how it progresses or different kinds of treatments,” Veldhuizen said.

Monique Clement

Communications specialist, Ira A. Fulton Schools of Engineering