A tissue engineered heart ventricle for studying rhythm disorders, cardiomyopathy

a tissue engineered heart ventricle
(Luke MacQueen and Michael Rosnach/Harvard University)

While engineered heart tissues can replicate muscle contraction and electrical activity in a dish, many aspects of heart disease can only adequately be captured in 3D. In a report published online yesterday by Nature Biomedical Engineering, researchers describe a scale model of a heart ventricle, built to replicate the chamber’s architecture, physiology and contractions. Cardiac researchers at Boston Children’s Hospital think it could help them find treatments for congenital heart diseases.

Building a 3D engineered heart ventricle

Collaborators from the Harvard School of Engineering and Applied Sciences (SEAS), the Wyss Institute for Biologically Inspired Engineering, the Harvard Stem Cell Institute and Boston Children’s engineered the ventricles by seeding rat or human heart cells onto 3D nanofiber scaffolds made of biodegradable polyester and gelatin fibers.

Guided by the scaffold, the cells aligned and assembled into beating ventricle chambers. The ventricles’ pressure, volume and contraction rate could be measured as they are in patients. In one test, for example, their beat rate increased when exposed to an adrenaline-like drug.

“The applications, from regenerative cardiovascular medicine to its use as an in vitro model for drug discovery, are wide and varied,” said Kit Parker, PhD, of SEAS, senior author of the study, in a press release.

Studying cardiomyopathies and arrhythmias

Coauthor William Pu, MD, director of Basic and Translational Cardiovascular Research at Boston Children’s, provided the human cells used for the study. He wants to use the engineered ventricles to better understand genetic forms of heart failure and rhythm disturbances that he sees in children with congenital heart disease.

The nanofibrous scaffold used to create an engineered heart ventricle
A micro-computed tomography reconstruction of a nanofibrous ventricle scaffold, measuring 1 cm from base to apex. (Disease Biophysics Group/Harvard SEAS)

“The current step was just to develop the technology,” says Pu, who is collaborating with Parker under an NIH “Tissue Chips 2.0” grant. “The next step would be to use these ventricles to model disease.”

The final goal, of course, is to test treatments. To date, Pu’s team has recruited more than 15 children and adolescents with three inherited heart conditions of interest: cardiomyopathies, diseases in which an abnormally large, thick or stiff heart muscle weakens the heart’s contractile function; catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare, potentially lethal arrhythmia; and arrhythmogenic cardiomyopathy, a condition involving both weakened heart muscle and arrhythmia.

Each patient is donating a blood sample, which is treated in the lab to generate pluripotent stem cells. These iPS cells are then transformed into heart-muscle cells or cardiomyocytes. And these cells, in turn, can be used to build functioning models of heart ventricles that carry the patient’s genetic defect.

“Since we know who these patients are, we can compare the model ‘phenotypes’ with our patients’ clinical condition,” Pu says.

Multiple heart models

Several years ago, Pu and Parker collaborated on a heart-on-a-chip model for Barth syndrome, a rare mitochondrial cardiomyopathy. The two-dimensional model consisted of stem-cell-derived cardiac cells from human patients, cultured on plastic sheets. The sheets were engineered to align the cells in a way that mimics the heart’s natural environment.

Studies with the chip revealed that heart cells in patients with Barth syndrome contracted weakly and produced an excess of reactive oxygen species (ROS). In the laboratory, curbing ROS production restored contractile function.

The two labs have also developed a tissue model for CPVT. It has led to insights on the mechanism of the rhythm disturbance and a possible strategy for blocking it.

“Our ultimate goal is to make models at all different levels – single-cell, pairs of cells, ‘heart-on-a chip’ type models and 3D engineered ventricles,” says Pu. “The simpler models allow for high-throughput drug screening, but 3D models like the ventricle model are more physiologically accurate. Once we do screening in the simpler models, we could then test our best candidates on the engineered ventricle to see how they affect heart function.”

Learn more about the technology from SEAS and the Harvard Stem Cell Institute and more about heart disease research at Boston Children’s Hospital.