Researchers from the Faculty of Applied Science and Engineering at the University of Toronto have developed a small-scale model of a human left heart ventricle in the laboratory. The bioartificial tissue construct is made of living heart cells and beats hard enough to pump liquid inside a bioreactor.
In the human heart, the left ventricle is the one that pumps freshly oxygenated blood into the aorta, and from there to the rest of the body. The new model developed in the lab could offer researchers a new way to study a wide range of heart diseases and conditions, as well as test potential therapies.
“With our model, we can measure the stroke volume – the amount of fluid expelled each time the ventricle contracts – as well as the pressure of this fluid,” explains Sargol Okhovatian, PhD student at the Institute of Biomedical Engineering. “Both were almost impossible to obtain with previous models.”
Okhovatian and Mohammad Hossein MohammadiU of T graduates with master’s degrees in chemical and biomedical engineering, are co-senior authors of a new paper in Advanced biology which describes the model they designed. Their multidisciplinary team was led by Milica Radisicprofessor in the Department of Chemical Engineering and Applied Chemistry and lead author of the paper.
The three researchers are members of the Center for Research and Applications in Fluidic Technologies (CRAFT). A unique partnership between the National Research Council of Canada and the U of T, CRAFT brings together world-renowned experts who design, build and test miniaturized devices to control fluid flow at the micron scale, a field known under the name of microfluidics.
“The unique facilities we have at CRAFT allow us to create sophisticated organ-on-chip models like this,” says Radisic.
“With these models, we can study not only cell function, but also tissue function and organ function, all without the need for invasive surgery or animal experimentation. We can also use them to screen large libraries of drug candidate molecules for positive or negative effects.
Many challenges faced by tissue engineers are related to geometry: although it is easy to grow human cells in two dimensions – for example, in a flat Petri dish – the results do not look much like real tissues or organs as they would appear in humans. body.
To go into three dimensions, Radisic and his team use tiny scaffolds made from biocompatible polymers. The scaffolds, which are often adorned with grooves or mesh-like structures, are seeded with heart muscle cells and left to grow in a liquid medium.
Over time, living cells grow together, forming tissue. The underlying shape or pattern of the scaffold encourages growing cells to align or stretch in a particular direction. The electrical impulses can even be used to control the rate at which they beat – a sort of workout gym for heart tissue.
For the bioartificial left ventricle, Okhovatian and Mohammadi created a flat sheet-like scaffold of three mesh-like panels. After seeding the scaffold with cells and letting them grow for about a week, the researchers wrapped the sheet around a hollow polymer shaft, which they call a mandrel.
The result: a tube made up of three overlapping layers of heart cells that beat in unison, pumping fluid out of the hole at the end. The inner diameter of the tube is 0.5 millimeters and its height is about 1 millimeter, making it the size of the ventricle in a human fetus around the 19e week of gestation.
“So far, there have only been a handful of attempts to create a true 3D model of a ventricle, as opposed to flat sheets of heart tissue,” says Radisic.
“Virtually all of these were made with a single layer of cells. But a real heart has many layers, and the cells in each layer are oriented at different angles. When the heart beats, these layers not only contract, they also twist, much like twisting a towel to squeeze the water out of it. This allows the heart to pump more blood than it otherwise would.
The team was able to replicate this twisting arrangement by modeling each of their three panels with grooves at different angles to each other.
In collaboration with the laboratory directed by Ren-Ke Lia professor at the Temerty School of Medicine and a principal investigator at the Toronto General Research Institute of the University Health Network, they measured stroke volume and pressure using a conductance catheter, the same tool used to assess these parameters in living patients.
At the moment, the model can only produce a small fraction – less than five percent – of the ejection pressure that a real heart could produce, but Okhovatian says that’s to be expected given the scale of the model.
“Our model has three layers, but a real heart would have eleven,” she says.
“We can add more layers, but that makes it difficult for oxygen to diffuse, so the cells in the middle layers start to die. Real hearts have vasculature, or blood vessels, to solve this problem, so we need to find a way to replicate this.
Okhovatian says that in addition to the vascularity issue, future work will focus on increasing cell density to increase ejection volume and pressure. She also wants to find a way to shrink or possibly remove the scaffolding, which a real heart wouldn’t have.
Although the proof-of-concept model represents significant progress, there is still a long way to go before fully functioning artificial organs are possible.
“We have to remember that it took us millions of years to evolve a structure as complex as the human heart,” says Radisic.
“We won’t be able to reverse engineer it in a few years, but with each incremental improvement, these models become more useful to researchers and clinicians around the world.”
“Every tissue engineer’s dream is to develop organs that are fully ready to be transplanted into the human body,” says Okhovatian.
“We are still a long way from that, but I feel like this bioartificial ventricle is an important stepping stone.”