By mimicking the spiral structure of the heart muscle, researchers are improving understanding of how the heart beats

Heart disease – the leading cause of death in the US – is so deadly in part because the heart, unlike other organs, cannot repair itself after injury. That’s why tissue engineering, ultimately including the wholesale manufacturing of a whole human heart for transplantation, is so important to the future of cardiac medicine.

To build a human heart from scratch, researchers must mimic the unique structures that make up the heart. This includes recreating spiral geometries, which create a spinning motion as the heart beats. It has long been theorized that this twisting motion is critical for pumping blood at high volumes, but prove it was difficult, in part because creating hearts with different geometries and alignments was challenging.

Now, bioengineers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed the first biohybrid model of human ventricles with spirally aligned beating heart cells, and they have shown that muscle alignment actually dramatically increases how much blood enters the ventricle. can pump with every contraction.

These advances were made possible using a new method of additive textile manufacturing, Focused Rotary Jet Spinning (FRJS), which enabled the high-throughput fabrication of spirally aligned fibers with diameters ranging from a few micrometers to hundreds of nanometers. Developed at SEAS by Kit Parker’s Disease Biophysics Group, FRYS fibers direct cell alignment, enabling the formation of controlled tissue engineered structures.

The research was published in Science.

“This work is a major step forward for organ biofabrication and brings us closer to our ultimate goal of building a human heart for transplantation,” said Parker, the Tarr Family Professor of Bioengineering and Applied Physics at SEAS and senior author of the article.

This work has its origins in an ancient mystery. In 1669, English physician Richard Lower—a man who counted John Locke among his colleagues and King Charles II among his patients—first noticed the spiral arrangement of cardiac muscles in his seminal work. A treatise on the heart.

Over the next three centuries, doctors and scientists built up a more comprehensive understanding of the structure of the heart, but the purpose of those spiral muscles has remained frustratingly difficult to study.

In 1969, Edward Sallin, former chair of the Department of Biomathematics at the University of Alabama Birmingham Medical School, argued that the helical alignment of the heart is critical to achieving large ejection fractions — the percentage of how much blood the ventricle pumps with each contraction. .

“Our goal was to build a model that would allow us to test Sallin’s hypothesis and study the relative importance of the helical structure of the heart,” said John Zimmerman, a postdoctoral researcher at SEAS and co-first author of the study. article.

To test Sallin’s theory, the SEAS researchers used the FRYS system to control the alignment of spun fibers on which to grow heart cells.

The first step of FRYS works like a cotton candy machine – a liquid polymer solution is loaded into a reservoir and forced out through a small opening by centrifugal force as the device rotates. As the solution leaves the reservoir, the solvent evaporates and the polymers solidify to form fibers. Then a directed airflow controls the orientation of the fiber as it is deposited on a collector. The team found that by tilting and rotating the collector, the fibers in the flow would align and twist around the collector as it rotated, mimicking the spiral structure of heart muscles.

The alignment of the fibers can be tuned by changing the angle of the collector.

“The human heart actually has multiple layers of spirally aligned muscles with different alignment angles,” said Huibin Chang, a postdoctoral researcher at SEAS and co-first author of the paper. “With FRYS, we can recreate those complex structures in a very precise way, forming one or even four-chambered ventricular structures.”

Unlike 3D printing, which slows down as features get smaller, FRYS can quickly spin fibers on the scale of one micron — or about fifty times smaller than a single human hair. This is important when it comes to building a heart from scratch. Take, for example, collagen, an extracellular matrix protein in the heart, which is also one micron in diameter. It would take more than 100 years to 3D print every piece of collagen in the human heart at this resolution. FRYS can do it in one day.

After spinning, the ventricles were seeded with rat cardiomyocyte cells or human stem cell-derived cardiomyocyte cells. Within about a week, several thin layers of beating tissue covered the scaffold, with the cells following the alignment of the fibers below.

The beating ventricles mimicked the same twisting or twisting motion that is present in the human heart.

The researchers compared ventricle deformation, rate of electrical signaling and ejection fraction between ventricles made of spirally aligned fibers and those made of circumferentially aligned fibers. They found that on each front, the spirally aligned tissue outperformed the circumferentially aligned tissue.

“Since 2003, our group has been working to understand the structure-function relationships of the heart and how disease pathologically compromises these relationships,” Parker said. “In this case, we went back to an untested observation about the spiral structure of the laminar architecture of the heart. Fortunately, Professor Sallin published a theoretical prediction more than half a century ago and we were able to build a new production platform that allowed us to to test his hypothesis and answer this age-old question.”

The team also showed that the process can be scaled up to the size of a real human heart and even larger, to the size of a minke whale heart (they didn’t seed the larger models with cells because it would cost billions of cardiomyocyte cells).

In addition to biofabrication, the team is also exploring other applications for their FRYS platform, such as food packaging.

The Harvard Office of Technology Development has protected the intellectual property related to this project and is exploring its potential for commercialization.

It was supported in part by the Harvard Materials Research Science and Engineering Center (DMR-1420570, DMR-2011754), the National Institutes of Health with the Center for Nanoscale Systems (S10OD023519), and the National Center for Advancing Translational Sciences (UH3TR000522, 1- UG3-HL-141798-01).

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