Big step forward for organ biofabrication: By recreating the helical structure of heart muscle, researchers increase understanding of how the heart beats - Azi News

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 is why tissue engineering, which ultimately includes the wholesale manufacture of whole human hearts for transplantation, is so important to the future of cardiac medicine.

To build the human heart from the ground up, researchers needed to replicate the unique structures that make up the heart. This includes recreating the helical geometry, which creates a circular motion when the heart beats. It has long been theorized that this circular motion is essential for pumping blood at high volumes, but proving it is difficult, in part because creating hearts with different geometries and alignments is a challenge.

Now, bioengineers from Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed the first biohybrid model of the human ventricle with helically aligned beating heart cells, and have shown that muscle alignment, in fact, dramatically increases how much blood is pumped. that the ventricle can pump with each contraction.

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

This research was published in Science.

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

This work is rooted in a centuries-old mystery. In 1669, the English physician Richard Lower – a man who counted John Locke among his comrades and King Charles II among his patients – first noted the spiral-like arrangement of the heart muscle in his seminal work. Tractatus de Corde.

Over the next three centuries, doctors and scientists have built a more comprehensive understanding of the structure of the heart but the purpose of the spiral muscles remains 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 alignment of the heart’s helix is ​​essential for achieving a large ejection fraction – the percentage of how much blood the ventricle pumps with each contraction.

“Our goal was to build a model in which we could test Sallin’s hypothesis and study the relative importance of the helical structure of the heart,” said John Zimmerman, a postdoctoral fellow at SEAS and co-author of the paper.

To test Sallin’s theory, the SEAS researchers used the FRJS system to control the alignment of the spun fibers in which they could grow heart cells.

The first step of the FRJS works like a cotton candy machine — a liquid polymer solution is fed into a reservoir and pushed out through a tiny hole by centrifugal force as the device rotates. As the solution leaves the reservoir, the solvent evaporates, and the polymer solidifies to form fibers. Then, the focused airflow controls the orientation of the fibers as they are deposited on the collector. The team found that by tilting and rotating the collector, the fibers in the stream would align and twist around the collector as it rotated, mimicking the helical structure of heart muscle.

Fiber alignment can be adjusted by changing the angle of the collector.

“The human heart actually has many layers of muscle arranged helices with different angles of alignment,” said Huibin Chang, a postdoctoral fellow at SEAS and co-author of the paper. “With FRJS, we were able to recreate these complex structures in a very precise way, forming single and even four-chambered ventricular structures.”

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

After spinning, the ventricles were seeded with either mouse cardiomyocytes or human stem cell-derived cardiomyocytes. In about a week, several thin layers of beating tissue covered the scaffold, with the cells following the alignment of the fibers beneath.

The beating ventricle mimics the same twisting or squeezing motion that exists in the human heart.

The researchers compared ventricular deformation, electrical signal velocity and ejection fraction between ventricles made of helical parallel fibers and those made of circularly aligned fibers. They found at each front, the helically aligned grid outperformed the circularly aligned grid.

“Since 2003, our group has been working to understand the structure-function relationship of the heart and how disease pathologically compromises this relationship,” says Parker. “In this regard, we return to discuss previously untested observations of the helical structure of the heart’s laminar architecture. Fortunately, Professor Sallin published theoretical predictions more than half a century ago and we were able to build a new manufacturing platform that would allow us to test his hypotheses and answer centuries of questions.”

The team also showed that the process could be scaled up to the size of an actual human heart and even larger, to the size of a Minke whale heart (they didn’t seed the larger model with cells because it would require billions of cardiomyocyte cells).

Apart from biofabrication, the team is also exploring other applications for their FRJS platform, such as food packaging.

The Harvard Technology Development Office has protected the intellectual property associated with this project and is exploring commercialization opportunities.

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

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