Heart disease is the leading cause for death in the United States. This is because unlike other organs, the heart can not heal itself after an injury. This is why tissue engineering is essential for the future of cardiac medicine. It includes the production of whole hearts for transplant.
Researchers must replicate the unique structures of the human heart in order to build one. Researchers must recreate helical geometries that create twisting motions as the heart beats. Although it’s long been known that the twisting motion is vital for pumping blood at high volumes, it has been difficult to prove this. This is partly due to difficulties in creating hearts with different geometries.
Bioengineers at Harvard John A. Paulson School of Engineering and Applied Sciences have created the first biohybrid human ventricles model with helically aligned beating heart cells. They have also shown that muscle alignment dramatically increases the amount of blood the ventricle can pump during each contraction.
Focused Rotary Jet Spinning, a new method to additive textile manufacturing, enabled this advancement. This allowed for high-throughput fabrication and alignment of helically aligned yarns with diameters ranging anywhere from several micrometers up to hundreds of nanometers. FRJS fibers, which were developed at SEAS by Kit Parker’s Disease Biophysics Group allow for cell alignment and the creation of controlled tissue-engineered structures.
The research was published in Science.
Parker, the Tarr family Professor of Bioengineering at SEAS, and the senior author of this paper, stated that “this work represents a major step forward in organ biofabrication. It brings us closer towards our ultimate goal to build a human heart for transplant.”
This work is rooted in centuries-old mystery. Richard Lower, an English physician and who was also a friend of John Locke and King Charles II, first observed the spiral-like arrangement between heart muscles in 1669. Tractatus de Corde.
Scientists and doctors have gained a better understanding of the structure of the heart over the following three centuries. But, it has been frustratingly difficult to understand the purpose of the spiraling muscles.
Edward Sallin, who was then the chair of the Department of Biomathematics of the University of Alabama Birmingham Medical School, stated that the heart’s helical alignment was critical for large ejection factors. This is the percentage of blood the ventricle pumps during each contraction.
John Zimmerman (postdoctoral fellow at SEAS, co-first author) stated that the goal of the paper was to build a model which could be used to test Sallin’s hypothesis as well as study the relative importance and function of the heart’s internal helical structure.
The FRJS system was used by the SEAS researchers to control the orientation of spun fibers that could be used for growing cardiac cells.
The first step in FRJS is similar to a cotton candy machine. A liquid polymer solution is placed into a reservoir. It is pushed out of the tiny opening using centrifugal force. The solution evaporates as the solvent is removed from the reservoir and the polymers become solidified to form fibers. A focused airstream then controls the orientation of each fiber as it is deposited onto a collector. The team discovered that by spinning the collector and angling it, the fibers would align with the collector and spin around it. This mimicked the helical structure in heart muscles.
You can adjust the angle of your collector to alter the alignment of the fibers.
Huibin Chang (postdoctoral fellow at SEAS) was co-first author. “With FRJS, it is possible to recreate complex structures in a really accurate way. It can even form single- and four-chamber ventricle structures.
FRJS spins fibers quickly at a single micron scale. This is 50 times faster than 3D printing. This is critical when creating a heart from scratch. Consider collagen, an example of extracellular matrix protein found in the heart. It is also only a micron in size. To 3D-print every single bit of collagen in the human ear at this resolution, it would take over 100 years. FRJS can print it in a day.
After spinning, the ventricles received rat or human stem cell derived cardiac cells. In about one week, thin layers of beating tissue had covered the scaffold. The cells were aligned with the fibers below.
The beat ventricles mimicked the twisting and wringing motions found in human hearts.
Researchers compared the speed of electrical signaling, ventricle deformation, and ejection fractions between ventricles made with helical and circumferentially aligned fibres. They found that the helically aligned tissue performed better than the circumferentially aligned on all fronts.
Parker said that the group has been working since 2003 to understand the structure-function relationships within the heart, and how disease can compromise these relationships. “In this instance, we returned to examine a never-tested observation about the helical structure and laminar architectures of the heart. Professor Sallin made a prediction over a century ago. We were able build a new manufacturing platform which allowed us to test this hypothesis and answer this centuries-old problem.
They also showed that the process can scale up to the actual size of a human heart, and even bigger to the Minke whale’s heart. However, they didn’t seed larger models with cells because it would require billions of cardiomyocytes.
In addition to biofabrication the team also looks into other applications for their FRJS system, such as food packaging.
The intellectual property related to this project has been protected by the Harvard Office of Technology Development and it is being explored for commercialization.
It was partly supported by Harvard Materials Research Science and Engineering Center, DMR-1420570, and DMR-11754, and the National Institutes of Health (S10OD023519), and National Center for Advancing Translational Sciences (UH3TR000522, 1-UG3 HL-141798-01).