Heart disease, the leading cause of death in the United States, is so deadly in part because the heart, unlike other organs, cannot be repaired after an injury. That’s why tissue engineering, which ultimately includes the wholesale manufacturing of an entire human heart for transplant, is so important to the future of cardiac medicine.
To build a human heart from the ground up, researchers must replicate the unique structures that make up the heart. This includes recreating helical geometries, which create a twisting motion as the heart beats. It has long been theorized that this torsional motion is critical to pumping blood at large volumes, but proving this has been difficult, in part because creating hearts with different geometries and alignments has been a challenge.
Now, bioengineers at Harvard School of Engineering and Applied Sciences (SEAS) John A. Paulson have developed the first biohybrid model of human ventricles with helically aligned heart cells and have shown that muscle alignment, in fact , dramatically increases how much blood the ventricle can pump with each contraction.
This breakthrough was made possible by a new additive textile manufacturing method, Focused Rotary Jet Spinning (FRJS), which allowed the manufacture of high-performance helically aligned fibers with diameters ranging from several micrometers to hundreds of nanometers. Developed at SEAS by Kit Parker’s disease biophysics group, FRJS fibers direct cell alignment, allowing the formation of controlled tissue engineering structures.
The research is published in Science.
“This work is a big step forward for organ biofabrication and brings us closer to our ultimate goal of building a human heart for transplant,” said Parker, a professor in the Tarr family of Bioengineering and Applied Physics at SEAS and author main document.
This work has its roots in a century-old mystery. In 1669, the English physician Richard Lower, a man who had John Locke among his colleagues and King Charles II among his patients, first observed the spiral arrangement of the heart muscles in his fundamental work Tractatus. of Ropes.
Over the next three centuries, doctors and scientists have built a more complete understanding of the structure of the heart, but the purpose of these spiral muscles has been frustratingly difficult to study.
In 1969, Edward Sallin, former president 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 the amount of blood that pump the ventricle with each contraction.
“Our goal was to build a model where we could test Sallin’s hypothesis and study the relative importance of the helical structure of the heart,” said John Zimmerman, a SEAS postdoctoral fellow and co-author of the paper.
To test Sallin’s theory, SEAS researchers used the FRJS system to control the alignment of the spun fibers on which they could grow heart cells.
The first step of FRJS works like a cotton candy machine: a liquid polymer solution is loaded into a tank and taken out through a small opening by centrifugal force as the device rotates. When the solution leaves the tank, the solvent evaporates and the polymers solidify to form fibers. A centered air stream then controls the orientation of the fiber as it is deposited in a manifold. The team found that by tilting and rotating the collector, the current fibers would align and rotate around the collector as it rotated, mimicking the helical structure of the heart muscles.
The alignment of the fibers can be adjusted by changing the angle of the manifold.
“The human heart actually has multiple layers of helically aligned muscles with different alignment angles,” said Huibin Chang, a SEAS postdoctoral fellow and co-author of the paper. “With FRJS, we can recreate these complex structures in a really precise way, forming simple ventricle and even four-chamber structures.”
Unlike 3D printing, which becomes slower as features are reduced, FRJS 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, a protein from the extracellular matrix in the heart, which is also a single micron in diameter. It would take more than 100 years to 3D print each piece of collagen from the human heart with this resolution. FRJS can do it in a single day.
After rotation, the ventricles were seeded with rat cardiomyocytes or cardiomyocyte cells derived from human stem cells. In about a week, several thin layers of beating tissue covered the scaffold, with the cells following the alignment of the fibers underneath.
The beating ventricles mimicked the same torsional or shortening motion present in human hearts.
The researchers compared ventricular strain, electrical signaling velocity, and ejection fraction between ventricles made of helically aligned fibers and those made of circumferentially aligned fibers. They found on all fronts, the helically aligned tissue surpassed the circumferential aligned tissue.
“Since 2003, our group has been working to understand the structure-function relationships of the heart and how disease pathologically compromises those relationships,” Parker said. “In this case, we again addressed an unproven observation about the helical 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 manufacturing platform. .this allowed us to test his hypothesis and address this centuries-old question “.
The team also showed that the process can be scaled to the size of a real human heart and even larger, the size of a Minke whale heart (they did not plant larger models with cells , as billions of cardiomyocyte cells would be needed). ).
In addition to biofabrication, the team is also exploring other applications for its FRJS platform, such as food packaging.
The Harvard Office of Technology Development has protected intellectual property related to this project and is exploring marketing opportunities.
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 Nanocale Systems (S10OD023519) and the National Center for Advancing Translational Sciences (UH3TR000522, 1-). UG3-HL-141798-01).