Heart disease -; the leading reason behind death within the U.S. -; is so deadly partly because the center, unlike other organs, cannot repair itself after injury. That’s the reason tissue engineering, ultimately including the wholesale fabrication of a complete human heart for transplant, is so essential for the long run of cardiac medicine.
To construct a human heart from the bottom up, researchers need to duplicate the unique structures that make up the center. This includes recreating helical geometries, which create a twisting motion as the center beats. It has been long theorized that this twisting motion is critical for pumping blood at high volumes, but proving that has been difficult, partly because creating hearts with different geometries and alignments has been difficult.
Now, bioengineers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed the primary biohybrid model of human ventricles with helically aligned beating cardiac cells, and have shown that muscle alignment does, in reality, dramatically increases how much blood the ventricle can pump with each contraction.
This advancement was made possible using a latest approach to additive textile manufacturing, Focused Rotary Jet Spinning (FRJS), which enabled the high-throughput fabrication of helically aligned fibers with diameters starting from several micrometers to tons of of nanometers. Developed at SEAS by Kit Parker’s Disease Biophysics Group, FRJS fibers direct cell alignment, allowing for the formation of controlled tissue engineered structures.
The research is published in Science.
“This work is a significant step forward for organ biofabrication and brings us closer to our ultimate goal of constructing a human heart for transplant,” said Parker, the Tarr Family Professor of Bioengineering and Applied Physics at SEAS and senior writer of the paper.
This work has its roots in a centuries old mystery. In 1669, English physician Richard Lower -; a person who counted John Locke amongst his colleagues and King Charles II amongst his patients -; first noted the spiral-like arrangement of heart muscles in his seminal work Tractatus de Corde.
Over the following three centuries, physicians and scientists have built a more comprehensive understanding of the center’s structure however the purpose of those spiraling muscles has remained frustratingly hard to review.
In 1969, Edward Sallin, former chair of the Department of Biomathematics on the University of Alabama Birmingham Medical School, argued that the center’s helical alignment is critical to achieving large ejection fractions -; the proportion of how much blood the ventricle pumps with each contraction.
“Our goal was to construct a model where we could test Sallin’s hypothesis and study the relative importance of the center’s helical structure,” said John Zimmerman, a postdoctoral fellow at SEAS and co-first writer of the paper.
To check Sallin’s theory, the SEAS researchers used the FRJS system to regulate the alignment of spun fibers on which they might grow cardiac cells.
Step one of FRJS works like a cotton candy machine -; a liquid polymer solution is loaded right into a reservoir and pushed out through a tiny opening by centrifugal force because the device spins. As the answer leaves the reservoir, the solvent evaporates, and the polymers solidify to form fibers. Then, a focused airstream controls the orientation of the fiber as they’re deposited on a collector. The team found that by angling and rotating the collector, the fibers within the stream would align and twist across the collector because it spun, mimicking the helical structure of heart muscles.
The alignment of the fibers may be tuned by changing the angle of the collector.
“The human heart actually has multiple layers of helically aligned muscles with different angles of alignment,” said Huibin Chang, a postdoctoral fellow at SEAS and co-first writer of the paper. “With FRJS, we are able to recreate those complex structures in a very precise way, forming single and even 4 chambered ventricle structures.”
Unlike 3D printing, which gets slower as features get smaller, FRJS can quickly spin fibers at the only micron scale – or about fifty times smaller than a single human hair. This is essential in relation to constructing a heart from scratch. Take collagen for example, an extracellular matrix protein in the center, which can be a single micron in diameter. It will take greater than 100 years to 3D print every little bit of collagen within the human heart at this resolution. FRJS can do it in a single day.
After spinning, the ventricles were seeded with rat cardiomyocyte or human stem cell derived cardiomyocyte cells. Inside about every week, several thin layers of beating tissue covered the scaffold, with the cells following the alignment of the fibers beneath.
The beating ventricles mimicked the identical twisting or wringing motion present in human hearts.
The researchers compared the ventricle deformation, speed of electrical signaling and ejection fraction between ventricles produced from helical aligned fibers and people produced from circumferentially aligned fibers. They found on every front, the helically aligned tissue outperformed the circumferentially aligned tissue.
“Since 2003, our group has worked to grasp the structure-function relationships of the center and the way disease pathologically compromises these relationships,” said Parker. “On this case, we went back to deal with a never tested remark concerning the helical structure of the laminar architecture of the center. Fortunately, Professor Sallin published a theoretical prediction greater than a half century ago and we were in a position to construct a latest manufacturing platform that enabled us to check his hypothesis and address this centuries-old query.”
The team also demonstrated that the method may be scaled as much as the scale of an actual human heart and even larger, to the scale of a Minke whale heart (they didn’t seed the larger models with cells as it will take billions of cardiomyocyte cells).
Besides biofabrication, the team also explores other applications for his or her FRJS platform, similar to food packaging.
The Harvard Office of Technology Development has protected the mental property referring to this project and is exploring commercialization opportunities.
Source:
Harvard John A. Paulson School of Engineering and Applied Sciences
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