The heart, unlike other organs, cannot mend itself after damage. Heart disease is the leading cause of death in the United States and is particularly lethal. As a result, tissue engineering will be critical for the advancement of cardiac medicine, eventually leading to the mass manufacture of a full human heart for transplant.
The study’s findings were reported in Science. Researchers must mimic the specific structures that make up the heart in order to develop a human heart from the ground up.
This involves reproducing helical geometries, which cause the heart to twist as it beats. It’s long been assumed that this twisting action is essential for pumping blood at big volumes, but demonstrating it has been tough, thanks in part to the difficulty of manufacturing hearts with diverse geometries and alignments.
Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) bioengineers have created the first biohybrid model of human ventricles with helically aligned beating cardiac cells, demonstrating that muscle alignment does, in fact, dramatically increase the amount of blood the ventricle can pump with each contraction.
This innovation was made feasible by Focused Rotary Jet Spinning (FRJS), a novel technology of additive textile manufacturing that permitted the high-throughput manufacture of helically aligned fibres with diameters ranging from several micrometres to hundreds of nanometers.
FRJS fibres, which were developed at SEAS by Kit Parker’s Disease Biophysics Group, direct cell alignment, permitting the production of controlled tissue engineered structures.
“This study is a significant step forward for organ biofabrication, bringing us closer to our ultimate objective of constructing a human heart for transplant,” said Parker, the Tarr Family Professor of Bioengineering and Applied Physics at SEAS and the paper’s senior author.
This piece is based on a centuries-old mystery. In his important book Tractatus de Corde, English surgeon Richard Lower, who listed John Locke among his colleagues and King Charles II among his patients, first recognised the spiral-like arrangement of cardiac muscles in 1669.
Over the following three centuries, physicians and scientists gained a more complete grasp of the heart’s anatomy, but the function of those spinning muscles remained frustratingly difficult to investigate.
Edward Sallin, former chair of the Department of Biomathematics at the University of Alabama Birmingham Medical School, stated in 1969 that the helical alignment of the heart is crucial to generating high ejection fractions (the proportion of blood the ventricle pumps with each contraction).
“Our objective was to develop a model where we could verify Sallin’s hypothesis and explore the relative relevance of the heart’s helical shape,” said co-first author and SEAS postdoctoral scholar John Zimmerman.
To put Sallin’s idea to the test, the SEAS researchers employed the FRJS system to manipulate the alignment of spun fibres on which cardiac cells might be grown.
The initial stage of FRJS operates like a cotton candy machine: a liquid polymer solution is poured into a reservoir and centrifugal force pushes it out through a small aperture as the device rotates. The solvent evaporates as the solution exits the reservoir, and the polymers solidify to form fibres. The orientation of the fibre is then controlled by a concentrated airstream when it is deposited on a collector. The researchers discovered that by angling and rotating the collector, the fibres in the stream aligned and twisted around it as it spun, resembling the helical pattern of heart muscles.
The fibre alignment may be adjusted by adjusting the collector angle.
“The human heart really contains numerous layers of helically aligned muscles with varied angles of alignment,” explained Huibin Chang, a postdoctoral fellow at SEAS and the paper’s co-first author. “With FRJS, we can precisely duplicate those complicated structures, generating single and even four chambered ventricle structures.”
Unlike 3D printing, which slows down as features become smaller, FRJS can rapidly spin fibres at the single micron scale – almost fifty times thinner than a single human hair. This is critical for constructing a heart from the ground up.
Consider collagen, an extracellular matrix protein found in the heart that is also a single micron in diameter. At this resolution, 3D printing every piece of collagen in the human heart would take more than 100 years. FRJS can do the task in a single day.
The ventricles were seeded with rat cardiomyocyte or human stem cell derived cardiomyocyte cells after spinning. Within a week, multiple thin layers of beating tissue had covered the scaffold, with the cells aligning with the fibres beneath.
The pounding ventricles resembled the twisting or wringing action of human hearts.
The researchers evaluated the deformation of the ventricle, the speed of electrical signalling, and the ejection % of ventricles composed of helical oriented fibres versus those built of circumferentially aligned fibres. They discovered that helically oriented tissue outperformed circumferentially aligned tissue on all fronts.
“Our group has been working since 2003 to understand the structure-function linkages of the heart and how illness pathologically impairs these interactions,” Parker explained. “In this case, we returned to address an untested finding concerning the helical structure of the heart’s laminar architecture. Professor Sallin, fortunately, wrote a theoretical forecast more than a half-century ago, and we were able to design a new manufacturing platform that allowed us to verify his idea and answer this centuries-old riddle.”
The researchers also proved that the method can be expanded up to the size of a human heart and even larger, to the size of a Minke whale heart (the larger models were not seeded with cells since it would require billions of cardiomyocyte cells).
Aside from biofabrication, the team is looking at additional uses for their FRJS technology, such as food packaging.