Biohybrid fish made from human cardiac cells swims like the heart beats
Device offers insights into artificial muscular pumps, a step toward
building an artificial heart

Date:
February 10, 2022
Source:
Harvard John A. Paulson School of Engineering and Applied Sciences
Summary:
Scientists have developed the first fully autonomous biohybrid fish
from human stem-cell derived cardiac muscle cells. The artificial
fish swims by recreating the muscle contractions of a pumping heart,
bringing researchers one step closer to developing a more complex
artificial muscular pump and providing a platform to study heart
disease like arrhythmia.



FULL STORY ========================================================================== Harvard University researchers, in collaboration with colleagues from
Emory University, have developed the first fully autonomous biohybrid
fish from human stem-cell derived cardiac muscle cells. The artificial
fish swims by recreating the muscle contractions of a pumping heart,
bringing researchers one step closer to developing a more complex
artificial muscular pump and providing a platform to study heart disease
like arrhythmia.


==========================================================================
"Our ultimate goal is to build an artificial heart to replace a
malformed heart in a child," said Kit Parker, the Tarr Family Professor
of Bioengineering and Applied Physics at the Harvard John A. Paulson
School of Engineering and Applied Sciences (SEAS) and senior author
of the paper. "Most of the work in building heart tissue or hearts,
including some work we have done, is focused on replicating the anatomical features or replicating the simple beating of the heart in the engineered tissues. But here, we are drawing design inspiration from the biophysics
of the heart, which is harder to do. Now, rather than using heart imaging
as a blueprint, we are identifying the key biophysical principles that
make the heart work, using them as design criteria, and replicating them
in a system, a living, swimming fish, where it is much easier to see if
we are successful." The research is published in Science.

The biohybrid fish developed by the team builds off previous research
from Parker's Disease Biophysics Group. In 2012, the lab used cardiac
muscle cells from rats to build a jellyfish-like biohybrid pump and in
2016 the researchers developed a swimming, artificial stingray also from
rat heart muscle cells.

In this research, the team built the first autonomous biohybrid device
made from human stem-cell derived cardiomyocytes. This device was inspired
by the shape and swimming motion of a zebrafish. Unlike previous devices,
the biohybrid zebrafish has two layers of muscle cells, one on each
side of the tail fin. When one side contracts, the other stretches. That stretch triggers the opening of a mechanosensitive protein channel, which causes a contraction, which triggers a stretch and so on and so forth,
leading to a closed loop system that can propel the fish for more than
100 days.

"By leveraging cardiac mechano-electrical signaling between two layers
of muscle, we recreated the cycle where each contraction results
automatically as a response to the stretching on the opposite side,"
said Keel Yong Lee, a postdoctoral fellow at SEAS and co-first author
of the study. "The results highlight the role of feedback mechanisms in muscular pumps such as the heart." The researchers also engineered an autonomous pacing node, like a pacemaker, which controls the frequency
and rhythm of these spontaneous contractions.

Together, the two layers of muscle and the autonomous pacing node
enabled the generation of continuous, spontaneous, and coordinated, back-and-forth fin movements.



========================================================================== "Because of the two internal pacing mechanisms, our fish can live longer,
move faster and swim more efficiently than previous work," said Sung-Jin
Park, a former postdoctoral fellow in the Disease Biophysics Group at SEAS
and co-first author of the study. "This new research provides a model to investigate mechano-electrical signaling as a therapeutic target of heart rhythm management and for understanding pathophysiology in sinoatrial
node dysfunctions and cardiac arrhythmia." Park is currently an Assistant Professor at the Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University School of Medicine.

Unlike a fish in your refrigerator, this biohybrid fish improves with
age. Its muscle contraction amplitude, maximum swimming speed, and muscle coordination all increased for the first month as the cardiomyocyte
cells matured.

Eventually, the biohybrid fish reached speeds and swimming efficacy
similar to zebrafish in the wild.

Next, the team aims to build even more complex biohybrid devices from
human heart cells.

"I could build a model heart out of Play-Doh, it doesn't mean I can
build a heart," said Parker. "You can grow some random tumor cells in
a dish until they curdle into a throbbing lump and call it a cardiac
organoid. Neither of those efforts is going to, by design, recapitulate
the physics of a system that beats over a billion times during your
lifetime while simultaneously rebuilding its cells on the fly. That is the challenge. That is where we go to work." The research was co-authored by
David G. Matthews, Sean L. Kim, Carlos Antonio Marquez, John F. Zimmerman, Herdeline Ann M. Ardona, Andre G. Kleber and George V. Lauder.

It was supported in part by National Institutes of Health National Center
for Advancing Translational Sciences grant UH3TR000522, and National
Science Foundation Materials Research Science and Engineering Center
grant DMR-142057.

========================================================================== Story Source: Materials provided by Harvard_John_A._Paulson_School_of_Engineering_and_Applied
Sciences. Original written by Leah Burrows. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Keel Yong Lee, Sung-Jin Park, David G. Matthews, Sean L. Kim, Carlos
Antonio Marquez, John F. Zimmerman, Herdeline Ann M. Ardon~a,
Andre G.

Kleber, George V. Lauder, Kevin Kit Parker. An autonomously swimming
biohybrid fish designed with human cardiac biophysics. Science,
2022; 375 (6581): 639 DOI: 10.1126/science.abh0474 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220210154212.htm

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