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A biohybrid fish generated from human cardiac cells moves in the same way as the heart does

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The device provides information about artificial muscle pumps, which is a step toward creating an artificial heart.

Scientists have created the first completely autonomous biohybrid fish using heart muscle cells obtained from human stem cells. The mechanical fish swims by imitating the muscle contractions of a pumping heart, taking researchers one step closer to producing a more complicated artificial muscular pump and giving a platform for research into heart illness such as arrhythmia.

Harvard University researchers have created the first completely autonomous biohybrid fish using human stem-cell generated heart muscle cells, in conjunction with Emory University colleagues. The mechanical fish swims by imitating the muscle contractions of a pumping heart, taking researchers one step closer to producing a more complicated artificial muscular pump and giving a platform for research into heart illness such as arrhythmia.

Kit Parker, the Tarr Family Professor of Bioengineering and Applied Physics at Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and senior author of the research, stated, “Our ultimate aim is to construct an artificial heart to replace a damaged heart in a kid.” “The majority of effort in developing cardiac tissue or hearts, including some of our own, is focused on reproducing anatomical aspects or the basic beating of the heart in synthetic tissues. However, we are taking design cues from the biophysics of the heart, which is a more difficult task. Instead of using heart imaging as a blueprint, we’re discovering the basic biophysical principles that make the heart function, utilizing them as design criteria, and recreating them in a system, a live, swimming fish, where we can see whether we’re successful.”

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The study was published in the journal Science.

The team’s biohybrid fish is based on prior research from Parker’s Disease Biophysics Group. In 2012, the scientists created a jellyfish-like biohybrid pump using rat cardiac muscle cells, and in 2016, they created a swimming, artificial stingray using rat heart muscle cells.

The scientists created the first autonomous biohybrid gadget using cardiomyocytes produced from human stem cells in this study. The design and swimming motion of a zebrafish inspired this invention. The biohybrid zebrafish, unlike earlier devices, contains two layers of muscle cells, one on each side of the tail fin. The opposite side expands while one side compresses. That stretch opens a mechanosensitive protein channel, which generates a contraction, which causes another stretch, and so on, creating a closed loop mechanism capable of propelling the fish for more than 100 days.

“We replicated the cycle where each contraction arises naturally as a reaction to the stretching on the opposite side by utilizing cardiac mechano-electrical communication between two layers of muscle,” said Keel Yong Lee, a postdoctoral fellow at SEAS and co-first author of the work. “The findings emphasize the importance of feedback systems in muscle pumps like the heart.”

The researchers also created an independent pacing node that regulates the frequency and rhythm of these spontaneous contractions, similar to a pacemaker. The autonomous pacing node and the two layers of muscle worked together to generate continuous, spontaneous, and coordinated back-and-forth fin motions.

“Our fish can live longer, move faster, and swim more effectively than earlier studies because of the two internal pacing systems,” said Sung-Jin Park, a former postdoctoral researcher at SEAS’ Disease Biophysics Group and co-first author of the paper. “This novel research offers a paradigm for investigating mechano-electrical signaling as a therapeutic target for heart rhythm control and for understanding pathophysiology in sinoatrial node dysfunctions and cardiac arrhythmia,” says the study’s lead author.

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Park is presently an Assistant Professor at Georgia Institute of Technology’s Coulter Department of Biomedical Engineering and Emory University School of Medicine.

Unlike a refrigerator fish, this biohybrid fish becomes better with age. As the cardiomyocyte cells grew, the amplitude of muscle contractions, maximal swimming speed, and muscular coordination all increased over the first month. The biohybrid fish eventually attained speeds and swimming efficiency comparable to wild zebrafish.

The team’s next goal is to create even more complicated biohybrid devices using human heart cells.

“Just because I can make a model heart out of Play-Doh doesn’t imply I can make a heart,” Parker said. “You can make a cardiac organoid by growing some random tumor cells in a dish until they curdle into a pulsating mass. By design, none of those initiatives will be able to recreate the mechanics of a system that beats over a billion times in your lifetime while also renewing its cells on the go. That is the problem. That’s where we’ll be working.”

David G. Matthews, Sean L. Kim, Carlos Antonio Marquez, John F. Zimmerman, Herdeline Ann M. Ardona, Andre G. Kleber, and George V. Lauder collaborated on the study.

The National Institutes of Health’s National Center for Advancing Translational Sciences grant UH3TR000522 and the National Science Foundation’s Materials Research Science and Engineering Center award DMR-142057 helped fund the research.

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