Harvard University researchers, working with Emory University colleagues, created the first completely autonomous biohybrid fish from human stem-cell generated heart muscle cells. The mechanical fish swims by mimicking the muscle contractions of a pumping heart, taking researchers one step closer to designing a more complicated artificial muscular pump and giving a platform for researchers to investigate heart diseases such as arrhythmia.
“Our ultimate aim is to construct an artificial heart to replace a damaged heart in a kid”, said Kit Parker, senior author of the research and Tarr Family Professor of Bioengineering and Applied Physics at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS). “The majority of effort in manufacturing cardiac tissue or hearts, including part of our work, is focused on mimicking anatomical traits or fundamental heart beating in synthetic tissues”. However, in this case, we are getting design inspiration from the biophysics of the heart, which is a more difficult task. Rather than utilising heart imaging as a blueprint, we are now discovering the basic biophysical principles that make the heart work, using them as design criteria, and duplicating them in a system, a live, swimming fish, where we can observe how effective we are.
The team’s biohybrid fish draws on prior research from Parker’s Disease Biophysics Group. The group created a jellyfish-like biohybrid pump out of rat heart muscle cells in 2012, and a swimming, artificial stingray out of rat heart muscle cells in 2016. The researchers created the first autonomous biohybrid device from human stem-cell generated cardiomyocytes in this study. The form and swimming motion of a zebrafish influenced the design of this gadget. Unlike previous devices, the biohybrid zebrafish has two layers of muscle cells, one on each side of the tail fin. The opposite side extends when one side contracts. This stretch activates a mechanosensitive protein channel, which induces a contraction, which causes another stretch, and so on, resulting in a closed loop mechanism capable of moving the fish for more than 100 days.
“By using cardiac mechano-electrical communication between two layers of muscle, we duplicated the cycle where each contraction develops spontaneously as a reaction to stretching on the opposite side”, said Keel Yong Lee, a postdoctoral scholar at SEAS and co-first author of the study. “The findings highlight the significance of feedback mechanisms in muscle pumps such as the heart”. The researchers also developed an autonomous pacing node, which functions similarly to a pacemaker in regulating the frequency and rhythm of these spontaneous contractions. The two muscle layers collaborated with the autonomous pacing node to create continuous, spontaneous, and coordinated back-and-forth fin movements.
“Because of the two internal pacing systems, our fish can live longer, move faster, and swim more effectively than prior studies”, said Sung-Jin Park, study co-first author and former postdoctoral researcher at SEAS’s Disease Biophysics Group. “This ground-breaking study creates a platform for further research into mechano-electrical signalling as a therapeutic target of heart rhythm regulation, as well as pathogenesis in sinoatrial node dysfunction and cardiac arrhythmia”.
Unlike a refrigerator fish, this biohybrid fish improves with age. As the cardiomyocyte cells grew, its muscle contraction amplitude, maximal swimming speed, and muscle coordination all increased over the first month. Eventually, the biohybrid fish attained speeds and swimming efficacy comparable to wild zebrafish. The team’s next objective is to develop more complex biohybrid devices utilising human heart cells.
“Just because I can create a Play-Doh model heart doesn’t imply, I can make a heart”, Parker pointed out. “In a lab, you can grow a bunch of random tumour cells until they curdle into a throbbing mass and call it a heart organoid”. Neither of those attempts is intended to recreate the mechanics of a system that beats over a billion times over your lifetime while also renewing its cells on the fly. That is the difficulty. 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. It was funded in part by the National Institutes of Health’s National Centre for Advancing Translational Sciences grant UH3TR000522, as well as the National Science Foundation’s Materials Research Science and Engineering Centre award DMR-142057.
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