Harvard College researchers, in collaboration with colleagues from Emory College, have developed the primary totally autonomous biohybrid fish from human stem-cell derived cardiac muscle cells. The bogus fish swims by recreating the muscle contractions of a pumping coronary heart, bringing researchers one step nearer to creating a extra complicated synthetic muscular pump and offering a platform to check coronary heart illness like arrhythmia.
“Our final purpose is to construct a man-made coronary heart to interchange a malformed coronary heart in a baby,” stated Package Parker, the Tarr Household Professor of Bioengineering and Utilized Physics on the Harvard John A. Paulson College of Engineering and Utilized Sciences (SEAS) and senior creator of the paper. “Many of the work in constructing coronary heart tissue or hearts, together with some work now we have completed, is targeted on replicating the anatomical options or replicating the straightforward beating of the center within the engineered tissues. However right here, we’re drawing design inspiration from the biophysics of the center, which is more durable to do. Now, slightly than utilizing coronary heart imaging as a blueprint, we’re figuring out the important thing biophysical rules that make the center work, utilizing them as design standards, and replicating them in a system, a dwelling, swimming fish, the place it’s a lot simpler to see if we’re profitable.”
The biohybrid fish developed by the crew builds off earlier analysis from Parker’s Illness Biophysics Group. In 2012, the lab used cardiac muscle cells from rats to construct a jellyfish-like biohybrid pump and in 2016 the researchers developed a swimming, synthetic stingray additionally from rat coronary heart muscle cells.
On this analysis, the crew constructed the primary autonomous biohybrid system made out of human stem-cell derived cardiomyocytes. This system was impressed by the form and swimming movement of a zebrafish. In contrast to earlier gadgets, the biohybrid zebrafish has two layers of muscle cells, one on all sides of the tail fin. When one aspect contracts, the opposite stretches. That stretch triggers the opening of a mechanosensitive protein channel, which causes a contraction, which triggers a stretch and so forth and so forth, resulting in a closed loop system that may propel the fish for greater than 100 days.
“By leveraging cardiac mechano-electrical signaling between two layers of muscle, we recreated the cycle the place every contraction outcomes robotically as a response to the stretching on the alternative aspect,” stated Keel Yong Lee, a postdoctoral fellow at SEAS and co-first creator of the examine. “The outcomes spotlight the function of suggestions mechanisms in muscular pumps resembling the center.”
The researchers additionally engineered an autonomous pacing node, like a pacemaker, which controls the frequency and rhythm of those spontaneous contractions. Collectively, the 2 layers of muscle and the autonomous pacing node enabled the technology of steady, spontaneous, and coordinated, back-and-forth fin actions.
“Due to the 2 inside pacing mechanisms, our fish can stay longer, transfer sooner and swim extra effectively than earlier work,” stated Sung-Jin Park, a former postdoctoral fellow within the Illness Biophysics Group at SEAS and co-first creator of the examine. “This new analysis gives a mannequin to research mechano-electrical signaling as a therapeutic goal of coronary heart rhythm administration and for understanding pathophysiology in sinoatrial node dysfunctions and cardiac arrhythmia.”
Park is presently an Assistant Professor on the Coulter Division of Biomedical Engineering at Georgia Institute of Expertise and Emory College College of Medication.
In contrast to a fish in your fridge, this biohybrid fish improves with age. Its muscle contraction amplitude, most swimming pace, and muscle coordination all elevated for the primary month because the cardiomyocyte cells matured. Ultimately, the biohybrid fish reached speeds and swimming efficacy just like zebrafish within the wild.
Subsequent, the crew goals to construct much more complicated biohybrid gadgets from human coronary heart cells.
“I might construct a mannequin coronary heart out of Play-Doh, it does not imply I can construct a coronary heart,” stated Parker. “You possibly can develop some random tumor cells in a dish till they curdle right into a throbbing lump and name it a cardiac organoid. Neither of these efforts goes to, by design, recapitulate the physics of a system that beats over a billion instances throughout your lifetime whereas concurrently rebuilding its cells on the fly. That’s the problem. That’s the place we go to work.”
The analysis 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 partially by Nationwide Institutes of Well being Nationwide Middle for Advancing Translational Sciences grant UH3TR000522, and Nationwide Science Basis Supplies Analysis Science and Engineering Middle grant DMR-142057.