Biohybrid fish on a hook. (Photo: Michael Rosnach, Keel Yong Lee, Sung-Jin Park, Kevin Kit Parker)

The first fully autonomous biohybrid fish from human stem-cell-derived cardiac muscle cells has been developed by Harvard University researchers in collaboration with colleagues from Emory University. 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 diseases 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).

"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,” he said.

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.

The researchers also engineered an autonomous pacing node, like a pacemaker, which controls the frequency and rhythm of these 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.

This biohybrid fish actually 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."