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Advances in 3D printing have opened up new opportunities for bioengineers to create cardiac tissues and structures throughout the last decade. Their goals include developing better in vitro platforms for discovering new therapeutics for heart disease, which is the leading cause of death in the United States, accounting for one out of every five deaths, and using 3D-printed heart muscle to determine which treatments might work best in individual patients. A more distant goal is to create implantable tissues capable of healing or replacing damaged or diseased elements within a patient’s heart.
Researchers from Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS) report the development of a new hydrogel ink infused with gelatin fibers that enables 3D printing of a functional heart ventricle that beats like a human heart in a paper published in Nature Materials. They observed that heart muscle cells printed in the shape of a ventricle can align and beat in unison, just like a human heart chamber.
“People have been trying to replicate organ structures and functions to test drug safety and efficacy as a way of predicting what might happen in the clinical setting,” says Suji Choi, research associate at SEAS and first author on the paper. But until now, 3D printing techniques alone have not been able to achieve physiologically-relevant alignment of cardiomyocytes, the cells responsible for transmitting electrical signals in a coordinated fashion to contract heart muscle.
“We started this project to address some of the inadequacies in 3D printing of biological tissues.” KEVIN “KIT” PARKER, Tarr Family Professor Of Bioengineering and Applied Physics, Head of The Disease Biophysics Group at Seas, Senior Author.
The innovation lies in the addition of fibers within a printable ink. “FIG ink is capable of flowing through the printing nozzle but, once the structure is printed, it maintains its 3D shape,” says Choi. “Because of those properties, I found it’s possible to print a ventricle-like structure and other complex 3D shapes without using extra support materials or scaffolds.”
Choi used a rotary jet spinning technology created by Parker’s team to generate microfiber materials in a manner similar to how cotton candy is spun to create the FIG ink. A co-author on the article, postdoctoral researcher Luke MacQueen, argued that fibers formed by the rotary jet spinning technology might be mixed with ink and 3D printed.
“When Luke developed this concept, the vision was to broaden the range of spatial scales that could be printed with 3D printers by dropping the bottom out of the lower limits, taking it down to the nanometer scale,” Parker says. “The advantage of producing the fibers with rotary jet spinning rather than electrospinning” – a more conventional method for generating ultrathin fibers – “is that we can use proteins that would otherwise be degraded by the electrical fields in electrospinning.”
Choi created a sheet of material that resembled cotton by spinning gelatin fibers with a rotary jet. She then utilized sonification (sound waves) to cut the sheet into fibers that were 80 to 100 micrometers long and 5 to 10 micrometers in diameter. The fibers were then distributed in a hydrogel ink.
“This concept is broadly applicable – we can use our fiber-spinning technique to reliably produce fibers in the lengths and shapes we want.” Suji Choi, Research Associate.
The most difficult component was determining the optimal fiber-to-hydrogel ratio in the ink to ensure fiber alignment and the overall integrity of the 3D-printed structure.
The cardiomyocytes lined up in tandem with the direction of the fibers inside the ink when Choi created 2D and 3D structures with FIG ink. Choi could control how the cardiac muscle cells aligned by altering the printing direction.
When she applied electrical stimulation to 3D-printed structures made with FIG ink, she found it triggered a coordinated wave of contractions in alignment with the direction of those fibers. In a ventricle-shaped structure, “it was very exciting to see the chamber actually pumping in a similar way to how real heart ventricles pump,” Choi says.
She discovered that by experimenting with different printing directions and ink compositions, she could induce even stronger contractions within ventricle-like forms.
“Compared to the real heart, our ventricle model is simplified and miniaturized,” she explains. The team is now aiming to create more realistic cardiac tissues with thicker muscle walls that can pump fluid more forcefully. Despite its lack of strength, the 3D-printed ventricle could pump 5-20 times more fluid volume than earlier 3D-printed heart chambers.
According to the researchers, the approach can also be used to create heart valves, dual-chambered tiny hearts, and other structures.
“FIGs are but one tool we have developed for additive manufacturing,” Parker says. “We have other methods in development as we continue our quest to build human tissues for regenerative therapeutics. The goal is not to be tool driven – we are tool agnostic in our search for a better way to build biology.”
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