Imagine a 3D printer using “bioinks” made of human cells and extracellular-matrix material to assemble, layer upon layer, flat swaths of tissue laced with vessels that could potentially serve as patches for damaged myocardium.
That’s what researchers at Tel Aviv University, Israel, reporting in the journal Advanced Science on April 15, say they’ve done. And in a more speculative proof-of-concept demonstration, they report also printing entire “hearts” made of similar myocyte and endothelial-cell inks, miniature ones they say are about the size of a rabbit’s heart.
The little printed flats of myocytes and endothelial cells, about 2 mm thick and able to conduct electrical signals, “closely fit” the immunological and biochemical properties of the human donor of the cells and other material that went into the bioinks, write the authors, led by PhD candidate Nadav Noor.
Earlier research from the same group suggested that such “personalized” tissue patches, were they to be used in patients, would be unlikely to provoke an immune response leading to rejection, senior author Tal Dvir, PhD, told theheart.org | Medscape Cardiology.
Dvir said his group printed the miniature hearts, which include some larger-caliber vessels and left and right “ventricles,” to demonstrate the technique’s potential for engineering entire organs without the fundamental immunologic pitfall of donor transplantations. If that happens, it would be in the far future.
Currently, the printed hearts are simplified versions of the real organ, “with only the major blood vessels.” As he and colleagues write, remaining challenges include techniques for generating the large number of cells required and for “long-term cultivation of the organs,” providing “biochemical and physical cues for maturation,” imaging a real heart’s entire vasculature to create the template, and 3D printing small-diameter vessels.
But patient-specific cardiac patches could possibly be a reality much sooner, he said. “Perhaps in 5 years it could be in clinical trials,” but that best-case scenario counts only the time likely needed for further research and development. It doesn’t include the unpredictable and protracted times such endeavors often need, for example, to form a company, secure financial backing, and work through regulatory hurdles, he cautioned.
“I think printing cells in a hydrogel of some biologic origin, or even some synthetic origin, is not new,” Doris A. Taylor, PhD, told theheart.org | Medscape Cardiology. “But the idea that you can generate a vascularized patch with a high fidelity of perfusion is kind of what’s been missing.”
High-resolution large and small structures are generally beyond the reach of current 3D bioprinting, but the current report “shows progress in that regard,” said Taylor, who is director of regenerative medicine research at the Texas Heart Institute, Houston.
“They’ve done an excellent job of 3D printing cardiac patches using human cells and human proteins,” she said. But, “in terms of building a truly vascularized heart on the size and scale of a human-sized heart, or a rabbit-sized heart, the data are less convincing.”
Taylor acknowledged that her research involves a “competing technology” for organ engineering. Her work and that of others on decellularization and recellularization of scaffolds from human and porcine hearts, she said, has produced structures with extensive vasculature, all valves, and four complete chambers, among other components missing in the current report’s 3D-printed hearts.
Although the patches and “hearts” described in the current report do come from human cells and may even prove to be immunologically compatible with the host, she said, in their current form, they really are not anatomically or biochemically like the real thing.
“I don’t see good physiology, I don’t see good function, I don’t see good electrical activity, and when I look at the histology, they don’t really show what look like mature cells.”
One of the field’s major challenges, she said, has been development of efficient ways to produce the vast number of pluripotent stem cells needed to engineer a complete organ. “If you’re going to build a human-sized heart, it takes 10s to 100s of billions of cells, and growing them is not trivial,” she said. “To do that routinely to generate an organ has been an unmet need in the field.”
But, Taylor added about the current research, “that being said, they’ve done this, and it’s a step forward for cardiac 3D printing.”
Development of the bioink for 3D printing, as described in the current report, started with omental tissue from which the cells and extracellular components were separated. Using established techniques, the cells are “reprogrammed” to become pluripotent stem cells and then differentiated into cardiomyocytes and endothelial cells, it states.
The extracellular matrix material is processed into a “personalized hydrogel,” a medium of collagenous nanofibers that “behave as a weak gel at room temperature” and become stronger when heated to human physiologic temperature.
As described, the myocytes and endothelial cells are separately combined with the hydrogel to create two bioinks, which the printer applies in layers to create the three-dimensional patches resembling vascularized myocardial tissue.
A similar process went into creating the heart-like structures, each about 20 mm by 14 mm; the printer guided by a data template derived from cardiac computed tomographic images.
The same techniques could potentially be applied to other tissues and organs, Dvir proposed. For example, “it could work with the liver or the kidneys, but this is something that needs to be studied and developed. I want to be careful and not oversell this technology.”
“The hurdles to building a heart are formidable,” Taylor said. “The level of vasculature and microvasculature, and cell–cell interaction, and electrical and mechanical physiology that has to go into the heart is unlike that in any other organ.”
That the field is willing to call something a “heart” when it is only shaped like one on a small scale, and maybe has cells that contract similarly to myocyte contractions, “shows that we have a long way to go to get to the real deal.”
Noor, Dvir, and their coauthors report that they have no conflicts. Taylor has previously declared she has no relevant conflicts. Images accompanying this story were included with the published report, which is published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheimand, and were reproduced according to the terms of the Creative Commons Attribution License.
Advanced Science. Published online April 15, 2019. Full text
TAU Scientists Print First 3D Heart Using Patient’s Own Cells and Materials. Monday, April 15, 2019. Press release
Curr Opin Organ Transplant. 2018;23:664-672. Abstract