In two decades, 3-D printing has grown from a niche manufacturing process to a $2.7-billion industry, responsible for the fabrication of all sorts of things: toys, wristwatches, airplane parts, food. Now scientists are working to apply similar 3-D–printing technology to the field of medicine, accelerating an equally dramatic change. But it’s much different, and much easier, to print with plastic, metal, or chocolate than to print with living cells.
“It’s been a tough slog in some ways, but we’re at a tipping point,” says Dean Kamen, founder of DEKA Research & Development, who holds more than 440 patents, many of them for medical devices.
In labs around the world, bioengineers have begun to print prototype body parts: heart valves, ears, artificial bone, joints, menisci, vascular tubes, and skin grafts.
Three factors are driving the trend: more sophisticated printers, advances in regenerative medicine, and refined CAD software. To print liver tissue at Organovo, Vivian Gorgen, a 25-year-old systems engineer, simply had to click “run program” with a mouse. Honeycomb-shaped liver tissue is a long way from a fully functioning organ, but it is a tangible step in that direction. “Getting to a whole organ-in-a-box that’s plug-and-play and ready to go, I believe that could happen in my lifetime,” says Presnell. “I cannot wait to see what people like Vivian do. The potential is just out of this world.”
3D Printing is just the start
Lipson’s first printed meniscus (knee tissue) looked promising, when he showed it to knee-replacement surgeons, they deemed it too weak to withstand the body’s routine abuse. “As somewhat of an outsider coming in [to biology], my impression was ‘Okay, I’m gonna put the cells in the right place, incubate it for a while, and we’re gonna have our meniscus,’ ” Lipson says. “There is more to making a meniscus than just putting the cells there. Real menisci are actually pounded every day, all the time, and they shape up and become stiff. So the pounding that’s in their environment is actually very much a part of their growth.”
A printer that can dispense the right ink, in other words, is only the first step. Cells have specific requirements, depending on the tissue they’re destined to become. In the case of a meniscus, it might mean developing a bioreactor that can approximate pounding or use heat, light, or auditory pulses to stress the tissue into formation. “For some tissues, even the simple ones, we don’t even know exactly what it takes to make the tissue behave like a real tissue,” says Lipson. “You can put the cells of a heart tissue in the right place together, but where’s the start button?”
Tissue Scaffolds or no Scaffolds
Scaffolds provide tissues with mechanical stability, and they can be used to deliver genes and growth factors to developing cells. But, as in the case of polymers, they can introduce foreign materials into the body and cause inflammation. Cell types also respond differently to certain scaffold materials, and so the more complex the organ, the more complicated the necessary framework—and the more difficult to predict how the cells will migrate around it. As a result, not everyone believes scaffolds are necessary, including Gabor Forgacs, Organovo’s co-founder and a biological physicist at the University of Missouri.
Forgacs’s plan is to print an organ composed entirely of living human tissue and let it assemble itself. “The magic,” he says, “happens after printing has taken place.” Therein lies the biggest misconception about bioprinting: What most people think of as the finished product—the newly printed cellular material—isn’t finished at all.
At Missouri, Forgacs studied morphogenesis, the process that determines how cells form organs during embryonic development. By arranging cellular aggregates—tiny spheres containing thousands of cells—into a circle, his lab could watch them fuse and form new structures. The aggregates accomplish this by working together. A molecule on one cell causes a receptor protein on the cell membrane to change shape, tugging on the cytoskeleton of a second cell. A cascade of communication ensues, eventually reaching the nucleus and triggering a change in gene expression.
A grant from the National Science Foundation enabled Forgacs and his team to experiment with bioprinters instead of laying down aggregates by hand, and the technology transformed their research. “What had taken us days, we could do in maybe two minutes,” he says. Using a bioprinter, Forgacs proved that aggregates containing different cell types also fuse, without any human intervention or environmental cues.
Tissue engineers shouldn’t place cells where they’d be in a finished organ, Forgacs says; they should arrange cells based on where they need to be to start forming an organ, as in an embryo. “The cells know what to do because they’ve been doing this for millions of years. They learned the rules of the game during evolution.”
Another key lies in printing cellular aggregates. “You will never build an extended biological structure, a big organ or tissue, by putting down individual cells,” Forgacs says. “A tissue is very well organized, according to very stringent rules, in cellular sets. A half-millimeter aggregate is already a little piece of tissue. Those pieces bind together and exchange information.”
Make the small capillaries and scale up the tissue
Ibrahim Ozbolat, a mechanical engineer at the University of Iowa, has also developed a bioprinter, which uses multiple arms moving in tandem, to deposit a vascular network and cellular aggregates at the same time.
“The major challenge,” Ozbolat says, “will be creating very small capillaries”—the hairlike blood vessels linking larger vessels to cells. He foresees wrestling with this in two years. Once researchers can scale up the size and complexity of the vascular system, graduating from biological parts and pieces to whole printed organs will become only a matter of time.
Bio Nano programmable matter CAD and photoshop software
What bioprinters so far lack—and what will enable the field’s next wave of breakthroughs—is biologically sophisticated software. With an inanimate object like a coffee mug, a 3-D scanner can create a CAD file in minutes and upload the design to a 3-D printer. There is no medical equivalent.
“An MRI doesn’t tell you where the cells are,” says Lipson. “We’re just completely in the dark in terms of the blueprints. That’s half the puzzle. There’s also no Photoshop—no tools to move cells around. That’s not a coincidence. It’s beyond what most computer software can handle. You can’t have a software model of a liver. It’s more complicated than a model for a jet plane.”
”Sensing an opportunity, Autodesk has teamed with Organovo to develop CAD programs that could be applied to bioprinting. “The areas we explore don’t always have an immediate business case to be made, but they may have one in the coming years,” says Carlos Olguin, head of Autodesk’s Bio/Nano/Programmable Matter Group
Tissue to accelerate clinical testing and identify problems with human tissue earlier
Next year, Organovo will begin selling its liver assay—a petri-dish-like well plate containing liver cells arranged in a 3-D structure 200 to 500 microns thick (two to five times as thick as a human hair). The potential market is vast. Every drug taken orally, whether a painkiller, an anti-inflammatory, or a new cancer pill, must pass a liver tox.
If bioprinted assays provide pharmaceutical researchers with better, quicker data, the entire drug-discovery process will accelerate. Moreover, they could lessen the need for extensive animal testing.
Ozbolat’s goal, at the University of Iowa, is to print pancreatic tissue for therapy instead. It would be made up of only the endocrine cells capable of producing insulin. Implanted in people, such tissue could regulate blood sugar and treat type 1 diabetes, he says.
Bioprinters could also prove invaluable for medical schools. Students now train on cadavers, but when it comes to procedures like cutting out cancer, nothing matches the real experience. Rather than printing healthy tissue, bioprinters could build organs with tumors or other defects so that surgeons could practice before entering an operating room.
Whole, transplantable organs that function properly will be the ultimate challenge, but also, in the long run, change lives most profoundly. In the U.S., more than 118,000 people are currently on the national donor waiting list
Bioprinting Cyborg parts
Bioprinters could even enable bionic organs—body parts that don’t just restore, but extend human ability. To that end, researchers at Princeton University have been experimenting with integrating electronics into bioprinting. Earlier this year, they created a matrix of hydrogel and bovine cells in the shape of an ear, incorporating silver nanoparticles to form a coiled antenna. The system could pick up radio frequencies beyond the range of normal human hearing. In a similar manner, bioengineers might one day incorporate sensors into other tissues—for example, creating a bionic meniscus that can monitor strain.
Related to cyborg printing are biocompatible MEMS
Researchers at Tel Aviv University has found a way to print biocompatible MEMS components, making them ideal for use in medical devices, like bionic arms. Microelectromechanical systems, better known as MEMS, are usually produced from silicon. Researchers have developed a novel micro-printing process that works with a highly flexible and non-toxic organic polymer. The resulting MEMS components can be more comfortably and safely used in the human body and they expend less energy.