Jeffrey Perkel has been a scientific writer and editor since 2000. He holds a PhD in Cell and Molecular Biology from the University of Pennsylvania, and did postdoctoral work at the University of Pennsylvania and at Harvard Medical School.
Three-dimensional printing has most definitely entered the mainstream. Entrepreneurial types are using the technique to build practically everything: protein models, fabrics, jewelry, dental implants and, believe it or not, pizza. The technology even figured in an episode of the television show The Big Bang Theory, in which two characters dropped $5,000 on a used 3D printer to create action figures—of themselves.
The biological sciences, and especially medical research, also stand to benefit from 3D printing. Researchers are using the technology to create or explore tissue-engineering scaffolds, anatomical models, personalized surgical implants and even artificial organs.
“3D printing just opens up a number of possibilities that we didn’t have before, from a number of standpoints,” says David Zopf, assistant professor of otolaryngology at the University of Michigan in Ann Arbor, Mich. “It’s really a tool, much like a lot of the tools we use in the operating room. And I think we’re just beginning to understand how to use that, and what the capabilities of the 3D printer are.”
Printing in three dimensions
Although the term “3D printing” has become ubiquitous, it does not describe a single process. Just as there are many ways to print on paper, 3D printing encompasses several discrete technologies.
Some 3D printers operate like ink-jet printers, while others use light to induce polymerization. Some use heat to melt and extrude plastic materials as if they were toothpaste, while others use a laser to fuse a powdery material into a solid object, a process called laser sintering.
“3D printing is an iterative, additive technology. Rather than starting with a block of material and removing what is undesirable in a subtractive process (as in sculpting or milling), additive manufacturing starts from nothing and selectively builds, one layer at a time, an object of interest according to computer instructions,” writes Jordan Miller, assistant professor of bioengineering at Rice University, in a 2014 essay [1].
The technology has multiple applications in biomedicine, including the creation of personalized implants for surgical procedures. Zopf and his colleagues, led by Glenn Green, associate professor of otolaryngology at the University of Michigan, used this approach to treat several children with tracheobronchomalacia, a potentially fatal defect in airway formation.
Tracheobronchomalacia “is like if you have a tent and the tent poles aren’t working,” Zopf explains. “The tent has lost its structure and collapses on itself. And the airway can do the same thing.”
In 2013, Zopf and his colleagues published a case study in The New England Journal of Medicine describing a splint that could be used to support the airway as the child grows [2]. Using computed tomography, the team created a personalized anatomic model of the child’s trachea. They then created a custom, bellowed cylinder—“similar to the hose of a vacuum cleaner”—that was open on one side tsto allow the airway to grow as the child aged; they sutured this to the outside of the trachea to hold the airway open.
In this case, they used laser sintering to fabricate the splint from polycaprolactone, a material used in bioresorbable sutures, which degrade over several years in the body. “We wanted something that ultimately does desorb,” Zopf explains, “because as the child’s airway continues to grow, we wanted to ensure it was not being constricted by the device.”
A follow-up study in Science Translational Medicine detailed the application of this procedure to three additional children [3]. In one of these cases, two splints were implanted in the same patient, and the design of one had to be tweaked to ensure it wouldn’t bump into its partner as the child grew. “This design modification was accomplished in three hours and printed the next day, demonstrating the adaptability and precision possible with 3D printing,” the authors wrote.
Kyle VanKoevering, a research fellow in the Green lab at the University of Michigan, also uses 3D printing in his work. An otolaryngologist with a bachelor’s degree in biomedical engineering, VanKoevering says he uses the technology to create medical models to plan surgical interventions—for instance, to plan precisely where in a patient’s mandible to cut to remove a tumor—and to pre-contour the titanium plates that are sometimes used to replace excised bone. “Anything we can do to cut time in the operating room is better for the patient,” he says.
He also is exploring the use of the technology to create surgical models for practicing delicate procedures. In particular, VanKoevering is interested in modeling the nose, which has a highly complicated internal structure. “Right now, the best simulation opportunity we have is cadaveric tissue,” he explains. “But 3D printers allow us to print that same material in a realistic material to allow trainees to practice surgical procedures. These 3D constructs could be easily replaced without cadavers.”
Bioprinting
Another biomedical application of 3D printing is bioprinting, a subset of 3D printing. In this case, the “ink” can be either cell aggregates or cells in hydrogel and they are positioned in a matrix (pre-designed 3D locations in the computer design for whatever is being constructed) by the printer.
Among other things, such models can be used to improve toxicology and drug testing in pharmaceutical development. For instance, Organovo, a company that specializes in bioprinting, has developed 3D model systems to replicate liver function as an alternative to traditional cell-culture and animal models, says CEO Keith Murphy. “Liver function is not replicated by cells in a dish, and animals don’t replicate human biology perfectly,” Murphy explains. As a result, “there can be toxicology missed [in those studies], and only in clinical trials do those come out.”
The company offers those models as a service to pharmaceutical clients. It is also pursuing organ-replacement strategies for human patients. Full-sized organs, of course, are years away, at least. But they may not be strictly necessary, Murphy notes. Many patients, for instance, are excluded from transplant waiting lists because of their advanced age or disease. Such patients might benefit, he explains, from a relatively simple “tissue patch” that could deliver, say, 15% of the function of an intact liver, which could both improve quality of life and at least delay the need for a transplant.
Likewise, Miller is developing bioprinting strategies to build what he calls “meso-scale” tissue constructs—pieces of lung or liver tissue in a hydrogel measuring just a milliliter in size. “That is a very good size for us to start building complexity,” he explains, “and to do this in a medium-throughput format.”
Ultimately, Miller hopes to create full-sized human organs. But even the simplest organ is exceptionally complex, Miller notes, and researchers don’t yet know how much of that complexity they must recapitulate to create a functioning replacement. For instance, he says, might a “seed organoid” be sufficient, provided there were cells available to remodel it? Or, could a primitive implanted vascular system be expanded in vivo to include the fine structure of capillaries and lymphatic vessels? And in any event, can the technology be expanded to use a patient’s own cells, to alleviate the need for immunosuppression following transplantation?
Miller estimates that any such transplants are at least “several decades away.” Yet with development advancing so rapidly, he says, “you can see why the field is getting so excited.” It will be exciting indeed to see where it goes from here.
References
[1] Miller, JS, “The billion cell construct: will three-dimensional printing get us there?” PLOS Biology, 12(6), e1001882, 2014. [PMID: 24937565]
[2] Zopf, DA, et al., “Bioresorbable airway splint created with a three-dimensional printer,” The New England Journal of Medicine, 368(21), 2043-2045, 2013. [PMID: 23697530]
[3] Morrison, RJ, et al., “Mitigation of tracheobronchomalacia with 3D-printed personalized medical devices in pediatric patients,” Science Translational Medicine, 7(285), 285ra64-285ra64, 2015. [PMID: 25925683]
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