Cover Story | Doctors are used to “playing God,” but now imagers, materials scientists, and biomedical engineers are vying to get in on the Game of Life. With barely a stop at “Go,” three-dimensional (3D) printing is emerging, almost exploding, in a dizzying array of medical settings; everything from facilitating training to improving outcomes, saving lives, and offering new treatments for, among many others, cardiovascular disease.

Three-dimensional printing seems to be one of those weird tech ideas talked about all over the place (the popular press seems to love the topic), but you probably haven’t focused closely on the topic. Unless you’re a fellow, because—let’s face it—they are often first in line to consider new technology. At its core, the name says it all: the technology refers to printing in three dimensions, rather than the usual two. But printing what? Shoes? Food? Body parts? And to what avail? Extra body parts would certainly be nice, but can you actually manufacture living tissue with functioning vasculature and enervated tissue on a printer?

At this point, you might be tempted to give a little head shake, grab another cup of coffee, and move on to things that seem more reasonable and practical, like the capital markets or national politics, but 3D printing appears to be here to stay. And just as we once scoffed at social media and are now all pinning and tweeting, 3D printing is poised to similarly ingratiate itself into our lives and offer important benefits, including the care of the heart.

In the cardiology arena, 3D printing applications can be categorized into three broad categories: making models to train and assist in procedures, printing customized heart parts, and—the moonshot—the 3D fabrication of an entire, implantable replacement heart. The first of these categories is well developed and becoming more widespread, the second is well on its way to bearing real results, and the third, well, there’s a reason it’s called the moonshot.

3D 101

Three-dimensional printing refers to the fabrication of graspable objects from a digital file. Commonly referred to as additive manufacturing, we also know it as rapid prototyping and additive fabrication, as those terms have been used interchangeably in the literature.

Indeed, as Frank J. Rybicki, MD, PhD, explained during a session devoted to the topic at the November 2014 American Heart Association Scientific Sessions, the variability in the terminology used is “enormous” across the literature on cardiovascular uses of 3D printing (about 70 papers so far). He added, “It’s like one of my math professors said, ‘There is no legitimate mathematician that doesn’t have his own notation.’”

Rybicki, who is the director of the Applied Imaging Science Laboratory and director of cardiac and vascular CT at Brigham and Women’s Hospital in Boston, MA, suggested that standardized language for 3D printing will facilitate getting Food and Drug Administration approvals for techniques, and, ultimately, getting reimbursement.

Basically, 3D printing works like this: to prepare a digital file from which to print a 3D object, a virtual design is fashioned in a computer-aided design (CAD) file using a 3D modeling program (to create a new object) or a 3D scanner (to copy an existing object). Once the CAD model is digitally uploaded to a 3D printer and the appropriate raw material also loaded, the printer head moves vertically and horizontally, extruding small beads that harden immediately when and where they are deposited. This material re-creates the digital file layer by layer, resulting in a three-dimensional object. Hence the term additive manufacturing, as opposed to most manufacturing (i.e., milling), which is subtractive. Printing can take anywhere from several minutes to several days to complete and may require removable or dissolvable supports to secure the form.

The technology has been in the making for about 30 years and actually includes several different technologies with names crafted by exuberant engineers, such as vat photopolymerization, material jetting, binder jetting, material extrusion, power bed fusion, sheet lamination, and direct energy deposition. They need a 3D dictionary to accompany their printers.

The raw material used in 3D manufacturing runs the gamut, from powdered titanium alloy and plaster to ceramic and glass to thermoplastic, photopolymers…and even chocolate (see sidebar, Pie (or Chocolate) in the Sky). Some methods rely on melting or softening materials, such as selective laser sintering and fused deposition modeling.

“We have the ability to print, basically, anything that one could possibly print,” said Rybicki.

Advantages of 3D printing include rapid prototyping, customization, its ability to handle complex geometry, and its relative low cost for low-volume manufacturing. On the flip side, disadvantages include the difficulty of designing 3D models, limitations of the materials used for fabrication, low repeatability, and the fact that it’s not (yet) cost effective for mass-scale manufacturing. Of course, medicine is looking for more highly personalized printing; thus, the latter limitation is not a deal-breaker unless all members of a large family want their own keepsake copy of dad’s heart anatomy.

“If you print two samples from the same design, they are very likely to have some differences,” explained Zhen Qian, PhD, of the Piedmont Heart Institute, in Atlanta, GA, at the AHA session on 3D. “So, reproducibility is still not very good.”

Modeling Behaviors

If a picture is worth a thousand words, what is a life-size and accurate model of a baby’s heart worth when that baby has a complex congenital defect that needs correction?

“I can hold the model in my hands and almost instantly tell what operation I’m going to need to do,” said Glen Van Arsdell, MD, head of cardiac surgery at The Hospital for Sick Children in Toronto, Ontario (popularly known as SickKids).

Shi-Joon Yoo, MD, leads the division of cardiac imaging at SickKids and is a leader in making heart models for congenital heart disease applications. As of late 2014, they’ve done 48 clinical cases at SickKids since 2009, including 24 double outlet right or left ventricles, five complex ventricular septal defects, three anomalous pulmonary venous connections, and one each of a complex tetralogy of Fallot and coarctation of the aorta. Thirty-three of their 48 cases involved double outlet right ventricles. “Surgeons really want to know the anatomy of the double outlet right ventricle before surgery,” he said. (FIGURE 1 shows a 3D printed heart model used to plan the surgical repair of complex congenital heart disease, presented at ACC.15 by Hannah Fraint, MD, et al., Columbia University Medical Center, New York City.)

In 2013, Yoo founded 3D HOPE (Human Organ Printing and Engineering) Medical, which uses a polyjet 3D printer to build models that have a consistency and flexibility similar to that of human myocardial tissue. "Ideally",  said Yoo, "imagers should have excellent imaging skills and good knowledge of the morphology, but in reality, we often see that there is missing information, gaps in knowledge and misunderstanding,” and it is these failings that the surgical models help to overcome. “The models make everything clear,” he said, "particularly as they can be made to simulate the surgical view."

“We used to learn the anatomy from specimens, but that has a lot of limitations,” said Yoo, adding that the models have been particularly well received by students and surgeons early in their careers. At SickKids, he and his colleagues have developed a complete set of models with an accompanying workbook to teach fellows about the double outlet right ventricle.

“Three-D printing takes you on a journey from cyber virtuality to physical reality,” said Yoo. It enables precise understanding of the anatomy, helping surgeons avoid unexpected scenes at the time of surgery and allowing for tailored approaches—patches, conduits, and more.

To make a heart model, imaging is the first step, primarily with computed tomography (CT) and magnetic resonance imaging. “We really like to use whole-heart 3D inversion recovery flash with intravascular contrast medium,” said Yoo. The contrast agent stays in the heart for three or four hours, offering ample time for artifact-free imaging.

Qian’s AHA talk focused on 3D printing in adult structural heart disease. “For structural heart disease, I think 3D printing has huge potential,” he said. “The heart is a complex structure, making 3D printing ideal for education and training purposes.”

Also, advances in cardiovascular imaging, tissue characterization, and functional imaging allow for excellent 3D and 4D anatomical imaging to utilize in 3D and 4D modeling. The latest is 4D printing, which adds the dimension of time. In this case, you get a solid object (3D) that changes shape over time (4D). (Think medical Transformers.) Since there is no such thing as a 4D printer, the key is the material used for fabrication, such as a gel that changes shape with time, temperature, or pressure.

“But most importantly, there is a trend towards personalized treatment,” said Qian. “3D printing is ideal for patient-specific modeling, and we can do rapid prototyping with fairly low cost and high efficiency.”

Intervention Planning

Three-dimensional printing of the aorta is particularly hot because of the rise in transcatheter aortic valve replacement (TAVR), said Qian. The aorta and aortic valve are fairly simple structures for 3D printing to handle, making rapid prototyping a promising technique for device testing and treatment planning.

But Qian’s Piedmont Heart group wanted to up the ante. They teamed with the Georgia Institute of Technology’s Manufacturing Institute and the school’s Biomedical Engineering Department to create a 3D printed aorta and aortic valve that would allow them to actually study the physiology of the organ.¹

They succeeded using commercially available photopolymers that offer material properties similar to human tissue and in-house printed strain sensors to extract physiological parameters, making 3D printed valves that exhibited comparable material properties with human tissues. They suggest that this rapid prototyping and in vitro strain assessment on a patient-specific level may improve pre-TAVR planning.

A Philadelphia, PA, group led by Brian O’Neil, MD, and Dee Dee Wang, MD, of the Temple Heart and Vascular Institute, Temple University, the Institute for Structural Heart Disease, and the Henry Ford Health System, respectively, used transesophageal echocardiography, CT, and 3D printing to model, print, and plan a transcatheter caval valve implantation (CAVI).²

The patient was a 57-year-old woman with severe tricuspid valve regurgitation who was referred for isolated tricuspid valve surgery and heart transplantation, but was deemed at prohibitive surgical risk. Pre-CAVI imaging was performed and a 3D model of the tricuspid valve and adjacent right atrium was printed to facilitate optimal device selection. The procedure was done and the result favorable.

In an accompanying editorial, Partho P. Sengupta, MD, and Jagat Narula, MD, PhD, noted that “techniques in 3-dimensional printing and advanced pre-procedural computational modeling will be pivotal for designing personalized approaches for operative planning and reducing operating time, the number of repeat interventions, and the overall cost of the procedures.”³

Just how rapid is this new approach? Feroze Mahmood, MD, and colleagues at Beth Israel Deaconess Medical Center in Boston, MA, recently published an example in JACC: Cardiovascular Imaging. In FIGURE 2, you can see that the resulting models (bottom) closely mimic the original 3D transesophageal echocardiographic (TEE) images (top), with a total time of about 90 minutes from image acquisition to final model generation.⁴

In a soon-to-be-published letter to the editor (JACC Imaging) Moses Mathur, MD, Pravin Patil, MD, and Alfred Bove, MD, PhD, all from Temple University School of Medicine, echoed the sentiments expressed by Rybicki earlier, saying that modelers need to be more precise in reporting their techniques. Also, Mathur and his colleagues noted that clinicians should understand how a 3D model is created, how it might differ anatomically from the real thing (because of processing noise), and how the materials used for the model compare to actual cardiac structures. They concluded that “the true incremental utility of 3D printing is its ability to provide testing via physical interaction. However, the accuracy of such an interaction will only be valid if the 3D model is also able to approximate the physical properties of the structure it represents.”

“It’s Alive!”

Traveling further along the spectrum from dynamic model printing is bioprinting or “the digital fabrication of living constructs encapsulating cells, biomolecules, and biological moieties in spatially patterned structures.”^5,6 Creating a physical replication of a living construct from a digital blueprint—even Dr. “Bones” McCoy of Star Trek never dreamt this one up. “I’m a doctor, Jim, not a biomedical engineer!”

“Bioprinting is largely the future of 3D printing,” said Rybicki. “Cell function and viability are preserved on the created 3D model and the key is placing appropriate cells at the appropriate location.” Doing this layer-by-layer precision positioning of biological materials, biochemicals, and living cells in such a way as to insure clinical restoration of tissue and organ function, and using technologies originally designed to print molten plastics and metals, obviously increases the complexity enormously.

“The central challenge is to reproduce the complex micro-architecture of extracellular matrix (ECM) components and multiple cell types in sufficient resolution to recapitulate biological function,” wrote Sean V. Murphy, PhD, and Anthony Atala, MD, from Wake Forest University School of Medicine, in a 2014 Nature Biotechnology review on 3D bioprinting.⁷

Rybicki explained that the idea of printing two-dimensional tissue, like skin, has been realized. Indeed, at the Wake Forest Institute for Regenerative Medicine, Murphy and Atala have even played with in vivo bioprinting in an animal model, wherein skin cells and associated materials are deposited directly onto a wound or burn defect. One potential use for this technique might be a portable bioprinting system for the battlefield where a high percentage of injuries involve skin.

One step up from printing skin is hollow tube printing, like tracheas, heart valves, or blood vessels. Some are in active development and likely to be the first types of bioprinted tissues implanted in patients.

Another quantum leap on the complexity scale: replacement hollow organs, such as a bladder, or solid organs—like a heart. These challenges will require significant advances in terms of bioprinting technology, vascularization and innervation, and biomaterial and cell requirements.

“Although the field is at an early stage, it has already succeeded in creating several tissues at human scale that are approaching the functionality required for transplantation,” according to Murphy and Atala. As well, researchers are moving away from trying to modify preexisting 3D printing technologies to designing 3D bioprinters better suited to handling biological components. The complexity seen at this level is hard to fathom. First, imaging is used not just create a 3D structure, but to provide detailed information on function at the cellular level. CAD design is merged with mathematical modeling to digitize the target organ. As with any implant, all materials must be suitable for transplantation and offer short-term stability and long-term durability. The most obvious way to do so according to Murphy, is by using an autologous source of cells or by using tolerance-induction strategies.

Researchers are working on bioprinting blood vessels, customized human heart valves, and vascular conduits. “Once you’ve mastered the technique of scaffolding and the entering of the cells, the idea that these cells will grow, survive, and be nurtured ex vivo—it’s a real possibility,” said Wang.

Welcome to another place and dimension...

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References

1. Qian Z, et al. Circulation. 2014;130:Abstract 20259.
2. O’Neil B, et al. JACC Cardiovasc Imaging. 2015; 8: 221-5.
3. Sengupta PP, Narula J. JACC Cardiovasc Imaging. 2015; 8; 232-4.
4. Mahmood F, et al. JACC Cardiovasc Imaging. 2015;8:227-9.
5. Starly B, Shirwaiker R. Chapter 3. Tissue Engineering and Regenerative Medicine. 2015; pp 57-77. Academic Press.
6. Mosadegh B, et al. Biomed Mater. 2015;10:034002.
7. Murphy SV, Atala A. Nat Biotechnol. 2014;32:773-85.

They’re Calling It the Moonshot... ...and for good reason. In May 1961, President John F. Kennedy set a national goal of “landing a man on the moon and returning him safely to the Earth” by the end of the decade. By July 20, 1969, this had been accomplished. In true “shoot for the moon” style, Stuart Williams, PhD, believes he will be able to 3D print a total human heart within the next 10 years. He’s even considering improving on the current model by printing replacement hearts with redundant blood supply, getting past that pesky LAD/widow maker issue. “I really think that if we put a large team together, which we are, we can get there within 10 years,” said Dr. Williams in the March CNN special, “Moonshots for the 21st Century,” with Fareed Zakaria. He believes the actual printing process will take “a single day.” With a PhD in cell biology and postdoctoral training in pathology, Williams is the director of the bioficial organs program at the Cardiovascular Innovation Institute at the University of Louisville. He is also the scientific advisor for Advanced Solutions Life Sciences (ASLS), the makers of the BioAssemblyBot (BAB) and Tissue Structure Information Modeling. BAB is a 6-axis robot that is the next evolution in 3D bioprinting. According to ASLS, it has the precision required to assemble cells systems and assays, experimental tissue models, organ models, microfluidic platforms, and implant systems. It can already print several parts of the heart—blood vessels, heart valves, and the heart’s walls—with living human cells. The researchers hope to use patient fat cells and convert them into viable myocardium. Already, his research has been tested in hand transplantation at the University of Louisville, in an effort to improve wound healing and stave off rejection.

3D Elsewhere in Medicine Beyond the CV world, the medical applications for 3D printing are multiplying. Here’s a short list of things we’ve already 3D printed or are trying to 3D print: prosthetics hands that cost less than $50 USD, drugs, orthotics, dental implants, bones (including part of a skull and a lower mandible), ear cartilage, tailor-made sensors, skin, and medical equipment. Researchers at the University of Michigan have twice printed customized bioresorbable tracheal splints that were implanted in babies with severe tracheobronchomalacia.1 Lest the pharmaceutical industry be left out, 3D bioprinting applications are being developed for drug discovery and toxicology uses. San Diego-based Organovo Holdings Inc. has bioprinted living liver tissue and is using it to test drug toxicity. They have also recently described their first fully cellular 3D-printed kidney tissue. Organovo doesn’t develop drugs themselves, but are using their proprietary 3D techniques to collaborate with other companies and research institutions to develop custom tissues for research and therapeutics. The company launched its first product last November, the exVive3D Human Liver Tissue, and in late April announced a multi-year research collaboration agreement with Merck to use the tissue as a supplement to in vitro and preclinical animal testing. Reference Zopf DA, et al. N Engl J Med. 2013;368:2043-5.

Pie (or Chocolate) in the Sky The nonmedical uses for 3D printing are limitless and everybody wants in on the game. Here’s a small list of nonmedical uses for 3D printing technology gleaned from the Wikipedia entry on the topic: architecture, construction, industrial design, automotive, aerospace, military, engineering, dentistry, fashion, footwear, jewelry, eyewear, education, geographic information systems, and food. Heard of the CocoJET? It’s a collaboration between 3D Systems and Hershey and it streams liquid chocolate—dark, milk, or white (even though white isn’t really chocolate!)—making on-demand candy. You can spec chocolate anything. Willy Wonka on steroids. Amazon has plans to create a system for 3D printing on demand. So, the delivery truck pulls up in front of your house and just prints your order. No drones needed. They’ve filed patent applications. Disney Research has 3D printed stuffed animals. Why? Who knows, but while most 3D printing involves laying down layers of material, they figured out a technique that imitates sewing. In 2012, Apple filed two liquid-metal patent applications related to 3D printing. Analysts believe Apple and Google may be working on entry points into the 3D printing market. (Think Apple doing for 3D printing what iTunes did for the music industry.) Autodesk, the $13 billion software company that makes AutoCAD, has already announced the release of a 3D printer, along with an open source and free platform called Spark. It’s been compared to Google Android, but for 3D printers. If you dream it, someone is probably doing it. But it’s not a fully-functioning implantable heart... yet. Now, if next Valentine’s Day you want to give the love of your life a 3D-printed chocolate heart; well, that’s probably do-able.

Keywords: CardioSource WorldNews, Biomedical Engineering, Imaging, Three-Dimensional, Bioprinting, ACC Publications

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