As a researcher reliant on mice for the study of autoimmune disease, I both dread and eagerly anticipate the day that animal models become obsolete. Although valid, mouse models of disease are an approximation of human illness at best, and even with a fully sequenced genome available, it can take decades to parse the myriad variations in gene expression, signalling pathways and resultant phenotypes, much less use this information to unmask the etiology of a related human disease. Thus, I was thrilled (but skeptical) when I learned that Tony Atala at the Wake Forest Institute for Regenerative Medicine had generated an entire human kidney in 2011 using a technology that has been garnering increasing attention in the media – 3D printing.

At the time, I did not know much about 3D printing beyond its controversial potential for weapons manufacturing. It turns out that while 3D printing has only recently become popular, the technology has been around for over thirty years. What was truly exciting to the scientist (and avid Star Trek fan) in me, however, was my discovery that 3D printing is one of the most promising up-and-coming methods for tissue engineering.

3D heart models with partial G-code for 3D printing (center). Rendered by Charles Tran.
3D heart models with partial G-code for 3D printing (center). Rendered by Charles Tran.

What is 3D Printing, Anyway?
The term “3D printing” is somewhat misleading. As Cornell researcher and professor Hod Lipson explains in his book, Fabricated, the procedure is much more accurately described by the phrase “additive manufacturing”, as it involves the sequential laying down (or building up) of layers of material to create a three-dimensional form. The entire process begins with the creation of a digital file for the desired object that describes its dimensions, internal structures and surface textures in as much detail as the computer-aided design (CAD) software will allow. This file serves as the necessary guide for the 3D “print head”. Depending on the type of 3D printer used, the actual creation of the object diverges at this juncture. In “selective deposition” printing, liquid or powdered material is exuded from the print head in thin layers, at which point the material is given time to solidify or is fused to the existing base. Alternatively, in “selective binding” printing, the formation of each object layer is achieved through laser-induced hardening or melting of a liquid or powdered light-sensitive thermopolymer (stereolithography and laser sintering, respectively). The final 3D-printed product undergoes post-processing to remove any residual chemical waste or scaffold materials, and is ready to be used, tested or shipped off to consumers.

The beauty and genius of 3D printing is that it frees product design from many of the limitations currently imposed by the realities of manufacturing and has an imaginative range of applications. Traditional manufacturing must rely on the creation and assembly of individual parts to create complex or multi-material constructs, and can yield vast amounts of waste due to the inefficiency of the casting process. In contrast, 3D printing is able to generate intricate, pre-assembled products without the need for moulds or multiple manufacturing platforms. At present, most commercial 3D printers print with various forms of plastic due to their durability and ease of use; however, the more advanced 3D printers used in manufacturing and research have a wide range of materials at their disposal, including metals, glass, ceramics and even food. While 3D printers are currently limited to printing with one material at a time, leading developers in 3D printing technology are now working to develop machines with multiple print heads linked to different design files, which would allow for the creation of finished products composed of more than one material. Within the next few years, it may even be possible to 3D print electronics, with the circuit boards printed directly into their plastic or rubber casings.

The Bionic Man
So how does this technology translate into the creation of human parts and the ushering in of a new era of tissue engineering? The answer lies in 3D printing’s ability to accurately and precisely replicate the human form, a feat that is increasingly important given the aging population in many developed countries. Already, 3D printing has revolutionized the creation of inert biomaterials. In 2012, the company Align 3D printed 17 million sets of Invisalign braces – clear, custom-made retainers that are designed based on an individual’s own teeth. Millions of contact lenses and hearing aids are also manufactured by 3D printing on an annual basis, and last year, a woman in her eighties received a new titanium 3D-printed jaw. Furthermore, artificial prosthetics, which have traditionally been made from a cut-and-paste mould, can now be 3D printed based on CT scans of the patient’s existing limb and even customized to suit their lifestyle and character, a service pioneered by the 3D printing company Bespoke Innovations.

The next step, of course, is to proceed from the creation of inorganic implants to the production of viable transplants that incorporate human tissue, and it is here that the real revolution of 3D printing comes to bear. Not only can 3D printers navigate the complexities of human tissue, creating scaffolds that allow for the ingrowth of muscles and vasculature, but they can also print live cells directly into these scaffolds, superseding the difficult seeding process long used for tissue generation. The process itself is relatively simple – cells harvested and grown from patient samples are suspended in a supportive “hydrogel” polymer and deposited by the 3D print head in thin layers that will eventually merge as adjoining cells secrete extracellular membrane and signalling factors. Like Atala’s group in the US, clinical researchers worldwide have been quick to see the potential in this technology, and the past five years have witnessed the creation of 3D-printed bone grafts, stem cells and heart valves. Even the University of Toronto has hopped on the 3D printing bandwagon, as last year the laboratory of Dr. Axel Guenther, in collaboration with the Department of Immunology’s Marc Jeschke, patented a bioprinter capable of fabricating human skin as an alternative to costly and harmful skin grafts, with the hope that these manufactured tissues will proceed to clinical trials within the next few years.

Illustration by Kieran Manion.
Illustration by Kieran Manion.

The ability to 3D print components of the human body has far-reaching implications for the future of medicine and research. Generating new tissue from a patient’s own cells not only drastically reduces the risk of an adaptive immune response and subsequent transplant rejection, but also eliminates the innate immune responses that can be precipitated by traditional biomaterials. Furthermore, the ability to manufacture human tissue would help alleviate the exorbitant cost and wait times for replacement organs, as well as reduce the complications associated with lifelong regimens of immunosuppressive drugs or anti-coagulants. With respect to the scientific community, 3D-printed human tissue has already been embraced as a means of bridging the gap between research studies and clinical trials. In addition to their model human kidney, and at the behest of the US Defense Threat Reduction Agency, Atala’s group at the Wake Forest Institute has developed a 3D-printed “body-on-a-chip”, a miniature body system derived from human tissue and supplied with an artificial vasculature that can be used to test novel drugs, chemicals and even bioweapons. In time, 3D-printed human tissue, organs and even organisms could foreseeably replace in vitro or animal models of disease.

Are We There Yet?
Despite its recent advances, 3D printing has a long way to go before it will be capable of producing fully functional human organs for either clinical use or accurate scientific study. At the biological level, the limiting factor is the cells themselves, which need extremely precise conditions for proper growth and differentiation, and can be difficult to acquire in capacities sufficient to support the high throughput requirements of 3D printing.  What’s more is that unlike a prosthetic limb, which is ready for use as soon as it has been made, living tissue printed in the artificial environment of a lab must be “started”. Cells must secrete the correct factors for future growth, survival and physiological function, and at present, there is no single, infallible way to initiate this process for the many different tissues that can be made. There is also the concern that tissues fabricated in a carefully controlled environment will not be able to withstand the more rigorous, stringent conditions and stresses present in the human body; for example, meniscus cartilage 3D printed in a laboratory loses its structure and cohesion when subjected to the forces found in a typical knee joint.

On the technological front, the problems are progressing more rapidly towards a solution. 3D printing may expand the realm of possibilities, but only insofar as our imaging and software capacities allow. Creating a 3D object in virtual space is difficult at the best of times, since the physical world as we sense it contains far more variables than can be captured by a digital render. The big data associated with the complexities of a human organ – different materials and different shapes, all intricately moving and interacting – is currently beyond the scope of design software.

The bottom line? “3D-printed body parts are still the stuff of fiction”, and for the time being, mice are here to stay.

References

  1. Atala, A. (2011, March 8). Anthony Atala: Printing a human kidney [Video File]. Retrieved from: http://www.ted.com/talks/anthony_atala_printing_a_human_kidney.html.
  2. Lipson, H. & Kurman, M. (2013). Fabricated: The New World of 3D Printing. Indianapolis, IN; John Wiley & Sons, Inc.
  3. “3D Printing Scales Up”. (2013, September 7). The Economist Technology Quarterly, 7-9. Retrieved from: http://www.economist.com/news/technology-quarterly/21584447-digital-manufacturing-there-lot-hype-around-3d-printing-it-fast
  4. Greenemeier, L. (2013, May). To Print the Impossible: Will 3-D printing transform conventional manufacturing? Scientific American, 44-47.
  5. Black, J. (2006). Biological Performance of Materials: Fundamentals of Biocompatibility. Boca Raton, FL; CRC Press.
  6. Van Blitterswijk, C. (2008). Tissue Engineering. Sand Diego, CA; Elsevier.
  7. Summit, S. (2011, Nov). Scott Summit: Beautiful artificial limbs [Video File]. Retrieved from: http://www.ted.com/talks/scott_summit_beautiful_artificial_limbs.html
  8. Fedorovich, N.E. et al. (2011). Organ printing: the future of bone regeneration? Trends in Biotechnology. 29 (12): 601-606.
  9. Jakab, K. et al. (2008). Tissue Engineering by Self-Assembly of Cells Printed into Topologically Defined Structures. Tissue Engineering: Part A. 14 (3): 413-421.
  10. Everett-Green, R. (2013, January 20). A 3-D machine that prints skin? How burn care could be revolutionized. The Globe and Mail. Retrieved from: http://www.theglobeandmail.com/life/health-and-fitness/health/a-3-d-machine-that-prints-skin-how-burn-care-could-be-revolutionized/article7540819/
  11. Miller, J. (2013, September 17). ‘Body on a Chip’ uses 3D printed organs to test vaccines. BBC News. Retrieved from: http://www.bbc.co.uk/news/technology-24125678
  12. Paikin, S (Host). (2013, June 5). The Agenda with Steve Paikin: 3D Printing: A Desktop Future [Video File]. TVO. Retrieved from: http://ww3.tvo.org/video/191986/3d-printing-desktop-future
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Kieran Manion

Design Director
Kieran Manion is a senior PhD student studying the breakdown of B cell tolerance in systemic lupus erythematosus in the Department of Immunology at the University of Toronto. In her spare time, she practises using digital platforms for general artwork and graphic design.
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