Reading the Fine Print
Streamlining, shortcutting, simplifying. The modern world thrives on efficiency, and the realms of science and medicine are no different. One day, patients will not have to wait for donor matches or organs; 3D bioprinters will be able to rapidly create tissue structures for all those in need. One day, testing experimental drugs on animals will not be necessary; human tissue scaffolds will be printed for the sole purpose of drug and toxicity testing. Invasive surgical procedures will be streamlined, organ transplant lists will be shortcutted, drug testing will be simplified. Recent and revolutionary, this methodology utilizes 3D model drawings as blueprints for tissue structures. Using Bioink, comprised of various cell aggregates, bioprinters are capable of manufacturing a variety of organs and biological machinery by building them up layer by layer. Ultimately, they can print a wide variety of tissues: bone to cartilage, vasculature to kidneys. They can aid in drug testing. They can prevent patient overflow on transplant lists. But most importantly, bioprinters can save lives.
Children's toys. Handguns. Entire cars. Manufacturing and prototyping in architecture, textiles, and technology have been revolutionized by the onset of 3D printing. These machines engage in a computerized additive process that creates solid, 3-dimensional objects from a digital model. While this technology continues to touch many fields of study, one of its most life-changing applications lies within the realm of medicine. 3D bioprinting artificially constructs living tissue by extruding neither metal nor plastic, but cells. Gradually building up biological structures layer by layer, bioprinters have the ability to craft anything from contoured cartilage to cardiac muscle, skin grafts to blood vessels . The creation of living, beating human hearts is no longer the stuff of science fiction stories; it is the future.
Background: The Methods and Materials behind the Basics of Bioprinting
The aim of 3D bioprinting is to marry multiple scientific fields to achieve successful fabrications of living tissue. The first step in this additive process is to draft a digital model of the desired object: artists use Computer Assisted Design (CAD) software to create 3D mockups of biological structures . The software's tools allow for detailed modeling and specific tailoring regarding the porosity of engineered tissues, and ultimately provide spatial information for the precise location of cells . Once the digital blueprint is complete, the scaffold is then realized via ink-jet bioprinting (uci).
The world's first commercialized bioprinter , Novogen MMX, was created by one of the leading pioneer companies in bioprinting: Organovo . Upon receiving a CAD drawing, Novogen begins by outputting a single layer of hydrogel-based "biopaper" . Secondly, cell aggregate-containing bioink spheroids are prepared and loaded into cartridges. Controlled by the CAD blueprint, the bioink is then deposited onto the water-based gel in specific patterns, depending on the tissue being produced . Overall, this alternating process of laying down biopaper and bioink is repeated in order to build the final project . After printing is done, the bioink spheroids fuse together as the biopaper dissolves away, leaving behind a complete and mature structure.
Part of what makes bioprinting so unique and revolutionary, is the fact that it is not necessary to print out every detail of an organ or a blood vessel; the cells in bioink are capable of rearranging themselves into the correct tissue order post printing . The technology allows for simultaneous cellular differentiation into multiple lineages; the printed tissue construct will ideally assemble, mature, and differentiate all on its own . For instance, printed blood vessels utilize an aggregate cocktail of endothelial, smooth muscle, and fibroblast cells. Upon being printed, the endothelial cells migrate to the inside of the vessel, the smooth muscle to the middle, and the fibroblasts to the outside. Additionally, in more intricate projects, delicate internal structures, such as capillaries, are also able to naturally form .
On the whole, inkjet 3D printers open the door for the rapid and accurate production of biological structures. With printing speeds hitting at least 600 drops per second, bioprinting is changing how medicine tackles issues such as drug engineering, surgical therapy, and transplantation.
The Creation of Man: Notable Medical Breakthroughs
Prior to July 1, 2012, one of the main problems with 3D bioprinting was preventing cells in larger structures from suffocating; without a functioning vascular system, living cells quickly die . For while alternating levels of biopaper and bioink are highly successful when printing complex shapes, the creation of vasculature has always been a major roadblock. However, last year, researchers at the University of Pennsylvania developed an innovative and creative solution. Instead of focusing on the body of the tissue system first, vasculature shapes of 3D free-standing filament networks are placed inside a mold. The aggregate solution the researchers created is a potent mix of sucrose and glucose, along with dextran to offer structural support. In order to stabilize the sugar molds, templates are coated with a thin polymer that will allow the coating to be easily dissolved. Similar to the "lost wax" technique, the vascular mold is removed once cells are added and begin to differentiate; once the mold dissolves, hollow tunnels are left behind for the purpose of nutrient and waste transport . What makes this technique so important is the fact that it can provide vital vascular structures to a variety of tissues.
Stemming from the work done at the University of Pennsylvania, one of the most recent and revolutionary achievements in bioprinting occurred a few weeks ago: on April 22nd, 2013, the first fully cellular 3D liver was created. Albeit being a miniature 3D model, the printed tissue is fully functional with cellular density, controlled spatial positioning, and multi-layering architecture, remaining stable over time. Furthermore, the novel 3D tissue engages in liver functions such as albumin, fibrinogen, and transferrin production, and cholesterol biosynthesis . In this one instance, Organovo did not merely create a functional liver; they paved the way for future successful, larger printed 3D structures.
A second 3D bioprinter developed by Organovo's research team, Envisiontec Bioplotter, specializes in the manufacturing of human bones and regenerative scaffolding . Using a variety of tissue cell aggregates, Envisiontec can print biodegradable polymers, ceramics, and fibrin-collagen hydrogels. Harnessing this technology, the Tissue and Regenerative Medicine lab at Columbia University has been researching bioprinting in bone and dental repairs. Bioprinted mesh scaffolds of teeth and hip bones were inserted into rats and rabbits, respectively, and infused with growth supplements. Due to the differentiation capabilities of bioprinted structures, these scaffolds promoted the growth of fresh ligaments and tissue . While still largely experimental, bone and regenerative scaffold printing has made leaps and bounds in the medical world; on March 4th, 2013, 3D printing helped replace over 75% of a patient's skull. The digitally scanned CAD images in such aforementioned operations enable tiny ridges in the tissue to be printed so that it may attach more readily, and that new cell growth is promoted . On the whole, technological breakthroughs are being made at a rapid pace and the tissue output from 3D printers is becoming nothing if not more sophisticated and efficient.
The Immediate Benefits of 3D Printers
Over the course of the past few decades, the exponentially growing industry of bioprinting has been steadily changing the way the world handles a variety of medical issues. Tedious and frustrating, transplant lists are always overflowing; in 2010 there were 93,000 people, in the United States alone, waiting for a kidney transplant . On a monthly basis, anywhere from 300 to 500 people need bone transplants . 3D printing's fast-paced technology would enable not only livers and bones, but other vital tissue structures as well, to be printed in record time . In addition, bioprinting organs would remove the need for screening processes and remove the risk of potential rejection complications. For the Bioink spheroids would be comprised of the patients' own cells, a fact that would ensure a successful implant operation . Printing tissues for those in need would not only vastly improve lives, it would save them.
Lastly, this newfound ability to print living, functional tissue opens the doors for a new breed of drug therapy testing. For instance, researchers could infuse cancerous cells into bioprinted human pancreatic tissue, and expose it to a variety of treatments in order to determine the best course of action. Currently, Organovo is working on developing cell cultures for drug and toxicity testing: in March 2012, the bioprinting company received $290,000 from the National Institute of Health to research the printing of liver cells for the sole purpose of toxicity testing . Ultimately, being able to create fully functioning human tissue would allow researchers to more accurately judge the efficacy of experimental treatments on very specific illnesses; conducting tests on animal tissue is not as conclusive, cost effective, or ethical .
In many ways, 3D bioprinting is the key to the kingdom for solving a plethora of current and pressing medical issues.; it provides efficient solutions to medical problems that have plagued humanity for decades.
Ethical Risks in a Printed World
While mitigating many problems that are interwoven with transplantation and drug testing, 3D printing could potentially cause some of its own. Being a new form of technology that is on the brink of being fully marketable, there are particular issues that could come to light as bioprinting takes off. The world of competitive athletics immediately comes to mind. Athletes in need of invasive surgical procedures would naturally turn to bioprinting; injecting regenerative scaffolding in the operation site, such as the knees joints or ankles, could drastically decrease restoration and healing time. While this aspect is undeniably beneficial, bioprinting-aided surgeries have the potential to augment natural athletic ability. For instance, increased elasticity and flexibility could result from such procedures due to new cell growth and the efficiency of bioprinted tissues .
In addition to restorative surgery, the cosmetic industry would also be touched by the onset of 3D printing. Inserting tissue scaffolding could lessen the degree of invasiveness, and could hence, increase the popularity of such operations. Restoring youthfulness or enhancing natural beauty are cosmetic procedures that could be made more effective with bioprinting due to how it promotes reparation and regeneration via new cell growth .
A Work in Progress: The Future of Bioprinting
In spite of a few issues that could accompany the maturation of 3D bioprinting, it will undoubtedly change the way society addresses certain medical problems. On the whole, the 3D printing industry has grown since its introduction to the world in the early 80's, and is still growing today. One of the partnerships that will pave the way for future success recently occurred: Organovo joined forces with Autodesk, a world leader in 3D design software, in order to develop the first software specialized for bioprinting. The product in question would work in conjunction with Organovo's Novogen MMX bioprinter in order to increase both the functionality and efficiency of designing 3D human tissue blueprints .
Meanwhile, researchers and developers are fine-tune bioprinting technology before harnessing its full potential commercially. For instance, even though Organovo just successfully created a functional miniature human liver, the company is already taking the action necessary in order to create full-sized organs. Even though it may be 5 to 10 years before this industry takes off and is used in everyday situations, the medical world benefits from each step taken for the sake of making printable, functional, human tissue not a mere possibility, but a guarantee.
1. R.L. Hotz. (2012, Sept. 18). "Printing Evolves: An Inkjet for Living Tissue". [Online]. Available: http://online.wsj.com/article/SB10000872396390443816804578002101200151098.html [April, 23 2013].
2. N. Firth. (2012, June 4). "Doctors to be Able to 'Print' New Organs for Transplant Patients". [Online]. Available: http://www.dailymail.co.uk/sciencetech/article-1283709/Doctors-able-print-new-organs-transplant-patients.html [April, 23 2013].
3. K. Velasco. (2008). "Engineering Tissue Constructs through Bioprinting". [Online]. Available: http://bme240.eng.uci.edu/students/08s/velascok/process.html [April, 23 2013].
4. C. Barnatt. (2013, March 1). "Bioprinting". [Online]. Available: http://www.explainingthefuture.com/bioprinting.html [April, 23 2013].
5. R. Fisher. (2006, Dec. 11). "Bio-ink Printer Makes Stem Cells Differentiate". [Online]. Available: http://www.newscientist.com/article/dn10771-bioink-printer-makes-stem-cells-differentiate.html [April, 23 2013].
6. E. Lerner. (2012, July 1). "Penn Researchers Improve Living Tissues with 3D Printed Vascular Networks Made from Sugar". [Online]. Available: http://www.upenn.edu/pennnews/news/penn-researchers-improve-living-tissues-3d-printed-vascular-networks-made-sugar [April, 23 2013].
7. Organovo . (2013, April 22). "Organovo Descibres First Fully Cellular 3D Bioprinted Liver Tissue". [Online]. Available: http://ir.organovo.com/news/press-releases/press-releases-details/2013/Organovo-Describes-First-Fully-Cellular-3D-Bioprinted-Liver-Tissue/default.aspx [April, 23 2013].
8. J. Hsu. (2013, March 6). "3D-Printed Skull Implant Ready for Operation". [Online]. Available: http://www.technewsdaily.com/17191-3d-printed-skull-implant.html [April, 23 2013].
9. M. Molitch-Hou. (2013, Feb. 6). "3D Bioprinting: Now with Human Embryonic Stem Cells". [Online]. Available: http://3dprintingindustry.com/2013/02/06/3d-bioprinting-now-with-human-embryonic-stem-cells/ [April, 23 2013].
10. Organovo . "3D Human Tissue for Research". [Online]. Available: http://www.organovo.com/3d-human-tissues/3d-human-tissues-research [April, 23 2013].
11. C. Frangold. (2013, Jan. 27). "The Growing Potential of 3D Bioprinting". [Online]. Available: http://seekingalpha.com/article/1135651-the-growing-potential-of-3d-bioprinting [April, 23 2013].