The replacement of failing human organs has been an important element in health care for several years now.
An organ can be defined as s specialized structure made up of various cells and tissue and adapted for the performance of a specific function.
As we grow old, or due to various diseases, our organs can deteriorate and become defective, making a transplant crucial for our survival .
A transplant is a surgical procedure where a healthy organ from a donor is placed into another body. Organ transplantation is relatively old and established procedure, the first attempts dating from the early 1900s. The kidney was the first human organ to be successfully transplanted in 1954. Liver, heart and pancreas transplants were successfully performed by the late 1960s, while lung and intestinal organ transplant procedures followed in the 1980s .
Thanks to modern medical techniques, over the course of the last century, organ transplantation has overcome major technical limitations and became the success it is today. Managing to suppress the body's immune response in order to avoid transplant rejection and discovering preservation solutions that are capable to store organs for prolonged periods of time, were the biggest breakthroughs in transplantology . Transplant rejection occurs when the transplanted organ is rejected by the recipient's immune system, which identifies the new organ as a threat and therefore destroys it .
One limitation to transplantation then, as now, is the lack of suitable donor organs . In the US, every ten minutes, someone is added to the national transplant waiting list. On average, 20 people die each day while waiting for a transplant . Europe is confronted with the same problem, as 18 patients die every day due to lack of viable organs . Luckily there is hope. With the purpose of overcoming organ shortage worldwide, scientists have directed their research at techniques to either bioengineer organs or artificially grow them.
A bioengineered organ is an engineered device or tissue that is implanted or integrated into a human, in order to replace a natural organ,
to duplicate or augment a specific function so the patient may return to a normal life as soon as possible .
The technology behind bioengineered organs involves obtaining complex three-dimensional (3D) scaffolds that allow cells to develop and function properly, and represents a promising, innovative approach to potentially manufacture an unlimited source of donor organs for transplantation .
Current approaches to achieving a bioengineered organ involve several steps:
1. Decellularization of naturally occurring human or animal tissues and organs, during which cellular antigens are removed, allowing the probable elimination of immunogenicity and thus preventing the immune system to reject the artificially created organ; this step is performed by using ionic and anionic detergents with different timings and concentrations and finally leads to a complex 3D scaffold.
2. Analysis of the scaffold, in which the scaffold is completely analysed in order to check the effective preservation of the original texture, and its biological properties.
3. Recellularization, which involves seeding of the scaffold with organ-specific cells. In the best-case scenario, these cells come directly from the patient who will receive the bioengineered organ, avoiding immunological problems. This last step represents the biggest challenge in bioengineering artificial organs, due to the substantial number of cells needed to occupy the entire volume of the 3D scaffold. In addition to the number of cells, scientists must maintain specific cell type proportions in order to create a full functional organ .
Back in 1885, Von Frey and Gruber were the first to make and use an artificial organ, a heart-lung apparatus. The artificial heart contraction was dependent on a thin film of blood and included several devices that contributed to monitoring the temperature, pressure, and blood gases during the delivery of blood . Over the following century, important progress has been made in the field of bioengineered organs, including arterial graphs made of cloth, the first widely used commercial dialyzing machine (the Baxter/Travenol recirculating U-200 twin-coil dialyzer), implantable permanent left ventricular assist systems for human use, and fully-implantable circulatory support systems .
However, the biggest achievement was first reported in 2006, when researchers at Wake Forest University School of Medicine, USA successfully engineered artificial urinary bladders in a laboratory and transplanted them into patients. To create the new bladders, the researchers took a biopsy from seven patients whose bladders functioned poorly. The team then placed muscle cells and cells from the bladder on a biodegradable bladder-shaped support and allowed them to grow for about two months. The team then transplanted these new bladders into their patients and monitored their recovery. All patients regained urinary control, proving for the first time in history that transplanting bioengineered bladders can be successfully achieved .
The liver is one of the largest, most challenging organs to recreate. In 2010 bioengineers at Wake Forest University Baptist Medical Center made the first step into overcoming those challenges. They grew miniature livers in the lab using decellularized animal livers as scaffold and seeded them with human cells. The engineered livers were about an inch in diameter and weighed about 5 grams. However, the livers would have to weigh about half a kilogram to meet the minimum needs of the human body and provide enough function. Although further research still needs to be conducted in order to grow the organs at the desired size, this was a huge step forward for medicine, as it confirmed the possibility of generating a functional human liver .
Succeeding to create artificial blood vessels in the lab from a patient's own cells could mean better treatments for cardiovascular disease, kidney disease and diabetes. In 2011, the Cytograft Tissue Engineering company, implanted blood vessels bioengineered in the lab to end-stage kidney disease patients. Eight months after, the grafts continued to work well, easing the access to dialysis .
Recently, a team of scientists from Massachusetts General Hospital and Harvard Medical School used adult skin cells and an extracellular matrix scaffold to regenerate functional human heart tissue. The hearts contained well-structured tissue that looked like immature hearts, and most surprisingly when the researchers gave the hearts a shock of electricity, they started beating. While this is not the first-time heart tissue has been engineered in the lab, it's the closest that scientists ever came to their end goal - a full functioning human heart .
The biggest benefits for patients are yet to come, as researchers are also investigating into using 3D printing to make artificial organs. 3D printing allows for the layer-by-layer construction of an organ structure to form a cell scaffold. This can be followed by the process of recellularization, in which cells of interest are pipetted directly onto the 3D scaffold structure. Modified inkjet printers have also been used to produce biological tissue. Printer cartridges are filled with a suspension of living cells and a smart gel - used for providing structure. When the process is completed, the gel is cooled and washed away, leaving behind only live cells. The concept of 3D printed blood vessels is currently being developed and could be of great use in congenital heart surgery. Current developments have been able to create the 3D structure of the cells within the liver, making the possibility of a 3D printed liver promising. Blueprints of renal tissue have already been created, being the first step to the possible construction of a 3D printed kidney .
Looking ahead, further experiments need to be done in order to analyze the potential interactions between the human body and the printing materials, before these organs can be successfully transplanted . The future trends of bio-engineered and 3D printed organs show opportunities for growth in almost every aspect. Although there are regulatory issues that need to be ironed out, the current developments hold a solid foundation for future progress. The FDA is expected to approve a bio-engineered artificial pancreas in 2018, which, if successful, would let patients live their lives without self-monitoring their blood sugar levels .
Although some bio-printing companies claim that they will be able to bioprint complex organs such as the heart within the next six years, no one knows for certain when these techniques will be approved as safe for human transplants . However, the increasing number of scientists working in the 3D bio-printing field, coupled with developments in an industry that is predicted to be worth more than $1,3 billion by 2021, means that we're not that far away.
Nowadays, scientists are successfully growing artificial hearts, livers, lungs, urethras and windpipes in laboratory settings.
Although science still has some obstacles to overcome before these artificially grown organs enter everyday hospitals,
amazing medical accomplishments have occurred . Rather than being built from 3D bioengineered scaffolds, the artificially grown organs come from lab-cultured cells.
The two terms, "bioengineered organ" and "artificially grown organ" should not be confused, as they are not the same.
While bioengineered organs are mostly made from decellularized organ scaffolds and patient derived cells, artificially grown organs are designed in the lab,
starting from pluripotent stem cells.
The first step into the "Age of Artificially Grown Organs" was made in 2012, when scientists from Seoul National University Hospital, South Korea were able to make a windpipe from stem cells and successfully implant it in a 2-year-old girl . A 10-year-old girl made medical history when doctors at the Sahlgrenska University Hospital in Gothenburg, Sweden created a vein from her own stem cells and transplanted it into her body to treat a life-threatening blockage .
When it comes to more complex organs, such as liver, heart or lungs, studies are still in pre-clinical stage, however the progress that was made over the past few years is spectacular. A team of researchers from Japan took things a step further by creating "tiny-livers". Starting from human umbilical cord blood cells and using a technique that mimicked what occurs during the normal development of a fetus, they created full functional livers. These "tiny-livers" were placed inside mice and soon began to form new arteries and veins. After 10 days, the livers began to produce human liver proteins. When transferred into mice with liver failure, the transplants increased their survival rates .
In 2013, a team affiliated with the Austrian Academy of Science in Vienna, created "mini-brains". Using embryonic stem cells or adult skin cells, they were able to grow a mini-brain presenting the structure of a 9-week-old fetus. The cerebral cortex, the retina, and in some instances, the memory-focused hippocampus were present. Even though scientists are still far from re-creating a brain in its entire complexity, this "mini-brain" model allows them to study structural and developmental defects, and possibly neurological disorders like schizophrenia .
The first "fully-functioning" lab-grown organ was a mouse thymus, created from mouse fibroblasts. The function of the artificial thymus was then tested, proving that after four weeks, the thymus was well-formed and capable of producing several types of T cells - a subtype of white blood cells involved in fighting diseases .
Recently, researchers at Johns Hopkins University School of Medicine have successfully generated mature heart muscle cells using stem cells. The mature heart muscle cells were created by implanting stem cells from a healthy adult or one with a type of heart disease into new-born rat hearts. The host hearts provided biological signals and the chemistry necessary for the implanted immature heart muscle cells to grow. The importance of this study is tremendous, as it gives researchers the ability to grow adult cardiac muscle from any patient's own stem cells .
However, when it comes to this innovative technique, scientists still have some concerns, most of them related to the screening - establishing whether the tissue/cells used to create the new organ are viable and to the financial aspect, as customizing new organs won't be cheap. Even with the concerns above, it's no wonder that the potential of artificially grown organs has generated numerous success stories.
Organs are highly complex structures, and even initially successful efforts face long regulatory pathways. However, the seriousness of organ shortage is fuelling medical R&D. Researchers strongly believe that we are very close to soon bioengineer or grow individualized organs for patients, starting from their own stem cells, so that transplant rejection and organ shortage will no longer be a concern.
1. Miller, G. E. (2006). Artificial Organs. Synthesis Lectures on Biomedical Engineering, 1(1), 1-72.
2. The transplantation history. https://www.unos.org/transplantation/history/ (accessed on 19.10.2017).
3. Watson, C. J. E., & Dark, J. H. (2012). Organ transplantation: Historical perspective and current practice. British Journal of Anaesthesia, 108(1), i29-i42.
4. Transplant rejection. https://en.wikipedia.org/wiki/Transplant_rejection (accessed on 19.10.2017).
5. United Network for organ Sharing. Statistics. https://www.unos.org/data/ (accessed on 19.10.2017).
6. European Day for Organ Donation and Transplantation 2017. https://www.coe.int/en/web/pristina/-/european-day-for-organ-donation-and-transplantation-2017 (accessed on 19.10.2017).
7. Artificial organs. https://en.wikipedia.org/wiki/Artificial_organ#cite_note-Abu-FarajHand12-1 (accessed on 22.10.2017).
8. Peloso, A., Dhal, A., Zambon, J. P., Li, P., Orlando, G., Atala, A., & Soker, S. (2015). Current achievements and future perspectives in whole-organ bioengineering. Stem Cell Research and Therapy, 6(1), 107.
9. About artificial organs. http://catherinealdrinbio.wixsite.com/artificial-organs/about (accessed on 22.10.2017).
10. Artificial Organ History: A Selective Timeline. http://echo.gmu.edu/bionics/exhibits.htm (accessed on 22.10.2017).
11. Atala, A., Bauer, S. B., Soker, S., Yoo, J. J., & Retik, A. B. (2006). Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet, 367(9518), 1241-1246.
12. Researchers Engineer Miniature Human Livers in the Lab. http://www.wakehealth.edu/News-Releases/2010/Researchers_Engineer_Miniature_Human_Livers_in_the_Lab.htm (accessed on 22.10.2017).
13. 10 Bioengineered Body Parts That Could Change Medicine. http://mashable.com/2013/07/23/bioengineered-body-parts/#ue7GLFRTtsqi (accessed on 22.10.2017).
14. Guyette, J. P., Charest, J. M., Mills, R. W., Jank, B. J., Moser, P. T., Gilpin, S. E., et al. (2016). Bioengineering Human Myocardium on Native Extracellular Matrix. Circulation Research, 118(1), 56-72.
15. Munoz-Abraham, Armando Salim; Rodriguez-Davalos, Manuel I.; Bertacco, Alessandra; Wengerter, Brian; Geibel, John P.; Mulligan, David C. (2016). "3-D Printing of Organs for Transplantation: Where Are We and Where Are We Heading?". Current Transplantation Reports, 3 (1): 93-9
16. The Surprising Future of Artificial Organ Transplants. https://www.forbes.com/sites/oppenheimerfunds/2016/09/26/the-surprising-future-of-artificial-organ-transplants/#463986472f59 (accessed on 22.10.2017).
17. Could 3-D printing solve the organ transplant shortage? https://www.theguardian.com/technology/2017/jul/30/will-3d-printing-solve-the-organ-transplant-shortage (accessed on 22.10.2017).
18. Windpipe made from stem cells implanted in 2-year-old girl. https://www.cbsnews.com/news/windpipe-made-from-stem-cells-implanted-in-2-year-old-girl/ (accessed on 19.10.2017).
19. Olausson, M., Patil, P. B., Kuna, V. K., Chougule, P., Hernandez, N., Methe, K., et al. (2012). Transplantation of an allogeneic vein bioengineered with autologous stem cells: A proof-of-concept study. The Lancet, 380(9838), 230-237.
20. Takebe, T., Zhang, R.-R., Koike, H., Kimura, M., Yoshizawa, E., Enomura, M., et al. (2014). Generation of a vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature Protocols, 9(2), 396-409.
21. Lancaster, M. A., Renner, M., Martin, C.-A., Wenzel, D., Bicknell, L. S., Hurles, M. E., et al. (2012). Cerebral organoids model human brain development and microcephaly. Nature, 501(1), 373-379.
22. Bredenkamp, N., Ulyanchenko, S., O'Neill, K. E., Manley, N. R., Vaidya, H. J., & Blackburn, C. C. (2014). An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nature Cell Biology, 16(9), 902-908.
23. Cho, G.-S., Lee, D. I., Tampakakis, E., Murphy, S., Andersen, P., Uosaki, H., Kwon, C. (2017). Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy. Cell Reports, 18(2), 571-582.