Tissue Engineering Could End Deadly Organ Transplant Waitlists
Over 115,000 people are currently awaiting organ transplantation for a lifesaving procedure, with over 80 percent needing kidney transplants. However, due to the shortage of viable organs, more than seven thousand people died in 2016. The process for organ transplantation is a long, difficult, and often times unsuccessful endeavor to save the lives of hundreds of thousands of critically ill individuals. Even for kidneys, which can be transplanted from live donors, the average wait time for a transplant was over three and a half years.
A variety of factors go into arranging an organ transplantation, all organized by a national non-profit, the United Network for Organ Sharing (UNOS). When a patient is recognized as being in need of a transplant, their physician assesses their health, the likelihood of long-term success for a transplant, and the patient’s survival benefit. A patient who is morbidly obese may not be a good general transplant candidate, and an alcoholic suffering from liver failure is not a good candidate for a liver transplant, compared to a healthy teenager with a lifestyle that will increase chances of long-term success.
Once the patient’s information has been submitted to UNOS, the long wait begins. Although over half of US adults are registered in some capacity as an organ donor, only 41,335 organs were donated in 2016 from both deceased and living donors. The only organs that can be transplanted from living donors are kidneys, because an individual can function perfectly well with only one, and livers, which can completely regenerate after being partly harvested. But the overwhelming majority of transplants originate with deceased donors, and the strict standards to which these transplants are held strongly affect the nationwide supply of viable organs. Because of the delicate nature of transplant procedures, organs available for transplant must be perfect. In fact, only three out of every thousand people die in a way that keeps their organs viable for transplantation. Infections, genetic conditions, trauma, and a lack of immuno-compatibility can all prevent a transplant.
When an organ donor dies, the organ harvesting process, which can save as many as eight lives, begins. The donor’s hospital immediately submits medically necessary information to UNOS about the donor and the specific organs. Following this, UNOS uses a computer algorithm to match a donor organ with a recipient based on the condition of the organ and the urgency of the recipient’s case. Once a match is made, a surgeon from the recipient hospital will often travel to the donor hospital (sometimes even by charter plane or helicopter as hearts and lungs must be transplanted within four to six hours), harvest the organ to be transplanted, and travel back with it personally. Upon return, the donor organ is transplanted into the recipient, where vasculature and connections to the nervous system are restored. If the procedure goes well, a patient will then recover in the hospital, and both the patient and the medical staff will watch patiently and work to make sure an immune rejection does not take place.
Although the organ transplantation process is long and often unsuccessful, a new era of medicine is rapidly emerging in which the donor/recipient relationship will drastically change. Histocompatibility issues will soon become history, and in the near future there will be little need for long periods spent waiting anxiously.
Alleviating the Back-up
Some Americans are often quick to criticize the amount our nation spends on defense; however, few realize the immense and frequent benefits of defense spending outside of typical defense industries. Examples of this include DARPA’s creation of ARPANET, the direct precursor to the modern internet, and the worldwide civilian GPS. In 2018, as part of the Trump administration’s annual defense budget request, $84.9 billion of the $639.1 billion defense budget would be allocated to research and development (R&D). In 2016, when the Obama administration requested $71.9 billion in R&D funding, nearly $1 billion was allocated to medical research and another $2 billion for basic science research. This is in addition to the over $2 billion allocated to medical research through the budget for the Defense Health Program.
A portion of this defense research funding has gone to projects in the fields of tissue engineering and regenerative medicine, both of which seek to build or repair body structures using a patient's own cells. In 2016, the Defense Department funded an eighty-seven-member team developing “next-generation manufacturing techniques for repairing and replacing cells, tissues and organs for wounded service members,” in hopes that injured military personnel would recover better from severe soft-tissue and organ injuries. However, this research translates directly into the civilian arena and could fundamentally change the organ transplant process for the better. Even better is the fact that this change is not too far away from clinical implementation.
Progress
A multitude of projects nationwide work to create viable replacements for organ donation and tissue replacement. One such example that has been clinically employed is the RenovaCare SkinGun. As the name implies, this technology “sprays” skin onto wounds. Today, severe burns and skin injuries are repaired with skin grafts, a process in which skin flaps are taken from other parts of the body and transplanted onto the injured site. This process has significant risks of infection, takes a long time to heal and very attentive hospital care, and does not yield high quality results aesthetically. The SkinGun, rather than using an autotransplant, takes a patient's own cells and layers them precisely on the wound. The stem cells which are harvested from another location on the patient's body are suspended in a solution and sprayed from the gun like ink, covering the wound. From there, the skin grows back naturally rather than from edge to edge. Although the SkinGun is not an organ transplantation technology, it does demonstrate the power of stem cells in healing complex wounds.
Internal organ transplantation, however, is much more complex. Unlike skin, which is generally just a few layers of different cell types on top of each other, internal organs are three-dimensional systems with unique and complex structures. In the field of tissue engineering, organs and tissues are generally broken into two categories. The first comprises relatively simple physical structures. They are generally hollow on the inside, like the trachea or bladder, or avascular, like the cornea. These organs and body tissues are relatively easy to produce artificially because they lack the complexity of solid structures. On the other hand, solid structures contain many differing types of cells, from connective tissues and muscles to nerve endings, vasculature, and electrophysiological structures. They include the heart, kidney, liver, and lungs. Although solid organs have proven to be significantly more difficult to produce than simpler structures, researchers have made significant progress in producing both types of organ.
Artificial organs are created in two ways. The first involves harvesting the extracellular matrix of an organ from a cadaver or donor. This process involves using detergents and other chemicals to wipe the organ clean of any cells or components unique to an individual patient, leaving behind a scaffold of proteins. Stem cells from the patient are then harvested and manipulated in the lab to become pluripotent stem cells than can be differentiated into the desired cell type; then the matrix is either soaked or perfused with a solution of the patient's cells in a tightly controlled environment called a bioreactor. After allowing enough time for adequate growth, the tissue or organ can then theoretically be transplanted. Another method, even more novel, involves the use of 3D printers. Rather than the plastic used by standard 3D printers, these unique devices use a solution of the patient's cells as ink. Instead of using a matrix from another source, the printer literally creates the organ from scratch, printing it layer by layer. The organ is then incubated for proper growth.
These techniques were on impressive display in the 2011 case of a Swedish patient with an inoperable tumor that blocked airflow through the trachea. Whereas previously few treatment options would have been possible, this patient had his full function restored by an artificial trachea grown from his own cells. Scans of the patient were sent to a lab in the United Kingdom in which a scaffold for a new trachea was made. The scaffold was then sent to the hospital in Sweden and soaked in a solution of the patient's own cells. Just days later, after the cells had taken hold and coated the new trachea, it was successfully transplanted into the patient. Several years previously, however, successful bladder transplants had been completed by a leader in the field of regenerative medicine, Dr. Anthony Atala of Wake Forest University. His Institute for Regenerative Medicine, the leader of the Armed Forces Institute of Regenerative Medicine, created a biodegradable scaffold on which a patient’s own cells can grow. Another operation, conducted by doctors at Johns Hopkins University in 2012, involved creating an outer ear using cartilage from the patient's body, implanting it under the skin on the forearm to allow for the cells to mature, and finally transferring it to the side of the patient’s head. Although none of these procedures have graduated from very limited clinical trials, and few if any long-term studies have been conducted, they demonstrate the promise of tissue engineering in clinical applications.
More recently, progress has been made in the lab on the creation of more complex, solid organs. Atala’s institute at Wake Forest has seen some success working with kidneys and livers. Both have been created in a controlled laboratory setting, and functional testing appears to be approaching in the coming years in animal models. In fact, in a 2011 TED video, Atala demonstrated the technology live, 3D-printing a laboratory kidney on stage. Another groundbreaking lab at Massachusetts General Hospital, led by Dr. Harald Ott, has been able to create functioning myocardial tissue implanted on a decellularized heart structure, and functional rat kidneys and lungs, and a different lab at Harvard led by Jennifer Lewis has successfully created the components of a nephron, the functional unit of a kidney. Lastly, a paper was published in the journal Nature explaining how bioprosthetic ovaries restored ovarian function in sterilize mice.
Impact
Although widespread clinical testing of tissue engineering is likely a decade or so into the future, the progress being made should excite physicians, patients, and scientists all over the world. These advances create the possibility of significantly reducing the dangers of organ transplantation by nearly eliminating the risk of organ rejection. Because regenerative medicine and most aspects of tissue engineering rely on a patient’s own cells, no histocompatibility issues emerge and immunosuppressive drugs will be needed in much lower doses. Although the scaffold is taken from another source, decellularization should keep it from provoking an immune response. This means that unlike organ donors now, who must be incredibly healthy and a perfect match for recipients, the histocompatibility of the patients or and most genetic conditions in the donor (excluding those that impact the structure of the desired organ) will no longer be issues. This will significantly increase the number of organ transplantations that can be performed, especially if the structure can be grown with the patient's own cells as well. Whereas organ transplantation currently has to be performed at the drop of a hat, whenever a compatible organ emerges, advances in the field will ideally turn the procedure into a scheduled surgery, rather than one anticipated for months or years.
As is the case with all new technologies there are both benefits and problems of integrating artificial organ transplantation into the current healthcare system. First, immense amounts of testing in the clinical setting is needed in order to verify the safety and effectiveness of lab grown organs and tissues. This will require long-term studies by scientists, working alongside the FDA, to gain approval. We still don’t know if lab-grown organs will continue to function well several years after a transplant, and testing costs an immense amount of money and can take over a decade. Additionally, physicians developing the transplantation procedures will have to convince insurance companies and the Centers for Medicare and Medicaid Services (CMS) that the benefits of tissue engineering procedures are worth the costs of such an advanced process. The weeks or months spent cultivating and closely monitoring the development of organs and tissues in the lab will cost huge sums of money. However, reduced numbers of surgeries and lower levels of infection in burn patients, transitioning transplant procedures from emergency to scheduled operations, eliminating the need for rapid transport back and forth to donor hospitals, and the reduction and elimination of lifetime use of immunosuppression drugs will all save money in the long run. In addition, a patient without the need for immunosuppression medications will be significantly healthier in the long term with a fully functioning immune system. Only time and carefully crafted clinical studies will determine if the net cost increases or decreases from the status-quo. However, the growth of organs and tissues could be commercialized and refined to create an efficient supply chain that can facilitate large numbers of transplant procedures. Just as companies allow mail-in samples for DNA sequencing, a company could receive cells from a biopsy with a CT scan of the patient, grow the tissue or organ, and then ship it to the patient’s hospital. This commercialization would likely spark political discussion and research on its impact on organ trafficking.
The system used for matching donors and recipients for organ transplant is the best we have at the moment, but it does not need to remain the status quo. Government and private-sector financial investment in the fields of tissue engineering and regenerative medicine can hopefully accelerate the process of reducing the waitlist for organ transplants and increasing the safety of such procedures. Whether the funding originates from the Department of Defense, National Institutes of Health, or pharmaceutical companies, this scientific research maintains the possibility of doing a great deal of good.
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