According to Max Eastman, “a smile is the universal welcome.” For individuals whose faces are severely disfigured due to trauma, burns or disease, a smile may be difficult, or even impossible, to express. Facial deformities may impair daily activities, such as eating, swallowing, breathing, and talking. Consequently, these individuals may hide from the public in an attempt to avoid curious stares from strangers. For those patients who have exhausted all conventional means of facial reconstruction, face transplantation offers the possibility of regaining muscle movement and sensory control in the face. For example, doctors hope that the surgical procedure will help patients to prevent drooling, display various emotions, and speak and eat more easily .
History of Transplantation
The first successful organ transplantation occurred in December 1954 – a patient diagnosed with kidney failure received a kidney donated by his identical twin sibling . However, it was not until November 2005 that even partial face transplantation was performed — this time on a patient who had been mauled by her Labrador retriever . The surgical procedures behind face transplantations are still in the experimental phase due to both the complexity of the facial structure, which involves many intricate connections between muscles and nerves, and to the unpredictable outcomes of the surgery. To date, only 14 facial transplantations (including partial face transplants) have been performed.
Figure 1 – Timeline of Surgical Milestones in the Field of Composite Tissue Allotransplantations (CTA). Leggenda Aurea (348 AD) refers to the miraculous transplantation performed by Saints Cosmos and Damian in which the limb of a recently deceased Ethiopian moor was transplanted to a Roman church custodian. Modified from [Source: (Pushpakumar, et. al. Clinical Considerations in Face Transplantation. 2010. Burns; 36: 951-958.)
The most extensive full face transplant completed to date occurred in March 2012 at the R Adams Cowley Shock Trauma Center at the University of Maryland Medical Center. The 37-year old patient, Richard Norris, lost his nose, lips, and significant movement of his mouth due to a gunshot to the face in 1997. To restore what Norris lost, doctors had to completely reconstruct his teeth, tongue, upper and lower jaw and all the facial tissue from his scalp to the base of his neck (Figure 2) .
Figure 2 – Three-dimensional facial reconstruction of the patient from computerized axial tomography (CAT) scans. (Left) Prior to the surgery, the bone structure of the upper jaw (maxilla; green-colored) and lower jaw (mandible; dark brown-colored) are highly deformed. (Middle) Prior to the transplant, the skeletal defects were removed. (Right) The transplant procedure grafted the upper jaw, lower jaw, and teeth, of a donor patient onto the recipient patient. [Source].
The human face is a complicated system. It is composed of a complex network of bone, cartilage, skin, subcutaneous tissue, muscles and nerves that must be properly connected in order for the face to function correctly (Figure 3). If the doctors gave Norris a new jaw, for example, but didn’t restore all of these connections, the jaw would be almost useless.  This complexity makes face transplants incredibly challenging, and is one of the reasons why they have not been attempted until recently.
Figure 3. Tissues of interest in craniofacial reconstruction. [Source: (Journal of Craniofacial Surgery 2012; 23(2): 530-536)]
Challenges of Face Transplantation
The challenges associated with a transplantation procedure are three-fold: surgical, psychological, and immunological. Surgically, doctors must come up with strategies to ensure that the face transplant yields both optimal appearance and function. Psychologically, it can be difficult for a patient to accept a new face that resembles neither his nor the donor’s original face. Immunologically, doctors must work to prevent the patient’s body from rejecting the transplant, which means that they need to prevent the immune system from recognizing the transplant as foreign and trying to fight it . This issue was discussed in depth in the previous Flash article (“Trials and Tribulations of a Transplant“), which provides an overview of the biology behind the immune rejection that can be elicited by the presence of a transplanted organ from a donor. Fortunately, scientists have made many recent advances to overcome these immunological challenges, and these innovations made the March 2012 face transplantation possible.
As described in the last issue of the Flash, patients who undergo transplantation procedures are often required to be on lifelong immunosuppression regimens post-operation to prevent rejection of the graft by the patient’s immune system. The immunosuppressive drugs are involved in blocking the ability of the immune system to properly function, thereby preventing the rejection of the transplanted organ and/or tissue (viewed as “foreign” by the body). Though the rejection of facial tissue is not immediately life threatening, immunosuppressive drugs can be risky, with complications including infection, diabetes, and cancer. To improve the cost-benefit ratio of face transplantation, researchers have looked for ways to reduce the risks of conventional long-term immunosuppression or to make these drug regimens unnecessary altogether.
A Breakthrough in Face Transplantation
An important milestone in overcoming graft rejection in face transplantation came from the Bartlett research group, who were part of the team involved in the March 2012 transplantation operation. They developed a nonhuman primate model of facial segment allotransplantation (transplantation from a donor of the same species) (Figure 4) to examine the contribution of vascularized bone to transplantation success, with success being defined by the amount of graft rejection observed after the procedure. A vascularized bone graft is one in which the blood supply is maintained through surgical joining of the donor blood vessels to the host vessels at the graft site. It was hypothesized that the use of vascularized bone would reduce the amount of graft rejection observed, and thus, reduce or eliminate the long-term immunosuppression required post-transplantation. Vascularized bone contains a continuous supply of bone marrow cells, which can produce new blood cells under certain conditions. It had been shown previously in an adult rat model that the stable engraftment of donor cells in regions of host blood cell production induced post-transplantation tolerance, and consequently, prevented the immune system from recognizing the transplant as foreign .
Figure 4 – Nonhuman primate model of partial face transplantation. (A) Facial grafts from donors were composed of the lower jaw, masseter (muscle involved in chewing), overlying skin, and associated blood supply. (B) Grafts were transplanted to recipients by surgically joining them to the femoral blood vessels in order to allow the donor bone marrow cells from the vascularized bone graft to become incorporated into the host bloodstream. (C) Grafts were placed into the lower abdominal wall of hosts .
The Bartlett research group demonstrated in face transplantations of cynomolgus monkeys that using high amounts of vascularized bone from the transplanted jaw reduced both the amount of tissue rejection observed and the amount of immunosuppression required post-operation. In contrast, face transplantations performed without vascularized bone resulted in early transplant rejection. Furthermore, the monkeys that received the traditional face transplant showed clinical signs of graft rejection that included skin redness, skin peeling, and blistering .
The new method of face transplantation improved outcomes greatly, however, it did not solve all of the problems associated with transplants. In the face transplantations performed with vascularized bone there was evidence of mild rejection when the tissue was examined on a microscopic level, but fortunately, there were no clinical signs of graft rejection – this indicates that the use of vascularized bone significantly reduces the host immune response against the donor graft. Unfortunately, the grafts were only able to survive for long periods of time if the recipients were taking immunosuppressants, suggesting that the addition of vascularized bone is not enough to completely prevent graft rejection by the immune system. Nevertheless, the Bartlett research group has provided evidence suggesting that the inclusion of vascularized bone in face transplantations leads to stable engraftment with a reduced requirement for immunosuppression. 
This advance from the Bartlett group is truly a landmark finding that made the March 2012 full face transplantation possible. Despite these advancements, however, there is still much work to do to improve the risk-benefit ratio of transplantation procedures. Future transplants will be more successful as current research in fields such as tissue engineering, immunology, toxicity, and regenerative medicine moves from the lab to the operating room.
Jessica W. Chen is a PhD student in the Biological and Biomedical Sciences Program at Harvard University.
 Lisa, Merolla. “Facing the Facts: A Look at the Face Transplant Controversy,” 2009. <http://www.jyi.org/features/ft.php?id=1320>
 “The Ultimate Gift: 50 Years of Organ Transplants,” 2004 December 21. < http://www.nytimes.com/2004/12/21/health/21orga.html?_r=1&pagewanted=print&position=>
 “University of Maryland completes most extensive full face transplant to date,” 2012 March 27. <http://www.umm.edu/news/releases/face-transplant.html>
 Dubernard, et. al. Outcomes 18 months after the First Human Partial Face Transplant. 2007. New England Journal of Medicine; 357:2451-2460.
 Barth RN, Rodriguez ED, Mundinger GS, Nam AJ, Ha JS, Hui-Chou H, Jones LS, Panda A, Shipley ST, Drachenberg CB, Kukuruga D, Bartlett ST. Vascularized Bone Marrow-Based Immunosuppression Inhibits Rejection of Vascularized Composite Allografts in Nonhuman Primates. 2011. American Journal of Transplantation; 11:1407-1416.