VCA is the practice of transferring functional anatomical units containing multiple tissue components, like a face or a hand, from one patient to reconstruct the defects of another. VCA bridges the gap between solid organ transplantation and microsurgical reconstruction. VCA has the potential to be of great benefit to patients with complex reconstructive problems. However, VCA requires life-long immunosuppression to prevent rejection of the transplanted tissues. Immunosuppression is associated with a higher risk of certain infections, malignancies, and organ toxicity.
VCA recipients must take many medications daily. Some are immunosuppressants, and others are intended to counter the side effects of immunosuppression. There is current interest in developing protocols for VCA that can eventually minimize or withdraw immunosuppression safely and without immune rejection. These protocols aim to induce "immune tolerance", which is the absence of a destructive immune response to a transplanted organ or tissue. Our group is currently conducting research in this area. In particular, we are developing a model for hind limb allotransplantation in murine models. This model will later be used for the validation of improved, safer immunosuppression regimens, assessment of rejection and induction of donor-specific immune tolerance.
Upper and lower extremity (UE and LE, respectively) loss has consequences including lifelong disability, decreased quality of life, and long-term costs. Despite advances in limb prostheses, the resulting sensory and motor function is severely limited. Whenever possible, surgical replantation (re-attachment of severed limb) is the preferred method of treatment. Transplantation is a newly emerging alternative for limb replacement when salvage is unsuccessful. Both replantation and transplantation of UE and LE require re-attachment of the severed limb within 4-hour window of ischemia time.
Amputations that occur in locations far from centers capable of replantation and suitable limb donors for transplantation are often located long distances from potential recipients. Often, the 4-hour time limit prohibits surgical limb salvage. We are developing an extracorporeal machine perfusion device to preserve amputated limbs by means of artificial perfusion. We expect to show that portable extracorporeal machine perfusion is capable of extending allowable limb ischemia time by a factor of 2 to 3. If successful, this work will promote access to limb salvage for victims of UE and LE loss.
Peripheral nerve damage that includes branched nerves such as the facial nerve have debilitating effects. There is no current option for complex branched nerve repairs except to cable-tie multiple autografts together. This approach requires multiple surgical sites with donor morbidity, increases anesthesia and facility costs and has limited outcomes. Furthermore, when repair of branched nerves is necessary in VCA interventions, it adds significant time to the procurement operation, as isolation of complex branched nerves such as the facial nerve is lengthy and involved. Also, because the nerve anatomy of the recipient is not well understood prior to the operation, often times surgeons are forced to use as many as 5 autologous cable grafts per site when they find that the length of the recipient's remaining nerves is not sufficient to connect to the allograft's nerves.
Autologous cable grafts end up being bulky and targeted reinnervation is lost. To address these limitations, we are investigating an off-the-shelf decellularized branched nerve product that is immunologically tolerated and has versatile dimensions and geometries. We are currently working on proof of principle studies in a large animal animal study to support commercialization and regulatory approval of this product.
Capsular contracture is the most common complication after silicone-based breast reconstruction. Capsular contracture can impart pain and deformity, and the only treatment available is surgical removal of the capsule. We are investigating whether injection of a collagenase product that is currently approved for treatment of another disease caused by abnormally high collagen production is useful in treating capsular contracture after silicone-based breast reconstruction. We are currently using small animal models in these investigations.
On April 9, 2009, we performed the second face transplantation in the United States. In September 2009, we received funds from the Department of Defense to perform and evaluate the procedural, psychosocial, and economic outcomes of Facial Transplantation, with our collaborators Louis Nguyen, MD, MPH, MBA, Megan Oser, PhD, Stuart Lipsitz, SCD, Melanie Parker, DPT, and others. We have performed a total of seven facial transplantation operations.
With over thirty facial transplantation procedures performed worldwide to date, many questions surrounding face transplantation planning, execution and outcomes are unknown. We are working on defining the most efficient design of face transplantation, focusing on motor and sensory re-integration in the recipient. In collaboration with our Radiology colleagues, we have thoroughly explored role of imaging in the preparation for face transplantation and we continue to explore the potential of modern imaging technologies in the follow-up of the face and hand transplant recipient.
Considerable effort has been placed in the analysis of our face transplantation experience. At present, in collaboration with Edward J. Caterson, MD, PhD, our team is studying the craniofacial relationships involved in face transplantation, trying to identify which cephalometric parameters may lead to the most appropriate match between donors and recipients. Additionally, we are working to identify the ideal craniofacial relationships that will guide allograft osteosynthesis, leading to proper restoration of skeletal anatomy and, as a result, improved long-term occlusal and airway function. We are also working on evaluating the restoration of upper airway in face transplant recipients and how it improves several functions.
We have performed 9 VCA operations to date and established a unique research repository of blood and tissues from VCA recipients and their donors, and have implemented protocols and policies to make these specimens available to affiliated investigators. A central resource is in place for handling, storing, and processing specimens – making cells, slides and tissues available to investigators from a wide array of disciplines.
We have brought together scientists from many disciplines and leveraged their wealth of experience in transplantation biology to jointly analyze emerging data, prioritize specimen use and next steps and create a community of sharing for rapid dissemination of findings and ideas. Our research address important scientific issues that focus on understanding the unique immunologic aspects of VCA. Others and we have shown that lesser degrees of immunosuppression are required to achieve higher rates of tolerance for VCA transplants than other solid tissues – and it is this phenomenon we seek to characterize, define and understand.
We are working to characterize the allograft state along a range of tolerance and immune reactivity using an increasingly sophisticated array of imaging technologies, circulating and tissue biomarkers, and protein and gene expression. With this characterization in hand we will examine the drivers of immune reactivity. Finally, we hope that mechanistic insight will provide novel means of enhancing allograft survival, first by demonstrating that modulation of allograft perfusion and/or immune state can change molecular and cellular events and subsequently affect clinical events, and second by providing novel strategies to induce favorable molecular and cellular events.
In the Spring of 2011, our team performed the first 3 full-face transplants in the United States and we are currently evaluating the outcome of our transplanted patients. Other potential recipients are presently being screened for enrollment and/or waiting for the gift of facial allograft donation.
Our program has also obtained approval to perform Hand Transplantation Surgery in bilateral or dominant hand amputees. This protocol will evaluate the procedural, psychosocial, and rehabilitation aspects of this surgery. In October 2011, our team performed a bilateral hand transplant in a quadruple amputee. Since then, we are closely monitoring our recipient as he goes through the various phases of recovery and rehabilitation.
In August of 2012, we obtained Institutional Review Board approval to perform Multiple Extremity Transplantation Surgery in patients with the amputation of any two combinations of upper and/or lower extremities. Our team is now screening candidates for this groundbreaking procedure.
In 2014, we obtained Institutional Review Board approval to perform Abdominal Wall Transplantation in patients with severe defects of the abdominal wall. Our team is now receiving referrals and screening candidates for this procedure.