DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

A Novel Application of Normothermic Machine Perfusion for Face Recovery to Reduce Intragraft Inflammation and Optimize Organ Viability

Principal Investigator: BRASSIL, JOHN
Institution Receiving Award: FUNCTIONAL CIRCULATION LLC
Program: RTR
Proposal Number: RT180059
Award Number: W81XWH-19-1-0743
Funding Mechanism: Investigator-Initiated Research Award - Multiple PI Option
Partnering Awards: RT180059P1
Award Amount: $620,408.50


PUBLIC ABSTRACT

In recent wars, incidence of trauma to the extremities and face is increasing. Many of our armed Service men and women experience severe injury to the arms, face, and groin that can result in significant disability and disfigurement. In fact, in Operation Iraqi Freedom and Operation Enduring Freedom, up to 40% of those wounded in combat had injuries to the extremities. Vascularized composite allotransplantation (VCA) is a field that offers reconstruction of devastating traumatic injuries, such as upper extremity loss or severe facial trauma, using transplantation to replace “like with like” tissue. In cases where injury is so severe that conventional reconstructive efforts are ineffective at restoring sufficient function and appearance to allow for significant improvement in quality of life, VCA is becoming increasingly more prevalent. With over 200 VCAs performed worldwide, this burgeoning field continues to improve in both functional outcomes and immunologic treatment.

However, there are still multiple significant hurdles in expanding the field for a more widespread reach to be able to treat more recipients in need of VCA. Many of the patients, in resuscitation efforts from the original injury, have multiple blood transfusions, skin grafts, and other operations that can expose them to outside blood and tissue and lead to formation of antibodies, increasing the likelihood of rejection of transplanted tissue. As well, because of the nature of the transplant, donors need to be matched for things such as size and appearance along with traditional need for immunologic matching, considerably decreasing the availability of upper extremity or facial transplants. With current techniques, the sensitive tissues of VCAs are only viable for a short number of hours from the time of procurement from the donor to when blood flow is restored as it is surgically reconstructed on the recipient. While strategies exist to decrease risk of rejection when a patient has antibodies, this often requires more time immediately before the procedure than is possible without tissue injury to the graft. This time constraint also substantially limits the geographic region for possible donors.

In solid organ transplant, such as kidney and liver, strategies exist to increase the time before needing to restore blood flow or the ischemia time. These strategies include cryopreservation, hypothermic perfusion, and normothermic machine perfusion (NMP). The approaches requiring tissue cooling over a prolonged period of time—cryopreservation and hypothermic perfusion—can lead to more tissue damage, which with such sensitive tissue, including muscle and skin, involved in a VCA, can cause more immune response and risk of rejection. However, other organs have had success with NMP increasing ischemic time without significant tissue damage. In preliminary studies, we have found that machine perfusion is feasible in maintaining swine facial grafts with good maintenance of tissue integrity. In this study, we propose to use NMP to further investigate its ability to preserve facial transplant grafts and thus greatly increase the number of patients that can benefit from reconstruction with a VCA. This is in direct response to the Fiscal Year 2018 Reconstructive Transplant Research Program Focus Area to revolutionize ex vivo VCA tissue preservation strategies to extend the timeline between procurement and transplantation.

This study will take methods of NMP and brief hypothermic perfusion previously shown to have success in other organ preservation and will utilize these methods with application for VCA. We will build a system that can provide the appropriate nutrients, oxygen, pressure, and temperature needed by the delicate tissues in order to maximize survival and efficacy. We will test this system on swine grafts to evaluate for efficacy; then we will use the preservation strategy on swine hemifacial grafts that we will transplant. In following the transplanted tissues, we will show that the system allows for rejection-free survival of VCA. We will include tests on multiple cadaveric human facial grafts to validate the optimal perfusion system.

The impact of this study will be far-reaching. It will eliminate much of the burden of time constraint that currently limits the availability of this treatment for many of our Wounded Warriors. It will give time for those whose injuries required treatment that caused sensitization to have treatments to make them eligible for transplant, and it will increase the geographic area from which transplants can be obtained. With the allowable planning this provides, we can care for our patients and Service men and women with VCA to restore function, appearance, and wholeness of self to better improve the lives of these patients.