Supercooled Ex-Vivo Porcine VCA Preservation to Extend the Timeline Between Procurement and Transplantation and Enable Tolerance Induction to Eliminate Immunotherapy Needs and Risks
Abstract
The recent wars in Iraq and Afghanistan have resulted in >1,500 amputations in wounded Warriors, and approximately 500 have suffered multiple extremity amputations. Of 4,000 or so facial injuries, around 50 were catastrophic. These statistics demonstrate the growing challenge of modern warfare in which improvements in body armor have reduced the number of fatalities in the field but, conversely, reflect the limitations of conventional reconstructive surgery in restoring our Service members to health and wholeness. More importantly, the number of civilians with similar injuries resulting in limb loss or devastating craniofacial injuries is much greater—of 2 million people living with limb loss, more than 185,000 amputations are performed annually; of 3 million facial injuries presenting to the emergency room each year, estimates suggest that 0.5% (15,000) are considered catastrophic and, if just 1% (of the 15,000) are candidates for face transplantation, that translates to 150 new cases every year. The immense benefits of hand/face transplantation (i.e., vascularized composite allografts [VCAs]) in restoring both the military and civilian populations have since been demonstrated successfully in more than 115 hand and 43 face VCA cases worldwide. There are two major limitations to wide application of VCA: immune rejection phenomenon (acute/chronic rejection and the consequences of lifelong immunosuppression) and organ preservation technology. Despite the use of potent immunosuppressive therapy, acute rejection of the VCA occurs in up to 90% of patients, most of whom experience at least one episode within the first year post-transplantation, and almost 60% develop multiple episodes. To prevent loss of the VCA, increased immunosuppression is required, resulting in additional morbidity. Mixed hematopoietic chimerism is the only successful strategy reported to induce immune tolerance in humans for kidney transplants. Current protocols in human trials require between 3 and 7 days to condition the recipient prior to receiving the organ. Therefore, strategies to preserve the donor VCA for a few days would enable the preconditioning of the recipient, thereby allowing the use of mixed-chimerism tolerance induction for VCA transplants. Unfortunately, current organ preservation technology allows for only a few hours of preservation for most organs, including VCA. In parallel, the extreme difficulty in finding matching donors is in stark contrast to solid organ transplants (e.g., kidneys, lungs, heart) in which the matching of donors and recipients is paramount to the longevity and function of both the transplant and patient. In fact, the matching of size, skin color, and gender currently take precedence in VCA. Moreover, VCAs are ethically, legally, and medically required to be taken from deceased donors (unlike for kidney and liver transplants). In turn, these requirements translate to a severe limitation in the potential number of VCA donors within geographic vicinity of a patient awaiting a limb/face transplant. Once again, extending the preservation duration of donor tissues from a few hours to a few days would reduce the logistic limitations and enable matching across the entire United States instead of regionally, as is currently possible. Additionally, the extension of tissue viability may be applied to related fields, such as trauma, in order for amputated body parts to be recovered and preserved so that the patient can be stabilized before definitive surgery. Our group has previously demonstrated that rat livers can be harvested from deceased donors, resuscitated with machine oxygen perfusion, and cold-preserved for up to 72 hours before transplantation into recipients with 100% survival. Further, in recent Department of Defense-funded studies, we adopted this technique and demonstrated 24-hour preservation of rat limbs with subzero nonfreezing storage. The objective of this study is to develop an extend
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910437
Entities
People
- Curtis L. Cetrulo, Jr
Organizations
- Massachusetts General Hospital
- United States Army