Soldiers and others who receive severe injuries to the hands and face often can benefit from a type of transplant known as vascularized composite allograft (VCA) — the transplantation of multiple tissues, including muscle, bone, nerve, skin, and blood vessels, as a functional unit (such as a hand or face) from a deceased donor to a recipient with a severe injury.
Recipients of VCA grafts require longtime immunosuppression so their body doesn’t reject the transplant — an event that in the case of a hand or face transplant could be devastating to the patient. Longtime immunosuppression presents problems of its own, however — including greater susceptibility to diseases such as cancer and infections including COVID-19 — so doctors are always looking to balance the amount of immunosuppression a VCA recipient needs with the chances their body will reject the transplant.
Christene A. Huang, PhD, a professor of plastic and reconstructive surgery and transplant surgery in the University of Colorado School of Medicine, is part of a research team that recently received a grant from the U.S. Department of Defense (DOD) to study noninvasive biomarkers of VCA rejection that would allow doctors to more quickly identify potential signs of rejection and adjust immunosuppression as necessary.
“If we can come up with a way of monitoring so that we can maintain a reasonable level of immunosuppression, but we can detect early signs of vascular rejection, then we can modulate the immunosuppression in a very targeted way and not have the patients subjected to lifelong high levels of immunosuppression,” Huang says. “That's the ultimate goal.”
Monitoring galectin-3
The DOD grant will fund preclinical large animal studies on galectin-3, a protein that can be detected in blood and saliva and has been found by Huang’s group to be increased in the circulation of rodent recipients of VCAs subjected to prolonged periods of ischemia — a condition in which the blood flow, and thus oxygen, is restricted or reduced in a part of the body. Organs and tissues subjected to prolonged ischemia trigger a severe inflammatory response in the recipient once the blood vessels are reconnected during transplantation. This is referred to as ischemia reperfusion injury, and studying the role of galectin-3 in this process is the topic of another DOD-funded grant in Huang’s laboratory.
“When you take an organ or any tissue out of a donor, you're subjecting it to a period of ischemia,” Huang says. “That's just inherent in transplant. We're studying that in a different context, but we expect that when we see VCA rejection, we're going to see an increase in galectin-3.”
Eventually, the goal would be for patients to be able to do a simple at-home saliva test to check for signs of graft rejection, though abnormal results would still need to be examined by a doctor.
The oxygen equation
The study also will look at the effectiveness of an optical tissue oxygenation measurement device developed by Conor Evans, PhD, of Massachusetts General Hospital. The lightweight, portable sensor measures oxygen levels in transplanted tissue — low levels of oxygen being another sign of possible graft rejection. The oxygen-sensing technology was developed from prior funding from the DOD through the Military Medical Photonics Program and the Transforming Technology for Warfighters Program.
The lightweight, portable sensor measures oxygen levels in transplanted tissue.
“In these transplants, one of the earliest clinical signs of a rejection is that the capillaries within the skin clog up; they'll begin showing thrombosis and other impediments to blood flow,” Evans says. “This sensor sits on the skin, and it can detect an impediment to blood flow with very high sensitivity.”
In the DOD-funded study, Huang will use the oxygen-sensing device to verify the inflammatory response indicated by the presence of galectin-3. The researchers ultimately hope to come up with a combination of the two biomarkers that could quickly and easily monitor patients for signs of VCA rejection.
“For a patient who had, say, a hand transplant and is taking immunosuppression, you're always worrying about whether or not to reduce that medication,” Huang says. “If you had a way of monitoring very carefully if there are any changes, that would be peace of mind. I think it's going to be a game-changer, because right now, these patients have to come in and get a biopsy if there's any sign of rejection.”
Return to duty
Successful identification of noninvasive rejection biomarkers will be welcome news to anyone with a VCA transplant, but especially for soldiers with hand, face, and other injuries who want to return to active duty as soon as possible. Evans says he saw evidence of that when he visitedvthe Center for the Intrepid, a rehabilitation facility at the San Antonio Medical Center in Texas that was established to treat amputees and burn victims.
“I interacted with a bunch of soldiers who had reconstructive surgeries to rebuild hands and feet, and when their commanding officer came around, the first thing these young men would say was, ‘Sir, when can I get back out there?’ The service to their fellow soldiers and the country dominates their sense of responsibility. I met really powerful young men and women who had catastrophic injuries, and all they wanted to do was get back out there for their buddies and their fellow soldiers.”
