A study by University of Arizona College of Medicine – Tucson researchers uncovered a potential treatment that may reduce scarring and promote the regeneration of healthy skin for survivors of blast wounds, burns and devastating injuries that can lead to disfiguring or debilitating scars.
As a wound closes, skin cells create collagen, which forms the building blocks of a scar. Scar tissue is stiff and inflexible, and excessive collagen production can result in scarring that can impede movement or facial expression if a scar covers a joint or the face, for example.
“Evolutionarily, after a large injury, our bodies want to close the wound as soon as possible to prevent infection and help control bleeding, even if it creates scar tissue,” said Kellen Chen, PhD, assistant research professor in the Department of Surgery and lead author on the paper. “With modern medicine, we’re trying to prevent that dysfunctional and unappealing scar tissue and instead promote regenerative healing to have more normal skin.”
When an injury occurs, a protein called focal adhesion kinase, or FAK, sets off the production of a collagen-rich “matrix” on which new scar tissue develops. Dr. Chen, in partnership with Geoffrey Gurtner, MD, FACS, senior author and chair of the Department of Surgery, conducted research at Stanford University and found that a FAK inhibitor, when added to a standard wound treatment, appeared to reduce scarring and promote the regeneration of healthy skin in animal models.
Normally, severe wounds are covered with surgically transplanted grafts of a patient’s healthy skin, along with a hydrogel dressing that protects the wound and decreases pain. Drs. Chen and Gurtner found that skin grafts treated with a hydrogel infused with the FAK inhibitor looked more like healthy skin, while untreated skin grafts produced more collagen and other “stiffer” proteins.
“Treated skin grafts are making less collagen, closer to levels found in normal, unwounded skin,” Dr. Chen said.
By turning down the volume on collagen production, the team hopes that wounds treated with a FAK inhibitor might be able to heal without producing excessive scar tissue that often hurts more than it helps.
The architecture of a scar
Dr. Chen said it’s not only the high levels of collagen that cause a scar to be stiff and inflexible — it’s also how collagen is arranged at the microscopic level. In healthy skin, collagen arranges itself like a net. But when a wound resists staying closed, tensive forces cause the collagens in the scar tissue to align like a bundle of ropes, producing scar tissue that is strong but lacks elasticity.
“We want the healing skin to look like that net, because it has that springiness while maintaining its original strength, without being stiff,” Dr. Chen said.
The study showed that the collagen present in skin grafts treated with a FAK inhibitor was configured more like a net than a bundle of ropes. Their hope is that the resulting scars will be smaller and more flexible and appear more like normal skin, giving healed skin grafts a fuller range of movement.
The next step is to design a clinical trial to investigate how FAK inhibitors might be incorporated into wound dressings to support the healing process in human skin grafts. There is already clinical safety data on FAK inhibitors, which have been investigated as orally delivered cancer treatments.
“A topical application will be safer and easier to incorporate in the clinic because it is very similar to what we already do,” Dr. Gurtner said.“Hydrogels are commonly used in burn care, so this technology can be rapidly incorporated into the current standards of care.”
Applying it directly to the skin allows researchers to use much lower doses of FAK inhibitors than those previously investigated.
“We’re using less than 1% of the maximum tolerated dose tested in clinical trials,” said Dr. Chen, who began his work as a graduate student, peering at collagens under the microscope to understand how physical stimuli caused them to organize into nets or bundles of ropes. He says following his investigations all the way to the precipice of a clinical trial has been enormously gratifying, especially as a longtime resident of the Western U.S.
“As wildfires continue to rage in Arizona, traumatic burn injuries pose a risk to the population and typically heal with dysfunctional scar tissue,” he said. “It’s been really rewarding to see our work grow from experiments in the lab to exploring how we can use this to improve people’s lives.”
Clinicians who see the effects of serious wounds on a daily basis say innovations in wound care are needed.
“In severe burns, lifesaving skin grafts lead to nerve entrapment and range-of-motion-limiting contractures, which can only be addressed with lifelong surgical procedures,” said Lourdes Castañón, MD, FACS, clinical assistant professor of surgery at the College of Medicine – Tucson and director of the Banner – University Medical Center Tucson Burn Program, who was not involved in the study. “From a clinical care and quality of life perspective, this research is encouraging for its potential to reduce scarring and promote healthy wound healing and skin regeneration for burn victims.”
The study was recently published in the journal Science Translational Medicine.
This research was supported in part by the U.S. Armed Forces Institute of Regenerative Medicine (W81XWH-13-2-0054), the National Institute of Dental and Craniofacial Research (U24DE026914), the Plastic Surgery Foundation (837107) and the National Institutes of Health (R01GM116892).