Stanford researchers score hit in 'scar wars'

- By Tracie White

STANFORD, Calif. - When Geoffrey Gurtner worked as a surgery resident at Boston Shriner's Hospital, he regularly treated children with disfiguring burns over their faces and bodies. These young patients would undergo 60 to 70 operations and, in the end, still look horrendous.

"As surgeons, we can save their lives," said Gurtner, MD, now associate professor of surgery at the Stanford University School of Medicine. "But we can't save the quality of their lives. These kids live diminished lives for an injury that is literally only skin deep."

The memory of these patients has haunted him over the years, sending him from the operating room into the research laboratory looking for solutions.

"The scalpel was obviously not the answer," he said.

Credit: Steve Gladfelter/VAS Kevin Cook

Kevin Cook, an activist for burn research, had burns over 85 percent of his body from a 1997 welding accident. Cook supports the efforts of medical school researchers to reduce or eliminate scarring.

Now, after six years of laboratory research drawing on his expertise in both surgery and biology, Gurtner has made the first real step toward meeting his goal of discovering how to reduce or, someday, eliminate scarring altogether. "I've finally hit on something," he said.

In a study to be published in the October issue of the journal FASEB (Federation of American Societies for Experimental Biology), Gurtner and colleagues provide new insight into the pathophysiology of scarring. It's the first step in an ongoing, multidisciplinary attempt at Stanford to battle disfiguring scarring - dubbed "Scar Wars" by one researcher. The study also provides the first animal model for scar research.

"This research allows us to understand for the first time why scars form," Gurtner said. "And it allows us to now move ahead and rationally design new therapeutic treatments for scarring." He predicted that discoveries of new therapies to significantly reduce scarring are only a year or two away.

New treatments are desperately needed by burn patients, said Kevin Cook, an activist for burn research and a patient at the Santa Clara Valley Medical Center. Cook suffered burns over 85 percent of his body in 1997 when diesel fuel spilled on him and ignited during a welding job.

Cook has had 50 operations, which have not significantly improved the disfiguration from the burns.

"I've had both eyes, my nose, my mouth, my ears operated on. My hands are constantly getting worse and worse. My mouth got to the point where I could barely fit a teaspoon of sugar through. My nostrils got so small I couldn't fit a Q-tip through," Cook said. "And every time you have surgery, it knocks you down."

Yvonne Karanas, MD, is a member of Gurtner's "Scar Wars" team and director of the burn center at Santa Clara Valley Medical Center in San Jose, where Cook is a patient. "I'm waiting with bated breath for solutions," said Karansas, who is also clinical assistant professor of surgery at Stanford. She spends much of her time caring for burn patients, and pointed out that in addition to suffering permanent disfigurations, her burn patients often endure lifelong limits on function that leave them unable to close their eyes or mouths because of scar formation.



"Right now, there are no good solutions," she said.

The endless surgeries can help somewhat with function, Cook said, but the permanent disfigurement is life changing, especially for patients with facial scars. "Your face is who you were. That was your identity," he said. "To lose your identity is a big factor."

The FASEB study began with the premise that applying mechanical stress to a wound - exerting pressure, pulling, pushing or stretching the skin - makes the scarring worse. This is common knowledge among surgeons, like Gurtner, who deal with skin and scarring on a daily basis, but not so among scientists in general.

"Surgeons know that, of course, tension is bad for wounds," said Michael Longaker, MD, the Deane P. and Louise Mitchell Professor in the School of Medicine, a stem cell biologist and expert in fetal surgery, and one of the study's authors. "Actually proving it is another thing. This paper nails it down."

Researchers chose mice to test their theory because mice, in general, don't scar. Small mice, like human fetuses, heal with little or no scarring.

"Size matters," Gurtner explained. Larger animals with thicker skin and bigger muscles have thicker scarring. "The mechanical force on mice is about one-tenth of that on humans. When you get to whales, they're actually identified by their scar patterns.

"The more mechanical stresses on the skin," he said, "the more promotion of scar formation."

The study's authors hypothesized that if the same amount of mechanical stress was applied to a mouse wound as is naturally exerted on a human wound, human-like scars would form in mice. To test this, they created a device that exerted mechanical pressures on the mouse equivalent to that exerted on humans.

As expected, the mice developed large scars as the wounds healed. "We were very excited to see thick, human-like scars in the mice," Longaker said. "Without an animal model for thick scars, our ability to develop targeted therapies has been severely limited. Now we have a model."

The study points out that the scarring or "over-healing" in these mice happened during a brief, seven-day period immediately after the wound occurred, indicating a critical time period exists early in the healing process where therapeutic treatment would be most successful.

By controlling the physical environment of a wound in humans, it may be possible to change the way the skin heals, the study concluded.

"My real focus is to show the importance of the environment in determining cell fate," Gurtner said. "Maybe through engineering we can change the physical forces on the healing wound and stop the scarring."

Gurtner has gathered a team of researchers from Stanford's schools of medicine and of engineering in fields ranging from dermatology to structural engineering to move ahead with plans toward designing future therapies.

"This research really looks at the core of why these scars develop," Karanas said. "If we can prevent it from happening, it's a lot better than trying to treat it once it's developed."

Some of the team's research involves investigating the structural differences in embryonic skin and adult skin. Scientists have known for decades that a fetus can heal without scarring. Gurtner's latest research may lend new light on why.

"Fetuses live in a very unloaded mechanical environment," Longaker said, referring to a mother's womb. "There are almost no forces, no stresses. Maybe by creating a similar environment, we can reduce scarring." The team has drawn in Reinhold Dauskardt, PhD, a world expert on skin mechanics and professor of materials science and engineering, to help investigate the problem.

"It turned out a lot of the work we're doing in our engineering department on the mechanical function of skin is very relevant when considering skin healing," Dauskardt said. "If we can control the mechanical environment of skin, and Dr. Gurtner has demonstrated that the environment is very important for how wounds heal, we can attempt to create the optimal environment to prevent wound scarring."

Stem cell research in the area of skin regeneration that would someday completely eliminate scarring also features prominently in the team's research. Gurtner has applied for a grant from the U.S. Department of Defense to fund research into decreasing scarring and promoting regenerative healing in injured soldiers.

"Let's assume that it's not OK to heal with scars," Longaker said. "No one is happy with scarring. How about no scars at all?"

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