Without a trace: can pharma reduce scarring?

We learn to accept scars as a fact of life – an inevitable consequence of injury or surgery. Pretty much everyone has at least one on their body. But the reason human skin is so prone to scarring has long eluded scientists. Michael Longaker at Stanford University has dedicated his career to the molecular mechanics of scarring and finding a way to stop it happening. 

"Scars are a useful evolutionary trait because they seal an opening in the skin far faster than normal skin could grow," Longaker explains. “If you heal slowly, you might get an infection or bleed to death.” 

Clearly, ancient humans needed to heal quickly to escape predators. But scars also have their disadvantages. “People ask me all the time if scars are really such a big deal,” says Longaker. “Only if you have one. Harry Potter may have loved his scar, but most patients do not.”

The consequences of scarring can be devastating, especially if it’s on the face or caused by a significant burn, he acknowledges. But the problems with scarring are more than just cosmetic. Scar tissue lacks hair follicles and sweat glands so struggles with temperature regulation. It is also much weaker than normal skin. 

Longaker’s path to scarring research started in the late 1980s when he was a general surgery resident at the University of California, San Francisco and working on a research project with paediatric surgeon Michael Harrison. 

“He was the first person to operate on unborn patients – these heroic operations when it would be too late to wait for birth,” reveals Longaker. 

Harrison noticed that when the children were born, there were no signs of surgical incision. In other words, the children were born without scarring. This discovery led Longaker to abandon his initial ambitions of becoming a heart surgeon to figure out why.

After 34 years of searching, Longaker and colleagues might have finally cracked the conundrum. In a paper published in Science, the Stanford researchers reveal the molecular mechanism that drives scar formation and show (in mice) how to make wounds heal with healthy skin instead of scar tissue.

Tension has a lot to answer for, says Longaker. His team found that if you lower the forces that pull at the edges of a healing incision, scar formation can be reduced. 

Picture a of bowl of jelly, he urges. “If you make an incision with a knife, it doesn’t gape open because there’s no residual strain.” 

This is what happens early in foetal development – the skin of the foetus is somewhat gelatinous. It’s the tightness of human skin that makes us prone to scarring. At the other end of our lives, skin loosens up again. 

Longaker says older people – especially those who have lived in sunny environments – have looser skin and therefore tend to be less prone to scarring after a surgical procedure. 

The researchers found that tension in the skin creates scars through the action of a gene called engrailed. This gene codes for a protein found in fibroblasts, which are the skin cells that cause scarring. 

In mice experiments, the scientists discovered a subpopulation of fibroblasts that don’t normally express engrailed. But they noticed that as soon as scarring occurs, this gene is switched on.

They then explored the role of mechanical stress and the engrailed gene. First, the scientists took mouse fibroblast cells that did not express engrailed and grew them in three different environments. The first was a soft gel that did not produce mechanical strain on the growing skin cells. 

Another was a stiff plastic dish that would produce mechanical strain. And the third was the same strain-inducing plastic but with the addition of a chemical that blocked mechanical-strain signalling in the skin cells. 

The scientists discovered that fibroblasts grown on the gel did not start expressing engrailed, but those on the stress-inducing plastic did. The third group of cells – whose signalling was blocked – also did not express the scarring gene. 

And when tension was applied to surgical incisions in mice, more fibroblasts started to express engrailed. As the wounds healed, a thicker scar was observed in this group compared to the mice who had not been put under tension.

Researchers then searched for a compound that might inhibit the scarring process by reducing tension. It was a stroke of luck when graduate student Shamik Mascharak gave the wounded mice verteporfin, a drug already approved by the FDA for macular degeneration. 

“After about ten days, hair started sprouting, which is incredibly unusual because there’s no hair in a scar. So that was pretty exciting,” says Longaker, who says the new mice skin looked completely normal under a microscope.  

To objectively compare the healed mice wounds to normal skin, Mascharak developed an artificial intelligence algorithm to detect subtle differences that can’t be seen by the human eye. 

His algorithm was unable to find any difference between normal skin and that regenerated with the assistance of verteporfin, suggesting that the drug had inhibited the scarring process without hindering healing speed. 

The next step for the team is to repeat the experiments in pigs – which have skin that is more like that of humans than mice skin is. If the results are validated, Longaker will then request authorisation for human trials from the FDA. 

The fact that verteporfin is already on the market gives the researchers an advantage. If human trials show good results, the drug could become available for this new purpose far more quickly than if the scientists were trailing an investigational compound. 

Longaker hopes the first human tests will investigate whether verteporfin prevents scarring from operations to repair cleft lips and pallets in young children. It might one day be standard practice for surgeons to inject verteporfin as they stitch up the incision. There could also be medical applications of the research outside of skin injury. 

Longaker says around 45% of Americans die from a disease that involves scarring in some form, such as liver fibrosis or damage after a heart attack. “Every time we operate on a patient or heal from an injury, we pay a price in terms of scarring. It would be really exciting to have something we can use to prevent this, not just for skin but perhaps many more types of injury.”