Plastic surgeon Dr Michael Longaker was an undergraduate at Michigan State University in 1979.
Now renowned for his work on scarring, back then Longaker’s interests lay more in sports than scientific research – that year he played with basketball superstar Earvin ‘Magic’ Johnson on his college team, the Spartans.
“I had no background in research, at all,” he says, “I was forced into the lab.”
After his medical degree, he reluctantly took up a one-year research post in the lab of paediatric surgeon Dr Michael Harrison, who was carrying out life-saving operations on babies in the womb.
He started seeing something surprising: when these babies were born, they didn’t have any scars from their surgeries. So Harrison said to Longaker, “Why don’t you look at how we heal before we are born?”
Longaker’s reservations about research were soon forgotten. He operated on foetal lambs and other unborn animals, becoming caught up in the idea of ‘scarless healing’ in the womb. His one year in the lab became four.
Harrison’s group wasn’t the first to report scarless healing.
The same year Longaker played with ‘Magic’ Johnson, an American pathologist published a paper about a baby boy born at an Illinois hospital when his mother was only 20 weeks pregnant.
The baby was sadly stillborn and, due to a rare condition where the amniotic sac gets wrapped around the foetus, suffered leg and finger amputations. But his wounds had healed without scars.
These discoveries in scarless healing led scientists to wonder: if we can heal without scars before we’re born, is there some way of switching that ability back on outside the womb?
This question has occupied Longaker’s thinking for four decades.
Today, at Stanford University in California, he says he gets “hundreds of emails a month” from people asking about their scars. He’s made it his life’s work to help them.
Outside the womb, scars are the price we pay for healing. Many of the 100 million scars people worldwide develop every year serve as painful reminders of past traumas, whether in the kitchen, operating theatre or war zones.
In the UK, for example, five million people live with scars that cause them emotional or physical distress. But, according to Longaker, scientists are now closing in on a solution to the problem.
“We’re standing at a threshold,” he hints. “We’ve laid a lot of track.”
When scarring begins
Back in Harrison’s lab, they still had to understand where perfect healing ended and scarring began.
Meanwhile, in the UK, cell biologist Prof Paul Martin, then at University College London, was doing parallel work in mice, which have a short, 21-day gestation.
“Our work was completely complementary,” says Martin, another stalwart of the scarring community, who met me in his office at the University of Bristol.
“As they were doing that in sheep and patients, we were doing it in mice. We found a stage in mouse development when you could wound a mouse and it didn’t scar – until embryonic day 14.”
In essence, it’s not until later in gestation (24 weeks in humans) that the process leading to scarring actually begins to develop.
Then, for the rest of our lives, we scar. The process begins with the body plugging the gap by forming a clot, which later becomes a scab, and dispatching immune cells to fight off infection.
After that come the ‘repair crews’: cells carrying fibrous proteins, mainly collagen, to patch over the wound.
As the repair progresses, some of these cells contract to zip up the wound, with the collagen being linked and reorganised to pull on the tension lines. This whole routine works to seal the wound, but the systems are flawed.
Problematic scar tissue is often the result of repair crews on overdrive laying down too much collagen in tightly packed bundles rather than the loose basket-weave-like structure of ordinary skin.
Humans are already tight-skinned animals, more like pigs than dogs or cats, according to Longaker, so our wounds are difficult to close.
“The forces required to close [an] incision are much stronger than the scar it’s forming,” he says, explaining that scars grow “wide and thick” to avoid being pulled apart.
Yet, even with all that extra collagen, he notes, scar tissue is never quite as strong as normal skin.
The two types of raised scars, keloid and hypertrophic, are both caused by excess collagen production, while indented atrophic scars (like those caused by acne) are the result of a lack of collagen.
For anyone with large scars, such as from widespread burns, the impact isn’t just cosmetic because as the scarred skin contracts, it restricts movement. Scars on the face, for instance, can impact speech and eating.
Finding the right tools
The foetal healing work suggests that all this misery could be avoided if only scientists could locate the biological buttons to deactivate scarring.
“What we’ve been trying to figure out for 30 years is what the buttons are,” says Martin. “And it looks like there are several.”
In the early days, however, scientists simply didn’t have the molecular tools to track them down. Surgeons and dermatologists did what they could to help.
Since the 1980s, for example, lasers and other ‘energy-based devices’ have been used to treat scars with heat – in theory, the body perceives the heat damage as a type of controlled injury and responds by replenishing or reorganising the collagen.
It’s by no means a quick fix, often requiring multiple treatments, and there’s no obvious right time to intervene.
“Since many scars improve over time, a conservative ‘wait-and-see’ approach has traditionally been taken,” explains Hye Jin (Leah) Chung, associate professor of dermatology at Harvard Medical School, Boston.
However, she adds that, based on emerging data, some experts now think earlier treatment may help.
Getting good results depends on matching the device type and its settings to the scar and skin type, taking extra care in people with darker skin or a history of keloids (raised scars that overgrow), who may be more prone to complications.
Other options include steroid injections, microneedling to stimulate the body’s healing response and loaded dressings filled with therapeutic agents.
Surgical scar revisions can improve the appearance of scars, although Longaker says the results tend to be disappointing, so he avoids doing them.
There’s a multi-billion dollar market for anti-scarring lotions and potions, some of which are supported by very thin evidence, while others, like those based on onion or green tea extracts, have shown some degree of benefit in trials.
None of these solutions reliably solves the problem, however, leading scientists to keep searching for the switches that turn off scarring. And, gradually, using modern cellular, molecular and genetic techniques, they’re tracking them down.
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Closing the gap
Recent years have seen a renewed focus on fibroblasts, the collagen-carrying cells of repair crews.
Once considered a uniform bunch, fibroblasts became more interesting to scarring researchers in 2015, when Longaker’s team showed they come in different versions – including one that activates in scarring.
“It gets angry and activated,” says Longaker. “And it starts to make collagen.”
The ‘angry’ fibroblasts (aka Engrailed-1 lineage positive fibroblasts), Longaker’s team found, activate during development, making up just one per cent of skin-associated fibroblasts in 10-day-old mouse embryos, but 22 per cent six days later.
And, crucially, destroying them in adult mice reduces scarring.
So, how do you get the angry fibroblasts to calm down? Fibroblasts don’t operate in isolation and are pushed and pulled into action by other triggers within what you might call the wider ‘woundiverse’.
For instance, they receive signals from the infection-fighting immune cells that colonise the wound early on. Scars, in fact, don’t even form without immune cells – genetically engineered adult mice that lack them heal perfectly, like embryos.
And guess when, during embryonic development, immune cells start showing up at wounds? Right around the time that scarring begins.
This timely association between the immune response and fibroblasts is no coincidence, according to Martin, who, while explaining this link, enthusiastically pretends to be a macrophage – a crucial immune cell.
“I’m a macrophage and you’re a fibroblast,” he says. “If I’m an aggressive, pro-inflammatory macrophage, I’ll say to you, ‘Make a scar’.
"If you’re the right sort of fibroblast, you’ll respond and make a scar… It’s more complex than that, but essentially, macrophages coming into wounds talk to fibroblasts and tell them to make scars.”
Of course, we can’t simply turn off our immune systems to stop scarring.
So Martin, Longaker and others continue to explore the woundiverse for more selective targets; buttons they can press that specifically target the angry fibroblasts or some aspect of the chain of events leading to scarring, without shutting down other essential systems.
One fibroblast-activating molecule called transforming growth factor beta (TGF-ß), for example, has long been a target of scarring researchers.
Tellingly, different versions of TGF-ß are active before and after birth, but simply providing the one that’s active in embryos hasn’t worked out.
Now, researchers are trialling scar-reducing gel dressings loaded with a natural protein, called decorin, that binds to a version of TGF-ß that’s more active after birth.
Though, as materials scientist Prof Liam Grover from the University of Birmingham explains, it might be acting on other components of the scarring system, too.
“Decorin is a very sticky molecule,” he says. “My view is that it makes the wound environment busy, sticks to a load of stuff and effectively reduces the likelihood of those molecules inducing [scarring].”
Right now, the team is beginning trials in burn patients, but Grover says it’ll take a couple of years to know if the dressings work, due to how long scars take to form.
Even as he waits, though, Grover is trying another approach to identifying new anti-scarring molecules: generating them with artificial intelligence (AI).
Partnering with computational scientists at the University of Warwick, Grover suggested molecules within the woundiverse that he would like to block.
The Warwick team looked at the shape of these molecules, then asked AI to generate thousands of structures for potential inhibitors.
Through computer modelling, these have been narrowed down to six, all of which are smaller (so easier to make) than decorin, and likely cheaper and more stable, but so far they’re untested.
Meanwhile, Longaker’s team is on the verge of clinical trials for an injectable drug based on another small molecule, verteporfin, which is conveniently already approved for treating the eye disease macular degeneration.
In 2021, the researchers showed that verteporfin targets a molecule called yes-associated protein (YAP), which appears to be sensitive to tension changes in wounds and prompts the angry scar-forming fibroblasts into action.
While its mechanisms are still not fully understood, Longaker says he always suspected tension had a part to play.
“I knew it had to do with physical forces, because in early gestation, the skin is gelatinous and in the last trimester, it becomes a barrier – tight,” he says. “We [have now shown] how fibroblasts sense forces, and tension is critical to activating them.”
By deactivating YAP, the researchers got wounds to heal without scars in adult mice. The healed tissue had hair follicles and sweat glands, which are usually missing in scars – “everything normal”, according to Longaker.
Then, in early 2025, they repeated the feat in pigs, an important milestone as their skin is so similar to ours.
The plan now is to trial verteporfin as a single injection alongside surgery for cleft palate scar revision, although the team is due to publish a paper in which they’ll claim it also works to ‘rescue’ months-old scars.
What’s more, there are other molecules involved in sensing tension and forces, including one called focal adhesion kinase (FAK).
Longaker’s long-time collaborator Prof Geoffrey Gurtner, now at the University of Arizona, is developing dressings filled with FAK-blocking molecules that reduce scars by encouraging the actions of gentler, pro-regenerative fibroblasts.
Seeing through scars
Another way to hone in on potential new targets and treatments is to watch scarring in real-time. Over the years, Martin has developed ways of visualising scarring as it happens. But not in pig or human skin.
Referring to one of the images displayed on his office wall, he demonstrates the stunning details he’s able to uncover in zebrafish, by following cells and molecules with fluorescent tags.
Zebrafish skin is translucent, so it’s possible to watch collagen being laid down as it happens, as well as observe the effects in fish whose scarring systems have been genetically manipulated.
The same studies in opaque pig or human skin would be useless. The actions of genes identified in humans can still be visualised in Martin’s fish, however.
The team has been hunting down genes associated with reduced scarring by looking at differences in how people scar – leaning on data from large genetic studies in the UK and Brazil.
“In Brazil, 90 per cent of mums have C-sections and in some you can barely see where the scar is, whereas others have a massive keloid scar,” Martin says. It’s those whose scars are barely visible that Martin is especially interested in.
So, it’s been a worldwide effort – and a slow creep towards solutions – but it seems like scarring scientists are edging ever closer to reactivating the perfect healing that we were all capable of in the womb.
“It isn’t a trivial problem,” Martin says, pointedly. “Which is why, I guess, it hasn’t been sorted quite yet.” Fixing it might affect our ability to tackle a whole range of related conditions, from liver cirrhosis (scarring of the liver) to cancer.
Perhaps not coincidentally, certain types of fibroblasts play a role in cancer – as do scarring proteins like YAP – and there are similarities between solid tumours and scar tissue.
Longaker, for his part, is well aware of the implications. For now, it’s one step at a time. “I will not stop.”
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