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TWENTY-FIVE years ago, a boy 鈥� we鈥檒l call him Jason 鈥� had major surgery that probably saved his life. His bladder had become blocked, meaning he faced kidney failure and probable death. To save him, surgeons opened up his lower abdomen and made a hole in his bladder to let the urine out. It would have been a routine operation, if Jason had already been born.

The surgery was performed as the 18-week-old fetus lay in his mother鈥檚 womb. What surprised the surgeons, though, was that Jason was born with barely a mark on him. 鈥淲e were astounded at how little scarring we got,鈥� says Michael Harrison of the University of California, San Francisco, who pioneered fetal surgery in the 1980s. As similar cases followed, it became apparent that human embryos can heal with little or no scarring up to the end of the second trimester.

The findings backed up anecdotal reports that wounds in the fetuses of many animals, from alligators to sheep, heal scar-free. 鈥淭he fetus seems to know how to regenerate rather than scar,鈥� Harrison says. 鈥淲e just need to figure out its secret.鈥�

The effort to uncover this secret is about far more than preventing unsightly scars, as vital as this is for some. Scars can impair everything from the movement of our limbs, to the working of our liver, to the beating of our heart. While we do not fully understand why some wounds can heal without scars, we do have some important clues 鈥� and a whole range of treatments designed to boost healing are now being tested on people.

So why do embryos and fetuses heal without scarring? Part of the reason is that the machinery needed to rebuild tissue is already active as part of the normal development process, says developmental biologist Paul Martin at the University of Bristol in the UK, who studies embryonic wound healing. 鈥淵ou can learn a lot about how to rebuild tissues from observing how they build themselves in the first place,鈥� he says.

Wound an embryonic fruit fly and it builds a network of protein cables in cells at the wound鈥檚 edge, which contract like a purse string, pulling them together. Cells at the leading edge then interlink like a zipper, closing the wound. It鈥檚 the same process that occurs normally as we develop, such as when the developing nervous system fuses into a tube shape.

In early embryos, there is also very little swelling and immune response to a wound. In adults, by contrast, the body mounts an inflammatory response. As blood clots form, they release chemicals that make immune cells rush to the scene. It is the start of a cascade of events, as the immune cells release more inflammatory signals and growth factors that summon other cells to the scene.

In the next step of adult wound healing, cells called fibroblasts enter the wound and secrete a supportive matrix of strengthening collagen fibres, while cells on the outside of the skin form a protective barrier. The wounded tissue is not rebuilt exactly as it was, however. In normal skin, the collagen fibres are laid down in a criss-cross pattern, making the skin soft and pliable. In scar tissue, the collagen is arranged in parallel bundles, making the new tissue less flexible.

It appears that inflammation, while needed to keep infection at bay and close wounds quickly, actually hinders healing. Martin has shown that in mice engineered to lack an inflammatory response, newborn pups heal faster and without scars.

Of course, just because we can heal without scarring in the womb, it does not necessarily mean that adults can ever expect to heal as effectively. That is why there is so much interest in a strain of mice called Murphy Roths Large (MRL), which were first studied because they get a kind of autoimmune disease. Then in the 1990s an experiment by biologist Ellen Heber-Katz at the Wistar Institute in Philadelphia, Pennsylvania, was ruined when the identification holes in the ears of her mice disappeared after three weeks. Not only had the skin regrown without any scars, but it also grew back with features that scar tissue lacks, such as hair follicles.

Regenerating hearts

鈥淚 realised that we just had to start studying these animals,鈥� Heber-Katz says. Later studies have revealed that the MRL mouse is pretty talented. Although some parts of its body do scar, such as brain tissue and the skin on its flanks, it can partially regrow amputated digits, regenerate its own liver up to four times faster than normal mice and regrow nerve cells after spinal cord injury. It was the animals鈥� ability to regenerate heart muscle, however, that really set tongues wagging.

In 2001, Heber-Katz reported that after having one of their heart chambers frozen, MRL mice take just two months to regrow near-normal heart muscle. A flurry of papers contested her claims, but earlier this year she was vindicated when a group led by Daniel Garry at the University of Texas found that while the hearts of MRL mice do not completely regenerate, they heal far better than other strains. 鈥淪ometimes people find it hard to accept new ideas,鈥� says Heber-Katz.

Despite the intense interest in the MRL mice, it is still not clear why they heal so well. Heber-Katz suspects that the mice may have unusually high levels of protease enzymes, which can break down collagen and other proteins that form the supporting matrix in the wound. She thinks the proteases help break down the disorganised collagen fibres that go to make up scars.

While some researchers try to tease out the genetic differences between MRL and normal mice, others are developing treatments based on studies of embryonic healing. Mark Ferguson of the University of Manchester in the UK became interested in the field two decades ago, when he tried to study cleft palate in embryonic alligators. His studies failed miserably because his surgical incisions healed perfectly, so Ferguson turned his attention to the differences between embryonic and adult mammalian healing. His work highlighted one particular family of growth factors called transforming growth factor beta proteins. Released by immune cells, TGF脗s initiate wound inflammation and are also involved in the formation of new skin. Embryonic wounds that heal without scarring have low levels of TGF脗1 and TGF脗2, but high levels of TGF脗3.

Ferguson found that lowering levels of TGF脗1 and TGF脗2, or boosting levels of TGF脗3, in the wounds of adult animals reduced or abolished scars. In 2000, he co-founded biotech company ReNovo, which specialises in scar prevention and reduction.

ReNovo now has a handful of products in the pipeline. Its most advanced is a form of TGF脗3 called Juvista, which has been tested on wounds in more than 1500 people, including Ferguson himself. 鈥淚 wouldn鈥檛 ask someone to volunteer for something that I wouldn鈥檛 take myself,鈥� he says.

Juvista is injected into a wound around the time of injury and makes wounds that would normally heal with little scarring, such as the neat incisions on Ferguson鈥檚 arms, even harder to see. 鈥淚t鈥檚 probably the first kind of preventive therapy that there is for scarring,鈥� he says. What is not yet clear is what difference it will make to wounds that usually scar badly. Ferguson thinks it will also help with burns and skin grafts, but no trials have yet been carried out.

The apparent success of Juvista is surprising because almost all previous attempts to boost healing by injecting or applying growth factors, including TGF脗3, have come to nothing. 鈥淣early every growth factor studied in rodents worked miraculously,鈥� says dermatologist David Margolis from the University of Pennsylvania in Philadelphia. 鈥淏ut in human trials, they failed spectacularly.鈥�

These earlier attempts, however, involved treating chronic wounds that refuse to heal, which are usually a result of some underlying disease such as diabetes or damaged veins. There is a big difference between trying to kick-start the healing process in the first place and reducing scarring, Ferguson points out.

The failure of these attempts, though, has spurred researchers to develop a slew of more innovative approaches. In some wounds, the added growth factors are probably being washed away by the wound fluid or being broken down by enzymes, says Jeffrey Hubbell of Kuros, a biomedical company based in Zurich, Switzerland. His solution is to anchor growth factors directly to a protein matrix in wounds, which probably mimics what happens in the natural healing process.

Hubbell鈥檚 team has made a matrix-binding form of platelet-derived growth factor. The PDGF and a matrix protein, fibrin, are kept in separate barrels in a single syringe. When the plunger is depressed, the two components mix as they drip onto the wound, where the fibrin starts to form a protective matrix within seconds. The idea is that PDGF will summon healing cells to the wound and boost their activity.

Trials of the PDGF-fibrin 鈥済el鈥� are already under way for treating diabetic ulcers, and in August Kuros began a trial of the gel as a kind of glue for holding skin grafts in place, replacing the metal staples normally used in burns patients. The hope is that the approach will speed healing and reduce scarring.

Another way to deliver growth factors is by gene therapy. Margolis鈥檚 team is using adenoviruses to get the gene for PDGF into cells in wounds. The gene is not integrated into the cells鈥� genome, so the cells should produce PDGF only for a week or so before the added DNA breaks down. The therapy has been tested on 12 patients with chronic foot ulcers. 鈥淪o far, it looks like it鈥檚 working,鈥� says Margolis. 鈥淭he whole wound looks like it is changing.鈥�

However, safety concerns after the death of Jesse Gelsinger in 1999, who had been given an adenovirus-based gene therapy, delayed Margolis鈥檚 trials for five years. Other teams are trying to avoid this hurdle. Hubbell has designed a gene-delivery system in which the DNA is wrapped in short pieces of protein rather than being carried by a virus. His team has used this approach to deliver the gene for vascular endothelial growth factor (VEGF) to wounds in mice. The treatment boosts the development of blood vessels, a key part of healing (Proceedings of the National Academy of Sciences, ).

The latest approach to boosting healing does not involve growth factors at all. The tests of Margolis鈥檚 gene therapy revealed something intriguing: the positive effects of PDGF gene therapy appear to go on for weeks after cells must have stopped making extra PDGF, suggesting that something else may be at work. Margolis suspects that PDGF summons some sort of skin stem cell to the wound, which then boosts the healing process.

And he鈥檚 not alone. An increasing number of researchers think that stem cells 鈥� primitive cells that can give rise to a range of other cell types 鈥� could help wounds heal. In a study published in May, Vincent Falanga, a dermatologist at Boston University School of Medicine in Massachusetts, showed that bone marrow stem cells can help chronic wounds heal more quickly 鈥� and with less scarring (Tissue Engineering, ).

His approach resembles Hubbell鈥檚: stem cells from each of the patients were mixed with the soluble form of the protein fibrinogen and placed in one compartment of a two-barrel syringe. In the other barrel was a coagulation protein called thrombin. When the mixture was dripped into a chronic wound, it reacted quickly to form fibrin, giving the stem cells a matrix to bed into and get to work.

How long the stem cells last and exactly how they improve the wound has yet to be determined. Nor is it clear if stem cells can improve the healing of normal wounds rather than just chronic wounds. Even if they can, there are obvious problems: the time needed to prepare a patient鈥檚 own stem cells means this approach might only be suitable for treating the wounds left by scheduled surgery, unless an off-the-shelf solution can be developed. Nevertheless, Hubbell鈥檚 study is one of an increasing number to highlight the potential of stem cells in wound healing.

So given the vast array of approaches in development, how close are we to cracking the problem? Some researchers, like Ferguson, hope we can find a single 鈥渕aster switch鈥� that will make wounds heal as beautifully as they do in embryos. Others are less optimistic. 鈥淭here鈥檚 unlikely to be one factor that will solve everything,鈥� says wound-healing expert Jeffrey Davidson of Vanderbilt University School of Medicine in Nashville, Tennessee.

Getting wounds to regenerate as new may require a combined approach 鈥� a mix of growth factors, or growth factor-secreting stem cells embedded in an artificial matrix, along with better systems for mechanically supporting wounds (see 鈥淔eel the force鈥�). That is not going to be cheap. Work by Davidson and others suggests that combinations of growth factors are more effective 鈥� but combining two growth factors doubles the research costs. 鈥淲e need to find that critical cocktail,鈥� Davidson says, 鈥渂ut no one seems to have pockets deep enough to move the field to the next level.鈥�

Nevertheless, if full regeneration is still some way off, treatments that accelerate healing and reduce scarring could be coming to a hospital near you fairly soon. 鈥淲e now understand a whole lot more about wound healing, and it has transformed the field,鈥� says Ferguson.