Ten years ago, I faced a man with one arm held above his head. He handed me a Stanley knife and asked me to make a cut in the skin under his arm which, very gingerly, and looking away, I did. I hated doing it. This was not some weird psychological experiment but one of the first demonstrations that anti-scarring treatments were possible. The man was Professor Mark Ferguson, of the School of Biological Sciences at Manchester University, and today his pristine underarm bears witness to the success of his treatments for scar-free wound healing, now completing their final clinical trials.
There aren’t many of us who don’t have a scar somewhere that makes us more self-conscious — at least when we don a bikini or swimming trunks. But aesthetics are the least of it. Scarring is a major medical problem following accidents and surgery. Scar tissue can restrict the movement of joints, prevent growth and cause great pain and psychological distress. Straps of internal scar tissue called adhesions, which typically form after surgery to the abdomen, pelvis and chest, stick organs together causing pain and even infertility, if the tugging of adhesions distorts Fallopian tubes. This week, a new study linked infertility with previous Caesarian sections — and scar tissue resulting from the surgery is one the suspected causes.
The number of hospital readmissions for adhesion-related complications rival the number of operations for heart bypass, hip replacement and appendix. And scarring after eye surgery can cause hazy vision and even blindness.
But there is one very curious thing about scarring that is now forming the basis for new products that could spell the end of unsightly and potentially dangerous scars within the next five years. Experiments have shown that in the early months of pregnancy, all baby mammals (including humans) heal perfectly. But, by adolescence, there is significant scarring, particularly when the wound is to the chest and shoulders.
Why? The answer lies in the body’s healing mechanisms. When the body is wounded, it releases a cocktail of chemicals called transforming growth factors (TGF) to promote skin growth and close the gap. Researchers have found that in embryonic wounds that heal without a scar, one of these chemicals, TGF-Beta 3, is found in high amounts, but two others, TGF-Beta 1 and 2, are found only in very small levels. In adult wounds, however, the reverse is true.
Now both these groups of substances contribute to healing. TGF-Beta 1 and 2 encourage an emergency repair for the hole, with protein fibres being arranged in parallel lines, creating the structure typical of scar tissue. TGF-Beta 3, on the other hand, speeds up the migration of the connective cells that normally make up skin tissue to the wound. At the wound site, they randomly insert themselves amongst collagen fibres, creating a strong basket-weave structure like normal skin.
What Professor Ferguson has found, however, is that even when a wound is major and needs “emergency” healing, there’s no need for the rather crude and unsightly skin structure of scar tissue. The regeneration brought by TGF-Beta 3 works just as well.
This can be demonstrated by the fact that, even in adults, the type of healing can vary according to the wound. Adults can both regenerate and scar within the same tissue depending on the injury. For example, tattoos, multiple small pinpricks with foreign material, heal with no scar. But removal of that same tattoo causes scars. This is probably because whereas the skin pricks encourage regeneration mode, the extraction of tissue during tattoo removal prompts the body to go into “scar mode”. It proves that adults are as capable of scar-free regenerative healing as babies in the womb.
So Professor Ferguson has found a way to use this knowledge. The basis of anti-scarring treatments is to apply substances which either increase TGF-Beta 3 or neutralise TGF-Beta 1 and 2. And after years investigating the mechanisms of wound healing, his biotech company Renovo has developed an anti-scarring product, Juvista, which is about to enter the final phase of clinical trials. Juvista is genetically engineered human TGF-Beta 3. Astonishingly, it should be able to prevent scarring in skin, nerves, blood vessels, ligaments and even eyes.
“We have a clear mission to be first to market with an anti-scarring drug,” says Ferguson. And what a market it is. In the US alone, there are 42 million surgical procedures each year.
Juvista is injected in a very low dose at the time of surgery into the wound margins and once again the next day. The response rate is about 70 per cent and the reduction of scarring is permanent. Even good scars that would normally result from plastic surgery are further improved, becoming difficult to detect, and poor scars that might result from major incisions and trauma are better. It’s already been used on more than 1,000 patients and has been the subject of two double-blind efficacy trials in the UK. It will file for US regulatory approval for skin use in 2008.
There are three other anti-scarring products in the pipeline. Juvidex inhibits TGF-Beta 1 and might be particularly useful in preventing or reducing adhesions following surgery. Prevascar is based on a molecule that inhibits inflammatory response and might be most effective for peripheral nerve injuries and for prevention of scarring following eye surgery.
Finally, Zesteem is a product based on oestrogen. It’s been known for many years that wounds in post-menopausal women heal more slowly. Adding oestrogen accelerates healing, but it needs to be delivered locally in a very specific way. Zesteem may be particularly useful in accelerating healing of sports injuries, hernia repair and wound healing in those who are sick. The phase two trial of this product reports next year.
Perhaps the most dazzling application of Juvista may be to prevent scarring within blood vessel walls after a coronary artery bypass, a condition called restenosis, which is a common reason for the failure of such procedures.
Why do we scar?
Scarring used to be thought of as a device that evolved to allow wounds to be closed quickly, preventing blood loss and infection.
Research by Professor Mark Ferguson, of Manchester University, indicates that skin can be healed even more quickly and strongly when the skin’s regenerative, rather than its scarring, processes are kicked into action.
Ferguson believes that scarring evolved not to heal big wounds more quickly, but to take care of smaller wounds such as bites and scrapes that were likely to be dirty and to cause life-threatening infection. For instance, the response to a thorn is to wall it off using scar tissue and then liquify tissue around it, forming pus which helps to expel the thorn.
Modern “clean” injuries inflicted by surgery, glass, or mechanical equipment are being healed by a primitive response intended for dirty wounds, says Ferguson. The result can be excessive scarring even from an ear piercing.
