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Scar wars

After injury, sometimes the worst enemy is 'exaggerated healing'

By Scott LaFee
UNION-TRIBUNE STAFF WRITER

July 16, 2003


MacroPore
SurgiWrap, a bioabsorbable film developed by San Diego-based MacroPore Biosurgery Inc., helps reduce internal scarring by creating a temporary physical barrier between tissues.
Wound healing is an obvious and fundamental need. Organisms that repair injuries quickly and effectively survive; those that don't, don't.

But the degree to which life displays this talent is wide and diverse. Some worms, for example, can rebuild whole portions of their bodies. Newts are able to regenerate entire limbs.

Humans and other mammals lack these superlative restorative skills. When we suffer significant injury, healing almost invariably results in scarring – nature's version of a spot weld.

In most cultures most of the time, scars are not desirable. Aesthetics aside, there are sound health reasons for wanting to avoid being scarred. Scar tissue is never as good as the original. It tends to be coarser, weaker and less elastic. It can be disfiguring, disabling or, occasionally, deadly.

Scarring is mending run amok, the result of "an exaggerated healing process," said Dr. Warren Garner, an associate professor of surgery at USC and director of the Burn Service at the Los Angeles County-USC Medical Center.

Doctors and medical researchers would like to sever that connection, to make healing scar-free, or as much as possible. The challenge is daunting, but the research is promising. It ranges from genetic manipulation to block cellular signals to form scars; to deciphering a healing secret unique to the unborn; to a growing arsenal of therapeutic treatments that includes wrapping internal organs in bioabsorbable film, enveloping damaged skin in sheets of silicon gel and using radiation and cryosurgery.

The healing process "Our understanding of the wound repair has made dramatic progress over the last 20 years," said Dr. Richard Gallo, an associate professor of medicine at UCSD and chief of dermatology for the Veterans Affairs San Diego Healthcare System.

"After a wound to the skin, the blood must clot, the immune system must start fighting against infection, then the wound must close. Clotting is well understood. The immune defense system is now partially understood. But the last step of repair is still a relatively underdeveloped science. A big mystery is what activates cells to start to heal, organize themselves into a new structure, then stop the repair process."

Even stripped down to its simplest description, the biological repair process is enormously complicated, involving a cascade of overlapping phases and multiple cellular players.

Numerous factors can disrupt or alter the normal healing process – and result in a more serious or problematic scar. At the site of the injury, for example, there must be space for new cells to grow, and effective communication between them. The injury must be well-supplied with blood carrying oxygen, nutrients and hormones. It must be free of infection.

There can be complications due to age, general health, how quickly the injury received treatment, degree of initial infection and genetic predisposition to scarring.

"Our knowledge of wound repair and scarring is a bit like that of most people and cars. We know that if you put your foot down on the accelerator, the car moves," said Garner at USC. "Most of us don't have any real knowledge of how the engine works."

Except for teeth, every living tissue in the human body can heal, but not all heal exactly the same way. "The general process is pretty much the same, but there are different factors involved with different tissues," said Dr. Marc Hedrick, medical director of MacroPore Biosurgery, a San Diego-based company that produces bioresorbable implants and conducts regenerative therapy research.

The liver, for example, is capable of completely rebuilding damaged tissue with no scarring. Kidneys and lungs possess lesser regenerative abilities and are thus more susceptible to damage that results in scarring. Injured heart tissue almost invariably scars, which may be life-threatening.

Born without scars
Gene therapy may ultimately provide a preventive solution to scarring.

"In my opinion," said Gallo at UCSD, "this is the only real way to make progress in treating scars. Once we better understand the genetics behind all the steps of wound repair, we can design a rational genetic approach. The goal is to make repair more like regeneration, and to do this without the risk of uncontrolled cell proliferation."

Some researchers are already pursuing this option. Two years ago, Dr. Mario Chojkier, a professor of medicine at UCSD, and colleagues at the Salk Institute, Veterans Administration San Diego Healthcare system and elsewhere, reported that they had successfully prevented excessive liver scarring in mice by tinkering with a protein involved in the process. They are now preparing for human clinical studies, with several biotechnology companies interested, Chojkier said.

Others are taking different approaches, including one that hopes to revive a remarkable healing ability that all humans possess – for a time.

In the 1980s, doctors discovered that unborn humans in the first 20 to 24 weeks of development do not scar.

"We could conduct in utero surgery where we take the fetus out of the womb, open its chest to correct a lung problem, then put it back into the womb and there would be no chest scar," said Hedrick, who specialized in surgery and pediatrics at UC San Francisco.

As yet, no one can fully explain why this happens in unborn children, but not in adults. There are many confounding variables.

Specifically, embryonic wounds appear to heal without an inflammatory phase, and the mechanism of cellular regrowth is different. Rather than closing cell by cell, fetal wounds close as a sheet of epithelial cells move forward in unison, pulled inward like a purse string.

In addition, the womb is a sterile place, though Hedrick notes that sterile wounds in adults still scar. In the womb, fetuses are bathed in high levels of hyaluronic acid, which helps collagen form in an organized way. Yet experiments applying hyaluronic acid to adult wounds have shown no significant ameliorative effect.

Researchers have noted that fetal wounds contain greater and lesser amounts of different forms of Transforming Growth Factor-beta (TGF-b), a family of proteins linked to scar formation. And at least one drug designed to inhibit TGF-b in patients suffering from fibrosis – scarring of the heart, lungs, kidneys or limbs – has begun clinical trials.

Chojkier says research into replicating fetal healing ability offers great allure and promise, but it is not without dangers or controversy.

"Certainly, the risks of having a great regenerative capability could have consequences for uncontrolled cell proliferation resulting in cancer growth," he said. In addition, such research involves using embryonic stem cells, which remain a subject of heated political and scientific debate.

In the meantime, researchers have made notable progress in treating – and sometimes preventing – scarring through physical means. For example, MacroPore began marketing last year a thin, clear film designed to reduce postoperative internal scarring in surgery patients.

SurgiWrap looks like ordinary plastic food wrap, except that it is made from polymerized lactic acid and is bioabsorbable. Its purpose is to keep separate healing tissues after surgery.

For example, after open-heart surgery, scar tissue will often form between the heart and the internal chest wall, connecting the two and reducing the heart's ability to beat freely and fully. By wrapping the heart in SurgiWrap, said Hedrick, doctors can block the binding effect.

"It doesn't affect the scarring process directly," said Hedrick, "but rather, it tricks it. The wrap acts like a force field between organs. Scarring goes sideways instead of connecting, and over three to six months, longer than the scarring maturation phase, the wrap is metabolized by the body into water and carbon dioxide."

More established treatments for existing scars are improving, too.

"Basically, a scar is the failure of a tissue, any tissue, to reorganize its cells in the same pattern as before injury," said Gallo at UCSD. "The physical approaches are all essentially giving the skin another chance to heal in a more cosmetically appropriate way." Surgery – Almost 5 percent of reconstructive surgeries in the United States are procedures to redress existing scars. Surgery, including those using lasers, is only modestly effective. Surgery usually replaces a targeted scar with a new scar, albeit one that may be less visible or troublesome.

Radiation – Exposure to X-rays is usually a culprit in scarring, a cause of fibrosis in internal tissues. But some research suggests that low-dose, superficial radiation can reduce the recurrence rate of some scar types after surgery. Radiation of scars is controversial, however, due to concerns about possible long-term side effects.

Cryotherapy – There has been some success using liquid nitrogen, with a temperature of minus 321 degrees. The nitrogen freezes the scar, causing a blister that in theory heals better, producing a smaller subsequent scar.

Steroids – Steroid injections can soften and flatten scars. The steroid is injected into the scar itself to reduce possible side effects caused by the drug being absorbed into the blood stream. These are only given under medical supervision.

Collagen – Collagen is injected beneath sunken scars to build up the level of skin tissue. The effect, however, is temporary because the collagen is eventually metabolized by the body, thus requiring repeated, regular injections.

Pressure garments – These are only worn under medical supervision, usually in cases where new scarring (as in a burn) covers a large area of skin. The garments are custom-made from a tight, elastic material and work best when worn 24 hours a day for six to 12 months. How exactly they work is not understood, though the continuous pressure on surface blood vessels likely plays a part. Over time, scars beneath pressure garments soften, flatten and become paler.

Silicone gel sheets – First developed in the 1980s and now available for self-treatment, silicone gel sheets look like transparent gelatin. They are soft, waterproof and flexible. Applied to skin, they work by flattening, softening and fading dark, raised scars.

Of course, not everyone wants to hide or remove their scars.

"Children wear them like medals," said the poet Leonard Cohen. "Lovers use them as secrets to reveal. A scar is what happens when the word is made flesh."

More fundamentally, a scar is proof, whether we like it or not, of being alive.

 

 

 

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posted by Beauxbeaux's Daddy at 5:19 PM