About Treatment of Burns and Wound Dressing/h1>

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by Carolyn J. Strange

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Last spring, a 68-year-old Northern California man suffered deep, third-degree burns when he dropped a cigarette and his pants leg caught fire. Unfortunately, such injuries are all too common. What's unusual is that this man became the first patient treated outside clinical trials with a new artificial skin that the Food and Drug Administration had just approved for marketing the month before.

A serious burn is one of the most horrendous traumas the body can suffer. Every year, about 51,000 Americans are hospitalized for burn treatment, according to the American Burn Association, and 5,500 die. The good news is that the incidence and severity of burn injuries have declined significantly over the past 20 years. And patient survival keeps improving.

"This is a very exciting area," says Charles Durfor, Ph.D., in FDA's division of general and restorative devices. "Thirty to forty years ago, many burn patients didn't live. Advances in treatment have created a whole new patient population that not only lives, but has an improving quality of life."

The first great strides were in getting patients through the initial shock, and preventing fluid loss. Controlling infection, a serious threat to burn patients, also improved. Specialized nutritional support has helped. Another leap occurred when doctors began surgically removing, or excising, all burned tissue from the wound as soon as possible. After stabilizing the patient and cleaning out the wound, the next step is to cover it.

"The sooner you close the wound, the sooner the patient gets better," says Robert Klein, M.D., medical director of the regional burn center at Children's Hospital Medical Center of Akron, Ohio.

"The problem is, we've never had an optimal way to do it," says Jerold Kaplan, M.D., director of the burn centers at Alta Bates Hospital in Berkeley, Calif., and at Children's Hospital in nearby Oakland. The need to cover wounds as quickly as possible while minimizing scarring and additional trauma has driven development of advanced wound dressings and skin substitutes. Kaplan treated the 68-year-old California man's wounds with Integra Artificial Skin Dermal Regeneration Template, from Integra LifeSciences Corp., Plainsboro, N.J. "Integra is a significant addition to the armamentarium of the burn surgeon," Kaplan says, and other surgeons agree.

Skin Deep

Surgeons also agree that no single product or technique is right for every burn situation. And so far, there's no true replacement for healthy, intact skin, which is the body's largest organ, and one of the most complex. It's the first line of defense against infection and dehydration, but it's more than just a physical barrier. Skin also helps control temperature, through adjustments of blood flow and evaporation of sweat. It's an important sensory organ, too.

Skin thickness varies with age and body location, but averages only 1 to 2 millimeters (0.04 to 0.08 inches) thick. Thick or thin, it has two layers. The thin outer epidermis is nourished from the thicker, more sensitive dermis below. The outermost surface is a tough, protective coating of dead, flat cells resembling paving stones. As these cells wear away, they're replaced from beneath. The innermost part of the epidermis consists of rapidly dividing cells, called keratinocytes, which produce keratin, a tough protein. Epidermis also contains a unique fatty substance that makes skin waterproof.

The skin's blood vessels, lymph vessels, and nerves are in the dermis. Hair follicles, sweat glands, and oil glands also reside deep in this layer, which is mainly connective tissue. A network of collagen, the most common protein in the body, gives flexibility and structural support to the skin. Fibroblasts are the dominant cell type. Dermis plays a role in preventing wound contraction and scarring.

Treatment of burns depends on how deep and extensive they are, and the overall health of the patient. First-degree burns (such as sunburns) affect only the epidermis; they may peel but generally heal quickly. Second-degree burns damage the skin more deeply, causing blisters but sparing some of the dermal layer. Unless they're extensive, these burns usually heal without serious scarring. Third-degree burns destroy the full skin thickness, sometimes exposing muscle or bone, and require specialized treatment and skin grafts to obtain complete wound healing and reduce scarring. Left alone, the body tries to close wounds quickly by contraction, which results in serious scarring that is not only disfiguring, but can also be disabling.

Currently, the best wound covering most often is the patient's own skin. Healthy skin from another body site can be transplanted, which is called an autograft (autos means self). Sometimes little slits are cut so the resulting meshed graft can be stretched to cover more area. A split-thickness graft takes only the upper skin layer, and the donor site usually heals within several days. The thinner the graft, the faster the donor site heals. Surgeons may even take additional thin grafts from healed sites. Full-thickness grafts usually give a better-looking final result, but sometimes they don't adhere and survive. Donor sites are limited and autografting isn't always possible.

"People with great big burns don't have enough of their own skin, so you have to have some other way of covering them," says David M. Heimbach, M.D., director of the University of Washington Burn Center at Harborview, Seattle. Some patients can't withstand the additional trauma of a donor site wound. Older patients heal slowly and have thinner skin to begin with. And grafting creates another scar.

Doctors often use temporary coverings while patients get stronger, or while donor sites heal for additional harvesting. Two traditional possibilities are an allograft (allos means other) of human skin, usually cadaver skin, or a xenograft (xenos means stranger, in this case from another species) of pig skin. Cadaver skin is preferable, but as with other donated organs, sometimes it's in short supply and transmission of infectious agents is a concern. Human skin is regulated under FDA's Human Tissue Program, which requires donor screening for HIV (the AIDS virus) and hepatitis. In any case, the immune system rejects allo- and xenografts in a matter of days or weeks, and they must be removed and replaced. To avoid such problems, researchers and manufacturers are developing better wound dressings.

Advanced Dressings

FDA recognizes two broad categories of wound dressings--interactive and noninteractive. A variety of noninteractive dressings are available for covering first- and second-degree burns and other wounds. An interactive dressing is intended to actively promote wound healing by interacting directly with body tissues. Manufacturers must submit safety and effectiveness data to FDA in a premarket approval application. FDA has approved two interactive wound dressings for use on third-degree burns: Integra Artificial Skin and Original BioBrane (Blue Label), marketed by Dow B. Hickam, Inc., New York.

BioBrane is a knitted nylon fabric bonded to an ultra-thin silicone rubber membrane coated with a protein (gelatin) derived from pig tissue. Clotting factors in the wound interact with the gelatin in the dressing, causing it to adhere to the wound within a day or so. The dressing remains in place until autografting becomes possible.

Integra is a two-layer membrane--a dermal layer that's a porous lattice of cross-linked collagen fibers, and a synthetic epidermal layer. The dermal layer acts as a biodegradable template that helps organize dermal tissue regeneration. Fibroblasts and other cells migrate into the lattice from surrounding healthy tissue, as do blood and lymph vessels. The fibroblasts degrade the temporary scaffold and recreate their own collagen matrix.

"The dermal part of the product is a permanent cover which the body converts into something which looks more like dermis than it looks like scar tissue," Heimbach says.

The outer synthetic layer provides the barrier functions of epidermis for two to three weeks; then the surgeon replaces it with a very thin autograft. "The ability to have the donor site be very thin and heal in just a few days is the big benefit," says Kaplan. "You're actually adding a procedure, but the end result is positive."

"It's a neat concept and it appears to work," says Heimbach, who has used Integra on more than 100 patients during clinical trials. He says the final results look much better than the alternative, meshed autografts. "We're excited about the new composite skin substitutes," he says.

Cultured Skin

Doctors prefer a thin graft to a thick one, but eliminating the donor site wound and scar altogether would be even better. That's done by growing the patient's skin in the lab, under special tissue culture conditions. Lab-grown skin products also have other potential uses for wounds other than burns, and for laboratory testing. (See accompanying articles.) From a postage stamp-sized piece of skin, technicians can grow enough skin in about three weeks to nearly cover the body. Some medical centers are equipped for this sort of cell culture, and Genzyme Tissue Repair, Cambridge, Mass., does it as a commercial service. Cultured skin has been available for treating burns for about a decade, and in certain circumstances it can work well.

"The problem here is you're putting on epidermis and not dermis," Kaplan says.

"Without both parts, you don't really have skin," Heimbach says. "You're grafting on scar tissue and that's not a satisfactory skin covering."

Less than 10 cells thick, it's also tricky to handle. "It's like gossamer," Kaplan says. And something has to cover the wound in the meantime. That's where Kaplan and others see a potentially useful combination. The patient's epidermis could be cultured during the two to three weeks while Integra's dermal layer becomes a suitable bed for grafting. "They're complementary," says Kaplan.

"You'd have the best of both worlds. You don't have any donor sites, and you have a good, durable, cosmetically acceptable cover," says Heimbach.

"Another approach we're actively working on is the one-step procedure," says Frederick Cahn, Ph.D., senior vice president, technology, Integra LifeSciences. The patient's own epidermal cells are isolated, as they would be for culturing, then seeded onto the dermal layer of Integra before it is applied to the wound. Both skin layers regenerate in place simultaneously, and only one surgical procedure is required. This procedure has worked well in animals, but hasn't been tried in humans yet.

Although physicians welcome new ways to help their patients, they're leery of "scar in a jar" products that might solve some problems while creating others. Last year, FDA held hearings on using the patient's own cells for structural repair in therapy, and heard a strong call for measures of efficacy. Based on the testimony presented, FDA has decided to regulate such therapy and is developing guidance documents to assist manufacturers in completing the premarket review process.

"FDA recognizes that the area of tissue substitutes is a rapidly evolving area--and that medical and biochemical practice are also growing rapidly--and it's working aggressively to make sure it doesn't stifle development while continuing to ensure patient safety," says FDA's Durfor.

Investigators have developed other variations on cultured skin in the hope of providing off-the-shelf, living, temporary or permanent dressings. Clinical trials are under way testing them on burns and other wounds. For example, Advanced Tissue Sciences, La Jolla, Calif., developed its Dermagraft-TC skin replacement to be used as an alternative to cadaver skin for burns.

Treatment for burns keeps improving, but burn surgeons still have another important concern. "I think 95 percent of the burns we see are completely preventable," says Heimbach. He credits smoke detectors for a huge drop in the number of burns and deaths from house fires, but he hasn't seen much change in the number of accidents caused by carelessness or ignorance.

"The answer to the burn problem is prevention. Once it happens, it's too late," Klein says. "Be careful so you never need us."

Carolyn J. Strange is a science and medical writer living in Northern California.

Hope for Wounds That Won't Go Away

It may be hard for a healthy person to imagine having a wound that just won't heal, but that problem plagues millions of Americans. Nonhealing wounds not only take an emotional toll, but also leave patients, their families, and society with a serious economic burden, ranging into billions of dollars.

The incidence of chronic wounds is far greater than burns and is expected to continue to increase as the population ages. Some of the treatment concerns are similar because the barrier function of skin is lost, putting the patient at risk for infection, and chronic wounds can be life threatening.

There are three general types of chronic wounds: pressure ulcers (bedsores or decubitus ulcers), venous ulcers, and diabetic ulcers. They have different causes, but the result is the same--localized tissue death. The factors that cause an ulcer to develop in the first place also interfere with healing. The cost per healed ulcer--when they heal at all--can climb into the tens of thousands of dollars, and as many as half recur within a year. Roughly three-quarters of a million American diabetics suffer with foot ulcers, which are responsible for more than 50,000 amputations a year.

Recent research efforts in pursuit of various growth factors to promote wound healing have been disappointing. Figuring out which growth factors to put in a wound--and when and at what dose--is a daunting, perhaps impossible, task. Some investigators have turned to cultured skin, arguing that applying cultured skin to wounds makes more sense than using growth factors because living cells already know how to produce growth factors at the right time and in the right amount.

Organogenesis Inc., of Canton, Mass., has developed Apligraf (formerly Graftskin), a two-layer living skin substitute derived from infant foreskins. The upper layer contains keratinocytes, the dominant cell type in the epidermis. The lower layer contains collagen and fibroblasts, the main constituents of dermis. Other cell types that trigger immunological response are absent, and, as a result, this engineered tissue is not rejected. Human trials of Apligraf for treating burns, diabetic ulcers, and for use in other skin surgeries are under way.

Cultured skin offers new hope for chronic wounds, but, as with burns, prevention is the best bet.


Skin Under Glass

In addition to its potential as an advanced wound dressing, cultured skin may also prove useful in laboratory testing. Many cosmetic, household product, pharmaceutical, and petrochemical companies are experimenting with cultured skin in the hope that in vitro (in glass, meaning in lab vessels) assays can replace or reduce animal testing for evaluating raw materials and final product formulations. FDA has long supported development of such methods, but the state of the science hasn't progressed yet to where it can fully replace animal testing, according to FDA's John Bailey, who heads the Office of Cosmetics and Colors in the agency's Center for Food Safety and Applied Nutrition.

Scientists can use isolated skin tissue to test skin penetration, irritation, toxicity, and other effects of various substances. Although cadaver skin works for some purposes, its uses are limited because the cells are dead. Cultured skin contains live, metabolizing cells that can better mimic how skin responds to various stimuli.

One example is the EpiDerm System, a model of human epidermis marketed by MatTek Corp., Ashland, Mass. Human-derived epidermal cells are grown under culture conditions that encourage formation of the characteristic cell subtypes and layers of epidermis. Another example is Skin2 , developed by Advanced Tissue Sciences, Inc., La Jolla, Calif. Some versions of Skin2 contain dermis as well as epidermis. These products are intended to be used for testing, not as dressings.

Lab-grown skin is used in two general ways. As a membrane to measure skin absorption, it doesn't work very well because it's much more permeable than skin, according to Robert L. Bronaugh, Ph.D., chief of the skin absorption and metabolism section in FDA's Office of Cosmetics and Colors. "A lot more work needs to be done before it can be used to simulate accurately the barrier properties of human skin," he says.

However, as an alternate test to measure irritation, cultured skin looks encouraging, according to Bronaugh. The U.S. Department of Transportation has approved the use of a Skin2 in vitro test kit as an alternative to animal testing of potentially corrosive materials. Although FDA wouldn't accept final safety data acquired from these in vitro assays, companies can use cultured skin in early screenings, and that saves animals, as well as money.


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