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U.S. Food and
Drug Administration
FDA Consumer magazine
May-June 2002
Table of Contents
by Linda Bren
When Darren Benton leaned over to light a homemade firecracker a few days before the Fourth of July in 2000, all he was expecting was a sizzle and a loud noise. But what he got was a flash fire that burned 90 percent of his face.
"I didn't feel anything at first," says Darren. But after looking at himself in the mirror, he got very scared. The 13-year-old's face was completely black, and his right hand and knee also were burned.
Darren's parents rushed him to the hospital. Two days later, after the swelling from his burns went down, surgeons at Children's Hospital in Washington, D.C., anesthetized Darren, scrubbed the dead skin off, and gently applied a wound dressing made of human cells and synthetic material.
For several days afterward, Darren stared out of two small eye slits cut in the bandages that swathed his face to hold the wound dressing in place. He sipped liquid food through a straw poked into another small slit in the bandages.
The surgeons couldn't predict whether his face would be scarred or discolored, says Darren's mother, Patricia Benton. "Children's Hospital hadn't been using [the wound dressing] very long, and they had never used it on a child's face, but they were very positive."
Darren left the hospital after a week, and six months later, he had "completely healed," says Bruce Benton, Darren's father. Except for the loss of a few freckles on the redheaded boy's face and a slightly paler color, "it was as if nothing had happened," he says. "It was a miracle," adds Darren's mother.
The skin covering used on Darren, called TransCyte, is one of several cellular wound dressings approved by the Food and Drug Administration. These products are helping to transform the treatment of burns and chronic wounds by decreasing the risk of infection, protecting against fluid loss, requiring fewer skin grafts, and promoting and speeding the healing process.
Each year, about 45,000 Americans are hospitalized for burn treatments and 4,500 deaths occur from fire and burns, according to the American Burn Association (ABA). Twenty years ago, burns covering half the body were routinely fatal, but today, even people with extensive and severe burns have a good chance of survival, says the ABA. Essential to survival is the process of quickly removing dead tissue and immediately covering the wound.
Surgeons discovered many years ago that dead tissue was a breeding ground for bacterial infections, says Charles Durfor, Ph.D., a chemist in the FDA's Plastic and Reconstructive Surgery Devices Branch. "So there was a tremendous advance in surgical care of burns when they started cutting off that dead tissue. All of a sudden the survivability rate went way up."
But once the dead skin has been removed, the blood and fluids that the skin holds within the body start evaporating and weeping, says Phillip Noguchi, M.D., director of the FDA's Division of Cellular and Gene Therapies. "People literally can dehydrate and die from exposure."
This is where the cellular wound dressings come in. "They provide a cover that keeps fluids from evaporating and prevents blood from oozing out," says Noguchi. "And some of these products grow in place and expand much like your own skin would do when you heal."
As the largest organ of the body, skin protects our internal organs and tissues from toxins, disease-carrying bacteria and viruses, bumps and bruises, and extreme heat and cold. Skin has a sensory function, too. Nerve endings near the surface give us a sense of touch and the ability to feel sensations such as hot and cold.
Two layers make up the skin: the epidermis, which is the thin top layer of tissue, and the dermis, which is the thicker bottom layer. The outermost surface of the epidermis is a tough, protective coating of dead cells called keratinocytes. Underneath these dead cells are live keratinocytes, which divide and replenish the outer layer as the dead cells fall off. Also found within the epidermis are cells that give skin its color (melanocytes) and cells that help protect the body against infection (Langerhans' cells).
The dermis, the lower layer of skin, consists of cells called fibroblasts. These fibroblasts produce collagen, the most common protein in the body, which gives structure and flexibility to the skin. The dermis also contains blood vessels, nerves, hair follicles, and oil and sweat glands.
Cellular wound dressings are sometimes called "artificial skin" or "skin substitutes," but FDA scientists prefer to avoid these labels. "Although they may look and feel like skin, these products do not function totally like skin," says Durfor. "Unlike real skin, they are missing hair follicles, sweat glands, melanocytes and Langerhans' cells."
In some respects, cellular wound dressings try to simulate the two layers of real skin. Some have a synthetic top layer structured like an epidermis. Over time, it peels away or is replaced with healthy skin through skin grafting. The bottom layer usually consists of a scaffold, or matrix, which supports cells that help promote the growth of new skin. Blood vessels, fibroblasts, and nerve fibers from healthy tissue surrounding a burn or wound cross into the matrix to mix with the wound dressing's cells. The matrix eventually disappears as a new dermis forms.
"No one has a full understanding of how these products work," says Durfor. "How they are involved in wound repair is a subject of great scientific interest."
"We do know that they promote a higher rate of healing," says Stephen Rhodes, head of the FDA's Plastic and Reconstructive Surgery Devices Branch. "More patients heal with these devices than with the standard of care, which includes compression bandages and gauze."
How a burn is treated and the type of cellular wound dressing used depends on the depth and extent of the burn and the overall health of the person burned.
Traditionally classified as first-, second-, or third-degree, burns are frequently classified by health professionals as superficial, partial thickness, or full thickness, depending on their depth and the amount of tissue damage. Superficial burns, such as a sunburn, redden the skin and damage only the epidermis, making it possible for the body to repair itself. Healthy cells from the dermis reproduce and migrate to the epidermis to heal the damaged skin.
Partial thickness burns cause blisters and damage all of the epidermis and part of the underlying dermis. Although these burns usually heal on their own when treated with cleaning and bandaging, if they are extensive or in a sensitive area, such as the face, they may benefit from the use of cellular wound dressings.
Full-thickness burns completely damage both the epidermis and the dermis, and may even destroy the underlying flesh and bones. The body is unable to heal itself properly because there are no healthy cells to regenerate. These burns require surgery to replace damaged skin with healthy skin, a process known as grafting. If these wounds are not treated, the body attempts to close them by forming scar tissue that contracts over time, leading to disfigurement and loss of motion in nearby joints.
In grafting of burn wounds, surgeons use healthy skin from another part of the person's own body (autografting) as a permanent treatment. But when the skin damage is so extensive that there is not enough healthy skin available to graft initially, surgeons may use cellular wound dressings. These temporary coverings help prevent infection and fluid loss until autografting can be performed. "And these products may allow surgeons to take thinner grafts because not as much dermis in the autograft is required," says Durfor.
An alternative to autografting is to use skin from another person (allograft) or from another species (xenograft) as a temporary covering to protect the wound.
Allografting uses skin from cadaver donors, and xenografting uses skin from animals. "Allografts provide the natural protection of human skin and are used most commonly. Xenografts of pigskin are sometimes used if allografts are not available," says Steven Boyce, Ph.D., director of the department of tissue engineering at Shriners Burns Hospital in Cincinnati. "Xenografts of pigskin are in plentiful supply and it's the closest anatomically to human skin."
Allografts and xenografts are temporary measures because, within several weeks, both types will be rejected and must be replaced with an autograft. "The immune system recognizes that the foreign cells do not belong to the patient," says Boyce. "Immune cells, called T-cells, will attack and destroy foreign cells in the grafts."
Grafts may not be necessary for partial-thickness burns, such as those suffered by Darren Benton; cellular wound dressings are more commonly used. "Almost 80 percent of burns in children are partial thickness," says Martin Eichelberger, M.D., director of emergency trauma and burn services at Children's Hospital in Washington, D.C., where Darren was treated. "The largest volume is from scalding."
Since the introduction of the cellular wound dressing TransCyte, Children's Hospital has used it to treat several hundred children, says Eichelberger. "It's changed our entire paradigm of care for partial thickness burns in children. The mean length of stay used to be 14 days; it's now down to one to two days." Before cellular wound dressings, when gauze was the traditional wound treatment, the pain could be so intense that the patient had to be sedated with morphine or another painkiller just to change the dressing, says Eichelberger. The development of advanced wound dressings such as TransCyte and Integra have changed that. "We're doing fewer skin grafts and we've cut our utilization of morphine by almost 80 percent," he says.
Biobrane and Integra were the first FDA-approved biologically based wound dressings. Biobrane is a temporary dressing for a variety of wounds including ulcers, lacerations, and full-thickness burns. It may also be used on wounds that develop on donor sites--the areas from which healthy skin is transplanted to cover damaged skin. Made by Bertek Pharmaceuticals, Research Triangle Park, N.C., Biobrane uses an ultrathin silicone film and nylon fabric, which is partially imbedded into the film. The nylon material contains a gelatin derived from pig tissue that interacts with clotting factors in the wound. Biobrane is trimmed away as the wound heals or until autografting becomes possible.
Integra Dermal Regeneration Template was approved in 1996 to treat full-thickness and some partial-thickness burns. Made by Integra LifeSciences Corp., Plainsboro, N.J., Integra is a two-layer membrane. The bottom layer, made of shark cartilage and collagen from cow tendons, acts as a matrix onto which a person's own cells migrate over two to three weeks. The cells gradually absorb the cartilage and collagen to create a new dermis, or "neo-dermis." This bottom layer is a permanent cover. The top layer is a protective silicone sheet that is peeled off after several weeks. A very thin layer of the person's own skin is then grafted onto the neo-dermis.
Both Biobrane and Integra use animal tissue; the more recently approved cellular wound dressings are made with human tissue. One of these products is OrCel, made by Ortec International Inc. of New York. Approved by the FDA in 2001 to treat donor sites in burn patients, OrCel is made of living human skin cells grown on a cow collagen matrix. OrCel was also approved the same year to help treat epidermolysis bullosa, a rare skin condition in children. (See "Humanitarian Use of Cellular Wound Dressing".)
TransCyte is made by Advanced Tissue Sciences Inc. of La Jolla, Calif., and was approved by the FDA in 1997. "TransCyte was the first product that FDA approved that delivered nonviable (dead) cellular material," says Rhodes. The product starts with living cells, but these cells die when frozen. TransCyte consists of human cells grown on nylon mesh, combined with a synthetic epidermal layer.
TransCyte is packaged and shipped in a frozen state to burn treatment facilities. The surgeon then thaws the product and stretches it over a burn site. In about one to two weeks, the TransCyte starts peeling off, not unlike a sunburn, and the surgeon trims it away as it peels.
TransCyte can be used as a temporary covering over full thickness and some partial-thickness burns until autografting is possible. It's also a temporary covering for some burn wounds that heal without autografting, as in Darren's case.
In addition to burn patients, people with chronic wounds can benefit from cellular wound dressings. Apligraf and Dermagraft are two products used for the treatment of diabetic foot ulcers. People with diabetes are particularly at risk for foot ulcers because of poor blood circulation in the legs and feet. If these ulcers do not heal, amputation of the foot may be required.
Apligraf, made by Organogenesis Inc., of Canton, Mass., was approved by the FDA in 1998 for leg ulcers caused by blood flow problems and in 2000 for treating the hard-to-heal diabetic foot ulcers. Apligraf is a two-layer wound dressing that contains live human skin cells combined with cow collagen.
"Apligraf is unique in that it's the first product approval that delivered live cells from a different donor," says Rhodes. As with OrCel and TransCyte, the donor cells come from circumcised infant foreskin. One small patch of cells, about the size of a postage stamp, from a single donor can be grown in the laboratory to produce tens of thousands of pieces of Apligraf.
Dermagraft, approved by the FDA in 2001, is a product of Advanced Tissue Sciences. Dermagraft is made from human cells placed on a dissolvable mesh material. Once placed on the wound or ulcer, the mesh material is gradually absorbed and the human cells grow and replace the damaged skin.
Although the FDA has been regulating biological products for 100 years, the agency continues to adapt its experiences and regulatory approaches to the review of new technologies, such as cellular wound dressings. Some of these dressings use living cells and have a shelf life of only three days, says Rhodes. Some use a single donor to produce thousands of units of a product. These are just a few of the characteristics that require the agency to revise or adapt its existing regulatory approaches to these products, he says.
To help ensure the safety and quality of products such as cellular wound dressings, the FDA initiated a new regulatory system and issued a final rule, published in 2001, that requires all human cell, tissue, and cellular- and tissue-based product manufacturers to register and list their products with the FDA.
The FDA also issued other proposed rules under the regulatory system to ensure donor suitability and "good tissue practice." "The cells must be screened for a host of infectious agents and diseases," says Rhodes. And they must be handled properly to avoid viral contamination of tissue and cross-contamination that could occur if a donor cell is mixed up with another donor cell by accident in the laboratory.
"We're always walking this very delicate line between trying to be as safe as possible while also allowing progress to be made," says Noguchi. "It is very much of a dynamic balance. At FDA, we want to make sure that what we approve can be used in a way that is predictable for physicians to prescribe or to use in treatment, to the best of our ability, to the best of medicine's ability, and to the best of science's ability."
Despite the challenges of the evolving regulatory climate, the FDA is excited about these products, says Durfor. "We're attempting to set a very reasonable approach for getting cellular material grown up in tissue culture out in the commercial market, while ensuring the safety and effectiveness of every product."
The technology of burn and wound care using cellular wound dressings and grafts continues to make tremendous strides forward. But most surgeons agree that nothing seems to work as well as a person's own skin.
Boyce of Shriners Burns Hospital and other researchers are experimenting with cultured skin grown from a burned person's own skin cells. With this method, cells are taken from a small patch of skin, grown in the laboratory, and combined with a collagen matrix. After this cultured skin is placed on the burned area, the matrix dissolves, and the transplanted cells reform skin tissue to heal the wound.
Boyce has found this method to be especially valuable for people who have burns over more than 50 percent of their bodies, which limits the amount of healthy skin available for grafting.
Boyce envisions other future efforts to be focused on improving cosmetic outcome after burn injury. "Smoothness and pliability may have been restored completely," says Boyce, "but better color matching to uninjured skin is needed." Also needed is new technology to make wound treatment faster, and to restore hair and glands of the skin that do not regenerate from grafts.
"Researchers continue to make advances, but the field is in its infancy," says Rhodes.
Children with a rare inherited, incurable disease called epidermolysis bullosa (EB) have a painful existence. In this disease, a genetic defect causes the skin to lack certain proteins that protect it from damage. Blisters and wounds develop easily on the fragile skin, particularly on fingers and toes. Life-threatening infections may set in when the wounds don't heal, and for those that do, they leave behind scar tissue. The scarring can make the fingers grow together into a gnarled fist that looks like a mitten, rendering it useless.
In 2001, the FDA approved OrCel, a cellular wound dressing, to help surgeons reconstruct the hands of people with EB. Once the fingers are surgically separated, OrCel is used to rebuild the "mitten hand."
OrCel is used on the fingers, thumb, and the palm of the hand, says Mark Eisenberg, M.D., developer of OrCel and co-founder of Ortec International, New York, the company that markets the product. It's also used on the wounds left after taking healthy skin from other parts of the body (donor sites) to help repair the hand. Depending on the severity of the disease, surgeons often must repeat the hand reconstruction, says Eisenberg. But OrCel significantly reduces the need for donor sites in these surgeries. Eisenberg originally developed the product and used it to treat his son, who had EB.
The FDA approved OrCel to help treat EB under a special program for humanitarian use devices (HUDs). A HUD is intended to benefit people with a disease or condition that affects fewer than 4,000 individuals in the United States each year. The regulations regarding HUDs exempt the product from extensive clinical studies while still requiring data to show evidence of safety. These reduced requirements help product developers offset their research and development costs for products that treat a relatively small population.
--L.B.
On April 17, 2001, Health and Human Services Secretary Tommy G. Thompson launched a national organ donor initiative to encourage Americans to "Donate the Gift of Life." "Fifteen Americans die each day while waiting for an organ to become available," says Thompson. "More than 75,000 men, women, and children now wait for a transplant … Every 16 minutes, another person joins the waiting list."
Many people don't realize that skin is an organ, but in fact it's the body's largest organ. And like other organ donations, skin donations are critically needed, says Phil Walters, director of the skin bank at Boston Shriners Hospital. Walters says the two most frequently asked questions he fields about skin donation are: is skin taken from a living donor, and can tissue surgically removed from a patient by procedures such as those performed to reduce obesity be donated? "The answer to both questions is no," says Walters. "Skin is procured from a deceased organ donor, just like any other donated organ."
No charge is made to the donor's family for donating organs. And it does not change the appearance of the donor's body or cause a delay in funeral arrangements.
For a downloadable donor card and brochure on organ and tissue donation, visit
www.organdonor.gov, or call the Health
Resources and Services Administration (HRSA) Information Center at 1-888-ASK-HRSA
(1-888-275-4772).
--L.B.
The Pentagon, headquarters for the American military and one of the world's largest office buildings, was one target of the terrorist attacks of Sept.11, 2001. A few miles from the Pentagon, at the Washington Hospital Center, surgeons worked around the clock to treat people who were severely burned from the Pentagon explosion.
Surgeons moved quickly to prevent infection by first removing burned tissue on each person, and then covering the open wounds using cadaver skin, pigskin, and two biosynthetic wound dressings approved by the FDA: Integra and TransCyte. All of the wound coverings were used temporarily to thwart bacterial infection until the burned person's body could heal itself or the person's own skin could be grafted. "They reduce the load of burned tissue, which has a poisonous effect to the body," says Marion Jordan, M.D., director of the Washington Hospital Center's burn center.
Jordan prefers to use skin donated from another person (known as cadaver skin, or human allograft). "Human allograft is still the best alternative to a person's own skin, but I rely on all of the products out there," says Jordan. "I believe each has a place [in the treatment of burns]."
The development of cellular wound dressings to treat burns and wounds is still in its infancy. "This is a small field, but it can have unusual, unexpected, and positive consequences," says Phillip Noguchi, M.D., director of the FDA's division of cellular and gene therapy. "We're committed to moving this area forward. Just as we move forward on many fronts, including fighting anthrax and smallpox, these other efforts will also have an impact on our ultimate response to terrorism."
--L.B.
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