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Brave New Skin

Nature knew what she was doing when she designed skin, the body’s largest organ. As a covering for the body, nothing else comes close as a first level of defense against infection, trauma, and dehydration. The problem is that skin is always in short supply for the 4 million people plagued by chronic wounds and the more than 50,000 people hospitalized for burn treatment in the United States each year.

Traditional treatments for these painful and often life-threatening conditions include dressings that protect smaller wounds and passively allow the body to heal. Treatment for large or stubborn wounds may entail skin grafting. But a skin-graft operation requires hospitalization and creates another wound at the donor site. And after a great deal of pain, trouble, and expense the graft simply doesn’t always survive.

Dissatisfied with these conventional treatments, researchers in the 1980s eagerly tried to isolate naturally occurring growth factors that promote healing. But the results with single growth factors have been generally disappointing because wound healing has turned out to be more complex than researchers originally thought, and figuring out which factors to daub on a wound, when, and at what dose remains a daunting task.

Scientists have therefore turned to cultured skin, hoping that it would not only provide a much needed covering but also be ready to use off the shelf without the need for donor matching. In fact, one novel type of cultured skin, called Apligraf Living Skin Equivalent, has shown great promise in that regard. According to its manufacturer, Organogenesis of Canton, Mass., when the living-skin tissue was used in clinical studies on patients with venous ulcers, which normally occur on the legs and feet as a result of abnormal blood drainage, wounds healed on average in 57 days. Comparable wounds treated with standard therapy using pressure dressings healed on average in 181 days. And 57 percent of patients who had battled their ulcers for more than a year saw their wounds close completely, compared with 17 percent of those receiving conventional treatment.

Other companies such as Advanced Tissue Sciences in La Jolla, Calif., are working on cultured-skin products, but the Organogenesis skin is unique because, unlike other products, it has two living layers-an outer epidermis and an underlying dermis. “Without both parts, you don’t really have skin,” says David Heimbach, director of the University of Washington Burn Center.

Epidermis, the thin, protective top layer, is nourished from the thicker, more sensitive layer of dermis below. As the dead, flat cells that compose the outermost part of the epidermis wear away, they’re replaced with rapidly dividing cells from below called keratinocytes, which produce a tough protein and a unique fatty substance that makes skin waterproof. The dermis-composed primarily of fibroblast cells-contains the skin’s blood vessels, lymph vessels, nerves, hair follicles, sweat glands, oil glands, and a network of the fibrous protein collagen, which gives skin flexibility and structural support.

The key to developing the new lab-grown skin is to cultivate only the dominant functional cells: keratinocytes and fibroblasts. While the immune system rejects other transplanted cells found in skin, for some unknown reason it accepts these two as benign.

The manufacturing process begins with skin that would normally be discarded-foreskins from circumcised infants. A bit of skin the size of a postage stamp can produce about four acres of skin equivalent. Once the tissue is broken down mechanically and enzymatically to the cellular level, highly selective growth conditions nourish only the keratinocytes and fibroblasts, thus purging the culture of unwanted cell types. Technicians then mix the fibroblasts with a specially prepared collagen solution, which forms a gel that the cells reshape to a dense lattice. Keratinocytes laid upon this layer attach and, when exposed to the air, start to form the epidermis.

The resulting skin looks, feels, and behaves like normal human skin. When wounded, it can even heal itself. And it can be grown in any size or shape, though for medical convenience Organogenesis provides it in three-inch disks and four-by-eight-inch rectangles-sizes burn surgeons are accustomed to using. The cultured skin also adapts remarkably well to its new environment. Indeed, none of the patients in the clinical trial showed any signs of immunological rejection. And, perhaps most remarkably, the patient’s own cells eventually replace the foreign tissue and the cells responsible for pigmentation return, along with normal skin color.

“The results have been dramatic,” says Morton Altman, a research consultant with the California College of Podiatric Medicine in San Francisco who helped test the cultured skin. Patients reported almost instantaneous pain reduction, and healing was rapid, he says.

Despite such enthusiasm, two hurdles remain. Organogenesis has applied for FDA approval and has received expedited review status. But a nod from the FDA, while still necessary, is no longer sufficient for success, says Howard Jones, who heads regulatory affairs and licensing for Curative Technologies, which closely monitors the skin-dressing market in the course of running a nationwide network of wound-care centers. In the new era of managed care, manufacturers must make a case for the cost-effectiveness of new products.

But while a price has not yet been set for its cultured skin, Organogenesis estimates that it could be priced at more than $1,000 for a venous-ulcer treatment, for example, and still prove cheaper than standard therapy. And the developers are confident they can produce it for less. Although cell culture can be a painstaking process, large production lots should provide economies of scale.

Should the product clear these hurdles, it will become the first engineered living tissue to make it to market. And this brave new skin may be only the beginning. Scientists are also developing other tissue products such as blood vessels, heart valves, cartilage, and even whole organs. As with cultured skin, they are finding that their most important allies are the cells that already know how to make these complex tissues.

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