Regenerating Skin

Skin is an important vital organ, a very effective, breathable, moisture seal, without which our wet, pulpy insides would immediately dry out. Skin also protects us against all the bacteria, mold, and parasites for whom the human body represents opportunity. The injuries of severe burn patients must quickly be covered and traditionally, this has involved the use of cadaver skin. Obviously, this treatment brings with it the risk of viral infection and is very expensive and time-consuming; sometimes the cadaver skin has too be stitched together from small segments. John Burke was looking for a way to avoid this ghastly business for his patients and himself. He hoped to create an artificial covering that would take the place of cadaver skins. His first attempts to do this were, in his words, "the most glorious messes...absolute catastrophes." Burke needed someone who understood materials. Ioannis Yannas wanted to associate with "a medical person, who would be in contact with the patient population, who would know the exact needs of that population, so I could design a product with those specifications in mind." The surgeon and the chemist , together, invented the "skin regeneration template" which Integra now markets as "Artificial Skin." Artificial Skin far exceeds John Burke's initial expectations. Instead of merely being a temporary covering protecting the patient, Artificial Skin actually allows the body to create a new dermis over the burn site.

Artificial Skin is made in two layers; the upper layer is an elastic silicon membrane which provides the moisture barrier, functionally replacing the epidermis, and the lower level consists of an synthetic matrix of collagen fibers (purified from bovine tendons) and chondroitin sulfate (a type of large carbohydrate extracted from shark cartilage). This synthetic matrix was designed to approximate the supporting layer of protein and carbohydrate normally secreted by dermal cells. Dermal cells, as well as most tissues in the body, exist spread on surface called an "extracellular matrix" consisting of proteins and carbohydrates. Collagen is the major protein found in extracellular matrices in the body. It is also the protein from which we make gelatin. Because the protein is in a disordered state in gelatin, it has no particular structural strength. In extracellular matrices, however, collagen exists as a long, stretched out protein that arranges itself in triple helical bundles, similar to rope or twisted cable, although on a microscopic scale. Along these bundles are numerous small attachment sites for cells. Unexpectedly, Burke and Yannas found that when the synthetic matrix supplied by Artificial Skin was applied to a wound site, dermal cells from around the wound site migrate into to the artificial matrix and attach to the collagen fibers. The bovine collagen is slowly degraded and replaced with authentic human collagen synthesized by the dermal cells. Blood vessels grow into the wound to vascularize the new tissue. After the dermal layer has had a chance to repair itself, the outer membrane can be removed and replaced with very thin epidermal transplant, once again providing a natural moisture seal. The resultant skin is functionally and cosmetically superior to that achieved with other methods of treatment.

Is there any magic formula for making a collagen matrix that will attract dermal cells to colonize it? "Yes, and it is magical in a way that doesn't make sense to most biologists I know," says Dr. Yannas, the chemist. The collagen must have a "specific surface" which involves the right density of attachment sites for cells. The rate at which the matrix degrades is also very important. The matrix must persist while the "inflammation rages on," but ultimately it must be degradable so that it can be replaced by authentic human collagen. Additionally, the bovine collagen must be treated to remove or mask immunogenic sites that might cause the body to reject Artificial Skin in the same way that it would reject a foreign skin graft, for instance.

Artificial skin illustrates some of the general principles involved in tissue engineering. Tissue is organized by the underlying extracellular matrix. The matrix itself, was originally secreted by the cells, themselves, or put in place by their predecessors during the process of embryogenesis. In a deep wound, such as a severe burn, the protein matrix itself is missing or severely damaged, and the original cells in the wound have died. The burn site itself is temporarily occupied with immune system cells, like macrophages and lymphocytes, which keep infection from spreading but have no innate ability to manufacture skin. There are no appropriate cells left to replace the matrix correctly, and there is no matrix left to organize the tissue. Artificial Skin solves the problem by providing a synthetic matrix, or scaffolding, on which new tissue can arrange itself. Integra claims to have had excellent results at healing burns with Artificial Skin, even in older patients, whose skin is already thin and brittle with age. So pleased are they, in fact, according to vice-president Robert Towarnicki, that Integra is now conducting clinical trials to expand its use to cosmetic plastic surgery, that is, to treat scarring caused by previous wounds or burns. This is, of course, a vastly larger market than the original indication.

Although Integra is the first to gain FDA approval, two other biotechnology companies, Advanced Tissue Sciences (ATS) and Organogenesis, are also advancing their own form of engineered skin. Both of these companies actually grow living human "skin" in the laboratory, and use it to patch the sites of wounds. The ultimate source of their skin cells is human infantile foreskins harvested by circumcision. The cells in foreskin will grow and divide in tissue culture, increasing in number, if given an appropriate medium containing nutrients and growth factors. Infant foreskin has more potential for cell division than does that from an adult; cell cycle time increases with age, and the ultimate number of divisions is finite. An infant's foreskin can theoretically grow into a lawn that would cover something on the order of six football fields! (assuming you could incubate football fields in a humidified, sterile chamber at body temperature in a pH buffered solution containing vitamins, amino acids, epidermal growth factors, insulin, glucose, etc.) ATS has not had to acquire a new foreskin since 1989, despite ongoing clinical trials of its products. It's Dermagraft-TC would compete with Integra's Artificial Skin for the same indications, given FDA approval.

ATS and Organogenesis are also addressing the acute need for treatment of diabetic ulcers. Ulcers in the extremities, particularly the feet, result from poor circulation, very common in diabetic patients. ATS estimates that 500,000 patients are treated per year, and that over 55,000 amputations are performed because of inability to heal the wounds. ATS is allied with Smith and Nephew, PLC, a British pharmaceutical giant with over $1.5 billion in sales. The deal with Smith and Nephew is illustrative of the hurdles that small biotechnology companies face. ATS got $10 million up front and will receive $5 million more assuming they win FDA approval of Dermagraft for diabetic ulcer treatment. FDA pre-market approval of a medical device, however, does not obligate Medicare or private insurance companies to pay for that product, an important point in this age of dwindling budgets and managed health care. ATS will receive another $5 million if they successfully lobby Medicare into approving reimbursement for their product. Additional funds, up to $40 million would be given, pro-rated according to gross sales achieved, according to Marie Burke, director of investor relations for ATS.