New skin growth: From test tube to body

Several manufacturers vie for recognition

The variety of skin replacement products emerging from research include full- and partial-thickness products, and one designed specifically for burn victims. Some have already received approval from the federal Food and Drug Administration (FDA). Those that haven’t are being used outside the United States.

Advanced Tissue Sciences (ATS) in La Jolla, CA, has developed two skin-replacement products, Dermagraft and Dermagraft TC. Dermagraft TC is intended as a temporary covering for full- and partial-thickness burns. It has been approved by the FDA and is currently in use in the United States.

Dermagraft, the second bioengineered skin product from ATS, is permanently implanted tissue intended for patients with diabetic foot ulcers. It is approved for use in Canada, the United Kingdom, Finland, and several other countries, but not yet in the United States. The FDA is currently reviewing a premarket approval application for Dermagraft under its expedited review process. An estimated 800,000 diabetic foot ulcer patients are treated in the United States each year, half of whom represent ATS’ potential initial U.S. target market. The company has partnered with Smith & Nephew PLC to market Dermagraft worldwide.

Dermagraft is a dermal tissue allograft composed of living, fully human dermal skin cells, and contains no epidermal components. A bioabsorbable mesh made of vicryl suture material is seeded with dermal fibroblast cells from human newborn foreskins that have been surgically discarded after circumcision.

The dermal cells are grown in a closed-tissue culture system with circulating nutrients. Once the fibroblasts begin to multiply, they secrete collagen, other matrix proteins, and growth factors to fabricate a human dermal tissue layer. A single donor foreskin is sufficient to produce 250,000 square feet of Dermagraft. Once finished, Dermagraft must be stored at -70 degrees C and shipped on dry ice to the clinical site.

"Dermagraft replaces only the dermis, which we transplant to another person without a rejection or immune problem," explains Gary Gentzkow, MD, executive director of worldwide medical affairs at ATS. "Epithelial cells, on the other hand, are recognized as foreign by the host, and for that reason we didn’t want to include them. The role that foreign epidermal cells might play in the healing process is unclear, and we’ve achieved excellent healing results with just the dermis and think that’s the way to proceed."

Despite the fact that Dermagraft is not a full-thickness product, it is still designed to permanently replace a patient’s destroyed dermis. In a 235-subject clinical trial lasting 12 weeks, 39% of Dermagraft patients were completely healed, compared with 32% of patients in the control group who received standard wound dressings.

At first glance, the difference doesn’t appear great, but after the specific therapeutic range for Dermagraft was factored in, the proportion of Dermagraft patients experiencing complete wound healing rose significantly, to 51%. Subsequent supplemental trials, conducted to show the equivalence of Dermagraft produced to commercial specifications, had similar results.

"We haven’t plumbed the limits of how many patients we can get to heal with Dermagraft," says Gentzkow. "Under the study protocol, we had to follow a specified dosing regimen under which patients received Dermagraft only during the first eight weeks. A lot of healing occurred in many patients, but not always compete healing. Now we have the opportunity to use more Dermagraft over a longer period of time, and we expect that we can heal more patients."

As always, cost plays an integral role in the future of any new medical product. ATS, according to Gentzkow, is comparing the cost of using Dermagraft to that of standard wound care regimens. An economic model developed in Canada and Great Britain, where Dermagraft is on the market, shows that the product saves money because wounds heal faster when it is applied, according to the company.

"Our cost-effectiveness model shows that the product will more than pay for itself by decreasing other costs, such as the need for regular clinic visits, debridement, new dressings, and costs associated with infections," says Gentzkow. The price of Dermagraft in the United States has not yet been announced.

Product includes dermis and epidermis

Organogenesis in Canton, MA, is banking on Apligraf, a full-thickness allogenic skin substitute. In contrast to Dermagraft, Apligraf incorporates both the dermis and epidermis, including the protective stratum corneum layer, and so is sometimes referred to as a living skin equivalent. It is the only bioengineered skin replacement that includes both the dermal and epidermal layers of skin.

"Because of its resemblance to skin, [Apligraf] offers both the advantages of a skin graft without the need for donor site harvest, while offering the ability to be reapplied when and if necessary during treatment," reported one group of researchers.1 If Apligraf is cut during its culturing phase, it will repair itself and close the incision.

Organogenesis also uses neonatal foreskins as a source for both the dermal and epidermal layers of its product. (See diagram for a synopsis of the Apligraf manufacturing process, p. 4.) Though Apligraf’s main use is for treatment of venous leg ulcers, other applications are also under investigation, such as skin replacement at donor site wounds, burns, diabetic ulcers, and pressure sores. Apligraf is currently awaiting FDA approval. The product has been approved and launched in Canada and Australia. The Canadian approval, granted in April, represents the first time any country has cleared a man-made living product for sale. Swiss pharmaceutical giant Novartis has licensed the worldwide rights to market Apligraf.

"We actually create an environment in which cells form a three-dimensional structure as they would in the human body," explains Carol Hausner, Organogenesis spokeswoman. She added that preparation of the wound site is an important determinant in the success of Apligraf. For instance, wounds that are well-debrided stand a greater chance of complete healing after Apligraf is applied.

Apligraf is about twice as thick (30/1000 of an inch) as a standard split-thickness skin graft, according to the company. Surgeons using the material in clinical trials report that it is durable and easy to handle. The cost for treating a venous ulcer with Apligraf has been estimated at more than $1,000.

In multicenter trials involving 233 subjects with chronic venous ulcers, Apligraf was found to be 60% more effective than standard compression in closing venous ulcers. Sixty-one percent of the subjects who received Apligraf experienced 50% wound closure at 57 days post-treatment. The median time to 100% wound closure was 57 days for those receiving Apligraf vs. 181 days for those receiving standard care, which consisted of multilayered compression including Tegapore, a zinc oxide-impregnated paste bandage, and Coban. Sixty-four percent of the Apligraf-treated patients achieved complete wound closure, while 44% of control patients achieved 100% closure.1

Apligraf, designed as a permanently implanted tissue replacement, shares many advantages with Dermagraft: No human donor skin is needed; the grafts can be applied multiple times on the same wound if necessary; grafts can be taken "off the shelf" when they are needed without delay.

Integra artificial skin, manufactured by Integra LifeSciences Corporation in Plainsboro, NJ, was developed primarily for severely burned patients. The product differs somewhat from Dermagraft and Apligraf. Its dermal layer consists of a porous lattice of fibers of cross-linked bovine collagen and glycosaminoglycan composite, and its epidermal layer is made of silicone. Integra contains no living cells. Instead, the dermal layer functions as a biodegradable template that induces organized regeneration of the recipient’s dermal tissue. It allows for the infiltration of fibroblasts, macrophages, lymphocytes, and endothelial cells, which form a neovascular network.

In the case of severe burns, the old dermis is excised and Integra is installed in its place. The original lattice is absorbed by the body within a month.

The silicone epidermal layer controls moisture fluctuations from the dermis and imparts its strength to Integra. This layer remains intact as the dermal layer degrades. Eventually, it must be surgically removed and replaced by a thin epidermal autograft.

"The researchers who developed Integra learned that if you implant an absorbable matrix in the body, and that matrix has a precisely engineered pore size, volume, and rate of absorption, it tricks the body’s own cells into building new tissue," explains George McKinney, PhD, chief operating officer.

Integra received FDA approval in March 1996 for use with burn patients. It has already received regulatory approval in 14 other countries.

McKinney says Integra also should prove extremely useful for application to chronic wounds, but the company’s immediate focus will remain on burn treatment.

Reference

1. ML Sabolinski, Alvarez O, Auletta M, et al. Cultured skin as a "smart material" for healing wounds: Experience in venous ulcers. Biomaterials 1996; 17:311-320.