SKIN : THE FIRST TISSUE-ENGINEERED PRODUCTS

Organogenesis, we have created a skin construct, Apligraf, that is unique in that it is made up of the two layers that constitute human skin, the dermis (inner layer) and the epidermis (outer layer). In May 1998 Apligraf was approved as a biomedical device by the U.S. Food and Drug Administration. It became the first device containing living human cells to win such approval. During the development of Apligraf, we at Organogenesis had to decide whether to attempt to win regulatory approval for products that were, in effect, precursors to Apligraf—either dermis or epidermis by itself—or to trust that we could develop our product before other companies beat us to it. We bet on two-layered skin because it was closer to true skin, and grafts of true skin clearly worked. In addition, the dermal substrate would enhance the epidermal layer’s survival. Our gamble paid off. The idea for Apligraf dates back almost two decades. While at the Massachusetts Institute of Technology, Eugene Bell noted that fibroblasts, the cells that form the dermis, could infiltrate a collagen gel and turn it into a fibrous, living matrix. Collagen is a fundamental part of the extracellular matrix, the biological “glue” that holds cells in place. In 1981 he found that keratinocytes, the cells of the epidermal layer, would grow on that dermal substrate, forming a primitive skin equivalent. He also determined that the construct could be grafted onto rats. Organogenesis was founded in 1985 to commercialize Bell’s technology. I brought my background in keratinocyte biology to the company in 1986. We were confident that artificial, bilayered skin would have clinical benefits. A temporary skin substitute made of collagen and another extracellular matrix constituent was created by John F. Burke, then at Shriners’ Hospital in Boston, and Ioannis V. Yannas of M.I.T. It had helped burn patients in clinical trials by preventing water loss and promoting dermal healing. In addition, Howard Green of Harvard Medical School had devised a method for growing sheets of epidermal cells for burn patients. An initial obstacle to developing Apligraf was obtaining a supply of collagen to support the growth of the cells. Suppliers could not guarantee us a sufficiently pure form of collagen with the correct properties. To overcome this, Paul Kemp of our company and his colleagues developed a way to derive collagen from bovine tendons. They also came up with a cold chemical sterilization technique that destroyed any contaminants without disrupting the collagen. My colleagues and I then set out to find the culture conditions that would provide the optimum number of living human keratinocytes. At the time, however, all known methods for culturing keratinocytes were covered by patents held by other companies, and some aspects of those techniques were undesirable for our purposes. Accordingly, we set out to develop our own, unique keratinocyte culture systems. In doing so, we gained a deeper understanding of keratinocyte growth that helped us develop our subsequent production procedures. We looked to newborn human foreskins collected from circumcisions as a source for fibroblasts and