Ready-to-Wear Flesh – production of skin-graft material at Organogenesis Inc

Karen Wright

Will snippets of skin grown in lab dishes put a new wrinkle in the ravages of aging?

THE DECADE-LONG EFFORT to grow human body parts in the lab has generated a lot of gossip. Rumor had it, for example, that lab-grown skin was made from the foreskin of circumcised infants and steeped in a brew of cow tendon. A company just south of Boston was said to be manufacturing the stuff in industrial quantities, spooling out damp pink sheets–the size of football fields–that could be cut to order.

A visit to the company in question reveals that the truth has been stretched more than the foreskin. Skin grafts produced by Organogenesis Inc. of Canton, Massachusetts, are indeed made from human foreskin cells mixed with proteins from bovine tendons. But the cells are separated and multiplied in culture banks before they’re processed. And the grafts are grown individually in shallow 3-inch-wide wells that yield perfectly round patches, not NFL-sized sheets.

Nancy Parenteau, chief scientific officer at Organogenesis, explains that a little foreskin goes a long way “Because it’s young tissue that has a lot of growth potential, you can make many, many units from one foreskin”–as many as 200,000 grafts from a piece no bigger than a postage stamp. The resulting product is a pale, paper-thin, semiopaque disk that fits in the palm of your hand. It’s a bit damp on the underside, a bit sticky, and gives just a little when you pull at the edges, like a mu shu pancake.

The grafts are most often used to treat venous leg ulcers, a common complication of vascular disease, obesity, and other conditions. The ulcers, which affect up to a million people in the United States, form because of sluggish circulation and, for the same reason, they heal slowly or not at all. In clinical studies, lab-grown grafts have hastened the rate of healing, at least in part by stimulating the host’s own skin to regenerate. For ulcers more than a year old, the grafts were twice as effective as the standard therapy It takes only 15 minutes to apply the graft to the wound and bind it with gauze dressing. Within a few weeks “it just becomes you,” as one observer put it.

Of course, applying grafts of a patient’s own skin would do the trick just as well. But using lab-grown skin saves both the cost and risk of a full-blown surgical procedure. During the year and a half the Organogenesis skin has been on the market, doctors have also used it to treat burns, skin-cancer lesions, diabetic foot ulcers, and genetic blistering diseases. The graft has even come full circle: “Every part of the body has been treated with this,” says Parenteau, “including the foreskin.”

Organogenesis procures the skin from mothers who agree before delivery to hand over their babies’ discards. The next step involves treating the tissue to remove the cells most likely to arouse a host’s immune response. Then the tissue is separated into two cell types: fibroblasts, which build the lower layer of the skin, called the dermis, and keratinocytes, which provide the protective top layer, the epidermis. The fibroblasts are added to culture dishes along with liquid nutrients and collagen, a protein building block of skin extracted from the tendons of butchered calves. Six days later, after the fibroblasts have established the lower, dermal layer, keratinocytes are added. When they have spread over the dermis, the whole matrix is lifted slightly above the culture medium on a cotton pad. The resulting exposure to air signals the keratinocytes to form a tough outer layer, called the stratum corneum, that resists injury and infection. The entire procedure takes 20 days from start to finish.

It sounds simple, but coaxing the cells to perform their natural repertoire of behavior in such an unnatural setting took years of trial-and-error experimentation. “I still remember the day we knew that our method of growing keratinocytes was going to work,” says Parenteau. “And then we had to repeat it 10 times before we got it to work again.”

Lab-grown skin is the first living product of tissue engineering to reach the market, in part because its structure is relatively simple compared with other organs and tissues. But disagreement has arisen about the best approach. The strategy Parenteau works with is noteworthy for its two-layer graft and its production volume: The company ships hundreds of patches weekly

Other labs are developing single-layer dermal grafts grown from the host’s own skin cells. The process requires only a dime-sized piece of healthy skin taken from just about anywhere on the body The strategy would be a boon to patients such as burn victims who don’t have enough undamaged skin to contribute ordinary grafts. Although it will inevitably cost much more, this approach is favored by researchers who fear that foreign grafts could carry infection. “It makes more sense to grow your own skin back,” says Charles Vacanti, director of the Center for Tissue Engineering at the University of Massachusetts Medical School.

Vacanti himself is using animals to experiment with customized grafts that are painted on their hosts one layer at a time. Instead of employing collagen for the skin’s structural scaffolding, he mixes the skin cells with a gelatin-like compound that hardens as it warms to body temperature, so the graft sticks and stays stuck. The idea is to get the cells into their natural environment as soon as possible.

“Any tissue develops differently in a dish than it does in a living recipient,” says Vacanti. “As much as we try to mimic the chemical environment [of the body] in an incubator, we just can’t. And it’ll be years before we figure out what all the environmental factors do. To have a fully normal tissue, it has to be at least partially generated in place, in situ.”

So far, even the most sophisticated lab-grown skin lacks some of the features of ordinary skin. The grafts don’t have any color, for instance, although they acquire the host’s pigmentation as they naturalize. And while nerve endings and blood vessels do migrate into the new skin, sweat glands and hair follicles don’t, even years after the graft is applied. Scientists at Organogenesis and other labs are working on ways to incorporate these features into the grafts themselves. Vacanti hopes someday to include every cell type found in natural skin in his customized system.

In the meantime, lab-grown skin won’t sweat, but it probably will crease, putting a wrinkle in any plans to banish crow’s-feet and other totems of advancing years. Parenteau says the grafts might be useful for disfiguring conditions that are only skin deep, such as acne, scars, and birthmarks. But a wizened appearance is the result of “divots and crevices” caused by cell breakdown beneath the skin and is better remedied by shoring up the infrastructure with collagen injections. With existing technology, she says, a skin transplant would provide at most a brief reprieve from the ravages of time. “We’re not confident that the cosmetic outcome would be any better than your natural, normal skin.”

No doubt scientists are working to overcome this glitch as well, in the hopes that lab-grown grafts will someday give aging faces skin as smooth as a baby’s, well, you know what.

COPYRIGHT 1999 Discover

COPYRIGHT 2000 Gale Group

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