A second skin

Special to The Times

SKIN doesn’t get any respect. We heedlessly scratch, scrape and bruise it, and intentionally scorch it in the summer sun in our quest for the perfect tan.

Yet consider what it does. The largest organ in the body, this 1.8-square-meter network of nerves, blood vessels, pigments, fibrous cells and sweat and oil glands keeps fluids in and bacteria out, cools us down, holds our other organs neatly inside our bodies and senses the environment, warning us of dangers such as extreme heat or cold.

Without the skin’s protective barrier, victims of massive burns are vulnerable to an onslaught of disease-carrying microbes and potentially fatal dehydration and shock. They lose their sense of touch and ability to regulate their body temperature. And when people age or develop diabetes, their skin loses resilience, leaving them prone to hard-to-heal wounds that can turn gangrenous, necessitating amputation.

To help curtail the annual 10,000 deaths from burn-related infections and 100,000 amputations needed because of diabetic foot ulcers, researchers are developing new artificial skin technologies in tissue engineering laboratories across the country, with the goal of creating substitute skin that looks and functions like normal skin -- with the same soft, smooth texture, strength, durability and color pigmentation.


If these synthetic skins can knit with the surrounding tissue and spur the growth of sweat glands, hair follicles and the blood vessels that nourish the skin cells with oxygen and nutrients, patients should heal more quickly, and with greatly reduced scarring.

These new skins aren’t perfect -- they lack blood vessels and pigment-forming cells, for example -- and for now the gold standard remains taking grafts from the patient’s body whenever possible. Artificial skins are only used when sufficient quantities of such skin grafts aren’t available, such as when someone sustains massive burns over more than half his or her body.

But in the not too distant future, scientists hope that artificial skin technology may advance to the point where it can replace the real thing, and we’ll be able to quickly and seamlessly patch burns and wounds without harvesting skin from other sites on our hides, and produce grafts that are even more functional.

“The holy grail is to develop a wound-healing technique that is even better than what the body does,” says biochemist Richard A. Ikeda, program director for wound healing at the National Institute of General Medical Sciences in Bethesda, Md.


A delicate procedure

Even under the best of circumstances, the healing of wounds is an imperfect process. The body doesn’t generate exact replicas of the skin that has been lost.

The problem lies with the response to injury of the lower part of the skin, called the dermis. Made primarily of proteins called collagen that give skin its firmness and pliability, the dermis is constantly being turned over, with new networks of collagen replacing the old.

But when it is damaged, a super-dense form of collagen is created to quickly cover over the wound -- so thick that no hair roots, sweat glands and few nerves can grow in it, and the skin loses functionality. And as the collagen heals, it shrinks, which pulls on the surrounding skin.


Such scarring is reduced with traditional skin grafts, but although this technology has improved, there are still serious problems with infections and getting those grafts to take. And, depending on the thickness of the graft, the replacement skin can lack certain features of skin, such as pigment, nerves or hairs.

Even so, can artificial skin ever hope to come close?

To be sure, some artificial skin products already exist, and have been available for more than a decade. Consisting of a fabric of human or other mammalian cells combined with synthetic or biocompatible materials, these fake skins are placed on a wound to provide a protective barrier against infection and prevent leakage of vital fluids. This gives the underlying tissue a chance to heal.

Some of the products slough off over time, while others become part of the permanent skin. But all fall far short of the goal of fully functional skin with all its complex bells and whistles.


Up to half of the grafts of these skins don’t take, for example. And the ones that do can thicken as they heal, forming scars that contract over time, leading to a loss of motion in joints and permanent disfigurement.

Plus, the skin that forms is not as strong or durable as real skin and can be painful long after the initial injury has healed, says Dr. Robert L. Sheridan, codirector of the Adult Burn Service at Massachusetts General Hospital and a surgeon at Harvard Medical School in Boston.

“These are not true replacements -- essentially they’re high-tech bandages that jump-start the healing process,” Ikeda says.

Scientists hope that the next wave of synthetic skins will do more.


Furthest along is an experimental skin substitute that was developed by University of Cincinnati scientists and has already been successfully used on more than 40 catastrophic burn victims -- including 15-year-old Alejandra Vega of Coldwater, Miss.

When a gas leak triggered an explosion in her home in May 2002, the then-11-year-old girl was engulfed in flames that scorched more than 70% of her body with third-degree burns.

“She was burned everywhere -- her face, arms, back, hands, legs, everything,” says her father, Eloy Vega. “We thought she was going to die.”

Because her injuries were so severe and extensive, time was of the essence and the wounds needed to be closed fast to prevent infection and fluid loss. At the Shriners Hospital for Children in Cincinnati, which specializes in pediatric burn injuries, surgeons worked quickly to scrub off the burned tissue, which can be a breeding ground for deadly infections, and temporarily closed her wounds with a dressing derived from human cadaver skin.


The body’s immune system rejects this foreign tissue within several weeks, so doctors normally graft healthy skin from another part of a person’s body as a permanent treatment. But Alejandra didn’t have enough skin for grafts. Her doctors opted to use the experimental skin substitute.

They collected a small piece of skin from her chest, one of the few places on her body that was not burned. In a laboratory, the cells were placed in a solution that prompted them to replicate. Some of her skin cells were also frozen in liquid nitrogen so they could be thawed out later when she required more grafts.

Within a month, scientists had generated enough cultured skin tissue to resurface all of her burns.

Though Alejandra has endured more than 10 skin-grafting surgeries in the last three years, it is probably half of what she would have had if she had used only grafts harvested from her own body. That’s because the technology cut down on the need for repeated harvests of her skin.


The high school honor student still has some trouble walking due to tightening of tissue over the grafts on her joints, and must undergo periodic grafts to replace heavily scarred tissue. But otherwise her life has gone back to normal: She goes to school, where she’s getting mostly A’s and Bs, she has plenty of friends and is headed toward college.

“We have our daughter back,” says Eloy Vega.

Artificial improvements

The skin substitute that Alejandra received is created through careful laboratory nurturing. First, doctors take a small biopsy of a patient’s skin. Then they isolate some cells from the epidermis and dermis, and place those cells in a special nutritive broth that stimulates them to reproduce.


A fabric made from collagen and a sticky molecule called glycosaminoglycan is used as a scaffolding, and the cells are attached to this matrix, where they begin to form the protective barriers of the skin. The entire process takes about a month.

Exposing the culture to the air triggers the skin’s external protective surface (the epidermal barrier) to form. Because of that, when the cultured tissue is applied to the patient, the wounds heal quickly, usually within one week.

“The ability to grow these cells in the laboratory enables us to generate sheets of skin that are about 100 times the area of the original skin biopsy,” says Steven T. Boyce, a University of Cincinnati tissue engineer who helped develop this technology.

“And,” he adds, “because the cells are from the patient, there is no rejection so the wound can be permanently closed.”


Boyce’s skin substitute is an advance on earlier attempts at artificial skin for several reasons.

It’s the only artificial skin that combines various useful elements: It uses cells taken from the patients, includes both epidermal and dermal layers of the skin (which helps the skin mesh with the body), actually begins to form a barrier before application and is effective in the treatment of deep burns.

A 2002 study conducted by Boyce’s research team showed that patients treated with the artificial skin required less donor skin from their own body, thus needing fewer surgical procedures to harvest skin. The result was less scarring, fewer infections and faster healing.

And because the cultured skin already had an epidermal barrier, the wounds closed quickly, reducing complications.


“Even in patients with burns over 80% of their body, we’ve been able to permanently close their wounds in less than two months,” says Boyce.

The study also found that softness and strength of the skin, as well as its smoothness and appearance after treatment, were similar to what could be obtained with conventional skin grafts harvested from a patient’s body -- still considered the prevailing standard of care in treatment.

The University of Cincinnati researchers are now gearing up for larger human trials in preparation for applying for Food and Drug Administration approval.

“This technology is taking us many steps closer to real skin, which is our goal -- to make something in the laboratory that is as close as possible to the structure and function of natural skin,” Boyce says.


Establishing vessels

To reach that pinnacle, the skin will need some other, crucial ingredients it doesn’t yet contain: pigment cells to restore skin color, and -- especially -- endothelial cells to form blood vessels that are required to supply the skin with oxygen and vital nutrients. Otherwise, the grafts may not live long enough to attach themselves to the surrounding skin; up to half of all skin grafts fail, mainly because they don’t have a blood supply.

That work is underway. Boyce has completed successful animal grafts of such skins and says he hopes to shortly begin clinical studies in these two areas.

Other scientists, too, are working on the blood vessel problem, which is deemed a crucial next step in developing better substitutes.


For example, researchers at the Yale University School of Medicine in New Haven, Conn., are trying to stimulate the growth of blood vessels in replacement skin in patients with poor blood circulation, such as diabetics or the elderly.

In a 2003 study on mice, they coaxed human endothelial cells to form new blood vessels within grafts. The cells had been genetically modified to churn out many copies of a gene (BCL-2) that improves blood vessel formation.

After two weeks, new blood vessels had formed in 75% of the grafts, feeding the skin with oxygen and nutrients. The Yale team, led by Dr. Jordan S. Pober, director of the vascular biology and transplantation program, hopes to begin human trials within the next two years.

Scientists at Clarkson University in Potsdam, N.Y., are also experimenting with methods of promoting the growth of blood vessels on a replacement skin, as well as sweat glands and hair follicles, which regular skin grafts often lack. Research is in the early stages, says Craig D. Woodworth, a cell biologist at Clarkson, “but the ultimate goal is to create a system that spontaneously forms a multilayered skin, in a way that is similar to what occurs naturally.”


Although an ideal artificial skin is still years away, scientists can see real, tangible progress in their efforts to mimic the hugely complex mesh of fibers, sweat glands, hair follicles and blood vessels that keep our bodies gently cushioned from the elements. “We’ve learned a lot in the past 10 years,” says Ikeda. “A real critical mass is forming around this technology.”