Materia Medica Malaysiana

Giving back patient his own skin

Need skin? Malaysian researchers have a world first — skin engineered from the patient for the patient. THERESA MANAVALAN checks out the future of bespoke skin made in Malaysia.

THE skin is so like the flesh of tender coconut. White and wobbly, soft and spongy and cold.

But this science is hot. Its Malaysian inventors are burning a new trail for engineered human tissue — in this case, skin to be used on burn victims or people with ulcers and wounds that refuse to heal. What makes this skin special is that it is made in the lab entirely from the patient who needs it. By using a one-centimetre square patch of the patient's skin, the cells are coaxed to multiply and shape themselves into skin with help from that very patient's blood plasma. It has done away with the non-human components associated with previous models of engineered skin tissue.

At Universiti Kebangsaan Malay- sia's medical school, Dr Ruszymah Idrus, an associate professor of physiology, has moved five years of research in engineered skin tissue to a new reality.

In a limited trial over the last six months, four patients with hopeless foot ulcers have had those ulcers surgically removed and the area covered with skin engineered from their own skin cells. The four — three diabetics, one with end-stage renal failure — had been living with severe ulcers that refused to heal. Their next option was amputation of the foot. They had had skin grafts but that procedure had failed on them. All had refused to try skin grafts again because of the pain.

Since their surgery, the areas covered with their engineered skin have healed completely. No scars have formed yet and the borders of engineered skin have set seamlessly with the patient's own skin. The little patch of engineered skin doesn't have skin pores or sweat glands. But, because engineered skin is a living thing, blood vessels and capillaries in the vicinity of the wound are already inching their way in.

"It's been so encouraging," says Dr Ruszymah, who began working on tissue engineering in 1999. "We hope to start a large-scale clinical trial soon." HUKM clinicians continue to monitor this small group. Already, the medical community is buzzing. Malaysian plastic surgeons are asking for engineered skin tissue, so are doctors and scientists overseas willing to work with a Malaysian team.

The science of engineered skin tissue is not that new. But what separates the UKM project from others around the world is that the entire thing is made from an individual's skin exclusively for that particular individual.

Other models of engineered skin tissue include a bovine layer which works well but is not popular with patients because of that.

This feature earned Dr Ruszymah and her team a gold medal with special mention at the April Geneva Inventions Show (Salon Internationale Des Inventions Geneve). That has set off alarm bells worldwide. Already, Dr Ruszymah's office is being flooded with e-mail and phone calls from interested investors, scientists and potential collaborators.

Engineered skin tissue is expected to be an alternative to skin grafting. Skin grafting, done globally, is a workable technique with good success rates but it has drawbacks. One is the pain. Diabetics are prone to infection. It leaves a scar on the harvested area. In patients with a large surface area to cover, it's a hopeless situation. For example, someone with 80 per cent burns would not be able to offer any of his remaining skin. Skin grafts fail when blood supply to the area is short.

For many years, doctors dealing with burns and skin ulcers have asked for an alternative that would overcome these issues.

Scientists began working on various ideas for skin in the 1970s but it wasn't until the mid-1990s that engineered human skin became a viable idea. That coincided with a new understanding of genetics and molecular biology which gave rise to innovative ways of working with living cells.

Skin is one of tissue engineering's success stories although it has its share of problems, the big one being getting the layers of skin to bond in the lab. Human skin is made of two major layers: the epidermis, the skin on the outside of the body, and the dermis, a spongy layer which lies immediately below. The cell structures of these two layers are entirely different. To make new skin, a one centimetre square patch of each layer is taken and separately cultured in different growth media. A growth media is a sterile solution loaded with nutrients to make the cells grow and mulitply. This is the easy part.

The hard part is getting these two layers to bond and behave like natural skin. In the past, the only way to do that was to mix the dermis cells with something else, usually tissue from cows and, in some cases, from rats. This type of engineered skin tissue has been commercialised and is known to work well. Malaysian plastic surgeons order it for their patients. They courier the patient's skin to the centre — the nearest one being Japan — and it takes about four weeks to cultivate enough skin for surgery. A petridish of such skin costs about RM2,000.

But already, some studies are reporting rejection to the bovine component. Besides, some patients don't like animal content.

The other technical problem in tissue engineering is coaching the cells to grow into a desired shape. Getting cells to multiply is fairly easy science but as a rule, they tend to grow haphazardly and become a hideous lump. To manage this, tissue engineers use a scaffold on which the cells can grow and form that shape. Scaffolds are made from a assortment of materials including chemicals with a molecular structure that would support cell growth, plastics and silicone.

Dr Ruszymah's team began by looking back to the patient. Working with a RM2 million grant from the National Biotechnology Directorate and collaborators from Universiti Putra Malaysia, Universiti Malaya and the Institute for Medical Research, they overcame the bonding problem and the bovine rejection issue in a single move. "We figured there might be something human we could use," says Dr Ruszymah, a UKM trained medic who went on to study molecular biology. "And we found it in blood. By using a human plasma derivative, we had one solution for both problems." The human plasma derivative — a now proprietary agent made from human plasma — has a mesh like a sponge which houses the cells as they grow. The epidermis and dermis cells are cultured and allowed to set with the human plasma derivative separately and then layered on each other.

"They bonded," says Dr Ruszymah. "That was the big event. This is now 100 per cent human and it comes from that individual patient." The finished skin is then mounted on surgical grade silk. The surgeon sews down the skin by suturing the silk to the patient's good skin. It takes about two weeks to heal (about the same for any other surgical wound). The sutures are biodegradable. The silk dries, curls up and lifts off the body. The engineered skin merges with the patients' good skin.

The next challenge? Shortening the time factor by at least half. It now takes three to four weeks to make skin this way. One problem is appearance. The colour of the new skin is rather pale, especially when placed right next to lustrous Asian skin. Yet another challenge: getting hair on to that skin.

"Now that would open the market for baldness treatments," says Dr Ruszymah.

But first things first. Dr Ruszymah has filed a patent with her husband Dr Aminuddin Saim, her co-inventor and the one who led her to tissue engineering. Dr Aminuddin, an ear, nose and throat surgeon formerly at UKM, had always been interested in creating tissue components for his patients. For some of them, it would help with the simple art of breathing. So he signed up in 1990 for a post-doctoral programme at the Tissue Engineering Centre, affiliated to Harvard University's medical school. This centre made world headlines in 1997 when its scientists, led by transplant surgeon Dr Jay Vacanti and chemical engineer Bob Langer grew a human ear on the back of a mouse. It was a popular Internet download for several years, a photograph that turned the collective stomach of a public queasy about biotechnology.

When Dr Ruszymah and Dr Aminuddin were there in 1999, animal rights activists were still seething but the mouse was a bona fide celebrity and had given rise to an entire new science called tissue engineering — creating human tissue to heal the sick and wounded.

When they returned, Dr Ruszymah and Dr Aminuddin applied for a grant from Yayasan Sultan Iskandar Johor which had issued their scholarships. With RM150,000, they set up a lab and began work on ear lobes for people with deformed ears. As a rule, cartilage requires minimum blood supply and nutrient, so growing it outside the body is achievable. But as it turned out, ears grown that way could not be surgically attached to a human being. While the ear itself was flawless, the human head and its complex network of blood vessels did not lend itself for the job. So, like many other tissue engineering labs around the world, they moved on to other body parts. At Dr Ruszymah's lab, researchers are already working on bone tissue using a similar process. This is intended to create material repair bones after fracture or disease. This would be an alternative to bone substitutes like metals and ceramics.