BODY BUILDING

Demand for livers for transplant far exceeds supply. But scientists may have the answer: livers grown in the lab. Roger Dobson on the rise of the test-tube organ

At the heart of the confidential files of the National Transplant Database is a list containing 159 names. Each of the men, women and children named on this list kept on a computer disk at the headquarters of the UK Transplant Support Services Authority in Bristol is awaiting a liver transplant.

Each is hoping that a suitable organ will be found soon, but some of them will have died because of the huge shortage of donor organs. Addenbrooke's, Britain's first and premier liver transplant unit, last year carried out 95 operations, but many more are needed and nine people there died waiting for a suitable organs to become available. In the US, 30,000 people have died of liver failure during the last 12 months, 10 times the number of donor organs that become available for transplant.

Similar shortages of organs face patients waiting for hearts and kidneys, and despite dozens of high profile campaigns, supply has never met demand, and is unlikely ever to do so as the numbers of patients and conditions that could benefit from a transplant continues to increase. Total waiting lists currently top 6,000 in the UK.

And even when they are available, transplanted organs, like cannibalised spare parts for cars, are often not as good as the original, and come with a Pandora's Box of new problems that have to be tackled, ranging from rejection and infection to outright failure.

There has been some progress with mechanical substitutes, like a mechanical liver that can keep people alive for one to five days until a donor is found, and artificial heart pumps, but, with the exception of kidney dialysis machines, much of the technology is in its infancy, untried and unproven.

With the gap between supply and demand widening, researchers are now looking at a radically new approach to producing organs which has, at least in theory, the potential to satisfy all demands.

A new breed of scientists, who mix medicine with engineering and molecular cell biology, argue that donor transplants and mechanical replacements are simply stop gaps, that the real solution for the future lies in tissue engineering, which literally means growing replacement parts for the body.

Dr Linda Griffith-Cima, a professor of chemical engineering at the Massachusetts Institute of Technology who is at the forefront of the burgeoning new science, is growing livers in her laboratory. The living tissue created in her trials is made from liver cells that have been encouraged to grow into mini livers each about the size of a 5p piece.

It has long been known that cells will multiply and grow in the right conditions, Scatter a few skin cells around in the lab, for instance, and a patch of skin will eventually result. But to create specific shapes and organs, and more sophisticated skin and other tissue, the cells really need a scaffolding to show them the way.

The biggest breakthrough so far for the tissue engineers has been artificial skin for use with, for instance, severely burnt patients who have usually lost their dermis, the inner, thicker layer of skin beneath the epidermis which contains the blood vessels and sensory organs. Unlike the surface skin, the dermis does not regenerate itself when it is damaged. And although the cells are there, they need some kind of scaffolding to encourage growth. Without it they form thinner and much weaker scar tissue.

Professor Ionannis Yannas, also of the MIT, and Professor John Burke from the Harvard Medical School, have developed their artificial skin from a two layer membrane, one made of collagen, a fibrous material from an animal's tendons, and the second from silicone rubber.

When this artificial skin is placed on a burn, it acts as a scaffolding for fibroblasts, the skin cells, to grow through and around. The thin layer of silicone, there to protect the wound in the early stages and prevent moisture loss, is peeled off as the wound heals. Once the job is complete, the scaffolding is destroyed by the body's enzymes.

The same basic principle is used by Professor Griffith-Cima to grow livers, and the key to its success is the scaffolding around which the liver cells form. In trials so far, she and her team, drawn from MIT and Harvard, have used computer-aided three dimensional printing to design the scaffolding which is then made from biodegradable polyester as used in conventional sutures. On the outside it looks like a round piece of solid white plastic, but the inside is a labyrinth of tiny channels with sponge-like walls. Just like the real thing, this "liver" framework has an artery at one end and a vein at the other linked by the network of small channels.

The scaffolding is injected with a few droplets containing up to 40 million liver cells, hepatocytes, mixed with blood cells. The mix is then placed inside the polymer liver structure which acts as a framework for the cells and tissue to grow around.

Within a few days, the cells begin assembling into the patterns found in nature. The liver cells form a lining inside the channels and the blood vessels form a layer on top of the liver cells. After that, the cells begin forming pillars that bridge one side of the channel with the opposite side and eventually a liver mass is formed.

Because the cells need an accurate frame to show them where to grow, the dimensions are crucial. If the channel diameters are too small or too large, nothing will happen.

A disadvantage with working with liver is that it is a far more complicated structure than, say, skin. "There has to be perfect blood flow. The liver gets 30 per cent of the blood every time your heart pumps, so there is an enormous challenge in ensuring the high quality circulation needed to provide oxygen and nutrients and carry off the waste. In the skin cells in your dermis there is only 5 per cent by volume blood cells so you don't need as much blood flow and the scaffolding is relatively easy to construct," said Professor Griffith- Cima.

One of the plus points of working with liver is that although it is the largest of the internal organs, it has powerful regenerative properties, like the tail of a chameleon or the spire of a starfish,and within six weeks of being cut in half a healthy liver will restore itself.

The long term goal is to implant a small laboratory-grown liver into the portal vein that leads from the digestive system to the liver. Once in place, the framework around which the liver has been built will dissolve in much the same way that internal sutures do, and leave behind a miniature liver. As a first step, the team hope to have a liver implanted in animal in about a year.

"We have created the biodegradeable polymers we need and we have put cells in and shown that they can organise themselves into structures that look like native liver. I have been involved in the work for eight years now and for the very first time I feel we have all the pieces in the puzzle and we now need to put them together," said Professor Griffith-Cima.

She points out that there are a number of big advantages in growing organs compared to recycling old ones.

"About 15 per cent of all liver transplants do not take hold. That means that in a day or two, another donor has to be found. Our approach would enable a surgeon to implant a functioning organ without taking out the old. That might be enough to restore normal function. We don't want to take the old liver out until we are sure the new one is functioning properly," she says.

Such a constant and regular supply of organs would be manna from heaven for people like Ruth Hughes, manager of the transplant unit at Addenbrooke's who is faced with increasing demand.

"Liver transplantation is becoming more a standard therapy since we did our first one here 20 or so years ago. With new drugs you can get very good results and because of that the therapy is available to a wider variety of people, those who are perhaps older than we would have treated before, and, new cases like the increasing number of hepatitis C patients," she says.

For Professor Griffith-Cima the greatest spur to successfully concluding her research is the youngsters she has seen dying as a result of liver failure in Boston Children's Hospital. She says that as an engineer she was taught to wait to make sure everything was perfect before it was put into use.

"In medicine it's different. If something has a chance of saving a life, you build it the best way you can and improve it later. That's the way you save the lives of children like these and that's why we are going for it." !

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