April 2002

From New Scientist

Artificial organs

Researchers have high hopes of building an artificial liver

THE man who grew a human ear on the back of a mouse has made a breakthrough that brings the prospect of an artificial liver much closer. He believes he has solved the problem of growing the complex networks of blood vessels that artificial organs would need to sustain themselves within the body.

Until now, researchers trying to build replacement body parts have been limited to making relatively simple tissue, such as thin sections of cartilage and skin. That's because it has not been possible to grow the deep networks of blood vessels that organs need to stay alive. But now Jay Vacanti at Massachusetts General Hospital in Boston and Jeffrey Borenstein at the nearby Draper Lab have shown that it can be done.

Artificial organs would be a boon because organ donations cannot keep pace with demand. In the US, some 80,000 people are waiting for kidney, liver or heart transplants. And of the 23,000 Americans who need a liver, only 5000 got their wish last year. Artificial organs would slash these waiting lists and solve the big problem of organ rejection by growing them from the patient'scells.

Tissue engineers can already grow simple body tissues such as knee cartilage. They start with a shaped, porous scaffold made from a biodegradable plastic like polylactic glycolic acid (PLGA). The scaffold is "seeded" by plunging it into a solution of the patient's cells and then immersing it in a nutrient solution. As the cells multiply and clump together, the scaffold dissolves, leaving a piece of cartilage ready for transplant.

The new cartilage can survive because oxygen and nutrients from surrounding body fluids diffuse into the cells. But this doesn't work for the thicker tissues typical of livers and kidneys because nutrients can only diffuse across a few cell layers. Instead, they need an internal blood supply to deliver nutrients to cells deep inside the organ. "Without a blood supply, the tissue dies," says Borenstein, a micro-engineering expert.

In a bid to beat the problem, Borenstein teamed up with transplant surgeon Vacanti, who in 1997 famously grew a human ear from cartilage cells on the back of a mouse. The idea the pair hatched involves copying the blood vessel network of a real liver and using 3D computer modelling and machining to mimic its construction.

First, they injected a liquid plastic into the blood vessels of a liver. Once the plastic had solidified, they dissolved the liver tissue, leaving a solid cast of the organ's blood vessels. From this model they were able to take measurements of vessel diameters, branching angles and the distances between vessels. They fed the numbers into software that built a 3D fractal-like computer model of a liver's blood supply. When they simulated blood flowing through the "liver", it had the same blood flow properties as the living system, says Borenstein.

The 3D blood vessel model is then "sliced up" inside the computer, dividing the model into a series of horizontal layers, each of which is used to make a silicon mould. PLGA is then poured into each mould to make the many slices that when sandwiched together, under pressure and heat, create a scaffold for the artificial liver. It's shot through with channels as small as the finest capillaries and as large as the organ's main veins and arteries.

The scaffold then has to be seeded with the cells that make up the solid part of the liver. As well as hepatocytes, which perform key liver functions such as breaking down toxins and metabolising proteins and carbohydrates, there are at least six other types of cells. Borenstein says there are two possible ways of seeding this complex network of different cell types. You could seed each layer separately with different cell types, or inject them from the outside. But the pair won't yet say how this is done.

To get the blood supply working, a solution of endothelial cells, the cells that normally line blood vessels, is pumped into the empty channels in the scaffold, where they stick to the walls. These cells grow in a nutrient to form a network of blood vessels within the scaffold which itself dissolves over a few months, leaving behind a functioning liver-at least, that's the aim. So far, only blood vessel networks grown this way have been tested in rats, with no leakage or obstruction of the blood flow.

This is still a long way from a working liver. Linda Griffith, a tissue engineer at MIT, says getting all the right cell types to grow in the right places in the "liver" is crucial. "In just a gram of liver, you have around 100 million cells and it'd be very hard to position each and every one," she says, suggesting that encouraging smaller numbers of different types of liver cells to self-assemble may help.

But there's another enemy waiting in the wings. "Currently, there's no way of keeping these implants sterile, and no one is really looking at that," warns tissue engineer Larry Hench at London's Imperial College. Bacteria love the warm nutrient solutions and would spread quickly. "If we can't sort this problem out, we could be stuck with lab-based solutions we can't use," he warns.

Author: Ian Sample

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New Scientist issue: 27 APRIL 2002

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