Jewish World Review

Scientists trying to manufacture organs for transplant | (KRT) If today is an average day, 17 people will die waiting for donor organs.

The situation is getting worse.

The transplant waiting list is already more than 80,000 names long. Another name is added every 13 minutes. Each year, only about a third of the people on the list get the organs they need.

Now some innovative scientists are trying to increase the supply by growing organs and replacement body parts in the lab.

The approach, known as tissue engineering, is only two decades old, but already scientists are learning to create skin, bones and almost every other body tissue virtually from scratch.

Some researchers are engineering their own solutions to the organ shortage.

A physicist at the University of Missouri hopes to build 3-D replicas of organs using a machine that resembles a dot matrix printer.

A Washington University group in St. Louis is trying to grow primitive pig parts into fully functional organs. The approach already has cured diabetes in some laboratory rats.

The most popular technique for engineering tissues involves building a scaffold in the shape of an organ. The scaffolds are usually gels of synthetic polymers and proteins. Tissue engineers call such a gel a "matrix."

After engineers weave a matrix, they seed it with cells. The cells grow, divide and spread inside the matrix like spores invading a Jell-O mold. The result is an organ that looks and works like the one it was designed to replace.

That's the general idea, at least. In reality, the process is much trickier.

One of the first problems is finding cells to do an engineer's bidding, said Robert S. Langer, a pioneer of tissue engineering at the Massachusetts Institute of Technology. Then there's the challenge of creating just the right matrix to nurture and support the cells while they grow into the correct shape. The organ must function correctly and avoid rejection by the body.

The hurdles may seem insurmountable, but tissue engineers already have grown skin that is used to treat burn victims, Langer said. Engineered bone, cartilage and corneas are in clinical trials, he said. Spinal cord repair kits and new blood vessels could follow soon.

Donate to JWR

But no one, not even Langer after nearly 20 years of trying, has been able to grow a liver. Or a pancreas. Or a kidney. Much work remains before that is possible, Langer says.

But maybe engineers don't have to do all the work.

"The most beautiful term one can use in describing a biological system is `self-assembling,' " said Gabor Forgacs, a physicist-turned-tissue engineer at the University of Missouri-Columbia. "No one will ever be able to mimic all the details of the biological program (of development), but the beauty is, there's no need for that."

Forgacs is working out a method that gets organs to build themselves.

Armed with a machine that works something like a dot matrix printer, a variety of gel recipes that the makers of Jell-O probably never dreamed of, and a few clumps of cells, Forgacs is printing organs.

The machine Forgacs uses is not a printer like the one linked to your personal computer. Instead, it's a device that spots drops of "bio-ink" in a pattern on a thin layer of gel "paper."

The organ printer's ink is composed of living cells. Each drop is packed with thousands of cells. The cells act like a fluid, flowing together and merging into a structure without boundaries. This liquid behavior is important to get cells in the right place at the right time during development, Forgacs said.

The physicist and his team demonstrated their technique in a report published last month in the Proceedings of the National Academy of Sciences. The scientists printed 10 dots containing 925 Chinese hamster ovary cells each in a circular pattern. The cells produced a protein called N-cadherin on their surface. The protein is an adhesion molecule, a type of molecular glue that helps cells stick together.

The dots of cells began to expand. As the dots touched, they merged with each other, forming a solid ring of cells. The experiment is the first step toward building a blood vessel. The next step is to build a tube of tissue by stacking alternating layers of gel and cells. The rings of cells will merge into a three dimensional tube.

As in any printing process, the paper is key. If the paper is too slick, the ink will smear; too porous and the ink may bleed.

In Forgacs' experiments, specially made gel matrixes serve as the printer's paper. The right matrix will help the cells hold the general pattern they were printed in.

Forgacs uses a special thermal gel matrix that will dissolve when the scientists raise the temperature, leaving the organ behind for transplant. Other tissue engineers have experimented with biodegradable scaffolds that melt inside the body once the replacement tissue is transplanted.

In the earliest printing experiments, Forgacs used a single variety of cells for the bio-ink. But blood vessels contain at least two types of cells - epithelial cells lining the inside and smooth muscle cells forming the outer wall.

Printing a blood vessel may be no more complicated than creating a ring of hamster ovary cells. Forgacs doesn't need to print separate rings of epithelial cells and muscle cells and then figure out how to glue them together. Instead, he plans to mix two kinds of cells and let them sort themselves into the proper arrangement.

This is where the physics comes in. Cells can sort themselves because of a property called surface tension. Liquids have different surface tensions, depending on their chemical composition. The property causes the fluid to either ball up or spread out. The molecules coating the surface of cells produce surface tension.

The result is much like the effect of dropping water into oil. The water molecules clump surrounded by oil. When water drops bump into each other, they flow together until all the water is collected in a puddle in the middle of the oil.

Forgacs and colleagues have shown previously that drops of epithelial cells and muscle cells will sort themselves to create an island of epithelia ringed with muscle, or vice versa, depending upon the gel matrix that surrounds the cells.

If the technique works, scientists one day may be able to remove damaged blood vessels from patients, grind the veins into bio-ink and print a new vessel.


Stem cells are a possible source of cells for tissue engineering.

Stem cells are primitive cells that specialize to form all the body's tissues. The cells contain all the instructions for forming every organ or tissue in the body, but haven't determined yet what they will be when they grow up. Scientists use chemicals and more mature cells to coax the stem cells into becoming certain kinds of tissues.

Embryonic stem cells can reproduce indefinitely, generating huge numbers of pliant cells that could be perfect for building new organs, Langer said.

But as the old adage states, more is not always better. During development, cells respond to certain cues and become an organ or tissue. Biologists have not learned all of the cues and don't always know how to prompt a stem cell into becoming a certain organ, said Dr. Leonard Zon, a pediatrician at Children's Hospital Boston and president of the International Society for Stem Cell Research.

If stem cells don't develop fully, they could grow into tumors when transplanted in a patient, some researchers fear.

Other scientists prefer to start with more advanced stem cells - so-called adult stem cells - such as the cells in bone marrow that will give rise to all the types of blood cells in the body, Zon said. Those cells don't need as much prodding to make the right type of tissue, but they aren't as plentiful as the embryonic cells. And scientists have found only a few varieties of adult stem cells. For instance, "we don't know if kidney stem cells exist," Zon said.

Simple tissues, such as cartilage, blood vessels, heart valves and cardiac muscle patches that could heal large scars in the heart, are likely to be the first products of stem cell engineering, said Dr. Catherine Verfaillie, director of the Stem Cell Institute at the University of Minnesota. But more complex organs, such as livers, kidneys, and lungs, which require many types of cells to arrange themselves in complicated three-dimensional structures "will obviously take quite a bit more time to accomplish," she said.

Scientists can transform stem cells into insulin-producing cells. Such cells hold great potential for treating diabetes. There's just one problem. The cells don't make insulin in response to glucose the way insulin-producing cells in a healthy pancreas would, said Dr. Marc Hammerman, an endocrinologist and director of the Renal Division at Washington University School of Medicine.

For 25 years, doctors have implanted adult pancreatic islet cells into diabetics, hoping to cure the disease. The procedure is still considered experimental and doesn't work well or for very long, Hammerman said. In 1991, doctors at Washington University performed the first successful islet cell transplant. Since then, doctors there have given 42 diabetics new islet cells. Only one patient was able to forgo insulin injections for more than a year.

Even if the transplants worked perfectly, there still would not be enough pancreases to go around, Hammerman said. Doctors harvest cells from about three pancreases to get the 700,000 to 1 million islets needed for a single transplant. And the transplant recipients must take powerful drugs to keep their bodies from rejecting the new cells.

Hammerman is treading a middle ground between stem cells and adult cell transplants. His path may help him avoid some of the pitfalls of each.

In Hammerman's lab recently, a quartet of white rats reared up on their hind legs and poked pink noses through the metal bars covering their transparent plastic cage. Sharon Rogers pulled a handful of rainbow-colored cereal loops from a bag and offered the rats a treat. These rats deserve to be spoiled, Rogers said. They're special.

Each rat has six kidneys_one of their own and five others taken from embryonic pigs.

The kidneys are not full-size pig organs. They start as organ primordia_pinhead-size collections of cells that form the first recognizable rudiments of an organ. The program for creating a kidney, liver or pancreas or other organ, has already been activated in the embryonic tissues, Hammerman said.

When transplanted into a rat, the organ primordia carry out their programming, growing into functional organs without additional instructions from the scientists.

Transplants of pancreas primordia have completely cured diabetic rats of their dependence on insulin, Hammerman said. The kidney primordia don't work as well, he admitted. They extend a rat's life for only 10 days to 12 days after the animal's functional kidneys are removed.

But the greatest advantage to using organ primordia may be the ability to avoid rejection.

The immune system grants special clearance to embryonic tissue, Hammerman said.

"When you transplant an adult organ, it's like transplanting a B-52," Hammerman said.

The immune system can easily detect the foreign organ on its radar. "But embryonic tissue is stealth," he said.

Pancreatic tissue is so stealthy it escapes the rat immune system's alert altogether, Hammerman said. The researchers withheld immune suppressing drugs from some rats in a control group. Those rats kept their new pancreases and were cured of their diabetes just like the rats that got drugs to prevent rejection.

But the ability to rebuff rejection also could be in the blood system. Organ primordia don't yet have a blood supply. As the organs develop, they attract veins and arteries.

Pig primordia implanted in a rat won't develop pig veins and arteries, Hammerman said. The new organs will hook up to rat blood vessels. Using the host's own blood vessels may cloak the transplanted organ from the host's immune system.

The researchers don't yet know whether pig organs will work as well in primates and people as they do in rats, Hammerman said.

Tissue engineers don't know how long patients will have to wait to get a designer organ. But stem cells, pig parts and printers one day could replace the need for donor organs.

Appreciate this type of reporting? Why not sign-up for the daily JWR update. It's free. Just click here.

Comment by clicking here.


© 2004, St. Louis Post-Dispatch Distributed by Knight Ridder/Tribune Information Services