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Rebuilding broken hearts
September, 27 2004
Toronto Star

A good heart is hard to find.

That's why researchers around the world are trying to grow their own.

Like the structural engineers who design a lofty skyscraper, tissue engineers are hard at work devising the best techniques for building the beating organ.

Heart disease is the leading cause of death in North America. In 1998, cardiovascular disease took the lives of more than 79,000 Canadians.

"Tissue engineering offers us a whole new potential," said Buddy Ratner, director of the University of Washington Engineered Biomaterials department. "It's very exciting."

Ratner is the lead investigator for the Bioengineered Autologous Tissues (BEAT) project. In 2000, the U.S. National Institutes of Health gave BEAT a five-year $10 million grant to get things started. The project's ultimate goal is to co-ordinate research in a variety of fields to build heart parts from living cells.

Ratner admits it's a lofty dream.

"I think this is certainly the most challenging project I've ever taken on," he said.

But it's one he thinks is worth pursuing.

Mechanical hearts have been around for decades. Unfortunately, the pumping machine isn't an ideal, long-term solution for most patients.

"They really do take patients out of near-death situations, but the devices are so awkward, infection prone and challenging for the lifestyle of a patient, that they will never be hugely used," said Ratner.

Heart transplants are another option for those with cardiovascular problems, and transplant surgery has improved over the years. According to a report released last week by the Canadian Institute for Health Information (CIHI), the survival rate for first-time heart transplant recipients treated between 1996 and 2001 reached 78 per cent. That's six percentage points greater than patients treated between 1990 and 1995.

The trouble is, there aren't enough hearts to go around. The donor population is small in number and aging, according to the CIHI. Last year, 30 Canadians died while waiting for a heart transplant.

Ratner believes part of the solution lies in heart "patches": sections of heart tissue that could be grown in vitro and later applied to a damaged heart.

"When you are born you have a certain number of heart cells," Ratner said. "They get bigger but they really don't grow. So if a person's heart is damaged ideally we'd like to take a sample of their heart tissue, expand it and develop living heart cells' paths with their own tissue."

Scientists can isolate the adult heart muscle cells, and keep them alive in a dish, but they won't grow on their own. Ratner said researchers are currently investigating ways to chemically treat the cells so they start dividing again.

Stem cells are another option for growing patches. Such cells are special because they can be coaxed into generating all kinds of cells, including heart muscle cells.

Chemical engineer Kim Woodhouse and her team at the University of Toronto are using embryonic stem cells from mice to perfect a kind of heart cell scaffolding. The polyurethane scaffold doesn't look very strong or impressive: it most closely resembles thin sheets of medical gauze. But the scaffold's appearance belies its careful construction.

"We can tune its mechanical and chemical properties," Woodhouse said.

The scaffold is intentionally designed to be elastic so the heart muscle cells, also known as cardiomyocytes, can pull on it. That tension helps the cardiomyocytes line up properly, so neighbouring cells can electrically stimulate each other and beat in unison.

Chemically, the scaffold is designed to gradually fall apart as the cardiomyocyte colony grows. Enzymes that naturally occur in the body cleave the chemical bonds that hold the scaffold together. Ideally, the scaffold's rate of breakdown will match the rate at which the heart patch would merge with a patient's organ.

Woodhouse's scaffold is based on one of tissue engineering's earliest success stories: artificial skin. Known commercially as Integra, the artificial skin was approved by the U.S. Federal Drug Administration in 1996 after decades of research. Like the heart patch, Integra employs a scaffold to assist tissue regeneration.

"It is used today for all manner of skin loss. These patients are not just burn patients - they are plastic surgery patients and also patients who suffer from chronic skin ulcers," said Ioannis Yannas of the Massachusetts Institute of Technology (MIT).

Yannas developed Integra with U.S. surgeon John Burke.

Normally, wounds heal in two ways: through contraction of the edges of the wound and the build-up of scar tissue. The Integra membrane, which is partly made of collagen, slows contraction and scar tissue formation so that proper skin cells can close the open wound. (Scars aren't actually made up of skin cells. They are composed of connective tissue that looks bad and doesn't play the functional role of skin, either.)

Unfortunately, a single scaffold won't work for all cell types. Organs have different cell densities and some applications require different kinds of cell organization.

The Integra scaffold is designed to orient the cells randomly so they are pulling in various directions instead of contracting in unison.

Woodhouse's scaffold, in contrast, is designed to line up the cells so they can coordinate their actions.

The BEAT project will also require more shapely structures than the flat sheets generated by an artificial skin scaffold. They'll need patches with some depth to them to repair hearts. To do that, researchers need to find a way to get nutrients to the innermost parts of the patch.

MIT researcher Gordana Vunjak-Novakovic and Milica Radisic, soon to join the University of Toronto, are working with a different kind of scaffold, designed to assist nutrient flow. Cells in the heart are very densely packed and are supported by an extensive network of blood vessels. Vunjak-Novakovic said she's producing "very nice, functional patches" after only eight days of culturing using what's known as a biomemetic approach.

"We are really trying to mimic - as close as we can - the conditions that underlie the development of the native heart," she said.

"We believe that the best approach to take is the one that really lifts recipes from developmental biology."

Consequently her scaffold is engineered with a very dense network of channels that act much like blood vessels, enabling the flow of oxygen and other essential nutrients to the heart muscle cells.

So far, Vunjak-Novakovic and her team (which operates outside of the BEAT project) have been using heart cells from rats and, more recently, human stem cells.

"We're just in the process of applying our method to human cells," she said. "We are honestly at the end of the beginning of the process."

Indeed, there are many unanswered questions when it comes to heart tissue regeneration.

Researchers are still toying with various scaffold and nutrient compositions, for example. It's not clear what kind of cells will best grow patches, either. There is also debate as to whether or not the cells really need to be lined up to beat in unison. Some researchers believe external stimulation by an electrical source might suffice.

Step into Vunjak-Novakovic's lab and you'll hear the tick, tick, tick of a pacemaker stimulating her heart patches, she said. Look in her bioreactor - a machine designed to supply nutrients and remove waste to tissue samples - and you'll see the tissue twitch.

The pacemaker provides a steady rhythm of electrical signals designed to stimulate the tissue as it grows.

"Stimulate, twitch. Stimulate, twitch. Stimulate, twitch," said Vunjak-Novakovic, describing the process.

Ultimately, researchers might want to figure out how to incorporate pacemaker cells, which regulate the beat of a native heart.

They also hope to develop a way to grow a network of real blood vessels in vitro, which could then be layered on to a sheet of nutrient-hungry cardiomyocytes.

Ratner said he thinks the patch could be completed by the end of the decade.

"The question then is what to do with it!" he said.

Ratner said if the 10 teams working on the BEAT initiative can create a living heart muscle within the next five years, their next goal would be to use that heart muscle to create a living fifth ventricle that might be used to assist patients with a failing left ventricle.

Another possibility is to use the patches for testing drugs.

"You can use engineered tissues in culture to test the effect of drugs or to perform other quantitative studies," said Vunjak-Novakovic.

It would have significant advantages over drug testing in animals, she said, because you could control environmental conditions with greater precision.

"In a rat, you cannot maintain all the parameters because the whole body is interfering," she said.

Researchers can also measure the effects of the drugs on the cells - such as their contraction and functional response - in more precise ways using a heart patch.

Tests would still need to be performed on animals, she said. But the heart patch tests would help researchers better understand the results from those studies.

The ultimate goal, of course, may be to build a whole human heart.

But that will require a great deal of additional work to bioengineer other functional structures such as heart valves.

In 1999, director of the University of Toronto's Institute of Biomaterials and Biomedical Engineering Michael Sefton said it could be done in 10 years with $5 billion (U.S.) in funding. Unfortunately, Sefton's Living Implants from Engineering project never found that funding. But Sefton said he still believes it can be done in a decade, given the money.

Until then, Sefton said, researchers will continue to work on small pieces of the puzzle with smaller budgets.

They will undoubtedly offer new insights into how our own hearts work, even if they never produce a fully functional heart.

"It's a challenge," Ratner said. "But we're starting to see glimmers of hope."

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