May 18, 2008
Growing Body Parts in the Lab Becomes Reality
COLUMBIA, Mo. -- Your heart is failing critically. A transplant would save your life, but the waiting list is long and the odds are stacked against you.
So instead, doctors extract some of your bone marrow, heart and muscle cells, go back to their laboratory and return in four to six weeks with ... a freshly grown heart.
Engineering body parts -- tissues and whole organs that are genetically compatible and available on demand -- sounds like science fiction. But researchers at medical centers around the world are working to make it a reality.
Already, a handful of children with spina bifida have received new bladders. Replacement blood vessels are being tested on dialysis patients. And researchers have re-created a beating rat heart.
Replacement parts grown in the lab may provide the best hope for fulfilling the unmet demand for organ transplants.
More than 95,000 people in the United States are on waiting lists for transplants. On average, one person dies every 90 minutes while waiting for an organ.
Other alternatives to organ transplants have proved elusive.
Transplants from animals, for example, face serious risks of rejection or viral infections. And mechanical organs, such as heart pumps, have been only a temporary solution.
"If we want to live forever, we need to do better," said Gabor Forgacs of the University of Missouri in Columbia.
Forgacs, a Hungarian-born biophysicist, directs the university's bioprinting program. In his basement lab, he is using a gleaming metal machine, a distant cousin of a computer printer, to build living blood vessels.
He has succeeded in making vessels that branch the way real veins and arteries do. He hopes to make replacement blood vessels that can be used in surgery, then fabricate human tissues with fully functioning blood systems that can be used to test new drugs. Ultimately, he wants to build replacement organs in his lab.
"That's everybody's dream," Forgacs said.
Tissue engineering, as Forgacs' field is called, is still very much in its infancy, the National Science Foundation says.
Even so, it has attracted more than $3.5 billion in investments for research, almost all from the private sector.
Because it relies on patients' cells, tissue engineering avoids the ethical controversies surrounding embryonic stem cells and therapeutic cloning.
Recent advances in growing human cells in the lab and in creating artificial materials that are compatible with living tissue have opened new possibilities for building organs.
But just like any infant, tissue engineering took some early tumbles.
Investors began pumping money into research and development in the 1990s. But the science had not advanced far enough. Some pioneering tissue engineering companies sought bankruptcy protection.
"I think it was very much hyped in the 1990s," said Robert Nerem, director of the Parker H. Petit Institute for Bioengineering and Bioscience at Georgia Tech. "Timelines were unrealistic; companies relied on investors with short time frames."
That first wave of tissue engineering did yield some useful products, such as artificial skin grafts that are used to treat diabetic skin ulcers. But many of the awe-inspiring breakthroughs that scientists are talking about are still many years away, Nerem cautioned.
"The real potential for tissue engineering is the vital organs, but we're a ways away from that, even though there's some exciting things being done," Nerem said.
Replacement parts for orthopedic surgery, such as bones, tendons and ligaments, may be 10 years from the operating room, Nerem said. Organs will take significantly longer.
One engineered organ that is available, though, is the urinary bladder.
Anthony Atala of Wake Forest University has successfully implanted new bladders in children, and they are being tested on adults.
It's a project Atala started 18 years ago.
"The research does go slow," he said. "You can only push the technology so fast."
But Atala, a pediatric urological surgeon, had strong motivations for proceeding with his research. Among his young patients were children with spina bifida whose bladders had malfunctioned, leaving them at risk of kidney failure.
Atala would perform surgery to replace their organs with new ones built from pieces of their intestines. But substituting the bladder with intestinal tissue can lead to long-term complications, from metabolic problems to infections and an increased risk of cancer.
"Here we were putting these things into babies with a life expectancy of 70 years," Atala said.
The first hurdle Atala faced was getting bladder cells to grow in the lab.
"They were thought to be types that couldn't grow well outside the body. We had to go through several years, and finally we were successful after much trial and error."
The next step was creating a "scaffold" that would hold the cells as they grew into the shape of a bladder. Atala devised a biodegradable scaffold made of collagen, the protein that gives structure to skin.
To make a new bladder, Atala plants the patient's cells onto the bladder-shaped scaffold. After about seven weeks, the cells have grown to cover the structure, and the new bladder is implanted. The patient's body adopts the new organ, branching out blood vessels to nourish it.
In 2006, Atala published results on the first seven children to receive the engineered bladders. Tests have shown that their new organs functioned as well as bladders fashioned from intestines, but without the complications.
A Pennsylvania-based company, Tengion Inc., is hoping to commercialize Atala's discovery, calling it the Neo-Bladder. The company is conducting clinical trials on children and adults as it seeks Food and Drug Administration approval.
Meanwhile, Atala and his team of more than 50 researchers are working to create a full catalog of body parts _ heart valves, blood vessels, livers, hearts, pancreases, even a uterus and a vagina for cancer patients.
"There's a definite learning curve, but with every organ we're accelerating the process," he said. "A lot of the strategies are the same, but you have to tweak it some."
It can take years to determine how well an engineered organ will work, Atala said. He followed each of his bladder patients for four years or more before publishing his study. His work on a liver and a uterus has been going on for 10 years.
"It's stuff you do slowly and carefully," Atala said. "We ask the acid question: Would you put this in your loved one, your child or spouse?"
Doris Taylor and her colleagues at the University of Minnesota say they were lucky to get an engineered heart beating as quickly as they did.
Taylor, a stem-cell researcher, recalled a chance hallway conversation four years ago with one of her colleagues.
"Cell therapy is our bread and butter, but wouldn't it be cool to make (patients) a new heart?" Taylor suggested.
"It was one of those ideas that made a lot of sense."
A member of her research team came up with a detergent solution that could be pumped into hearts taken from rats to wash away the cells. What was left was the heart's natural scaffold of translucent connective tissue.
"We had something that had the geometry and architecture of a heart," she said. "It was pretty clear to me we probably couldn't have built that in my lifetime."
Heart cells from newborn rats were cultured in the lab and injected into the walls of the scaffolds. The cells were kept alive with nutrients. After about a week, the newly reformed heart began to beat.
"I can't tell you how exciting it was," Taylor said. "It was flabbergasting. It was thrilling. It was one of those eureka moments in life."
If this technique can be adapted for human hearts, it will eliminate many of the problems of heart transplants, Taylor said. Because a patient's cells would be used, there would be no problem of rejection.
A donor heart must be transplanted within four hours. But if a donor heart is to be used only as a scaffold, it can be taken from a body that has been dead for a day or longer.
Taylor thinks she has gotten around the problem of how to build scaffolds for complex organs. The same approach could be used to grow kidneys, livers, lungs or pancreases, she said.
Forgacs is trying to engineer tissue without using scaffolds.
"That has been a big challenge to find the right scaffold for each cell type or for more than one cell type," he said.
Instead, Forgacs is using his machinery to "print" cells in the shape of blood vessels.
Forgacs loads two heads of his bioprinter with tiny spheres of 10,000 or more cells. Another printer head lays down a film of gel that serves as "biopaper." In this biopaper, the machine prints a circle of spheres. On top of the spheres goes another layer of biopaper and a second circle of spheres. The process is repeated until a cylinder is created.
"High precision, fairly quick _ there's really no limit to it," Forgacs said.
The spheres and gel are incubated until the spheres fuse together and the vessel matures. Each sphere contains a mixture of the cells that form the three layers of a blood vessel.
"Now comes the magic," Forgacs said. "Under appropriate conditions, the cells sort themselves."
Cells that form the outer layer of the vessel migrate to the outside, while the cells that form the smooth inner layer migrate inward. Muscle cells find their way in between.
A California company, Cytograft Tissue Engineering, is using a different method to engineer blood vessels. It is testing them on kidney dialysis and heart bypass patients.
The Cytograft vessels start with sheets of tissue grown in the lab. The sheets are rolled over a rod to form the tissue into a cylinder.
Forgacs said his tissue-printing technique would make it possible to create the structures of branching blood vessels needed to nourish the tissues of an engineered organ.
"There's no method other than ours that can produce a branched tube," he said. "We can build anything you want."
"It's really changing the paradigm to be scaffold-free," said Glenn Prestwich, a chemist at the University of Utah-Salt Lake City and one of Forgacs' collaborators. "We have a very simple technology and ask for the cells to do the heavy lifting."
When it comes to making spare parts for people, technology can only go so far, Forgacs said: "You have to rely on nature. And if you don't, I think this whole activity is futile."
1. Make an organ-shaped "scaffold" from collagen, then seed it with cells from the patient. Urinary bladders have been implanted in people.
2. Wash cells from an organ, leaving behind its natural scaffold, then seed with cells from the patient. Researchers have re-created rat hearts.
3. Go scaffold-free by "printing" clumps of cells into the shape of an organ, layer by layer. Vessels similar to veins and arteries have been created.