Tissue Engineers Use 3D Plastic Molds To Create Organs

Biochemistry that makes alchemy look easy

By Joseph D'Agnese|Monday, October 24, 2005
RELATED TAGS: BIOTECHNOLOGY

Each year desperately ill hospital patients—currently some 89,000 men, women, and children in the United States alone—languish waiting for a transplant of a liver, kidney, heart, or other essential organs. The doctors who attend them know there are not enough organs to go around. Many patients die waiting.

To improve those odds, tissue engineers are trying to harness the power of stem cells by designing three-dimensional plastic molds, called scaffolds or matrices, that resemble organs or body parts. When a soup of nutrients and stem cells is squirted over a matrix, stem cells may grow into a hunk of tissue that can later be transplanted into a waiting patient. Somehow, the matrix imparts critical organizing information to the cells.

Researchers have successfully created simple tissues such as skin, cartilage, and bone. More complex structures—an ear and teeth—have also been grown. But the hope is that a complex organ, like a kidney or a heart, can be built.

Customized hearts, arteries, or valves would be a boon because substitutes leave much to be desired. Prosthetic devices can’t grow with young patients. Donor valves, whether from cadavers or pigs, fail after 10 to 15 years and sentence the recipient to a lifetime of immunosuppressive drugs to combat rejection. A heart, artery, or valve built from a patient’s own cells may never be rejected.

In what are among the earliest clinical trials, German researchers have created hybrid replacement valves. They started by removing valves from donor cadavers. Then they stripped the valves of rejection-provoking cells, leaving only an elastin-and-collagen matrix, and seeded the valves with stem cells taken from a vein in the leg or arm. The stem cells knit themselves into this donor matrix and, when the valve was transplanted, functioned well for more than three years. Critics of the protocol say it’s not ideal, because donor heart valves are still in short supply. So researchers are hammering away on two fronts: nailing down how stem cells work—and constructing better matrices.


The body shop
Laboratory-grown skin and cartilage are now a big business. But engineering complex structures such as arteries and heart valves, which are in great demand in the United States and elsewhere, remains a challenge.

7 - Number of days it takes to grow a tissue-engineered artery in vitro before implantation in a sheep

77 - Number of days it takes for the original plastic matrix to becompletely consumed by the sheep's own cells

30 - Number of weeks it takes to grow teeth from tooth-bud cells implanted in animal test subjects

6 - Number of weeks it takes to grow a functioning bladder in vitro

20 - Number of days it takes for donor skin to be grown into marketable sheets of skin 3 inches in diameter

$75 million - Annual U.S. sales of tissue-engineered sheets of skin


Robert Langer, a professor of chemical and biomedical engineering at MIT, is one of the two fathers of tissue engineering. In the early 1980s, he and colleague Joseph Vacanti, a Harvard University medical professor and a pediatric surgeon at the Massachusetts General Hospital, were the first to demonstrate a method for growing living tissues by seeding a biodegradable scaffold with human stem cells. Last April Langer won the $500,000 Albany Medical Center Prize in Medicine and Biomedical Research, one of the nation’s top medical awards. As Langer explains, designing polymers that work effectively with living cells is harder than it looks.

If I needed tissue-engineered material today, what is on-the-shelf ready for me?
L:
If you needed skin, you could get that. If you needed cartilage, there are variations of cartilage. But a lot of things are in clinical trials. Among those things in clinical trials are other cartilages, bone, corneas, blood vessels—that’s all in humans. Then there’s a lot in animal trials: intestines, spinal cords, vocal cords. Most of these use some form of matrix, even the corneas.

What’s the main challenge facing you?
L:
Well, I wish it was just one! On the material side, it’s creating the right materials that are highly biocompatible and that stimulate the right growth and cell behavior. Then there’s the reactive side. When you are trying to grow the tissue in a test tube, what are the right media and conditions that you need to use? Do you shake the cells? If so, how? That makes a huge difference. A few years ago, Laura Niklason, one of my postdocs, showed that the only way we could make a blood vessel was to shake it. In real life the vessels are hooked up to your heart. So we actually made little tubes, put the different cells on them, and hooked them to a pulsatile pump, which was like a little heart. It pumped, and the valves we made developed the strength to withstand real blood pressure.

So cells will respond when they’re stimulated in the right way?
L
: That’s right. A more recent study on heart muscle cells is another example. Gordana Vunjak, who works in our lab, got heart muscle cells to grow, begin pumping, and work much better by stimulating them electrically.

If these tissue matrices work well, why spend so much time designing different ones? Why reinvent the wheel?
L:
I wish it were that simple. None of these things work perfectly. For some of the tissues, we want a really elastic matrix. In 2002 Yadong Wang, another of my postdocs, created something called biorubber. It made a really, really rubbery matrix to simulate elastic tissues like blood vessels, heart muscle, ureters, and more. Before that we were using different polymers that were far more stiff.

How do these polymers break down in the body and not cause a problem?
L:
We design them to do that. We build in bonds that will be hydrolyzed by water. The building blocks—the components of these materials—are generally things already in the body or have been found to be safe in the body. One example is glycerol. Over time the cells colonize the shape, or the action of the body will break down the polymers. It is absorbed and doesn’t cause a problem.

How many different matrices have you devised?
L:
We have actually created a library of materials. The question is, how do you get different cells to differentiate? How do you get the different cell types you want or get them to grow at the rate you want? For some of these cells, nothing has ever been found that works well. Just to take an example: Nobody has figured out how to get human embryo cells to grow without using mouse feeder-cell layers to stimulate growth. So human stem cells grown in vitro are contaminated. That’s just to point out that we’re hardly done. There are many unanswered questions.

It’s no coincidence that the tissue-engineered products on the market are things that have few blood vessels. The thicker the organ, the harder it is to make because you must build so many blood vessels. How do you hope to build more complex organs?
L:
Joseph Vacanti and I have been working on that with the Draper Laboratory. We’ve been working on microfabrication, almost nanofabrication, to create networks of vessels. For some of them, we are etching the vessels on a silicon chip. It’s still early, but we’ve been able to get it to work reasonably well.

How would you get the thickness of larger organs like livers or kidneys?
L:
Well, you would grow one layer on a chip or matrix and then stack one on top of another. Hopefully, that way you would get the blood to flow over several layers, just like in real life.

How does the government’s limits on embryonic stem cell research affect you?
L:
We use adult stem cells, and we use the human embryonic cell lines that the government has already approved. It’s a little bit hard to know how much it curtails you because it’s something we can’t do. I personally think it’s good to go down as many roads as possible to solve a problem, so to have some shut off to me is a bad thing. But we’ve been able to do quite a bit with the cell lines that are available.

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