It’s a decade from now, and an elderly man gets the grim news that his heart is rapidly decaying and that the left ventricle-the chamber that squeezes blood out to the body-needs to be replaced. His physician takes a biopsy of the heart cells that are still healthy and ships the tissue to a lab that is really an organ factory. There, workers use the patient’s own cells and special polymers to fashion and grow a replacement part-certified by the original manufacturer. In three months, the new ventricle is frozen, packaged and sent to the hospital, where the patient undergoes a standard surgical procedure: the insertion of a living implant created from his own tissue. The surgery saves his life.
Not long ago, the notion of designing and growing living replacement body parts-a process now known as tissue engineering-seemed pure fantasy. But researchers in biotechnology are confident that the day will come when scenarios like the one above will be real and commonplace, thanks to advances made in the last decade in “biomaterials” that are compatible with living cells and the cultivation of new tissue, and to a far better understanding of how cells actually behave. The only question is, when? Some predict that within 20 years, possibly sooner, replacement ventricles, bladders, and the like will be readily available. For complex organs like lungs, though, it could take until mid-century.
A Run On Organs
For ill patients, breakthroughs in tissue-engineered organs can’t come soon enough. The shortage of donor organs is infamous. In 1999 (the most recent year for which complete data are available) there were more than 72,000 people in the United States alone on transplant waiting lists, according to statistics from the United Network for Organ Sharing. By year’s end, over 6,100 people had died waiting.
Dozens of groups in industry and academia are hoping to prevent those deaths, working on techniques for fashioning new organs out of cells from embryos, cadavers or patients themselves, combined with special biomaterials. Most current work in the commercial realm focuses on tissues, valves and other components of organs (see “Tissue Engineering in Industry” below). Already, there are a handful of tissue-engineered products on the market-skin, bone, and cartilage implants and patches-the first successes in a young field.
Michael Ehrenreich, president of Techvest, a New York-based investment company that closely follows the biotech sector, feels such achievements are only an indication of what’s to come, and he is blunt about where tissue engineering is now. “Skin. Big deal. It’s a proof of concept,” says Ehrenreich. “At the end of the day, many of us are going to die from some sort of organ failure. That’s what’s going to drive this market. And nobody’s really tackled a vascularized organ yet.”
Ehrenreich has touched on one of the more vexing problems facing tissue engineers: most organs need their own vasculature, or network of blood vessels, to get the nutrients they need to survive and to perform their intended functions. So before researchers can build a full-sized organ, such as a liver, say, or a set of lungs, they must learn to manufacture blood vessels.
Tissue Engineering in Industry
in the Pipeline
|Advanced Tissue Sciences ||La Jolla, CA |
Skin (TransCyte, Dermagraft); cartilage, ligaments and tendons; blood vessels and heart valves
|Genzyme Biosurgery ||Cambridge, MA ||Cartilage cells (Carticel); cartilage graft (Carticel II) ||CryoLife ||Kennesaw, GA ||Heart valves and blood vessels; ligaments||Curis ||Cambridge, MA ||Cartilage gel to prevent urinary reflux (Chondrogel); bladder||LifeCell ||Branchburg, NJ ||Skin (AlloDerm); blood vessels; ligaments and tendons||Organogenesis ||Canton, MA ||Skin (Apligraf, Vitrix); blood vessels|
Important progress on that front came two years ago, when MIT biomedical engineers Robert Langer and Laura Niklason (now at Duke University Medical Center) grew entire blood vessels from a few cells collected from pigs. Niklason, who led the effort and did much of the work during a stint in Langer’s lab, started by taking small biopsies from the carotid arteries of six-month-old miniature swine. She isolated smooth muscle cells from each tissue sample and used those cells to seed the outer surface of a tubular scaffold built of a biodegradable polymer used in sutures. Next, Niklason cultured each new vessel in its own special growth chamber called a bioreactor. Bioreactors are standard in tissue engineering, but in this case there was a twist.
As Langer explains, “What we did is we set up these little pumps that beat like a heart and hooked them up to the artificial blood vessels.” The researchers found that the pulsation encouraged the muscle cells to migrate inward, enveloping microscopic fragments of the polymer, and ultimately made the blood vessels much stronger. After growing the vessels in the pulsing environment for several weeks, they added endothelial cells-the thin, flat cells that line the inside of many tissues, including blood vessels-to their inner surfaces, and grew them for a few more days.
“That single change totally changed everything,” says Langer. “We were actually able to make blood vessels that looked like real vessels.” They functioned like real blood vessels too, staying open and clot-free for several weeks when the researchers grafted them into large arteries in the pigs’ legs. “The key to getting this to work was to mimic what the body did” by growing the vessels in an environment that pulsed just as a real circulatory system does, says Langer.
Beagle Bladders and Human Hearts
Even without the technology to build extensive vascular systems, one tissue-engineered organ has made it almost all the way to human trials: the bladder. Anthony Atala, a urologist and director of tissue engineering at Children’s Hospital, Boston, decided to try to build a bladder in part because it seemed like the easiest organ to begin with. In landmark work done in the late 1990s, Atala’s team built new bladders for six beagles. The researchers started by taking a one-centimeter-square biopsy from each dog’s natural bladder, isolating the lining cells and the muscle cells from the biopsy, and culturing each cell type separately.
After a month, Atala’s team had grown enough cells-300 million of each type-to construct an artificial bladder. They used the muscle cells to sheathe the outside of a bladder-shaped polymer scaffold, and the lining cells to cover the inside. The researchers implanted each new bladder into a dog after removing the dog’s own bladder. The researchers discovered that not only did blood vessels from the surrounding tissue grow into the tissue-engineered bladder and keep its tissues healthy, but the dogs also had almost as much bladder capacity as dogs with original equipment.
The early work went so well that Atala and Cambridge, MA-based Curis hope to begin the first tests of the new bladder in humans sometime this year. Still, Atala is realistic about what he’s already accomplished. For one thing, he has not yet answered the question of how long a bioengineered bladder will last. “With the bladder, it’s going to be several years until we know what the long-term results will be,” he explains. “We certainly have a good history with skin. Twenty years down the road we know it’s fine. With cartilage in the knee, we have a four- or five-year history from the time it was first placed in patients.” But with the bladder, Atala says, “We just don’t know.”
In the meanwhile, Atala’s lab has begun to tackle the kidney and has already built small kidneylike units capable of producing urine. Still, given that the kidney is a highly complex structure that includes as many as 20 different types of cells, researchers have to clear many technical hurdles before making full-sized organs for the nearly 48,000 people waiting on kidney transplant lists in the United States alone.
Tissue-engineering a heart will also be a formidable task, but there are a couple of reasons to believe concrete steps in that direction will be made in the not-too-distant future. For one thing, the heart comprises fewer than 10 different cell types. Perhaps even more important, there are two large research consortia targeting the organ. One is the LIFE initiative (for “Living Implants from Engineering”), begun in 1998 and coordinated by the University of Toronto’s Michael Sefton, with the help of a steering committee that includes Massachusetts General Hospital’s Vacanti and MIT’s Langer. The initiative has marshaled 60 academic and government researchers from North America, Europe and Japan to work on the body’s critical pump. Says Sefton, “If we can solve the heart, then the other organs will follow.”
Sefton readily admits that a project as enormous as building the heart is, on the face of it, ridiculous. Still, he believes that by breaking the job down into component tasks-isolating human cardiac muscle cells, say, or building flexible scaffolds to support those cells-a consortium of researchers will be able to make it happen.
That model is also being tested, Sefton says, in a university/industry collaboration led by the University of Washington. Financed by a $10 million grant from the National Institutes of Health and including more than 40 researchers, the University of Washington project has broken its undertaking into a series of goals. The first is to generate a tissue-engineered patch that can be grafted onto a damaged heart. Longer term, the researchers hope to build implantable left ventricles, a goal Sefton sees as a “mini-moonshot” that could be achieved within the decade. But a fully functional bioengineered heart, Sefton says, will likely cost billions of dollars-and neither the LIFE initiative nor the University of Washington’s has raised that kind of money yet.
Straight from the Factory
Ultimately, any method for building new human organs will have to win approval from the U.S. Food and Drug Administration. And that means organ builders will need a standardized, reproducible manufacturing process, says MIT bioengineer Linda Griffith. To achieve that goal, Griffith and her colleagues have turned to a device invented by MIT engineer Emanuel Sachs and used for rapid prototyping and the manufacture of a variety of parts and tools: a three-dimensional powder printer, or 3DP machine.
The machine builds up complex shapes layer by layer, based on a computer file capable of depicting the object as a series of horizontal slices. A roller pushes a thin layer of powder across a flat base plate resting on top of a piston. Next, an inkjet printer head distributes a glue, or binder, to solidify the powder only where the blueprint for that slice calls for solid material. The piston then ratchets the plate down by the thickness of the layer, and the process begins again. When all the layers have been printed, the new object can be removed from the machine, and the excess powder falls away.
By adapting the printer to use polymer powders, multiple print heads and special binders, Griffith and her collaborators created a tool capable of mass-producing polymer scaffolds for new tissues and organs. Not only does the printer allow the researchers to control a scaffold’s shape with great precision, it also allows them to build in chemical modifications to the structure’s surface that help tell different types of cells exactly where and how they should grow.
It’s just that sort of fine control that may help tissue engineers conquer even the most complicated organs. Indeed, Griffith is now-along with Vacanti and Princeton, NJ-based Therics-working out ways to manufacture livers and other organs with three-dimensional printing. Griffith already knows a great deal about growing liver tissue; she worked on the details while leading an effort to develop a liver-cell-based biological-weapon detector for the U.S. Defense Advanced Research Projects Agency. The hope is that scientific knowledge, combined with three-dimensional-printing technology, will make building a liver for implantation possible.
If everything pans out as Griffith, Vacanti and their colleagues hope, manufacturing machines could someday hum in FDA-certified organ factories. It’s too soon to know if those factories will churn out entire organs on site, or if they’ll instead produce and ship elaborate scaffold structures on which doctors will grow patients’ own cells, right in the hospital. But either approach, if successful, promises one thing: an end to transplant waiting lists.