By ROBERT LEE HOTZ
Need an artery for bypass surgery or custom cartilage for that worn-out knee?
Need a new knee? What about an artery for bypass surgery? Some researchers are experimenting with techniques that build human tissue using patients’ own cells. WSJ’s Robert Lee Hotz reports.
In about a dozen major university and corporate laboratories, biomedical engineers are working on ways to print living human tissue, in the hope of one day producing personalized body parts and implants on demand. Still far from clinical use, these tissue-engineering experiments represent the next step in a process known as computerized adaptive manufacturing, in which industrial designers turn out custom prototypes and finished parts using inexpensive 3-D computer printers.
Instead of extruding plastic, metal or ceramics, these medical printers squirt an ink of living cells. Researchers call it by the shorthand bioprinting.
The machines can build up tissue structures, layer by layer, into all sorts of 3-D shapes, such as tubes suitable for blood vessels, contoured cartilage for joints, or patches of skin and muscle for living Band-Aids, recent laboratory studies have demonstrated.
“You can print a tissue dot by dot,” says bioengineer Gordana Vunjak-Novakovic at Columbia University’s Laboratory for Stem Cell and Tissue Engineering. “Bioprinting is a very clever technology which actually brought a completely new use to something very old that we all have at home, which is the inkjet printer.”
At Cornell University in Ithaca, N.Y., researchers are printing experimental heart valves, knee cartilage and bone implants. At Wake Forest University in North Carolina, bioengineers are printing kidney cells. Their colleagues are working on a portable unit to print healing tissue directly into burns or wounds. At the University of Missouri-Columbia, researchers have printed viable blood vessels and sheets of beating heart muscle.
Eventually, biomedical engineers hope to print out tailored tissues suitable for surgery and entire organs that could be used in transplants, to eliminate long delays for patients awaiting suitable donor organs and the risk their bodies may reject the tissue.
“Clearly, this is technology with many applications,” says biophysicist Gabor Forgacs at Missouri-Columbia, who helped to pioneer bioprinting.
The technology faces many hurdles. It may be five years or more before even the simplest of these experimental prototypes is ready for clinical testing. Problems range from the challenge of keeping large tissue structures alive to the lack of computerized tools for personalized organ design.
“A lot of biotech companies are sniffing around to see what the
market value of all this bioprinting might be,” says robotics engineer Hod Lipson, head of Cornell’s Creative Machines Lab and co-author of “Fabricated: The New World of 3D Printing.”
Leading the way is a closely held, San Diego-based company called Organovo Inc., which introduced the first commercial 3-D bioprinters in 2010, using technology developed by Dr. Forgacs at Missouri-Columbia and by researchers at Clemson University.
So far, the company has made 10 of its “NovoGen” bioprinters, at a cost of several hundred thousand dollars each. The company won’t disclose precise cost information.
“It allows us to print a tissue structure that is a functional, living, human tissue,” says Organovo Chief Executive Keith Murphy.
Organovo doesn’t sell them yet, but keeps the equipment for its own product-development projects. It does share them with other researchers through partnerships with Pfizer Inc., United Therapeutics Corp., and Harvard Medical School, among others. Mr. Murphy declined to disclose the details of these arrangements or say what bioprinted cell products were in development.
The programmable printer has laser-guided printing nozzles that can extrude inks composed of different cell mixtures. In each drop of ink is a solution that contains about 10,000 to 30,000 cells. The bio-ink is a mix usually cultured from stem cells taken from a donor’s bone marrow or fat. Those cells can then be grown into the many different cell types necessary for tissues.
“You use building blocks of cells to make a 3-D structure, almost like building something out of Legos,” Mr. Murphy says. “The cells do all the finishing touches themselves.”
To contain the cell structure in the desired form, the printer lays down layers of water-soluble gel at the same time. “It is like printing a mold at the same time that you print the cells,” says Sharon Presnell, Organovo’s chief technology officer. “That helps it get the shape.”
Once printing is complete, the tissue usually can support itself after about 24 hours. Then the gel mold can be removed. The tissue is kept alive in a bioreactor bathed in nutrients. Generally, it takes another three weeks before the tissue gains its full strength, as the cells build bonds between themselves.
Printed in a tube, such as a blood vessel, the finished tissue can withstand about six times the force of normal human blood pressure—still only half the strength of a natural blood vessel.
Every organ type and tissue structure has its own complicated internal architecture. At Organovo, researchers believe that there are basic cell patterns that, once fully understood, can be readily duplicated by bioprinting.
“Most tissues are repeating units,” she says. “The liver is a series of globules. The kidney is a set of pyramids. The body is a set of tubes.”
So far, bioprinting works best to make relatively simple cell structures a few hundred microns thick—the thickness of a few human hairs—comprising about 20 layers or so of cells. Among other things, larger printed tissues such as cartilage often aren’t strong enough on their own to withstand normal wear and tear.
More important, biomedical engineers say they haven’t yet mastered ways to print the microscopic networks of capillaries that run between layers of cells to keep normal tissue alive.
“One of the big challenges is figuring out how to feed these tissues,” says Christopher Chen, director of the University of Pennsylvania’s Tissue Microfabrication Laboratory in Philadelphia.
But even these rudimentary three-dimensional lattices of human cells could be valuable for drug discovery efforts and preclinical safety testing, researchers say.
Grouped together in a 3-D structure, human cells behave more normally than when they are cultured in a single isolated layer, as is customary in most laboratory tests, researchers say. That means clusters of bioprinted cells may be more realistic for pharmaceutical assays, compared with traditional lab cultures and animal tests, which can often produce medically misleading results.
“We will see more and more of bioprinting for the purpose of testing and developing drugs,” says Mr. Lipson at Cornell.
In the near term, Organovo has concentrated on developing 3-D cell cultures suitable for drug-discovery assays and toxicity tests, a global market currently valued at about $11 billion a year, according to BCC Research. In March, the National Institutes of Health gave the company a $290,000 grant to study ways to print 3-D liver cells—an important cell type for toxicology tests.
Advances are needed in the computer programs that will allow clinicians to routinely turn patients’ CT scans and X-rays into digital diagrams for printed body parts, researchers say. “We have machines that can make almost anything, but we don’t have the design tools,” says Mr. Lipson. “In bioprinting, there is no computer-aided design software for body parts.”
In the long run, bioprinting is bound to generate ethical concerns, as tissue engineers move from replacing and renewing body parts to improving them, Mr. Lipson says.
“The issue of enhancement has always been around, but this makes it more urgent,” he says. “If you are an athlete with improved knee cartilage, would you be disqualified because you were bouncier?”
Write to Robert Lee Hotz at email@example.com
A version of this article appeared September 18, 2012, on page D1 in the U.S. edition of The Wall Street Journal, with the headline: Printing Evolves: An Inkjet for Living Tissue.