Skin Factory
A Stuttgart Lab's Pioneering Effort to Cultivate Human Flesh
By Johann Grolle
A mechanical arm snaps up a small plastic container full of a sloshing pink solution. A laser beam flits over the liquid, then another robot rolls up on a steel track, motor purring, and drizzles a few drops through hair-thin pipettes. A monitor records temperature, carbon dioxide and humidity levels.
A soft whirring is the only sound in this laboratory at the Fraunhofer Institute for Interfacial Engineering and Biotechnology (IGB) in the southwestern German city of Stuttgart. Sterile and sealed behind glass, these machines have just begun to produce an unusual product: human skin.
Each month, this skin factory will produce 5,000 discs of tissue about the size of a one-cent coin, with a projected price of €50 ($72) per unit. The product is a whitish color, almost transparent, though project director Heike Walles says it can also come in shades of brown.
The Birth of Tissue Engineering
The pieces of tissue swimming in their nutrient solution may look less than impressive, but the pilot project here is about more than just manufacturing skin. The process is meant to pave the way for a new era, one in which human tissue becomes an industrial product. The miracle of incarnation, which once only took place in the darkness of the uterus, is now happening under the cold neon light of an assembly facility controlled by robots.
This means that Heike Walles, the 48-year-old head of the institute's Cell and Tissue Engineering department, has finally reached her goal. A biochemist, Welles has dedicated her entire career to culturing tissue. One image that especially fueled her interest in this futuristic field was the famous photograph from the Vacanti laboratory at Harvard University. There, 15 years ago, brothers Jay and Chuck Vacanti created an ear-shaped cartilage structure and grafted it onto the back of a mouse.
When the Vacantis presented the world with photographs of their project, they also offered a bold vision of the future of medicine. They promised the dawning of a new era in the history of transplant medicine. Since human tissue could be custom-made, they said, there would never be a shortage of donor organs again.
The Vacantis also described how fully functional human hearts would grow in flasks and how livers would rise in incubators like loaves of bread. Chuck Vacanti even said it would be possible to produce entire limbs and provided a sketch of a synthetic arm. The brothers called their new industry "tissue engineering."
The First Pioneering Steps
Drawn by these promises, Walles signed on with the cardiac surgery department at Hannover Medical School (MHH) to learn about the production of arteries and heart valves. But she quickly realized just how naive the visionaries' dreams had been. "Researchers promised far too much at the beginning," she says. "At the time, it helped foster acceptance for the new technology. But, these days, patients and society are disappointed -- and rightly so."
Of course, tissue engineers continued to make headlines. Researchers at the Vacantis' lab then went one better by presenting the public with a heart the size of a cherry that beat away for 40 days inside an incubator. They even transplanted a synthetic lung into a rat that kept it alive for several hours. The scientists also instructed an artist in the art of cultivating tissue so that he could grow a steak in a petri dish. (The artist eventually admitted that the artificial meat had a horrible texture and taste hard-to-define taste.)
Elsewhere, surgeons reported success in human trials as well. In North Carolina, for example, doctors grew bladders from stem cells, which they then succeeded in implanting in children with malformed organs.
In an even more spectacular experiment in the northern German city of Kiel, doctors ventured to reconstruct a patient's jaw after it had been eaten away by a tumor. They designed the desired section of bone on a computer, used the design to fashion a mesh frame of titanium wire, and then sowed this with the 56-year-old patient's bone marrow cells. Then they allowed it to mature in his back muscle for seven weeks before attaching it to his face.
Circulation Problems
Still, all of these efforts were isolated cases and heroic pioneering acts that never made their way into daily clinical practice. Indeed, tissue engineering remains a refined handcraft, one that requires a great deal of tinkering and patience. Bioengineering laboratories now grow dozens of different cell types on spongy, rubbery or gelatinous frameworks, but most of these constructions are not suited for use in humans.
Blood circulation, in particular, has presented researchers with many problems, and attempts have repeatedly failed to produce blood vessels that can supply synthetic organs with oxygen and nourishment.
Cartilage is the only type of tissue uncomplicated enough to be manipulated with relative ease. Each year, surgeons in Germany implant around 600 pieces of artificial cartilage, and the number of patients with lab-grown cartilage cells infused into their damaged knee joints or spinal disks has climbed into the thousands. But scientists looking to make other types of tissue ready for clinical use find themselves facing far greater obstacles.
Walles speaks about how she also tried one of these projects once. She reaches for a blood-red object on her desk, a tube approximately the width of a finger, with delicate capillaries woven around it. The object is a replica of a trachea transplant Walles once developed with her husband, cardiothoracic surgeon Thorsten Walles.
For example, a suicidal 28-year-old man had swallowed drain cleaner because his girlfriend had left him. Though doctors were able to save his life, his trachea had suffered irreparable corrosion.
The bioengineers at the IGB promised to create a replacement. As their basis, they took a section of pig intestine and the veins that supplied it. Then, they stripped it of its porcine cells until all that was left was a fiber framework, which they sowed with human vascular, connective tissue and muscle cells.
The researchers created custom-made transplants of this kind for four patients, of which the 28-year-old was the third. "It was an incredible amount of very difficult, time-consuming work," Walles says. Doing so might make sense for helping a couple of seriously injured patients, she says, but it would be very hard to introduce as a standard technique in clinical practice.
Walles' experience in tissue engineering has only strengthened her conviction that this type of laborious tinkering will never lead to the emergence of a new branch of medicine. Indeed, she believes it will only be possible to create new products satisfying the requirements for widespread medical use if machines can be made to do the arduous, hands-on work now performed by lab technicians.
To that end, Walles set her sights on learning everything she could about stress tests and error analysis from engineers and process technicians. For their part, the technicians now had to teach their robots to handle human tissues rather than the fiber optics and condensers they were used to. The result is a manufacturing process bearing little resemblance to a traditional scientific laboratory.
Legal Hurdles to Testing
This laboratory produces strictly standardized compounds designed to meet legal requirements. In the beginning, regulatory authorities weren't quite sure how to approach these various synthetic cells, organs and tissues. "The question was: What are we really dealing with here? Are these body parts, drugs or medical-technology products?" explains Klaus Cichutek, head of the Paul Ehrlich Institute (PEI), the agency within Germany's Federal Ministry of Health responsible for regulating vaccines and other biological medicine products.
Since then, the EU has decided that tissues grown outside the human body -- regardless of whether they are skin, bone, liver or nerves -- are to be treated as pharmacological substances. This means that instead of simply trying out new methods on patients, as is common with surgery, tissue engineers must pass a licensing procedure set forth in pharmaceutical law.
"At the moment, the European Medicines Agency is perhaps our biggest hurdle," says Michael Sittinger, a cell biologist at Berlin's Charité Hospital who has been involved in tissue engineering for 20 years. Sittinger recently patented a type of cell specific to heart tissue that he hopes to use to treat cases of chronic cardiac insufficiency, and he is drafting a proposal for a clinical study.
The tissue engineers in Stuttgart believe that the chances that their industrially manufactured skin will receive approval are very good. Even so, they are not planning on rushing their products into standard clinical practice. They first have their sights set on finding clients in the chemical, pharmaceutical and cosmetic industries before putting them on the market for skin grafts for burn victims or people with wounds that are difficult to heal.
In 2006, the European Parliament passed a new regulation on chemicals and their safe use that drastically increased the number of animal tests required before a product can be approved for market use. Since then, an urgent search has been on for alternative methods of testing how new substances affect skin. This is precisely where the manufacturing facility in Stuttgart could come into play.
In other words, this method of tissue engineering is unlikely to start saving human lives any time soon. But it may stand between thousands of animals and death.
Translated from the German by Ella Ornstein
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