Six years ago Michael Sefton of the University of Toronto challenged his colleagues in the fledgling field of tissue engineering to build a functioning human heart within 10 years. With the isolation of human embryonic stem cells later that year, Sefton's challenge seemed all the more relevant: stem cells, after all, are nature's starting point for building working organs.
Now Sefton admits that the deadline on his Living Implants from Engineering ("LIFE") initiative was naive, and he thinks it will be at least another 10 to 20 years. "We need to be able to walk before we can run," he says, "and the worry today is, Can we make a vascularized piece of tissue or a tissue with two or three cell types in a controlled way?"
Thin sheets of skin and single blood vessels have been grown in the laboratory, and some versions have already been put through human clinical trials. Yet any whole organ would be a complex three-dimensional edifice comprising specialized cells, nerves and muscle, all interwoven with a dense web of veins and capillaries diffusing oxygen and nutrients. The main hurdles have been just getting multiple cell types to grow and work in harmony and spurring formation of the blood vessels required to nourish tissues more than a few hundredths of a millimeter thick.
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By mimicking the natural 3-D shape in which an organ grows, tissue engineers are trying to get adjacent cells to "talk" to one another and complete the task of building the desired tissues. This approach has yielded "ink-jet"-dispensed dollops of cell aggregates "printed" in simple patterns that flow together, linking up into larger pieces of tissue. The next step will be to "print" designs using multiple cell types and eventually to print them layer on layer to create larger structures. A similar technique suspends living cells in a clear hydrogel matrix that can be layered or molded into 3-D shapes. Neither tactic has yielded the all-important vascular network needed to sustain thicker tissues.
More progress has been made by seeding stem cells onto a variety of simple scaffolds impregnated with growth-promoting chemicals. Last fall, for example, researchers from the Massachusetts Institute of Technology and the Technion-Israel Institute of Technology reported generating tissues of neural, liver and cartilage cells, as well as formation of a "3D vessel-like network" on a biodegradable polymer scaffold seeded with human embryonic stem cells. When transplanted into a mouse, the constructs remained intact and appeared to connect with the animal's blood supply.
Still, scientists working with stem cells, embryonic or otherwise, admit that they are just beginning to learn tricks for controlling the kind of tissue the cells become and just starting to discern the cues cells give to one another as well as take from their natural environment during the course of organ development. "We don't have anything like [nature's] exquisite repertoire of tools," Sefton says.
And so most models for growing entire organs involve using some kind of living "bioreactor." In some cases, it could be the same patient in need of the organ. Anthony Atala of Wake Forest University, who once grew a simple bladder in a beaker and transplanted it into a dog, teamed up more recently with Robert P. Lanza, also now with Wake Forest, and others to grow a mini kidney inside a cow. Kidney progenitor cells were taken from a fetal clone of the cow in question, then implanted into the cow's body, where they developed into proto-organs with all the cell types of a normal kidney. These "renal units" even produced a urinelike liquid.
The idea of seeding an organ and letting the body do the rest of the construction might work for a kidney, because the patient could be treated with dialysis while the new organ was being generated, according to Jeffrey L. Platt, director of transplantation biology at the Mayo Clinic. For a patient suffering from lung or heart failure, however, growing a new organ would put too much strain on an already weak body. But every advance toward creating ever more complex tissues might yield a lifesaving patch for a moderately damaged heart or liver, Platt says, along with fresh insight into how nature builds bigger body parts.