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Tissue Engineering Opens the Door to Replacement Organs
  
By Nancy Touchette

The first kidney transplant, performed nearly 50 years ago, opened the possibility of replacing worn or damaged body parts. Today, with demand for replacement tissues and organs far exceeding the supply, creating new organs in the laboratory is one of medicine’s important goals.

Thanks to the development of novel biological materials and advances in stem cell biology, scientists are making functioning organs and tissues from scratch. The day when a doctor can order a ready-made kidney or bladder is still many years away, but several types of organs and tissues are now being tested in humans.

Scanning electron micrograph of a collagen scaffold without (left) and with (right) added human penile cells.

One of the most promising technologies for making artificial organs stems from work by Anthony Atala of Children’s Hospital in Boston, Massachusetts. Using biodegradable materials and a patient’s own cells, Atala and his colleagues have constructed functioning organs, some of which have already been tested in patients. One bioartificial organ, the urethra, may soon win approval from the U.S. Food and Drug Administration.

Atala, who discussed his research recently at the fourth Annual Conference on Regenerative Medicine in Washington, D.C., is getting ready to test an artificial bladder in people. Other organs, including the kidney, penis, vagina, and uterus, are being developed and tested in animals.

“This is not imaginary science anymore,” says William Haseltine, CEO of Human Genome Sciences in Rockville, Maryland, and conference chair. “Functional tissues made from cells and biomaterials are being implanted in humans. And Atala has pioneered the field both as a practitioner and as a theorist in creating organs for implantation.”

Atala’s concept is simple. Mold an artificial structure out of biodegradable materials, seed it with a patient’s own cells, and transplant it into the patient. Then hope that a blood supply will reach the structure, allowing cells to grow in the shape of the scaffold. Eventually, the artificial scaffold degrades and the patient is left with a functioning organ.

X-ray picture of a bioartificial bladder 11 months after implantion into a beagle.

Using a patient’s own cells to construct a new organ offers a great advantage because it avoids the problem of rejection by the immune system. But it also means that each organ must be tailor-made to the individual and organs cannot yet be made for “off-the-shelf” distribution.

“The fact that you can do this on a bench-top does not mean you can easily make organs for the size of the market that needs to be addressed,” says Robert Nerem, director of the Parker H. Petit Institute for Bioengineering and Bioscience at the Georgia Institute of Technology in Atlanta.

Nerem predicts that it will take 6 to 10 years before artificial organs are approved and readily available for use in humans. “If you need a Tony Atala in every medical center, this is not going to happen anytime soon,” he says.

For Atala, an early hurdle was figuring out how to culture cells and stimulate them to form sufficient amounts of the cell types needed to grow into the organ or tissue of choice.

“We can now take a one-centimeter piece of tissue from a biopsy and culture the cells,” says Atala. “After eight weeks in culture, we can generate enough cells to cover a football field.”

Atala’s first success came in 1999 when he and his team transplanted bioartificial bladders into six beagles. Within a few months, the bladders were functioning and the dogs were able to urinate normally.

Since then, they developed a human bladder and clinical trials in humans are being planned. Clinical trials to repair small areas of human urethras using a scaffold made of collagen, without added cells, are complete, and FDA approval is pending.

The researchers also developed a method for treating urinary incontinence that is currently in clinical trials in humans. A mixture of the patient’s own cells and a synthetic gel is injected into the bladder, where the cells take root and eventually narrow the bladder opening.

Last year Atala published studies showing that when cultured cells from rabbit vaginas were seeded onto a polymer scaffold and then implanted into mice, the cells formed all the tissue layers found in a normal vagina. The cells contract and can be stimulated electrically, much like normal vaginal tissue.

Other ambitious projects are also in the works. For example, an artificial uterus and an artificial vagina are being tested in rabbits, and the researchers are also testing how rabbits fare when equipped with a functional bioartificial penis.

Atala and his colleagues are also making tissues and organs from cloned cells. This approach involves removing the nucleus of a mature animal cell and placing it in an egg to form an embryonic stem cell. The cells are then cultured and used to seed artificial scaffolds.

Using cloned cow cells, Atala and his colleagues have created functioning renal structures, similar to those found in kidneys. Three months after implantation, the artificial renal units contained all the cells of a functioning kidney and were producing urine that collected in an attached plastic bag. The next step is to create a functional kidney using human cells.

However, Atala is cautious about moving bioartificial organs into trials in humans until all the problems in animals are resolved.

“We have to develop all of these systems step by step, in stages,” says Atala. “We don’t want to move too fast and get ourselves in a position where we are trying to stop a runaway stagecoach.”

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Lanza, R.P. et al. Generation of histocompatible tissues using nuclear transplantation. Nature Biotech. 20, 689-696 (2002).

 

El-Kassaby, A.W. et al. Urethral stricture repair with an off-the-shelf collagen matrix. J. Urology 169, 170-173 (2003).

 

Falke, G. et al. Formation of corporal tissue architecture in vivo using human cavernosal muscle and endothelial cells seeded on collagen matrices. Tissue Engineering 9, 871-879 (2003).

 

DeFilippo, R.E. et al. Engineering of vaginal tissue in vivo. Tissue Engineering 9, 301-306 (2003).

 

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