Sunday, August 5, 2012

Procedure to save the esophagus feeds effort to build human organs - Pittsburgh Post Gazette

Mike Wright's new esophagus continues to work like "a newborn baby's" -- his way of describing the organ he came within weeks of losing in 2010.

The 56-year-old Columbus, Ohio, man -- the world's second to undergo experimental esophagus-replacement surgery in Pittsburgh, his occurring in January 2010 -- remains the biggest cheerleader for the still-experimental surgery soon to be tested in a human clinical trial.

Blair Jobe, a West Penn Allegheny Health Systems surgeon formerly with the University of Pittsburgh Medical Center, is scheduling the clinical trial to begin in September and involving as many as 40 patients who have Barrett's disease with dysplasia (abnormal cell growth) or early-stage esophageal cancer.

The trial will test whether regrowth of the esophagus lining, as occurred with Mr. Wright, produces better results than the current practice of removing the entire esophagus to treat esophageal cancer, then creating a makeshift esophagus with a portion of the stomach. This highly invasive procedure, known as esophagectomy, is the mainstay of therapy for the majority of esophageal cancers and results in a 50-percent complication rate and a long-term quality of life issue, Dr. Jobe said.

Dr. Jobe's success in treating six patients to date without failure represents the latest advance in pioneering tissue-engineering research done at the University of Pittsburgh and UPMC's McGowan Institute for Regenerative Medicine. The current line of research began with the development of two-dimensional tissue replacement, including tubes or tracts and skin, with efforts now under way to replace tendons. The research is progressing to creating whole human organs.

PG graphic: Esophagus repair
(Click image for larger version)

Dr. Jobe said the replacement of esophageal linings in six patients represents "proof of principle for this approach, and we must now validate the results in a clinical trial in order to responsibly introduce this technique into clinical practice." He said there is still a problem of strictures, or a narrowing of the "food tube," in places after the lining restores itself. "But the strictures were stretched open with an outpatient procedure."

It's an issue to be addressed in the clinical trial.

The efforts of Dr. Jobe and the McGowan Institute reflect a worldwide trend in using tissue engineering to treat disease and repair damage. To date, 10 successful procedures to generate functional new tissue to repair tracheas have been reported, while eight patients have received new tissue-engineered bladders. Doctors still must study the patient outcomes, particularly if the procedures were done on a large scale, Dr. Jobe said.

Stephen Badylak, deputy director of the McGowan Institute and noted worldwide for his research in tissue engineering, developed the esophagus-replacement strategy and led research in removing cells from pig tissue to create a scaffolding that can regenerate damaged tissue. The scaffolding material, now available commercially, has been used 3 million times worldwide to repair linings, wounds and skin, with efforts under way to repair tendons.

It's the basis of the esophagus-replacement process. With six successes to date, Dr. Badylak said, "We're batting a thousand, but the numbers are still very low and further studies are definitely warranted." The scaffolding is a key element in research to create new human organs.

Evolution did the hard work of tissue engineering with its method of signalling stem cells to create the needed tissue, Dr. Badylak said. "We have realized the ideal scaffolding during 100 million years of evolution. The hardest part was done by Mother Nature."

The scaffolding is "extracellular matrix," or ECM -- a matrix or tissue framework developed from pig tissue from which all the pig's cells have been removed. The ECM naturally contains growth factors and proteins among other molecules that appear to signal the recipient's adult stem cells, and possibly other cells, to transform themselves into site-specific cells needed at that particular location of the body.

Esophagus replacement can be done only in patients with Barrett's disease with dysplasia or early-stage esophageal cancer that has yet to penetrate the deep esophageal layers. Penetrating the deeper layers, the cancer gains access to lymph nodes that allow the cancer to metasticize to other areas of the body. Unfortunately, the majority of esophageal cancers are discovered at a late stage when the novel approach couldn't be used.

For the right candidate for the surgery, Dr. Jobe cuts the cylindrical tube of lining at either end of the damaged area, as if he were removing a damaged piece of pipe, before pulling it out of the throat in a way similar to taking off a tube sock. If nothing else were done, resultant scarring would prevent swallowing and clog the throat. The ECM process regenerates healthy tissue without scarring.

Next Dr. Jobe uses pig ECM that Dr. Badylak developed and now produced commercially to form a new esophageal lining. The ECM tube is soaked until it is flaccid and then slipped over a collapsed spring-like stent. Once in place, the stent is expanded until it presses the ECM against the esophageal wall where the lining had been removed. In a process known as wallpapering, the stent holds the ECM in place until it adheres to the wall.

In a matter of days the ECM fully attaches to the esophagus wall to serve as a framework for stem cells or other cells to migrate there and heed signals from the ECM or from neighboring esophagus cells to transform into esophageal lining. Soon after the surgery with the stent in place, the patient can consume liquids. Full replacement of the lining occurs within several weeks.

In time, the pig ECM is replaced naturally with human tissue. Mr. Wright said he can eat and drink anything he wants without any difficulty in swallowing. In a second laparoscopic procedure, Dr. Jobe also created a new sphincter at the end of his esophagus to prevent acid reflux that Mr. Wright had suffered from since childhood. That's what caused the Barrett's disease, which in turn induced esophageal cancer.

Such success stories are adding to the knowledge of how the ECM works, with mysteries still unresolved.

Research is under way to determine whether organs need similar ECM to generate specific cells or if any ECM would work. Researchers also are studying what growth factors and other molecules ECM contains and their impact on cell replacement.

The research has turned attention to whole organs.

Dr. Badylak's lab has removed all cells from pig livers to develop a three-dimensional liver ECM, representing an important step in establishing a framework for regenerating a human liver. The next major step is to get the right tissue to grow inside the organ to make it functional. The ultimate goal is producing human organs using a pig ECM. The use of the patient's own adult stem cells would allow it be transplanted into that patient without rejection and eliminate the long wait for a donor organ.

His lab also has produced an ECM by removing the cells from the heart of a 600-pound sow, showing that the process is possible. His research team also is developing ECM for areas of the brain and spine with eventual hope of repairing brain or spinal injuries.

The effort of creating organs is no longer fantastical, although it remains futuristic. Dr. Badylak said all problems researchers face with organ creation are solvable and predicted that the liver and lungs will be the first successes followed by the kidney. The heart poses a more difficult task.

A team led by Anthony Atala, director of the Wake Forest School of Medicine's Institute for Regenerative Medicine, recently announced that it has produced a kidney ECM from a pig kidney.

Tracy C. Grikscheit, assistant professor of surgery at the University of Southern California's Children's Hospital in Los Angeles, is the principal investigator in research projects working to regenerate the entire alimentary system from esophagus to the rectum. She's already succeeded in regenerating the small intestine in animals by using a porous, synthetic scaffolding system rather than animal ECM.

"I think that we all understand stem cells better in this decade and the basic components of tissue engineering," Dr. Grikscheit said, noting that this decade could be the time when "we will start seeing human clinical trials and success in human tissue engineering" leading to whole human organs.

Mr. Wright already proclaims tissue engineering to be more than a success.

"It's a miracle," he said.

Dr. Jobe said the procedure enabled preservation of the esophagus and allowed Mr. Wright to avoid the risks of esophagectomy. Early discovery of his cancer is what saved his life. Mr. Wright's procedure helped to lay groundwork for others with Barrett's with dysplasia or early stage cancer to have their esophagi restored to normal function.

The problem can be fixed before it turns into a real problem, he said.

"I'm a thousand times better now and with no acid buildup," Mr. Wright said. "My esophagus is better than it was when I was a newborn baby."

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