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Tissue engineering holds promise for By Jane M. Sanders |
TOM HARTER WAS FINISHING his sophomore year at the U.S. Naval Academy when symptoms of increased hunger, thirst, urination and weight loss sent him to the infirmary. A doctor there quickly diagnosed Type 1 diabetes, and Harter began a life of insulin dependency.
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Now 47, Harter has an insulin pump, giving him some freedom, but still requiring a rigid daily regimen, which has helped him avoid common diabetic complications, such as organ failure, heart disease and vision loss. The disease has not slowed the pace of this successful businessman's life. Still, Harter hopes for more.
"If there was a new therapy to treat diabetes, I'd be first in line for it," Harter says. "Caring for yourself is still an ongoing challenge every day.... You have to battle your blood sugar. If it goes too high, you're affecting all your organs. If it goes too low, you go into insulin shock.... So what I'm saying is, I think I've attacked diabetes very well, but it's still a hassle I'd love to get rid of."
Researchers in the Georgia Tech/Emory Center for the Engineering of Living Tissues (GTEC) want to give Harter and the four million other insulin-dependent diabetics in the United States a life free of diabetic regimens and disease complications that cost more than an estimated $20 billion annually. They are developing an implantable, tissue-engineered artificial pancreas, which will regulate insulin for more than a year before needing replacement in a minor surgical procedure. Researchers also plan to initiate studies toward development of an artificial liver – a temporary liver support device at first and later a long-term artificial organ.
"Our focus is enabling technology, not products," says research manager Athanassios Sambanis, an associate professor in the Georgia Tech School of Chemical Engineering. "We want to enable the manufacture of metabolic and secretory organs at a clinically relevant scale, and make them immune-acceptable and available off the shelf."
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Researchers are well into their work on the pancreas, but intensive studies on the liver will not begin until 2002. "We are expanding into the liver area because the problem of liver failure is at the heart of the transplantation crisis," Sambanis explains. "Also, the temporary device and later the liver substitute are good test beds for core enabling technologies."
Despite promising results, it will be probably 10 to 20 years before these technologies result in routine procedures in humans, Sambanis cautions.
So GTEC researchers are pursuing the use of allogeneic cells – that is, donor cells from the same species. Other labs are providing continuous pancreatic cell lines that are genetically engineered to grow in a culture. GTEC researchers led by surgeon Collin Weber at Emory University are implanting encapsulated continuous cell lines in diabetic mice and monitoring the restoration of a normal blood glucose level, as well as the animals' immune response. Weber is using novel immune suppression strategies to enhance acceptance.
"This solves the cell availability problem," Sambanis explains. "Researchers can make an unlimited quantity of these cells in the lab. But there's still the problem of immune acceptance. To enable this, we are encapsulating the cells in a semi-permeable membrane that allows nutrients in and insulin out, but excludes larger molecules, such as antibodies and cells, including lymphocytes. This provides immune protection. It's not complete, but it helps a lot."
Another promising approach is the use of autologous cells – that is, the patient's own cells. In the case of the diabetic, researchers led by physician Peter Thulé at Emory University and the Atlanta Veterans Administration Medical Center are targeting liver cells. Thulé combines promoters (the region of a gene that determines whether it is "turned on" or expressed) from two liver-specific genes to create a promoter that mediates insulin production in response to blood glucose levels. Liver cells harvested in a biopsy could theoretically be infected with a virus carrying a glucose-responsive insulin gene, and subsequently be re-injected into the donor. In a more direct gene therapy approach, physicians could deliver insulin to a patient via a simple intravenous injection of a virus.
Gene therapies to regulate insulin production could result in a tremendous improvement in the quality of life for diabetics, but they are five to 10 years away from clinical practice, Thulé estimates.
Ioannis Constantinidis, director of radiological sciences at Emory University, is developing a non-invasive method for determining the level of metabolic function in an implanted bioartifical pancreas. The technique, called nuclear magnetic resonance imaging, will also reveal whether the implant is integrating with surrounding tissue as it should.
"When you have to stick your finger five times a day to determine what to eat and what activities you can do, day in and day out, that becomes so intrusive in your life," he adds. "If you could get the same result and not have to do anything, it would be great. So gene therapy could provide a huge lifestyle benefit, even if the health benefits were similar to current therapies."
Engineered cells from a patient's cell bank also could seed an artificial pancreas for implantation. Thulé and Sambanis are developing ways to encapsulate these cells, allowing more or less insulin output, as needed. The capsule isolates these genetically engineered cells in the area where they are implanted, making them easier to retrieve and reducing the risk of an immune system response, Thulé explains.
Joe LeDoux, also an assistant professor in BME, is developing retroviral delivery mechanisms for engineering non-pancreatic cells to secrete insulin in response to glucose.
In a related project, Sambanis hopes to improve the secretion dynamics of genetically engineered cells, further altering them to respond more rapidly to glucose levels. And he and his colleagues are also developing cell biomaterial hybrids that enable and enhance cell function.
Researchers are facing other challenges in the development of the bioartificial pancreas. These include designing the capsules so that they can accommodate a high number of properly functioning, insulin-secreting cells (this reduces the volume of the implant that is needed to achieve a physiologic effect); the low-temperature preservation of the capsules so they can be available off the shelf; and the avoidance of excessive fibrosis after implantation in the patient.
"The long-term objective is to develop a prognostic test to tell patients how well the construct is functioning and to predict when they will need to come back to the doctor," Constantinidis explains.
In addition to lab studies in bioreactors, Constantinidis recently began studying the use of NMR in monitoring implants in the abdomens of mice over several months. He implants "beads" – cells engineered to produce insulin in response to glucose, trapped in a natural gel-like biomaterial, and surrounded by a semi-permeable membrane. For this prototype, the beads are contained in a silicone O-ring, making the implant easier to study with NMR.
"We need to understand what we're seeing with NMR," Constantinidis says. "How can we harness the information? We see certain changes – brighter parts and darker parts. Does the contrast indicate viability? Can we quantify and monitor these changes over time?"
Constantinidis hopes his findings will yield insight for optimizing the design of the bioartificial pancreas.
"I believe we will see bioartificial organs in my lifetime," Constantinidis says. "The imaging techniques that we use are already applied to patients' native tissues ... so imaging will not be the limiting factor."
"Any procedures we do must be safe and efficient in the long term," Sambanis emphasizes. "The artificial pancreas is not a cure, but it will be a significant improvement in the quality of life for diabetics. And it will significantly reduce long-term complications such as cataracts and cardiac disease."
A challenge for GTEC researchers is the type of cells to use for creating a tissue-engineered artificial pancreas. In diabetics, insulin-producing cells are not properly functioning or are dead. Donor cells from cadavers are not readily available; it would take 200,000 to 300,000 cadavers a year to generate enough islets, or clusters of insulin-producing cells, to treat 100,000 diabetics for one year. Pig islets have been studied as another possible cell source, but their immune acceptance in humans is a large obstacle.
courtesy Emory University
Meanwhile, Julia Babensee, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering (BME), is conducting fundamental research on the immune responses caused by antigens presented by free and encapsulated cells. Her results will provide insight for better design of capsules to promote immune acceptance.
Even though the artificial pancreas is more than a decade from clinical practice, researchers want to be prepared to monitor the organ when it does become a reality. So Ioannis Constantinidis, director of radiological sciences at Emory University, is developing a non-invasive method for determining how well the implant is functioning metabolically and whether it's integrating with surrounding tissue as it should. Constantinidis uses nuclear magnetic resonance (NMR) spectroscopy and imaging, the same technology used for MRIs in humans, to monitor tissue-engineered implants – first the artificial pancreas and later cardiovascular implants and other tissue-engineered constructs.
Though diabetes is a chronic and sometimes devastating disease, it is usually not immediately life threatening. That fact gives researchers an advantage, Sambanis says. They can design therapies that involve cell banking over a two-month period, while patients needing blood vessel replacements usually don't have the luxury of time, he adds.
For more information, contact Athanassios Sambanis, School of Chemical Engineering, Georgia Tech, Atlanta, GA 30332-0100. (Telephone: 404-894-2869)
(E-mail: athanassios.sambanis@che.gatech.edu)
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Last updated: Nov. 12, 2001