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Helping Hearts
Researchers are developing enabling technologies
for cardiovascular substitutes.
By Jane M. Sanders
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WITHIN SEVEN HOURS one day this past spring, Jerry Klein went from a treadmill stress test to operating room table for heart bypass surgery. It was the most surreal day of his life, he recalls.
courtesy of Jan Stegemann
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GTEC director Robert Nerem and doctoral students Jan Stegemann and Stephanie Kladakis have designed a model of a blood vessel wall. They are testing the model to determine the optimal mechanical and biochemical conditions for the implant's appropriate response to normal physiological stimuli.
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A 95 percent blockage in the "left main pump" of his heart stunned Klein, despite his family history of heart disease. In his early 50s, Klein has been an avid weight lifter and exercise enthusiast for 15 years.
"My training (in the gym) saved my life," he says. "I felt a burning sensation in my throat and upper left side of my chest when I worked out. I knew my body, and I knew something was wrong."
Klein – who has returned to work as a senior producer at CNN Sports Illustrated and resumed an exercise regimen – is a success story among the 600,000 patients who undergo heart bypass surgery in the United States every year. (Surgeons perform another 100,000 peripheral artery bypasses each year. And an estimated 25 million people in the U.S. and Europe have artery disease and may need surgery in the future.)
For now, surgeons must bypass diseased arteries with veins harvested from the patient, or, in the case of large vessels, a synthetic substitute made from Dacron or Goretex. Both options can present problems – a patient's veins are often of poor quality, and clots can quickly form in synthetics. Sometimes surgeons cannot use either option, and the patient's condition worsens over time.
courtesy of Emory Univ.
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Tissue engineering researchers are studying the use of donor cells with novel strategies for achieving immune acceptance. Chris Larsen, left, an Emory University transplant surgeon, believes co-stimulation blockade, a procedure he developed with surgical colleague Tom Pearson, may be part of the solution.
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Hope is on the horizon, though, because researchers in the Georgia Tech/Emory Center for the Engineering of Living Tissues (GTEC) are developing a blood vessel substitute – initially for small-diameter vessels. Soon, they plan to expand their research in tissue-engineered heart valves and add studies on myocardial patches (which repair the middle muscular layer of the heart wall).
Specifically, GTEC researchers are developing enabling technologies for (1) controlling biological responses; (2) creating immune acceptance; (3) predicting clinical effectiveness; and (4) engineering biological scaffolds, which are three-dimensional structures in which cells can be seeded to create a construct (basically, an implant) that mimics native tissue function and structure. Meanwhile, researchers are also conducting studies to gain fundamental knowledge in cell biology, biomaterials, biomechanics, implant and transplant immunology, and genetic engineering.
In the laboratory of Robert Nerem, GTEC director and head of cardiovascular substitutes studies, researchers are investigating cell sources for tissue-engineered blood vessels. Specifically, they are exploring the use of smooth muscle cells to seed a collagen gel implant coated with endothelial cells. (Endothelial cells line blood vessel walls.)
Nerem and doctoral students Jan Stegemann and Stephanie Kladakis have designed a model of a blood vessel wall. They are testing the model to determine the optimal mechanical and biochemical conditions for the implant's appropriate response to normal physiological stimuli.
Stegemann is engineering smooth muscle cells to suitably contract and interact with endothelial cells. Kladakis has worked with Nerem to quantify and enhance endothelial cell migration in the blood vessel wall model in the presence of simulated blood flow. Results from both students' experiments are promising, Nerem says.
In related studies, Steve Hanson, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, is characterizing the function of endothelial cells (which form the endothelium) and determining their potential use in tissue-engineered blood vessels.
courtesy of Stephanie Kladakis
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This microscopic image of endothelial cells shows the effects of exposure to shear stress.
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"Researchers want to mimic nature and engineer living tissues that will exhibit the important biological functions of native blood vessels," Hanson explains. "The key issue in tissue-engineered vessels is the endothelium, which confers many of the properties needed to maintain blood flow."
The potential to use endothelial cells in tissue-engineered vessels is greater now due, in part, to recent research at the University of Minnesota. Scientists there developed a method for extracting endothelial cell precursors called angioblasts from whole blood using simple centrifugation techniques. The research showed a robust proliferation of these circulating endothelial cells in the lab, representing a new, easy and quick source of endothelial cells for use in tissue-engineered implants.
Hanson and his colleagues have replicated the University of Minnesota findings in the their laboratory using blood samples from baboons and humans. Now, they have begun animal experiments to compare the functions of circulating endothelial cells to endothelial cells derived from other tissues. Hanson, Nerem and their students are collaborating on research to determine the capacity of endothelial cells to migrate and proliferate on different substrate surfaces and to learn the cells' response to shear forces.
Other researchers are grappling with the immune response issues associated with the use of endothelial cells in tissue-engineered cardiovascular substitutes. "Endothelial cells are the show stoppers," Nerem explains. "They are very difficult to accept immunologically."
photo by Gary Meek
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Elliot Chaikof, an associate professor of surgery at Emory and adjunct professor of biomedical and chemical engineering at Georgia Tech, is studying collagen, which ensures that tissues are strong, and elastin, which allows tissues to stretch and recoil. Using genetic engineering techniques, Chaikof and Vincent Conticello, an Emory chemistry professor, are developing an artificial biopolymer that mimics elastin. Combined with collagen and other materials, it could become a significant building block for artificial blood vessels similar in function to normal ones.
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One possible approach is to implant a graft without an endothelium and engineer it to recruit the patient's own endothelial cells. Another method is to provide a transitional endothelial-like lining using an immune-acceptable cell. Yet another possibility is the use of embryonic stem cells to make endothelial cells, an investigation by University of Georgia researcher and GTEC collaborator Steve Stice.
A fourth approach is the use of donor cells with novel strategies for achieving immune acceptance. Chris Larsen, an Emory University transplant surgeon and director of the Emory Transplant Center, believes co-stimulation blockade, a procedure he and his colleagues developed, may be part of the solution. They give patients an agent to selectively block an immune response to a transplanted organ. Doctors concurrently use a second strategy called hematopoietic chimerism (named after the mythical Greek animal called a chimera, which was composed of parts from various animals). With this approach, doctors perform a partial bone marrow transplant – meaning when they transplant an organ or tissue graft, they also introduce bone marrow from the same donor. The co-stimulation blockade should prevent an immune response to the marrow.
"This process re-educates the recipient's immune system so it doesn't reject tissue from a donor," Larsen explains. "The bone marrow-derived cells play a crucial role in defining what the immune system recognizes as self and not self."
Larsen's research results to date are promising. In rodents, researchers have recorded a 98 percent transplant success rate using co-stimulation blockage and hematopoietic chimerism. In primates, barriers still exist, though the results are yielding hope, Larsen adds.
GTEC research also encompasses the development of biomaterials that mimic the building blocks of normal blood vessels.
courtesy of Jan Stegemann
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Graduate student Jan Stegemann is engineering smooth muscle cells to suitably contract and interact with endothelial cells. Results from his experiments are promising.
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Elliot Chaikof, an associate professor of surgery at Emory and adjunct professor of biomedical and chemical engineering at Georgia Tech, is studying collagen, which ensures that tissues are strong, and elastin, which allows tissues to stretch and recoil. Both building blocks provide an optimal mechanical environment for cells to function, he explains.
Using genetic engineering techniques, Chaikof and Vincent Conticello, an Emory chemistry professor, are developing an artificial biopolymer that mimics elastin. Combined with collagen and other materials, it could become a significant building block for artificial blood vessels similar in function to normal ones. It may also have application in tissue-engineered heart valves and cartilage.
"We want to fully characterize the mechanical properties of the polymer, optimize the design characteristics and integrate the structures with collagen so they closely mimic target properties of normal blood vessels," Chaikof explains.
"We also want to characterize how well these structures function in animal models. So we're still a number of years away from clinical studies. But we are approaching organ design from a viewpoint of taking rational incremental steps forward."
Meanwhile, fundamental research at GTEC is showing the role of mechanical forces in tissue engineering. Ray Vito, a professor in the Georgia Tech School of Mechanical Engineering, is using an organ culture system designed by his colleague David Ku, a Regents professor in the School of Mechanical Engineering and a professor of strategic management and engineering entrepreneurship in the College of Management, as a test bed for understanding the mechanical environment of cells. (The culture system keeps arteries and vascular graft implants alive in the lab for up to two weeks.) Ultimately, researchers will use information from these studies to establish a rational basis for tissue-engineered design.
photo by Gary Meek
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Ray Vito, a professor in the Georgia Tech School of Mechanical Engineering, and graduate student Yu Shin Kim, foreground, are using an organ culture system designed at Georgia Tech as a test bed for understanding the mechanical environment of cells. Ultimately, researchers will use information from these studies to establish a rational basis for tissue-engineered design.
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"What's going on mechanically has an influence in determining the function of cells present in a vessel or tissue-engineered implant," Vito explains. "We've found some surprising things by looking at the heterogeneous microstructure of blood vessels. Mechanics could influence function."
Experiments in Nerem's lab correspond to Vito's findings. Researchers have found that the application of cyclic strain force to Nerem's bioartificial blood vessel model during tissue culturing in the lab improves its mechanical strength and structural organization.
And Nerem and colleagues have shown that mechanical forces regulate vascular biology, specifically the role of smooth muscle cells in enhancing the properties of the arterial wall.
In research on tissue-engineered heart valves, GTEC assistant director Ajit Yoganathan and graduate student Yun Xing are investigating the mechanically diverse forces – specifically, physiological pressure and shear stress – that affect heart valve leaflet cells. (Heart valve leaflets are the flaps that cover the valve openings.)
The researchers are subjecting leaflets to a specially designed pulse-type pressure system. Other experiments will apply shear stress to leaflets. Researchers know from previous studies the estimated level of shear stress to mimic what occurs in the body.
Results of this research will provide insight into the function of native heart valves and yield a standard of comparison for future tissue-engineered heart valves.
Research is ongoing at the Massachusetts Institute of Technology and Harvard University to develop tissue-engineered heart valves. Yoganathan hopes to contribute to this work by using information on cell response to mechanical environments to predict an optimal design for bioreactors used to test tissue-engineered heart valves in the laboratory.
For more information, contact Robert Nerem, Georgia Tech/Emory Center for the Engineering of Living Tissues, 315 Ferst Drive, Atlanta, GA 30332-0363. (Telephone: 404-894-2768) (E-mail: robert.nerem@ibb.gatech.edu).
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Last updated: Nov. 12, 2001
