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(Reprinted with permission from the Fall 2007 issue of Ward Rounds, the quarterly magazine of Northwestern University's Feinberg School of Medicine, article written by Michael Nyquist)
In November 2006 vascular surgeon Melina R. Kibbe, MD, GME ’03, assistant professor of surgery, was selected by NUCATS as one of four winners of the first Drew Senyei, MD, Translational Research Awards. Her project, “Development of an Endothelial Progenitor Cell–Lined Spontaneous Nitric Oxide-Releasing Prosthetic Graft for Vascular Surgery,” seeks to improve existing prosthetic grafts to treat peripheral arterial disease. “When people have blockages in the lower extremities, we perform a bypass graft using one of the patient’s own veins,” says Dr. Kibbe. “After five years, approximately 70 percent of vein grafts are still open. When those fail or a vein isn’t available because the patient had a coronary artery bypass operation, for example, we use expanded polytetrafluoroethylene [Gore-Tex®] grafts. They’ve been used since the 1970s and are the best alternative we have.” However, the Gore-Tex grafts “fail at an alarming rate,” Dr. Kibbe relates. “After two years, only 30 percent of these are still functioning. Sometimes we can insert a new graft, but a significant number of patients will end up with amputations because of this failure.” The problem occurs where the Gore-Tex graft and native artery meet. Explains Dr. Kibbe, “The compliance mismatch between the two causes neointimal hyperplasia, an aggressive growth of the vascular smooth muscle cells that line the interior of the artery. Eventually the cells encroach on the lumen and it clots up, creating a new blockage.” The surgery itself damages the one cell–thick endothelial layer inside the artery, preventing nitric oxide (NO) production at the junction. “NO inhibits the proliferation and migration of those smooth muscle cells,” continues Dr. Kibbe. “It also protects and stimulates endothelial cells, which produce more NO. If we can make this Gore-Tex graft act more like a vein graft by releasing NO, we will have a major impact on the treatment for peripheral vascular occlusive disease.” To that end she works with her Senyei award coinvestigator, Guillermo A. Ameer, ScD, assistant professor of biomedical engineering in the McCormick School of Engineering and Applied Science. Dr. Ameer previously developed a polymer for tissue engineering called poly(diol citrate), or POC, which they used to line the Gore-Tex grafts. In bench experiments led by co-investigator David A. Dean, PhD, associate professor of medicine, the researchers showed that endothelial progenitor cells adhered to a POC-coated graft, growing across the material in sheets. “In humans, endothelial cells do not stick to the graft,” says Dr. Kibbe. “POC stimulates endothelial cells and inhibits platelet adhesion.”  | Current treatment
To treat blockages in the lower legs (above, left) due to peripheral arterial disease, vascular surgeon Dr. Melina Kibbe uses prosthetic grafts (center) for bypass surgery when a vein is not available. Nearly 70 percent of these grafts fail within two years due to neointimal hyperplasia (right, the graft is not visible via angiogram because blood flow is blocked). Dr. Kibbe is testing a nitric oxide–releasing polymer coating for prosthetic grafts so they behave more like vein grafts. |
Following these and other in vitro experiments, Dr. Kibbe surgically placed pairs of Gore-Tex grafts in a pig model, one normal and one POC-coated, showing that POC is biocompatible, elastomeric, and biodegradable. This is important because of its intended application in the lower leg where normal movement includes bending and stretching as well as the hope that the patient’s own endothelial cells will grow inside the Gore-Tex tube and provide NO to the vascular environment.
To expedite that process, Dr. Kibbe explains, “The POC material coating the interior of the graft can carry a NO donor, such as polyethylenamine. When polyethylenamine comes in contact with hydrogen ions in an aqueous solution, such as blood, it undergoes hydrolysis and NO is spontaneously released. We’re trying to optimize our design to get the most nitric oxide released for the longest time.” They’re testing the best prototype in pig models. If these preclinical studies prove successful, Dr. Kibbe expects their POC-coated Gore-Tex graft to draw interest from medical device manufacturers, the NIH, and venture capitalists. In her presentation to the Senyei award selection committee, she noted that $47 million worth of Gore-Tex grafts were sold in 2005. “We’re modifying an existing graft,” she emphasizes. “Companies are already making them, and we want to get an improved product to patients. This is translational science at its best.” | |
