Grande-Allen, assistant professor of bioengineering, hopes to use the new system to identify some of the first drug therapies that are specifically tailored for patients with valve disease, but until just a few months ago, the test chamber -- called a bioreactor -- was an idea without a sponsor. That changed last fall, when the National Science Foundation and the Pfizer Research Foundation each agreed to fund aspects of the project. This month, the National Institutes of Health added its own award, bringing the total project commitment to more than $750,000.
"From previous studies of diseased values that were removed during valve replacement surgeries and autopsies, we've identified significant structural and chemical differences between diseased and healthy valves," said Grande-Allen. "The tissue is completely different, which indicates that the body has rebuilt or remodeled the valves based upon a set of biochemical rules we don't yet understand."
Pfizer's support for Grande-Allen's research followed her January 2005 publication of surprising new findings that showed that the basic biochemical composition of heart valves in patients with congestive heart failure was markedly different than those with healthy hearts. The Journal of the American College of Cardiology recently named the paper to its "Highlights of the Year" list for 2005.
In future work, Grande-Allen would like to simulate what happens inside a living heart. One aspect of the research involves recreating the mechanical stimulation -- the stretching, pulling and compressing -- as well as the fluid movements and pressures found inside a living heart.
Grande-Allen's initial goal is to build bioreactors that can provide this stimulation and keep the tissues in pig heart valves alive for a period of weeks. Pig valves were chosen because the tissues are very similar to those found in humans. In previous studies, Grande-Allen's group proved it could keep cells alive in pig valve tissues for up to seven weeks, more than three times longer than anyone had previously showed. But additional studies determined that the cells in the valves changed dramatically once they were removed from the rough-and-tumble environment inside a beating heart.
Once tested -- a process that could take up to year -- Grande-Allen's bioreactors will be used to simulate conditions that have been linked with valve disease – like the progressive buildup of neurohormones in the blood of patients with chronic heart disease or the elevated levels of serotonin in patients with abdominal carcinomas. In another experiment, Grande-Allen hopes to recreate the process that causes thick, calloused plaques to form on valves in the presence of fenfluramine, one of the drugs used in the now-infamous and banned diet-drug combo Fen-Phen.
Pfizer's support, given under the foundation's Atorvastatin Research Award program, is aimed at determining whether Atorvastatin, a commonly prescribed anti-cholesterol drug, might also protect against valve disease. The program is designed to support outstanding investigators at the early stages of their careers in academic research. It gives only 20 awards each year and draws applicants from a wide range of health-related disciplines.
"By the time these grants run out, we should have a well-tested bioreactor that's capable of recreating the movements, pressure and flow rates that occur inside the heart," said Grande-Allen. "That will be a very valuable tool that could be turned to a broad range of experiments aimed at the underlying mechanisms of blood pressure, fibrosis and other ailments."