Bubbles far tinier than the tip of a needle, yet tough enough to withstand the pounding of the heart, may make ultrasound an even more useful tool for physicians, helping them find liver tumors and analyze circulatory problems and heart disease.
Two University of Rochester scientists are seeking a patent on "bubbicles" -- tiny particles filled with microscopic-sized bubbles -- for use as agents which boost the contrast in ultrasound images. Using ultrasound to diagnose liver tumors and circulatory problems is cheaper and safer than using computerized tomography (CT) scans or X-rays. But without a contrast agent to highlight certain tissues, some tumors and blood vessels do not show up on an ultrasound image. Air is an ideal contrast agent for ultrasound, since air reflects ultrasound much more strongly than body tissues. Until now, however, no one has been able to make bubbles which emerge from the heart intact and last for several hours in the body.
"Most bubbles don't survive the journey through the left side of the heart. What we have developed is a very stable bubble, where the air is trapped within otherwise solid particles," says Michael Violante, associate professor of radiology at the University's Medical Center. Violante created the bubbles along with Kevin Parker, associate professor of electrical engineering and radiology and director of the Rochester Center for Biomedical Ultrasound.
Violante presented early test results last month at the International Meeting of Contrast Media Researchers in Cambridge, England. Afterwards, several companies expressed interest in the product. Violante and Parker have filed for a patent and are discussing licensing arrangements.
Scientists around the world have been trying to develop an ultrasound contrast agent since the idea was first proposed at the University of Rochester more than two decades ago by a team headed by Raymond Gramiak, professor emeritus of radiology. While air enhances contrast, researchers have found that making bubbles which hold together long enough to survive in the blood is difficult. So far no ultrasound bubble contrast agents have been approved by the Food and Drug Administration, though two for use in imaging the heart are currently in clinical trials.
"The bubble contrast agents that are now being tested appear good for cardiac imaging," says Violante. "But they can't get past the heart to image other organs or smaller blood vessels. Ours is the first bubble agent that has a chance at liver imaging." The bubbicles would improve detection of liver tumors by distinguishing healthy tissue from tumors. Tumor tissue does not filter out bubbicles from the blood and so appears significantly darker than healthy tissue, whose signal is enhanced because it does absorb bubbicles.
Bubbicles could help diagnose other conditions too, by allowing physicians to use ultrasound to view blood flow in the smallest and deepest blood vessels of the body. Doctors could evaluate a patient's heart disease with a simple scan of the coronary arteries, search for blood clots deep within a patient's legs, or search for areas of disturbed blood flow in tissues, possibly indicating the presence of a tumor.
To make the bubbicles, Parker and Violante trap air within iodipamide ethyl ester (IDE) particles which are less than one micron (one millionth of a meter) in diameter. Violante previously patented the carefully controlled precipitation process which produces the micron-sized, uniform, spherical IDE particles. The IDE provides a hydrophobic scaffolding, serving as a natural repellant to water in the bloodstream. Inside the IDE particle the air is stored.
"We trap bubbles inside very small pores, so tiny that the water can't get in to displace the air," says Violante.
Tests so far show that bubbicles also enhance CT images of the liver. This would make it possible for doctors to use ultrasound to routinely screen patients for liver tumors, then take a closer look with CT at those patients whose scans show anomalies.
Both Violante and Parker stress that, while initial results are promising, they need to do more tests before bubbicles could be used in patients.
This project was funded in part by the National Institutes of Health. Also working on the project were former graduate student Theresa Tuthill, now an assistant professor at the University of Dayton, and Raymond Baggs, associate professor of laboratory animal medicine.
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