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A compromise between a free, "naked" hemoglobin molecule and nature's red cell packaging is to enclose hemoglobin in a fatty bubble called a liposome, forming a structure called a "neohemocyte." Biologically, this makes sense. "Evolution spent an awful lot of time and energy wrapping hemoglobin in a membrane. So, maybe it isn't surprising that when you unwrap the package, there is trouble," says Fratantoni.

At the University of California at San Francisco, pharmaceutical chemist C. Anthony Hunt, Ph.D., is wrapping hemoglobin in the same type of capsules used to enclose ink in "carbonless carbon" paper and scents in "scratch 'n sniff" papers. But so far in animal studies, the immune system rapidly seeks and destroys these neohemocytes.

Brave New Blood Vessels

Delivery of blood through open vessels is crucial to cardiovascular function. Block a vessel with plaque or a clot, and blood flow backs up, robbing nearby tissues of vital oxygen. Blood can only flow through a smooth conduit. So far, none of the several methods to unclog or replace blocked arteries keeps them smooth indefinitely. Plaque that is scraped away or pressed against the artery wall recurs. A transplanted blood vessel may provoke the recipient's immune system to reject it, and taking a vessel from the patient's own body involves surgery at two sites rather than just one.

Synthetic blood vessels cause problems too. "There is a great need for a living artery equivalent that has the properties of an actual artery," says Eugene Bell, Ph.D., chief scientific officer of Organogenesis, Inc., in Cambridge, Massachusetts. "No small-caliber, synthetic vascular graft presently exists that will remain unplugged by blood clots."

That company's "living blood vessel equivalent," now being tested in animals, is a flexible yet strong tubule mimicking the triple-decker structure of real blood vessels. It is built of an inner layer of tile-like cells (called endothelium), a middle layer of smooth muscle, and an outer layer of connective tissue. The cells, which come from human cadaver arteries, are grown in the laboratory and then molded into the tubules. A very important step is the removal of molecules on the cells that are most likely to trigger an immune attack. A woven-in Dacron mesh lends strength to the tubules.

The blood vessel equivalent can be made in any length or width, and can tolerate the pressure exerted by blood hurtling through the circulatory system. The vessel replacements can be stitched to their natural counterparts so seamlessly that blood clots are not likely to form. Bell foresees eventual use of the living blood vessel equivalent in cardiac bypass surgery, and in replacing damaged arteries in the brain and legs.

Another possible blood vessel replacement is Dacron vessels coated with the patient's own endothelial cells. Because the body recognizes these cells as "self," it does not reject the replacement vessel. By adding certain growth factors, the cells are coaxed to knit a one-cell-thick endothelial lining on the interior of the Dacron tubules smooth enough to prevent clotting. In cell culture experiments conducted by Stuart Williams, Ph.D., and co-workers at Jefferson Medical College in Philadelphia, the lining began to form immediately.

Valves

Heart valves are flaps of tissue embedded in thin sheets of connective tissue. Located at strategic points in the heart, the valves keep blood flowing in one direction. About seven different types of artificial valves are approved for use by FDA. Some are similar to the first device, which resembled a ball in a cage. It was implanted in a 52-year-old man in 1961 by Albert Starr, M.D., and M.L. Edwards, M.D.

"It's hard to beat the original Starr-Edwards model," says John Watson, chief of the devices and technology branch of the National Heart, Lung, and Blood Institute. "Claude Pepper was one of the original people in Congress who helped form the institute, and he subsequently received a Starr-Edwards valve. He lived for 20 years and died from something unrelated. The fundamental design has been refined in terms of surgical technique and clinical management, but really there have been no significant breakthroughs."

But opinion varies. Says William Letsing, M.D., of FDA's Office of Device Evaluation, "The Starr-Edwards is a 1960s type valve. Many newer models, such as the St. Jude, have much better hemodynamics and a higher state of technology."

When natural heart valves do not close properly, are abnormally thick, or are damaged by rheumatic endocarditis (a complication of rheumatic fever that can also sometimes follow strep throat), replacement valves are lifesaving. After open-heart surgery became possible in the 1950s, surgeons first tried to treat valve disease by scraping away the calcium deposits causing the problem. But it was clear that replacing, rather than repairing, the valve would be more effective. Today mechanical prosthetic heart valves are built of a ceramic and a metal (such as titanium). Pig valves and cow pericardium (outer heart muscle) are also fashioned into valves that are mounted on synthetic bases called stents.

About 75,000 people receive replacement heart valves in the United States each year. Mechanical models are generally used for those under 65 because of superior long-term durability, and for children, who tend to deposit calcium on biological valves. Older patients are usually given animal models that do not last as long because they are less likely to calcify or be blocked by clots and may not require replacement. Many patients with mechanical replacement valves must take anti-clotting drugs because they otherwise would have a considerably increased risk of a dangerous clot forming.

But even a medical device as successful as heart valves can be improved. Charles Peskin, Ph.D., a mathematician at New York University, uses computer modeling to design better valves. Depicting the heart and its circulation in three dimensions, he alters the curvatures of the discs and angles of the pivot points so that the smoothest possible blood flow is achieved.

"We think of clotting purely as a chemical process, but it also depends on fluid mechanics," Peskin says." If the blood stagnates in a pool, a clot will form. We're trying to design a valve so there will be no regions of stagnation." One of Peskin's heart valve designs is being patented, but his device is still a long way from an FDA application.

Tags: Heart Disease

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www.fda.gov
FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.