The human cardiovascular system is highly efficient, yet enormously complex. A thousand times each day, the muscular heart pumps five quarts of blood through the arteries, to the smaller arterioles and finally the microscopic capillaries, and then through ever larger venules and veins, back to the heart.

The journey of blood through the capillaries alone covers more than 60,000 miles! In such an intricate and interconnected system, it's easy to see how a single glitch can profoundly affect health.

Medical researchers have devised some ingenious ways to replace malfunctioning cardiovascular parts. Substitute heart valves have been in use for three decades, and replacement blood, blood vessels, and even a heart are being developed.

Many of these inventions are carefully crafted combinations of synthetic materials and biological substances, designed to hopefully equal nature, yet at the same time mimic the body closely enough so that the immune system does not reject the new part. Plus, these products must present a smooth surface for blood to flow over. Even the tiniest uneven surface can rupture a passing platelet, triggering the chemical cascade of clotting that can obstruct blood flow to a vital organ.

Red Blood Cell Substitutes

Blood is a complex mixture of red cells, white cells, and platelets, suspended in a watery, protein-rich plasma. Because these components must be present in specific proportions, duplicating nature's recipe is a daunting task. But the rise in blood-borne infections, such as hepatitis and AIDS, has made the idea of a blood substitute quite appealing. The next best thing, many researchers think, is a substance that can do the work of red blood cells in transporting and delivering oxygen to the body's tissues and removing wastes. The hemoglobin protein in red blood cells normally carries out this function.

A safe and effective red cell substitute must meet strict criteria. "It must be absolutely disease-free, have a long storage life, and it must do the job for an extended period of time," says Joseph Stocks, M.D., a blood banking expert at the Maine Medical Center in Portland.

Several types of chemicals can carry oxygen. In 1965, Leland Clark, Ph.D., at the University of Cincinnati, showed that some chemicals soak up so much oxygen that they could supply the vital gas to an animal immersed in it. He dropped a mouse into a beaker filled with silicone oil. The animal's lungs quickly filled and it sank — but kept breathing! Silicone oil proved too toxic, so Clark next worked with the perfluorochemicals (PFCs), organic compounds containing the element fluorine.

Clinical trials with PFCs began in 1978, and the first red cell replacement using these chemicals was approved by the Food and Drug Administration in January 1990. The product, Fluosol, is a mixture of two PFCs, a mild detergent, and lipid molecules from egg yolk. Its use is very restricted.

"Fluosol was approved as an oxygen-carrying drug in limited amounts, to be used during balloon angioplasty in the coronary arteries," explains Joseph Fratantoni, M.D., of FDA's Center for Biologics Evaluation and Research.

With balloon angioplasty, an inflated balloon is used to press plaque against artery walls, opening up the blocked vessel. Blood flow to the neighboring area is temporarily impeded during the procedure, which may cause chest pain and change in heart muscle function. But Fluosol, infused through a narrow tube in the balloon, keeps the area oxygenated.

Previous attempts to deliver blood through the balloon failed because a very small tube must be used, and the red cells are too large to squeeze through. But a Fluosol particle is only 1/900th the volume of a red blood cell, and the preparation is half as thick as blood. With the protective effect of Fluosol, it may be possible to extend the angioplasty technique to more patients.

Fluosol may have other applications. Clinical trials are under way to examine its use following administration of "clot-busting" drugs such as streptokinase and tissue-plasminogen activator. After a clot is dissolved, the rush of blood through the opened region can damage tissue. Fluosol may stem this tide by allowing a steadier trickle of fluid past as the clot breaks apart. It may also help to save heart muscle normally deprived of oxygen during a heart attack and to oxygenate donated organs awaiting transplant.

An obvious red cell substitute is the hemoglobin molecule itself, which would probably not trigger an immune reaction if freed from the red blood cells that normally contain it. (Such an immune reaction can occur if a mismatched blood transfusion, containing cells from incompatible blood types, is given.)

There would be no compatability problem with freed hemoglobin, but it could carry disease, unless purified. Researchers at Somatogen Inc. in Broomfield, Colo., have circumvented these problems by mass-producing human hemoglobin in genetically engineered bacteria and yeast, providing a pure and abundant source of the molecule, much as human insulin is supplied to diabetics.

But use of single hemoglobin molecules outside of their red cell carriers presents several problems. The molecules are broken in two in the body, and can then squeeze through the one-cell-thick walls of the capillaries and easily enter the kidney tubules to be excreted before delivering oxygen where it's needed. In addition, without co-factors contained in the red cell, hemoglobin cannot efficiently bind oxygen delivered by the lungs, and also loses antioxidant biochemicals that normally protect surrounding cells from damage by too much oxygen.

Fortunately, clever chemists have already overcome these technological hurdles. They link individual hemoglobin molecules together, or chemically augment them. This provides the bulk the molecules need to stay in circulation. The molecule can even be further modified so that it not only binds and transports oxygen, but relinquishes it easily to oxygen-depleted tissues.

Several companies are applying these chemical manipulations to human hemoglobin derived from donated blood, starting with a "crosslinking" technique developed by Quest Blood Substitute, Inc., in Detroit. Werner Wahl, Ph.D., vice president for science and technology at Quest, explains: "When you crosslink hemoglobin molecules, you add a chemical reagent to tie two or more of them together. There are lots of kinds of chemicals you can use, but some are better than others. Exactly how you crosslink determines the characteristics of the hemoglobin."

Each company then introduces its own chemical modifications. One substitute, for example, follows crosslinking with a special pasteurization process to eliminate viral contaminants.

Tags: Heart Disease

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