In 1957, Thomas Chang, an undergraduate at McGill University, decided his research project would be to make the first artificial cell and from this project reported the preparation of artificial red blood cells. That project grew into today's dynamic field of biomedical research in which "designer cells" are a major focus. Chang is credited with inventing microencapsulation, which allows biochemicals to be contained inside artificial membranes and, ever since that development, he and many other researchers have been on a quest to develop viable artificial blood to replace whole blood in transfusions. However, success has remained elusive. A safe, effective blood substitute is highly desirable because it would eliminate several problems of using fresh blood, including supply shortages in the face of increasing demand; short shelf life even under refrigeration; transmission of hepatitis, the AIDS virus, and other viral diseases, and the need for careful blood typing. The primary job of artificial blood is to duplicate the oxygen-carrying function of hemoglobin, an iron-containing protein within the red cells of natural blood. Researchers and manufacturers have taken two approaches: so-called "white blood" using perfluorochemicals (or fluorocarbons), and "red blood" made from modified hemoglobin.
The potential of fluorocarbons, a family of organic molecules, was dramatically demonstrated in 1966 by American physician Leland C. Clark, Jr., of the University of Cincinnati when he completely immersed a mouse in liquid fluorocarbon and discovered it could continue to breathe. Researchers subsequently determined that liquid fluorocarbon has the ability to dissolve large amounts of oxygen. The early fluorocarbons could not be used in human medicine, however, because they concentrated in the liver and spleen causing toxic side-effects. In 1973 Clark found that perfluorodecalin was completely eliminated from the body through exhalation; however, the drawback of this substance was that it could form large droplets capable of blocking capillaries. Ryoichi Naito, a chemist at the Japanese pharmaceutical firm of Green Cross, found he could overcome this problem by adding a second fluorocarbon, perfluoropropylamine, to the first. The result was a milky white solution called Fluosol-DA. In 1989, Fluosol was approved by the U.S. Food and Drug Administration (FDA) for use during balloon angioplasty. During the time the inflated balloon cuts off blood supply to some tissues, injected Fluosol can carry oxygen to the deprived tissue cells. While much has been done to improve perfluorochemicals, they are limited to low doses because of toxic side-effects. Also, because they lack the oxygen binding characteristics of hemoglobin, sufficient oxygen carriage occurs only when patients are breathing 100% oxygen.
This means only small quantities (amounting to one to two units of whole blood) can be used- -sufficient only to offset the need for this amount of blood during surgery.
A different approach to blood substitution has centered on hemoglobin isolated from the red blood cell and, by 1998, six North American companies were conducting modified hemoglobin clinical trials in humans, some progressing to Phase III clinical trials, in the continuing search for an appropriate substitute for blood. Use of free hemoglobin was suggested back in the nineteenth century, but modern researchers several decades ago discovered that such use had several severe problems. Outside the red blood cell, hemoglobin holds on tightly to oxygen and does not release enough to the tissue cells. Free hemoglobin also breaks down into two halves that are filtered out by the kidneys, which often causes severe kidney damage. To eliminate these difficulties, researchers have worked on various methods of effectively modifying hemoglobin. One approach has been to chemically link the hemoglobin subunits together, forming a bigger molecule (polymer) that will not break down. Although researchers were concerned that the giant molecules could damage body organs, animal tests were encouraging. Surgeon Gerald Moss of the University of Chicago licensed his multi-molecule linkage technique to Northfield Laboratories of Illinois and, in 1987, Northfield began clinical trials of modified hemoglobin in humans. The first round of tests were successful, but during the second round in 1989 several trauma patients suffered allergic reactions to the hemoglobin product. An FDA Advisory Committee investigated and learned of a German trial conducted by physician Konrad Messmer at Heidelberg University in the early 1980s in which the two volunteers suffered kidney failure after receiving a modified hemoglobin product. The FDA concluded that many organs of the body could be damaged by hemoglobin-based blood substitutes, and abruptly halted Northfield's human trials. Somatogen Inc. of Boulder, Colorado, used the understanding of hemoglobin's atomic structure discovered by Max Perutz to produce a genetically engineered modified hemoglobin that gave up its oxygen more easily and did not break down quickly. Somatogen produced its hemoglobin in yeast or bacteria rather than human or animal substances and sought approval for human testing in the early 1990s. Biopure of Boston began working with modified hemoglobin from cows in 1984 and began human trials of its product in Guatemala in 1990. DNX, a biotechnology company in Princeton, New Jersey, announced in 1991 that it had produced genetically-engineered pigs that made normal human hemoglobin. Some components of plasma, too, could be synthesized by the early 1990s. Genentech of California produced a plasma that promotes coagulation in hemophiliacs. All these approaches hold promise, but researchers remain uncertain about the cause of the toxic side effects produced by hemoglobin blood substitutes.
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