"Clinical trials in humans are ongoing using products from a number of companies. In the case of polyhemoglobin, Northfield is now in Phase III (large-scale efficacy) clinical trials that infuse up to 5,000 milliliters of blood substitutes into surgical patients. The company is using pyridoxalated glutaraldehyde cross-linked human hemoglobin. Biopure is in Phase II (small-scale efficacy) clinical trials using pyridoxalated glutaraldehyde cross-linked bovine hemoglobin. Hemosol is in Phase II clinical trials in surgical patients, using a new cross-linker to form a molecule known as o-raffinose cross-linked human polyhemoglobin. In the case of intramolecularly cross-linked hemoglobin, Baxter is now in Phase III clinical trials in a large number of surgical patients; the company is using Diaspirin cross-linked human hemoglobin. Somatogen is now deep into their Phase II clinical trials with their recombinant human hemoglobin. In conjugated hemoglobin, Enzon is now in Phase II clinical trials, and Apex is now in Phase I (safety) clinical trials.
"The basic ideas of cross-linked hemoglobin and encapsulated hemoglobin date back to the 1960s (see T.M.S. Chang in Science, Vol. 146, page 524; 1964, and H. F. Bunn and J. H. Jandl in the Transactions of the Association of American Physicians, Vol. 81, page 147; 1968). Concentrated efforts to develop blood substitutes for public use only seriously started after 1986 because of public concerns regarding HIV in donor blood. Unfortunately, a product must undergo years of research and development followed by clinical trials before it is ready for use in patients. It will take at least another one to two years for blood substitutes to be available for routine use. Had there been a serious development effort in the 1960s, blood substitutes would have already been available in 1986. As it is, the public has continued to be exposed to the potential, though extremely rare, hazard of HIV in donor blood.
"The present, first-generation blood substitutes are mainly effective for short-term uses because of their brief circulation time. They also do not have the enzymes needed to protect the body against oxidants such as oxygen radicals. Unchecked, oxygen radicals may cause reperfusion injuries and other problems. Enzymes are also important in preventing hemoglobin from being oxidized to methemoglobin, which cannot carry oxygen. Researchers are studying ways to solve this problem, including cross-linking the required enzymes to hemoglobin or further modifying the molecular structure of hemoglobin. These advances will appear in second-generation blood substitutes.
"Even in those second-generation substitutes, the hemoglobin molecules will not be protected by a red blood cell membrane. Thus, researchers are working on more complicated, third-generation blood substitutes that will encapsulate hemoglobin and the required enzymes inside artificial red blood cells. One method is to encapsulate hemoglobin inside lipid vesicles about 0.2 microns (millionths of a meter) in diameter. This technique also increases the circulation time. A more recent approach is to use nanotechnology to encapsulate hemoglobin and enzymes inside biodegradable polylactic acid membrane nanocapsules some 0.15 microns in diameter.
"The first modified-hemoglobin blood substitutes should soon be ready for use in clinical applications. Yet researchers are now facing many of the same problems as in the 1960s and 1970s. Granting agencies focus their resources to national priorities; blood substitutes research is not generally considered an urgent item. At the same time, private industry does not normally support the kind of long-term R&D needed to improve the present, imperfect substitutes. Developers of blood substitutes have formed an international network--the International Society for Artificial Cells, Blood Substitutes and Immobilization Biotechnology (www.physio.mcgill.ca/artcell/isabi.htm)--to promote their effort and encourage national committees and commissions around the world to include blood substitutes as a priority area in national medical policies.