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Blood substitutes: refocusing an elusive goal

Few would argue that an oxygen-carrying product that is universally compatible, safe, capable of prolonged storage under adverse conditions, simple to use and inexpensive could be an important adjunct to medical practice. Yet, such a product is not available, despite enormous efforts and expenditures by private and public institutions. Recently, one of the world's healthcare giants announced that their efforts to commercialize one product (diaspirin cross-linked haemoglobin; DCLHb), based on cell-free haemoglobin, had failed, despite the investment of over 15 years of development (Saxena et al, 1999; Sloan et al, 1999). The slow progress towards a red cell substitute is disappointing, but extensive research now underway has pointed out that accomplishing the goal is more difficult than was initially believed. All higher organisms have circulatory systems that feature cellular components for the delivery of oxygen (red cells). Mixtures of cells and plasma have unique properties of flow and gas transport in the microvasculature that are very different from the more homogeneous systems on which current red cell substitutes are based. Critical features of the cell/plasma system include very low solubility of gases in the plasma phase, diffusion barriers resulting from heterogeneous mixing and streaming of red cells in various degrees, depending on vessel diameter. In the normal circulation, microvascular haematocrit is significantly lower than large-vessel haematocrit, which establishes heterogeneity not only of oxygen content, but also of viscosity and shear forces on the endothelium. With the availability of new oxygen-carrying solutions, many of these properties have been studied in detail, leading to new formulations that overcome the key limitations of the preceding solutions. It is now possible to design oxygencarrying solutions that more realistically function in biological systems that have evolved around the cell/plasma system. The purpose of this review is to briefly describe the various products that have been studied over the past 15± 20 years and to summarize their key properties. Some of the relevant discoveries of the way cell-free oxygen carriers function and how these new discoveries may be applied to the design of more successful solutions to the blood substitute problem will be considered.