Synthetic erythrocytes

Synthetic erythrocytes (SEs) are made by incorporation of stroma-free hemoglobin (SFH) or lipid-heme into liposomes. They form spontaneously at the interface between the phospholipid material and aqueous solution. SEs are spheroid vesicles with diameters between 0.01 and 4 microns, capable of carrying and delivering oxygen in a manner similar to red blood cells (RBCs). Oxygen-dissociation curve is virtually identical to that of RBCs, with P50 = 28 torr, and adjustable by the addition of 2,3-DPG or inositol hexaphosphate. Liposome/heme containing lipid-heme, a synthetic O2-carrying substance, is capable of carrying as much O2 as RBCs. Liposome-encapsulated SFHs have smaller O2-carrying capacity, but can be made to equal that of RBCs. Viscosity of SE suspensions is somewhat higher than blood's viscosity, but has otherwise similar rheologic properties. A large number of in vivo experiments with laboratory animals prove the ability of SEs to maintain life after virtually complete removal of blood. Cardiorespiratory functions remain near-normal, blood chemistry exhibits reversible mild changes, and vital organs do not show significant abnormalities. Blood coagulation is not affected. Hemoglobin does not appear in urine and plasma, indicating mechanical stability in circulation and absence of diffusion through the membrane. SEs do not cause significant acute toxicity. The absence of blood groups makes them a universal blood donor. However, massive doses suppress the reticuloendothelial system (RES). The animals undergoing total exchange transfusions may die of septic shock, apparently caused by nonsterile infusate in combination with strong suppression of the RES. Longevity of SEs in circulation is proportional to the dose. At doses corresponding to more than 90% exchange transfusions, half-life is longer than 24 h. Since all materials used in preparation of SEs are naturally occurring in blood, SEs are easily metabolized and eliminated without allergic reactions. The absence of membrane proteins and chemical stability of SFH and phospholipids promises long shelf-life. SE suspensions are difficult to sterilize, particularly against the viruses that may be present in SFH. However, the use of sterile procedures during manufacturing, and extraction of hemoglobin from animals bred under strict infection control may eliminate that problem.