Microcirculatory basis for the design of artificial blood

Artificial blood or blood substitutes are being developed using molecular solutions of modified free hemoglobin. When these products are used and the red blood cell mass is reduced below the transfusion trigger, there is a condition of extreme hemodilution which is characterized by a significant reduction of blood viscosity and NO production, reflex vasoconstriction, decreased functional capillary density, and impaired microvascular function. This combination of events may be lethal because decreased NO availability may also increase the intrinsic oxygen consumption of the tissue. Current developments in the understanding of the physiology of the microcirculation in extreme hemodilution, and the physical events associated with the substitution of red blood cells with molecular hemoglobin solutions show that a viable "artificial blood"; can be obtained from a new formulation of the product, where viscosity is such that when introduced in the circulation the resulting viscosity of blood is close to normal, the dissociation curve is left shifted and the concentration of hemoglobin is in the range of 3-5 g Hb/dl. This formulation redistributes viscous losses in the circulation causing higher capillary pressure which maintains functional capillary density, a key parameter in tissue survival. Furthermore the increased plasma viscosity increases shear stress in the microcirculation, enhancing the production shear dependent vasodilators, thus counteracting the vasoconstrictor effects due to NO scavenging by free hemoglobin solutions. A principal feature of this formulation is that it maintains microvascular function when the transfusion trigger is passed and the circulation is subjected to extreme hemodilution.