Methods and compositions for optimization of oxygen transport by cell-free systems

Abstract

Compositions, and methods of use thereof, for use as blood substitute products comprise aqueous mixtures of oxygen-carrying and non-oxygen carrying plasma expanders and methods for the use thereof. The oxygen-carrying component may consist of any hemoglobin-based oxygen carrier, while the non-oxygen carrying plasma expander my consist of any suitable diluent.

We claim:  
     
         1 . An aqueous cell-free composition comprising hemoglobin, said hemoglobin present in a concentration of between 0.1 and 4.0 g/dl, and said aqueous composition having a viscosity that is greater than 2.5 cP.  
     
     
         2 . The composition of  claim 1 , wherein said viscosity of said aqueous composition is between 2.5 and 4 cP.  
     
     
         3 . The composition of  claim 1 , wherein said hemoglobin has increased affinity for molecular oxygen as compared to red blood cells.  
     
     
         4 . The composition of  claim 3 , wherein said red blood cells are mammalian.  
     
     
         5 . The composition of  claim 4 , wherein said red blood cells are human.  
     
     
         6 . The composition of  claim 1 , wherein said composition has a P50 of less than 28 mm Hg.  
     
     
         7 . The composition of  claim 1 , wherein said composition further comprises a diluent selected from the group consisting of proteins, glycoproteins, polysaccharides, and colloids.  
     
     
         8 . The composition of  claim 1 , wherein said diluent comprises starch.  
     
     
         9 . The composition of  claim 8 , wherein said starch comprises pentastarch.  
     
     
         10 . The composition of  claim 1 , wherein said hemoglobin is surface-modified.  
     
     
         11 . The composition of  claim 10 , wherein said hemoglobin is surface-modified with a polyalkylene oxide.  
     
     
         12 . An aqueous cell-free composition comprising surfaced-modified hemoglobin, said surface-modified hemoglobin present in a concentration of between 0.1 and 4.0 g/dl, said aqueous composition having a viscosity that is greater than 2.5 cP.  
     
     
         13 . The composition of  claim 11 , wherein said viscosity is between 2.5 and 4 cP.  
     
     
         14 . The composition of  claim 12 , wherein said hemoglobin has increased affinity for molecular oxygen as compared to mammalian red blood cells.  
     
     
         15 . The composition of  claim 12 , wherein said hemoglobin has a P50 of less than 28 mm Hg.  
     
     
         16 . The composition of  claim 12 , wherein said composition further comprises a diluent selected from the group consisting of proteins, glycoproteins, polysaccharides, and colloids.  
     
     
         17 . The composition of  claim 12 , wherein said hemoglobin is surface-modified with a polyalkylene oxide.  
     
     
         18 . An aqueous cell-free composition comprising a mixture of hemoglobin and a diluent, said hemoglobin present in a concentration between 0.1 and 4 g/dl, and said wherein said diluent is selected from the group consisting of proteins, glycoproteins, polysaccharides, and colloids, and wherein said aqueous composition has a viscosity of at least 2.5 cP.  
     
     
         19 . The composition of  claim 18 , wherein said viscosity is between 2.5 and 4 cP.  
     
     
         20 . The composition of  claim 18 , wherein said hemoglobin has increased affinity for molecular oxygen as compared to mammalian red blood cells.  
     
     
         21 . The composition of  claim 18 , wherein said composition has a P50 of less than 28 mm Hg.  
     
     
         22 . The composition of  claim 18 , wherein said hemoglobin is surface-modified.  
     
     
         23 . The composition of  claim 22 , wherein said hemoglobin is surface-modified with a polyalkylene oxide.  
     
     
         24 . A method comprising: 
 a) providing: i) an animal, and ii) an aqueous cell-free composition comprising hemoglobin, said hemoglobin present in a concentration of between 0.1 and 4.0 g/dl, and said aqueous composition having a viscosity that is greater than 2.5 cP; and    b) administering said aqueous composition to said animal.    
     
     
         25 . The method of  claim 24 , wherein said animal is human.  
     
     
         26 . The method of  claim 25 , wherein said human has symptoms selected from the group consisting of symptoms of hypovolemic shock symptoms, hypoxia, chronic lung disease, ischemia, stroke, trauma, hemodilution, cardioplegia, cancer, anemia, sickle-cell anemia.  
     
     
         27 . The method of  claim 24 , wherein said hemoglobin has increased affinity for molecular oxygen as compared to human red blood cells.  
     
     
         28 . The method of  claim 24 , wherein said composition has a P50 of less than 28 mm Hg.  
     
     
         29 . The method of  claim 24 , wherein said composition further comprises a diluent selected from the group consisting of proteins, glycoproteins, polysaccharides, and colloids.  
     
     
         30 . The method of  claim 24 , wherein said hemoglobin is surface-modified.  
     
     
         31 . The method of  claim 30 , wherein said hemoglobin is surface-modified with a polyalkylene oxide.  
     
     
         32 . A method comprising: 
 a) providing: i) an organ, and ii) an aqueous cell-free composition comprising hemoglobin, said hemoglobin present in a concentration of between 0.1 and 4.0 g/dl, and said aqueous composition having a viscosity that is greater than 2.5 cP; and    b) perfusing said organ with said aqueous composition.    
     
     
         33 . The method of  claim 32 , wherein said composition has a viscosity of between 2.5 and 4 cP.  
     
     
         34 . The method of  claim 32 , wherein said organ is selected from the group consisting of kidneys, liver, spleen, heart, pancreas, lung, and muscle.  
     
     
         35 . The method of  claim 32 , wherein said composition further comprises a diluent.  
     
     
         36 . The method of  claim 35 , wherein said diluent comprises starch.  
     
     
         37 . The method of  claim 36 , wherein said starch comprises pentastarch.  
     
     
         38 . The method of  claim 32 , wherein said hemoglobin is surface-modified.  
     
     
         39 . The method of  claim 38 , wherein said hemoglobin is surface-modified with a polyalkylene oxide.  
     
     
         40 . A method, comprising: 
 a) providing i) liganded hemoglobin, ii) means for treating hemoglobin, and iii) means for surface decorating hemoglobin;    b) treating said liganded hemoglobin with said treating means under conditions such that a treated hemoglobin is produced having greater affinity for molecular oxygen than unliganded hemoglobin; and    c) surface decorating said treated hemoglobin with said surface decorating means.    
     
     
         41 . The method of  claim 40 , wherein said means for treating is selected from the group consisting of crosslinking means and polymerizing means.  
     
     
         42 . The method of  claim 40 , wherein said surface decoration of step(c) comprises reacting said treated hemoglobin with a polyalkylene oxide.  
     
     
         43 . A method, comprising: 
 a) providing i) liganded hemoglobin, ii) means for treating hemoglobin selected from the group consisting of crosslinking means and polymerizing means, and iii) means for surface decorating hemoglobin;    b) treating said liganded hemoglobin with said treating means under conditions such that a treated hemoglobin is produced having greater affinity for molecular oxygen than unliganded hemoglobin; and    c) surface decorating said treated hemoglobin with said surface decorating means.    
     
     
         44 . The method of  claim 43 , wherein said surface decoration of step(c) comprises reacting said treated hemoglobin with a polyalkylene oxide.