Red blood cell substitutes: fluorocarbon emulsions and haemoglobin solutions

Abstract

The problems posed by transfusion of homologous blood have led to the development of substances able to replace the gas transporting properties of blood. Perfluorocarbons (PFCs) emulsions and modified haemoglobin (Hb) solutions have been developed for this goal and are now tested in clinical assays. PFCs are synthetic fluorinated hydrocarbons, capable of dissolving large quantities of oxygen (O2; without binding) at high inspired concentrations of O2, and of delivering this O2 to the tissues. They are administered as emulsions containing particles with a diameter of approximately 0.2 micron, capable of entering the microcirculation. They are eliminated unchanged by the lungs within several days. Fluosol-DA 20% was the first PFC emulsion used in clinical practice. Currently, Oxygent, a second generation PFC emulsion, is being evaluated in clinical studies. The PFCs are not blood substitutes, but rather a means to ensure tissue oxygenation during extreme haemodilution. Solutions of free Hb do not have the antigenic characteristics of the blood groups, and do not require compatibility testing. They are fully saturated with O2 at ambient FiO2. The Hbs used are derived from either human or bovine sources, or via recombinant DNA technology. In order to maintain satisfactory intravascular half-life and O2 affinity, the Hb molecules are modified by adding internal crosslinks, by polymerization, and/or by encapsulation. After promising animal studies, several of these modified Hb solutions are now being studied in Phase III clinical trials. Among them, diaspirin cross-linked haemoglobin (DCLHb) has been used in cardiac and orthopaedic surgery, and for resuscitation of traffic accident victims. The initial results of multicentre trials are now being analysed.

Blood Transfusion in the 21st Century

“…However, PFC's are also water insoluble and must be emulsified for intravenous use, limiting their effectiveness due to low PFC content such that high concentrations of supplemental oxygen must be given in order to achieve a therapeutic effect. Fluosol-DA (Green Cross Corp., Osaka, Japan/Alpha Therapeutic, Los Angeles, CA), a first-generation PFC, received FDA approval in 1989 for use in coronary balloon angioplasty but was withdrawn from the market just 5 years later since it was found to be cumbersome to store (requiring frozen storage) and prepare for therapeutic use as well as the fact that improvements in angioplasty catheter technology eliminated the need for Fluosol 45,46 .…”

“…Second generation PFC's, which have higher PFC content, such as Oxygent (Alliance Pharmaceutical Corp., La Jolla, CA) and Oxyfluor (Hemagen, Inc., St. Louis, MO) were subsequently developed and tested but have not been approved by the FDA 45,46 . HBOC's, on the other hand, are manufactured from human or bovine hemoglobin, and at least one recombinant (genetically-engineered) product was developed 45,47 .…”

“…In addition, HBOC's have a rather short plasma half-life and have altered oxygen-binding properties 45 . Manufacturers have introduced various alterations to their proprietary HBOC's in order to stabilize the cell-free hemoglobin and circumvent these problems including, intramolecular crosslinking, polymerization, pegylation, pyridoxilation, and encapsulation 45,46 . 45 .…”

Oxygen Carriers in Cardiac Surgery

“…However, its use is limited by the potential risks of transmission of bovine diseases and production of antibodies when infused in large quantities. 2,7 To avoid the inconveniences of free extracellular hemoglobin, the hemoglobin molecule was modified to prolong the intravascular half-life, to slow renal elimination, and to maintain an oxygen affinity similar to that of hemoglobin in the erythrocytes. The following modifications have been used: internal stabilization of the tetrameric molecule by a covalent bond that cross-links the hemoglobin � or � dimers, polymerization of the cross-linked dimers, conjugation with larger molecules, pyridoxylation to reduce the affinity for oxygen and encapsulation within synthetic lipid membranes.…”

Use of cyanobacterial gas vesicles as oxygen carriers in cell culture

“…Researchers have similarly taken advantage of the high oxygen solubilities in perfluorochemicals (and some hydrocarbons) and used their emulsions or dispersions to increase oxygen supply to cells (Ho et al 1990;Ju et al 1991a;Junker et al 1990;Nagase et al 2005). The biologically inert perfluorochemicals have also long been pursued in formulations of artificial blood substitutes (Keipert 1995;Kim and Greenburg 2004;Remy et al 1999). These emulsions or dispersions are, however, inherently unstable and there are potential side effects associated with the high concentrations of surfactants used for making the emulsions (Ju and Armiger 1992;King et al 1987).…”