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Artificial Blood: What Is It? Will I Use It?
Since the 17th century, blood transfusions have been attempted to offset blood loss from trauma and childbirth, or as a therapeutic modality during leeching or bloodletting. Until the identification of isoagglutinating antibodies, however, transfusions were fraught with significant early complications. These early complications sparked interest in using hemoglobin as an oxygen carrier in plasma. Early trials of these solutions proved disastrous as well, with significant immediate complications resulting from infusions of stroma-free human hemoglobin solutions.1 These complications were most often acute renal failure thought to be the result of direct hemoglobin nephrotoxicity.2
History Of Artificial Blood
Development of a hemoglobin-based blood substitute was pursued vigorously by the military as a means to have an oxygen-carrying plasma expander available for battlefield use. Despite research throughout the Vietnam War, a clinically effective blood substitute was unable to be developed.
During this era of blood substitute research in the 1960s, Dr. Leland Clark began experimenting with a class of compounds known as perfluorocarbons. Oxygen has approximately 100 times greater solubility in perfluorocarbon solutions than in plasma. As a result, the amount of oxygen dissolved in plasma may be sufficient to sustain life, without the need for RBC-contained hemoglobin to provide additional oxygen. The hydrophobic nature of these compounds necessitated further development of perfluorocarbon emulsions prior to considering these compounds for use as a plasma oxygen carrier.
The use of Pluronic 64 as an emulsifying agent for perfluorocarbons enabled the production of Fluosol by the Green Cross Corporation of Japan. Clinical trials with this perfluorocarbon, however, were disappointing. Fluosol was present only in low concentrations in the emulsion, and Pluronic 64 caused rare but significant complications when the emulsion was infused intravenously. Further development of emulsion technologies resulted in the production of compounds which utilized smaller chain perfluorocarbon molecules to more effectively emulsify the perfluorocarbons, allowing higher concentrations of active agent in the emulsion and thus higher oxygen carrying capabilities. The improved stability of the newer emulsions are vastly superior to the first generations of perfluorocarbons; current emulsions can be stored at 4°C for extended periods of time (months) without appreciable degradation of activity.
Physiology Of Oxygen Transport
Normal oxygen transport is primarily a function of erythrocyte-contained hemoglobin. The heme-iron moiety of the hemoglobin molecule allows binding and release of oxygen, dependent upon the partial oxygen tension to which the hemoglobin is exposed. The tetrameric structure of the protein portion allows hemoglobin to bind four oxygen molecules within binding pockets in each protein subunit.
Modification of the ability of oxygen to bind to hemoglobin occurs naturally. Hemoglobin oxygen interactions result in structural conformational changes to facilitate loading and unloading of oxygen in the pulmonary circulation and peripheral tissues, respectively. The efficiency of oxygen binding and release can be altered by acid-base balance, the partial pressure of carbon dioxide, temperature, and 2,3-diphospho-glycerate. The resulting shift of the sigmoidal oxy-hemoglobin dissociation curve serves as a natural regulatory mechanism for the delivery of oxygen to tissues. In neutral pH, in the absence of any other modifying substances or conditions, the P50 of native hemoglobin outside of the RBC is 17 mmHg. Thus, the internal milieu of the RBC is critical to the effective delivery of oxygen to tissues.
Since the 17th century, blood transfusions have been attempted to offset blood loss from trauma and childbirth, or as a therapeutic modality during leeching or bloodletting. Until the identification of isoagglutinating antibodies, however, transfusions were fraught with significant early complications. These early complications sparked interest in using hemoglobin as an oxygen carrier in plasma. Early trials of these solutions proved disastrous as well, with significant immediate complications resulting from infusions of stroma-free human hemoglobin solutions.1 These complications were most often acute renal failure thought to be the result of direct hemoglobin nephrotoxicity.2
History Of Artificial Blood
Development of a hemoglobin-based blood substitute was pursued vigorously by the military as a means to have an oxygen-carrying plasma expander available for battlefield use. Despite research throughout the Vietnam War, a clinically effective blood substitute was unable to be developed.
During this era of blood substitute research in the 1960s, Dr. Leland Clark began experimenting with a class of compounds known as perfluorocarbons. Oxygen has approximately 100 times greater solubility in perfluorocarbon solutions than in plasma. As a result, the amount of oxygen dissolved in plasma may be sufficient to sustain life, without the need for RBC-contained hemoglobin to provide additional oxygen. The hydrophobic nature of these compounds necessitated further development of perfluorocarbon emulsions prior to considering these compounds for use as a plasma oxygen carrier.
The use of Pluronic 64 as an emulsifying agent for perfluorocarbons enabled the production of Fluosol by the Green Cross Corporation of Japan. Clinical trials with this perfluorocarbon, however, were disappointing. Fluosol was present only in low concentrations in the emulsion, and Pluronic 64 caused rare but significant complications when the emulsion was infused intravenously. Further development of emulsion technologies resulted in the production of compounds which utilized smaller chain perfluorocarbon molecules to more effectively emulsify the perfluorocarbons, allowing higher concentrations of active agent in the emulsion and thus higher oxygen carrying capabilities. The improved stability of the newer emulsions are vastly superior to the first generations of perfluorocarbons; current emulsions can be stored at 4°C for extended periods of time (months) without appreciable degradation of activity.
Physiology Of Oxygen Transport
Normal oxygen transport is primarily a function of erythrocyte-contained hemoglobin. The heme-iron moiety of the hemoglobin molecule allows binding and release of oxygen, dependent upon the partial oxygen tension to which the hemoglobin is exposed. The tetrameric structure of the protein portion allows hemoglobin to bind four oxygen molecules within binding pockets in each protein subunit.
Modification of the ability of oxygen to bind to hemoglobin occurs naturally. Hemoglobin oxygen interactions result in structural conformational changes to facilitate loading and unloading of oxygen in the pulmonary circulation and peripheral tissues, respectively. The efficiency of oxygen binding and release can be altered by acid-base balance, the partial pressure of carbon dioxide, temperature, and 2,3-diphospho-glycerate. The resulting shift of the sigmoidal oxy-hemoglobin dissociation curve serves as a natural regulatory mechanism for the delivery of oxygen to tissues. In neutral pH, in the absence of any other modifying substances or conditions, the P50 of native hemoglobin outside of the RBC is 17 mmHg. Thus, the internal milieu of the RBC is critical to the effective delivery of oxygen to tissues.
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