[citation needed] The main categories of "oxygen-carrying" blood substitutes being pursued are hemoglobin-based oxygen carriers (HBOC)[1] and perfluorocarbon emulsions.
[4] At the beginning of the 20th century, the development of modern transfusion medicine initiated through the work of Landsteiner and co-authors opened the possibility to understanding the general principle of blood group serology.
[6][7] Restrictions in applied transfusion medicine, especially in disaster situations such as World War II, laid the grounds for accelerated research in the field of blood substitutes.
[8] Early attempts and optimism in developing blood substitutes were very quickly confronted with significant side effects, which could not be promptly eliminated due to the level of knowledge and technology available at that time.
[10][12] The first approved oxygen-carrying blood substitute was a perfluorocarbon-based product called Fluosol-DA-20, manufactured by Green Cross of Japan.
This liquid is then mixed with antibiotics, vitamins, nutrients and salts, producing a mixture that contains about 80 different components, and performs many of the vital functions of natural blood.
[citation needed] Perfluorocarbon-based blood substitutes are completely man-made; this provides advantages over blood substitutes that rely on modified hemoglobin, such as unlimited manufacturing capabilities, ability to be heat-sterilized, and PFCs' efficient oxygen delivery and carbon dioxide removal.
PFCs are removed from the bloodstream within 48 hours by the body's normal clearance procedure for particles in the blood – exhalation.
[citation needed] Its use was associated with a reduction in ischemic complications and with an increase in pulmonary edema and congestive heart failure.
[1] Unmodified cell-free haemoglobin is not useful as a blood substitute because its oxygen affinity is too high for effective tissue oxygenation, the half-life within the intravascular space that is too short to be clinically useful, it has a tendency to undergo dissociation in dimers with resultant kidney damage and toxicity, and because free haemoglobin tends to take up nitric oxide, causing vasoconstriction.
[4][24][25][26] Efforts to overcome this toxicity have included making genetically engineered versions, cross-linking, polymerization, and encapsulation.
[citation needed] PolyHeme was developed over 20 years by Northfield Laboratories and began as a military project following the Vietnam War.
It is human haemoglobin, extracted from red blood cells, then polymerized, then incorporated into an electrolyte solution.
[32] Dextran-Haemoglobin was developed by Dextro-Sang Corp as a veterinary product, and was a conjugate of the polymer dextran with human haemoglobin.
[10] A pyridoxylated Hb conjugated with polyoxyethylene was created by scientists at Ajinomoto and eventually developed by Apex Biosciences, a subsidiary of Curacyte AG; it was called "PHP" and failed in a Phase III trial published in 2014, due to increased mortality in the control arm,[10][33] which led to Curacyte shutting down.