1. Historical Summary
- Please click on images to be linked to their references. All images are referenced.
The earliest experiments with blood substitutes were motivated by the fact that most human-to-human blood transfusions were unsuccessful due to a lack of understanding of blood groups. Unfortunately, people's reactions to transfused animal milk turned out to be very severe.
After the discovery of blood groups in 1901, it became possible to match donors and recipients to prevent most adverse reactions to transfusion. This allowed blood donor services to take off. During the fist half of the 20th century, the primary motivation for finding a blood substitute was to deal with times when banked blood ran out or was unavailable. Efforts focused on extracting hemoglobin from animal blood or expired human blood, and using the hemoglobin as an oxygen carrier in a fluid medium. Free hemoglobin was found to be toxic to the kidneys, so hemoglobin was modified by cross-linking, conjugation, or recombination.
In the 1980's, with the explosion of HIV, concerns about the safetly of the blood supply stimulated renewed interest in the search for an artificial blood substitute. Experiments in the 1960's had shown that perfluorocarbon (PFC) solutions could be used to deliver oxygen to mice; these experiments paved the way for developing PFCs as red blood cell substitutes. The first blood substitute to be approved by the FDA was Fluosol-DA, a PFC made by the Green Cross Corp of Japan. It was withdrawn just five years later, probably because it was cumbersome to store and prepare, as well as the fact that there was no clear clinical benefit. Another PFC-based oxygen carrier, Perftoran, was approved for use in Russia in 1996, although there is not much information about it readily available. A hemoglobin-based oxygen carrier, Hemopure (made by Biopure), was approved for use in South Africa in 2001.
Other companies have not had much luck with hemoglobin-based oxygen carriers. The experience has taught scientists that the human circulation and oxygen kinetics are more complicated than previously thought. Meanwhile, careful screening of the blood supply has reduced the risk of HIV infection from transfusion to about 1 in 2 million in the US. This has reduced the urgency of the search for a blood substitute. But applications for blood substitutes still exist, and so the research and development continues.
purple items are significant scientific discoveries
orange items are related to disease
red items are related to hemoglobin-based blood substitutes
green items are related to perfluorocarbon-based blood substitutes
- 1628: William Harvey describes the circulatory system
- 1600s: Sheep's blood suggested for wounded soldiers
- mid-1600’s: Sir Christopher Wren suggests using ale, wine or opium as substitutes for blood
- 1666-1677: animal-to-animal transfusions, animal-to-human transfusions
- 1677: animal-to-human transfusions outlawed in England
- 1795: first successful human-to-human transfusion
- 1818: human-to-human transfusions begin, success rate reportedly ~50%
- mid 1870’s: experiments with alternatives to human blood - milk from cows, goats, humans; severe reactions.
- 1884: 0.9% normal saline transfused
- 1901: Karl Landsteiner discovers A, B, O blood groups
- 1907: typing/crossmatching of donors and recipients utilized
- 1921: first blood donor service in England
- 1937: first blood donor service in the US
- 1937: Amberson experiments with bovine hemoglobin in saline solution transfusion to animals
- 1939: Rh blood group discovered
- 1943: first recorded case of transfusion-transmitted hepatitis
- 1949: Amberson used experimental hemoglobin-saline solution to treat severe postpartum hemorrhage after supplies of compatible banked blood were exhausted; patient died of renal failure
- 1959: molecular structure of hemoglobin determined by Max Perutz
- 1966: report of mice immersed in a perfluorocarbon liquid saturated with oxygen; mice survived up to 10 minutes
- 1978: first clinical trial of HBOCs: Savitsky infuses stroma-free hemoglobin solution to normal human volunteers, resulting in significant systemic toxicity
- 1985: risk of HIV infection from 1 unit of transfused blood is 1 in 2,500 in the US
- 1985: US Army and Baxter begin program to develop red blood cell substitute, eventually called HemAssist
- 1989: Fluosol-DA (Green Cross Corp., Japan) FDA approved for use during angioplasty
- 1994: Fluosol-DA withdrawn from market
- 1996: Perftoran (Perftoran, Russia) approved in Russia for use in severe anemia, hemorrhagic/traumatic shock, cerebral ischemia, cardiac surgery
- 1998: HemAssist (Baxter) Phase III trial suspended for use in traumatic/hemorrhagic shock, elective surgery
- 1998: Oxyglobin approved by US FDA for anaemia in dogs
- 1999: Oxyglobin approved by EU EMEA for anaemia in dogs
- 2001: Hemopure (Biopure) approved in South Africa for acutely anemic adult surgical patients
- 2001: Oxygent (Alliance Corp.) Phase III cardiac surgery study terminated early
- 2001: Oxygent (Alliance Corp.) Phase III European study completed for use in acute normovolemic hemodilution in elective noncardiac surgery
- 2002: Biopure filed biologic license application (BLA) with the FDA to market Hemopure in the US
- 2003: Hemolink (Hemosol) Phase IIb cardiac surgery trial suspended
- 2004: PHP (Curacyte) Phase IIc clinical trial completed for treatment of distributive shock
- 2005: PolyHeme (Northfield Laboratories) is in Phase III trial for prehospital treatment of severely injured bleeding trauma patients
- 2005: risk of HIV infection from 1 unit of transfused blood is 1 in 2,000,000 in the US