By Usman Waheed, Department of Molecular Biology, Quaid-i-Azam University, Islamabad
When William Harvey first described the circulation of blood in 1616, scientists start thinking about whether blood could be removed and replaced by other liquids, for example wine and milk,. They thought that by doing so, diseases could be cured and even that personalities could be changed. Obviously, there were some interesting but disappointing experiments! In 1667, the first fully documented human transfusion was made but many recipients died. No real progress occurred until 1901 when Karl Landsteiner, an Austrian immunologist and geneticist, discovered the blood groups (awarded Nobel Prize in 1930). This made blood transfusions a routine procedure.
Blood is now safe, due to improved collection and screening by blood banks. But it still has to be cross-matched and can be stored for 35 days before it has to be discarded. There has been a need for blood replacements for as long as patients have been bleeding to death because of a serious injury. The quest to create artificial blood that can be infused safely at any time and in any place with long shelf life, regardless of the blood type has remained a big business, with more than one billion pounds being spent over the last 20 years internationally in an attempt to create a true alternative to blood. Artificial blood is used to fill fluid volume or carry oxygen and other blood gases in the cardiovascular system. The other terms commonly used are blood substitutes or blood surrogates. These terms are not correct since no substitutes have yet been invented that can replace the other vital functions of blood: coagulation and immune defense. The replacement solutions being developed today are more accurately described as Volume expanders and Oxygen carriers/therapeutics.
- Volume expanders are widely available and in simple words, these are certain passive materials which raise the blood quantity. They are of two types, mainly colloid based like Voluven, Haemaccel, gelofusin etc. and crystalloid based where Ringer’s lactate, normal saline are examples.
- Oxygen carriers/therapeutics are of two types which differ in the way they transport oxygen. One is based on Perfluorocarbons (PFCs), and the other on haemoglobin based oxygen carriers (HBOCs).
Perfluorocarbons (PFCs):
Perfluorocarbons (PFCs) are used to carry and release oxygen and are mixed with a number of other things, including salts, nutrients, antibiotics, and vitamins, to create a composite as close to real blood as possible. Perfluorocarbons may in fact have some benefits over real red blood cells, in the form of their small size, which allows them to travel through capillaries. Perfluorocarbons are cheap to produce and are completely free of biological materials so there is no risk of infectious agents contaminating them. PFCs are biologically inert materials that can dissolve about 50 times more oxygen than blood plasma but have two significant hurdles to overcome before they can be utilized as artificial blood. First, they are not soluble in water, which means to get them to work they must be combined with emulsifiers—fatty compounds called lipids that are able to suspend tiny particles of perfluorocarbon in the blood. Second, they have the ability to carry much less oxygen than hemoglobin-based products.
In 1989, Fluosol ®, a PFC produced by Green Cross Corp. of Osaka, Japan, became the first of its kind to receive FDA approval but was discontinued in 1994 because the amount needed to provide a benefit was too high. Other Perfluorocarbon-based artificial blood under development includes PHER-O, PERFTEC, and Oxycyte. The improved versions of perfluorocarbon emulsions are being developed but have not yet reached the market.
Haemoglobin Based Oxygen Carriers (HBOCs):
Von Stark (1898) was the first to treat anaemic patients with haemoglobin (Hb) solution. But he did not pursue the studies further even though his results were encouraging. Currently, haemoglobin based oxygen carriers (HBOCs) represent an interesting class of blood substitutes, which are undergoing advanced clinical trials. Hemoglobin carries oxygen from the lungs to the other tissues in the body. Artificial blood based on hemoglobin takes advantage of this natural function. Hemoglobin-based oxygen carriers (HBOCs) utilize the same oxygen-carrying protein molecule found in blood. HBOCs differ from red blood cells in that the hemoglobin is not contained within a membrane. The membrane of a red blood cell contains the antigen molecules that determine the ‘type’ of the blood (A, B, AB or O). Because HBOCs have no membranes, they do not need to be cross-matched by type and can be given to any patient without previous testing and can be stored for longer periods facilitating the work of blood bank. There are a number of different hemoglobin-based artificial bloods under development, including Hemospan, Oxyglobin, Hemopure, and PolyHeme. Most products are currently in Phase III clinical trial which is the final step in safety and efficacy data collection prior to submission for FDA approval. Hemopure was however being approved for use only in South Africa.
Two main problems arise when hemoglobin is removed from the red blood cells. First, the red cell membrane protects hemoglobin from degradation and protects tissues from the toxic effects of free hemoglobin. Second, when oxygen is being delivered by a cell-free carrier instead of red blood cells, complex biological mechanisms alter the flow through the smallest blood vessels (the arterioles and capillaries). By making use of the processes like self linking, recombinant DNA technologies, polymerization and encapsulation, hemoglobin could be extracted and could be used in a safer way too. The general benefits of HBOCs over transfused RBCs are faster & better O2 distribution, ready to use, long shelf life, universally compatible, no equipment or refrigeration and can also be use by Jehovah’s Witnesses*.
*Jehovah’s Witnesses believe that the Bible prohibits ingesting blood and that Christians should therefore not accept blood transfusions or donate or store their own blood for transfusion. This religious group advocates of what they call bloodless surgery
Since oxygen therapeutics are not yet widely available, the scientists are experimenting with varieties of dried blood, which take up less room, weigh less and can be used much longer than blood plasma. The powder can then be mixed into liquid form when needed. Likewise scientists from the University of Sheffield are developing an artificial ”plastic blood”, which could act as a substitute for real blood in emergency situations having huge impact on military applications. Because the artificial blood is made from a plastic, it is light to carry and easy to store. Cost will be a major restriction but the blood substitutes cost will fall as manufacturing becomes refined after clinical evaluation stage.
Blood transfusion is an essential part of health care. Every country shares the need to ensure the quality, safety and accessibility of blood transfusion. In developing countries blood transfusion services have traditionally been accorded low priority in health care services. As a result mostly there is an absence of adequate and nationwide access to safe, efficacious and affordable blood supply.
There is an urgent need for these blood substitutes because of risks associated with blood transfusions and pending worldwide blood shortages. The future advancements in biotechnology, biochemistry and genetic engineering, can play a promising role to generate an effective blood substitute, which will definitely have an impact on transfusion medicine and the transfusion services. Reaching into the unforeseeable future, it is only possible to hope that eventually blood substitutes will be able to cover worldwide shortages, and be cheap and stable enough to be distributed in third world countries where much of the blood supplies are contaminated. This new system of blood transfusion service with the ongoing molecular research will confer a new dimension to transfusion medicine. Let’s hope that no patient dies due to unavailability of blood.
“If this really works all the way, then mankind will have taken a big step forward. This is like landing on the moon.”
— Dr. Pierre LaFolie
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