Blood substitutes
Encyclopedia
A blood substitute is a substance used to mimic and fulfill some functions of biological
blood
, usually in the oxygen-carrying sense. They aim to provide an alternative to blood transfusion
, which is transferring blood or blood-based products from one person into another.
The main categories of such oxygen-carrying blood substitutes are hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbon-based oxygen carriers (PFBOCs). Unfortunately, oxygen transport has proven very difficult to achieve artificially, and all efforts as of 2011 have failed to overcome the challenges. Oxygen therapeutics are in clinical trials in the U.S. and Europe, and Hemopure
is available in South Africa
.
whose main function is to carry oxygen
, as does natural haemoglobin. The use of oxygen-carrying blood substitutes is often called oxygen therapeutics. The initial goal of oxygen carrying blood substitutes is merely to mimic blood
's oxygen transport capacity. There is additional longer range research on true artificial red
and white blood cell
s which could theoretically compose a blood substitute with higher fidelity to human blood. Unfortunately, oxygen transport, one function that distinguishes real blood from other volume expanders, has been very difficult to reproduce.
There are two basic approaches to constructing an oxygen therapeutic. The first is perfluorocarbons (PFCs), chemical compounds which can carry and release oxygen. The specific PFC usually used is perfluorodecalin
. The second is haemoglobin derived from humans, animals, or artificially via recombinant
technology
.
Blood substitutes are useful for the following reasons:
The U.S. Military is one of the greatest proponents of oxygen therapeutics, mainly because of the vital need and benefits in a combat scenario. Since oxygen therapeutics are not yet widely available, the United States Army
is experimenting with varieties of dried blood
, which take up less room, weigh less and can be used much longer than blood plasma
. Saline has to be added prior to use. These properties make it better for first aid during combat
than whole blood or packed red cells.
According to studies of outcomes of transfusions given to trauma patients in 2008, blood substitutes yielded a 30% increase in the risk of death and about a threefold increase in the chance of having a heart attack of for the recipients. More than 3,711 patients were tested in sixteen studies using five types of artificial blood. Public Citizen
sued the U.S. Food and Drug Administration
(FDA) to attain information on the duration of these studies which were found to have been conducted from 1998 until 2007.The FDA permits artificial blood transfusions in the USA without informed consent under a special exemption from requirements of informed consent during traumatic care.
s must be made by dispersing small drops of PFC in water
. This liquid is then mixed with antibiotics, vitamin
s, nutrient
s and salt
s, producing a mixture that contains about 80 different components, and performs many of the vital functions of natural blood. PFC particles are about 1/40 the size of the diameter of a red blood cell
(RBC). This small size can enable PFC particles to traverse capillaries through which no RBCs are flowing. In theory this can benefit damaged, blood-starved tissue
, which conventional red cells cannot reach. PFC solutions can carry oxygen so well that mammal
s, including human
s, can survive breathing liquid PFC solution, called liquid breathing
.
Perfluorocarbon-based blood substitutes are completely man-made; this provides advantages over blood substitutes that rely on modified haemoglobin, such as unlimited manufacturing capabilities, ability to be heat-sterilized, and PFCs’ efficient oxygen delivery and carbon dioxide removal. PFCs in solution act as an intravascular oxygen carrier to temporarily augment oxygen delivery to tissues. PFCs are removed from the bloodstream within 48 hours by the body's normal clearance procedure for particles in the blood – exhalation. PFC particles in solution can carry several times more oxygen per cubic centimeter (cc) than blood, while being 40 to 50 times smaller than haemoglobin.
ing, polymerization
, and encapsulation. These are needed because the red cell is not a simple container for haemoglobin, but a complex entity with many biomolecular features.
s as a means of producing an alternate source of transfusable blood. A study performed by Giarratana et al. describes a large-scale ex-vivo production of mature human blood cells using hematopoietic stem cells, and may represent the first significant steps in this direction. Moreover, the blood cells produced in culture possess the same haemoglobin content and morphology as do native red blood cells. The authors of the study also contend that the red blood cells they produced have a near-normal lifespan, when compared to native red blood cells—an important characteristic of which current haemoglobin-based blood substitutes are found to be deficient. The major obstacle with this method of producing red blood cells is cost. Now, the complex three-step method of producing the cells would make a unit of these red blood cells too expensive. However, the study is the first of its kind to demonstrate the possibility of producing red blood cells which closely resemble native red blood cells on a large scale.
Scientists from the experimental arm of the Pentagon
of United States
began creating artificial blood to transport blood to remote areas and transfuse blood to wounded soldiers more quickly in 2010. The blood is made from the hematopoietic stem cells removed from umbilical cord
between the mother and fetus of humans after birth using a method called blood pharming. Pharming has been used in the past on animals and plants to create medical substances in large quantities. Each cord can produce approximately 20 units of blood or three blood transfusions. The blood is being produced for the Defense Advanced Research Projects Agency
by Arteriocyte. The Food and Drug Administration
has examined and approved the safety of this blood from previously submitted O-negative blood. Using this particular artificial blood will reduce the costs per unit of blood from $5,000 to equal or less than $1,000. This blood will also serve as a blood donor to all blood types. Pharmed blood may be used in human trials in 2013.
s : Researchers at the Dendritech Corporation have begun research, aided by a 2 year, $750,000 grant from the US Army, into the use of dendrimers as substitute oxygen carriers. The precise nature of the research cannot be disclosed, as the company’s patent application has not yet been approved. Researchers hope that dendrimer technology will be the first truly cost-efficient blood substitute.
Biodegradable micelles : To enhance circulation times, recombinant or polymerized haemoglobin can be encapsulated within micellar-forming amphiphilic block copolymers. These systems are typically between 30–100 nm in diameter. The hydrophobic core of the polymer micelle is able to solubilize the similarly hydrophobic haemoglobin protein, while the water soluble corona (which is usually polyethylene glycol
) provides a steric barrier to protein absorption, and provides protection from clearance by the reticuloendothelial system (RES).
Placental umbilical cord blood : Cord blood collected asceptically from the placenta after the birth of a healthy baby can be used safely as a blood substitute. It has a higher haemoglobin content and growth factors than normal blood from an adult, which has the potential to benefit patients in varying diseases.
Hemerythrin
: A team of Romanian researchers from the Babes-Bolyai University
announced in 2010 that they discovered a colorless substance that can replace blood. The substance is based on hemerythrin
, and it was tested on mice with encouraging results.
perform various functions. In addition, the blood composition includes additional molecules and electrolytes to function properly. Some of these components are substitutable with modern technology, and may, at least, be added to an oxygen-carrying blood substitute to create a more complete blood substitute.
Volume expander
s may theoretically be called a blood substitutes as well, but in practice they are usually not within the scope of blood substitutes. Still, they are sometimes called "plasma substitutes".
discovered blood pathways in 1616, many people tried to use fluids such as beer, urine, milk, and animal blood as blood substitute. The demand for more blood substitutes began during the Vietnam War
as wounded soldiers were unable to be treated at hospitals due to blood shortages.
Major worldwide blood shortages have led scientists to synthesize and test artificial blood. Infected blood is a major problem for many countries. Each year 10–15 million units of blood are transfused without being tested first for HIV
and hepatitis
. The second largest cause of new HIV infections in Nigeria
comes from transfused blood. A major problem associated with donated blood is that after it is stored it loses Nitric Oxide
and causes vasoconstriction
for the recipient.
The first approved oxygen-carrying blood substitute was a perfluorocarbon-based product called Fluosol
-DA-20, manufactured by Green Cross of Japan. It was approved by the Food and Drug Administration
(FDA) in 1989. Because of limited success, complexity of use and side effects, it was withdrawn in 1994. However, Fluosol-DA remains the only oxygen therapeutic ever fully approved by the FDA.
In the 1990s, because of the risk of undetected blood bank contamination from AIDS
, hepatitis C
and other emergent diseases such as Creutzfeldt-Jakob disease, there was additional motivation to pursue oxygen therapeutics. Significant progress was achieved, and a haemoglobin-based oxygen therapeutic called Hemopure was approved for Phase III trial (in elective orthopedic surgery) in the U.S., and more widely approved for human use in South Africa.
In December 2003, a new haemoglobin-based oxygen therapeutic, PolyHeme
, began field tests in a Phase III trial on emergency patients (in trauma settings) in the U.S. PolyHeme was the 15th experiment to be approved by the Food and Drug Administration since 1996. Patient consent is not necessary under the special category created by the FDA for these experiments. In late 2005, an independent panel verified, after the fourth and final review of 500 trauma patients enrolled in this study by that date, that no statistical evidence of safety concerns had arisen so far in the study. This study concluded in mid-2006 with final enrollment of 720 patients. Wired news reported that the trial failed when 47 of the 350 people given PolyHeme died compared to 35 deaths out of 363 in the control group. Debate exists as to whether or not the difference in the mortality rate is attributable to the small sample size. The fact that the experimental subjects did not give consent is a significant factor.
In 2010, Hard to Treat Diseases, Inc. (HTD) merged with an anonymous Canadian biotechnology company in hopes to enhance donated blood or hemoglobin based blood substitutes to have a shelf life of 42 days and higher levels of Nitric Oxide when packaged.
Biology
Biology is a natural science concerned with the study of life and living organisms, including their structure, function, growth, origin, evolution, distribution, and taxonomy. Biology is a vast subject containing many subdivisions, topics, and disciplines...
blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, usually in the oxygen-carrying sense. They aim to provide an alternative to blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
, which is transferring blood or blood-based products from one person into another.
The main categories of such oxygen-carrying blood substitutes are hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbon-based oxygen carriers (PFBOCs). Unfortunately, oxygen transport has proven very difficult to achieve artificially, and all efforts as of 2011 have failed to overcome the challenges. Oxygen therapeutics are in clinical trials in the U.S. and Europe, and Hemopure
Hemopure
Hemopure, developed by Biopure , is an hemoglobin-based oxygen carrier based on chemically stabilized bovine hemoglobin. It has been developed for potential use in humans as an oxygen delivering bridge in cases when blood is not available or is not an option...
is available in South Africa
South Africa
The Republic of South Africa is a country in southern Africa. Located at the southern tip of Africa, it is divided into nine provinces, with of coastline on the Atlantic and Indian oceans...
.
Oxygen-carrying substitutes
An oxygen-carrying blood substitute, sometimes called artificial haemoglobin, is an artificially made blood substituteBlood substitute
A blood substitute is a substance used to mimic and fulfill some functions of biological blood, usually in the oxygen-carrying sense...
whose main function is to carry oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
, as does natural haemoglobin. The use of oxygen-carrying blood substitutes is often called oxygen therapeutics. The initial goal of oxygen carrying blood substitutes is merely to mimic blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
's oxygen transport capacity. There is additional longer range research on true artificial red
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
and white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s which could theoretically compose a blood substitute with higher fidelity to human blood. Unfortunately, oxygen transport, one function that distinguishes real blood from other volume expanders, has been very difficult to reproduce.
There are two basic approaches to constructing an oxygen therapeutic. The first is perfluorocarbons (PFCs), chemical compounds which can carry and release oxygen. The specific PFC usually used is perfluorodecalin
Perfluorodecalin
Perfluorodecalin is a fluorocarbon, a derivative of decalin in which all of the hydrogen atoms are replaced by fluorine atoms. It is chemically and biologically inert, and stable up to 400°C. Several applications make use of its ability to dissolve gases....
. The second is haemoglobin derived from humans, animals, or artificially via recombinant
Recombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
technology
Motivation
Oxygen therapeutics, even if widely available, would not eliminate the use of human blood, which performs various functions besides oxygen transport. However oxygen therapeutics have major advantages over human blood in various situations, especially traumaPhysical trauma
Trauma refers to "a body wound or shock produced by sudden physical injury, as from violence or accident." It can also be described as "a physical wound or injury, such as a fracture or blow." Major trauma can result in secondary complications such as circulatory shock, respiratory failure and death...
.
Blood substitutes are useful for the following reasons:
- Donations are increasing by about 2–3% annually in the United States, but demand is climbing by between 6–8% as an aging population requires more operations that often involve blood transfusion.
- Although the blood supply in many countries is very safe, this is not the case for all regions of the world. Blood transfusion is the second largest source of new HIVHIVHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infections in NigeriaNigeriaNigeria , officially the Federal Republic of Nigeria, is a federal constitutional republic comprising 36 states and its Federal Capital Territory, Abuja. The country is located in West Africa and shares land borders with the Republic of Benin in the west, Chad and Cameroon in the east, and Niger in...
. In certain regions of southern Africa, it is believed that as much as 40% of the population has HIV/AIDS, although testing is not financially feasible. A disease-free source of blood substitutes would be incredibly beneficial in these regions. - In battlefield scenarios, it is often impossible to administer rapid blood transfusions. Medical care in the armed services would benefit from a safe, easy way to manage blood supply.
- Great benefit could be derived from the rapid treatment of patients in trauma situations. Because these blood substitutes do not contain any of the antigens that determine blood type, they can be used across all types without immunologic reactions.
- While it is true that receiving a unit of transfused blood in the US does not carry many risks, with only 10 to 20 deaths per million units, blood substitutes could eventually improve on this. There is no practical way to test for prion-transmitted diseases in donated blood, such as Mad Cow and Creutzfeld-Jacob disease, and other disease could emerge as problems for the blood supply, including smallpoxSmallpoxSmallpox was an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor. The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning "spotted", or varus, meaning "pimple"...
and SARS. - Transfused bloodBlood transfusionBlood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
is currently more cost effective, but there are reasons to believe this may change. For example, the cost of blood substitutes may fall as manufacturing becomes refined. - Blood substitutes can be stored for much longer than transfusable blood, and can be kept at room temperature. Most haemoglobin-based oxygen carriers in trials today carry a shelf life of between 1 and 3 years, compared to 42 days for donated blood, which needs to be kept refrigerated.
- Blood substitutes allow for immediate full capacity oxygen transport, as opposed to transfused blood which can require about 24 hours to reach full oxygen transport capacity due to 2,3-diphosphoglycerate depletion. Also, in comparison, natural replenishment of lost red blood cells usually takes months, so an oxygen-carrying blood substitute can perform this function until blood is naturally replenished.
- Oxygen carrying blood substitutes also would become an alternative for those patients that refuse blood transfusions for religious or cultural reasons, such as Jehovah's WitnessesJehovah's Witnesses and blood transfusionsJehovah'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...
.
The U.S. Military is one of the greatest proponents of oxygen therapeutics, mainly because of the vital need and benefits in a combat scenario. Since oxygen therapeutics are not yet widely available, the United States Army
United States Army
The United States Army is the main branch of the United States Armed Forces responsible for land-based military operations. It is the largest and oldest established branch of the U.S. military, and is one of seven U.S. uniformed services...
is experimenting with varieties of dried blood
Dried Blood
Dried Blood is an EP recorded by the German industrial act :wumpscut:.-Summary:Dried Blood is the fourth release by :wumpscut:, his first EP, and his first release on Ant-Zen Records....
, which take up less room, weigh less and can be used much longer than blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
. Saline has to be added prior to use. These properties make it better for first aid during combat
Combat
Combat, or fighting, is a purposeful violent conflict meant to establish dominance over the opposition, or to terminate the opposition forever, or drive the opposition away from a location where it is not wanted or needed....
than whole blood or packed red cells.
Risks
Haemoglobin-based blood substitutes may increase the odds of deaths and heart attacks.According to studies of outcomes of transfusions given to trauma patients in 2008, blood substitutes yielded a 30% increase in the risk of death and about a threefold increase in the chance of having a heart attack of for the recipients. More than 3,711 patients were tested in sixteen studies using five types of artificial blood. Public Citizen
Public Citizen
Public Citizen is a non-profit, consumer rights advocacy group based in Washington, D.C., United States, with a branch in Austin, Texas. Public Citizen was founded by Ralph Nader in 1971, headed for 26 years by Joan Claybrook, and is now headed by Robert Weissman.-Lobbying Efforts:Public Citizen...
sued the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) to attain information on the duration of these studies which were found to have been conducted from 1998 until 2007.The FDA permits artificial blood transfusions in the USA without informed consent under a special exemption from requirements of informed consent during traumatic care.
Perfluorocarbon based
Perfluorochemicals will not mix with blood, therefore emulsionEmulsion
An emulsion is a mixture of two or more liquids that are normally immiscible . Emulsions are part of a more general class of two-phase systems of matter called colloids. Although the terms colloid and emulsion are sometimes used interchangeably, emulsion is used when both the dispersed and the...
s must be made by dispersing small drops of PFC in water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
. This liquid is then mixed with antibiotics, vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
s, nutrient
Nutrient
A nutrient is a chemical that an organism needs to live and grow or a substance used in an organism's metabolism which must be taken in from its environment. They are used to build and repair tissues, regulate body processes and are converted to and used as energy...
s and salt
Salt
In chemistry, salts are ionic compounds that result from the neutralization reaction of an acid and a base. They are composed of cations and anions so that the product is electrically neutral...
s, producing a mixture that contains about 80 different components, and performs many of the vital functions of natural blood. PFC particles are about 1/40 the size of the diameter of a red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
(RBC). This small size can enable PFC particles to traverse capillaries through which no RBCs are flowing. In theory this can benefit damaged, blood-starved tissue
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
, which conventional red cells cannot reach. PFC solutions can carry oxygen so well that mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s, including human
Human
Humans are the only living species in the Homo genus...
s, can survive breathing liquid PFC solution, called liquid breathing
Liquid breathing
Liquid breathing is a form of respiration in which a normally air-breathing organism breathes an oxygen-rich liquid , rather than breathing air....
.
Perfluorocarbon-based blood substitutes are completely man-made; this provides advantages over blood substitutes that rely on modified haemoglobin, such as unlimited manufacturing capabilities, ability to be heat-sterilized, and PFCs’ efficient oxygen delivery and carbon dioxide removal. PFCs in solution act as an intravascular oxygen carrier to temporarily augment oxygen delivery to tissues. PFCs are removed from the bloodstream within 48 hours by the body's normal clearance procedure for particles in the blood – exhalation. PFC particles in solution can carry several times more oxygen per cubic centimeter (cc) than blood, while being 40 to 50 times smaller than haemoglobin.
| Name | Sponsor | Description |
|---|---|---|
| Oxygent | Alliance Pharmaceuticals | Currently approved for Phase II Trials in US and Phase II Trails in Europe. Developed to reduce the need for donor blood during surgery. PFCs are surrounded by a lecithin Lecithin Lecithin is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues, and in egg yolk, composed of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides, and phospholipids .The word lecithin was originally coined in 1847 by... surfactant Surfactant Surfactants are compounds that lower the surface tension of a liquid, the interfacial tension between two liquids, or that between a liquid and a solid... in a water-based solution. The lecithin is digested intracellularly. Oxygent has done well overall in most clinical trials, but recently, a cardiac surgery Cardiac surgery Cardiovascular surgery is surgery on the heart or great vessels performed by cardiac surgeons. Frequently, it is done to treat complications of ischemic heart disease , correct congenital heart disease, or treat valvular heart disease from various causes including endocarditis, rheumatic heart... study found participants to be slightly more likely to suffer a stroke Stroke A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage... if treated with Oxygent rather than by standard care. |
| Oxycyte Oxycyte Oxycyte is a third-generation perfluorocarbon therapeutic oxygen carrier invented by Leland Clark and developed by Oxygen Biotherapeutics, Inc.... |
Oxygen Biotherapeutics | Currently approved for Phase II-b Trials in the United States. Targeted as an oxygen therapeutic rather than a blood substitute, with successful small scale open label human trials treating traumatic brain injury Traumatic brain injury Traumatic brain injury , also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism , or other features... at Virginia Commonwealth University. |
| PHER- | Sanguine Corp | In research |
| Perftoran | Russia | Approved for Russian clinical application in 1996. Registered in Mexico as PERFTEC, distributed by KEM Laboratory (Mexico). Status: Approved an authorized blood substitute in Mexico in 2005. |
Haemoglobin based
Haemoglobin is the main component of red blood cells, comprising about 33% of the cell mass. Haemoglobin-based products are called haemoglobin-based oxygen carriers (HBOCs). However, pure haemoglobin separated from red cells cannot be used, since it causes renal toxicity. It can be treated to avoid this, but it still has incorrect oxygen transport characteristics when separated from red cells. Various other steps are needed to form haemoglobin into a useful and safe oxygen therapeutic. These may include cross-linkCross-link
Cross-links are bonds that link one polymer chain to another. They can be covalent bonds or ionic bonds. "Polymer chains" can refer to synthetic polymers or natural polymers . When the term "cross-linking" is used in the synthetic polymer science field, it usually refers to the use of...
ing, polymerization
Polymerization
In polymer chemistry, polymerization is a process of reacting monomer molecules together in a chemical reaction to form three-dimensional networks or polymer chains...
, and encapsulation. These are needed because the red cell is not a simple container for haemoglobin, but a complex entity with many biomolecular features.
| Name | Sponsor | Description |
|---|---|---|
| Hemopure | Biopure Corp | Current approved for Phase III trials in the United States and was more widely approved in South Africa but regulatory status is now uncertain. Hemopure is Biopure’s first-in-class product for human use, and is a Haemoglobin-Based Oxygen Carrier (HBOC) solution. It is made of chemically stabilized, cross-linked bovine (cow) haemoglobin in a salt solution. Many safety measures are taken to render free of pathogens, including herd control and monitoring. Hemopure molecules can be up to 1/1,000 the size of RBCs, facilitating oxygen transport and off-loading to the tissues. Hemopure is currently in Phase III clinical trials in the US, and is approved for use in South Africa in surgical patients who are anemic, thereby reducing or eliminating the need for blood transfusions for these patients. Biopure Corp. terminated most of its workforce in November 2008 for financial reasons. In November 2008 the company’s sales personnel in South Africa were laid off. Sales are continuing, but the company is not actively marketing to customers. In addition, the South Africa regulatory authority notified the company in October 2008 that it had decided to revoke its marketing authorization for Hemopure. The company is appealing that decision. The appeal may take one year to complete and in the meantime the company is permitted to market product. |
| Oxyglobin | Biopure Corp | Currently approved for veterinary use US and Europe. Oxyglobin solution is the first and only oxygen therapeutic to be both US FDA and European Commission approved for veterinary use. It consists of chemically stabilized bovine haemoglobin in a balanced salt solution and contains no red blood cells. The cross-linked haemoglobin, several tetramers bound together, works by circulation in the plasma and supplying oxygen to tissues. Introduced to veterinary clinics and hospitals in March 1998 and nationally distributed by October 1998, Oxyglobin has been used primarily for blood transfusions and for treatment of anemia Anemia Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin... in dogs. Currently, Oxyglobin can only be used in canines Canidae Canidae is the biological family of carnivorous and omnivorous mammals that includes wolves, foxes, jackals, coyotes, and domestic dogs. A member of this family is called a canid . The Canidae family is divided into two tribes: Canini and Vulpini... and not in humans. The current supply of Oxyglobin is low, because the company is spending most of its resources on Hemopure, a blood substitute designed for human use. |
| PolyHeme | Northfield Laboratories | Completed US Phase III Trial, failed FDA approval. PolyHeme is a haemoglobin-based oxygen carrier and, as the only blood substitute to have completed a Phase III trial, represents the leading technology in this field. Developed and manufactured by Chicago based Northfield Laboratories, Inc., Polyheme originally began as a military project following the Vietnam War, and has since shown great potential for both military and civilian use. PolyHeme uses human haemoglobin as the oxygen-carrying molecule in solution, and the extraction and filtration of this haemoglobin from red blood cells is the first step in production. Then, using a multi-step polymerization process, the purified haemoglobin is associated into tetramers and, as the final step, is incorporated into an electrolyte solution. The polymerization of the haemoglobin represents the critical step in this process because, as demonstrated by failed attempts at blood substitutes, when haemoglobin remains disassociated, it tends to take up nitric oxide, causing vasoconstriction. Also, free haemoglobin can be taken up by the kidney, causing dysfunction and failure, similar to a hemolytic transfusion reaction. Northfield Laboratories came under scrutiny for the Phase III trial they conducted in over 20 level 1 trauma centers across the country. The controversy arose from the fact that the participants in this study were incapable of giving their consent due to the nature of their injuries. Even though this practice is sanctioned by the FDA as necessary emergency research, patients’ rights groups have begun to protest the study. In April 2009, Northfield Laboratories announced receipt of an FDA letter regarding its PolyHeme Biologic License Application Biologic License Application As defined by the US FDA, a Biologic License Application is: Biological products are approved for marketing under the provisions of the Public Health Service Act. The Act requires a firm who manufactures a biologic for sale in interstate commerce to hold a license for the product... (BLA) for the treatment of life-threatening haemoglobin levels when red blood cells may not be available. The BLA was not approved, and the letter stated "in the absence of clinical benefit, the risk:benefit assessment of the product in trauma is unfavorable.” In June 2009, Northfield Laboratories filed Chapter 11 bankruptcy. |
| Hemospan | Sangart | Currently in Phase II trails in the United States, Hemospan is produced by the company Sangart, which was founded by Dr. Robert M. Winslow in 1998. Produced in powder form, the powder can then be mixed into liquid form and transfused immediately, regardless of a patient’s blood type. This technology relies on coupling with polyethylene glycol (PEG) to eliminate the toxicity associated with free haemoglobin. Sangart believes their product can be stored for years and that they have optimized certain factors involved in oxygen delivery in the production of Hemospan, so that their product ultimately presents the right amount of oxygen to the blood vessel wall. In the past four years, Hemospan has shown promise as a possible commercial product, yielding positive results in both Phase Ib/II and Phase II clinical trails. |
| Dextran-Haemoglobin | Dextro-Sang Corp | Currently in vetrinary trials. Created by the Dexto-Sang Corporation, Dextran-Haemoglobin is a conjugate of the polymer dextran with human haemoglobin molecules. The safety of dextran has already been established, due to its wide use as a plasma volume expander. Conjugation of haemoglobin to dextran increases its half-life inside the body, and prevents tissue damage that occurs with free haemoglobin from processing by the kidneys and exit into the extracellular space. |
| Hemotech | HemoBiotech | Current approved for Phase I trails. HemoBiotech, based in Dallas, TX is developing HemoTech, a human blood substitute developed in 1985 by researchers, Mario Feola, MD and Jan Simoni, PHD, DVM from the Texas Tech University Health Sciences Center Texas Tech University Health Sciences Center The Texas Tech University Health Sciences Center offers programs in Allied Health Sciences, Biomedical Sciences, Medicine, Nursing, and Pharmacy. TTUHSC's main campus is in Lubbock, but campuses are also located in Abilene, Amarillo, Dallas, El Paso and the Permian Basin... (TTUHSC). HemoBiotech has been able to identify and nullify the source of toxicity issues associated with previous blood substitute candidates. HemoTech, which is expected to be compatible will all blood types and a shelf life of 180+ days compared to 41 days for donated human blood. HemoTech's lack of toxicity is believed to be due to Hemobiotech's proprietary chemical modification of haemoglobin. The company believes the use of bovine blood provides an additional advantage over products developed from outdated human red blood cells or from perfluorochemicals (PFCs), as bovine blood is more readily available and more cost-effective to use. Limited tests have shown it to be clear of the vasoconstriction and inflammatory toxicity issues that have hampered competitors. |
Withdrawn
- Fluorasol-DA, by Green Cross. Status: withdrawn in 1994 due to usage complexity, limited clinical benefit and complications
- HemAssist, by Baxter InternationalBaxter InternationalBaxter International Inc. , is an American health care company with headquarters in Deerfield, Illinois. The company primarily focuses on products to treat hemophilia, kidney disease, immune disorders and other chronic and acute medical conditions...
. Status: withdrawn in 1998 due to higher than expected mortality - Hemolink, by Hemosol, Inc. Status: Phase III clinical trials were discontinued in 2003 when cardiac surgery patients receiving the product experienced higher rates of adverse cardiovascular-related events. Some very limited ongoing investigation is still being conducted as of 2007, including the possibility of a future modified Hemolink product.
Stem cells
Recently, the scientific community has begun to explore the possibility of using stem cellStem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s as a means of producing an alternate source of transfusable blood. A study performed by Giarratana et al. describes a large-scale ex-vivo production of mature human blood cells using hematopoietic stem cells, and may represent the first significant steps in this direction. Moreover, the blood cells produced in culture possess the same haemoglobin content and morphology as do native red blood cells. The authors of the study also contend that the red blood cells they produced have a near-normal lifespan, when compared to native red blood cells—an important characteristic of which current haemoglobin-based blood substitutes are found to be deficient. The major obstacle with this method of producing red blood cells is cost. Now, the complex three-step method of producing the cells would make a unit of these red blood cells too expensive. However, the study is the first of its kind to demonstrate the possibility of producing red blood cells which closely resemble native red blood cells on a large scale.
Scientists from the experimental arm of the Pentagon
The Pentagon
The Pentagon is the headquarters of the United States Department of Defense, located in Arlington County, Virginia. As a symbol of the U.S. military, "the Pentagon" is often used metonymically to refer to the Department of Defense rather than the building itself.Designed by the American architect...
of United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
began creating artificial blood to transport blood to remote areas and transfuse blood to wounded soldiers more quickly in 2010. The blood is made from the hematopoietic stem cells removed from umbilical cord
Umbilical cord
In placental mammals, the umbilical cord is the connecting cord from the developing embryo or fetus to the placenta...
between the mother and fetus of humans after birth using a method called blood pharming. Pharming has been used in the past on animals and plants to create medical substances in large quantities. Each cord can produce approximately 20 units of blood or three blood transfusions. The blood is being produced for the Defense Advanced Research Projects Agency
Defense Advanced Research Projects Agency
The Defense Advanced Research Projects Agency is an agency of the United States Department of Defense responsible for the development of new technology for use by the military...
by Arteriocyte. The Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
has examined and approved the safety of this blood from previously submitted O-negative blood. Using this particular artificial blood will reduce the costs per unit of blood from $5,000 to equal or less than $1,000. This blood will also serve as a blood donor to all blood types. Pharmed blood may be used in human trials in 2013.
Other potential techniques
DendrimerDendrimer
Dendrimers are repetitively branched molecules. The name comes from the Greek word "δένδρον" , which translates to "tree". Synonymous terms for dendrimer include arborols and cascade molecules. However, dendrimer is currently the internationally accepted term. A dendrimer is typically symmetric...
s : Researchers at the Dendritech Corporation have begun research, aided by a 2 year, $750,000 grant from the US Army, into the use of dendrimers as substitute oxygen carriers. The precise nature of the research cannot be disclosed, as the company’s patent application has not yet been approved. Researchers hope that dendrimer technology will be the first truly cost-efficient blood substitute.
Biodegradable micelles : To enhance circulation times, recombinant or polymerized haemoglobin can be encapsulated within micellar-forming amphiphilic block copolymers. These systems are typically between 30–100 nm in diameter. The hydrophobic core of the polymer micelle is able to solubilize the similarly hydrophobic haemoglobin protein, while the water soluble corona (which is usually polyethylene glycol
Polyethylene glycol
Polyethylene glycol is a polyether compound with many applications from industrial manufacturing to medicine. It has also been known as polyethylene oxide or polyoxyethylene , depending on its molecular weight, and under the tradename Carbowax.-Available forms:PEG, PEO, or POE refers to an...
) provides a steric barrier to protein absorption, and provides protection from clearance by the reticuloendothelial system (RES).
Placental umbilical cord blood : Cord blood collected asceptically from the placenta after the birth of a healthy baby can be used safely as a blood substitute. It has a higher haemoglobin content and growth factors than normal blood from an adult, which has the potential to benefit patients in varying diseases.
Hemerythrin
Hemerythrin
Hemerythrin is an oligomeric protein responsible for oxygen transport in the marine invertebrate phyla of sipunculids, priapulids, brachiopods, and in a single annelid worm, magelona. Recently, hemerythrin was discovered in methanotrophic bacterium Methylococcus capsulatus...
: A team of Romanian researchers from the Babes-Bolyai University
Babes-Bolyai University
The Babeș-Bolyai University in Cluj-Napoca is an university in Romania. With almost 50,000 students, the university offers 105 specialisations, of which there are 105 in Romanian, 67 in Hungarian, 17 in German, and 5 in English...
announced in 2010 that they discovered a colorless substance that can replace blood. The substance is based on hemerythrin
Hemerythrin
Hemerythrin is an oligomeric protein responsible for oxygen transport in the marine invertebrate phyla of sipunculids, priapulids, brachiopods, and in a single annelid worm, magelona. Recently, hemerythrin was discovered in methanotrophic bacterium Methylococcus capsulatus...
, and it was tested on mice with encouraging results.
Other functions than carrying oxygen
The functions of blood are many. Normally, for example, white blood cells defend against disease, platelets promote clotting, and blood proteinsBlood proteins
Blood proteins, also termed serum proteins or plasma proteins, are proteins found in blood plasma. Serum total protein in blood is 7g/dl...
perform various functions. In addition, the blood composition includes additional molecules and electrolytes to function properly. Some of these components are substitutable with modern technology, and may, at least, be added to an oxygen-carrying blood substitute to create a more complete blood substitute.
Volume expander
Volume expander
A volume expander is a type of intravenous therapy that has the function of providing volume for the circulatory system. It may be used for fluid replacement.-Physiology:...
s may theoretically be called a blood substitutes as well, but in practice they are usually not within the scope of blood substitutes. Still, they are sometimes called "plasma substitutes".
History
After William HarveyWilliam Harvey
William Harvey was an English physician who was the first person to describe completely and in detail the systemic circulation and properties of blood being pumped to the body by the heart...
discovered blood pathways in 1616, many people tried to use fluids such as beer, urine, milk, and animal blood as blood substitute. The demand for more blood substitutes began during the Vietnam War
Vietnam War
The Vietnam War was a Cold War-era military conflict that occurred in Vietnam, Laos, and Cambodia from 1 November 1955 to the fall of Saigon on 30 April 1975. This war followed the First Indochina War and was fought between North Vietnam, supported by its communist allies, and the government of...
as wounded soldiers were unable to be treated at hospitals due to blood shortages.
Major worldwide blood shortages have led scientists to synthesize and test artificial blood. Infected blood is a major problem for many countries. Each year 10–15 million units of blood are transfused without being tested first for HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
and hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
. The second largest cause of new HIV infections in Nigeria
Nigeria
Nigeria , officially the Federal Republic of Nigeria, is a federal constitutional republic comprising 36 states and its Federal Capital Territory, Abuja. The country is located in West Africa and shares land borders with the Republic of Benin in the west, Chad and Cameroon in the east, and Niger in...
comes from transfused blood. A major problem associated with donated blood is that after it is stored it loses Nitric Oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
and causes vasoconstriction
Vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...
for the recipient.
The first approved oxygen-carrying blood substitute was a perfluorocarbon-based product called Fluosol
Fluosol
Fluosol is an artificial blood substitute which is milky in color. Its main ingredients are perfluorodecalin or perfluorotributylamine in Fluosol-DA and Fluosol-43 respectively, perfluorochemicals suspended in an albumin emulsion. It was developed in Japan and first tested in the United States in...
-DA-20, manufactured by Green Cross of Japan. It was approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) in 1989. Because of limited success, complexity of use and side effects, it was withdrawn in 1994. However, Fluosol-DA remains the only oxygen therapeutic ever fully approved by the FDA.
In the 1990s, because of the risk of undetected blood bank contamination from AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
, hepatitis C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
and other emergent diseases such as Creutzfeldt-Jakob disease, there was additional motivation to pursue oxygen therapeutics. Significant progress was achieved, and a haemoglobin-based oxygen therapeutic called Hemopure was approved for Phase III trial (in elective orthopedic surgery) in the U.S., and more widely approved for human use in South Africa.
In December 2003, a new haemoglobin-based oxygen therapeutic, PolyHeme
PolyHeme
PolyHeme is a temporary oxygen-carrying blood substitute made from human hemoglobin that is currently in development for emergency treatment of trauma situations where large volumes of blood are lost, with emphasis on situations where fresh blood for transfusion is not readily available...
, began field tests in a Phase III trial on emergency patients (in trauma settings) in the U.S. PolyHeme was the 15th experiment to be approved by the Food and Drug Administration since 1996. Patient consent is not necessary under the special category created by the FDA for these experiments. In late 2005, an independent panel verified, after the fourth and final review of 500 trauma patients enrolled in this study by that date, that no statistical evidence of safety concerns had arisen so far in the study. This study concluded in mid-2006 with final enrollment of 720 patients. Wired news reported that the trial failed when 47 of the 350 people given PolyHeme died compared to 35 deaths out of 363 in the control group. Debate exists as to whether or not the difference in the mortality rate is attributable to the small sample size. The fact that the experimental subjects did not give consent is a significant factor.
In 2010, Hard to Treat Diseases, Inc. (HTD) merged with an anonymous Canadian biotechnology company in hopes to enhance donated blood or hemoglobin based blood substitutes to have a shelf life of 42 days and higher levels of Nitric Oxide when packaged.
See also
- Artificial Cells, Blood Substitutes, and BiotechnologyArtificial Cells, Blood Substitutes, and BiotechnologyArtificial Cells, Blood Substitutes, and Biotechnology is an academic journal that publishes review articles on the development of artificial cells, tissue engineering, artificial organs, blood substittues, cell therapy, gene and drug delivery systems, bioencapsulation nanosensors, nanodevices and...
(journal) - Blood transfusionBlood transfusionBlood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
- Bloodless surgeryBloodless surgeryBloodless surgery is a term that was popularized at the beginning of the 20th century by the practice of an internationally famous orthopedic surgeon, Adolf Lorenz, who was known as "the bloodless surgeon of Vienna." This expression reflected Lorenz's methods for treating patients with noninvasive...
- Theatrical bloodTheatrical bloodTheatrical blood or stage blood is anything used as a substitute for blood in a theatrical or cinematic performance. For example, in the special effects industry, when a director needs to simulate an actor being shot or cut, a wide variety of chemicals and natural products can be used...
- Haemoglobin-based oxygen carriers