A blood substitute (also called artificial blood or blood surrogate) is a substance used to mimic and fulfill some functions of
biological
Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary in ...
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...
. It aims to provide an alternative to
blood transfusion
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
, which is transferring blood or
blood-based products from one person into another. Thus far, there are no well-accepted ''oxygen-carrying'' blood substitutes, which is the typical objective of a
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
transfusion; however, there are widely available non-blood
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 or during surgery to prevent nausea and vomiting after surgery.
Physiology
When blood is ...
s for cases where only volume restoration is required. These are helping doctors and surgeons avoid the risks of disease transmission and immune suppression, address the chronic blood donor shortage, and address the concerns of
Jehovah's Witnesses
Jehovah's Witnesses is a millenarian restorationist Christian denomination with nontrinitarian beliefs distinct from mainstream Christianity. The group reports a worldwide membership of approximately 8.7 million adherents involved in ...
and others who have religious objections to receiving transfused blood.
The main categories of "oxygen-carrying" blood substitutes being pursued are hemoglobin-based oxygen carriers (HBOC) and
perfluorocarbon emulsions Perfluorocarbon emulsions are emulsions containing either bubbles or droplets which have perfluorocarbons inside them. Some of them are commonly used in medicine as ultrasound contrast agents, and others have been studied for use as oxygen therapeu ...
. Oxygen therapeutics are in clinical trials in the
U.S.
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country Continental United States, primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., ...
and
Europe
Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...
, and
Hemopure
A blood substitute (also called artificial blood or blood surrogate) is a substance used to mimic and fulfill some functions of biological blood. It aims to provide an alternative to blood transfusion, which is transferring blood or blood-based ...
is available in
South Africa
South Africa, officially the Republic of South Africa (RSA), is the southernmost country in Africa. It is bounded to the south by of coastline that stretch along the South Atlantic and Indian Oceans; to the north by the neighbouring countri ...
.
History
After
William Harvey
William Harvey (1 April 1578 – 3 June 1657) was an English physician who made influential contributions in anatomy and physiology. He was the first known physician to describe completely, and in detail, the systemic circulation and proper ...
discovered blood pathways in 1616, many people tried to use fluids such as beer, urine, milk, and non-human animal blood as blood substitute.
Sir Christopher Wren
Sir Christopher Wren PRS FRS (; – ) was one of the most highly acclaimed English architects in history, as well as an anatomist, astronomer, geometer, and mathematician-physicist. He was accorded responsibility for rebuilding 52 churches ...
suggested wine and opium as blood substitute.
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
A blood type (also known as a blood group) is a classification of blood, based on the presence and absence of antibodies and inherited antigenic substances on the surface of red blood cells (RBCs). These antigens may be proteins, carbohydrates ...
serology. Simultaneously, significant progress was made in the fields of heart and circulation physiology as well as in the understanding of the mechanism of oxygen transport and tissue oxygenation.
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.
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. The
emergence of HIV in the 1980s renewed impetus for development of infection-safe blood substitutes.
Public concern about the safety of the blood supply was raised further by
mad cow disease
Bovine spongiform encephalopathy (BSE), commonly known as mad cow disease, is an incurable and invariably fatal neurodegenerative disease of cattle. Symptoms include abnormal behavior, trouble walking, and weight loss. Later in the course of t ...
.
The continuous decline of blood donation combined with the increased demand for blood transfusion (increased ageing of population, increased incidence of invasive diagnostic, chemotherapy and extensive surgical interventions, terror attacks, international military conflicts) and positive estimation of investors in biotechnology branch made for a positive environment for further development of blood substitutes.
Efforts to develop blood substitutes have been driven by a desire to replace
blood transfusion
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
in emergency situations, in places where infectious disease is endemic and the risk of
contaminated blood products is high, where refrigeration to preserve blood may be lacking, and where it might not be possible or convenient to find
blood type
A blood type (also known as a blood group) is a classification of blood, based on the presence and absence of antibodies and inherited antigenic substances on the surface of red blood cells (RBCs). These antigens may be proteins, carbohydrate ...
matches.
Approaches
Efforts have focused on molecules that can carry
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
, and most work has focused on recombinant
hemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
, which normally carries oxygen, and
perfluorocarbons
Fluorocarbons are chemical compounds with carbon-fluorine bonds. Compounds that contain many C-F bonds often has distinctive properties, e.g., enhanced stability, volatility, and hydrophobicity. Fluorocarbons and their derivatives are commerci ...
(PFC), chemical compounds which can carry and release oxygen.
The first approved oxygen-carrying blood substitute was a perfluorocarbon-based product called Fluosol
A blood substitute (also called artificial blood or blood surrogate) is a substance used to mimic and fulfill some functions of biological blood. It aims to provide an alternative to blood transfusion, which is transferring blood or blood-based ...
-DA-20, manufactured by Green Cross of Japan. It was approved by the Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(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. As of 2017 no hemoglobin-based product had been approved.[
]
Perfluorocarbon based
Perfluorochemicals are not water soluble
In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution.
The extent of the solubil ...
and will not mix with blood, therefore emulsion
An emulsion is a mixture of two or more liquids that are normally immiscible (unmixable or unblendable) owing to liquid-liquid phase separation. Emulsions are part of a more general class of two-phase systems of matter called colloids. Althoug ...
s must be made by dispersing small drops of PFC in water
Water (chemical formula ) is an inorganic, transparent, tasteless, odorless, and nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living organisms (in which it acts as a ...
. This liquid is then mixed with antibiotics
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...
, vitamin
A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an Nutrient#Essential nutrients, essential micronutrient that an organism needs in small quantities for the proper functioning of its ...
s, nutrient
A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...
s and salt
Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...
s, producing a mixture that contains about 80 different components, and performs many of the vital functions of natural blood. PFC particles are about the size of the diameter of a red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
(RBC). This small size can enable PFC particles to traverse capillaries
A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
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
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
s, including human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
s, can survive breathing liquid PFC solution, called liquid breathing
Liquid breathing is a form of respiration in which a normally air-breathing organism breathes an oxygen-rich liquid (such as a perfluorocarbon), rather than breathing air.
By selecting a liquid that is capable of holding large amounts of oxyg ...
.
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 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 hemoglobin.
Fluosol was made mostly of 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 di ...
or perfluorotributylamine
Perfluorotributylamine (PFTBA), also referred to as FC43, is a colorless liquid with the formula N(C4F9)3. The compound consists of three butyl groups connected to an amine center, in which all of the hydrogen atoms have been replaced with fluori ...
suspended in an albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
emulsion. It was developed in Japan
Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the north ...
and first tested in the United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...
in November 1979. In order to "load" sufficient amounts of oxygen into it, people who had been given it had to breathe pure oxygen by mask or in a hyperbaric chamber
A diving chamber is a vessel for human occupation, which may have an entrance that can be sealed to hold an internal pressure significantly higher than ambient pressure, a pressurised gas system to control the internal pressure, and a supply of ...
. It was approved by the FDA in 1989, and was approved in eight other countries. Its use was associated with a reduction in ischemic complications and with an increase in pulmonary edema and congestive heart failure. Due to difficulty with the emulsion storage of Fluosol use (frozen storage and rewarming), its popularity declined and its production ended in 1994.[
Oxygent was a second-generation, ]lecithin
Lecithin (, from the Greek ''lekithos'' "yolk") is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues which are amphiphilic – they attract both water and fatty substances (and so ar ...
-stabilized emulsion
An emulsion is a mixture of two or more liquids that are normally immiscible (unmixable or unblendable) owing to liquid-liquid phase separation. Emulsions are part of a more general class of two-phase systems of matter called colloids. Althoug ...
of a PFC that was under development by Alliance Pharmaceuticals. In 2002 a Phase III study was halted early due an increase in incidences of strokes in the study arm.
Haemoglobin based
Haemoglobin
Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
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).
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.
Efforts to overcome this toxicity have included making genetically engineered
Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including t ...
versions, cross-link
In chemistry and biology a cross-link is a bond or a short sequence of bonds that links one polymer chain to another. These links may take the form of covalent bonds or ionic bonds and the polymers can be either synthetic polymers or natural ...
ing, polymerization
In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer, monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are ...
, and encapsulation.[
HemAssist, a diaspirin cross-linked haemoglobin (DCLHb) was developed by ]Baxter Healthcare
Baxter International Inc. is an American multinational healthcare company with headquarters in Deerfield, Illinois.
The company primarily focuses on products to treat kidney disease, and other chronic and acute medical conditions. The compan ...
; it was the most widely studied of the haemoglobin-based blood substitutes, used in more than a dozen animal and clinical studies. It reached Phase III clinical trials, in which it failed due to increased mortality in the trial arm, mostly due to severe vasoconstriction complications. The results were published in 1999.
Hemolink (Hemosol Inc., Mississauga, Canada) was a haemoglobin solution that contained cross-linked an o-rafinose polymerised human haemoglobin.[ Hemosol struggled after Phase II trials were halted in 2003 on safety concerns and declared bankruptcy in 2005.
Hemopure was developed by Biopure Corp and was a chemically stabilized, cross-linked bovine (cow) haemoglobin in a salt solution intended for human use; the company developed the same product under the trade name Oxyglobin for veterinary use in dogs. Oxyglobin was approved in the US and Europe and was introduced to veterinary clinics and hospitals in March 1998. Hemopure was approved in South Africa and Russia. Biopure filed for bankruptcy protection in 2009. Its assets were subsequently purchased by HbO2 Therapeutics in 2014.
PolyHeme was developed over 20 years by ]Northfield Laboratories
Northfield Laboratories Inc. (former NASDAQ: NFLD) was the maker of PolyHeme, a hemoglobin-based oxygen carrier (HBOC). The company was based in Evanston, Illinois, with Dr. Steven A. Gould as its chief executive officer. As of May 31, 2005, ...
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. In April 2009, the FDA rejected Northfield's Biologic License Application
A biologics license application (BLA) is defined by the U.S. Food and Drug Administration (FDA) as follows:
The biologics license application is a request for permission to introduce, or deliver for introduction, a biologic product into inters ...
and in June 2009, Northfield filed for bankruptcy.
Dextran-Haemoglobin was developed by Dextro-Sang Corp as a veterinary product, and was a conjugate of the polymer dextran with human haemoglobin.
Hemotech was developed by HemoBiotech and was a chemically modified haemoglobin.
Somatogen developed a genetically engineered and crosslinked tetramer it called Optro. It failed in a phase II trial that was published in 2014 and development was halted.[
A pyridoxylated Hb conjugated with ]polyoxyethylene
Polyethylene glycol (PEG; ) is a polyether compound derived from petroleum with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEO) or polyoxyethylene (POE), depending on its molecular we ...
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,[ which led to Curacyte shutting down.
Similarly, Hemospan was developed by Sangart, and was a ]pegylated
PEGylation (or pegylation) is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol (PEG, in pharmacy called macrogol) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein ...
haemoglobin provided in a powdered form. While early trials were promising Sangart ran out of funding and closed down.[
]
Stem cells
Stem cell
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
s offer a possible means of producing transfusable blood. A study performed by Giarratana et al. describes a large-scale ex-vivo production of mature human blood cells using hematopoietic stem cell
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
s. The cultured cells possessed the same haemoglobin content and morphology as native red blood cells. The authors contend that the cells had a near-normal lifespan, when compared to natural red blood cells.
Scientists from the experimental arm of the United States Department of Defense
The United States Department of Defense (DoD, USDOD or DOD) is an executive branch department of the federal government charged with coordinating and supervising all agencies and functions of the government directly related to national secu ...
began creating artificial blood for use in remote areas and transfuse blood to wounded soldiers more quickly in 2010.[Edwards, L. (July 13, 2010)]
Artificial blood developed for the battlefield
Retrieved November 30, 2010 The blood is made from the hematopoietic
Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...
stem cells removed from the umbilical cord
In placental mammals, the umbilical cord (also called the navel string, birth cord or ''funiculus umbilicalis'') is a conduit between the developing embryo or fetus and the placenta. During prenatal development, the umbilical cord is physiologic ...
between human mother and newborn using a method called blood pharming
Pharming is a cyberattack intended to redirect a website's traffic to another, fake site by installing a malicious program on the computer. Pharming can be conducted either by changing the hosts file on a victim's computer or by exploitation of a ...
. 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. The blood is being produced for the Defense Advanced Research Projects Agency
The Defense Advanced Research Projects Agency (DARPA) is a research and development agency of the United States Department of Defense responsible for the development of emerging technologies for use by the military.
Originally known as the Adv ...
by Arteriocyte. The Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
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 common blood types
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the ci ...
. Pharmed blood may be used in human trials in 2013.
See also
* '' Artificial Cells, Blood Substitutes, and Biotechnology''
* Blood plasma substitute (disambiguation)
* Blood transfusion
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
* Bloodless surgery
Bloodless surgery is a non-invasive surgical method developed by orthopedic surgeon, Adolf Lorenz, who was known as "the bloodless surgeon of Vienna". His medical practice was a consequence of his severe allergy to carbolic acid routinely used in ...
* Erythromer
* Induced blood stem cells
* Theatrical blood
Theatrical blood, stage blood or fake 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 ...
References
External links
How Artificial Blood Works
at HowStuffWorks
HowStuffWorks is an American commercial infotainment website founded by professor and author Marshall Brain, to provide its target audience an insight into the way many things work. The site uses various media to explain complex concepts, termin ...
{{DEFAULTSORT:Blood Substitutes
Synthetic biology
Transfusion medicine