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 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 transfusion; however, there are widely available non-blood volume expanders 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 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-based oxygen carriers (PFBOC). Oxygen therapeutics are in clinical trials in the U.S. and Europe, and Hemopure is available in South Africa.
Video Blood substitute
Oxygen-carrying substitutes
An oxygen-carrying blood substitute, sometimes called artificial haemoglobin, is an artificially made red blood cell substitute whose main function is to carry oxygen, as does natural hemoglobin. The use of oxygen-carrying blood substitutes is often called oxygen therapeutics to differentiate from true blood substitutes. 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 cells 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 (PFC), chemical compounds which can carry and release oxygen. The specific PFC usually used is either perfluorodecalin or dodecafluoropentane emulsion (DDFPe). The second approach is haemoglobin derived from humans, animals, or artificially via recombinant technology, or via stem cell production of red blood cells in vitro.
Maps Blood substitute
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 trauma.
Blood substitutes are useful for the following reasons. 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 HIV infections in Nigeria. 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 Creutzfeldt-Jakob disease, and other disease could emerge as problems for the blood supply, including smallpox and SARS.
Transfused 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 Witnesses.
Synthetic oxygen carriers may also show potential for cancer treatment, as their reduced size allows them to diffuse more effectively through poorly vasculated tumour tissue, increasing the effectiveness of treatments like photodynamic therapy and chemotherapy.
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.
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 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 obtain 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 US without informed consent under a special exemption from requirements of informed consent during traumatic care.
Current therapeutics
Perfluorocarbon based
Perfluorochemicals are not water soluble, so will not mix with blood, therefore emulsions must be made by dispersing small drops of PFC in water. This liquid is then mixed with antibiotics, vitamins, nutrients and salts, producing a mixture that contains about 80 different components, and performs many of the vital functions of natural blood. 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 mammals, including humans, 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.
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-linking, polymerization, and encapsulation. These are needed because the red blood cell is not a simple container for haemoglobin, but a complex entity with many biomolecular features.
Hyperbranched polymer-protected porphyrins
In 2007, scientists from the chemistry department of the University of Sheffield created artificial blood "from plastic". Unlike donated blood which has a shelf life of 35 days, the artificial blood lasted longer without the need for refrigeration.
The "plastic" blood consists of an iron-containing porphyrin which is permanently bonded to a hyperbranched polymer (HBP or dendrimer) "shell" which protects the fragile porphyrin. This is similar to hemoglobin in blood, which consists of an iron containing porphyrin reversibly bonded to a protein "shell".
The accompanying research showed that the protected porphyrin was far less susceptible to oxidation than a free porphyrin, while still able to bind oxygen reversibly. A later paper investigated using non-covalent bonding to attach the iron-containing porphyrin. This mimics natural heme-proteins more accurately, as well as providing the ability to recycle the HBP when the contained porphyrin becomes damaged.
Withdrawn
Oxygent, by Alliance Pharmaceuticals. In 2007 Alliance discontinued its clinical development in France and sought development in China. As of 2016 it appears that there was no development in China.
Fluosol-DA, by Alpha Therapeutic Corp.of Los Angeles, CA, a subsidiary of Green Cross Corp., Osaka, Japan. Status: withdrawn in 1994 due to usage complexity, limited clinical benefit and complications
HemAssist, by Baxter International. 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.
Potential techniques
Stem cells
Recently, the scientific community has begun to explore the possibility of using stem cells 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 the 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.
The blood created by Marc Turner of the University of Edinburgh used iPS stem cells instead. However, this project too found that the cost to produce such blood was very high.
In 2013 a group scientists from IIT - Madras, India claimed that they were able to generate a quadrillion pure red blood cells from a million stem cells collected from umbilical cords in just a few weeks. The method used is claimed to be different than existing techniques, and they look forward to mass production in the near future. The scientists have applied for patents in India and look forward to an international patent.
Other potential techniques
Dendrimers: 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. Sheffield University's "HBP protected porphyrins" (plastic blood) are another example of dendrimer technology.
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.
Respirocytes: are hypothetical, microscopic, artificial red blood cells that can emulate the function of its organic counterpart with increased efficiency.
Other functions than carrying oxygen
The functions of blood are many. Normally, for example, white blood cells defend against disease, platelets allow clotting, and blood proteins 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 expanders could conceptually be called blood substitutes as well, but they are usually not within the scope of blood substitutes. Still, they are sometimes called "plasma substitutes".
History
After William Harvey discovered blood pathways in 1616, many people tried to use fluids such as beer, urine, milk, and non-human 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 HIV, 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 haemoglobin based blood substitutes to have a shelf life of 42 days and higher levels of Nitric Oxide when packaged.
In 2011, Luc Douay (Université Pierre et Marie Curie) set up a proof-of-concept of creating artificial blood from hematopoietic stem cells.
In 2013, IIT Madras was approved to mass-produce artificial blood made from stem cells.
In 2015, Marc Turner of the university of Edinburgh produced blood from iPS stemcells.
See also
- Artificial Cells, Blood Substitutes, and Biotechnology (journal)
- Blood transfusion
- Bloodless surgery
- Theatrical blood
- Haemoglobin-based oxygen carriers
- Blood plasma substitute (disambiguation)
- Induced Blood stem cells
- Erythromer
References
Source of the article : Wikipedia
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