Blood substitute

For the rugby union and rugby league term, see blood replacement.

A blood substitute (also called artificial blood or blood surrogates) 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).[1][2] Oxygen therapeutics are in clinical trials in the U.S. and Europe, and Hemopure is available in South Africa.

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 perfluorodecalin.[3] The second is haemoglobin derived from humans, animals, or artificially via recombinant technology, or via stem cell production of red blood cells in vitro.[4]

History

After William Harvey discovered blood pathways in 1616, many people tried to use fluids such as beer, urine, milk, and animal blood as blood substitute.[2][5] 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.[6] 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.[7] 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.[8]

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.[9]

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.[8]

In 2013, IIT Madras was approved to mass-produce artificial blood.[10]

Advantages over human blood

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:

  1. 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.[7]
  2. 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.[7]
  3. 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.[7]
  4. 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.
  5. 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 smallpox and SARS.[7]
  6. 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.[7]
  7. 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,[7] compared to 42 days for donated blood, which needs to be kept refrigerated.
  8. 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.[6]
  9. 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.
  10. 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.[11]

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.[12][13][14]

According to studies of outcomes of transfusions given to trauma patients in 2008,[15] 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.[16] 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 US without informed consent under a special exemption from requirements of informed consent during traumatic care.

Current therapeutics

Perfluorocarbon based

Perfluorochemicals 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.

Name Sponsor Description
Oxygent Alliance Pharmaceuticals Currently approved for Phase II Trials in US and Phase II Trials in Europe. Developed to reduce the need for donor blood during surgery. PFCs are surrounded by a lecithin surfactant in a water-based solution. The lecithin is digested intracellularly. Oxygent has done well overall in most clinical trials, but recently, a cardiac surgery study found participants to be slightly more likely to suffer a stroke if treated with Oxygent rather than by standard care.
Oxycyte 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 at Virginia Commonwealth University.[17]
PHER-O
2		 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.[18] 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.[19]

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.[20] 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.[21]
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 in dogs. Currently, Oxyglobin can only be used in canines 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,[22] 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 (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.” [23] In June 2009, Northfield Laboratories filed Chapter 11 bankruptcy.

Hemospan Sangart Currently in Phase II trials in the United States, Hemospan is produced by the company Sangart, which was founded by 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 trials.
Dextran-Haemoglobin Dextro-Sang Corp Currently in veterinary 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 trials. 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 (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.

Hyperbranched polymer-protected porphyrins

In 2007, scientists from the chemistry department of the University of Sheffield created artificial blood "from plastic".[24] 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.[25] 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.[26]

Withdrawn

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.[27] 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 costly. 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.[28] 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.[28] This blood will also serve as a blood donor to all blood types. Pharmed blood may be used in human trials in 2013.

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.[29]

Other potential techniques

Dendrimers
Researchers at the Dendritech Corporation[30] 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.[31]
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".

See also

References

  1. ↑ Henkel-Honke, T.; Oleck, M. (2007). "Artificial oxygen carriers: A current review" (PDF). AANA Journal 75 (3): 205–211. PMID 17591302.
  2. 1 2 Brown University Division of Biology and Medicine. (2006). History. Retrieved December 3, 2010.
  3. ↑ Stephan C, Schlawne C, Grass S, Waack IN, Ferenz KB, Bachmann M, Barnert S, Schubert R, Bastmeyer M, de Groot H, Mayer C (2014). "Artificial oxygen carriers based on perfluorodecalin-filled poly(n-butyl-cyanoacrylate) nanocapsules". J Microencapsul 31 (3): 284–92. doi:10.3109/02652048.2013.843600.
  4. ↑ Giarratana MC, Rouard H, Dumont A, Kiger L, Safeukui I, Le Pennec PY, François S, Trugnan G, Peyrard T, Marie T, Jolly S, Hebert N, Mazurier C, Mario N, Harmand L, Lapillonne H, Devaux JY, Douay L (Nov 2011). "Proof of principle for transfusion of in vitro-generated red blood cells". Blood 118 (19): 5071–9. doi:10.1182/blood-2011-06-362038. PMID 21885599.
  5. ↑ Sarkar, S. (2008). "Artificial Blood". Indian Journal of Critical Care Medicine 12 (3): 140–144. doi:10.4103/0972-5229.43685. PMC 2738310. PMID 19742251.
  6. 1 2 Schimmeyer, S. (2002, November 1). Illumin: article: The Search for a Blood Substitute. Retrieved December 2, 2010.
  7. 1 2 3 4 5 6 7 Brown University Division of Biology and Medicine. (2006). Home Page. Retrieved December 3, 2010
  8. 1 2 Dow Jones & Co. (2010, November 12). Hard to Treat Diseases, Inc. (HTDS) Targets Merger with Biotechnology Company- MarketWatch. Retrieved December 4, 2010
  9. ↑ Controversial Blood Substitute May Be a Killer | Wired Science | Wired.com. Blog.wired.com (2007-05-24). Retrieved on 2011-11-21.
  10. ↑ http://timesofindia.indiatimes.com/india/IIT-Madras-ready-for-mass-production-of-artificial-blood/articleshow/17990139.cms
  11. ↑ Won Kim, Hae (2005-04-01). "Investment in blood substitutes: Worth the effort?". Brown University. Archived from the original on 2011-05-22. Retrieved 2012-03-19.
  12. ↑ ABC News: Experimental Blood Substitutes Unsafe, Study Finds. Abcnews.go.com (2008-04-28). Retrieved on 2011-11-21.
  13. ↑ Wired Magazine, August 2008, Update: Dire Prognosis for Once-Promising Artificial Blood. Wired.com. Retrieved on 2011-11-21.
  14. ↑ Natanson, C.; Kern, S. J.; Lurie, P.; Banks, S. M.; Wolfe, S. M. (2008). "Cell-Free Hemoglobin-Based Blood Substitutes and Risk of Myocardial Infarction and Death: A Meta-analysis". JAMA: the Journal of the American Medical Association 299 (19): 2304–2312. doi:10.1001/jama.299.19.jrv80007. PMID 18443023.
  15. ↑ Davis, R. (2008, April 28). Study: Blood substitute increases risk of death. Retrieved December 2, 2010
  16. ↑ Stein, R. (2008, April 29). FDA Faulted for Approving Studies of Artificial Blood. Retrieved December 2, 2010
  17. ↑ Yoffee, Lynn (May 1, 2008). "Oxycyte is on track as oxygen carrier, not as 'faux' blood.". Cardiovascular Device & Drugs. Retrieved 2010-06-30.
  18. ↑ Amberson, William; Jennings J.; Rhode C. (1949). "Clinical Experience with Hemoglobin-Saline Solutions". Journal of Applied Physiology 1 (7): 469–489. PMID 18104040.
  19. ↑ Kim, H. W.; Greenburg, A. G. (2004). "Artificial Oxygen Carriers as Red Blood Cell Substitutes: A Selected Review and Current Status". Artificial Organs 28 (9): 813–828. doi:10.1111/j.1525-1594.2004.07345.x. PMID 15320945.
  20. ↑ "Biopure exploring strategic options". Biopure (press release). Retrieved 2009-03-21.
  21. ↑ "Biopure Corporation Annual Report for the fiscal year ended October 31, 2008".
  22. ↑ Vermeulen Windsant, I. C.; Snoeijs, M. G.; Hanssen, S. J.; Altintas, S.; Heijmans, J. H.; Koeppel, T. A.; Schurink, G. W. H.; Buurman, W. A.; Jacobs, M. J. (2010). "Hemolysis is associated with acute kidney injury during major aortic surgery". Kidney International 77 (10): 913–920. doi:10.1038/ki.2010.24. PMID 20182411.
  23. ↑ "Northfield Receives Complete Response Letter for PolyHeme(R) BLA".
  24. ↑ "Sheffield scientists develop artificial blood". Sheffield University Research and Innovation. 2007-05-22. Archived from the original on 2009-04-14. Retrieved 2012-03-18.
  25. ↑ Twyman, L. J.; Ge, Y. (2006). "Porphyrin cored hyperbranched polymers as heme protein models". Chemical Communications (15): 1658. doi:10.1039/b600831n.
  26. ↑ Twyman, L. J.; Ellis, A.; Gittins, P. J. (2012). "Pyridine encapsulated hyperbranched polymers as mimetic models of haeme containing proteins, that also provide interesting and unusual porphyrin-ligand geometries". Chemical Communications (Royal Society of Chemistry) 48 (1): 154–156. doi:10.1039/c1cc14396d. PMID 22039580.
  27. ↑ Rousseau GF, Giarratana MC, Douay L (Jan 2014). "Large-scale production of red blood cells from stem cells: what are the technical challenges ahead?". Biotechnol J. 9 (1): 28–38. doi:10.1002/biot.201200368.
  28. 1 2 Edwards, L. (July 13, 2010). Artificial blood developed for the battlefield. Retrieved November 30, 2010
  29. ↑ [Times of India - News http://timesofindia.indiatimes.com/india/IIT-Madras-ready-for-mass-production-of-artificial-blood/articleshow/17990139.cms]
  30. ↑ "Dendritech awarded $750,000 grant to continue blood substitute work". Retrieved 2012-03-19.
  31. ↑ "Cluj doctors create artificial blood-replacing substance". Bucharest Herald. 18 September 2010. Retrieved 25 September 2010.
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