The quest for a blood substitute has endured for centuries. Only recently, however, has medical science made significant breakthroughs in mimicking blood’s role of bringing oxygen to body tissues.
Artificial blood can be roughly divided into two types: volume replacers, and oxygen therapeutics. Volume replacers, namely saline solutions and colloid-based liquids, bolster the total volume of blood plasma. This is crucial when blood is lost, since low blood volume can lead to systemic shock, a life-threatening condition where the amount of blood going to tissues is inadequate. On the other hand, the body’s natural oxygen transport molecule, hemoglobin, becomes more efficient at carrying oxygen when less oxygen is present in the body (2). Therefore, offsetting the loss of total blood volume allows the remaining hemoglobin to continue to circulate and function throughout the body (2). Over the past 50 years, volume expanders have become standard in hospitals and medical settings, but these materials are not what many imagine when thinking of synthetic blood.
Oxygen therapeutics actively transport oxygen, mimicking the function of hemoglobin. Presently, therapeutics achieves this in one of two ways: using perfluorocarbons (PFCs), or hemoglobin-based oxygen carriers (HBOCs) (3). Both types of therapeutic have been successful to different degrees, but both suffer from the same shortcomings that have plagued attempts to create satisfactory blood substitutes for centuries.
History
Western medicine’s quest to find a replacement for blood can be traced back to as early as the 17th century, when the first substitutes were developed to offset fluid loss from childbirth and the common “medical” techniques of leeching and bloodletting. Such fluids as beer, milk, urine, plant resin, and sheep blood were used. Most types of fluids resulted in the patients’ deaths, but people found that milk was relatively successful. By the early 19th century, patients suffering from Asiatic cholera were injected with milk, and many actually improved since milk served as a rudimentary volume expander. Still, milk was not an effective replacement for plasma, and with a high enough dosage had significant side effects of its own (4).
The early 20th century saw the development of some mildly successful volume expanders, including the proliferation of saline (4). The establishment of blood banks in WWII brought a temporary halt to artificial blood research. Interest in an artificial substitute did not spike again until the Vietnam War in the 1960’s, when blood banks’ supplies proved inadequate (4).
The most notable development of this era was the creation of perfluorocarbons (PFCs). Researcher Leland Clark experimented with this class of compound, finding that it was potentially 100 times better at carrying oxygen than hemoglobin. The fluorine-based molecule is a long-chain polymer similar in structure to other synthetic materials like Teflon. Experiments found that mice could survive when fully submerged in PFC solution, and rats could temporarily have all their blood replaced with PFC and survive (3).
With the experimental success of PFCs, a product named Fluosol by Green Cross of Japan was quickly developed. However, adverse results in clinical trials caused the FDA to withdraw support a few years after initial approval in 1993 (3).
It was also at this time that methods for extracting hemoglobin were further investigated by researchers. Stroma-free designs were developed, allowing hemoglobin based oxygen carriers (HBOCs) to be transfused to any blood types. However, like PFCs, medical complications limited their development. (6)
Blood is always in demand since the rate of blood transfusions greatly outpace the influx of blood donations.
Oxygen Therapeutics
Presently, researchers are still working on limiting the negative side effects of PFCs and HBOCs, and have yet to gain complete FDA approval for human usage for any type of therapeutic (11).
Ideally, a substitute should be compatible with all blood types. It should also be able to transport oxygen more efficiently than blood, and have an extended shelf life of at least a year (in comparison to a month for donated blood). PFCs and HBOCs approach these objectives in entirely differently ways.
PFC is a hydrophobic molecule, so in order to be introduced to the body, it must be emulsified in a mixture of water, antibiotics, salts, and nutrients. The molecules themselves are only a fraction of the size of the body’s own red blood cells, which enables it to transport more oxygen to areas of the body red blood cells have difficulty reaching, such as capillaries. As previously mentioned, PFC can transport as much as 100 times more oxygen then blood (3).
However, PFC is not without its fault. Because the molecule is biologically inert, it accumulates in the liver. Over time, PFC is re-released into the plasma as a gas, and eventually exhaled through the lungs, but the time spent in the reticuloendothelial system can be dangerous to the body. Platelet count often decreases, and with great enough doses, the immune system can be overloaded, and the body thus made more susceptible to infection. Early variants of PFC could stay in the body as long as two weeks (7).
The goal of the most prominent PFC currently in development, Oxygent by Alliance Pharmaceutical, is to replace the need for donor blood in surgery. Oxygent can be removed from the body within 48 hours, and clinical trails have proved the substance relatively stable. Still there have been several reported cases of post-surgical complications, namely stroke and heart failure. These complications have withheld Oxygent, and similar PFCs from receiving FDA approval (11).
On the other hand, hemoglobin-based substitutes suffer from a different shortcoming. Hemoglobin covalently binds oxygen, but isolated molecules tend to break down into more toxic products, often leading to acute renal failure when introduced to the body (3). Without the necessary bonds and cross-links with red blood cells, concentrated doses of hemoglobin would simply overwhelm and destroy the kidneys.
Research into HBOCs has been focused on modifying the hemoglobin molecule to ensure better stability and greater affinity to oxygen. Several HBOCs are currently in development which use both animal extracted hemoglobin and molecules grown on E. coli bacteria (11).
Hemopure by Biopure Corporation uses hemoglobin extracted from cows. The substitute saw wide distribution in South Africa up until 2008, when South Africa deauthorized its sale. The product still remains in phase III clinical trails in the US, but its future there also remains uncertain (11).
This phase III limbo is largely due to the failings of another major HBOC, PolyHeme by Northfield Laboratories. After completing a two-year phase III clinical trail in 2005, PolyHeme was close to being released on the market. However, in a study of 350 trauma patients given PolyHeme, 47 died in contrast to 35 of 363 in the control group. Following the results of this trial, the FDA declined Polyheme’s approval in 2009 stating that “in the absence of clinical benefit, the risk:benefit assessment of the product in trauma is unfavorable” (5).
The Future
Despite the present lack of an FDA approved substitute, artificial blood is still a relevant scientific objective, and research continues.
The demand for blood is still growing. Presently, 39,000 units of blood are needed every day, and about one in seven people entering a hospital require blood. The rate of blood giving is greatly outpaced by the rate of blood transfusions in an aging U.S. population (9). In New York City alone, 25 percent of blood used comes from Europe (11).
Blood is also needed in developing countries. According to a 2000 NIH study, 10-15 million units of blood are annually transfused throughout the globe without testing for HIV and other diseases. This is particularly true for areas with high HIV-infected population such as South Africa where the percentage of people infected with HIV can be as high as 40 percent (10).
New techniques such as stem cells and entirely different types of blood substitutes are being developed. All of these techniques hold potential, but it may still be several years before an effective blood substitute enters the global market.
References
1. N. A. Campbell, J. B. Reece, M. R. Taylor, E. J. Simon, and J. L. Dickey. Biology: Concepts and Connections. San Francisco, CA. Perason Education, Inc. 2009.
2. B. J. Leone, “Artificial Blood: What Is It? Will I Use It?” Dec. 1998. Mayo Clinic. http://www.dcmsonline.org/jax-medicine/1998journals/december98/artificialblood.htm. Nov 30, 2009. Leone, Bruce J. “Artificial Blood: What Is It? Will I Use It?” Duval County Medical Society (1998)
3. H. A. Oberman. “Early History of Blood Substitutes: Transfusion of Milk” Department of Pathology, University of Michigan Medical Center. Ann Arbor Michigan. 1969
4. B. Japsen, “FDA shoots down Northfield Labs’ blood substitute.” April 30, 2009. Chicago Tribune. Dec 4, 2009. http://archives.chicagotribune.com/2009/apr/30/business/chi-northfield-labs-polyheme-apr30.
5. R. Lee, N. Atsumi, E. E. J. Jacobs, W. G. Austen, G.J. Vlahakes. Ultrapure, stroma-free, polymerized bovine hemoglobin solution: evaluation of renal toxicity. Journal of Surgical Research. 1989.
6. P. E. Keipert, “Oxygen therapeutics (“blood substitutes”) where are they, and what can we expect?” Alliance Pharmaceutical Corp. San Diego, CA. 2003. http://www.ncbi.nlm.nih.gov/pubmed/15174622?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5. Jan 8, 2009.
7. R. Lee, N. Atsumi, E. E. J. Jacobs, W. G. Austen, G.J. Vlahakes. Ultrapure, stroma-free, polymerized bovine hemoglobin solution: evaluation of renal toxicity. Journal of Surgical Research. 1989;47:407-411.
8. “Blood is Always Needed” America’s Blood Centers. http://www.americasblood.org/go.cfm?do=Page.View&pid=7. Jan 8, 2009.
9. A. Raufu, “Rising HIV infection through blood transfusion worries Nigerian health experts” Aids Anal Afr. 2000 Jun-Jul. http://www.ncbi.nlm.nih.gov/pubmed/12349722?dopt=Abstract. Jan 8, 2009.
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