By Pierce Hoenigman, Fall 2022.
Every two seconds, someone in the US needs a blood transfusion due to injury, cancer, or disease.[1] Acquiring, testing, and transporting all the blood necessary to fuel the nation’s hospitals is a monumental task and comes with many unique problems. Yet while the US possesses infrastructure to accommodate the need for blood, other parts of the world are not so lucky; low income countries receive one sixth of the blood donations that high income countries receive. Donation is further complicated by the higher prevalence of blood borne diseases such as HIV, which restrict the donor pool.[2] Additionally, blood must be stored in chilled environments to prevent contamination, which requires facilities that may not be present in low income nations.[2] Furthermore, testing, processing, and transport of blood in these countries often fails to meet international standards.[3] A low cost synthetic blood with a longer shelf life and applicability toward multiple blood types would solve many problems regarding human blood. Researchers around the world are searching for an answer with these ideal properties, but how close are they?
The most straightforward blood alternative is hemoglobin-based oxygen carriers (HBOCs). These molecules are derived from hemoglobin, the molecule in red blood cells which binds to oxygen at the lungs and releases it throughout the body, an integral process since oxygen transport is the most crucial role of blood. Hemoglobin cannot function as an oxygen carrier on its own in the bloodstream; the presence of hemoglobin outside red blood cells causes arterial walls to constrict, leading to heart attacks and strokes. [4] To slip by undetected, the structure of hemoglobin has been altered by researchers to be less recognizable by the body while still preserving functionality.[3] Further challenges include the extraction of these proteins from the bloodstream by the kidneys and the increase in osmotic pressure that individual proteins outside of a cell create.[3] To solve these challenges, researchers have modified the proteins to stick to each other in the bloodstream, lowering osmotic pressure and filtration by the kidneys.[3] While the current stage of HBOC development has managed to overcome these issues, further optimization of HBOC protein clumping and kidney filtration evasion would increase the half life of these blood substitutes above the current 24 hours.[3] Half life is a measure of the time at which 50% of the compound remains in the bloodstream. In this case, a longer half-life is preferred to use less of the compound and better stabilize the patient. A final concern is that cows make up the primary source of hemoglobin for modification into HBOCs, risking unlikely but possible sample contamination by mad cow disease.[3] Nevertheless, Polyheme, a cow-derived HBOC, has achieved FDA approval while Hemopure and Hemolink are under current review.[4]
Another solution involves molecules known as perfluorocarbons. Completely unlike hemoglobin, these are long chains of carbons attached to fluorines, and are chemically and biologically inert.[3] Better, since these molecules are not derived from blood in any way, they are acceptable to Jehovah’s Witnesses and other religious groups who cannot accept transfused blood.[4] Dangerously lowered blood pressure in recipients hindered the first generation of this technology, however this issue has been resolved in more recent generations. As with HBOCs, the half-life of 24 hours for perfluorocarbons remains to be optimized.[3] Flusol DA is a perfluorocarbon approved for use during heart surgery, and Oxygent is another product undergoing FDA trials.[3]
While HBOCs and perfluorocarbons are the two dominant categories of blood substitute, cellular oxygen carriers have recently gained importance. These are human red blood cells produced in a lab. While we are not yet capable of assembling a human cell from scratch, scientists have recently been able to harness stem cells to proliferate human cells outside of the body. Stem cells are like a blank slate: depending on what chemical signals they receive, they will differentiate into specialized cells. Therefore, by introducing a hormone known as erythropoietin to stem cells, researchers can modify them to become red blood cell-producing cells.[3] This is ideal, as these red blood cells function exactly the same as ones produced by the body, and stem cells from O negative donors will produce blood that all patients can receive [3] Unfortunately, upscaling this technology has proven difficult; one pint of blood requires thousands of liters of cell culture.[3] Also, human stem cell supply is limited, especially by government policies, and induced stem cells (essentially normal cells which are wiped of their specialization) are not as effective. Still, improving the function of induced stem cells and studying blood producing cells in the body could make cellular oxygen carrier production viable in the future.[3]
Two questions arise following our survey of the current state of artificial blood technology and its challenges: is artificial blood viable for the future? And why aren’t blood substitutes currently on the market more widespread? The answer to the first question is unfortunately impossible to predict, but despite drawbacks, all of these concepts have proven to be viable. Even if some of these avenues for research become infeasible due to the hurdles previously mentioned, one approach will likely become successful. However, the viability of artificial blood is contingent on the factors that address the second question. The current system of blood donation works well in the countries that possess the capital to invest in artificial blood technology, so there is little incentive for these countries to finance this field. Why switch to a costly new product if millions of people donate a better version for free? It is the places that need blood most, unfortunately, that do not possess the funds to invest in blood substitutes. While these nations may simply need to make the best of a bad situation, research that may yield life changing results for millions continues to progress, albeit gradually.
[1] American Red Cross. 2017. “Blood Needs & Blood Supply.” Redcrossblood.org. https://www.redcrossblood.org/donate-blood/how-to-donate/how-blood-donations-help/blood-needs-blood-supply.html.
[2] World Health Organization: WHO. 2019. “Blood Safety and Availability.” Who.int. World Health Organization: WHO. June 14. https://www.who.int/news-room/fact-sheets/detail/blood-safety-and-availability.
[3] Veen, Theun van, and John A. Hunt. 2014. “Tissue Engineering Red Blood Cells: A Therapeutic.” Journal of Tissue Engineering and Regenerative Medicine 9 (7): 760–70. doi:10.1002/term.1885.
[4] Squires, Jerry E. 2002. “Artificial Blood.” Science 295 (5557): 1002–5. doi:10.1126/science.1068443.