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Blood substitute
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<h2 id="history">History</h2> <p>After <a href="/facts/William_Harvey/w6WokymW">William Harvey</a> discovered blood pathways in 1616, many people tried to use fluids such as beer, urine, milk, and non-human animal blood as blood substitute.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> <a href="/facts/Sir_Christopher_Wren/yKSh7QUa">Sir Christopher Wren</a> suggested wine and opium as blood substitute.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> </p><p>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 <a href="/facts/Blood_group/zdxFTV6F">blood group</a> serology.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> 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.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> 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 <a href="/facts/HIV/ulY2rgzu">emergence of HIV</a> in the 1980s renewed impetus for development of infection-safe blood substitutes.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> Public concern about the safety of the blood supply was raised further by <a href="/facts/Mad_cow_disease/UKYCrfRh">mad cow disease</a>.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> 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.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p><p>Efforts to develop blood substitutes have been driven by a desire to replace <a href="/facts/Blood_transfusion/fb0Mk6Dx">blood transfusion</a> in emergency situations, in places where infectious disease is endemic and the risk of <a href="/facts/Contaminated_haemophilia_blood_products/GhIc9KqK">contaminated blood products</a> is high, where refrigeration to preserve blood may be lacking, and where it might not be possible or convenient to find <a href="/facts/Blood_type/zdxFTV6F">blood type</a> matches.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p><p>In 2023, <a href="/facts/DARPA/Uf9sarhT">DARPA</a> announced funding for twelve universities and labs for synthetic blood research. Human trials would be expected to happen between 2028-2030.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p> <h2 id="approaches">Approaches</h2> <p>Efforts have focused on molecules that can carry <a href="/facts/Oxygen/acyn6o8r">oxygen</a>, and most work has focused on recombinant <a href="/facts/Hemoglobin/RsD1MzYA">hemoglobin</a>, which normally carries oxygen, and <a href="/facts/Perfluorocarbons/jA9N6aoT">perfluorocarbons</a> (PFC), chemical compounds which can carry and release oxygen.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p><p>The first approved oxygen-carrying blood substitute was a per<a href="/facts/Fluorocarbon/jA9N6aoT">fluorocarbon</a>-based product called <a href="/facts/Fluosol/YuTH5Fp9">Fluosol</a>-DA-20, manufactured by <a href="/facts/Green_Cross_(Japan)/u4lbUsoI">Green Cross</a> of Japan. It was approved by the <a href="/facts/Food_and_Drug_Administration/rCEnh9WB">Food and Drug Administration</a> (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.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> </p> <h3>Perfluorocarbon based</h3> <p>Perfluorochemicals are not <a href="/facts/Water_soluble/kLE9h3Jb">water soluble</a> and will not mix with blood, therefore <a href="/facts/Emulsion/YMSqSCuH">emulsions</a> must be made by dispersing small drops of PFC in <a href="/facts/Water/0lkXnJPK">water</a>. This liquid is then mixed with <a href="/facts/Antibiotics/sF1kIfxg">antibiotics</a>, <a href="/facts/Vitamin/SnW0LYBL">vitamins</a>, <a href="/facts/Nutrient/34bn4skK">nutrients</a> and <a href="/facts/Salt_(chemistry)/lsSKwGpn">salts</a>, 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 <a href="/facts/Red_blood_cell/Kggpq8Jh">red blood cell</a> (RBC). This small size can enable PFC particles to traverse <a href="/facts/Capillaries/4BIzKJAe">capillaries</a> through which no RBCs are flowing. In theory this can benefit damaged, blood-starved <a href="/facts/Biological_tissue/H7CpML7A">tissue</a>, which conventional red cells cannot reach. PFC solutions can carry oxygen so well that <a href="/facts/Mammal/phSwTzBo">mammals</a>, including <a href="/facts/Human/rlcTENsr">humans</a>, can survive breathing liquid PFC solution, called <a href="/facts/Liquid_breathing/P4leT65x">liquid breathing</a>. </p><p>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. </p><p>Fluosol was made mostly of <a href="/facts/Perfluorodecalin/ql4B0s6x">perfluorodecalin</a> or <a href="/facts/Perfluorotributylamine/yD8kWqvq">perfluorotributylamine</a> suspended in an <a href="/facts/Albumin/gDmSgAH2">albumin</a> emulsion. It was developed in <a href="/facts/Japan/U5mz0SRT">Japan</a> and first tested in the <a href="/facts/United_States/P0sCdLe5">United States</a> in November 1979.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> 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 <a href="/facts/Hyperbaric_chamber/K0uRU4RY">hyperbaric chamber</a>.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> It was approved by the FDA in 1989,<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> 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.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> Due to difficulty with the emulsion storage of Fluosol use (frozen storage and rewarming), its popularity declined and its production ended in 1994.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> </p> <table><tbody><tr><th>Name</th><th>Sponsor</th><th>Description</th></tr><tr><td><a href="/facts/Oxycyte/cHsLdtl0">Oxycyte</a></td><td>Oxygen Biotherapeutics</td><td>Tested in a Phase II-b Trials in the United States. Targeted as an <a href="/facts/Oxygen_therapeutic/38BdReab">oxygen therapeutic</a> rather than a blood substitute, with successful small-scale open label human trials treating <a href="/facts/Traumatic_brain_injury/DTq110vw">traumatic brain injury</a> at Virginia Commonwealth University.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> The trial was later terminated.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a></td></tr><tr><td>PHER-O2</td><td>Sanguine Corp</td><td>In research</td></tr><tr><td>Perftoran</td><td>Russia</td><td>Contains <a href="/facts/Perfluorodecalin/ql4B0s6x">perfluorodecalin</a> and perfluoro-N-(4-methylcyclohexyl)-piperidine along with a <a href="/facts/Surfactant/zgVX6g8o">surfactant</a>, Proxanol-268. It was developed in Russia and as of 2005 was marketed there.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a></td></tr><tr><td>NVX-108</td><td>NuvOx Pharma</td><td>In a Phase Ib/II clinical trial where it raises tumor oxygen levels prior to radiation therapy in order to radiosensitize them.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a></td></tr></tbody></table> <p>Oxygent was a second-generation, <a href="/facts/Lecithin/RNfeGIJ2">lecithin</a>-stabilized <a href="/facts/Emulsion/YMSqSCuH">emulsion</a> of a PFC that was under development by Alliance Pharmaceuticals.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a><a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> In 2002 a Phase III study was halted early due an increase in incidences of strokes in the study arm.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> </p> <h3>Haemoglobin based</h3> <p><a href="/facts/Haemoglobin/RsD1MzYA">Haemoglobin</a> 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).<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a><a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a><a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> </p><p>Efforts to overcome this toxicity have included making <a href="/facts/Genetically_engineered/vwdlDR61">genetically engineered</a> versions, <a href="/facts/Cross-link/zeQ9hEAA">cross-linking</a>, <a href="/facts/Polymerization/1hmBz7Ur">polymerization</a>, and encapsulation.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> </p><p>HemAssist, a diaspirin cross-linked haemoglobin (DCLHb) was developed by <a href="/facts/Baxter_Healthcare/5mQzURvL">Baxter Healthcare</a>; it was the most widely studied of the haemoglobin-based blood substitutes, used in more than a dozen animal and clinical studies.<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> It reached Phase III clinical trials, in which it failed due to increased mortality in the trial arm, mostly due to severe vasoconstriction complications.<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a><a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a> The results were published in 1999.<a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> </p><p>Hemolink (Hemosol Inc., Mississauga, Canada) was a haemoglobin solution that contained cross-linked an o-rafinose polymerised human haemoglobin.<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a> Hemosol struggled after Phase II trials were halted in 2003 on safety concerns<a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> and declared bankruptcy in 2005.<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> </p><p>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.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a> Its assets were subsequently purchased by HbO2 Therapeutics in 2014. </p><p>PolyHeme was developed over 20 years by <a href="/facts/Northfield_Laboratories/DXCrNmQt">Northfield Laboratories</a> 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 <a href="/facts/Biologic_License_Application/KHGqbmy6">Biologic License Application</a><a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> and in June 2009, Northfield filed for bankruptcy.<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> </p><p>Dextran-Haemoglobin was developed by Dextro-Sang Corp as a veterinary product, and was a conjugate of the polymer dextran with human haemoglobin. </p><p>Hemotech was developed by HemoBiotech and was a chemically modified haemoglobin. </p><p>Somatogen developed a genetically engineered and crosslinked tetramer it called Optro. It failed in a phase II trial and development was halted.<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> </p><p>A pyridoxylated Hb conjugated with <a href="/facts/Polyoxyethylene/tC7xBFwr">polyoxyethylene</a> 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,<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a><a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> which led to Curacyte shutting down.<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a> </p><p>Similarly, Hemospan was developed by Sangart, and was a <a href="/facts/PEGylation/SKK6XB02">pegylated</a> haemoglobin provided in a powdered form. While early trials were promising Sangart ran out of funding and closed down.<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a> </p> <h3>Stem cells</h3> <p><a href="/facts/Stem_cell/qgB9dFrI">Stem cells</a> offer a possible means of producing transfusable blood. A study performed by Giarratana et al.<a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a> describes a large-scale ex-vivo production of mature human blood cells using <a href="/facts/Hematopoietic_stem_cell/RQNE9IRu">hematopoietic stem cells</a>. 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. </p><p>Scientists from the experimental arm of the <a href="/facts/United_States_Department_of_Defense/dWAvf7e3">United States Department of Defense</a> began creating artificial blood for use in remote areas and transfuse blood to wounded soldiers more quickly in 2010.<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> The blood is made from the <a href="/facts/Hematopoietic/VRDwMymd">hematopoietic</a> stem cells removed from the <a href="/facts/Umbilical_cord/WIBgdrmF">umbilical cord</a> between human mother and newborn using a method called blood <a href="/facts/Pharming_(genetics)/4sI0WlE6">pharming</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 <a href="/facts/Defense_Advanced_Research_Projects_Agency/Uf9sarhT">Defense Advanced Research Projects Agency</a> by Arteriocyte. The <a href="/facts/Food_and_Drug_Administration/rCEnh9WB">Food and Drug Administration</a> 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.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a> This blood will also serve as a blood donor to all common <a href="/facts/Blood_types/zdxFTV6F">blood types</a>.<a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><i><a href="/facts/Artificial_Cells%2c_Blood_Substitutes%2c_and_Biotechnology/lXPLcvTM">Artificial Cells, Blood Substitutes, and Biotechnology</a></i></li> <li><a href="/facts/Blood_plasma_substitute_(disambiguation)/d4mv6ckw">Blood plasma substitute (disambiguation)</a></li> <li><a href="/facts/Blood_transfusion/fb0Mk6Dx">Blood transfusion</a></li> <li><a href="/facts/Bloodless_surgery/HKphxD72">Bloodless surgery</a></li> <li><a href="/facts/Erythromer/gP0Tva2N">Erythromer</a></li> <li><a href="/facts/Respirocyte/9FsTRdcu">Respirocyte</a></li> <li><a href="/facts/Theatrical_blood/5JJ6o6dg">Theatrical blood</a></li> <li><a href="/facts/Vaska%2527s_complex/uT2meu8D">Vaska's complex</a>: carries oxygen and hydrogen</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://science.howstuffworks.com/innovation/everyday-innovations/artificial-blood3.htm">How Artificial Blood Works</a> at <a href="/facts/HowStuffWorks/ncIRjUIA">HowStuffWorks</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Cohn, Claudia S.; Cushing, Melissa M. (2009-04-01). "Oxygen Therapeutics: Perfluorocarbons and Blood Substitute Safety". Critical Care Clinics. Hemoglobin-based Oxygen Carriers (HBOCs): The Future in Resuscitation?. 25 (2): 399–414. doi:10.1016/j.ccc.2008.12.007. PMID 19341916. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Henkel-Honke, T.; Oleck, M. (2007). "Artificial oxygen carriers: A current review" (PDF). AANA Journal. 75 (3): 205–211. PMID 17591302. Archived from the original (PDF) on 2016-03-04. Retrieved 2016-02-09. <a href="https://web.archive.org/web/20160304185434/http://www.aana.com/newsandjournal/Documents/henkelhanke205-211.pdf" target="_blank">https://web.archive.org/web/20160304185434/http://www.aana.com/newsandjournal/Documents/henkelhanke205-211.pdf</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>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. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738310" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738310</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Squires JE (2002). "Artificial blood". Science. 295 (5557): 1002–5. Bibcode:2002Sci...295.1002S. doi:10.1126/science.1068443. PMID 11834811. S2CID 35381400. <a href="/wiki/Science_(journal)" target="_blank">/wiki/Science_(journal)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Boulton, FE (December 2013). "Blood transfusion; additional historical aspects. Part 1. The birth of transfusion immunology". Transfusion Medicine (Oxford, England). 23 (6): 375–81. doi:10.1111/tme.12075. PMID 24003949. S2CID 9038280. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Feigl, EO (January 1983). "Coronary physiology". Physiological Reviews. 63 (1): 1–205. doi:10.1152/physrev.1983.63.1.1. PMID 6296890. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Lahiri, S (April 2000). "Historical perspectives of cellular oxygen sensing and responses to hypoxia". Journal of Applied Physiology. 88 (4): 1467–73. doi:10.1152/jappl.2000.88.4.1467. PMID 10749843. S2CID 18810282. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Reid TJ (2003). "Hb-based oxygen carriers: are we there yet?". Transfusion. 43 (2): 280–7. doi:10.1046/j.1537-2995.2003.00314.x. PMID 12559026. S2CID 21410359. <a href="https://zenodo.org/record/1236512" target="_blank">https://zenodo.org/record/1236512</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Squires JE (2002). "Artificial blood". Science. 295 (5557): 1002–5. Bibcode:2002Sci...295.1002S. doi:10.1126/science.1068443. PMID 11834811. S2CID 35381400. <a href="/wiki/Science_(journal)" target="_blank">/wiki/Science_(journal)</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Squires JE (2002). "Artificial blood". Science. 295 (5557): 1002–5. Bibcode:2002Sci...295.1002S. doi:10.1126/science.1068443. PMID 11834811. S2CID 35381400. <a href="/wiki/Science_(journal)" target="_blank">/wiki/Science_(journal)</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP (1999). "Transfusion medicine. First of two parts--blood transfusion". N. Engl. J. Med. 340 (6): 438–47. doi:10.1056/NEJM199902113400606. PMID 9971869. <a href="/wiki/N._Engl._J._Med." target="_blank">/wiki/N._Engl._J._Med.</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP (1999). "Transfusion medicine. First of two parts--blood transfusion". N. Engl. J. Med. 340 (6): 438–47. doi:10.1056/NEJM199902113400606. PMID 9971869. <a href="/wiki/N._Engl._J._Med." target="_blank">/wiki/N._Engl._J._Med.</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Alayash, AI (4 January 2017). "Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?". Biomolecules. 7 (1): 2. doi:10.3390/biom7010002. PMC 5372714. PMID 28054978. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Webster, Hanna (4 February 2023). "DARPA puts $46.4M toward synthetic blood development". EMS1. Retrieved 2023-02-17. <a href="https://www.ems1.com/research/articles/darpa-puts-464m-toward-synthetic-blood-development-9Lh6u4pBF3sV3tud/" target="_blank">https://www.ems1.com/research/articles/darpa-puts-464m-toward-synthetic-blood-development-9Lh6u4pBF3sV3tud/</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Alayash, AI (4 January 2017). "Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?". Biomolecules. 7 (1): 2. doi:10.3390/biom7010002. PMC 5372714. PMID 28054978. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Remy B, Deby-Dupont G, Lamy M (1999). "Red blood cell substitutes: fluorocarbon emulsions and haemoglobin solutions". Br. Med. Bull. 55 (1): 277–98. doi:10.1258/0007142991902259. PMID 10695091. <a href="https://doi.org/10.1258%2F0007142991902259" target="_blank">https://doi.org/10.1258%2F0007142991902259</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Alayash, AI (4 January 2017). "Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?". Biomolecules. 7 (1): 2. doi:10.3390/biom7010002. PMC 5372714. PMID 28054978. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>"Artificial Blood Given to Jehovah's Witness in First American Use". The New York Times. 21 November 1979. <a href="https://www.nytimes.com/1979/11/21/archives/artificial-blood-given-to-jehovahs-witness-in-first-american-use.html" target="_blank">https://www.nytimes.com/1979/11/21/archives/artificial-blood-given-to-jehovahs-witness-in-first-american-use.html</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>Marieb, Elaine Nicpon. Human Anatomy & Physiology. 4th ed. Menlo Park, California: Addison Wesley Longman, Inc. 1998. 650. <a href="#fnref:19" class="footnote-back-ref">↩</a></p></li> <li id="fn:20"><p>Bruno, S.; Ronda, L.; Faggiano, S.; Bettati, S.; Mozzarelli, A. (2010). "Oxygen Delivery via Allosteric Effectors of Hemoglobin and Blood Substitutes". Burger's Medicinal Chemistry and Drug Discovery. doi:10.1002/0471266949.bmc048.pub2. ISBN 978-0471266945. <a href="978-0471266945" target="_blank">978-0471266945</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></p></li> <li id="fn:21"><p>Wall, T. C.; Califf, R. M.; Blankenship, J.; Talley, J. D.; Tannenbaum, M.; Schwaiger, M.; Gacioch, G.; Cohen, M. D.; Sanz, M.; Leimberger, J. D. (1994). "Intravenous Fluosol in the treatment of acute myocardial infarction. Results of the Thrombolysis and Angioplasty in Myocardial Infarction 9 Trial. TAMI 9 Research Group". Circulation. 90 (1): 114–120. doi:10.1161/01.CIR.90.1.114. PMID 8025985. <a href="http://circ.ahajournals.org/content/90/1/114.abstract" target="_blank">http://circ.ahajournals.org/content/90/1/114.abstract</a> <a href="#fnref:21" class="footnote-back-ref">↩</a></p></li> <li id="fn:22"><p>Alayash, AI (4 January 2017). "Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?". Biomolecules. 7 (1): 2. doi:10.3390/biom7010002. PMC 5372714. PMID 28054978. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714</a> <a href="#fnref:22" class="footnote-back-ref">↩</a></p></li> <li id="fn:23"><p>Yoffee, Lynn (May 1, 2008). "Oxycyte is on track as oxygen carrier, not as 'faux' blood". Cardiovascular Device & Drugs. Retrieved 2021-11-28. <a href="https://www.bioworld.com/articles/446955" target="_blank">https://www.bioworld.com/articles/446955</a> <a href="#fnref:23" class="footnote-back-ref">↩</a></p></li> <li id="fn:24"><p>"Safety and Tolerability of Oxycyte in Patients With Traumatic Brain Injury (TBI) (STOP-TBI)". 11 November 2014. <a href="https://clinicaltrials.gov/ct2/show/NCT00908063" target="_blank">https://clinicaltrials.gov/ct2/show/NCT00908063</a> <a href="#fnref:24" class="footnote-back-ref">↩</a></p></li> <li id="fn:25"><p>Maevsky, E; Ivanitsky, G; Bogdanova, L; Axenova, O; Karmen, N; Zhiburt, E; Senina, R; Pushkin, S; Maslennikov, I; Orlov, A; Marinicheva, I (2005). "Clinical results of Perftoran application: present and future". Artificial Cells, Blood Substitutes, and Biotechnology. 33 (1): 37–46. doi:10.1081/BIO-200046654. PMID 15768564. S2CID 39902507. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:25" class="footnote-back-ref">↩</a></p></li> <li id="fn:26"><p>"The Effects of NVX-108 as a Radiation Sensitizer in Glioblastoma (GBM)". 26 February 2019. <a href="https://clinicaltrials.gov/ct2/show/NCT02189109" target="_blank">https://clinicaltrials.gov/ct2/show/NCT02189109</a> <a href="#fnref:26" class="footnote-back-ref">↩</a></p></li> <li id="fn:27"><p>Vorob'ev, S. I. (2009-08-19). "First- and second-generation perfluorocarbon emulsions". Pharmaceutical Chemistry Journal. 43 (4): 209–218. doi:10.1007/s11094-009-0268-1. ISSN 0091-150X. S2CID 4890416. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:27" class="footnote-back-ref">↩</a></p></li> <li id="fn:28"><p>Cohn, Claudia S.; Cushing, Melissa M. (2009-04-01). "Oxygen Therapeutics: Perfluorocarbons and Blood Substitute Safety". Critical Care Clinics. Hemoglobin-based Oxygen Carriers (HBOCs): The Future in Resuscitation?. 25 (2): 399–414. doi:10.1016/j.ccc.2008.12.007. PMID 19341916. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:28" class="footnote-back-ref">↩</a></p></li> <li id="fn:29"><p>Cohn, Claudia S.; Cushing, Melissa M. (2009). "Oxygen Therapeutics: Perfluorocarbons and Blood Substitute Safety". Critical Care Clinics. 25 (2): 399–414. doi:10.1016/j.ccc.2008.12.007. PMID 19341916. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:29" class="footnote-back-ref">↩</a></p></li> <li id="fn:30"><p>Niiler, Eric (2002-10-01). "Setbacks for blood substitute companies". Nature Biotechnology. 20 (10): 962–963. doi:10.1038/nbt1002-962. ISSN 1087-0156. PMID 12355103. S2CID 9147818. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:30" class="footnote-back-ref">↩</a></p></li> <li id="fn:31"><p>Cohn, Claudia S.; Cushing, Melissa M. (2009-04-01). "Oxygen Therapeutics: Perfluorocarbons and Blood Substitute Safety". Critical Care Clinics. Hemoglobin-based Oxygen Carriers (HBOCs): The Future in Resuscitation?. 25 (2): 399–414. doi:10.1016/j.ccc.2008.12.007. PMID 19341916. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:31" class="footnote-back-ref">↩</a></p></li> <li id="fn:32"><p>Squires JE (2002). "Artificial blood". Science. 295 (5557): 1002–5. Bibcode:2002Sci...295.1002S. doi:10.1126/science.1068443. PMID 11834811. S2CID 35381400. <a href="/wiki/Science_(journal)" target="_blank">/wiki/Science_(journal)</a> <a href="#fnref:32" class="footnote-back-ref">↩</a></p></li> <li id="fn:33"><p>Amberson, William; Jennings J.; Rhode C. (1949). "Clinical Experience with Hemoglobin-Saline Solutions". Journal of Applied Physiology. 1 (7): 469–489. doi:10.1152/jappl.1949.1.7.469. PMID 18104040. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:33" class="footnote-back-ref">↩</a></p></li> <li id="fn:34"><p>Jiin-Yu Chen; Michelle Scerbo; George Kramer (August 2009). "A Review of Blood Substitutes: Examining The History, Clinical Trial Results, and Ethics of Hemoglobin-Based Oxygen Carriers". Clinics (Sao Paulo). 64 (8): 803–813. doi:10.1590/S1807-59322009000800016. PMC 2728196. PMID 19690667. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728196" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728196</a> <a href="#fnref:34" class="footnote-back-ref">↩</a></p></li> <li id="fn:35"><p>Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM (May 2008). "Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis". JAMA. 299 (19): 2304–12. doi:10.1001/jama.299.19.jrv80007. PMC 10802128. PMID 18443023. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10802128" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10802128</a> <a href="#fnref:35" class="footnote-back-ref">↩</a></p></li> <li id="fn:36"><p>Alayash, AI (4 January 2017). "Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?". Biomolecules. 7 (1): 2. doi:10.3390/biom7010002. PMC 5372714. PMID 28054978. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714</a> <a href="#fnref:36" class="footnote-back-ref">↩</a></p></li> <li id="fn:37"><p>Reid TJ (2003). "Hb-based oxygen carriers: are we there yet?". Transfusion. 43 (2): 280–7. doi:10.1046/j.1537-2995.2003.00314.x. PMID 12559026. S2CID 21410359. <a href="https://zenodo.org/record/1236512" target="_blank">https://zenodo.org/record/1236512</a> <a href="#fnref:37" class="footnote-back-ref">↩</a></p></li> <li id="fn:38"><p>Alayash, AI (4 January 2017). "Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?". Biomolecules. 7 (1): 2. doi:10.3390/biom7010002. PMC 5372714. PMID 28054978. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714</a> <a href="#fnref:38" class="footnote-back-ref">↩</a></p></li> <li id="fn:39"><p>Reid TJ (2003). "Hb-based oxygen carriers: are we there yet?". Transfusion. 43 (2): 280–7. doi:10.1046/j.1537-2995.2003.00314.x. PMID 12559026. S2CID 21410359. <a href="https://zenodo.org/record/1236512" target="_blank">https://zenodo.org/record/1236512</a> <a href="#fnref:39" class="footnote-back-ref">↩</a></p></li> <li id="fn:40"><p>Sloan, EP; Koenigsberg, M; Weir, WB; Clark, JM; O'Connor, R; Olinger, M; Cydulka, R (February 2015). "Emergency Resuscitation of Patients Enrolled in the US Diaspirin Cross-linked Hemoglobin (DCLHb) Clinical Efficacy Trial". Prehospital and Disaster Medicine. 30 (1): 54–61. doi:10.1017/S1049023X14001174. PMID 25499006. S2CID 206310955. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:40" class="footnote-back-ref">↩</a></p></li> <li id="fn:41"><p>Alayash, AI (4 January 2017). "Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?". Biomolecules. 7 (1): 2. doi:10.3390/biom7010002. PMC 5372714. PMID 28054978. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714</a> <a href="#fnref:41" class="footnote-back-ref">↩</a></p></li> <li id="fn:42"><p>Zehr, Leonard (June 21, 2003). "Tests leave Hemosol in critical condition". Globe and Mail. <a href="https://www.theglobeandmail.com/report-on-business/tests-leave-hemosol-in-critical-condition/article1162984/" target="_blank">https://www.theglobeandmail.com/report-on-business/tests-leave-hemosol-in-critical-condition/article1162984/</a> <a href="#fnref:42" class="footnote-back-ref">↩</a></p></li> <li id="fn:43"><p>"Hemosol declares insolvency; shares under review by TSX". CBC News. November 25, 2005. <a href="http://www.cbc.ca/news/business/hemosol-declares-insolvency-shares-under-review-by-tsx-1.550185" target="_blank">http://www.cbc.ca/news/business/hemosol-declares-insolvency-shares-under-review-by-tsx-1.550185</a> <a href="#fnref:43" class="footnote-back-ref">↩</a></p></li> <li id="fn:44"><p>Biopure files for relief PR Newswire, July 16, 2009. <a href="https://web.archive.org/web/20000511202648/http://prnewswire.com/gh/cnoc/comp/131224.html" target="_blank">https://web.archive.org/web/20000511202648/http://prnewswire.com/gh/cnoc/comp/131224.html</a> <a href="#fnref:44" class="footnote-back-ref">↩</a></p></li> <li id="fn:45"><p>"FDA rejects Northfield's blood substitute". FierceBiotech. May 1, 2009. <a href="https://www.fiercebiotech.com/biotech/fda-rejects-northfield-s-blood-substitute" target="_blank">https://www.fiercebiotech.com/biotech/fda-rejects-northfield-s-blood-substitute</a> <a href="#fnref:45" class="footnote-back-ref">↩</a></p></li> <li id="fn:46"><p>"Northfield Laboratories to liquidate under Chapter 11". Reuters. 2 June 2009. Retrieved 2017-12-31. <a href="https://www.reuters.com/article/northfieldlaboratories/northfield-laboratories-to-liquidate-under-chapter-11-idUSBNG20947820090602" target="_blank">https://www.reuters.com/article/northfieldlaboratories/northfield-laboratories-to-liquidate-under-chapter-11-idUSBNG20947820090602</a> <a href="#fnref:46" class="footnote-back-ref">↩</a></p></li> <li id="fn:47"><p>Alayash, AI (4 January 2017). "Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?". Biomolecules. 7 (1): 2. doi:10.3390/biom7010002. PMC 5372714. PMID 28054978. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714</a> <a href="#fnref:47" class="footnote-back-ref">↩</a></p></li> <li id="fn:48"><p>Alayash, AI (4 January 2017). "Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?". Biomolecules. 7 (1): 2. doi:10.3390/biom7010002. PMC 5372714. PMID 28054978. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714</a> <a href="#fnref:48" class="footnote-back-ref">↩</a></p></li> <li id="fn:49"><p>Vincent, JL; Privalle, CT; Singer, M; Lorente, JA; Boehm, E; Meier-Hellmann, A; Darius, H; Ferrer, R; Sirvent, JM; Marx, G; DeAngelo, J (January 2015). "Multicenter, randomized, placebo-controlled phase III study of pyridoxalated hemoglobin polyoxyethylene in distributive shock (PHOENIX)". Critical Care Medicine. 43 (1): 57–64. doi:10.1097/CCM.0000000000000554. PMID 25083980. S2CID 11133338. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:49" class="footnote-back-ref">↩</a></p></li> <li id="fn:50"><p>"Curacyte". Curacyte. Retrieved 30 December 2017. <a href="http://www.curacyte.eu/" target="_blank">http://www.curacyte.eu/</a> <a href="#fnref:50" class="footnote-back-ref">↩</a></p></li> <li id="fn:51"><p>Alayash, AI (4 January 2017). "Hemoglobin-Based Blood Substitutes and the Treatment of Sickle Cell Disease: More Harm than Help?". Biomolecules. 7 (1): 2. doi:10.3390/biom7010002. PMC 5372714. PMID 28054978. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372714</a> <a href="#fnref:51" class="footnote-back-ref">↩</a></p></li> <li id="fn:52"><p>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. PMID 24408610. S2CID 28721848. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:52" class="footnote-back-ref">↩</a></p></li> <li id="fn:53"><p>Edwards, L. (July 13, 2010). Artificial blood developed for the battlefield. Retrieved November 30, 2010 <a href="http://www.physorg.com/news198221258.html" target="_blank">http://www.physorg.com/news198221258.html</a> <a href="#fnref:53" class="footnote-back-ref">↩</a></p></li> <li id="fn:54"><p>Edwards, L. (July 13, 2010). Artificial blood developed for the battlefield. Retrieved November 30, 2010 <a href="http://www.physorg.com/news198221258.html" target="_blank">http://www.physorg.com/news198221258.html</a> <a href="#fnref:54" class="footnote-back-ref">↩</a></p></li> <li id="fn:55"><p>"Blood Pharming". Armed with Science. Archived from the original on 2019-04-30. <a href="https://web.archive.org/web/20190430165830/https://science.dodlive.mil/2013/11/29/blood-pharming/" target="_blank">https://web.archive.org/web/20190430165830/https://science.dodlive.mil/2013/11/29/blood-pharming/</a> <a href="#fnref:55" class="footnote-back-ref">↩</a></p></li> </ol>