Blood substitute

Source: Wikipedia, the free encyclopedia.
For the rugby union and rugby league term, see blood replacement.

A blood substitute (also called artificial blood or blood surrogate) is a substance used to mimic and fulfill some functions of

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)[1] and perfluorocarbon emulsions.[2] Oxygen therapeutics are in clinical trials in the U.S. and European Union, and Hemopure is available in South Africa.

History

After

Sir Christopher Wren suggested wine and opium as blood substitute.[4]

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

blood group serology.[5] 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.[6][7]

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.

mad cow disease.[4][9] 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.[9]

Efforts to develop blood substitutes have been driven by a desire to replace blood transfusion in emergency situations, in places where infectious disease is endemic and the risk of contaminated blood products is high, where refrigeration to preserve blood may be lacking, and where it might not be possible or convenient to find blood type matches.[10]

In 2023, DARPA announced funding twelve universities and labs for synthetic blood research. Human trials would be expected to happen between 2028-2030.[11]

Approaches

Efforts have focused on molecules that can carry

perfluorocarbons (PFC), chemical compounds which can carry and release oxygen.[10][12]

The first approved oxygen-carrying blood substitute was a per

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. As of 2017 no hemoglobin-based product had been approved.[10]

Perfluorocarbon based

Perfluorochemicals are not

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.[citation needed
]

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.[citation needed]

Fluosol was made mostly of

hyperbaric chamber.[14] It was approved by the FDA in 1989,[15] and was approved in eight other countries.[citation needed] Its use was associated with a reduction in ischemic complications and with an increase in pulmonary edema and congestive heart failure.[16] Due to difficulty with the emulsion storage of Fluosol use (frozen storage and rewarming), its popularity declined and its production ended in 1994.[10]

Name Sponsor Description
Oxycyte
 Oxygen Biotherapeutics Tested in a 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] The trial was later terminated.[18]
PHER-O
2 		Sanguine Corp In research
Perftoran Russia Contains perfluorodecalin and perfluoro-N-(4-methylcyclohexyl)-piperidine along with a surfactant, Proxanol-268. It was developed in Russia and as of 2005 was marketed there.[19]
NVX-108 NuvOx Pharma In a Phase Ib/II clinical trial where it raises tumor oxygen levels prior to radiation therapy in order to radiosensitize them.[20]

Oxygent was a second-generation, lecithin-stabilized emulsion of a PFC that was under development by Alliance Pharmaceuticals.[21][1][22] In 2002 a Phase III study was halted early due an increase in incidences of strokes in the study arm.[23]

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).[1]

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.[4][24][25][26]

Efforts to overcome this toxicity have included making

genetically engineered versions, cross-linking, polymerization, and encapsulation.[10]

HemAssist, a diaspirin cross-linked haemoglobin (DCLHb) was developed by

Baxter Healthcare; it was the most widely studied of the haemoglobin-based blood substitutes, used in more than a dozen animal and clinical studies.[8] It reached Phase III clinical trials, in which it failed due to increased mortality in the trial arm, mostly due to severe vasoconstriction complications.[10][8] The results were published in 1999.[27]

Hemolink (Hemosol Inc., Mississauga, Canada) was a haemoglobin solution that contained cross-linked an o-rafinose polymerised human haemoglobin.[10] Hemosol struggled after Phase II trials were halted in 2003 on safety concerns[28] and declared bankruptcy in 2005.[29]

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.[30] Its assets were subsequently purchased by HbO2 Therapeutics in 2014.[citation needed]

PolyHeme was developed over 20 years by

Biologic License Application[31] and in June 2009, Northfield filed for bankruptcy.[32]

Dextran-Haemoglobin was developed by Dextro-Sang Corp as a veterinary product, and was a conjugate of the polymer dextran with human haemoglobin.[citation needed]

Hemotech was developed by HemoBiotech and was a chemically modified haemoglobin.

Somatogen developed a genetically engineered and crosslinked tetramer it called Optro. It failed in a phase II trial and development was halted.[10]

A pyridoxylated Hb conjugated with

polyoxyethylene 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,[10][33] which led to Curacyte shutting down.[34]

Similarly, Hemospan was developed by Sangart, and was a pegylated haemoglobin provided in a powdered form. While early trials were promising Sangart ran out of funding and closed down.[10]

Stem cells

Stem cells offer a possible means of producing transfusable blood. A study performed by Giarratana et al.[35] describes a large-scale ex-vivo production of mature human blood cells using hematopoietic stem cells. 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.[citation needed]

Scientists from the experimental arm of the

blood types.[37]

See also

References

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  11. ^ Webster, Hanna (4 February 2023). "DARPA puts $46.4M toward synthetic blood development". EMS1. Retrieved 2023-02-17.
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  13. ^ "Artificial Blood Given to Jehovah's Witness in First American Use". The New York Times. 21 November 1979.
  14. ^ Marieb, Elaine Nicpon. Human Anatomy & Physiology. 4th ed. Menlo Park, California: Addison Wesley Longman, Inc. 1998. 650.
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  17. ^ Yoffee, Lynn (May 1, 2008). "Oxycyte is on track as oxygen carrier, not as 'faux' blood". Cardiovascular Device & Drugs. Retrieved 2021-11-28.
  18. ^ "Safety and Tolerability of Oxycyte in Patients With Traumatic Brain Injury (TBI) (STOP-TBI)". 11 November 2014.
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  20. ^ "The Effects of NVX-108 as a Radiation Sensitizer in Glioblastoma (GBM)". 26 February 2019.
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  29. ^ "Hemosol declares insolvency; shares under review by TSX". CBC News. November 25, 2005.
  30. ^ Biopure files for relief PR Newswire, July 16, 2009.
  31. ^ "FDA rejects Northfield's blood substitute". FierceBiotech. May 1, 2009.
  32. ^ "Northfield Laboratories to liquidate under Chapter 11". Reuters. 2 June 2009. Retrieved 2017-12-31.
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  36. ^ a b Edwards, L. (July 13, 2010). Artificial blood developed for the battlefield. Retrieved November 30, 2010
  37. ^ "Blood Pharming". Armed with Science. Archived from the original on 2019-04-30.

External links

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