Page 67 - JSOM Fall 2023

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Substitute Blood Products Summary capacity, leaving room for future improvements. Exam-
ples of surface-modified and/or cross-linked HBOCs in var-
Artificial blood and blood components have several distinct ious stages of development and approval include Hemotech
advantages over donated blood. First, after they are manufac- ( HemoBiotech), Hemospan (MP4OX; Sangart), Hemo pure
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tured, blood substitutes are sterilized to destroy any viral or (HBOC-201; Hemoglobin Oxygen Therapeutics), 20–23 Oxy-
bacterial agents, thereby eliminating the risk of transmitting in- globin (HBOC-301; Hemoglobin Oxygen Therapeutics),
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fectious diseases; although human blood products are screened PolyHeme (polymerized human hemoglobin, pyridoxylated;
®
for pathogenicity, there is still a risk of infection from pathogens Northfield Laboratories), 25,26 Diaspirin (DCLHb; Baxter
such as human immunodeficiency virus and syphilis, as well as Health care), 27,28 and ErythroMer (KaloCyte). 29,30
hepatitis B and C. Second, artificial blood products may have
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longer shelf lives and less stringent storage requirements than Liposome-encapsulated HBOCs (LEHs) feature hemoglobin
donated blood, making them easier to manipulate and use. that has been packaged inside a stable lipid membrane with
Third, blood substitutes can be engineered to be blood-type embedded cholesterol for additional integrity. As a result,
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specific, thus avoiding immunologic reactions. Lastly, patients LEHs are both smaller than natural RBCs and have a much
whose religious beliefs prevent them from accepting donor longer shelf-life. The main drawback involves the shortened
blood may be willing to accept blood substitutes. 13 half-life while in circulation. Researchers have addressed
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this by placing an actin matrix in the liposome’s aqueous core,
Given the predicted future strain on supply, as well as growing which extended the half-life and augmented the overall sta-
concerns of a major conflict abroad, RBC substitutes offer a bility and solubility of one LEH. Of note, OxyBridge (VIR-
™
solution for the medical field that can have a lifesaving effect HBOC; VirTech Bio), derived from human hemoglobin, is one
on patients suffering from battlefield injuries, blood diseases LEH in development with some demonstrated potential in
such as hemophilia, and deficiencies in blood coagulation fac- multiple animal studies. 32,33
tors. The compatibility, effectiveness, and viability of RBC sub-
stitutes are stringently established before administration. The Perfluorocarbons
manufacturers of these products must consider rate of delivery, Perfluorocarbon-based artificial oxygen carriers (PFOCs) are
packed-cell volume, quantity, and types of blood components another RBC substitute. As their name suggests, PFOCs are
because transfusions can cause a number of adverse reactions derived from perfluorocarbons and are structurally like hy-
that would be a further insult to an already injured patient. 14,15 drocarbons, with fluorine atoms instead of hydrogen atoms.
Conventional RBC substitutes belong in one of two main cate- Synthetically engineered to carry both O and CO through
2
gories: HBOCs or perfluorocarbons; however, recent advances mechanisms other than covalent bonding, PFOCs have been
2
in biomanufacturing capabilities continue to produce addi- used to oxygenate premature babies with respiratory distress
tional options. RBC substitute product names and characteris- syndromes. Examples of PFOCs in various stages of devel-
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tics, and the status of current clinical trials, are summarized in opment and approval include Perftoran (Vidaphor; Perftoran
®
Table 3. Reported adverse-event profiles of select products are USA), Oxycyte (Synthetic Blood International), 36–38 Oxygent
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summarized in Table 4. (Alliance Pharmaceutical), PHER-O2 (Sanguine), and Flio-
39
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sol-DA (perfluorocarbon emulsion; Green Cross). 41
Hemoglobin-Based Oxygen Carriers
HBOCs, which covalently bind oxygen-like native hemoglo- Biomanufactured Red Blood Cells
bin, can be genetically engineered or derived from hemoglo- Within the past 20 years, many research groups have fo-
bin in expired human blood or bovine blood. Three types cused on using human umbilical cord blood (UCB) cells to
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of HBOCs are currently in development: surface-modified generate enucleated RBCs from CD34 -positive UCB cells in
+
HBOCs, cross-linked HBOCs, and liposome-encapsulated culture. 42–44 However, scaling up production levels remains a
HBOCs. key issue to produce sufficient numbers of RBCs necessary
for transfusions and other medical treatments. The future of
In surface-modified HBOCs, large molecules such as polyeth- scalability of these UCB cells and other RBC substitutes could
ylene glycol chains are added to lysine groups on the surface rely on bioprinting technologies. nScrypt, a company that de-
membrane. Surface-modified HBOCs are smaller than eryth- signs and manufactures 3D printing devices, has developed
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rocytes, which better facilitates their entry into small vessels a ruggedized bioprinter for use in military environments.
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that are otherwise not easily reached by conventional RBCs. The research division of nScrypt, known as Sciperio, has been
This property is clinically relevant to treating ischemic strokes, collaborating jointly to provide on-demand human blood to
where occluded vessels prevent adequate perfusion by RBCs. the military at the point of injury through the development
of RBCs. This project will use several nScrypt print heads to
Cross-linked HBOCs feature more enhanced oxygen-carrying supply necessary growth enhancers to a bioreactor, which will
capacities through intermolecularly cross-linked alpha and enable cellular amplification and differentiation to generate a
beta subunits. This cross-linking reduces hemoglobin’s af- scalable effect. 46
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finity for oxygen, thus enabling more efficient delivery, and
reduces renal filtration, thereby augmenting retention within Another group of researchers has synthesized cells using do-
the host. One inherent disadvantage of the cross-linked vari- nated human RBCs coated with a layer of silica. The sil-
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ant is its inability to convert Fe (ferric state) to Fe (ferrous ica coating is layered with negatively and positively charged
3+
2+
state), the only absorbable form of iron. To account for this, polymers, after which the silica is dissolved, leaving a flexible
researchers have developed a cross-linked HBOC using methe- scaffolding over which natural RBC membranes are layered
moglobin with attached reducing agents to convert iron in the to create artificial RBCs. These synthetic cells, which are sim-
heme group from the Fe state to the Fe state in normal he- ilar in charge, shape, and size to RBCs, move through model
3+
2+
moglobin. However, this variant features a lower O - carrying
2 capillaries with relative ease and last up to 48 hours in mice. 47
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