Artificial O2 Carriers: Status in 2005

Abstract

Donor blood is a limited resource and its transfusion is associated with significant adverse effects. Therefore, alternatives have been searched, the ultimate being artificial oxygen (O2) carriers. There are two main groups of artificial O2 carriers: hemoglobin based and perfluorocarbon emulsions. The hemoglobin molecule in hemoglobin based artificial O2 carriers needs to be stabilized to prevent dissociation of the alpha2beta2-hemoglobin tetramer into alphabeta-dimers in order to prolong intravascular retention and to eliminate nephrotoxicity. Other modifications serve to decrease O2 affinity in order to improve O2 off-loading to tissues. In addition, polyethylene glycol may be surface conjugated to increase molecular size. Finally, certain products are polymerized to increase the hemoglobin concentration at physiologic colloid oncotic pressure. Perfluorocarbons are carbon-fluorine compounds characterized by a high gas dissolving capacity for O2 and CO2 and chemical and biologic inertness. Perfluorocarbons are not miscible with water and therefore need to be brought into emulsion for intravenous application. Development, product specification, physiologic effects, efficacy to decrease the need for donor blood in surgery and side effects of the following products are described: Diaspirin cross-linked hemoglobin (HemAssist), human recombinant hemoglobin (rHb1.1 and rHb2.0), polymerized bovine hemoglobin-based O2 carrier (HBOC-201), human polymerized hemoglobin (PolyHeme), hemoglobin raffimer (Hemolink), maleimide-activated polyethylene glycol-modified hemoglobin (MP4) and perflubron emulsion (Oxygent). In addition, enzyme cross-linked poly-hemoglobin, hemoglobin containing vesicles (nano-dimension artificial red blood cells) and an allosteric modifier (RSR13) are discussed. The most advanced products are in clinical phase III trials but no product has achieved market approval yet in the US, Europe or Canada.

Development of Recombinant Hemoglobin-Based Oxygen Carriers

“…The simplest interpretation of Figure 4C is that the low rate of NOD reduces the toxicity of rHb3011 with respect to hypertension. The rHb3011 molecule has also been shown to reduce or prevent gastrointestinal dysmotility (54), and its genetic background was built into the last Baxter HBOC prototype, rHb2.0, which also showed no hypertensive side effect (56,84,110,116,142,155). However, rHb2.0 was later shown to cause complement activation in initial safety trials in humans (40), which, as shown in Figure 5, appears to be due to high rates of autooxidation, hemin loss, and/or globin denaturation, properties that were not optimized in the second-generation product, but have been shown to lead to endothelial damage and inflammatory responses (8-10).…”

Haemoglobin, oxygen carriers and perioperative organ perfusion

“…Modified haemoglobin has similar O 2 loading and transport capacity as the native blood, with sigmoid dissociation curve [50]. Thus even with relatively low PaO 2 a sufficient amount of O 2 can be transported.…”

“…A third group, particulate haemoglobin preparations able to carry other useful substances such as enzymes are also studied, but their development is still far from any clinical application [48][49][50][51].…”

“…Extracellular human haemoglobin (α2-β2-tetramers) dissociates into α-β-dimers which are nephrotoxic. In order to prevent this, the haemoglobin has to be chemically or genetically modified [50].…”

Artificial Blood- A Game Changer for Future Medicine: Where are we Today?

“…Artificial blood aims to deliver an alternative to blood transfusion, which is transferring bloodbased products from a person to another one [1]. Hemoglobin is the main component of red blood cells, comprising about 33% of the cell mass.…”