Overview of Potential Clinical Applications of Hemoglobin Vesicles (HbV) as Artificial Red Cells, Evidenced by Preclinical Studies of the Academic Research Consortium

Abstract

Hemoglobin (Hb) is the most abundant protein in whole blood. This fact implies that the oxygen binding and releasing function of Hb is the most vital for sustaining life. All Hb is compartmentalized in red blood cells (RBCs) with corpuscular Hb concentration of about 35 g/dL, covered with a thin biomembrane. In spite of its abundance, Hb sometimes shows toxicity once it is leaked from RBCs. The shielding effect of the RBC membrane is physiologically important. Based on this structural importance, we have studied artificial red cells (Hb vesicles, HbV) as artificial oxygen carriers, which encapsulate a purified and concentrated Hb solution in phospholipid vesicles, mimicking the cellular structure of RBCs. Our academic research consortium has clarified the safety and efficacy of this HbV, aiming at clinical applications. Because of some superior characteristics to those of RBCs, HbV has the potential for use not only as a transfusion alternative but also for oxygen and carbon monoxide therapeutics, perfusate for transplant organs, and photosensitizer. In this review paper, such potential applications are summarized.

Artificial Oxygen Carriers—Past, Present, and Future—a Review of the Most Innovative and Clinically Relevant Concepts

“…HbVesicles are human Hgb encapsulated by a biocompatible liposome (Azuma et al, 2017). They are 250-280 nm in diameter, decorated with PEG 5000 and have a p 50 value between 9 and 30 mm Hg that is adjusted with pyridoxalphosphate (Sakai, 2017). Depending on the Hgb core (Hb-CO or HbO 2 ) HbVesicles can be used as a CO or O 2 carrier.…”

“…HbVesicles do not contribute to the colloid osmotic pressure. HbVesicles have been studied in preclinical animal blood exchange and hemorrhagic shock models and were also tested in different areas such as isolated organ perfusion, extracorporeal membrane oxygenation priming, apnoe and two-dimensional cell cultures (Kohno et al, 2017;Sakai, 2017).…”

Prolonged functional life span of artificial red cells in blood circulation by repeated methylene blue injections

“…or unknown pathogens; (iii) possibility of blood type mismatching by human error, and (iv) blood supply-demand unbalance in an aging society because the majority of blood donors are young people while recipients include many elder people. Hemoglobin-vesicle (HbV) is one HBOC encapsulating purified and concentrated Hb solution in phospholipid vesicles (liposomes) [4,5] We believe the importance of the cellular structure of red blood cells (RBCs) for retardation of any gas reactions, absence of colloid osmotic pressure, prevention of dissociation of Hb tetramer to dimers [6], etc. Actually, Hb-V showed sufficient oxygencarrying capacity in the studies of animal experimental models such as hemorrhagic shock resuscitation, hemodilution, oxygenation of ischemic tissues, etc.…”

“…Actually, Hb-V showed sufficient oxygencarrying capacity in the studies of animal experimental models such as hemorrhagic shock resuscitation, hemodilution, oxygenation of ischemic tissues, etc. [5].…”

In vivoevaluation of electron mediators for the reduction of methemoglobin encapsulated in liposomes using electron energies produced by red blood cell glycolysis

“…Haemoglobin-vesicles (HbVs) are a type of HBOC in which a purified and concentrated Hb solution is encapsulated with phospholipid bilayer membranes (liposomes). Earlier in vivo studies have clarified the oxygen carrying capacity, safety and efficacy of HbV as a transfusion alternative [9,10]. One remaining issue of HbV is autoxidation of the encapsulated ferrous HbO 2 to form ferric methemoglobin (metHb) that does not bind oxygen.…”