Review of Hemoglobin‐Vesicles as Artificial Oxygen Carriers

Abstract

Blood transfusion systems have greatly benefited human health and welfare. Nevertheless, some problems remain: infection, blood type mismatching, immunological response, short shelf life, and screening test costs. Blood substitutes have been under development for decades to overcome such problems. Plasma component substitutes have already been established: plasma expanders, electrolytes, and recombinant coagulant factors. Herein, we focus on the development of red blood cell (RBC) substitutes. Side effects hindered early development of cell-free hemoglobin (Hb)-based oxygen carriers (HBOCs) and underscored the physiological importance of the cellular structure of RBCs. Well-designed artificial oxygen carriers that meet requisite criteria are expected to be realized eventually. Encapsulation of Hb is one idea to shield the toxicities of molecular Hbs. However, intrinsic issues of encapsulated Hbs must be resolved: difficulties related to regulating the molecular assembly, and management of its physicochemical and biochemical properties. Hb-vesicles (HbV) are a cellular type of HBOC that overcome these issues. The in vivo safety and efficacy of HbV have been studied extensively. The results illustrate the potential of HbV as a transfusion alternative and promise its use for other clinical applications that remain unattainable using RBC transfusion.

In Vivo Distribution of Liposome‐Encapsulated Hemoglobin Determined by Positron Emission Tomography

“…Liposomal nanocapsules would be labeled with [ 18 F]fluorodeoxyglucose (11,12) or water-insoluble [ 18 F]fluorodipalmitin (13), although the labeling of liposome with these radioactive probes usually requires modification or reconstitution of its membrane. Furthermore, liposomal drugs are the products of multiple steps (4,5), requiring much longer process than the halflives of commonly used positron emitter nuclei, 11 C (20 min) or 18 F (108 min). Thus, labeling preformulated DDS drugs or substituting components of liposome is impractical.…”

“…Recently, human hemoglobin was encapsulated in liposome nanocapsule (liposome-encapsulated hemoglobin [LEH] to be an artificial oxygen carrier as a substitute for red blood cells (RBCs) (4,5). In order to clarify the behavior of LEH in vivo, noninvasive, real-time imaging of their movement is desirable.…”

Bio‐inspired nanomedicine strategies for artificial blood components

“…In an analogous approach, Djordjevich et al reported on encapsulation of Hb in micron and sub-micron size lipid vesicles (liposome-encapsulated Hb or LEH), with membrane made of phospholipids and cholesterol. 31,82-84 This design was to essentially mimic the physiological state of Hb in RBCs where it is encased within the cell membrane in a protected environment that preserved the suitable redox mechanisms for Hb function. A number of variations of this design followed, e.g., ‘neohemocytes’, ‘TRM-645 Neo Red Cells’ etc., where the primary focus was to maintain uniform Hb-encapsulation levels and uniform size distribution of the vesicles, prevent vesicle destabilization or fusion over time, and thereby enhance vesicle stability upon storage while maintaining the RBC-mimetic oxygen transport properties of the encapsulated Hb.…”

Blood Substitutes

“…This effect could be supplemented by conjugation of the vesicle surface membrane with polyethylene glycol [56]. Moreover, PEG-conjugation seemed to enhance convective O 2 -transport at the site of microcirculation [22] and prevent the aggregation of Hb-liposomes in the plasma [66,87]. Another promising technique of encapsulation consists in the assembly of biodegradable nanocapsules (diameter less than 0.2 µm) made of polylactic acid.…”