To improve the outcome of trauma victims and of patients undergoing high-blood-loss surgical procedures and to avoid the many serious complications of blood transfusions, there is a critical need for an oxygen- carrying blood substitute. This study is aimed at engineering novel hemoglobin (Hb) and actin (Ac) containing liposomes (LEAcHb). These vesicles are expected to have increased half-lives in circulation via two key features of this novel system. First these liposomes are composed of lipid that is conjugated with poly(ethylene glycol) (PEG). This feature reduces recognition of these liposomes by the reticuloendothelial system (RES). Secondly, these vesicles are both mechanically stable and able to adopt an ellipsoidal shape in solution, since the cytoskeletal polymer actin acts as a scaffold and stabilizes the vesicles while in the systemic circulation. Hence, they are highly resilient to blood shear gradients. In fact these novel vesicles can dynamically self-heal themselves when exposed to high shear stresses encountered in the blood stream. The objective of this application is to understand how LEAcHb vesicle structure and mechanics can be engineered to create mechanically stable and shape changing vesicular dispersions for use as artificial blood substitutes. We postulate that control of liposome structure and mechanics can be engineered by varying liposome size and concentration of encapsulated actin. We plan to test our hypothesis and accomplish the objective of this application by pursuing three specific aims: 1) Determine the structure and mechanics of individual actin-hemoglobin containing liposomes, and relate this to the rheology and average bending elasticity of actin-hemoglobin containing liposome dispersions. 2) Determine the oxygen binding properties at equilibrium, kinetics of O2 and NO binding/release, kinetics of Hb autoxidation and hemin release, kinetics of H2O2 and O2_ mediated oxidation of Hb, stability, complement activation, in vivo performance, circulatory half-life, and biodistribution of LEAcHb dispersions. 3) Physiological assessment of the hemodynamic effects of various blood volume replacement regimens using LEAcHb dispersions. The proposed work is both innovative and significant, because novel LEAcHb hybrid vesicles with engineered structural and mechanical characteristics will be created for use as an artificial blood substitute. ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Biomaterials and Biointerfaces Study Section (BMBI)
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Mitchell, Phyllis
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Ohio State University
Engineering (All Types)
Schools of Engineering
United States
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Roche, Camille J; Talwar, Abhinav; Palmer, Andre F et al. (2015) Evaluating the capacity to generate and preserve nitric oxide bioactivity in highly purified earthworm erythrocruorin: a giant polymeric hemoglobin with potential blood substitute properties. J Biol Chem 290:99-117
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Cabrales, Pedro; Rameez, Shahid; Palmer, Andre F (2012) Hemoglobin encapsulated poly(ethylene glycol) surface conjugated vesicles attenuate vasoactivity of cell-free hemoglobin. Curr Drug Discov Technol 9:224-34
Elmer, Jacob; Zorc, Katie; Rameez, Shahid et al. (2012) Hypervolemic infusion of Lumbricus terrestris erythrocruorin purified by tangential-flow filtration. Transfusion 52:1729-40
Rameez, Shahid; Banerjee, Uddyalok; Fontes, Jorge et al. (2012) The Reactivity of Polymersome Encapsulated Hemoglobin with Physiologically Important Gaseous Ligands: Oxygen, Carbon Monoxide and Nitric Oxide. Macromolecules 45:2385-2389
Rameez, Shahid; Guzman, Nicole; Banerjee, Uddyalok et al. (2012) Encapsulation of hemoglobin inside liposomes surface conjugated with poly(ethylene glycol) attenuates their reactions with gaseous ligands and regulates nitric oxide dependent vasodilation. Biotechnol Prog 28:636-45
Zhang, Ning; Palmer, Andre F (2012) Liposomes surface conjugated with human hemoglobin target delivery to macrophages. Biotechnol Bioeng 109:823-9
Styslinger, Thomas J; Zhang, Ning; Bhatt, Veer S et al. (2012) Site-selective glycosylation of hemoglobin with variable molecular weight oligosaccharides: potential alternative to PEGylation. J Am Chem Soc 134:7507-15

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