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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL078840-05
Application #
7642288
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Mitchell, Phyllis
Project Start
2006-07-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
5
Fiscal Year
2009
Total Cost
$349,106
Indirect Cost
Name
Ohio State University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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
Palmer, Andre F; Intaglietta, Marcos (2014) Blood substitutes. Annu Rev Biomed Eng 16:77-101
Castro, C; Ortiz, D; Palmer, A F et al. (2014) Hemodynamics and tissue oxygenation after hemodilution with ultrahigh molecular weight polymerized albumin. Minerva Anestesiol 80:537-46
Kassa, Tigist W; Zhang, Ning; Palmer, Andre F et al. (2013) Design, synthesis, and activity of 2,3-diphosphoglycerate analogs as allosteric modulators of hemoglobin O2 affinity. Artif Cells Nanomed Biotechnol 41:109-15
Baek, Jin Hyen; Zhou, Yipin; Harris, David R et al. (2012) Down selection of polymerized bovine hemoglobins for use as oxygen releasing therapeutics in a guinea pig model. Toxicol Sci 127:567-81
Zhou, Yipin; Cabrales, Pedro; Palmer, Andre F (2012) Simulation of NO and O2 transport facilitated by polymerized hemoglobin solutions in an arteriole that takes into account wall shear stress-induced NO production. Biophys Chem 162:45-60
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; 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
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

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