(verbatim) We plan to design, develop, and produce an economic oxygen carrying plasma expander based on modified molecular human hemoglobin engineered with properties that insure the maintenance of microvascular function, leading to improved survival and tissue oxygenation relative to blood, for treatment of trauma victims within 48 hours of injury. The program is vertically integrated, including production of purified hemoglobin from red blood cells by means of a modified, self contained plasma fractionation centrifuge ~at directly produces the necessary molecular modifications and a unit of artificial blood ready for use. This approach eliminates the need for fabrication of large, clean facilities and reduces cost. Furthermore it allows for production in remote areas. Our bioengineering design principle is that when a blood replacement fluid is introduced in the circulation it should cause the resulting blood viscosity to remain sufficiently elevated to insure the adequate generation of shear stress at the-blood/tissue interface, which we have demonstrated to be necessary to provide normal capillary blood flow the key -determinant of tissue survival. According to this principle even small amounts of cell-free hemoglobin (l-2 g/dl) are very effective in improving survival after hemorrhage. Due to this low-dose effect at least two units of product can be obtained from each unit of collected normal blood. The molecular modification to be pursued is surface modification with polyethylene glycol (PEG), and other modifications that will result in molecules with large radius. Different formulations of product are envisioned including a low volume concentrated solution that will restore blood volume by autotransfusion. The program encompasses all aspects of artificial blood production from obtaining the raw materials to the final commercial product and is aimed at; establishing a blood transfusion technology that delivers a-blood replacement biomaterial that is cost effective and as efficacious as blood. The envisioned artificial blood will be universal, requiring no typing, will have long shelf life and will be easy to store.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Resource-Related Research Projects (R24)
Project #
1R24HL064395-01
Application #
6054947
Study Section
Special Emphasis Panel (ZRG1-SSS-M (02))
Project Start
2000-05-05
Project End
2005-04-30
Budget Start
2000-05-05
Budget End
2001-04-30
Support Year
1
Fiscal Year
2000
Total Cost
$1,112,548
Indirect Cost
Name
University of California San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Tsai, Amy G; Cabrales, Pedro; Young, Mark A et al. (2015) Effect of oxygenated polyethylene glycol decorated hemoglobin on microvascular diameter and functional capillary density in the transgenic mouse model of sickle cell anemia. Artif Cells Nanomed Biotechnol 43:10-7
Mooij, H L; Cabrales, P; Bernelot Moens, S J et al. (2014) Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function. J Am Heart Assoc 3:e001274
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
Namgung, Bumseok; Ju, Meongkeun; Cabrales, Pedro et al. (2013) Two-phase model for prediction of cell-free layer width in blood flow. Microvasc Res 85:68-76
Salazar Vázquez, Beatriz Y; Hightower, C Makena; Yalcin, Ozlem et al. (2013) Semisynthetic hybrid biopolymers for non-pharmacological intervention of the microcirculation. Curr Drug Metab 14:540-6
Martini, Judith; Cabrales, Pedro; Fries, Dietmar et al. (2013) Effects of fibrinogen concentrate after shock/resuscitation: a comparison between in vivo microvascular clot formation and thromboelastometry*. Crit Care Med 41:e301-8
Hightower, C Makena; Salazar Vázquez, Beatriz Y; Cabrales, Pedro et al. (2013) Plasma expander and blood storage effects on capillary perfusion in transfusion after hemorrhage. Transfusion 53:49-59
Cabrales, Pedro; Intaglietta, Marcos (2013) Blood substitutes: evolution from noncarrying to oxygen- and gas-carrying fluids. ASAIO J 59:337-54
Park, Sang Woo; Intaglietta, Marcos; Tartakovsky, Daniel M (2012) Impact of endothelium roughness on blood flow. J Theor Biol 300:152-60
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

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