In the first period, work in this BRP demonstrated that MP4 (PEG-modified hemoglobin) overcomes the most significant hurdle to the development of modified hemoglobin-based blood substitutes, namely vasoconstriction. MP4 promotes tissue oxygenation through a combination of O2 transport and maintenance of functional capillary density in spite of its counterintuitive properties, including increased O2 affinity, viscosity and oncotic pressure. MP4 is superior to blood in its ability to resuscitate animals from severe, uncontrolled hemorrhage, and it has been shown to be safe in human clinical trials. In this present application we will test the hypothesis that MP4 is an effective carrier of the heme ligands O2, carbon monoxide (CO)and nitric oxide (NO), and will carry out the related physiological studies in order to understand its effectiveness as a blood substitute and identify new clinical applications for its use. We will test the hypothesis that PEG-Hb formulations are vasodilators which interact with the circulation in ways not related to NO scavenging by Hb. We propose that MP4's properties are in part due to an increased nitrite reductase activity and NO transport. We will develop a procedure for using MP4 to deliver CO and exploit that CO-MP4 is exceptionally stable, even at elevated temperatures, making it valuable in field use for trauma. Project 1 has a GMP facility that provides MP4 of consistent quality and properties. It will develop and produce new PEG-Hb compounds with goals to optimize concentration without increasing colloid osmotic pressure and augment O2 delivery capacity so as to increase the applicability of MP4 to a wider range of clinical uses. Properties will be screened via biochemical analysis, mathematical modeling, and systemic experiments in rats including the effect on myocardial infarction. Project 2 will examine PEG-Hbs' effects on the glycocalyx integrity, how PEG-Hbs'presence influences reactive O2 species (ROS), and will investigate the combined effect of PEG-Hb and enhanced plasma viscosity. MP4 will be used as a delivery vehicle for CO to provide cellular protection during ischemia &hemorrhage. Microcirculation studies will use the awake hamster window chamber model, with direct measurements of O2 and NO levels, flow and diameter in blood vessels and functional capillary density. This research combines physiological analysis of transfusion, fundamentals of engineering transport processes and mechanotransduction with the expertise of two laboratories with more than 12 years of collaboration. Effective blood substitutes will significantly increase the safety and efficacy of blood transfusions in civilian and military settings, streamline and simplify transfusion medicine. Applications for a new type of blood substitute will be developed, one that provides a fundamentally different treatment of ischemia, based on enhancement of microvascular flow, cardiac and renal functions, repair of the endothelium and delivery of heme ligands (O2, NO and CO).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064395-10
Application #
8136445
Study Section
Erythrocyte and Leukocyte Biology Study Section (ELB)
Program Officer
Mitchell, Phyllis
Project Start
2000-05-05
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
10
Fiscal Year
2011
Total Cost
$703,322
Indirect Cost
Name
University of California San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Oronsky, Bryan; Scicinski, Jan; Reid, Tony et al. (2016) RRx-001, a novel clinical-stage chemosensitizer, radiosensitizer, and immunosensitizer, inhibits glucose 6-phosphate dehydrogenase in human tumor cells. Discov Med 21:251-65
Yalcin, Ozlem; Ortiz, Daniel; Williams, Alexander T et al. (2015) Perfusion pressure and blood flow determine microvascular apparent viscosity. Exp Physiol 100:977-87
Yalcin, Ozlem; Ortiz, Daniel; Tsai, Amy G et al. (2014) Microhemodynamic aberrations created by transfusion of stored blood. Transfusion 54:1015-27
Ortiz, Daniel; Briceño, Juan Carlos; Cabrales, Pedro (2014) Microhemodynamic parameters quantification from intravital microscopy videos. Physiol Meas 35:351-67
Ortiz, Daniel; Barros, Marcelo; Yan, Su et al. (2014) Resuscitation from hemorrhagic shock using polymerized hemoglobin compared to blood. Am J Emerg Med 32:248-55
Ortiz, Daniel; Cabrales, Pedro; Briceño, Juan C (2013) Transport of nitric oxide by perfluorocarbon emulsion. Biotechnol Prog 29:1565-72
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
Cabrales, Pedro; Intaglietta, Marcos (2013) Blood substitutes: evolution from noncarrying to oxygen- and gas-carrying fluids. ASAIO J 59:337-54
Vásquez, Diana M; Ortiz, Daniel; Alvarez, Oscar A et al. (2013) Hemorheological implications of perfluorocarbon based oxygen carrier interaction with colloid plasma expanders and blood. Biotechnol Prog 29:796-807
Chatpun, Surapong; Cabrales, Pedro (2012) Exogenous intravascular nitric oxide enhances ventricular function after hemodilution with plasma expander. Life Sci 90:39-46

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