Bioengineering Design of Artificial Blood

人工血液的生物工程设计

• 批准号: 7682841
• 负责人: Marcos Intaglietta
• 金额: $ 71.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-05 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682841
• 关键词: Acids; Affinity; Amines; Animal Model; Animals; Apoptosis; Binding; Biochemical; Biological Assay; Biomedical Engineering; Blood; Blood Circulation; Blood Substitutes; Blood Transfusion; Blood Vessels; Blood Volume; Blood capillaries; Caliber; Carbon Monoxide; Cardiac; Cardiac Output; Cell Death; Characteristics; Chloride Ion; Chlorides; Clinical; Clinical Trials; Collaborations; Colloids; Conscious; Coronary Occlusions; Data; Development; Diffusion; Digestion; Dose; Drug Formulations; Effectiveness; Endothelium; Endotoxins; Engineering; Equation; Erythrocytes; Europe; Freezing; Gases; Generic Drugs; Glycocalyx; Goals; Hamsters; Heart; Heart Rate; Heme; Hemodilution; Hemoglobin; Hemorrhage; High Pressure Liquid Chromatography; Homeostasis; Hour; Human; Hydration status; Infarction; Ischemia; Laboratories; Length; Ligand Binding; Ligands; Lysine; Maintenance; Maleimides; Measurement; Measures; Medicine; Membrane Proteins; Metabolic; Methods; Microcirculation; Military Personnel; Modeling; Molecular Conformation; Molecular Models; Molecular Weight; Monitor; Myocardial Infarction; Myocardial Ischemia; Names; Necrosis; Nitric Oxide; Nitrite Reductase; Osmolalities; Osmotic Pressure; Oxygen; PEG-hemoglobin; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Physiological; Plasma; Polyethylene Glycols; Polymers; Preparation; Procedures; Production; Property; Proteins; Radial; Rattus; Reaction; Renal function; Reperfusion Therapy; Research; Research Personnel; Research Project Grants; Research Proposals; Resuscitation; Role; Safety; Site; Solutions; Staging; Structure; Sulfhydryl Compounds; Surface; Sweden; System; TNFRSF5 gene; Temperature; Test Result; Testing; Thermodynamics; Time; Toxic effect; Transfusion; Transport Process; Trauma; Vasodilator Agents; Viscosity; Weight; Work; alkyl group; awake; base; capillary; chemical synthesis; clinical application; crosslink; density; design; hemodynamics; improved; in vivo; light scattering; mathematical model; methyl 4-mercaptobutyrimidate; molecular dynamics; molecular modeling; molecular size; myocardial infarct sizing; novel; oxygen transport; pressure; repaired; research study; resistance factors; simulation; tissue oxygenation; triphenyltetrazolium; vasoconstriction

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).

在第一个阶段，在此BRP中的工作表明MP4（PEG修饰的血红蛋白）克服了最多 发展基于血红蛋白的血液替代品的巨大障碍，即 血管收缩。 MP4通过O2传输和维护的组合促进组织氧合 功能性毛细管密度尽管具有违反直觉的特性，包括O2亲和力增加， 粘度和肿瘤压力。 MP4的能力优于血液，可以使动物从严重， 不受控制的出血，并且在人类临床试验中已被证明是安全的。在现在 应用我们将检验以下假设：MP4是血红素配体O2的有效载体 一氧化碳（CO）和一氧化氮（NO），并将进行相关的生理研究 了解其作为血液替代品的有效性，并确定其使用的新临床应用。我们将 检验钉 - hb制剂是血管扩张剂的假设，以与循环相互作用的方式而不是 与HB无清理有关。我们建议MP4的特性部分是由于亚硝酸盐增加 还原酶活性，无运输。我们将制定使用MP4提供CO和利用的程序 即使在升高的温度下，该CoMP4也非常稳定，使其在现场使用中很有价值 创伤。项目1具有GMP设施，可提供一致的质量和特性的MP4。它将发展 并产生具有目标的新的PEG-HB化合物，以优化浓度而不增加胶体 渗透压力和增强O2输送能力，以提高MP4的适用性 临床用途范围。属性将通过生化分析，数学建模和 大鼠的全身实验，包括对心肌梗塞的影响。项目2将检查PEG-HBS' 对糖脂完整性的影响，PEG-HBS的存在如何影响反应性O2种（ROS），并将 研究PEG-HB和增强血浆粘度的综合作用。 MP4将用作交付 CO在缺血和出血期间提供细胞保护的车辆。微循环研究将使用 醒目的仓鼠窗室模型，直接测量O2，没有水平，流动和 血管中的直径和功能毛细管密度。这项研究结合了对 输血，工程运输过程的基本原理和机械转移，并具有专业知识 两个实验室有超过12年的合作。有效的血液替代物将显着 提高民用和军事环境中输血的安全性和功效，简化并简化 输血医学。将开发新型血液替代品的申请 基于微血管流动，心脏和心脏的增强，对缺血的根本不同治疗 肾功能，修复内皮和血红素配体的递送（O2，NO和CO）。