Mechanically Stable Blood Substitutes

机械稳定的血液替代品

• 批准号: 7141258
• 负责人: Andre Francis Palmer
• 金额: $ 4.27万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2006-08-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7141258
• 关键词: actins; biomaterial development /preparation; blood /plasma substitute; hemodynamics; hemoglobin; laboratory rat; liposomes; polyethylene glycols; shear stress

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：为了改善创伤受害者和经历高失血外科手术的患者的结果，并避免输血的许多严重并发症，迫切需要携氧血液替代品。本研究的目的是工程化的新型血红蛋白（Hb）和肌动蛋白（Ac）的脂质体（LEAcHb）。这些囊泡预期通过这种新系统的两个关键特征在循环中具有增加的半衰期。首先，这些脂质体由与聚（乙二醇）（PEG）缀合的脂质组成。该特征减少了网状内皮系统（RES）对这些脂质体的识别。其次，这些囊泡是机械稳定的，并且能够在溶液中采用椭圆形形状，因为细胞骨架聚合物肌动蛋白充当支架并在体循环中稳定囊泡。因此，它们对血液剪切梯度具有高度弹性。事实上，这些新的囊泡可以动态自我愈合时，暴露于高剪切应力遇到的血流。本申请的目的是了解如何LEAcHb囊泡结构和力学可以被工程化，以创建机械稳定和形状变化的囊泡分散体用作人工血液替代品。我们假设，控制脂质体的结构和力学可以通过改变脂质体的大小和浓度的封装肌动蛋白。我们计划通过追求三个具体目标来测试我们的假设并实现本申请的目的：1）确定含有单独肌动蛋白-血红蛋白的脂质体的结构和力学，并将其与含有肌动蛋白-血红蛋白的脂质体分散体的流变学和平均弯曲弹性相关联。2)测定平衡时的氧结合特性、O2和NO结合/释放动力学、Hb自氧化和氯化血红素释放动力学、H2 O2和O2介导的Hb氧化动力学、稳定性、补体激活、体内性能、循环半衰期和LEAcHb分散体的生物分布。3)使用LEAcHb分散体对各种血容量替代方案的血液动力学效应进行生理学评估。拟议的工作是创新和重要的，因为新的LEAcHb混合囊泡工程的结构和机械特性将被创建用于作为人工血液替代品。