Eliminating Mediators of Toxicity from Stored Blood

消除储存血液中的毒性介质

• 批准号: 8773644
• 负责人: Sergey S Shevkoplyas
• 金额: $ 36.5万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773644
• 关键词: Anticoagulants; Antigens; Apoptosis; Area; Biochemical; Biological Assay; Blood; Blood Clot; Blood Donations; Blood Transfusion; Blood capillaries; Blood coagulation; CD47 gene; Cell Aging; Cell physiology; Cells; Clinical; Code; Critical Illness; Cytolysis; Data; Deterioration; Devices; Drug Formulations; Erythrocyte Transfusion; Erythrocytes; Excision; Failure; Filtration; Glucose; Goals; Hematocrit procedure; Hematology; Hemoglobin; Heterogeneity; Hospital Records; Hospitals; Individual; Infection; Inflammation; Inflammatory; Infusion procedures; Inpatients; Lateral; Life; Lung; Mainstreaming; Measures; Mechanics; Mediator of activation protein; Medicine; Metabolism; Methemoglobin; Microfluidic Microchips; Morbidity - disease rate; Morphology; Myocardial Infarction; Operating Rooms; Outcome; Oxygen; Patients; Performance; Phosphatidylserines; Plasma; Plastics; Problem Solving; Procedures; Process; Property; Proteins; Safety; Saline; Sample Size; Shapes; Solutions; Spherocytes; Spleen; Staging; Stream; Surface; Suspension substance; Suspensions; Technology; Testing; Time; Tissues; Toxic effect; Toxin; Transfusion; Treatment Efficacy; Whole Blood; adverse outcome; base; capillary; cell age; cell injury; design; high throughput technology; human subject; improved; in vitro testing; in vivo; innovation; milliliter; mortality; novel strategies; oxidative damage; prototype; research study; scale up

DESCRIPTION (provided by applicant): With nearly 15 million units of red blood cells (RBCs) transfused to about 5 million patients in the U.S. every year, RBC transfusion is one of the most commonly prescribed therapies for hospital inpatients. In recent years, ample clinical evidence has accumulated that a significant proportion of morbidity and mortality in critically ill patientsis due to the toxic effects of RBC transfusions. Most transfusions involve RBCs that had been stored in an anticoagulant-preservative solution at 1-6 C for up to 6 weeks. The biochemical, mechanical and functional properties of RBCs deteriorate progressively - by the end of allowable storage up to 1% of stored RBCs undergo lysis, and as many as 25% of the remaining RBCs are irreparably damaged, non-viable cells. Moreover, the RBC storage medium accumulates known mediators of toxicity as byproducts of RBC metabolism and degradation. Infusion of these toxic mediators and the irreparably damaged cells into the recipient during transfusion reduces the therapeutic efficacy of transfusion and contributes to multiple adverse outcomes in 1-2% of U.S. citizens. The goal of this project is to devise a high-throughput technology for in-line removal of irreparably damaged cells and toxic mediators in the storage medium from units of stored RBCs in real-time, during the transfusion process. This project will initially focus on the design and performance optimization of the proposed technology on milliliter-size samples of stored RBCs. To support the design iterations, we will develop an auxiliary hematology-on-a-chip device for measuring all relevant geometric, mechanical and biochemical properties for thousands of individual RBCs at high throughput. At the second stage of the project, we will scale up the optimized design for processing clinical-size RBC units. We will perform a broad panel of in vitro tests to characterize the quality of processed RBCs. To perform an integrative test of the primary RBC function, we will develop another auxiliary device for measuring the ability of stored RBCs to load / offload oxygen in artificial capillary networks directly. The anticipated outcome of this project is a full-scale prototype of the proposed device that can be used to further test the processed well- preserved stored RBCs for pro-inflammatory and pro-thrombotic activity, and post-transfusion viability and intravascular survival in human subjects in vivo. Conventional paradigm postulates that all stored RBCs in a bag are homogeneous with respect to the storage-induced deterioration of their properties, and consequently attempts to 'rejuvenate' stored RBCs through manipulation of the overall storage conditions and re-formulation of additive solutions. Our approach challenges this conventional paradigm by leveraging the heterogeneity of stored RBCs to enable transfusion of only well-preserved cells, free from irreparably damaged cells and toxins in the storage medium. This is an entirely novel approach with a potentially game-changing, transformative impact on the safety and efficacy of transfusions administered throughout the practice of medicine.

描述（由申请人提供）：每年在美国，近1500万单位的红细胞（RBC）输给了约500万名患者，RBC输血是医院住院患者最常见的处方疗法之一。近年来，大量的临床证据积累了，由于RBC输血的毒性作用，重症患者的发病率和死亡率很大一部分。大多数输血都涉及在1-6 C抗凝抗凝蛋白溶液中存储的RBC，持续6周。 RBC的生化，机械和功能特性逐渐恶化 - 到达允许存储的结束时，最多1％的储存RBC经历了裂解，其余的RBC中有多达25％的RBC被无法弥补的损坏，不可损害，不可行的细胞。此外，RBC存储培养基积累了已知的毒性介体作为RBC代谢和降解的副产品。输注这些有毒介质和在输血过程中不可弥补的细胞损坏的细胞降低了输血的治疗功效，并在1-2％的美国公民中导致多种不良结果。该项目的目的是设计一种高通量技术，用于在输血过程中实时储存的RBC的单位在储存培养基中串联损坏的细胞和有毒介质的串联去除。该项目最初将重点关注毫升尺寸的RBC样品对拟议技术的设计和性能优化。为了支持设计迭代，我们将开发一种辅助血液学片段，用于测量数千个在高通量处的单个RBC的所有相关几何，机械和生化特性。在项目的第二阶段，我们将扩大用于处理临床大小的RBC单元的优化设计。我们将执行大量体外测试，以表征加工RBC的质量。为了对主要RBC函数进行集成测试，我们将开发另一个辅助设备，用于测量存储的RBC直接在人工毛细管网络中加载 /卸载氧的能力。该项目的预期结果是该设备的全尺度原型，可用于进一步测试保存完好的储存的RBC，以实现促炎和促血管性活性，转移后的存活率以及人类受试者中人类受试者的血管内存活率。常规的范式假定，在存储诱导的其性质恶化方面，所有存储的RBC均均匀，因此试图通过操纵整体存储条件和重新配置添加剂解决方案来“使” RBC“重新生存”。我们的方法通过利用储存的RBC的异质性来挑战这种常规的范式，以使仅保存完好的细胞能够输血，该细胞不受储存介质中不可避免地损坏的细胞和毒素。这是一种完全新颖的方法，具有对整个医学实践中采用输血的安全性和功效的潜在改变，变革性的影响。