Eliminating Mediators of Toxicity from Stored Blood

消除储存血液中的毒性介质

基本信息

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
项目类别：
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

项目摘要

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）：美国每年向约 500 万患者输注近 1500 万单位红细胞 (RBC)，红细胞输注是医院住院患者最常用的治疗方法之一。近年来，积累的大量临床证据表明，危重患者的发病率和死亡率很大一部分是由于红细胞输注的毒性作用造成的。大多数输血涉及的红细胞已在 1-6°C 的抗凝剂防腐溶液中保存长达 6 周。红细胞的生化、机械和功能特性逐渐恶化 - 在允许储存结束时，多达 1% 的储存红细胞会发生裂解，而剩余的红细胞中多达 25% 是不可修复的受损、无活力的细胞。此外，红细胞储存介质会积累已知的毒性介质，作为红细胞代谢和降解的副产物。在输血过程中将这些有毒介质和不可修复的受损细胞输注到接受者体内会降低输血的治疗效果，并导致 1-2% 的美国公民出现多种不良后果。该项目的目标是设计一种高通量技术，用于在输血过程中实时在线去除存储介质中不可修复的受损细胞和有毒介质。该项目最初将重点关注所提出的技术在存储红细胞的毫升大小样本上的设计和性能优化。为了支持设计迭代，我们将开发一种辅助芯片血液学设备，用于高通量测量数千个红细胞的所有相关几何、机械和生化特性。在该项目的第二阶段，我们将扩大处理临床规模红细胞单位的优化设计。我们将进行广泛的体外测试来表征加工红细胞的质量。为了对红细胞的主要功能进行综合测试，我们将开发另一种辅助装置，用于直接测量储存的红细胞在人工毛细血管网络中加载/卸载氧气的能力。该项目的预期成果是所提出装置的全尺寸原型，可用于进一步测试处理后保存完好的红细胞的促炎和促血栓活性，以及输血后活力和血管内存活率。体内的受试者。传统范例假设袋子中所有储存的红细胞在储存引起的性能恶化方面都是同质的，因此试图通过控制整体储存条件和重新配制添加剂溶液来“恢复”储存的红细胞的活力。我们的方法挑战了这种传统模式，利用储存红细胞的异质性，仅输注保存完好的细胞，而储存介质中不含不可修复的受损细胞和毒素。这是一种全新的方法，对整个医学实践中输血的安全性和有效性具有潜在的颠覆性、变革性影响。