Redefining Clinical Viscosity in Sickle Cell Diseaseby Leveraging Microfluidic Technologies

利用微流体技术重新定义镰状细胞病的临床粘度

• 批准号: 10022309
• 负责人: Wilbur A Lam
• 金额: $ 73.7万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022309
• 关键词: Adhesions; Affect; Animal Model; Architecture; Biochemical; Biologic Characteristic; Biological; Biological Factors; Biophysics; Blood; Blood Cells; Blood Circulation; Blood Platelets; Blood Transfusion; Blood Vessels; Blood Viscosity; Blood specimen; Caliber; Caring; Cell Communication; Cells; Chronic; Clinical; Clinical Research; Coagulation Process; Collaborations; Complex; Computational Technique; Computer Models; Coupled; Data; Devices; Endothelium; Engineering; Erythrocytes; Experimental Hematology; Fiber; Functional disorder; Genetic; Goals; Grant; Guidelines; Hematocrit procedure; Hematological Disease; Hematology; Hemoglobin; Hemoglobin concentration result; Hyperviscosity; In Vitro; Inflammatory; Lead; Leukocytes; Life; Liquid substance; Measures; Mediating; Mendelian disorder; Methods; Microcirculation; Microfluidics; Modeling; National Heart, Lung, and Blood Institute; Necrosis; Oxygen; Pathologic Processes; Patients; Physicians; Physiological; Plasma; Process; Property; Proteins; Regimen; Research; Resistance; Reticulocytes; Risk Factors; Sampling; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Statistical Models; Stroke; System; Technology; Testing; Time; Transfusion; Veno-Occlusive Disease; Venous; Viscosity; Whole Blood; Wood material; Work; acute chest syndrome; biophysical properties; cohort; cytokine; endothelial dysfunction; evidence base; experience; experimental study; falls; hemoglobin polymer; in vitro Assay; in vitro Model; in vivo; individual patient; microfluidic technology; microsystems; multidisciplinary; mutant; novel; novel therapeutic intervention; novel therapeutics; prevent; public health relevance; reconstitution; sound; tool; vaso-occlusive crisis

Project Summary/Abstract Sickle cell disease (SCD) is a devastating monogenic disease in which mutant hemoglobin polymerizes into rigid fibers leading to red cell (RBC) stiffening, and, canonically, to increased blood viscosity and to the pathologic process of vaso-occlusion. The concept of blood viscosity is clinically important, as physicians are instructed to use blood transfusions judiciously to avoid “hyperviscosity” but are also hampered by clinical transfusion guidelines that are scientifically oversimplified and not evidence-based. This overly simplified view of blood viscosity is problematic for several reasons. First, the guidelines overlook the reality that blood viscosity depends on blood vessel size, shear rate, and oxygen tension (which directly affects RBC stiffness) in SCD, in addition to hemoglobin (Hb) concentrations. Furthermore, in the microcirculation, where SCD pathophysiology takes place and the caliber of the blood vessel approaches the size of the blood cells, a complex fluid such as blood cannot be described by its “bulk” viscosity. Finally, the last several decades of research have revealed that SCD also involves endothelial dysfunction and aberrant adhesion and a multitude of cell-cell interactions involving reticulocytes, platelets, and leukocyte subpopulations, all of which are further modulated by hemolytic byproducts, coagulation proteins, and inflammatory cytokines. Therefore, the multifactorial interactions of these complex biophysical and biological characteristics synergize to alter the “effective” viscosity of blood, especially in the microcirculation. These complex processes that contribute to effective viscosity in SCD cannot be quantitatively studied in in vivo animal models, and no existing in vitro assays can integrate all of these variables. To that end, for this MPI R01 grant, Drs. Wood and Lam, who both have extensive and complementary expertise in microsystems engineering and experimental hematology, in close collaboration with Dr. Kemp, a systems biologist, will apply a multi-disciplinary experimental and computational approach to develop an in vitro model of the vasculature that incorporates all of the relevant physical, biological, and biochemical variables that contribute to increased effective blood viscosity and therefore, vaso-occlusion in SCD. The vast amounts of data generated by our experiments will then be computationally and statistically modeled to construct a comprehensive understanding of effective blood viscosity in the context of SCD vaso-occlusion. Successful completion of this project will also serve as an analytical platform that will ultimately lead to patient-specific transfusion regimens catered towards each patient’s individual hematologic profile. Moreover, the approach and methods developed here will be the basis to developing new therapeutic strategies for SCD.

项目摘要/摘要 镰状细胞疾病（SCD）是一种毁灭性的单基因疾病，其中突变体血红蛋白聚合化 进入导致红细胞（RBC）僵硬的刚性纤维，并从规范上增加血液粘度和到达 血管封闭的病理过程。血液粘度的概念在临床上很重要，因为医生是 被指示明智地使用输血以避免“过度粘度”，但也受到临床的阻碍 输血指南在科学上过度简化而不是基于证据的指南。这个过于简化的视图 血液粘度的问题是有问题的。首先，该指南忽略了血液粘度的现实 取决于血管的大小，剪切速率和氧张力（直接影响RBC刚度）在SCD中 增加血红蛋白（HB）浓度。此外，在微循环中，SCD病理生理学 发生，血管的口径接近血细胞的大小，一种复杂的液体，例如 血液无法通过其“大量”粘度来描述。最后，最后几十年的研究表明 SCD还涉及内皮功能障碍和异常粘附以及多种细胞相互作用 涉及网状细胞，血小板和白细胞亚群，所有这些都通过溶血进一步调节 副产物，凝结蛋白和炎性细胞因子。因此，这些相互作用的多因素相互作用 复杂的生物物理和生物学特征协同改变血液的“有效”粘度，尤其是 在微循环中。这些促成SCD中有效粘度的复杂过程不能是 在体内动物模型中进行了定量研究，没有现有的体外测定可以整合所有这些变量。 为此，对于此MPI R01赠款，Drs。伍德和林，他们都有广泛而完整的 微型系统工程和实验血液学方面的专业知识与Kemp博士密切合作 系统生物学家将采用多学科实验和计算方法来开发体外 结合了所有相关的物理，生物学和生化变量的脉管系统模型 有助于增加有效的血液粘度，因此有助于SCD中的血管结合。大量数据 然后，由我们的实验生成的计算和统计建模将进行构造 在SCD血管批准的情况下，全面了解有效的血液粘度。成功的 该项目的完成还将作为一个分析平台，最终将导致特定于患者 输血方案适合每个患者的个体血液学特征。而且，方法和 这里开发的方法将是为SCD制定新的治疗策略的基础。