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.

项目概要/摘要 镰状细胞病 (SCD) 是一种破坏性单基因疾病，突变血红蛋白发生聚合 变成刚性纤维，导致红细胞 (RBC) 硬化，并且通常会增加血液粘度并导致 血管闭塞的病理过程 血液粘度的概念在临床上很重要，正如医生所认为的那样。 指示明智地使用输血以避免“高粘血症”，但也受到临床的阻碍 输血指南在科学上过于简单化，而且没有证据支持。这种过于简化的观点。 首先，该指南忽视了血液粘度的现实。 取决于 SCD 中的血管大小、剪切速率和氧张力（直接影响红细胞硬度）， 除了血红蛋白 (Hb) 浓度之外，在微循环中，SCD 的病理生理学也是如此。 发生并且血管的口径接近血细胞的大小，血细胞是一种复杂的流体，例如 最后，过去几十年的研究表明，血液不能用其“整体”粘度来描述。 SCD 还涉及内皮功能障碍和异常粘附以及多种细胞间相互作用 网织红细胞、血小板和白细胞亚群，所有这些都受到溶血作用的进一步调节 副产物、凝血蛋白和炎症细胞因子，因此，这些因素是多因素相互作用的。 复杂的生物物理和生物特性协同作用改变血液的“有效”粘度，特别是 这些在 SCD 中产生有效粘度的复杂过程是不可能的。 在体内动物模型中进行定量研究，并且现有的体外测定无法整合所有这些变量。 为此，Wood 博士和 Lam 博士在 MPI R01 资助中拥有广泛且互补的资源。 与 Kemp 博士密切合作，在微系统工程和实验血液学方面拥有专业知识 系统生物学家，将应用多学科实验和计算方法来开发体外 脉管系统模型，包含所有相关的物理、生物和生化变量 有助于增加有效血液粘度，从而导致 SCD 中的血管闭塞。 然后，我们的实验生成的数据将通过计算和统计建模来构建 全面了解 SCD 血管闭塞成功情况下的有效血液粘度。 该项目的完成还将作为一个分析平台，最终将导致针对患者的具体情况 输血方案适合每个患者的个体血液学特征。 这里开发的方法将成为开发新的 SCD 治疗策略的基础。