A microfluidic platform to study sickle blood rheology

镰状细胞病（SCD）是一种毁灭性的遗传性疾病，影响超过1300万人 仅在美国，每年的医疗保健费用就超过10亿美元。SCD的起源是一种突变体 一种血红蛋白分子（镰状血红蛋白或HbS），在脱氧时聚合成坚硬的纤维。这些 纤维会导致血液流变学发生巨大变化，最终导致血管完全闭塞， 组织梗塞器官损伤甚至死亡尽管经过100多年的研究， 血管闭塞过程仍然难以捉摸，结果是缺乏治疗选择和低质量的治疗。 数百万患有这种疾病的人的生命。低氧浓度是必要的 镰状病发病率和死亡率的条件，但氧气之间的定量关系 在压力、血管大小和血红蛋白的生理状态下的浓度和镰状细胞血液流变学 浓度未知。最终，镰状细胞病的临床进展要求我们了解如何 在血管阻塞发生之前，患者的组织氧水平是否会下降，压力和 血管扩张调节不同氧浓度下血管闭塞的可能性， 血管闭塞是血红蛋白浓度的轻微变化。因此，我们在这些研究中的具体目标是 目的：（1）确定镰刀形血液流变学与血氧浓度的定量关系; (2)量化血管大小和血压对镰状血液流变学和血管扩张之间关系的影响。 （3）量化镰状血红蛋白浓度对 镰状血液流变学和氧浓度。我们的主要假设是血液和 粘度和氧浓度包括多个功能区，其特征在于临界氧 阈值，并且这种关系对血管大小、血压和体内HbS浓度敏感。 由于这些参数无法在体内控制，我们将使用体外微流体平台， 控制系统地改变这些参数，并量化对镰状血液流变学的影响。相位 镰状血液流变学的空间，例如氧阈值，可以通过治疗例如药物 其调节血红蛋白氧结合亲和力。因此，这里开发的平台非常适合 测试这些疗法。这些研究中发现的参数也可以作为疾病的生物标志物 严重程度，以指示哪些患者最需要护理或患者何时最有并发症的风险。 总的来说，这些研究的结果将更清楚地了解镰状血液流变学如何依赖于 关键的生理参数，这项工作将产生新的平台和生物标志物，用于患者监测 以及优先考虑实验性疗法。

Sickle cell disease (SCD) is a devastating hereditary disorder that affects more than 13 million people worldwide with health care costs in the U.S. alone exceeding $1 billion per year. The origin of SCD is a mutant hemoglobin molecule (sickle hemoglobin or HbS) that polymerizes into rigid fibers when deoxygenated. These fibers cause large changes in blood rheology and can ultimately result in complete occlusion of blood vessels, tissue infarction, organ damage, and even death. Despite more than 100 years of research, a clear picture of the vaso-occlusive process remains elusive, and the result is a dearth of treatment options and poor quality of life for the millions of individuals who suffer from this disease. Low oxygen concentration is the one necessary condition for morbidity and mortality in sickle disease, but the quantitative relationship between oxygen concentration and sickle cell blood rheology in physiologic regimes of pressure, vessel size, and hemoglobin concentration is unknown. Ultimately, clinical progress in sickle cell disease requires that we understand how low can a patient's tissue oxygen level fall before a vaso-occlusion will occur, how changes in pressure and vessel dilation modulate the probability of vaso-occlusion at different oxygen concentrations, and how sensitive vaso-occlusion is to slight changes in hemoglobin concentration. Thus, our Specific Aims in these studies are to: (1) Determine the quantitative relationship between sickle blood rheology and blood oxygen concentration; (2) Quantify the effect of vessel size and blood pressure on the relationship between sickle blood rheology and oxygen concentration; (3) Quantify the effect of sickle hemoglobin concentration on the relationship between sickle blood rheology and oxygen concentration. Our primary hypothesis is that the relationship between blood viscosity and oxygen concentration comprises multiple functional regimes, characterized by critical oxygen thresholds, and that this relationship is sensitive to vessel size, blood pressure, and HbS concentration in vivo. Because these parameters cannot be controlled in vivo, we will use an in vitro microfluidic platform with oxygen control to systematically vary these parameters and quantify the effects on sickle blood rheology. The phase space of sickle blood rheology, such as the oxygen thresholds, may be modulated by treatments such as drugs that modulate hemoglobin oxygen binding affinity. Thus, the platforms developed here would be ideal for testing such therapies. The parameters uncovered in these studies may also serve as biomarkers for disease severity to indicate which patients are most in need of care or when patients are most at risk of complications. Overall, the results of these studies will be a clearer understanding of how sickle blood rheology depends on critical physiologic parameters, and this work will produce new platforms and biomarkers for patient monitoring and for prioritizing experimental therapies.