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，影响着1300多万人 全球每年仅美国的医疗保健费用就超过10亿美元。SCD的起源是一种突变 脱氧时聚合成坚硬纤维的血红蛋白分子(镰状血红蛋白或HBS)。这些 纤维会引起血液流变学的巨大变化，最终会导致血管完全闭塞， 组织梗塞，器官损伤，甚至死亡。尽管进行了100多年的研究，但对 血管闭塞的过程仍然难以捉摸，结果是治疗选择的缺乏和质量的低下。 为数百万患有这种疾病的人提供生命。低氧浓度是必要的 镰刀病发病和死亡的条件，但氧与 压力、血管大小和血红蛋白生理状态下的浓度和镰状细胞血液流变学 浓度是未知的。归根结底，镰状细胞疾病的临床进展要求我们了解 在血管闭塞发生之前，患者的组织氧水平会下降到什么程度，压力和 血管扩张调节不同氧气浓度下血管闭塞的可能性，以及敏感性如何 血管闭塞是为了使血红蛋白浓度发生轻微变化。因此，我们在这些研究中的具体目标是 目的：(1)测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刀形血液流变学与高血压关系的影响。 氧浓度；(3)量化影响镰刀状血红蛋白浓度之间的关系 镰刀状血液流变学和氧气浓度。我们的主要假设是，血液和 粘度和氧浓度由多个官能区组成，以临界氧为特征 这种关系对血管大小、血压和体内HBS浓度很敏感。 由于这些参数不能在体内控制，我们将使用体外氧气微流控平台 以系统地改变这些参数并量化对镰刀状血液流变学的影响。这一阶段 镰刀状血液流变学的空间，如氧阈值，可能会被药物等治疗所调节 调节血红蛋白氧结合亲和力的物质。因此，这里开发的平台将非常适合 测试这样的疗法。这些研究中发现的参数也可以作为疾病的生物标记。 严重程度指示哪些患者最需要护理或患者何时最有可能出现并发症。 总体而言，这些研究的结果将更清楚地了解镰刀状血液流变学是如何依赖于 关键生理参数，这项工作将产生新的平台和生物标记物用于患者监测 以及对实验疗法的优先考虑。

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.