Department of Biomedical Engineering, University of Minnesota, Minneapolis 55409, USA.
Lab Chip. 2022 Oct 25;22(21):4141-4150. doi: 10.1039/d2lc00623e.
Sickle cell blood demonstrates oxygen-dependent flow behavior as a result of HbS polymerization during hypoxia, and these rheological changes provide a biophysical metric that can be used to quantify the pathological behavior of the blood. Relating these rheological changes directly to hemoglobin oxygen saturation would improve our understanding of SCD pathogenesis and the potential effects of therapeutic drugs. Towards this end, we have developed a microfluidic platform capable of spectrophotometric quantification of Hb-O saturation and simultaneous evaluation of the accompanying rheological changes in SCD blood flow. We demonstrated the ability to measure changes in Hb-O affinity and a restoration of oxygen-independent blood flow behavior after incubation with voxelotor, an oxygen affinity modifying drug approved for use in SCD. We also identified regimes in Hb-O saturation where the effects of HbS polymerization begin to take effect in contributing to pathological flow behavior, independent of voxelotor treatment. In contrast, incubation with voxelotor recovered oxygen-dependent blood flow over a range of , providing a framework for understanding voxelotor's therapeutic effect in lowering the at which the requisite Hb-O saturation is reached to observe pathological blood flow. These results help explain the mechanistic effects of voxelotor and show the potential of this platform to identify affinity-modifying compounds and evaluate their therapeutic effect on blood flow.
镰状细胞血液在缺氧时由于 HbS 聚合而表现出氧依赖性流动行为，这些流变学变化提供了一种可以用来量化血液病理行为的生物物理指标。将这些流变学变化直接与血红蛋白氧饱和度相关联，可以提高我们对 SCD 发病机制和治疗药物潜在影响的理解。为此，我们开发了一种微流控平台，能够对 Hb-O 饱和度进行分光光度定量，并同时评估 SCD 血流中伴随的流变学变化。我们证明了在与 voxelotor（一种用于 SCD 的氧亲和力修饰药物）孵育后，能够测量 Hb-O 亲和力的变化，并恢复氧非依赖性血流行为。我们还确定了 Hb-O 饱和度的范围，其中 HbS 聚合的影响开始对病理流动行为产生影响，而与 voxelotor 治疗无关。相比之下，voxelotor 的孵育在一定的范围内恢复了氧依赖性血流，为理解 voxelotor 通过降低达到观察病理血流所需的 Hb-O 饱和度来降低疾病严重程度的治疗效果提供了框架。这些结果有助于解释 voxelotor 的机制作用，并展示了该平台识别亲和力修饰化合物并评估其对血流治疗效果的潜力。
