Simultaneous quantification of blood rheology and oxygen saturation to evaluate affinity-modifying therapies in sickle cell disease.
Simultaneous quantification of blood rheology and oxygen saturation to evaluate affinity-modifying therapies in sickle cell disease.
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DOI：
10.1039/d2lc00623e
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发表时间：
2022-10-25
期刊：
影响因子：
6.1
通讯作者：
Wood DK
中科院分区：
文献类型：
--
作者：
Hansen S;Wood DK
在低氧条件下，由于HBS聚合，镰状细胞血液表现出氧依赖的流动行为，这些流变性变化提供了一种生物物理指标，可以用来量化血液的病理行为。将这些流变学变化直接与血红蛋白血氧饱和度联系起来，将有助于我们更好地了解SCD的发病机制和治疗药物的潜在作用。为此，我们开发了一种微流控平台，能够对Hb-O2饱和度进行分光光度定量，并同时评估SCD血流的伴随流变学变化。我们展示了在与Voxelotor孵育后，测量Hb-O2亲和力的变化和恢复氧非依赖性血流行为的能力，Voxelotor是一种被批准用于SCD的氧亲和力修改药物。我们还确定了在HB-O2饱和的情况下，HBS聚合的影响开始在病理性流动行为中发挥作用的区域，独立于体素释放治疗。相比之下，与Voxelotor孵育在一定范围内恢复了氧依赖的血流，为了解Voxelotor在降低Hb-O2饱和度以观察病理性血流方面的治疗效果提供了一个框架。这些结果有助于解释体素促进剂的机制效应，并显示该平台在识别亲和力修饰化合物和评估其对血流的治疗效果方面的潜力。
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-O2 saturation and simultaneous evaluation of the accompanying rheological changes in SCD blood flow. We demonstrated the ability to measure changes in Hb-O2 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-O2 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-O2 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.
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