Kinetics of sickle cell biorheology and implications for painful vasoocclusive crisis
Kinetics of sickle cell biorheology and implications for painful vasoocclusive crisis
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DOI：
10.1073/pnas.1424111112
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发表时间：
2015-02-03
影响因子：
11.1
通讯作者：
Suresh, Subra
中科院分区：
文献类型：
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作者：
Du, E.;Diez-Silva, Monica;Suresh, Subra
我们开发了一种基于微流体的模型来量化调节镰状细胞病（SCD）病理生理学的细胞水平过程。该体外模型能够对细胞镰化、去镰化和细胞流变学的动力学进行定量研究。我们创造了短期和长期缺氧条件来模拟微脉管系统中正常和延迟的传输场景。我们使用 25 名镰状血红蛋白 (HbS) 水平从 64% 到 90.1% 不等的 SCD 患者的血液样本，研究了血流过程中细胞生物物理变化与血液学参数、HbS 水平和羟基脲 (HU) 治疗的相关性。根据这些测量结果，我们确定了两例严重的 SCD 病例，这些病例也根据基于基因型的疾病严重程度分类被独立验证为严重。这些结果表明该方法作为疾病严重程度的诊断指标的潜力。此外，我们研究了细胞密度在细胞镰状动力学中的作用。我们观察到 HU 治疗的效果主要在相对密集的细胞群中，并且镰状部分随着细胞密度的增加而增加。这些结果支持了这样一种可能性：这里开发的微流体平台提供了一种独特的定量方法来评估与 SCD 相关的血管闭塞事件所涉及的动力学、流变学和血液学因素，并开发用于疾病严重程度的替代诊断工具以补充其他方法。这些见解还可能有助于更好地了解 SCD 的致病基础和药物反应机制。
We developed a microfluidics-based model to quantify cell-level processes modulating the pathophysiology of sickle cell disease (SCD). This in vitro model enabled quantitative investigations of the kinetics of cell sickling, unsickling, and cell rheology. We created short-term and long-termhypoxic conditions to simulate normal and retarded transit scenarios in microvasculature. Using blood samples from 25 SCD patients with sickle hemoglobin (HbS) levels varying from 64 to 90.1%, we investigated how cell biophysical alterations during blood flow correlated with hematological parameters, HbS level, and hydroxyurea (HU) therapy. From these measurements, we identified two severe cases of SCD that were also independently validated as severe from a genotype-based disease severity classification. These results point to the potential of this method as a diagnostic indicator of disease severity. In addition, we investigated the role of cell density in the kinetics of cell sickling. We observed an effect of HU therapy mainly in relatively dense cell populations, and that the sickled fraction increased with cell density. These results lend support to the possibility that the microfluidic platform developed here offers a unique and quantitative approach to assess the kinetic, rheological, and hematological factors involved in vasoocclusive events associated with SCD and to develop alternative diagnostic tools for disease severity to supplement other methods. Such insights may also lead to a better understanding of the pathogenic basis and mechanism of drug response in SCD.