Sickle cell vasoocclusion and rescue in a microfluidic device
Sickle cell vasoocclusion and rescue in a microfluidic device
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DOI：
10.1073/pnas.0707122105
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发表时间：
2007-12-18
影响因子：
11.1
通讯作者：
Mahadevan, L.
中科院分区：
文献类型：
--
作者：
Higgins, J. M.;Eddington, D. T.;Mahadevan, L.
镰状细胞病的病理生理学因将分子基因型与生物体表型联系起来的多尺度过程而复杂化：血红蛋白聚合在毫秒内发生，显微镜下细胞镰状化在几秒或更短时间内[Eaton WA，Hofrichter J（1990）Adv Protein Chem 40：63-279]，以及在几分钟的时间尺度内的宏观血管闭塞，最后一种是危象所必需的[邦恩HF（1997）N Engl J Med 337：762-769]。使用一个最小的，但强大的人工微流体环境，我们表明，这是可能的，以唤起，控制和抑制集体血管闭塞或堵塞事件在镰状细胞病。我们使用几何，物理，化学和生物学手段的组合来量化干扰事件发生的相空间，以及它的溶解，并发现氧依赖性镰状血红蛋白聚合和熔化本身就足以重建干扰和救援。我们进一步表明，在闭塞的异质性的一个关键来源来自缓慢的集体堵塞的封闭，流动悬浮液的软细胞，改变他们的形态和流变学相对较快。最后，我们量化和调查的影响，小分子聚合抑制剂和治疗性红细胞交换这个动态过程。我们的实验研究在分子、聚合物、细胞和组织水平上整合了与闭塞相关的集体过程的动力学;为定量了解限速过程奠定了基础;并为优化和个性化治疗以及确定新疗法提供了潜在的工具。
The pathophysiology of sickle cell disease is complicated by the multiscale processes that link the molecular genotype to the organismal phenotype: hemoglobin polymerization occurring in milliseconds, microscopic cellular sickling in a few seconds or less [Eaton WA, Hofrichter J (1990) Adv Protein Chem 40:63-279], and macroscopic vessel occlusion over a time scale of minutes, the last of which is necessary for a crisis [Bunn HF (1997) N Engl J Med 337:762-769]. Using a minimal but robust artificial microfluidic environment, we show that it is possible to evoke, control, and inhibit the collective vasoocclusive or jamming event in sickle cell disease. We use a combination of geometric, physical, chemical, and biological means to quantify the phase space for the onset of a jamming event, as well as its dissolution, and find that oxygen-dependent sickle hemoglobin polymerization and melting alone are sufficient to recreate jamming and rescue. We further show that a key source of the heterogeneity in occlusion arises from the slow collective jamming of a confined, flowing suspension of soft cells that change their morphology and rheology relatively quickly. Finally, we quantify and investigate the effects of small-molecule inhibitors of polymerization and therapeutic red blood cell exchange on this dynamical process. Our experimental study integrates the dynamics of collective processes associated with occlusion at the molecular, polymer, cellular, and tissue level; lays the foundation for a quantitative understanding of the rate-limiting processes; and provides a potential tool for optimizing and individualizing treatment, and identifying new therapies.