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Characterization of red blood cell microcirculatory parameters using a bioimpedance microfluidic device.

ABSTRACT: This paper describes the use of a microfluidic device comprising channels with dimensions mimicking those of the smallest capillaries found in the human microcirculation. The device structure, associated with a pair of microelectrodes, provides a tool to electrically measure the transit time of red blood cells through fine capillaries and thus generate an electrical signature for red blood cells in the context of human erythroid genetic disorders, such as sickle cell disease or hereditary spherocytosis, in which red cell elasticity is altered. Red blood cells from healthy individuals, heated or not, and red blood cells from patients with sickle cell disease or hereditary spherocytosis where characterized at a single cell level using our device. Transit time and blockade amplitude recordings were correlated with microscopic observations, and analyzed. The link between the electrical signature and the mechanical properties of the red blood cells is discussed in the paper, with greater transit time and modified blockade amplitude for heated and pathological red blood cells as compared to those from healthy individuals. Our single cell-based methodology offers a new and complementary approach to characterize red cell mechanical properties in human disorders under flow conditions mimicking the microcirculation.

SUBMITTER: Xu T

PROVIDER: S-EPMC7299978 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abnormal red blood cell (RBC) deformability contributes to hemolysis, thrombophilia, inflammation, and microvascular occlusion in various circulatory diseases. A quantitative and objective assessment of microvascular occlusion mediated by RBCs with abnormal deformability would provide valuable insights into disease pathogenesis and therapeutic strategies. To that end, we present a new functional microfluidic assay, OcclusionChip, which mimics two key architectural features of the capillary bed in the circulatory system. First, the embedded micropillar arrays within the microchannel form gradient microcapillaries, from 20 μm down to 4 μm, which mimic microcapillary networks. These precisely engineered microcapillaries retain RBCs with impaired deformability, such that stiffer RBCs occlude the wider upstream microcapillaries, while less stiff RBCs occlude the finer downstream microcapillaries. Second, the micropillar arrays are coupled with two side passageways, which mimic the arteriovenous anastomoses that act as shunts in the capillary bed. These side microfluidic anastomoses prevent microchannel blockage, and enable versatility and testing of clinical blood samples at near-physiologic hematocrit levels. Further, we define a new generalizable parameter, Occlusion Index (OI), which is an indicative index of RBC deformability and the associated microcapillary occlusion. We demonstrate the promise of OcclusionChip in diverse pathophysiological scenarios that result in impaired RBC deformability, including mercury toxin, storage lesion, end-stage renal disease, malaria, and sickle cell disease (SCD). Hydroxyurea therapy improves RBC deformability and increases fetal hemoglobin (HbF%) in some, but not all, treated patients with SCD. HbF% greater than 8.6% has been shown to improve clinical outcomes in SCD. We show that OI associates with HbF% in 16 subjects with SCD. Subjects with higher HbF levels (HbF > 8.6%) displayed significantly lower OI (0.88% ± 0.10%, N = 6) compared with those with lower HbF levels (HbF ≤ 8.6%) who displayed greater OI (3.18% ± 0.34%, N = 10, p < 0.001). Moreover, hypoxic OcclusionChip assay revealed a significant correlation between hypoxic OI and subject-specific sickle hemoglobin (HbS) level in SCD. OcclusionChip enables versatile in vitro assessment of microvascular occlusion mediated by RBCs in a wide range of clinical conditions. OI may serve as a new parameter to evaluate the efficacy of treatments improving RBC deformability, including hemoglobin modifying drugs, anti-sickling agents, and genetic therapies.

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Characterization of red blood cell microcirculatory parameters using a bioimpedance microfluidic device.

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