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Dynamic deformability of sickle red blood cells in microphysiological flow.

ABSTRACT: In sickle cell disease (SCD), hemoglobin molecules polymerize intracellularly and lead to a cascade of events resulting in decreased deformability and increased adhesion of red blood cells (RBCs). Decreased deformability and increased adhesion of sickle RBCs lead to blood vessel occlusion (vaso-occlusion) in SCD patients. Here, we present a microfluidic approach integrated with a cell dimensioning algorithm to analyze dynamic deformability of adhered RBC at the single-cell level in controlled microphysiological flow. We measured and compared dynamic deformability and adhesion of healthy hemoglobin A (HbA) and homozygous sickle hemoglobin (HbS) containing RBCs in blood samples obtained from 24 subjects. We introduce a new parameter to assess deformability of RBCs: the dynamic deformability index (DDI), which is defined as the time-dependent change of the cell's aspect ratio in response to fluid flow shear stress. Our results show that DDI of HbS-containing RBCs were significantly lower compared to that of HbA-containing RBCs. Moreover, we observed subpopulations of HbS containing RBCs in terms of their dynamic deformability characteristics: deformable and non-deformable RBCs. Then, we tested blood samples from SCD patients and analyzed RBC adhesion and deformability at physiological and above physiological flow shear stresses. We observed significantly greater number of adhered non-deformable sickle RBCs than deformable sickle RBCs at flow shear stresses well above the physiological range, suggesting an interplay between dynamic deformability and increased adhesion of RBCs in vaso-occlusive events.

SUBMITTER: Alapan Y

PROVIDER: S-EPMC4947547 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Dynamic deformability of sickle red blood cells in microphysiological flow.

Alapan Y Y Matsuyama Y Y Little J A JA Gurkan U A UA

Technology 20160219 2

In sickle cell disease (SCD), hemoglobin molecules polymerize intracellularly and lead to a cascade of events resulting in decreased deformability and increased adhesion of red blood cells (RBCs). Decreased deformability and increased adhesion of sickle RBCs lead to blood vessel occlusion (vaso-occlusion) in SCD patients. Here, we present a microfluidic approach integrated with a cell dimensioning algorithm to analyze dynamic deformability of adhered RBC at the single-cell level in controlled mi ...[more]

PMID: 27437432

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Project description:In this work, we compared the dynamics of motion in a linear shear flow of individual red blood cells (RBCs) from healthy and pathological donors (Sickle Cell Disease (SCD) or Sickle Cell-β-thalassemia) and of low and high densities, in a suspending medium of higher viscosity. In these conditions, at lower shear rates, biconcave discocyte-shaped RBCs present an unsteady flip-flopping motion, where the cell axis of symmetry rotates in the shear plane, rocking to and fro between an orbital angle ±ϕ observed when the cell is on its edge. We show that the evolution of ϕ depends solely on RBC density for healthy RBCs, with denser RBCs displaying lower ϕ values than the lighter ones. Typically, at a shear stress of 0.08 Pa, ϕ has values of 82 and 72° for RBCs with average densities of 1.097 and 1.115, respectively. Surprisingly, we show that SCD RBCs display the same ϕ-evolution as healthy RBCs of same density, showing that the flip-flopping behavior is unaffected by the SCD pathology. When the shear stress is increased further (above 0.1 Pa), healthy RBCs start going through a transition to a fluid-like motion, called tank-treading, where the RBC has a quasi-constant orientation relatively to the flow and the membrane rotates around the center of mass of the cell. This transition occurs at higher shear stresses (above 0.2 Pa) for denser cells. This shift toward higher stresses is even more remarkable in the case of SCD RBCs, showing that the transition to the tank-treading regime is highly dependent on the SCD pathology. Indeed, at a shear stress of 0.2 Pa, for RBCs with a density of 1.097, 100% of healthy RBCs have transited to the tank-treading regime vs. less than 50% SCD RBCs. We correlate the observed differences in dynamics to the alterations of RBC mechanical properties with regard to density and SCD pathology reported in the literature. Our results suggest that it might be possible to develop simple non-invasive assays for diagnosis purpose based on the RBC motion in shear flow and relying on this millifluidic approach.

Project description:The loss of the red blood cells (RBCs) deformability is related with many human diseases, such as malaria, hereditary spherocytosis, sickle cell disease, or renal diseases. Hence, during the last years, a variety of technologies have been proposed to gain insights into the factors affecting the RBCs deformability and their possible direct association with several blood pathologies. In this work, we present a simple microfluidic tool that provides the assessment of motions and deformations of RBCs of end-stage kidney disease (ESKD) patients, under a well-controlled microenvironment. All of the flow studies were performed within a hyperbolic converging microchannels where single-cell deformability was assessed under a controlled homogeneous extensional flow field. By using a passive microfluidic device, RBCs passing through a hyperbolic-shaped contraction were measured by a high-speed video microscopy system, and the velocities and deformability ratios (DR) calculated. Blood samples from 27 individuals, including seven healthy controls and 20 having ESKD with or without diabetes, were analysed. The obtained data indicates that the proposed device is able to detect changes in DR of the RBCs, allowing for distinguishing the samples from the healthy controls and the patients. Overall, the deformability of ESKD patients with and without diabetes type II is lower in comparison with the RBCs from the healthy controls, with this difference being more evident for the group of ESKD patients with diabetes. RBCs from ESKD patients without diabetes elongate on average 8% less, within the hyperbolic contraction, as compared to healthy controls; whereas, RBCs from ESKD patients with diabetes elongate on average 14% less than the healthy controls. The proposed strategy can be easily transformed into a simple and inexpensive diagnostic microfluidic system to assess blood cells deformability due to the huge progress in image processing and high-speed microvisualization technology.

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Dynamic deformability of sickle red blood cells in microphysiological flow.

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Dynamic deformability of sickle red blood cells in microphysiological flow.

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