Red Blood Cell Passage through Narrow Capillaries: Sensitivity to Stiffness and Shape
Document TypePhD thesis
Access StatusOpen Access
© 2020 Arman Namvar
Red blood cells (RBCs) squeeze through narrow capillaries as they transport oxygen to tissues and carbon dioxide to the lungs. The deformability of RBCs has been shown to depend on the viscoelasticity of the cell membrane and cytoplasm as well as the surface area to volume ratio (SA:V ratio) of the cell. In certain pathological diseases such as malaria, RBCs undergo restructuring of the membrane structure and modifications to the cell shape, which significantly reduce their deformability. Nonetheless, it is still unclear which factor has the greatest impact on the passage of RBCs through small capillaries. Here, we present a systematic analysis designed to identify the individual contributions of cell stiffness and SA:V ratio to the ability of RBCs to traverse narrow capillaries in a microfluidic device. We modified cellular rigidity using glutaraldehyde fixation, changed SA:V ratio by altering the buffer osmolarity and probed RBCs passage through microchannels. Our results showed that dramatic stiffening (~8 fold) had little effect (~6% retardation) on the ability of RBCs of the same geometry to traverse the channels. On the other hand, a moderate decrease (~13%) in the SA:V ratio affected the traversal of RBCs of similar stiffness more markedly (~19% decrease). We further studied RBCs infected by two different species of malaria parasites known to affect humans, Plasmodium falciparum and knowlesi. We found that P. falciparum rigidified the host RBC, but infected RBCs penetrated into microchannels with similar efficiency to uninfected RBCs. By contrast, P. knowlesi reduced the SA:V ratio of the host RBC resulting in restricted passage. We found that the earliest stage immature RBCs (reticulocytes) exhibited a similar SA:V ratio to mature RBCs and, despite being 30% larger, travelled into microchannels as efficiently as mature cells. Our finite element (FE) model provides a coherent rationale for our experimental observations, indicating that cell stiffness changes do not significantly affect RBC traversal in small capillaries due to the highly nonlinear mechanical behaviour of the cell membrane. Our numerical simulations predict that RBCs with low SA:V ratios are more prone to trapping in small capillaries (within the physiological size range) than RBCs with high membrane stiffness. Therefore, therapies targetting surface area to volume ratio of RBCs may be more effective than those that target cell stiffness.
KeywordsRed blood cell; Cell mechanics; Cell stiffness; Cell shape; Microfluidics; Computational modelling; Malaria; Plasmodium falciparum; Plasmodium knowlesi; Reticulocyte
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