Biomechanical properties of red blood cells in health and disease towards microfluidics

Abstract

Red blood cells (RBCs) possess a unique capacity for undergoing cellular deformation to navigate across various human microcirculation vessels, enabling them to pass through capillaries that are smaller than their diameter and to carry out their role as gas carriers between blood and tissues. Since there is growing evidence that red blood cell deformability is impaired in some pathological conditions, measurement of RBC deformability has been the focus of numerous studies over the past decades. Nevertheless, reports on healthy and pathological RBCs are currently limited and, in many cases, are not expressed in terms of well-defined cell membrane parameters such as elasticity and viscosity. Hence, it is often difficult to integrate these results into the basic understanding of RBC behaviour, as well as into clinical applications. The aim of this review is to summarize currently available reports on RBC deformability and to highlight its association with various human diseases such as hereditary disorders (e.g., spherocytosis, elliptocytosis, ovalocytosis, and stomatocytosis), metabolic disorders (e.g., diabetes, hypercholesterolemia, obesity), adenosine triphosphate-induced membrane changes, oxidative stress, and paroxysmal nocturnal hemoglobinuria. Microfluidic techniques have been identified as the key to develop state-of-the-art dynamic experimental models for elucidating the significance of RBC membrane alterations in pathological conditions and the role that such alterations play in the microvasculature flow dynamics.

Figures

FIG. 1.

Scanning electron microscopy (SEM) micrographs of a typical healthy RBC (scale = 1 μm) (A) and of the RBC membrane, showing globular structure (scale = 100 nm) (B). Adapted from Ref. .

FIG. 2.

Overview of methods for characterizing the biomechanical properties of RBCs. (A) Aspiration of an RBC into a micropipette. (B) Topography of a healthy RBC by full-field laser interferometry. The scale bar is 2 μm, and the colorbar scales are in μm. Adapted from Ref. . (C) Three-dimensional (3D) topographical image of an RBC as measured by AFM. (D) The distribution of the magnitude of the acoustic velocity around a levitated cell (undeformed). The acoustic velocity magnitude is in m/s. Adapted from Ref. . (E) Optical tweezers stretch an RBC that was loaded using a force ranging from 0 to 340 pN. From left to right: experimental observations, computed contour maps of the constant maximum principal strain distribution and one half of the full 3D biconcave shape (simulations with the cytosol). Adapted from Ref. . (F) Microcapillary flow (diameter = 10 μm): RBC transient shape at start-up using the same experimental conditions. Flow is from left to right. Adapted from Ref. .

FIG. 3.

Microfluidic experimental studies of RBC flow using microcirculation-mimicking models. (A) RBC membrane elastic modulus and surface viscosity are measured by using a converging-diverging geometry. Adapted from Ref. and Reproduced by permission of The Royal Society of Chemistry. (B1) Low- and (B2) high-magnification images of deformed erythrocytes in glass microchannels. Adapted from Ref. . (C) Flowing of RBCs in channels of different widths. (D1) Schematic diagram of a chamber unit for RBC deformability measurement (SiCMA chip), and (D2) Fabricated SiCMA chip with an enlarged view of the chamber array.

FIG. 4.

Techniques used to measure a specific RBC biomechanical property.

FIG. 5.

Microscopy imaging of RBCs (top panel) and ektacytometry curves, in which grey and black lines pertain to control and patient cells, respectively (bottom panel), for: (A) Hereditary spherocytosis. Black arrows indicate the typical spherocytic shape, red arrows indicate acanthocytes (RBCs with spiked membranes), and blue arrows indicate basophilic red cell due to the anemic state; (B) elliptocytic (red arrows) and ovalocytic red cells (blue arrows); (C) stomatocytic red cells (black arrows). Adapted from Ref. .

FIG. 6.

SEM images of diabetic RBCs: (A) RBC showing lengthened ultrastructure; (C) RBC showing smooth membrane (Scale = 1 μm). Adapted from Ref. .

FIG. 7.

SEM images of cholesterol-enriched RBCs. Adapted from Ref. .