Normalization of Blood Viscosity According to the Hematocrit and the Shear Rate

C. Trejo-Soto, A. Hernandez-Machado

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In this article, we describe the general features of red blood cell membranes and their effect on blood flow and blood rheology. We first present a basic description of membranes and move forward to red blood cell membranes’ characteristics and modeling. We later review the specific properties of red blood cells, presenting recent numerical and experimental microfluidics studies that elucidate the effect of the elastic properties of the red blood cell membrane on blood flow and hemorheology. Finally, we describe specific hemorheological pathologies directly related to the mechanical properties of red blood cells and their effect on microcirculation, reviewing microfluidic applications for the diagnosis and treatment of these diseases.

Microfluidics approach to the mechanical properties of red blood cell membrane and their effect on blood rheology

C.Trejo-Soto, G.R. Lazaro, I. Pagonabarraga, A. Hernandez-Machado

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In this article, we describe the general features of red blood cell membranes and their effect on blood flow and blood rheology. We first present a basic description of membranes and move forward to red blood cell membranes’ characteristics and modeling. We later review the specific properties of red blood cells, presenting recent numerical and experimental microfluidics studies that elucidate the effect of the elastic properties of the red blood cell membrane on blood flow and hemorheology. Finally, we describe specific hemorheological pathologies directly related to the mechanical properties of red blood cells and their effect on microcirculation, reviewing microfluidic applications for the diagnosis and treatment of these diseases.

Membrane rigidity regulates E. coli proliferation rates

S. Salinas-Almaguer, M. Mell, V.G. Almenro-Vedia, M. Calero, K.V. M. Robledo-Sanchez, J.C. Ruiz-Suarez, T. Alarcon, R. A. Barrio, A. Hernández-Machado, F. Monroy

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Combining single cell experiments, population dynamics and theoretical methods of membrane mechanics, we put forward that the rate of cell proliferation in E. coli colonies can be regulated by modifiers of the mechanical properties of the bacterial membrane. Bacterial proliferation was modelled as mediated by cell division through a membrane constriction divisome based on FtsZ, a mechanically competent protein at elastic interaction against membrane rigidity. Using membrane fluctuation spectroscopy in the single cells, we revealed either membrane stiffening when considering hydrophobic long chain fatty substances, or membrane softening if short-chained hydrophilic molecules are used. Membrane stiffeners caused hindered growth under normal division in the microbial cultures, as expected for membrane rigidification. Membrane softeners, however, altered regular cell division causing persistent microbes that abnormally grow as long filamentous cells proliferating apparently faster. We invoke the concept of effective growth rate under the assumption of a heterogeneous population structure composed by distinguishable individuals with different FtsZ-content leading the possible forms of cell proliferation, from regular division in two normal daughters to continuous growing filamentation and budding. The results settle altogether into a master plot that captures a universal scaling between membrane rigidity and the divisional instability mediated by FtsZ at the onset of membrane constriction.

Blood rheological characterization of β-thalassemia trait and iron deficiency using front microrheometry

L.Mendez-Mora, M.Cabello-Fusares, J.Ferre-Torres, C.Riera-Llobet, E. Krishnevskaya, C.Trejo-Soto, S.Payan-Pernia, I.Hernandez Rodríguez, C.Morales Indiano, T. Alarcon, J.-Ll. Vives-Corrons, A.Hernandez-Machado

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The purpose of this work is to develop a hematocrit-independent method for the detection of beta-thalassemia trait (β-TT) and iron deficiency anemia (IDA), through the rheological characterization of whole blood samples from different donors. The results obtained herein are the basis for the development of a front microrheometry point-of-care device for the diagnosis and clinical follow-up of β-TT patients suffering hematological diseases and alterations in the morphology of the red blood cell (RBC). The viscosity is calculated as a function of the mean front velocity by detecting the sample fluid-air interface advancing through a microfluidic channel. Different viscosity curves are obtained for healthy donors, β-TT and IDA samples. A mathematical model is introduced to compare samples of distinct hematocrit, classifying the viscosity curve patterns with respect to the health condition of blood. The viscosity of the fluid at certain shear rate values varies depending on several RBC factors such as shape and size, hemoglobin (Hb) content, membrane rigidity and hematocrit concentration. Blood and plasma from healthy donors are used as reference. To validate their potential clinical value as a diagnostic tool, the viscosity results are compared to those obtained by the gold-standard method for RBC deformability evaluation, the Laser-Optical Rotational Red Cell Analyzer (LoRRCA).

Pitting of malaria parasites in microfluidic devices mimicking spleen interendothelial slits

A. Elizalde-Torrent, C. Trejo-Soto, L. Mendez-Mora, , M. Nicolau, O. Ezama, M. Gualdron-Lopez , C. Fernandez-Becerra, T. Alarcon, A. Hernandez-Machado, H.A. del Portillo

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The spleen is a hematopoietic organ that participates in cellular and humoral immunity. It also serves as a quality control mechanism for removing senescent and/or poorly deformable red blood cells (RBCs) from circulation. Pitting is a specialized process by which the spleen extracts particles, including malaria parasites, from within circulating RBCs during their passage through the interendothelial slits (IES) in the splenic cords. To study this physiological function in vitro, we have developed two microfluidic devices modeling the IES, according to the hypothesis that at a certain range of mechanical stress on the RBC, regulated through both slit size and blood flow, would force it undergo the pitting process without affecting the cell integrity. To prove its functionality in replicating pitting of malaria parasites, we have performed a characterization of P. falciparum-infected RBCs (P.f.-RBCs) after their passage through the devices, determining hemolysis and the proportion of once-infected RBCs (O-iRBCs), defined by the presence of a parasite antigen and absence of DAPI staining of parasite DNA using a flow cytometry-based approach. The passage of P.f.-RBCs through the devices at the physiological flow rate did not affect cell integrity and resulted in an increase of the frequency of O-iRBCs. Both microfluidic device models were capable to replicate the pitting of P.f.-RBCs ex vivo by means of mechanical constraints without cellular involvement, shedding new insights on the role of the spleen in the pathophysiology of malaria.

Red blood cell in low Reynolds number flow: a vorticity-based characterization of shapes in two dimensions

A.F. Gallen,M. Castro, A. Hernandez-Machado

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Studies on the mechanical properties of red blood cells improve the diagnosis of some blood-related diseases. Some existing numerical methods have successfully simulated the coupling between a fluid and red blood cells. This paper introduces an alternative phase-field model formulation of two-dimensional cells that solves the vorticity and stream function that simplifies the numerical implementation. We integrate red blood cell dynamics immersed in a Poiseuille flow and reproduce previously reported morphologies (slippers or parachutes). In the case of flow in a very wide channel, we discover a new metastable shape referred to as ‘anti-parachute’ that evolves into a horizontal slipper centered on the channel. This sort of metastable morphology may contribute to the dynamical response of the blood.

Microrheometer for Biofluidic Analysis: Electronic Detection of the Fluid-Front Advancement

Lourdes Méndez Mora, Maria Cabello Fusarés, Josep Ferré Torres, Carla Riera Llobet, Samantha López, Claudia Trejo Soto, Tomas Alarcón & Aurora Hernández-Machado

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The motivation for this study was to develop a microdevice for the precise rheological characterization of biofluids, especially blood. The method presented was based on the principles of rheometry and fluid mechanics at the microscale. Traditional rheometers require a considerable amount of space, are expensive, and require a large volume of sample. A mathematical model was developed that, combined with a proper experimental model, allowed us to characterize the viscosity of Newtonian and non?Newtonian fluids at different shear rates. The technology presented here is the basis of a point?of?care device capable of describing the nonlinear rheology of biofluids by the fluid/air interface front velocity characterization through a microchannel. The proposed microrheometer uses a small amount of sample to deliver fast and accurate results, without needing a large laboratory space. Blood samples from healthy donors at distinct hematocrit percentages were the non?Newtonian fluid selected for the study. Water and plasma were employed as testing Newtonian fluids for validation of the system. The viscosity results obtained for the Newtonian and non?Newtonian fluids were consistent with pertinent studies cited in this paper. In addition, the results achieved using the proposed method allowed distinguishing between blood samples with different characteristics.

Dipole–dipole interactions control the interfacial rheological response of cyclodextrin/ surfactant solutions

J. Roberto Romero-Arias, Alberto S. Luviano, Miguel Costas, Aurora Hernández-Machado & Rafael A. Barrio

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Recent surface rheological study has shown that aqueous solutions of a-cyclodextrin (aCD) with anionic surfactants (S) display a remarkable viscoelasticity at the liquid/air interface, which has not been observed in similar systems. The dilatational modulus is various orders of magnitude larger than those for the binary mixtures aCD + water and S + water. The rheological response has been qualitatively related to the bulk distribution of species, the 2 : 1 inclusion complexes (aCD2 : S) playing a fundamental role. In this work, we have developed a model that considers dipole–dipole interactions between 2 : 1 inclusion complexes ordered on the liquid/air interface. When the model is applied to the specific experimental conditions, the dependencies on concentration and temperature of the dilatational modulus and the surface tension were found to be in excellent agreement with the data, indicating clearly that dipole–dipole interactions determine and control the rheological behavior of the interface.

On Gaussian curvature and membrane fission

Mara Denisse Rueda-Contreras, Andreu F. Gallen, J. Roberto Romero-Arias, Aurora Hernandez-Machado & Rafael A. Barrio

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We propose a three-dimensional mathematical model to describe dynamical processes of membrane fission. The model is based on a phase field equation that includes the Gaussian curvature contribution to the bending energy. With the addition of the Gaussian curvature energy term numerical simulations agree with the predictions that tubular shapes can break down into multiple vesicles. A dispersion relation obtained with linear analysis predicts the wavelength of the instability and the number of formed vesicles. Finally, a membrane shape diagram is obtained for the different Gaussian and bending modulus, showing different shape regimes.

An integrated detection method for flow viscosity measurements in microdevices

Angeles Ivon Rodriguez-Villarreal, Laura Ortega Taña, Joan Cid, Aurora Hernández-Machado, Tomas Alarcon, Pere Miribel-Catala, Jordi Colomer-Farrarons

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Point-of-care devices can analyze or characterize a sample in a short time. New technologies in medical science seek integrations of different measurement techniques for a complete analysis. This study describes the fabrication method, tests, and results of microtechnology as an approach for an integrated rheometer. The portable device measured the average flow velocity to calculate its viscosity. The whole system encompasses a microdevice integrated to a data acquisition system powered by USB and controlled by full custom software. As a result, we obtained an easy-to-handle and fabricate hand-held microrheometer. The device was tested using Newtonian fluids such as Mili-Q water, an aqueous solution of Ethyleneglycol at 40% and 25% and Non-Newtonian blood samples. The whole device can provide the non-linear viscosity of a 0.08 ml blood sample in less than 30 seconds, in a wide range of shear rate with an accuracy of 93%. More importantly, due to its detection method and simplicity, it can be enclosed within almost any fluidic microsystem, including biomedical applications.