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The present work focuses on the in-silico investigation of the steady-state blood flow in straight microtubes, incorporating advanced constitutive modeling for human blood and blood plasma. The blood constitutive model accounts for the interplay between thixotropy and elasto-visco-plasticity via a scalar variable that describes the level of the local blood structure at any instance. The constitutive model is enhanced by the non-Newtonian modeling of the plasma phase, which features bulk viscoelasticity. Incorporating microcirculation phenomena such as the cell-free layer (CFL) formation or the Fåhraeus and the Fåhraeus-Lindqvist effects is an indispensable part of the blood flow investigation. The coupling between them and the momentum balance is achieved through correlations based on experimental observations. Notably, we propose a new simplified form for the dependence of the apparent viscosity on the hematocrit that predicts the CFL thickness correctly. Our investigation focuses on the impact of the microtube diameter and the pressure-gradient on velocity profiles, normal and shear viscoelastic stresses, and thixotropic properties. We demonstrate the microstructural configuration of blood in steady-state conditions, revealing that blood is highly aggregated in narrow tubes, promoting a flat velocity profile. Additionally, the proper accounting of the CFL thickness shows that for narrow microtubes, the reduction of discharged hematocrit is significant, which in some cases is up to 70%. At high pressure-gradients, the plasmatic proteins in both regions are extended in the flow direction, developing large axial normal stresses, which are more significant in the core region. We also provide normal stress predictions at both the blood/plasma interface (INS) and the tube wall (WNS), which are difficult to measure experimentally. Both decrease with the tube radius; however, they exhibit significant differences in magnitude and type of variation. INS varies linearly from 4.5 to 2 Pa, while WNS exhibits an exponential decrease taking values from 50 mPa to zero.

This work focuses on the advanced modeling of the thixotropic nature of blood, coupled with an elasto-visco-plastic formulation by invoking a consistent and validated model for TEVP materials. The proposed model has been verified for the adequate description of the rheological behavior of suspensions, introducing a scalar variable that describes dynamically the level of internal microstructure of rouleaux at any instance, capturing accurately the aggregation and disaggregation mechanisms of the RBCs. Also, a non-linear fitting is adopted for the definition of the model’s parameters on limited available experimental data of steady and transient rheometric flows of blood samples. We present the predictability of the new model in various steady and transient rheometric flows, including startup shear, rectangular shear steps, shear cessation, triangular shear steps and LAOS tests. Our model provides predictions for the elasto-thixotropic mechanism in startup shear flows, demonstrating a non-monotonic relationship of the thixotropic index on the shear-rate. The intermittent shear step test reveals the dynamics of the structural reconstruction, which in turn is associated with the aggregation process. Moreover, our model offers robust predictions for less examined tests such as uniaxial elongation, in which normal stress was found to have considerable contribution. Apart from the integrated modeling of blood rheological complexity, our implementation is adequate for multi-dimensional simulations due to its tensorial formalism accomplished with a single time scale for the thixotropic effects, resulting in a low computational cost compared to other TEVP models.

We study the steady hemodynamics in physiological elastic microvessels proposing an advanced fluid–structure interaction model. The arteriolar tissue is modeled as a two-layer fiber-reinforced hyperelastic material representing its Media and Adventitia layers. The constitutive model employed (Holzapfel et al. in J Elast 61:1–48, 2000) is parametrized via available data on stress–strain experiments for arterioles. The model is completed by simulating the blood/plasma flow in the lumen, using the thixotropic elasto-viscoplastic model in its core, and the linear Phan-Thien and Tanner viscoelastic model in its annular part. The Cell-Free Layer (CFL) and the Fåhraeus and Fåhraeus-Lindqvist effects are considered via analytical expressions based on experimental data (Giannokostas et al. in Materials (Basel) 14:367, 2021b). The coupling between tissue deformation and blood flow is achieved through the experimentally verified pressure-shear hypothesis (Pries et al. Circ Res 77:1017–1023, 1995). Our calculations confirm that the increase in the reference inner radius produces larger expansion. Also, by increasing the intraluminal pressure, the thinning of the walls is more pronounced and it may reach 40% of the initial thickness. Comparing our predictions with those in rigid-wall microtubes, we conclude that apart from the vital importance of vasodilation, there is an up to 25% reduction in wall shear stress. The passive vasodilation contributes to the decrease in the tissue stress fields and affects the hemodynamic features such as the CFL thickness, reducing the plasma layer when blood flows in vessels with elastic walls, in quantitative agreement with previous experiments. Our calculations verify the correctness of the pressure-shear hypothesis but not that of the Laplace law.

Background: Blood viscoelasticity and plasma protein levels can play an important role in the diagnosis and prognosis of cancer. However, the role of histones and DNA in modulating blood clot properties remains to be investigated. This study investigates the differences in blood viscoelasticity and plasma protein levels among cancer patients, individuals with other diseases, and healthy individuals. Methods: Blood samples were collected from 101 participants, including 45 cancer patients, 22 healthy individuals, and 34 individuals with other diseases. Rheological properties of clots formed in vitro by reconstituted elements of fibrinogen or plasma were analyzed with an Anton Paar Rheometer, USA. Plasma protein levels of D-dimer, TPA, EPCR, fibrinogen, and histone H3 were measured through ELISA. Blood clots were formed with or without DNA and histones (H3) by adding thrombin and calcium to plasma samples, and were evaluated for viscoelasticity, permeability, and degradation. Results: Cancer patients show higher blood viscoelasticity and plasma D-dimer levels compared to healthy individuals and individuals with other diseases. Our in vitro analysis showed that the addition of histone to the plasma results in a significant decrease in viscoelasticity and mean fiber thickness of the clot formed thereafter. In parallel studies, using plasma from patients, DNA and histones were detected in fibrin clots and were associated with less degradation by t-PA. Moreover, our results show that the presence of DNA and histones not only increases clots’ permeability, but also makes them more prone to degradation. Conclusions: Plasma histones and DNA affect the structure of the clot formed and induce defective fibrinolysis. Moreover, the increased viscoelastic properties of plasma from cancer patients can be used as potential biomarkers in cancer prognosis.

The biomechanical properties of blood have been used to detect haematological diseases and disorders. The simultaneous measurement of multiple haemorheological properties has been considered an important aspect for separating the individual contributions of red blood cells (RBCs) and plasma. In this study, three haemorheological properties (viscosity, time constant, and RBC aggregation) were obtained by analysing blood flow, which was set to a square-wave profile (steady and transient flow). Based on a simplified differential equation derived using a discrete circuit model, the time constant for viscoelasticity was obtained by solving the governing equation rather than using the curve-fitting technique. The time constant (λ) varies linearly with respect to the interface in the coflowing channel (β). Two parameters (i.e., average value: <λ>, linear slope: dλdβ) were newly suggested to effectively represent linearly varying time constant. <λ> exhibited more consistent results than dλdβ. To detect variations in the haematocrit in blood, we observed that the blood viscosity (i.e., steady flow) is better than the time constant (i.e., transient flow). The blood viscosity and time constant exhibited significant differences for the hardened RBCs. The present method was then successfully employed to detect continuously varying haematocrit resulting from RBC sedimentation in a driving syringe. The present method can consistently detect variations in blood in terms of the three haemorheological properties.

The mechanical stability and deformability of erythrocytes are vital for their function as they traverse capillaries, where shear stress can reach up to 10 Pa under physiological conditions. Human serum albumin (HSA) is known to help maintain erythrocyte stability by influencing cell shape, membrane integrity, and resistance to hemolysis. However, the precise mechanisms by which albumin exerts these effects remain debated, with some studies indicating a stabilizing role and others suggesting the opposite. This review highlights that under high shear rates, albumin molecules may undergo unfolding due to normal stress differences. Such structural changes can significantly alter albumin’s interactions with the erythrocyte membrane, thereby affecting cell mechanical stability. We discuss two potential scenarios explaining how albumin influences erythrocyte mechanics under shear stress, considering both the viscoelastic properties of blood and those of the erythrocyte membrane. Based on theoretical analyses and experimental evidence from the literature, we propose that albumin’s effect on erythrocyte mechanical stability depends on (i) the transition between unfolded and folded states of the protein and (ii) the impact of shear stress on the erythrocyte membrane’s ζ-potential. Understanding these factors is essential for elucidating the complex relationship between albumin and erythrocyte mechanics in physiological and pathological conditions.

As rheological properties are substantially influenced by red blood cells (RBCs) and plasma, the separation of their individual contributions in blood is essential. The estimation of multiple rheological factors is a critical issue for effective early detection of diseases. In this study, three rheological properties (i.e., viscoelasticity, RBC aggregation, and blood junction pressure) are measured by analyzing the blood velocity and image intensity in a microfluidic device. Using a single syringe pump, the blood flow rate sets to a pulsatile flow pattern (Qb[t] = 1 + 0.5 sin(2πt/240) mL/h). Based on the discrete fluidic circuit model, the analytical formula of the time constant (λb) as viscoelasticity is derived and obtained at specific time intervals by analyzing the pulsatile blood velocity. To obtain RBC aggregation by reducing blood velocity substantially, an air compliance unit (ACU) is used to connect polyethylene tubing (i.d. = 250 µm, length = 150 mm) to the blood channel in parallel. The RBC aggregation index (AI) is obtained by analyzing the microscopic image intensity. The blood junction pressure (β) is obtained by integrating the blood velocity within the ACU. As a demonstration, the present method is then applied to detect either RBC-aggregated blood with different concentrations of dextran solution or hardened blood with thermally shocked RBCs. Thus, it can be concluded that the present method has the ability to consistently detect differences in diluent or RBCs in terms of three rheological properties.

Blood elasticity is quantified using a single compliance model by analyzing pulsatile blood flow. However, one compliance coefficient is influenced substantially by the microfluidic system (i.e., soft microfluidic channels and flexible tubing). The novelty of the present method comes from the assessment of two distinct compliance coefficients, one for the sample and one for the microfluidic system. With two compliance coefficients, the viscoelasticity measurement can be disentangled from the influence of the measurement device. In this study, a coflowing microfluidic channel was used to estimate blood viscoelasticity. Two compliance coefficients were suggested to denote the effects of the polydimethylsiloxane (PDMS) channel and flexible tubing (C1), as well as those of the RBC (red blood cell) elasticity (C2), in a microfluidic system. On the basis of the fluidic circuit modeling technique, a governing equation for the interface in the coflowing was derived, and its analytical solution was obtained by solving the second-order differential equation. Using the analytic solution, two compliance coefficients were obtained via a nonlinear curve fitting technique. According to the experimental results, C2/C1 is estimated to be approximately 10.9–20.4 with respect to channel depth (h = 4, 10, and 20 µm). The PDMS channel depth contributed simultaneously to the increase in the two compliance coefficients, whereas the outlet tubing caused a decrease in C1. The two compliance coefficients and blood viscosity varied substantially with respect to homogeneous hardened RBCs or heterogeneous hardened RBCs. In conclusion, the proposed method can be used to effectively detect changes in blood or microfluidic systems. In future studies, the present method can contribute to the detection of subpopulations of RBCs in the patient’s blood.

The determination of fibrinogen levels is one of the most important coagulation measurements in medicine. It plays a crucial part in diagnostic and therapeutic decisions, often associated with time-critical conditions. The commonly used measurement is the Clauss fibrinogen assay (CFA) where plasma is activated by thrombin reagent and which is conducted by mechanical/turbidimetric devices. As quartz crystal microbalance sensors with dissipation (QCM-D) based devices have a small footprint, can be operated easily and allow measurements independently from sample transportation time, laboratory location, availability and opening hours, they offer a great opportunity to complement laboratory CFA measurements. Therefore, the objective of the work was to (1) transfer the CFA to the QCM-D method; (2) develop an easy, time- and cost-effective procedure and (3) compare the results with references. Different sensor coatings (donor’s own plasma; gold surface) and different QCM-D parameters (frequency signal shift; its calculated turning point; dissipation signal shift) were sampled. The results demonstrate the suitability for a QCM-D-based CFA in physiological fibrinogen ranges. Results were obtained in less than 1 min and in very good agreement with a standardized reference (Merlin coagulometer). The results provide a good basis for further investigation and pave the way to a possible application of QCM-D in clinical and non-clinical routine in the medical field.

Air compliance has been used effectively to stabilize fluidic instability resulting from a syringe pump. It has also been employed to measure blood viscosity under constant shearing flows. However, due to a longer time delay, it is difficult to quantify the aggregation of red blood cells (RBCs) or blood viscoelasticity. To quantify the mechanical properties of blood samples (blood viscosity, RBC aggregation, and viscoelasticity) effectively, it is necessary to quantify contributions of air compliance to dynamic blood flows in microfluidic channels. In this study, the effect of air compliance on measurement of blood mechanical properties was experimentally quantified with respect to the air cavity in two driving syringes. Under periodic on–off blood flows, three mechanical properties of blood samples were sequentially obtained by quantifying microscopic image intensity () and interface (α) in a co-flowing channel. Based on a differential equation derived with a fluid circuit model, the time constant was obtained by analyzing the temporal variations of β = 1/(1–α). According to experimental results, the time constant significantly decreased by securing the air cavity in a reference fluid syringe (~0.1 mL). However, the time constant increased substantially by securing the air cavity in a blood sample syringe (~0.1 mL). Given that the air cavity in the blood sample syringe significantly contributed to delaying transient behaviors of blood flows, it hindered the quantification of RBC aggregation and blood viscoelasticity. In addition, it was impossible to obtain the viscosity and time constant when the blood flow rate was not available. Thus, to measure the three aforementioned mechanical properties of blood samples effectively, the air cavity in the blood sample syringe must be minimized (Vair, R = 0). Concerning the air cavity in the reference fluid syringe, it must be sufficiently secured about Vair, R = 0.1 mL for regulating fluidic instability because it does not affect dynamic blood flows.