Publications

The effects of cell size and deformability on the lateral migration and deformation of living cells flowing through a rectangular microchannel has been numerically investigated and compared with the experimental data on the inertial microfluidics-based approach for detection and separation of cells. The results of this work indicate that the cells move closer to the centerline if they are bigger and/or more deformable and that their equilibrium position is largely determined by the solvent (cytosol) viscosity, which is much less than the polymer (cytoskeleton) viscosity measured in most rheological systems. Simulations also suggest that decreasing channel dimensions leads to larger differences in equilibrium position for particles of different viscoelastic properties, giving design guidance for the next generation of microfluidic cellseparation chips.

The endovascular treatment of intracranial aneurysms remains a challenge, especially when the aneurysm is large in size and has irregular, non-spherical geometry. In this paper, we use computational fluid dynamics to simulate blood flow in a vertebro-basilar junction giant aneurysm for the following three cases: 1) an empty aneurysm, 2) an aneurysm filled with platinum coils, and 3) an aneurysm filled with a yield stress fluid material. In the computational model, blood and the coil-filled region are treated as a non-Newtonian fluid and an isotropic porous medium, respectively. The results show that yield stress fluids can be used for aneurysm embolization provided the yield stress value is 20 Pa or higher. Specifically, flow recirculation in the aneurysm and the size of the inflow jet impingement zone on the aneurysm wall are substantially reduced by yield stress fluid treatment. Overall, this study opens up the possibility of using yield stress fluids for effective embolization of large-volume intracranial aneurysms.

Multicellular tumor spheroids are widely used as in vitro models for testing of anticancer drugs. The advantage of this approach is that it can predict the outcome of a drug treatment on human cancer cells in their natural three-dimensional environment without putting actual patients at risk. Several methods were utilized in the past to grow submillimeter-size tumor spheroids. However, these small models are not very useful for preclinical studies of tumor ablation where the goal is the complete destruction of tumors that can reach several centimeters in diameter in the human body. Here, we propose a PDMS well method for large tumor spheroid culture. Our experiments with HepG2 hepatic cancer cells show that three-dimensional aggregates of tumor cells with a volume as large as 40 mm³ can be grown in cylindrical PDMS wells after the initial culture of tumor cells by the hanging drop method. This is a 320 times more than the maximum volume of tumor spheroids formed inside hanging drops (0.125 mm³).

Cavitation activity and temperature rise have been investigated in a tissue-mimicking material and excised bovine liver treated with ethanol and insonated with a 0.825 MHz focused acoustic transducer. The acoustic power was varied from 1.3 W to 26.8 W to find the threshold leading to the onset of inertial cavitation. Cavitation events were quantified by three independent techniques: B-mode ultrasound imaging, needle hydrophone measurements, and passive cavitation detection. Temperature in or near the focal zone was measured by thermocouples embedded in the samples. The results of this study indicate that the treatment of tissue phantoms and bovine liver samples with ethanol reduces their threshold power for inertial cavitation. This in turn leads to a sudden rise in temperature in ethanol-treated samples at a lower acoustic power than that in untreated ones. The analysis of passive cavitation detection data shows that once the threshold acoustic power is reached, inertial cavitation becomes a major contributor to acoustic scattering in ethanol-treated phantoms and bovine liver samples as compared to control. This study opens up the possibility of improved tumour ablation therapy via a combination of percutaneous ethanol injection and high-intensity focused ultrasound.

There is a need for accurate yield stress measurements, especially in the case of low yield stress complex materials such as biological samples. This task cannot be accomplished with conventional rotational rheometers due to significant wall slip effects and the necessity to operate the device at very low shear rates, often beyond the limit that such rheometers can achieve. In this paper, we focus on the slotted plate method proposed recently for low yield stress measurements. Using computational fluid dynamics, we study the effects of plate geometry on the measurement accuracy of the slotted plate method. Results of this study indicate that both wall slip effects and pressure drag force can be substantially reduced by adopting a thin plate with sharp front and rear edges, high slot area ratio, and large number of slots. If the plate has 30 degree triangular edges, a slot area ratio of 80%, and 12 slots, the slotted plate method overpredicts the yield stress of a 0.09 wt.% Carbopol dispersion (yield stress of 9.17 Pa) by only 8.4% under no slip conditions and underpredicts the yield stress by 12.3% under free slip conditions. Similar results were obtained for human saliva characterized by a very low yield stress (0.073 Pa).

When deformable particles (e.g., drops or living cells) are perfused through a flow channel, they drift into a specific lateral position that depends on their size and mechanical properties. This characteristic can be used for deformability-based particle sorting. Using a fully three-dimensional algorithm for viscoelastic drop dynamics, we study numerically the effects of particle size, bulk shear viscosity and elasticity, interfacial (or cortical) tension, and fluid inertia on lateral migration and deformation of small liquid drops and leukocytes (white blood cells) in a rectangular microfluidic flow chamber. Our numerical data show that there is an almost linear increase in the lateral equilibrium position of liquid drops or leukocytes with the particle diameter-to-channel height ratio increased from 0.1 to 0.5. Excluding the case of drops with high interfacial tension, an increase in bulk viscosity of these particles leads to a substantial decrease in their equilibrium position. Overall, the results of this work indicate that 1) drops with different bulk viscosities can be efficiently separated in a rectangular microchannel if their interfacial tension is low or the flow rate is sufficiently high; and 2) the microfluidic technology is well suited for the separation of leukocytes with different cytoplasmic viscosities and relaxation times, but it is much less sensitive to cortical tension. This investigation opens up the possibility of using microfluidic systems for deformability-based flow cytometry.

Rolling leukocytes deform and show a large area of contact with endothelium under physiological flow conditions. We studied the effect of cytoplasmic viscosity on leukocyte rolling using our novel three-dimensional numerical algorithm that treats leukocyte as a compound droplet in which the core phase (nucleus) and the shell phase (cytoplasm) are viscoelastic fluids. The algorithm includes the mechanical properties of the cell cortex by cortical tension and considers leukocyte microvilli that deform viscoelastically and form viscous tethers at supercritical force. Stochastic binding kinetics describes binding of adhesion molecules. The leukocyte cytoplasmic viscosity plays a critical role in leukocyte rolling on an adhesive substrate. High-viscosity cells are characterized by high mean rolling velocities, increased temporal fluctuations in the instantaneous velocity, and a high probability for detachment from the substrate. A decrease in the rolling velocity, drag and torque with the formation of a large, flat contact area in low-viscosity cells leads to a dramatic decrease in the bond force and stable rolling. Using values of viscosity consistent with step aspiration studies of human neutrophils (5 to 30 Pa·s), our computational model predicts the velocities and shape changes of rolling leukocytes as observed in vitro and in vivo.

In our previous report, we showed that a rheometer equipped with a double concentric cylinder geometry with slotted rotor could effectively reduce wall slip effects and thus it could be used as an alternative to a rheometer with a vane geometry in yield stress measurements. Here, we use three-dimensional CFD simulation to compare these two geometries for rheological measurements of power law and yield stress fluids. Our results indicate that the double concentric cylinder rheometer with slotted rotor (DCCR/SR) is able to accurately measure rheological properties of a wider spectrum of test fluids than a vane rheometer because of significant reduction of the end and secondary flow effects.

Fluid shear stress has been implicated as a regulator of sprouting angiogenesis. However, whether endothelial cells within capillary sprouts in vivo experience physiologically relevant shear stresses remains unclear. The objective of our study is to estimate the shear stress distribution along the length of a capillary sprout through computational modeling of blood flow in a blind ended channel branching off a host vessel. In this model, we use sprout geometries typical for rat mesenteric microvasculature and consider three types of boundary conditions: 1) non-permeable vessel wall, 2) uniformly permeable vessel wall, and 3) a non-permeable vessel wall with open slots (representative of endothelial clefts). Our numerical simulation predicts that for each boundary condition a local maximum shear stress (13.9, 8.9, and 13.3 dyne/cm2 respectively) occurs at the entrance of a 50 um long, 6 um diameter sprout branching at 90 degrees off of a 11 um diameter host vessel. The shear stress drops below 0.2 dyne/cm2, a threshold for endothelial cell activation, within 4.1 um of the entrance for the non-permeable wall case and 4.2 um for the uniformly permeable wall case. Shear stress magnitudes within the sprout are above 0.2 dyne/cm2 for longer sprout scenarios and peaked at 5.9 dyne/cm2 at endothelial cell clefts. These results provide a first estimate of relative fluid shear stress magnitudes along a capillary sprout and highlight the importance of investigating endothelial cell responses to flow conditions during angiogenesis in tumors and other altered microenvironments.

We present a Navier-Stokes/Oldroyd-B immersed boundary algorithm that captures the interaction of a flexible structure with a viscoelastic fluid. In particular, we study the effects of bulk viscoelasticity on freely decaying shape oscillations of an Oldroyd-B fluid droplet suspended in an Oldroyd-B matrix. Our numerical data indicate that if the fluid viscosity is low, viscoelasticity plays a modulating role in the drop shape relaxation; specifically, it increases the oscillation frequency and decreases the decay rate when the fluid relaxation time is above a critical value. In the high-viscosity limit, i.e., when a Newtonian droplet is expected to return to a spherical shape with an aperiodic decay, an increase in the relaxation time eventually results in the reappearance of the oscillations. Both these results are in line with the prediction of small deformation theory for viscoelastic droplet oscillations. The algorithm was also validated by direct comparison with linear asymptotics.