Search

We conducted a systematic numerical investigation of spherical, prolate and oblate particles in an inertial shear flow between two parallel walls, using smoothed particle hydrodynamics (SPH). It was previously shown that above a critical Reynolds number, spherical particles experience a supercritical pitchfork bifurcation of the equilibrium position in shear flow between two parallel walls, namely that the central equilibrium position becomes unstable, leading to the emergence of two new off-centre stable positions (Fox et al. , J. Fluid Mech. , vol. 915, 2021). This phenomenon was unexpected given the symmetry of the system. In addition to confirming this finding, we found, surprisingly, that ellipsoidal particles can also return to the centre position from the off-centre positions when the particle Reynolds number is further increased, while spherical particles become unstable under this increased Reynolds number. By utilizing both SPH and the finite element method for flow visualization, we explained the underlining mechanism of this reverse of bifurcation by altered streamwise vorticity and symmetry breaking of pressure. Furthermore, we expanded our investigation to include asymmetric particles, a novel aspect that had not been previously modelled, and we observed similar trends in particle dynamics for both symmetric and asymmetric ellipsoidal particles. While further validation through laboratory experiments is necessary, our research paves the road for development of new focusing and separation methods for shaped particles. [ABSTRACT FROM AUTHOR]

Soft objects squeezing through small apertures are crucial for many in vivo and in vitro processes. Red blood cell transit time through splenic inter-endothelial slits (IESs) plays a crucial role in blood filtration and disease progression, while droplet velocity through constrictions in microfluidic devices is important for effective manipulation and separation processes. As these transit phenomena are not well understood, we sought to establish analytical and numerical solutions of viscous droplet transit through a rectangular slit. This study extends from our former theory of a circular pore because a rectangular slit is more realistic in many physiological and engineering applications. Here, we derived the ordinary differential equations (ODEs) of a droplet passing through a slit by combining planar Poiseuille flow, the Young–Laplace equations, and modifying them to consider the lubrication layer between the droplet and the slit wall. Compared to the pore case, we used the Roscoe solution instead of the Sampson one to account for the flow entering and exiting a rectangular slit. When the surface tension and lubrication layer were negligible, we derived the closed-form solutions of transit time. When the surface tension and lubrication layer were finite, the ODEs were solved numerically to study the impact of various parameters on the transit time. With our solutions, we identified the impact of prescribed pressure drop, slit dimensions, and droplet parameters such as surface tension, viscosity, and volume on transit time. In addition, we also considered the effect of pressure drop and surface tension near critical values. For this study, critical surface tension for a given pressure drop describes the threshold droplet surface tension that prevents transit, and critical pressure for a given surface tension describes the threshold pressure drop that prevents transit. Our solutions demonstrate that there is a linear relationship between pressure and the reciprocal of the transit time (referred to as inverse transit time), as well as a linear relationship between viscosity and transit time. Additionally, when the droplet size increases with respect to the slit dimensions, there is a corresponding increase in transit time. Most notably, we emphasize the initial antagonistic effect of surface tension which resists droplet passage but at the same time decreases the lubrication layer, thus facilitating passage. Our results provide quantitative calculations for understanding cells passing through slit-like constrictions and designing droplet microfluidic experiments. [ABSTRACT FROM AUTHOR]

Microfluidic methods have proven to be effective in separation and isolation of cells for a wide range of biomedical applications. Among these methods, physical trapping is a label-free isolation approach that relies on cell size as the selective phenotype to retain target cells on-chip for follow-up analysis and imaging. In silico models have been used to optimize the design of such hydrodynamic traps and to investigate cancer cell transmigration through narrow constrictions. While most studies focus on computational fluid dynamics (CFD) analysis of flow over cells and/or pillar traps, a quantitative analysis of mechanical interaction between cells and trapping units is missing. The existing literature centers on longitudinally extended geometries (e.g., micro-vessels) to understand the biological phenomenon rather than designing an effective cell trap. In this work, we aim to make an experimentally informed prediction of the critical pressure for a cell to pass through a trapping unit as a function of cell morphology and trapping unit geometry. Our findings show that a hyperelastic material model accurately captures the stress-related softening behavior observed in cancer cells passing through micro-constrictions. These findings are used to develop a model capable of predicting and extrapolating critical pressure values. The validity of the model is assessed with experimental data. Regression analysis is used to derive a mathematical framework for critical pressure. Coupled with CFD analysis, one can use this formulation to design efficient microfluidic devices for cell trapping and potentially perform downstream analysis of trapped cells. [ABSTRACT FROM AUTHOR]

We derived equations and closed-form solutions of transit time for a viscous droplet squeezing through a small circular pore with a finite length at microscale under constant pressures. Our analyses were motivated by the vital processes of biological cells squeezing through small pores in blood vessels and sinusoids and droplets squeezing through pores in microfluidics. First, we derived ordinary differential equations (ODEs) of a droplet squeezing through a circular pore by combining Sampson flow, Poiseuille flow, and Young–Laplace equations and took into account the lubrication layer between the droplet and the pore wall. Second, for droplets wetting the wall with small surface tension, we derived the closed-form solutions of transit time. For droplets with finite surface tension, we solved the original ODEs numerically to predict the transit time. After validations against experiments and finite element simulations, we studied the effects of pressure, viscosity, pore/droplet dimensions, and surface tension on the transit time. We found that the transit time is inversely linearly proportional to pressure when the surface tension is low compared to the critical surface tension for preventing the droplet to pass and becomes nonlinear when it approaches the critical tension. Remarkably, we showed that when a fixed percentage of surface tension to critical tension is applied, the transit time is always inversely linearly proportional to pressure, and the dependence of transit time on surface tension is nonmonotonic. Our results provided a quick way of quantitative calculations of transit time for designing droplet microfluidics and understanding cells passing through constrictions. [ABSTRACT FROM AUTHOR]

Particle migration dynamics in viscoelastic fluids in spiral channels have attracted interest in recent years due to potential applications in the 3D focusing and label-free sorting of particles and cells. Despite a number of recent studies, the underlying mechanism of Dean-coupled elasto-inertial migration in spiral microchannels is not fully understood. In this work, for the first time, we experimentally demonstrate the evolution of particle focusing behavior along a channel downstream length at a high blockage ratio. We found that flow rate, device curvature, and medium viscosity play important roles in particle lateral migration. Our results illustrate the full focusing pattern along the downstream channel length, with side-view imaging yielding observations on the vertical migration of focused streams. Ultimately, we anticipate that these results will offer a useful guide for elasto-inertial microfluidics device design to improve the efficiency of 3D focusing in cell sorting and cytometry applications. [ABSTRACT FROM AUTHOR]

Nanoindentation probing on nacre obtained from Haliotis rufescens shells has demonstrated that nacre displays a combined viscoplastic-viscoelastic time dependent response. Additionally, it is found that the moisture/water content of nacre contributes to its time dependent behavior and overall mechanical properties. Detailed finite element simulations allow for the determination of constitutive parameters used to calibrate specific time dependent material models which are, in turn, compared to those found via independent measurement as reported in the literature. The results lead to a new paradigm for nacre’s attractive structural composite behavior and thereby to new potential pathways for biomimetics.

Various signals in tissue microenvironments are often unevenly distributed around cells. Cellular responses to asymmetric cell‐matrix adhesion in a 3D space remain generally unclear and are to be studied at the single‐cell resolution. Here, the authors developed a droplet‐based microfluidic approach to manufacture a pure population of single cells in a microscale layer of compartmentalized 3D hydrogel matrices with a tunable spatial presentation of ligands at the subcellular level. Cells elongate with an asymmetric presentation of the integrin adhesion ligand Arg‐Gly‐Asp (RGD), while cells expand isotropically with a symmetric presentation of RGD. Membrane tension is higher on the side of single cells interacting with RGD than on the side without RGD. Finite element analysis shows that a non‐uniform isotropic cell volume expansion model is sufficient to recapitulate the experimental results. At a longer timescale, asymmetric ligand presentation commits mesenchymal stem cells to the osteogenic lineage. Cdc42 is an essential mediator of cell polarization and lineage specification in response to asymmetric cell‐matrix adhesion. This study highlights the utility of precisely controlling 3D ligand presentation around single cells to direct cell polarity for regenerative engineering and medicine. [ABSTRACT FROM AUTHOR]

We verify both theoretically and by simulation that an AC electric field, with a frequency much higher than the dissociation rate, can significantly accelerate the dissociation rate of biological molecules under isothermal conditions. The cumulative effect of the AC field is shown to break a key bottleneck by reducing the entropy (and increasing the free energy of the local minimum) via the alignment of the molecular dipole with the field. For frequencies below a resonant frequency which corresponds to the inverse Debye dipole relaxation time, the dissociation rate can be accelerated by a factor that scales as ω ( ϵ ′ (ω) − 1) E 0 2 , where ω is the field frequency, E0 is the field amplitude, and ϵ′(ω) is the frequency-dependent real permittivity of the molecule. At large amplitudes, we find that the accelerated melting rate becomes universal, independent of duplex size and sequence, which is in drastic contrast to Ohmic thermal melting. We confirm our theory with isothermal all-atomic molecular dynamics simulation of short DNA duplexes with known melting rates, demonstrating several orders in enhancement with realistic fields. [ABSTRACT FROM AUTHOR]

Growth of the microfluidics field has triggered numerous advances in focusing and separating microparticles, with such systems rapidly finding applications in biomedical, chemical, and environmental fields. The use of shear-thinning viscoelastic fluids in microfluidic channels is leading to evolution of elasto-inertial focusing. Herein, we showed that the interplay between the elastic and shear-gradient lift forces, as well as the secondary flow transversal drag force that is caused by the non-zero second normal stress difference, lead to different particle focusing patterns in the elasto-inertial regime. Experiments and 3D simulations were performed to study the effects of flowrate, particle size, and the shear-thinning extent of the fluid on the focusing patterns. The Giesekus constitutive equation was used in the simulations to capture the shear-thinning and viscoelastic behaviors of the solution used in the experiments. At low flowrate, with Weissenberg number Wi ~ O(1), both the elastic force and secondary flow effects push particles towards the channel center. However, at a high flowrate, Wi ~ O(10), the elastic force direction is reversed in the central regions. This remarkable behavior of the elastic force, combined with the enhanced shear-gradient lift at the high flowrate, pushes particles away from the channel center. Additionally, a precise prediction of the focusing position can only be made when the shear-thinning extent of the fluid is correctly estimated in the modeling. The shear-thinning also gives rise to the unique behavior of the inertial forces near the channel walls which is linked with the 'warped' velocity profile in such fluids. [ABSTRACT FROM AUTHOR]

Inertial migration of spherical particles has been investigated extensively using experiments, theory, and computational modeling. Yet, a systematic investigation of the effect of particle shape on inertial migration is still lacking. Herein, we numerically mapped the migration dynamics of a prolate particle in a straight rectangular microchannel using smoothed particle hydrodynamics at moderate Reynolds number flows. After validation, we applied our model to 2:1 and 3:1 shape aspect ratio particles at multiple confinement ratios. Their effects on the final focusing position, rotational behavior, and transitional dynamics were studied. In addition to the commonly reported tumbling motion, for the first time, we identified a new logrolling behavior of a prolate ellipsoidal particle in the confined channel. This new behavior occurs when the confinement ratio is above an approximate threshold value of K = 0.72. Our microfluidic experiments using cell aggregates with similar shape aspect ratio and confinement ratio confirmed this new predicted logrolling motion. We also found that the same particle can undergo different rotational modes, including kayaking behavior, depending on its initial cross-sectional position and orientation. Furthermore, we examined the migration speed, angular velocity, and rotation period as well as their dependence on both particle shape aspect ratio and confinement ratio. Our findings are especially relevant to the applications where particle shape and alignment are used for sorting and analysis, such as the use of barcoded particles for biochemical assays through optical reading, or the shape-based enrichment of microalgae, bacteria, and chromosomes. [ABSTRACT FROM AUTHOR]

Red blood cells (RBCs) are cleared from the circulation when they become damaged or display aging signals targeted by macrophages. This process occurs mainly in the spleen, where blood flows through submicrometric constrictions called inter‐endothelial slits (IES), subjecting RBCs to large‐amplitude deformations. In this work, RBCs are circulated through microfluidic devices containing microchannels that replicate the IES. The cyclic mechanical stresses experienced by the cells affect their biophysical properties and molecular composition, accelerating cell aging. Specifically, RBCs quickly transition to a more spherical, less deformable phenotype that hinders microchannel passage, causing hemolysis. This transition is associated with the release of membrane vesicles, which self‐extinguishes as the spacing between membrane‐cytoskeleton linkers becomes tighter. Proteomics analysis of the mechanically aged RBCs reveals significant losses of essential proteins involved in antioxidant protection, gas transport, and cell metabolism. Finally, it is shown that these changes make mechanically aged RBCs more susceptible to macrophage phagocytosis. These results provide a comprehensive model explaining how physical stress induces RBC clearance in the spleen. The data also suggest new biomarkers of early "hemodamage" and inflammation preceding hemolysis in RBCs subjected to mechanical stress. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) PPE36, a cell-wall-associated protein, is highly specific and conserved for the Mtb complex group. Although PPE36 has been proven essential for iron utilization, little is known about it in regulating host immune responses. Here we exhibited that PPE36 was preferentially enriched in Mtb virulent strains and could efficiently inhibit host inflammatory responses and increase bacterial loads in infected macrophages and mice. In exploring the underlying mechanisms, we found that PPE36 could robustly inhibit the activation of inflammatory NF-κB and MAPK (Erk, p38, and Jnk) pathways by promoting E3 ligase Smurf1-mediated ubiquitination and proteasomal degradation of MyD88 protein. Our research revealed a previously unknown function of PPE36 on modulating host immune responses and provided some clues to the development of novel tuberculosis treatment strategies based on immune regulation. [ABSTRACT FROM AUTHOR]

Similar to global trends, the incidence rate of tuberculosis (TB) in China declined from 2000 to 2018. In this study, we aimed to evaluate TB trends in northern Guizhou Province and identify risk factors associated with rifampicin-resistant (RR) and concurrent extrapulmonary TB (EPTB). We analyzed data of TB patients hospitalized in Affiliated Hospital of Zunyi Medical University from 2011 to 2018, and assessed correlations between demographic characteristics of patients and RR-TB as well as concurrent EPTB. Our results showed that numbers of new, retreated, RR-TB and concurrent EPTB cases increased gradually from 2011 to 2018. Retreated patients had the highest odds of RR-TB but a lower likelihood of concurrent EPTB compared to new patients. Patients between 21 and 40 years of age had a higher likelihood of RR-TB compared to those 20 years and younger. Female patients and patients from Bijie city as well as the Miao ethnic minority had higher odds of concurrent EPTB. In summary, our data demonstrate upward trends in new, rifampicin-resistant and concurrent extrapulmonary TB cases in northern Guizhou Province of China, which should not be overlooked especially during and post the COVID-19 pandemic because TB is a greater long-term global health threat than COVID-19. [ABSTRACT FROM AUTHOR]

Advances in engineered hydrogels reveal how cells sense and respond to 3D biophysical cues. However, most studies rely on interfacing a population of cells in a tissue‐scale bulk hydrogel, an approach that overlooks the heterogeneity of local matrix deposition around individual cells. A droplet microfluidic technique to deposit a defined amount of 3D hydrogel matrices around single cells independently of material composition, elasticity, and stress relaxation times is developed. Mesenchymal stem cells (MSCs) undergo isotropic volume expansion more rapidly in thinner gels that present an Arg‐Gly‐Asp integrin ligand. Mathematical modeling and experiments show that MSCs experience higher membrane tension as they expand in thinner gels. Furthermore, thinner gels facilitate osteogenic differentiation of MSCs. By modulating ion channels, it is shown that isotropic volume expansion of single cells predicts intracellular tension and stem cell fate. The results suggest the utility of precise microscale gel deposition to control single cell functions. [ABSTRACT FROM AUTHOR]

We developed a boundary integral formulation to simulate a red blood cell (RBC) squeezing through a submicron slit under prescribed inlet and outlet pressures. The main application of this computational study is to investigate splenic filtrations of RBCs and the corresponding in vitro mimicking microfluidic devices, during which RBCs regularly pass through inter-endothelial slits with a width less than 1.0 µm. The diseased and old RBCs are damaged or destroyed in this mechanical filtration process. We first derived the boundary integral equations of a RBC immersed in a confined domain with prescribed inlet and outlet pressures. We applied a unified self-adaptive quadrature to accurately evaluate singular and nearly singular integrals, which are especially important in this fluid-structure interaction problem with strong lubrication. A multiscale model is applied to calculate forces from the RBC membrane, and it is coupled to boundary integral equations to simulate the fluid-structure interaction. After multi-step verifications and validations against analytical and experimental results, we systematically investigated the effects of pressure drop, volume-to-surface-area ratio, internal viscosity, and membrane stiffness on RBC deformation and internal stress. We found that spectrins of RBCs could be stretched by more than 2.5 times under high hydrodynamic pressure and that the bilayer tension could be more than 500 pN/μm, which might be large enough to open mechanosensitive channels but too small to rupture the bilayer. On the other hand, we found that the bilayer-cytoskeletal dissociation stress is too low to induce bilayer vesiculation. [ABSTRACT FROM AUTHOR]

Gametocyte maturation in Plasmodium falciparum is a critical step in the transmission of malaria. While the majority of parasites proliferate asexually in red blood cells, a small fraction of parasites undergo sexual conversion and mature over 2 weeks to become competent for transmission to a mosquito vector. Immature gametocytes sequester in deep tissues while mature stages must be able to circulate, pass the spleen and present themselves to the mosquito vector in order to complete transmission. Sequestration of asexual red blood cell stage parasites has been investigated in great detail. These studies have demonstrated that induction of cytoadherence properties through specific receptor-ligand interactions coincides with a significant increase in host cell stiffness. In contrast, the adherence and biophysical properties of gametocyte-infected red blood cells have not been studied systematically. Utilizing a transgenic line for 3D live imaging, in vitro capillary assays and 3D finite element whole cell modelling, we studied the role of cellular deformability in determining the circulatory characteristics of gametocytes. Our analysis shows that the red blood cell deformability of immature gametocytes displays an overall decrease followed by rapid restoration in mature gametocytes. Intriguingly, simulations suggest that along with deformability variations, the morphological changes of the parasite may play an important role in tissue distribution in vivo. Taken together, we present a model, which suggests that mature but not immature gametocytes circulate in the peripheral blood for uptake in the mosquito blood meal and transmission to another human host thus ensuring long-term survival of the parasite. [ABSTRACT FROM AUTHOR]