Modeling the Mechanosensitivity of Neutrophils Passing through a Narrow Channel.

Recent experiments have found that neutrophils may be activated after passing through microfluidic channels and filters. Mechanical deformation causes disassembly of the cytoskeleton and a sudden drop of the elastic modulus of the neutrophil. This fluidization is followed by either activation of the neutrophil with protrusion of pseudopods or a uniform recovery of the cytoskeleton network with no pseudopod. The former occurs if the neutrophil traverses the narrow channel at a slower rate. We propose a chemo-mechanical model for the fluidization and activation processes. Fluidization is treated as mechanical destruction of the cytoskeleton by sufficiently rapid bending. Loss of the cytoskeleton removes a pathway by which cortical tension inhibits the Rac protein. As a result, Rac rises and polarizes through a wave-pinning mechanism if the chemical reaction rate is fast enough. This leads to recovery and reinforcement of the cytoskeleton at the front of the neutrophil, and hence protrusion and activation. Otherwise the Rac signal returns to a uniform pre-deformation state and no activation occurs. Thus, mechanically induced neutrophil activation is understood as the competition between two timescales: that of chemical reaction and that of mechanical deformation. The model captures the main features of the experimental observation.

A biomechanical model for fluidization of cells under dynamic strain.

Recent experiments have investigated the response of smooth muscle cells to transient stretch-compress (SC) and compress-stretch (CS) maneuvers. The results indicate that the transient SC maneuver causes a sudden fluidization of the cell while the CS maneuver does not. To understand this asymmetric behavior, we have built a biomechanical model to probe the response of stress fibers to the two maneuvers. The model couples the cross-bridge cycle of myosin motors with a viscoelastic Kelvin-Voigt element that represents the stress fiber. Simulation results point to the sensitivity of the myosin detachment rate to tension as the cause for the asymmetric response of the stress fiber to the CS and SC maneuvers. For the SC maneuver, the initial stretch increases the tension in the stress fiber and suppresses myosin detachment. The subsequent compression then causes a large proportion of the myosin population to disengage rapidly from actin filaments. This leads to the disassembly of the stress fibers and the observed fluidization. In contrast, the CS maneuver only produces a mild loss of myosin motors and no fluidization.

Simulation of malaria-infected red blood cells in microfluidic channels: Passage and blockage.

Malaria-infected red blood cells (iRBCs) become less deformable with the progression of infection and tend to occlude microcapillaries. This process has been investigated in vitro using microfluidic channels. The objective of this paper is to provide a quantitative basis for interpreting the experimental observations of iRBC occlusion of microfluidic channels. Using a particle-based model for the iRBC, we simulate the traverse of iRBCs through a converging microfluidic channel and explore the progressive loss of cell deformability due to three factors: the stiffening of the membrane, the reduction of the cell's surface-volume ratio, and the growing solid parasites inside the cell. When examined individually, each factor tends to hinder the passage of the iRBC and lengthen the transit time. Moreover, at sufficient magnitude, each may lead to obstruction of narrow microfluidic channels. We then integrate the three factors into a series of simulations that mimic the development of malaria infection through the ring, trophozoite, and schizont stages. These simulations successfully reproduce the experimental observation that with progression of infection, the iRBC transitions from passage to blockage in larger and larger channels. The numerical results suggest a scheme for quantifying iRBC rigidification through microfluidic measurements of the critical pressure required for passage.