[Show abstract][Hide abstract] ABSTRACT: Mitochondria are dynamic cell organelles that constantly undergo fission and fusion events. These dynamical processes, which tightly regulate mitochondrial morphology, are essential for cell physiology. Here we propose an elastocapillary mechanical instability as a mechanism for mitochondrial fission. We experimentally induce mitochondrial fission by rupturing the cell’s plasma membrane. We present a stability analysis that successfully explains the observed fission wavelength and the role of mitochondrial morphology in the occurrence of fission events. Our results show that the laws of fluid mechanics can describe mitochondrial morphology and dynamics.
[Show abstract][Hide abstract] ABSTRACT: Drug-eluting stents (DES), which release anti-proliferative drugs into the arterial wall in a controlled manner, have drastically reduced the rate of in-stent restenosis and revolutionized the treatment of atherosclerosis. However, late stent thrombosis remains a safety concern in DES, mainly due to delayed healing of the endothelial wound inflicted during DES implantation. We present a framework to optimize DES design such that restenosis is inhibited without affecting the endothelial healing process. To this end, we have developed a computational model of fluid flow and drug transport in stented arteries and have used this model to establish a metric for quantifying DES performance. The model takes into account the multi-layered structure of the arterial wall and incorporates a reversible binding model to describe drug interaction with the cells of the arterial wall. The model is coupled to a novel optimization algorithm that allows identification of optimal DES designs. We show that optimizing the period of drug release from DES and the initial drug concentration within the coating has a drastic effect on DES performance. Paclitaxel-eluting stents perform optimally by releasing their drug either very rapidly (within a few hours) or very slowly (over periods of several months up to one year) at concentrations considerably lower than current DES. In contrast, sirolimus-eluting stents perform optimally only when drug release is slow. The results offer explanations for recent trends in the development of DES and demonstrate the potential for large improvements in DES design relative to the current state of commercial devices.
PLoS ONE 06/2015; 10(6):e0130182. DOI:10.1371/journal.pone.0130182 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nanoparticles offer a promising medical tool for targeted drug delivery, for example to treat inflamed endothelial cells during the development of atherosclerosis. To inform the design of such therapeutic strategies, we develop a computational model of nanoparticle internalization into endothelial cells, where internalization is driven by receptor-ligand binding and limited by the deformation of the cell membrane and cytoplasm. We specifically consider the case of nanoparticles targeted against ICAM-1 receptors, of relevance for treating atherosclerosis. The model computes the kinetics of the internalization process, the dynamics of binding, and the distribution of stresses exerted between the nanoparticle and the cell membrane. The model predicts the existence of an optimal nanoparticle size for fastest internalization, consistent with experimental observations, as well as the role of bond characteristics, local cell mechanical properties, and external forces in the nanoparticle internalization process.
PLoS ONE 04/2015; 10(4):e0122097. DOI:10.1371/journal.pone.0122097 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The dynamics of cellular adhesion and deadhesion, which play key roles in many cellular processes, have most often been studied at the scale of single bonds or single cells. However, multicellular adhesion and deadhesion are also central processes in tissue mechanics, morphogenesis, and pathophysiology, where collective tissue phenomena may introduce additional effects that are absent at the single-cell level. In this paper we present experiments on the adhesion of cellular aggregates and a laboratory model system to study tissue mechanics. We introduce a technique to measure the forces and energies involved in the detachment of an aggregate from a substrate (which can be viewed as a cellular tack assay) and in the fracture between two partially fused aggregates, as a function of the adhesion time, the pulling speed, and the cadherin density at the cell surface. We develop a model based on polymer physics to interpret the observations. We identify a significant contribution to the adhesion energy of viscous dissipation mechanisms present at the tissue scale that are absent at the single-cell level, as well as a significant effect of the speed at which the separation force is applied.
[Show abstract][Hide abstract] ABSTRACT: Dewetting is the spontaneous withdrawal of a liquid film from a non-wettable surface by nucleation and growth of dry patches. Two recent reports now propose that the principles of dewetting explain the physical phenomena underpinning the opening of transendothelial cell macroaperture (TEM) tunnels, referred to as cellular dewetting. This was discovered by studying a group of bacterial toxins endowed with the property of corrupting actomyosin cytoskeleton contractility. For both liquid and cellular dewetting, the growth of holes is governed by a competition between surface forces and line tension. We also discuss how the dynamics of TEM opening and closure represent remarkable systems to investigate actin cytoskeleton regulation by sensors of plasma membrane curvature and investigate the impact on membrane tension and the role of TEM in vascular dysfunctions.
Biology of the Cell 11/2012; 105(3). DOI:10.1111/boc.201200063 · 3.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Analogies with inert soft condensed matter—such as viscoelastic liquids, pastes, foams, emulsions, colloids, and polymers—can
be used to investigate the mechanical response of soft biological tissues to forces. A variety of experimental techniques
and biophysical models have exploited these analogies allowing the quantitative characterization of the mechanical properties
of model tissues, such as surface tension, elasticity, and viscosity. The framework of soft matter has been successful in
explaining a number of dynamical tissue behaviors observed in physiology and development, such as cell sorting, tissue spreading,
or the escape of individual cells from a tumor. However, living tissues also exhibit active responses, such as rigidity sensing
or cell pulsation, that are absent in inert soft materials. The soft matter models reviewed here have provided valuable insight
in understanding morphogenesis and cancer invasion and have set bases for using tissue engineering within medicine.
[Show abstract][Hide abstract] ABSTRACT: Pathogenic bacteria can cross from blood vessels to host tissues by opening transendothelial cell macroapertures (TEMs). To induce TEM opening, bacteria intoxicate endothelial cells with proteins that disrupt the contractile cytoskeletal network. Cell membrane tension is no longer resisted by contractile fibers, leading to the opening of TEMs. Here we model the opening of TEMs as a new form of dewetting. While liquid dewetting is irreversible, we show that cellular dewetting is transient. Our model predicts the minimum radius for hole nucleation, the maximum TEM size, and the dynamics of TEM opening, in good agreement with experimental data. The physical model is then coupled with biological experimental data to reveal that the protein missing in metastasis (MIM) controls the line tension at the rim of the TEM and opposes its opening.
[Show abstract][Hide abstract] ABSTRACT: RhoA-inhibitory bacterial toxins, such as Staphylococcus aureus EDIN toxin, induce large transendothelial cell macroaperture (TEM) tunnels that rupture the host endothelium barrier and promote bacterial dissemination. Host cells repair these tunnels by extending actin-rich membrane waves from the TEM edges. We reveal that cyclic-AMP signaling produced by Bacillus anthracis edema toxin (ET) also induces TEM formation, which correlates with increased vascular permeability. We show that ET-induced TEM formation resembles liquid dewetting, a physical process of nucleation and growth of holes within a thin liquid film. We also identify the cellular mechanisms of tunnel closure and reveal that the I-BAR domain protein Missing in Metastasis (MIM) senses de novo membrane curvature generated by the TEM, accumulates at the TEM edge, and triggers Arp2/3-dependent actin polymerization, which induces actin-rich membrane waves that close the TEM. Thus, the balance between ET-induced TEM formation and resealing likely determines the integrity of the host endothelium barrier.
[Show abstract][Hide abstract] ABSTRACT: During embryonic development and wound healing, the mechanical signals transmitted from cells to their neighbors induce tissue rearrangement and directional movements. It has been observed that forces exerted between cells in a developing tissue under stress are not always monotonically varying, but they can be pulsatile. Here we investigate the response of model tissues to controlled external stresses. Spherical cellular aggregates are subjected to one-dimensional stretching forces using micropipette aspiration. At large enough pressures, the aggregate flows smoothly inside the pipette. However, in a narrow range of moderate aspiration pressures, the aggregate responds by pulsed contractions or "shivering." We explain the emergence of this shivering behavior by means of a simple analytical model where the uniaxially stretched cells are represented by a string of Kelvin-Voigt elements. Beyond a deformation threshold, cells contract and pull on neighboring cells after a time delay for cell response. Such an active behavior has previously been found to cause tissue pulsation during dorsal closure of Drosophila embryo.
Proceedings of the National Academy of Sciences 08/2011; 108(33):13387-92. DOI:10.1073/pnas.1105741108 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oscillating water tunnels are experimental facilities commonly used in coastal engineering research. They are intended to reproduce near-bed hydrodynamic and sediment transport phenomena at a realistic scale. In an oscillating water tunnel, a piston generates an oscillatory motion that propagates almost instantaneously to the whole tunnel; consequently, flow is uniform along the tunnel, unlike the propagating wave motion in the sea or in a wave flume. This results in subtle differences between the boundary-layer hydrodynamics of an oscillating water tunnel and of a propagating wave, which may have a significant effect in the resulting sediment transport. In this paper, we present a zeroth-order analytical model of the turbulent boundary-layer hydrodynamics in an oscillating water tunnel. By using a time-varying eddy viscosity and by accounting for the constraints arising from the tunnel's geometry, the model predicts the oscillating water tunnel hydrodynamics and yields analytical expressions to compute bed shear stresses for asymmetric and skewed waves, both in the absence or presence of an imposed current. These expressions are applied to successfully quantify bedload sediment transport in oscillating water tunnel experiments.
[Show abstract][Hide abstract] ABSTRACT: Experimental studies of sediment transport rates due to nearshore waves are often conducted in oscillating water tunnels (OWTs). In an OWT, the oscillatory motion produced by the piston propagates almost instantaneously along the entire tunnel. Consequently, unlike the wave motion in the sea or in a wave flume, flow in an OWT is uniform along the tunnel, and second-order wave propagation effects (such as Longuet-Higgins's streaming) are absent. The effect of these hydrodynamic differences between OWT and sea waves on sediment transport rates has generally been neglected. In this paper we present a simple, practical formulation to evaluate bed shear stresses and bedload transport rates due to asymmetric and skewed waves plus a current in an OWT, based on fitting the exact results of a rigorous, analytical model of the OWT wave-current boundary layer. By then accounting for real wave effects we find that wave propagation significantly affects the predicted period-averaged net sediment transport rates. Such real wave effects can therefore not be neglected when comparing nearshore transport models with OWT data.
[Show abstract][Hide abstract] ABSTRACT: Due to the kinematic reversibility of Stokes flow, a body executing a reciprocal motion (a motion in which the sequence of body configurations remains identical under time reversal) cannot propel itself in a viscous fluid in the limit of negligible inertia; this result is known as Purcell's scallop theorem. In this limit, the Reynolds numbers based on the fluid inertia and on the body inertia are all zero. Previous studies characterized the breakdown of the scallop theorem with fluid inertia. In this paper we show that, even in the absence of fluid inertia, certain dense bodies undergoing reciprocal motion are able to swim. Using Lorentz's reciprocal theorem, we first derive the general differential equations that govern the locomotion kinematics of a dense swimmer. We demonstrate that no reciprocal swimming is possible if the body motion consists only of tangential surface deformation (squirming). We then apply our general formulation to compute the locomotion of four simple swimmers, each with a different spatial asymmetry, that perform normal surface deformations. We show that the resulting swimming speeds (or rotation rates) scale as the first power of a properly defined 'swimmer Reynolds number', demonstrating thereby a continuous breakdown of the scallop theorem with body inertia.
[Show abstract][Hide abstract] ABSTRACT: Prediction of nearshore sediment transport is a fundamental, open problem in coastal engineering. In this paper, we extend an existing model to predict bedload due to pure asymmetric and skewed waves to the case of combined waves and currents. The choice of the appropriate bed roughness to compute bedload is discussed. Predictions based on different choices of roughness are compared with available experimental data. Depending on whether a current is present or absent, agreement between predictions and measurements is obtained for a different choice of the roughness. Rather than using a different roughness parameterization for the two cases, these results suggest the necessity of revising the model that predicts the bed shear stress used in the calculation of bedload transport.
Coastal Engineering 2008 - 31st International Conference; 01/2009
[Show abstract][Hide abstract] ABSTRACT: According to the scallop theorem, a swimmer executing a time-reversible (or ``reciprocal'') motion cannot propel itself in the limit of zero Reynolds number. How much inertia is necessary for a reciprocal motion to become propulsive? Here, we study the breakdown of the scallop theorem for dense swimmers, for which only particle inertia is significant. We apply Lorentz's reciprocal theorem to derive general differential equations that govern the locomotion kinematics of a dense swimmer. We then apply these results to several spatially-asymmetric swimmers and show that they are able to propel themselves at any arbitrarily small value of the particle Reynolds number, even in the absence of fluid inertia.
[Show abstract][Hide abstract] ABSTRACT: 1 Prediction of nearshore sediment transport is a fundamental, open problem in coastal engineering. In this paper, we extend an existing model to predict bedload due to pure asymmetric and skewed waves to the case of combined waves and currents. The choice of the appropriate bed roughness to compute bedload is discussed. Predictions based on different choices of roughness are compared with available experimental data. Depending on whether a current is present or absent, agreement between predictions and measurements is obtained for a different choice of the roughness. Rather than using a different roughness parameterization for the two cases, these results suggest the necessity of revising the model that predicts the bed shear stress used in the calculation of bedload transport.
[Show abstract][Hide abstract] ABSTRACT: A simple conceptual formulation to compute seabed shear stress due to asymmetric and skewed waves is presented. This formulation generalizes the sinusoidal wave case and uses a variable friction factor to describe the physics of the boundary layer and to parameterize the effects of wave shape. Predictions of bed shear stresses agree with numerical computations using a standard boundary layer model with a k–ε turbulence closure. The bed shear stress formulation is combined with a Meyer-Peter and Müller-type formula to predict sheet flow bedload transport under asymmetric and skewed waves for a horizontal or sloping bed. The predictions agree with oscillatory water tunnel measurements from the literature.
[Show abstract][Hide abstract] ABSTRACT: produced by the piston propagates almost instantaneously to the entire tunnel. Consequently, unlike the wave motion in the sea or in a wave flume, flow in an OWT is uniform along the tunnel, and wave propagation effects (such as Longuet-Higgins's streaming) are absent. The effect of these hydrodynamic differences between OWT and sea waves on sediment transport rates has generally been neglected. In this paper we present the results of an analytical study of the hydrodynamics of an OWT, from which we obtain practical formulas to predict OWT bedload transport rates. Our results suggest that the differences in boundary-layer hydrodynamics between OWT and sea waves significantly affect sediment transport rates. Such differences must be accounted for when extrapolating OWT measurements to field conditions.