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Biomedical subjects

R Skalak

Publications and source records attributed to R Skalak.

At least 37 records · Page 2Linked to original sources
PubMed1995

Time-dependent behavior of interstitial fluid pressure in solid tumors: implications for drug delivery.

Elevated interstitial fluid pressure (IFP) may constitute a significant physiological barrier to drug delivery in solid tumors. Strategies for overcoming this barrier have not been developed to date. To identify and characterize various mechanisms regulating IFP and to develop strategies for overcoming the IFP barrier, we modeled the tumor as a poroelastic solid. We used this model to simulate the effect of changes in microvascular pressure and tumor blood flow (TBF) on IFP. To test model predictions, the effects of changes in arterial pressure and TBF on IFP were measured using a tissue-isolated tumor preparation. IFP in the center of an isolated tumor was predicted to follow variation of the arterial pressure with a time delay of the order of magnitude of 10 s, and this delay was found to be 11 +/- 6 s experimentally. Following a cessation of TBF, the time constant of the drop in IFP was predicted to be of the order of 1000 s and was found to be 1500 +/- 900 s experimentally. The former time scale is characteristic of transcapillary fluid exchange, and the latter of percolation of fluid through the interstitial matrix. Relying on the good agreement between theoretical predictions and experimental data, we estimated the effect of blood pressure modulation on macromolecular uptake in solid tumors. Our results show that no appreciable increase of macromolecular uptake should occur either by an acute or by a chronic increase of blood pressure. On the other hand, higher uptake would result from periodic modulation of blood pressure. Therefore, the effectiveness of a vasoconstrictor such as angiotensin II to increase macromolecular delivery should be significantly enhanced by periodic rather than bolus or continuous administration of the vasoactive agent.

Animals↗
PubMed1995

A stochastic model of leukocyte rolling.

Selectin-mediated leukocyte rolling under flow is an important process in leukocyte recruitment during inflammation. The rolling motion of individual cells has been observed to fluctuate randomly both in vivo and in vitro. This paper presents a stochastic model of the micromechanics of cell rolling and provides an analytical method of treating experimental data. For a homogeneous cell population, the velocity distribution is obtained in an analytical form, which is in good agreement with experimentally determined velocity histograms obtained previously. For a heterogeneous cell population, the model provides a simple, analytical method of separating the contributions of temporal fluctuations and population heterogeneity to the variance of measured rolling velocities. The model also links the mean and variance of rolling velocities to the molecular events underlying the observed cellular motion, allowing characterization of the distribution and release rate of the clusters of molecular bonds that tether the cell to substratum. Applying the model to the analysis of data obtained for neutrophils rolling on an E-selectin-coated surface at a wall shear stress of 1.2 dyn/cm2 yields estimations of the average distance between bond clusters (approximately micron) and the average time duration of a bond cluster resisting the applied fluid force (approximately 0.5 s).

Cell Membrane↗
PubMed1995

Membrane model of endothelial cells and leukocytes. A proposal for the origin of a cortical stress.

Previous models of the erythrocyte membrane have been based on the assumption that the resting curvature of the membrane is either flat or has a small curvature relative to the overall cell dimension. In contrast, several recent experimental observations, both in leukocytes and in endothelial cells, suggest that local regions of the membrane may have high membrane curvature in the resting state. The resting curvature may be of the order of plasmalemmal vesicles in endothelial cells or surface membrane folds on leukocytes. A tension is required to unfold the membrane with strain energy which depends largely on mean curvature. It is proposed that the tendency of endothelial or leukocyte membranes to wrinkle in the unstressed state may provide a restoring force, i.e. a cortical tension.

Biomechanical Phenomena↗
PubMed1993

Development of a device for measuring adherence of skin grafts to the wound surface.

Adherence of a biological graft to the wound surface is the most important factor influencing the ultimate success of graft viability. A machine has been developed to test the adherence of biological graft materials to a substrate such as a wound surface. The peeling mode, which yields reproducible quantitative measurements of adherence, is a standard method for testing adhesives. The device is designed to continuously measure the force required to peel the graft from the substrate at a constant rate. This force is a function of the energy of adhesion per unit area of adhered surface. This device has been used to measure the peeling force of (2 x 2 cm) skin grafts which are applied to full-thickness wounds on mice. Results of tests on adherence of autografts on mice show that the peeling force increases significantly with time over the first 9 days of healing. Thus, this device is useful in quantitative comparison of various skin grafting techniques and artificial grafts.

Adhesiveness↗
PubMed1993

Design and construction of a linear shear stress flow chamber.

A new parallel plate flow chamber that has a linear variation of shear stress, starting from a predetermined maximum value at the entrance and falling to zero at the exit, has been designed and tested. This is in contrast to the usual rectangular channel plan which produces a constant shear stress over the entire length. The new design is based on the theory of Hele-Shaw flow between parallel plates. To verify the efficacy of the flow channel, the effect of fluid shear stress on platelet adhesion to a fibrinogen-coated glass surface was tested. The percentage of attached platelets after 5 min of shear stress is shown to be a function of shear stress. With this new flow chamber, cell-cell interactions can be studied efficiently over a wide range of shear stress using a single run at constant discharge.

Endothelium, Vascular↗
PubMed1993

Active motion of polymorphonuclear leukocytes in response to chemoattractant in a micropipette.

A novel experimental method of producing and observing the active motion of polymorphonuclear leukocytes (PMNs) using a micropipette technique has been recently developed (Usami et al., 1992). The present paper develops a quantitative theory for the chemoattractant gradients and cell locomotion observed in these experiments. In previous experimental methods (e.g., the Boyden chamber, the Zygmond chamber and the Dunn chamber) for study chemotaxis of leukocytes, fibroblasts, and PMNs, the exact nature of the concentration gradient of the chemoattractant is unknown. The cells may themselves modify the local gradient of the chemoattractant. In experiments using the micropipette, an internal source of chemoattractant provides well-defined boundary and initial conditions which allow the computation of the chemoattractant concentration gradient during the active locomotion of the PMNs. Since the cell completely fills the pipette lumen, convection is limited to the motion of the cells themselves. In coordinates moving with cell, it is assumed that diffusion is the only mechanism of mass transport of the chemoattractant (fMLP). Computations of the fMLP concentration during locomotion of the cell were carried out for a range of rates of fMLP binding by the receptors expressed on the front face of the cell membrane. The results show that the front face of the cell is subjected to increasing fMLP concentration during the cell motion. The sequence of events involve receptor binding of fMLP, signal transduction, polymerization of the cell cytoskeleton at the membrane of the front face, spatially dependent adhesion to the pipette wall, and localized contraction of the cytoskeleton. This sequence of events leads to the steady locomotion of the leukocytes in the micropipette. The computation of the distribution of the fMLP concentration during cell locomotion with constant velocity in micropipette experiments shows that the cell is exposed to increasing concentration of fMLP. This suggests that chemotaxis maybe induced by temporal gradient of an attractant.

Cell Movement↗
PubMed1993

Mechanical models of pseudopod formation.

The active locomotion of polymorphonuclear leukocytes into a glass pipette has been recently reported using formyl-methionyl-leucyl-phenylalanine (fMLP) as a chemoattractant. The frontal portion of the leukocyte appears clear and free of granules as observed in pseudopod formation. Three possible mechanisms for pseudopod formation are considered: (1) pressure-flow generated by actin-myosin contraction at the rear of the cell or at the base of the pseudopod; (2) osmotic pressure generated at the cell membrane, interior to the cell; and (3) actin polymerization of the cell membrane at the leading edge of the pseudopod. Experimental data on the movement of F-actin toward the rear of the cell, away from the front, favors polymerization of G-actin to F-actin at the leading edge. The active role of osmotic pressure and contraction at the base of the pseudopod are possible but not yet proven.

Actins↗
PubMed1992

Leukocyte deformability: finite element modeling of large viscoelastic deformation.

An axisymmetric deformation of a viscoelastic sphere bounded by a prestressed elastic thin shell in response to external pressure is studied by a finite element method. The research is motivated by the need for understanding the passive behavior of human leukocytes (white blood cells) and interpreting extensive experimental data in terms of the mechanical properties. The cell at rest is modeled as a sphere consisting of a cortical prestressed shell with incompressible Maxwell fluid interior. A large-strain deformation theory is developed based on the proposed model. General non-linear, large strain constitutive relations for the cortical shell are derived by neglecting the bending stiffness. A representation of the constitutive equations in the form of an integral of strain history for the incompressible Maxwell interior is used in the formulation of numerical scheme. A finite element program is developed, in which a sliding boundary condition is imposed on all contact surfaces. The mathematical model developed is applied to evaluate experimental data of pipette tests and observations of blood flow.

Elasticity↗
PubMed1992

Locomotion forces generated by a polymorphonuclear leukocyte.

There have been very few studies which have measured the physical forces generated by cells during active movements. A special micropipette system has been designed to make it possible to observe cell motion within the pipette and to apply a pressure to counter the chemotactic migration of the cell. This provides a direct measure of the locomotion force generated by the cell. The average velocity of forward motion is 0.33 microns/s in the absence of counter-pressure. The application of a positive counter-pressure (C-P) causes a decrease in the velocity of the forward motion of the cell. At 17 cm H2O of C-P, the cell velocity drops to zero and even moves backward with a higher C-P. The results show that the decrement of velocity is linearly related to the magnitude of the C-P with a complete stoppage at a pressure of 17 cm H2O which corresponds to a force of 0.003 dyn. The maximum work rate of the cell is approximately 2.5 x 10(-8) erg/s.

Biomechanical Phenomena↗
PubMed1991

TEM immunogold staining of C3 from plasma onto titanium oxides.

Immunogold staining in conjunction with TEM was used to observe C3 adsorption from plasma in relation to the underlying titanium structure of thermal, anodic, and electropolished oxides. Heat treatments and oxide thickness were found to have no significant effect on the adsorption behavior of C3, while surface oxide type possibly has. Surface concentration of C3 was found to be time- and plasma concentration-dependent. Evidence is given for the possible involvement of C3 in protein exchange, i.e., the Vroman effect. Diluted plasma resulted in a random distribution of gold colloids, whereas clustering occurred with undiluted plasma. Although C3 concentrations present on grain boundaries followed the same trend as that found on the surface, C3 was found to have a higher grain boundary than bulk concentration for 0.1% plasma.

Adsorption↗
PubMed1991

Folding of red blood cells in capillaries and narrow pores.

The geometric features of red blood cells in narrow channels in vivo and in vitro were studied by electron microscopy. In rabbit myocardial capillaries about half of the red cells were folded. In polycarbonate filters with pore diameters of 2.2-4.5 microns approximately one third of the trapped red blood cells were folded. The frequency of folding did not depend on the applied pressure, which ranged from 0.1 to 8.0 cm H2O. The folding of the red blood cells in filter pores was used to estimate the bending stiffness of the membrane. An analysis based on the large deformation theory of bending of an elastic sheet was developed. Using pressures of 0.2 and 1.0 cm H2O, the bending stiffness of human red cell membranes was estimated to be approximately 2.4 - 11.6 x 10(-12) dyn-cm, which is in good agreement with other methods. A limiting radius of curvature of about 85 nm was found at higher pressures.

Animals↗
PubMed1991

Cytoplasmic rheology of passive neutrophils.

The rheological properties of leukocytes are important to their effectiveness in the microcirculation. Previous studies based on in vitro data from micropipette experiments suggest that a Maxwell fluid bounded by a cortical shell with persistent tension is a realistic model for non-activated neutrophils in both the rapid and slow deformation phases. However, various viscoelastic coefficients have been obtained depending on the degree of cell deformation. In the present paper it is demonstrated that the cytoplasmic apparent viscosity and elasticity vary continuously, depending on the degree of deformation. These apparent variations are due to the inhomogeneous nature of the neutrophil internal structure. It is shown that the nucleus is much stiffer than the cytoplasm. The composite structure of the cell results in the deformation-dependent properties.

Cell Nucleus↗
PubMed1990

Two-dimensional analysis of two-file flow of red cells along capillaries.

The effect of a tank-treading motion of the red cell membrane on a staggered "zipper"-type red cell flow in capillaries is examined, using a two-dimensional theoretical model. An approximately triangular cell with a thin flexible membrane enclosing a viscous fluid is adopted as a model of the red cell. The motion of model red cells arranged periodically along a two-dimensional channel in an idealized zipper-type arrangement is analyzed numerically by a finite element method applied to the Stokes equations for the flow both inside and outside the model cells. It is shown that, if the viscosity ratio of the internal fluid to the suspending fluid is lower than a critical value, there exists a stable zipper-type arrangement of cells. In that arrangement, the cells remain stationary relative to each other with the membrane tank-treading. In contrast, inhibiting tank-treading by increasing the viscosity ratio above the critical value induces a cyclic oscillatory motion of red cells. The critical viscosity ratio increases if the channel is narrowed or if the spacing between cells is reduced. The present results suggest that the membrane tank-treading tends to stabilize zipper-type arrangements of red cells in capillaries at high hematocrit.

Capillaries↗
PubMed1990

Passive deformations and active motions of leukocytes.

The purpose of this paper is to review the development of continuum mechanics models of single leukocytes in both passive deformations and active motions and to indicate some future directions. Models of passive deformations describe the overall rheological behavior of single leukocytes under externally applied forces and predict the average mechanical properties from experimental data. Various "apparent" viscoelastic coefficients are obtained depending on the models assumed and the types of test used. Models of spontaneous motions postulate active driving mechanisms which must be derived internally from the cell itself and probably have different bases for different kind of motions. For pseudopod protrusion on leukocytes, energy transduction from chemical potential to mechanical work associated with actin polymerization at the tip of the projection is assumed to supply the motive power. For pseudopod retraction, active contraction due to actin-myosin interaction is assumed to be the driving force. The feasibility of the hypotheses are tested via numerical examples and comparison of the theoretical results with experimental measurements.

Biomechanical Phenomena↗
PubMed1990

The dynamics of shear disaggregation of red blood cells in a flow channel.

Red blood cell (RBC) rouleaux were formed in a flow channel in the presence of 2 g/dl dextran (molecular weight 76,000). The partial separation of RBC rouleau doublets adhering to the floor of the flow channel in response to small oscillatory shear stresses was observed experimentally. Theoretical analyses on displacement and drag force were performed to determine whether the motion of the cell involves membrane rotation (i.e., rolling) or sliding. From the experimental data and the results of theoretical analyses, it is concluded that, under the conditions of the experiments, the RBCs in a doublet separate from each other by rolling, rather than sliding of the sheared cell.

Biomechanical Phenomena↗
PubMed1990

Rheological aspects of red blood cell aggregation.

The rheological aspects of red blood cell aggregation include molecular phenomena, cell viscoelasticity, and bulk flow rheology. At the molecular level, rates at which bonds are formed and broken, the chemical energy liberation from bond formation, the elasticity of the cross-bridges and lateral mobility of cross-linking molecules must all be considered for a complete description of bond formation and distribution. Lateral migration of binding molecules occurs due to diffusion in the surface of the membrane but may also be influenced by the stresses in the membrane during separation of adhering cells. In red blood cell disaggregation, fluorescent probes have shown concentration of ligands in the region of contact close to the line of separation. The chemical potential decrement that occurs when a bond is formed provides the energy source that may deform red blood cells in the process of aggregation. The degree of aggregation and the extent of cell deformation depends on the viscoelastic properties of the cell as well as the dynamics of bond formation and repulsive potential of surface charges present, which is governed by an equation representing a balance of these energies. In flowing blood, the hydrodynamic forces applied by the plasma and surrounding cells must be added to the bond forces and elastic response of the cell. Under sufficiently strong aggregation, plug flow or large aggregates may result. At high shear rates, aggregation may be prevented due to the small contact time and high shear stresses so that no effects of aggregation may be observed. At intermediate shear stresses, transitory contact, adhesion and disaggregation may occur between neighboring cells. Such phenomena have not been analyzed in detail, but simplified models suggest that plug-like flow can occur due to hydrodynamic cell-cell interaction even when cells are not aggregated.

Erythrocyte Aggregation↗
PubMed1989

Velocity distribution on the membrane of a tank-treading red blood cell.

The kinematics of an area-conserving tank-treading disk-shaped red blood cell membrane is studied using the stream function method suggested by Secomb and Skalak (Q. Jl Mech. appl. Math. 35, Pt 2, 233-247, 1982). Two simple area-conserving velocity fields are superimposed to satisfy the continuity condition at the curved edges of the disk. A differential equation for the trajectory of any material point of the membrane is derived. The requirement of synchrony of the cycle for all membrane points leads to an integral equation which determines a magnitude function. An approximate solution is made possible by assuming small trajectory deflections.

Biomechanical Phenomena↗