Biomedical subjects

T W Secomb

Publications and source records attributed to T W Secomb.

At least 55 records · Page 3Linked to original sources

PubMed1996

Microvascular studies on the origins of perfusion-limited hypoxia.

Two forms of hypoxia are thought to exist in tumours: (1) hypoxia caused by limitations of its diffusion (chronic hypoxia); and (2) hypoxia caused by changes in perfusion (acute hypoxia). Indirect information suggests the existence of perfusion-limited hypoxia, but there is no direct proof that fluctuations in blood flow can lead to hypoxia, nor is there any information regarding potential causes of fluctuant flow. In this study, we have begun to explore these questions using R3230AC tumours transplanted into rat dorsal-flap window chambers. Two types of fluctuant flow have been observed. The first type, usually confined to single vessels, is typified by instability of flow magnitude and direction, and total vascular stasis occurs, but only for a few seconds at a time (4% incidence). The second type of fluctuation occurs in groups of vessels and is cyclic, with cycle times ranging from 20-60 min. Total vascular stasis does not necessarily occur, but the fluctuations in red cell flux are accompanied by changes in vascular oxygen content, as measured by microelectrodes. Another source of chronic hypoxia has also been identified in these experiments. Nine per cent (9%) of vessels examined had plasma flow, but very low or absent red cell flux over periods of many minutes.

Animals↗

PubMed1996

Biophysical aspects of blood flow in the microvasculature.

The main function of the microvasculature is transport of materials. Water and solutes are carried by blood through the microvessels and exchanged, through vessel walls, with the surrounding tissues. This transport function is highly dependent on the architecture of the microvasculature and on the biophysical behavior of blood flowing through it. For example, the hydrodynamic resistance of a microvascular network, which determines the overall blood flow for a given perfusion pressure, depends on the number, size and arrangement of microvessels, the passive and active mechanisms governing their diameters, and on the apparent viscosity of blood flowing in them. Suspended elements in blood, especially red blood cells, strongly influence the apparent viscosity, which varies with several factors, including vessel diameter, hematocrit and blood flow velocity. The distribution of blood flows and red cell fluxes within a network, which influences the spatial pattern of mass transport, is determined by the mechanics of red cell motion in individual diverging bifurcations. Here, our current understanding of the biophysical processes governing blood flow in the microvasculature is reviewed, and some directions for future research are indicated.

Animals↗

PubMed1995

Effect of increasing vascular hydraulic conductivity on delivery of macromolecular drugs to tumor cells.

PURPOSE: To examine the assumption that increasing the hydraulic conductivity Lp of microvessels (by such strategies as radiation, hyperthermia, or inducing inflammation) improves the transport of macromolecular drugs to tumors. METHODS AND MATERIALS: A theoretical model is used to investigate the effect of varying Lp on macromolecular transport in spherical tumor nodules. The model is generalized to nonspherical tumors. The equations governing fluid flow in the tumors are solved numerically to obtain the pressure in the interior, and macromolecule fluxes are deduced using Starling's equation. RESULTS: Because of the interaction of two opposing effects, the filtration rate at the tumor center is maximized at an "optimum" value of Lp, which depends strongly on tumor size. Only for tumor nodules smaller than about 0.2 cm across is this value lower than the actual estimated value. By considering spheroidal tumor nodules, it is found that dependence on shape is much weaker than dependence on size, except for extremely elongated or flattened shapes. CONCLUSIONS: While total fluid filtration for the entire tumor region always increases with increasing Lp, the local filtration rate at points inside the tumor decreases if the tumor is larger than about 0.2 cm, leading to a less uniform distribution of the drug, and therapeutic disadvantage. Increased vessel leakiness is an unlikely explanation for reported experimental findings that hyperthermia and inflammation result in more uniform distributions of monoclonal antibodies throughout tumors much larger than 0.2 cm.

Antibodies, Monoclonal↗

PubMed1995

Structure and hemodynamics of microvascular networks: heterogeneity and correlations.

The objective of this study was to quantify the heterogeneity of topological, morphological, and hemodynamic parameters in microvascular networks and to identify functionally relevant correlations among these parameters. Seven networks in the rat mesentery (383-913 vessel segments per network) were examined, and measurements were made of segment generation, diameter, length, and hematocrit in all segments (n = 3,129) and of flow velocity (only in 3 networks, 1,321 segments). In addition, hematocrit, flow rate, and pressure were derived for all segments from a mathematical simulation. All parameters obtained exhibit heterogeneous distributions with coefficients of variation ranging from 0.28 (capillary diameter) to > 1.5 (volume flow and pressure gradient). Several strong correlations exist between parameters, e.g., discharge hematocrit increases with vessel diameter, and shear rate increases with intravascular pressure. Because of such correlations, the extrapolation from average values for "typical vessels" to network properties can lead to substantial errors. For example, the mean network transit time estimated based on averaged quantities is 6.5 s, which is about 60% higher than the true value (4.08 s). Simplified models of the vascular bed may therefore be inadequate to describe functional properties of the microcirculation.

Animals↗

PubMed1995

Design principles of vascular beds.

Hemodynamic parameters were determined in each vessel segment of six complete microvascular networks in the rat mesentery by using a combination of experimental measurements and theoretical stimulations. For a total number of 2592 segments, a strong unified dependence of wall shear stress on intravascular pressure for arterioles, capillaries, and venules was obtained. All three types of segments exhibit an essentially identical variation of shear stress from high to low values (from approximately 100 to 10 dyne/cm2) as intravascular pressure falls from 70 to 15 mm Hg. On the basis of these observations, it is proposed that vascular beds grow and adapt so as to maintain the shear stress in each vessel at a level that depends on local transmural pressure. In contrast to Murray's classic 'minimum-cost' hypothesis, which implies uniformity of wall shear rate throughout the vasculature, the proposed design principle provides an explanation for the functionally important arteriovenous asymmetry of wall shear rates and flow resistance in the circulation.

Animals↗

PubMed1995

Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors.

The extent of hypoxic regions in a tumor tissue depends on the arrangement, blood flow rate and blood oxygen content of microvessels, and on the tissue's oxygen consumption rate. Here, the effects of blood flow rate, blood oxygen content and oxygen consumption on hypoxic fraction are simulated theoretically, for a region whose microvascular geometry was derived from observations of a transplanted mammary andenocarcinoma (R3230AC) in a rat dorsal skin flap preparation. In the control state, arterial PO2 is 100 mmHg, consumption rate is 2.4 cm3 O2/100 g/min, and hypoxic fraction (tissue with PO2 < 3 mmHg) is 30%. Hypoxia is abolished by a reduction in consumption rate of at least 30%, relative to control, or an increase in flow rate by a factor of 4 or more, or an increase in arterial PO2 by a factor of 11 or more. These results suggest that reducing oxygen consumption rate may be more effective than elevating blood flow or oxygen content as a method to reduce tumor hypoxia.

Adenocarcinoma↗

PubMed1995

Mechanics of blood flow in the microcirculation.

The microcirculation in most tissues consists of an intricate network of very narrow tubes. In analyses of blood flow through the microcirculation, inertial effects can be neglected, but continuum models for blood cannot be assumed, since blood is a concentrated suspension of cells with dimensions comparable to vessel diameters. These cells strongly influence blood flow. About 45% of blood volume consists of red blood cells, whose key mechanical properties are known. A red cell has a fluid interior, surrounded by a flexible membrane, which strongly resists area changes, but bends and shears easily. White blood cells are comparable in size but much less numerous. They are less flexible than red cells and capable of active locomotion. Other suspended elements are much smaller than red cells: This review focuses on the mechanics of red cell motion in the microcirculation. Experimental and theoretical studies of blood flow in uniform tubes, bifurcations and networks are discussed. Comparisons between predicted and observed flows in networks imply that resistance to blood flow in living microvessels is higher than that in uniform tubes with corresponding diameters. Living microvessels have non-uniform geometries, and red cells must deform continually to traverse them. Theoretical results are presented implying that these transient deformations contribute to increased flow resistance in the microcirculation.

Animals↗

PubMed1994

Determination of local oxygen consumption rates in tumors.

At any location in a respiring tissue, partial pressure of oxygen (PO2) is influenced by the local oxygen consumption rate. Consumption rates in vascular tumor tissues have previously been estimated for macroscopic regions. Using oxygen electrodes, we measured PO2 profiles across microregions (87 microns to 286 microns wide) of tumors (R3230AC mammary adenocarcinoma) in a rat dorsal skin flap preparation and mapped adjacent microvessels. By comparing measured PO2 values with theoretical simulations, we deduced local consumption rates. Results for six profiles ranged from 0.83 to 2.22 cm3 O2/100 g/min. The mean (+/- SD) was 1.52 +/- 0.51 cm3 O2/100 g/min. This technique permits investigation of variations in consumption at a microregional level.

Animals↗

PubMed1994

A model for motion and sedimentation of cylindrical red-cell aggregates during slow blood flow in narrow horizontal tubes.

When blood flows slowly in a narrow tube, red-cell aggregation results in formation of an approximately cylindrical "core" of red cells, which moves as a rigid body. The core is denser than the surrounding fluid, and sedimentation is observed in horizontal tubes. To model this, the Stokes flow of a fluid surrounding a long solid cylinder (the core) contained in a long hollow cylinder (the tube) is considered. The cylinder axes are parallel but not coincident. An exact analytic expression for the resistance coefficient for motion perpendicular to the axes is given. This coefficient increases rapidly with the ratio of core radius to tube radius, and core eccentricity. The predicted rate of sedimentation is comparable to that observed experimentally. The apparent viscosity of a two-phase medium consisting of a core of aggregated particles and surrounding pure fluid is calculated. For a core radius corresponding to experimental conditions, the apparent viscosity increases rapidly with increasing eccentricity of the core.

Blood Flow Velocity↗

PubMed1994

Simulation of O2 transport in skeletal muscle: diffusive exchange between arterioles and capillaries.

Theoretical simulations of oxygen transport in skeletal muscle are used to study the role of arterioles in oxygen delivery. A three-dimensional configuration of capillaries and arterioles in a cuboidal tissue region is simulated, based on observations of hamster cheek pouch retractor muscle. Equations describing convective and diffusive oxygen transport are solved using a Green's function method. In resting muscle, predicted oxygen saturation of capillary blood increases as it flows toward arterioles, and adjacent capillaries flowing in opposite directions show very similar variations in saturation. Diffusive oxygen loss from arterioles equals about 85% of consumption. Capillaries absorb much of this oxygen (equal to approximately 45% of consumption) and deliver it at downstream locations. Thus diffusive exchange between arterioles and capillaries plays an important part in distributing oxygen throughout the tissue. At higher flow and consumption rates, the relative amounts of oxygen diffusing out of arterioles and into capillaries decrease. The results are consistent with the hypothesis that oxygen content of arteriolar blood participates in metabolic regulation of blood flow.

Animals↗

PubMed1994

Resistance to blood flow in microvessels in vivo.

Resistance to blood flow through peripheral vascular beds strongly influences cardiovascular function and transport to tissue. For a given vascular architecture, flow resistance is determined by the rheological behavior of blood flowing through microvessels. A new approach for calculating the contribution of blood rheology to microvascular flow resistance is presented. Morphology (diameter and length), flow velocity, hematocrit, and topological position were determined for all vessel segments (up to 913) of terminal microcirculatory networks in the rat mesentery by intravital microscopy. Flow velocity and hematocrit were also predicted from mathematical flow simulations, in which the assumed dependence of flow resistance on diameter, hematocrit, and shear rate was optimized to minimize the deviation between measured and predicted values. For microvessels with diameters below approximately 40 microns, the resulting flow resistances are markedly higher and show a stronger dependence on hematocrit than previously estimated from measurements of blood flow in narrow glass tubes. For example, flow resistance in 10-microns microvessels at normal hematocrit is found to exceed that of a corresponding glass tube by a factor of approximately 4. In separate experiments, flow resistance of microvascular networks was estimated from direct measurements of total pressure drop and volume flow, at systemic hematocrits intentionally varied from 0.08 to 0.68. The results agree closely with predictions based on the above-optimized resistance but not with predictions based on glass-tube data. The unexpectedly high flow resistance in small microvessels may be related to interactions between blood components and the inner vessel surface that do not occur in smooth-walled tubes.

Animals↗

PubMed1993

Analysis of oxygen transport to tumor tissue by microvascular networks.

We present theoretical simulations of oxygen delivery to tumor tissues by networks of microvessels, based on in vivo observations of vascular geometry and blood flow in the tumor microcirculation. The aim of these studies is to investigate the impact of vascular geometry on the occurrence of tissue hypoxia. The observations were made in the tissue (thickness 200 microns) contained between two glass plates in a dorsal skin flap preparation in the rat. Mammary adenocarcinomas (R3230 AC) were introduced and allowed to grow, and networks of microvessels in the tumors were mapped, providing data on length, geometric orientation, diameter and blood velocity in each segment. Based on these data, simulations were made of a 1 mm x 1 mm region containing five unbranched vascular segments and a 0.25 mm x 0.35 mm region containing 22 segments. Generally, vessels were assumed to lie in the plane midway between the glass plates, at 100 microns depth. Flow rates in the vessels were based on measured velocities and diameters. The assumed rate of oxygen consumption in the tissue was varied over a range of values. Using a Green's function method, partial pressure of oxygen (PO2) was computed at each point in the tissue region. As oxygen consumption is increased, tissue PO2 falls, with hypoxia first appearing at points relatively distant from the nearest blood vessel. The width of the well-oxygenated region is comparable to that predicted by simpler analyses. Cumulative frequency distributions of tissue PO2 were compared with predictions of a Krogh-type model with the same vascular densities, and it was found that the latter approach, which assumes a uniform spacing of vessels, may underestimate the extent of the hypoxic tissue. Our estimates of the maximum consumption rate that can be sustained without tissue hypoxia were substantially lower than those obtained from the Krogh-type model. We conclude that the heterogeneous structure of tumor microcirculation can have a substantial effect on the occurrence of hypoxic micro-regions.

Adenocarcinoma↗

PubMed1993

Effect of cell arrangement and interstitial volume fraction on the diffusivity of monoclonal antibodies in tissue.

We present theoretical calculations relating the effective diffusivity of monoclonal antibodies in tissue (Deff) to the actual diffusivity in the interstitium (Dint) and the interstitial volume fraction phi. Measured diffusivity values are effective values, deduced from concentration profiles with the tissue treated as a continuum. By using homogenization theory, the ratio Deff/Dint is calculated for a range of interstitial volume fractions from 10 to 65%. It is assumed that only diffusion in the interstitial spaces between cells contributes to the effective diffusivity. The geometries considered have cuboidal cells arranged periodically, with uniform gaps between cells. Deff/Dint is found to generally be between (2/3) phi and phi for these geometries. In general, the pathways for diffusion between cells are not straight. The effect of winding pathways on Deff/Dint is examined by varying the arrangement of the cells, and found to be slight. Also, the estimates of Deff/Dint are shown to be insensitive to typical nonuniformities in the widths of gaps between cells. From our calculations and from published experimental measurements of the effective diffusivity of an IgG polyclonal antibody both in water and in tumor tissue, we deduce that the diffusivity of this molecule in the interstitium is one-tenth to one-twentieth its diffusivity in water. We also conclude that exclusion of molecules from cells (an effect independent of molecular weight) contributes as much as interstitial hindrance to the reduction of effective diffusivity, for small interstitial volume fractions (around 20%). This suggests that the increase in the rate of delivery to tissues resulting from the use of smaller molecular-weight molecules (such as antibody fragments or bifunctional antibodies) may be less than expected.

Animals↗

PubMed1992

Analysis of oxygen exchange between arterioles and surrounding capillary-perfused tissue.

A theoretical model is used to analyze oxygen transport in a three-dimensional tissue region containing an arteriole surrounded by an array of capillaries in planes perpendicular to the arteriole. Convective removal of oxygen from the vicinity of the arteriole by nearby capillaries is shown to increase diffusive oxygen loss from the arteriole. This effect depends on the locations of the capillaries, particularly those nearest to the arteriole. The arteriolar oxygen efflux is comparable to that predicted by a previous model which used a continuum approach, but the efflux does not increase with increasing perfusion as rapidly as predicted by the continuum model. Even a small capillary flow rate strongly influences the oxygen field surrounding the arteriole.

Arterioles↗

PubMed1992

Perivascular oxygen tensions in a transplantable mammary tumor growing in a dorsal flap window chamber.

Fischer 344 rats with R3230 Ac mammary carcinomas implanted in dorsal flap window chambers served as a model to obtain measurements of perivascular and stromal oxygen tension in normal and tumor tissues using Whalen recessed-tip microelectrodes (3- to 6-microns tip). Perivascular measurements were made adjacent to vessels with continuous blood flow. Thus the measurements and models provided are reflective of conditions leading to chronic hypoxia. Perivascular oxygen tensions averaged 72 +/- 13 mmHg in normal tissue vessels adjacent to tumor, 26 +/- 5 mmHg in tumor periphery, and 12 +/- 3 mmHg in tumor central vessels. There was a significant trend toward lower perivascular oxygen tensions in the tumor center (Kruskal-Wallis test, P = 0.002). A similar tendency was seen with a limited number of stromal measurements. Krogh cylinder models, which incorporate these data for perivascular oxygen tension, along with morphometric data obtained from the same tumor model suggest that hypoxic regions will exist between tumor vessels in the tumor center unless O2 consumption rates are well below 0.6 ml/100 g/min. The low perivascular measurements observed near the tumor center combined with the theoretical considerations suggest, for this model at least, that tissue oxygenation may best be improved by increasing red cell velocity and input pO2 and reducing oxygen consumption. The low perivascular oxygen tensions observed near the center also suggest that conditions conducive to increased red cell rigidity exist, that drugs which can decrease red cell rigidity could improve tumor blood flow and oxygenation, and that the endothelium of those vessels may be susceptible to hypoxia-reoxygenation injury.

Animals↗

PubMed1992

Effects of bradykinin on the hemodynamics of tumor and granulating normal tissue microvasculature.

Bradykinin (BK) is an important endogenous mediator of microvascular flow modulation. Since the structure of the microcirculation is very different in tumor tissues than in normal tissues, bradykinin may elicit different responses in tumors. This study was designed to test the hypothesis that local administration of bradykinin increases blood flow preferentially in normal tissue relative to adjacent tumor tissue, resulting in a "vascular steal" phenomenon. Microvessel diameters (D), velocities (Vc), length densities, shear rates, and intermittent flow frequencies were measured every 10 min before, during, and after 40 min exposure to BK in rats with dorsal flap window chambers 9 days after tumor implantation. Separate studies were made of normal vessels outside the tumor margin, the hypervascular tumor periphery, and the tumor center. Bradykinin was administered with a suffusion medium flowing over the tissue at 1-2 ml/min with a BK concentration of 1.6 x 10(7) M. Administration of BK created five distinct changes in normal and tumor vessel function that varied over time, but coincidentally reached a maximum effect after 20 min exposure to BK. In normal vessels, increased Vc and D led to increased flow, which reached a peak 20 min after onset of suffusion with BK. In contrast, in centrally located tumor vessels, decreased D and Vc were observed in most vessels during the initial 10-20 min of suffusion. In addition, there was a significant increase in intermittent flow frequency in tumor central vessels, which peaked after 20 min of suffusion with BK. These five separate observations that coincided at 20 min of suffusion are consistent with a "vascular steal" phenomenon. The increase in normal microvessel D and Vc at 20 min suggests that BK causes vasodilation in arterioles. The coincident decrease in tumor microvessel D and Vc suggests that tumor feeding vessels are less able to respond to BK by vasodilating. The concomitant increase in intermittent flow frequency in tumor vessels suggests that a reduction in pressure drop occurred after 20 min exposure to BK, which is also consistent with "vascular steal." Since BK is also known to increase vascular permeability, it is possible that increases in interstitial fluid pressure brought on by exposure to BK contributed to the observed reduction in tumor blood flow. In normal vessels, reduced D and Vc, relative to peak values, were noted after 40 min suffusion with BK. Adherence of leukocytes to the vessel walls was prominent and microthrombi were also observed during this period. No evidence of such adhesion was seen in tumor vessels, although microthrombi were observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗

PubMed1991

Red blood cell mechanics and capillary blood rheology.

Blood contains a high vol fraction of erythrocytes (red blood cells), which strongly influence its flow properties. Much is known about the mechanical properties of red cells, providing a basis for understanding and predicting the rheological behavior of blood in terms of the behavior of individual red cells. This review describes quantitative theoretical models that relate red cell mechanics to flow properties of blood in capillaries. Red cells often flow in single file in capillaries, and rheological parameters can then be estimated by analyzing the motion and deformation of an individual red cell and the surrounding plasma in a capillary. The analysis may be simplified by using lubrication theory to approximate the plasma flow in the narrow gaps between the cells and the vessels walls. If red cell shapes are assumed to be axisymmetric, apparent viscosities are predicted that agree with determinations in glass capillaries. Red cells flowing in microvessels typically assume nonaxisymmetric shapes, with cyclic "tank-treading" motion of the membrane around the interior. Several analyses have been carried out that take these effects into account. These analyses indicate that nonaxisymmetry and tank-treading do not significantly influence the flow resistance in single-file or two-file flow.

Biomechanical Phenomena↗

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↗