Annals of Biomedical Engineering

McIntyre, Cameron; Grill, Warren

doi: 10.1114/1.262pmid: 10784087

The goal of this study was to identify stimulus parameters and electrode geometries that were effective in selectively stimulating targeted neuronal populations within the central nervous system (CNS). Cable models of neurons that included an axon, initial segment, soma, and branching dendritic tree, with geometries and membrane dynamics derived from mammalian motoneurons, were used to study excitation with extracellular electrodes. The models reproduced a wide range of experimentally documented excitation patterns including current-distance and strength-duration relationships. Evaluation of different stimulus paradigms was performed using populations of fifty cells and fifty fibers of passage randomly positioned about an extracellular electrode(s). Monophasic cathodic or anodic stimuli enabled selective stimulation of fibers over cells or cells over fibers, respectively. However, when a symmetrical charge-balancing stimulus phase was incorporated, selectivity was greatly diminished. An anodic first, cathodic second asymmetrical biphasic stimulus enabled selective stimulation of fibers, while a cathodic first, anodic second asymmetrical biphasic stimulus enabled selective stimulation of cells. These novel waveforms provided enhanced selectivity while preserving charge balancing as is required to minimize the risk of electrode corrosion and tissue injury. Furthermore, the models developed in this study can predict the effectiveness of electrode geometries and stimulus parameters for selective activation of specific neuronal populations, and in turn represent useful tools for the design of electrodes and stimulus waveforms for use in CNS neural prosthetic devices. © 2000 Biomedical Engineering Society.

Cho, Michael; Thatte, Hemant; Lee, Raphael; Golan, David

doi: 10.1114/1.263pmid: 10784088

Electrical stimulation has been used to promote wound healing. The mechanisms by which such stimulation could interact with biological systems to accelerate healing have not been elucidated. One potential mechanism could involve stimulation of macrophage migration to the site of a wound. Here we report that oscillatory electric fields induce human macrophage migration. Macrophages exposed to a 1 Hz, 2 V/cm field show an induced migration velocity of 5.2±0.4 ×10-2 μm/min and a random motility coefficient of 4.8±1.4 ×10-2 μm2/min on a glass substrate. Electric field exposure induces reorganization of microfilaments from ring-like structures at the cell periphery to podosomes that are confined to the contact sites between cell and substrate, suggesting that the cells are crawling on glass. Treatment of cells with monoclonal antibodies directed against β 2-integrins prior to field exposure prevents cell migration, indicating that integrin-dependent signaling pathways are involved. Electric fields cause macrophage migration on laminin or fibronectin coated substrates without inducing podosome formation or changes in cellular morphology. The migration velocity is not significantly altered but the random movement is suppressed, suggesting that cell movements on a laminin- or fibronectin-coated surface are not mediated by cell crawling. It is suggested that electric field-induced macrophage migration utilizes several modes of cell movement, including cell crawling and possibly cell rolling. ©

Entcheva, Emilia

doi: 10.1114/1.264pmid: 10784089

This theoretical study was provoked by and designed to interpret, complement and extend the implications of recent experimental observations by Wikswo and Lin (PACE, 21:940, 1998) on the epicardial surface of rabbit hearts. Using a macroscopic bidomain representation of the cardiac structure and the finite element method, we model the response of the heart to uniform electric fields applied under different angles. To overcome intra- and interspecies differences in the geometric and structural characteristics of the cardiac muscle, the analysis is conducted for an idealized ellipsoidal heart. Although idealized, this heart model incorporates important structural features, i.e., fiber curvature, transmural fiber rotation, and unequal anisotropy for the intra- and extracellular domains. This study shows that regions of maximum polarization of opposite sign may develop along an axis, significantly deviating from the axis of the applied electric field. The polarization evoked inside the ventricular wall seems to be a major contributor to this phenomenon. Nonperiodic structural inhomogeneities on multicellular level (endocardial “trabeculation” in our model) result in local unaligned polarization dipoles weakening the magnitude of the global polarization dipole and reducing its deviation from the axis of stimulation. Our results might be helpful in improving current understanding of defibrillation mechanisms. © 2000 Biomedical Engineering Society.

Beard, Daniel; Bassingthwaighte, James

doi: 10.1114/1.273pmid: 10784090

For highly diffusive solutes the kinetics of blood–tissue exchange is only poorly represented by a model consisting of sets of independent parallel capillary–tissue units. We constructed a more realistic multicapillary network model conforming statistically to morphometric data. Flows through the tortuous paths in the network were calculated based on constant resistance per unit length throughout the network and the resulting advective intracapillary velocity field was used as a framework for describing the extravascular diffusion of a substance for which there is no barrier or permeability limitation. Simulated impulse responses from the system, analogous to tracer water outflow dilution curves, showed flow-limited behavior over a range of flows from about 2 to 5 ml min−1 g−1, as is observed for water in the heart in vivo. The present model serves as a reference standard against which to evaluate computationally simpler, less physically realistic models. The simulated outflow curves from the network model, like experimental water curves, were matched to outflow curves from the commonly used axially distributed models only by setting the capillary wall permeability–surface area (PS) to a value so artifactually low that it is incompatible with the experimental observations that transport is flow limited. However, simple axially distributed models with appropriately high PSs will fit water outflow dilution curves if axial diffusion coefficients are set at high enough values to account for enhanced dispersion due to the complex geometry of the capillary network. Without incorporating this enhanced dispersion, when applied to experimental curves over a range of flows, the simpler models give a false inference that there is recruitment of capillary surface area with increasing flow. Thus distributed models must account for diffusional as well as permeation processes to provide physiologically appropriate parameter estimates. © 2000 Biomedical Engineering Society.

Zhu, Liang

doi: 10.1114/1.266pmid: 10784091

The purpose of this work is to evaluate the capacity of the heat loss from the carotid artery in the human neck and thus, to provide indirect evidence of the existence of selective brain cooling in humans during hyperthermia. A theoretical model is developed to describe the effects of blood flow rate and vascular geometry on the thermal equilibration in the carotid artery based on the blood flow and the anatomical vascular geometry in the human neck. The potential for cooling of blood in the carotid artery on its way to the brain by heat exchange with the jugular vein and by radial heat conduction loss to the cool neck surface is evaluated. It is shown that the cooling of the arterial blood can be as much as 1.1°C lower than the body core temperature, which is in agreement with previous experimental measurements of the difference between the tympanic and body core temperatures. The model also evaluates the relative contributions of countercurrent heat exchange and radial heat conduction to selective brain cooling. It is found that these mechanisms are comparable with each other. Results of the present study will help provide a better understanding of the thermoregulation during hyperthermia. © 2000 Biomedical Engineering Society.

Downey, Dawn; Seagrave, Richard

doi: 10.1114/1.267pmid: 10784092

A model of the human body that integrates the variables involved in temperature regulation and blood gas transport within the cardiovascular and respiratory systems is presented here. It expands upon previous work to describe the competition between skin and muscles when both require increased blood flows during exercise and/or heat stress. First, a detailed study of the control relations used to predict skin blood flow was undertaken. Four other control relations employed in the model were also examined and modified as indicated by empirical results found in literature. Internal responses to exercise and/or heat stress can affect both thermoregulation and the cardiorespiratory system. Dehydration was studied in addition to complete water replacement during similar environmental and exercise situations. Control relations for skin blood flow and evaporative heat loss were modified and a water balance was added to study how the loss of water through sweat can be limiting. Runoff from sweating as a function of relative humidity was introduced along with evaporation, and these results were compared to data to validate the model. © 2000 Biomedical Engineering Society.

Quick, Christopher; Berger, David; Hettrick, Douglas; Noordergraaf, Abraham

doi: 10.1114/1.268pmid: 10784093

A new method has been developed to estimate total arterial compliance from measured input pressure and flow. In contrast to other methods, this method does not rely on fitting the elements of a lumped model to measured data. Instead, it relies on measured input impedance and peripheral resistance to calculate the relationship of arterial blood volume to input pressure. Generally, this transfer function is a complex function of frequency and is called the apparent arterial compliance. At very low frequencies, the confounding effect of pulse wave reflection disappears, and apparent compliance becomes total arterial compliance. This study reveals that frequency components of pressure and flow below heart rate are generally necessary to obtain a valid estimate of compliance. Thus, the ubiquitous practice of estimating total arterial compliance from a single cardiac cycle is suspect under most circumstances, since a single cardiac cycle does not contain these frequencies. © 2000 Biomedical Engineering Society.

Clingan, P.; Friedman, M.

doi: 10.1114/1.269pmid: 10784094

The effects of the outflow of aortic blood through the celiac and renal arteries on the flow field in the external iliac arteries were studied under steady and physiologically realistic pulsatile flow conditions. Laser Doppler velocimetry (LDV) measurements were made close to the medial, lateral, ventral, and dorsal walls of the external iliac branches of a clear, flow-through replica of a porcine aorta and its daughter vessels. The outflow from each branch of the replica was controlled so that the infrarenal aortic flow rate and the flow partition at the aortic trifurcation were the same for all experiments. LDV measurements were made with flow exiting through both the renal and celiac artery ostia, only the celiac ostium, and neither ostium. The steady flow results indicate that while the outflow through the renal arteries did not have a significant effect on near wall shear rate in the external iliac arteries, the flow through the celiac artery did. However, in pulsatile flow, three indices of near wall velocity in the iliac arteries were unaffected by celiac artery outflow, while a fourth showed a small effect that can be attributed to differences in minimum velocity. These results indicate that reliable simulations of blood flow in the external iliac arteries can be carried out without including the renal and celiac vessels, provided that the correct infrarenal flow wave is used. They also demonstrate that the flow field downstream of a region, such as a branch, that strongly alters the flow, can be nearly independent of the velocity field entering the region. © 2000 Biomedical Engineering Society.

Adler, Andy; Bates, Jason

doi: 10.1114/1.270pmid: 10784095

The forces of parenchymal interdependence in the lung are potent inhibitors of airway smooth muscle shortening, as evidenced by the marked dependence of bronchial responsiveness on lung volume. In this study we developed a mathematical-computer model of the effects of parenchymal interdependence on airway smooth muscle shortening. A three-dimensional network of cuboidal alveolar walls was tethered at its boundaries and surrounded a single airway with mechanical properties identical to the alveolar parenchyma. The walls were assigned highly nonlinear properties so that the pressure-volume behavior of the model matched that measured in dogs. Constriction of the airway was achieved by increasing the circumferential tension in the airway wall, and then solving the force-balance equations of the model to calculate the equilibrium configurations of the airway wall and all the interconnecting alveolar walls. The changes in airway resistance predicted by the model at various transpulmonary pressures (P tp were compared to those obtained by the alveolar capsule oscillator technique in dogs during induced bronchoconstriction at various P tp (Balassy et al., J. Appl. Physiol. 78:875–880, 1995). The model matched the data reasonably well at P tp values above about 0.5 kPa, but was too responsive at lower P tp We were able to make the model match the data at all P tpby including an additional stiffness term, such as might conceivably arise from the airway wall itself. ©

Wu, J.; Herzog, W.

doi: 10.1114/1.271pmid: 10784096

Experimental evidence suggests that cells are extremely sensitive to their mechanical environment and react directly to mechanical stimuli. At present, it is technically difficult to measure fluid pressure, stress, and strain in cells, and to determine the time-dependent deformation of chondrocytes. For this reason, there are no data in the published literature that show the dynamic behavior of chondrocytes in articular cartilage. Similarly, the dynamic chondrocyte mechanics have not been calculated using theoretical models that account for the influence of cell volumetric fraction on cartilage mechanical properties. In the present investigation, the location- and time-dependent stress-strain state and fluid pressure distribution in chondrocytes in unconfined compression tests were simulated numerically using a finite element method. The technique involved two basic steps: first, cartilage was approximated as a macroscopically homogenized material and the mechanical behavior of cartilage was obtained using the homogenized model; second, the solution of the time-dependent displacements and fluid pressure fields of the homogenized model was used as the time-dependent boundary conditions for a microscopic submodel to obtain average location- and time-dependent mechanical behavior of cells. Cells and extracellular matrix were assumed to be biphasic materials composed of a fluid phase and a hyperelastic solid phase. The hydraulic permeability was assumed to be deformation dependent and the analysis was performed using a finite deformation approach. Numerical tests were made using configurations similar to those of experiments described in the literature. Our simulations show that the mechanical response of chondrocytes to cartilage loading depends on time, fluid boundary conditions, and the locations of the cells within the specimen. The present results are the first to suggest that chondrocyte deformation in a stress-relaxation type test may exceed the imposed system deformation by a factor of 3–4, that chondrocyte deformations are highly dynamic and do not reach a steady state within about 20 min of steady compression (in an unconfined test), and that cell deformations are very much location dependent. © 2000 Biomedical Engineering Society.