Showing papers in "Annals of Biomedical Engineering in 1999"

Development and application of cell-based biosensors.

Abstract: Biosensors incorporate a biological sensing element that converts a change in an immediate environment to signals conducive for processing. Biosensors have been implemented for a number of applications ranging from environmental pollutant detection to defense monitoring. Biosensors have two intriguing characteristics: (1) they have a naturally evolved selectivity to biological or biologically active analytes; and (2) biosensors have the capacity to respond to analytes in a physiologically relevant manner. In this paper, molecular biosensors, based on antibodies, enzymes, ion channels, or nucleic acids, are briefly reviewed. Moreover, cell-based biosensors are reviewed and discussed. Cell-based biosensors have been implemented using microorganisms, particularly for environmental monitoring of pollutants. Biosensors incorporating mammalian cells have a distinct advantage of responding in a manner that can offer insight into the physiological effect of an analyte. Several approaches for transduction of cellular signals are discussed: these approaches include measures of cell metabolism, impedance, intracellular potentials, and extracellular potentials. Among these approaches, networks of excitable cells cultured on microelectrode arrays are uniquely poised to provide rapid, functional classification of an analyte and ultimately constitute a potentially effective cell-based biosensor technology. Three challenges that constitute barriers to increased cell-based biosensor applications are presented: analytical methods, reproducibility, and cell sources. Possible future solutions to these challenges are discussed.

Theoretical study of the effects of vascular smooth muscle contraction on strain and stress distributions in arteries.

Abstract: To study the effects of smooth muscle contraction and relaxation on the strain and stress distribution in the vascular wall, a mathematical model was proposed. The artery was assumed to be a thick-walled orthotropic tube made of nonlinear, incompressible elastic material. Considering that the contraction of smooth muscle generates an active circumferential stress in the wall, a numerical study was performed using data available in the literature. The results obtained showed that smooth muscle contraction affects the residual strains which exist in a ring segment cut out from the artery and exposed to no external load. When the ring specimen is cut radially, it springs open with an opening angle. The predicted monotonic increase of the opening angle with increasing muscular tone was in agreement with recent experimental results reported in the literature. It was shown that basal muscular tone, which exists under physiological conditions, reduces the strain gradient in the arterial wall and yields a near uniform stress distribution. During temporary changes in blood pressure, the increase in muscular tone induced by elevated pressure tends to restore the distribution of circumferential strain in the arterial wall, and to maintain the flow-induced wall shear stress to normal level.

Three-dimensional human head finite-element model validation against two experimental impacts.

Abstract: The impact response of a three-dimensional human head model has been determined by simulating two cadaver tests. The objective of this study was to validate a finite-element human head model under different impact conditions by considering intracranial compressibility. The current University Louis Pasteur model was subjected initially to a direct head impact, of short (6 ms) duration, and the simulation results were compared with published experimental cadaver tests. The model response closely matched the experimental data. A long duration pulse was chosen for the second impact and this necessitated careful consideration of the head–neck joint in order to replicate the experimental kinematics. The skull was defined as a rigid body and was subjected to six velocities. Output from the model did not accurately match the experimental results and this clearly indicates that it is important to validate a finite-element head model under various impact conditions to define the range of validity. Lack of agreement for the second impact is attributed to the nonlinearity in the dynamic behavior of intracranial stress, a problem that is not reported in the literature. © 1999 Biomedical Engineering Society.

Dependence of intertrabecular permeability on flow direction and anatomic site.

Abstract: The structure-function relationships for the permeability of trabecular bone may have relevance for tissue engineering, total joint replacements, and whole bone mechanics. To investigate such relationships, we used a constant flow rate permeameter to determine the intrinsic permeability of trabecular bone specimens, oriented longitudinally or transversely to the principal trabecular orientation, from the human vertebral body (n=20), human proximal femur (n=12), and bovine proximal tibia (n=24). Overall, the intertrabecular permeability ranged from 2.68 × 1011 to 2.00 × 108 m2. Significant negative nonlinear relations between intertrabecular permeability and volume fraction were found for each group except the longitudinal bovine proximal tibial specimens (r2=0.34-0.80). The average permeability ratio, a measure of the anisotropy, was 2.05, 6.60, and 23.3 for the human vertebral body, bovine tibia, and human femur, respectively. The permeability depended strongly on flow direction relative to the principal trabecular orientation (p < 0.0001) and anatomic site (p < 0.0001). In addition to providing a comprehensive description of intertrabecular permeability as a function of anatomic site and flow direction, these data provide substantial insight into the underlying structure-function relationships. © 1999 Biomedical Engineering Society. PAC99: 8719-j

Computational Simulation of Platelet Deposition and Activation: I. Model Development and Properties

Abstract: To better understand the mechanisms leading to the formation and growth of mural thrombi on biomaterials, we have developed a two-dimensional computational model of platelet deposition and activation in flowing blood. The basic formulation is derived from prior work by others, with additional levels of complexity added where appropriate. It is comprised of a series of convection-diffusion-reaction equations which simulate platelet-surface and platelet-platelet adhesion, platelet activation by a weighted linear combination of agonist concentrations, agonist release and synthesis by activated platelets, platelet-phospholipid-dependent thrombin generation, and thrombin inhibition by heparin. The model requires estimation of four parameters to fit it to experimental data: shear-dependent platelet diffusivity and resting and activated platelet-surface and platelet-platelet reaction rate constants. The model is formulated to simulate a wide range of biomaterials and complex flows. In this article we present the basic model and its properties; in Part II (Sorensen et al., Ann. Biomed. Eng. 27:449–458, 1999) we apply the model to experimental results for platelet deposition onto collagen. © 1999 Biomedical Engineering Society.

Method for quantitative analysis of glycosaminoglycan distribution in cultured natural and engineered cartilage.

Abstract: Cartilage tissue engineering can provide a valuable tool for controlled studies of tissue development. As an example, analysis of the spatial distribution of glycosaminoglycans (GAG) in sections of cartilaginous tissues engineered under different culture conditions could be used to correlate the effects of environmental factors with the structure of the regenerated tissue. In this paper we describe a computer-based technique for quantitative analysis of safranin-O stained histological sections, using low magnification light microscopy images. We identified a parameter to quantify the intensity of red color in the sections, which in turn was proportional to the biochemically determined wet weight fraction of GAG in corresponding tissue samples, and to describe the spatial distribution of GAG as a function of depth from the section edge. A broken line regression model was then used to determine the thickness of an external region, with lower GAG fractions, and the spatial rate of change in GAG content. The method was applied to the quantitatation of GAG distribution in samples of natural and engineered cartilage, cultured for 6 weeks in three different vessels: static flasks, mixed flasks, and rotating bioreactors. © 1999 Biomedical Engineering Society. PAC99: 8780Rb, 8715Mi, 8763Lk

Mechanics of leukocyte deformation and adhesion to endothelium in shear flow

Abstract: The mechanics of leukocyte [white blood cell (WBC)] deformation and adhesion to endothelial cells (EC) in shear flow has been investigated. Experimental data on transient WBC–EC adhesion were obtained from in vivo measurements. Microscopic images of WBC–EC contact during incipient WBC rolling revealed that for a given wall shear stress, the contact area increases with time as new bonds are formed at the leading edge, and then decreases with time as the trailing edge of the WBC membrane peels away from the EC. A two-dimensional model (2D) was developed consisting of an elastic ring adhered to a surface under fluid stresses. This ring represents an actin-rich WBC cortical layer and contains an incompressible fluid as the cell interior. All molecular bonds are modeled as elastic springs distributed in the WBC–EC contact region. Variations of the proportionality between wall shear stress (τ w ) in the vicinity of the WBC and the resulting drag force (F s ), i.e., Fs/τw, reveal its decrease with WBC deformation and increasing vessel channel height (2D). The computations also find that the peeling zone between adherent WBC and EC may account for less than 5% of the total contact interface. Computational studies describe the WBC–EC adhesion and the extent of WBC deformation during the adhesive process. © 1999 Biomedical Engineering Society. PAC99: 8717-d, 8719Tt, 8717Aa

Accuracy of computational hemodynamics in complex arterial geometries reconstructed from magnetic resonance imaging.

Abstract: Purpose: Combining computational blood flow modeling with three-dimensional medical imaging provides a new approach for studying links between hemodynamic factors and arterial disease. Although this provides patient-specific hemodynamic information, it is subject to several potential errors. This study quantifies some of these errors and identifies optimal reconstruction methodologies. Methods: A carotid artery bifurcation phantom of known geometry was imaged using a commercial magnetic resonance (MR) imager. Three-dimensional models were reconstructed from the images using several reconstruction techniques, and steady and unsteady blood flow simulations were performed. The carotid bifurcation from a healthy, human volunteer was then imaged in vivo, and geometric models were reconstructed. Results: Reconstructed models of the phantom showed good agreement with the gold standard geometry, with a mean error of approximately 15% between the computed wall shear stress fields. Reconstructed models of the in vivo carotid bifurcation were unacceptably noisy, unless lumenal profile smoothing and approximating surface splines were used. Conclusions: All reconstruction methods gave acceptable results for the phantom model, but in vivo models appear to require smoothing. If proper attention is paid to smoothing and geometric fidelity issues, models reconstructed from MR images appear to be suitable for use in computational studies of in vivo hemodynamics. © 1999 Biomedical Engineering Society. PAC99: 8719Uv, 8761-c, 0705Pj, 8710+e

Optimization of cardiac fiber orientation for homogeneous fiber strain during ejection.

Abstract: The strain of muscle fibers in the heart is likely to be distributed uniformly over the cardiac walls during the ejection period of the cardiac cycle. Mathematical models of left ventricular (LV) wall mechanics have shown that the distribution of fiber strain during ejection is sensitive to the orientation of muscle fibers in the wall. In the present study, we tested the hypothesis that fiber orientation in the LV wall is such that fiber strain during ejection is as homogeneous as possible. A finite-element model of LV wall mechanics was set up to compute the distribution of fiber strain at the beginning (BE) and end (EE) of the ejection period of the cardiac cycle, with respect to a middiastolic reference state. The distribution of fiber orientation over the LV wall, quantified by three parameters, was systematically varied to minimize regional differences in fiber shortening during ejection and in the average of fiber strain at BE and EE. A well-defined optimum in the distribution of fiber orientation was found which was not significantly different from anatomical measurements. After optimization, the average of fiber strain at BE and EE was 0.025 ± 0.011 (mean ± standard deviation) and the difference in fiber strain during ejection was 0.214 ± 0.018. The results indicate that the LV structure is designed for maximum homogeneity of fiber strain during ejection. © 1999 Biomedical Engineering Society.

In vivo three-dimensional surface geometry of abdominal aortic aneurysms.

Abstract: Abdominal aortic aneurysm (AAA) is a local, progressive dilation of the distal aorta that risks rupture until treated. Using the law of Laplace, in vivo assessment of AAA surface geometry could identify regions of high wall tensions as well as provide critical dimensional and shape data for customized endoluminal stent grafts. In this study, six patients with AAA underwent spiral computed tomography imaging and the inner wall of each AAA was identified, digitized, and reconstructed. A biquadric surface patch technique was used to compute the local principal curvatures, which required no assumptions regarding axisymmetry or other shape characteristics of the AAA surface. The spatial distribution of AAA principal curvatures demonstrated substantial axial asymmetry, and included adjacent elliptical and hyperbolic regions. To determine how much the curvature spatial distributions were dependent on tortuosity versus bulging, the effects of AAA tortuosity were removed from the three-dimensional (3D) reconstructions by aligning the centroids of each digitized contour to the z axis. The spatial distribution of principal curvatures of the modified 3D reconstructions were found to be largely axisymmetric, suggesting that much of the surface geometric asymmetry is due to AAA bending. On average, AAA surface area increased by 56% and abdominal aortic length increased by 27% over those for the normal aorta. Our results indicate that AAA surface geometry is highly complex and cannot be simulated by simple axisymmetric models, and suggests an equally complex wall stress distribution. © 1999 Biomedical Engineering Society.

Computational simulation of platelet deposition and activation: II. Results for Poiseuille flow over collagen.

Abstract: We have previously described the development of a two-dimensional computational model of platelet deposition onto biomaterials from flowing blood (Sorensen et al., Ann. Biomed. Eng. 27:436–448, 1999). The model requires estimation of four parameters to fit it to experimental data: shear-dependent platelet diffusivity and three platelet-deposition-related reaction rate constants. These parameters are estimated for platelet deposition onto a collagen substrate for simple parallel-plate flow of whole blood in both the presence and absence of thrombin. One set of experimental results is used as a benchmark for model-fitting purposes. The “trained” model is then validated by applying it to additional test cases from the literature for parallel-plate Poiseuille flow over collagen at both higher and lower wall shear rates, and in the presence of various anticoagulants. The predicted values agree very well with the experimental results for the training cases, and good reproduction of deposition trends and magnitudes is obtained for the heparin, but not the citrate, validation cases. The model is formulated to be easily extended to synthetic biomaterials, as well as to more complex flows. © 1999 Biomedical Engineering Society.

Generalized sensitivity functions in physiological system identification.

Abstract: Parameters of physiological models are commonly associated in an input–output experiment with a specific pattern of the system response. This association is often made on an intuitive basis by traditional sensitivity analysis, i.e., by inspecting the variations of model output trajectories with respect to parameter variations. However, this approach provides limited information since, for instance, it ignores correlation among parameters. The aim of this study is to propose a new set of sensitivity functions, called the generalized sensitivity functions (GSF), for the analysis of input–output identification experiments. GSF are based on information theoretical criteria and provide, as compared to traditional sensitivity analysis, a more accurate picture on the information content of measured outputs on individual model parameters at different times. Case studies are presented on an input–output model and on two structural circulatory and respiratory models. GSF allow the definition of relevant time intervals for the identification of specific parameters and improve the understanding of the role played by specific model parameters in describing experimental data. © 1999 Biomedical Engineering Society. PAC99: 8710+e, 8719Uv

Vortex shedding in steady flow through a model of an arterial stenosis and its relevance to mural platelet deposition.

Abstract: In this study, the development of unsteady vortical formations in the separated flow region distal to a stenosis throat is presented and compared with the platelet deposition measurements, to enhance our understanding of the mecha- nisms involved in platelet kinetics in flowing blood Qualitative and quantitative flow visualization and numerical simulations were performed in a model of a streamlined axisymmetric stenosis with an area reduction of 84% at the throat of the stenosis Measurements were performed at Reynolds numbers ~Re!, based on upstream diameter and average velocity, ranging from 300 to 1800 Both the digital particle image visualization method employed and the numerical simulations were able to capture the motion of the vortices through the separated flow region Periodic shedding of vortices began at approximately Re5375 and continued for the full range of Re studied The locales at which these vortices are initiated, their size, and their life span, were a function of Re The numerical simulations of turbulent flow through the stenosis model entailed a detailed depiction of the process of vortex shedding in the separated flow region downstream of the stenosis These flow patterns were used to elucidate the mechanisms involved in blood plate- let kinetics and deposition in the area in and around an arterial stenosis The unsteady flow development in the recirculation region is hypothesized as the mechanism for observed changes in the distribution of mural platelet deposition between Re 5300, 900, and 1800, despite only a marginal variation in the size and shape of the recirculation zone under these flow con- ditions © 1999 Biomedical Engineering Society @S0090-6964~99!00306-9#

How heterogeneous bronchoconstriction affects ventilation distribution in human lungs: a morphometric model.

Abstract: Convective dependent flow heterogeneities associated with airways proximal to the acini are the dominant cause of abnormal ventilation distribution during induced bronchoconstriction (Verbanck, S., D. Schuermans, A. Van Muylem, M. Paira, M. Noppen, and W. Vincken. Ventilation distribution during histamine provocation. J. Appl. Physiol. 83:1907-1916, 1997). We applied a morphometric model of the human lung to predict flow distributions among the acini during heterogeneous bronchoconstriction and relate these distributions to impairments in the mechanical properties of the lung. The model has an asymmetrical branching airway system. Heterogeneous constriction was invoked by defining an airway constriction distribution with a mean (mu) and coefficient of variation (CV) and either a Gaussian or log normal distribution. The lung resistance (RL) and elastance (EL) were most sensitive to severely heterogeneous constriction that produced a few highly constricted or closed airways dispersed randomly throughout the periphery. Ventilation distribution in the healthy lung was effectively homogeneous over the frequency range of 0.1-5.0 Hz. With homogeneous or mildly heterogeneous constriction (CV< or =20%) ventilation remained fairly homogeneous at low frequencies (< or =0.1 Hz) but rapidly became heterogeneous as frequency increased. Conversely, a low mean but severely heterogeneous constriction that produced random airway closure produced abnormal ventilation distribution in most acini at all frequencies, and some acini received up to 25 times the normal ventilation. This suggests that certain forms of heterogeneity can lead to shear induced lung injury even at common mechanical ventilation rates.

Estimation of the shear stress on the surface of an aortic valve leaflet

Abstract: The limited durability of xenograft heart valves and the limited supply of allografts have sparked interest in tissue engineered replacement valves. A bioreactor for tissue engineered valves must operate at conditions that optimize the biosynthetic abilities of seeded cells while promoting their adherence to the leaflet matrix. An important parameter is shear stress, which is known to influence cellular behavior and may thus be crucial in bioreactor optimization. Therefore, an accurate estimate of the shear stress on the leaflet surface would not only improve our understanding of the mechanical environment of aortic valve leaflets, but it would also aid in bioreactor design. To estimate the shear stress on the leaflet surface, two-component laser-Doppler velocimetry measurements have been conducted inside a transparent polyurethane valve with a trileaflet structure similar to the native aortic valve. Steady flow rates of 7.5, 15.0, and 22.5 L/min were examined to cover the complete range possible during the cardiac cycle. The laminar shear stresses were calculated by linear regression of four axial velocity measurements near the surface of the leaflet. The maximum shear stress recorded was 79 dyne/cm2, in agreement with boundary layer theory and previous experimental and computational studies. This study has provided a range of shear stresses to be explored in bioreactor design and has defined a maximum shear stress at which cells must remain adherent upon a tissue engineered construct. © 1999 Biomedical Engineering Society. PAC99: 8719Rr, 8768+z, 8719Hh, 4262Be, 4727Nz, 0630Gv

Measurement of Orientation and Distribution of Cellular Alignment and Cytoskeletal Organization

Abstract: Endothelial cells elongate and align with the direction of applied fluid shear stress. Previously, automated methods for analysis of cell orientation distribution have used Fourier- or fractal-based methods. We used intensity gradients in images of control and sheared endothelial cells to measure orientation distributions. Automated measurements of mean orientation and angular deviation compared favorably with manual measurements. There was a significantly greater angular deviation in images of control cells compared with sheared cells. Automated methods were also used to quantify organization of cytoskeletal fibers using the local angular deviation and a measure of the local coalignment of fibers called the coalignment ratio. The local angular deviation of microtubules and microfilaments was significantly smaller in sheared cells compared with control. The coalignment of cytoskeletal fibers was significantly greater in sheared cells. We conclude that image intensity gradients can be used rapidly, accurately, and objectively to measure cell orientation distributions and cytoskeletal filament organization. © 1999 Biomedical Engineering Society. PAC99: 8716Ka, 8717-d, 8719Rr, 8764Rr, 0705Pj

Technique to determine inspiratory impedance during mechanical ventilation: implications for flow limited patients.

Abstract: We present the design of an enhanced ventilator waveform ~EVW! for routine measurement of inspiratory resis- tance ~R! and elastance ~E! spectra in ventilator-dependent and/or severely obstructed flow-limited patients. The EVW de- livers an inspiratory tidal volume of fresh gas with a flow pattern consisting of multiple sinusoids from 0.156 to 8.1 Hz and permits a patient-driven exhalation to the atmosphere or positive end-expiratory pressure. Weighted least-squares esti- mates of the coefficients in a sinusoidal series approximation of the EVW inspirations yielded inspiratory R and E spectra. We first validated the EVW approach using simulated pressure and flow data under different physiological conditions, noise levels, and harmonic distortions. We then applied the EVW in four intubated patients during anesthesia and paralysis: two with mild airway obstruction and two with severe emphysema and flow limitation. While the level of inspiratory R was similar in both groups of patients, the inspiratory E of the emphysema- tous patients demonstrated a pronounced frequency-dependent increase consistent with severe peripheral airway obstruction. We conclude that the EVW offers a potentially practical and efficient approach to monitor lung function in ventilator- dependent patients, especially those with expiratory flow limi- tation. © 1999 Biomedical Engineering Society. @S0090-6964~99!02203-1#

Computational blood flow modeling based on in vivo measurements.

Abstract: Study of the relationship between hemodynamics and atherogenesis requires accurate three-dimensional descriptions of in vivo arterial geometries. Common methods for obtaining such geometries include in vivo medical imaging and postmortem preparations (vessel casts, pressure-fixed vessels). We sought to determine the relative accuracy of these methods. The aorto–iliac (A/I) region of six rabbits was imaged in vivo using contrast-enhanced magnetic resonance imaging (MRI). After sacrifice, the geometry of the A/I region was preserved via vascular casts in four animals, and ex situ pressure fixation (while preserving dimensions) in the remaining two animals. The MR images and postmortem preparations were used to build computer representations of the A/I bifurcations, which were then used as input for computational blood flow analyses. Substantial differences were seen between MRI-based models and postmortem preparations. Bifurcation angles were consistently larger in postmortem specimens, and vessel dimensions were consistently smaller in pressure-fixed specimens. In vivo MRI-based models underpredicted aortic dimensions immediately proximal to the bifurcation, causing appreciable variation in the aorto–iliac parent/child area ratio. This had an important effect on wall shear stress and separation patterns on the “hips” of the bifurcation, with mean wall shear stress differences ranging from 15% to 35%, depending on the model. The above results, as well as consideration of known and probable sources of error, suggests that in vivo MRI best replicates overall vessel geometry (vessel paths and bifurcation angle). However, vascular casting seems to better capture detailed vessel cross-sectional dimensions and shape. It is important to accurately characterize the local aorto–iliac area ratio when studying in vivo bifurcation hemodynamics. © 1999 Biomedical Engineering Society.

Kinetic model for integrin-mediated adhesion release during cell migration.

Abstract: Under many circumstances, cell migration speed is limited by the rate of cell-substratum detachment at the cell rear. We have constructed a mathematical model to integrate how the biophysical and biochemical interactions between integrins, the cytoskeleton, and the matrix affect rear retraction and linkage dissociation mechanisms. Our model also examines how applied forces and integrin clustering affect retraction kinetics. The model predicts two distinct detachment phenotypes. In the first, detachment is extremely rapid, dominated by integrin extracellular-matrix dissociation, and it occurs at high forces or low adhesiveness. In the second, detachment is much slower, dominated by integrin-cytoskeleton dissociation, and it occurs at low forces or high adhesiveness. The amount of integrin extracted from the rear of the cell is an assay for the detachment phenotype. During rapid detachment cells leave little integrin on the substratum whereas during slow detachment a large fraction of integrin rips from the membrane. This model delineates parameters which can be exploited to regulate cell speed in each detachment regime. The model also offers an explanation as to why some cell types, such as leukocytes or keratocytes, are able to detach easily and move very quickly while other cell types, such as fibroblasts, tend to migrate more slowly and release many more integrins during detachment.

Reflex Torque Response to Movement of the Spastic Elbow: Theoretical Analyses and Implications for Quantification of Spasticity

Abstract: A parametric model of the human reflex torque response to a large-amplitude, constant angular velocity elbow extension was developed in order to help quantify spasticity in hemiparetic stroke patients, and to better understand its pathophysiology. The model accounted for the routinely observed leveling of torque (i.e., a plateau) at a mean angular increment of 51°±10° s.d. (n=98) after the initial rise. This torque “plateau” was observed in all eight subjects, and in 98 of 125 trials across 25 experimental sessions. The occurrence of this plateau cannot be explained by decreases in elbow flexor moment arms during elbow extension. Rather, the plateau is attributable to a consistent leveling in muscle activation as confirmed both qualitatively from recordings of rectified, smoothed electromyograph (EMG) activity, and quantitatively using an EMG coefficient model. A parametric model was developed in which the pattern of muscle activation in the stretch reflex response of elbow flexors was described as a cumulative normal distribution with respect to joint angle. Two activation functions, one related to biceps and the other to brachioradialis/brachialis, were incorporated into the model in order to account for observations of a bimodal angular stiffness profile. The resulting model yielded biologically plausible parameters of the stretch reflex response which may prove useful for quantifying spasticity. In addition, the model parameters had clear pathophysiological analogs, which may help us understand the nature of the stretch reflex response in spastic muscles. © 1999 Biomedical Engineering Society.

Pulse pressure method and the area method for the estimation of total arterial compliance in dogs: sensitivity to wave reflection intensity.

Abstract: We estimated total arterial compliance (C) in eight anesthetized mongrel dogs with (i) the area method (AM), (ii) the pulse pressure method (PPM), and (iii) the stroke volume-to-pulse pressure ratio (SV/PP). Average compliance was C_AM=1.11 ± 0.7 ml mm Hg1 using AM; CPPM=0.60 ± 0.31 ml mm Hg-1 using PPM and CSV/PP=0.87 ± 0.49 ml mm Hg-1 using SV/PP. Mean aortic pressure was 64 ± 23 mm Hg. The overall agreement between CAM and CPPM was relatively poor (CAM=0.15+1.61 CPPM; r2=0.48), with a consistent overestimation of the area method with respect to the pulse pressure method. There was a significant correlation (r= -0.78) between the relative difference between PPM and AM, and the modulus of the first harmonic of the wave reflection coefficient |Γ| which was low in our dog population (0.37 ± 0.18). SV/PP overestimated PPM, but both methods were highly correlated (CSV/PP=0.06+1.60 CPPM; r2=0.97). CSV/PP and CAM were similar only for |Γ| > 0.4. The effect of isolated changes of |Γ| on PPM, AM, and SV/PP was studied using the linear wave separation technique. The area method appeared very sensitive to the wave reflection intensity. For low reflection coefficients, the diastolic wave profile was flattened and compliance was overestimated. PPM and SV/PP were relatively independent of |Γ| and remained even applicable for |Γ| = 0. We believe that the pulse pressure method is the most consistent method for the estimation of total arterial compliance in hemodynamic conditions characterized by a low wave reflection intensity. © 1999 Biomedical Engineering Society.

Assessment of active and passive restraint during guided reaching after chronic brain injury.

Abstract: We report the use of a mechatronic device for assessing arm movement impairment after chronic brain injury. The device, called the “Assisted Rehabilitation and Measurement Guide,” is designed to guide reaching movements across the workspace, to measure movement and force generation, and to apply controlled forces to the arm along linear reaching paths. We performed a series of experiments using the device in order to identify the contribution of active muscle and passive tissue restraint to decreased active range of motion of guided reaching (i.e., “workspace deficits”) in a group of five chronic, spastic hemiparetic, brain-injured subjects. Our findings were that passive tissue restraint was increased in the spastic arms, as compared to the contralateral, nonparetic arms. Active muscle restraint, on the other hand, was typically comparable in the two arms, as quantified by measurements of active arm stiffness at the workspace boundary during reaching. In all subjects, there was evidence of movement-generated weakness, consistent with a small contribution of spasticity to workspace deficits. These results demonstrate the feasibility of mechatronic assessment of the causes of decreased functional movement, and could provide a basis for enhanced treatment planning and monitoring following brain injury. © 1999 Biomedical Engineering Society.

Dynamics of the intrauterine fluid-wall interface.

Abstract: Intrauterine fluid movements, which are responsible for embryo transport to a successful implantation site at the fundus, may be induced by myometrial contractions. Myometrial contractions in nonpregnant uteri were studied from in vivo measurements of intrauterine pressures with fluid-filled catheters and by visual observations of high-speed replaying of ultrasound images of the uterus. Transvaginal ultrasound (TVUS) images of sagittal cross sections of the nonpregnant uterus were scanned with an intravaginal ultrasound probe. Images at consecutive times (2 s apart) were digitized and processed by employing modern techniques of image processing. The sets of images were compared to evaluate time variation of the fluid–wall interface with respect to amplitude, frequencies, and wavelength of myometrial contractions. Analysis of TVUS images from 11 volunteers during the proliferative phase revealed that myometrial contractions are fairly symmetric and are propagated from the cervix towards the fundus at a frequency of about 0.01-0.09 Hz. The wavelength, amplitude, and velocity of the fluid–wall interface during a typical contractile wave were found to be 10-30 mm, 0.05-0.2 mm, and 0.5-1.9 mm/s, respectively. Additional data acquisition from a large number of normal subjects is needed to build a data base to predict normal characteristics of myometrial contractions in a nonpregnant uterus, in order to better understand their role in the preimplantation process. © 1999 Biomedical Engineering Society. PAC99: 8717Jj, 8719St, 4380Qf, 8763Df

Quantitative assessment of steady and pulsatile flow fields in a parallel plate flow chamber.

Abstract: Steady and pulsatile flows were imaged and quantified in a parallel plate flow chamber that was designed to allow constant variation of the volumetric flow rate and to minimize pressure gradients across the width of the flow field. Results indicated that both the steady and pulsatile flow fields were uniform across the width of the flow chamber as shown by linear regression analysis. Further, the dynamic effects of the fluid pulse were transmitted almost instantaneously across the length of the flow field. These findings verify that parallel plate devices designed in this manner are suitable for delivering uniform steady and pulsatile shear stress to adherent cell populations in vitro.

Effect of cell migration on the maintenance of tension on a collagen matrix.

Abstract: Although it is known that cells promote structural reorganization of the collagen architecture, how individual cells exert mechanical tension on the matrix is not clearly understood. In the present study we have investigated the mechanical interaction of individual corneal fibroblasts with a collagen matrix using an improved version of our previously described in vitro force-measurement system (Roy, P. et al. Exp. Cell Res. 232:106-117, 1997). The elastic distortion of the collagen matrix exerted by cells was temporally recorded and analyzed using a two-dimensional finite-element model to quantify the forces exerted on the matrix. Time-lapse videomicroscopy of serum-cultured cells on the matrix for up to 6 h revealed that individual fibroblasts generated measurable tension on the matrix during pseudopodial extension and slow retraction. Fast retraction, an event observed during active cell migration, was associated with dramatic release of tension on the matrix. An apparent inverse correlation was observed between cell translocation and maintenance of matrix tension. Additional experiments with cells under serum-free conditions revealed that these cells fail to generate any detectable tension on the matrix despite undergoing filopodial extension and retraction. Since serum-free cells do not form focal adhesions or stress fibers, these experimental data suggest that contractility of nonmotile cells, coupled with strong cell-matrix adhesion, is the most favorable mechanism of generating and maintaining tension on the extracellular matrix.

Effects of nucleus on leukocyte recovery.

Abstract: The rheological properties of a leukocyte significantly affect its biological and mechanical characteristics. To date, existing physical models of leukocyte are not capable of quantitatively explaining the wide range of deformation and recovery behaviors observed in experiment. However, a compound drop model has gained some success. In the present work, we investigate the effect of nucleus size and position, and the relative rheological properties of cytoplasm and nucleus, on cell recovery dynamics. Two nucleus sizes corresponding to that of neutrophil and lymphocyte are considered. Direct comparison between numerical simulations and experimental observation is made. Results indicate that the time scale ratio between the nucleus and cytoplasm plays an important role in cell recovery characteristics. Comparable time scales between the two cell components yield favorable agreement in recovery rates between numerical and experimental observations; disparate time scales, on the other hand, result in recovery behavior and cell shapes inconsistent with experiments. Furthermore, it is found that the nucleus eccentricity exhibits minimum influence on all major aspects of the cell recovery characteristics. The present work offers additional evidence in support of the compound cell model for predicting the rheological behavior of leukocytes. © 1999 Biomedical Engineering Society.

Hemodynamic effect of cerebral vasospasm in humans: a modeling study.

Abstract: A mathematical model of cerebral hemodynamics during vasospasm is presented. The model divides arterial hemodynamics into two cerebral territories: with and without spasm. It also includes collateral circulation between the two territories, cerebral venous hemodynamics, cerebrospinal fluid circulation, intracranial pressure (ICP) and the craniospinal storage capacity. Moreover, the pial artery circulation in both territories is affected by cerebral blood flow (CBF) autoregulation mechanisms. In this work, a numerical value to model parameters was given assuming that vasospasm affects only a single middle cerebral artery (MCA). In a first stage, the model is used to simulate some clinical results reported in the literature, concerning the patterns of MCA velocity, CBF and pressure losses during vasospasm. The agreement with clinical data turns out fairly good. In a second stage, a sensitivity analysis on some model parameters is performed (severity of caliber reduction, longitudinal extension of the spasm, autoregulation gain, ICP, resistance of the collateral circulation, and mean systemic arterial pressure) to clarify their influence on hemodynamics in the spastic territory. The results suggest that the clinical impact of vasospasm depends on several concomitant factors, which should be simultaneously taken into account to reach a proper diagnosis. In particular, while a negative correlation between MCA velocity and cross sectional area can be found until CBF is well preserved, a positive correlation may occur when CBF starts to decrease significantly. This might induce false-negative results if vasospasm is assessed merely through velocity measurements performed by the transcranial Doppler technique. © 1999 Biomedical Engineering Society. PAC99: 8719Uv, 8719La, 8710+e

Computationally efficient model for simulating electrical activity in cardiac tissue with fiber rotation.

Abstract: Transmural rotation of cardiac fibers may have a large influence on the initiation, stabilization, and termination of several life threatening cardiac arrhythmias. However, three-dimensional modeling of reentry in cardiac tissue is computationally demanding, as a tissue on the order of centimeters in size must be used to sustain reentry and several seconds must be simulated. Numerical accuracy requires time steps on the order of microseconds and spatial discretization on the order of microns. Consequently, the resultant numerical systems are extremely large. In this article, a computationally efficient model of a three-dimensional block of cardiac tissue with fiber rotation is presented. Computational speedup is achieved by using a discrete cable model which allowed for system order reduction, and also by using a scheme for tracking the activation wave front which identified regions requiring integration with a small time step. Simulating 1.2 s of activity of the approximately 2 x 10(6) cells constituting a block measuring 2.0 x 4.0 x 0.29 cm was performed in 26 h. Effects of model parameters on performance are discussed. The effect of fiber rotation on the spread of electrical activity after point source stimulation and a cross shock protocol is clearly demonstrated.

Practical real-time computing system for biomedical experiment interface.

Abstract: Many biomedical experiments require a precisely timed real-time (RT) computer interface. Because commonly used desktop operating systems are inherently non-real-time, real-time laboratory computer systems are often based on outdated DOS software or expensive proprietary real-time operating systems. Here we discuss a real-time computing system, based on the free RT-LINUX operating system, which we have developed for adaptive pacing control in a clinical cardiac electrophysiology laboratory. This powerful, flexible, and inexpensive system demonstrates that RT-LINUX is well suited for real-time biomedical experiment interface.

Two methods for identifying Wiener cascades having noninvertible static nonlinearities.

Abstract: Two methods are proposed for identifying the component elements of a Wiener cascade that is comprised of a dynamic linear element (L) followed by a static nonlinearity (N). Both methods avoid potential problems of instability in a procedure presented by Paulin [M. G. Paulin, Biol. Cybern. 69: 67–76, 1993], which itself is a modification of a method described earlier by Hunter and Korenberg [I. W. Hunter and M. J. Korenberg, Biol. Cybern. 55: 135–144, 1996]. The latter method is a rapidly convergent iterative procedure that produces accurate estimates of the L and N elements from short data records, provided that the static nonlinearity N is invertible. Subsequently, Paulin introduced a modification that removed this limitation and enabled identification of Wiener cascades with nonmonotonic static nonlinearities. However, Paulin presented his modification employing an autoregressive moving average (ARMA) model representation for the dynamic linear element. To remove the possibility that the estimated ARMA model could be unstable, we recast the procedure by utilizing instead a rapid method for finding an impulse response representation for the dynamic linear element. However, in this form the procedure did not have good convergence properties, so we introduced two key ideas, both of which provide effective alternatives for identifying Wiener cascades whether or not the static nonlinearities therein are invertible. The new procedures are illustrated on challenging examples involving high-degree polynomial static nonlinearities, of odd or even symmetry, a high-pass linear element, and output noise corruption of 50%. © 1999 Biomedical Engineering Society. PAC99: 8710+e, 0210Nj, 0250-r