Jeffrey J. Heys

Spatiotemporal temperature distribution and cancer cell death in response to extracellular hyperthermia induced by gold nanorods.

Plasmonic nanoparticles have shown promise in hyperthermic cancer therapy, both in vitro and in vivo. Previous reports have described hyperthermic ablation using targeted and nontargeted nanoparticles internalized by cancer cells, but most reports do not describe a theoretical analysis for determining optimal parameters. The focus of the current research was first to evaluate the spatiotemporal temperature distribution and cell death induced by extracellular hyperthermia in which gold nanorods (GNRs) were maintained in the dispersion outside human prostate cancer cells. The nanorod dispersion was irradiated with near-infrared (NIR) laser, and the spatiotemporal distribution of temperature was determined experimentally. This information was employed to develop and validate theoretical models of spatiotemporal temperature profiles for gold nanorod dispersions undergoing laser irradiation and the impact of the resulting heat generation on the viability of human prostate cancer cells. A cell injury/death model was then coupled to the heat transfer model to predict spatial and temporal variations in cell death and injury. The model predictions agreed well with experimental measurements of both temperature and cell death profiles. Finally, the model was extended to examine the impact of selective binding of gold nanorods to cancer cells compared to nonmalignant cells, coupled with a small change in cell injury activation energy. The impact of these relatively minor changes results in a dramatic change in the overall cell death rate. Taken together, extracellular hyperthermia using gold nanorods is a promising strategy, and tailoring the cellular binding efficacy of nanorods can result in varying therapeutic efficacies using this approach.

Permeability and diffusion in vitreous humor: implications for drug delivery.

AbstractPurpose. Previous experimental work suggests that convection maybe important in determining the biodistribution of drugs implanted orinjected in the vitreous humor. To develop accurate biodistributionmodels, the relative importance of diffusion and convection inintravitreal transport must be assessed. This requires knowledge of both thediffusivity of candidate drugs and the hydraulic conductivity of thevitreous humor. Methods. Hydraulic conductivity of cadaveric bovine vitreous humorwas measured by confined compression tests at constant loads of 0.15and 0.2 N and analyzed numerically using a two-phase model. Diffusioncoefficient of acid orange 8, a model compound, in the same mediumwas measured in a custom-built diffusion cell. Results. Acid orange 8 diffusivity within vitreous humor is about halfthat in free solution. When viscous effects are properly accounted for,the hydraulic conductivity of bovine vitreous humor is 8.4 ± 4.5 ×10−7 cm2/Pa s. Conclusions. We predict that convection does not contributesignificantly to transport in the mouse eye, particularly forlow-molecular-weight compounds. For delivery to larger animals, such as humanswe conclude that convection accounts for roughly 30% of the totalintravitreal drug transport. This effect should be magnified forhigher-molecular-weight compounds, which diffuse more slowly, and inglaucoma, which involves higher intraocular pressure and thus potentiallyfaster convective flow. Thus, caution should be exercised in theextrapolation of small-animal-model biodistribution data to human scale.

Modeling Passive Mechanical Interaction Between Aqueous Humor and Iris

Certain forms of glaucoma are associated with displacement of the iris from its normal contour. We present here a mathematical model of the coupled aqueous humor-iris system that accountsfor the contribution of aqueous humor flow and passive iris deformability to the iris contour. The aqueous humor is modeled as a Newtonian fluid, and the iris is modeled as a linear elastic solid. The resulting coupled equation set is solved by the finite element method with mesh motion in response to iris displacement accomplished by tracking a pseudo-solid overlying the aqueous humor. The model is used to predict the iris contour in healthy and diseased eyes. The results compare favorably with clinical observations, supporting the hypothesis that passive iris deformation can produce the iris contours observed using ultrasound biomicroscopy.

A boussinesq model of natural convection in the human eye and the formation of Krukenberg's spindle.

AbstractThe cornea of the human eye is cooled by the surrounding air and by evaporation of the tear film. The temperature difference between the cornea and the iris (at core body temperature) causes circulation of the aqueous humor in the anterior chamber of the eye. Others have suggested that the circulation pattern governs the shape of the Krukenberg spindle, a distinctive vertical band of pigment on the posterior cornea surface in some pathologies. We modeled aqueous humor flow the human eye, treating the humor as a Boussinesq fluid and setting the corneal temperature based on infrared surface temperature measurements. The model predicts convection currents in the anterior chamber with velocities comparable to those resulting from forced flow through the gap between the iris and lens. When paths of pigment particles are calculated based on the predicted flow field, the particles circulate throughout the anterior chamber but tend to be near the vertical centerline of the eye for a greatest period of time. Further, the particles are usually in close proximity to the cornea only when they are near the vertical centerline. We conclude that the convective flow pattern of aqueous humor is consistent with a vertical pigment spindle.

Impact of acute moderate elevation in left ventricular afterload on diastolic transmitral flow efficiency: analysis by vortex formation time.

BACKGROUND The formation of a vortex alongside a diastolic jet signifies an efficient blood transport mechanism. Vortex formation time (VFT) is an index of the optimal conditions for vortex formation. It was hypothesized that left ventricular (LV) afterload impairs diastolic transmitral flow efficiency and therefore shifts the VFT out of its optimal range. METHODS In 9 open-chest pigs, LV afterload was elevated by externally constricting the ascending aorta and increasing systolic blood pressure to 130% of baseline value for 3 minutes. RESULTS Systolic LV function decreased, diastolic filling velocity increased only during the late (atrial) phase from 0.46 +/- 0.06 to 0.63 +/- 0.19 m/s (P = .0231), and end-diastolic LV volume and heart rate remained unchanged. VFT decreased from 4.09 +/- 0.27 to 2.78 +/- 1.03 (P = .0046). CONCLUSION An acute, moderate elevation in LV afterload worsens conditions for diastolic vortex formation, suggesting impaired blood transport efficiency.

An Alternative Least-Squares Formulation of the Navier-Stokes Equations with Improved Mass Conservation

The focus of this paper is on incompressible flows in three dimensions modeled by least-squares finite element methods (LSFEM) and using a novel reformulation of the Navier-Stokes equations. LSFEM are attractive because the resulting discrete equations yield symmetric, positive definite systems of algebraic equations and the functional provides both a local and global error measure. On the other hand, it has been documented for existing reformulations that certain types of boundary conditions and high-aspect ratio domains can yield very poor mass conservation. It has also been documented that improved mass conservation with LSFEM can be achieved by strengthening the coupling between the pressure and velocity. The new reformulation presented here is demonstrated to provide both improved multigrid convergence rates because it is differentially diagonally dominant and improved mass conservation over existing methods because it increases the pressure-velocity coupling along the inflow and outflow boundaries.

Revisiting the Simplified Bernoulli Equation

Background: The assessment of the severity of aortic valve stenosis is done by either invasive catheterization or non-invasive Doppler Echocardiography in conjunction with the simplified Bernoulli equation. The catheter measurement is generally considered more accurate, but the procedure is also more likely to have dangerous complications. Objective: The focus here is on examining computational fluid dynamics as an alternative method for analyzing the echo data and determining whether it can provide results similar to the catheter measurement. Methods: An in vitro heart model with a rigid orifice is used as a first step in comparing echocardiographic data, which uses the simplified Bernoulli equation, catheterization, and echocardiographic data, which uses computational fluid dynamics (i.e., the Navier-Stokes equations). Results: For a 0.93cm2 orifice, the maximum pressure gradient predicted by either the simplified Bernoulli equation or computational fluid dynamics was not significantly different from the experimental catheter measurement (p > 0.01). For a smaller 0.52cm2 orifice, there was a small but significant difference (p < 0.01) between the simplified Bernoulli equation and the computational fluid dynamics simulation, with the computational fluid dynamics simulation giving better agreement with experimental data for some turbulence models. Conclusion: For this simplified, in vitro system, the use of computational fluid dynamics provides an improvement over the simplified Bernoulli equation with the biggest improvement being seen at higher valvular stenosis levels.

Modeling arthropod filiform hair motion using the penalty immersed boundary method

Crickets are able to sense their surrounding environment through about 2000 filiform hairs located on a pair of abdominal cerci. The mechanism by which the cricket is able to sense a wide range of input signals using these filiform hairs of different length and orientation is of great interest. Most of the previous filiform hair models have focused on a single, rigid hair in an idealized air field. Here, we present a model of the cercus and filiform hairs that are mechanically coupled to the surrounding air, and the model equations are based on the penalty immersed boundary method. The key difference between the penalty immersed boundary method and the traditional immersed boundary method is the addition of forces to account for density differences between the immersed solid (the filiform hairs) and the surrounding fluid (air). The model is validated by comparing the model predictions to experimental results, and then the model is used to examine the interactions between multiple hairs. With multiple hairs, there is little interaction when the hairs are separated by more than 1mm, and, as they move closer, they interact through viscous coupling, which reduces the deflection of the hairs due to the air movement. We also examine the computational scalability of the algorithm and show that the computational costs grow linearly with the number of hairs being modeled.

Flow Velocity Vector Fields by Ultrasound Particle Imaging Velocimetry In Vitro Comparison With Optical Flow Velocimetry

We performed an in vitro study to assess the precision and accuracy of particle imaging velocimetry (PIV) data acquired using a clinically available portable ultrasound system via comparison with stereo optical PIV.

Quantitative Characterization of the Filiform Mechanosensory Hair Array on the Cricket Cercus

Background Crickets and other orthopteran insects sense air currents with a pair of abdominal appendages resembling antennae, called cerci. Each cercus in the common house cricket Acheta domesticus is approximately 1 cm long, and is covered with 500 to 750 filiform mechanosensory hairs. The distribution of the hairs on the cerci, as well as the global patterns of their movement vectors, have been characterized semi-quantitatively in studies over the last 40 years, and have been shown to be very stereotypical across different animals in this species. Although the cercal sensory system has been the focus of many studies in the areas of neuroethology, development, biomechanics, sensory function and neural coding, there has not yet been a quantitative study of the functional morphology of the receptor array of this important model system. Methodology/Principal Findings We present a quantitative characterization of the structural characteristics and functional morphology of the cercal filiform hair array. We demonstrate that the excitatory direction along each hairs movement plane can be identified by features of its socket that are visible at the light-microscopic level, and that the length of the hair associated with each socket can also be estimated accurately from a structural parameter of the socket. We characterize the length and directionality of all hairs on the basal half of a sample of three cerci, and present statistical analyses of the distributions. Conclusions/Significance The inter-animal variation of several global organizational features is low, consistent with constraints imposed by functional effectiveness and/or developmental processes. Contrary to previous reports, however, we show that the filiform hairs are not re-identifiable in the strict sense.