Biomedical subjects

F Stuart Foster

Publications and source records attributed to F Stuart Foster.

At least 19 recordsLinked to original sources

PubMed2006

Nonlinear ultrasound propagation through layered liquid and tissue-equivalent media: computational and experimental results at high frequency.

Nonlinear propagation has been demonstrated to have a significant impact on ultrasound imaging. An efficient computational algorithm is presented to simulate nonlinear ultrasound propagation through layered liquid and tissue-equivalent media. Results are compared with hydrophone measurements. This study was undertaken to investigate the role of nonlinear propagation in high frequency ultrasound micro-imaging. The acoustic field of a focused transducer (20 MHz centre frequency, f-number 2.5) was simulated for layered media consisting of water and tissue-mimicking phantom, for several wide-bandwidth source pulses. The simulation model accounted for the effects of diffraction, attenuation and nonlinearity, with transmission and refraction at layer boundaries. The parameter of nonlinearity, B/A, of the water and tissue-mimicking phantom were assumed to be 5.2 and 7.4, respectively. The experimentally measured phantom B/A value found using a finite-amplitude insert-substitution method was shown to be 7.4 +/- 0.6. Relative amounts of measured second and third harmonic pressures as a function of the fundamental pressures at the focus were in good agreement with simulations. Agreement within 3% was found between measurements and simulations of the beam widths of the fundamental and second harmonic signals following propagation through the tissue phantom. The results demonstrate significant nonlinear propagation effects for high frequency imaging beams.

Computer Simulation↗

PubMed2006

Hemodynamics in the mouse aortic arch as assessed by MRI, ultrasound, and numerical modeling.

Mice are widely used to study arterial disease in humans, and the pathogenesis of arterial diseases is known to be strongly influenced by hemodynamic factors. It is, therefore, of interest to characterize the hemodynamic environment in the mouse arterial tree. Previous measurements have suggested that many relevant hemodynamic variables are similar between the mouse and the human. Here we use a combination of Doppler ultrasound and MRI measurements, coupled with numerical modeling techniques, to characterize the hemodynamic environment in the mouse aortic arch at high spatial resolution. We find that the hemodynamically induced stresses on arterial endothelial cells are much larger in magnitude and more spatially uniform in the mouse than in the human, an effect that can be explained by fluid mechanical scaling principles. This surprising finding seems to be at variance with currently accepted models of the role of hemodynamics in atherogenesis and the known distribution of atheromatous lesions in mice.

Animals↗

PubMed2006

Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors.

The contribution of bone marrow-derived circulating endothelial progenitor cells (CEPs) to tumor angiogenesis has been controversial, primarily because of their low numbers in blood vessels of untreated tumors. We show that treatment of tumor-bearing mice with vascular disrupting agents (VDAs) leads to an acute mobilization of CEPs, which home to the viable tumor rim that characteristically remains after such therapy. Disruption of this CEP spike by antiangiogenic drugs or by genetic manipulation resulted in marked reductions in tumor rim size and blood flow as well as enhanced VDA antitumor activity. These findings also provide a mechanistic rationale for the enhanced efficacy of VDAs when combined with antiangiogenic drugs.

Angiogenesis Inhibitors↗

PubMed2006

Transgenic expression of Angiopoietin 1 in the liver leads to changes in lymphatic and blood vessel architecture.

To investigate the possible role of the Angiopoietins in vessel remodelling, we overexpressed one of the angiopoietins, Angiopoietin-1 (Ang1), in the hepatocytes of mice by means of the conditional binary transgenic system. Animals were examined by Doppler ultrasound, and dissected livers were analyzed by immunohistochemical staining. Double transgenic mice presented with enlarged spleens and kidneys, enlarged, disorganized blood vessels located near the surface of the liver, sprouting, dilation, and disorganization of liver lymphatics, and turbulent flow in about 1/4 of the blood vessels sampled. Most of these characteristics completely resolved within 12 weeks of turning off the expression of the Ang1 transgene, illustrating a dependence on the continual presence of Ang1 for maintenance of the vascular phenotype. Conditional Angiopoietin-1 overexpression in the liver of mice leads to a phenotype highly reminiscent of portal hypertension illustrating that Ang1 can drive both vascular and lymphatic vessel remodelling and may play a role in portal hypertension.

Actins↗

PubMed2006

Targeted anti-vascular endothelial growth factor receptor-2 therapy leads to short-term and long-term impairment of vascular function and increase in tumor hypoxia.

Because antiangiogenic therapies inhibit the growth of new tumor-associated blood vessels, as well as prune newly formed vasculature, they would be expected to reduce the supply of oxygen and thus increase tumor hypoxia. However, it is not clear if antiangiogenic treatments lead only to consistent and sustained increases in hypoxia, or transient decreases in tumor hypoxia along with periods of increased hypoxia. We undertook a detailed analysis of an orthotopically transplanted human breast carcinoma (MDA-MB-231) over a 3-week treatment period using DC101, an anti-vascular endothelial growth factor receptor 2 antibody. We observed consistent reductions in microvascular density, blood flow (measured by high-frequency micro-ultrasound), and perfusion. These effects resulted in an increase in the hypoxic tumor fraction, measured with an exogenous marker, pimonidazole, concurrent with an elevation in hypoxia-inducible factor-1alpha expression, an endogenous marker. The increase in tumor hypoxia was evident within 5 days and remained so throughout the entire course of treatment. Vascular perfusion and flow were impaired at days 2, 5, 7, 8, 14, and 21 after the first injection, but not at 4 hours. A modest increase in the vessel maturation index was detected after the 3-week treatment period, but this was not accompanied by an improvement in vascular function. These results suggest that sustained hypoxia and impairment of vascular function can be two consistent consequences of antiangiogenic drug treatment. The implications of the results are discussed, particularly with respect to how they relate to different theories for the counterintuitive chemosensitizing effects of antiangiogenic drugs, even when hypoxia is increased.

Angiogenesis Inhibitors↗

PubMed2006

Investigating perfluorohexane particles with high-frequency ultrasound.

Submicron particles filled with liquid perfluorocarbon are currently being studied as a potential ultrasound-targeted contrast agent. The objective of this study was to evaluate the scattering properties of these particles. Sets of perfluorohexane-filled particles of different average sizes (300 nm to 1000 nm) were produced with a constant total volume fraction. The attenuation coefficient was measured in the 15- to 50-MHz frequency range and was found to increase smoothly with frequency and to be independent of the amplitude and bandwidth of the transmitted pulse. The values range from 0.31 to 0.64 dB/mm at 30 MHz for mean particle size ranging from 970 to 310 nm, respectively. The backscattering spectra of the particle solutions were measured and showed no sign of nonlinear scattering. The backscattering coefficient increased with the power 3.9 +/- 0.3 of the frequency. These results confirm that liquid perfluorocarbon droplets behave as linear Rayleigh scatterers.

Contrast Media↗

PubMed2006

Ultrahigh frame rate retrospective ultrasound microimaging and blood flow visualization in mice in vivo.

To overcome frame rate limitations in high-frequency ultrasound microimaging, new data acquisition techniques have been implemented for 2-D (B-scan) and color flow visualization. These techniques, referred to as retrospective B-scan imaging (RBI) and retrospective color flow imaging (RCFI) are based on the use of the electrocardiogram (ECG) to trigger signal acquisitions. B-scan and color flow images are reconstructed by retrospectively assembling the processed data on a line-by-line basis. Retrospective techniques are used to produce the first in vivo B-scan and color flow images of mouse carotid arteries at frame rates up to 10,000 fps. Retrospective B-scan images of mouse heart were also produced at frame rates of 1000 fps using a version of RBI implemented on a commercial imaging system (Vevo660, VisualSonics, Toronto, ON, Canada). This technology enables detailed in vivo biomechanical studies of dynamic tissues such as the myocardium of the mouse heart with high temporal resolution.

Animals↗

PubMed2006

A model for reflectivity enhancement due to surface bound submicrometer particles.

Submicrometer particles filled with liquid perfluorocarbon have been shown to increase the ultrasound reflectivity of surfaces onto which they bind and, consequently, are seen as potential targeted contrast agents. The objective of this study is to explain the reflectivity enhancement as a result of the presence of randomly distributed particles on a surface. A model is presented where the diffraction-weighted scattering of all particles is summed over the exposed surface. Experiments were performed at frequencies ranging from 15 MHz to 60 MHz, with glass microbeads and perfluorohexane particles deposited on the surface of agar and Aqualene, a rubber closely matched to water, to confirm the validity of the model. Results showed that the model predicts the surface density and the frequency dependence of the reflectivity enhancement up to a density corresponding to twice the maximum packing of spheres on a surface (200% confluence fraction) for glass beads and a fifth (20% confluence fraction) for perfluorohexane particles. This suggests the possibility of predicting signal enhancement due to a bound contrast agent in simple geometries.

Contrast Media↗

PubMed2006

Performance and characterization of new micromachined high-frequency linear arrays.

A new approach for fabricating high frequency (> 20 MHz) linear array transducers, based on laser micromachining, has been developed. A 30 MHz, 64-element, 74-microm pitch, linear array design is presented. The performance of the device is demonstrated by comparing electrical and acoustic measurements with analytical, equivalent circuit, and finite-element analysis (FEA) simulations. All FEA results for array performance have been generated using one global set of material parameters. Each fabricated array has been integrated onto a flex circuit for ease of handling, and the flex has been integrated onto a custom printed circuit board test card for ease of testing. For a fully assembled array, with an acoustic lens, the center frequency was 28.7 MHz with a one-way -3 dB and -6 dB bandwidth of 59% and 83%, respectively, and a -20 dB pulse width of -99 ns. The per-element peak acoustic power, for a +/- 30 V single cycle pulse, measured at the 10 mm focal length of the lens was 590 kPa with a -6 dB directivity span of about 30 degrees. The worst-case total cross talk of the combined array and flex assembly is for nearest neighboring elements and was measured to have an average level -40 dB across the -6 dB bandwidth of the device. Any significant deviation from simulation can be explained through limitations in apparatus calibration and in device packaging.

Computer-Aided Design↗

PubMed2005

Abnormal cardiac inflow patterns during postnatal development in a mouse model of Holt-Oram syndrome.

Tbx5(del/+) mice provide a model of human Holt-Oram syndrome. In this study, the cardiac functional phenotypes of this mouse model were investigated with 30-MHz ultrasound by comparing 12 Tbx5(del/+) mice with 12 wild-type littermates at 1, 2, 4, and 8 wk of age. Cardiac dimensions were measured with two-dimensional and M-mode imaging. The flow patterns in the left and right ventricular inflow channels were evaluated with Doppler flow sampling. Compared with wild-type littermates, Tbx5(del/+) mice showed significant changes in the mitral flow pattern, including decreased peak velocity of the left ventricular (LV) early filling wave (E wave), increased peak velocity of the late filling wave (A wave), and decreased or even reversed peak E-to-A ratio. The prolongation of LV isovolumic relaxation time was detected in Tbx5(del/+) neonates as early as 1 wk of age. In Tbx5(del/+) mice, LV wall thickness appeared normal but LV chamber dimension was significantly reduced. LV systolic function did not differ from that in wild-type littermates. In contrast, the Doppler flow spectrum in the enlarged tricuspid orifice of Tbx5(del/+) mice demonstrated increased peak velocities of both E and A waves and increased total time-velocity integral but unchanged peak E/A. In another 13 mice (7 Tbx5(del/+), 6 wild-type) at 2 wk of age, significant correlation was found between Tbx5 gene expression level in ventricular myocardium and LV filling parameters. In conclusion, the LV diastolic function of Tbx5(del/+) mice is significantly deteriorated, whereas the systolic function remains normal.

Animals↗

PubMed2005

Non-invasive high-frequency vascular ultrasound elastography.

Non-invasive vascular elastography (NIVE) was recently introduced to characterize mechanical properties of superficial arteries. In this paper, the feasibility of NIVE and its applicability in the context of high-frequency ultrasound imaging is investigated. First, experiments were performed in vitro on vessel-mimicking phantoms. Polyvinyl alcohol cryogel was used to create two double-layer vessels with different mechanical properties. In both cases, the stiffness of the inner layer was made softer. Radial stress was applied within the lumen of the phantoms by applying incremental static pressure steps with a column of a flowing mixture of water-glycerol. The vessel phantoms were insonified at 32 MHz with an ultrasound biomicroscope to provide cross-section sequences of radio-frequency (RF) ultrasound data. The Lagrangian speckle model estimator (LSME) was used to assess the two-dimensional-strain tensors, and the composite Von Mises elastograms were computed. A new implementation of the LSME based on the optical flow equations was introduced. Deformation parameters were estimated using an inversion algorithm. For each in vitro experiment, both layers of approximately 1 mm were distinguished. Second, the use of the method for the purpose of studying small vessels (MicroNIVE) in genetically engineered rodents was introduced. Longitudinal scans of the carotid artery were performed at 40 MHz. The in vivo results give confidence in the feasibility of MicroNIVE as a potential tool to non-invasively study the impact of targeted genes on vascular remodelling in rodents.

Algorithms↗

PubMed2005

Thermal assessment of 40-MHz pulsed Doppler ultrasound in human eye.

Tissue exposure to diagnostic pulsed Doppler ultrasound (US) can cause significant temperature rises. Temperature rise induced by US biomicroscopy (UBM) system (VS40, VisualSonics, Toronto, ON, Canada) was measured in ex vivo human and rabbit eyes with a 26-gauge K-type needle thermocouple. The operating frequency was 40 MHz with a free field I(SPTA) of 2.6 mW/cm(2) (B-mode) and 11.9 W/cm(2) (Doppler). Peak negative pressures were 5.22 MPa (B-mode) and 7.32 MPa (Doppler), resulting in MIs of 0.83 (B-mode) and 1.05 (Doppler mode). In Doppler mode, mean temperature rises of 2.27 degrees C and 1.93 degrees C were measured for the human lens and ciliary body after a 3-min insonation, vs. 2.66 degrees C for the rabbit lens. Our results indicate that US-induced temperature rise decreases with decreasing number of cycles, decreasing pulse-repetition frequency (PRF) or increased transmit attenuation, and is consistent with simple models of heating. To limit risk of temperature rises of 1 degrees C in human ciliary body, use of the maximum settings of 16 cycles (0.400 micros pulse duration), 20-kHz PRF should include 3-dB transmit attenuation, and exposure time should be limited. For insonation of the lens, exposure settings no higher than nine cycles (0.225-micros pulse duration) and 10-kHz PRF should be employed and exposure time limited to minimize risk of temperature increases of 1 degree C.

Aged↗

PubMed2005

Three-dimensional ultrasound biomicroscopy for xenograft growth analysis.

We reported the use of high-frequency ultrasound biomicroscopy (UBM) in the quantitative analysis of early tumor growth in mice bearing melanoma xenografts in a noninvasive longitudinal assay. Initially, measurements of tumor width, depth and length were obtained using on-screen UBM calipers in real time and tumor volume was calculated with the standard ellipsoid formula w d l pi/6. We were able to detect initiating minute tumor nodules, with the lower limit of detection at approximately 0.01 mm(3) in volume. Successive parallel cross-sectional UBM images (33 microm step) encompassing the complete length of these tumors were also obtained and reconstructed into 3-D representations. Subsequent segmentational volumetric analysis provided a measure of tumor volume. Volume measurements using the two techniques were highly correlated when all 33 xenografts were studied (r = 0.9813, p < 0.0001) and a lower degree of correlation was measured with a subset of early small tumors (r = 0.7973, n = 16, p = 0.0004). Further analysis demonstrated that 3-D segmentational volumetric analysis yielded volume estimates that were often smaller than the caliper-and-formula calculation for most early developing xenografts. Thus, 3-D UBM imaging and segmentation is expected to be especially valuable for small tumors that were observed to grow in irregular shapes other than ellipsoids.

Animals↗

PubMed2005

In vivo assessment of postnatal murine ocular development by ultrasound biomicroscopy.

PURPOSE: Ultrasound biomicroscopy (UBM) can noninvasively provide anatomical information about mouse ocular structures. We present the quantitation of postnatal murine eye development using UBM. MATERIALS AND METHODS: The eyes from CD-1 mice were examined at 1, 2, 4, 6, and 8 weeks of postnatal development using 40 MHz UBM. Patterns of ocular tissue growth including the lens, globe, and anterior chamber were calculated. RESULTS: Postnatal CD-1 lens and globe volumes are consistent with an exponential decay of growth during the first 8 postnatal weeks. Anterior chamber depth increases most sharply in the first 2 postnatal weeks but continues to increase up to the 8th postnatal week. Anterior segment angle was observed to increase from 1 to 4 weeks. CONCLUSIONS: UBM can be used to obtain in vivo quantitative measurements of postnatal murine ocular structures. Our ability to obtain ocular anatomical information will facilitate future assessments of mouse models of human disease.

Animals↗

PubMed2005

High frequency nonlinear B-scan imaging of microbubble contrast agents.

It previously was shown that it is possible to produce nonlinear scattering from microbubble contrast agents using transmit frequencies in the 14-32 MHz range, suggesting the possibility of performing high-frequency, nonlinear microbubble imaging. In this study, we describe the development of nonlinear microbubble B-scan imaging instrumentation capable of operating at transmit center frequencies between 10 and 50 MHz. The system underwent validation experiments using transmit frequencies of 20 and 30 MHz. Agent characterization experiments demonstrate the presence of nonlinear scattering for the conditions used in this study. Using wall-less vessel phantoms, nonlinear B-scan imaging is performed using energy in one of the subharmonic, ultraharmonic, and second harmonic frequency regions for transmit frequencies of 20 and 30 MHz. Both subharmonic and ultraharmonic imaging modes achieved suppression of tissue signals to below the noise floor while achieving contrast to noise ratios of up to 26 and 17 dB, respectively. The performance of second harmonic imaging was compromised by nonlinear propagation and offered no significant contrast improvement over fundamental mode imaging. In vivo experiments using the subharmonic of a 20 MHz transmit pulse show the successful detection of microvessels in the rabbit ear and in the mouse heart. The results of this study demonstrate the feasibility of nonlinear microbubble imaging at high frequencies.

Animals↗

PubMed2005

High-frequency, nonlinear flow imaging of microbubble contrast agents.

It has been shown that nonlinear scattering can be stimulated from microbubble contrast agents at high-transmit frequencies (14-32 MHz). This work was extended to demonstrate the feasibility of nonlinear contrast imaging through modifications of existing ultrasound biomicroscopy linear B-scan imaging instrumentation. In this study, we describe the development and evaluation of prototype coherent flow imaging instrumentation for nonlinear microbubble imaging using transmit frequencies from 10 to 50 MHz. Phantom validation experiments were conducted to demonstrate color and power flow imaging using nonlinear 10 MHz (subharmonic) scattering induced by a 20 MHz transmit frequency. In vivo flow imaging of a rabbit ear microvessel was successfully performed. This work indicates the feasibility of performing flow imaging at high frequencies using nonlinear scattering from microbubbles.

Animals↗

PubMed2005

Quantitation of hemodynamic function during developmental vascular regression in the mouse eye.

PURPOSE: Ultrasound biomicroscopy (UBM) utilizes frequencies higher than conventional diagnostic ultrasound and can noninvasively provide anatomic and functional information about mouse ocular structures in vivo at high resolution. Vascular development can also be assessed with high-frequency Doppler imaging, which permits detection and characterization of ocular blood flow not detectable at lower, conventional Doppler frequencies. METHODS: The eyes of CD-1 mice were examined daily from the day of birth to postnatal day (P)16. Hyaloid vascular system anatomy was imaged with UBM and microcomputed tomography (microCT). Blood flow velocity was also measured with Doppler UBM imaging in the hyaloid artery, vasa hyaloidea propria, tunica vasculosa lentis, and retina. RESULTS: In the mouse, the hyaloid vasculature degenerated from a well-defined structure at birth by progressive loss of branches. Hyaloid regression coincided with a progressive decrease in blood velocity detected in the hyaloid vascular structures, which is thought to be one of the major triggering factors of the regression in these vessels. At P13, no further blood flow was detected in the CD-1 mouse hyaloid vasculature. An inverse relationship was also shown between peak blood velocity in the lens and retina. CONCLUSIONS: UBM imaging provides a valuable means of rapidly and noninvasively characterizing ocular development in vivo. MicroCT scans have also provided intralumenal images of hyaloid vascular structure. This is the first study of vascular structure and function during the dynamic process of hyaloid vascular regression during mouse neonatal eye development and the first three-dimensional images of the complex hyaloid vascular structure.

Animals↗

PubMed2004

Comprehensive transthoracic cardiac imaging in mice using ultrasound biomicroscopy with anatomical confirmation by magnetic resonance imaging.

High-frequency ultrasound biomicroscopy (UBM) has recently emerged as a high-resolution means of phenotyping genetically altered mice and has great potential to evaluate the cardiac morphology and hemodynamics of mouse mutants. However, there is no standard procedure of in vivo transthoracic cardiac imaging using UBM to comprehensively phenotype the adult mice. In this paper, the characteristic mouse thoracic anatomy is elucidated using magnetic resonance (MR) imaging on fixed mice. Besides the left parasternal and apical windows commonly used for transthoracic ultrasound cardiac imaging, a very useful right parasternal window is found. We present strategies for optimal visualization using UBM of key cardiac structures including: 1) the right atrial inflow channels such as the right superior vena cava; 2) the right ventricular inflow tract via the tricuspid orifice; 3) the right ventricular outflow tract to the main pulmonary artery; 4) the left atrial inflow channel, e.g., pulmonary vein; 5) the left ventricular inflow tract via the mitral orifice; 6) the left ventricular outflow tract to the ascending aorta; 7) the left coronary artery; and 8) the aortic arch and associated branches. Two-dimensional ultrasound images of these cardiac regions are correlated to similar sections in the three-dimensional MR data set to verify anatomical details of the in vivo UBM imaging. Dimensions of the left ventricle and ascending aorta are measured by M-mode. Flow velocities are recorded using Doppler at six representative intracardiac locations: right superior vena cava, tricuspid orifice, main pulmonary artery, pulmonary vein, mitral orifice, and ascending aorta. The methodologies and baseline measurements of inbred mice provide a useful guide for investigators applying the high-frequency ultrasound imaging to mouse cardiac phenotyping.

Animals↗