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Ultrasound in medicine & biology  2010;36(5):853-857.
The goal of this murine investigation was to evaluate the effect of an antivascular ultrasound treatment on the growth of an implanted melanoma and the consequent survival rate. Following the intravenous injection of 0.2 mL ultrasound contrast agent (Definity), therapy (n = 15) was performed on 1 mL tumors for 3 minutes with low intensity, continuous ultrasound (3 MHz; 2.4 ± 0.1−2 [ISATA]); control mice (n = 17) received a sham treatment. Mice were euthanized once the tumor had reached 3 mL and survival percentage versus time curves were plotted. The median survival time (time for tumor to reach 3 mL) for the treated group was 23 days and for the control group was 18 days; the difference was statistically significant (P ≤ 0.0001). Antivascular ultrasound therapy reduced the growth rate of an implanted melanoma and increased survival time. The ultrasound therapy provides a further example of tumor vascular disruption and its future clinical potential should be investigated.
PMCID: PMC2905813  PMID: 20381952
Low-intensity ultrasound therapy; Ultrasound contrast agent; Antivascular; Angiogenesis; Melanoma
2.  Recombinant Protein-Stabilized Monodisperse Microbubbles with Tunable Size Using a Valve-Based Microfluidic Device 
Langmuir  2014;30(42):12610-12618.
Microbubbles are used as contrast enhancing agents in ultrasound sonography and more recently have shown great potential as theranostic agents that enable both diagnostics and therapy. Conventional production methods lead to highly polydisperse microbubbles, which compromise the effectiveness of ultrasound imaging and therapy. Stabilizing microbubbles with surfactant molecules that can impart functionality and properties that are desirable for specific applications would enhance the utility of microbubbles. Here we generate monodisperse microbubbles with a large potential for functionalization by combining a microfluidic method and recombinant protein technology. Our microfluidic device uses an air-actuated membrane valve that enables production of monodisperse microbubbles with narrow size distribution. The size of microbubbles can be precisely tuned by dynamically changing the dimension of the channel using the valve. The microbubbles are stabilized by an amphiphilic protein, oleosin, which provides versatility in controlling the functionalization of microbubbles through recombinant biotechnology. We show that it is critical to control the composition of the stabilizing agents to enable formation of highly stable and monodisperse microbubbles that are echogenic under ultrasound insonation. Our protein-shelled microbubbles based on the combination of microfluidic generation and recombinant protein technology provide a promising platform for ultrasound-related applications.
PMCID: PMC4211726  PMID: 25265041
Ultrasound in medicine & biology  2007;33(12):1901-1910.
This study investigated whether a microbubble-containing ultrasound contrast agent had a role in the antivascular action of physiotherapy ultrasound on tumor neovasculature. Ultrasound images (B-mode and contrast-enhanced power Doppler [0.02mL Definity]) were made of 22 murine melanomas (K173522). The tumor was insonated (ISATA = 1.7 W cm−2, 1 MHz, continuous output) for 3 min and the power Doppler observations of the pre- and post-insonation tumor vascularities were analyzed. Significant reductions (p = 0.005 for analyses of color weighted fractional area) in vascularity occurred when a contrast-enhanced power Doppler study occurred prior to insonation. Vascularity was unchanged in tumors without a pre-therapy Doppler study. Histological studies revealed tissue structural changes that correlated with the ultrasound findings. The underlying etiology of the interaction between the physiotherapy ultrasound beam, the microbubble-containing contrast agent and the tumor neovasculature is unknown. It was concluded that contrast agents play an important role in the antivascular effects induced by physiotherapy ultrasound.
PMCID: PMC2423191  PMID: 17720299
Ultrasound imaging; Cancer therapy; Physiotherapy; Antivascular; Tumor angiogenesis; Power Doppler; Insonation; Ultrasound bioeffects; Microbubble contrast agent
Ultrasound in medicine & biology  2005;31(10):1403-1410.
This study was aimed at determining if physiotherapy ultrasound (US) affected the fragile and leaky angiogenic blood vessels in a tumor. In 22 C3HV/HeN mice, a subcutaneous melanoma (K173522) was insonated (1, 2 or 3 min) with continuous 1-MHz low-intensity (spatial-average temporal-average = 2.28 W cm−2), physiotherapy US. Contrast-enhanced (0.1 mL Optison®) power Doppler US observations were made and histogram analyses of the images were performed. Before insonation, all but 7% of the tumor was perfused. The avascular area in tumors receiving 3-min treatment increased to 82% (p < 0.001). A linear regression analysis showed that each min of insonation led to a 25% reduction in tumor vascularity; the antivascular activity persisted for 24 h. Histology demonstrated disruption of vascular walls and tumor cell death in areas of vascular congestion and thrombosis. Physiotherapy US particularly targeted the vascular structures, and the effects on tumor cells appeared to be secondary to the resultant ischemia.
PMCID: PMC2442571  PMID: 16223644
Angiogenesis; Antivascular; Cancer therapy; Ultrasound; Physiotherapy; Mouse; Melanoma
5.  Three-Dimensional Ultrasound-Derived Physical Mitral Valve Modeling 
The Annals of thoracic surgery  2014;98(2):691-694.
Advances in mitral valve repair and adoption have been partly attributed to improvements in echocardiographic imaging technology. To further educate and guide repair surgery, we have developed a methodology to quickly produce physical models of the valve using novel 3D echocardiographic imaging software in combination with stereolithographic printing.
Quantitative virtual mitral valve shape models were developed from 3D transesophageal echocardiographic images using software based on semi-automated image segmentation and continuous medial representation (cm-rep) algorithms. These quantitative virtual shape models were then used as input to a commercially available stereolithographic printer to generate a physical model of the each valve at end systole and end diastole.
Physical models of normal and diseased valves (ischemic mitral regurgitation and myxomatous degeneration) were constructed. There was good correspondence between the virtual shape models and physical models.
It was feasible to create a physical model of mitral valve geometry under normal, ischemic and myxomatous valve conditions using 3D printing of 3D echocardiographic data. Printed valves have the potential to guide surgical therapy for mitral valve disease.
PMCID: PMC4382862  PMID: 25087790
mitral valve repair; mitral valve replacement; mitral regurgitation; tissue engineering; echocardiography
6.  Validation of semiautomated and locally resolved aortic wall thickness measurements from computed tomography 
Journal of vascular surgery  2014;61(4):1034-1040.
Aortic wall thickness (AWT) is important for anatomic description and biomechanical modeling of aneurysmal disease. However, no validated, noninvasive method for measuring AWT exists. We hypothesized that semiautomated image segmentation algorithms applied to computed tomography angiography (CTA) can accurately measure AWT.
Aortic samples from 10 patients undergoing open thoracoabdominal aneurysm repair were taken from sites of the proximal or distal anastomosis, or both, yielding 13 samples. Aortic specimens were fixed in formalin, embedded in paraffin, and sectioned. After staining with hematoxylin and eosin and Masson’s trichrome, sections were digitally scanned and measured. Patients’ preoperative CTA Digital Imaging and Communications in Medicine (DICOM; National Electrical Manufacturers Association, Rosslyn, Va) images were segmented into luminal, inner arterial, and outer arterial surfaces with custom algorithms using active contours, isoline contour detection, and texture analysis. AWT values derived from image data were compared with measurements of corresponding pathologic specimens.
AWT determined by CTA averaged 2.33 ± 0.66 mm (range, 1.52–3.55 mm), and the AWT of pathologic specimens averaged 2.36 ± 0.75 mm (range, 1.51–4.16 mm). The percentage difference between pathologic specimens and CTA-determined AWT was 9.5% ± 4.1% (range, 1.8%–16.7%). The correlation between image-based measurements and pathologic measurements was high (R = 0.935). The 95% limits of agreement computed by Bland-Altman analysis fell within the range of −0.42 and 0.42 mm.
Semiautomated analysis of CTA images can be used to accurately measure regional and patient-specific AWT, as validated using pathologic ex vivo human aortic specimens. Descriptions and reconstructions of aortic aneurysms that incorporate locally resolved wall thickness are feasible and may improve future attempts at biomechanical analyses.
PMCID: PMC4121383  PMID: 24388698
7.  Effects of age and smoking on endothelial function assessed by quantitative cardiovascular magnetic resonance in the peripheral and central vasculature 
Both age and smoking promote endothelial dysfunction and impair vascular reactivity. Here, we tested this hypothesis by quantifying new cardiovascular magnetic resonance (CMR)-based biomarkers in smokers and nonsmokers.
Study population: young non-smokers (YNS: N = 45, mean age = 30.2 ± 0.7 years), young smokers (YS: N = 39 mean age 32.1 ± 0.7 years), older non-smokers (ONS: N = 45, mean age = 57.8 ± 0.6 years), and older smokers (OS: N = 40, mean age = 56.3 ± 0.6 years), all without overt cardiovascular disease. Vascular reactivity was evaluated following cuff-induced hyperemia via time-resolved blood flow velocity and oxygenation (SvO2) in the femoral artery and vein, respectively. SvO2 dynamics yielded washout time (time to minimum SvO2), resaturation rate (upslope) and maximum change from baseline (overshoot). Arterial parameters included pulse ratio (PR), hyperemic index (HI) and duration of hyperemia (TFF). Pulse-wave velocity (PWV) was assessed in aortic arch, thoracoabdominal aorta and iliofemoral arteries. Ultrasound-based carotid intimal-medial thickness (IMT) and brachial flow-mediated dilation were measured for comparison.
Age and smoking status were independent for all parameters. Smokers had reduced upslope (−28.4%, P < 0.001), increased washout time (+15.3%, P < 0.01), and reduced HI (−19.5%, P < 0.01). Among non-smokers, older subjects had lower upslope (−22.7%, P < 0.01) and overshoot (−29.4%, P < 0.01), elevated baseline pulse ratio (+14.9%, P < 0.01), central and peripheral PWV (all P < 0.05). Relative to YNS, YS had lower upslope (−23.6%, P < 0.01) and longer washout time (13.5%, P < 0.05). Relative to ONS, OS had lower upslope (−33.0%, P < 0.01). IMT was greater in ONS than in YNS (+45.6%, P < 0.001), and also in YS compared to YNS (+14.7%, P < 0.05).
Results suggest CMR biomarkers of endothelial function to be sensitive to age and smoking independent of each other.
PMCID: PMC4332734  PMID: 25884943
Vascular reactivity; Oximetry; Velocimetry; Pulse wave velocity; Smoking; Aging; Cardiovascular magnetic resonance
8.  Statistical Assessment of Normal Mitral Annular Geometry Using Automated 3D Echocardiographic Analysis 
The Annals of thoracic surgery  2013;97(1):71-77.
The basis of mitral annuloplasty ring design has progressed from qualitative surgical intuition to experimental and theoretical analysis of annular geometry with quantitative imaging techniques. In this work, we present an automated 3D echocardiographic (3DE) image analysis method that can be used to statistically assess variability in normal mitral annular geometry to support advancement in annuloplasty ring design.
3D patient-specific models of the mitral annulus were automatically generated from 3DE images acquired from subjects with normal mitral valve structure and function. Geometric annular measurements including annular circumference (AC), annular height (AH), septolateral diameter (SLD), intercommissural width (ICW), and the AH to ICW ratio (AHCWR) were automatically calculated. A mean 3D annular contour was computed, and principal component analysis (PCA) was used evaluate variability in normal annular shape.
The following mean ± standard deviations were obtained from 3DE image analysis: 107.0 ± 14.6 mm (AC), 7.6 ± 2.8 mm (AH), 28.5 ± 3.7 mm (SLD), 33.0 ± 5.3 mm (ICW), and 22.7 ± 6.9 % (AHCWR). PCA indicated that shape variability was primarily related to overall annular size, with more subtle variation in the skewness and height of the anterior annular peak, independent of annular diameter.
Patient-specific 3DE-based modeling of the human mitral valve enables statistical analysis of physiologically normal mitral annular geometry. The tool can potentially lead to the development of a new generation of annuloplasty rings that restore the diseased mitral valve annulus back to a truly normal geometry.
PMCID: PMC4134944  PMID: 24090576
mitral valve; mitral valve repair; echocardiography
9.  Automated segmentation and geometrical modeling of the tricuspid aortic valve in 3D echocardiographic images 
The aortic valve has been described with variable anatomical definitions, and the consistency of 2D manual measurement of valve dimensions in medical image data has been questionable. Given the importance of image-based morphological assessment in the diagnosis and surgical treatment of aortic valve disease, there is considerable need to develop a standardized framework for 3D valve segmentation and shape representation. Towards this goal, this work integrates template-based medial modeling and multi-atlas label fusion techniques to automatically delineate and quantitatively describe aortic leaflet geometry in 3D echocardiographic (3DE) images, a challenging task that has been explored only to a limited extent. The method makes use of expert knowledge of aortic leaflet image appearance, generates segmentations with consistent topology, and establishes a shape-based coordinate system on the aortic leaflets that enables standardized automated measurements. In this study, the algorithm is evaluated on 11 3DE images of normal human aortic leaflets acquired at mid systole. The clinical relevance of the method is its ability to capture leaflet geometry in 3DE image data with minimal user interaction while producing consistent measurements of 3D aortic leaflet geometry.
PMCID: PMC3918680  PMID: 24505702
medial axis representation; deformable modeling; multi-atlas segmentation; aortic valve; 3D echocardiography
10.  Glenoid Cartilage Mechanical Properties Decrease after Rotator Cuff Tears in a Rat Model 
Journal of Orthopaedic Research  2012;30(9):1435-1439.
Rotator cuff repairs are commonly performed to reduce pain and restore function. Tears are also treated successfully without surgical intervention; however, the effect that a torn tendon has on the glenohumeral cartilage remains unknown. Clinically, a correlation between massive rotator cuff tears and glenohumeral arthritis has often been observed. This may be due to a disruption in the balance of forces at the shoulder, resulting in migration of the humeral head and subsequently, abnormal loading of the glenoid. Our lab previously demonstrated changes in ambulation and intact tendon mechanical properties following supraspinatus and infraspinatus rotator cuff tendon tears in a rat model. Therefore, the purpose of this study was to investigate the effects of supraspinatus and infraspinatus rotator cuff tears on the glenoid cartilage. Nine rats underwent unilateral detachment of the supraspinatus and infraspinatus tendons and were sacrificed after four weeks. Cartilage thickness significantly decreased in the antero-inferior region of injured shoulders. In addition, equilibrium elastic modulus significantly decreased in the center, antero-superior, antero-inferior, and superior regions. These results suggest that altered loading after rotator cuff injury may lead to damage to the joint with significant pain and dysfunction. Clinically, understanding the mechanical processes involved with joint damage will allow physicians to better advise patients.
PMCID: PMC3374903  PMID: 22407524
glenoid cartilage; rotator cuff; animal model; glenohumeral arthritis
11.  Semi-Automated Mitral Valve Morphometry and Computational Stress Analysis Using 3D Ultrasound 
Journal of Biomechanics  2012;45(5):903-907.
In vivo human mitral valves (MV) were imaged using real-time 3D transesophageal echocardiography (rt-3DTEE), and volumetric images of the MV at mid-systole were analyzed by user-initialized segmentation and 3D deformable modeling with continuous medial representation, a compact representation of shape. The resulting MV models were loaded with physiologic pressures using finite element analysis (FEA). We present the regional leaflet stress distributions predicted in normal and diseased (regurgitant) MVs. Rt-3DTEE, semi-automated leaflet segmentation, 3D deformable modeling, and FEA modeling of the in vivo human MV is tenable and useful for evaluation of MV pathology.
PMCID: PMC3294138  PMID: 22281408
12.  High Frequency Ultrasound for Evaluation of Intimal Thickness 
The measurement of carotid intima-medial thickness is a well validated measure of cardiovascular risk. Although atherosclerosis occurs in the intima, this arterial layer is not measured alone due to limitation in ultrasound resolution with standard frequency probes.
We evaluated the feasibility of using a 55-MHz ultrasound system with high resolution to measure intima thickness in several vascular territories compared to a “standard” frequency probe.
The intima and medial thickness was measured in the brachial, radial and tibial arteries in 10 healthy subjects and 5 subjects with peripheral arterial disease. The high frequency ultrasound probe showed superior resolution compared to the standard frequency probe allowing for measurement of intima separately from media.
The intima can be measured independently of media with a high degree of reproducibility using a high frequency probe. This technology may allow for early detection of cardiovascular risk and extend knowledge about the physiological changes in the early atherosclerotic development.
PMCID: PMC2762201  PMID: 19647399
13.  Delta projection imaging on contrast-enhanced ultrasound to quantify tumor microvasculature and perfusion 
Academic radiology  2009;16(1):71-78.
Rationale and Objectives
To assess the delta (Δ) projection image processing technique for visualizing tumor microvessels and for quantifying the area of tissue perfused by them on contrast-enhanced ultrasound images.
Materials and Methods
The Δ-projection algorithm was implemented to quantify perfusion by tracking the running maximum of the difference (Δ) between the contrast-enhanced ultrasound image sequence and a baseline image. Twenty-five mice with subcutaneous K1735 melanomas were imaged first with contrast-enhanced grayscale and then with contrast-enhanced power Doppler (minexCPD) ultrasound. Δ-projection images were reconstructed from the grayscale images, then used to evaluate the evolution of tumor vascularity during the course of contrast enhancement. The extent of vascularity (ratio of the perfused area to the tumor area) for each tumor was determined quantitatively from Δ-projection images and compared with the extent of vascularity determined from contrast-enhanced power Doppler images. Δ-projection and minexCPD measurements were compared using linear regression analysis.
Δ-projection was successfully performed in all 25 cases. The technique allowed dynamic visualization of individual blood vessels as they filled in real-time. Individual tumor blood vessels were distinctly visible during early image enhancement. Later, as an increasing number of blood vessels were filled with the contrast agent, clusters of vessels appeared as regions of perfusion, and identification of individual vessels became difficult. Comparisons were made between the perfused area of tumors in Δ-projections and in minexCPD images. The Δ-projection perfusion measurements correlated linearly with minexCPD.
Δ-projection visualized tumor vessels and enabled quantitative assessment of the tumor area perfused by the contrast agent.
PMCID: PMC2644424  PMID: 19064214
Ultrasound contrast agents; power Doppler; angiogenesis; vascular disrupting agent; tumor perfusion
14.  Dose–response relationship of ultrasound contrast agent in an in vivo murine melanoma model 
Cancer Imaging  2007;7(1):216-223.
Many factors affect the sensitivity and reliability of tumor vasculature assessment at the small doses of contrast agent necessary for imaging mice. In this study we investigate the dose–response relationship of ultrasound contrast agent for a minimal exposure power Doppler technique (minexPD) in a murine melanoma model. K1735 murine melanomas grown in 25 C3H/HeN mice were imaged by power Doppler ultrasound using different doses of contrast agents, Optison® and Definity®. Six mice were treated with an antivascular agent, combretastatin A4-phosphate (CA4P), and imaged before and after treatment. The color-weighted fractional area (CWFA) of the peak-enhanced image was measured to assess tumor perfusion on a relative scale of 0 to 100. CWFA increased logarithmically with dose (R2=0.97). Treatment with CA4P resulted in pronounced reduction in tumor perfusion 2 h after contrast injection, but perfusion recovered in the tumor periphery after 2 days. CWFA was significantly different between pre- and post-treatment for all doses at 2 h and 2 days (p < 0.05, respectively). There was no significant difference detectable between the two contrast agents, Optison® and Definity® (p = 0.46). In vivo tumor enhancement in mice increases as logarithmic function with dose. Although the extent of enhancement is dose dependent, the difference between pre- and post-therapy enhancement is relatively unchanged and uniform at varying doses. The two contrast agents tested in this study performed equally well. These results suggest that quantitative contrast-enhanced power Doppler imaging is an effective method for monitoring therapy response of tumors in mice.
PMCID: PMC2151329  PMID: 18083651
Contrast-enhanced ultrasound; dose; antivascular; cancer; mouse; melanoma
15.  Cerebral hemodynamics in preterm infants during positional intervention measured with diffuse correlation spectroscopy and transcranial Doppler ultrasound 
Optics express  2009;17(15):12571-12581.
Four very low birth weight, very premature infants were monitored during a 12° postural elevation using diffuse correlation spectroscopy (DCS) to measure microvascular cerebral blood flow (CBF) and transcranial Doppler ultrasound (TCD) to measure macrovascular blood flow velocity in the middle cerebral artery. DCS data correlated significantly with peak systolic, end diastolic, and mean velocities measured by TCD (pA =0.036, 0.036, 0.047). Moreover, population averaged TCD and DCS data yielded no significant hemodynamic response to this postural change (p>0.05). We thus demonstrate feasibility of DCS in this population, we show correlation between absolute measures of blood flow from DCS and blood flow velocity from TCD, and we do not detect significant changes in CBF associated with a small postural change (12°) in these patients.
PMCID: PMC2723781  PMID: 19654660
16.  Epidermal Growth Factor Receptor Inhibition Modulates the Microenvironment by Vascular Normalization to Improve Chemotherapy and Radiotherapy Efficacy 
PLoS ONE  2009;4(8):e6539.
Epidermal growth factor receptor (EGFR) inhibitors have shown only modest clinical activity when used as single agents to treat cancers. They decrease tumor cell expression of hypoxia-inducible factor 1-α (HIF-1α) and vascular endothelial growth factor (VEGF). Hypothesizing that this might normalize tumor vasculature, we examined the effects of the EGFR inhibitor erlotinib on tumor vascular function, tumor microenvironment (TME) and chemotherapy and radiotherapy sensitivity.
Methodology/Principal Findings
Erlotinib treatment of human tumor cells in vitro and mice bearing xenografts in vivo led to decreased HIF-1α and VEGF expression. Treatment altered xenograft vessel morphology assessed by confocal microscopy (following tomato lectin injection) and decreased vessel permeability (measured by Evan's blue extravasation), suggesting vascular normalization. Erlotinib increased tumor blood flow measured by Power Doppler ultrasound and decreased hypoxia measured by EF5 immunohistochemistry and tumor O2 saturation measured by optical spectroscopy. Predicting that these changes would improve drug delivery and increase response to chemotherapy and radiation, we performed tumor regrowth studies in nude mice with xenografts treated with erlotinib and either radiotherapy or the chemotherapeutic agent cisplatin. Erlotinib therapy followed by cisplatin led to synergistic inhibition of tumor growth compared with either treatment by itself (p<0.001). Treatment with erlotinib before cisplatin led to greater tumor growth inhibition than did treatment with cisplatin before erlotinib (p = 0.006). Erlotinib followed by radiation inhibited tumor regrowth to a greater degree than did radiation alone, although the interaction between erlotinib and radiation was not synergistic.
EGFR inhibitors have shown clinical benefit when used in combination with conventional cytotoxic therapy. Our studies show that targeting tumor cells with EGFR inhibitors may modulate the TME via vascular normalization to increase response to chemotherapy and radiotherapy. These studies suggest ways to assess the response of tumors to EGFR inhibition using non-invasive imaging of the TME.
PMCID: PMC2716529  PMID: 19657384

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