Ultrasound (US) is used widely in the context of breast cancer. While it is advantageous for a number of reasons, it has low specificity and requires the use of a contrast agent. Its use as a standalone diagnostic and real-time imaging modality could be achieved by development of a tumor-targeted ultrasound contrast agent (UCA); functionalizing the UCA with a tumor-targeting agent would also allow the targeted administration of anti-cancer drugs at the tumor site. In this article, clinical US techniques are used to show that mesoporous silica nanoparticles (MSNs), functionalized with the monoclonal antibody Herceptin®, can be used as an effective UCA by increasing US image contrast. Furthermore, in vitro assays show the successful localization and binding of the MSN-Herceptin conjugate to HER2+ cancer cells, resulting in tumor-specific cytotoxicity. These results demonstrate the potential of MSNs as a stable, biocompatible, and effective therapeutic and diagnostic (“theranostic”) agent for US-based breast cancer imaging, diagnosis, and treatment.

Non-invasive, easy-to-use and accurate measurements of wall shear stress (WSS) in human blood vessels have always been challenging in clinical applications. Echo particle image velocimetry (Echo PIV) has shown promise for clinical measurements of local hemodynamics and wall shear rate. So far, however, the method has only been validated under simple flow conditions. In this study, we validated Echo PIV under in-vitro and in-vivo conditions. For in-vitro validation, we used an anatomically-correct, compliant carotid bifurcation flow phantom with pulsatile flow conditions, using optical particle image velocimetry (optical PIV) as the reference standard. For in-vivo validation, we compared Echo PIV-derived two dimensional velocity fields obtained at the carotid bifurcation in 5 normal subjects against phase-contrast MRI-derived velocity measurements obtained at the same locations. For both studies, time-dependent, two-dimensional two-component velocity vectors, peak/centerline velocity, flow rate and wall shear rate (WSR) waveforms at the common carotid artery (CCA), carotid bifurcation and distal internal carotid artery (ICA) were examined. Linear regression, correlation analysis and Bland-Altman analysis were used to quantify the agreement of different waveforms measured by the two techniques. In-vitro results showed that Echo PIV produced good images of time-dependent velocity vector maps over the cardiac cycle with excellent temporal (up to 0.7 msec) and spatial (~0.5 mm) resolutions and quality, on par with optical PIV results. Further, good agreement was found between Echo PIV and optical PIV results for velocity and WSR measurements. In-vivo results also showed good agreement between Echo PIV velocities and PC-MRI velocities. We conclude that Echo PIV provides accurate velocity vector and WSR measurements in the carotid bifurcation and has significant potential as a clinical tool for cardiovascular hemodynamics evaluation.

Vascular endothelial cells lining the arteries are sensitive to wall shear stress (WSS) exerted by flowing blood. An important component of the pathophysiology of vascular diseases, WSS is commonly estimated by centerline ultrasound Doppler velocimetry (UDV). However, the accuracy of this method is uncertain. We have previously validated the use of a novel, ultrasound-based, particle image velocimetry technique (echo PIV) to compute 2-D velocity vector fields, which can easily be converted into WSS data. We compared WSS data derived from UDV and echo PIV in the common carotid artery of 27 healthy participants. Compared with echo PIV, time-averaged WSS was lower using UDV (28 ± 35%). Echo PIV revealed that this was due to considerable spatiotemporal variation in the flow velocity profile, contrary to the assumption that flow is steady and the velocity profile is parabolic throughout the cardiac cycle. The largest WSS underestimation by UDV was found during peak systole (118 ± 16%) and the smallest during mid-diastole (4.3± 46%). The UDV method underestimated WSS for the accelerating and decelerating systolic measurements (68 ± 30% and 24 ± 51%), whereas WSS was overestimated for end-diastolic measurements (-44 ± 55%). Our data indicate that UDV estimates of WSS provided limited and largely inaccurate information about WSS and that the complex spatiotemporal flow patterns do not fit well with traditional assumptions about blood flow in arteries. Echo PIV-derived WSS provides detailed information about this important but poorly understood stimulus that influences vascular endothelial pathophysiology.

Abstract-Aortic input impedance represents the hydraulic load presented by the systemic circulation to the left ventricle of the heart and is increased in patients with cardiovascular disease. Aging is a strong independent risk factor for cardiovascular disease and could exert this effect partly through an increase in modulus of aortic input impedance. We used a novel noninvasive technique to determine aortic input impedance in 71 healthy men and women aged 20 to 69 years. We found that the aortic input impedance spectrum was shifted rightward with advancing age, characterized by a 37% increase in the frequency of the minimum modulus between the third and seventh decade (PϽ0.0001). The frequency of the minimum modulus correlated with age in all subjects (rϭ0.48; PϽ0.0001), in men (rϭ0.43; PϽ0.005), and in women (rϭ0.53; Pϭ0.001). Although several physical characteristics were associated with the frequency of the minimum modulus (bivariate correlation), a regression model that included age and these physical characteristics showed that age was the only independent predictor of the frequency of the minimum modulus. We conclude that aortic input impedance increases with advancing age in healthy men and women. This increase in aortic input impedance may be an important mechanism by which age increases the risk of cardiovascular disease in humans. Key Words: aorta Ⅲ applanation tonometry Ⅲ Doppler echocardiography Ⅲ hemodynamics Ⅲ ventricular-vascular coupling I n humans, age-associated alterations to the structural and functional properties of the arterial system are a key antecedent to cardiovascular disease. 1,2 Of particular importance is an increase in the stiffness of the large elastic arteries with advancing age and associated changes in arterial hemodynamics. One hemodynamic consequence of vascular stiffening is an increase in left ventricular afterload. 2 Although ventricular afterload is commonly inferred from the measurement of peripheral artery blood pressure, the zenith and nadir of a peripheral artery pressure cycle provides limited physiological insight into the pulsatile and nonpulsatile loads encountered by the left ventricle. The aortic input impedance (AII) modulus, determined from central blood pressure and aortic blood flow measurements and defined as the ratio of pressure to flow harmonics, more comprehensively characterizes the hydraulic load presented by the entire arterial system to the left ventricle throughout ventricular ejection. [2][3][4][5] Previously, AII has been measured in humans using invasive and noninvasive methods of blood pressure and blood flow. Invasive measurements of aortic blood flow and pressure require aortic catheterization and have been limited to small clinical cohorts, 4,6,7 providing limited insight into the influence of healthy aging on AII. Noninvasive studies of AII have typically reported several parameters derived from the AII frequency spectrum, but there is no consensus regarding the most appropriate parameter. In a recent uncertainty analysis, we found that ...