An IVUS transducer for microbubble therapies.

There is interest in examining the potential of modified intravascular ultrasound (IVUS) catheters to facilitate dual diagnostic and therapeutic roles using ultrasound plus microbubbles for localized drug delivery to the vessel wall. The goal of this study was to design, prototype, and validate an IVUS transducer for microbubble-based drug delivery. A 1-D acoustic radiation force model and finite element analysis guided the design of a 1.5-MHz IVUS transducer. Using the IVUS transducer, biotinylated microbubbles were displaced in water and bovine whole blood to the streptavidin-coated wall of a flow phantom by a 1.5-MHz center frequency, peak negative pressure = 70 kPa pulse with varying pulse repetition frequency (PRF) while monitoring microbubble adhesion with ultrasound. A fit was applied to the RF data to extract a time constant (τ). As PRF was increased in water, the time constant decreased (τ = 32.6 s, 1 kHz vs. τ = 8.2 s, 6 kHz), whereas in bovine whole blood an adhesion-no adhesion transition was found for PRFs ≥ 8 kHz. Finally, a fluorophore was delivered to an ex vivo swine artery using microbubbles and the IVUS transducer, resulting in a 6.6-fold increase in fluorescence. These results indicate the importance of PRF (or duty factor) for IVUS acoustic radiation force microbubble displacement and the potential for IVUS and microbubbles to provide localized drug delivery.

Real-time targeted molecular imaging using singular value spectra properties to isolate the adherent microbubble signal.

Ultrasound-based real-time molecular imaging in large blood vessels holds promise for early detection and diagnosis of various important and significant diseases, such as stroke, atherosclerosis, and cancer. Central to the success of this imaging technique is the isolation of ligand-receptor bound adherent microbubbles from free microbubbles and tissue structures. In this paper, we present a new approach, termed singular spectrum-based targeted molecular (SiSTM) imaging, which separates signal components using singular value spectra content over local regions of complex echo data. Simulations were performed to illustrate the effects of acoustic target motion and harmonic energy on SiSTM imaging-derived measurements of statistical dimensionality. In vitro flow phantom experiments were performed under physiologically realistic conditions (2.7 cm s⁻¹ flow velocity and 4 mm diameter) with targeted and non-targeted phantom channels. Both simulation and experimental results demonstrated that the relative motion and harmonic characteristics of adherent microbubbles (i.e. low motion and large harmonics) yields echo data with a dimensionality that is distinct from free microbubbles (i.e. large motion and large harmonics) and tissue (i.e. low motion and low harmonics). Experimental SiSTM images produced the expected trend of a greater adherent microbubble signal in targeted versus non-targeted microbubble experiments (P < 0.05, n = 4). The location of adherent microbubbles was qualitatively confirmed via optical imaging of the fluorescent DiI signal along the phantom channel walls after SiSTM imaging. In comparison with two frequency-based real-time molecular imaging strategies, SiSTM imaging provided significantly higher image contrast (P < 0.001, n = 4) and a larger area under the receiver operating characteristic curve (P < 0.05, n = 4).

Real-time technique for improving molecular imaging and guiding drug delivery in large blood vessels: in vitro and ex vivo results.

Ultrasound-based molecular imaging employs targeted microbubbles to image vascular pathology. This approach also has the potential to monitor molecularly targeted microbubble-based drug delivery. We present an image-guided drug delivery technique that uses multiple pulses to translate, image, and cavitate microbubbles in real time. This technique can be applied to both imaging of pathology in large arteries (sizes and flow comparable to those in humans) and guiding localized drug delivery in blood vessels. The microbubble translation (or pushing) efficacy of this technique was compared in a variety of flow media: saline, viscous saline (4 cp), and bovine blood. It was observed that the performance of this approach was marginally better (by 6, 4, and 2 dB) in viscous saline than in bovine blood with varying levels of hematocrit (40%, 30%, and 10%). The drug delivery efficacy of this technique was evaluated by in vitro and ex vivo experiments. High-intensity pulses mediated fluorophore (DiI) deposition on endothelial cells (in vitro) without causing cell destruction. Ex vivo fluorophore delivery experiments conducted on swine carotids of 2 and 5 mm cross-section diameter demonstrated a high degree of correspondence in spatial localization of the fluorophore delivery between the ultrasound and composite fluorescence microscopy images of the arterial cross sections.

A non-linear three-dimensional model for quantifying microbubble dynamics.

A three-dimensional non-linear model for simulating microbubble response to acoustic insonation is presented. A 1 mum radius microbubble stimulated using positive and inverted 2.4 MHz pulses produced radius-time curves that matched (error <10%) with the experimental observation. A bound 2.3 mum radius microbubble insonated using 2.25 MHz 6 cycle pulse was observed to oscillate with max/min oscillations 45% lower than that of the free microbubble, this correlated ( approximately 10% error) with the observations of Garbin et al. [Appl. Phys. Lett. 90, 114103 (2007)]. The adherent microbubble oscillated asymmetrically in the plan view and symmetrically in the elevation view, consistent with the previous experimental results.

Dual frequency method for simultaneous translation and real-time imaging of ultrasound contrast agents within large blood vessels.

A dual frequency excitation method for simultaneous translation and selective real-time imaging of microbubbles is presented. The method can distinguish signals originating from free flowing and static microbubbles. This method is implemented on a programmable scanner with a broadband linear array. The programmable interface allows for dynamic variations in the acoustic parameters and aperture attributes, enabling application of this method to large blood vessels located at varying depths. The performance of the method was evaluated in vitro (vessel diameter 2mm) by quantifying the sensitivity of the method to various acoustic, microbubble, and fluid flow parameters. It was observed that the static microbubble response maximized at the approximate resonance frequency of the microbubble population (estimated from a coulter counter measurement), thus, signifying the need for dual frequency excitation. The static microbubble signal declined from 25 to 12 dB with increasing centerline flow velocities (2.65-15.9cm/s); indicating the applicable range of flow velocities. The maximum intensity of the static microbubbles signal scaled with variations in the microbubble concentration. The rate of increment of static microbubble signal was independent of microbubble concentration. It was deduced that the rate of increment of the static microbubble signal is primarily a function of the pulse frequency, whereas the maximum static microbubble signal intensity is dependent on three parameters: (a) the pulse frequency, (b) the flow velocity and (c) the microbubble concentration. The proposed dual frequency sequence may enable the application of radiation force for optimizing the effect of targeted imaging and modulating drug delivery in large blood vessels with high flow velocities.

On the differences between two-dimensional and three-dimensional simulations for assessing elastographic image quality: a simulation study.

In this work, we introduced an elastographic simulation framework, which estimates upper bounds on elastographic image quality by accounting for three-dimensional (3D) tissue motion and the 3D nature of the ultrasound beam. For the boundary conditions and the range of applied strains considered in this study, it was observed that for applied strains smaller than 0.7%, fast two-dimensional (2D) simulations and 3D simulations predicted similar upper bounds on elastographic signal-to-noise (SNR(e)) and contrast-to-noise ratios (CNR(e)); however, for applied strains greater than 0.7%, the predictions by 2D simulations grossly overestimated the achievable results when compared with upper bound results from 3D simulations. It was also found that linear increments in the elevational-to-lateral beamwidth ratio (beam ratio) resulted in nonlinear degradation in the achievable upper bounds on elastographic signal-to-noise ratio. For the modulus contrast ratio of ten between the target and the background, the peak difference in the prediction of contrast-to-noise by 2D and 3D simulations was approximately 10 dB, whereas, for modulus contrast ratio of 1.5, the peak difference increased to approximately 30 dB. No significant difference was observed between the spatial resolution predicted by 2D and 3D simulations; however, increase in beam ratio resulted in decrease in target detectability, especially at lower modulus contrast ratios.