Abhay V. Patil

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.

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.

3D prostate elastography: algorithm, simulations and experiments.

A multi-resolution hybrid strain estimator is presented. The estimator is locally initialized by the B-mode tracking stage. Nonlinear and linear stretching regimes are applied in successive RF tracking stages for refining the estimated axial and lateral displacements. A staggering operator is used to derive the strain images from the reconstructed axial displacements. Simulations and experiments, conducted at a center frequency of 12 MHz, 40% fractional bandwidth, on a 128 element transducer with 0.2 mm pitch, with elastographic window length of 2 mm and overlap of 90%, demonstrate a 3-6 dB improvement in the elastographic contrast-to-noise ratio over the results obtained using conventional multi-stage stretching based strain estimators. The average image cross-correlation coefficient obtained using the proposed algorithm was improved by 6-8%. 3D elastographic simulations conducted to study the performance of a 3D elastographic imaging framework predict achievable axial and lateral resolutions of approximately five and ten wavelengths, respectively. A close correspondence between inclusions reconstructed from experimental elastograms and the known physical shape of actual 3D inclusions demonstrates the potential application of 3D elastography for identifying and classifying the detected lesions (invisible in sonograms) on the basis of their shape.

Ultrasound catheter for microbubble based drug delivery

An intravascular ultrasound (IVUS) catheter was designed to guide and locally deliver microbubbles carrying therapeutic agents. Optimal insonation parameters were determined by modeling microbubble translational displacements using the coupled 1D Rayleigh-Plesset and Drag-displacement equations. A transducer assembly was designed based on the results of microbubble simulations and a Finite Element Analysis (FEA) Model. The transducer components were fabricated then assembled into a 1.4 mm (OD) catheter tube. Hydrophone tests were performed to measure transducer output and the resulting output was compared to the FEA model. The final catheter was tested for gene delivery effectiveness by transfecting cells with a cytomegalovirus - plasmid kinase (CMV-PK) Red plasmid DNA. Wall-less flow phantom experiments were also performed to demonstrate the effectiveness of translating microbubbles across a vessel using ultrasound radiation force by measuring change in image intensity of a B-mode scan of the vessel. The resulting change in image intensity was approximately 15 dB. A follow-up experiment with the wall-less flow phantom was performed where microbubbles were initially translated and then burst, resulting in an intensity change of up to 12 dB and then a decrease after destruction back down to 0 dB.

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.

3D Segmentation of the Prostate via Poisson Inverse Gradient Initialization

Accurate segmentation and volumetric assessment of the enlarged prostate is critical to assessment of cancer progression. Moreover, 3D segmentation is necessary for treatment in both radiotherapy and brachytherapy. We propose a 3D segmentation solution for ultrasound images of the prostate based on deformable surfaces. The deformable surfaces are propelled by the vector field convolution (VFC) external force model. This external force has both computational efficiency and solution quality advantages over existing techniques such as gradient vector flow (GVF). A salient aspect of the segmentation solution proposed here is the ability to automatically initialize the deformable surface in 3D. The initialization method exploits a novel Poisson inverse gradient technique that essentially solves the inverse problem from the external force field to the external energy and determines the most likely coarse segmentation. We validate our 3D segmentation on simulated images of the prostate. Furthermore, simulated data show that PIG initialization leads to a 60% reduction in segmentation error for high curvature contours.

P1C-1 Multi-Resolution Hybrid Strain Estimator for Elastography

In this work, we present a multi-resolution hybrid strain estimator. Elastographic simulations and phantom experiments conducted to evaluate the performance of this algorithm demonstrate that for the strain range and the boundary conditions considered in this study, the elastographic contrast-to-noise-ratio obtained using the proposed algorithm was on average 3 dB greater than that obtained using adaptive strain estimation algorithm proposed by Srinivasan et al. [Srinivasan, et. al., 2002], The average image cross-correlation coefficient was approximately 6-8 % higher than that obtained using the adaptive strain estimation algorithm [Srinivasan, et. al., 2002]

Isolation of signal from stationary microbubbles adhered to vessel walls using an adaptive regression filtering technique

The singular value filter (SVF) is proposed for isolation of adherent microbubble signal in ultrasound-based targeted molecular imaging. The SVF method involves signal decomposition of complex echo data such that ensembles are re-expressed along a new basis determined from principal component analysis (PCA) using the singular value decomposition (SVD) method. In contrast to many previously proposed PCA-based approaches, filter coefficients in SVF are dictated by a weighting function allowing for non-binary coefficients and based upon a signal model of the underlying source signals. The weighting function allows for filter coefficients to be determined adaptively from the shape of the singular value spectra of local regions of echo data, which is quantified using a parameter called the normalized singular spectrum area (NSSA). Simulations in FIELD II are performed to quantify the effects of acoustic scatterer motion characteristics, such as motion and decorrelation, on NSSA. Results confirm that the singular value spectrum flattens, and thus NSSA increases, monotonically with increased axial shift of scatterers between A-lines and increased differential motion. The SVF filter is validated experimentally in an ex vivo porcine artery with adherent microbubbles collecting on the lower wall due to application of acoustic radiation force. SVF was compared to a low-pass infinite impulse response (IIR) filter operating on pulse inversion (PI) data. Results from our ex vivo experiments indicate that signal from adherent microbubbles exhibits higher dimensionality and thus higher NSSA than signal from vessel wall and free microbubbles. SVF provided > 40dB contrast of adherent microbubble signal over vessel wall and > 32dB contrast of adherent microbubble over free microbubble signal.

A 3D nonlinear FEA model for simulation of microbubble behavior

Microbubbles provide the basis for perfusion measurement, early detection of molecular signatures of disease and as a vehicle for drug, or gene, delivery. Although the response of a single microbubble to ultrasound has been characterized by radially symmetric 1D models and high speed camera-based experiments, a plethora of mechanisms, such as bubble-bubble interaction, and adherent bubble response are poorly understood. With few exceptions, 1D model are generally valid at moderate acoustic pressures, but are incapable of predicting phenomena such as higher order mode oscillations or onset of bubble shell rupture. It has been hypothesized that second or higher order mode oscillations are a precursor to bubble shell rupture and subsequent cavitation. In addition, parameters, such as shell stress and shell strain may have threshold values related to bubble shell fracture. In this work, we propose a full 3D FEA (finite element analysis) model that can simulate temporal variations in asymmetric 3D radial, translational bubble motion, various shell parameters such as regional stress /strain, and bubble pulse echo response. Preliminary simulations were conducted to assess the performance of the model for broadband cases, including: 1) single cycle pulse excitation, 2) single cycle of free and wall-bound bubble, 3) predicting translational displacements in response to primary radiation force, and 4) tracking variations in shell stresses and strain for low (180 KPa) and high (330 KPa) peak negative pressure acoustic waveforms. For the acoustic and bubble parameters published by Dayton, the maximum displacement predicted using the 3D FEA model was within 10% of the previously published experimental data. For approximately similar bubble and acoustic parameters (using inverted pulses), the spectrum of the backscattered data from a free bubble was found to be similar to the experimental and simulated results The spectrum of the adherent bubble response was found to be downshifted with respect to that of a free bubble; similar results have been reported by Payne et al . The adherent bubble was found to oscillate asymmetrically in the planes orthogonal to the azimuth-elevation plane or the plane perpendicular to the face of the transducer (edge of the model where an external pulse is applied).

3D FEA model for quantifying bound/free microbubble: Displacement, stress, and resonance frequencies

Molecularly targeted ultrasound contrast agents provide for the potential to form an image responsive to early expression of molecular pathology in vivo and ex vivo. While 1D models are routinely employed to estimate the dynamics of the microbubbles for imaging and therapeutic applications, these models are incapable of capturing asymmetric microbubble behavior or space-variant mechanical properties of microbubbles shell. Additionally, information arising from asymmetric boundary conditions may provide insight into multiple microbubble interaction, and microbubble cavitation limits. In this work, we apply a previously reported 3D FEA model to quantify the difference between free/adherent microbubbles behavior and propose a shell stress/strain bounds hypothesis for estimating the free/adherent microbubble cavitation threshold. From 3D FEA simulations and high-speed camera experiments, it is concluded that linear and nonlinear temporal variation in shell stress/strain (as a function of insonation pressure) is an indicator of stable and unstable microbubble oscillation regime. Furthermore, it is also inferred that adherent microbubbles have higher thresholds for unstable cavitation than free microbubbles. Additionally, adherent microbubbles are predicted to possess higher natural resonance frequencies than free microbubbles of similar sizes.