Micro-Ultrasound Molecular Imaging

__Abstract__ Perhaps using sound to identify objects, those which remained mysterious to sight and touch senses, is one of the very early diagnostic tools mankind has ever used. We all can distinguish the sound of a plastic cup from one made of glass when tapped by a finger nail no matter how similar they look. The sounds that we hear and those that we don’t, are mechanical vibrations (acoustic waves) traveling through a compressible and expandable (elastic) medium such as air or water. We can recognize the sound of a glass cup from a plastic one because of the fact that such mechanical vibrations of the particles of materials with dissimilar properties are unlike. Perhaps the most characteristic properties of an acoustic wave are its amplitude and its pitch (frequency). The amplitude of a sound determines how loud the sound is. The frequency of a sound is an indicator of how fast are the mechanical vibrations of the medium substances

Self-demodulation effect on subharmonic response of ultrasound contrast agent

In this work the use of the self-demodulation (S-D) signal as a mean of microbubble excitation at the subharmonic (SH) frequency to enhance the SH emission of ultrasound contrast agent (UCA) is studied. SH emission from the UCA is of interest since it is produced only by the UCA and is free of the artifacts produced in harmonic imaging modes. The S-D wave is a low-frequency signal produced by nonlinear propagation of an ultrasound wave in the medium. Single element transducer experiments and numerical simulations were conducted at 10 MHz to study the effect of the S-D signal on the SH response of the UCA by modifying the envelope of the excitation bursts. For 6 and 20 transmitted cycles, the SH response is increased up to 25 dB and 22 dB because of the S-D stimulation for a burst with a rectangular envelope compared with a Gaussian envelope burst. Such optimized excitations were used in an array-based micro-ultrasound system (Vevo 2100, VisualSonics Inc., Toronto, ON, Canada) at 18 MHz for in vitro validation of SH imaging. This study suggests that a suitable design of the envelope of the transmit excitation to generate a S-D signal at the SH frequency can enhance the SH emission of UCA and real-time SH imaging is feasible with shorter transmit burst (6- cycle) and low acoustic pressure (-150 KPa) at high frequencies (>15 MHz)

Quantification of Bound Microbubbles in Ultrasound Molecular Imaging

Molecular markers associated with diseases can be visualized and quantified noninvasively with targeted ultrasound contrast agent (t-UCA) consisting of microbubbles (MBs) that can bind to specific molecular targets. Techniques used for quantifying t-UCA assume that all unbound MBs are taken out of the blood pool few minutes after injection and only MBs bound to the molecular markers remain. However, differences in physiology, diseases, and experimental conditions can increase the longevity of unbound MBs. In such conditions, unbound MBs will falsely be quantified as bound MBs. We have developed a novel technique to distinguish and classify bound from unbound MBs. In the post-processing steps, first, tissue motion was compensated using block-matching (BM) techniques. To preserve only stationary contrast signals, a minimum intensity projection (MinIP) or 20th-percentile intensity projection (PerIP) was applied. The after-flash MinIP or PerIP was subtracted from the before-flash MinIP or PerIP. In this way, tissue artifacts in contrast images were suppressed. In the next step, bound MB candidates were detected. Finally, detected objects were tracked to classify the candidates as unbound or bound MBs based on their displacement. This technique was validated in vitro, followed by two in vivo experiments in mice. Tumors (n = 2) and salivary glands of hypercholesterolemic mice (n = 8) were imaged using a commercially available scanner. Boluses of 100 mu L of a commercially available t-UCA targeted to angiogenesis markers and untargeted control UCA were injected separately. Our results show considerable reduction in misclassification of unbound MBs as bound ones. Using our method, the ratio of bound MBs in salivary gland for images with targeted UCA versus control UCA was improved by up to two times compared with unprocessed images

Quantification of bound microbubbles in ultrasound molecular imaging

Molecular markers associated with diseases can be visualized and quantified noninvasively with targeted ultrasound contrast agent (t-UCA) consisting of microbubbles (MBs) that can bind to specific molecular targets. Techniques used for quantifying t-UCA assume that all unbound MBs are taken out of the blood pool few minutes after injection and only MBs bound to the molecular markers remain. However, differences in physiology, diseases, and experimental conditions can increase the longevity of unbound MBs. In such conditions, unbound MBs will falsely be quantified as bound MBs. We have developed a novel technique to distinguish and classify bound from unbound MBs. In the post-processing steps, first, tissue motion was compensated using block-matching (BM) techniques. To preserve only stationary contrast signals, a minimum intensity projection (MinIP) or 20th-percentile intensity projection (PerIP) was applied. The after-flash MinIP or PerIP was subtracted from the before-flash MinIP or PerIP. In this way, tissue artifacts in contrast images were suppressed. In the next step, bound MB candidates were detected. Finally, detected objects were tracked to classify the candidates as unbound or bound MBs based on their displacement. This technique was validated in vitro, followed by two in vivo experiments in mice. Tumors (n = 2) and salivary glands of hypercholesterolemic mice (n = 8) were imaged using a commercially available scanner. Boluses of 100 μL of a commercially available t-UCA targeted to angiogenesis markers and untargeted control UCA were injected separately. Our results show considerable reduction in misclassification of unbound MBs as bound ones. Using our method, the ratio of bound MBs in salivary gland for images with targeted UCA versus control UCA was improved by up to two times compared with unprocessed images

Microbubble Composition and Preparation for High-Frequency Contrast-Enhanced Ultrasound Imaging: In Vitro and in Vivo Evaluation

Although high-frequency ultrasound imaging is gaining attention in various applications, hardly any ultrasound contrast agents (UCAs) dedicated to such frequencies (>15 MHz) are available for contrast-enhanced ultrasound (CEUS) imaging. Moreover, the composition of the limited commercially available UCAs for high-frequency CEUS (hfCEUS) is largely unknown, while shell properties have been shown to be an important factor for their performance. The aim of our study was to produce UCAs in-house for hfCEUS. Twelve different UCA formulations A-L were made by either sonication or mechanical agitation. The gas core consisted of C4F10 and the main coating lipid was either 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC; A-F formulation) or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC; G-L formulation). Mechanical agitation r

Prototype 3D real-time imaging system based on a sparse PZT spiral array

© 2018 IEEE. 3D ultrasound imaging is costly and complicated mostly due to the need of controlling 2D probes with high numbers of elements (≥1024). Sparse arrays are a convenient way to reduce system complexity maintaining reasonable performance. A 256-element density tapered spiral array has been recently designed and realized in a piezoelectric probe prototype. The probe has been connected to the ULA-OP 256 open scanner, which can be programmed to permit volumetric scanning in real-time. This paper reports on the first experimental measurements of transmit ultrasound fields produced by such prototype system, including multi-line transmit fields that, in combination with parallel receive beamforming, may permit real-time volumetric imaging. An average -21.3dB side-lobe level (SLL) was measured on the transmit fields., while volume rates of 35 volumes per second can be achieved.status: publishe

Refraction-Corrected Transcranial Ultrasound Imaging through the Human Temporal Window using a Single Probe

Transcranial ultrasound imaging is a diagnostic modality with numerous applications, but unfortunately it is hindered by phase aberration caused by the skull. In this paper, we propose to reconstruct a transcranial B-mode image with a refraction-corrected synthetic aperture imaging scheme. First, the compressional sound velocity of the aberrator (i.e., the skull) is estimated using the bidirectional headwave technique. The medium is described with four layers (i.e., lens, water, skull, water), and a fast marching method calculates the travel times between individual array elements and image pixels. Finally, a delay-and-sum algorithm is used for image reconstruction with coherent compounding. The point spread function (PSF) in a wire phantom image, reconstructed with the conventional technique (using a constant sound speed throughout the medium) and the proposed method, was quantified with numerical synthetic data and experiments with a bone-mimicking plate and a human skull, and compared to the PSF achieved in a ground truth image of the medium without the aberrator (i.e., the bone plate or skull). A phased-array transducer (P4-1, ATL/Philips, 2.5 MHz, 96 elements, pitch = 0.295 mm) was used for the experiments. The results with the synthetic signals, the bone-mimicking plate and the skull indicated that the proposed method reconstructs the scatterers with an average lateral/axial localization error of 0.06 mm/0.14 mm, 0.11 mm/0.13 mm and 1.0 mm/0.32 mm, respectively. With the human skull, an average contrast ratio (CR) and full-width-half-maximum (FWHM) of 37.1 dB and 1.75 mm was obtained with the proposed approach, respectively. This corresponds to an improvement of CR and FWHM by 7.1 dB and 36% compared to the conventional method, respectively. These numbers were 12.7 dB and 41% with the bone-mimicking plate

A single-cable PVDF transducer readout IC for intravascular photoacoustic imaging

This paper presents a custom-designed single-cable readout IC for the reception of the broadband photoacoustic (PA) signal in intravascular photoacoustic (IVPA) imaging. The readout IC is intended for direct integration behind a broadband polyvinylidene fluoride (PVDF) transducer in an IVPA catheter tip to match the impedance between the small PVDF element and the connecting cable. The capability of the readout IC to work with a single cable that combines the output signal and the power supply ensures the mechanical flexibility of the IVPA catheter. Electrical measurements show that the readout IC provides a flat frequency response from 1 MHz to 20 MHz with a 6 mA external current supply. The acoustical measurements involving the readout IC and the PVDF transducer demonstrate a 60 dB dynamic range, a sensitivity of 3.8 μV/Pa at 2.25 MHz, and a broad receiving bandwidth from 2 MHz to 15 MHz.</p