Peter N. Burns

A high-frequency pulsed-wave Doppler ultrasound system for the detection and imaging of blood flow in the microcirculation.

Previous work with a 40-MHz continuous-wave Doppler ultrasound system has demonstrated the potential of high-frequency Doppler ultrasound (HFD), operating in the frequency range 20-200 MHz, to detect blood flow in the microcirculation. This paper describes a directional, pulsed-wave high-frequency Doppler ultrasound (PW HFD) system that was designed and constructed further to investigate this potential. The PW HFD system electronics have a dynamic range of > 80 dB, a noise floor of 250 nV, a directional isolation of 45 dB and operate over the frequency range 1-200 MHz. The system is tested using a focused PVDF transducer that is tuned for maximum sensitivity at 50 MHz, has a -6 dB lateral beamwidth of 70 microns and -6 dB depth-of-focus of 0.90 mm. This permits the practical use of sample volumes with dimensions 70 microns laterally by 90-900 microns axially. The PW HFD system can operate in duplex mode by either sharing the Doppler transducer or using a second PVDF transducer for imaging. Tests with string and capillary flow phantoms demonstrate that the PW HFD system is capable of detecting velocities on the order of the blood velocities found in the capillaries (0.5 mm/s) and arterioles (5 mm/s) with suitable velocity (30-300 microns/s) and temporal (15-100 ms) resolutions. In vivo measurements demonstrate that PW HFD can detect and measure blood velocities of less than 5 mm/s in arterioles and venules with diameters as small as 20 microns and 35 microns, respectively, using a sample volume of only 70 microns laterally by 150 microns axially. Preliminary experiments with high-frequency colour Doppler (HFCD) and high-frequency power Doppler (HFPD) imaging are also presented.

A high-frequency continuous-wave Doppler ultrasound system for the detection of blood flow in the microcirculation

Basic ultrasound physics and several clinical and experimental observations suggest that high-frequency Doppler ultrasound (HFD) operating in the frequency range 20-100 MHz holds the promise of detecting blood flow in the microcirculation. This article describes a directional, continuous-wave (CW), 1- to 200-MHz Doppler ultrasound system. The system electronics have a dynamic range of 100 dB, a noise floor of 10 nV and a directional isolation of 50 dB. The development of a 40-MHz Doppler transducer composed of two, 81-micron-thick, lithium niobate crystals that have been air-backed and transmission-line tuned for maximum sensitivity is described. This device is used to test the CW Doppler system using string and capillary phantoms and in vivo tissue. We show that HFD can detect and measure velocities on the order of the blood velocities found in the capillaries (1 mm/s) and arterioles (5 mm/s) with suitable velocity (50-500 microns/s) and temporal (20-250 ms) resolutions. In vivo measurements demonstrate that HFD is sensitive to the detection of blood flow in small vessels.

In vitro characterization of the subharmonic ultrasound signal from Definity microbubbles at high frequencies

Ultrasound microbubble contrast agents have been demonstrated to scatter subharmonic energy at one-half the driving frequency. At ultrasound frequencies in the 20-40 MHz range, the subharmonic offers the potential to differentiate the blood in the microcirculation from the surrounding tissue. It is unknown whether current contrast agents, manufactured to be resonant between 2 and 12 MHz, are ideal for subharmonic imaging at higher frequencies. We performed numerical simulations of the Keller-Miksis model for the behavior of a single bubble and experimental investigations of Definity microbubbles in water. The results supported the hypothesis that off-resonant bubbles, excited at their second harmonic, may be primarily responsible for the observed subharmonic energy. For frequencies between 20 and 32 MHz and 32 and 40 MHz, the optimal bubble diameters for the generation of subharmonics in vitro were determined experimentally to be 1.2-5 microm and less than 1.2 microm, respectively. Definity may be a suitable ultrasound contrast agent for subharmonic imaging at 20 MHz with peak-negative pressures between 380 and 590 kPa and pulses greater than or equal to four cycles in duration.

High-frequency subharmonic pulsed-wave Doppler and color flow imaging of microbubble contrast agents.

A recent study has shown the feasibility of subharmonic (SH) flow imaging at a transmit frequency of 20 MHz. This paper builds on these results by examining the performance of SH flow imaging as a function of transmit pressure. Further, we also investigate the feasibility of SH pulsed-wave Doppler (PWD) imaging. In vitro flow experiments were performed with a 1-mm-diameter wall-less vessel cryogel phantom using the ultrasound contrast agent Definity and an imaging frequency of 20 MHz. The phantom results show that there is an identifiable pressure range where accurate flow velocity and power estimates can be made with SH imaging at 10 MHz (SH10), above which velocity estimates are biased by radiation force effects and unstable bubble behavior, and below which velocity and power estimates are degraded by poor SNR. In vivo validation of SH PWD was performed in an arteriole of a rabbit ear, and blood velocity estimates compared well with fundamental (F20) mode PWD. The ability to suppress tissue signals using SH signals may enable the use of higher frame rates and improve sensitivity to microvascular flow or slow velocities near large vessel walls by reducing or eliminating the need for clutter filters.

THE EFFECT OF REFRACTION AND ASSUMED SPEEDS OF SOUND IN TISSUE AND BLOOD ON DOPPLER ULTRASOUND BLOOD VELOCITY MEASUREMENTS

The combined effect of three assumptions relating to refraction, the speed of sound in tissue and the speed of sound in blood on the accuracy of Doppler ultrasound blood velocity measurements has been investigated. A theoretical relationship giving the net velocity measurement error introduced by these three assumptions has derived using a model in which tissue and blood layers are separated by straight, parallel boundaries. This net error is dependent on the assumed and actual speed of sound in tissue, the assumed speed of sound in blood and the Doppler angle, but is effectively independent of the actual speed of sound in blood. For clinical blood velocity measurements, the net error is estimated to be as much as an 8% overestimation of the actual velocity, higher than previously predicted for any of the factors individually. The relationship also predicts a net velocity measurement error in experimental flow systems and string phantoms which is dependent on the speed of sound in the liquid bath. A water bath at room temperature will give an overestimation of approximately 2%. Experimental investigations using conventional and modified string phantoms and a 5-MHz linear phased array system support these conclusions. The effect of perturbing the layers from their parallel orientation has also been considered theoretically and has provided additional support for the above conclusions. These results may help more accurate Doppler velocity measurements in both experimental and clinical settings.

Nanoparticle-loaded perfluorocarbon droplets for imaging and therapy

Nanoscale perfluorocarbon droplets that are in the liquid phase at physiological temperatures, but which can be converted to gas using ultrasound, offer potential as a contrast agent for the detection and therapy of solid tumours. Nanoparticles such as quantum dots can also be encapsulated within PFC droplets, enabling multi-modal imaging and controlled nanoparticle release. In this work, experiments were conducted to investigate the impact of nanoparticle incorporation on droplet conversion at low and high ultrasound frequencies. It was found that incorporation of quantum dots lowered the inertial cavitation threshold at 1 MHz by 20%. In contrast, quantum dot nanoparticles did not significantly alter the conversion threshold of perfluorohexane or perfluoropentane droplets at 18 MHz. It was also shown that perfluoropentane droplets could be converted to gas and imaged at high frequency in hepatomas in mice, using brief high pressure bursts to achieve the phase conversion. Finally, optically fluorescent quantum dots incorporated within droplets were used to demonstate the feasibility of assessing biodistribution in rabbits using fluorescence histology.

High-frequency doppler ultrasound examination of blood flow in the anterior segment of the eye

PURPOSE To show that extending Doppler imaging into the high-frequency domain could allow detection and characterization of blood flow in small arterioles and capillaries. METHODS A 40-MHz continuous wave Doppler system and a 60-MHz pulsed-wave Doppler system were constructed, tested, and used to examine the ciliary body region in two normal volunteers. RESULTS Ciliary body circulation in the region of the great circle of the iris, which is undetectable by conventional 7.5-MHz duplex Doppler, was consistently and reproducibly detectable by high-frequency (40-MHz and 60-MHz) Doppler systems. CONCLUSION High-frequency Doppler imaging may provide a unique new tool for the characterization and assessment of anterior segment ocular blood flow.

CEUS: An essential component in a multimodality approach to small nodules in patients at high-risk for hepatocellular carcinoma

Contrast-enhanced ultrasound (CEUS) plays an essential role in the evaluation of small nodules in livers at high-risk for hepatocellular carcinoma (HCC) and offers unique advantages over CT/MRI. These include the sensitive depiction of arterial hypervascularity of HCC, better demonstration of rapid washout for non-HCC malignancy as well as of very late washout of HCC. Visualization of early vascular filling patterns for benign hypervascular lesions is of indisputable value. A frequently uncounted benefit of CEUS includes the value of its performance following nodule detection at ultrasound surveillance, including one-stop exclusion of typical benignancy, preclusion of arterial pseudolesions shown on CT/MR, and the avoidance of miscorrelation of a nodule on surveillance and subsequent diagnostic imaging. Therefore, CEUS can effectively be used in the diagnostic algorithm for new liver nodules detected during HCC surveillance. Despite the fact that CEUS is actively used as a major diagnostic test for HCC in Asia, Europe, and Canada with increasing demands in clinical practice, CEUS is not included in the diagnostic tests for HCC in some major practice guidelines. In this manuscript, we focus on small nodules in patients at high-risk for HCC, and review some of the unique advantages of CEUS that contribute to lesion characterization and subsequent patient management, showing why CEUS should be an essential component of the diagnostic algorithm for HCC.

Use of microbubble ultrasound contrast agent to demonstrate the iris valve effect in human eye bank eyes

PURPOSE To demonstrate that the interface between the normal iris and the lens surface functions as a flap valve. METHOD Microbubble ultrasound contrast agent was injected into the anterior and posterior chambers of human eye bank eyes and the distribution of contrast imaged with high-frequency ultrasound. RESULTS Contrast agent did not enter the posterior chamber when injected into the anterior chamber, but contrast agent injected into the posterior chamber easily flowed into the anterior chamber. CONCLUSIONS The iris-lens interface normally functions as a flap valve, preventing retrograde flow from the anterior to the posterior chamber. A temporary increase in anterior chamber pressure thus results in iris concavity in pigmentary dispersion syndrome.

American Institute of Ultrasound in Medicine Recommendations for Contrast-Enhanced Liver Ultrasound Imaging Clinical Trials

Received January 25, 2007, from Orlando Regional Healthcare, Orlando, Florida USA (L.G.); Sunnybrook Health Sciences Center, Toronto, Ontario, Canada (P.B.); Yale University School of Medicine, New Haven, Connecticut USA (J.C.); Hammersmith Hospital, London, England (D.C.); University of Michigan Health System, Ann Arbor, Michigan (J.B.F.); Thomas Jefferson University Hospital, Philadelphia, Pennsylvania USA (B.G., D.M.); University of California San Diego Medical Center, San Diego, California USA (R.M.); University of Alabama at Birmingham, Birmingham, Alabama USA (M.R.); and University of Toronto, Toronto, Ontario, Canada (S.W.). Manuscript accepted for publication January 29, 2007. These recommendations were developed by the AIUM in consultation with the following companies: Bracco Imaging SpA, Bristol-Myers Squibb Medical Imaging, GE Healthcare, National Electrical Manufacturers Association, Philips Medical Systems Ultrasound, Siemens Medical Solutions, Inc, and SonoSite. The AIUM acknowledges these companies for the background that they provided; it was essential to the development of this document. Address correspondence to Lennard Greenbaum, MD, Winnie Palmer Hospital for Women & Babies, The Hughes Center for Fetal Diagnostics, 83 W Miller St, Orlando, FL 32806 USA. E-mail: lengreenbaum@msn.com Abbreviations AIUM, American Institute of Ultrasound in Medicine; ALARA, as low as reasonably achievable; CEUS, contrast-enhanced ultrasound; CT, computed tomographic; FDA, Food and Drug Administration; MI, mechanical index; MR, magnetic resonance; PVC, premature ventricular contraction Preamble