Sandeep K. Kasoji

Phantom evaluation of stacked-type dual-frequency 1–3 composite transducers: A feasibility study on intracavitary acoustic angiography

In this paper, we present phantom evaluation results of a stacked-type dual-frequency 1-3 piezoelectric composite transducer as a feasibility study for intracavitary acoustic angiography. Our previous design (6.5/30 MHz PMN-PT single crystal transducer) for intravascular contrast ultrasound imaging exhibited a contrast-to-tissue ratio (CTR) of 12 dB with a penetration depth of 2.5 mm. For improved penetration depth (>3 mm) and comparable contrast-to-tissue ratio (>12 dB), we evaluated a lower frequency 2/14 MHz PZT 1-3 composite transducer. Superharmonic imaging performance of this transducer and a detailed characterization of key parameters for acoustic angiography are presented. The 2/14 MHz arrangement demonstrated a -6 dB fractional bandwidth of 56.5% for the transmitter and 41.8% for the receiver, and produced sufficient peak-negative pressures (>1.5 MPa) at 2 MHz to induce a strong nonlinear harmonic response from microbubble contrast agents. In an in-vitro contrast ultrasound study using a tissue mimicking phantom and 200 μm cellulose microvessels, higher harmonic microbubble responses, from the 5th through the 7th harmonics, were detected with a signal-to-noise ratio of 16 dB. The microvessels were resolved in a two-dimensional image with a -6dB axial resolution of 615 μm (5.5 times the wavelength of 14 MHz waves) and a contrast-to-tissue ratio of 16 dB. This feasibility study, including detailed explanation of phantom evaluation and characterization procedures for key parameters, will be useful for the development of future dual-frequency array transducers for intracavitary acoustic angiography.

Cavitation Enhancing Nanodroplets Mediate Efficient DNA Fragmentation in a Bench Top Ultrasonic Water Bath

A perfluorocarbon nanodroplet formulation is shown to be an effective cavitation enhancement agent, enabling rapid and consistent fragmentation of genomic DNA in a standard ultrasonic water bath. This nanodroplet-enhanced method produces genomic DNA libraries and next-generation sequencing results indistinguishable from DNA samples fragmented in dedicated commercial acoustic sonication equipment, and with higher throughput. This technique thus enables widespread access to fast bench-top genomic DNA fragmentation.

Management of Indeterminate Cystic Kidney Lesions: Review of Contrast-enhanced Ultrasound as a Diagnostic Tool

Indeterminate cystic kidney lesions found incidentally are an increasingly prevalent diagnostic challenge. Standard workup includes Bosniak classification with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). However, these tests are costly and not without risks. Contrast-enhanced ultrasound (CEUS) is a relatively new technique with lower risk of adverse events than iodine-containing contrast or gadolinium. In our review of the evidence for characterization of cystic kidney lesions with CEUS, CEUS displayed sensitivity (89%-100%) and negative predictive value (86%-100%) comparable to contrast-enhanced CT or MRI, with no decrease in specificity compared with CT and only a slight decrease compared with MRI.

A Pilot Clinical Study in Characterization of Malignant Renal-cell Carcinoma Subtype with Contrast-enhanced Ultrasound

Malignant renal cell carcinoma (RCC) is a diverse set of diseases, which are independently difficult to characterize using conventional MRI and CT protocols due to low temporal resolution to study perfusion characteristics. Because different disease subtypes have different prognoses and involve varying treatment regimens, the ability to determine RCC subtype non-invasively is a clinical need. Contrast-enhanced ultrasound (CEUS) has been assessed as a tool to characterize kidney lesions based on qualitative and quantitative assessment of perfusion patterns, and we hypothesize that this technique might help differentiate disease subtypes. Twelve patients with RCC confirmed pathologically were imaged using contrast-enhanced ultrasound. Time intensity curves were generated and analyzed quantitatively using 10 characteristic metrics. Results showed that peak intensity (p = 0.001) and time-to-80% on wash-out (p = 0.004) provided significant differences between clear cell, papillary, and chromophobe RCC subtypes. These results suggest that CEUS may be a feasible test for characterizing RCC subtypes.

Diagnostic accuracy of contrast-enhanced ultrasound for characterization of kidney lesions in patients with and without chronic kidney disease

BackgroundPatients with chronic kidney disease are at increased risk of cystic kidney disease that requires imaging monitoring in many cases. However, these same patients often have contraindications to contrast-enhanced computed tomography and magnetic resonance imaging. This study evaluates the accuracy of contrast-enhanced ultrasound (CEUS), which is safe for patients with chronic kidney disease, for the characterization of kidney lesions in patients with and without chronic kidney disease.MethodsWe performed CEUS on 44 patients, both with and without chronic kidney disease, with indeterminate or suspicious kidney lesions (both cystic and solid). Two masked radiologists categorized lesions using CEUS images according to contrast-enhanced ultrasound adapted criteria. CEUS designation was compared to histology or follow-up imaging in cases without available tissue in all patients and the subset with chronic kidney disease to determine sensitivity, specificity and overall accuracy.ResultsAcross all patients, CEUS had a sensitivity of 96% (95% CI: 84%, 99%) and specificity of 50% (95% CI: 32%, 68%) for detecting malignancy. Among patients with chronic kidney disease, CEUS sensitivity was 90% (95% CI: 56%, 98%), and specificity was 55% (95% CI: 36%, 73%).ConclusionsCEUS has high sensitivity for identifying malignancy of kidney lesions. However, because specificity is low, modifications to the classification scheme for contrast-enhanced ultrasound could be considered as a way to improve contrast-enhanced ultrasound specificity and thus overall performance. Due to its sensitivity, among patients with chronic kidney disease or other contrast contraindications, CEUS has potential as an imaging test to rule out malignancy.Trial registrationThis trial was registered in clinicaltrials.gov, NCT01751529.

Development of transmitters in dual-frequency transducers for interventional contrast enhanced imaging and acoustic angiography

Spatial limitation can be a challenge to interventional ultrasound transducers for dual-frequency contrast-enhanced ultrasound imaging, or acoustic angiography. A low frequency (<; 3 MHz) transmission with moderate peak negative pressure (PNP) and short pulse length is not easily attainable within limited dimensions. In this paper, a new design of the low frequency transmitter of dual-frequency transducers is presented. 1-3 composites for interventional transmitter design were analyzed by the Krimholtz-Leedom-Matthaei (KLM) model and finite element analysis (FEA). The dual frequency transducer prototype with a 2 MHz 1-3 composite transmitter and a 14 MHz receiver was fabricated and characterized, followed by microbubble detection tests. The transmitter showed the peak negative pressure (PNP) of -1.5 MPa. The -6 dB pulse echo fractional bandwidth for the transmitter and receiver were 61 % and 45 %, respectively. The prototyped dual frequency transducer was used to successfully excite microbubbles and to detect super harmonic responses from microbubbles. The measured harmonic signal showed a 12 dB contrast-to-noise ratio (CNR).

Dual-frequency super harmonic imaging piezoelectric transducers for transrectal ultrasound

In this paper, a 2/14 MHz dual-frequency single-element transducer and a 2/22 MHz sub-array (16/48-elements linear array) transducer were developed for contrast enhanced super-harmonic ultrasound imaging of prostate cancer with the low frequency ultrasound transducer as a transmitter for contrast agent (microbubble) excitation and the high frequency transducer as a receiver for detection of nonlinear responses from microbubbles. The 1-3 piezoelectric composite was used as active materials of the single-element transducers due to its low acoustic impedance and high coupling factor. A high dielectric constant PZT ceramic was used for the sub-array transducer due to its high dielectric property induced relatively low electrical impedance. The possible resonance modes of the active elements were estimated using finite element analysis (FEA). The pulse-echo response, peak-negative pressure and bubble response were tested, followed by in vitro contrast imaging tests using a graphite-gelatin tissue-mimicking phantom. The single-element dual frequency transducer (8 × 4 × 2 mm3) showed a -6 dB fractional bandwidth of 56.5% for the transmitter, and 41.8% for the receiver. A 2 MHz-transmitter (730 μm pitch and 6.5 mm elevation aperture) and a 22 MHz-receiver (240 μm pitch and 1.5 mm aperture) of the sub-array transducer exhibited -6 dB fractional bandwidth of 51.0% and 40.2%, respectively. The peak negative pressure at the far field was about -1.3 MPa with 200 Vpp, 1-cycle 2 MHz burst, which is high enough to excite microbubbles for nonlinear responses. The 7th harmonic responses from micro bubbles were successfully detected in the phantom imaging test showing a contrast-to-tissue ratio (CTR) of 16 dB.

Optimization of multi-pulse sequences for nonlinear contrast agent imaging using a cMUT array.

Capacitive micromachined ultrasonic transducer (cMUT) technology provides advantages such as wide frequency bandwidth, which can be exploited for contrast agent imaging. Nevertheless, the efficiency of traditional multi-pulse imaging schemes, such as pulse inversion (PI), remains limited because of the intrinsic nonlinear character of cMUTs. Recently, a new contrast imaging sequence, called bias voltage modulation sequence (BVM), has been specifically developed for cMUTs to suppress their unwanted nonlinear behavior. In this study, we propose to optimize contrast agent detection by combining the BVM sequence with PI and/or chirp reversal (CR). An aqueous dispersion of lipid encapsulated microbubbles was exposed to several combinations of multi-pulse imaging sequences. Approaches were evaluated in vitro using 9 inter-connected elements of a cMUT linear array (excitation frequency of 4 MHz; peak negative pressure of 100 kPa). For sequences using chirp excitations, a specific compression filter was designed to compress and extract several nonlinear components from the received microbubble responses. A satisfactory cancellation of the nonlinear signal from the source is achieved when BVM is combined with PI and CR. In comparison with PI and CR imaging modes alone, using sequences incorporating BVM increases the contrast-to-tissue ratio by 10.0 dB and 4.6 dB, respectively. Furthermore, the combination of BVM with CR and PI results in a significant increase of the contrast-to-noise ratio (+29 dB). This enhancement is attributed to the use of chirps as excitation signals and the improved preservation of several nonlinear components contained within the contrast agent response.

Early assessment of tumor response to radiation therapy using high-resolution quantitative microvascular ultrasound imaging

Measuring changes in tumor volume using anatomical imaging weeks to months post radiation therapy (RT) is currently the clinical standard for indicating treatment response to RT. For patients whose tumors do not respond successfully to treatment, this approach is suboptimal as timely modification of the treatment approach may lead to better clinical outcomes. We propose to use tumor microvasculature as a biomarker for early assessment of tumor response to RT. Acoustic angiography is a novel contrast ultrasound imaging technique that enables high-resolution microvascular imaging and has been shown to detect changes in microvascular structure due to cancer growth. Data suggest that acoustic angiography can detect longitudinal changes in the tumor microvascular environment that correlate with RT response. Methods: Three cohorts of Fisher 344 rats were implanted with rat fibrosarcoma tumors and were treated with a single fraction of RT at three dose levels (15 Gy, 20 Gy, and 25 Gy) at a dose rate of 300 MU/min. A simple treatment condition was chosen for testing the feasibility of our imaging technique. All tumors were longitudinally imaged immediately prior to and after treatment and then every 3 days after treatment for a total of 30 days. Both acoustic angiography (using in-house produced microbubble contrast agents) and standard b-mode imaging was performed at each imaging time point using a pre-clinical Vevo770 scanner and a custom modified dual-frequency transducer. Results: Results show that all treated tumors in each dose group initially responded to treatment between days 3-15 as indicated by decreased tumor growth accompanied with decreased vascular density. Untreated tumors continued to increase in both volume and vascular density until they reached the maximum allowable size of 2 cm in diameter. Tumors that displayed complete control (no tumor recurrence) continued to decrease in size and vascular density, while tumors that progressed after the initial response presented an increase in tumor volume and volumetric vascular density. The increase in tumor volumetric vascular density in recurring tumors can be detected 10.25 ± 1.5 days, 6 ± 0 days, and 4 ± 1.4 days earlier than the measurable increase in tumor volume in the 15, 20, and 25 Gy dose groups, respectively. A dose-dependent growth rate for tumor recurrence was also observed. Conclusions: In this feasibility study we have demonstrated the ability of acoustic angiography to detect longitudinal changes in vascular density, which was shown to be a potential biomarker for tumor response to RT.

Oxygen microbubbles improve radiotherapy tumor control in a rat fibrosarcoma model – A preliminary study

Cancer affects 39.6% of Americans at some point during their lifetime. Solid tumor microenvironments are characterized by a disorganized, leaky vasculature that promotes regions of low oxygenation (hypoxia). Tumor hypoxia is a key predictor of poor treatment outcome for all radiotherapy (RT), chemotherapy and surgery procedures, and is a hallmark of metastatic potential. In particular, the radiation therapy dose needed to achieve the same tumor control probability in hypoxic tissue as in normoxic tissue can be up to 3 times higher. Even very small tumors (<2–3 mm3) comprise 10–30% of hypoxic regions in the form of chronic and/or transient hypoxia fluctuating over the course of seconds to days. We investigate the potential of recently developed lipid-stabilized oxygen microbubbles (OMBs) to improve the therapeutic ratio of RT. OMBs, but not nitrogen microbubbles (NMBs), are shown to significantly increase dissolved oxygen content when added to water in vitro and increase tumor oxygen levels in vivo in a rat fibrosarcoma model. Tumor control is significantly improved with OMB but not NMB intra-tumoral injections immediately prior to RT treatment and effect size is shown to depend on initial tumor volume on RT treatment day, as expected.