Publications by authors named "Paul A Dayton"

198 Publications

A Handheld Imaging Probe for Acoustic Angiography with an Ultra-Wideband Capacitive Micromachined Ultrasonic Transducer (CMUT) Array.

IEEE Trans Ultrason Ferroelectr Freq Control 2022 May 6;PP. Epub 2022 May 6.

This paper presents an imaging probe with a 256-element ultra-wideband (UWB) 1D CMUT array designed for acoustic angiography (AA). This array was fabricated on a borosilicate glass wafer with a reduced bottom electrode and an additional central plate mass to achieve the broad bandwidth. A custom 256-channel handheld probe was designed and implemented with integrated low-noise amplifiers and supporting power circuitry. This probe was used to characterize the UWB CMUT, which has a functional 3-dB frequency band from 3.5 to 23.5 MHz. A mechanical index (MI) of 0.33 was achieved at 3.5 MHz at a depth of 11 mm. These promising measurements are then combined to demonstrate AA. Use of alternate amplitude modulation (aAM) combined with a frequency analysis of the measured transmit signal demonstrates the suitability of the UWB CMUT for AA. This is achieved through measuring only a low level of unwanted high-frequency harmonics in both the transmit signal and the reconstructed image in the areas other than the contrast bubbles.
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http://dx.doi.org/10.1109/TUFFC.2022.3172566DOI Listing
May 2022

Effects of Injection Volume and Route of Administration on Dolutegravir In Situ Forming Implant Pharmacokinetics.

Pharmaceutics 2022 Mar 11;14(3). Epub 2022 Mar 11.

Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Due to the versatility of the in situ forming implant (ISFI) drug delivery system, it is crucial to understand the effects of formulation parameters for clinical translation. We utilized ultrasound imaging and pharmacokinetics (PK) in mice to understand the impact of administration route, injection volume, and drug loading on ISFI formation, degradation, and drug release in mice. Placebo ISFIs injected subcutaneously (SQ) with smaller volumes (40 μL) exhibited complete degradation within 30-45 days, compared to larger volumes (80 μL), which completely degraded within 45-60 days. However, all dolutegravir (DTG)-loaded ISFIs along the range of injection volumes tested (20-80 μL) were present at 90 days post-injection, suggesting that DTG can prolong ISFI degradation. Ultrasound imaging showed that intramuscular (IM) ISFIs flattened rapidly post administration compared to SQ, which coincides with the earlier T for drug-loaded IM ISFIs. All mice exhibited DTG plasma concentrations above four times the protein-adjusted 90% inhibitory concentration (PA-IC90) throughout the entire 90 days of the study. ISFI release kinetics best fit to zero order or diffusion-controlled models. When total administered dose was held constant, there was no statistical difference in drug exposure regardless of the route of administration or number of injections.
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http://dx.doi.org/10.3390/pharmaceutics14030615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948873PMC
March 2022

Polyvinyl Alcohol Cryogels for Acoustic Characterization of Phase-Change Contrast Agents.

Ultrasound Med Biol 2022 05 1;48(5):954-960. Epub 2022 Mar 1.

Department of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, North Carolina, USA; Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Chapel Hill, North Carolina, USA.

Phase-change contrast agents (PCCAs) consisting of lipid-encapsulated low-boiling-point perfluorocarbons can be used in conjunction with ultrasound for diagnostic and therapeutic applications. One benefit of PCCAs is site-specific activation, whereby the liquid core is acoustically vaporized into a bubble detectable via ultrasound imaging. For further evaluation of PCCAs in a variety of applications, it is useful to disperse these nanodroplets into an acoustically compatible stationary matrix. However, many traditional phantom preparations require heating, which causes premature thermal activation of low-boiling-point PCCAs. Polyvinyl alcohol (PVA) cryogels do not require heat to set. Here we propose a simple method for the incorporation of the low-boiling-point PCCAs using octafluoropropane (OFP) and decafluorobutane (DFB) into PVA cryogels for a variety of acoustic characterization applications. We determined the utility of the phantoms by activating droplets with a focused transducer, visualizing the lesions with ultrasound imaging. At 1 MHz, droplet activation was consistently observed at 2.0 and 4.0 MPa for OFP and DFB, respectively.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2022.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9012345PMC
May 2022

Development of a Robotic Shear Wave Elastography System for Noninvasive Staging of Liver Disease in Murine Models.

Hepatol Commun 2022 Feb 24. Epub 2022 Feb 24.

SonoVol, Inc., Durham, NC, USA.

Shear wave elastography (SWE) is an ultrasound-based stiffness quantification technology that is used for noninvasive liver fibrosis assessment. However, despite widescale clinical adoption, SWE is largely unused by preclinical researchers and drug developers for studies of liver disease progression in small animal models due to significant experimental, technical, and reproducibility challenges. Therefore, the aim of this work was to develop a tool designed specifically for assessing liver stiffness and echogenicity in small animals to better enable longitudinal preclinical studies. A high-frequency linear array transducer (12-24 MHz) was integrated into a robotic small animal ultrasound system (Vega; SonoVol, Inc., Durham, NC) to perform liver stiffness and echogenicity measurements in three dimensions. The instrument was validated with tissue-mimicking phantoms and a mouse model of nonalcoholic steatohepatitis. Female C57BL/6J mice (n = 40) were placed on choline-deficient, L-amino acid-defined, high-fat diet and imaged longitudinally for 15 weeks. A subset was sacrificed after each imaging timepoint (n = 5) for histological validation, and analyses of receiver operating characteristic (ROC) curves were performed. Results demonstrated that robotic measurements of echogenicity and stiffness were most strongly correlated with macrovesicular steatosis (R  = 0.891) and fibrosis (R  = 0.839), respectively. For diagnostic classification of fibrosis (Ishak score), areas under ROC (AUROCs) curves were 0.969 for ≥Ishak1, 0.984 for ≥Ishak2, 0.980 for ≥Ishak3, and 0.969 for ≥Ishak4. For classification of macrovesicular steatosis (S-score), AUROCs were 1.00 for ≥S2 and 0.997 for ≥S3. Average scanning and analysis time was <5 minutes/liver. Conclusion: Robotic SWE in small animals is feasible and sensitive to small changes in liver disease state, facilitating in vivo staging of rodent liver disease with minimal sonographic expertise.
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http://dx.doi.org/10.1002/hep4.1912DOI Listing
February 2022

Validation of a combined ultrasound and bioluminescence imaging system with magnetic resonance imaging in orthotopic pancreatic murine tumors.

Sci Rep 2022 01 7;12(1):102. Epub 2022 Jan 7.

SonoVol, Inc, Durham, NC, USA.

Preclinical mouse solid tumor models are widely used to evaluate efficacy of novel cancer therapeutics. Recent reports have highlighted the need for utilizing orthotopic implantation to represent clinical disease more accurately, however the deep tissue location of these tumors makes longitudinal assessment challenging without the use of imaging techniques. The purpose of this study was to evaluate the performance of a new multi-modality high-throughput in vivo imaging system that combines bioluminescence imaging (BLI) with robotic, hands-free ultrasound (US) for evaluating orthotopic mouse models. Long utilized in cancer research as independent modalities, we hypothesized that the combination of BLI and US would offer complementary advantages of detection sensitivity and quantification accuracy, while mitigating individual technological weaknesses. Bioluminescent pancreatic tumor cells were injected into the pancreas tail of C57BL/6 mice and imaged weekly with the combination system and magnetic resonance imaging (MRI) to serve as a gold standard. BLI photon flux was quantified to assess tumor activity and distribution, and US and MRI datasets were manually segmented for gross tumor volume. Robotic US and MRI demonstrated a strong agreement (R = 0.94) for tumor volume measurement. BLI showed a weak overall agreement with MRI (R = 0.21), however, it offered the greatest sensitivity to detecting the presence of tumors. We conclude that combining BLI with robotic US offers an efficient screening tool for orthotopic tumor models.
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http://dx.doi.org/10.1038/s41598-021-03684-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741958PMC
January 2022

An Analysis of Sonothrombolysis and Cavitation for Retracted and Unretracted Clots Using Microbubbles Versus Low-Boiling-Point Nanodroplets.

IEEE Trans Ultrason Ferroelectr Freq Control 2022 02 27;69(2):711-719. Epub 2022 Jan 27.

The thrombolysis potential of low-boiling-point (-2 °C) perfluorocarbon phase-change nanodroplets (NDs) has previously been demonstrated on aged clots, and we hypothesized that this efficacy would extend to retracted clots. We tested this hypothesis by comparing sonothrombolysis of both unretracted and retracted clots using ND-mediated ultrasound (US+ND) and microbubble-mediated ultrasound (US+MB), respectively. Assessment data included clot mass reduction, cavitation detection, and cavitation cloud imaging in vitro. Acoustic parameters included a 7.9-MPa peak negative pressure and 180-cycle bursts with 5-Hz repetition (the corresponding duty cycle and time-averaged intensity of 0.09% and 1.87 W/cm, respectively) based on prior studies. With these parameters, we observed a significantly reduced efficacy of US+MB in the retracted versus unretracted model (the averaged mass reduction rate from 1.83%/min to 0.54%/min). Unlike US+MB, US+ND exhibited less reduction of efficacy in the retracted model (from 2.15%/min to 1.04%/min on average). The cavitation detection results correlate with the sonothrombolysis efficacy results showing that both stable and inertial cavitation generated in a retracted clot by US+ND is higher than that by US+MB. We observed that ND-mediated cavitation shows a tendency to occur inside a clot, whereas MB-mediated cavitation occurs near the surface of a retracted clot, and this difference is more significant with retracted clots compared to unretracted clots. We conclude that ND-mediated sonothrombolysis outperforms MB-mediated therapy regardless of clot retraction, and this advantage of ND-mediated cavitation is emphasized for retracted clots. The primary mechanisms are hypothesized to be sustained cavitation level and cavitation clouds in the proximity of a retracted clot by US+ND.
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http://dx.doi.org/10.1109/TUFFC.2021.3137125DOI Listing
February 2022

Acoustic Angiography: Superharmonic Contrast-Enhanced Ultrasound Imaging for Noninvasive Visualization of Microvasculature.

Methods Mol Biol 2022 ;2393:641-655

Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA.

Acoustic angiography is a contrast-enhanced ultrasound technique that relies on superharmonic imaging to form high-resolution, three-dimensional maps of the microvasculature. In order to obtain signal separation between tissue and contrast, acoustic angiography has been performed with dual-frequency transducers with nonoverlapping bandwidths. This enables a high contrast-to-tissue ratio, and the choice of a high frequency receiving element provides high resolution. In this chapter, we describe the technology behind acoustic angiography as well as the step-by-step implementation of this contrast enhanced microvascular imaging technique.
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http://dx.doi.org/10.1007/978-1-0716-1803-5_34DOI Listing
January 2022

Genome-wide cancer-specific chromatin accessibility patterns derived from archival processed xenograft tumors.

Genome Res 2021 Nov 23. Epub 2021 Nov 23.

Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

Chromatin accessibility states that influence gene expression and other nuclear processes can be altered in disease. The constellation of transcription factors and chromatin regulatory complexes in cells results in characteristic patterns of chromatin accessibility. The study of these patterns in tissues has been limited because existing chromatin accessibility assays are ineffective for archival formalin-fixed, paraffin-embedded (FFPE) tissues. We have developed a method to efficiently extract intact chromatin from archival tissue via enhanced cavitation with a nanodroplet reagent consisting of a lipid shell with a liquid perfluorocarbon core. Inclusion of nanodroplets during the extraction of chromatin from FFPE tissues enhances the recovery of intact accessible and nucleosome-bound chromatin. We show that the addition of nanodroplets to the chromatin accessibility assay formaldehyde-assisted isolation of regulatory elements (FAIRE), does not affect the accessible chromatin signal. Applying the technique to FFPE human tumor xenografts, we identified tumor-relevant regions of accessible chromatin shared with those identified in primary tumors. Further, we deconvoluted non-tumor signal to identify cellular components of the tumor microenvironment. Incorporation of this method of enhanced cavitation into FAIRE offers the potential for extending chromatin accessibility to clinical diagnosis and personalized medicine, while also enabling the exploration of gene regulatory mechanisms in archival samples.
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http://dx.doi.org/10.1101/gr.275219.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8647830PMC
November 2021

Imaging methods to evaluate tumor microenvironment factors affecting nanoparticle drug delivery and antitumor response.

Cancer Drug Resist 2021 19;4:382-413. Epub 2021 Jun 19.

UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.

Standard small molecule and nanoparticulate chemotherapies are used for cancer treatment; however, their effectiveness remains highly variable. One reason for this variable response is hypothesized to be due to nonspecific drug distribution and heterogeneity of the tumor microenvironment, which affect tumor delivery of the agents. Nanoparticle drugs have many theoretical advantages, but due to variability in tumor microenvironment (TME) factors, the overall drug delivery to tumors and associated antitumor response are low. The nanotechnology field would greatly benefit from a thorough analysis of the TME factors that create these physiological barriers to tumor delivery and treatment in preclinical models and in patients. Thus, there is a need to develop methods that can be used to reveal the content of the TME, determine how these TME factors affect drug delivery, and modulate TME factors to increase the tumor delivery and efficacy of nanoparticles. In this review, we will discuss TME factors involved in drug delivery, and how biomedical imaging tools can be used to evaluate tumor barriers and predict drug delivery to tumors and antitumor response.
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http://dx.doi.org/10.20517/cdr.2020.94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8597952PMC
June 2021

Nanoparticle Delivery of miR-122 Inhibits Colorectal Cancer Liver Metastasis.

Cancer Res 2022 01 9;82(1):105-113. Epub 2021 Nov 9.

Department of Radiation Oncology, UNC School of Medicine, Chapel Hill, North Carolina.

Liver metastasis is a leading cause of cancer morbidity and mortality. Thus, there has been strong interest in the development of therapeutics that can effectively prevent liver metastasis. One potential strategy is to utilize molecules that have broad effects on the liver microenvironment, such as miR-122, a liver-specific miRNA that is a key regulator of diverse hepatic functions. Here we report the development of a nanoformulation miR-122 as a therapeutic agent for preventing liver metastasis. We engineered a galactose-targeted lipid calcium phosphate (Gal-LCP) nanoformulation of miR-122. This nanotherapeutic elicited no significant toxicity and delivered miR-122 into hepatocytes with specificity and high efficiency. Across multiple colorectal cancer liver metastasis models, treatment with Gal-LCP miR-122 treatment effectively prevented colorectal cancer liver metastasis and prolonged survival. Mechanistic studies revealed that delivery of miR-122 was associated with downregulation of key genes involved in metastatic and cancer inflammation pathways, including several proinflammatory factors, matrix metalloproteinases, and other extracellular matrix degradation enzymes. Moreover, Gal-LCP miR-122 treatment was associated with an increased CD8/CD4 T-cell ratio and decreased immunosuppressive cell infiltration, which makes the liver more conducive to antitumor immune response. Collectively, this work presents a strategy to improve cancer prevention and treatment with nanomedicine-based delivery of miRNA. SIGNIFICANCE: Highly specific and efficient delivery of miRNA to hepatocytes using nanomedicine has therapeutic potential for the prevention and treatment of colorectal cancer liver metastasis.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-2269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8732321PMC
January 2022

In Vivo Porcine Aged Deep Vein Thrombosis Model for Testing Ultrasound-based Thrombolysis Techniques.

Ultrasound Med Biol 2021 12 28;47(12):3447-3457. Epub 2021 Sep 28.

Department of Pediatric Cardiology, University of Michigan, Ann Arbor, Michigan, USA.

As blood clots age, many thrombolytic techniques become less effective. To fully evaluate these techniques for potential clinical use, a large animal aged-clot model is needed. Previous minimally invasive attempts to allow clots to age in an in vivo large animal model were unsuccessful because of the clot clearance associated with relatively high level of cardiac health of readily available research pigs. Prior models have thus subsequently used invasive surgical techniques with the associated morbidity, animal stress and cost. We propose a method for forming sub-acute venous blood clots in an in-vivo porcine model. The age of the clots can be controlled and varied. By using an intravenous scaffold to anchor the clot to the vessel wall during the aging process, we can show that sub-acute clots can consistently be formed with a minimally invasive, percutaneous approach. The clot formed in this study remained intact for at least 1 wk in all subjects. Therefore, we established a new minimally invasive, large animal aged-clot model for evaluation of thrombolytic techniques.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578380PMC
December 2021

Characterization of the Ultrasound Localization Microscopy Resolution Limit in the Presence of Image Degradation.

IEEE Trans Ultrason Ferroelectr Freq Control 2022 01 31;69(1):124-134. Epub 2021 Dec 31.

Ultrasound localization microscopy (ULM) has been able to overcome the diffraction limit of ultrasound imaging. The resolution limit of ULM has been previously modeled using the Cramér-Rao lower bound (CRLB). While this model has been validated in a homogeneous medium, it estimates a resolution limit, which has not yet been achieved in vivo. In this work, we investigated the effects of three sources of image degradation on the resolution limit of ULM. The Fullwave simulation tool was used to simulate acquisitions of transabdominal contrast-enhanced data at depth. The effects of reverberation clutter, trailing clutter, and phase aberration were studied. The resolution limit, in the presence of reverberation clutter alone, was empirically measured to be up to 39 times worse in the axial dimension and up to 2.1 times worse in the lateral dimension than the limit predicted by the CRLB. While reverberation clutter had an isotropic impact on the resolution, trailing clutter had a constant impact on both dimensions across all signal-to-trailing-clutter ratios (STCR). Phase aberration had a significant impact on the resolution limit over the studied analysis ranges. Phase aberration alone degraded the resolution limit up to 70 and 160 [Formula: see text] in the lateral and axial dimensions, respectively. These results illustrate the importance of phase aberration correction and clutter filtering in ULM postprocessing. The analysis results were demonstrated through the simulation of the ULM process applied to a cross-tube model that was degraded by each of the three aforementioned sources of degradation.
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http://dx.doi.org/10.1109/TUFFC.2021.3112074DOI Listing
January 2022

Transcranial Neuromodulation Array With Imaging Aperture for Simultaneous Multifocus Stimulation in Nonhuman Primates.

IEEE Trans Ultrason Ferroelectr Freq Control 2022 01 31;69(1):261-272. Epub 2021 Dec 31.

Even simple behaviors arise from the simultaneous activation of multiple regions in the brain. Thus, the ability to simultaneously stimulate multiple regions within a brain circuit should allow for better modulation of function. However, performing simultaneous multifocus ultrasound neuromodulation introduces challenges to transducer design. Using 3-D Fullwave simulations, we have designed an ultrasound neuromodulation array for nonhuman primates that: 1) can simultaneously focus on multiple targets and 2) include an imaging aperture for additional functional imaging. This design is based on a spherical array, with 128 15-mm elements distributed in a spherical helix pattern. It is shown that clustering the elements tightly around the 65-mm imaging aperture located at the top of the array improves targeting at shallow depths, near the skull surface. Spherical arrays have good focusing capabilities through the skull at the center of the array, but focusing on off-center locations is more challenging due to the natural geometric configuration and the angle of incidence with the skull. In order to mitigate this, the 64 elements closest to the aperture were rotated toward and focusing on a shallow target, and the 64 elements farthest from the aperture were rotated toward and focusing on a deeper target. Data illustrated that this array produced focusing on the somatosensory cortex with a gain of 4.38 and to the thalamus with a gain of 3.82. To improve upon this, the array placement was optimized based on phase aberration simulations, allowing for the elements with the largest impact on the gain at each focal point to be found. This optimization resulted in an array design that can focus on the somatosensory cortex with a gain of 5.19 and the thalamus with a gain of 4.45. Simulations were also performed to evaluate the ability of the array to focus on 28 additional brain regions, showing that off-center target regions can be stimulated, but those closer to the skull will require corrective steps to deliver the same amount of energy to those locations. This simulation and design process can be adapted to an individual monkey or human skull morphologies and specific target locations within individuals by using orientable 3-D printing of the transducer case and by electronic phase aberration correction.
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http://dx.doi.org/10.1109/TUFFC.2021.3108448DOI Listing
January 2022

Safety Evaluation of a Forward-Viewing Intravascular Transducer for Sonothrombolysis: An in Vitro and ex Vivo Study.

Ultrasound Med Biol 2021 11 23;47(11):3231-3239. Epub 2021 Aug 23.

Department of Mechanical and Aerospace Engineering, North Carolina State University, Raleigh, North Carolina, USA. Electronic address:

Recent in vitro work has revealed that a forward-viewing intravascular (FVI) transducer has sonothrombolysis applications. However, the safety of this device has yet to be evaluated. In this study, we evaluated the safety of this device in terms of tissue heating, vessel damage and particle debris size during sonothrombolysis using microbubbles or nanodroplets with tissue plasminogen activator, in both retracted and unretracted blood clots. The in vitro and ex vivo sonothrombolysis tests using FVI transducers revealed a temperature rise of less than 1°C, no vessel damage as assessed by histology and no downstream clot particles >500 µm. These in vitro and ex vivo results indicate that the FVI transducer poses minimal risk for sonothrombolysis applications and should be further evaluated in animal models.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487993PMC
November 2021

Dual-Frequency Intravascular Sonothrombolysis: An In Vitro Study.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 12 23;68(12):3599-3607. Epub 2021 Nov 23.

Thrombo-occlusive disease is one of the leading causes of death worldwide. There has been active research on safe and effective thrombolysis in preclinical and clinical studies. Recently, the dual-frequency transcutaneous sonothrombolysis with contrast agents [microbubbles (MBs)] has been reported to be more efficient in trigging the acoustic cavitation, which leads to a higher lysis rate. Therefore, there is increasing interest in applying dual-frequency technique for more significant efficacy improvement in intravascular sonothrombolysis since a miniaturized intravascular ultrasound transducer typically has a limited power output to fully harness cavitation effects. In this work, we demonstrated this efficacy enhancement by developing a new broadband intravascular transducer and testing dual-frequency sonothromblysis in vitro. A broadband intravascular transducer with a center frequency of 750 kHz and a footprint size of 1.4 mm was designed, fabricated, and characterized. The measured -6-dB fractional bandwidth is 68.1%, and the peak negative pressure is 1.5 MPa under the driving voltage of 80 V. By keeping one frequency component at 750 kHz, the second frequency component was selected from 450 to 650 kHz with an interval of 50 kHz. The in vitro sonothrombolysis tests were conducted with a flow model and the results indicated that the MB-mediated, dual-frequency (750+500 kHz) sonothrombolysis yields an 85% higher lysis rate compared with the single-frequency treatment, and the lysis rate of dual-frequency sonothrombolysis increases with the difference between the two frequency components. These findings suggest a dual-frequency excitation technique for more efficient intravascular sonothrombolysis than conventional single-frequency excitation.
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http://dx.doi.org/10.1109/TUFFC.2021.3103409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645157PMC
December 2021

Effect of Acoustic Parameters and Microbubble Concentration on the Likelihood of Encapsulated Microbubble Coalescence.

Ultrasound Med Biol 2021 10 31;47(10):2980-2989. Epub 2021 Jul 31.

Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Chapel Hill, North Carolina, USA.

Microbubble contrast agents are commonly used for therapeutic and diagnostic imaging applications. Under certain conditions, these contrast agents can coalesce on ultrasound application and form larger bubbles than the initial population. The formation of large microbubbles potentially influences therapeutic outcomes and imaging quality. We studied clinically relevant ultrasound parameters related to low-pressure therapy and contrast-enhanced ultrasound imaging to determine their effect on microbubble coalescence and subsequent changes in microbubble size distributions in vitro. Results indicate that therapeutic ultrasound at low frequencies, moderate pressures and high duty cycles are capable of forming bubbles greater than two times larger than the initial bubble distribution. Furthermore, acoustic parameters related to contrast-enhanced ultrasound imaging that are at higher frequency, low-pressure and low-duty cycle exhibit no statistically significant changes in bubble diameter, suggesting that standard contrast ultrasound imaging does not cause coalescence. Overall, this work suggests that the microbubble coalescence phenomenon can readily occur at acoustic parameters used in therapeutic ultrasound, generating bubbles much larger than those found in commercial contrast agents, although coalescence is unlikely to be significant in diagnostic contrast-enhanced ultrasound imaging. This observation warrants further expansion of parameter ranges and investigation of resulting effects.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547186PMC
October 2021

A multi-pillar piezoelectric stack transducer for nanodroplet mediated intravascular sonothrombolysis.

Ultrasonics 2021 Jul 9;116:106520. Epub 2021 Jul 9.

The Department of Mechanical and Aerospace Engineering at North Carolina State University, Raleigh, NC 27695, USA. Electronic address:

We aim to develop a nanodroplet (ND)-mediated intravascular ultrasound (US) transducer for deep vein thrombosis treatments. The US device, having an efficient forward directivity of the acoustic beam, is capable of expediting the clot dissolution rate by activating cavitation of NDs injected onto a thrombus. We designed and prototyped a multi-pillar piezoelectric stack (MPPS) transducer composed of four piezoelectric stacks. Each stack was made of five layers of PZT-4 plates, having a dimension of 0.85 × 0.85 × 0.2 mm. The transducer was characterized by measuring the electrical impedance and acoustic pressure, compared to simulation results. Next, in-vitro tests were conducted in a blood flow mimicking system using the transducer equipped with an ND injecting tube. The miniaturized transducer, having an aperture size of 2.8 mm, provided a high mechanical index of 1.52 and a relatively wide focal zone of 3.4 mm at 80 V, 0.96 MHz electric input. The mass-reduction rate of the proposed method (NDs + US) was assessed to be 4.1 and 4.6 mg/min with and without the flow model, respectively. The rate was higher than that (1.3-2.7 mg/min) of other intravascular ultrasound modalities using micron-sized bubble agents. The ND-mediated intravascular sonothrombolysis using MPPS transducers was demonstrated with an unprecedented lysis rate, which may offer a new clinical option for DVT treatments. The MPPS transducer generated a high acoustic pressure (~3.1 MPa) at a distance of approximately 2.2 wavelengths from the small aperture, providing synergistic efficacy with nanodroplets for thrombolysis without thrombolytic agents.
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http://dx.doi.org/10.1016/j.ultras.2021.106520DOI Listing
July 2021

Harnessing ultrasound-stimulated phase change contrast agents to improve antibiotic efficacy against methicillin-resistant biofilms.

Biofilm 2021 Dec 11;3:100049. Epub 2021 May 11.

Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599, USA.

Bacterial biofilms, often associated with chronic infections, respond poorly to antibiotic therapy and frequently require surgical intervention. Biofilms harbor persister cells, metabolically indolent cells, which are tolerant to most conventional antibiotics. In addition, the biofilm matrix can act as a physical barrier, impeding diffusion of antibiotics. Novel therapeutic approaches frequently improve biofilm killing, but usually fail to achieve eradication. Failure to eradicate the biofilm leads to chronic and relapsing infection, is associated with major financial healthcare costs and significant morbidity and mortality. We address this problem with a two-pronged strategy using 1) antibiotics that target persister cells and 2) ultrasound-stimulated phase-change contrast agents (US-PCCA), which improve antibiotic penetration. We previously demonstrated that rhamnolipids, produced by , could induce aminoglycoside uptake in gram-positive organisms, leading to persister cell death. We have also shown that US-PCCA can transiently disrupt biological barriers to improve penetration of therapeutic macromolecules. We hypothesized that combining antibiotics which target persister cells with US-PCCA to improve drug penetration could improve treatment of methicillin resistant (MRSA) biofilms. Aminoglycosides alone or in combination with US-PCCA displayed limited efficacy against MRSA biofilms. In contrast, the anti-persister combination of rhamnolipids and aminoglycosides combined with US-PCCA dramatically improved biofilm killing. This novel treatment strategy has the potential for rapid clinical translation as the PCCA formulation is a variant of FDA-approved ultrasound contrast agents that are already in clinical practice and the low-pressure ultrasound settings used in our study can be achieved with existing ultrasound hardware at pressures below the FDA set limits for diagnostic imaging.
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http://dx.doi.org/10.1016/j.bioflm.2021.100049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173270PMC
December 2021

Magneto-sonothrombolysis with combination of magnetic microbubbles and nanodroplets.

Ultrasonics 2021 Jun 6;116:106487. Epub 2021 Jun 6.

Department of Mechanical and Aerospace Engineering, North Carolina State University, Raleigh, NC 27695, USA. Electronic address:

This paper reports a novel technique using the rotational magnetic field oscillation and low-intensity sub-megahertz ultrasound stimulation of magnetic microbubbles (MMBs) to promote the nanodroplets (NDs) phase transition and improve the permeation of NDs into the blood clot fibrin network to enhance the sonothrombolysis efficiency. In this study, the influence of different treatment methods with a combination of MMBs and NDs on the thrombolysis rate of both unretracted and retracted clots were investigated, including the stable and inertial cavitation, tPA effects, MMBs/NDs concentration ratio, sonication factors (input voltage, duty cycle) and rotational magnetic field factors (flux density, frequency). We demonstrated that tPA-mediated magneto-sonothrombolysis in combining NDs with MMBs could significantly enhance in vitro lysis of both unretracted clots (85 ± 8.3%) and retracted clots (57 ± 6.5%) in a flow model with 30 min treatment. The results showed that the combination of MMBs and NDs substantially improves in vitro lysis of blood clots with an unprecedented lysis rate.
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http://dx.doi.org/10.1016/j.ultras.2021.106487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645658PMC
June 2021

Implementation of a Novel 288-Element Dual-Frequency Array for Acoustic Angiography: In Vitro and In Vivo Characterization.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 08 26;68(8):2657-2666. Epub 2021 Jul 26.

Acoustic angiography is a superharmonic contrast-enhanced ultrasound imaging method that produces high-resolution, 3-D maps of the microvasculature. Previous acoustic angiography studies have used twoelement, annular,mechanicallyactuated transducers(called "wobblers") to image microvasculature in preclinical tumor models with high contrast-to-tissue ratio and resolution, but these earlywobbler transducerscould not achieve the depth and sensitivity required for clinical acoustic angiography. In this work, we present a system for performing acoustic angiography with a novel dual-frequency(DF) transducer-a coaxially stacked DF array (DFA). We evaluate the DFA system bothin vitro andin vivo and demonstrate improvements in sensitivity and imaging depth up to 13.1 dB and 10 mm, respectively, compared with previous wobbler probes.
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http://dx.doi.org/10.1109/TUFFC.2021.3074025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375591PMC
August 2021

Magnetic Resonance Detection of Gas Microbubbles via HyperCEST: A Path Toward Dual Modality Contrast Agent.

Chemphyschem 2021 06 19;22(12):1219-1228. Epub 2021 May 19.

Department of Physics & Astronomy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Gas microbubbles are an established clinical ultrasound contrast agent. They could also become a powerful magnetic resonance (MR) intravascular contrast agent, but their low susceptibility-induced contrast requires high circulating concentrations or the addition of exogenous paramagnetic nanoparticles for MR detection. In order to detect clinical in vivo concentrations of raw microbubbles via MR, an alternative detection scheme must be used. HyperCEST is an NMR technique capable of indirectly detecting signals from very dilute molecules (concentrations well below the NMR detection threshold) that exchange hyperpolarized Xe. Here, we use quantitative hyperCEST to show that microbubbles are very efficient hyperCEST agents. They can accommodate and saturate millions of Xe atoms at a time, allowing for their indirect detection at concentrations as low as 10 femtomolar. The increased MR sensitivity to microbubbles achieved via hyperCEST can bridge the gap for microbubbles to become a dual modality contrast agent.
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http://dx.doi.org/10.1002/cphc.202100183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494452PMC
June 2021

Characterization of an Array-Based Dual-Frequency Transducer for Superharmonic Contrast Imaging.

IEEE Trans Ultrason Ferroelectr Freq Control 2021 07 29;68(7):2419-2431. Epub 2021 Jun 29.

Superharmonic imaging with dual-frequency imaging systems uses conventional low-frequency ultrasound transducers on transmit, and high-frequency transducers on receive to detect higher order harmonic signals from microbubble contrast agents, enabling high-contrast imaging while suppressing clutter from background tissues. Current dual-frequency imaging systems for superharmonic imaging have been used for visualizing tumor microvasculature, with single-element transducers for each of the low- and high-frequency components. However, the useful field of view is limited by the fixed focus of single-element transducers, while image frame rates are limited by the mechanical translation of the transducers. In this article, we introduce an array-based dual-frequency transducer, with low-frequency and high-frequency arrays integrated within the probe head, to overcome the limitations of single-channel dual-frequency probes. The purpose of this study is to evaluate the line-by-line high-frequency imaging and superharmonic imaging capabilities of the array-based dual-frequency probe for acoustic angiography applications in vitro and in vivo. We report center frequencies of 1.86 MHz and 20.3 MHz with -6 dB bandwidths of 1.2 MHz (1.2-2.4 MHz) and 14.5 MHz (13.3-27.8 MHz) for the low- and high-frequency arrays, respectively. With the proposed beamforming schemes, excitation pressure was found to range from 336 to 458 kPa at its azimuthal foci. This was sufficient to induce nonlinear scattering from microbubble contrast agents. Specifically, in vitro contrast channel phantom imaging and in vivo xenograft mouse tumor imaging by this probe with superharmonic imaging showed contrast-to-tissue ratio improvements of 17.7 and 16.2 dB, respectively, compared to line-by-line micro-ultrasound B-mode imaging.
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http://dx.doi.org/10.1109/TUFFC.2021.3065952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459708PMC
July 2021

A fully automated method for late ventricular diastole frame selection in post-dive echocardiography without ECG gating.

Undersea Hyperb Med 2021 First Quarter;48(1):73-80

Joint Department of Biomedical Engineering, The University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, U.S.

Venous gas emboli (VGE) are often quantified as a marker of decompression stress on echocardiograms. Bubble-counting has been proposed as an easy to learn method, but remains time-consuming, rendering large dataset analysis impractical. Computer automation of VGE counting following this method has therefore been suggested as a means to eliminate rater bias and save time. A necessary step for this automation relies on the selection of a frame during late ventricular diastole (LVD) for each cardiac cycle of the recording. Since electrocardiograms (ECG) are not always recorded in field experiments, here we propose a fully automated method for LVD frame selection based on regional intensity minimization. The algorithm is tested on 20 previously acquired echocardiography recordings (from the original bubble-counting publication), half of which were acquired at rest (Rest) and the other half after leg flexions (Flex). From the 7,140 frames analyzed, sensitivity was found to be 0.913 [95% CI: 0.875-0.940] and specificity 0.997 [95% CI: 0.996-0.998]. The method's performance is also compared to that of random chance selection and found to perform significantly better (p≺0.0001). No trend in algorithm performance was found with respect to VGE counts, and no significant difference was found between Flex and Rest (p>0.05). In conclusion, full automation of LVD frame selection for the purpose of bubble counting in post-dive echocardiography has been established with excellent accuracy, although we caution that high quality acquisitions remain paramount in retaining high reliability.
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March 2021

Ultrasound in decompression research: fundamentals, considerations, and future technologies.

Undersea Hyperb Med 2021 First Quarter;48(1):59-72

Joint Department of Biomedical Engineering, The University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, U.S.

It is widely accepted that bubbles are a necessary but insufficient condition for the development of decompression sickness. However, open questions remain regarding the precise formation and behavior of these bubbles after an ambient pressure reduction (decompression), primarily due to the inherent difficulty of directly observing this phenomenon in vivo. In decompression research, information about these bubbles after a decompression is gathered via means of ultrasound acquisitions. The ability to draw conclusions regarding decompression research using ultrasound is highly influenced by the variability of the methodologies and equipment utilized by different research groups. These differences play a significant role in the quality of the data and thus the interpretation of the results. The purpose of this review is to provide a technical overview of the use of ultrasound in decompression research, particularly Doppler and brightness (B)-mode ultrasound. Further, we will discuss the strengths and limitations of these technologies and how new advancements are improving our ability to understand bubble behavior post-decompression.
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March 2021

Assessing Polycystic Kidney Disease in Rodents: Comparison of Robotic 3D Ultrasound and Magnetic Resonance Imaging.

Kidney360 2020 10;1(10):1126-1136

SonoVol, Inc., Durham, North Carolina.

Polycystic kidney disease (PKD) is an inherited disorder characterized by renal cyst formation and enlargement of the kidney. PKD severity can be staged noninvasively by measuring total kidney volume (TKV), a promising biomarker that has recently received regulatory qualification. In preclinical mouse models, where the disease is studied and potential therapeutics are evaluated, the most popular noninvasive method of measuring TKV is magnetic resonance imaging (MRI). Although MRI provides excellent 3D resolution and contrast, these systems are expensive to operate, have long acquisition times, and, consequently, are not heavily used in preclinical PKD research. In this study, a new imaging instrument, based on robotic ultrasound (US), was evaluated as a complementary approach for assessing PKD in rodent models. The objective was to determine the extent to which TKV measurements on the robotic US scanner correlated with both and reference standards (MRI and Vernier calipers, respectively). A cross-sectional study design was implemented that included both PKD-affected mice and healthy wild types, spanning sex and age for a wide range of kidney volumes. It was found that US-derived TKV measurements and kidney lengths were strongly associated with both MRI and Vernier caliper measurements ( =0.94 and 0.90, respectively). In addition to measuring TKV, renal vascular density was assessed using acoustic angiography (AA), a novel contrast-enhanced US methodology. AA image intensity, indicative of volumetric vascularity, was seen to have a strong negative correlation with TKV ( =0.82), suggesting impaired renal vascular function in mice with larger kidneys. These studies demonstrate that robotic US can provide a rapid and accurate approach for noninvasively evaluating PKD in rodent models.
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http://dx.doi.org/10.34067/kid.0003912020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842280PMC
October 2020

Nanodroplet-mediated catheter-directed sonothrombolysis of retracted blood clots.

Microsyst Nanoeng 2021 6;7. Epub 2021 Jan 6.

Department of Mechanical & Aerospace Engineering, North Carolina State University, Raleigh, NC 27695 USA.

One major challenge in current microbubble (MB) and tissue plasminogen activator (tPA)-mediated sonothrombolysis techniques is effectively treating retracted blood clots, owing to the high density and low porosity of retracted clots. Nanodroplets (NDs) have the potential to enhance retracted clot lysis owing to their small size and ability to penetrate into retracted clots to enhance drug delivery. For the first time, we demonstrate that a sub-megahertz, forward-viewing intravascular (FVI) transducer can be used for ND-mediated sonothrombolysis, in vitro. In this study, we determined the minimum peak negative pressure to induce cavitation with low-boiling point phase change nanodroplets and clot lysis. We then compared nanodroplet mediated sonothrombolysis to MB and tPA mediate techniques. The clot lysis as a percent mass decrease in retracted clots was 9 ± 8%, 9 ± 5%, 16 ± 5%, 14 ± 9%, 17 ± 9%, 30 ± 8%, and 40 ± 9% for the control group, tPA alone, tPA + US, MB + US, MB + tPA + US, ND + US, and ND + tPA + US groups, respectively. In retracted blood clots, combined ND- and tPA-mediated sonothrombolysis was able to significantly enhance retracted clot lysis compared with traditional MB and tPA-mediated sonothrombolysis techniques. Combined nanodroplet with tPA-mediated sonothrombolysis may provide a feasible strategy for safely treating retracted clots.
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http://dx.doi.org/10.1038/s41378-020-00228-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787976PMC
January 2021

Quantitative sub-resolution blood velocity estimation using ultrasound localization microscopy ex-vivo and in-vivo.

Biomed Phys Eng Express 2020 04 21;6(3):035019. Epub 2020 Apr 21.

Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and the North Carolina State University, Chapel Hill, North Carolina, United States of America. Instituto de Ciencias de la Ingeniería, Universidad de O'Higgins, Avenida Libertador Bernardo O'Higgins 611, Rancagua, Chile.

Super-resolution ultrasound imaging relies on the sub-wavelength localization of microbubble contrast agents. By tracking individual microbubbles, the velocity and flow within microvessels can be estimated. It has been shown that the average flow velocity, within a microvessel ranging from tens to hundreds of microns in diameter, can be measured. However, a 2D super-resolution image can only localize bubbles with sub-wavelength resolution in the imaging plane whereas the resolution in the elevation plane is limited by conventional beamwidth physics. Since ultrasound imaging integrates echoes over the elevation dimension, velocity estimates at a single location in the imaging plane include information throughout the imaging slice thickness. This slice thickness is typically a few orders or magnitude larger than the super-resolution limit. It is shown here that in order to estimate the velocity, a spatial integration over the elevation direction must be considered. This operation yields a multiplicative correction factor that compensates for the elevation integration. A correlation-based velocity estimation technique is then presented. Calibrated microtube phantom experiments are used to validate the proposed velocity estimation method and the proposed elevation integration correction factor. It is shown that velocity measurements are in excellent agreement with theoretical predictions within the considered range of flow rates (10 to 90 μl/min) in a microtube with a diameter of 200 μm. Then, the proposed technique is applied to two in-vivo mouse tail experiments imaged with a low frequency human clinical transducer (ATL L7-4) with human clinical concentrations of microbubbles. In the first experiment, a vein was visible with a diameter of 140 μm and a peak flow velocity of 0.8 mm s. In the second experiment, a vein was observed in the super-resolved image with a diameter of 120 μm and with maximum local velocity of ≈4.4 mm s. It is shown that the parabolic flow profiles within these micro-vessels are resolvable.
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http://dx.doi.org/10.1088/2057-1976/ab7f26DOI Listing
April 2020

Focused Ultrasound for Immunomodulation of the Tumor Microenvironment.

J Immunol 2020 11;205(9):2327-2341

Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;

Focused ultrasound (FUS) has recently emerged as a modulator of the tumor microenvironment, paving the way for FUS to become a safe yet formidable cancer treatment option. Several mechanisms have been proposed for the role of FUS in facilitating immune responses and overcoming drug delivery barriers. However, with the wide variety of FUS parameters used in diverse tumor types, it is challenging to pinpoint FUS specifications that may elicit the desired antitumor response. To clarify FUS bioeffects, we summarize four mechanisms of action, including thermal ablation, hyperthermia/thermal stress, mechanical perturbation, and histotripsy, each inducing unique vascular and immunological effects. Notable tumor responses to FUS include enhanced vascular permeability, increased T cell infiltration, and tumor growth suppression. In this review, we have categorized and reviewed recent methods of using therapeutic ultrasound to elicit an antitumor immune response with examples that reveal specific solutions and challenges in this new research area.
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http://dx.doi.org/10.4049/jimmunol.1901430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583653PMC
November 2020

A Comparison of Sonothrombolysis in Aged Clots between Low-Boiling-Point Phase-Change Nanodroplets and Microbubbles of the Same Composition.

Ultrasound Med Biol 2020 11 14;46(11):3059-3068. Epub 2020 Aug 14.

Joint Department of Biomedical Engineering, The University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, USA. Electronic address:

We present enhanced cavitation erosion of blood clots exposed to low-boiling-point (-2°C) perfluorocarbon phase-change nanodroplets and pulsed ultrasound, as well as microbubbles with the same formulation under the same conditions. Given prior success with microbubbles as a sonothrombolysis agent, we considered that perfluorocarbon phase-change nanodroplets could enhance clot disruption further beyond that achieved with microbubbles. It has been hypothesized that owing to their small size and ability to penetrate into a clot, nanodroplets could enhance cavitation inside a blood clot and increase sonothrombolysis efficacy. The thrombolytic effects of lipid-shell-decafluorobutane nanodroplets were evaluated and compared with those of microbubbles with the same formulation, in an aged bovine blood clot flow model. Seven different pulsing schemes, with an acoustic intensity (I) range of 0.021-34.8 W/cm were applied in three different therapy scenarios: ultrasound only, ultrasound with microbubbles and ultrasound with nanodroplets (n = 5). Data indicated that pulsing schemes with 0.35 W/cm and 5.22 W/cm produced a significant difference (p < 0.05) in nanodroplet sonothrombolysis performance compared with compositionally identical microbubbles. With these excitation conditions, nanodroplet-mediated treatment achieved a 140% average thrombolysis rate over the microbubble-mediated case. We observed distinctive internal erosion in the middle of bovine clot samples from nanodroplet-mediated ultrasound, whereas the microbubble-mediated case generated surface erosion. This erosion pattern was supported by ultrasound imaging during sonothrombolysis, which revealed that nanodroplets generated cavitation clouds throughout a clot, whereas microbubble cavitation formed larger cavitation clouds only outside a clot sample.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146824PMC
November 2020

An Improved CMUT Structure Enabling Release and Collapse of the Plate in the Same Tx/Rx Cycle for Dual-Frequency Acoustic Angiography.

IEEE Trans Ultrason Ferroelectr Freq Control 2020 11 9;67(11):2291-2302. Epub 2020 Jun 9.

This study demonstrates, in detail, the potential of using capacitive micromachined ultrasonic transducers (CMUTs) for acoustic angiography of the microvasculature. It is known that when ultrasound contrast agents (microbubbles) are excited with moderate acoustic pressure around their resonance (2-4 MHz), they produce higher order harmonics (greater than third harmonic) due to their nonlinear behavior. To date, the fundamental challenge has been the availability of a transducer that can generate the transmit signals to excite the microbubbles at low frequencies and, in the same cycle, confocally detect harmonics in the higher frequencies. We present a novel device structure and dual-mode operation of a CMUT that operates with a center frequency of 4.3 MHz and 150% bandwidth in the conventional mode for transmitting and a center frequency of 9.8 MHz and a 125.5% bandwidth in collapse mode for receiving. Output pressure of 1.7 MPa is achieved on the surface of a single unfocused transducer. The mechanical index at the transducer surface is 0.56. FEM simulations are performed first to show the functionality of the proposed device, and then, the device fabrication is described in detail. Finally, we experimentally demonstrate the ability to detect the microbubble signals with good contrast, and the background reflection is adequately suppressed, indicating the feasibility of the presented approach for acoustic angiography.
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http://dx.doi.org/10.1109/TUFFC.2020.3001221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951756PMC
November 2020
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