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Contrast-enhanced ultrasonography (CEUS) has revolutionized diagnostic imaging by significantly improving the accuracy and capabilities of ultrasound technology. By utilizing contrast agents, CEUS offers enhanced visualization of blood flow, superior detection of vascular diseases, and delineation of pathological from healthy tissues. Real-time imaging capabilities afforded by CEUS have been shown to be instrumental in guiding interventions and assessing treatment efficacy, thereby contributing to personalized patient care and improved clinical outcomes. This document provides a comprehensive review of the current benefits, limitations, and future directions of contrast-enhanced ultrasonography. It acknowledges the potential for allergic reactions, the necessity for specialized training, high costs, and the occurrence of image artifacts as drawbacks, while also anticipating advancements in targeted agents and imaging techniques. Moreover, the document emphasizes the need for ongoing research to evaluate the long-term safety and efficacy of contrast agents and their impact across various medical disciplines. Despite the challenges, the integration of CEUS into clinical practice holds enormous potential to further refine diagnostic processes and enhance patient management. [ABSTRACT FROM AUTHOR]

The second harmonic (SH) of ultrasound contrast agents (UCAs) is widely used in contrast‐enhanced ultrasound imaging; however, is affected by the nonlinearity of surrounding tissue. Suppression of the tissue component based on the total least‐squares (STLS) algorithm is proposed to enhance the SH imaging of UCAs. The image blocks of pulse‐inversion‐based SH images before and after UCA injections are set as the reference and input of the total least‐squares model, respectively. The optimal coefficients of the model are obtained by minimizing the Frobenius norm of perturbations in the input and output signals. After processing all image blocks, the complete SH image of UCAs is obtained by subtracting the optimal output of the model (i.e., the estimated tissue SH image) from the SH image after UCA injection. Simulation and in vivo experiments confirm that the STLS approach offers clearer capillaries. For in vivo experiments, the STLS‐based contrast‐to‐tissue ratios and contrasts increase by 26.90% and 56.27%, as well as 26.99% and 56.43%, respectively, compared with those based on bubble‐echo deconvolution and pulse inversion bubble‐wavelet imaging methods. The STLS approach enhances the SH imaging of UCAs by effectively suppressing more tissue SH components, having the potential to provide more accurate diagnostic information for clinical applications. [ABSTRACT FROM AUTHOR]

Both microbubble ultrasound contrast agents and acoustic phase change droplets (APCD) have been explored in hepatocellular carcinoma (HCC). This work aimed to evaluate changes to the HCC microenvironment following either microbubble or APCD destruction in a syngeneic pre-clinical model. Mouse RIL-175 HCC tumors were grown in the right flank of 64 immunocompetent mice. Pre-treatment, photoacoustic volumetric tumor oxygenation, and power Doppler measurements were obtained using a Vevo 3100 system (VisualSonics, Toronto, Canada). The experimental groups received a 0.1 mL bolus injection of either Definity ultrasound contrast agent (Lantheus Medical Imaging) or APCD fabricated by condensing Definity. Following injection, ultrasound destruction was performed using flash-replenishment sequences on a Sequoia with a 10L4 probe (Siemens) for the duration of enhancement. Tumor oxygenation and power Doppler measurements were then repeated immediately post-ultrasound treatment. Twenty-four hours post-treatment, animals were euthanized, and tumors were harvested and stained for CD31, Cleaved Caspase 3 and CD45. Imaging biomarkers demonstrated a significant reduction in percent vascularity following either microbubble or APCD destruction in the tumor microenvironment (p < 0.022) but no significant changes in tumor oxygenation (p = 0.12). Similarly, immunohistochemistry data demonstrated a significant decrease in CD31 expression (p < 0.042) and an increase in apoptosis (p < 0.014) in tumors treated with destroyed microbubbles or APCD relative to controls. Finally, a significant increase in CD45 expression was observed in tumors treated with APCD (p = 0.046), indicating an increase in tumor immune response. Ultrasound-triggered destruction of both microbubbles and APCD reduces vascularity, increases apoptosis, and may also increase immune response in this HCC model. [ABSTRACT FROM AUTHOR]

Objective. Super-resolution ultrasonography offers the advantage of visualization of intricate microvasculature, which is crucial for disease diagnosis. Mapping of microvessels is possible by localizing microbubbles (MBs) that act as contrast agents and tracking their location. However, there are limitations such as the low detectability of MBs and the utilization of a diluted concentration of MBs, leading to the extension of the acquisition time. We aim to enhance the detectability of MBs to reduce the acquisition time of acoustic data necessary for mapping the microvessels. Approach. We propose utilizing phase patterned waves (PPWs) characterized by spatially patterned phase distributions in the incident beam to achieve this. In contrast to conventional ultrasound irradiation methods, this irradiation method alters bubble interactions, enhancing the oscillation response of MBs and generating more significant scattered waves from specific MBs. This enhances the detectability of MBs, thereby enabling the detection of MBs that were undetectable by the conventional method. The objective is to maximize the overall detection of bubbles by utilizing ultrasound imaging with additional PPWs, including the conventional method. In this paper, we apply PPWs to ultrasound imaging simulations considering bubble–bubble interactions to elucidate the characteristics of PPWs and demonstrate their efficacy by employing PPWs on MBs fixed in a phantom by the experiment. Main results. By utilizing two types of PPWs in addition to the conventional ultrasound irradiation method, we confirmed the detection of up to 93.3% more MBs compared to those detected using the conventional method alone. Significance. Ultrasound imaging using additional PPWs made it possible to increase the number of detected MBs, which is expected to improve the efficiency of bubble detection. [ABSTRACT FROM AUTHOR]

Zhengjun Ma,1 Yanmei Zhang,1 Yupu Zhu,2 Minxuan Cui,2 Yutao Liu,2 Yun-You Duan,1 Li Fan,2 Li Zhang1 1Department of Ultrasound Medicine, Tangdu Hospital, Air Force Medical University, Xi’an, People’s Republic of China; 2Department of Pharmaceutical Chemistry and Analysis, School of Pharmacy, Air Force Medical University, Xi’an, People’s Republic of ChinaCorrespondence: Li Fan; Li Zhang, Email xxfanny@fmmu.edu.cn; lilyzhang319_20@hotmail.comIntroduction: Recently, nanobubbles (NBs) have gained significant traction in the field of tumor diagnosis and treatment owing to their distinctive advantages. However, the application of NBs is limited due to their restricted size and singular reflection section, resulting in low ultrasonic reflection.Methods: We synthesized a nano-scale ultrasound contrast agent (IR783-SiO2NPs@NB) by encapsulating SiO2 nanoparticles in an IR783-labeled lipid shell using an improved film hydration method. We characterized its physicochemical properties, examined its microscopic morphology, evaluated its stability and cytotoxicity, and assessed its contrast-enhanced ultrasound imaging capability both in vitro and in vivo.Results: The results show that IR783-SiO2NPs@NB had a “donut-type” composite microstructure, exhibited uniform particle size distribution (637.2 ± 86.4 nm), demonstrated excellent stability (30 min), high biocompatibility, remarkable tumor specific binding efficiency (99.78%), and an exceptional contrast-enhanced ultrasound imaging capability.Conclusion: Our newly developed multiple scattering NBs with tumor targeting capacity have excellent contrast-enhanced imaging capability, and they show relatively long contrast enhancement duration in solid tumors, thus providing a new approach to the structural design of NBs.Keywords: ultrasound contrast agents, nanobubbles, CEUS, scattering cross-section, SiO2 NPs

To evaluate the inter-observer variability and the intra-observer repeatability of pulmonary transit time (PTT) measurement using contrast-enhanced ultrasound (CEUS) in healthy rabbits, and assess the effects of dilution concentration of ultrasound contrast agents (UCAs) on PTT. Thirteen healthy rabbits were selected, and five concentrations UCAs of 1:200, 1:100, 1:50, 1:10, and 1:1 were injected into the right ear vein. Five digital loops were obtained from the apical 4-chamber view. Four sonographers obtained PTT by plotting the TIC of right atrium (RA) and left atrium (LA) at two time points (T1 and T2). The frame counts of the first appearance of UCAs in RA and LA had excellent inter-observer agreement, with intra-class correlations (ICC) of 0.996, 0.988, respectively. The agreement of PTT among four observers was all good at five different concentrations, with an ICC of 0.758–0.873. The reproducibility of PTT obtained by four observers at T1 and T2 was performed well, with ICC of 0.888–0.961. The median inter-observer variability across 13 rabbits was 6.5% and the median variability within 14 days for 4 observers was 1.9%, 1.7%, 2.2%, 1.9%, respectively; The PTT of 13 healthy rabbits is 1.01 ± 0.18 second. The difference of PTT between five concentrations is statistically significant. The PTT obtained by a concentration of 1:200 and 1:100 were higher than that of 1:1, while there were no significantly differences in PTT of a concentration of 1:1, 1:10, and 1:50. PTT measured by CEUS in rabbits is feasible, with excellent inter-observer and intra-observer reliability and reproducibility, and dilution concentration of UCAs influences PTT results. [ABSTRACT FROM AUTHOR]

Subharmonic aided pressure estimation (SHAPE) is a technique that utilizes subharmonic signals from microbubble contrast agents for pressure estimation. Validation of the SHAPE technique relies on synchronous measurements of in vivo pressures using contrast microbubbles and a pressure catheter (reference standard). For the guidance and placement of pressure catheter in vivo, iodinated contrast is used with fluoroscopy. Therefore, during data acquisition for validation studies of the SHAPE technique, both contrast microbubbles and iodinated contrast are present simultaneously within the vasculature. This study aims to elucidate the effects of iodinated contrast (Visipaque, GE HealthCare) on subharmonic signal amplitude from contrast microbubbles (Definity, Lantheus Medical Imaging, Inc.). In an acrylic water tank, 0.06 mL of Definity and varied amounts of Visipaque (0.14, 0.43, 0.85, and 1.70 mL) were added to 425 mL of deionized water. Ultrasound scanning was performed with a SonixTablet scanner (BK Medical Systems) using optimized parameters for SHAPE with Definity (f transmit/receive = 3.0/1.5 MHz; chirp down pulse). Subharmonic data was acquired and analyzed at 9 different incident acoustic outputs (n = 3). Results showed an increase in subharmonic signal amplitude from Definity microbubbles in the presence of 0.14 mL Visipaque by 2.8 ± 1.3 dB (p <.001), no change with 0.85 mL Visipaque (0.7 ± 1.2 dB; p =.09) and a decrease in subharmonic amplitude in the presence of 1.70 mL Visipaque by 1.9 ± 0.7 dB (p <.001). While statistically significant effect on subharmonic signal amplitude of Definity microbubbles was noted due to the mixture, the magnitude of the effect was minimal (~2.8 dB) and unlikely to impact in vivo SHAPE measurements. [ABSTRACT FROM AUTHOR]

Endobronchial ultrasound (EBUS) is commonly used to guide transbronchial needle biopsies for the staging of lymph nodes in non-small cell lung cancer patients. Although contrast-enhanced ultrasound (CEUS) and microbubbles (MBs) can improve the diagnostic accuracy in tumors, the ability of contrast-enhanced EBUS (CE-EBUS) to image MBs has not yet been comprehensively evaluated. In this study, we assessed the ability of a CE-EBUS system (Olympus EU-ME2 PREMIER and BF-UC180F bronchoscope) to detect laboratory-synthesized MBs in comparison to clinical (Toshiba Aplio SSA-790A) and pre-clinical (VisualSonics Vevo 2100) CEUS systems in vitro and in vivo , respectively. Agar flow phantoms and reference tissue were used to assess CE-EBUS MB imaging in vitro, and A549 tumor-bearing athymic nude and AE17-OVA tumor-bearing C57BL/6 mice were used to assess MB detectability and perfusion in vivo , respectively. Results revealed that despite the lower sensitivity of CE-EBUS to MB concentration in comparison to clinical CEUS, CE-EBUS yielded a similar contrast-to-tissue ratio (CTR) in vitro of 28.9 ± 4.5 dB for CE-EBUS, compared with 29.7 ± 2.6 dB for clinical CEUS (p < 0.05). In vivo , CE-EBUS generated a perfusion curve highly correlated with that obtained with the pre-clinical CEUS system (Pearson correlation coefficient = 0.927, p < 0.05). Moreover, CE-EBUS yielded a CTR 2.7 times higher than that obtained with the pre-clinical ultrasound system. These findings together suggest that CE-EBUS can perform contrast imaging comparable to that produced by commercial pre-clinical and clinical ultrasound systems, with potential for clinical characterization of mediastinal lymph nodes in lung cancer patients. [ABSTRACT FROM AUTHOR]

Ultrasound contrast agent (UCA) use is increasing. Recent isolated reports observed a rise in pain‐related adverse events with the intravenous administration of the UCA Definity in adults with sickle cell disease. To date, no studies have investigated the incidence of similar adverse events with UCA Lumason or Optison. We describe our experience regarding the safety of Lumason and Optison in children with sickle cell disease and trait who underwent contrast‐enhanced ultrasound exams in our department with intravenous, intravesical, and other intracavitary routes. No pain‐related or other adverse events were observed in this pediatric population with any route of UCA administration. [ABSTRACT FROM AUTHOR]

Contrast-enhanced ultrasonography (CEUS) has revolutionized diagnostic imaging by significantly improving the accuracy and capabilities of ultrasound technology. By utilizing contrast agents, CEUS offers enhanced visualization of blood flow, superior detection of vascular diseases, and delineation of pathological from healthy tissues. Real-time imaging capabilities afforded by CEUS have been shown to be instrumental in guiding interventions and assessing treatment efficacy, thereby contributing to personalized patient care and improved clinical outcomes. This document provides a comprehensive review of the current benefits, limitations, and future directions of contrast-enhanced ultrasonography. It acknowledges the potential for allergic reactions, the necessity for specialized training, high costs, and the occurrence of image artifacts as drawbacks, while also anticipating advancements in targeted agents and imaging techniques. Moreover, the document emphasizes the need for ongoing research to evaluate the long-term safety and efficacy of contrast agents and their impact across various medical disciplines. Despite the challenges, the integration of CEUS into clinical practice holds enormous potential to further refine diagnostic processes and enhance patient management.

Abstract Ultrasound contrast agents (UCAs) have a well-established role in clinical cardiology. Contrast echocardiography has evolved into a routine technique through the establishment of contrast protocols, an excellent safety profile, and clinical guidelines which highlight the incremental prognostic utility of contrast enhanced echocardiography. This document aims to provide practical guidance on the safe and effective use of contrast; reviews the role of individual staff groups; and training requirements to facilitate its routine use in the echocardiography laboratory.

Yanan Feng,1,2,&ast; Yongsheng Hao,3,&ast; Yuanyuan Wang,3 Weijian Song,1,4 Shanxin Zhang,1 Dong Ni,5 Fei Yan,3 Litao Sun1 1Cancer Center, Department of Ultrasound Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People’s Republic of China; 2Department of Abdominal Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China; 3Center for Cell and Gene Circuit Design, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, People’s Republic of China; 4Bengbu Medical College, Bengbu, 233030, People’s Republic of China; 5Medical Ultrasound Image Computing (MUSIC) Laboratory, Shenzhen University, Shenzhen, 518055, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Litao Sun; Fei Yan, Tel +86 13946037056, Email litaosun1971@sina.com; fei.yan@siat.ac.cnPurpose: Ultrasound molecular imaging (UMI) has proven promising to diagnose the onset and progression of diseases such as angiogenesis, inflammation, and thrombosis. However, microbubble-based acoustic probes are confined to intravascular targets due to their relatively large particle size, greatly reducing the application value of UMI, especially for extravascular targets. Extradomain B fibronectin (ED-B FN) is an important glycoprotein associated with tumor genesis and development and highly expressed in many types of tumors. Here, we developed a gas vesicles (GVs)-based nanoscale acoustic probe (ZD2-GVs) through conjugating ZD2 peptides which can specially target to ED-B FN to the biosynthetic GVs.Materials and Methods: ED-B FN expression was evaluated in normal liver and tumor tissues with immunofluorescence and Western blot. ZD2-GVs were prepared by conjugating ZD2 to the surface of GVs by amide reaction. The inverted microscope was used to analyze the targeted binding capacity of ZD2-GVs to MB49 cells (bladder cancer cell line). The contrast-enhanced imaging features of GVs, non-targeted control GVs (CTR-GVs), and targeted GVs (ZD2-GVs) were compared in three MB49 tumor mice. The penetration ability of ZD2-GVs in tumor tissues was assessed by fluorescence immunohistochemistry. The biosafety of GVs was evaluated by CCK8, blood biochemistry, and HE staining.Results: Strong ED-B FN expression was observed in tumor tissues while little expression in normal liver tissues. The resulting ZD2-GVs had only 267.73 ± 2.86 nm particle size and exhibited excellent binding capability to the MB49 tumor cells. The in vivo UMI experiments showed that ZD2-GVs produced stronger and longer retention in the BC tumors than that of the non-targeted CTR-GVs and GVs. Fluorescence immunohistochemistry confirmed that ZD2-GVs could penetrate the tumor vascular into the interstitial space of the tumors. Biosafety analysis revealed there was no significant cytotoxicity to these tested mice.Conclusion: Thus, ZD2-GVs can function as a potential UMI probe for the early diagnosis of bladder cancer.Graphical Abstract: Keywords: ultrasound contrast agents, gas vesicles, ultrasound molecular imaging, tumor diagnosis

Ultrasonically excited microbubbles (MBs) have numerous applications in various fields, such as drug delivery, and imaging. Ultrasonically excited MBs are known to be nonlinear oscillators that generate secondary acoustic emissions in the media when excited by a primary ultrasound wave. The propagation of acoustic waves in the liquid is limited to the speed of sound, resulting in each MB receiving the primary and secondary waves at different times depending on their distance from the ultrasound source and the distance between MBs. These delays are referred to as primary and secondary delays, respectively. A previous study demonstrated that the inclusion of secondary delays in a model describing the interactions between MBs exposed to ultrasound results in an increase in the linear resonance frequency of MBs as they approach each other. This work investigates the impact of various MB properties on the change in linear resonance frequency resulting from changes in inter-bubble distances. The effects of shell properties, including the initial surface tension, surface dilatational viscosity of the shell monolayer, elastic compression modulus of the shell, and the initial radius of the MBs, are examined. MB size is a significant factor influencing the rate of linear resonance frequency increase with increasing concentration. Moreover, it is found that the shell properties of MBs play a negligible role in the rate of change in linear resonance frequency of MBs as the inter-bubble distances change.The findings of this study have implications for various applications of MBs in the biomedical field. By understanding the impact of inter-bubble distances and shell properties on the linear resonance frequency of MBs, the utilization of MBs in applications reliant on their resonant behavior can be optimized.

Breast cancer stands as the most frequent malignancy and leading cause of death among women. Early and accurate detection of this pathology represents a crucial factor in enhancing both incidence and mortality rates. Ultrasound (US) examination has been extensively adopted in clinical practice due to its non-invasiveness, affordability, ease of implementation, and wide accessibility, thus representing a valuable first-line diagnostic tool for the study of the mammary gland. In this scenario, recent developments in nanomedicine are paving the way for new interpretations and applications of US diagnostics, which are becoming increasingly personalized based on the molecular phenotype of each tumor, allowing for more precise and accurate evaluations. This review highlights the current state-of-the-art of US diagnosis of breast cancer, as well as the recent advancements related to the application of US contrast agents to the field of molecular diagnostics, still under preclinical study. [ABSTRACT FROM AUTHOR]

Ultrasound contrast agents (UCAs) have a well-established role in clinical cardiology. Contrast echocardiography has evolved into a routine technique through the establishment of contrast protocols, an excellent safety profile, and clinical guidelines which highlight the incremental prognostic utility of contrast enhanced echocardiography. This document aims to provide practical guidance on the safe and effective use of contrast; reviews the role of individual staff groups; and training requirements to facilitate its routine use in the echocardiography laboratory. [ABSTRACT FROM AUTHOR]

Sonoporation is the process where intracellular drug delivery is facilitated by ultrasound-driven microbubble oscillations. Several mechanisms have been proposed to relate microbubble dynamics to sonoporation including shear and normal stress. The present work aims to gain insight into the role of microbubble size on sonoporation and thereby into the relevant mechanism(s) of sonoporation. To this end, we measured the sonoporation efficiency while varying microbubble size using monodisperse microbubble suspensions. Sonoporation experiments were performed in vitro on cell monolayers using a single ultrasound pulse with a fixed frequency of 1 MHz while the acoustic pressure amplitude and pulse length were varied at 250, 500, and 750 kPa, and 10, 100, and 1000 cycles, respectively. Sonoporation efficiency was quantified using flow cytometry by measuring the FITC-dextran (4 kDa and 2 MDa) fluorescence intensity in 10,000 cells per experiment to average out inherent variations in the bioresponse. Using ultra-high-speed imaging at 10 million frames per second, we demonstrate that the bubble oscillation amplitude is nearly independent of the equilibrium bubble radius at acoustic pressure amplitudes that induce sonoporation (≥ 500 kPa). However, we show that sonoporation efficiency is strongly dependent on the equilibrium bubble size and that under all explored driving conditions most efficiently induced by bubbles with a radius of 4.7 μm. Polydisperse microbubbles with a typical ultrasound contrast agent size distribution perform almost an order of magnitude lower in terms of sonoporation efficiency than the 4.7-μm bubbles. We elucidate that for our system shear stress is highly unlikely the mechanism of action. By contrast, we show that sonoporation efficiency correlates well with an estimate of the bubble-induced normal stress. [Display omitted] [ABSTRACT FROM AUTHOR]

The objective of this work was to study microbubble-enhanced temperature elevation with high-intensity focused ultrasound (HIFU) at different acoustic pressures and under image guidance. The microbubbles were administered with either local or vascular injections (that mimic systemic injections) in perfused and non-perfused ex vivo porcine liver under ultrasound image guidance. Porcine liver was insonified for 30 s with a single-element HIFU transducer (0.9 MHz, 0.413 ms, 82% duty cycle, focal pressures of 0.6–3.5 MPa). Contrast microbubbles were injected either locally or through the vasculature. A needle thermocouple at the focus measured temperature elevation. Diagnostic ultrasound (Philips iU22, C5-1 probe) guided placement of the thermocouple and delivery of microbubbles and monitored the procedure in real time. At lower acoustic pressures (0.6 and 1.2 MPa) in non-perfused liver, inertial cavitation of the injected microbubbles led to greater temperatures at the focus compared with HIFU-only treatments. At higher pressures (2.4 and 3.5 MPa) native inertial cavitation in the tissue (without injecting microbubbles) resulted in temperature elevations similar to those after injecting microbubbles. The heated area was larger when using microbubbles at all pressures. In the presence of perfusion, only local injections provided a sufficiently high concentration of microbubbles necessary for significant temperature enhancement. Local injections of microbubbles provide a higher concentration of microbubbles in a smaller area, avoiding acoustic shadowing, and can lead to higher temperature elevation at lower pressures and increase the size of the heated area at all pressures. [ABSTRACT FROM AUTHOR]

The sensitivity of the acoustic response of microbubbles, specifically a strong correlation between their subharmonic response and the ambient pressure, has motivated development of a non-invasive subharmonic-aided pressure estimation (SHAPE) method. However, this correlation has previously been found to vary depending on the microbubble type, the acoustic excitation and the hydrostatic pressure range. In this study, the ambient pressure sensitivity of microbubble response was investigated. The fundamental, subharmonic, second harmonic and ultraharmonic responses from an in-house lipid-coated microbubble were measured for excitations with peak negative pressures (PNPs) of 50–700 kPa and frequencies of 2, 3 and 4 MHz in the ambient overpressure range 0–25 kPa (0–187 mmHg) in an in vitro setup. The subharmonic response typically has three stages—occurrence, growth and saturation—with increasing excitation PNP. We find distinct decreasing and increasing variations of the subharmonic signal with overpressure that are closely related to the threshold of subharmonic generation in a lipid-shelled microbubble. Above the excitation threshold, that is, in the growth-saturation phase, subharmonic signals decreased linearly with slopes as high as –0.56 dB/kPa with ambient pressure increase; below the threshold excitation (at atmospheric pressure), increasing overpressure triggers subharmonic generation, indicating a lowering of subharmonic threshold, and therefore leads to an increase in subharmonic with overpressure, the maximum enhancement being ∼11 dB for 15 kPa overpressure at 2 MHz and 100 kPa PNP. This study indicates the possible development of novel and improved SHAPE methodologies. [ABSTRACT FROM AUTHOR]

Rationale and objectivesBreast cancer is the leading type of cancer among women. Visualization and characterization of breast lesions based on vascularity kinetics was evaluated using three-dimensional (3D) contrast-enhanced ultrasound imaging in a clinical study.Materials and methodsBreast lesions (n = 219) were imaged using power Doppler imaging (PDI), 3D contrast-enhanced harmonic imaging (HI), and 3D contrast-enhanced subharmonic imaging (SHI) with a modified Logiq 9 ultrasound scanner using a 4D10L transducer. Quantitative metrics of vascularity derived from 3D parametric volumes (based on contrast perfusion; PER and area under the curve; AUC) were generated by off-line processing of contrast wash-in and wash-out. Diagnostic accuracy of these quantitative vascular parameters was assessed with biopsy results as the reference standard.ResultsVascularity was observed with PDI in 93 lesions (69 benign and 24 malignant), 3D HI in 8 lesions (5 benign and 3 malignant), and 3D SHI in 83 lesions (58 benign and 25 malignant). Diagnostic accuracy for vascular heterogeneity, PER, and AUC ranged from 0.52 to 0.75, while the best logistical regression model (vascular heterogeneity ratio, central PER, and central AUC) reached 0.90.Conclusion3D SHI successfully detects contrast agent flow in breast lesions and characterization of these lesions based on quantitative measures of vascular heterogeneity and 3D parametric volumes is promising.

Microbubbles have been the earliest and most widely used ultrasound contrast agents by virtue of their unique features: such as non-toxicity, intravenous injectability, ability to cross the pulmonary capillary bed, and significant enhancement of echo signals for the duration of the examination, resulting in essential preclinical and clinical applications. The use of microbubbles functionalized with targeting ligands to bind to specific targets in the bloodstream has further enabled ultrasound molecular imaging. Nevertheless, it is very challenging to utilize targeted microbubbles for molecular imaging of extravascular targets due to their size. A series of acoustic nanomaterials have been developed for breaking free from this constraint. Especially, biogenic gas vesicles, gas-filled protein nanostructures from microorganisms, were engineered as the first biomolecular ultrasound contrast agents, opening the door for more direct visualization of cellular and molecular function by ultrasound imaging. The ordered protein shell structure and unique gas filling mechanism of biogenic gas vesicles endow them with excellent stability and attractive acoustic responses. What’s more, their genetic encodability enables them to act as acoustic reporter genes. This article reviews the upgrading progresses of ultrasound contrast agents from microbubbles to biogenic gas vesicles, and the opportunities and challenges for the commercial and clinical translation of the nascent field of biomolecular ultrasound.

Nanoscale ultrasound contrast agents, or nanobubbles, are being explored in preclinical applications ranging from vascular and cardiac imaging to targeted drug delivery in cancer. These sub-micron particles are approximately 10x smaller than clinically available microbubbles. This allows them to effectively traverse compromised physiological barriers and circulate for extended periods of time. While various aspects of nanobubble behavior have been previously examined, their behavior in human whole blood has not yet been explored. Accordingly, herein we examined, for the first time, the short and long-term effects of blood components on nanobubble acoustic response. We observed differences in the kinetics of backscatter from nanobubble suspensions in whole blood compared to bubbles in phosphate buffered saline (PBS), plasma, or red blood cell solutions (RBCs). Specifically, after introducing nanobubbles to fresh human whole blood, signal enhancement, or the magnitude of nonlinear ultrasound signal, gradually increased by 22.8 ± 13.1% throughout our experiment, with peak intensity reached within 145 s. In contrast, nanobubbles in PBS had a stable signal with negligible change in intensity (−1.7 ± 3.2%) over 8 min. Under the same conditions, microbubbles made with the same lipid formulation showed a −56.8 ± 6.1% decrease in enhancement in whole blood. Subsequent confocal, fluorescent, and scanning electron microscopy analysis revealed attachment of the nanobubbles to the surface of RBCs, suggesting that direct interactions, or hitchhiking, of nanobubbles on RBCs in the presence of plasma may be a possible mechanism for the observed effects. This phenomenon could be key to extending nanobubble circulation time and has broad implications in drug delivery, where RBC interaction with nanoparticles could be exploited to improve delivery efficiency.

Intravenous contrast-enhanced ultrasound (CEUS) can serve as a diagnostic or problem-solving tool in pediatric imaging. CEUS of abdominal solid organs has been reported for a number of indications. The approach to the examination broadly falls into two categories: evaluation of a focal lesion or surveillance of an organ or organs for lesions or perfusion abnormalities. A consistent, technical imaging protocol for both of these clinical scenarios facilitates integration of routine use of CEUS in an imaging department. Here we review the CEUS imaging protocols for abdominal organs in children, including technical and solid-organ-specific considerations. [ABSTRACT FROM AUTHOR]

Currently available cytotoxic treatments have limited effect on pancreatic ductal adenocarcinoma (PDAC) because desmoplastic stroma limits drug delivery. Efforts have been made to overcome these barriers by drug targeting the tumor microenvironment. Results so far are promising, but without clinical impact. Our aim was to investigate whether ultrasound and microbubbles could improve the uptake and therapeutic response of conventional chemotherapy. Orthotopic pancreatic tumors growing in mice were treated with commercially available FOLFIRINOX (fluorouracil, irinotecan, oxaliplatin and calcium folinate) and SonoVue microbubbles combined with focused ultrasound. Tumor uptake of platinum (Pt) was measured by inductively coupled plasma mass spectroscopy (ICP-MS), and tumor volumes were measured by ultrasound imaging. Uptake of Pt, the active ingredient of oxaliplatin, was significantly increased after ultrasound treatment of orthotopic PDAC tumors. Multiple injections with FOLFIRONOX increased the amount of Pt in tumors. However, the enhanced accumulation did not improve therapeutic response. Increased uptake of Pt confirms that ultrasound and microbubbles have potential in clinical practice with existing drugs. The lack of therapeutic response, despite increased uptake in tumor tissue, emphasizes the importance of studying how to overcome stromal barriers. [ABSTRACT FROM AUTHOR]

Collapse of lipidic ultrasound contrast agents under high-frequency compressive load has been historically interpreted by the vanishing of surface tension. By contrast, buckling of elastic shells is known to occur when costly compressible stress is released through bending. Through quasi-static compression experiments on lipidic shells, we analyse the buckling events in the framework of classical elastic buckling theory and deduce the mechanical characteristics of these shells. They are then compared with that obtained through acoustic characterization. This article is part of the theme issue 'Probing and dynamics of shock sensitive shells'. [ABSTRACT FROM AUTHOR]

Ultrasound (US)–targeted microbubble (MB) cavitation (UTMC)–mediated therapies have been found to restore perfusion and enhance drug/gene delivery. Because of the potentially longer circulation time and relative ease of storage and reconstitution of polymer-shelled MBs compared with lipid MBs, we investigated the dynamic behavior of polymer microbubbles and their therapeutic potential for sonoreperfusion (SRP) therapy. The fate of polymer MBs during a single long tone-burst exposure (1 MHz, 5 ms) at various acoustic pressures and MB concentrations was recorded via high-speed microscopy and passive cavitation detection (PCD). SRP efficacy of the polymer MBs was investigated in an in vitro flow system and compared with that of lipid MBs. Microscopy videos indicated that polymer MBs formed gas-filled clusters that continued to oscillate, fragment and form new gas-filled clusters during the single US burst. PCD confirmed continued acoustic activity throughout the 5-ms US excitation. SRP efficacy with polymer MBs increased with pulse duration and acoustic pressure similarly to that with lipid MBs but no significant differences were found between polymer and lipid MBs. These data suggest that persistent cavitation activity from polymer MBs during long tone-burst US excitation confers excellent reperfusion efficacy. [ABSTRACT FROM AUTHOR]

Evidence for the safe use of Lumason® (SonoVue®), an ultrasound enhancing agent (UEA), in special patient populations is critical to enable healthcare professionals to make informed decisions concerning its use in such patients. Herein, we provide insight on the safety and tolerability of Lumason® in special patient populations. Findings are presented from clinical pharmacology studies conducted in patients with compromised cardiopulmonary conditions, from a retrospective study performed in critically ill patients, and from post-marketing surveillance data from over 20 years of market use of Lumason® (SonoVue®). No detrimental effects of Lumason® on cardiac electrophysiology were observed in patients with coronary artery disease (CAD), and no significant effects on pulmonary hemodynamics were noted in patients with pulmonary hypertension or congestive heart failure. Similarly, no effects on several assessments of pulmonary function (e.g., FVC) were observed in patients with chronic obstructive pulmonary disease (COPD), and no clinically meaningful changes in O2 saturation or other safety parameters were observed after administration of Lumason® to patients with diffuse interstitial pulmonary fibrosis (DIPF). The retrospective study of critically ill patients revealed no significant difference for in-hospital mortality between patients administered Lumason® for echocardiography versus those who had undergone echocardiography without contrast agent. Post-marketing surveillance revealed very low reporting rates (RR) for non-serious and serious adverse events and that serious hypersensitivity reactions were rare. These findings confirm that Lumason® is a safe and well tolerated UEA for use in special populations and critically ill patients.

Silica particles are convenient ultrasound imaging contrast agents because of their long imaging time and ease of modification; however, they require a relatively high insonation power for imaging and have low biodegradability. In this study, 2 μm ultrathin asymmetric hollow silica particles doped with iron (III) (Fe(III)-SiO2) are synthesized to produce biodegradable hard shelled particles with a low acoustic power threshold comparable with commercial soft microbubble contrast agents (Definity) yet with much longer in vivo ultrasound imaging time. Furthermore, high intensity focused ultrasound ablation enhancement with these particles shows a 2.5-fold higher temperature elevation than with Definity at the same applied power. The low power visualization improves utilization of the silica shells as an adjuvant in localized immunotherapy. The data are consistent with asymmetric engineering of hard particle properties that improve functionality of hard versus soft particles.

Abstract Ultrasound contrast agents (UCAs), which are groups of engineered microbubbles, have been recently studied for drug delivery applications, since the cavitation of bubbles can increase the temporary permeability of nearby cells. However, the internal volume of UCAs is generally filled with gas, hence loading drug molecules into UCAs is limited. In this study, an echogenic liposome with a liquid and gas core is proposed as an alternative carrier of genetic material for ultrasound‐mediated drug delivery. The structure of the synthesized echogenic liposome was analysed via transmission electron microscopy and confocal microscopy with fluorescent labels. The protection of siRNA by the echogenic liposomes was also verified by exposure to RNase. The results indicate that at least 10% of the total siRNA used in the experiment was successfully protected by the proposed echogenic liposome. Additionally, the release of siRNA from the liposomes could be successfully achieved with 1 W/cm2 ultrasound sonication at 1 MHz; parameters low enough to be used in generic ultrasound therapeutic systems. Although further studies to clarify the responses to incident ultrasound fields and to quantitatively analyse the internal liquid volume for drug loading are required, the proposed echogenic liposome has great potential for ultrasound‐mediated gene delivery.

Noninvasive and accurate assessment of intracardiac pressures has remained an elusive goal of noninvasive cardiac imaging. The purpose of this study was to investigate if errors in intracardiac pressures obtained noninvasively using contrast microbubbles and the subharmonic-aided pressure estimation (SHAPE) technique are <5 mm Hg. In a nonrandomized institutional review board–approved clinical trial (NCT03243942), patients scheduled for a left-sided and/or right-sided heart catheterization procedure and providing written informed consent were included. A standard-of-care catheterization procedure was performed advancing clinically used pressure catheters into the left and/or right ventricles and/or the aorta. After pressure catheter placement, patients received an infusion of Definity microbubbles (n = 56; 2 vials diluted in 50 mL of saline; infusion rate: 4-10 mL/min) (Lantheus Medical Imaging). Then SHAPE data was acquired using a validated interface developed on a SonixTablet scanner (BK Medical Systems) synchronously with the pressure catheter data. A conversion factor (mm Hg/dB) was derived from SHAPE data and measurements with a SphygmoCor XCEL PWA device (ATCOR Medical) and was combined with SHAPE data from the left and/or the right ventricles to obtain clinically relevant systolic and diastolic ventricular pressures. The mean value of absolute errors for left ventricular minimum and end diastolic pressures were 2.9 ± 2.0 and 1.7 ± 1.2 mm Hg (n = 26), respectively, and for right ventricular systolic pressures was 2.2 ± 1.5 mm Hg (n = 11). Two adverse events occurred during Definity infusion; both were resolved. These results indicate that the SHAPE technique with Definity microbubbles is encouragingly efficacious for obtaining intracardiac pressures noninvasively and accurately. (Noninvasive, Subharmonic Intra-Cardiac Pressure Measurement; NCT03243942) [Display omitted] [ABSTRACT FROM AUTHOR]