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Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide. [ABSTRACT FROM AUTHOR]

Objective: The goal of this study was to evaluate the performance of different commercial ultrasound contrast microbubbles (MBs) when measuring bladder phantom pressure with sub-harmonic-aided pressure estimation (SHAPE) methodology. We hypothesized that SHAPE performance is dependent on MB formulation. This study aimed to advance the SHAPE application for bladder pressure measurements in humans., Methods: Using a previously designed and built bladder phantom, we tested four different commercial agents: Definity, Lumason, Sonazoid and Optison. A standard clinical cystometrogram (CMG) system was used to infuse a MB-saline mixture into the bladder phantom to measure pressure. Ultrasound imaging was performed using the GE Healthcare LOGIQ E10 scanner., Results: All agents showed a predicted inverse linear relationship between change in pressure and SHAPE signal. However, they differ from each other in terms of stability, linear correlation, sensitivity to pressure and error. Generally, Definity and Lumason showed the highest performance during the SHAPE-based bladder phantom pressure assessments., Conclusion: Our results show that the SHAPE signal decreases as bladder phantom pressures increases, regardless of the agent or CMG phase, suggesting the possibility of using SHAPE for measuring bladder pressure without a catheter. However, the efficacy of SHAPE in measuring pressure varies by MB formulation. These observations support using Lumason and Definity in a human subject feasibility study as we advance toward a catheter-free solution for measuring voiding bladder pressure via SHAPE., Competing Interests: Conflict of interest There are no conflicts of interest to be reported for this publication., (Copyright © 2024 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Acoustic droplet vaporization (ADV) offers a dynamic approach for generating bubbles on demand, presenting new possibilities in biomedical applications. Although ADV has been investigated in various biomedical applications, its potential in tissue characterization remains unexplored. Here, we investigated the effects of surrounding media on the radial dynamics and acoustic emissions of ADV bubbles using theoretical and experimental methodologies. For theoretical studies, bubble dynamics were combined with the Kelvin-Voigt material constitutive model, accounting for viscoelasticity of the media. The radial dynamics and acoustic emissions of the ADV-bubbles were recorded via ultra-high-speed microscopy and passive cavitation detection, respectively. Perfluoropentane phase-shift droplets were embedded in tissue-mimicking hydrogels of varying fibrin concentrations, representing different elastic moduli. Radial dynamics and the acoustic emissions, both temporal and spectral, of the ADV-bubbles depended significantly on fibrin elastic modulus. For example, an increase in fibrin elastic modulus from ≈0.2 kPa to ≈6 kPa reduced the maximum expansion radius of the ADV-bubbles by 50%. A similar increase in the elastic modulus significantly impacted both linear (e.g., fundamental) and nonlinear (e.g., subharmonic) acoustic responses of the ADV-bubbles, by up to 10 dB. The sensitivity of ADV to the surrounding media was dependent on acoustic parameters such as driving pressure and the droplets concentration. Further analysis of the acoustic emissions revealed distinct ADV signal characteristics, which were significantly influenced by the surrounding media., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Ultrasound imaging is a safe diagnostic tool that has become ubiquitous, in part due to its portability, effectiveness, and safety record. The latter is aided be adherence to regulatory limits, safety guidelines, and the "as low as reasonably achievable" principle. Operators receive feedback on potential tissue heating and mechanical effects through output display standard that shows the thermal index and mechanical index. To prevent the spread of infections, ultrasound transducers require varying levels of disinfection based on procedure invasiveness, following detailed infection control protocols, even in resource-limited settings. Ergonomic sonography practices are emphasized to prevent work-related musculoskeletal disorders (WRMSD), with professional organizations encouraging the use of ergonomically designed equipment and proper body positioning during scans. Operators should understand and properly apply ergonomic practices. Administrators play a key role by providing ergonomic equipment, education on WRMSD prevention, and creating workplace policies., Competing Interests: Disclosure The authors have no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to quantify the accuracy of partial volume-corrected three-dimensional volume flow (3DVF) measurements as a function of spatial sampling beam density using carefully-designed parametric analyses in order to inform the target applications of 3DVF., Methods: Experimental investigations employed a mechanically-swept curvilinear ultrasound array to acquire 3D color flow (6.3 MHz) images in flow phantoms consisting of four lumen diameters (6.35, 4.88, 3.18 and 1.65 mm) with volume flow rates of 440, 260, 110 and 30 mL/min, respectively. Partial volume-corrected three-dimensional volume flow (3DVF) measurements, based on the Gaussian surface integration principle, were computed at five regions of interest positioned between depths of 2 and 6 cm in 1 cm increments. At each depth, the color flow beam point spread function (PSF) was also determined, using in-phase/quadrature data, such that 3DVF bias could then be related to spatial sampling beam density. Corresponding simulations were performed for a laminar parabolic flow profile that was sampled using the experimentally-measured PSFs. Volume flow was computed for all combinations of lumen diameters and the PSFs at each depth., Results: Accurate 3DVF measurements, i.e., bias less than ±20%, were achieved for spatial sampling beam densities where at least 6 elevational color flow beams could be positioned across the lumen. In these cases, greater than 8 lateral color flow beams were present. PSF measurements showed an average lateral-to-elevational beam width asymmetry of 1:2. Volume flow measurement bias increased as the color flow beam spatial sampling density within the lumen decreased., Conclusion: Applications of 3DVF, particularly those in the clinical domain, should focus on areas where a spatial sampling density of 6 × 6 (lateral x elevational) beams can be realized in order to minimize measurement bias. Matrix-based ultrasound arrays that possess symmetric PSFs may be advantageous to achieve adequate beam densities in smaller vessels., Competing Interests: Conflict of interest Pinter, SZ: Equipment support, General Electric Healthcare Company. Rubin, JM: Research and equipment support, General Electric Healthcare Company. Hall, AL: At time of data acquisition, Employee, General Electric Healthcare Company. Fowlkes, JB: Research and equipment support, General Electric Healthcare Company. Kripfgans, OD: Research and equipment support, General Electric Healthcare Company., (Copyright © 2024 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: Optimal management of fetuses diagnosed as small for gestational age based on an estimated fetal weight of <10th percentile represents a major clinical problem. The standard approach is to increase fetal surveillance with serial biometry and antepartum testing to assess fetal well-being and timing of delivery. Observational studies have indicated that maternal rest in the left lateral position improves maternal cardiac output and uterine blood flow. However, maternal bed rest has not been recommended based on the results of a randomized clinical trial that showed that maternal rest does not improve fetal growth in small-for-gestational-age fetuses. This study was conducted to revisit this question., Objective: This study aimed to determine whether maternal bed rest was associated with an increase in the fetal biometric parameters that reflect growth after the diagnosis of a small-for-gestational-age fetus., Study Design: A retrospective study was conducted on fetuses who were diagnosed as small for gestational age because of an estimated fetal weight of <10th percentile for gestational age. The mothers were asked to rest in the left lateral recumbent position. Fetal biometry was performed 2 weeks after the diagnosis. All fetuses before entry into the study had a previous ultrasound that demonstrated an estimated fetal weight of >10th percentile. To assess the response to bed rest, the change in fetal biometric parameters (estimated fetal weight, head circumference, abdominal circumference, and femur length) after the recommendation of bed rest was computed for 2 periods: (1) before the diagnosis of a weight of <10th percentile vs at the time of diagnosis of a weight of <10th percentile and (2) at the time of diagnosis of a weight of <10th percentile vs 2 weeks after maternal bed rest. For repeated measures, proportions were compared using the McNemar test, and percentile values were compared using the Bonferroni Multiple Comparison Test. A P value of <.05 was considered significant. To describe changes in the estimated fetal weight without bed rest, 2 control groups in which the mothers were not placed on bed rest after the diagnosis of a small-for-gestational-age fetus were included., Results: A total of 265 fetuses were observed before and after maternal bed rest. The following were observed in this study: (1) after 2 weeks of maternal rest, 199 of 265 fetuses (75%) had a fetal weight of >10th percentile; (2) the median fetal weight percentile increased from 6.8 (interquartile range, 4.4-8.4) to 18.0 (interquartile range, 9.5-29.5) after 2 weeks of bed rest; (3) similar trends were noted for the head circumference, abdominal circumference, and femur length. In the groups of patients who were not asked to be on bed rest, a reassignment to a weight of >10th percentile at a follow-up examination only occurred in 7 of 37 patients (19%) in the Texas-Michigan group and 13 of 111 patients (12%) in the Colorado group compared with the bed rest group (199/265 [75%]) (P<.001)., Conclusion: Patients who were prescribed 2 weeks of bed rest after the diagnosis of a fetal weight of <10th percentile had an increase in weight of >10th percentile in 199 of 265 fetuses (75%). This increase in fetal weight was significantly higher than that in the 2 control groups in which bed rest was not prescribed. This observation suggests that bed rest improves fetal growth in a subset of patients., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The etiology of ureteral dilation in primary nonrefluxing, nonobstructing megaureters is still not well understood. Impaired ureteral peristalsis has been theorized as one of the contributing factors. However, ureteral peristalsis and its "normal" function is not well defined. In this study, using mathematical modeling techniques, we aim to better understand how ureteral peristalsis works. This is the first model to consider clinically observed, back-and-forth, cyclic wall longitudinal motion during peristalsis. We hypothesize that dysfunctional ureteral peristalsis, caused by insufficient peristaltic amplitudes (e.g., circular muscle dysfunction) and/or lack of ureteral wall longitudinal motion (e.g., longitudinal muscle dysfunction), promotes peristaltic reflux (i.e., retrograde flow of urine during an episode of peristalsis) and may result in urinary stasis, urine accumulation, and consequent dilation., Methods: Based on lubrication theory in fluid mechanics, we developed a two-dimensional (planar) model of ureteral peristalsis. In doing so, we treated ureteral peristalsis as an infinite train of sinusoidal waves. We then analyzed antegrade and retrograde flows in the ureter under different bladder-kidney differential pressure and peristalsis conditions., Results: There is a minimum peristaltic amplitude required to prevent peristaltic reflux. Ureteral wall longitudinal motion decreases this minimum required amplitude, increasing the nonrefluxing range of peristaltic amplitudes. As an example, for a normal bladder-kidney differential pressure of 5 cmH 2 O, ureteral wall longitudinal motion increases nonrefluxing range of peristaltic amplitude by 65%. Additionally, ureteral wall longitudinal motion decreases refluxing volumetric flow rates. For a similar normal bladder pressure example of 5 cmH 2 O, refluxing volumetric flow rate decreases by a factor of 18. Finally, elevated bladder pressure, not only increases the required peristaltic amplitude for reflux prevention but it increases maximum refluxing volumetric flow rates. For the case without wall longitudinal motion, as bladder-kidney differential pressure increases from 5 to 40 cmH 2 O, minimum required peristaltic amplitude to prevent reflux increases by 40% while the maximum refluxing volumetric flow rate increases by approximately 100%., Conclusion: The results presented in this study show how abnormal ureteral peristalsis, caused by the absence of wall longitudinal motion and/or lack of sufficient peristaltic amplitudes, facilitates peristaltic reflux and retrograde flow. We theorize that this retrograde flow can lead to urinary stasis and urine accumulation in the ureters, resulting in ureteral dilation seen on imaging studies and elevated infection risk. Our results also show how chronically elevated bladder pressures are more susceptible to such refluxing conditions that could lead to ureteral dilation., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Introduction: This study was designed to test the efficacy of an ultrasound flow measurement method to evaluate placental function in a hyperandrogenic sheep model that produces placental morphologic changes and an intrauterine growth restriction (IUGR) phenotype., Materials and Methods: Pregnant ewes were assigned randomly between control (n = 12) and testosterone-treatment (T-treated, n = 22) groups. The T-treated group was injected twice weekly intramuscularly (IM) with 100 mg testosterone propionate. Control sheep were injected with corn oil vehicle. Lambs were delivered at 119.5 ± 0.48 days gestation. At the time of delivery of each lamb, flow spectra were generated from one fetal artery and two fetal veins, and the spectral envelopes examined using fast Fourier transform analysis. Base 10 logarithms of the ratio of the amplitudes of the maternal and fetal spectral peaks (LRSP) in the venous power spectrum were compared in the T-treated and control populations. In addition, we calculated the resistive index (RI) for the artery defined as ((peak systole - min diastole)/peak systole). Two-tailed T-tests were used for comparisons., Results: LRSPs, after removal of significant outliers, were -0.158 ± 0.238 for T-treated and 0.057 ± 0.213 for control (p = 0.015) animals. RIs for the T-treated sheep fetuses were 0.506 ± 0.137 and 0.497 ± 0.086 for controls (p = 0.792) DISCUSSION: LRSP analysis distinguishes between T-treated and control sheep, whereas RIs do not. LRSP has the potential to identify compromised pregnancies., Competing Interests: Declaration of competing interest Submission of this work verifies that the work described herein has not been published previously (except in the form of an abstract), and it is not under consideration for publication elsewhere. The publication has been approved by all authors, and approved by the University of Michigan Medical School through the Institutional Animal Care and Use Committee (IACUC), and if accepted, it will not be published elsewhere in the same form in English or any other language, including electronically without consent of the copyright holder., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Phase-shift droplets provide a flexible and dynamic platform for therapeutic and diagnostic applications of ultrasound. The spatiotemporal response of phase-shift droplets to focused ultrasound, via the mechanism termed acoustic droplet vaporization (ADV), can generate a range of bioeffects. Although ADV has been used widely in theranostic applications, ADV-induced bioeffects are understudied. Here, we integrated ultra-high-speed microscopy, confocal microscopy, and focused ultrasound for real-time visualization of ADV-induced mechanics and sonoporation in fibrin-based, tissue-mimicking hydrogels. Three monodispersed phase-shift droplets-containing perfluoropentane (PFP), perfluorohexane (PFH), or perfluorooctane (PFO)-with an average radius of ∼6  μ m were studied. Fibroblasts and tracer particles, co-encapsulated within the hydrogel, were used to quantify sonoporation and mechanics resulting from ADV, respectively. The maximum radial expansion, expansion velocity, induced strain, and displacement of tracer particles were significantly higher in fibrin gels containing PFP droplets compared to PFH or PFO. Additionally, cell membrane permeabilization significantly depended on the distance between the droplet and cell ( d ), decreasing rapidly with increasing d . Significant membrane permeabilization occurred when d was smaller than the maximum radius of expansion. Both ultra-high-speed and confocal images indicate a hyper-local region of influence by an ADV bubble, which correlated inversely with the bulk boiling point of the phase-shift droplets. The findings provide insight into developing optimal approaches for therapeutic applications of ADV., Competing Interests: The authors have no conflicts to disclose., (© 2023 Author(s).)

Microporosity in hydrogels is critical for directing tissue formation and function. We have developed a fibrin-based smart hydrogel, termed an acoustically responsive scaffold (ARS), which responds to focused ultrasound in a spatiotemporally controlled, user-defined manner. ARSs are highly flexible platforms due to the inclusion of phase-shift droplets and their tunable response to ultrasound through a mechanism termed acoustic droplet vaporization (ADV). Here, we demonstrated that ADV enabled consistent generation of micropores in ARSs, throughout the entire thickness (∼5.5 mm), utilizing perfluorooctane phase-shift droplets. Size characteristics of the generated micropores were quantified in response to critical parameters including acoustic properties, droplet size, and shear elastic modulus of fibrin using confocal microscopy. The findings showed that the length of the generated micropores correlated directly with excitation frequency, peak rarefactional pressure, pulse duration, droplet size, and indirectly with the shear elastic modulus of the fibrin matrix. The ADV-generated micropores in ARSs were further compared with cavitation-mediated micropores in fibrin gels without droplets. Additionally, the Keller-Miksis equation was used to predict an upper bound for micropore formation in ARSs at varying driving frequencies and droplet sizes. Finally, our in vivo studies showed that host cell migration following ADV-induced micropore formation was frequency-dependent, with up to 2.6 times higher cell migration at lower frequencies. Overall, these findings demonstrate a new potential application of ADV in hydrogels. STATEMENT OF SIGNIFICANCE: Interconnected micropores within a hydrogel can facilitate many cell-mediated processes. Most techniques for generating micropores are typically not biocompatible or do not enable controlled, in situ micropore formation. We used an ultrasound-based technique, termed acoustic droplet vaporization, to generate microporosity in smart hydrogels termed acoustically responsive scaffolds (ARSs). ARSs contain a fibrin matrix doped with a phase-shift droplet. We demonstrate that unique acoustic properties of phase-shift droplets can be tailored to yield spatiotemporally controlled, on-demand micropore formation. Additionally, the size characteristics of the ultrasound-generated micropores can be modulated by tuning ultrasound parameters, droplet properties, and bulk elastic properties of fibrin. Finally, we demonstrate significant, frequency-dependent host cell migration in subcutaneously implanted ARSs in mice following ultrasound-induced micropore formation in situ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objectives: The long-term goal of this study is to investigate the efficacy of a novel, ultrasound-based technique called subharmonic-aided pressure estimation (SHAPE) to measure bladder pressure as a part of a cystometrogram (CMG) in a urodynamic test (ie, pressure-flow study). SHAPE is based on the principle that subharmonic emissions from ultrasound contrast microbubbles (MBs) decrease linearly with an increase in ambient pressure. We hypothesize that, using the SHAPE technique, we can measure voiding bladder pressure catheter-free. This is of importance because the CMG catheter, due to its space-occupying property and non-physiological effects, can undermine the reliability of the test during voiding and cause misdiagnosis. In this study, we tested this hypothesis and optimized the protocol in a controlled benchtop environment., Materials and Methods: A bladder phantom was designed and built, capable of simulating clinically relevant bladder pressures. Laboratory-made lipid-shelled MBs (similar in composition to the commercial agent, DEFINITY) was diluted in 0.9% normal saline and infused into the bladder phantom using the CMG infusion system. A typical simulated CMG consists of 1 filling and 4 post-filling events. During CMG events, the bladder phantom is pressurized multiple times at different clinically relevant levels (small, medium, and large) to simulate bladder pressures. Simultaneous with pressurization, MB subharmonic signal was acquired. For each event, the change in MB subharmonic amplitude was correlated linearly with the change in bladder phantom pressure, and the SHAPE conversion factor (slope of the linear fit) was determined. In doing so, a specific signal processing technique (based on a small temporal window) was used to account for time-decay of MB subharmonic signal during a simulated CMG., Results: A strong inverse linear relationship was found to exist between SHAPE and bladder phantom pressures for each of the CMG filling and post-filling events ( r2> 0.9, root mean square error < 0.3 dB, standard error <0.01 dB, and P < 0.001). SHAPE showed a transient behavior in measuring bladder phantom pressure. The SHAPE conversion factor (in dB/cm H 2 O) varied between filling and post-filling events, as well as by post-filling time. The magnitude of the SHAPE conversion factor tended to increase immediately after filling and then decreases with time., Conclusions: Microbubble subharmonic emission is an excellent indicator of bladder phantom pressure variation. The strong correlation between SHAPE signal and bladder phantom pressure is indicative of the applicability of this method in measuring bladder pressure during a CMG. Our results suggest that different SHAPE conversion factors may be needed for different events during a CMG (ie, at different time points of a CMG). These findings will help us better protocolize this method for introduction into human subjects and allow us to take the next step toward developing a catheter-free voiding CMG using SHAPE., Competing Interests: Conflicts of interest and sources of funding: This research has been partially supported by grants from The Societies for Pediatric Urology, the University of Michigan Mcubed Program, the Michigan Institute for Clinical and Health Research, and the Departments of Urology and Radiology at the University of Michigan. The support for ultrasound scanner used in this study (GE LOGIQ E10) comes from General Electric Healthcare (Wauwatosa, WI) with technical support from Dr Kirk Wallace., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The goal of this study was to evaluate ultrasound contrast microbubbles (MB) stability during a typical cystometrogram (CMG) for bladder pressure measurement application using the subharmonic-aided pressure estimation technique. A detailed study of MB stability was required given two unique characteristics of this application: first, bulk infusion of MBs into the bladder through the CMG infusion system, and second, duration of a typical CMG which may last up to 30 min. To do so, a series of size measurement and contrast-enhanced ultrasound imaging studies under different conditions were performed and the effects of variables that we hypothesized have an effect on MB stability, namely, i) IV bag air headspace, ii) MB dilution factor, and iii) CMG infusion system were investigated. The results verified that air volume in intravenous (IV) bag headspace was not enough to have a significant effect on MB stability during a CMG. We also showed that higher MB dosage results in a more stable condition. Finally, the results indicated that the CMG infusion system adversely affects MB stability. In summary, to ensure MB stability during the entire duration of a CMG, lower filling rates (limited by estimated bladder capacity in clinical applications) and/or higher MB dosage (limited by FDA regulations and shadowing artifact) and/or the consideration of alternative catheter design may be needed., Competing Interests: Declaration of Competing Interest There are not conflicts of interest to be reported for this publication., (Copyright © 2022 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Measurement of blood flow to the brain in neonates would be a very valuable addition to the medical diagnostic armamentarium. Such conditions such as assessment of closure of a patent ductus arteriosus (PDA) would greatly benefit from such an evaluation. However, measurement of cerebral blood flow in a clinical setting has proven very difficult and, as such, is rarely employed. Present techniques are often cumbersome, difficult to perform and potentially dangerous for very low birth weight (VLBW) infants. We have been developing an ultrasound blood volume flow technique that could be routinely used to assess blood flow to the brain in neonates. By scanning through the anterior fontanelles of 10 normal, full-term newborn infants, we were able to estimate total brain blood flows that closely match those published in the literature using much more invasive and technically demanding methods. Our method is safe, easy to do, does not require contrast agents and can be performed in the baby's incubator. The method has the potential for monitoring and assessing blood flows to the brain and could be used to routinely assess cerebral blood flow in many different clinical conditions., (Copyright © 2022 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Excessive liver fat (steatosis) is now the most common cause of chronic liver disease worldwide and is an independent risk factor for cirrhosis and associated complications. Accurate and clinically useful diagnosis, risk stratification, prognostication, and therapy monitoring require accurate and reliable biomarker measurement at acceptable cost. This article describes a joint effort by the American Institute of Ultrasound in Medicine (AIUM) and the RSNA Quantitative Imaging Biomarkers Alliance (QIBA) to develop standards for clinical and technical validation of quantitative biomarkers for liver steatosis. The AIUM Liver Fat Quantification Task Force provides clinical guidance, while the RSNA QIBA Pulse-Echo Quantitative Ultrasound Biomarker Committee develops methods to measure biomarkers and reduce biomarker variability. In this article, the authors present the clinical need for quantitative imaging biomarkers of liver steatosis, review the current state of various imaging modalities, and describe the technical state of the art for three key liver steatosis pulse-echo quantitative US biomarkers: attenuation coefficient, backscatter coefficient, and speed of sound. Lastly, a perspective on current challenges and recommendations for clinical translation for each biomarker is offered., (© RSNA, 2022.)

Objectives: Placental blood flow analysis is complicated by having both maternal and fetal flow components. Using the Fast Fourier Transform (FFT) of the umbilical venous pulse wave spectra (PW) envelope, we could simultaneously assess maternal/fetal blood flow in the placenta and investigate if normal and intrauterine growth restriction (IUGR)/pre-eclamptic pregnancies could be distinguished., Methods: This retrospective study included normal gestations (N = 11) and gestations with IUGR, pre-eclampsia, or both (N = 13). Umbilical vein PW were acquired and spectral envelopes were identified as a function of time and analyzed by FFT. Base-10 logarithms of the ratios of the maternal/fetal spectral peaks (LRSP) were compared in normal and IUGR/pre-eclamptic populations (two-tailed t-test). Body mass index (BMI), gestational age at scan time, placental position, and weight-normalized umbilical vein blood volume flow (two-tailed t-test, analysis of variance [ANOVA] analysis) were tested. P < .05 was considered significant., Results: The LRSP for normal and IUGR/pre-eclamptic pregnancies were 0.141 ± 0.180 and -0.072 ± 0.262 (mean ± standard deviation), respectively (P = .033). We detected differences between normal gestations and combinations of LRSP and weight-normalized umbilical venous blood flows. Placental effects based on LRSPs and blood flow may act synergistically in cases with both pre-eclampsia and IUGR (P = .014). No other significant associations were seen., Conclusions: In this preliminary study, we showed that umbilical venous flow contains markers related to placental maternal/fetal blood flow, which can be used to assess IUGR and pre-eclampsia. When coupled with umbilical cord blood flow, this new marker may potentially identify the primary causes of the two conditions., (© 2021 American Institute of Ultrasound in Medicine.)

Background: As of 2022, breast cancer continues to be the most diagnosed cancer worldwide. This problem persists within the United States as well, as the American Cancer Society has reported that ∼12.5% of women will be diagnosed with invasive breast cancer over the course of their lifetime. Therefore, a clinical need continues to exist to address this disease from a treatment and therapeutic perspective. Current treatments for breast cancer and cancers more broadly include surgery, radiation, and chemotherapy. Adjuncts to these methods have been developed to improve the clinical outcomes for patients. One such adjunctive treatment is mild hyperthermia therapy (MHTh), which has been shown to be successful in the treatment of cancers by increasing effectiveness and reduced dosage requirements for radiation and chemotherapies. MHTh-assisted treatments can be performed with invasive thermal devices, noninvasive microwave induction, heating and recirculation of extracted patient blood, or whole-body hyperthermia with hot blankets., Purpose: One common method for inducing MHTh is by using microwave for heat induction and magnetic resonance imaging for temperature monitoring. However, this leads to a complex, expensive, and inaccessible therapy platform. Therefore, in this work we aim to show the feasibility of a novel all-acoustic MHTh system that uses focused ultrasound (US) to induce heating while also using US tomography (UST) to provide temperature estimates. Changes in sound speed (SS) have been shown to be strongly correlated with temperature changes and can therefore be used to indirectly monitor heating throughout the therapy. Additionally, these SS estimates allow for heterogeneous SS-corrected phase delays when heating complex and heterogeneous tissue structures., Methods: Feasibility to induce localized heat in tissue was investigated in silico with a simulated breast model, including an embedded tumor using continuous wave US. Here, both heterogenous acoustic and thermal properties were modeled in addition to blood perfusion. We further demonstrate, with ex vivo tissue phantoms, the feasibility of using ring-based UST to monitor temperature by tracking changes in SS. Two phantoms (lamb tissue and human abdominal fat) with latex tubes containing varied temperature flowing water were imaged. The measured SS of the water at each temperature were compared against values that are reported in literature., Results: Results from ex vivo tissue studies indicate successful tracking of temperature under various phantom configurations and ranges of water temperature. The results of in silico studies show that the proposed system can heat an acoustically and thermally heterogenous breast model to the clinically relevant temperature of 42°C while accounting for a reasonable time needed to image the current cross section (200 ms). Further, we have performed an initial in silico study demonstrating the feasibility of adjusting the transmit waveform frequency to modify the effective heating height at the focused region. Lastly, we have shown in a simpler 2D breast model that MHTh level temperatures can be maintained by adjusting the transmit pressure intensity of the US ring., Conclusions: This work has demonstrated the feasibility of using a 256-element ring array transducer for temperature monitoring; however, future work will investigate minimizing the difference between measured SS and the values shown in literature. A hypothesis attributes this bias to potential volumetric average artifacts from the ray-based SS inversion algorithm that was used, and that moving to a waveform-based SS inversion algorithm will greatly improve the SS estimates. Additionally, we have shown that an all-acoustic MHTh system is feasible via in silico studies. These studies have indicated that the proposed system can heat a tumor within a heterogenous breast model to 42°C within a narrow time frame. This holds great promise for increasing the accessibility and reducing the complexity of a future all-acoustic MHTh system., (© 2022 American Association of Physicists in Medicine.)

Acoustic droplet vaporization (ADV) has been proven to enhance high intensity focused ultrasound (HIFU) thermal ablation of tumor. It has also been demonstrated that triggering droplets before HIFU exposure could be a potential way to control both the size and the shape of the thermal lesion. In this paper, a numerical model is proposed to predict the thermal lesion created in ADV enhanced HIFU treatment. Bubble oscillation was coupled into a viscoelastic medium in the model to more closely represent real applications in tissues. Several physical processes caused by continuous wave ultrasound and elevated temperature during the HIFU exposure were considered, including rectified diffusion, gas solubility variation with temperature in the medium, and boiling. Four droplet concentrations spanning two orders of magnitude were calculated. The bubble cloud formed from triggering of the droplets by the pulse wave ultrasound, along with the evolution of the shape and location of the bubble cloud and thermal lesion during the following continuous wave exposure was obtained. The increase of bubble void fraction caused by continuous wave exposure was found to be consistent with the experimental observation. With the increase of droplet concentration, the predicted bubble cloud shapes vary from tadpole to triangular and double triangular, while the thermal lesions move toward the transducer. The results show that the assumptions used in this model increased the accuracy of the results. This model may be used for parametrical study of ADV enhanced HIFU treatment and be further used for treatment planning and optimization in the future., (Copyright © 2022 by ASME.)

Acoustically-responsive scaffolds (ARSs) are composite hydrogels that respond to ultrasound in an on-demand, spatiotemporally-controlled manner due to the presence of a phase-shift emulsion. When exposed to ultrasound, a gas bubble is formed within each emulsion droplet via a mechanism termed acoustic droplet vaporization (ADV). In previous in vitro and in vivo studies, we demonstrated that ADV can control regenerative processes by releasing growth factors and/or modulating micromechanics in ARSs. Precise, spatial patterning of emulsion within an ARS could be beneficial for ADV-induced modulation of biochemical and biophysical cues. However, precise patterning is limited using conventional bulk polymerization techniques. Here, we developed an extrusion-based method for bioprinting ARSs with micropatterned structures. Emulsions were loaded within bioink formulations containing fibrin, hyaluronic acid and/or alginate. Experimental as well as theoretical studies elucidated the interrelations between printing parameters, needle geometry, rheological properties of the bioink, and the process-induced mechanical stresses during bioprinting. The shear thinning properties of the bioinks enabled use of lower extrusion pressures resulting in decreased shear stresses and shorter residence times, thereby facilitating high viability for cell-loaded bioinks. Bioprinting yielded greater alignment of fibrin fibers in ARSs compared to conventionally polymerized ARSs. Bioprinted ARSs also enabled generation of ADV at high spatial resolutions, which were otherwise not achievable in conventional ARSs, and acoustically-driven collapse of ADV-induced bubbles. Overall, bioprinting could aid in optimizing ARSs for therapeutic applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Vascularization is a critical step following implantation of an engineered tissue construct in order to maintain its viability. The ability to spatially pattern or direct vascularization could be therapeutically beneficial for anastomosis and vessel in-growth. However, acellular and cell-based strategies to stimulate vascularization typically do not afford this control. We have developed an ultrasound-based method of spatially- controlling regenerative processes using acellular, composite hydrogels termed acoustically-responsive scaffolds (ARSs). An ARS consists of a fibrin matrix doped with a phase-shift double emulsion (PSDE). A therapeutic payload, which is initially contained within the PSDE, is released by an ultrasound-mediated process called acoustic droplet vaporization (ADV). During ADV, the perfluorocarbon (PFC) phase within the PSDE is vaporized into a gas bubble. In this study, we generated ex situ four different spatial patterns of ADV within ARSs containing basic fibroblast growth factor (bFGF), which were subcutaneously implanted in mice. The PFC species within the PSDE significantly affected the morphology of the ARS, based on the stability of the gas bubble generated by ADV, which impacted host cell migration. Irrespective of PFC, significantly greater cell proliferation (i.e., up to 2.9-fold) and angiogenesis (i.e., up to 3.7-fold) were observed adjacent to +ADV regions of the ARSs compared to -ADV regions. The morphology of the PSDE, macrophage infiltration, and perfusion in the implant region were also quantified. These results demonstrate that spatially-defined patterns of ADV within an ARS can elicit spatially-defined patterns of angiogenesis. Overall, these finding can be applied to improve strategies for spatially-controlling vascularization. STATEMENT OF SIGNIFICANCE: Vascularization is a critical step following implantation of an engineered tissue. The ability to spatially pattern or direct vascularization could be therapeutically beneficial for inosculation and vessel in-growth. However, acellular and cell-based strategies to stimulate vascularization typically do not afford this control. We have developed an ultrasound-based method of spatially-controlling angiogenesis using acellular, composite hydrogels termed acoustically-responsive scaffolds (ARSs). An ARS consists of a fibrin matrix doped with a phase-shift double emulsion (PSDE). An ultrasound-mediated process called acoustic droplet vaporization (ADV) was used to release basic fibroblast growth factor (bFGF), which was initially contained within the PSDE. We demonstrate that spatially-defined patterns of ADV within an ARS can elicit spatially-defined patterns of angiogenesis in vivo. Overall, these finding can improve strategies for spatially-controlling vascularization., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

In our previous studies, we have developed a prototype interstitial needle sensing probe that can acquire broadband A-line photoacoustic (PA) signals encoding both tissue microarchitecture and histochemical information comparable to that accessible by histology. Paving the road toward clinical translation of this technology, we replaced the piezoelectric hydrophone in the needle PA probe with a fiber optic hydrophone that enabled both broader bandwidth and sufficient signal-to-noise ratio (SNR) for PA signal detection. Such an all-optical design also facilitated disposability and significantly reduced the footprint of the needle PA sensing probe. Experiments were performed on well-controlled phantoms and human prostate tissues. The microarchitectures in each sample were quantitatively evaluated by both the nonlinear spectral slope of the PA signal power spectrum and the generalized gamma (GG) parameter a by implementing envelope statistics to the PA signal. In the studies on phantoms containing optically absorbing microspheres with various sizes and concentrations, the nonlinear spectral slope showed a strong correlation of r=-0.80 with the microsphere dimensions, and a relatively weak correlation of r=-0.54 with the microsphere concentrations, while the GG parameter a showed a strong correlation with the microsphere dimensions (r=0.72) and a moderate correlation with the microsphere concentrations (r=0.63). In the studies on human prostate tissues containing progressive cancer stages, both the nonlinear spectral slope and the GG parameter a demonstrated a statistically significant difference between benign and nonaggressive cancer tissues (p<0.01), and between nonaggressive and aggressive cancer tissues (p<0.01). In addition, a multivariate analysis combining the two quantitative measurements demonstrated the boundaries among the different progressive stages of prostate cancer., Competing Interests: The authors declare no conflicts of interest., (© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Objective: We aimed to assess longitudinal wall motion of the common carotid artery (CCA) using velocity vector imaging (VVI)., Methods: From October 2018 to July 2019, we prospectively performed VVI of 204 CCAs (102 adult volunteers, 57 men, 45 women) in young (n = 40, 20-44 y), mid-age (n = 30, 45-64 y), and senior (n = 32, ≥65 y) groups. VVI parameters of CCA included longitudinal motion pattern, motion parameters (strain, strain rate, displacement), and time-to-peak motion parameters (time-to-peak strain, time-to-peak strain rate, time-to-peak displacement). Statistical analyses included one-way ANOVA post-hoc testing to examine the difference in VVI parameters among the 3 age groups and in paired groups; unpaired t tests to examine the difference in VVI parameters between CCAs with and without atherosclerotic plaque, between hypertensive and normotensive subjects without atherosclerotic plaque; linear regression to analyze correlations of VVI parameters to age, carotid intima-media thickness; and intraclass correlation coefficient to test inter- and intra-observer reliability in performing VVI of the CCA., Results: Differences in VVI parameters and patterns among the 3 age groups, between hypertensive and normotensive, and CCAs with and without plaque were significant (p < .01). CCA motion- and time-to-peak motion parameters were correlated to age (R 2 = 0.63-0.56) and carotid intima-media thickness (R 2 = 0.29-0.22). CCA wall motion dyssynchrony was remarkable in seniors. The repeatability and reproducibility for performing carotid artery VVI were good (intraclass correlation coefficient > 0.85)., Conclusions: VVI is feasible to assess changes in longitudinal CCA wall mechanical properties and synchrony with aging, atherosclerosis, and hypertension., (© 2020 American Institute of Ultrasound in Medicine.)

Objectives: We are studying a new method for estimating blood volume flow that uses 3-dimensional ultrasound to measure the total integrated flux through an ultrasound-generated Gaussian surface that intersects the umbilical cord. This method makes none of the assumptions typically required with standard 1-dimensional spectral Doppler volume flow estimates. We compared the variations in volume flow estimates between techniques in the umbilical vein., Methods: The study was Institutional Review Board approved, and all 12 patients gave informed consent. Because we had no reference standard for the true umbilical vein volume flow, we compared the variations of the measurements for the flow measurement techniques. At least 3 separate spectral Doppler and 3 separate Gaussian surface measurements were made along the umbilical vein. Means, standard deviations, and coefficients of variation (standard deviation/mean) for the flow estimation techniques were calculated for each patient. P < .05 was considered significant., Results: The ranges of the mean volume flow estimates were 174 to 577 mL/min for the spectral Doppler method and 100 to 341 mL/min for the Gaussian surface integration (GSI) method. The mean standard deviations (mean ± SD) were 161 ± 95 and 45 ± 48 mL/min for the spectral Doppler and GSI methods, respectively (P < .003). The mean coefficients of variation were 0.46 ± 0.17 and 0.18 ± 0.14 for the spectral Doppler and GSI methods respectively (P < 0.002)., Conclusions: The new volume flow estimation method using 3-dimensional ultrasound appears to have significantly less variation in estimates than the standard 1-dimensional spectral Doppler method., (© 2020 American Institute of Ultrasound in Medicine.)

The motivation behind this study is to understand how ureterovesical junction (UVJ) deformation during urine storage in the bladder affects vesicoureteral reflux (VUR), when urine flows backward from the bladder toward the kidneys. Using nonlinear, large deformation finite element simulations, the deformation of the bladder wall during urine storage is modeled in this study. The bladder wall is assumed to be a homogeneous, isotropic, hyperelastic spherical shell with a finite thickness. The UVJ is defined as a straight elliptical cylindrical hole through the bladder wall at the reference configuration before inflation. Broad parametric studies on different UVJ configurations are performed as the bladder inner surface stretches by a factor of 2.2 from an initial radius corresponding to bladder volumes of 10% to slightly over physiologic capacity. For each considered UVJ configuration, a simple fluid analysis of the tunnel flow resistance compares different bladder inner surface stretch ratios. Our model shows that the deformation of the UVJ depends on its orientation with respect to the bladder wall radial and circumferential directions. We show that as the UVJ insertion angle increases, the UVJ cross section decreases and its tunnel length increases during urine storage causing the closure of the UVJ and a rise in its flow resistance. The modeling results indicate that UVJ closure could be explained by bladder wall deformation rather than the local differential pressure. Our findings are consistent with the accepted primary anti-reflux mechanism of the UVJ being dependent on the tunnel length-to-diameter ratio and consequently the UVJ insertion angle., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS), first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications.The 2012 guideline requires updating as previously the differences of the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including the United States Food and Drug Administration (FDA) approval as well as the extensive Asian experience, to produce a truly international perspective.These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCA) and are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis to improve the management of patients., Competing Interests: Christoph F Dietrich: Speaker honoraria, Bracco, Hitachi, GE, Mindray, Supersonic, Pentax, Olympus, Fuji, Boston Scientific, AbbVie, Falk Foundation, Novartis, Roche; Advisory Board Member, Hitachi, Mindray, Siemens; Research grant, GE, Mindray, SuperSonic Richard G Barr: Speaker honoraria, Bracco, Hitachi, GE, Mindray, Supersonic, Philips, Siemens, Lantheus, Canon; Advisory Board – Lanteus and Bracco Diagnostics; Board Member – ICUS; Research Grants – Siemens Ultrasound, Philips Ultrasound, GE Ultrasound, GE Medical, Mindray, SuperSonic Imagine, B and K Ultrasound Annalisa Berzigotti: Research grant, Bracco Byung Ihn Choi: Speaker honoraria, Samsung Dirk André Clevert: Speaker honoraria, Bracco, GE, Samsung, Philips, Siemens, Falk Foundation Jean-Michel Correas: Speaker Honoraria, Canon MS, Hitachi MS, Philips US, SuperSonic Imagine, Novartis, Johnson & Johnson; Speaker honoraria, Bracco SA: Principal investigator of BR1-127 et SonoCap studies; Speaker honoraria, Guerbet SA: Principal investigator of NsSafe and Secure studies Odd Helge Gilja: Speaker honoraria, GE Healthcare, Takeda AS; Advisory Consulting, GE, Takeda and Samsung Vito Cantisani: Speaker honoraria, Samsung, Bracco, Canon J. Brian Fowlkes: Research grants, Philips Healthcare, GE Healthcare; Stock Ownership, Histosonics Adrian Lim: Advisory Board, Canon Medical Systems, Carestream; Research grant – Philips Medical Systems; Speaker honoraria – Canon, Bracco Maria Franca Meloni: Speaker honoraria, Bracco Christian Jenssen: Speaker honoraia, Hitachi, Bracco, Falk Foundation; Expert witness, Hitachi Mirko D’Onofrio: Speaker honoraria, Bracco, Siemens; Advisory Board, Bracco, Siemens, Hitachi; Research grant, Hitach; Congress Support, Bracco, Siemens Fabio Piscaglia: Speaker honoraria, Bracco, Bayer, EISAI, Guerbet; Advisory board honoraria: Bayer, EISAI; Research Contract: ESAOTE Masatoshi Kudo: Speaker honoraria, Bayer, Eisai, MSD, Ajinomoto; Research Grants, Chugai, Otsuka, Takeda, Taiho, Sumitomo Dainippon, Daiichi Sankyo, MSD, Eisai, Bayer, Abbvie, Medico’s Hirata, Astellas Pharma, Bristol-Myers Squibb; Advisory Consulting, Kowa, MSD, BMS, Bayer, Chugai, Taiho, Eisai, Ono pharmaceutical Yi Dong: Speaker honoraria, Bracco, Siemens Yuko Kono: Equipment support Canon, GE; Contast agent support Lantheus, Bracco Andrej Lyshchik: Speaker honoraria, GE Healthcare, Siemens, Canon; Advisory Board, Bracco Diagnostics; Consulting, GE Healthcare; Speaker panel, GE Healthcare, SonoScape; Royalties, Elsevier Zheng Rongqin: Speaker honoraria, Bracco, Esaote; Research grant, Philips; Congress support, Bracco Paul Sidhu: Speaker honoraria, Bracco, Siemens, Hitachi, GE healthcare, Philips, Samsung, Advisory Board ITREAS Ltd The following have declared no conflict of interest: Peter Burns, Cristina Chammas, Nitin G Chaubal, Pintong Huang, Andre Ignee, Nathalie Lassau, Jae-Young Lee, Yasunori Minami, Carlos Nicolau, Christian Nolsoe, Xin-Wu Cui, Adrian Saftoiu, Guido Torzilli, Ping Liang, Fuminori Moriyasu, Xiaoyan Xie, (Thieme. All rights reserved.)

Hydrogels are commonly used in regenerative medicine for the delivery of growth factors (GFs). The spatial and temporal presentations of GFs are critical for directing regenerative processes, yet conventional hydrogels do not enable such control. We have developed a composite hydrogel, termed an acoustically-responsive scaffold (ARS), where release of a GF is non-invasively and spatiotemporally-controlled using focused ultrasound. The ARS consists of a fibrin matrix doped with a GF-loaded, phase-shift emulsion. The GF is released when the ARS is exposed to suprathreshold ultrasound via a mechanism termed acoustic droplet vaporization. In this study, we investigate how different spatial patterns of suprathreshold ultrasound can impact the biological response upon in vivo implantation of an ARS containing basic fibroblast growth factor (bFGF). ARSs were fabricated with either perfluorohexane (bFGF-C6-ARS) or perflurooctane (bFGF-C8-ARS) within the phase-shift emulsion. Ultrasound generated stable bubbles in bFGF-C6-ARS, which inhibited matrix compaction, whereas transiently stable bubbles were generated in bFGF-C8-ARS, which decreased in height by 44% within one day of implantation. The rate of bFGF release and distance of host cell migration were up to 6.8-fold and 8.1-fold greater, respectively, in bFGF-C8-ARS versus bFGF-C6-ARS. Ultrasound increased the formation of macropores within the fibrin matrix of bFGF-C8-ARS by 2.7-fold. These results demonstrate that spatially patterning suprathreshold ultrasound within bFGF-C8-ARS can be used to elicit a spatially-directed response from the host. Overall, these findings can be used in developing strategies to spatially pattern regenerative processes. STATEMENT OF SIGNIFICANCE: Hydrogels are commonly used in regenerative medicine for the delivery of growth factors (GFs). The spatial and temporal presentations of GFs are critical for directing regenerative processes, yet conventional hydrogels do not enable such control. We have developed a composite hydrogel, termed an acoustically-responsive scaffold (ARS), where GF release is non-invasively and spatiotemporally-controlled using focused ultrasound. The ARS consists of a fibrin matrix doped with a phase-shift emulsion loaded with GF, which is released when the ARS is exposed to ultrasound. In this in vivo study, we demonstrate that spatially patterning ultrasound within an ARS containing basic fibroblast growth factor (bFGF) can elicit a spatially-directed response from the host. Overall, these findings can be used in developing strategies to spatially pattern regenerative processes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

An ultrasound standing wave field (SWF) has been utilized in many biomedical applications. Here, we demonstrate how a SWF can enhance drug release using acoustic droplet vaporization (ADV) in an acoustically-responsive scaffold (ARS). ARSs are composite fibrin hydrogels containing payload-carrying, monodispersed perfluorocarbon (PFC) emulsions and have been used to stimulate regenerative processes such as angiogenesis. Elevated amplitudes in the SWF significantly enhanced payload release from ARSs containing dextran-loaded emulsions (nominal diameter: 6 μm) compared to the -SWF condition, both at sub- and suprathreshold excitation pressures. At 2.5 MHz and 4 MPa peak rarefactional pressure, the cumulative percentage of payload released from ARSs reached 84.1 ± 5.4% and 66.1 ± 4.4% under + SWF and -SWF conditions, respectively, on day 10. A strategy for generating a SWF for an in situ ARS is also presented. For dual-payload release studies, bi-layer ARSs containing a different payload within each layer were exposed to temporally staggered ADV at 3.25 MHz (day 0) and 8.6 MHz (day 4). Sequential payload release was demonstrated using dextran payloads as well as two growth factors relevant to angiogenesis: basic fibroblast growth factor (bFGF) and platelet-derived growth factor BB (PDGF-BB). In addition, bubble growth and fibrin degradation were characterized in the ARSs under +SWF and -SWF conditions. These results highlight the utility of a SWF for modulating single and dual payload release from an ARS and can be used in future therapeutic studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background Quantitative blood flow (QBF) measurements that use pulsed-wave US rely on difficult-to-meet conditions. Imaging biomarkers need to be quantitative and user and machine independent. Surrogate markers (eg, resistive index) fail to quantify actual volumetric flow. Standardization is possible, but relies on collaboration between users, manufacturers, and the U.S. Food and Drug Administration. Purpose To evaluate a Quantitative Imaging Biomarkers Alliance-supported, user- and machine-independent US method for quantitatively measuring QBF. Materials and Methods In this prospective study (March 2017 to March 2019), three different clinical US scanners were used to benchmark QBF in a calibrated flow phantom at three different laboratories each. Testing conditions involved changes in flow rate (1-12 mL/sec), imaging depth (2.5-7 cm), color flow gain (0%-100%), and flow past a stenosis. Each condition was performed under constant and pulsatile flow at 60 beats per minute, thus yielding eight distinct testing conditions. QBF was computed from three-dimensional color flow velocity, power, and scan geometry by using Gauss theorem. Statistical analysis was performed between systems and between laboratories. Systems and laboratories were anonymized when reporting results. Results For systems 1, 2, and 3, flow rate for constant and pulsatile flow was measured, respectively, with biases of 3.5% and 24.9%, 3.0% and 2.1%, and -22.1% and -10.9%. Coefficients of variation were 6.9% and 7.7%, 3.3% and 8.2%, and 9.6% and 17.3%, respectively. For changes in imaging depth, biases were 3.7% and 27.2%, -2.0% and -0.9%, and -22.8% and -5.9%, respectively. Respective coefficients of variation were 10.0% and 9.2%, 4.6% and 6.9%, and 10.1% and 11.6%. For changes in color flow gain, biases after filling the lumen with color pixels were 6.3% and 18.5%, 8.5% and 9.0%, and 16.6% and 6.2%, respectively. Respective coefficients of variation were 10.8% and 4.3%, 7.3% and 6.7%, and 6.7% and 5.3%. Poststenotic flow biases were 1.8% and 31.2%, 5.7% and -3.1%, and -18.3% and -18.2%, respectively. Conclusion Interlaboratory bias and variation of US-derived quantitative blood flow indicated its potential to become a clinical biomarker for the blood supply to end organs. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Forsberg in this issue.

Acoustically-responsive scaffolds (ARSs), which are composite fibrin hydrogels, have been used to deliver regenerative molecules. ARSs respond to ultrasound in an on-demand, spatiotemporally-controlled manner via a mechanism termed acoustic droplet vaporization (ADV). Here, we study the ADV-induced, time-dependent micromechanical and microstructural changes to the fibrin matrix in ARSs using confocal fluorescence microscopy as well as atomic force microscopy. ARSs, containing phase-shift double emulsion (PSDE, mean diameter: 6.3 μm), were exposed to focused ultrasound to generate ADV - the phase transitioning of the PSDE into gas bubbles. As a result of ADV-induced mechanical strain, localized restructuring of fibrin occurred at the bubble-fibrin interface, leading to formation of locally denser regions. ADV-generated bubbles significantly reduced fibrin pore size and quantity within the ARS. Two types of ADV-generated bubble responses were observed in ARSs: super-shelled spherical bubbles, with a growth rate of 31 μm per day in diameter, as well as fluid-filled macropores, possibly as a result of acoustically-driven microjetting. Due to the strain stiffening behavior of fibrin, ADV induced a 4-fold increase in stiffness in regions of the ARS proximal to the ADV-generated bubble versus distal regions. These results highlight that the mechanical and structural microenvironment within an ARS can be spatiotemporally modulated using ultrasound, which could be used to control cellular processes and further the understanding of ADV-triggered drug delivery for regenerative applications.

To assess the feasibility of ultrasound imaging in depicting the changes in kidney size, hemodynamics and cortex viscoelasticity after hydration, we prospectively performed 2-D ultrasound shear wave elastography (SWE) and Doppler sonography of bilateral kidneys in 30 volunteers. Kidney length, cortex shear wave velocity (SWV), shear wave dispersion (SWD), interlobar artery peak systolic velocity (PSV), end-diastolic velocity (EDV) and resistive index (RI) were measured before and 60 min after with and without drinking water (1 L). The differences in kidney length, SWV, PSV, EDV and color pixel intensity before and after hydration were significant (p < 0.001), whereas these differences were not significant without hydration (p > 0.05). SWD and RI did not significantly differ with or without hydration. Inter- and intra-observer reliability in performing SWE and Doppler sonography was good. The use of Doppler sonography and ultrasound SWE to evaluate the effect of hydration on kidney size, hemodynamics and viscoelasticity seem to be feasible., Competing Interests: Conflict of interest disclosure The authors have no conflicts of interest to disclose., (Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Ultrasound-induced vaporization of liquid perfluorocarbon (PFC) droplets into microbubbles, termed acoustic droplet vaporization (ADV), has potential therapeutic and diagnostic applications. Recently, we demonstrated how ADV-a threshold-based phenomenon-can modulate the release of biomolecules from composite hydrogels, thereby stimulating regenerative processes, such as angiogenesis. These composite hydrogels, called acoustically responsive scaffolds (ARSs), consist of monodispersed, micron size PFC emulsions embedded within a fibrin matrix. This study investigated the effects of frequency of excitation (2.25, 5, 7.5 and 10 MHz) and volume fraction (0.05%, 0.2% and 1% [v/v]) of monodispersed, double emulsions in the ARSs on the ADV threshold. We determined and compared the ADV thresholds via acoustic methods, including active detection, passive detection and attenuation, as well as an echogenicity-based method using B-mode imaging. The ADV threshold determined via these four techniques showed an increasing trend with frequency of excitation. Further analysis of the wave propagation showed that the amplitudes of high frequency harmonics were diminished in ARSs with high volume fractions of emulsion. The ADV threshold inversely correlated with the volume fraction of emulsion at the lowest excitation frequency. However, at higher frequencies, possibly due to the high acoustic reflectivity of the PFC emulsions, the ADV threshold correlated directly with the volume fraction of the emulsion. Additionally, the ADV efficiency correlated with the supra-threshold acoustic pressure. Overall, these results elucidate fundamental acoustic properties of the ARSs, which can be used in future applications., (Copyright © 2019 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background Three-dimensional (3D) fractional moving blood volume (FMBV) derived from 3D power Doppler US has been proposed for noninvasive approximation of perfusion. However, 3D FMBV has never been applied in animals against a ground truth. Purpose To determine the correlation between 3D FMBV and the reference standard of fluorescent microspheres (FMS) for measurement of renal perfusion in a porcine model. Materials and Methods From February 2017 to September 2017, adult pigs were administered FMS before and after measurement of renal 3D FMBV at baseline (100%) and approximately 75%, 50%, and 25% flow levels by using US machines from two different vendors. The 3D power Doppler US volumes were converted and segmented, and correlations between FMS and 3D FMBV were made with simple linear regression ( r 2 ). Similarity and reproducibility of manual segmentation were determined with the Dice similarity coefficient and 3D FMBV reproducibility (intraclass correlation coefficient [ICC]). Results Thirteen pigs were studied with 33 flow measurements. Kidney volume (mean Dice similarity coefficient ± standard deviation, 0.89 ± 0.01) and renal segmentation (coefficient of variation = 12.6%; ICC = 0.86) were consistent. The 3D FMBV calculations had high reproducibility (ICC = 0.97; 95% confidence interval: 0.96, 0.98). The 3D FMBV per-pig correlation showed excellent correlation for US machines from both vendors (mean r 2 = 0.96 [range, 0.92-1.0] and 0.93 [range, 0.78-1.0], respectively). The correlation between 3D FMBV and perfusion measured with microspheres was high for both US machines ( r 2 = 0.80 [ P < .001] and 0.70 [ P < .001], respectively). Conclusion The strong correlation between three-dimensional (3D) fractional moving blood volume (FMBV) and fluorescent microspheres indicates that 3D FMBV shows excellent correlation to perfusion and good reproducibility. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Morrell et al in this issue.

The challenge of translating pro-angiogenic growth factors for therapeutic purposes has stimulated a myriad of biomaterials-based, delivery approaches. Many techniques rely on incorporating a growth factor into a hydrogel. The kinetics of release can be tuned based on the physiochemical properties of the growth factor and scaffold. We have developed an acoustically-responsive scaffold (ARS), whereby release of a growth factor is non-invasively and spatiotemporally controlled in an on-demand manner using focused ultrasound. An ARS consists of a fibrin matrix doped with a growth factor-loaded, sonosensitive emulsion. In this study, we used an ARS to investigate the impact of basic fibroblast growth factor (bFGF) release on endothelial tubule formation. The co-culture model of angiogenic sprouting consisted of endothelial cell-coated microbeads and dispersed fibroblasts. bFGF release correlated with the acoustic pressure applied while sprout length correlated with both the volume of bFGF-loaded emulsion in the ARS and acoustic pressure. Minimal bFGF release and sprouting were observed in the absence of ultrasound exposure. Staggering the release of bFGF via multiple ultrasound exposures did not affect sprouting. Additionally, sprouting did not display a dependence on the distance between each microbead and the ARS. Overall, these results highlight the potential of using ultrasound to control regenerative processes via the controlled delivery of a growth factor. STATEMENT OF SIGNIFICANCE: Due to the ineffectiveness of conventional routes of administration, implantable hydrogels are often used as matrices to deliver growth factors (GFs). Spatial control of release is typically realized using anisotropic constructs while temporal control is obtained by modifying matrix properties and GF-scaffold interactions. In this study, we demonstrate how focused ultrasound can be used to non-invasively and spatiotemporally control release of basic fibroblast growth factor (bFGF), in an on-demand manner, from a composite hydrogel. The acoustically-responsive scaffold (ARS) consists of a bFGF-loaded, monodispersed double emulsion embedded within a fibrin matrix. We demonstrate how controlled release of bFGF can stimulate endothelial network formation. These results may be of interest to groups working on controlled release strategies for GFs, especially in the context of stimulating angiogenesis., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Hydrogels are commonly used for the delivery of bioactive molecules, especially growth factors and cytokines capable of stimulating tissue regeneration. Regenerative processes are regulated by the concentrations and spatiotemporal presentations of these molecules. With conventional hydrogels, these critical delivery parameters cannot be actively modulated after implantation. We have developed composite hydrogel scaffolds where payload release is non-invasively modulated, in an on-demand manner, using ultrasound (US). These acoustically-responsive scaffolds (ARSs) consist of a fibrin matrix doped with a payload-carrying, perfluorocarbon (PFC) double emulsion. Previously, acoustic droplet vaporization (ADV) was used to trigger release of a pro-angiogenic growth factor, encapsulated in the ARS, which stimulated blood vessel formation in vivo. In the present study, we assess how characteristics of the monodispersed emulsion, fibrin matrix, and US impact ADV thresholds and the release efficiency of a dextran payload. ADV thresholds increased with the molecular weight of the PFC in the emulsion and inversely with the volume fraction of emulsion in the ARS. Payload release from ARSs with perfluoroheptane (C7) or perfluorooctane (C8) emulsions was dependent on the number of z-planes of US used to generate ADV and inversely dependent on the lateral spacing. Conversely, release from ARSs with perfluoropentane (C5) or perfluorohexane (C6) emulsions was less dependent on these US exposure parameters. After ADV, payload diffusion decreased significantly in ARSs with C5 or C6 emulsions compared with ARSs with C7 or C8 emulsions. The expansion of the ARS after ADV decreased with the molecular weight of the PFC. Non-selective release increased with the molecular weight of the PFC and thrombin concentration. Overall, these findings can be used for optimization of ARS properties and US parameters in future therapeutic applications., (Copyright © 2019 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide. Many patients are not eligible for curative therapies, such as surgical resection of the tumor or a liver transplant. Transarterial embolization is one therapy clinically used in these cases; however, this requires a long procedure and careful placement of an intraarterial catheter. Gas embolization has been proposed as a fast, easily administered, more spatially selective, and less invasive alternative. Here, we demonstrate the feasibility and efficacy of using acoustic droplet vaporization to noninvasively generate gas emboli within vasculature. Intravital microscopy experiments were performed using the rat cremaster muscle to visually observe the formation of occlusions. Large gas emboli were produced within the vasculature in the rat cremaster, effectively occluding blood flow. Following these experiments, the therapeutic efficacy of gas embolization was investigated in an ectopic xenograft model of hepatocellular carcinoma in mice. The treatment group exhibited a significantly lower final tumor volume (ANOVA, p = 0.008) and growth rate than control groups - tumor growth was completely halted. Additionally, treated tumors exhibited significant necrosis as determined by histological analysis. To our knowledge, this study is the first to demonstrate the therapeutic efficacy of gas embolotherapy in a tumor model.

Following collapse of a histotripsy cloud, residual microbubbles may persist for seconds, distributed throughout the focus. Their presence can attenuate and scatter subsequent pulses, hindering treatment speed and homogeneity. Previous studies have demonstrated use of separate low-amplitude (~1 MPa) pulses interleaved with histotripsy pulses to drive bubble coalescence (BC), significantly improving treatment speed without sacrificing homogeneity. We propose that by using electronic focal steering (EFS) to direct the therapy focus throughout specially-designed EFS sequences, it is possible to use low-gain regions of the therapy beam to accomplish BC during EFS without any additional acoustic sequence. First, to establish proof of principle for an isolated focus, a 50-foci EFS sequence was constructed with the first position isolated near the geometric focus and remaining positions distributed post-focally. EFS sequences were evaluated in tissue-mimicking phantoms with gas concentrations of 20% and 100% with respect to saturation. Results using an isolated focus demonstrated that at 20% gas concentration, 49 EFS pulses were sufficient to achieve BC in all samples for pulse repetition frequency (PRF)  ⩽  800 Hz and 84.1%  ±  3.0% of samples at 5 kHz PRF. For phantoms prepared with 100% gas concentration, BC was achieved by 49 EFS pulses in 39.2%  ±  4.7% of samples at 50 Hz PRF and 63.4%  ±  15.3% of samples at 5 kHz. To show feasibility of using the EFS-BC method to ablate a large volume quickly, a 1000-foci EFS sequence covering a volume of approximately 27 ml was tested. Results indicate that the BC effect was similarly present. A treatment rate of 27  ±  6 ml min -1 was achieved, which is signficantly faster than standard histotripsy and ultrasound thermal ablation. This study demonstrates that histotripsy with EFS can achieve BC without employing a separate acoustic sequence which has the potential to accelerate large-volume ablation while minimizing energy deposition.

Background: Bubbles formed by acoustic droplet vaporization (ADV) have proven to be an effective method for significant enlargement of the thermal lesions produced by high intensity focused ultrasound (HIFU). We investigated the influences of bubble cloud shape and droplet concentration on HIFU thermal lesions, as these relate to the ADV technique., Methods: Unlike previous studies where the droplets were simultaneously vaporized with the HIFU exposure for thermal lesion formation, droplets were vaporized by pulse wave (PW) ultrasound prior to continuous wave (CW) ultrasound heating in this experimental study. Under different experimental conditions, we recorded and quantified by the image processing methods the morphology and size of the bubble clouds created and the corresponding thermal lesions formed., Results: The results demonstrated that different ADV droplet concentrations produced a variety of thermal lesion shapes and sizes. The lesion volume could be increased using PW ultrasound followed by CW exposure, especially for higher droplet concentrations, e.g. 3.41 × 10 6 /mL yielded a tenfold increase over that seen using CW alone., Conclusion: These findings could lead to optimization of HIFU therapy by selecting a bubble forming strategy and droplet concentrations, especially using lower ultrasound powers which is desirable in clinical applications.

We have investigated limited angle transmission tomography to estimate speed of sound (SOS) distributions for breast cancer detection. That requires both accurate delineations of major tissues, in this case by segmentation of prior B-mode images, and calibration of the relative positions of the opposed transducers. Experimental sensitivity evaluation of the reconstructions with respect to segmentation and calibration errors is difficult with our current system. Therefore, parametric studies of SOS errors in our bent-ray reconstructions were simulated. They included mis-segmentation of an object of interest or a nearby object, and miscalibration of relative transducer positions in 3D. Close correspondence of reconstruction accuracy was verified in the simplest case, a cylindrical object in homogeneous background with induced segmentation and calibration inaccuracies. Simulated mis-segmentation in object size and lateral location produced maximum SOS errors of 6.3% within 10 mm diameter change and 9.1% within 5 mm shift, respectively. Modest errors in assumed transducer separation produced the maximum SOS error from miscalibrations (57.3% within 5 mm shift), still, correction of this type of error can easily be achieved in the clinic. This study should aid in designing adequate transducer mounts and calibration procedures, and in specification of B-mode image quality and segmentation algorithms for limited angle transmission tomography relying on ray tracing algorithms., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Three-dimensional (3-D) ultrasound imaging is a promising modality for many medical applications. Unfortunately, it generates voluminous data in the front end, making it unattractive for high-volume-rate portable medical applications. We apply synthetic aperture sequential beamforming (SASB) to greatly compress the front-end receive data. Baseline 3-D SASB has a low volume rate, because subapertures fire one by one. In this paper, we propose to increase the volume rate of 3-D SASB without degrading imaging quality through: 1) transmitting and receiving simultaneously with four subapertures and 2) using linear chirps as the excitation waveform to reduce interference. We design four linear chirps that operate on two overlapped frequency bands with chirp pairs in each band having opposite chirp rates. Direct implementation of this firing scheme results in grating lobes. Therefore, we design a sparse array that mitigates the grating lobe levels through optimizing the locations of transducer elements in the bin-based random array. Compared with the baseline 3-D SASB, the proposed method increases the volume rate from 8.56 to 34.2 volumes/s without increasing the front-end computation requirement. Field-II-based cyst simulations show that the proposed method achieves imaging quality comparable with baseline 3-D SASB in both shallow and deep regions.

Objectives: To investigate the association between umbilical vein blood volume flow and the condition of preeclampsia in an at-risk maternal patient cohort. Umbilical vein volume flow was quantified by a 3-dimensional (3D) sonographic technique that overcomes several limitations of standard sonographic flow measurement methods., Methods: A total of 35 patients, each with a singleton pregnancy, were recruited to provide 5 patients with preeclampsia, derived as a subset from a 26-patient at-risk group, and 9 patients with normal pregnancies. An ultrasound system equipped with a 2.0-8.0-MHz transducer was used to acquire multivolume 3D color flow and power mode data sets to compute the mean umbilical vein volume flow in patients with normal pregnancies and preeclampsia., Results: The gestational ages of the pregnancies ranged from 29.7 to 34.3 weeks in the patients with preeclampsia and from 25.9 to 34.7 weeks in the patients with normal pregnancies. Comparisons between patients with normal pregnancies and those with preeclampsia showed weight-normalized flow with a moderately high separation between groups (P = .11) and depth-corrected, weight-normalized flow with a statistically significant difference between groups (P = .035). Umbilical vein volume flow measurements were highly reproducible in the mean estimate, with an intrapatient relative SE of 12.1% ± 5.9% and an intrameasurement relative SE of 5.6% ± 1.9 %. In patients who developed pregnancy-induced hypertension or severe pregnancy-induced hypertension, umbilical vein volume flow suggested gestational hypertensive disorder before clinical diagnosis., Conclusions: Results indicate that mean depth-corrected, weight-normalized umbilical vein volume flow is reduced in pregnancies complicated by preeclampsia and that volume flow may indicate hypertensive disorder earlier in gestation. Volume flow measurements are highly reproducible, and further study in a larger clinical population is encouraged to determine whether 3D volume flow can complement the management of preeclampsia and, in general, at-risk pregnancy., (© 2017 by the American Institute of Ultrasound in Medicine.)

Purpose: Transrectal ultrasound (TRUS)-guided biopsy is the standard procedure for evaluating the presence and aggressiveness of prostate cancer. TRUS biopsy involves tissue removal, and suffers from low core yield as well as high false negative rate. A less invasive and more accurate diagnostic procedure for prostate cancer is therefore highly desired. Combining the optical sensitivity and ultrasonic resolution to resolve the spatial distribution of the major molecular components in tissue, photoacoustic (PA) technology could be an alternative approach for the diagnosis of prostate cancer. The purpose of this study was to examine the feasibility of identifying aggressive prostate cancer using interstitial PA measurements., Methods: Seventeen patients with prebiopsy magnetic resonance imaging (MRI), TRUS biopsies, and planned prostatectomies were enrolled in this study. The interstitial PA measurements were achieved using our recently developed needle PA probe, which was inserted into the ex vivo prostates in the fashion of a biopsy needle. A total of 70 interstitial PA measurements were acquired. The PA measurements were quantified by a previously established PA physio-chemical analysis (PAPCA) method. The histology has confirmed the nonaggressive and aggressive cancerous conditions at the insertion locations. The diagnostic accuracy was also compared to that provided by the prebiopsy MRI., Results: The quantitative study shows significant differences between the individual parameters of the nonaggressive and the aggressive cancerous regions (P < 0.005). Multivariate analysis of the quantitative features achieved a diagnostic accuracy of 78.6% for differentiating nonaggressive and aggressive prostate cancer tissues., Conclusions: The proposed procedure has shown promises in the diagnosis of aggressive prostate cancer., (© 2018 American Association of Physicists in Medicine.)