Microbubble Ultrasound Contrast Research Articles

A Comparative Study of Commercially Available Ultrasound Contrast Agents for Sub-harmonic-Aided Pressure Estimation (SHAPE) in a Bladder Phantom

ObjectiveThe 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. MethodsUsing 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. ResultsAll 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. ConclusionOur 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.

Contrast-Enhanced Ultrasound of the Indeterminate Renal Mass, From the AJR "How We Do It" Special Series.

Contrast-enhanced ultrasound (CEUS) is distinguished from CT and MRI by the use of microbubble ultrasound contrast agents (UCAs) with intravascular blood pool distribution. When performing CEUS, low-intensity ultrasound allows real-time tissue subtraction imaging, whereas high-intensity ultrasound leads to microbubble destruction, enabling visualization of the contrast inflow pattern. CEUS has exceptional contrast resolution that enables the detection of even minimal blood flow, achieving very high NPV for ruling out vascular perfusion and providing high frame rates in the evaluation of tissue perfusion dynamics. UCAs undergo hepatic metabolism and pulmonary clearance, ensuring safety in patients with renal impairment. CEUS excels in distinguishing solid from cystic renal masses, with higher sensitivity than CT or MRI for detection of lesion enhancement. CEUS can aid the further characterization of both solid and cystic lesions and may have particular applications in the surveillance of cystic masses and surveillance after renal cell carcinoma ablation. This review describes the use of CEUS to help characterize indeterminate renal masses, based on the authors' institutional experience. The article highlights key differences between CEUS and CT or MRI, and provides practical insights for performing and interpreting CEUS of renal masses.

Application of ultrasound microbubble contrast to evaluate the effect of sitaxentan on renal microvascular perfusion in beagles undergoing cardiopulmonary bypass.

We aimed to evaluate the effect of sitaxentan on renal microvascular perfusion via application of ultrasound microbubble contrast. Male beagles were randomly divided into: Sham, cardiopulmonary bypass (CPB) and sitaxentan-infused (Sit) groups (n = 6). The ascending slope rate (ASR), area under the curve (AUC), derived peak intensity, and time to peak (TTP) were obtained via ultrasound microbubble contrast before CPB (T1), after 1 h CPB (T2), at end of CPB (T3), and 2 h after CPB (T4). Compared with the Sham group, the CPB group had lower ASR of the renal cortex and medulla at T2-4, higher AUC and TTP at T3-4, and lower derived peak intensity at T4. The ASR at T2-4 in the Sit group was lower, TTP was higher at T2-4, and AUC was higher at T3-4 (P < 0.05). Compared with the CPB group, the Sit group had higher ASR of the renal cortex and medulla at T3-4 and AUC and TTP at T3-4 (P < 0.05). Compared with that at T1, the ASR of the renal cortex and medulla at T2-4 in the CPB group was lower, and AUC and TTP were higher at T3-4. The ASR of the renal cortex and medulla at T2-4 in the Sit group was lower, TTP was higher at T2-4, and AUC was higher at T4 (P < 0.05). Ultrasound microbubble contrast could be effectively used to evaluate renal microvascular perfusion peri-CPB in beagles, which was prone to decrease and could be improved via pretreatment with sitaxentan.

Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine.

The present study aimed to screen the best time window for the transplantation of bone marrow mesenchymal stem cells (MSCs) after acute myocardial infarction (MI) through targeted ultrasound microbubbles loaded with SDF-1α antibody. Thirty-six MI miniswine were randomly divided into six experimental groups according to the duration after infarction (1 day, 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks after infarction). MSCs were labeled with BrdU and then injected through the coronary artery in the stem cell transplantation group to detect the number of transplanted MSCs at different time points after MI. Three miniswine were randomly selected as the control group (sham operation: open chest without ligation of the coronary artery). All SDF-1α groups and control groups were injected with a targeted microbubble ultrasound contrast agent. The values of the myocardial perfusion parameters (A, β, and A × β) were determined. A T, β T, and (A × β)T varied with time and peaked 1 week after MI (P < 0.05). The number of transplanted stem cells in the myocardium through coronary injection of MSCs at 1 week was the greatest and consistent with the changing tendency of A T, β T, and (A × β)T (r = 0.658, 0.778, 0.777, P < 0.05). β T(X), (A × β)T(X), and the number of transplanted stem cells was used to establish the regression equation as follows: Y = 36.11 + 17.601X; Y = 50.023 + 3.348X (R 2 = 0.605, 0.604, P < 0.05). The best time window for transplanting stem cells was 1 week after MI. The myocardial perfusion parameters of the SDF-1α targeted contrast agent can be used to predict the number of transplanted stem cells in the myocardial tissue.

Microbubble contrast agent as a minimally invasive pressure sensor at body temperature and reduced concentrations in an ultrasound flow phantom

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): MRC. Background Cardiac catheterisation is the gold standard for assessing cardiac pressures. However, this is an invasive and costly procedure. A minimally invasive alternative may be to use the subharmonic signal of microbubble ultrasound contrast agents to estimate pressure using echocardiography (Sub-Harmonic Assisted Pressure Estimation: SHAPE). Purpose The aim of this work was to investigate the ability of SHAPE to track dynamic diastolic pressures in a flow phantom at body temperature and at reduced microbubble concentrations. Methods A priming dose of 0.4 mL/L of sulphur hexafluoride microbubbles was circulated through a silicone tube using a peristaltic pump at a flow rate of 375 mL/min (generating 376 pressure cycles/min and maximum pressure gradient of 1.9 mmHg/ms; Fig. 1). The ULtrasound Advanced Open Platform (ULA-OP) was used with a cardiac phased array transducer to transmit a pulse-inversion sequence at 2.1 MHz. Radiofrequency data were recorded at five acoustic pressures (71–228 kPa peak-negative). To investigate the effects of temperature, the subharmonic-pressure relationship was measured over 60 min at both room and body temperature (37°C). Microbubble concentration was maintained by regular top-up (0.15 mL/L every 3–5 min). To investigate the effect of lower concentrations on the subharmonic-pressure relationship, a priming dose of 0.4, 0.3 or 0.2 mL/L was administered before a single acquisition was made. The system was immediately purged before testing the next concentration. The subharmonic (1.05 MHz) amplitude of the microbubbles was calculated over a 40% bandwidth. A solid-state catheter recorded ground-truth pressures. Correlation coefficient (r) and sensitivity (dB/mmHg) of the subharmonic signal to the pressure values were calculated. Results The mean correlation coefficient (r = 0.91 ± 0.04; Fig. 2) and sensitivity (0.20 ± 0.04 dB/mmHg) at body temperature (n = 20) were significantly greater than those for the same batch of microbubbles at room temperature (r = 0.81 ± 0.07 and 0.14 ± 0.02; n = 18; p &amp;lt; 0.05) at the optimal acoustic pressure (Fig. 2). No significant differences in the subharmonic-pressure relationship were observed between the three different microbubble concentrations (Correlation: r = 0.96 ± 0.00, 0.96 ± 0.01, 0.97 ± 0.01. Sensitivity: 0.26 ± 0.02, 0.26 ± 0.03, 0.28 ± 0.02 mmHg/dB for 0.4, 0.3 and 0.2 mL/L, respectively; n = 3) at the optimal acoustic pressure. Conclusions SHAPE can accurately track diastolic pressures five times faster than the average resting heart rate at body temperature and with reduced microbubble concentrations. SHAPE is a potential method for assessing cardiac diastolic pressures using ultrasound in a minimally invasive fashion, being suitable for use in patients with faster microbubble clearance or in the event of delayed acquisition. The use of SHAPE fits into routine clinical procedures and has the potential to improve the diagnosis and monitoring of cardiovascular diseases.

Time evolution of ambient pressure sensitivity of microbubbles subharmonic response as a function of hydrostatic pressure and the filling gas

The ultrasound contrast microbubbles have shown a great ability to produce nonlinear oscillations in response to acoustic excitation which results in the generation of harmonics and subharmonics of the excitation. The subharmonic response of ½ order changes significantly with a change in hydrostatic pressure in the physiological range. This property is being investigated for subharmonic aided pressure estimation (SHAPE), a noninvasive alternative to current methods for vascular pressure measurement in critical organs. In this study, the ambient pressure sensitivity of the subharmonic response of microbubbles with different gas cores and shells was investigated over 25–700 kPa acoustic pressure and the hydrostatic pressure range of 0–25 kPa. The subharmonic showed different trends of increase and decrease with hydrostatic pressure. The sensitivity has shown gradual change over time which was observed to be related to the hydrostatic pressure magnitude and the gas core. These findings could help to calibrate the SHAPE.

Ultrasound Contrast Stability for Urinary Bladder Pressure Measurement.

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.

Immunotheranostic microbubbles (iMBs) - a modular platform for dendritic cell vaccine delivery applied to breast cancer immunotherapy

BackgroundTherapeutic strategies engaging the immune system against malignant cells have revolutionized the field of oncology. Proficiency of dendritic cells (DCs) for antigen presentation and immune response has spurred interest on DC-based vaccines for anti-cancer therapy. However, despite favorable safety profiles in patients, current DC-vaccines have not yet presented significant outcome due to technical barriers in active DC delivery, tumor progression, and immune dysfunction. To maximize the therapeutic response, we present here a unique cell-free DC-based vaccine capable of lymphoid organ targeting and eliciting T-cell-mediated anti-tumor effect.MethodsWe developed this novel immunotheranostic platform using plasma membranes derived from activated DCs incorporated into ultrasound contrast microbubbles (MBs), thereby offering real-time visualization of MBs’ trafficking and homing in vivo. Human PBMC-derived DCs were cultured ex vivo for controlled maturation and activation using cell membrane antigens from breast cancer cells. Following DC membrane isolation, immunotheranostic microbubbles, called DC-iMBs, were formed for triple negative breast cancer treatment in a mouse model harboring a human reconstituted immune system.ResultsOur results demonstrated that DC-iMBs can accumulate in lymphoid organs and induce anti-tumor immune response, which significantly reduced tumor growth via apoptosis while increasing survival length of the treated animals. The phenotypic changes in immune cell populations upon DC-iMBs delivery further confirmed the T-cell-mediated anti-tumor effect.ConclusionThese early findings strongly support the potential of DC-iMBs as a novel immunotherapeutic cell-free vaccine for anti-cancer therapy.

Pressure Measurement in a Bladder Phantom Using Contrast-Enhanced Ultrasonography-A Path to a Catheter-Free Voiding Cystometrogram.

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. 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. 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. 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.

Microbubbles Contrast Agents: General Overview as Diagnostics and Therapeutic Agent.

Recent discoveries have unfolded many powerful emerging applications in the field of drug delivery science. For the past few years, ultrasound mediated microbubble contrast agents have been an emerging modality for diagnostic and drug delivery applications. Microbubbles are small spherical bubbles composed of a gas core encapsulated by a shell with different materials. The composition of the microbubble determines its stiffness, encapsulation efficiency, stability, and clearance from the system. A gas-filled microbubble, when activated by an acoustic pulse, can produce large volumetric oscillations and, once administered intravenously, can act as a cavitating nuclei, allowing for a wide range of ultrasound-assisted drug delivery applications. Microbubbles offer a fantastic approach to ultrasound triggered drug delivery with various drug loading techniques and targeting strategies for the uptake of bioactive substances such as polynucleotides, proteins, genes, and small-molecule drugs. Microbubbles can be used for several diagnostic and therapeutic purposes for accurate detection and treatment of various life-threatening diseases.

Probing the mechanisms of sonodynamic therapy

Drugs that can be activated by a physical stimulus at a target site offer great potential for limiting toxic side effects, e.g., in cancer therapy. In photodynamic therapy, light is used as the stimulus, but clinical applications are limited due to the poor penetration of light in tissue. Multiple studies have demonstrated that ultrasound can also be used to activate some light-responsive drugs. This potentially extends the range of therapeutic applications considerably, but the mechanisms underpinning drug activation, dubbed sonodynamic therapy (SDT), remain unclear. It was recently demonstrated that multi-bubble sonoluminescence could be detected from a suspension of microbubble ultrasound contrast agents when exposed to ultrasound under conditions similar to those used in SDT. Moreover, the addition of an SDT drug produced a reduction in optical emissions at the wavelength corresponding to its activation. Numerous questions, however, remain and the aim of this talk is to review recent studies of SDT and new evidence for the roles of sonoluminescence, sonoporation, and other phenomena hypothesized to play a role in its mechanism of action.

Short-Term Efficacy of Transcranial Focused Ultrasound to the Hippocampus in Alzheimer's Disease: A Preliminary Study.

Preclinical studies have suggested that low-intensity transcranial focused ultrasound (tFUS) may have therapeutic potential for Alzheimer’s disease (AD) by opening the blood–brain barrier (BBB), reducing amyloid pathology, and improving cognition. This study investigated the effects of tFUS on BBB opening, regional cerebral metabolic rate of glucose (rCMRglu), and cognitive function in AD patients. Eight patients with AD received image-guided tFUS to the right hippocampus immediately after intravenous injection of microbubble ultrasound contrast agents. Patients completed magnetic resonance imaging (MRI), 18F-fluoro-2-deoxyglucose positron emission tomography (PET), and cognitive assessments before and after the sonication. No evidence of transient BBB opening was found on T1 dynamic contrast-enhanced MRI. However, immediate recall (p = 0.03) and recognition memory (p = 0.02) were significantly improved on the verbal learning test. PET image analysis demonstrated increased rCMRglu in the right hippocampus (p = 0.001). In addition, increases of hippocampal rCMRglu were correlated with improvement in recognition memory (Spearman’s ρ = 0.77, p = 0.02). No adverse event was observed. Our results suggest that tFUS to the hippocampus of AD patients may improve rCMRglu of the target area and memory in the short term, even without BBB opening. Further larger sham-controlled trials with loger follow-up are warranted to evaluate the efficacy and safety of tFUS in patients with AD.

Towards controlled drug delivery in brain tumors with microbubble-enhanced focused ultrasound.

Brain tumors are particularly challenging malignancies, due to their location in a structurally and functionally distinct part of the human body - the central nervous system (CNS). The CNS is separated and protected by a unique system of brain and blood vessel cells which together prevent most bloodborne therapeutics from entering the brain tumor microenvironment (TME). Recently, great strides have been made through microbubble (MB) ultrasound contrast agents in conjunction with ultrasound energy to locally increase the permeability of brain vessels and modulate the brain TME. As we elaborate in this review, this physical method can effectively deliver a wide range of anticancer agents, including chemotherapeutics, antibodies, and nanoparticle drug conjugates across a range of preclinical brain tumors, including high grade glioma (glioblastoma), diffuse intrinsic pontine gliomas, and brain metastasis. Moreover, recent evidence suggests that this technology can promote the effective delivery of novel immunotherapeutic agents, including immune check-point inhibitors and chimeric antigen receptor T cells, among others. With early clinical studies demonstrating safety, and several Phase I/II trials testing the preclinical findings underway, this technology is making firm steps towards shaping the future treatments of primary and metastatic brain cancer. By elaborating on its key components, including ultrasound systems and MB technology, along with methods for closed-loop spatial and temporal control of MB activity, we highlight how this technology can be tuned to enable new, personalized treatment strategies for primary brain malignancies and brain metastases.

Synthesis, rheological characterization, and proposed application of pre‐polyglycerol sebacate as ultrasound contrast agent based on theoretical estimation

AbstractElastomers are employed in the field of acoustics as sound enhancers and making tissue‐mimicking phantoms for ultrasound imaging due to their good viscoelastic properties. Polyglycerol sebacate (PGS) is a relatively new biocompatible, biodegradable elastomer with low elastic modulus prepared via two‐step melt condensation reaction. The first step yields a soluble pre‐polymer while the second results in a cured insoluble tough elastomer. The elasticity of polymer is dependent upon curing time. Attractive aspects of pre‐PGS to be used as ultrasound contrast agent lie in its excellent viscoelastic properties, that is, low elastic modulus, near to lipids. This can give it acoustic properties of lipid microbubbles while keeping a stable response of polymeric microbubbles. In this study, pre‐PGS was synthesized via the melt‐condensation method and characterized by FTIR, NMR, TGA, melt flow index, contact angle, titration, and uniaxial compressive testing. Viscosity was measured by the Ostwald technique. These viscoelastic measurements were used to predict the acoustic response of pre‐PGS shell‐based microbubbles by running equations in MATLAB. Pre‐PGS showed an elastic modulus of 1.26 MPa and thermal stability up to 100°C. PGS showed much more elasticity than commercially available Sonovue ultrasound contrast agent, also it has low viscosity (0.016 Pa s) and density (1186 kg/m), due to which it has a low damping coefficient (4.32 × 106) compared to Sonovue (7.63 × 107), giving better oscillations in an acoustic field with higher scattering cross‐sectional area than standard Sonovue microbubbles. Based on these simulations pre‐PGS with 50%–60% degree of esterification showed excellent viscoelastic properties which make it an ideal material for microbubble ultrasound contrast agent.

First-Pass Arrival Interval of Ultrasound Contrast Medium in the Hepatic Artery and Portal Vein as a Marker for Assessment of Liver Transplant Recipients

This study measures the first-pass arrival times in the hepatic artery and portal vein of the transplanted liver using contrast-enhanced ultrasound (CEUS) and assess its correlation with graft performance in the early posttransplant period. This study evaluated 35 liver transplant recipients who underwent CEUS examination within 1 month of transplant surgery. CEUS under contrast-specific harmonic imaging mode were recorded for 60 seconds immediately after intravenous administration of microbubble ultrasound contrast medium (Sonazoid, GE Healthcare, Oslo, Norway). The recorded video clips were reviewed by 2 readers to determine the first-pass arrival times in the hepatic artery and portal vein, and the difference between the 2 was defined as the arterial-portal arrival interval (APAI). Laboratory data on the same date of CEUS examination were collected as indicators to correlate with APAI. The intra- and inter-rater reliability for APAI measurement were excellent, with intraclass correlation coefficients > .95. The mean APAI was 4.5 ± 1.8 seconds (range, 2.0-10.5 seconds). The APAI was positively correlated with the serum total bilirubin level (r=0.357, P = .035) and negatively correlated with the platelet count (r=-0.354, P = .037). At the 5 second cutoff point, a total serum bilirubin of >8 mg/dL was reported in 5 of 11 patients (45.4%) with APAI of >5 seconds and in only 3 of 24 patients (12.5%) with APAI of <5 seconds (P < .05). The APAI is a quantitative marker that links the hemodynamics and the clinical status of the liver graft.

Multivariable Dependence of Acoustic Contrast of Fluorocarbon and Xenon Microbubbles under Flow

Microbubbles (MBs) are 1 to 10 µm gas particles stabilized by an amphiphilic shell capable of responding to biomedical ultrasound with strong acoustic signals, allowing them to be commonly used in ultrasound imaging and therapy. The composition of both the shell and the core determines their stability and acoustic properties. While there has been extensive characterization of the dissolution, oscillation, cavitation, collapse and therefore, ultrasound contrast of MBs under static conditions, few reports have examined such behavior under hydrodynamic flow. In this study, we evaluate the interplay of ultrasound parameters (five different mechanical indices [MIs]), MB shell parameter (shell stiffness), type of gas (perfluorocarbon for diagnostic imaging and xenon as a therapeutic gas), and a flow parameter (flow rate) on the ultrasound signal of phospholipid-stabilized MBs flowing through a latex tube embedded in a tissue-mimicking phantom. We find that the contrast gradient (CG), a metric of the rate of decay of contrast along the length of the tube, and the contrast peak (CP), the location where the maximum contrast is reached, depend on the conditions of flow, imaging, and MB material. For instance, while the contrast near the flow inlet of the field of view is highest for a softer shell (dipalmitoylphosphatidylcholine [DPPC], C16) than for stiffer shells (distearoylphosphatidylcholine [DSPC], C18, and dibehenoylphosphatidylcholine [DBPC], C22), the contrast decay is also faster; stiffer shells provide more resistance and hence lead to slower MB dissolution/destruction. At higher flow rates, the CG is low for a fixed length of time because each MB is exposed to ultrasound for a shorter period. The CG becomes high for low flow rates, especially at high incident pressures (high MI), causing more MB destruction closer to the inlet of the field of view. Also, the CP shifts toward the inlet at low flow rates, high MIs, and low shell stiffness. We also report the first demonstration of sustained ultrasound flow imaging of a water-soluble, therapeutic gas MB (xenon). We find that an increased MB concentration is necessary for obtaining the same signal magnitude for xenon MBs. In summary, this study builds a framework depicting how multiple variables simultaneously affect the evolution of MB ultrasound contrast under flow. Depending on the MB composition, imaging conditions, transducer positioning, and image processing, building on such a framework could potentially allow for extraction of additional diagnostic information than is commonly analyzed for physiological flow.

A pilot clinical study of low-intensity transcranial focused ultrasound in Alzheimer's disease.

PurposeIncreasing attention has been paid to low-intensity transcranial focused ultrasound (tFUS) for its potential therapeutic effects in Alzheimer's disease (AD). While preclinical studies have shown promising therapeutic effects of low-intensity tFUS in AD models, its efficacy and safety remain unclear in humans. In this pilot study, we investigated the effects of low-intensity tFUS on blood-brain barrier opening, the regional cerebral metabolic rate of glucose (rCMRglu), and cognition in patients with AD.MethodsAfter receiving institutional review board approval, four patients with AD received tFUS to the hippocampus immediately after an intravenous injection of a microbubble ultrasound contrast agent. Sonication was delivered at low-intensity, at a pressure level below the threshold for blood-brain barrier opening. Patients underwent brain magnetic resonance imaging, 18F-fluoro-2-deoxyglucose positron emission tomography, and neuropsychological assessments before and after the tFUS procedure. A whole-brain voxel-wise paired t test was conducted to compare rCMRglu before and after tFUS.ResultsThe sonication, as anticipated, did not show evidence of active blood-brain barrier opening on T1 dynamic contrast-enhanced magnetic resonance imaging. rCMRglu in the superior frontal gyrus (P<0.001), middle cingulate gyrus (P<0.001), and fusiform gyrus increased after tFUS (P=0.001). Patients demonstrated mild improvement in measures of memory, executive, and global cognitive function following tFUS. No adverse events were reported.ConclusionThese results suggest that hippocampal sonication with low-intensity tFUS may have beneficial effects on cerebral glucose metabolism and cognitive function in patients with AD. Further larger studies are needed to confirm the therapeutic efficacy of tFUS in AD.

Molecular imaging diagnosis of atherosclerotic vulnerable plaque in rabbit carotid artery using a self-assembled nanoscale ultrasound microbubble contrast agent.

This study aimed to prepare an anti-Vascular cell adhesion protein 1 (VCAM-1) nanoscale ultrasound microbubble contrast agent using the hyperbranched self-assembly method for the molecular imaging diagnosis of atherosclerotic vulnerable plaques in rabbits. Twenty-five rabbits with carotid atherosclerosis were randomly divided into 5 groups, and the ear vein was injected with agents as follows: Groups A and B: nanoscale ultrasound microbubble contrast agent with and without anti-VCAM-1 agent; Groups C and D: SonoVue ultrasonic microbubble contrast agent, with and without anti-VCAM-1 agent; Control group: saline. The molecular imaging diagnosis of the atherosclerotic plaque, involved the examination of its vulnerability in the rabbit carotid artery was performed using the contrast ultrasound mode. The arrival and peaking time of the anti-VCAM-1 nanoscale ultrasound microbubble contrast agent (Group A) for plaque occurred earlier than those of the other groups (p < 0.05), and with it, the plaque showed the strongest enhancement (p < 0.05), followed by the SonoVue ultrasound microbubble contrast agent with anti-VCAM-1 group (Group C) and the self-made nanoscale ultrasound microbubble contrast agent group (Group B). No development was observed in the plaques of the SonoVue ultrasound microbubble contrast agent group and the control group. The anti-VCAM-1 nanoscale ultrasonic microbubble contrast agent, prepared using the self-assembly method, can facilitate the development effect of the carotid atherosclerotic vulnerable plaque, providing a basis for the molecular imaging diagnosis of carotid atherosclerotic vulnerable plaques.

A Noninvasive Ultrasound Based Technique to Identify Treatment Responders in Patients with Portal Hypertension

Subharmonic aided pressure estimation (SHAPE) is based on the inverse relationship between the subharmonic amplitude of ultrasound contrast microbubbles and ambient pressure. The aim of this study was to verify if SHAPE can accurately monitor disease progression in patients identified with portal hypertension. A modified Logiq 9 scanner with a 4C curvi-linear probe (GE, Waukesha, WI) was used to acquire SHAPE data (transmitting and receiving at 2.5 and 1.25 MHz, respectively) using Sonazoid (GE Healthcare, Oslo, Norway; FDA IND 124,465). Twenty-one (median age 59 years; 12 Males) of the 178 patients enrolled in this institutional review board approved study (14F.113) were identified as having clinically significant portal hypertension based on their hepatic venous pressure gradient results ≥ 10 mmHg. Repeat SHAPE examinations were done every 6.2 months. Liver function tests and clinical indicators were used to establish treatment response. Of the 21 portal hypertensive subjects, 11 had successful follow up scans with an average follow up time of 6.2 months. There was a significantly larger SHAPE signal reduction in the group who were classified as treatment responders (n = 10; -4.01±3.61 dB) compared to the single nonresponder (2.33 dB; p < 0.001). Results for responders matched the corresponding clinical outcomes of improved model for end stage liver disease (MELD) scores, improvement in underlying cause of portal hypertension, improved liver function tests and reduced ascites. SHAPE can potentially monitor disease progression in portal hypertensive patients and hence, may help clinicians in patient management. A larger study would further validate this claim.

Recognizing the Role of the Reticuloendothelial System in the Late Phase of US Contrast Agents.

Recognizing the Role of the Reticuloendothelial System in the Late Phase of US Contrast Agents.