Microbubble Contrast Research Articles

Diagnóstico por imagem na medicina veterinária: avanços, aplicações e perspectivas futuras

Abstract. Imaging diagnostics in veterinary medicine have seen significant advancements over the years due to technological evolution, which has also driven procedures and examinations in human medicine. The objective of this article is to discuss these advancements and future prospects in veterinary imaging, as well as to assess their impacts on the clinical routine of small animals. It is concluded that ||elastography and microbubble contrast are among the most promising available imaging methods, capable of aiding in more accurate and early diagnoses, as well as monitoring various treatments and procedures, thereby contributing to the advancement of veterinary sciences.

A Comprehensive and Repeatable Contrast-Enhanced Ultrasound Quantification Approach for Clinical Evaluations of Tumor Blood Flow.

The aim of this study is to define a comprehensive and repeatable contrast-enhanced ultrasound (CEUS) imaging protocol and analysis method to quantitatively assess lesional blood flow. Easily repeatable CEUS evaluations are essential for longitudinal treatment monitoring. The quantification method described here aims to provide a structure for future clinical studies. This retrospective analysis study included liver CEUS studies in 80 patients, 40 of which contained lesions (primarily hepatocellular carcinoma, n = 28). Each patient was given at least 2 injections of a microbubble contrast agent, and 60-second continuous loops were acquired for each injection to enable evaluation of repeatability. For each bolus injection, 1.2 mL of contrast was delivered, whereas continuous, stationary scanning was performed. Automated respiratory gating and motion compensation algorithms dealt with breathing motion. Similar in size regions of interest were drawn around the lesion and liver parenchyma, and time-intensity curves (TICs) with linearized image data were generated. Four bolus transit parameters, rise time (RT), mean transit time (MTT), peak intensity (PI), and area under the curve (AUC), were extracted either directly from the actual TIC data or from a lognormal distribution curve fitted to the TIC. Interinjection repeatability for each parameter was evaluated with coefficient of variation. A 95% confidence interval was calculated for all fitted lognormal distribution curve coefficient of determination (R2) values, which serves as a data quality metric. One-sample t tests were performed between values obtained from injection pairs and between the fitted lognormal distribution curve and direct extraction from the TIC calculation methods to establish there were no significant differences between injections and measurement precision, respectively. Average interinjection coefficient of variation with both the fitted curve and direct calculation of RT and MTT was less than 21%, whereas PI and AUC were less than 40% for lesion and parenchyma regions of interest. The 95% confidence interval for the R2 value of all fitted lognormal curves was [0.95, 0.96]. The 1-sample t test for interinjection value difference showed no significant differences, indicating there was no relationship between the order of the repeated bolus injections and the resulting parameters. The 1-sample t test between the values from the fitted lognormal distribution curve and the direct extraction from the TIC calculation found no statistically significant differences (α = 0.05) for all perfusion-related parameters except lesion and parenchyma PI and lesion MTT. The scanning protocol and analysis method outlined and validated in this study provide easily repeatable quantitative evaluations of lesional blood flow with bolus transit parameters in CEUS data that were not available before. With vital features such as probe stabilization ideally performed with an articulated arm and an automated respiratory gating algorithm, we were able to achieve interinjection repeatability of blood flow parameters that are comparable or surpass levels currently established for clinical 2D CEUS scans. Similar values and interinjection repeatability were achieved between calculations from a fitted curve or directly from the data. This demonstrated not only the strength of the protocol to generate TICs with minimal noise, but also suggests that curve fitting might be avoided for a more standardized approach. Utilizing the imaging protocol and analysis method defined in this study, we aim for this methodology to potentially assist clinicians to assess true perfusion changes for treatment monitoring with CEUS in longitudinal studies.

Capillary-scale Microvessel Imaging with High-frequency Ultrasound Localization Microscopy in Mouse Brain.

Ultrasound localization microscopy is a super-resolution vascular imaging technique which has garnered substantial interest as a tool for small animal neuroimaging, neuroscience research, and the characterization of vascular pathologies. In the pursuit of increasingly high-fidelity reconstructions of microvasculature, there remains several outstanding questions concerning this sub-diffraction imaging technology, including the accurate reconstruction of microvessels approaching the capillary scale and the pragmatic challenges associated with long data acquisition times. In the context of small animal neurovascular imaging, we posit that increasing the ultrasound imaging frequency is a straightforward approach to enable higher concentrations of microbubble contrast agents, thus increasing the likelihood of microvascular/capillary mapping and decreasing the imaging duration. We demonstrate that higher frequency imaging results in improved ULM fidelity and more efficient microbubble localization due to a smaller microbubble point-spread function that is easier to localize, and which can achieve a higher localizable concentration within the same unit volume of tissue. A select example of in vivo capillary-level vascular reconstruction is demonstrated for the highest frequency imaging probe, which has substantial implications for neuroscientists investigating microvascular function in disease states, regulation, and brain development. High frequency ULM yielding a spatial resolution of 7.1μm, as measured by Fourier ring correlation, throughout the entire depth of the brain, highlighting this technology as a highly relevant tool for neuroimaging research.

A review of multiparametric ultrasound imaging in the clinical setting: scrotal contents

AbstractThe innovative techniques in ultrasound have added a new dimension to investigating superficially located areas such as the contents of the scrotal sac. High frequency transducers, improved technology with the addition of elastography, contrast enhanced ultrasound and microvascular imaging has resulted in a further improvement in diagnostic capabilities. The ability to clearly demonstrate the presence or absence of vascularity within the area under investigation adds an additional dimension to operator confidence in establishing the presence of infarction, global or segmental, or the walls and cavity of an abscess in the testis or epididymis. Increased vascularity of a tumor aids the differential diagnosis based on the flow dynamics of the microbubble contrast, benign lesions likely to retain contrast. Elastography has the ability to ascertain the stiffness of tissue, and when used in conjunction with other ultrasound methods adds to the understanding of the likelihood of a malignant abnormality being present. All the different techniques come under the umbrella term ‘multiparametric ultrasound’, with the application in the scrotal sac detailed in this article.

High-Resolution Power Doppler Using Null Subtraction Imaging.

To improve the spatial resolution of power Doppler (PD) imaging, we explored null subtraction imaging (NSI) as an alternative beamforming technique to delay-and-sum (DAS). NSI is a nonlinear beamforming approach that uses three different apodizations on receive and incoherently sums the beamformed envelopes. NSI uses a null in the beam pattern to improve the lateral resolution, which we apply here for improving PD spatial resolution both with and without contrast microbubbles. In this study, we used NSI with three types of singular value decomposition (SVD)-based clutter filters and noise equalization to generate high-resolution PD images. An element sensitivity correction scheme was also proposed as a crucial component of NSI-based PD imaging. First, a microbubble trace experiment was performed to evaluate the resolution improvement of NSI-based PD over traditional DAS-based PD. Then, both contrast-enhanced and contrast free ultrasound PD images were generated from the scan of a rat brain. The cross-sectional profile of the microbubble traces and microvessels were plotted. FWHM was also estimated to provide a quantitative metric. Furthermore, iso-frequency curves were calculated to provide a resolution evaluation metric over the global field of view. Up to six-fold resolution improvement was demonstrated by the FWHM estimate and four-fold resolution improvement was demonstrated by the iso-frequency curve from the NSI-based PD microvessel images compared to microvessel images generated by traditional DAS-based beamforming. A resolvability of [Formula: see text] was measured from the NSI-based PD microvessel image. The computational cost of NSI-based PD was only increased by 40 percent over the DAS-based PD.

Pulsed focused ultrasound alters the proteomic profile of the tumor microenvironment in a syngeneic mouse model of glioblastoma.

Glioblastoma (GBM), a lethal primary adult malignancy, is difficult to treat because of the restrictive nature of the blood-brain barrier (BBB), blood-tumor barrier (BTB), and the immunosuppressive tumor microenvironment (TME). Since pulsed focused ultrasound (pFUS) is currently used to improve therapeutic deliveries across these barriers, this study aims to characterize the impact of pFUS on the TME proteomics upon opening the BBB and BTB. We utilized MRI-guided, pFUS with ultrasound contrast microbubbles (termed 'pFUS' herein) to selectively and transiently open the BBB and BTB investigating proteomic modifications in the TME. Utilizing an orthotopically-allografted mouse GL26 GBM model (Ccr2RFP/wt - Cx3cr1GFP/wt), pFUS's effect on glioma proteomics was evaluated using a Luminex 48-plex assay. pFUS treated tumors exhibited increases in pro-inflammatory cytokines, chemokines, and trophic factors (CCTFs). Proteomic changes in tumors tend to peak at 24 h after single pFUS session (1x), with levels then plateauing or declining over the subsequent 24 h. Tumors receiving three pFUS sessions (3x) showed elevated CCTFs levels peaking as early as 6 h after the third session. pFUS together with microbubbles induces a sterile inflammatory response in the TME of a mouse GBM tumor. Moreover, this proinflammatory shift can be sustained and perhaps primed for more rapid responses upon multiple sessions of pFUS. These findings raise the intriguing potential that pFUS-induced BBB and BTB opening may not only be effective in facilitating the therapeutic agent delivery, but also be harnessed to modify the TME to assist immunotherapies in overcoming immune evasion in GBM.

Nonlinear sound-sheet microscopy: imaging opaque organs at the capillary and cellular scale.

Light-sheet fluorescence microscopy has revolutionized biology by visualizing dynamic cellular processes in three dimensions. However, light scattering in thick tissue and photobleaching of fluorescent reporters limit this method to studying thin or translucent specimens. Here we show that non-diffractive ultrasonic beams used in conjunction with a cross-amplitude modulation sequence and nonlinear acoustic reporters enable fast and volumetric imaging of targeted biological functions. We report volumetric imaging of tumor gene expression at the cm 3 scale using genetically encoded gas vesicles, and localization microscopy of currently uncharted cerebral capillary networks using intravascular microbubble contrast agents. Nonlinear sound-sheet microscopy provides a ∼64x acceleration in imaging speed, ∼35x increase in imaged volume and ∼4x increase in classical imaging resolution compared to the state-of-the-art in biomolecular ultrasound.

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 efficacy of novel phase convertible nanodroplets for safe CEUS imaging

Microbubble contrast agents in ultrasound/echocardiography are used to increase the echogenicity of the target tissues, thereby raising the contrast resolution of the resultant image. Recently, the trend has shifted toward the development of phase-convertible nanodroplets as ultrasound contrast agents due to their promising theragnostic potential by switching capability at the active site. Herein, we fabricated pre-PGS- perfluoropentane phase convertible nanodroplets and checked their in vitro and in vivo enhancement and safety profile. For this, we performed experiments on 20 male Wistar rats and 2 dogs. Biochemical assays of both rats and dogs included complete blood profiles, liver function tests, and renal function tests. For rat vitals, monitoring and histopathological analysis were also performed. Converted nanodroplets showed excellent contrast enhancement, better than Sonovue upon in vitro testing, with an enhancement time of up to 14 min. In vivo, experiments showed comparable opacification of the ventricles of both rats and dogs. All biochemical assays remained within the normal range during the study period. The histopathological analysis did not show any signs of drug-induced toxicity, showing the safety of these nanodroplets. Pre-PGS-PFP nanodroplets hold great potential for use in echocardiography and abdominal imaging in both human and veterinary applications after clinical trials.

Randomized Feasibility Study Evaluating Multiple FDA-approved Microbubbles for CEUS Lymphography.

Prior studies on contrast-enhanced ultrasound (CEUS) lymphography for preoperative mapping before lymphaticovenous anastomosis surgery in patients with extremity lymphedema have been limited to using only Lumason and Sonazoid as microbubble contrast agents. The purpose of this study was to determine the feasibility of using two other Food & Drug Administration-approved microbubble agents, Optison and Definity, for imaging lymphatic vessels in the upper extremities. Nine female adults with unilateral upper extremity lymphedema anticipating lymphaticovenous anastomosis surgery underwent CEUS lymphography of the unaffected upper extremity randomized to either Lumason, Definity, or Optison. Lymphatic vessels were visualized in all but one case when undilated Definity was used. In the eight upper extremities where lymphatic vessels were visualized, an average of eight intradermal injections of microbubbles were performed in the extremity. Lymphatic vessels could be identified in 57% (36 of 63) of the injections. The effective dilution for each of the microbubble agents is provided. This was the first successful demonstration of lymphatic vessel visualization using either Definity or Optison. Broadening the range of available microbubble agents for CEUS lymphography could improve accessibility to the procedure and provide potentially safer alternatives.

Microbubble Contrast-Enhanced Transcutaneous Ultrasound Enables Real-Time Spinal Cord Perfusion Monitoring Following Posterior Cervical Decompression

Ultrasound imaging is inexpensive, portable, and widely available. The development of a real-time transcutaneous spinal cord perfusion monitoring system would allow more precise targeting of mean arterial pressure goals following acute spinal cord injury (SCI). There has been no prior demonstration of successful real-time cord perfusion monitoring in humans. Four adult patients who had undergone posterior cervical decompression and instrumentation at a single center were enrolled into this prospective feasibility study. All participants had undergone cervical laminectomies spanning ≥2 contiguous levels ≥2months prior to inclusion with no history of SCI. The first 2 underwent transcutaneous ultrasound without contrast and the second 2 underwent contrast-enhanced ultrasound (CEUS) with intravenously injected microbubble contrast. Using noncontrast ultrasound with or without Doppler (n= 2), the dura, spinal cord, and vertebral bodies were apparent however ultrasonography was insufficient to discern intramedullary perfusion or clear white-gray matter differentiation. With application of microbubble contrast (n= 2), it was possible to quantify differential spinal cord perfusion within and between cross-sectional regions of the cord. Further, it was possible to quantify spinal cord hemodynamic perfusion using CEUS by measuring peak signal intensity and the time to peak signal intensity after microbubble contrast injection. Time-intensity curves were generated and area under the curves were calculated as a marker of tissue perfusion. CEUS is a viable platform for monitoring real-time cord perfusion in patients who have undergone prior cervical laminectomies. Further development has the potential to change clinical management acute SCI by tailoring treatments to measured tissue perfusion parameters.

Microvascular recovery with ultrasound in myocardial infarction post-PCI trial.

Persistent microvascular obstruction (MVO) after successful percutaneous coronary intervention (PCI) in acute ST segment elevation myocardial infarction (STEMI) has been well-described. MVO predicts lack of recovery of left ventricular function and increased mortality. Sonothrombolysis utilizing diagnostic ultrasound induced cavitation of commercially available microbubble contrast has been effective at reducing infarct size and improving left ventricular ejection fraction (LVEF) when performed both pre- and post-PCI. However, the effectiveness of post-PCI sonothrombolysis alone after successful PCI has not been demonstrated. A prospective randomized controlled trial was performed in 50 consecutive consenting patients with anterior STEMI who underwent a continuous microbubble infusion immediately following successful PCI. Intermittent high mechanical index (MI) impulses were applied only in the sonthrombolysis group. Delayed enhancement magnetic resonance imaging (MRI) was performed at 48h and again at 6-8weeks to assess for differences in infarct size, LVEF, and MVO. There were no differences between groups in age, gender, and cardiovascular risk factors. Significant (>2 segments) MVO following successful PCI was observed in 66% of patients. Although sonothrombolysis reduced the extent of MVO acutely, there were no differences in infarct size, LVEF, or extent of MVO by MRI at 48h. Twenty-eight patients returned for a follow up MRI at 6-8weeks. LVEF improved only in the sonothrombolysis group (∆LVEF 7.81±4.57% with sonothrombolysis vs. 1.77±7.02% for low MI only, p=.011). Post-PCI sonothrombolysis had minimal effect on reducing myocardial infarct size but improved left ventricular systolic function in patients with acute anterior wall STEMI.

Super-Resolution Ultrasound Imaging for Monitoring the Therapeutic Efficacy of a Vascular Disrupting Agent in an Animal Model of Breast Cancer.

Evaluate the use of super-resolution ultrasound (SRUS) imaging for the early detection of tumor response to treatment using a vascular-disrupting agent (VDA). A population of 28 female nude athymic mice (Charles River Laboratories) were implanted with human breast cancer cells (MDA-MB-231, ATCC) in the mammary fat pad and allowed to grow. Ultrasound imaging was performed using a Vevo 3100 scanner (FUJIFILM VisualSonics Inc) equipped with the MX250 linear array transducer immediately before and after receiving bolus injections of a microbubble (MB) contrast agent (Definity, Lantheus Medical Imaging) via the tail vein. Following baseline ultrasound imaging, VDA drug (combretastatin A4 phosphate, CA4P, Sigma Aldrich) or control saline was injected via the placed catheter. After 4 or 24 hours, repeat ultrasound imaging along the same tumor cross-section occurred. Direct intratumoral pressure measurements were obtained using a calibrated sensor. All raw ultrasound data were saved for offline processing and SRUS image reconstruction using custom MATLAB software (MathWorks Inc). From a region encompassing the tumor space and the entire postprocessed ultrasound image sequence, time MB count (TMC) curves were generated in addition to traditional SRUS maps reflecting MB enumeration at each pixel location. Peak enhancement (PE) and wash-in rate (WIR) were extracted from these TMC curves. At termination, intratumoral microvessel density (MVD) was quantified using tomato lectin labeling of patent blood vessels. SRUS images exhibited a clear difference between control and treated tumors. While there was no difference in any group parameters at baseline (0 hour, P > .09), both SRUS-derived PE and WIR measurements in tumors treated with VDA exhibited significant decreases by 4 (P = .03 and P = .05, respectively) and 24 hours (P = .02 and P = .01, respectively), but not in control group tumors (P > .22). Similarly, SRUS derived microvascular maps were not different at baseline (P = .81), but measures of vessel density were lower in treated tumors at both 4 and 24 hours (P < .04). An inverse relationship between intratumoral pressure and both PE and WIR parameters were found in control tumors (R2 > .09, P < .03). SRUS imaging is a new modality for assessing tumor response to treatment using a VDA.

Diagnostic value of contrast-enhanced ultrasonography for patent foramen ovale detection.

Patent foramen ovale (PFO) has been associated with migraine, cryptogenic stroke (CS), and hypoxemia. However, which examination method is most reliable remains controversial. This study sought to investigate the diagnostic value of contrast-enhanced ultrasonography (cU), including contrast-enhanced transcranial Doppler (cTCD), contrast transthoracic echocardiography (cTTE), and contrast transesophageal echocardiography (cTEE), for PFO; and to determine the best diagnostic strategy. This retrospective observational study included a total of 147 consecutive patients suspected PFO at The First Hospital of Shanxi Medical University between October 2019 and January 2022. The patients also underwent cTCD, cTTE, and cTEE examinations. The standard for the diagnosis of PFO was confirmation of the presence of PFO by color Doppler flow signals or contrast microbubbles (MBs) passing through the foramen ovale. A total of 123 patients were diagnosed with PFO and 24 patients without PFO during the study period. The detectable rates of cTCD, cTTE, and cTEE were 120 (97.56%), 110 (89.43%), and 121 (98.37%), respectively. The sensitivity between cTCD and cTEE for PFO were comparable [97.56%, 95% confidence interval (CI): 92.5% to 99.4% vs. 98.37%, 95% CI: 93.7% to 99.7%; P>0.99], and the sensitivity of both were higher than that of cTTE (89.43%, 95% CI: 82.3% to 94.0%; P=0.02 and P=0.001, respectively). In addition, the specificity of cTEE for PFO was significantly higher than that of cTCD (100%, 95% CI: 82.3% to 100.0% vs. 75.00%, 95% CI: 53.0% to 89.4%; P<0.001) and cTTE (100%, 95% CI: 82.3% to 100.0% vs. 75.00%, 95% CI: 53.0% to 89.4%; P<0.001). Further, the semi-quantitative classification ability of cTCD for PFO with right-to-left shunt (RLS) was significantly higher than that of cTTE and cTEE (P=0.02 and P<0.001, respectively), and that of cTTE was significantly higher than that of cTEE (P=0.01). The Spearman analysis showed that the degree of RLS was positively correlated with the inner diameter of the PFO (r=0.695, P<0.001). The combination of cTCD and cTEE may provide a favorable strategy for the diagnosis of PFO.

Super-resolution ultrasound and microvasculomics: a consensus statement.

This is a summary of a consensus statement on the introduction of "Ultrasound microvasculomics" produced by The Chinese Artificial Intelligence Alliance for Thyroid and Breast Ultrasound. The evaluation of microvessels is a very important part for the assessment of diseases. Super-resolution ultrasound (SRUS) microvascular imaging surpasses traditional ultrasound imaging in the morphological and functional analysis of microcirculation. SRUS microvascular imaging relies on contrast microbubbles to gain sensitivity to microvessels and improves the spatial resolution of ultrasound blood flow imaging for a more detailed depiction of vascular structures and hemodynamics. This method has been applied in preclinical animal models and pilot clinical studies, involving areas including neurology, oncology, nephrology, and cardiology. However, the current quantitative parameters of SRUS images are not enough for precise evaluation of microvessels. Therefore, by employing omics methods, more quantification indicators can be obtained, enabling a more precise and personalized assessment of microvascular status. Ultrasound microvasculomics-a high-throughput extraction of image features from SRUS images - is one novel approach that holds great promise but needs further validation in both bench and clinical settings. CLINICAL RELEVANCE STATEMENT: Super-resolution Ultrasound (SRUS) blood flow imaging improves spatial resolution. Ultrasound microvasculomics is possible to acquire high-throughput information of features from SRUS images. It provides more precise and abundant micro-blood flow information in clinical medicine. KEY POINTS: This consensus statement reviews the development and application of super-resolution ultrasound (SRUS). The shortcomings of the current quantification indicators of SRUS and strengths of the omics methodology are addressed. "Ultrasound microvasculomics" is introduced for a high-throughput extraction of image features from SRUS images.

Modulating Nonlinear Acoustic Response of Phospholipid-Coated Microbubbles with pH for Ultrasound Imaging.

Activatable microbubble contrast agents for contrast-enhanced ultrasound have a potential role for measuring physiologic and pathologic states in deep tissues, including tumor acidosis. In this study, we describe a novel observation of increased harmonic oscillation of phosphatidylcholine microbubbles (PC-MBs) in response to lower ambient pH using a clinical ultrasound scanner. MB echogenicity and nonlinear echoes were monitored at neutral and acidic pH using B-mode and Cadence contrast pulse sequencing (CPS), a harmonic imaging technique at 7.0 and 1.5 MHz. A 3-fold increase in harmonic signal intensity was observed when the pH of PC-MB suspensions was decreased from 7.4 to 5.5 to mimic normal and pathophysiological levels that can be encountered in vivo. This pH-mediated activation is tunable based on the chemical structure and length of phospholipids composing the MB shell. It is also reliant on the presence of phosphate groups, as the use of lipids without phosphate instead of phospholipids completely abrogated this phenomenon. The increased harmonic signal likely is the result of increased MB oscillation caused by a decrease of the interfacial tension induced at a lower pH, altering the lipid conformation. While relative signal changes are interpreted clinically as mostly related to blood flow, pH effects could be significant contributors, particularly when imaging tumors. While our observation can be used clinically, it requires further research to isolate the effect of pH from other variables. These findings could pave the way toward for the development of new smart ultrasound contrast agents that expand the clinical utility of contrast-enhanced ultrasound.

Effect of particle aspect ratio in targeted drug delivery in abdominal aortic aneurysm

Aneurysm is a permanent irreversible bulge in the artery that can occur with higher prevalence among elderly individuals. Although invasive surgical procedures can prevent their development, they come with considerable side effects. Recently, treatments based on targeted drug delivery have gained a lot of attention to suppress aneurysm growth. Numerical simulations have been shown to be of great role in the prediction of blood hemodynamics and vascular wall behaviour in the case of an aneurysm. Moreover, the utilization of high-fidelity approaches such as the Lagrangian frame of reference can address the motion characteristics of microbubble (MB) contrast agents in particulate flows. This study aims to investigate the effect of particle aspect ratio on the adhesion of oblate spheroid particles to the vascular wall. Accordingly, a two-way fluid–structure interaction (FSI) method consisting of a hyperelastic material model for the vessel along with a non-Newtonian, compressible model for blood was employed to simulate an abdominal aortic aneurysm (AAA). Moreover, the ligand–receptor binding concept has been utilized to address the quantification of MBs adhesion. Five sets of aspect ratios ranging from 1 to 9 have been investigated and results indicated that with the increase of the aspect ratio the rate of adhesion decreases. Two drastic changes in the particle number occurred due to the diastolic peak and negative velocity profile, respectively. However, it was concluded that the hydrodynamic of the MBs in terms of velocity and wall distance is rather insensible to the particle shape.

465 Focused Ultrasound-Mediated Blood-Spinal Cord Barrier Permeabilization: A Promising Targeted Approach for Treating Chronic Spinal Cord Injury in Rat Models

INTRODUCTION: Focused ultrasound (FUS) with microbubble contrast agents can temporarily disrupt the blood-brain barrier (BBB), enabling drug delivery. FUS may also offer a minimally invasive method for delivering therapeutic agents to the affected area in chronic spinal cord injury (SCI) by transiently opening the blood-spinal cord barrier (BSCB). METHODS: Nine female Sprague-Dawley rats underwent a T9-T11 laminectomy with contusion SCI and were randomly allocated into FUS or control group. Three weeks later, FUS was administered intravenously with microbubbles. A pressure sweep was performed until ultra-harmonics were captured using a wideband hydrophone. We administered 2% Evans blue (EB) immediately after FUS confirmed the BSCB permeability. Transcardial perfusion was performed 2 hours later, and spinal cords were collected. Spectrophotometry was used to determine the EB concentration. Statistical analysis was performed using a student t-test. RESULTS: Five rats were treated with FUS while four were used as controls. Successful feedback control was achieved with FUS, and ultra-harmonics were observed in the FUS group at a mean peak pressure of 0.5 MPa. Macroscopic identification of EB in the spinal cord sections of animals exposed to FUS confirmed the localized opening of the BSCB. Spectrophotometry revealed an increase in EB concentration in the FUS group compared to controls: Mean EB concentration was 0.03 μg in the FUS group versus 0.016 μg in controls at 1-cm above the injury (p &lt; 0.001); 0.27 μg versus 0.093 μg at the injury site (p &lt; 0.001); and 0.25 μg versus 0.18 μg at 1-cm below the injury(p &lt; 0.001). CONCLUSIONS: FUS increases the permeability of the BSCB in a chronic contusion SCI rat model. This suggests that FUS-mediated BSCB permeabilization may hold promise as a targeted approach for improving therapeutic outcomes in the treatment of chronic SCI.

Acoustic response and ambient pressure sensitivity characterization of SonoVue for noninvasive pressure estimation.

Subharmonic aided pressure estimation (SHAPE) is a noninvasive pressure measurement technique based on the pressure dependent subharmonic signal from contrast microbubbles. Here, SonoVue microbubble with a sulfur hexafluoride (SF6) core, was investigated for use in SHAPE. The study uses excitations of 25-700 kPa peak negative pressure (PNP) and 3 MHz frequency over eight pressurization cycles between atmospheric pressure and overpressures, ranging from 0 to 25 kPa (0 to 186 mm Hg). The SonoVue subharmonic response was characterized into two types. Unlike other microbubbles, SonoVue showed significant subharmonic signals at low excitations (PNPs, 25-400 kPa), denoted here as type I subharmonic. It linearly decreased with increasing overpressure (-0.52 dB/kPa at 100 kPa PNP). However, over multiple pressurization-depressurization cycles, type I subharmonic changed; its value at atmospheric pressure decreased over multiple cycles, and at later cycles, it recorded an increase in amplitude with overpressure (highest, +13 dB at 50 kPa PNP and 10 kPa overpressure). The subharmonic at higher excitations (PNP > 400 kPa), denoted here as type II subharmonic, showed a consistent decrease with the ambient pressure increase with strongest sensitivity of -0.4 dB/kPa at 500 kPa PNP.

Scenarios for the appearance of strange attractors in a model of three interacting microbubble contrast agents

We study nonlinear dynamics in a model of three interacting encapsulated gas bubbles in a liquid. The model is a system of three coupled nonlinear oscillators with an external periodic force. Such bubbles have numerous applications, for instance, they are used as contrast agents in ultrasound visualization. Certain types of bubbles oscillations may be beneficial or undesirable depending on a given application and, hence, the dependence of the regimes of bubbles oscillations on the control parameters is worth studying. We demonstrate that there is a wide variety of types of dynamics in the model by constructing a chart of dynamical regimes in the control parameters space. Here we focus on hyperchaotic attractors characterized by three positive Lyapunov exponents and strange attractors with one or two positive Lyapunov exponents possessing an additional zero Lyapunov exponent, which have not been observed previously in the context of bubbles oscillations. We also believe that we provide a first example of a hyperchaotic attractor with additional zero Lyapunov exponent. Furthermore, the mechanisms of the onset of these types of attractors are still not well studied. We identify two-parametric regions in the control parameter space where these hyperchaotic and chaotic attractors appear and study one-parametric routes leading to them. We associate the appearance of hyperchaotic attractors with three positive Lyapunov exponents with the inclusion of a periodic orbit with a three-dimensional unstable manifold, while the onset of chaotic oscillations with an additional zero Lyapunov exponent is connected to the partial synchronization of bubbles oscillations. We propose several underlying bifurcation mechanisms that explain the emergence of these regimes. We believe that these bifurcation scenarios are universal and can be observed in other systems of coupled oscillators.