Definity Microbubbles Research Articles

An Unsupervised Approach for Treatment Effectiveness Monitoring Using Curvature Learning

Contrast-enhanced ultrasound could assess whether cancer chemotherapeutic agents work in days, rather than waiting 2–3 months, as is typical using the Response Evaluation Criteria in Solid Tumors (RECIST), therefore avoiding toxic side effects and expensive, ineffective therapy. A total of 40 mice were implanted with human colon cancer cells: treatment-sensitive mice in control (n = 10, receiving saline) and treated (n = 10, receiving bevacizumab) groups and treatment-resistant mice in control (n = 10) and treated (n = 10) groups. Each mouse was imaged using 3D dynamic contrast-enhanced ultrasound with Definity microbubbles. Curvature learning, an unsupervised learning approach, quantized pixels into three classes—blue, yellow, and red—representing normal, intermediate, and high cancer probability, both at baseline and after treatment. Next, a curvature learning score was calculated for each mouse using statistical measures representing variations in these three color classes across each frame from cine ultrasound images obtained during contrast administration on a given day (intra-day variability) and between pre- and post-treatment days (inter-day variability). A Wilcoxon rank-sum test compared score distributions between treated, treatment-sensitive mice and all others. There was a statistically significant difference in tumor score between the treated, treatment-sensitive group (n = 10) and all others (n = 30) (p = 0.0051). Curvature learning successfully identified treatment response, detecting changes in tumor perfusion before changes in tumor size. A similar technique could be developed for humans.

Cavitation monitoring, treatment strategy, and acoustic simulations of focused ultrasound blood-brain barrier disruption in patients with glioblastoma

PurposeWe report our experience disrupting the blood-brain barrier (BBB) to improve drug delivery in glioblastoma patients receiving temozolomide chemotherapy. The goals of this retrospective analysis were to compare MRI-based measures of BBB disruption and vascular damage to the exposure levels, acoustic emissions data, and acoustic simulations. We also simulated the cavitation detectors. MethodsMonthly BBB disruption (BBBD) was performed using a 220 kHz hemispherical phased array focused ultrasound system (Exablate Neuro, InSightec) and Definity microbubbles (Lantheus) over 38 sessions in nine patients. Exposure levels were actively controlled via the cavitation dose obtained by monitoring subharmonic acoustic emissions. The acoustic field and sensitivity profile of the cavitation detection system were simulated. Exposure levels and cavitation metrics were compared to the level of BBBD evident in contrast-enhanced MRI and to hypointense regions in T2*-weighted MRI. ResultsOur treatment strategy evolved from using a relatively high cavitation dose goal to a lower goal and longer sonication duration and ultimately resulted in BBBD across the treatment volume with minimal petechiae. Subsonication-level feedback control of the exposure using acoustic emissions also improved consistency. Simulations of the acoustic field suggest that reflections and standing waves appear when the focus is placed near the skull, but their effects can be mitigated with aberration correction. Simulating the cavitation detectors suggest variations in the sensitivity profile across the treatment volume and between patients. A correlation was observed with the cavitation dose, BBBD and petechial hemorrhage in 8/9 patients, but substantial variability was evident. Analysis of the cavitation spectra found that most bursts did not contain wideband emissions, a signature of inertial cavitation, but biggest contribution to the cavitation dose – the metric used to control the procedure – came from bursts with wideband emissions. ConclusionUsing a low subharmonic cavitation dose with a longer duration resulted in BBBD with minimal petechiae. The correlation between cavitation dose and outcomes demonstrates the benefits of feedback control based on acoustic emissions, although more work is needed to reduce variability. Acoustic simulations could improve focusing near the skull and inform our analysis of acoustic emissions. Monitoring additional frequency bands and improving the sensitivity of the cavitation detection could provide signatures of microbubble activity associated with BBB disruption that were undetected here and could improve our ability to achieve BBB disruption without vascular damage.

Enhancing Curcumin’s therapeutic potential in cancer treatment through ultrasound mediated liposomal delivery

Improving the efficacy of chemotherapy remains a key challenge in cancer treatment, considering the low bioavailability, high cytotoxicity, and undesirable side effects of some clinical drugs. Targeted delivery and sustained release of therapeutic drugs to cancer cells can reduce the whole-body cytotoxicity of the agent and deliver a safe localized treatment to the patient. There is growing interest in herbal drugs, such as curcumin, which is highly noted as a promising anti-tumor drug, considering its wide range of bioactivities and therapeutic properties against various tumors. Conversely, the clinical efficacy of curcumin is limited because of poor oral bioavailability, low water solubility, instability in gastrointestinal fluids, and unsuitable pH stability. Drug-delivery colloid vehicles like liposomes and nanoparticles combined with microbubbles and ultrasound-mediated sustained release are currently being explored as effective delivery modes in such cases. This study aimed to synthesize and study the properties of curcumin liposomes (CLs) and optimize the high-frequency ultrasound release and uptake by a human breast cancer cell line (HCC 1954) through in vitro studies of culture viability and cytotoxicity. CLs were effectively prepared with particles sized at 81 ± 2 nm, demonstrating stability and controlled release of curcumin under ultrasound exposure. In vitro studies using HCC1954 cells, the combination of CLs, ultrasound, and Definity microbubbles significantly improved curcumin’s anti-tumor effects, particularly under specific conditions: 15 s of continuous ultrasound at 0.12 W/cm2 power density with 0.6 × 107 microbubbles/mL. Furthermore, the study delved into curcumin liposomes’ cytotoxic effects using an Annexin V/PI-based apoptosis assay. The treatment with CLs, particularly in conjunction with ultrasound and microbubbles, amplified cell apoptosis, mainly in the late apoptosis stage, which was attributed to heightened cellular uptake within cancer cells.

Using ultrasound-targeted microbubble cavitation to open the blood–brain barrier for drug delivery in Alzheimer’s disease

Drug delivery for Alzheimer’s disease (AD) is challenging due to restricted diffusion across the blood–brain barrier (BBB). Ultrasound-targeted microbubble cavitation (UTMC) can be used to transiently open the BBB. We hypothesized that opening the BBB with UTMC would increase the brain concentration of LY2886721 (LY), an orally administered drug developed for AD, in 5XFAD mice, a model of AD. We treated the right hemisphere using an RK-50 system (FUS Instruments Inc). Definity microbubbles were injected, and ultrasound (1.45 MHz, 2 Hz pulse repetition frequency, 10 ms pulse length, 0.6 MPa for 30 s) was applied to 11 locations across the right hemisphere. Thirty minutes after UTMC, mice were administered LY (30 mg/kg p.o.). In one cohort, 45 min after dosing with LY, there was an increase in the concentration of LY in the UTMC-treated hemisphere compared to the non-UTMC treated hemisphere (p < 0.05). In a second cohort, 2.5 h after dosing with LY, there was a decrease in soluble Aβ;40 (p < 0.05), insoluble Aβ;40 (p < 0.05), and insoluble Aβ;42 (p < 0.05) in the UTMC-treated hemisphere compared to the non-UTMC treated hemisphere. UTMC can be used to open the BBB to increase the concentration of LY and decrease Aβ in a preclinical model of AD.

The Effect of Mixing Iodinated Contrast Media and Ultrasound Contrast Agents on Subharmonic Signals.

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

Fibrin-targeted phase shift microbubbles for the treatment of microvascular obstruction.

Rationale: Microvascular obstruction (MVO) following percutaneous coronary intervention (PCI) is a common problem associated with adverse clinical outcomes. We are developing a novel treatment, termed sonoreperfusion (SRP), to restore microvascular patency. This entails using ultrasound-targeted microbubble cavitation (UTMC) of intravenously administered gas-filled lipid microbubbles (MBs) to dissolve obstructive microthrombi in the microvasculature. In our prior work, we used standard-sized lipid MBs. In the present study, to improve upon the efficiency and efficacy of SRP, we sought to determine the therapeutic efficacy of fibrin-targeted phase shift microbubbles (FTPSMBs) in achieving successful reperfusion of MVO. We hypothesized that owing to their much smaller size and affinity for thrombus, FTPSMBs would provide more effective dissolution of microthrombi when compared to that of the corresponding standard-sized lipid MBs. Methods: MVO in the rat hindlimb was created by direct injection of microthrombi into the left femoral artery. Definity MBs (Lantheus Medical Imaging) were infused through the jugular vein for contrast-enhanced ultrasound imaging (CEUS). A transducer was positioned vertically above the hindlimb for therapeutic US delivery during the concomitant administration of various therapeutic formulations, including (1) un-targeted MBs; (2) un-targeted phase shift microbubbles (PSMBs); (3) fibrin-targeted MB (FTMBs); and (4) fibrin-targeted PSMBs (FTPSMBs). CEUS cine loops with burst replenishment were obtained at baseline (BL), 10 min post-MVO, and after each of two successive 10-minute SRP treatment sessions (TX1, TX2) and analyzed (MATLAB). Results: In-vitro binding affinity assay showed increased fibrin binding peptide (FBP) affinity for the fibrin clots compared with the untargeted peptide (DK12). Similarly, in our in-vitro model of MVO, we observed a higher binding affinity of fluorescently labeled FTPSMBs with the porcine microthrombi compared to FTMBs, PSMBs, and MBs. Finally, in our hindlimb model, we found that UTMC with FTPSMBs yielded the greatest recovery of blood volume (dB) and flow rate (dB/sec) following MVO, compared to all other treatment groups. Conclusions: SRP with FTPSMBs achieves more rapid and complete reperfusion of MVO compared to FTMBs, PSMBs, and MBs. Studies to explore the underlying physical and molecular mechanisms are underway.

Cavitation Feedback Control of Focused Ultrasound Blood-Brain Barrier Opening for Drug Delivery in Patients with Parkinson's Disease.

Magnetic resonance-guided focused ultrasound (MRgFUS), in conjunction with circulating microbubbles, is an emerging technology that can transiently enhance the permeability of the blood-brain barrier (BBB) locally and non-invasively to facilitate targeted drug delivery to the brain. In this clinical trial, the feasibility and safety of BBB modulation in the putamen were evaluated for biweekly therapeutic agent delivery in patients with Parkinson's disease. The performance of the clinical MRgFUS system's cavitation feedback controller for active power modulation throughout the exposures was examined. The putamen was targeted unilaterally by an ExAblate Neuro MRgFUS system operating at 220 kHz. Definity microbubbles were infused via a saline bag gravity drip at a rate of 4 µL/kg per 5 min. A cavitation emissions-based feedback controller was employed to modulate the acoustic power automatically according to prescribed target cavitation dose levels. BBB opening was measured by Gadolinium (Gd)-enhanced T1-weighted MR imaging, and the presence of potential micro-hemorrhages induced by the exposures was assessed via T2*-weighted MR imaging. A total of 12 treatment sessions were carried out across four patients, with target cavitation dose levels ranging from 0.20-0.40. BBB permeability in the targeted putamen was elevated successfully in all treatments, with a 14% ± 6% mean increase in Gd-enhanced T1-weighted MRI signal intensity relative to the untreated contralateral side. No indications of red blood cell extravasations were observed on MR imaging scans acquired one day following each treatment session. The cavitation emissions-based feedback controller was effective in modulating acoustic power levels to ensure BBB permeability enhancement while avoiding micro-hemorrhages, however, further technical advancements are warranted to improve its performance for use across a wide variety of brain diseases.

Noninvasive Evaluation of Cardiac Chamber Pressures Using Subharmonic-Aided Pressure Estimation With Definity Microbubbles

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

CTNI-20. RESULTS OF A PHASE 1/2 CLINICAL TRIAL OF BLOOD-BRAIN BARRIER (BBB) OPENING WITH THE SONOCLOUD-9 IMPLANTABLE ULTRASOUND DEVICE IN RECURRENT GLIOBLASTOMA PATIENTS RECEIVING IV CARBOPLATIN

Abstract Low intensity pulsed ultrasound in combination with microbubbles can be used to temporarily disrupt the blood-brain barrier (BBB). A phase 1/2 clinical study (NCT03744026) was initiated to demonstrate the safety and efficacy of BBB disruption using an implantable ultrasound system (SonoCloud-9) in patients with recurrent glioblastoma receiving carboplatin chemotherapy. The SonoCloud-9 device, which contains nine, 1-MHz, 10-mm diameter ultrasound emitters (Carthera, Paris, France) was placed at the end of tumor resection and replaced the bone flap. The device was activated 9-14 days after surgery for a duration of 270 seconds every four weeks until progression or treatment completion, concomitantly with IV DEFINITY microbubbles (10 ml/kg, Lantheus, Billerica, US). The Phase 1 cohort consisted of an escalation of BBB disruption volume by activation of 3 (n = 3), 6 (n = 3), then 9 (n = 3) emitters of the device. Dose limiting toxicity (DLT) was assessed during the first two weeks after the 1st sonication. A subsequent expansion cohort consisted of patients treated with nine emitters in which the primary endpoint was assessment of BBB opening on MRI using gadolinium (&amp;lt; 1 hr after sonication). All patients received carboplatin either after (n = 21) or before (n = 12) device activation to disrupt the BBB. In addition, a sub-study was performed to investigate carboplatin concentration enhancement in the peritumoral region with sonication at time of device implantation. Study accrual is complete with 33 patients having been implanted and received at least one sonication. A total of 101 sonications were performed (range = 1-10 sonication sessions/patient). No DLTs were observed. Five serious adverse events (all resolved) were considered as possibly related to the study procedure. BBB disruption was confirmed by gadolinium enhancement after sonication. In three patients who underwent intraoperative sonication and carboplatin administration, a 7.58-fold increase in brain/plasma drug levels was demonstrated. Updated survival results will be presented.

Synergistic effects of microbubble-mediated focused ultrasound and radiotherapy in a F98 glioma model

Combined microbubble-mediated focused ultrasound (FUS) and radiation therapy (RT) has been shown to improve outcomes in tumors outside the brain. Here, we study the effects of FUS + RT in a F98 glioma model. Tumor cells were implanted into the brains of 45 Fischer rats (n = 4–8 per group): Controls, FUS, RT (4,8,15-Gy), and FUS + RT (4,8,15-Gy). 9 days after implantation, tumors were targeted using FUS (1–2 W, 220 kHz, 5 ms bursts, 1 Hz PRF, 180 s, 20 μL/kg Definity microbubbles), followed by RT. Tumor progression was monitored using MRI. At 4Gy, FUS + RT increased tumor doubling time by 11% compared to RT only and Controls (P &amp;lt; 0.01). At higher doses, where RT alone had a significant effect, there were no significant differences in doubling time compared to RT alone. Tumor volumes were reduced by 21–57% (4Gy) and 20–48% (15Gy) compared with RT alone (P &amp;lt; 0.05). No significant benefit was observed at 8Gy. A moderate, but not significant, increase in median survival was observed: 28 versus 27days (4Gy), 30 versus 29days (8Gy), and 35 vs. 33 days (15Gy). However, at 4Gy, FUS + RT significantly improved survival by 6% compared to the control group (median survival = 27days), while RT only offered no improvement. This study indicates that FUS + RT may improve therapeutic outcomes in glioblastoma, particularly at low RT doses, where RT alone has no therapeutic benefit.

OS07.3.A Phase 1/2 clinical trial of blood-brain barrier opening with the SonoCloud-9 implantable ultrasound device in recurrent glioblastoma patients receiving IV carboplatin

Abstract Background Low intensity pulsed ultrasound (LIPU) in combination with microbubbles is a promising approach for brain drug delivery. A phase 1/2 clinical study (NCT03744026) was initiated to demonstrate the safety and efficacy of blood-brain barrier (BBB) disruption over a large volume using an implantable ultrasound system (SonoCloud-9) in patients with recurrent glioblastoma receiving carboplatin chemotherapy. Material and Methods The SonoCloud-9 device (Carthera, Paris, France) was placed at the end of tumor resection and replaced the bone flap. The device was activated 9-14 days after surgery for a duration of 270 seconds every 4 weeks until progression or treatment completion, concomitantly with IV DEFINITY microbubbles (10 μl/kg, Lantheus, Billerica, US). The Phase 1 cohort consisted of an escalation of BBB disruption volume by activation of 3 (n=3), 6 (n=3), then 9 (n=3) emitters of the device. Dose limiting toxicity (DLT) was assessed during the first 2 weeks after the 1st sonication. A subsequent expansion cohort consisted of patients treated with 9 emitters in which the primary endpoint was assessment of BBB opening on MRI using gadolinium (&amp;lt;1 hr after sonication). All patients received carboplatin either after (n=21) or before (n=12) device activation to disrupt the BBB. In addition, a sub-study was performed to investigate carboplatin concentration enhancement in the peritumoral region with sonication at time of device implantation. Results Study accrual is complete with 38 patients enrolled and 33 patients having been implanted and received at least one sonication+carboplatin. A total of 101 sonications were performed (range=1-10 sonication sessions/patient). No DLTs were observed. A total of 14 SAEs were observed including five events considered as possibly treatment related. BBB disruption was confirmed by gadolinium enhancement after sonication. In an analysis of 60 treatments in 27 patients that had all nine emitters active, 90% of activated emitters led to BBB opening in gray and/or white matter with good repeatability of BBB opening. In 3 patients who underwent intraoperative sonication and carboplatin administration, a 7.58-fold increase in brain/plasma drug levels was demonstrated. Updated and mature outcome results will be presented. Conclusion These results confirm the safety and feasibility of repeated BBB disruption using an implantable ultrasound system. LIPU substantially increases drug levels in the peritumoral brain.

Synergistic enhancement of cell death by triple combination therapy of docetaxel, ultrasound and microbubbles, and radiotherapy on PC3 a prostate cancer cell line

The application of ultrasound and microbubbles (USMB) has been shown to enhance both chemotherapy and radiotherapy. This study investigated the potential of triple combination therapy comprised of USMB, docetaxel (Taxotere: TXT) chemotherapy and XRT to enhance treatment efficacy. Prostate cancer (PC3) cells in suspension were treated with various combinations of USMB, chemotherapy and radiotherapy. Cells were treated with ultrasound and microbubbles (500 kHz pulse center frequency, 580 kPa peak negative pressure, 10 μs pulse duration, 60 s insonation time and 2% Definity microbubbles (v/v)), XRT (2 Gy), and Taxotere (TXT) at concentrations ranging from 0.001 to 0.1 nM for 5- and 120-minutes duration. Following treatment, cell viability was assessed using a clonogenic assay. Therapeutic efficiency of the combined treatments depended on chemotherapy and microbubble exposure conditions. Under the exposure conditions of the study, the triple combination therapy synergistically enhanced clonogenic cell death compared to single and double combination therapy. Cell viability of ∼2% was achieved with the triple combination therapy corresponding to ∼29, ∼37, and ∼38 folds decrease compared to XRT (57%), USMB (74%) and TXT (76%) alone conditions, respectively. In addition, the triple combination therapy decreased cell viability by ∼29, ∼19- and ∼11 folds compared to TXT2hr + USMB (58%), TXT2hr + XRT (37%), and USMB + XRT (22%), respectively.The in vivo PC3 tumours showed that USMB significantly enhanced cell death through detection of apoptosis (TUNEL) with both TXT and TXT + XRT. The study demonstrated that the triple combination therapy can significantly enhance cell death in prostate cancer cells both in vitro and in vivo under relatively low chemotherapy and ionizing radiation doses.

Abstract 14089: Phase Shift Microbubbles for the Treatment of Microvascular Obstruction

Introduction: Microvascular obstruction (MVO) following coronary intervention is a common problem associated with worse clinical outcome, and has no consistent therapy. We are developing a new technique termed sonoreperfusion (SRP), to restore microvascular patency. This entails the use of ultrasound (US) to cause microbubble (MB) cavitation to dissolve microthrombi; this MB cavitation creates shear stress, activates nitric oxide release, and results in thrombolysis. In this pilot study, to further optimize SRP, we have used Phase Shift Microbubbles (PSMBs) (Microvascular Therapeutics, Inc). Owing to their much smaller size relative to standard MBs (~400 nm vs 3 μm) and greater microthrombus penetration, we will test the hypothesis that PSMBs attain successful reperfusion of MVO, and ultimately, will provide more rapid SRP, in our model of MVO. Methods: MVO of the rat ( n =3) hindlimb was created by direct injection of microthrombi into the left femoral artery, followed by infusion of therapeutic PSMBs. Definity MBs (Lantheus Medical Imaging) were infused through the jugular vein for contrast enhanced ultrasound imaging (CEUS). A transducer was positioned vertically above the hindlimb for therapeutic US pulses during concomitant administration of PSMBs. CEUS cine loops with burst replenishment were obtained at baseline (BL), 10 min post MVO, and after each of the two SRP treatment sessions (TX1, TX2) and analyzed (MATLAB). Results: Fig. 1 depicts a typical example demonstrating successful creation of MVO and complete reperfusion after SRP treatment. Data are expressed as mean ± standard error. Blood volume (dB) at BL (15.3 ± 1.1), MVO (5.2 ± 1.3), TX1 (19.8 ± 2.4), TX2 (17.9 ± 1.8) and flow rate (dB/sec) at BL (2.7 ± 0.4), MVO (0.2 ± 0.1) TX1 (2.1 ± 0.5), TX2 (2.7 ± 0.4). Conclusions: US targeted PSMB cavitation causes successful rapid reperfusion of rat hindlimb following MVO. Studies to explore the underlying molecular mechanisms associated with SRP of PSMBs are underway.

In vivo assessment of prostate cancer response using quantitative ultrasound characterization of ultrasonic scattering properties

BackgroundThe study here investigated quantitative ultrasound (QUS) parameters to assess tumour response to ultrasound-stimulated microbubbles (USMB) and hyperthermia (HT) treatment in vivo. Mice bearing prostate cancer xenografts were exposed to various treatment conditions including 1% (v/v) Definity microbubbles stimulated at ultrasound pressures 246 kPa and 570 kPa and HT duration of 0, 10, 40, and 50 min. Ultrasound radiofrequency (RF) data were collected using an ultrasound transducer with a central frequency of 25 MHz. QUS parameters based on form factor models were used as potential biomarkers of cell death in prostate cancer xenografts.ResultsThe average acoustic concentration (AAC) parameter from spherical gaussian and the fluid-filled spherical models were the most efficient imaging biomarker of cell death. Statistical significant increases of AAC were found in the combined treatment groups: 246 kPa + 40 min, 246 kPa + 50 min, and 570 kPa + 50 min, in comparison with control tumours (0 kPa + 0 min). Changes in AAC correlates strongly (r2 = 0.62) with cell death fraction quantified from the histopathological analysis.ConclusionScattering property estimates from spherical gaussian and fluid-filled spherical models are useful imaging biomarkers for assessing tumour response to treatment. Our observation of changes in AAC from high ultrasound frequencies was consistent with previous findings where parameters related to the backscatter intensity (AAC) increased with cell death.

A phase I/IIa study to evaluate the safety and efficacy of blood-brain barrier (BBB) opening with the SonoCloud-9 implantable ultrasound device in recurrent glioblastoma patients receiving IV carboplatin.

2049 Background: Low intensity pulsed ultrasound (LIPU) in conjunction with intravenous microbubbles can transiently and reversibly disrupt the blood-brain barrier (BBB), allowing for an increase in the tissue concentration of chemotherapy agents in the brain. Mass spectrometry data from preclinical models (mouse, swine) showed a &gt; 5x enhancement in carboplatin brain concentrations, which correlated well with the spatial distribution of a Gadolinium (Gd) contrast agent used for magnetic resonance imaging (MRI). Methods: The primary objective of this phase I/IIa study (NCT03744026) was to demonstrate the safety of BBB disruption using LIPU in patients with recurrent glioblastoma. This study was a 3+3 design using escalating numbers (3, 6, 9) of activated 1 MHz ultrasound emitters. Nine patients were treated in the escalation phase and another 12 patients were treated with 9 emitters in the expansion phase. Eligibility included recurrent GBM (any recurrence) with a maximum tumor size of &lt; 70 mm. The SonoCloud-9 device (CarThera, Paris, France) was implanted during tumor debulking/resection surgery and replaced the bone flap, with the device targeting the tumor and surrounding peritumoral brain. The device was activated every four weeks for a duration of 270 seconds, concomitantly with IV DEFINITY microbubbles (10 ml/kg), to disrupt the BBB prior to administration of carboplatin (AUC 4-6). MRI was performed to verify safety and evaluate efficacy of BBB disruption with Gd enhancement. Results: No DLTs were observed. The overall tolerance of the SonoCloud-9 implant was good, with two transient, manageable grade 3 wound infections and one grade 1 acquired meningocele event considered as probably related to the overall procedure. The most frequent neurologic adverse events were grade 1 blurred vision (5%) and dizziness (5%). Conclusions: Significant Gd enhancement was observed after more than 90% of sonication sessions, suggesting effective BBB disruption and carboplatin enhancement. Clinical trial information: NCT03744026.

Efficacy of Sonothrombolysis Using Acoustically Activated Perflutren Nanodroplets versus Perflutren Microbubbles

Nanoscale-diameter liquid droplets from commercially available microbubbles may optimize thrombus permeation and subsequent thrombus dissolution (TD). Thrombi were made using fresh porcine arterial whole blood and placed in an in vitro vascular simulation. A diagnostic ultrasound probe in contact with a tissue-mimicking phantom tested intermittent high-mechanical-index (HMI) fundamental multipulse (focused ultrasound [FUS], 1.8 MHz) versus harmonic single-pulse (HUS, 1.3 MHz) modes during a 10-min infusion of Definity nanodroplets (DNDs), Definity microbubbles (DMBs) or saline. The ability of FUS and intravenous DNDs to improve epicardial and microvascular flow was then tested in four pigs with left anterior descending thrombotic occlusion. Sixty in vitro thrombi were tested, 20 in each group. Percentage TD was significantly higher for DND-treated thrombi than DMB-treated thrombi and controls (DNDs: 42.4%, DMBs: 26.7%, saline: 15.0%; p < 0.0001 vs. control). The highest %TD was seen in the HMI FUS-treated DND group (51 ± 17% TD). HMI FUS detected droplet activation within the risk area in three of four pigs with left anterior descending thrombotic occlusion and re-canalized the epicardial vessel in two. DNDs with intermittent diagnostic HMI ultrasound resulted in significantly more intravascular TD than DMBs and have potential for coronary and risk area thrombolysis.

Abstract 15714: Intra-cardiac Pressure Estimation Using Subharmonic Aided Pressure Estimation (SHAPE) - A Clinical Evaluation

Introduction: Subharmonic aided pressure estimation (SHAPE) utilizes ambient pressure sensitivity of subharmonic signals from ultrasound contrast agents. The objective was to evaluate SHAPE with Definity (Lantheus Medical Imaging, Inc.) and Sonazoid (GE Healthcare) microbubbles for intra-cardiac pressure estimation. Hypothesis: Errors between SHAPE and pressures obtained during cardiac catheterization ≤ 5 mmHg. Methods: IRB approved this study. Consenting patients received an infusion of Definity (56 patients; 2 vials in 50 mL of saline; infusion rate: 4-10 mL/min) or Sonazoid (77 patients; rate (mL/hour) = 0.18 x weight in kg co-infused with saline at 120 mL/hour) during cardiac catheterization. Subharmonic data was acquired using a SonixTablet (PA 4/2 array; BK Ultrasound) synchronously with pressures from the left and right ventricles and the aorta (for left heart catheterizations only). Subharmonic data (in dB) was converted to pressure values (in mmHg) using calibration factors (mmHg/dB) based on data obtained from the aorta - utilizing pressures from the aorta either during the catheterization procedure or pressures obtained using a SphygmoCor (AtCor Medical Pty. Ltd.) device after the catheterization procedure. Clinically relevant pressures between the SHAPE technique and the pressure catheter were compared. Results: Correlation coefficient between the subharmonic and pressure data was -0.8 ± 0.1. With Definity, mean absolute errors ranged from 2.9 ± 1.5 to 5.0 ± 4.2 mmHg and from 4.4 ± 5.7 to 23.7 ± 28.3 mmHg for calibration factors utilizing aortic pressures from pressure catheter and SphygmoCor, respectively. For Sonazoid microbubbles, these errors ranged from 7.9 ± 12.0 to 10.1 ± 12.4 mmHg and from 7.2 ± 11.5 to 15.0 ± 23.2 mmHg, respectively. Two adverse events occurred during Definity infusion; these were resolved with return to baseline conditions. Conclusion: SHAPE may be useful for estimating intra-cardiac pressures noninvasively.

Consistent opening of the blood brain barrier using focused ultrasound with constant intravenous infusion of microbubble agent

The blood brain barrier (BBB) is a major obstacle to the delivery of therapeutics to the brain. Focused ultrasound (FUS) in combination with microbubbles can non-invasively open the BBB in a targeted manner. Bolus intravenous injections of microbubbles are standard practice, but dynamic influx and clearance mechanisms prevent delivery of a uniform dose with time. When multiple targets are selected for sonication in a single treatment, uniform serum concentrations of microbubbles are important for consistent BBB opening. Herein, we show that bubble infusions were able to achieve consistent BBB opening at multiple target sites. FUS exposures were conducted with different Definity microbubble concentrations at various acoustic pressures. To quantify the effects of infusion on BBB opening, we calculated the MRI contrast enhancement rate. When infusions were performed at rates of 7.2 µl microbubbles/kg/min or below, we were able to obtain consistent BBB opening without injury at all pressures. However, when infusion rates exceeded 20 µl/kg/min, signs of injury occurred at pressures from 0.39 to 0.56 MPa. When compared to bolus injections, a bubble infusion offers a more controlled and consistent approach to multi-target BBB disruption.

Echo-Focusing in Transcranial Focused Ultrasound Thalamotomy for Essential Tremor: A Feasibility Study.

Transcranial magnetic resonance-guided focused ultrasound (TcMRgFUS) systems currently employ computed tomography (CT)-based aberration corrections, which may provide suboptimal trans-skull focusing. The objective of this study was to evaluate a contrast agent microbubble imaging-based transcranial focusing method, echo-focusing (EF), during TcMRgFUS for essential tremor. A clinical trial of TcMRgFUS thalamotomy using EF for the treatment of essential tremor was conducted (NCT03935581; funded by InSightec [Tirat Carmel, Israel]). Patients (n = 12) were injected with Definity (Lantheus Medical Imaging, North Billerica, MA) microbubbles, and EF was performed using a research feature add-on to a commercial TcMRgFUS system (ExAblate Neuro, InSightec). Subablative thermal sonications carried out using (1) EF and (2) CT-based aberration corrections were compared via magnetic resonance thermometry, and the optimal focusing method for each patient was employed for TcMRgFUS thalamotomy. EF aberration corrections provided increased sonication efficiency, decreased focal size, and equivalent targeting accuracy relative to CT-based focusing. EF aberration corrections were employed successfully for lesion formation in all 12 patients, 3 of whom had previously undergone unsuccessful TcMRgFUS thalamotomy via CT-based focusing. There were no adverse events related directly to the EF procedure. EF is feasible and appears safe during TcMRgFUS thalamotomy for essential tremor and improves on the trans-skull focal quality provided by existing CT-based focusing methods. © 2020 International Parkinson and Movement Disorder Society.

A Clinical System for Non-invasive Blood–Brain Barrier Opening Using a Neuronavigation-Guided Single-Element Focused Ultrasound Transducer

Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is currently being investigated in clinical trials. Here, we describe a portable clinical system with a therapeutic transducer suitable for humans, which eliminates the need for in-line magnetic resonance imaging (MRI) guidance. A neuronavigation-guided 0.25-MHz single-element FUS transducer was developed for non-invasive clinical BBB opening. Numerical simulations and experiments were performed to determine the characteristics of the FUS beam within a human skull. We also validated the feasibility of BBB opening obtained with this system in two non-human primates using U.S. Food and Drug Administration (FDA)-approved treatment parameters. Ultrasound propagation through a human skull fragment caused 44.4 ± 1% pressure attenuation at a normal incidence angle, while the focal size decreased by 3.3 ± 1.4% and 3.9 ± 1.8% along the lateral and axial dimension, respectively. Measured lateral and axial shifts were 0.5 ± 0.4 mm and 2.1 ± 1.1 mm, while simulated shifts were 0.1 ± 0.2 mm and 6.1 ± 2.4 mm, respectively. A 1.5-MHz passive cavitation detector transcranially detected cavitation signals of Definity microbubbles flowing through a vessel-mimicking phantom. T1-weighted MRI confirmed a 153 ± 5.5 mm3 BBB opening in two non-human primates at a mechanical index of 0.4, using Definity microbubbles at the FDA-approved dose for imaging applications, without edema or hemorrhage. In conclusion, we developed a portable system for non-invasive BBB opening in humans, which can be achieved at clinically relevant ultrasound exposures without the need for in-line MRI guidance. The proposed FUS system may accelerate the adoption of non-invasive FUS-mediated therapies due to its fast application, low cost and portability.