Passive Cavitation Imaging Research Articles

2D spatiotemporal passive cavitation imaging and evaluation during ultrasound thrombolysis based on diagnostic ultrasound platform

Acoustic cavitation plays a critical role in various biomedical applications. However, uncontrolled cavitation can lead to undesired damage to healthy tissues. Therefore, real-time monitoring and quantitative evaluation of cavitation dynamics is essential for understanding underlying mechanisms and optimizing ultrasound treatment efficiency and safety. The current research addressed the limitations of traditionally used cavitation detection methods by developing introduced an adaptive time-division multiplexing passive cavitation imaging (PCI) system integrated into a commercial diagnostic ultrasound platform. This new method combined real-time cavitation monitoring with B-mode imaging, allowing for simultaneous visualization of treatment progress and 2D quantitative evaluation of cavitation dosage within targeted area. An improved delay-and-sum (DAS) algorithm, optimized with a minimum variance (MV) beamformer, is utilized to minimize the side lobe effect and improve the axial resolution typically associated with PCI. In additional to visualize and quantitatively assess the cavitation activities generated under varied acoustic pressures and microbubble concentrations, this system was specifically applied to perform 2D cavitation evaluation for ultrasound thrombolysis mediated by different solutions, e.g., saline, nanodiamond (ND) and nitrogen-annealed nanodiamond (N-AND). This research aims to bridge the gap between laboratory-based research systems and real-time spatiotemporal cavitation evaluation demands in practical uses. Results indicate that this improved 2D cavitation monitoring and evaluation system could offer a useful tool for comprehensive evaluating cavitation-mediated effects (e.g., ultrasound thrombolysis), providing valuable insights into in-depth understanding of cavitation mechanisms and optimization of cavitation applications.

An improved scheme for passive cavitation imaging in high intensity focused ultrasound

Passive cavitation imaging (PCI) is an effective technique for monitoring high intensity focused ultrasound (HIFU) procedure due to the correlation between cavitation activities and the therapeutic effects. Nevertheless, current PCI techniques are unable to recognize noise signals from non-cavitation situations, and they fail to accurately visualize the highly dynamic cavitation activities due to the lack of a stable baseline reference. In this study, a deep learning-based cavitation detection network (CD-NET) was proposed to determine whether passively received channel signals originated from cavitation activities or were merely noises. Additionally, a cavitation intensity baseline was derived to better display the drastically time-varying cavitation activities. The CD-NET model was trained and validated with data collected from in-vitro and ex-vivo HIFU sonication experiments, and then tested by in-vivo rabbit experiments. Both CD-NET models, trained with data from the in-vitro agar phantoms and ex-vivo bovine liver tissues, successfully distinguished between cavitation and non-cavitation activities from the same study object, achieving accuracies as high as 99.7% and 99.5%, respectively. In addition, the models trained on in-vitro and ex-vivo datasets achieved accuracies of 88.1% and 91.4%, respectively, when detecting cavitation events from unseen in-vivo data. The results demonstrate that the improved PCI scheme, utilizing the CD-NET model and a data-derived cavitation baseline, is resistant to noise from non-cavitation situations and can depict the dynamic characteristics of cavitation more reliably. In conclusion, this study addressed two practical challenges in PCI techniques, allowing for better monitoring of cavitation-related HIFU sonication in clinical applications.

Histotripsy and Catheter-Directed Lytic: Efficacy in Highly Retracted Porcine Clots In Vitro

ObjectiveStandard treatment for deep vein thrombosis (DVT) involves catheter-directed anticoagulants or thrombolytics, but the chronic thrombi present in many DVT cases are often resistant to this therapy. Histotripsy has been found to be a promising adjuvant treatment, using the mechanical action of cavitating bubble clouds to enhance thrombolytic activity. The objective of this study was to determine if histotripsy enhanced recombinant tissue plasminogen activator (rt-PA) thrombolysis in highly retracted porcine clots in vitro in a flow model of occlusive DVT. MethodsHighly retracted porcine whole blood clots were treated for 1 h with either catheter-directed saline (negative control), rt-PA (lytic control), histotripsy, DEFINITY and histotripsy or the combination of rt-PA and histotripsy with or without DEFINITY. Five-cycle, 1.5 MHz histotripsy pulses with a peak negative pressure of 33.2 MPa and pulse repetition frequency of 40 Hz were applied along the clot. B-Mode and passive cavitation images were acquired during histotripsy insonation to monitor bubble activity. ResultsClots subjected to histotripsy with and without rt-PA exhibited greater thrombolytic efficacy than controls (7.0% flow recovery or lower), and histotripsy with rt-PA was more efficacious than histotripsy with saline (86.1 ± 10.2% compared with 61.7 ± 19.8% flow recovery). The addition of DEFINITY to histotripsy with or without rt-PA did not enhance either thrombolytic efficacy or cavitation dose. Cavitation dose generally did not correlate with thrombolytic efficacy. ConclusionEnhancement of thrombolytic efficacy was achieved using histotripsy, with and without catheter-directed rt-PA, in the presence of physiologic flow. This suggests these treatments may be effective as therapy for DVT.

Real-time assessment of focused ultrasound-induced bioeffects in elastic tissues

Highly elastic tissues have proven resistant to fractionation via focused ultrasound (fUS); however, our previous work in rat tendon has demonstrated a small window of parameters conducive to mild mechanical disruption. For therapeutic applications, there is a need to assess the extent of fUS-induced mechanical bioeffects in real time in order to avoid over- or under-treatment. Here, elastic collagen hydrogels (TeloCol®-10), as well as healthy and collagenase-soaked ex vivo bovine tendons, were exposed to fUS at 1.1–3.68 MHz (p + ≤ 127 MPa, p− ≤ 35 MPa) using 10-ms pulses repeated at 1 Hz. Cavitation signals were collected using simultaneous passive cavitation imaging (PCI) and passive cavitation detection (PCD) to monitor fUS treatment in real time. Preliminary data in polyacrylamide hydrogels and ex vivo bovine tendon show no consistent trends between simultaneous PCI and PCD signals; this is potentially due to different orientations of the receiving transducers, which we will further investigate. However, neither PCI nor PCD trends were consistently linked to a mechanical bioeffect. Therefore, we are exploring the addition of Doppler ultrasound to PCI/PCD to help link the fUS exposure to the desired bioeffect. [Work supported by NIHR01EB032860]

Active targeting of nanotherapeutics using power cavitation imaging with a linear array transducer

Power cavitation imaging (PCI) is an emerging strategy for monitoring blood–brain barrier (BBB) opening, enabling spatial discrimination of cavitation intensity through power Doppler-analogous processing of passive cavitation images. Single-element cavitation detectors, while beneficial in signal monitoring for cavitation controllers, provide limited spatial information, conferring the need for an image-guided approach to ensure accurate cavitation localization and regulation. This study aims to evaluate the capability of PCI to spatially correlate real-time acoustic cavitation emissions with mechanical bioeffects as a predictor of P-selectin-targeted nanocarrier delivery. Preliminary sonoporation experiments were performed in vitro with brain tissue derived mouse endothelial cells and 3 kDa tetramethylrhodamine (TMR)-dextran. A focused ultrasound transducer (0.5 MHz, 5000 cycles/pulse, 5 Hz PRF, 30 second treatment duration) was used to sonicate cells in small volume (25 μl) cell suspension. Homogenous distribution of TMR-dextran in the cytosol and nucleus was observed via fluorescence microscopy at lower pressures (7% ± 2% fluorescent cells), while higher pressures had no significant differences above control (3% ± 2% vs 1% nontreated) due to microbubble destruction. Future experiments will correlate sonoporation with P-selectin expression and validate a linear array PCI system against contrast-enhanced MRI as a guide for P-selectin-targeted nanocarrier delivery in mouse models of medulloblastoma.

3-D Passive Cavitation Imaging Using Adaptive Beamforming and Matrix Array Transducer With Random Apodization.

With the development of promising cavitation-based treatments, the interest in cavitation monitoring with passive acoustic mapping (PAM) is significantly increasing. While most of studies regarding PAM are performed in 2-D, 3-D imaging modalities are getting more attention relying on either custom-made or commercial matrix probes. Unless specific phased-arrays are used for a specific application, limitations due to probe apertures often results in poor performances of the 3-D mapping, due to the use of a delay-and-sum (DAS) classic beamformer, which results in strong artifacts and large main lobe sizes. In this article, 3D-PAM is achieved by performing adaptive beamforming in the frequency domain (FD) in 3-D, and using a random sparse apodization of a commercial matrix array driving only 256 elements among the 1024 available. It reduces the computation time and makes use of only one 256-channel research platform. Three beamformers have been implemented in 3-D and in the FD: the DAS beamformer, which corresponds to the beamformer used in previous 3D-PAM studies, the robust capon beamformer (RCB), an adaptive algorithm widely used in 2D-PAM for its high performances, and the MidWay (MW) beamformer, an adaptive algorithm with a computation complexity equivalent to the one of DAS. These algorithms are evaluated both in simulations and experiments with a harmonic source at different positions, and are also applied to real cavitation signals. The results show that, in the case of matrix arrays of small aperture such as generic commercial matrix probes, the DAS beamformer leads to large main lobe sizes, while adaptive beamformers largely improve the performances of the mapping. The low computation time and its parameter-free character make MW beamformer a good compromise for 3D-PAM applications. It thus appears that a random sparse apodization combined with adaptive beamforming is a good solution to achieve high-performance 3D-PAM with manageable devices.

An Inverse Method Using Cross-Spectral Matrix Fitting for Passive Cavitation Imaging.

High-intensity focused ultrasound (HIFU) can produce cavitation, which requires monitoring for specific applications such as sonoporation, targeted drug delivery, or histotripsy. Passive acoustic mapping has been proposed in the literature as a method for monitoring cavitation, but it lacks spatial resolution, primarily in the axial direction, due to the absence of a time reference. This is a common issue with passive imaging compared to standard pulse-echo ultrasound. In order to improve the axial resolution, we propose an adaptation of the cross spectral matrix fitting (CMF) method for passive cavitation imaging, which is based on the resolution of an inverse problem with different regularizations that promote sparsity in the reconstructed cavitation maps: Elastic Net (CMF-ElNet) and sparse Total Variation (CMF-spTV). The results from both simulated and experimental data are presented and compared to state-of-the-art approaches, such as the frequential delay-and-sum (DAS) and the frequential robust capon beamformer (RCB). We show the interest of the method for improving the axial resolution, with an axial full width half maximum (FWHM) divided by 3 and 5 compared to RCB and DAS, respectively. Moreover, CMF-based methods improve contrast-to-noise ratio (CNR) by more than 15 dB in experimental conditions compared to RCB. We also show the advantage of the sparse Total Variation (spTV) prior over Elastic Net (ElNet) when dealing with cloud-shaped cavitation sources, that can be assumed as sparse grouped sources.

Quantifying the Effect of Acoustic Parameters on Temporal and Spatial Cavitation Activity: Gauging Cavitation Dose.

Cavitation-enhanced delivery of therapeutic agents is under development for the treatment of cancer and neurodegenerative and cardiovascular diseases, including sonothrombolysis for deep vein thrombosis. The objective of this study was to quantify the spatial and temporal distribution of cavitation activity nucleated by Definity infused through the EKOS catheter over a range of acoustic parameters controlled by the EKOS endovascular system. Three insonation protocols were compared in an in vitro phantom mimicking venous flow to measure the effect of peak rarefactional pressure, pulse duration and pulse repetition frequency on cavitation activity energy, location and duration. Inertial and stable cavitation activity was quantified using passive cavitation imaging, and a metric of cavitation dose based on energy density was defined. For all three insonation protocols, cavitation was sustained for the entire 30min Definity infusion. The evolution of cavitation energy during each pulse duration was similar for all three protocols. For insonation protocols with higher peak rarefactional acoustic pressures, inertial and stable cavitation doses also increased. A complex relationship between the temporal behavior of cavitation energy within each pulse and the pulse repetition frequency affected the cavitation dose for the three insonation protocols. The relative predominance of stable or inertial cavitation dose varied according to insonation schemes. Passive cavitation images revealed the spatial distribution of cavitation activity. Our cavitation dose metric based on energy density enabled the impact of different acoustic parameters on cavitation activity to be measured. Depending on the type of cavitation to be promoted or suppressed, particular pulsing schemes could be employed in future studies, for example, to correlate cavitation dose with sonothrombolytic efficacy.

A Convolutional Neural Network for Beamforming and Image Reconstruction in Passive Cavitation Imaging.

Convolutional neural networks (CNNs), initially developed for image processing applications, have recently received significant attention within the field of medical ultrasound imaging. In this study, passive cavitation imaging/mapping (PCI/PAM), which is used to map cavitation sources based on the correlation of signals across an array of receivers, is evaluated. Traditional reconstruction techniques in PCI, such as delay-and-sum, yield high spatial resolution at the cost of a substantial computational time. This results from the resource-intensive process of determining sensor weights for individual pixels in these methodologies. Consequently, the use of conventional algorithms for image reconstruction does not meet the speed requirements that are essential for real-time monitoring. Here, we show that a three-dimensional (3D) convolutional network can learn the image reconstruction algorithm for a 16×16 element matrix probe with a receive frequency ranging from 256 kHz up to 1.0 MHz. The network was trained and evaluated using simulated data representing point sources, resulting in the successful reconstruction of volumetric images with high sensitivity, especially for single isolated sources (100% in the test set). As the number of simultaneous sources increased, the network's ability to detect weaker intensity sources diminished, although it always correctly identified the main lobe. Notably, however, network inference was remarkably fast, completing the task in approximately 178 s for a dataset comprising 650 frames of 413 volume images with signal duration of 20μs. This processing speed is roughly thirty times faster than a parallelized implementation of the traditional time exposure acoustics algorithm on the same GPU device. This would open a new door for PCI application in the real-time monitoring of ultrasound ablation.

Developing a focused ultrasound treatment for tendinopathies in a large animal model

Current treatments for tendinopathies produce mixed success rates, with 0-84% of patients showing improvement. Our prior work in rats suggests mild microdamage induced by focused ultrasound (fUS) may perform better than traditional treatments for tendinopathies, like dry needling. Here, we work to scale our work in rats to larger animal models and develop treatment monitoring. Ex vivo bovine digital flexor tendons were obtained and injected with collagenase to induce chronic tendinopathy. One day later, tendons were treated with focused ultrasound at 1.1–3.68 MHz, with 1–10ms pulses at pressures up to p + = 127 MPa/p− = 35 MPa repeated at 0.2–1 Hz for up to 20 min. Treatments were monitored with passive cavitation detection (PCD; Sonic Concepts Y-107) and Philips/ATL L7-4 controlled by the Verasonics research ultrasound system in passive cavitation imaging (PCI) mode. Samples were collected for histological analysis. Preliminary results suggest that lower pulse repetition frequencies produce mild mechanical microdamage with no evidence of thermal necrosis. PCI and PCD results show no consistent trends to indicate the intended mechanical microdamage bioeffect has been achieved. Work is continuing to determine the treatment parameters that produce the intended bioeffects in the smallest time and to develop a means to monitor treatment progress. [Work supported by NIHR01EB032860.]

Interdependence of Tissue Temperature, Cavitation, and Displacement Imaging During Focused Ultrasound Nerve Sonication.

Focused ultrasound (FUS) peripheral neuromodulation has been linked to nerve displacement caused by the acoustic radiation force; however, the roles of cavitation and temperature accumulation on nerve modulation are less clear, as are the relationships between these three mechanisms of action. Temperature directly changes tissue stiffness and viscosity. Viscoelastic properties have been shown to affect cavitation thresholds in both theoretical and ex vivo models, but the direct effect of temperature on cavitation has not been investigated in vivo. Here, cavitation and tissue displacement were simultaneously mapped in response to baseline tissue temperatures of either 30 °C or 38 °C during sciatic nerve sonication in mice. In each mouse, the sciatic nerve was repeatedly sonicated at 1.1-MHz, 4-MPa peak-negative pressure, 5-ms pulse duration, and either 15- or 30-Hz pulse repetition frequency (PRF) for 10 s at each tissue temperature. Cavitation increased by 1.8-4.5 dB at a tissue temperature of 38 °C compared to 30 °C, as measured both by passive cavitation images and cavitation doses. Tissue displacement also increased by 1.3- [Formula: see text] at baseline temperatures of 38 °C compared to 30 °C. Histological findings indicated small increases in red blood cell extravasation in the 38 °C baseline temperature condition compared to 30 °C at both PRFs. A strong positive correlation was found between the inertial cavitation dose and displacement imaging noise, indicating the potential ability of displacement imaging to simultaneously detect inertial cavitation in vivo. Overall, tissue temperature was found to modulate both in vivo cavitation and tissue displacement, and thus, both tissue temperature and cavitation can be monitored during FUS to ensure both safety and efficiency.

Passive Cavitation Imaging Artifact Reduction Using Data-Adaptive Spatial Filtering.

Passive cavitation imaging (PCI) with a clinical diagnostic array results in poor axial localization of bubble activity due to the size of the point spread function (PSF). The objective of this study was to determine if data-adaptive spatial filtering improved PCI beamforming performance relative to standard frequency-domain delay, sum, and integrate (DSI) or robust Capon beamforming (RCB). The overall goal was to improve source localization and image quality without sacrificing computation time. Spatial filtering was achieved by applying a pixel-based mask to DSI- or RCB-beamformed images. The masks were derived from DSI, RCB, or phase or amplitude coherence factors (ACFs) using both receiver operating characteristic (ROC) and precision-recall (PR) curve analyses. Spatially filtered passive cavitation images were formed from cavitation emissions based on two simulated sources densities and four source distribution patterns mimicking cavitation emissions induced by an EkoSonic catheter. Beamforming performance was assessed via binary classifier metrics. The difference in sensitivity, specificity, and area under the ROC curve (AUROC) differed by no more than 11% across all algorithms for both source densities and all source patterns. The computational time required for each of the three spatially filtered DSIs was two orders of magnitude less than that required for time-domain RCB and thus this data-adaptive spatial filtering strategy for PCI beamforming is preferable given the similar binary classification performance.

Initiating and imaging cavitation from infused echo contrast agents through the EkoSonic catheter

Ultrasound-enhanced delivery of therapeutic-loaded echogenic liposomes is under development for vascular applications using the EkoSonic Endovascular System. In this study, fibrin-targeted echogenic liposomes loaded with an anti-inflammatory agent were characterized before and after infusion through an EkoSonic catheter. Cavitation activity was nucleated by Definity or fibrin-targeted, drug-loaded echogenic liposomes infused and insonified with EkoSonic catheters. Passive cavitation imaging was used to quantify and map bubble activity in a flow phantom mimicking porcine arterial flow. Cavitation was sustained during 3-min infusions of Definity or echogenic liposomes along the distal 6 cm treatment zone of the catheter. Though the EkoSonic catheter was not designed specifically for cavitation nucleation, infusion of drug-loaded echogenic liposomes can be employed to trigger and sustain bubble activity for enhanced intravascular drug delivery.

Investigating the change in point spread function and resolution of random apodization passive cavitation images

Passive cavitation imaging is an important technique in measuring cavitation dynamics, localizing concomitant bioeffects, and guiding various ultrasound therapies. The canonical algorithm for passive cavitation imaging operates via a delay, sum, and integrate method. With standard diagnostic arrays, this method yields poor axial resolution. We hypothesized that using a random apodization, minimum projection compounding technique could overcome this limitation. The random apodization approach randomly selected only half of the elements to be included in the delay, sum, and integrate algorithm to form a PCI. This process was repeated 30 times using the same data set but a different random subset of half the elements to create 30 images. The final image was obtained via a minimum intensity projection across the 30 images. The improvement of image quality can be tracked by comparing the point spread function (PSF), and the distance at which two cavitation sources can still be resolved, relative to when using the standard algorithm. The PSF reduced by 86% ± 9% when the random apodization was applied. Lateral and axial resolution exhibited qualitative changes associated with a lower PSF, but no quantitative change in resolution, based on the Rayleigh criteria, was observed.

Contribution of bubble activity to the efficacy of histotripsy and catheter-directed recombinant tissue plasminogen activator for treatment of porcine thrombi in vitro

Histotripsy has been shown to be a promising adjuvant treatment for deep vein thrombosis (DVT), using the mechanical action of bubble clouds to enhance thrombolytic activity and reduce the risk of complications. The objective of this study was to compare the effects of histotripsy with and without recombinant tissue-plasminogen activator, rt-PA in a physiologic, in vitro model mimicking porcine DVT. Highly retracted porcine whole blood clots were treated for 1 h with catheter-directed infusions of either saline or rt-PA [0.04 mg/ml] at 25 ml/h, either with or without histotripsy exposure. Five-cycle, 1.5 MHz histotripsy pulses with a peak negative pressure of 32 MPa and pulse repetition frequency of 40 Hz were applied along the catheter at 0.3 mm/s and repeated 1 mm on either side. This application pattern was repeated 6 times, totaling approximately 120 to 144 K pulses per clot. B-mode and passive cavitation images were acquired every 10pulses. The combination of rt-PA and histotripsy was more efficacious for recanalization than saline with histotripsy, saline, or rt-PA alone. Histotripsy exposure, but not rt-PA, improved mass loss (p < 0.01). These in vitro data support our hypothesis that the mechanical action of histotripsy-induced bubble clouds enhances catheter-directed thrombolytic.

Development of an optically transparent, tendon-mimicking hydrogel for histotripsy

Collagenous, anisotropic tissues such as tendon are resilient to liquefaction by histotripsy, despite verification of cavitation activity using B-mode imaging. In previous published work, dehydrated fibrin gels were shown to mimic tendon bubble dynamics but are limited in thickness due to high opacity. Here, we aim to fabricate a thicker, more optically transparent hydrogel possessing similar cavitation dynamics to tendon. Highly transparent collagen hydrogels (TeloCol®, 10 mg/mL) were fabricated, and axial sound speeds were measured to determine anisotropy. Hydrogels were then exposed to 1.5-MHz focused ultrasound with 10-ms pulses at 1-Hz for 60 s with p + =127 MPa, p− = 35 MPa. Cavitation activity was monitored with high-speed photography and passive cavitation imaging using a Philips/ATL L7-4 transducer and Vantage® ultrasound system. Despite exhibiting low degrees of anisotropy like other non-dehydrated gels (<1.2), peak cavitation energy was >20% lower than soft-tissue mimicking polyacrylamide. Additionally, both resilience to fractionation and transparency were notably improved compared to previously tested PureCol® collagen formulations. Different levels of collagen dehydration will be explored to further increase resilience to liquefaction and assess the role of water content in histotripsy fractionation. [Work supported by NIH R01EB032860.]

Histotripsy Bubble Dynamics in Elastic, Anisotropic Tissue-Mimicking Phantoms.

Elastic, anisotropic tissue such as tendon has proven resistant to mechanical fractionation by histotripsy, a subset of focused ultrasound that uses the creation, oscillation and collapse of cavitation bubbles to fractionate tissue. Our objective was to fabricate an optically transparent hydrogel that mimics tendon for evaluation of histotripsy bubble dynamics. Ex vivo bovine deep digital flexor tendons were obtained (n=4), and varying formulations of polyacrylamide (PA), collagen and fibrin hydrogels (n=3 each) were fabricated. Axial sound speeds were measured at 1 MHz for calculation of anisotropy. All samples were treated with a 1.5-MHz focused ultrasound transducer with 10-ms pulses repeated at 1 Hz (p+=127 MPa, p-=35 MPa); treatments were monitored with passive cavitation imaging and high-speed photography. Dehydrated fibrin gels were found to be the most similar to tendon in cavitation emission energy (fibrin=0.69 ± 0.24, tendon=0.64 ± 0.19 [× 1010 V2]) and anisotropy (fibrin=3.16 ± 1.12, tendon=19.4). Bubble cloud area in dehydrated fibrin (0.79 ± 0.14 mm2) was significantly smaller than most other tested hydrogels. Finally, anisotropy was found to have moderately strong linear relationships with cavitation energy and bubble cloud size (r=-0.65 and -0.80, respectively). Dehydrated fibrin shows potential as a repeatable, transparent, tissue-mimicking hydrogel for evaluation of histotripsy bubble dynamics in elastic, anisotropic tissues.

Comparison of passive beamformers for isolating cavitation activity originating in the spinal canal

Focused ultrasound application to the spinal cord, through the intact spine, is confounded by the presence of substantial prefocal cavitation, in the posterior soft tissue and musculature. When constructing cavitation images to localize and control intracanal cavitation, the prefocal cavitation zones dwarf the signals from the canal, destructing the localization ability of the imaging inside the sensitive cord tissue—even when conventional phase and amplitude corrections are applied. In this study, multiple beamforming formulations are investigated to mitigate the influence of prefocal cavitation on transvertebral cavitation imaging, while preserving the localization ability in the canal. The performance of a standard delay-and-sum-integrate beamformer (DAS) is compared to delay-multiply-and-sum-integrate beamformer (DMAS), and the DMAS algorithm is tested with a paired multiplicative compounding method (pDMAS) that leverages the dual aperture approach required for transvertebral focused ultrasound sonications. The focal point spread function of the beamformers in passive cavitation images (tint = 7 μs) were 7.9 × 2.2 × 1.3 mm (DAS), 6.9 × 1.7 × 1.1 (DMAS), and 6.5 × 2.9 × 1.7 mm (pDMAS) at 800 kHz. These beamforming approaches are evaluated for localization ability and clinical feasibility through cavitation imaging of prefocal and focal sources with in silico models and ex vivo human vertebrae.

Preliminary investigations on cavitation effects in the crystalline lens

Presbyopia is the age-related stiffening of the crystalline lens, reducing near vision. One of the main mechanisms of this lens stiffening is the formation of disulfide bonds. We propose ultrasonic cavitation to interact with the lens structure, disrupt disulfide bonds and restore flexibility. Here, we present early results on the feasibility of the technique. Cavitation was nucleated inside the porcine lenses using confocal transducers and signals emitted in the focal area were acquired using an imaging array and reconstructed using frequency-domain passive cavitation imaging. Peak negative pressure of 23MPa for 20-μs pulses at 1.1 MHz provided a clear chance of nucleating cavitation with our system. Exposures were performed during 10 seconds of cavitation at a PRF of 250 Hz. Cavitation clouds were clearly visible in B-mode images for both 6-months old and 3-years old porcine eyes. To provide initial safety data, the absence of cataract was confirmed on transparency images. Histology revealed no damage to the lens structure. A gel phantom with a disulfide bond-dependent hardening is proposed to investigate the potential for cavitation to disrupt the disulfide bonds.

Using a novel rapid alternating steering angles pulse sequence to evaluate the impact of theranostic ultrasound-mediated ultra-short pulse length on blood-brain barrier opening volume and closure, cavitation mapping, drug delivery feasibility, and safety.

Background: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is a noninvasive, safe and reversible technique for targeted drug delivery to the brain. Most preclinical systems developed to perform and monitor BBB opening are comprised of a separate geometrically focused transducer and passive cavitation detector (PCD) or imaging array. This study builds upon previous work from our group developing a single imaging phased array configuration for simultaneous BBB opening and monitoring called theranostic ultrasound (ThUS), leveraging ultra-short pulse lengths (USPLs) and a novel rapid alternating steering angles (RASTA) pulse sequence design for simultaneous bilateral sonications with target-specific USPL. The RASTA sequence was further employed to evaluate the impact of USPL on BBB opening volume, power cavitation imaging (PCI) pixel intensity, BBB closing timeline, drug delivery efficiency, and safety. Methods: A P4-1 phased array transducer driven by a Verasonics Vantage ultrasound system was operated using a custom script to run the RASTA sequence which consisted of interleaved steered, focused transmits and passive imaging. Contrast-enhanced magnetic resonance imaging (MRI) confirmed initial opening volume and closure of the BBB by longitudinal imaging through 72 hours post-BBB opening. For drug delivery experiments, mice were systemically administered a 70 kDa fluorescent dextran or adeno-associated virus serotype 9 (AAV9) for fluorescence microscopy or enzyme-linked immunosorbent assay (ELISA) to evaluate ThUS-mediated molecular therapeutic delivery. Additional brain sections were also H&E-stained to evaluate histological damage, and IBA1- and GFAP-stained to elucidate the effects of ThUS-mediated BBB opening on stimulation of key cell types involved in the neuro-immune response, microglia and astrocytes. Results: The ThUS RASTA sequence induced distinct BBB openings simultaneously in the same mouse where volume, PCI pixel intensity, level of dextran delivery, and AAV reporter transgene expression were correlated with brain hemisphere-specific USPL, consistent with statistically significant differences between 1.5, 5, and 10-cycle USPL groups. BBB closure after ThUS required 2-48 hours depending on USPL. The potential for acute damage and neuro-immune activation increased with USPL, but such observable damage was nearly reversed 96 hours post-ThUS. Conclusion: ThUS is a versatile single-array technique which exhibits the potential for investigating a variety of non-invasive therapeutic delivery applications in the brain.