Bubble Activity Research Articles

Characterisation of Gas Vesicles as Cavitation Nuclei for Ultrasound Therapy using Passive Acoustic Mapping.

Genetically encodable gas filled particles known as gas vesicles (GVs) have shown promise as a biomolecular contrast agent for ultrasound imaging and have the potential to be used as cavitation nuclei for ultrasound therapy. In this study, we used passive acoustic mapping techniques to characterize GV-seeded cavitation, utilizing 0.5 and 1.6 MHz ultrasound over peak rarefactional pressures ranging from 100 to 2200 kPa. We found that GVs produce cavitation for the duration of the first applied pulse, up to at least 5000 cycles, but that bubble activity diminishes rapidly over subsequent pulses. At 0.5 MHz the frequency content of cavitation emissions was predominantly broadband in nature, whilst at 1.6 MHz narrowband content at harmonics of the main excitation frequency dominated. Simulations and high-speed camera imaging suggest that the received cavitation emissions come not from individual GVs but instead from the coalescence of GV-released gas into larger bubbles during the applied ultrasound pulse. These results will aid the future development of GVs as cavitation nuclei in ultrasound therapy.

Numbering-up and stability strategies of bubbles in yield stress fluids in asymmetric parallelized microchannel

Preparation of foams within microchannels is a clean and capable of precisely controlled synthesis. In this work, high throughput production of bubbles in Carbopol gels (0.05 wt%, 0.1 wt%, 0.2 wt%) in asymmetric parallel channels is investigated. Bubbles in Carbopol gels are strongly unstable, and the asymmetry of the microchannel makes bubble instability more pronounced. A “slug-slug” flow pattern is observed for only 0.05 wt% Carbopol and microchannels with back cavities, and the bubble train is highly unstable. The strategy proposed in this article solves the challenge of numbering-up of bubbles produced in YSFs by strategically reducing the gas pressure, and the stability of bubble train and activation rate of microchannel are improved, which is of great engineering significance for the high-throughput production of high-quality foam materials.

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.

Quantifying the chemical activity of cavitation bubbles in a cluster.

Acoustic cavitation bubbles drive chemical processes through their dynamic lifecycle in liquids. These bubbles are abundant within sonoreactors, where their behavior becomes complex within clusters. This study quantifies their chemical effects within well-defined clusters using a new laser-based method. We focus a laser beam into water, inducing a breakdown that generates a single cavitation bubble. This bubble undergoes multiple collapses, releasing several shockwaves. These shockwaves propagate into the surrounding medium, leading to the formation of secondary bubbles near a reflector, separated from the input laser beam. We evaluate the chemical activity of these bubble clusters of various sizes by KI dosimetry, and to gain insights into their dynamics, we employ high-speed imaging. Hydrophone measurements show that conversion from focused shockwave energy to chemical reactions increases to a maximum of 16.5%. Additional increases in shockwave energy result in denser bubble clusters and a slightly decreased conversion rate, falling to 14.9%, highlighting the key role of bubble dynamics in the transformation of mechanical to chemical energy and as a result in the efficiency of the sonoreactors. The size and frequency of bubble collapses influence the cluster's chemical reactivity. We introduce a correlation for predicting the conversion rate of cluster energy to chemical energy, based on the cluster's energy density. The maximum conversion rate occurs at a cluster energy density of 2500 J/L, linked to a cluster with an average bubble diameter of 91 m, a bubble density of 3500 bubbles/ml, and a bubble-to-bubble distance ratio of 8.

Subharmonics are not the full story—Searching for acoustic signatures of cavitation and other fantastic beasts

Cavitation induced bio-effects are being exploiting in a wide range of applications from physiotherapy to brain surgery. The acoustic emissions generated by bubble activity are extremely useful in enabling real time treatment monitoring. The relationship between the spectral characteristics of these emissions and bubble dynamics is, however, complex. Here we report data from experiments with simultaneous ultra-high-speed optical imaging and passive acoustic mapping of individual microbubbles exposed to 50 cycles of ultrasound at 0.5 MHz with varying peak negative pressures. The spectral content of the acoustic emissions from individual microbubble was compared to the bubble dynamics observed by the imaging. As expected from prior work, both the number of discrete harmonics and broadband content in the emissions increased with increasing amplitude of bubble oscillation. There was no clear correlation, however, between the presence of ultra and sub-harmonic components and bubble behaviour. Indeed, these components were frequently absent. Moreover, phenomena such as microjetting, fragmentation and coalescence, that could produce very different effects in tissue, were indistinguishable acoustically. The results thus indicate that the definition of cavitation thresholds or doses should be very carefully considered depending on the therapeutic effect (or avoidance of unwanted bioeffects) required for a particular application.

Size and pressure dependent activity of lipid coated bubbles and finite element simulation of the propgation of focused ultrasound through bubbly media

Use of nanodroplets as alternative to bubbles is limited to high pressure applications due to their high vaporization threshold (>1 MPa). For low pressure applications (e.g <800 kPa) and stable bubble activity, size isolated micron or sub-micron bubbles may be used to tackle the pre-focal bubble activity and attenuation. Numerical simulations of the Marmottant model were ran for bubble sizes of 0.45, 1, 2, and 4 μm in response to 1 MHz ultrasound with pressures between 10 and 700 kPa. All agents were volume matched to 20 μl/kg of Definity considering inter-bubble interactions. The pressure-dependent attenuation and the total acoustic power (TAP) were calculated for each population. Finite element simulations (FEMS) were run by taking account the pressure dependent attenuation and sound speed. Using size isolated bubbles an experimental passive cavitation case study was performed for the same exposure conditions and sizes. Numerical results show that TAP and attenuation of the bubbles are size dependent. Bigger bubbles have stronger responses at lower pressures. However, smaller agents exhibit a size-dependent pressure threshold behavior (PT) above which their attenuation and TAP grow stronger than their bigger counterparts in qualitative agreement with experiments. FEMS show that the PT of oscillations may be used to reduce pre-focal attenuation for ultrasound propagation with minimal loss.

Focused ultrasound pulse repetition frequency impacts bubble activity and tracer delivery during blood-brain barrier opening

The impact of pulse repetition frequency (PRF) on microbubble activity and blood-brain barrier (BBB) opening, for a fixed total number of pulses, is unclear. We studied bubble response to a range of PRFs (0.125, 0.25, 0.5, 1, and 2 Hz) by monitoring bubble emissions during focused ultrasound (FUS) sonications of the rat brain (274.3 kHz). When a location was treated with a test PRF and a control PRF of 1 Hz, at the same pressure, the change in the harmonic amplitude compared to the control decreased with increasing PRF, with a median change of 73.8% at 0.125 Hz and −38.3% at 2 Hz. Significant changes were not observed with repeated sonications at the same PRF. Furthermore, between PRFs of 0.25 and 1 Hz, no difference was observed in the threshold for broadband emissions, which are linked to the potential for tissue damage. Fluorescence imaging was used to estimate the concentration of Trypan Blue (TB) dye following a fixed-pressure 75-pulse exposure for PRFs of 1 and 0.25 Hz in rats. A 0.25 Hz PRF led to a 68.2% increase in the mean concentration measured at the target, with a 53.9% increase in the mean harmonic sum compared with a 1 Hz PRF. Finally, a harmonic emissions-based controller at a PRF of 0.25 Hz yielded similar TB delivery, with fewer instances of petechiae observed through histology, compared to the same controller at 1 Hz. These results may be adapted to improve the clinical safety margin of FUS-mediated BBB opening and to improve the sensitivity to detecting small harmonic signals from cavitating microbubbles.

Cavitation cloud formation and surface damage of a model stone in a high-intensity focused ultrasound field

This work investigates the fundamental role of cavitation bubble clouds in stone comminution by focused ultrasound. The fragmentation of stones by ultrasound has applications in medical lithotripsy for the comminution of kidney stones or gall stones, where their fragmentation is believed to result from the high acoustic wave energy as well as the formation of cavitation. Cavitation is known to contribute to erosion and to cause damage away from the target, yet the exact contribution and mechanisms of cavitation remain currently unclear. Based on in situ experimental observations, post-exposure microtomography and acoustic simulations, the present work sheds light on the fundamental role of cavitation bubbles in the stone surface fragmentation by correlating the detected damage to the observed bubble activity. Our results show that not all clouds erode the stone, but only those located in preferential nucleation sites whose locations are herein examined. Furthermore, quantitative characterizations of the bubble clouds and their trajectories within the ultrasonic field are discussed. These include experiments with and without the presence of a model stone in the acoustic path length. Finally, the optimal stone-to-source distance maximizing the cavitation-induced surface damage area has been determined. Assuming the pressure magnitude within the focal region to exceed the cavitation pressure threshold, this location does not correspond to the acoustic focus, where the pressure is maximal, but rather to the region where the acoustic beam and thereby the acoustic cavitation activity near the stone surface is the widest.

Enhancement of Boiling Histotripsy by Steering the Focus Axially During the Pulse Delivery.

Boiling histotripsy (BH) is a pulsed high-intensity focused ultrasound (HIFU) method relying on the generation of high-amplitude shocks at the focus, localized enhanced shock-wave heating, and bubble activity driven by shocks to induce tissue liquefaction. BH uses sequences of 1-20 ms long pulses with shock fronts of over 60 MPa amplitude, initiates boiling at the focus of the HIFU transducer within each pulse, and the remainder shocks of the pulse then interact with the boiling vapor cavities. One effect of this interaction is the creation of a prefocal bubble cloud due to reflection of shocks from the initially generated mm-sized cavities: the shocks are inverted when reflected from a pressure-release cavity wall resulting in sufficient negative pressure to reach intrinsic cavitation threshold in front of the cavity. Secondary clouds then form due to shock-wave scattering from the first one. Formation of such prefocal bubble clouds has been known as one of the mechanisms of tissue liquefaction in BH. Here, a methodology is proposed to enlarge the axial dimension of this bubble cloud by steering the HIFU focus toward the transducer after the initiation of boiling until the end of each BH pulse and thus to accelerate treatment. A BH system comprising a 1.5 MHz 256-element phased array connected to a Verasonics V1 system was used. High-speed photography of BH sonications in transparent gels was performed to observe the extension of the bubble cloud resulting from shock reflections and scattering. Volumetric BH lesions were then generated in ex vivo tissue using the proposed approach. Results showed up to almost threefold increase of the tissue ablation rate with axial focus steering during the BH pulse delivery compared to standard BH.

In-situ gas flow separation between biochar and the heat carrier in a circulating fluidized bed reactor for biomass pyrolysis

The circulating fluidized bed (CFB) reactor is extensively utilized in biomass fast pyrolysis, which typically employs a heat carrier as a heat transfer medium. The regeneration of the heat carrier relies on carbon combustion. However, direct combustion of carbon for heating purposes results in ash accumulation, leading to decreased yields of bio-oil and biochar. To overcome the limitations of conventional techniques and address the challenges associated with separating biochar from the heat carrier, a novel in-situ gas flow bed separator was designed. This separator enables continuous, rapid, and highly efficient separation of biochar and the heat carrier. The impact of various operational conditions on separation efficiency was investigated, and the operational range that yields effective and efficient separation was obtained. The entrainment effect of bubble wakes on particles and the mechanism of binary particles distribution in the bubble hole in the gas flow bed were investigated by numerical simulation and a high-speed digital camera. The results show that bubble activity, as well as the density and size disparities of binary particles, significantly influence the separation process. When the mass ratio of binary particles and U/Umf (the ratio of fluidization velocity to the minimum fluidization velocity) were 30/1 and 1.67, the separation efficiency of carbon and the heat carrier could reach 99%. This innovative technology holds tremendous potential for substantially enhancing product yields in CFB systems, thereby significantly increasing their competitiveness in fast pyrolysis applications.

In silico assessment of histotripsy-induced changes in catheter-directed thrombolytic delivery.

Introduction: For venous thrombosis patients, catheter-directed thrombolytic therapy is the standard-of-care to recanalize the occluded vessel. Limitations with thrombolytic drugs make the development of adjuvant treatments an active area of research. One potential adjuvant is histotripsy, a focused ultrasound therapy that lyses red blood cells within thrombus via the spontaneous generation of bubbles. Histotripsy has also been shown to improve the efficacy of thrombolytic drugs, though the precise mechanism of enhancement has not been elucidated. In this study, in silico calculations were performed to determine the contribution of histotripsy-induced changes in thrombus diffusivity to alter catheter-directed therapy. Methods: An established and validated Monte Carlo calculation was used to predict the extent of histotripsy bubble activity. The distribution of thrombolytic drug was computed with a finite-difference time domain (FDTD) solution of the perfusion-diffusion equation. The FDTD calculation included changes in thrombus diffusivity based on outcomes of the Monte Carlo calculation. Fibrin degradation was determined using the known reaction rate of thrombolytic drug. Results: In the absence of histotripsy, thrombolytic delivery was restricted in close proximity to the catheter. Thrombolytic perfused throughout the focal region for calculations that included the effects of histotripsy, resulting in an increased degree of fibrinolysis. Discussion: These results were consistent with the outcomes of in vitro studies, suggesting histotripsy-induced changes in the thrombus diffusivity are a primary mechanism for enhancement of thrombolytic drugs.

Histotripsy induces apoptosis and reduces hypoxia in a neuroblastoma xenograft model

Background Neuroblastoma (NB) is the most common extracranial solid tumor of childhood, and high-risk disease is resistant to intensive treatment. Histotripsy is a focused ultrasound therapy under development for tissue ablation via bubble activity. The goal of this study was to assess outcomes of histotripsy ablation in a xenograft model of high-risk NB. Methods Female NCr nude mice received NGP-luciferase cells intrarenally. Under ultrasound image guidance, histotripsy pulses were applied over a distance of 4–6 mm within the tumors. Bioluminescence indicative of tumor viability was quantified before, immediately after, and 24 h after histotripsy exposure. Tumors were immunostained to assess apoptosis (TUNEL), endothelium (endomucin), pericytes (αSMA), hypoxia (pimonidazole), vascular endothelial growth factor A (VEGFA), and platelet-derived growth factor-B (PDGF-B). The apoptotic cytokine TNFα and its downstream effector cleaved caspase-3 (c-casp-3) were assessed with SDS-PAGE. Results Histotripsy induced a 50% reduction in bioluminescence compared to untreated controls, with an absence of nuclei in the treatment core surrounded by a dense rim of TUNEL-positive cells. Tumor regions not targeted by histotripsy also showed an increase in TUNEL staining density. Increased apoptosis in histotripsy samples was consistent with increases in TNFα and c-casp-3 relative to controls. Treated tumors exhibited a decrease in hypoxia, VEGF, PDGF-B, and pericyte coverage of vasculature compared to control samples. Further, increases in vasodilation were found in histotripsy-treated specimens. Conclusions In addition to ablative effects, histotripsy was found to drive tumor apoptosis through intrinsic pathways, altering blood vessel architecture, and reducing hypoxia.

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.

Multi-parametric observations of intermittent hydrothermal water discharge in West Crater of Iwo-Yama volcano, Kirishima Volcanic Complex, Japan

From April to July 2021, West Crater at Iwo-Yama, Kirishima Volcanic Complex, Japan, was repeatedly filled with hydrothermal water and subsequently evacuated. The overall cycle lasted 14–70 h, and the course of a single cycle followed this sequence of phases: (i) steam effusion disappeared 20–40 min before hydrothermal water discharge; (ii) hydrothermal water discharge occurred, generating a hydrothermal water pool; (iii) steam effusion resumed and gradually increased; and (iv) drain-back (evacuation) of the hydrothermal water occurred 1–1.5 h before the onset of the next hydrothermal water discharge. We used multi-parametric observations (optical camera, thermometer, electric self-potential (SP) electrodes, seismometer, acoustic sensor, and tiltmeter) to investigate the cause of the cyclic hydrothermal water discharge. A change in SP data occurred approximately 2 h before the onset of hydrothermal water discharge. However, the change in SP was small when hydrothermal water discharge did not occur. The temporal change in SP is inferred to have been caused by groundwater flow through the region below West Crater, implying that groundwater flow was occurring 2 h before hydrothermal water discharge. The polarity of SP change suggests that groundwater flowed toward the region underlying the vents. Seismic signals in the frequency range of < 20 Hz decreased 15–45 min after the onset of change in SP. This seismic signal pattern is inferred to have been caused by bubble activity in boiling fluid. We interpret that the inflow of cold groundwater inhibited boiling activity in the conduit, which in turn caused the cessation of both steam effusion and seismic activity. SP data suggest that the inflow of cold groundwater gradually decreased before hydrothermal water discharge. Pressurization sufficient to force the water in the upper part of the conduit to ascend could have built up in the lower part of the conduit owing to a decrease in the input of groundwater into the upper part of the conduit and the continuing supply of steam bubbles and hot water. This increase in pressure finally led to hydrothermal water discharge at the surface. We suggest that the inflow of cold groundwater into the geyser conduit was the key control on the occurrence and cyclicity of hydrothermal water discharge in West Crater at Iwo-Yama.Graphical

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.

An in silico model of clot degradation under the action of histotripsy and thrombolytic drugs

For venous thrombosis patients, catheter-directed thrombolytic drugs remain the standard-of-care to restore vascular flow. Improved outcomes are observed when thrombolytic drugs are combined with histotripsy, a focused ultrasound therapy that breaks down tissue via bubble activity. To gain insight into the mechanisms of this combination approach, an in silico model of bubble/thrombolytic/clot interaction was developed. A Monte Carlo-like simulation was used to gauge the extent of histotripsy ablation. The local tissue properties that dictate bubble nucleation were adjusted based on annotated histological sections of venous thrombi. The distribution of thrombolytic drug within the clot was computed using a finite-difference time domain solution of the perfusion-diffusion equation. Fibrin degradation was computed using the known reaction rate of thrombolytic drug. Predictions of ablation were dependent on the clot subgroup, with a reduction in the extend of ablation as the concentration of fibrin increased. Thrombolytic drug was more uniformly distributed throughout the clot when the effects of histotripsy ablation were consistent, consistent with recent in vitro measurements. Overall, the findings here indicate histotripsy primarily enhances the activity of thrombolytic drugs is via debulking red blood cells within a clot.

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 &amp;lt; 0.01). These in vitro data support our hypothesis that the mechanical action of histotripsy-induced bubble clouds enhances catheter-directed thrombolytic.

Monitoring of Atmospheric Corrosion of Aircraft Aluminum Alloy AA2024 by Acoustic Emission Measurements

Atmospheric corrosion of aluminum aircraft structures occurs due to a variety of reasons. A typical phenomenon leading to corrosion during aircraft operation is the deliquescence of salt contaminants due to changes in the ambient relative humidity (RH). Currently, the corrosion of aircraft is controlled through scheduled inspections. In contrast, the present contribution aims to continuously monitor atmospheric corrosion using the acoustic emission (AE) method, which could lead to a structural health monitoring application for aircraft. The AE method is frequently used for corrosion detection under immersion-like conditions or for corrosion where stress-induced cracking is involved. However, the applicability of the AE method to the detection of atmospheric corrosion in unloaded aluminum structures has not yet been demonstrated. To address this issue, the present investigation uses small droplets of a sodium chloride solution to induce atmospheric corrosion of uncladded aluminum alloy AA2024-T351. The operating conditions of an aircraft are simulated by controlled variations in the RH. The AE signals are measured while the corrosion site is visually observed through video recordings. A clear correlation between the formation and growth of pits, the AE and hydrogen bubble activity, and the RH is found. Thus, the findings demonstrate the applicability of the AE method to the monitoring of the atmospheric corrosion of aluminum aircraft structures using current measurement equipment. Numerous potential effects that can affect the measurable AE signals are discussed. Among these, bubble activity is considered to cause the most emissions.

Assessment of bubble activity generated by histotripsy combined with echogenic liposomes

Objective. Histotripsy is a form of focused ultrasound therapy that uses the mechanical activity of bubbles to ablate tissue. While histotripsy alone degrades the cellular content of tissue, recent studies have demonstrated it effectively disrupts the extracellular structure of pathologic conditions such as venous thrombosis when combined with a thrombolytic drug. Rather than relying on standard administration methods, associating thrombolytic drugs with an ultrasound-triggered echogenic liposome vesicle will enable targeted, systemic drug delivery. To date, histotripsy has primarily relied on nano-nuclei inherent to the medium for bubble cloud generation, and microbubbles associated with echogenic liposomes may alter the histotripsy bubble dynamics. The objective of this work was to investigate the interaction of histotripsy pulse with echogenic liposomes. Approach. Bubble clouds were generated using a focused source in an in vitro model of venous flow. Acoustic emissions generated during the insonation were passively acquired to assess the mechanical activity of the bubble cloud. High frame rate, pulse inversion imaging was used to track the change in echogenicity of the liposomes following histotripsy exposure. Main results. For peak negative pressures less than 20 MPa, acoustic emissions indicative of stable and inertial bubble activity were observed. As the peak negative pressure of the histotripsy excitation increased, harmonics of the excitation were observed in OFP t-ELIP solutions and plasma alone. Additional observations with high frame rate imaging indicated a transition of bubble behavior as the pulse pressure transitioned to shock wave formation. Significance. These observations suggest that a complex interaction between histotripsy pulses and echogenic liposomes that may be exploited for combination treatment approaches.

Finding the bubbles in therapeutic ultrasound—For better or for worse

Cavitation has played a variety of roles in therapeutic ultrasound since the field began. Bubble activity has been seen as both a harmful side effect and the means to the therapeutic end. Throughout this range, the monitoring of bubble activity has been an important goal for numerous reasons including safety considerations, progression of treatment, and determining therapeutic efficacy. Methods of cavitation monitoring have been summarized in various contexts including the ASA effort led by Wesley Nyborg, PhD that generated the American National Standards Institute (ANSI) S1.24 TR-2002 (R2007) entitled ANSI Technical Report—Bubble Detection and Cavitation Monitoring. More recently a six-part virtual series, The Detecting, Mapping, and Quantifying Bubble Activity in Therapeutic Ultrasound workshop (https://www.fusfoundation.org/posts/bubble-activity-in-therapeutic-ultrasound-workshop-series/) was held in 2021, sponsored by The Focused Ultrasound Foundation, in partnership with the American Institute of Ultrasound in Medicine’s Future Fund. A summary was released as a white paper. This presentation will provide an introduction to the field of bubble and cavitation detection and monitoring and a summary of this most recent workshop and associated follow-on efforts.