Peak Negative Pressure Research Articles

SCOUT: Skull-Corrected Optimization for Ultrasound Transducers

Transcranial focused ultrasound has been studied for non-invasive and localized treatment of many brain diseases. The biggest challenge for focusing ultrasound onto the brain is the skull, which attenuates ultrasound and changes its propagation direction, leading to pressure drop, focus shift, and defocusing. We presented an optimization algorithm which automatically found the optimal location for placing a single-element focused transducer. At this optimal location, the focus shift was in an acceptable range and the ultrasound was tightly focused. The algorithm simulated the beam profiles of placing the transducer at different locations and compared the results. Locations with a normalized peak-negative pressure (PNP) above threshold were first found. Then, the optimal location was identified as the location with the smallest focal volume. The optimal location found in this study had a normalized PNP of 0.966 and a focal volume of 6.8% smaller than without the skull. A Zeta navigation system was used to automatically place the transducer and track the error caused by movement. These results demonstrated that the algorithm could find the optimal transducer location to avoid large focus shift and defocusing. With the Zeta navigation system, our algorithm can help to make transcranial focused ultrasound treatment safer and more successful.

Break Wave Lithotripsy for Urolithiasis: Results of the First-in-Human International Multi-Institutional Clinical Trial.

This study reports on a prospective, multicenter, single-arm, clinical trial utilizing the SonoMotion (San Mateo, California) Break Wave lithotripsy (BWL) device to fragment urinary stones. Patients with a urinary stone underwent a single treatment of 30 minutes and peak negative pressure of 4.5 to 8 MPa. Subjects were contacted and outcomes assessed at 7, 14, and 35 days after treatment, with clinical follow-up and CT imaging 70 ± 14 days postprocedure. The primary objectives were to assess the safety (hematomas, complications, etc) and effectiveness of BWL (any fragmentation, residual fragments ≤4 mm or ≤2 mm, and completely stone-free rate) as assessed via noncontrast CT-kidneys, ureters, and bladder. Forty-four patients with a ureteral (43%) or renal (57%) stone were treated across 5 centers. Stone fragmentation occurred in 88% of cases; 70% had fragments ≤ 4 and 51% ≤ 2 mm, while 49% were completely stone free on CT; no serious adverse events were reported. Eighty-six percent of patients received either no analgesic medication at all (50%) or minor analgesia (36%). After determining optimal therapy settings, 36 patients were treated and the effectiveness improved exhibiting fragmentation in 92% (33/36), residual fragments ≤ 4 mm in 75% and 58% with fragments ≤ 2 mm with 58% completely stone free. Effectiveness was less in subjects with lower pole stones with 81% fragmentation, 71% having fragments ≤ 4 mm, 29% with fragments ≤ 2 mm, and 29% completely stone free; of distal ureteral stone patients, 89% were completely stone free. BWL offered safe and effective noninvasive stone therapy requiring little to no anesthesia and was carried out successfully in nonoperative environments. ClinicalTrials.gov identifier: NCT03811171.

The molecular impact of sonoporation: A transcriptomic analysis of gene regulation profile

Sonoporation has long been known to disrupt intracellular signaling, yet the involved molecules and pathways have not been identified with clarity. In this study, we employed whole transcriptome shotgun sequencing (RNA-seq) to profile sonoporation-induced gene responses after membrane resealing has taken place. Sonoporation was achieved by microbubble-mediated ultrasound (MB-US) exposure in the form of 1 MHz ultrasound pulsing (0.50 MPa peak negative pressure, 10 % duty cycle, 30 s exposure period) in the presence of microbubbles (1:1 cell-to-bubble ratio). Using propidium iodide (PI) and calcein respectively as cell viability and cytoplasmic uptake labels, post-exposure flow cytometry was performed to identify three viable cell populations: 1) unsonoporated cells, 2) sonoporated cells with low uptake, and 3) sonoporated cells with high uptake. Fluorescence-activated cell sorting was then conducted to separate the different groups followed by RNA-seq analysis of the gene expressions in each group of cells. We found that sonoporated cells with low or high calcein uptake showed high similarity in the gene responses, including the activation of multiple heat shock protein (HSP) genes and immediate early response genes mediating apoptosis and transcriptional regulation. In contrast, unsonoporated cells exhibited a more extensive gene expression alteration that included the activation of more HSP genes and the upregulation of diverse apoptotic mediators. Four oxidative stress-related and three immune-related genes were also differentially expressed in unsonoporated cells. Our results provided new information for understanding the intracellular mobilization in response to sonoporation at the molecular level, including the identification of new molecules in the sonoporation-induced apoptosis regulatory network. Our data also shed light on the innovative therapeutic strategy which could potentially leverage the responses of viable unsonoporated cells as a synergistic effector in the microenvironment to favor tumor treatment.

Focused Ultrasound Combined With Microbubbles Attenuate Symptoms in Heroin-Addicted Mice

ObjectiveTo explore the efficacy and mechanisms of stimulating the nucleus accumbens (NAc) in heroin-addicted mice using focused ultrasound and microbubbles (MBs). MethodsThe conditioned place preference (CPP) method was employed to establish a heroin-addicted mice model. Mice were randomized into control (C), heroin (H), heroin + ultrasound (H + U) and H + U + MBs. Ultrasound (2 MHz fundamental frequency, 1.34 MPa peak-negative pressure, 1 MHz pulse repetition frequency, 5% duty cycle, 15 min/d, over 2 d) was applied to stimulate the NAc in the latter 2 groups. Whereas H + U + MBs received an injection of sulfur hexafluoride MBs during the stimulation. Subsequently, CPP scores, open-field test (OFT), and elevated plus-maze test (EPMT) were conducted to assess behavioral changes in addiction memory, anxiety and exercise status. HE staining was performed to detect pathological structures. Neurotransmitters such as dopamine (DA), serotonin (5-HT) and glutamate (Glu) were detected using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Transmission electron microscopy (TEM) was used to observe ultrastructural changes of synapses in NAc. Immunohistochemistry (IHC) was utilized to detect Cleaved Caspase-3 in the NAc region. Western blotting (WB) was used to detect the protein expression of Cleaved Caspase-3, Bax and Bcl-2 in NAc. ResultsHE staining showed small patches of erythrocyte exudation were observed in the NAc and adjacent areas in H + U + MBs. The CPP scores of H + U + MBs were lower (p < 0.05) than H. After ultrasound treatment, all indices of the OFT and EPMT in H + U + MBs were significantly higher than H (p < 0.05). UPLC-MS/MS revealed that the levels of DA, 5-HT and Glu in H + U + MBs were lower than H (p < 0.01). TEM showed decrease the number of synapses (p < 0.05), and noticeable swelling of mitochondria, membrane damage, as well as damage to the cristae. Further detection by IHC and WB showed that the pro-apoptotic proteins Cleaved Caspase-3 and Bax increased and Bcl-2 decreased as anti-apoptotic proteins after ultrasound combined with MBs (p < 0.05). ConclusionFocused ultrasound combined with MBs stimulate the NAc can weaken the addictive memory and improve anxiety of heroin-related mice. The mechanical effect of ultrasound combined with the cavitation effect may be a potential treatment for addiction.

Pulsed focused ultrasound ablation assisted by a surface modified catheter for thrombolysis: a feasibility study

Interventional procedures for the recanalization of blood vessels to treat deep vein thrombosis carry a high risk of vessel wall injuries or hemorrhaging. Focused ultrasound (FUS) has been used to non-invasively break down blood clots that occlude the vessels in both in vitro and in vivo studies. Previous studies have either used thrombolytic drugs or ultrasound contrast agents (e.g., microbubbles) in combination with FUS. Several studies have applied very high peak-negative-pressures (PNP) during FUS treatment to achieve successful thrombolysis without the use of contrast agents. In the current study, we demonstrated that cavitation activity could be significantly enhanced by placing a nitinol wire, whose surface was roughed by laser etching, in the focal region of a FUS field. We demonstrated in vitro in a mock thrombosis that the thrombolysis efficacy of a 500 kHz FUS transducer was significantly enhanced using a surface-etched nitinol wire as compared to an unetched nitinol wire, whereas FUS-alone at the same pressure level did not result in any thrombolysis. These results suggest that a surface modified nitinol catheter exposed to FUS can result in intense cavitation activities leading to enhanced thrombolysis without the use of additional pharmacological or contrast agents.

Peak factors of wind load for main frame design of rooftop structures

ABSTRACT Technology is being developed to unitize structures installed on apartment rooftops during construction. The rooftop is located at the top of a high-rise building with a flexible structure. However, the rooftop structure itself is close to a rigid body and is not integrated with the building. Therefore, it is difficult to calculate the gust effect coefficient of the rooftop structure. The peak factor provided by the Korean Design Standard (KDS) uses an equation for general buildings and may be inaccurate to a certain extent when used to calculate the wind load on rooftop structures. Therefore, in this study, wind pressure tests were conducted on three research models to calculate the appropriate peak factors for rooftop structures. For each model, the peak factor trend was analyzed according to the wind pressure coefficient, and the peak factor was presented. When the evaluation time was 10 min, the positive pressure peak factor converged to three and the negative pressure peak factor converged to four. Additionally, a formula for calculating the peak factor of rooftop structures based on the wind load evaluation time is proposed. Hence, the peak factor of rooftop structures can be calculated based on various evaluation times.

Microbubbles bound to drug-eluting beads enable ultrasound imaging and enhanced delivery of therapeutics

Transarterial chemoembolization (TACE) is an image-guided minimally invasive treatment for liver cancer which involves delivery of chemotherapy and embolic material into tumor-supplying arteries to block blood flow to a liver tumor and to deliver chemotherapy directly to the tumor. However, the released drug diffuses only less than a millimeter away from the beads. To enhance the efficacy of TACE, the development of microbubbles electrostatically bound to the surface of drug-eluting beads loaded with different amounts of doxorubicin (0–37.5 mg of Dox/mL of beads) is reported. Up to 400 microbubbles were bound to Dox-loaded beads (70–150 microns). This facilitated ultrasound imaging of the beads and increased the release rate of Dox upon exposure to high intensity focused ultrasound (HIFU). Furthermore, ultrasound exposure (1 MPa peak negative pressure) increased the distance at which Dox could be detected from beads embedded in a tissue-mimicking phantom, compared with a no ultrasound control.

Manipulating long-term fates of sonoporated cells by regulating intracellular calcium for improving sonoporation-based delivery

Sonoporation-based delivery has great promise for noninvasive drug and gene therapy. After short-term membrane resealing, the long-term function recovery of sonoporated cells affects the efficiency and biosafety of sonoporation-based delivery. It is necessary to identify the key early biological signals that influence cell fate and to develop strategies for manipulating the long-term fates of sonoporated cells. Here, we used a customized experimental platform with a single cavitating microbubble induced by a single ultrasound pulse (frequency: 1.5 MHz, pulse length:13.33 μs, peak negative pressure: ∼0.40 MPa) to elicit single-site reversible sonoporation on a single HeLa cell model. We used a living-cell microscopic imaging system to trace the long-term fates of sonoporated HeLa cells in real-time for 48 h. Fluorescence from intracellular propidium iodide and Fluo-4 was used to evaluate the degree of sonoporation and intracellular calcium fluctuation (ICF), respectively. Changes in cell morphology were used to assess the long-term cell fates (i.e., proliferation, arrest, or death). We found that heterogeneously sonoporated cells had different long-term fates. With increasing degree of sonoporation, the probability of normal (proliferation) and abnormal fates (arrest and death) in sonoporated cells decreased and increased, respectively. We identified ICF as an important early event for triggering different long-term fates. Reversibly sonoporated cells exhibited stronger proliferation and restoration at lower extents of ICF. We then regulated ICF dynamics in sonoporated cells using 2-APB or BAPTA treatment to reduce calcium release from intracellular organelles and enhance intracellular calcium clearance, respectively. This significantly enhanced the proliferation and restoration of sonoporated cells and reduced the occurrence of cell-cycle arrest and death. Finally, we found that the long-term fates of sonoporated cells at multiple sites and neighboring cells were also dependent on the extent of ICF, and that 2-APB significantly enhanced their viability and reduced death. Thus, using a single HeLa cell model, we demonstrated that regulating intracellular calcium can effectively enhance the proliferation and restoration capabilities of sonoporated cells, therefore rescuing the long-term viability of sonoporated cells. These findings add to our understanding of the biophysical process of sonoporation and help design new strategies for improving the efficiency and biosafety of sonoporation-based delivery.

Numerical investigation of the number of excitation elements-dependent acoustic field characteristics of a histotripter

Abstract Histotripsy is an emerging ultrasound technology for disintegrating various soft tissues noninvasively and accureately. However, it is difficult to characterize the acoustic field of a histotripter using the existing measurement methods (i.e., hydrophones) because of the damage potential of bubble cavitation on the sensing element under such high irradiation power. In this work, according to a quantitative relationship between the acoustic pressure and ultrasonic focusing gain G, nonlinearity β, attenuation coefficient α, a numerical reconstruction method is proposed to accurately and reliably estimate the acoustic field of a histotripter. The k-Wave toolbox was used to calculate the acoustic field produced from identical sectors on a common concave surface by gradually increasing the number of excitation elements (i.e., up to 256 that cover the whole surface). The excitation frequency is 0.8 MHz, and the initial pressure at the transducer surface is 0.4 MPa. The focusing gains, peak positive and negative pressure, positive to negative peak acoustic pressure ratio, and harmonic distributions in the focal region under different numbers of excited elements were analysed. It is found that when about a quarter of the transducer surface is excited (64 elements), the nonlinear effect becomes obvious, resulting in significant peak pressures and harmonics. Furthermore, the relationship between the positive and negative pressure peaks (p + and p ¬) and the number of excited elements fits a quadratic curve function quite well (R = 0.999). Altogether, the proposed method can be applied to estimate the acoustic pressure at an extremely high intensity that exceeds the range of current measurement apparatus. Acoustic pressures using a low number of excited elements are measured first and then extrapolated to the full surface coverage using the built-in regression models. In the near future, the field calculation scheme for the therapeutic focused transducers with higher irradiation power and larger dimensions, as well as experimental work, will be done to further validate our model.

Analysis of train-induced aerodynamic characteristics and pressure-relief measures relating to fully enclosed noise barriers installed on railway bridges

Fully enclosed noise barriers (FENBs) are increasingly being installed on high-speed railway bridges for noise pollution control. However, the aerodynamic effects of high-speed trains passing FENBs have an adverse impact on barrier durability and generate micro-pressure waves. In this paper, a numerical model of a train passing an FENB on a bridge is established. The aerodynamic pressure distribution along the FENB is analyzed for both a single train and two trains passing one another. The propagation characteristics and evolution mechanisms of pressure waves are then investigated. The results show that the pressure is lower at the ends of the FENB and higher in the middle along the direction of train travel. The peak positive and negative pressures at the mid-span are 1.95 and 4.47 times higher than those at the ends, respectively. This distribution is caused by the propagation, superposition, reflection, and attenuation of pressure waves. Compression waves account for 78.9% of the peak positive pressure. An amplification factor must be considered when estimating the impact of two trains passing one another. Analysis of five pressure-relief schemes shows that arranging a single pressure-relief hole at a high-pressure location effectively alleviates the over-pressure in the FENB. The overall pressure-relief effect is an exponential function of the single opening area. Considering a constant opening area, arranging several relief holes at equal spacing optimizes the adverse pressure distribution compared with the single-hole relief scheme. The equivalent forces of the multi-hole scheme are 3.35% and 7.58% lower than in the single-hole scheme.

In vitro experimental study on interventional ultrasound-mediated microbubble cavitation lithotripsy

Abstract Ultrasound-mediated microbubble cavitation lithotripsy as a new minimally invasive approach has received great attention for the treatment of urinary stones. However, the attenuation of ultrasonic waves in human tissues and stone displacement during lithotripsy are two key issues limiting the development of this technology. In this paper, a method of interventional ultrasound-mediated microbubble cavitation lithotripsy is proposed, which can realize the in-situ delivery of ultrasonic waves and microbubbles. A piezoelectric ultrasound transducer with the center frequency of 461 kHz and output peak to peak acoustic pressures of 3.2 MPa is fabricated, and microbubbles with the concentration of 1.33×109/ml are synthesized. An extracorporeal experiment platform is built and in vitro tests of ultrasound mediated microbubble cavitation lithotripsy are conducted by using microbubbles with different concentrations and water. The results show that the proposed interventional ultrasound-mediated microbubble cavitation lithotripsy is an efficient method for the fragmentation of ureteral stones. The maximum mass reduction of the stone is 9.4 mg within 30 minutes of treatment under the combined action of ultrasound with the peak-negative pressure of 1.6 MPa and center frequency of 461 kHz and microbubbles with the concentration of 3.325×107/ml. The research results will provide a technical basis for further optimization of subsequent tentative schemes, in vivo experiments with animals and future clinical applications.

Ultrasound-assisted laser therapy for selective removal of melanoma cells.

The current study explores the potential of ultrasound-assisted laser therapy (USaLT) to selectively destroy melanoma cells. The technology was tested on an ex vivo melanoma model, which was established by growing melanoma cells in chicken breast tissue. Ultrasound-only and laser-only treatments were used as control groups. USaLT was able to effectively destroy melanoma cells and selectively remove 66.41% of melanoma cells in the ex vivo tumor model when an ultrasound peak negative pressure of 2MPa was concurrently applied with a laser fluence of 28mJ/cm2 at 532nm optical wavelength for 5min. The therapeutic efficiency was further improved with the use of a higher laser fluence, and the treatment depth was improved to 3.5mm with the use of 1,064nm laser light at a fluence of 150mJ/cm2. None of the laser-only and ultrasound-only treatments were able to remove any melanoma cells. The treatment outcome was validated with histological analyses and photoacoustic imaging. This study opens the possibility of USaLT for melanoma that is currently treated by laser therapy, but at a much lower laser fluence level, hence improving the safety potential of laser therapy.

Reduction in lower urinary tract mucosal microtrauma as an effect of reducing eyelet sizes of intermittent urinary catheters

Intermittent catheterization (IC) utilizing conventional eyelets catheters (CECs) for bladder drainage has long been the standard of care. However, when the tissue of the lower urinary tract comes in close proximity to the eyelets, mucosal suction often occurs, resulting in microtrauma. This study investigates the impact of replacing conventional eyelets with a drainage zone featuring multiple micro-holes, distributing pressure over a larger area. Lower pressures limit the suction of surrounding tissue into these micro-holes, significantly reducing tissue microtrauma. Using an ex vivo model replicating the intra-abdominal pressure conditions of the bladder, the intra-catheter pressure was measured during drainage. When mucosal suction occurred, intra-catheter images were recorded. Subsequently affected tissue samples were investigated histologically. The negative pressure peaks caused by mucosal suction were found to be very high for the CECs, leading to exfoliation of the bladder urothelium and breakage of the urothelial barrier. However, a micro-hole zone catheter (MHZC) with a multi-eyelet drainage zone showed significantly lower pressure peaks, with over 4 times lower peak intensity, thus inducing far less extensive microtraumas. Limiting or even eliminating mucosal suction and resulting tissue microtrauma may contribute to safer catheterizations in vivo and increased patient comfort and compliance.

Investigating the potential of catheter-assisted pulsed focused ultrasound ablation for atherosclerotic plaques.

Atherosclerosis is a condition in which an adhesive substance called plaque accumulates over time inside the arteries. Plaque buildup results in the constriction of arteries, causing a shortage of blood supply to tissues and organs. Removing atherosclerotic plaques controls the development of acute ischemic stroke and heart diseases. It remains imperative for positive patient outcomes. This study sought to develop a minimally invasive technique for removing arterial plaques by applying focused ultrasound (FUS) energy on the metal surface of a nitinol catheter wire to induce inertial cavitation. The induced cavitation can deplete plaque mechanically inside the arteries, leading towards improved recanalization of blood vessels. The enhanced cavitation effect induced by combining FUS with a metal catheter was first verified by exposing agar phantom gels with or without a 0.9-mm diameter nitinol wire to an acoustic field produced by a 0.5-MHz FUS transducer. The phenomenon was further confirmed in pork belly fat samples with or without a 3-mm diameter nitinol catheter wire. Cavitation was monitored by detecting the peaks of emitted ultrasound signals from the samples using a passive cavitation detector (PCD). Cavitation threshold values were determined by observing the jump in the peak amplitude of signals received by the PCD when the applied FUS peak negative pressure (PNP) increased. To simulate arterial plaque removal, FUS with or without a catheter was used to remove tissues from pork belly fat samples and the lipid cores of human atherosclerotic plaque samples using 2500-cycle FUS bursts at 10% duty cycle and a burst repetition rate of 20Hz. Treatment outcomes were quantified by subtracting the weight of samples before treatment from the weight of samples after treatment. All measurements were repeated 5 times (n=5) unless otherwise indicated, and paired t-tests were used to compare the means of two groups. A p-value of <0.05 will be considered significant. Our results showed that with a nitinol wire, the cavitation threshold in agar phantoms was reduced to 2.6MPa from 4.3MPa PNP when there was no nitinol wire in the focal region of FUS. For pork belly fat samples, cavitation threshold values were 1.0 and 2.0MPa PNP, with and without a catheter wire, respectively. Pork belly fat tissues and lipid cores of atherosclerotic plaques were depleted at the interface between a catheter and the samples at 2 and 4MPa FUS PNP, respectively. The results showed that with a catheter wire in the focal region of a 3-min FUS treatment session, 24.7 and 25.6mg of lipid tissues were removed from pork belly fat and human atherosclerotic samples, respectively. In contrast, the FUS-only group showed no reduction in sample weight. The differences between FUS-only and FUS-plus-catheter groups were statistically significant (p<0.001 for the treatment on pork belly samples, and p<0.01 for the treatment on human atherosclerotic samples). This study demonstrated the feasibility of catheter-assisted FUS therapy for removing atherosclerotic plaques.

Shear stress preconditioning and microbubble flow pattern modulate ultrasound-assisted plasma membrane permeabilization

The recent and exciting success of anti-inflammatory therapies for ischemic heart disease (e.g. atherosclerosis) is hindered by the lack of site-specific and targeted therapeutic deposition. Microbubble-mediated focused ultrasound, which uses circulating, lipid-encapsulated intravascular microbubbles to locally enhance endothelial permeability, offers an exciting approach. Atherosclerotic plaques preferentially develop in regions with disturbed blood flow, and microbubble-endothelial cell membrane interactions under such flow conditions are not well understood. Here, using an acoustically-coupled microscopy system, endothelial cells were sonicated (1 MHz, 20 cycle bursts, 1 ms PRI, 4 s duration, 300 kPa peak-negative pressure) under perfusion with Definity™ bubbles to examine microbubble-mediated endothelial permeabilization under a range of physiological conditions. Endothelial preconditioning under prolonged shear influenced physiology and the secretome, inducing increased expression of pro-angiogenesis analytes, decreasing levels of pro-inflammatory ones, and increasing the susceptibility of ultrasound therapy. Ultrasound treatment efficiency was positively correlated with concentrations of pro-angiogenic cytokines (e.g. VEGF-A, EGF, FGF-2), and negatively correlated with pro-inflammatory chemokines (e.g. MCP-1, GCP-2, SDF-1). Furthermore, ultrasound therapy under non-reversing pulsatile flow (∼4–8 dyne/cm2, 0.5–1 Hz) increased permeabilization up to 2.4-fold compared to shear-matched laminar flow, yet treatment under reversing oscillatory flow resulted in more heterogeneous modulation. This study provides insight into the role of vascular physiology, including endothelial biology, into the design of a localized ultrasound drug delivery system for ischemic heart disease.

Exploration of shock–droplet interaction based on high-fidelity simulation and improved theoretical model

Shock–droplet interaction in the early stage involves intricate wave structures. Investigating this phenomenon is inherently challenging due to the fine spatial and temporal scales involved. Past research has suggested that the occurrence of cavitation, marked by a negative peak pressure, is linked to the focus of the reflected expansion wave. In this study, a high-fidelity compressible numerical approach is utilized to replicate the initial phase of shock–droplet interactions. The location of the negative peak pressure is meticulously documented and compared with experimental measurement and numerical results. Results indicate a strong alignment between the negative peak pressure positions identified through numerical simulations and the focal points identified in theoretical models for low gas–liquid wave velocity ratios. However, this alignment is notably disrupted when dealing with higher gas–liquid wave velocity ratios. Further enhancements are made to the theoretical model, enabling a more precise depiction of internal wave structures and focus points, particularly under conditions of high gas–liquid wave velocity ratios. The study delves into the various factors influencing internal pressure fluctuations within the liquid droplet, categorizing them into four phases: the shock wave effect, relaxation effect, fluctuation effect, and expansion wave effect. Analysing the pressure decrease portion reveals that while the converging of the reflected expansion wave leads to a substantial pressure drop, it accounts for only a fraction of the total pressure variation. Consequently, any model predicting negative peak pressure positions must comprehensively consider all contributing factors.

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.

Radiation enhancement using focussed ultrasound-stimulated microbubbles for breast cancer: A Phase 1 clinical trial.

Preclinical studies have demonstrated that tumour cell death can be enhanced 10- to 40-fold when radiotherapy is combined with focussed ultrasound-stimulated microbubble (FUS-MB) treatment. The acoustic exposure of microbubbles (intravascular gas microspheres) within the target volume causes bubble cavitation, which induces perturbation of tumour vasculature and activates endothelial cell apoptotic pathways responsible for the ablative effect of stereotactic body radiotherapy. Subsequent irradiation of a microbubble-sensitised tumour causes rapid increased tumour death. The study here presents the mature safety and efficacy outcomes of magnetic resonance (MR)-guided FUS-MB (MRgFUS-MB) treatment, a radioenhancement therapy for breast cancer. This prospective, single-center, single-arm Phase 1 clinical trial included patients with stages I-IV breast cancer with in situ tumours for whom breast or chest wall radiotherapy was deemed adequate by a multidisciplinary team (clinicaltrials.gov identifier: NCT04431674). Patients were excluded if they had contraindications for contrast-enhanced MR or microbubble administration. Patients underwent 2 to 3 MRgFUS-MB treatments throughout radiotherapy. An MR-coupled focussed ultrasound device operating at 800 kHz and 570 kPa peak negative pressure was used to sonicate intravenously administrated microbubbles within the MR-guided target volume. The primary outcome was acute toxicity per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Secondary outcomes were tumour response at 3 months and local control (LC). A total of 21 female patients presenting with 23 primary breast tumours were enrolled and allocated to intervention between August/2020 and November/2022. Three patients subsequently withdrew consent and, therefore, 18 patients with 20 tumours were included in the safety and LC analyses. Two patients died due to progressive metastatic disease before 3 months following treatment completion and were excluded from the tumour response analysis. The prescribed radiation doses were 20 Gy/5 fractions (40%, n = 8/20), 30 to 35 Gy/5 fractions (35%, n = 7/20), 30 to 40 Gy/10 fractions (15%, n = 3/20), and 66 Gy/33 fractions (10%, n = 2/20). The median follow-up was 9 months (range, 0.3 to 29). Radiation dermatitis was the most common acute toxicity (Grade 1 in 16/20, Grade 2 in 1/20, and Grade 3 in 2/20). One patient developed grade 1 allergic reaction possibly related to microbubbles administration. At 3 months, 18 tumours were evaluated for response: 9 exhibited complete response (50%, n = 9/18), 6 partial response (33%, n = 6/18), 2 stable disease (11%, n = 2/18), and 1 progressive disease (6%, n = 1/18). Further follow-up of responses indicated that the 6-, 12-, and 24-month LC rates were 94% (95% confidence interval [CI] [84%, 100%]), 88% (95% CI [75%, 100%]), and 76% (95% CI [54%, 100%]), respectively. The study's limitations include variable tumour sizes and dose fractionation regimens and the anticipated small sample size typical for a Phase 1 clinical trial. MRgFUS-MB is an innovative radioenhancement therapy associated with a safe profile, potentially promising responses, and durable LC. These results warrant validation in Phase 2 clinical trials. clinicaltrials.gov, identifier NCT04431674.

Noninvasive release of tendons using MRI guided focused ultrasound: a hybrid therapy using long-pulse focused ultrasound followed by thermal ablation

Introduction Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thermal ablation is an effective noninvasive ultrasonic therapy to disrupt in vivo porcine tendon but is prone to inducing skin burns. We evaluated the safety profile of a novel hybrid protocol that minimizes thermal spread by combining long-pulse focused ultrasound followed by thermal ablation. Methods In-vivo Achilles tendons (hybrid N = 15, thermal ablation alone N = 21) from 15 to 20 kg Yorkshire pigs were randomly assigned to 6 treatment groups in two studies. The first (N = 21) was ablation (600, 900, or 1200 J). The second (N = 15) was hybrid: pulsed FUS (13.5 MPa peak negative pressure) followed by ablation (600, 900, or 1200 J). Measurements of ankle range of motion, tendon temperature, thermal dose (240 CEM43), and assessment of skin burn were performed in both groups. Results Rupture was comparable between the two protocols: 1/5 (20%), 5/5 (100%) and 5/5 (100%) for hybrid protocol, compared to 2/7 (29%), 6/7 (86%) and 7/7 (100%) for the ablation-only protocol with energies of 600, 900, and 1200 J, respectively. The hybrid protocol produced lower maximum temperatures, smaller areas of thermal dose, fewer thermal injuries to the skin, and fewer full-thickness skin burns. The standard deviation for the area of thermal injury was also smaller for the hybrid protocol, suggesting greater predictability. Conclusion This study demonstrated a hybrid MRgFUS protocol combining long-pulse FUS followed by thermal ablation to be noninferior and safer than an ablation-only protocol for extracorporeal in-vivo tendon rupture for future clinical application for noninvasive release of contracted tendon.

Cavitation-induced pressure saturation: a mechanism governing bubble nucleation density in histotripsy

Objective. Histotripsy is a noninvasive focused ultrasound therapy that mechanically disintegrates tissue by acoustic cavitation clouds. In this study, we investigate a mechanism limiting the density of bubbles that can nucleate during a histotripsy pulse. In this mechanism, the pressure generated by the initial bubble expansion effectively negates the incident pressure in the vicinity of the bubble. From this effect, the immediately adjacent tissue is prevented from experiencing the transient tension to nucleate bubbles. Approach. A Keller–Miksis-type single-bubble model was employed to evaluate the dependency of this effect on ultrasound pressure amplitude and frequency, viscoelastic medium properties, bubble nucleus size, and transducer geometric focusing. This model was further combined with a spatial propagation model to predict the peak negative pressure field as a function of position from a cavitating bubble. Main results. The single-bubble model showed the peak negative pressure near the bubble surface is limited to the inertial cavitation threshold. The predicted bubble density increased with increasing frequency, tissue viscosity, and transducer focusing angle. The simulated results were consistent with the trends observed experimentally in prior studies, including changes in density with ultrasound frequency and transducer F-number. Significance. The efficacy of the therapy is dependent on several factors, including the density of bubbles nucleated within the cavitation cloud formed at the focus. These results provide insight into controlling the density of nucleated bubbles during histotripsy and the therapeutic efficacy.