Peak Negative Pressure Research Articles

Microbubble dynamics in brain microvessels.

Focused ultrasound stimulation of microbubbles is being tested in clinical trials for its ability to deliver drugs across the blood-brain barrier (BBB). This technique has the potential to treat neurological diseases by preferentially delivering drugs to targeted regions. Yet despite its potential, the physical mechanisms by which microbubbles alter the BBB permeability remain unclear, as direct observations of microbubbles oscillating in brain microvessels have never been previously recorded. The purpose of this study was to reveal how microbubbles respond to ultrasound when within the microvessels of living brain tissue. Microbubbles in acute brain slices acquired from juvenile rats perfused with a concentrated solution of SonoVue® and dye were exposed to ultrasound pulses typically used in BBB disruption (center frequency: 1 MHz, peak-negative pressure: 0.2-1 MPa, pulse length: up to 10 ms) and observed using high-speed microscopy at up to 10 million frames per second. We observed that microbubbles can exert mechanical stresses on a wide region of tissue beyond their initial location and immediate surroundings. A single microbubble can apply mechanical stress to parenchymal tissues several micrometers away from the vessel. Microbubbles can travel at high velocities within the microvessels, extending their influence across tens of micrometers during a single pulse. With longer pulses and higher pressures, microbubbles could penetrate the vessel wall and move through the parenchyma. The probability of extravasation scales approximately with mechanical index, being rare at low pressures, but much more common at a mechanical index ≥ 0.6. These results present the first direct observations of ultrasound-driven microbubbles within brain tissue, and illustrate a range of microbubble behaviors that have the potential to lead to safe drug delivery or tissue damage.

The Compression-Dominated Ultrasound Response of Poly(n-butyl cyanoacrylate) Hard-Shelled Microbubbles Induces Significant Sonoporation and Sonopermeation Effects In Vitro.

The process of locally increasing the permeability of cell membranes or cell layers is referred to as sonoporation or sonopermeation, respectively, and opens up perspectives for drug delivery in cancer treatment by facilitating enhanced local drug accumulation. These effects are mediated by ultrasound-activated microbubbles in close proximity to cells. Here, the selection of ultrasound settings according to the intended effect on the biological tissue remains a challenge, especially for broadly size-distributed microbubbles, which show a heterogeneous response to ultrasound. For this purpose, we have analyzed the general response of narrower size-distributed poly(n-butyl cyanoacrylate) hard-shelled microbubbles to ultrasound via ultra-high-speed imaging and evaluated their ability to stimulate sonoporation and sonopermeation in vitro compared to lipid soft-shelled microbubbles. Ultra-high-speed imaging of hard-shelled microbubbles revealed either a compression-dominated or compression-only response at peak negative acoustic pressures higher than 165 kPa and an onset of bursting at 500 kPa. The in vitro experiments demonstrated that the hard-shelled microbubbles induced significant sonoporation and sonopermeation effects, also when only compressing at 300 kPa peak neagtive pressure. Compared to soft-shelled microbubbles, the effects were less prominent, which was attributed to differences in their ultrasound responses and size distributions. This in vitro validation of hard-shelled microbubbles qualifies them for future in vivo applications, which would benefit from their narrow size distribution, thereby allowing more control of their therapeutic effect by suitably adjusting the ultrasound parameters.

Strategy and mechanism of roll attitude regulation for a flying wing aircraft via leading-edge vortex and recirculation zone manipulation

The flying wing configuration represents an advanced tailless aerodynamic design. However, due to its lack of lateral-directional stability, it tends to experience wing rock at high angles of attack, posing challenges for attitude control. This manuscript proposes a synergistic control strategy based on the mechanism of leading-edge vortex (LEV) control and recirculation zone (RZ) control, achieved through inward-directed jets at the leading edge. Wind tunnel experiments demonstrate that this strategy enables a continuously variable regulation of the roll attitude between 27° to the right and 27° to the left, exhibiting control capabilities comparable to ailerons. Furthermore, quantitative analysis of the flow field and pressure indicates interactions between the jet and the flow structures cause asymmetrical effects on the pressures on both wing sides, thus generating a positive rolling moment. Specifically, the jet-induced vortex (JIV) generated by LEV control lifts the LEV, distancing it from the wing surface, thereby reducing the vortex lift. Additionally, JIV enhances the normal oscillation of the LEV, leading to LEV breakdown and a decrease in the induced negative pressure peak. RZ control injects momentum into the RZ and reduces its size, thereby suppressing flow separation and enhancing the negative pressure on that side of the wing. The above investigation establishes a crucial foundation for substituting conventional mechanical control surfaces and achieving virtual aerodynamic surface control.

Characterizing Microbubble-Mediated Permeabilization in a Vessel-on-a-Chip Model.

Drug transport from blood to extravascular tissue can locally be achieved by increasing the vascular permeability through ultrasound-activated microbubbles. However, the mechanism remains unknown, including whether short and long cycles of ultrasound induce the same onset rate, spatial distribution, and amount of vascular permeability increase. Accurate models are necessary for insights into the mechanism so a microvessel-on-a-chip is developed with a membrane-free extravascular space. Using these microvessels-on-a-chip, distinct differences between 2MHz ultrasound treatments are shown with 10 or 1000 cycles. The onset rate is slower for 10 than 1000 cycles, while both cycle lengths increase the permeability in spot-wise patterns without affecting microvessel viability. Significantly less vascular permeability increase and sonoporation are induced for 10 versus 1000 cycles at 750kPa (i.e., the highest studied peak negative acoustic pressure (PNP)). The PNP threshold for vascular permeability increases is 750 versus 550kPa for 10 versus 1000 cycles, while this is 750 versus 220kPa for sonoporation. Vascular permeability increases do not correlate with αvβ3-targeted microbubble behavior, while sonoporation correlates with αvβ3-targeted microbubble clustering. In conclusion, the further mechanistic unraveling of vascular permeability increase by ultrasound-activated microbubbles in a developed microvessel-on-a-chip model aids the safe and efficient development of microbubble-mediated drug transport.

Combined drug delivery and treatment monitoring using a single high frequency ultrasound system

Ultrasound-mediated drug delivery is typically performed using transducers with center frequencies ≤ 1 MHz to promote acoustic cavitation. Such frequencies are not commonly used for diagnostic ultrasound due to limited spatial resolution. Therefore, delivery and monitoring of therapeutic ultrasound typically requires two transducers to enable both treatment and imaging. This study investigates the feasibility of using a single commercial ultrasound imaging transducer operating at 5 MHz for both drug delivery and real-time imaging. We compared a single-transducer system (STS) at 5 MHz with a conventional dual-transducer system (DTS) using a 1.1 MHz therapeutic transducer and an imaging probe. in vitro experiments demonstrated that the STS could achieve comparable extravasation depth and area as the DTS, with higher drug deposition observed at 5 MHz. Additionally, extravasation patterns were influenced by peak negative pressure (PNP) and duty cycle, with the narrower beam width at 5 MHz offering potential advantages for targeted drug delivery. in vivo experiments in a murine bladder cancer model confirmed the efficacy of the STS for real-time imaging and drug delivery, with cavitation dose correlating with drug deposition. The results suggest that a single-transducer approach may enhance the precision and efficiency of ultrasound-mediated drug delivery, potentially reducing system complexity and cost.

A predictive large-eddy simulation framework for the analysis of wind loads on a realistic low-rise building geometry

The accuracy of large-eddy simulations (LESs) for predicting wind-induced pressure loads remains an important topic of inquiry. This paper aims to advance this topic by validating an LES workflow for predicting wind pressures on a realistic low-rise building model exposed to a suburban neutral surface layer. We compare two wind tunnel data sets and LES predictions, obtained using a two-step workflow. First, we ensure that an accurate representation of the surface layer wind flow is obtained at the building location. Next, we assess the resulting wind loads on the building model. Using this workflow, we demonstrate consistent agreement between LES predictions and wind tunnel tests, where the discrepancies between the LES and wind tunnel results mimic the discrepancies between the two wind tunnel tests. This finding underscores that the pressure signals in certain locations are sensitive to inevitable, small differences in the approach flow. LES-based flow visualization uncovered that the most negative pressure peaks, which occur on the building roof, arise from hairpin-like vortices that are lifted from the separation region near the upstream roof edge. The results shed light on the complex dynamics of wind-induced pressure loads and contribute to quantifying the reliability of LES for wind load estimation.

Metabolomic profile of cerebral tissue after acoustically-mediated blood-brain barrier opening in a healthy rat model: a focus on the contralateral side.

Microbubble (MB)-assisted ultrasound (US) is an innovative modality for the non-invasive, targeted, and efficient delivery of therapeutic molecules into the brain. Previously, we reported the first metabolomic signature of blood-brain barrier opening (BBBO) induced by MB-assisted US. In the present study, the neurometabolic consequences of acoustically-mediated BBBO on cerebral tissue were investigated using multimodal metabolomics approaches. Sinusoid US waves (1 MHz, peak negative pressure 0.6 MPa, burst length 10 ms, total treatment time 30 s, MB bolus dose 0.7 × 105 MBs/g) were applied on the rats' right striatum (ipsilateral side). Brain was collected and both striata were then dissected 3 h, 2 days, and 1 week after BBBO. After tissue preparation, the samples were analyzed using nuclear magnetic resonance spectrometry (NMRS) and high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS). Our findings showed a slight disruption of metabolic pathways in contralateral striata of animals. Analyses of metabolic pathways indicated changes in amino acid metabolisms. In addition, tryptophan derivate dosages revealed the perturbation of a central metabolite of the kynurenine pathway (i.e., 3-hydroxy-kynurenine). In conclusion, the acoustically-mediated BBBO of the ipsilateral cerebral hemisphere induced significant change in metabolism of contralateral one.

A meta-analysis of the effect of ultrasound activation parameters on phase-change nanodroplets in imaging and therapy

Phase-change nanodroplets (PCNDs) have been used in ultrasound imaging, targeted drug delivery, blood-brain-barrier (BBB) opening, sonothrombolysis and histotripsy for over a decade. For these ultrasound applications, PCNDs provide higher in vivo lifetime than microbubbles (MBs), the potential for extravasation inside tumour and on demand activation, which is the transition of the liquid-core of nanodroplets to gaseous microbubbles through acoustic droplet vaporisation (ADV). Operating above the ADV threshold can offer repeatable activation of PCNDs and the subsequent oscillation of acoustically activated PCNDs, which is advantageous in imaging and therapeutic applications. Efficient and repeatable activation of PCNDs require a good understanding of ultrasound parameters and nanodroplet composition for different biomedical applications. Therefore, this article presents a meta-analysis of the effect of ultrasound activation parameters on ADV for various PCNDs in different biomedical applications. About 7,500 articles were considered for this study, but only 45 articles were chosen and evaluated in the meta-analysis based on the following criteria: 1): activation parameters, including ultrasound frequency, peak negative pressure, transmit pulse length or duration have been clearly mentioned, 2), droplets range in nanometre size (<1 µm), 3), experiments are performed at a temperature of 37°C and 4) ADV threshold has been clearly mentioned and observations are not due to inertial cavitation (IC). From selected publications, we recorded the activation frequency (0.06–16 MHz), ultrasound pressure (0.18–14.9 MPa), activation pulse length (µs-ms range) and nanodroplet size for different types of perfluorocarbon PCNDs (C3F8, C4F10, C5F12 and C6F14) and evaluated the relation of these parameters to each other. Finally, a Root Mean Square (RMS)-like power metric, which is a combination of ultrasound peak negative pressure and square root of ultrasound pulse length, is proposed for identifying the ADV threshold behaviour instead of using pressure or mechanical index values.

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.

Effects of Different Gas Cores on the Ambient Pressure Sensitivity of the Subharmonic Response of SonoVue

ObjectiveSubharmonic Aided Pressure Estimation (SHAPE) is a noninvasive technique for estimating organ-level blood pressure using the strong correlation between the subharmonic signal and ambient pressure. The compressible gas core of microbubbles enables them to generate linear and nonlinear acoustic responses when exposed to ultrasound. Here, the sulfur hexafluoride (SF6) gas core of SonoVue (known as Lumason in the United States), a clinical contrast agent, was exchanged with a perfluorobutane (PFB) core to investigate its effect on the SHAPE response. MethodsExcitations of 25–700 kPa peak negative pressure (PNP) and 3 MHz transmission frequency were used to study in vitro the effects of overpressure changes ranging from 5 to 25 kPa (37–186 mm Hg). ResultsUnlike SonoVue with SF6, at low PNPs (<400 kPa), SonoVue with a PFB gas core exhibited no subharmonic at the atmospheric pressure, but during pressurization, a stable subharmonic response (maximum of 25 dB at 100 kPa PNP and 20 kPa Overpressure) appeared. SonoVue with a PFB gas core showed an increase in subharmonics with overpressure at high PNPs (>400 kPa), which was not observed before in normal SonoVue or other lipid microbubbles. With negligible size distribution difference between these two microbubbles, these effects on subharmonic generation are likely due to the gas core, casting new light on the mechanism by which ambient overpressure affects subharmonic. ConclusionThis study may inform future SHAPE technique developments.

Volumetric Passive Acoustic Mapping and Cavitation Detection of Nanobubbles under Low-Frequency Insonation.

Gas bubbles, commonly used in medical ultrasound (US), witness advancements with nanobubbles (NB), providing improved capabilities over microbubbles (MB). NBs offer enhanced penetration into capillaries and the ability to extravasate into tumors following systemic injection, alongside prolonged circulation and persistent acoustic contrast. Low-frequency insonation (<1 MHz) with NBs holds great potential in inducing significant bioeffects, making the monitoring of their acoustic response critical to achieving therapeutic goals. We introduce a US-guided focused US system comprising a one-dimensional (1D) motorized rotating imaging transducer positioned within a low-frequency therapeutic transducer (center frequencies of 105 and 200 kHz), facilitating precise monitoring of NB cavitation activity in three-dimensional (3D) and comparison with MBs. Passive cavitation detection (PCD) revealed frequency-dependent responses, with NBs exhibiting significantly higher stable and inertial cavitation doses compared to MBs of the same gas volume when excited at a center frequency of 105 kHz and peak negative pressures ranging from 100 to 350 kPa. At 200 kHz, MBs showed higher cavitation doses than NBs. PCD showed that 105 kHz enhanced both NBs' and MBs' oscillations compared to 200 kHz. The system was further used for 3D passive acoustic mapping (PAM) to provide spatial resolution alongside PCD monitoring. Two-dimensional PAM was captured for each rotation angle and used to generate a complete 3D PAM reconstruction. Experimental results obtained from a tube phantom demonstrated consistent contrast PAM full-width half-maximum (FWHM) as a function of rotation angle, with similar FWHM between MBs and NBs. Frequency-selective PAM maps distinguished between stable and inertial cavitation via the harmonic, ultraharmonic and broadband content, offering insights into cavitation dynamics. These findings highlight NBs' superior performance at lower frequencies. The developed 3D-PAM technique with a 1D transducer presents a promising technology for real-time, noninvasive monitoring of cavitation-based US therapies.

Ultrasound-responsive collagen scaffolds for tissue engineering

Homogeneous nutrient distribution throughout three-dimensional (3-D) scaffolds remains a key challenge in tissue engineering. The buildup of cells on scaffold edges and rapid nutrient uptake along the periphery often cause large regions of the centre to be left unoccupied by cells. Microstreaming associated with acoustic cavitation has been exploited to enhance mass transport in oncological drug delivery and transdermal vaccination, making it an attractive mechanism for promoting nutrient and oxygen distribution in tissue engineering scaffolds. In this work, we seek to use protein cavitation nuclei to synthesize ultrasound-responsive collagen scaffolds. Cavitation nuclei were embedded into the scaffold during fabrication and then exposed to 0.5 MHz focused ultrasound at peak negative pressures ranging from 0.5 to 2.7 MPa to induce inertial cavitation. Acoustic data was collected using passive cavitation detection (PCD) and post processed to isolate harmonics and broadband emissions. We compare the benefits and disadvantages of including cavitation nuclei in the scaffold fabrication process versus adding them to surrounding media during ultrasound exposure, discussing potential use of embedded protein nuclei to induce cell migration and differentiation. Additionally, we examine the effects of cavitation, exposure time, and peak negative pressure on the microstructure of collagen scaffolds, namely, pore size, interconnectivity, and percolation diameter.

Assessment of an image-guided histotripsy system for renal cell carcinoma

Renal cell carcinoma cancer (RCC) is the sixth most common cancer in the United States. Although surgery remains the primary choice for the initial treatment, the number of patients who qualify decreases annually due to an aging population with multiple comorbidities. Histotripsy, a non-thermal focused ultrasound technique that ablates tissue through the generation of bubble clouds, has emerged as a promising non-invasive treatment for RCC. In this study, an image-guided histotripsy system for targeting RCC was build and characterized. A focused histotripsy transducer was developed with an elliptical geometry (12/9.6-cm major/minor dimensions), 8-cm focal length, and 1-MHz fundamental frequency. The acoustic field of the transducer was assessed in the linear and nonlinear regimes. Histotripsy pulses with a 10-cycle duration were capable of generating bubbles for peak negative pressures greater than 20 MPa. The transducer was equipped with a port for a curvilinear imaging probe to facilitate therapy guidance. Bubble detection was performed in a scattering phantom with ultrafast imaging. An image processing pipeline was developed that achieved a bubble-to-tissue ratio greater than 19 dB. Overall, this system has the capacity to serve as a prototype tool for both preclinical and clinical investigations into histotripsy treatment of RCC.

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.

Evaluation of a Multimodal Confocal Therapeutic Focused Ultrasound Apparatus: Bridging Cavitation, Thermal Ablation, and Histotripsy in Preclinical Treatments

ObjectivesThe development of versatile and user-friendly preclinical platforms is vital for therapeutic ultrasound research. We introduce a flexible ultrasound-guided focused ultrasound (FUS) platform with two confocal therapeutic transducers, allowing thermal and mechanical modalities, and present its design and, features, with validation of potential applications in preclinical studies. MethodsThe probe's acoustic properties, energy delivery efficiency, and thermal and mechanical modalities are characterized. A computational model predicts thermal effects while optimizing treatment parameters. Ex vivo tissue samples are used to validate system performance, safety, and usability. In vivo experiments on mice with MC38 tumors are presented with immunohistochemistry (IHC) to validate treatment outcomes. ResultsElectroacoustic conversion efficiency levels were 80% and 40% for 1.1 MHz and 3.3 MHz, respectively. Confocal therapy transducers at 1.1 MHz and 3.3 MHz successfully demonstrated cavitation histotripsy and thermal treatments. At 1.1 MHz, for histotripsy, −20 MPa negative peak pressure is achieved, while at 3.3 MHz used for thermal ablation a maximum of 35 MPa is reached for positive peak pressure. Numerical analysis provides thermal treatment planning, aligning with in vitro and in vivo experiments for lesion prediction. Real-time in vivo cavitation monitoring was consistent with in vitro chemical dosimetry, ensuring treatment uniformity. ConclusionThe ultrasound platform induces thermal or mechanical lesions with precise spatial resolution, validated by IHC tissue characterization. Integrated cavitation monitoring enables real-time treatment monitoring. Coupling with thermal simulations provides optimization of thermal treatment parameters. This versatile “all-in-one” therapeutic platform supports multiple treatment modalities including cavitation, thermal ablation, and histotripsy, facilitating direct comparisons to assess their efficacy in diverse therapeutic settings.

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.