Peak Negative Pressure Research Articles

A Study on the Acoustic Response of Pickering Perfluoropentane Droplets in Different Media.

Acoustic droplet vaporization (ADV) is the physical process of liquid-to-gas phase transition mediated by pressure variations in an ultrasound field. In this study, the acoustic response of novel particle-stabilized perfluoropentane droplets was studied in bulk and confined media. The oil/water interface was stabilized by cellulose nanofibers. First, their acoustic responses under idealized conditions were examined to assess their susceptibility to undergo ADV. Second, the droplets were studied in a more realistic setting and placed in a confined medium. Lastly, an imaging setup was developed and tested on the droplets. The acoustic response could be seen when the amplitude of the peak negative pressure (PNP) was above 200 kPa, suggesting that this is the vaporization pressure threshold for these droplets. Increasing the PNP resulted in a decrease in signal intensity over time, suggesting a more destructive behavior. The imaging setup was able to differentiate between the droplets and the surrounding tissue. Results obtained within this study suggest that these droplets have potential in terms of ultrasound-mediated diagnostics and therapy.

Sensitization of nerve cells to ultrasound stimulation through Piezo1-targeted microbubbles

Neuromodulation by ultrasound (US) has recently drawn considerable attention due to its great advantages in noninvasiveness, high penetrability across the skull and highly focusable acoustic energy. However, the mechanisms and safety from US irradiation still remain less understood. Recently, documents revealed Piezo1, a mechanosensitive cation channel, plays key role in converting mechanical stimuli from US through its trimeric propeller-like structure. Here, we developed a Piezo1-targeted microbubble (PTMB) which can bind to the extracellular domains of Piezo1 channel. Due to the higher responsiveness of bubbles to mechanical stimuli from US, significantly lower US energy for these PTMB-binding cells may be needed to open these mechanosensitive channels. Our results showed US energy at 0.03 MPa of peak negative pressure can achieve an equivalent level of cytoplasmic Ca2+ transients which generally needs 0.17 MPa US intensity for the control cells. Cytoplasmic Ca2+ elevations were greatly reduced by chelating extracellular calcium ions or using the cationic ion channel inhibitors, confirming that US-mediated calcium influx are dependent on the Piezo1 channels. No bubble destruction and obvious temperature increase were observed during the US exposure, indicating cavitation and heating effects hardly participate in the process of Ca2+ transients. In conclusion, our study provides a novel strategy to sensitize the response of nerve cells to US stimulation, which makes it safer application for US-mediated neuromodulation in the future.

Single-cell mapping of focused ultrasound-transfected brain

Gene delivery via focused ultrasound (FUS) mediated blood-brain barrier (BBB) opening is a disruptive therapeutic modality. Unlocking its full potential will require an understanding of how FUS parameters (e.g., peak-negative pressure (PNP)) affect transfected cell populations. Following plasmid (mRuby) delivery across the BBB with 1 MHz FUS, we used single-cell RNA-sequencing to ascertain that distributions of transfected cell types were highly dependent on PNP. Cells of the BBB (i.e., endothelial cells, pericytes, and astrocytes) were enriched at 0.2 MPa PNP, while transfection of cells distal to the BBB (i.e., neurons, oligodendrocytes, and microglia) was augmented at 0.4 MPa PNP. PNP-dependent differential gene expression was observed for multiple cell types. Cell stress genes were upregulated proportional to PNP, independent of cell type. Our results underscore how FUS may be tuned to bias transfection toward specific brain cell types in vivo and predict how those cells will respond to transfection.

Endocavity Histotripsy for Efficient Tissue Ablation-Transducer Design and Characterization.

A 34-mm aperture transducer was designed and tested for proof of concept to ablate tissues using an endocavity histotripsy device. Several materials and two drivers were modeled and tested to determine an effective piezoelectric-matching layer combination and driver design. The resulting transducer was fabricated using 1.5 MHz porous PZT and PerFORM 3-D printed acoustic lenses and was driven with a multicycle class-D amplifier. The lower frequency, compared to previously developed small form factor histotripsy transducers, was selected to allow for more efficient volume ablation of tissue. The transducer was characterized and tested by measuring pressure field maps in the axial and lateral planes and pressure output as a function of driving voltage. The axial and lateral full-width-half-maximums of the focus were found to be 6.1 and 1.1 mm, respectively. The transducer was estimated to generate 34.5-MPa peak negative focal pressure with a peak-to-peak driving voltage of 1345 V. Performance testing was done by ablating volumes of bovine liver tissues ( n = 3 ). The transducer was found to be capable of ablating tissues at its full working distance of 17 mm.

Experimental and numerical study of aerodynamic pressures on platform screen doors at the overtaking station of a high-speed subway

As one of the means of urban rail transit, the subway plays a very important role in alleviating urban traffic pressure. With the continuous improvement of subway train speed, the pressure loads on platform screen doors (PSDs) are significant for the safety of subway line operation and the development of high-speed subways. In this study, taking a high-speed subway line as the research object, the aerodynamic pressures on the PSD are studied by experimental and numerical methods. The influence of the train's speed passing through the station, the distance between PSD and the central line of the track, and the air shaft at both ends of the station on the aerodynamic pressure of PSD are analyzed. The results demonstrate that the peak positive and peak negative pressures on the PSD are caused by the head and tail of the train passing through the PSD, respectively. The peak pressure on the PSD is proportional to the square of the train speed. Moreover, the peak value basically decreases along the length of the platform and uniformly distributed in the vertical direction. For a high-speed subway line, the peak aerodynamic pressure of the PSD of the overtaking station can be reduced by increasing the distance between PSD and the central line of the track. Moreover, the air shaft at the exit of the station has little effect on the PSD's aerodynamic pressure. However, when the air shaft at the station entrance is closed, the peak positive pressure of the PSD decreases, and the peak negative pressure increases. Therefore, in the high-speed subway line, the air shaft should be set at both the subway station entrance and exit.

Nanodroplet-mediated catheter-directed sonothrombolysis of retracted blood clots

One major challenge in current microbubble (MB) and tissue plasminogen activator (tPA)-mediated sonothrombolysis techniques is effectively treating retracted blood clots, owing to the high density and low porosity of retracted clots. Nanodroplets (NDs) have the potential to enhance retracted clot lysis owing to their small size and ability to penetrate into retracted clots to enhance drug delivery. For the first time, we demonstrate that a sub-megahertz, forward-viewing intravascular (FVI) transducer can be used for ND-mediated sonothrombolysis, in vitro. In this study, we determined the minimum peak negative pressure to induce cavitation with low-boiling point phase change nanodroplets and clot lysis. We then compared nanodroplet mediated sonothrombolysis to MB and tPA mediate techniques. The clot lysis as a percent mass decrease in retracted clots was 9 ± 8%, 9 ± 5%, 16 ± 5%, 14 ± 9%, 17 ± 9%, 30 ± 8%, and 40 ± 9% for the control group, tPA alone, tPA + US, MB + US, MB + tPA + US, ND + US, and ND + tPA + US groups, respectively. In retracted blood clots, combined ND- and tPA-mediated sonothrombolysis was able to significantly enhance retracted clot lysis compared with traditional MB and tPA-mediated sonothrombolysis techniques. Combined nanodroplet with tPA-mediated sonothrombolysis may provide a feasible strategy for safely treating retracted clots.

Tests of dynamic impact from trains on noise barriers

The article presents an investigation on the dynamic impact from passing trains on noise barriers. The effect was an investigation along two railway line sections: on the first section the barriers were located less than 3.8 m from the track axis and considerable distress of the barriers was observed; on the second section barriers of the same type were located 4.6 m from the track axis and no distress was noted. A method for determination of displacement occurring under aerodynamic loading is presented, based on measurement of vibration acceleration and calculation of double integral. The obtained results are compared with measurements from an interferometric radar. Parameters for analysis and assessment of the magnitude of dynamic impact from passing trains are proposed. The results of the analyses performed on the two railway line sections are compared. The article also presents laboratory tests of an undamaged noise barrier panel. Conclusions are formulated regarding the use of noise barriers susceptible to fatigue due to alternating positive and negative aerodynamic pressure peaks.

A High-Frequency Phased Array System for Transcranial Ultrasound Delivery in Small Animals.

Existing systems for applying transcranial focused ultrasound (FUS) in small animals produce large focal volumes relative to the size of cerebral structures available for interrogation. The use of high ultrasonic frequencies can improve targeting specificity; however, the aberrations induced by rodent calvaria at megahertz frequencies severely distort the acoustic fields produced by single-element focused transducers. Here, we present the design, fabrication, and characterization of a high-frequency phased array system for transcranial FUS delivery in small animals. A transducer array was constructed by micromachining a spherically curved PZT-5H bowl (diameter = 25 mm, radius of curvature = 20 mm, fundamental frequency = 3.3 MHz) into 64 independent elements of equal surface area. The acoustic field generated by the phased array was measured at various target locations using a calibrated fiber-optic hydrophone, both in free-field conditions as well as through ex vivo rat skullcaps with and without hydrophone-assisted phase aberration corrections. Large field-of-view acoustic field simulations were carried out to investigate potential grating lobe formation. The focal beam size obtained when targeting the array's geometric focus was [Formula: see text] mm in water. The array can steer the FUS beam electronically over cylindrical volumes of 4.5 mm in diameter and 6 mm in height without introducing grating lobes. Insertion of a rat skullcap resulted in substantial distortion of the acoustic field ( [Formula: see text]% [Formula: see text]); however, phase corrections restored partial focal quality ( [Formula: see text]% [Formula: see text]). Using phase corrections, the array is capable of generating a trans-rat skull peak negative focal pressure of up to ~2.0 MPa, which is sufficient for microbubble-mediated blood-brain barrier permeabilization at this frequency.

Visuomotor Transformations Are Modulated by Focused Ultrasound over Frontal Eye Field

Neuromodulation with focused ultrasound (FUS) is being widely explored as a non-invasive tool to stimulate focal brain regions because of its superior spatial resolution and coverage compared with other neuromodulation methods. The precise effects of FUS stimulation on specific regions of the brain are not yet fully understood. Here, we characterized the behavioral effects of FUS stimulation directly applied through a craniotomy over the macaque frontal eye field (FEF). In macaque monkeys making directed eye movements to perform visual search tasks with direct or arbitrary responses, focused ultrasound was applied through a craniotomy over the FEF. Saccade response times (RTs) and error rates were determined for trials without or with FUS stimulation with pulses at a peak negative pressure of either 250 or 425 kPa. Both RTs and error rates were affected by FUS. Responses toward a target located contralateral to the FUS stimulation were approximately 3 ms slower in the presence of FUS in both monkeys studied, while only one exhibited a slowing of responses for ipsilateral targets. Error rates were lower in one monkey in this study. In another search task requiring making eye movements toward a target (pro-saccades) or in the opposite direction (anti-saccades), the RT for pro-saccades increased in the presence of FUS stimulation. Our results indicate the effectiveness of FUS to modulate saccadic responses when stimulating FEF in awake, behaving non-human primates.

Influence of High Intensity Focused Ultrasound on the Microstructure and c-di-GMP Signaling of Pseudomonas aeruginosa Biofilms.

Bacterial biofilms are typically more tolerant to antimicrobials compared to bacteria in the planktonic phase and therefore require alternative treatment approaches. Mechanical biofilm disruption from ultrasound may be such an alternative by circumventing rapid biofilm adaptation to antimicrobial agents. Although ultrasound facilitates biofilm dispersal and may enhance the effectiveness of antimicrobial agents, the resulting biological response of bacteria within the biofilms remains poorly understood. To address this question, we investigated the microstructural effects of Pseudomonas aeruginosa biofilms exposed to high intensity focused ultrasound (HIFU) at different acoustic pressures and the subsequent biological response. Confocal microscopy images indicated a clear microstructural response at peak negative pressures equal to or greater than 3.5 MPa. In this pressure amplitude range, HIFU partially reduced the biomass of cells and eroded exopolysaccharides from the biofilm. These pressures also elicited a biological response; we observed an increase in a biomarker for biofilm development (cyclic-di-GMP) proportional to ultrasound induced biofilm removal. Cyclic-di-GMP overproducing mutant strains were also more resilient to disruption from HIFU at these pressures. The biological response was further evidenced by an increase in the relative abundance of cyclic-di-GMP overproducing variants present in the biofilm after exposure to HIFU. Our results, therefore, suggest that both physical and biological effects of ultrasound on bacterial biofilms must be considered in future studies.

Evaluation of the properties of daughter bubbles generated by inertial cavitation of preformed microbubbles

Inertial cavitation (IC) of the preformed microbubbles is being investigated for ultrasound imaging and therapeutic applications. However, microbubbles rupture during IC, creating smaller daughter bubbles (DBs), which may cause undesired bioeffects in the target region. Thus, it is important to determine the properties of DBs to achieve controllable cavitation activity for applications. In this study, we theoretically calculated the dissolution dynamics of sulfur hexafluoride bubbles. Then, we applied a 1-MHz single tone burst with different peak negative pressures (PNPs) and pulse lengths (PLs), and multiple 5-MHz tone bursts with fixed acoustic conditions to elicit IC of the preformed SonoVue microbubbles and scattering of DBs, respectively. After the IC and scattering signals were received by a 7.5-MHz transducer, time- and frequency-domain analysis was performed to obtain the IC dose and scattering intensity curve. The theoretical dissolution curves and measured scattering intensity curves were combined to determine the effect of the incident pulse parameters on the lifetime, mean radius and distribution range of DBs. Increased PNP reduced the lifetime and mean size of the DBs population and narrowed the size distribution. The proportion of small DBs (less than resonance size) increased from 36.83% to 85.98% with an increase in the PNP from 0.6 to 1.6 MPa. Moreover, increased PL caused a shift of the DB population to the smaller bubbles with shorter lifetime and narrower distribution. The proportion of small bubbles increased from 25.74% to 95.08% as the PL was increased from 5 to 100 µs. Finally, increased IC dose caused a smaller mean size, shorter lifetime and narrower distribution in the DB population. These results provide new insight into the relationship between the incident acoustic parameters and the properties of DBs, and a feasible strategy for achieving controllable cavitation activity in applications.

Ultrasound and microbubbles (USMB) potentiated doxorubicin penetration and distribution in 3D breast tumour spheroids

Ultrasound and microbubbles (USMB) has been shown to improve chemotherapy in vitro cell suspension and monolayer models. These models are limited in their ability to study the potential of USMB in enhancing drug penetration within a three-dimensional (3D) tissue model which can in part reproduce the organization of a microtumour recapitulating cell-cell interactions and diffusion of molecules through the tissue. The 3D tumour spheroid models are considered as bridge for filling the gap between 2D in vitro monolayer cultured cells and animal models. In this study, we developed a 3D MDA-MB-231 breast cancer spheroid model and investigated the potential of USMB in enhancing drug penetration and distribution within the spheroid. The 3D spheroids were exposed to USMB (770 kPa Peak negative pressure, 1 MHz pulse frequency, 8 μs pulse duration and 2 m s pulse repetition period; and Definity at 1.7% v/v concentration) and doxorubicin (Dox) at 50 μM concentration. The short- and long-term effects on the spheroids were assessed using flow cytometry and Laser scanning confocal microscopy (LSCM). The application of USMB enhanced penetration of Dox into deeper regions of tumour spheroid. The Dox distribution was assessed using 3D optical sectioning and radial profiling at different z-planes of the spheroids. The flow cytometry data confirms that the USMB increases the Dox uptake per cell by 25% with 1.2 fold increase in total Dox fluorescence. No significant differences were observed in the long-term spheroid size with Dox + USMB compared to Dox alone. However, the spheroids appear more dispersed with the combined treatment of Dox + USMB compared to Dox alone. The tumour model show the enhanced chemotherapeutic effect in 3D tumour spheroids of USMB along with increased penetration and accumulation of chemotherapeutic molecules into deeper spheroid regions.

Comparative study of full-scale and model-scale wind pressure measurements on a gable roof low-rise building

A full-scale experimental low-rise building with gable roof was constructed in a typhoon-prone area in China, aiming to study the wind effects on a typical low-rise building during tropical cyclones. Meanwhile, it was also intended to provide reliable full-scale measurements for verification of widely used simulation techniques, such as wind tunnel testing and numerical simulation. This paper presents a detailed comparative study of the wind effects on the experimental building between the full-scale measurements during six tropical cyclones and the wind tunnel test results on a 1:50 scaled model of the low-rise building, including point pressure coefficients, area-averaged pressure coefficients and wind pressure probability density functions. The model-scale and full-scale mean pressure coefficients exhibits a good agreement. However, significant differences are found for the root-mean-square (RMS) and peak negative pressure coefficients on the gable end roof under oblique winds. The probable causes for these discrepancies including inadequacy of large-scale turbulence, mismatch of Reynolds number and elevation angles (vertical wind angle of attack) in the wind tunnel test are explored based on the field measurements.

Microbubbles Containing Lysolipid Enhance Ultrasound-Mediated Blood-Brain Barrier Breakdown In Vivo.

Ultrasound and microbubbles (MBs) offer a noninvasive method of temporarily enhancing blood-brain barrier (BBB) permeability to therapeutics. To reduce off-target effects, it is desirable to minimize the ultrasound pressures required. It has been shown that a new formulation of MBs containing lysolipids (Lyso-MBs) can increase the cellular uptake of a model drug in vitro. The aim of this study is to investigate whether Lyso-MBs can also enhance BBB permeability in vivo. Female BALB/c mice are injected with either Lyso-MBs or control MBs and gadolinium-DTPA (Gd-DTPA) and exposed to ultrasound (500 kHz, 1Hz pulse repetition frequency, 1 ms pulse length, peak-negative pressures 160-480 kPa)for 2 min. BBB permeabilization is measured via magnetic resonance imaging (7.0 T) of Gd-DTPA extravasation and subsequent histological examination of brain tissue to assess serum immunoglobulin G (IgG) extravasation (n = 8 per group). An approximately twofold enhancement in BBB permeability is produced by the Lyso-MBs at the highest ultrasound pressure compared with the control. These findings indicate that modifying the composition of phospholipid-shelled MBs has the potential to improve the efficiency of BBB opening, without increasing the ultrasound pressure amplitude required. This is particularly relevant for delivery of therapeutics deep within the brain.

Therapeutic Ultrasound Parameter Optimization for Drug Delivery Applied to a Murine Model of Hepatocellular Carcinoma

Ultrasound and microbubble (USMB)-mediated drug delivery is a valuable tool for increasing the efficiency of the delivery of therapeutic agents to cancer while maintaining low systemic toxicity. Typically, selection of USMB drug delivery parameters used in current research settings are either based on previous studies described in the literature or optimized using tissue-mimicking phantoms. However, phantoms rarely mimic in vivo tumor environments, and the selection of parameters should be based on the application or experiment. In the following study, we optimized the therapeutic parameters of the ultrasound drug delivery system to achieve the most efficient in vivo drug delivery using fluorescent semiconducting polymer nanoparticles as a model nanocarrier. We illustrate that voltage, pulse repetition frequency and treatment time (i.e., number of ultrasound pulses per therapy area) delivered to the tumor can successfully be optimized in vivo to ensure effective delivery of the semiconducting polymer nanoparticles to models of hepatocellular carcinoma. The optimal in vivo parameters for USMB drug delivery in this study were 70 V (peak negative pressure = 3.4 MPa, mechanical index = 1.22), 1-Hz pulse repetition frequency and 100-s therapy time. USMB-mediated drug delivery using in vivo optimized ultrasound parameters caused an up to 2.2-fold (p < 0.01) increase in drug delivery to solid tumors compared with that using phantom-optimized ultrasound parameters.

Tumor perfusion enhancement by ultrasound stimulated microbubbles potentiates PD-L1 blockade of MC38 colon cancer in mice

Cancer immunotherapy holds tremendous promise as a strategy for eradicating solid tumors, and its therapeutic effect highly relies on sufficient CD8+ T cells infiltration. Here, we demonstrate that ultrasound stimulated microbubble cavitation (USMC) promotes tumor perfusion, thereby increasing CD8+ T cells infiltration and anti-PD-L1 antibody delivery, then further enhancing the PD-L1 blockade of MC38 colon cancer in mice. Firstly, we optimized the mechanic index (MI) of ultrasound, and found that USMC with MI of 0.4 (equal to peak negative pressure of 0.8MPa) significantly improved the peak intensity and area under curve of tumor contrast-enhanced ultrasound. Also, flow cytometry exhibited higher percentage of infiltrating CD8+ T cells in the USMC (MI=0.4)-treated tumors than that of the control. We further explored the combination therapy of optimized USMC with anti-PD-L1 antibody. The combination therapy enhanced tumor perfusion and even led to the tumor vascular normalization. More importantly, flow cytometry showed that the combination not only increased the percentage and absolute number of tumor infiltrating CD8+ T cells, but also promoted the expression of Ki67 as well as the secretions of IFN γ and granzyme B, therefore, the combination therapy achieved greater tumor growth inhibition and longer survival than that of the monotherapies. These suggest that USMC is a promising therapeutic modality for combining immune checkpoint blockade against solid tumors.

3D microcalcification detection using a color Doppler twinkling artifact with optimized transmit conditions: Preliminary results.

Mammography is the only method that has been proven to detect breast microcalcifications (MCs), but the sensitivity of mammography varies according to breast density. This paper proposes an ultrasound (US) color Doppler twinkling artifact (CDTA) method with optimized transmit conditions to identify breast MCs without ionizing radiation. The transmit conditions for US color Doppler imaging (CDI) were optimized to enhance the sensitivity of the twinkling artifact (TA) that arises from random scattering on rough surfaces of breast MCs. To validate the proposed breast MC detection method, a chicken breast phantom with MC particles (groups of particles <400 and <240 ) was fabricated and scanned by a digital mammography system and an US research platform by an L11-5v linear array probe with a three-dimensional (3D) motion tracking system. From the phantom experiment, the proposed 3D CDTA imaging method with optimized transmit conditions (i.e., a center frequency of 5.0MHz, an f-number of 1.3, and a peak negative pressure of 1.83MPa) successfully detected all 16 MC particles, comparable to detection with mammography. For a human breast surgical specimen in the ex vivo study, all 10 MC clusters, marked by a radiologist on the mammogram, were identified with the proposed 3D CDTA imaging method. In the phantom and ex vivo breast specimen studies, the proposed 3D CDTA imaging method successfully detected MCs, and the spatial localization was highly correlated with the mammogram results. These results indicate that the proposed 3D CDTA imaging method has great potential for the detection of MCs without ionizing radiation.

Comparing rapid short-pulse to tone burst sonication sequences for focused ultrasound and microbubble-mediated blood-brain barrier permeability enhancement

ObjectiveTranscranial focused ultrasound and microbubble (FUS + MB) exposure enables targeted, noninvasive drug delivery to the brain. Given the protective nature of the blood-brain barrier (BBB), the development of sonication strategies that maximize therapeutic efficacy while minimizing the risk of tissue damage are essential. This work aimed to compare the safety of 10 ms tone bursts, widely used in the field, to a recently described rapid short-pulse (RaSP) sequence, while accounting for drug delivery potential. Materials and methodsForty-one male wild-type mice received FUS + MB exposure (1.78 MHz driving frequency; 0.5 Hz burst repetition frequency; 250 s duration; 40 μl/kg Definity) at a range of fixed pressure amplitudes. A RaSP sequence (13 five-cycle pulses/10 ms burst) was compared to 10 ms tone bursts (B10). For animals in cohort #1 (n = 26), T1 mapping was used to quantify gadobutrol extravasation. Three targets, temporarily separated by 10 min, were sonicated in each brain to compare the time dependence of BBB permeability enhancement between sequences. Red blood cell (RBC) extravasation was quantified to assess vascular damage. For animals in cohort #2 (n = 18), a single target was sonicated per brain. BBB permeability enhancement was compared between sequences by T1 mapping and the extravasation of a 3 kDa fluorescent dextran. ResultsAt a peak negative pressure of 400 kPa, the B10 sequence produced an order of magnitude greater gadobutrol and dextran extravasation compared to RaSP (p < 0.01). When accounting for BBB permeability enhancement magnitude, as measure by T1 mapping, no differences were observed between sequences in the pattern of dextran or albumin extravasation in tissue sections; however, the frequency of RBC extravasation was found to be 5 times greater with the RaSP sequence (p = 0.02). At pressure amplitudes resulting in similar levels of gadobutrol extravasation, no significant differences were observed in the time dependence of BBB permeability enhancement between sequences. ConclusionWhen accounting for the magnitude of BBB permeability enhancement, and thus the potential for drug delivery, the RaSP sequence tested here did not produce measurable improvements over the B10 sequence and may present an increased risk of vascular damage.

Evaluation of low-intensity pulsed ultrasound on doxorubicin delivery in 2D and 3D cancer cell cultures

The aim of our study was to evaluate the influence of low-intensity pulsed US on the delivery of doxorubicin (DOX) into MDA-MB-231 triple-negative breast cancer and A549 non-small cell lung cancer cell 2D and 3D cultures. US with pulse repetition frequency of 10 Hz and 1 MHz center frequency was generated with peak negative pressure of 0.5 MPa and 50% duty cycle. SonoVue microbubbles were used. Spheroids were formed using 3D Bioprinting method. DOX delivery in 2D and 3D cultures was assessed using fluorescence microscopy. US without the addition of microbubbles did not enhance the penetration of DOX into monolayer-cultured cells and tumor spheroids. In the presence of microbubbles US improved the delivery of DOX into the edge end middle zones of A549 and MDA-MB-231 spheroids. Application of low-intensity pulsed US in combination with microbubbles may be a promising approach to enhance the delivery of DOX into tumor spheroids.

A de-mixing approach for the management of large negative peaks in wind tunnel data

Large negative peak pressures commonly take place near the edges of buildings due to the presence of local corner vortices and impingement of shear layers. As a result, Probability Density Functions (PDF) of the measured pressure signals exhibit one or more components which contributes to the non-Gaussianity of the pressure loading. These mixed flows can be modeled with mixture models. Whenever several processes coexist, and when one of them is leading in the tail of the statistical distribution, it is natural to construct the extreme value model with only this process leading in the tail and not with the mixed observed pressures. In this paper, we propose a method that is based on the autocorrelation of the pressure coefficient to de-mix the measured signals. This information improves the de-mixing process where classical methods would struggle. Indeed, the two phenomena to be separated and identified might be characterized by significantly different time-scales, which are not reflected in the PDF. In this paper, the large negative pressures measured on a flat roof are analyzed and decomposed into two elementary processes, namely, the flapping corner vortex and the turbulent flow detaching from the sharp upstream edges. This paper finally shows that an accurate decomposition of the recorded pressures into their underlying modes provides a more meaningful evaluation of extreme pressures.