Presence Of Microbubbles Research Articles

Enhanced oil removal from oily sand by injecting micro-macrobubbles in swirl elution

Environmental contamination by petroleum hydrocarbons was exacerbated by oil pipeline breaks, marine oil spills and discharges from industrial production. To further improve the removal performance of petroleum hydrocarbons in solid particles, the deoiling experiments of swirl elution with micro-macrobubbles on oily sands were carried out in this paper. Experiment results indicated that when particles fell from the center of the bubble, the collision efficiency was 99.3%. The instantaneous contact angle (ICA) between the macrobubbles and the oil layer was improved in the presence of microbubbles. Furthermore, the maximum ICA of bubbles attaching to the oil layer was found to occur at pH 9 in the system of oily sand mixtures ranging from pH 5 to pH 14. This finding indicated that the slightly alkaline solution was more advantageous for bubbles to attach to the oil layer than the highly alkaline solution. The optimum condition for the elution of oily sand in the mixture of pH 7–14 was pH 12, and the oil removal efficiency was 85.4% for 10 min. The oil removal efficiency of swirl elution (SE) with bubbles on oily sand at pH 12 for 10 min was superior to either SE without bubbles or air flotation (AF). The results show that the swirl elution with bubbles can effectively enhance the oil removal efficiency of oily sands and provide guidance for controlling the environmental petroleum hydrocarbon contamination and reducing the usage of surfactants.

Real-Time Intravital Multiphoton Microscopy to Visualize Focused Ultrasound and Microbubble Treatments to Increase Blood-Brain Barrier Permeability

The blood-brain barrier (BBB) is a key challenge for the successful delivery of drugs to the brain. Ultrasound exposure in the presence of microbubbles has emerged as an effective method to transiently and locally increase the permeability of the BBB, facilitating para- and transcellular transport of drugs across the BBB. Imaging the vasculature during ultrasound-microbubble treatment will provide valuable and novel insights on the mechanisms and dynamics of ultrasound-microbubble treatments in the brain. Here, we present an experimental procedure for intravital multiphoton microscopy using a cranial window aligned with a ring transducer and a 20x objective lens. This set-up enables high spatial and temporal resolution imaging of the brain during ultrasound-microbubble treatments. Optical access to the brain is obtained via an open-skull cranial window. Briefly, a 3-4 mm diameter piece of the skull is removed, and the exposed area of the brain is sealed with a glass coverslip. A 0.82 MHz ring transducer, which is attached to a second glass coverslip, is mounted on top. Agarose (1% w/v) is used between the coverslip of the transducer and the coverslip covering the cranial window to prevent air bubbles, which impede ultrasound propagation. When sterile surgery procedures and anti-inflammatory measures are taken, ultrasound-microbubble treatments and imaging sessions can be performed repeatedly over several weeks. Fluorescent dextran conjugates are injected intravenously to visualize the vasculature and quantify ultrasound-microbubble induced effects (e.g., leakage kinetics, vascular changes). This paper describes the cranial window placement, ring transducer placement, imaging procedure, common troubleshooting steps, as well as advantages and limitations of the method.

Real-Time Intravital Multiphoton Microscopy to Visualize Focused Ultrasound and Microbubble Treatments to Increase Blood-Brain Barrier Permeability.

The blood-brain barrier (BBB) is a key challenge for the successful delivery of drugs to the brain. Ultrasound exposure in the presence of microbubbles has emerged as an effective method to transiently and locally increase the permeability of the BBB, facilitating para- and transcellular transport of drugs across the BBB. Imaging the vasculature during ultrasound-microbubble treatment will provide valuable and novel insights on the mechanisms and dynamics of ultrasound-microbubble treatments in the brain. Here, we present an experimental procedure for intravital multiphoton microscopy using a cranial window aligned with a ring transducer and a 20x objective lens. This set-up enables high spatial and temporal resolution imaging of the brain during ultrasound-microbubble treatments. Optical access to the brain is obtained via an open-skull cranial window. Briefly, a 3-4 mm diameter piece of the skull is removed, and the exposed area of the brain is sealed with a glass coverslip. A 0.82 MHz ring transducer, which is attached to a second glass coverslip, is mounted on top. Agarose (1% w/v) is used between the coverslip of the transducer and the coverslip covering the cranial window to prevent air bubbles, which impede ultrasound propagation. When sterile surgery procedures and anti-inflammatory measures are taken, ultrasound-microbubble treatments and imaging sessions can be performed repeatedly over several weeks. Fluorescent dextran conjugates are injected intravenously to visualize the vasculature and quantify ultrasound-microbubble induced effects (e.g., leakage kinetics, vascular changes). This paper describes the cranial window placement, ring transducer placement, imaging procedure, common troubleshooting steps, as well as advantages and limitations of the method.

Blood-Brain Barrier Opening by Individualized Closed-Loop Feedback Control of Focused Ultrasound.

Objective and Impact Statement. To develop an approach for individualized closed-loop feedback control of microbubble cavitation to achieve safe and effective focused ultrasound in combination with microbubble-induced blood-brain barrier opening (FUS-BBBO). Introduction. FUS-BBBO is a promising strategy for noninvasive and localized brain drug delivery with a growing number of clinical studies currently ongoing. Real-time cavitation monitoring and feedback control are critical to achieving safe and effective FUS-BBBO. However, feedback control algorithms used in the past were either open-loop or without consideration of baseline cavitation level difference among subjects. Methods. This study performed feedback-controlled FUS-BBBO by defining the target cavitation level based on the baseline stable cavitation level of an individual subject with "dummy" FUS sonication. The dummy FUS sonication applied FUS with a low acoustic pressure for a short duration in the presence of microbubbles to define the baseline stable cavitation level that took into consideration of individual differences in the detected cavitation emissions. FUS-BBBO was then achieved through two sonication phases: ramping-up phase to reach the target cavitation level and maintaining phase to control the stable cavitation level at the target cavitation level. Results. Evaluations performed in wild-type mice demonstrated that this approach achieved effective and safe trans-BBB delivery of a model drug. The drug delivery efficiency increased as the target cavitation level increased from 0.5 dB to 2 dB without causing vascular damage. Increasing the target cavitation level to 3 dB and 4 dB increased the probability of tissue damage. Conclusions. Safe and effective brain drug delivery was achieved using the individualized closed-loop feedback-controlled FUS-BBBO.

High intensity focused ultrasound and microbubbles induce targeted mild hyperthermia suitable for enhanced drug delivery

High intensity focused ultrasound (HIFU) can elevate the temperature leading to tissue ablation (>60 °C). Mild hyperthermia (39–45 °C) can enhance drug delivery such as in the activation of thermosensitive liposomes for chemotherapy and in radiotherapy. The addition of microbubbles during HIFU could greatly enhance the heating process and increase the treatment area while operating at lower intensities. Here, we present a parametric study of microbubble-enhanced mild hyperthermia with HIFU in ex vivo porcine liver. A 30-s treatment at 0.9 MHz, 372 000 cycles, 82% duty cycle was used, and at estimated non-derated (water) pressures of 0.63, 1.25, 2.50 and 3.75 MPa. The microbubbles were injected locally in the treatment area. The measured temperature rise was greater with microbubbles than without at low acoustic pressures (0.63 and 1.25 MPa). At higher pressures (2.50 and 3.75 MPa), the presence of microbubbles did not have an effect on the measured temperature rise possibly due to inertial cavitation. Our results agree with predictions from a numerical model that solves the coupled acoustic-bubble flow fields with a two-way coupled Euler–Lagrange model. Future work will utilize the numerical model and new measurements to optimize targeted mild hyperthermia before applying it to enhanced drug delivery.

A Microfluidic Platform for Cavitation-Enhanced Drug Delivery.

An endothelial-lined blood vessel model is obtained in a PDMS (Polydimethylsiloxane) microfluidic system, where vascular endothelial cells are grown under physiological shear stress, allowing -like maturation. This experimental model is employed for enhanced drug delivery studies, aimed at characterising the increase in endothelial permeability upon microbubble-enhanced ultrasound-induced (USMB) cavitation. We developed a multi-step protocol to couple the optical and the acoustic set-ups, thanks to a 3D-printed insonation chamber, provided with direct optical access and a support for the US transducer. Cavitation-induced interendothelial gap opening is then analysed using a customised code that quantifies gap area and the relative statistics. We show that exposure to US in presence of microbubbles significantly increases endothelial permeability and that tissue integrity completely recovers within 45 min upon insonation. This protocol, along with the versatility of the microfluidic platform, allows to quantitatively characterise cavitation-induced events for its potential employment in clinics.

Influence of microbubbles on the production of spray-dried inhalable particles

The aim of this work was to study the effect of gas microbubbles on the production of particles suitable for inhalatory administration by a spray drying technology. An antiasthmatic model drug (sodium cromoglycate) was selected in order to evaluate the effect of different gases (air, CO2 and N2) and spray drying operating conditions on the particles aerosolization performance. To this end, gas supersaturated aqueous drug solutions were obtained in a pressurized vessel and then processed by spray drying. The process yield, morphology, size, bulk and tap densities, moisture content and aerosolization properties of the particles were evaluated. The presence of microbubbles in the spray drying feed led to powders with smaller mean geometric sizes than particles obtained without bubbles. The gas-water solubility emerged as a key parameter to obtain inhalatory particles with good aerosolization properties. High water-soluble gases led to bigger particles, while low soluble ones allow to produce smaller particles. The use of air (with an intermediate water solubility respect to CO2 and N2) and an adequate set of spray drying operating conditions allowed to obtain sodium cromoglycate particles with superior aerosolization properties than a commercial formulation. Overall, a novel, simple and low-cost method to produce inhalatory particles with excellent aerosolization properties was developed by supersaturating the spray drying liquid feed without using pore-forming agents during the production step, or carriers in the final formulation.

Microbubble-Facilitated Ultrasound Catheter Ablation Causes Microvascular Damage and Fibrosis

High-intensity ultrasound (US) ablation produces deeper myocardial lesions than radiofrequency ablation. The presence of intravascular microbubble (MB) contrast agents enhances pulsed-wave US ablation via cavitation-related histotripsy, potentially facilitating ablation in persistently perfused/conducting myocardium. US ablation catheters were developed and tested in the presence of MBs using ex vivo and in vivo models. High-frame-rate videomicroscopy and US imaging of gel phantom models confirmed MB destruction by inertial cavitation. MB-facilitated US ablation in an ex vivo perfused myocardium model generated shallow (2 mm) lesions and, in an in vivo murine hindlimb model, reduced perfusion by 42% with perivascular hemorrhage and inflammation, but no myonecrosis.

Ultrasound in the presence of microbubbles in a dynamic invitro microfluidic blood-brain barrier model

Controllable, localized permeability of the blood-brain barrier (BBB) has been a goal of health professionals for enhanced delivery of drugs and therapeutic compounds for cancer and other neurological medical conditions. The transient permeability induced by transcranial ultrasound exposure in the presence of microbubbles has been shown to be a promising option, but little is known about the exact mechanism and response on a cellular level. A microfluidic device developed to recreate the in vivo microenvironment, including physiological fluid flow, was seeded with human cerebral microvessel endothelial cells surrounded by a matrix of astrocytes. The devices were exposed to ultrasound with and without the presence of microbubbles. The ultrasound parameters ranged in frequency from 0.5 to 1.55 MHz, duty factor from 0.0001–0.001 and pulse repetition frequency of 1 Hz–10 Hz. Microbubble size, composition, and concentration within the pumped fluid were also varied, along with varied flow rate. The transepithelial electrical resistance (TEER) and cell morphology were monitored throughout and post ultrasound exposure to understand the effects on permeability and cell viability. With this controlled variation of the ultrasound and microbubble parameters, a greater understanding of the induced permeability could lead to more success for clinical utilization.

Investigation of ultrasound exposure in the presence of microbubbles on a LumeNEXT blood-brain barrier model

The blood-brain barrier (BBB) is notoriously difficult to penetrate for the delivery of drugs and therapeutic compounds due to the unique nature of the tight junctions between endothelial cells. Ultrasound in the presence of microbubbles has been discovered to transiently open the BBB, however, little is known about the mechanism and the effects of excitation parameters at a cellular level. In this study, a static vascular lumen in vitro model, LumeNEXT, was utilized to investigate the excitation parameters in a controlled manner. Fibrin lumen hydrogels were lined with human cerebral microvessel endothelial and astrocyte cells. Cells were exposed to ultrasound with and without the presence of microbubbles. The devices were exposed to ultrasound parameters ranging in frequency from 0.5 to 1.55MHz, duty factor from 0.0001–0.001 and pulse repetition frequency of 1–10 Hz. Acoustic and thermal characterization of the device was performed. Effects of microbubble size and composition on the endothelial permeability were also investigated. The transepithelial electrical resistance (TEER) and cell morphology were monitored post-ultrasound exposure to investigate endothelial permeability duration and extent. Understanding the fundamentals of ultrasound-induced permeability in a controlled manner can lead to further investigations and optimization for in vivo and clinical settings.

A novel model using Lumbricus terrestris, earthworms, for microvessel rupture induced by high-intensity therapeutic ultrasound exposure in the presence of microbubbles

A novel model using <i>Lumbricus terrestris</i>, earthworms, for microvessel rupture induced by high-intensity therapeutic ultrasound exposure in the presence of microbubbles

Degradation of aqueous atrazine using persulfate activated by electrochemical plasma coupling with microbubbles: removal mechanisms and potential applications

Persulfate (PS) activated by dielectric barrier discharge (DBD) integrated with microbubbles (MBs) was designed to decompose atrazine (ATZ) from aqueous solutions. The degradation efficiency reached 89% at a discharge power of 85W, a PS concentration of 1mM, and a air flow rate of 30mL/min after 75min treatment. Heat caused by DBD favoured ATZ removal. Besides, the effect of PS dosage, discharge power and initial pH values on ATZ removal was evaluated. The calculated energy yield revealed that it was economical and promising to treat 1L of ATZ-wastewaters. The existence of SO42−, Cl−, CO32− and HCO3− lead to negative effects, while positive effect was observed when the presence of MBs and humic acid. The identification results of radicals and degradation intermediates suggested that multiple synergistic effects (such as heat, eaq− and H•) activated PS, and 1O2/reactive nitrogen species, •OH and SO4−• with contributions of 18%, 26%, and 29%, were main species attacking ATZ. ATZ degradation pathways including olefination, alkylic-oxidation, dealkylation, and dechlorination were proposed. An environment-friendly and a novel method for enhancing the PS-activation and ATZ-decomposition was provided, which fully utilised the electric-chemical conversion of DBD and high mass transfer efficiency of MBs.

Curcumin Encapsulated Lecithin Nanoemulsions: An Oral Platform for Ultrasound Mediated Spatiotemporal Delivery of Curcumin to the Tumor

Systemic toxicity caused by conventional chemotherapy is often regarded as one of the major challenges in the treatment of cancer. Over years, the trigger-based modality has gained much attention as it holds the spatiotemporal control over release and internalization of the drug. In this article, we are reporting an increase in the anti-tumor efficacy of curcumin due to ultrasound pulses. MDA MB 231 breast cancer and B16F10 melanoma cells were incubated with lecithin-based curcumin encapsulated nanoemulsions and exposed to ultrasound in the presence and absence of microbubble. Ultrasound induced sonoporation enhanced the cytotoxicity of curcumin in MDA MB 231 and B16F10 cancer cells in the presence of microbubble by 100- and 64-fold, respectively. To study the spatiotemporal delivery of curcumin, we developed B16F10 melanoma subcutaneous tumor on both the flanks of C57BL/6 mice but only the right tumor was exposed to ultrasound. Insonation of the right tumor spatially enhanced the cytotoxicity and enabled the substantial regression of the right tumor compared to the unexposed left tumor which grew continuously in size. This study showed that the ultrasound has the potential to target and increase the drug’s throughput to the tumor and enable effective treatment.

Microstreaming inside Model Cells Induced by Ultrasound and Microbubbles.

Studies on the bioeffects produced by ultrasound and microbubbles have focused primarily on transport in bulk tissue, drug uptake by individual cells, and disruption of biological membranes. Relatively little is known about the physical perturbations and fluid dynamics of the intracellular environment during ultrasound exposure. To investigate this, a custom acoustofluidic chamber was designed to expose model cells, in the form of giant unilamellar vesicles, to ultrasound and microbubbles. The motion of fluorescent tracer beads within the lumen of the vesicles was tracked during exposure to laminar flow (∼1 mm s-1), ultrasound (1 MHz, ∼150 kPa, 60 s), and phospholipid-coated microbubbles, alone and in combination. To decouple the effects of fluid flow and ultrasound exposure, the system was also modeled numerically by using boundary-driven streaming field equations. Both the experimental and numerical results indicate that all conditions produced internal streaming within the vesicles. Ultrasound alone produced an average bead velocity of 6.5 ± 1.3 μm/s, which increased to 8.5 ± 3.8 μm/s in the presence of microbubbles compared to 12 ± 0.12 μm/s under laminar flow. Further research on intracellular forces in mammalian cells and the associated biological effects in vitro and in vivo are required to fully determine the implications for safety and/or therapy.

New insights on the role of ROS in the mechanisms of sonoporation-mediated gene delivery.

Reactive oxygen species (ROS) are hypothesized to play a role in the sonoporation mechanisms. Nevertheless, the acoustical phenomenon behind the ROS production as well as the exact mechanisms of ROS action involved in the increased cell membrane permeability are still not fully understood. Therefore, we investigated the key processes occurring at the molecular level in and around microbubbles subjected to ultrasound using computational chemistry methods. To confirm the molecular simulation predictions, we measured the ROS production by exposing SonoVue® microbubbles (MBs) to ultrasound using biological assays. To investigate the role of ROS in cell membrane permeabilization, cells were subjected to ultrasound in presence of MBs and plasmid encoding reporter gene, and the transfection level was assessed using flow cytometry. The molecular simulations showed that under sonoporation conditions, ROS can form inside the MBs. These radicals could easily diffuse through the MB shell toward the surrounding aqueous phase and participate in the permeabilization of nearby cell membranes. Experimental data confirmed that MBs favor spontaneous formation of a host of free radicals where HO was the main ROS species after US exposure. The presence of ROS scavengers/inhibitors during the sonoporation process decreased both the production of ROS and the subsequent transfection level without significant loss of cell viability. In conclusion, the exposure of MBs to ultrasound might be the origin of chemical effects, which play a role in the cell membrane permeabilization and in the in vitro gene delivery when generated in its proximity.

Effect of salinity on air dissolution, size distribution of microbubbles, and hydrodynamics of a dissolved air flotation (DAF) system

In the present study, air dissolution, size distribution and hydrodynamics of microbubbles in a dissolved air flotation system were experimentally investigated. The amount of dissolved air was calculated by Henry’s laws of gas dissolution and compared with measured values from the liquid displacement technique. The measured air concentrations were 23.2 and 10.1 mg/l for freshwater and saline water (30 g/L), respectively, which were much lower than those calculated by Henry’s equations. Shadow imaging technique was applied to measure the size distributions of microbubbles for saline and freshwater. Whilst the size of microbubbles for freshwater were between 40–250 μm, the corresponding values for the saline water were smaller and varied between 20–160 μm. Particle image velocimetry (PIV) was also applied to map flow patterns and velocities of microbubbles for saline and freshwater. The results indicated that the flow patterns were mostly affected by the flow itself rather than the salinity and the presence of microbubbles since there was not a noticeable change between single-phase (flow without microbubbles) and two-phase flows. While the range of the velocities was between 0–64 mm/s for the freshwater, it did not exceed 48 mm/s for the saline water.

Influence of Gas Microbubbles on the Wettability of Coal Surfaces

Using low-ash OS coal as a model, a method is developed for creating a hydrophobic coal surface by means of microbubbles in a gas–liquid suspension. Air microbubbles are generated by decompression. The influence of the pressure in the gas saturation of water on the size and stability of the microbubbles is established. It is shown that, in the presence of microbubbles, a hydrophobic air layer is formed at the coal surface. That provides the basis for the attachment of flotational bubbles.

P806 Cavitation phenomenon in mechanical valves: not only microbubbles

Abstract Introduction It is well described the presence of microbubbles (MBs) which are high-velocity, small, bright echoes presences that occur with the closing/opening of the mechanical double disk valve, more frequently in mitral position but less frequent growth of the cavitation bubbles are described. We considered the echo studies of patients with growth of cavitation bubbles and we evaluate the possible impact of the hemodynamic parameters of their formation and then misdiagnosis with endocarditis. Methods We analyzed retrospectively the echocardiographic studies of 49 patients with growth of cavitation bubbles and we went back to all studies until the date of surgery if available, to see in how many of those echos, this phenomenon was present. Patient"s blood pressure (BP) and heart rate (HR) measurement were available for each echo study. For the present analysis the last echo study with or without growth of cavitation bubbles were considered. The last echo study without growth of cavitation bubbles was considered as control group. Results Fourty nine patients (M26/F23) with mean age of 46.5 ± 13.6 years were identify as having growth of the cavitation bubbles and a total of 325 echo studies were reviewed. All patients had mitral valve replacement but 4, that had only aortic mechanical valve. 43% had mitral-aortic valve replacement and 5 had 3 or 4 valves replaced. The follow-up period was of 3697 ± 2481 days, 52%±31% of the echo studies reviewed had growth of the cavitation bubbles. At the time of the study systolic BP was 124 ± 12.5 vs 121.1 ± 16.4 mmHg, p = 0.1 (echo study with versus without growth cavitation respectively), diastolic 72.7 ± 10.1 vs 69.4 ± 14.9 mmHg, p= 0.2; HR 81.3 ± 19.4 vs 73.7 ± 14.1 bpm, p = 0.05. No statistical differences in trans mitral gradients were found between the two groups (peak 11.8 ± 3.9 vs 11.7 ± 4.3 mmHg, p = 0.7; mean 4.6 ± 1.9 vs 4.2 ± 1 mmHg.6p = 0.1). 33 TEE were performed and in 50% of cases because of suspecion of endocarditis. Only 2 TEE were positive for endocarditis and one positive for pannus and high gradients across the valve in addition to cavitation. Conclusion Cavitation phenomenon in mechanical valves, in particular mitral bi-leaflet valve is well known but growth of cavitation bubbles is seldom described. We found that this fenomenon is frequently present although not constant, is related with increased HR and can be responsible of misdiagnosis with endocarditis. Abstract P806 Figure.

Effect of scattered pressures from oscillating microbubbles on neuronal activity in mouse brain under transcranial focused ultrasound stimulation.

Previous studies have indicated that the presence of microbubbles (MBs) during sonication has an impact on neuronal activity, while the underlying mechanisms remain to be revealed. In this study, a model for the scattered pressures produced by the pulsating lipid-encapsulated MBs in mouse brain was developed to numerically investigate the effect of MBs on neuronal activity during transcranial focused ultrasound stimulation. The additional summed scattered pressure (Psummed_scat) from the oscillating MBs was calculated from the model. The level of neuronal activity was experimentally verified using an immunofluorescence assay with antibodies against c-fos. The pressure difference (ΔP) between acoustic pressures at which the same level of neuronal activity is excited by ultrasound stimulation with and without MBs was obtained from the experiments. The results showed that Psummed_scat accounts for about half of the ΔP when the MBs experience a "compression-only" response. The Psummed_scat suddenly increased at a critical acoustic pressure, around which a rapid enhancement of ΔP obtained from experiment also occurred. This work suggested that the additional scattered pressures from pulsating MBs are probably a mechanism that affects neuronal activity under transcranial focused ultrasound stimulation.

Translational Prospects of ultrasound-mediated tumor immunotherapy: Preclinical advances and safety considerations

Immunotherapy is considered as a promising therapeutic approach for cancer treatment. This therapy focuses on the specificity and memory of the immune system against malignant cells to achieve a sustained cure with minimal toxicity. However, the effectiveness of immunotherapy is often limited by the insufficient delivery and low accumulation of therapeutic molecules in tumors. Ultrasound exposures with the presence of microbubbles can be used as an effective method to greatly increase cell membrane permeability and enhance tissue accessibility to drugs or genes, thereby improving the access of therapeutic molecules into non-permeable tissues and enhancing the therapeutic outcomes. In this review, we discuss challenges in current tumor immunotherapy and feasible approaches that could potentially overcome these obstacles with the help of ultrasound; thereafter, we elaborate on the recent advantages of ultrasound-mediated delivery approach in tumor immunotherapy.