69 results found
Perryman R, Renziehausen A, Shaye H, et al., 2022, Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma, Proceedings of the National Academy of Sciences of USA, Vol: 119, ISSN: 0027-8424
Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a novel therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G protein or β-arrestin recruitment. The architecture and interactions of EMA401 in AT2R differ drastically from complexes of AT2R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2 tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation and increased levels of apoptosis in an orthotopic xenograft model of GBM.
Chattenton D, Rivens I, Jiang Z, et al., 2022, DRUG DELIVERY TO THE PONS USING SHORT-PULSE FOCUSED ULTRASOUND AND MICROBUBBLE EXPOSURE FOR THE TREATMENT OF DIFFUSE MIDLINE GLIOMA, Publisher: OXFORD UNIV PRESS INC, Pages: 35-35, ISSN: 1522-8517
Sujarittam K, Choi JJ, 2022, The relationship between bubble concentration and the acoustic emission energy of separate frequency bands, JASA Express Letters, Vol: 2, ISSN: 2691-1191
This letter presents the relationship between bubble concentration and the energy ratio of low to high frequency bands of their acoustic emissions. Two sensors, placed perpendicular and concentric to a transmitter, captured the emissions from sonicated microbubbles. Emissions from different bubbles arrived at the perpendicular sensor with small time differences. Low frequencies with periods longer than the time differences interfered constructively, while higher frequencies interfered both constructively and destructively. The low-frequency (2nd–3rd harmonics) to high-frequency (7th–12th harmonics) energy ratio increased with the bubble concentration. The relationship was not observed with the concentric sensor, where the time differences were larger.
Jiang Z, Sujarittam K, Yildiz BI, et al., 2022, Passive cavitation detection with a needle hydrophone array, IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, Vol: 69, Pages: 233-240, ISSN: 0885-3010
Therapeutic ultrasound and microbubble technologies seek to drive systemically administered microbubbles into oscillations that safely manipulate tissue or release drugs. Such procedures often detect the unique acoustic emissions from microbubbles with the intention of using this feedback to control the microbubble activity. However, most sensor systems reported introduce distortions to the acoustic signal. Acoustic shockwaves, a key emission from microbubbles, are largely absent in reported recording, possibly due to the sensors being too large or too narrowband, or having strong phase distortions. Here, we built a sensor array that countered such limitations with small, broadband sensors and a low phase distorting material. We built 8 needle hydrophones with polyvinylidene fluoride (PVDF, diameter: 2 mm) then fit them into a 3D-printed scaffold in a two-layered, staggered arrangement. Using this array, we monitored microbubbles exposed to therapeutically-relevant ultrasound pulses (center frequency: 0.5 MHz, peak-rarefactional pressure: 130-597 kPa, pulse length: 4 cycles). Our tests revealed that the hydrophones were broadband with the best having a sensitivity of -224.8± 3.2 dB re 1 V/μPa from 1 to 15 MHz. The array was able to capture shockwaves generated by microbubbles. The signal-to-noise (SNR) ratio of the array was approximately 2 times higher than individual hydrophones. Also, the array could localize microbubbles (-3dB lateral resolution: 2.37 mm) and determine the cavitation threshold (between 161 kPa and 254 kPa). Thus, the array accurately monitored and localized microbubble activities, and may be an important technological step towards better feedback control methods and safer and more effective treatments.
Morse SV, Mishra A, Chan TG, et al., 2021, Liposome delivery to the brain with rapid short-pulses of focused ultrasound and microbubbles., Journal of Controlled Release, Vol: 341, Pages: 605-615, ISSN: 0168-3659
Liposomes are clinically used drug carriers designed to improve the delivery of drugs to specific tissues while minimising systemic distribution. However, liposomes are unable to cross the blood-brain barrier (BBB) and enter the brain, mostly due to their large size (ca. 100 nm). A noninvasive and localised method of delivering liposomes across the BBB is to intravenously inject microbubbles and apply long pulses of ultrasound (pulse length: >1 ms) to a targeted brain region. Recently, we have shown that applying rapid short pulses (RaSP) (pulse length: 5 μs) can deliver drugs with an improved efficacy and safety profile. However, this was tested with a relatively smaller 3-kDa molecule (dextran). In this study, we examine whether RaSP can deliver liposomes to the murine brain in vivo. Fluorescent DiD-PEGylated liposomes were synthesized and injected intravenously alongside microbubbles. The left hippocampus of mice was then sonicated with either a RaSP sequence (5 μs at 1.25 kHz in groups of 10 ms at 0.5 Hz) or a long pulse sequence (10 ms at 0.5 Hz), with each pulse having a 1-MHz centre frequency (0.35 and 0.53 MPa). The delivery and distribution of the fluorescently-labelled liposomes were assessed by fluorescence imaging of the brain sections. The safety profile of the sonicated brains was assessed by histological staining. RaSP was shown to locally deliver liposomes across the BBB at 0.53 MPa with a more diffused and safer profile compared to the long pulse ultrasound sequence. Cellular uptake of liposomes was observed in neurons and microglia, while no uptake within astrocytes was observed in both RaSP and long pulse-treated brains. This study shows that RaSP allows a targeted and safe delivery of liposomal drugs into the murine brain with potential to deliver drugs into neuronal and glial targets.
Chan TG, Ruehl CL, Morse SV, et al., 2021, Modulation of amyloid-beta aggregation by metal complexes with a dual binding mode and their delivery across the blood-brain barrier using focused ultrasound, Chemical Science, Vol: 12, Pages: 9485-9493, ISSN: 2041-6520
One of the key hallmarks of Alzheimer's disease is the aggregation of the amyloid-β peptide to form fibrils. Consequently, there has been great interest in studying molecules that can disrupt amyloid-β aggregation. While a handful of molecules have been shown to inhibit amyloid-β aggregation in vitro, there remains a lack of in vivo data reported due to their inability to cross the blood–brain barrier. Here, we investigate a series of new metal complexes for their ability to inhibit amyloid-β aggregation in vitro. We demonstrate that octahedral cobalt complexes with polyaromatic ligands have high inhibitory activity thanks to their dual binding mode involving π–π stacking and metal coordination to amyloid-β (confirmed via a range of spectroscopic and biophysical techniques). In addition to their high activity, these complexes are not cytotoxic to human neuroblastoma cells. Finally, we report for the first time that these metal complexes can be safely delivered across the blood–brain barrier to specific locations in the brains of mice using focused ultrasound.
Jiang Z, Dickinson RJ, Hall TL, et al., 2021, A PZT-PVDF stacked transducer for short-pulse ultrasound therapy and monitoring, IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, Vol: 68, Pages: 2164-2171, ISSN: 0885-3010
Therapeutic ultrasound technologies using microbubbles require a feedback control system to perform the treatment in a safe and effective manner. Current feedback control technologies utilize the microbubble’s acoustic emissions to adjust the treatment acoustic parameters. Typical systems use two separated transducers: one for transmission and the other for reception. However, separating the transmitter and receiver leads to foci misalignment. This limitation could be resolved by arranging the transmitter and receiver in a stacked configuration. Taking advantage of an increasing number of short-pulse-based therapeutic methods, we have constructed a PZT-PVDF stacked transducer design that allows the transmission and reception of short-pulse ultrasound from the same location. Our design had a piston transmitter composed of a PZT disc (1 MHz, 12.7 mm in diameter), a backing layer, and two matching layers. A layer of Polyvinylidene fluoride (PVDF) (28 μm in thickness, 12.7 mm in diameter) was placed at the front surface of the transmitter for reception. Transmission and reception from the same location was demonstrated in pulse-echo experiments where PZT transmitted a pulse and both PZT and PVDF received the echo. The echo signal received by the PVDF was 0.43 μs shorter than the signal received by the PZT. Reception of broadband acoustic emissions using the PVDF was also demonstrated in experiments where microbubbles were exposed to ultrasound pulses. Thus, we have shown that our PZT-PVDF stack design has unique transmission and reception features that could be incorporated into a multi-element array design that improves focal superimposing, transmission efficiency, and reception sensitivity.
Martin E, Hurrell A, Choi J, et al., 2021, Quantifying the effects of standing waves within the skull for ultrasound mediated opening of the blood-brain-barrier, IEEE International Ultrasonics Symposium (IEEE IUS), Publisher: IEEE, ISSN: 1948-5719
Davies HJ, Morse SV, Copping MJ, et al., 2021, Imaging with therapeutic acoustic wavelets–short pulses enable acoustic localization when time of arrival is combined with delay and sum, IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, Vol: 68, Pages: 178-190, ISSN: 0885-3010
—Passive acoustic mapping (PAM) is an algorithm that reconstructs the location of acoustic sourcesusing an array of receivers. This technique can monitor therapeutic ultrasound procedures to confirm the spatial distribution and amount of microbubble activity induced. CurrentPAM algorithms have an excellentlateral resolution but havea poor axial resolution, making it difficult to distinguishacoustic sources within the ultrasound beams. With recentstudies demonstrating that short-length and low-pressurepulses—acoustic wavelets—have the therapeutic function,we hypothesizedthat the axial resolution could be improvedwith a quasi-pulse-echo approach and that the resolutionimprovement would depend on the wavelet’s pulse length.This article describes an algorithm that resolves acousticsources axially using time of flight and laterally using delayand-sum beamforming, which we named axial temporalposition PAM (ATP-PAM). The algorithm accommodates arapid short pulse (RaSP) sequence that can safely deliverdrugs across the blood–brain barrier. We developed ouralgorithm with simulations (k-wave) and in vitro experiments for one-, two-, and five-cycle pulses, comparingour resolution against that of two current PAM algorithms.We then tested ATP-PAM in vivo and evaluated whether thereconstructed acoustic sources mapped to drug delivery
Bezer JH, Koruk H, Rowlands CJ, et al., 2020, Elastic deformation of soft tissue-mimicking materials using a single microbubble and acoustic radiation force, Ultrasound in Medicine and Biology, Vol: 46, Pages: 3327-3338, ISSN: 0301-5629
Mechanical effects of microbubbles on tissues are central to many emerging ultrasound applications. Here, we investigated the acoustic radiation force a microbubble exerts on tissue at clinically relevant therapeutic ultrasound parameters. Individual microbubbles administered into a wall-less hydrogel channel (diameter: 25-100 µm, Young's modulus: 2-8.7 kPa) were exposed to an acoustic pulse (centre frequency: 1 MHz, pulse length: 10 ms, peak-rarefactional pressures: 0.6-1.0 MPa). Using high-speed microscopy, each microbubble was tracked as it pushed against the hydrogel wall. We found that a single microbubble can transiently deform a soft tissue-mimicking material by several micrometres, producing tissue loading-unloading curves that were similar to those produced using other indentation-based methods. Indentation depths were linked to gel stiffness. Using a mathematical model fitted to the deformation curves, we estimated the radiation force on each bubble (typically tens of nanonewtons) and the viscosity of the gels. These results provide insight into the forces exerted on tissues during ultrasound therapy and indicate a potential source of bio-effects.
Sujarittam K, Choi JJ, 2020, Angular dependence of the acoustic signal of a microbubble cloud, The Journal of the Acoustical Society of America, Vol: 148, Pages: 2958-2972, ISSN: 0001-4966
Microbubble-mediated ultrasound therapies have a common need for methods that can noninvasively monitor the treatment. One approach is to use the bubbles' acoustic emissions as feedback to the operator or a control unit. Current methods interpret the emissions' frequency content to infer the microbubble activities and predict therapeutic outcomes. However, different studies placed their sensors at different angles relative to the emitter and bubble cloud. Here, it is evaluated whether such angles influence the captured emissions such as the frequency content. In computer simulations, 128 coupled bubbles were sonicated with a 0.5-MHz, 0.35-MPa pulse, and the acoustic emissions generated by the bubbles were captured with two sensors placed at different angles. The simulation was replicated in experiments using a microbubble-filled gel channel (0.5-MHz, 0.19–0.75-MPa pulses). A hydrophone captured the emissions at two different angles. In both the simulation and the experiments, one angle captured periodic time-domain signals, which had high contributions from the first three harmonics. In contrast, the other angle captured visually aperiodic time-domain features, which had much higher harmonic and broadband content. Thus, by placing acoustic sensors at different positions, substantially different acoustic emissions were captured, potentially leading to very different conclusions about the treatment outcome.
Morse SV, Boltersdorf T, Chan TG, et al., 2020, In vivo delivery of a fluorescent FPR2/ALX-targeted probe using focused ultrasound and microbubbles to image activated microglia, RSC Chemical Biology, Vol: 1, Pages: 385-389, ISSN: 2633-0679
To image activated microglia, a small-molecule FPR2/ALX-targeted fluorescent probe was locally delivered into the brain using focused ultrasound and microbubbles. The probe did not co-localise with neurons or astrocytes but accumulated in activated microglia, making this a potential imaging tool for future drug discovery programs focused on neurological disorders.
In therapeutic ultrasound using microbubbles, it is essential to drive the microbubbles into the correct type of activity and the correct location to produce the desired biological response. Although passive acoustic mapping (PAM) is capable of locating where microbubble activities are generated, it is well known that microbubbles move rapidly within the ultrasound beam. We propose a technique that can image microbubble movement by estimating their velocities within the focal volume. Microbubbles embedded within a wall-less channel of a tissue-mimicking material were sonicated using 1-MHz focused ultrasound. The acoustic emissions generated by the microbubbles were captured with a linear array (L7-4). PAM with robust Capon beamforming was used to localize the microbubble acoustic emissions. We spectrally analyzed the time trace of each position and isolated the higher harmonics. Microbubble velocity maps were constructed from the position-dependent Doppler shifts at different time points during sonication. Microbubbles moved primarily away from the transducer at velocities on the order of 1 m/s due to primary acoustic radiation forces, producing a time-dependent velocity distribution. We detected microbubble motion both away and towards the receiving array, revealing the influence of acoustic radiation forces and fluid motion due to the ultrasound exposure. High-speed optical images confirmed the acoustically-measured microbubble velocities. Doppler PAM enables passive estimation of microbubble motion and may be useful in therapeutic applications, such as drug delivery across the blood-brain barrier, sonoporation, sonothrombolysis and drug release.
Morse SV, Boltersdorf T, Harriss BI, et al., 2020, Neuron labeling with rhodamine-conjugated Gd-based MRI contrast agents delivered to the brain via focused ultrasound, Theranostics, Vol: 10, Pages: 2659-2674, ISSN: 1838-7640
Gadolinium-based magnetic resonance imaging contrast agents can provide information regarding neuronal function, provided that these agents can cross the neuronal cell membrane. Such contrast agents are normally restricted to extracellular domains, however, by attaching cationic fluorescent dyes, they can be made cell-permeable and allow for both optical and magnetic resonance detection. To reach neurons, these agents also need to cross the blood-brain barrier. Focused ultrasound combined with microbubbles has been shown to enhance the permeability of this barrier, allowing molecules into the brain non-invasively, locally and transiently. The goal of this study was to investigate whether combining fluorescent rhodamine with a gadolinium complex would form a dual-modal contrast agent that could label neurons in vivo when delivered to the mouse brain with focused ultrasound and microbubbles.Methods: Gadolinium complexes were combined with a fluorescent, cationic rhodamine unit to form probes with fluorescence and relaxivity properties suitable for in vivo applications. The left hemisphere of female C57bl/6 mice (8-10 weeks old; 19.07 ± 1.56 g; n = 16) was treated with ultrasound (centre frequency: 1 MHz, peak-negative pressure: 0.35 MPa, pulse length: 10 ms, repetition frequency: 0.5 Hz) while intravenously injecting SonoVue microbubbles and either the 1 kDa Gd(rhodamine-pip-DO3A) complex or a conventionally-used lysine-fixable Texas Red® 3 kDa dextran. The opposite right hemisphere was used as a non-treated control region. Brains were then extracted and either sectioned and imaged via fluorescence or confocal microscopy or imaged using a 9.4 T magnetic resonance imaging scanner. Brain slices were stained for neurons (NeuN), microglia (Iba1) and astrocytes (GFAP) to investigate the cellular localization of the probes.Results: Rhodamine fluorescence was detected in the left hemisphere of all ultrasound treated mice, while none was detected in the right contr
Koruk H, Choi JJ, 2019, Displacement of a bubble located at a fluid-viscoelastic medium interface, Journal of the Acoustical Society of America, Vol: 145, ISSN: 0001-4966
A model for estimating the displacement of a bubble located at a fluid-viscoelastic medium interface in response to acoustic radiation force is presented by extending the model for a spherical object embedded in a bulk material. The effects of the stiffness and viscosity of the viscoelastic medium and the amplitude and duration of the excitation force on bubble displacement were investigated using the proposed model. The results show that bubble displacement has a nonlinear relationship with excitation duration and viscosity. The time at which the steady state is reached increases with increasing medium viscosity and decreasing medium stiffness.
Morse SV, Pouliopoulos AN, Chan TG, et al., 2019, Rapid short-pulse ultrasound delivers drugs uniformly across the murine blood-brain barrier with negligible disruption, Radiology, Vol: 291, Pages: 459-466, ISSN: 0033-8419
Background Previous work has demonstrated that drugs can be delivered across the blood-brain barrier by exposing circulating microbubbles to a sequence of long ultrasound pulses. Although this sequence has successfully delivered drugs to the brain, concerns remain regarding potentially harmful effects from disrupting the brain vasculature. Purpose To determine whether a low-energy, rapid, short-pulse ultrasound sequence can efficiently and safely deliver drugs to the murine brain. Materials and Methods Twenty-eight female wild-type mice underwent focused ultrasound treatment after injections of microbubbles and a labeled model drug, while three control mice were not treated (May-November 2017). The left hippocampus of 14 mice was exposed to low-energy short pulses (1 MHz; five cycles; peak negative pressure, 0.35 MPa) of ultrasound emitted at a rapid rate (1.25 kHz) in bursts (0.5 Hz), and another 14 mice were exposed to standard long pulses (10 msec, 0.5 Hz) containing 150 times more acoustic energy. Mice were humanely killed at 0 (n = 5), 10 (n = 3), or 20 minutes (n = 3) after ultrasound treatment. Hematoxylin-eosin (H-E) staining was performed on three mice. The delivered drug dose and distribution were quantified with the normalized optical density and coefficient of variation. Safety was assessed by H-E staining, the amount of albumin released, and the duration of permeability change in the blood-brain barrier. Statistical analysis was performed by using the Student t test. Results The rapid short-pulse sequence delivered drugs uniformly throughout the parenchyma. The acoustic energy emitted from the microbubbles also predicted the delivered dose (r = 0.97). Disruption in the blood-brain barrier lasted less than 10 minutes and 3.4-fold less albumin was released into the brain than with long pulses. No vascular or tissue damage from rapid short-pulse exposure was observable using H-E staining. Conclusion The rapid short-pulse ultrasound sequence is a minimally
El Ghamrawy A, de Comtes F, Koruk H, et al., 2019, Acoustic streaming in a soft tissue microenvironment, Ultrasound in Medicine and Biology, Vol: 45, Pages: 208-217, ISSN: 0301-5629
We demonstrated that sound can push fluid through a tissue-mimicking material. Although acoustic streaming in tissue has been proposed as a mechanism for biomedical ultrasound applications, such as neuromodulation and enhanced drug penetration, streaming in tissue or acoustic phantoms has not been directly observed. We developed a material that mimics the porous structure of tissue and used a dye and a video camera to track fluid movement. When applied above an acoustic intensity threshold, a continuous focused ultrasound beam (spatial peak time average intensity: 238 W/cm2, centre frequency: 5 MHz) was found to push the dye axially, that is, in the direction of wave propagation and in the radial direction. Dye clearance increased with ultrasound intensity and was modelled using an adapted version of Eckart's acoustic streaming velocity equation. No microstructural changes were observed in the sonicated region when assessed using scanning electron microscopy. Our study indicates that acoustic streaming can occur in soft porous materials and provides a mechanistic basis for future use of streaming for therapeutic or diagnostic purposes.
Saharkhiz N, Koruk H, Choi JJ, 2018, The effects of ultrasound parameters and microbubble concentration on acoustic particle palpation, Journal of the Acoustical Society of America, Vol: 144, Pages: 796-805, ISSN: 0001-4966
The elasticity of tissue-an indicator of disease progression-can be imaged by ultrasound elasticity imaging technologies. An acoustic particle palpation (APP) has recently been developed-the use of ultrasonically driven acoustic particles (e.g., microbubbles)-as an alternative method of tissue deformation. APP has the potential to improve the resolution, contrast, and depth of ultrasound elasticity imaging; but the tissue displacement dynamics and its dependence on acoustic pressure, center frequency, and microbubble concentration remains unknown. Here, displacements of at least 1 μm were produced by applying ultrasound onto a microbubble solution (concentration: 10 × 106 microbubbles ml-1) placed within a tunnel surrounded by a 5% gelatin phantom. Displacements of more than 10 μm were produced using a 1, 3.5, or 5 MHz center frequency pulse with peak-rarefactional pressures of 470, 785, and 1210 kPa, respectively. The deformation of the distal wall varied spatially and temporally according to the different parameters investigated. At low pressures, the deformation increased over several milliseconds until it was held at a nearly constant value. At high pressures, a large deformation occurred within a millisecond followed by a sharp decrease and long stabilization. Ultrasound exposure in the presence of microbubbles produced tissue deformation (p < 0.05) while without microbubbles, no deformation was observed.
Chan T, Morse S, Copping M, et al., 2018, Targeted delivery of DNA-Au nanoparticles across the blood-brain barrier using focused ultrasound, ChemMedChem, Vol: 13, Pages: 1311-1314, ISSN: 1860-7187
Nanoparticles have been widely studied as versatile platforms for in vivo imaging and therapy. However, their use to image and/or treat the brain is limited, as they are often unable to cross the blood–brain barrier (BBB). To overcome this problem, herein we report the use of focused ultrasound in vivo to successfully deliver DNA‐coated gold nanoparticles to specific locations in the brains of mice.
Koruk H, Choi JJ, 2018, Displacement of a bubble by acoustic radiation force into a fluid-tissue interface., Journal of the Acoustical Society of America, Vol: 143, Pages: 2535-2540, ISSN: 0001-4966
Microbubbles in an ultrasound beam experience a primary Bjerknes force, which pushes the microbubbles against a fluid-tissue interface and deforms the tissue. This interaction has been used to measure tissue elasticity and is a common interaction in many therapeutic and diagnostic applications, but the mechanisms of deformation, and how the deformation dynamic depends on the bubble and ultrasound parameters, remain unknown. In this study, a mathematical model is proposed for the displacement of a bubble onto a fluid-tissue interface and the tissue deformation in response to the primary Bjerknes force. First, a model was derived for static loading and the model's prediction of bubble-mediated tissue displacement and stresses in tissue were explored. Second, the model was updated for dynamic loading. The results showed that the bubble is both displaced by the applied force and changes its shape. The bubble displacement changes nonlinearly with the applied force. The stress values in tissue are quite high for a distance within one radius of the bubble from the bubble surface. The model proposed here is permissible in human tissue and can be used for biomedical ultrasound applications, including material characterization.
Lazarus C, Pouliopoulos AN, Tinguely M, et al., 2017, Clustering dynamics of microbubbles exposed to low-pressure 1-MHz ultrasound, Journal of the Acoustical Society of America, Vol: 142, Pages: 3135-3146, ISSN: 0001-4966
Ultrasound-driven microbubbles have been used in therapeutic applications to deliver drugs acrosscapillaries and into cells or to dissolve blood clots. Yet the performance and safety of these applica-tions have been difficult to control. Microbubbles exposed to ultrasound not only volumetricallyoscillate, but also move due to acoustic radiation, or Bjerknes, forces. The purpose of this work wasto understand the extent to which microbubbles moved and clustered due to secondary Bjerknesforces. A microbubble population was exposed to a 1-MHz ultrasound pulse with apeak-rarefactional pressure of 50–100 kPa and a pulse length of 20 ms. Microbubbles exposed tolow-pressure therapeutic ultrasound were observed to cluster at clustering rates of 0.01–0.02 micro-bubbles per duration (in ms) per initial average inter-bubble distance (inlm), resulting in 1 to 3clustered microbubbles per initial average inter-bubble distance (inlm). Higher pressures causedfaster clustering rates and a larger number of clustered microbubbles. Experimental data revealedclustering time scales, cluster localizations, and cluster sizes that were in reasonable agreementwith simulations using a time-averaged model at low pressures. This study demonstrates that clus-tering of microbubbles occurs within a few milliseconds and is likely to influence the distributionof stimuli produced in therapeutic applications.
Morse SV, Pouliopoulos AN, Chan T, et al., 2017, Rapid short-pulse (RaSP) sequences improve the distribution of drug delivery to the brain in vivo, IEEE UFFC, Publisher: IEEE, ISSN: 1948-5719
Focused ultrasound and microbubbles have been shown to locally and noninvasively open the blood-brain barrier. Despite encouraging results in human patients, several performance and safety features, such as poor drug distribution, high drug accumulation along vessels and small sites of red blood cell extravasation, have been unavoidable. We have recently developed a new ultrasound sequence - rapid short-pulse (RaSP) sequence - designed to suppress these adverse features by promoting safer modes of cavitation activity throughout capillaries. In our RaSP sequences, low-pressure short ultrasonic pulses are emitted at kHz pulse repetition frequencies (PRF) and grouped into bursts. We have shown in vitro that RaSP sequences prolong microbubble lifetime and increase their mobility, enhancing the distribution of acoustic cavitation activity. Here we evaluate the ability of RaSP sequences to improve the in vivo performance and safety of ultrasound-mediated drug delivery to the brain.
Zhang C, Yao Z-C, Ding Q, et al., 2017, Tri-needle coaxial electrospray engineering of magnetic polymer yolk-shell particles possessing dual-imaging modality, multiagent compartments, and trigger release potential, ACS Applied Materials and Interfaces, Vol: 9, Pages: 21485-21495, ISSN: 1944-8244
Particulate platforms capable of delivering multiple actives as well as providing diagnostic features have gained considerable interest over the last few years. In this study, magnetic polymer yolk–shell particles (YSPs) were engineered using a tri-needle coaxial electrospraying technique enabling dual-mode (ultrasonic and magnetic resonance) imaging capability with specific multidrug compartments via an advanced single-step encapsulation process. YSPs comprised magnetic Fe3O4 nanoparticles (MNPs) embedded in the polymeric shell, an interfacing oil layer, and a polymeric core (i.e., composite shell–oil interface–polymeric core). The frequency of the ultrasound backscatter signal was modulated through YSP loading dosage, and both T1- and T2-weighted magnetic resonance imaging signal intensities were shown to decrease with increasing MNP content (YSP outer shell). Three fluorescent dyes (selected as model probes with varying hydrophobicities) were coencapsulated separately to confirm the YSP structure. Probe release profiles were tuned by varying power or frequency of an external auxiliary magnetic field (AMF, 0.7 mT (LAMF) or 1.4 mT (HAMF)). In addition, an “inversion” phenomenon for the AMF-enhanced drug release process was studied and is reported. A low YSP cytotoxicity (5 mg/mL) and biocompatibility (murine, L929) was confirmed. In summary, magnetic YSPs demonstrate timely potential as multifunctional theranostic agents for dual-imaging modality and magnetically controlled coactive delivery.
Heymans SV, Martindale CF, Suler A, et al., 2017, Simultaneous Ultrasound Therapy and Monitoring of Microbubble-Seeded Acoustic Cavitation Using a Single-Element Transducer, IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, Vol: 64, Pages: 1234-1244, ISSN: 0885-3010
Ultrasound-driven microbubble (MB) activity is used in therapeutic applications such as blood clot dissolution and targeted drug delivery. The safety and performance of these technologies are linked to the type and distribution of MB activities produced within the targeted area, but controlling and monitoring these activities in vivo and in real time has proven to be difficult. As therapeutic pulses are often milliseconds long, MB monitoring currently requires a separate transducer used in a passive reception mode. Here, we present a simple, inexpensive, integrated setup, in which a focused single-element transducer can perform ultrasound therapy and monitoring simultaneously. MBs were made to flow through a vesselmimicking tube, placed within the transducer's focus, and were sonicated with therapeutic pulses (peak rarefactional pressure: 75-827 kPa, pulse lengths: 200 μs and 20 ms). The MB-seeded acoustic emissions were captured using the same transducer. The received signals were separated from the therapeutic signal with a hybrid coupler and a high-pass filter. We discriminated the MB-generated cavitation signal from the primary acoustic field and characterized MB behavior in real time. The simplicity and versatility of our circuit could make existing single-element therapeutic transducers also act as cavitation detectors, allowing the production of compact therapeutic systems with real time monitoring capabilities.
Pouliopoulos A, Caiqin L, Tinguely M, et al., 2016, Rapid short-pulse sequences enhance the spatiotemporal uniformity of acoustically driven microbubble activity during flow conditions, Journal of the Acoustical Society of America, Vol: 140, ISSN: 0001-4966
Despite the promise of microbubble-mediated focused ultrasound therapies, in vivo findings have revealed over-treated and under-treated regions distributed throughout the focal volume. This poor distribution cannot be improved by conventional pulse shapes and sequences, due to their limited ability to control acoustic cavitation dynamics within the ultrasonic focus. This paper describes the design of a rapid short-pulse (RaSP) sequence which is comprised of short pulses separated by μs off-time intervals. Improved acoustic cavitation distribution was based on the hypothesis that microbubbles can freely move during the pulse off-times. Flowing SonoVue® microbubbles (flow velocity: 10 mm/s) were sonicated with a 0.5 MHz focused ultrasound transducer using RaSP sequences (peak-rarefactional pressures: 146–900 kPa, pulse repetition frequency: 1.25 kHz, and pulse lengths: 5–50 cycles). The distribution of cavitation activity was evaluated using passive acoustic mapping. RaSP sequences generated uniform distributions within the focus in contrast to long pulses (50 000 cycles) that produced non-uniform distributions. Fast microbubble destruction occurred for long pulses, whereas microbubble activity was sustained for longer durations for shorter pulses. High-speed microscopy revealed increased mobility in the direction of flow during RaSP sonication. In conclusion, RaSP sequences produced spatiotemporally uniform cavitation distributions and could result in efficient therapies by spreading cavitation throughout the treatment area.
Pouliopoulos A, Choi JJ, 2016, Superharmonic microbubble Doppler effect in ultrasound therapy, Physics in Medicine and Biology, Vol: 61, ISSN: 1361-6560
The introduction of microbubbles in focused ultrasound therapies has enabled a diverse range of non-invasive technologies: sonoporation to deliver drugs into cells, sonothrombolysis to dissolve blood clots, and blood-brain barrier opening to deliver drugs into the brain. Current methods for passively monitoringthe microbubble dynamics responsible for these therapeutic effects can identify the cavitation position by passive acoustic mapping and cavitation mode by spectral analysis. Here, we introduce a new feature that can be monitored: microbubble effective velocity. Previous studies have shown that echoes from short imaging pulses had a Doppler shift that was produced by the movement of microbubbles. Therapeutic pulses are longer (>1,000 cycles) and thus produce a larger alteration of microbubble distribution due to primary and secondary acoustic radiation force effects which cannot be monitored using pulse-echo techniques.In our experiments, we captured and analysed the Doppler shift during long therapeutic pulses using a passive cavitation detector. A population of microbubbles (5×104-5×107 microbubbles ml-1) was embedded in a vessel (inner diameter: 4mm) and sonicated using a 0.5 megahertz focused ultrasound transducer (peak-rarefactional pressure: 75-366 kPa, pulse length: 50,000 cycles or 100 milliseconds) within a water tank. Microbubble acoustic emissions were captured with a coaxially aligned 7.5 megahertz passive cavitation detector and spectrally analysed to measure the Doppler shift for multiple harmonics above the 10th harmonic (i.e., superharmonics). A Doppler shift was observed on the order of tens of kilohertz with respect to the primary superharmonic peak and is due to the axial movement of the microbubbles. The position, amplitude and width of the Doppler peaks depended on the acoustic pressure and the microbubble concentration. Higher pressures increased the effective velocity of the microbubblesup to 3m/s, prior to the onset of bro
Koruk H, El Ghamrawy A, Pouliopoulos AN, et al., 2015, Acoustic particle palpation for measuring tissue elasticity, Applied Physics Letters, Vol: 107, Pages: 223701-1-223701-4, ISSN: 0003-6951
We propose acoustic particle palpation – the use of sound to press a population of acoustic particles against an interface – as a method for measuring the qualitative and quantitative mechanical properties of materials. We tested the feasibility of this method by emitting ultrasound pulses across a tunnel of an elastic material filled with microbubbles. Ultrasound stimulated the microbubble cloud to move in the direction of wave propagation, press against the distal surface, and cause deformations relevant for elasticity measurements. Shear waves propagated away from the palpation site with a velocity that was used to estimate the material’s Young’s modulus.
Shamout FE, Pouliopoulos AN, Lee P, et al., 2015, Enhancement of non-invasive trans-membrane drug delivery using ultrasound and microbubbles during physiologically relevant flow, Ultrasound in Medicine and Biology, Vol: 41, Pages: 2435-2448, ISSN: 0301-5629
Coviello C, Kozick R, Choi J, et al., 2015, Passive acoustic mapping utilizing optimal beamforming in ultrasound therapy monitoring, JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA, Vol: 137, Pages: 2573-2585, ISSN: 0001-4966
Pouliopoulos AN, Bonaccorsi S, Choi JJ, 2014, Exploiting flow to control the in vitro spatiotemporal distribution of microbubble-seeded acoustic cavitation activity in ultrasound therapy, PHYSICS IN MEDICINE AND BIOLOGY, Vol: 59, Pages: 6941-6957, ISSN: 0031-9155
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