Enhancement of Non-Invasive Trans-Membrane Drug Delivery Using Ultrasound and Microbubbles During Physiologically Relevant Flow

Shamout, Farah E.; Pouliopoulos, Antonios N.; Lee, Patrizia; Bonaccorsi, Simone; Towhidi, Leila; Krams, Rob; Choi, James J.

doi:10.1016/j.ultrasmedbio.2015.05.003

Cited by 35 publications

(27 citation statements)

References 59 publications

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“…RaSP sonication can be implemented in a variety of in vivo applications such as bloodbrain barrier opening (Hynynen et al, 2001;Konofagou, 2012), sonoporation (Hu et al, 2013;Shamout et al, 2015;Zhou et al, 2008), clot dissolution (Bader et al, 2015;Holland et al, 2002) and targeted drug delivery (Ferrara et al, 2007). Cancer treatment is expected to benefit from RaSP sequence sonication, since a uniform drug distribution within the tumour core and periphery is essential for successful treatment.…”

Section: Clinical Importancementioning

confidence: 99%

Rapid short-pulse sequences enhance the spatiotemporal uniformity of acoustically driven microbubble activity during flow conditions

Pouliopoulos

Tinguely

et al. 2016

The Journal of the Acoustical Society of America

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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

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Section: Clinical Importancementioning

confidence: 99%

Rapid short-pulse sequences enhance the spatiotemporal uniformity of acoustically driven microbubble activity during flow conditions

Pouliopoulos

Tinguely

et al. 2016

The Journal of the Acoustical Society of America

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“…This parallel plate chamber limits cell culture to conventional monolayers on rigid boundaries and static conditions. In order to incorporate flow, others have used a commercially available microchannel flow setup (µ-Slide, Ibidi GmbH, Munich, Germany) [19], [20]. In addition, a biologically and acoustically compatible device was developed by Carugo et al [21] for monolayer cell culture under flow.…”

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confidence: 99%

Acoustic Characterization of a Vessel-on-a-Chip Microfluidic System for Ultrasound-Mediated Drug Delivery

Beekers

Rooij

Verweij

et al. 2018

IEEE Trans. Ultrason., Ferroelect., Freq. Contr.

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Ultrasound in the presence of gas-filled microbubbles can be used to enhance local uptake of drugs and genes. To study the drug delivery potential and its underlying physical and biological mechanisms, an in vitro vessel model should ideally include 3-D cell culture, perfusion flow, and membrane-free soft boundaries. Here, we propose an organ-on-a-chip microfluidic platform to study ultrasound-mediated drug delivery: the OrganoPlate. The acoustic propagation into the OrganoPlate was determined to assess the feasibility of controlled microbubble actuation, which is required to study the microbubble-cell interaction for drug delivery. The pressure field in the OrganoPlate was characterized non-invasively by studying experimentally the well-known response of microbubbles and by simulating the acoustic wave propagation in the system. Microbubble dynamics in the OrganoPlate were recorded with the Brandaris 128 ultrahigh-speed camera (17 million frames/s) and a control experiment was performed in an OptiCell, an in vitro monolayer cell culture chamber that is conventionally used to study ultrasound-mediated drug delivery. When insonified at frequencies between 1 and 2 MHz, microbubbles in the OrganoPlate experienced larger oscillation amplitudes resulting from higher local pressures. Microbubbles responded similarly in both systems when insonified at frequencies between 2 and 4 MHz. Numerical simulations performed with a 3-D finite-element model of ultrasound propagation into the OrganoPlate and the OptiCell showed the same frequency-dependent behavior. The predictable and homogeneous pressure field in the OrganoPlate demonstrates its potential to develop an in vitro 3-D cell culture model, well suited to study ultrasound-mediated drug delivery.

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“…Real-time estimation of the effective microbubble velocities (figures 4(c) and 6(c)) would allow for increased control of the induced bioeffect. Microbubbles need to move towards a surface or vessel wall to induce desired bioeffects in applications such as clot dissolution (Acconcia et al 2013, 2014, 2015, Bader et al 2015), intracellular drug delivery (Fan et al 2014, Shamout et al 2015), acoustic particle palpation (Koruk et al 2015), and molecular imaging or therapy (Dayton et al 1999). Passive monitoring of the Doppler effect through analysis of superharmonic microbubble emissions allows users to track microbubble velocities using standard passive cavitation detection systems.…”

Section: Discussionmentioning

confidence: 99%

“…In-house manufactured microbubbles were prepared following previously described methods (Pouliopoulos et al 2014, Shamout et al 2015). We measured the microbubble characteristics using optical microscopy and an automated counting algorithm (Sennoga et al 2010), finding an average size of 1.2 ± 0.8 μ m and a diameter range of 0.5–8.9 μ m. The microbubble solution was diluted in phosphate buffer saline (PBS) to a concentration of 5 × 10 7 microbubbles ml −1 .…”

Section: Methodsmentioning

confidence: 99%

Superharmonic microbubble Doppler effect in ultrasound therapy

Pouliopoulos

Choi

2016

Phys. Med. Biol.

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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 monitoring the 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 analyzed 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: 4 mm) and sonicated using a 0.5 MHz focused ultrasound transducer (peak-rarefactional pressure: 75–366 kPa, pulse length: 50 000 cycles or 100 ms) within a water tank. Microbubble acoustic emissions were captured with a coaxially aligned 7.5 MHz passive cavitation detector and spectrally analyzed 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 kHz 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 microbubbles up to 3 m s−1, prior to the onset of broadband emissions, which is an indicator for high magnitude inertial cavitation. Although the microbubble redistribution was shown to persist for the entire sonication period in dense populations, it was constrained to the first few milliseconds in lower concentrations. In conclusion, superharmonic microbubble Doppler effects can provide a quantitative measure of effective velocities of a sonicated microbubble population and could be used for monitoring ultrasound therapy in real-time.

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Enhancement of Non-Invasive Trans-Membrane Drug Delivery Using Ultrasound and Microbubbles During Physiologically Relevant Flow

Cited by 35 publications

References 59 publications

Rapid short-pulse sequences enhance the spatiotemporal uniformity of acoustically driven microbubble activity during flow conditions

Rapid short-pulse sequences enhance the spatiotemporal uniformity of acoustically driven microbubble activity during flow conditions

Acoustic Characterization of a Vessel-on-a-Chip Microfluidic System for Ultrasound-Mediated Drug Delivery

Superharmonic microbubble Doppler effect in ultrasound therapy

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