Identifying the Inertial Cavitation Threshold and Skull Effects in a Vessel Phantom Using Focused Ultrasound and Microbubbles

Tung, Yu-Chi; Choi, James J.; Baseri, Babak; Konofagou, Elisa E.

doi:10.1016/j.ultrasmedbio.2010.02.009

Cited by 78 publications

(77 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both stable and inertial cavitation have been observed to both mechanically agitate the microvascular wall (8) and cause extravasation of vascular agents (7,21). Previous reports using longer PLs of 10 or 20 ms have analyzed the acoustic emissions radiating from the acoustically driven microbubbles and have indicated that BBB disruption may occur with stable cavitation or nonviolent inertial cavitation (22)(23). However, it is difficult to infer to the type of cavitation activity present in our experiments due to the shorter duration of the PL used and the fact that we are operating at PRPs near the threshold of BBB disruption.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Choi¹,

Selert²,

Vlachos³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

137

141

View full text Add to dashboard Cite

Focused ultrasound activation of systemically administered microbubbles is a noninvasive and localized drug delivery method that can increase vascular permeability to large molecular agents. Yet the range of acoustic parameters responsible for drug delivery remains unknown, and, thus, enhancing the delivery characteristics without compromising safety has proven to be difficult. We propose a new basis for ultrasonic pulse design in drug delivery through the blood-brain barrier (BBB) that uses principles of probability of occurrence and spatial distribution of cavitation in contrast to the conventionally applied magnitude of cavitation. The efficacy of using extremely short (2.3 μs) pulses was evaluated in 27 distinct acoustic parameter sets at low peak-rarefactional pressures (0.51 MPa or lower). The left hippocampus and lateral thalamus were noninvasively sonicated after administration of Definity microbubbles. Disruption of the BBB was confirmed by delivery of fluorescently tagged 3-, 10-, or 70-kDa dextrans. Under some conditions, dextrans were distributed homogeneously throughout the targeted region and accumulated at specific hippocampal landmarks and neuronal cells and axons. No histological damage was observed at the most effective parameter set. Our results have broadened the design space of parameters toward a wider safety window that may also increase vascular permeability. The study also uncovered a set of parameters that enhances the dose and distribution of molecular delivery, overcoming standard trade-offs in avoiding associated damage. Given the short pulses used similar to diagnostic ultrasound, new critical parameters were also elucidated to clearly separate therapeutic ultrasound from disruption-free diagnostic ultrasound.F ocused ultrasound (FUS) and microbubble-based drug delivery systems (DDSs) can increase the dose of an agent in a target volume and has potential in applications such as blood-brain barrier (BBB) disruption for the treatment of neurological diseases (1, 2), molecular and viral treatment of tumors (3), gene therapy for treating heart conditions (4), and enhancement of renal ultrafiltration (5). In each method, biologically inert and preformed microbubbles, with a lipid or polymer shell, a stabilized gas core, and a diameter less than 10 μm, are systemically administered and subsequently exposed to noninvasively delivered FUS pulses. Microbubbles within the target volume are "acoustically activated" in a complex range of behaviors known as acoustic cavitation. In stable cavitation, the microbubbles expand and contract with the acoustic pressure rarefaction and compression over several cycles (6). This activity has been associated with a range of bioeffects including displacement of the vessel wall through dilation and contractions (7,8). Large radial bubble expansions may induce inertial cavitation activity, which may lead to bubble collapse due to the inertia of the surrounding media and affect the vascular physiology (8). Each type and magnitude of cavitation activity results...

show abstract

Section: Discussionmentioning

confidence: 99%

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Choi¹,

Selert²,

Vlachos³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

137

141

View full text Add to dashboard Cite

show abstract

“…McDannold et al (24) proposed the potential of using microbubble emissions to control the BBBD, based on a correlation found between the strength of second/ third harmonic components and MRI contrast enhancement post BBBD. This potential has been further suggested by several BBBD works with cavitation monitoring (21,(25)(26)(27) and other microbubble-mediated therapies (28,29). O'Reilly and Hynynen (30) designed an active controller that increases the acoustic pressure until ultraharmonic emission is detected and then reduces it by a predetermined amount.…”

mentioning

confidence: 99%

“…However, this controller becomes openloop after ultraharmonics are detected, leaving the rest of the sonication uncontrolled. Moreover, its performance relies on the detection of ultraharmonics, which may be challenging in the presence of the skull (25), in the varying ambient pressure (31), or in the case of a high broadband noise level. Having a method to further control the exposure level would be desirable and could enhance confidence that an appropriate exposure level is maintained.…”

mentioning

confidence: 99%

Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

Sun

Zhang

Power

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

199

172

View full text Add to dashboard Cite

Cavitation-facilitated microbubble-mediated focused ultrasound therapy is a promising method of drug delivery across the blood-brain barrier (BBB) for treating many neurological disorders. Unlike ultrasound thermal therapies, during which magnetic resonance thermometry can serve as a reliable treatment control modality, real-time control of modulated BBB disruption with undetectable vascular damage remains a challenge. Here a closedloop cavitation controlling paradigm that sustains stable cavitation while suppressing inertial cavitation behavior was designed and validated using a dual-transducer system operating at the clinically relevant ultrasound frequency of 274.3 kHz. Tests in the normal brain and in the F98 glioma model in vivo demonstrated that this controller enables reliable and damage-free delivery of a predetermined amount of the chemotherapeutic drug (liposomal doxorubicin) into the brain. The maximum concentration level of delivered doxorubicin exceeded levels previously shown (using uncontrolled sonication) to induce tumor regression and improve survival in rat glioma. These results confirmed the ability of the controller to modulate the drug delivery dosage within a therapeutically effective range, while improving safety control. It can be readily implemented clinically and potentially applied to other cavitation-enhanced ultrasound therapies.drug delivery | focused ultrasound | acoustic cavitation | treatment control | blood-brain barrier

show abstract

“…Nonetheless, cavitation is a very complicated process that not only depends on the pressure but also on the amount of dissolved gas and other properties of the fluid or tissue. Moreover, cavitation thresholds in the brain are variable and still largely unknown [101,61,100,62]. In this paper, we are only concerned with the possibility of cavitation in the saline solution in the transwell, which was not de-gassed in the experiment reported here.…”

mentioning

confidence: 99%

Computational and In Vitro Studies of Blast-Induced Blood-Brain Barrier Disruption

Razo

Morofuji

Meabon

et al. 2016

SIAM J. Sci. Comput.

View full text Add to dashboard Cite

Abstract. There is growing concern that blast-exposed individuals are at risk of developing neurological disorders later in life. Therefore, it is important to understand the dynamic properties of blast forces on brain cells, including the endothelial cells that maintain the blood-brain barrier (BBB), which regulates the passage of nutrients into the brain and protects it from toxins in the blood. To better understand the effect of shock waves on the BBB we have investigated an in vitro model in which BBB endothelial cells are grown in transwell vessels and exposed in a shock tube, confirming that BBB integrity is directly related to shock wave intensity. It is difficult to directly measure the forces acting on these cells in the transwell container during the experiments, and so a computational tool has been developed and presented in this paper.Two-dimensional axisymmetric Euler equations with the Tammann equation of state were used to model the transwell materials, and a high-resolution finite volume method based on Riemann solvers and the Clawpack software was used to solve these equations in a mixed Eulerian/Lagrangian frame. Results indicated that the geometry of the transwell plays a significant role in the observed pressure time series in these experiments. We also found that pressures can fall below vapor pressure due to the interaction of reflecting and diffracting shock waves, suggesting that cavitation bubbles could be a damage mechanism. Computations that include a simulated hydrophone inserted in the transwell suggest that the instrument itself could significantly alter blast wave properties. These findings illustrate the need for further computational modeling studies aimed at understanding possible blastinduced BBB damage.

show abstract

Identifying the Inertial Cavitation Threshold and Skull Effects in a Vessel Phantom Using Focused Ultrasound and Microbubbles

Cited by 78 publications

References 32 publications

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles

Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

Computational and In Vitro Studies of Blast-Induced Blood-Brain Barrier Disruption

Contact Info

Product

Resources

About