Angular dependence of the acoustic signal of a microbubble cloud.

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.

An Ultrasound Array of Emitter-Receiver Stacks for Microbubble-Based Therapy.

Most therapeutic ultrasound devices place emitters and receivers in separate locations, so that the long therapeutic pulses (>1 ms) can be emitted while receivers monitor the procedure. However, with such placement, emitters and receivers are competing for the same space, producing a trade-off between emission efficiency and reception sensitivity. Taking advantage of recent studies demonstrating that short-pulse ultrasound can be used therapeutically, we aimed to develop a device that overcomes such trade-offs. The array was composed of emitter-receiver stacks, which enabled both emission and reception from the same location. Each element was made of a lead zirconate titanate (PZT)-polyvinylidene fluoride (PVDF) stack. The PZT (frequency: 500 kHz, diameter: 16 mm) was used for emission and the PVDF (thickness: 28 µm, diameter: 16 mm) for broadband reception. 32 elements were assembled in a 3D-printed dome-shaped frame (focal length: 150 mm; [Formula: see text]-number: 1) and was tested in free-field and through an ex-vivo human skull. In free-field, the array had a 4.5 × 4.5 × 32 mm focus and produced a peak-negative pressure (PNP) of 2.12 MPa at its geometric center. The electronic steering range was ±15 mm laterally and larger than ±15 mm axially. Through the skull, the array produced a PNP of 0.63 MPa. The PVDF elements were able to localize broadband microbubble emissions across the skull. We built the first multi-element array for short-pulse and microbubble-based therapeutic applications. Stacked arrays overcome traditional trade-offs between the transmission and reception quality and have the potential to create a step change in treatment safety and efficacy.

The relationship between bubble concentration and the acoustic emission energy of separate frequency bands.

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.

Passive Cavitation Detection With a Needle Hydrophone Array.

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 eight needle hydrophones with polyvinylidene fluoride (PVDF, diameter: 2 mm) then fit them into a 3-D-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, pulselength: four cycles). Our tests revealed that the hydrophones were broadband with the best having a sensitivity of -224.8 dB ± 3.2 dB re 1 V/ µ Pa from 1 to 15 MHz. The array was able to capture shockwaves generated by microbubbles. The signal-to-noise ratio (SNR) of the array was approximately two times higher than individual hydrophones. Also, the array could localize microbubbles (-3 dB lateral resolution: 2.37 mm) and determine the cavitation threshold (between 161 and 254 kPa). Thus, the array accurately monitored and localized microbubble activities, and may be an important technological step toward better feedback control methods and safer and more effective treatments.

Imaging With Therapeutic Acoustic Wavelets-Short Pulses Enable Acoustic Localization When Time of Arrival is Combined With Delay and Sum.

Passive acoustic mapping (PAM) is an algorithm that reconstructs the location of acoustic sources using an array of receivers. This technique can monitor therapeutic ultrasound procedures to confirm the spatial distribution and amount of microbubble activity induced. Current PAM algorithms have an excellent lateral resolution but have a poor axial resolution, making it difficult to distinguish acoustic sources within the ultrasound beams. With recent studies demonstrating that short-length and low-pressure pulses-acoustic wavelets-have the therapeutic function, we hypothesized that the axial resolution could be improved with a quasi-pulse-echo approach and that the resolution improvement would depend on the wavelet's pulse length. This article describes an algorithm that resolves acoustic sources axially using time of flight and laterally using delay-and-sum beamforming, which we named axial temporal position PAM (ATP-PAM). The algorithm accommodates a rapid short pulse (RaSP) sequence that can safely deliver drugs across the blood-brain barrier. We developed our algorithm with simulations (k-wave) and in vitro experiments for one-, two-, and five-cycle pulses, comparing our resolution against that of two current PAM algorithms. We then tested ATP-PAM in vivo and evaluated whether the reconstructed acoustic sources mapped to drug delivery within the brain. In simulations and in vitro, ATP-PAM had an improved resolution for all pulse lengths tested. In vivo, experiments in mice indicated that ATP-PAM could be used to target and monitor drug delivery into the brain. With acoustic wavelets and time of flight, ATP-PAM can locate acoustic sources with a vastly improved spatial resolution.

Doppler Passive Acoustic Mapping.

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 rapidly move 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 toward 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.