Ultrasonic contrast agent shell rupture detected by inertial cavitation and rebound signals

Abstract

Determining the rupture pressure threshold of ultrasound contrast agent microbubbles has significant applications for contrast imaging, development of therapeutic agents, and evaluation of potential bioeffects. Using a passive cavitation detector, this work evaluates rupture based on acoustic emissions from single, encapsulated, gas-filled microbubbles. Sinusoidal ultrasound pulses were transmitted into weak solutions of Optison at different center frequencies (0.9, 2.8, and 4.6 MHz), pulse durations (three, five, and seven cycles of the center frequencies), and peak rarefactional pressures (0.07 to 5.39 MPa). Pulse repetition frequency was 10 Hz. Signals detected with a 13-MHz, center-frequency transducer revealed postexcitation acoustic emissions (between 1 and 5 micros after excitation) with broadband spectral content. The observed acoustic emissions were consistent with the acoustic signature that would be anticipated from inertial collapse followed by "rebounds" when a microbubble ruptures and thus generates daughter/free bubbles that grow and collapse. The peak rarefactional pressure threshold for detection of these emissions increased with frequency (e.g., 0.53, 0.87, and 0.99 MPa for 0.9, 2.8, and 4.6 MHz, respectively; five-cycle pulse duration) and decreased with pulse duration. The emissions identified in this work were separated from the excitation in time and spectral content, and provide a novel determination of microbubble shell rupture.

Fig. 1

Experimental configuration of the passive cavitation detector.

Fig. 2

Lowest amplitude excitation 4.6 MHz, seven-cycle waveform. (a) Pressure waveform measured at the transducer focus. (b) Corresponding amplitude spectrum.

Fig. 3

Highest amplitude excitation 4.6 MHz, seven-cycle waveform. (a) Pressure waveform measured at the transducer focus. (b) Corresponding amplitude spectrum.

Fig. 4

PCD measurements (13-MHz receiver) for a 4.6-MHz, seven-cycle, 0.95-MPa peak rarefactional pressure excitation. (a) Time waveform. (b) Corresponding time-frequency spectrogram.

Fig. 5

PCD measurements (13-MHz receiver) for a 4.6-MHz, seven-cycle, 2.82-MPa excitation. (a) Time waveform. (b) Corresponding time-frequency spectrogram.

Fig. 6

Peak positive and negative voltages measured by the 13-MHz PCD receiver as a function of incident peak rarefactional pressure for Optison^TM microbubbles excited with a 4.6-MHz pressure waveform. (a) Three-cycle PD. (b) Five-cycle PD. (c) Seven-cycle PD. Error bars show standard deviations. The arrows indicate the incident peak rarefactional pressure thresholds at which the first IC pulse was detected (minimum rupture threshold).

Fig. 7

Minimum rupture thresholds obtained using inertial collapse criterion (error bars represent uncertainties in the hydrophone measurement of the incident peak rarefactional pressure).

Fig. 8

Bubble dynamics simulations. (a) Measured waveform used as driving pressure. (b) Radius-time curve for a microbubble with an intact shell. (c) Radius-time curve for a microbubble with a shell that ruptures when the radius first exceeds 3 μm. (d) Radiated pressure from intact bubble (b). (e) Radiated pressure from ruptured bubble (c) with the inertial collapse and rebounds identified.