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The subharmonic threshold for ultrasound contrast agents has been defined as a 20-25 dB difference between the fundamental and subharmonic (2/1) spectral components of the backscatter signal. However, this Fourier-based criterion assumes a linear time-invariant signal. A more appropriate criterion for short cycle and frequency-modulated waveforms is proposed with an adaptive signal-processing approach based on the empirical mode decomposition (EMD) method. The signal is decomposed into an orthogonal basis known as intrinsic mode functions (IMFs) and a subharmonic threshold is defined with respect to the energy ratio of the subharmonic IMF component to that of the incident signal. The method is applied to backscatter data acquired from two polymer-shelled contrast agents, Philips (#38, mean diameter 2.0 [Formula: see text]) and Point Biomedical (#12027, mean diameter 3.9 [Formula: see text]). The acoustic backscatter signals are investigated for a single contrast agent subjected to monofrequency (20 MHz, 20 cycles) and chirp (15-25 MHz, 20 cycles) forcing for incident pressures ranging from 0.5 to 2.4 MPa. In comparison to the spectral peak difference (20 dB) criterion, the EMD method is more sensitive in determining subharmonic signals.

Polymer-shelled ultrasound contrast agents (UCAs) may expel their encapsulated gas subject to ultrasound-induced shell buckling or rupture. Nonlinear oscillations of this gas bubble can produce a subharmonic component in the ultrasound backscatter. This study investigated the relationship between this gas-release mechanism and shell-thickness-to-radius ratios (STRRs) of polymer-shelled UCAs. Three types of polylactide-shelled UCAs with STRRs of 7.5, 40, and 100 nm/μm were studied. Each UCA population had a nominal mean diameter of 2 μm. UCAs were subjected to increasing static overpressure ranging from 2 to 330 kPa over a duration of 2 h in a custom-designed test chamber while being imaged using a 200× magnification video microscope at a frame rate of 5 frames/s. Digitized video images were binarized and processed to obtain the cross-sectional area of individual UCAs. Integration of the normalized cross-sectional area over normalized time, defined as buckling factor (Bf), provided a dimensionless parameter for quantifying and comparing the degree of pre-rupture buckling exhibited by the UCAs of different STRRs in response to overpressure. The UCAs with an STRR of 7.5 nm/μm exhibited a distinct shell-buckling phase before shell rupture (Bf < 1), whereas the UCAs with higher STRRs (40 and 100 nm/μm) did not undergo significant prerupture buckling (Bf ≈ 1). The difference in the overpressure response was correlated with the subharmonic response produced by these UCAs. When excited using 20-MHz ultrasound, individual UCAs (N = 3000) in populations that did not exhibit a buckling phase produced a subharmonic response that was an order of magnitude greater than the UCA population with a prominent pre-rupture buckling phase. These results indicate the mechanism of gas expulsion from these UCAs might be a relevant factor in determining the level of subharmonic response in response to high-frequency ultrasound.

This two-part study investigated shell rupture of ultrasound contrast agents (UCAs) under static overpressure conditions and the subharmonic component from UCAs subjected to 20-MHz tonebursts. Five different polylactide-shelled UCAs with shell-thickness-to-radius ratios (STRRs) of 7.5, 30, 40, 65, and 100 nm/¿m were subjected to static overpressure in a glycerol-filled test chamber. A video microscope imaged the UCAs as pressure varied from 2 to 330 kPa over 90 min. Images were postprocessed to obtain the pressure threshold for rupture and the diameter of individual microbubbles. Backscatter from individual UCAs was investigated by flowing a dilute UCA solution through a wall-less flow phantom placed at the geometric focus of a 20-MHz transducer. UCAs were subjected to 10- and 20-cycle tonebursts of acoustic pressures ranging from 0.3 to 2.3 MPa. A method based on singular-value decomposition (SVD) was employed to obtain a cumulative subharmonic score (SHS). Different UCA types exhibited distinctly different rupture thresholds that were linearly related to their STRR, but uncorrelated with UCA size. The rupture threshold for the UCAs with an STRR = 100 nm/μm was more than 4 times greater than the UCAs with an STRR = 7.5 nm/μm. The polymer-shelled UCAs produced substantial subharmonic response but the subharmonic response to 20- MHz excitation did not correlate with STRRs or UCA-rupture pressures. The 20-cycle excitation resulted in an SHS that was 2 to 3 times that of UCAs excited with 10-cycle tonebursts.