Sensitivity improvement of subharmonic-based pressure measurement using phospholipid-coated monodisperse microbubbles.

The use of the subharmonic signal from microbubbles exposed to ultrasound is a promising safe and cost-effective approach for the non-invasive measurement of blood pressure. Achieving a high sensitivity of the subharmonic amplitude to the ambient overpressure is crucial for clinical applications. However, currently used microbubbles have a wide size distribution and diverse shell properties. This causes uncertainty in the response of the subharmonic amplitude to changes in ambient pressure, which limits the sensitivity. The aim of this study was to use monodisperse microbubbles to improve the sensitivity of subharmonic-based pressure measurements. With the same shell materials and gas core, we used a flow-focusing microfluidic chip and a mechanical agitation method to fabricate monodisperse (∼2.45-µm mean radius and 4.7 % polydisperse index) and polydisperse microbubbles (∼1.51-µm mean radius and 48.4 % polydisperse index), respectively. We varied the ultrasound parameters (i.e., the frequency, peak negative pressure (PNP) and pulse length), and found that there was an optimal excitation frequency (2.8 MHz) for achieving maximal subharmonic emission for monodisperse microbubbles, but not for polydisperse microbubbles. Three distinct regimes (occurrence, growth, and saturation) were identified in the response of the subharmonic amplitude to increasing PNP for both monodisperse and polydisperse microbubbles. For the polydisperse microbubbles, the subharmonic amplitude decreased either monotonically or non-monotonically with ambient overpressure, depending on the PNP. By contrast, for the monodisperse microbubbles, there was only a monotonic decrease at all PNPs. The maximum sensitivity (1.18 dB/kPa, R2 = 0.97) of the subharmonic amplitude to ambient overpressure for the monodisperse microbubbles was ∼6.5 times higher than that for the polydisperse microbubbles (0.18 dB/kPa, R2 = 0.88). These results show that monodisperse microbubbles can achieve a more consistent response of the subharmonic signal to changes in ambient overpressure and greatly improve the measurement sensitivity.

Improving temporal stability of stable cavitation activity of circulating microbubbles using a closed-loop controller based on pulse-length regulation.

Stable cavitation (SC) has shown great potential for novel therapeutic applications. The spatiotemporal distribution of the SC activity of microbubbles circulating in a target region is not only correlated with the uniformity of treatment, but also with some undesirable effects. Therefore, it is important to achieve controllable and desirable SC activity in target regions for improved therapeutic efficiency and biosafety. This study proposes a closed-loop feedback controller based on pulse length (PL) regulation to improve the temporal stability of SC activity. Microbubbles circulating in a physiological flowing phantom were exposed to a 1 MHz focused transducer. The SC signals produced were initially received by another 7.5 MHz plane transducer, followed by high-speed signal acquisition and real-time processing. Based on the real-time-measured SC intensity excited by the current acoustic pulse, the proposed closed-loop feedback controller used three proportional coefficients to regulate the peak negative pressure (PNP) and PL of the next acoustic pulse during the acceleration and stable stages, respectively. The results show that the rise time and the temporal stability of the SC intensity of the microbubbles circulating in these two stages were improved significantly by the optimized proportional coefficients used in the proposed controller. Importantly, when compared with the traditional closed-loop feedback controller based on PNP regulation, the proposed closed-loop feedback controller based on PL regulation reduced the probability of a transition between stable and inertial cavitation, thus avoiding the risk of disadvantageous bioeffects in practical applications. These results demonstrate the effectiveness of the proposed PL-based closed-loop feedback controller and provide a feasible strategy for realization of controllable cavitation activity in applications.

Evaluation of the properties of daughter bubbles generated by inertial cavitation of preformed microbubbles.

Inertial cavitation (IC) of the preformed microbubbles is being investigated for ultrasound imaging and therapeutic applications. However, microbubbles rupture during IC, creating smaller daughter bubbles (DBs), which may cause undesired bioeffects in the target region. Thus, it is important to determine the properties of DBs to achieve controllable cavitation activity for applications. In this study, we theoretically calculated the dissolution dynamics of sulfur hexafluoride bubbles. Then, we applied a 1-MHz single tone burst with different peak negative pressures (PNPs) and pulse lengths (PLs), and multiple 5-MHz tone bursts with fixed acoustic conditions to elicit IC of the preformed SonoVue microbubbles and scattering of DBs, respectively. After the IC and scattering signals were received by a 7.5-MHz transducer, time- and frequency-domain analysis was performed to obtain the IC dose and scattering intensity curve. The theoretical dissolution curves and measured scattering intensity curves were combined to determine the effect of the incident pulse parameters on the lifetime, mean radius and distribution range of DBs. Increased PNP reduced the lifetime and mean size of the DBs population and narrowed the size distribution. The proportion of small DBs (less than resonance size) increased from 36.83% to 85.98% with an increase in the PNP from 0.6 to 1.6 MPa. Moreover, increased PL caused a shift of the DB population to the smaller bubbles with shorter lifetime and narrower distribution. The proportion of small bubbles increased from 25.74% to 95.08% as the PL was increased from 5 to 100 µs. Finally, increased IC dose caused a smaller mean size, shorter lifetime and narrower distribution in the DB population. These results provide new insight into the relationship between the incident acoustic parameters and the properties of DBs, and a feasible strategy for achieving controllable cavitation activity in applications.