Acoustic characterization of ultrasound contrast agents with lipid-coated monodisperse microbubbles
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Lipid-coated microbubbles, which have been widely used in diagnostic ultrasound as contrast agents, also show promising applications in medical therapy. The knowledge of acoustic behaviors and shell properties with respect to Ultrasound Contrast Agents (UCA) microbubbles can greatly enhance and extend their clinical applications. A polydimethylsiloxane (PDMS-based microfluidic flow-focusing device was fabricated to produce lipid-coated microbubbles with narrow size distribution and controllable mean diameters (3-12µm). These monodisperse microbubbles show unique acoustic properties compared with commercial UCA microbubbles with wide size distribution, which makes it possible to investigate the relationship between microbubble size and attenuation coefficient, resonance frequency, or backscattering experimentally. Our studies show that monodisperse microbubbles can be tailored for optimal contrast enhancement in ultrasound imaging. By using an ultrasound spectroscopy method, the frequency-dependent attenuation coefficient for monodisperse microbubbles and polydisperse microbubbles were measured and compared. The results showed that decreasing the width of the microbubble size distribution would lead to a reduction in the bandwidth, and an increase in the magnitude ofthe attenuation spectrum. The resonance frequency determined by the attenuation coefficient peak was inversely proportional to the mean diameter of the monodisperse microbubble suspension. These conclusions corroborated the theoretical predications. The dependence of resonance frequency on acoustic pressure and lipid composition have also been examined and compared with theoretical calculations. The results demonstrated that the lipid shell of microbubbles behaviors nonlinearly, even at low pressure, which results in a decrease of resonance frequency as incident pressure was increased, approaching the resonance frequency of uncoated bubbles. Moreover, the length of the lipid hydrocarbon chain impacts the dependences of shell stiffness, attenuation coefficient, and resonance frequency on the excitation pressure. The frequency-dependent backscattering coefficients for monodisperse microbubbles have been investigated using a broadband pulses technique over different sizes, concentrations and pressures. The experimental results showed the same size-dependent resonance peaks as attenuation coefficient. It demonstrated that increasing the acoustic pressure caused a frequency shift of resonance peak, but no significant changes on magnitude. A linear dependence on microbubble concentration for backscatter coefficient was confirmed. In addition, the pressure-dependent backscattering coefficients at 2.25 MHz were studied. It is interesting to note that with the increase of incident pressure, the change of backscattering coefficients values, increase or decrease, were strongly dependent on the mean size of microbubbles.
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