Scaling of the viscoelastic shell properties of phospholipid encapsulated microbubbles with ultrasound frequency

• In-house phospholipid microbubbles were fabricated with decreasing mean sizes.
• Frequency dependent microbubble shell properties persist at high frequencies.
• Shell stiffness increased while shell viscosity decreased with increasing frequency.

Phospholipid encapsulated microbubbles are widely employed as clinical diagnostic ultrasound contrast agents in the 1–5 MHz range, and are increasingly employed at higher ultrasound transmit frequencies. The stiffness and viscosity of the encapsulating “shells” have been shown to play a central role in determining both the linear and nonlinear response of microbubbles to ultrasound. At lower frequencies, recent studies have suggested that shell properties can be frequency dependent. At present, there is only limited knowledge of how the viscoelastic properties of phospholipid shells scale at higher frequencies. In this study, four batches of in-house phospholipid encapsulated microbubbles were fabricated with decreasing volume-weighted mean diameters of 3.20, 2.07, 1.82 and 1.61 μm. Attenuation experiments were conducted in order to assess the frequency-dependent response of each batch, resulting in resonant peaks in response at 4.2, 8.9, 12.6 and 19.5 MHz, respectively. With knowledge of the size measurements, the attenuation spectra were then fitted with a standard linearized bubble model in order to estimate the microbubble shell stiffness Sp and shell viscosity Sf, resulting in a slight increase in Sp (1.53–1.76 N/m) and a substantial decrease in Sf (0.29 × 10−6–0.08 × 10−6 kg/s) with increasing frequency. These results performed on a single phospholipid agent show that frequency dependent shell properties persist at high frequencies (up to 19.5 MHz).