Monodisperse Versus Polydisperse Ultrasound Contrast Agents: Non-Linear Response, Sensitivity, and Deep Tissue Imaging Potential.

It has been proposed that monodisperse microbubble ultrasound contrast agents further increase the signal-to-noise ratio of contrast-enhanced ultrasound imaging. Here, the sensitivity of a polydisperse pre-clinical agent was compared experimentally with that of its size- and acoustically sorted derivatives by using narrowband pressure- and frequency-dependent scattering and attenuation measurements. The sorted monodisperse agents had up to a two-orders-of-magnitude increase in sensitivity, that is, in the average scattering cross section per bubble. Moreover, we found, for the first time, that the highly non-linear response of acoustically sorted microbubbles can be exploited to confine scattering and attenuation to the focal region of ultrasound fields used in clinical imaging. This property is a result of minimal pre-focal scattering and attenuation and can be used to minimize shadowing effects in deep tissue imaging. Moreover, it potentially allows for more localized therapy using microbubbles through the spatial control of resonant microbubble oscillations.

Bubble sorting in pinched microchannels for ultrasound contrast agent enrichment.

Ultrasound contrast agent (UCA) suspensions contain encapsulated microbubbles with a wide size distribution, with radii between 1 and 10 µm. Medical transducers generally operate at a narrow frequency bandwidth, severely limiting the fraction of bubbles that resonates to the driving ultrasound. Thus, the sensitivity of contrast enhanced ultrasound imaging, molecular imaging with targeted bubbles, and drug delivery with microbubbles can be improved by narrowing down the size distribution of the bubble suspension. Here, we use a low-cost lab-on-a-chip method for the sorting of microbubbles by their size without external actuation, based on a microfluidic separation technique known as pinched flow fractionation (PFF). We show by numerical investigation that the inclusion of particle rotation in the pinched segment is essential for an accurate description of the sorting behavior of particles with sizes close to the pinched segment width. Successful enrichment of a polydisperse contrast agent into a bubble suspension with a narrow size distribution (radius 1.56 ± 0.30 µm) was achieved with a PFF-based microdevice. This sorting technique can be readily parallelized, and may thus lead to an easy-to-use and robust device capable of enriching ultrasound contrast agents, leading to an improvement in the sensitivity of contrast ultrasound imaging.