Abstract
Micron-sized lipid-stabilised bubbles of heavy gas have been utilised as contrast agents for diagnostic ultrasound (US) imaging for many years. Typically bubbles between 1 and 8 μm in diameter are produced to enhance imaging in US by scattering sound waves more efficiently than surrounding tissue. A potential area of interest for Contrast Enhanced Ultrasound (CEUS) are bubbles with diameters <1 μm or 'nanobubbles.' As bubble diameter decreases, ultrasonic resonant frequency increases, which could lead to an improvement in resolution for high-frequency imaging applications when using nanobubbles. In addition, current US contrast agents are limited by their size to the vasculature in vivo. However, molecular-targeted nanobubbles could penetrate into the extra-vascular space of cancerous tissue providing contrast in regions inaccessible to traditional microbubbles. This paper reports a new microfluidic method for the generation of sub-micron sized lipid stabilised particles containing perfluorocarbon (PFC). The nanoparticles are produced in a unique atomisation-like flow regime at high production rates, in excess of 10(6) particles per s and at high concentration, typically >10(11) particles per mL. The average particle diameter appears to be around 100-200 nm. These particles, suspected of being a mix of liquid and gaseous C4F10 due to Laplace pressure, then phase convert into nanometer sized bubbles on the application of US. In vitro ultrasound characterisation from these nanoparticle populations showed strong backscattering compared to aqueous filled liposomes of a similar size. The nanoparticles were stable upon injection and gave excellent contrast enhancement when used for in vivo imaging, compared to microbubbles with an equivalent shell composition.
Highlights
Micron-sized lipid-stabilised bubbles of heavy gas have been utilised as contrast agents for diagnostic ultrasound (US) imaging for many years
Following the nozzle the 3D-expansion in the outlet caused a pressure drop in the outlet, inducing atomisation-like break-up of the gas cone and releasing bubbles in a fine spray. This atomisationlike behaviour produces a high concentration of microbubbles in the 108–109 bubbles per mL with a size range between 1 and 8 μm, when counted optically (×60 optical magnification)
When the focus of the microscope was adjusted to go through a whole depth of the bubble sample, very tiny particles were observed moving with Brownian motion beneath the microbubble layer on top suggesting there was a population of sub-micron particles produced during this regime that cannot be counted optically
Summary
Micron-sized lipid-stabilised bubbles of heavy gas have been utilised as contrast agents for diagnostic ultrasound (US) imaging for many years. We show that this same microchip and microspray regime leads to the facile production of high concentrations of nano-sized lipid stabilised PFC particles, ~1011–1012 mL−1, which dependent on their composition, size and surface tension exist in either their gaseous or liquid phase. When the focus of the microscope was adjusted to go through a whole depth of the bubble sample, very tiny particles were observed moving with Brownian motion beneath the microbubble layer on top (see ESI† S1) suggesting there was a population of sub-micron particles produced during this regime that cannot be counted optically.
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