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      On-chip generation of microbubbles as a practical technology for manufacturing contrast agents for ultrasonic imaging.

      Lab on a Chip
      Chemistry, Pharmaceutical, methods, Contrast Media, pharmacology, Diffusion, Dimethylpolysiloxanes, chemistry, Drug Delivery Systems, Fluorocarbons, Lipids, Microarray Analysis, Microbubbles, Microfluidic Analytical Techniques, Microfluidics, Microscopy, Fluorescence, Models, Chemical, Pressure, Silicones, Ultrasonography, instrumentation

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          Abstract

          This paper presents a new manufacturing method to generate monodisperse microbubble contrast agents with polydispersity index (sigma) values of <2% through microfluidic flow-focusing. Micron-sized lipid shell-based perfluorocarbon (PFC) gas microbubbles for use as ultrasound contrast agents were produced using this method. The poly(dimethylsiloxane) (PDMS)-based devices feature expanding nozzle geometry with a 7 microm orifice width, and are robust enough for consistent production of microbubbles with runtimes lasting several hours. With high-speed imaging, we characterized relationships between channel geometry, liquid flow rate Q, and gas pressure P in controlling bubble sizes. By a simple optimization of the channel geometry and Q and P, bubbles with a mean diameter of <5 microm can be obtained, ideal for various ultrasonic imaging applications. This method demonstrates the potential of microfluidics as an efficient means for custom-designing ultrasound contrast agents with precise size distributions, different gas compositions and new shell materials for stabilization, and for future targeted imaging and therapeutic applications.

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