Formulation of Monodisperse Contrast Agents in Microfluidic Systems for Ultrasonic Imaging

Background: Ultrasound imaging may be used to produce a 2D image of the body's internal structures. However, since blood is much less (1000x less) echogenic than tissue, small vessels, blood pool volume and blood flow all are difficult, if not impossible, to image using traditional ultrasound techniques. Researchers discovered, however, that by introducing micro-bubbles (USCAs) into the circulation many of the limitations surrounding blood imaging could be overcome. Of the recent developments in ultrasound imaging, undoubtedly one of the most promising is the use of targeted contrast agents. Ligands to biologically active molecules are incorporated into the shells of the USCAs, causing them to adhere to and accumulate at the tissue expressing the complementary proteins, allowing researchers to visualize sites of for example, inflammation, angiogenesis, and apoptosis. Conventional methods used to produce microbubble suspensions rely on simple agitation (e.g., shaking and sonication) to entrain a portion of the bulk gas phase into the bulk aqueous phase. The random nature of this homogenization process generally result in a highly polydisperse distribution. Thus a large portion of the contrast agent population is effectively wasted, reducing the sensitivity of the imaging system. Technology: Researchers at the University of CA have developed a method that takes advantage of the resonance characteristics of USCAs to measure in vivo concentrations of analytes using ultrasound. By designing USCAs whose physical characteristics change as a function of the local micro-environment we can measure changes in the frequency and intensity of resonance and thereby determine the concentration of the analyte. The method involves a microfluidic flow-focusing system for producing monodisperse microbubble contrast agents in the appropriate size range desired for ultrasonic imaging. Application: Our experience with lipid vesicles in microfluidic devices and other control parameters will also allow us to custom design microbubbles for future targeted imaging and therapeutic applications.

For example, the tagged USCAs would be injected into the bloodstream. Binding reactions with their complementary analytes would be determined by the level of that analyte in the bloodstream. These binding events would affect the mass, rigidity, and diameter of the USCA shell, thereby altering the resonance frequency of the shell. This shift in resonance frequency could be measured with standard ultrasound equipment.

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