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Ultrasound is developing rapidly as one of the most widespread clinical imaging modalities, owing to its excellent temporal and spatial resolution, safety, portability and cost efficiency. The utility and scope of ultrasound is enhanced by the use of microbubble contrast agents, which reveal underlying anatomical and physiological features that would otherwise be difficult to detect. Below is a maximum intensity projection (MIP) video of microbubbles perfusing into a neuroblastoma tumor in a mouse, taken in collaboration with Jessica Kandel at the University of Chicago and Darrell Yamashiro at Columbia University.
Ultrasound Molecular Imaging
One of our goals is to engineer microbubbles and nanodrops to image the expression of key molecules associated with disease and the response to therapy.
Buried-ligand microbubbles and ultrasound radiation force. (A) The ultrasound contrast agent is a microbubble of 4-5 µm diameter filled with perfluorobutane (PFB) gas and coated with a phospholipid monolayer shell. A side view of the shell shows the buried-ligand architecture, which comprises a shorter (2000 Da) PEG tethered to cyclo Arg-Gly-Asp (cRGD) peptide surrounded by a longer (5000 Da) PEG overbrush. Also shown is a surface rendering of complement C3 protein. (B) A high-speed videomicroscopy streak image of the diameter of a microbubble over time shows acoustic radiation force acting on a microbubble to displace it axially away from the ultrasound transducer superimposed with surface dilations. These surface dilations expose the cRGD ligand for binding to the target αVβ3 integrin receptor. REFERENCE
Microbubble interactions with higher intensity ultrasound can be used to induce more violent effects (localized to the pico-liter volume surrounding each microbubble) to deliver drugs and enhance local tissue uptake. The video below shows ultrasound-imaging guided drug delivery to a tumor. The b-mode to the left shows anatomy of the tumor, while the “subharmonic” mode to the right shows intravascular microbubbles. A second therapeutic ultrasound pulse is then sent in – destroying microbubbles and delivering drugs – which is imaged as a loss in microbubble signal in a spot at the tumor (upper left portion of the kidney). This video was taken by Dr. Shashank Sirsi in collaboration with Jessica Kandel at the University of Chicago.
Gene therapy using focused ultrasound and microbubbles can provide safe and efficient delivery of nucleic acids to target cells in vitro and in vivo. Several research groups throughout the world are working to develop this technology for clinical translation. Our group is working on the design of new microbubble and nanodrop formulations, such as polyplex-loaded microbubbles, and ultrasound systems to achieve this goal.
Injectable oxygen microbubbles is a novel technology being developed in our lab to treat local and systemic hypoxia. The microbubbles are biocompatible and provide a very large surface area for oxygen transport. Our approach to develop this technology is to mimic the remarkable low-surface-tension and high-gas-permeability properties of the lung alveolar lining.