title: Molecular Acoustic Angiography: A New Technique for High-resolution Superharmonic Ultrasound Molecular Imaging.
abstract: Ultrasound molecular imaging utilizes targeted microbubbles to bind to vascular targets such as integrins, selectins and other extracellular binding domains. After binding, these microbubbles are typically imaged using low pressures and multi-pulse imaging sequences. In this article, we present an alternative approach for molecular imaging using ultrasound that relies on superharmonic signals produced by microbubble contrast agents. Bound bubbles were insonified near resonance using a low frequency (4 MHz) element and superharmonic echoes were received at high frequencies (25-30 MHz). Although this approach was observed to produce declining image intensity during repeated imaging in both in vitro and in vivo experiments because of bubble destruction, the feasibility of superharmonic molecular imaging was demonstrated for transmit pressures, which are sufficiently high to induce shell disruption in bound microbubbles. This approach was validated using microbubbles targeted to the αvβ3 integrin in a rat fibrosarcoma model (n = 5) and combined with superharmonic images of free microbubbles to produce high-contrast, high-resolution 3-D volumes of both microvascular anatomy and molecular targeting. Image intensity over repeated scans and the effect of microbubble diameter were also assessed in vivo, indicating that larger microbubbles yield increased persistence in image intensity. Using ultrasound-based acoustic angiography images rather than conventional B-mode ultrasound to provide the underlying anatomic information facilitates anatomic localization of molecular markers. Quantitative analysis of relationships between microvasculature and targeting information indicated that most targeting occurred within 50 μm of a resolvable vessel (>100 μm diameter). The combined information provided by these scans may present new opportunities for analyzing relationships between microvascular anatomy and vascular targets, subject only to limitations of the current mechanically scanned system and microbubble persistence to repeated imaging at moderate mechanical indices.
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Shelton
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, USA.
authors.forename: Brooks D
authors.initials: BD
authors.lastname: Lindsey
authors.affiliation: Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: James K
authors.initials: JK
authors.lastname: Tsuruta
authors.affiliation: Department of Medical Biophysics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: F Stuart
authors.initials: FS
authors.lastname: Foster
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, USA; Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Electronic address: padayton@email.unc.edu.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dayton
mesh_terms: D000792:Angiography; D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000493:pharmacokinetics*; D054459:Elasticity Imaging Techniques / Q000295:instrumentation* / Q000379:methods; D004867:Equipment Design; D019544:Equipment Failure Analysis; D005354:Fibrosarcoma / Q000000981:diagnostic imaging / Q000378:metabolism*; D005466:Fluorocarbons; D007089:Image Enhancement / Q000295:instrumentation* / Q000379:methods; D007090:Image Interpretation, Computer-Assisted / Q000295:instrumentation / Q000379:methods; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D057054:Molecular Imaging; D009842:Oligopeptides / Q000493:pharmacokinetics*; D019047:Phantoms, Imaging; D051381:Rats; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D003287:Contrast Media; D005466:Fluorocarbons; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; C108042:perfluorobutane
keywords: Angiogenesis; Biomarker; Microbubble; Microvasculature; Targeted imaging