title: Optical Verification of Microbubble Response to Acoustic Radiation Force in Large Vessels With In Vivo Results.
abstract: OBJECTIVE
  The objective of this study was to optically verify the dynamic behaviors of adherent microbubbles in large blood vessel environments in response to a new ultrasound technique using modulated acoustic radiation force.
  
  
  METHODS
  Polydimethylsiloxane (PDMS) flow channels coated with streptavidin were used in targeted groups to mimic large blood vessels. The custom-modulated acoustic radiation force beam sequence was programmed on a Verasonics research scanner. In vitro experiments were performed by injecting a biotinylated lipid-perfluorobutane microbubble dispersion through flow channels. The dynamic response of adherent microbubbles was detected acoustically and simultaneously visualized using a video camera connected to a microscope. In vivo verification was performed in a large abdominal blood vessel of a murine model for inflammation with injection of biotinylated microbubbles conjugated with P-selectin antibody.
  
  
  RESULTS
  Aggregates of adherent microbubbles were observed optically under the influence of acoustic radiation force. Large microbubble aggregates were observed solely in control groups without targeted adhesion. Additionally, the dispersion of microbubble aggregates were demonstrated to lead to a transient acoustic signal enhancement in control groups (a new phenomenon we refer to as "control peak"). In agreement with in vitro results, the control peak phenomenon was observed in vivo in a murine model.
  
  
  CONCLUSIONS
  This study provides the first optical observation of microbubble-binding dynamics in large blood vessel environments with application of a modulated acoustic radiation force beam sequence. With targeted adhesion, secondary radiation forces were unable to produce large aggregates of adherent microbubbles. Additionally, the new phenomenon called control peak was observed both in vitro and in vivo in a murine model for the first time. The findings in this study provide us with a better understanding of microbubble behaviors in large blood vessel environments with application of acoustic radiation force and could potentially guide future beam sequence designs or signal processing routines for enhanced ultrasound molecular imaging.
authors.affiliation: From the *Department of Biomedical Engineering, †Division of Cardiovascular Medicine, and ‡Electrical and Computer Engineering, University of Virginia, Charlottesville, VA.
authors.forename: Shiying
authors.initials: S
authors.lastname: Wang
authors.forename: Claudia Y
authors.initials: CY
authors.lastname: Wang
authors.forename: Sunil
authors.initials: S
authors.lastname: Unnikrishnan
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Klibanov
authors.forename: John A
authors.initials: JA
authors.lastname: Hossack
authors.forename: F William
authors.initials: FW
authors.lastname: Mauldin
mesh_terms: D000327:Adsorption / Q000528:radiation effects; D000818:Animals; D001808:Blood Vessels / Q000737:chemistry* / Q000000981:diagnostic imaging / Q000528:radiation effects*; D003287:Contrast Media / Q000737:chemistry / Q000528:radiation effects; D054459:Elasticity Imaging Techniques / Q000379:methods*; D005260:Female; D005466:Fluorocarbons / Q000737:chemistry* / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D045423:Microbubbles; D011829:Radiation Dosage; D013016:Sound
chemical_list: D003287:Contrast Media; D005466:Fluorocarbons; C108042:perfluorobutane