title: The delayed onset of subharmonic and ultraharmonic emissions from a phospholipid-shelled microbubble contrast agent.
abstract: Characterizing the non-linear response of microbubble contrast agents is important for their efficacious use in imaging and therapy. In this article, we report that the subharmonic and ultraharmonic response of lipid-shelled microbubble contrast agents exhibits a strong temporal dependence. We characterized non-linear emissions from Targestar-p microbubbles (Targeson Inc., San Diego, CA, USA) periodically for 60 min, at 10 MHz excitation frequency. The results revealed a considerable increase in the subharmonic and ultraharmonic response (nearly 12-15 and 5-8 dB) after 5-10 min of agent preparation. However, the fundamental and the harmonic response remained almost unchanged in this period. During the next 50 min, the subharmonic, fundamental, ultraharmonic, and harmonic responses decreased steadily by 2-5 dB. The temporal changes in the non-linear behavior of the agent appeared to be primarily mediated by gas-exchange through the microbubble shell; temperature and prior acoustic excitation based mechanisms were ruled out. Further, there was no measurable change in the agent size distribution by static diffusion. We envisage that these findings will help obtain reproducible measurements from agent characterization, non-linear imaging, and fluid-pressure sensing. These findings also suggest the possibility for improving non-linear imaging by careful design of ultrasound contrast agents.
authors.affiliation: Department of Electrical and Computer Engineering, University of Rochester, Rochester, NY, USA.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Shekhar
authors.affiliation: Department of Electrical and Computer Engineering, University of Rochester, Rochester, NY, USA.
authors.forename: Ivy
authors.initials: I
authors.lastname: Awuor
authors.affiliation: Targeson Inc., San Diego, CA, USA.
authors.forename: Keri
authors.initials: K
authors.lastname: Thomas
authors.affiliation: Targeson Inc., San Diego, CA, USA; Department of Bioengineering, University of California at San Diego, La Jolla, CA, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Rychak
authors.affiliation: Department of Electrical and Computer Engineering, University of Rochester, Rochester, NY, USA; Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA. Electronic address: m.doyley@rochester.edu.
authors.forename: Marvin M
authors.initials: MM
authors.lastname: Doyley
mesh_terms: D003198:Computer Simulation; D003287:Contrast Media / Q000737:chemistry* / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D008422:Materials Testing; D045423:Microbubbles; D008956:Models, Chemical; D010743:Phospholipids / Q000737:chemistry* / Q000528:radiation effects; D011829:Radiation Dosage; D014463:Ultrasonography / Q000379:methods*
chemical_list: D003287:Contrast Media; D010743:Phospholipids
keywords: Cavitation; Harmonic imaging; Microbubble characterization; Microbubbles; Non-linear ultrasound imaging; Subharmonic generation; Ultraharmonic generation; Ultrasound contrast agents