title: Microbubble Composition and Preparation for High-Frequency Contrast-Enhanced Ultrasound Imaging: In Vitro and In Vivo Evaluation.
abstract: Although high-frequency ultrasound imaging is gaining attention in various applications, hardly any ultrasound contrast agents (UCAs) dedicated to such frequencies (>15 MHz) are available for contrast-enhanced ultrasound (CEUS) imaging. Moreover, the composition of the limited commercially available UCAs for high-frequency CEUS (hfCEUS) is largely unknown, while shell properties have been shown to be an important factor for their performance. The aim of our study was to produce UCAs in-house for hfCEUS. Twelve different UCA formulations A-L were made by either sonication or mechanical agitation. The gas core consisted of C4F10and the main coating lipid was either 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC; A-F formulation) or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC; G-L formulation). Mechanical agitation resulted in UCAs with smaller microbubbles (number weighted mean diameter ~1 [Formula: see text]) than sonication (number weighted mean diameter ~2 [Formula: see text]). UCA formulations with similar size distributions but different main lipid components showed that the DPPC-based UCA formulations had higher nonlinear responses at both the fundamental and subharmonic frequencies in vitro for hfCEUS using the Vevo2100 high-frequency preclinical scanner (FUJIFILM VisualSonics, Inc.). In addition, UCA formulations F (DSPC-based) and L (DPPC-based) that were made by mechanical agitation performed similar in vitro to the commercially available Target-Ready MicroMarker (FUJIFILM VisualSonics, Inc.). UCA formulation F also performed similar to Target-Ready MicroMarker in vivo in pigs with similar mean contrast intensity within the kidney ( n = 7 ), but formulation L did not. This is likely due to the lower stability of formulation L in vivo. Our study shows that DSPC-based microbubbles produced by mechanical agitation resulted in small microbubbles with high nonlinear responses suitable for hfCEUS imaging.
authors.forename: Verya
authors.initials: V
authors.lastname: Daeichin
authors.forename: Tom
authors.initials: T
authors.lastname: van Rooij
authors.forename: Ilya
authors.initials: I
authors.lastname: Skachkov
authors.forename: Bulent
authors.initials: B
authors.lastname: Ergin
authors.forename: Patricia A C
authors.initials: PA
authors.lastname: Specht
authors.forename: Alexandre
authors.initials: A
authors.lastname: Lima
authors.forename: Can
authors.initials: C
authors.lastname: Ince
authors.forename: Johan G
authors.initials: JG
authors.lastname: Bosch
authors.forename: Antonius F W
authors.initials: AF
authors.lastname: van der Steen
authors.forename: Nico
authors.initials: N
authors.lastname: de Jong
authors.forename: Klazina
authors.initials: K
authors.lastname: Kooiman
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000737:chemistry*; D005260:Female; D045423:Microbubbles; D013552:Swine; D014463:Ultrasonography / Q000379:methods*
chemical_list: D003287:Contrast Media