Microbubble Composition and Preparation for High-Frequency Contrast-Enhanced Ultrasound Imaging: In Vitro and in Vivo Evaluation

Verya Daeichin, Tom van Rooij, Ilya Skachkov, Bulent Ergin, Patricia A.C. Specht, Alexandre Lima, Can Ince, Johan G. Bosch, Antonius F.W. Van Der Steen, Nico De Jong, Klazina Kooiman

    Research output: Contribution to journalArticleScientificpeer-review

    11 Citations (Scopus)
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    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 C4F10 and 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 μm) than sonication (number weighted mean diameter ∼2 μm} ). 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.

    Original languageEnglish
    Article number7784837
    Pages (from-to)555-567
    Number of pages13
    JournalIEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control
    Issue number3
    Publication statusPublished - 1 Mar 2017


    • Contrast agent
    • Contrast-enhanced ultrasound (CEUS) imaging
    • High-frequency
    • in vitro
    • in vivo
    • Microbubble

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