A multi-pulse ultrasound technique for imaging of thick-shelled microbubbles demonstrated in vitro and in vivo

PLoS One. 2022 Nov 3;17(11):e0276292. doi: 10.1371/journal.pone.0276292. eCollection 2022.

Abstract

Contrast enhanced ultrasound is a powerful diagnostic tool and ultrasound contrast media are based on microbubbles (MBs). The use of MBs in drug delivery applications and molecular imaging is a relatively new field of research which has gained significant interest during the last decade. MBs available for clinical use are fragile with short circulation half-lives due to the use of a thin encapsulating shell for stabilization of the gas core. Thick-shelled MBs can have improved circulation half-lives, incorporate larger amounts of drugs for enhanced drug delivery or facilitate targeting for use in molecular ultrasound imaging. However, methods for robust imaging of thick-shelled MBs are currently not available. We propose a simple multi-pulse imaging technique which is able to visualize thick-shelled polymeric MBs with a superior contrast-to-tissue ratio (CTR) compared to commercially available harmonic techniques. The method is implemented on a high-end ultrasound scanner and in-vitro imaging in a tissue mimicking flow phantom results in a CTR of up to 23 dB. A proof-of-concept study of molecular ultrasound imaging in a soft tissue inflammation model in rabbit is then presented where the new imaging technique showed an enhanced accumulation of targeted MBs in the inflamed tissue region compared to non-targeted MBs and a mean CTR of 13.3 dB for stationary MBs. The presence of fluorescently labelled MBs was verified by confocal microscopy imaging of tissue sections post-mortem.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Contrast Media*
  • Drug Delivery Systems / methods
  • Microbubbles*
  • Phantoms, Imaging
  • Rabbits
  • Ultrasonography / methods

Substances

  • Contrast Media

Grants and funding

SB: Liaison Committee between the Central Norway Regional Health Authority (RHA) and the Norwegian University of Science and Technology (NTNU) SB and RH: Research Council of Norway (240410/F20) SB, SE, LD, KC and RH: European commission (7th framework program, 3MiCRON (245572) project).