Stimulus-responsive ultrasound contrast agents for clinical imaging: Motivations, demonstrations, and future directions

Andrew P. Goodwin, Matthew A. Nakatsuka, Robert F. Mattrey

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Microbubble ultrasound contrast agents allow imaging of the vasculature with excellent resolution and signal-to-noise ratios. Contrast in microbubbles derives from their interaction with an ultrasound wave to generate signal at harmonic frequencies of the stimulating pulse; subtracting the elastic echo caused by the surrounding tissue can enhance the specificity of these harmonic signals significantly. The nonlinear acoustic emission is caused by pressure-driven microbubble size fluctuations, which in both theoretical descriptions and empirical measurements was found to depend on the mechanical properties of the shell that encapsulates the microbubble as well as stabilizes it against the surrounding aqueous environment. Thus biochemically induced switching between a rigid 'off' state and a flexible 'on' state provides a mechanism for sensing chemical markers for disease. In our research, we coupled DNA oligonucleotides to a stabilizing lipid monolayer to modulate stiffness of the shell and thereby induce stimulus-responsive behavior. In initial proof-of-principle studies, it was found that signal modulation came primarily from DNA crosslinks preventing the microbubble size oscillations rather than merely damping the signal. Next, these microbubbles were redesigned to include an aptamer sequence in the crosslinking strand, which not only allowed the sensing of the clotting enzyme thrombin but also provided a general strategy for sensing other soluble biomarkers in the bloodstream. Finally, the thrombin-sensitive microbubbles were validated in a rabbit model, presenting the first example of an ultrasound contrast agent that could differentiate between active and inactive clots for the diagnosis of deep venous thrombosis.

Original languageEnglish (US)
Pages (from-to)111-123
Number of pages13
JournalWiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2015

Fingerprint

Microbubbles
Medical imaging
Contrast Media
Motivation
Demonstrations
Ultrasonics
Thrombin
DNA
Oligonucleotides
Biomarkers
Acoustic emissions
Crosslinking
Lipids
Monolayers
Signal to noise ratio
Enzymes
Damping
Stiffness
Modulation
Tissue

ASJC Scopus subject areas

  • Bioengineering
  • Medicine (miscellaneous)
  • Biomedical Engineering

Cite this

Stimulus-responsive ultrasound contrast agents for clinical imaging : Motivations, demonstrations, and future directions. / Goodwin, Andrew P.; Nakatsuka, Matthew A.; Mattrey, Robert F.

In: Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, Vol. 7, No. 1, 01.01.2015, p. 111-123.

Research output: Contribution to journalArticle

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