Invivo ultrasound visualization of non-occlusive blood clots with thrombin-sensitive contrast agents

Matthew A. Nakatsuka, Christopher V. Barback, Kirsten R. Fitch, Alexander R. Farwell, Sadik C. Esener, Robert F. Mattrey, Jennifer N. Cha, Andrew P. Goodwin

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

The use of microbubbles as ultrasound contrast agents is one of the primary methods to diagnose deep venous thrombosis. However, current microbubble imaging strategies require either a clot sufficiently large to produce a circulation filling defect or a clot with sufficient vascularization to allow for targeted accumulation of contrast agents. Previously, we reported the design of a microbubble formulation that modulated its ability to generate ultrasound contrast from interaction with thrombin through incorporation of aptamer-containing DNA crosslinks in the encapsulating shell, enabling the measurement of a local chemical environment by changes in acoustic activity. However, this contrast agent lacked sufficient stability and lifetime in blood to be used as a diagnostic tool. Here we describe a PEG-stabilized, thrombin-activated microbubble (PSTA-MB) with sufficient stability to be used invivo in circulation with no change in biomarker sensitivity. In the presence of actively clotting blood, PSTA-MBs showed a 5-fold increase in acoustic activity. Specificity for the presence of thrombin and stability under constant shear flow were demonstrated in a home-built invitro model. Finally, PSTA-MBs were able to detect the presence of an active clot within the vena cava of a rabbit sufficiently small as to not be visible by current non-specific contrast agents. By activating in non-occlusive environments, these contrast agents will be able to detect clots not diagnosable by current contrast agents.

Original languageEnglish (US)
Pages (from-to)9559-9565
Number of pages7
JournalBiomaterials
Volume34
Issue number37
DOIs
StatePublished - Dec 1 2013
Externally publishedYes

Keywords

  • Clotting
  • DNA
  • Invitro test
  • Invivo test
  • Thrombosis

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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  • Cite this

    Nakatsuka, M. A., Barback, C. V., Fitch, K. R., Farwell, A. R., Esener, S. C., Mattrey, R. F., Cha, J. N., & Goodwin, A. P. (2013). Invivo ultrasound visualization of non-occlusive blood clots with thrombin-sensitive contrast agents. Biomaterials, 34(37), 9559-9565. https://doi.org/10.1016/j.biomaterials.2013.08.040