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 journalArticlepeer-review

24 Scopus citations


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
Issue number37
StatePublished - Dec 2013
Externally publishedYes


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

ASJC Scopus subject areas

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


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