In vivo ultrasound visualization of non-occlusive blood clots with thrombin-sensitive contrast agents |
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Authors: | Matthew A. Nakatsuka Christopher V. Barback Kirsten R. Fitch Alexander R. Farwell Sadik C. Esener Robert F. Mattrey Jennifer N. Cha Andrew P. Goodwin |
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Affiliation: | 1. Department of Nanoengineering, University of California, San Diego, 9500 Gilman Dr. #0448, La Jolla, CA 92093-0448, USA;2. Department of Radiology, University of California, San Diego, 410 Dickinson Street, San Diego, CA 92121, USA;3. Department of Chemical and Biological Engineering, University of Colorado, Boulder, 596 UCB, Boulder, CO 80309, USA |
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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 in vivo 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 in vitro 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. |
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Keywords: | Thrombosis In  vitro test In  vivo test Clotting DNA |
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