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

doi:10.1016/j.biomaterials.2013.08.040

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 journal › Article › peer-review

24 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 language	English (US)
Pages (from-to)	9559-9565
Number of pages	7
Journal	Biomaterials
Volume	34
Issue number	37
DOIs	https://doi.org/10.1016/j.biomaterials.2013.08.040
State	Published - Dec 2013
Externally published	Yes

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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10.1016/j.biomaterials.2013.08.040

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@article{ec3776e3ff4647fb9b2736ff8f7e687f,

title = "Invivo ultrasound visualization of non-occlusive blood clots with thrombin-sensitive contrast agents",

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.",

keywords = "Clotting, DNA, Invitro test, Invivo test, Thrombosis",

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

note = "Funding Information: Research was supported by NIH R21-EB012758 , NIH R00-CA153935 (A.P.G.), the UCSD In Vivo Cellular and Molecular Imaging Center (NIH P50-CA128346 ), and University of Colorado Boulder startup funds (A.P.G.). The authors would like to thank Professor Mark Borden at the University of Colorado Boulder for the use of his Acuson Sequoia{\texttrademark} C512 Ultrasound Imager for in vitro studies and his Beckman Coulter Multisizer{\texttrademark} 3, as well as the Ultrasound Group of Siemens Medical Solutions USA for providing their Acuson Sequoia{\texttrademark} C512 scanner to UCSD through an equipment loan for the in vivo studies. The authors would also like to thank Dr. Jameel Feshitan and Dr. Shashank Sirsi for instrument training, and Jacqueline Corbeil and Rosemarie Ramirez for aid during rabbit surgery. ",

year = "2013",

month = dec,

doi = "10.1016/j.biomaterials.2013.08.040",

language = "English (US)",

volume = "34",

pages = "9559--9565",

journal = "Biomaterials",

issn = "0142-9612",

publisher = "Elsevier BV",

number = "37",

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T1 - Invivo ultrasound visualization of non-occlusive blood clots with thrombin-sensitive contrast agents

AU - Nakatsuka, Matthew A.

AU - Barback, Christopher V.

AU - Fitch, Kirsten R.

AU - Farwell, Alexander R.

AU - Esener, Sadik C.

AU - Mattrey, Robert F.

AU - Cha, Jennifer N.

AU - Goodwin, Andrew P.

N1 - Funding Information: Research was supported by NIH R21-EB012758 , NIH R00-CA153935 (A.P.G.), the UCSD In Vivo Cellular and Molecular Imaging Center (NIH P50-CA128346 ), and University of Colorado Boulder startup funds (A.P.G.). The authors would like to thank Professor Mark Borden at the University of Colorado Boulder for the use of his Acuson Sequoia™ C512 Ultrasound Imager for in vitro studies and his Beckman Coulter Multisizer™ 3, as well as the Ultrasound Group of Siemens Medical Solutions USA for providing their Acuson Sequoia™ C512 scanner to UCSD through an equipment loan for the in vivo studies. The authors would also like to thank Dr. Jameel Feshitan and Dr. Shashank Sirsi for instrument training, and Jacqueline Corbeil and Rosemarie Ramirez for aid during rabbit surgery.

PY - 2013/12

Y1 - 2013/12

N2 - 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.

AB - 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.

KW - Clotting

KW - DNA

KW - Invitro test

KW - Invivo test

KW - Thrombosis

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JO - Biomaterials

JF - Biomaterials

IS - 37

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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