Enhancement of vascular permeability with low-frequency contrast-enhanced ultrasound in the chorioallantoic membrane model

Susanne M. Stieger, Charles F. Caskey, Roger H. Adamson, Shengping Qin, Fitz Roy E Curry, Erik R Wisner, Katherine W. Ferrara

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Purpose: To characterize the effect of low-frequency contrast material-enhanced ultrasound on the vascular endothelium and to determine the parameters and techniques required to deliver a therapeutic agent by using the chorioallantoic membrane (CAM) model. Materials and Methods: All in vivo animal procedures were conducted with institutional Animal Care and Use Committee approval. Extravasation of 8.5-nm-diameter fluorescein isothiocyanate-labeled dextran was evaluated in the vasculature of a chick CAM model. Intravital microscopy was performed during contrast-enhanced ultrasound exposure (1.00 or 2.25 MHz): results were compared with results of electron microscopy of the insonated regions. Data acquired after insonation with greater mechanical stress (n = 30 animals) (mechanical index [MI] > 1.3) and with lower mechanical stress (n = 86 animals) (MI < 1.13) were compared with measurements in control conditions (n = 46 animals). The diameter of affected vessels; number of extravasation sites; extravasation rate, area, and location; and changes in endothelial cells and basement membrane were evaluated. Differences were tested with analysis of variance or the Student t test. Results: After ultrasound application, convective transport of the model drug was observed through micron-sized openings with a mean fluid velocity of 188.6 μm/sec in the low-stress class and 362.5 μm/sec in the high-stress class. Electron microscopy revealed micron-sized focal endothelial gaps and disseminated blebs, vacuoles, and lilopodia extending across tens of microns. The threshold pressure for extravasation was 0.5 MPa for a transmitted center frequency of 1.00 MHz (MI = 0.5) and 1.6 MPa for a frequency of 2.25 MHz (MI = 1.06): thus, the frequency dependence of the threshold was not predicted simply by the MI. Conclusion: Low-frequency contrast-enhanced ultrasound can increase vascular permeability and result in convective extravasation of an 8.5-nm-diameter model drug.

Original languageEnglish (US)
Pages (from-to)112-121
Number of pages10
JournalRadiology
Volume243
Issue number1
DOIs
StatePublished - Apr 2007

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Chorioallantoic Membrane
Capillary Permeability
Mechanical Stress
Electron Microscopy
Animal Care Committees
Vascular Endothelium
Blister
Vacuoles
Basement Membrane
Pharmaceutical Preparations
Contrast Media
Analysis of Variance
Endothelial Cells
Cell Membrane
Students
Pressure
Therapeutics

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

Enhancement of vascular permeability with low-frequency contrast-enhanced ultrasound in the chorioallantoic membrane model. / Stieger, Susanne M.; Caskey, Charles F.; Adamson, Roger H.; Qin, Shengping; Curry, Fitz Roy E; Wisner, Erik R; Ferrara, Katherine W.

In: Radiology, Vol. 243, No. 1, 04.2007, p. 112-121.

Research output: Contribution to journalArticle

Stieger, Susanne M. ; Caskey, Charles F. ; Adamson, Roger H. ; Qin, Shengping ; Curry, Fitz Roy E ; Wisner, Erik R ; Ferrara, Katherine W. / Enhancement of vascular permeability with low-frequency contrast-enhanced ultrasound in the chorioallantoic membrane model. In: Radiology. 2007 ; Vol. 243, No. 1. pp. 112-121.
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abstract = "Purpose: To characterize the effect of low-frequency contrast material-enhanced ultrasound on the vascular endothelium and to determine the parameters and techniques required to deliver a therapeutic agent by using the chorioallantoic membrane (CAM) model. Materials and Methods: All in vivo animal procedures were conducted with institutional Animal Care and Use Committee approval. Extravasation of 8.5-nm-diameter fluorescein isothiocyanate-labeled dextran was evaluated in the vasculature of a chick CAM model. Intravital microscopy was performed during contrast-enhanced ultrasound exposure (1.00 or 2.25 MHz): results were compared with results of electron microscopy of the insonated regions. Data acquired after insonation with greater mechanical stress (n = 30 animals) (mechanical index [MI] > 1.3) and with lower mechanical stress (n = 86 animals) (MI < 1.13) were compared with measurements in control conditions (n = 46 animals). The diameter of affected vessels; number of extravasation sites; extravasation rate, area, and location; and changes in endothelial cells and basement membrane were evaluated. Differences were tested with analysis of variance or the Student t test. Results: After ultrasound application, convective transport of the model drug was observed through micron-sized openings with a mean fluid velocity of 188.6 μm/sec in the low-stress class and 362.5 μm/sec in the high-stress class. Electron microscopy revealed micron-sized focal endothelial gaps and disseminated blebs, vacuoles, and lilopodia extending across tens of microns. The threshold pressure for extravasation was 0.5 MPa for a transmitted center frequency of 1.00 MHz (MI = 0.5) and 1.6 MPa for a frequency of 2.25 MHz (MI = 1.06): thus, the frequency dependence of the threshold was not predicted simply by the MI. Conclusion: Low-frequency contrast-enhanced ultrasound can increase vascular permeability and result in convective extravasation of an 8.5-nm-diameter model drug.",
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AU - Stieger, Susanne M.

AU - Caskey, Charles F.

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AU - Curry, Fitz Roy E

AU - Wisner, Erik R

AU - Ferrara, Katherine W.

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