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Enhancement of Vascular Permeability with Low-Frequency Contrast-enhanced Ultrasound in the Chorioallantoic Membrane Model¹

¹ From the Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, 2112 Tupper Hall, Davis, CA 95616 (S.M.S., E.R.W.); Department of Biomedical Engineering, University of California, Davis, Calif (C.F.C., S.Q., K.W.F.); and Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Calif (R.H.A., F.E.C.). Received January 27, 2006; revision requested March 28; revision received April 25; accepted May 31; final version accepted August 1. Supported by National Institutes of Health CA 103828. Address correspondence to S.M.S. (e-mail: smstieger{at}ucdavis.edu).

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 filopodia 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.

Supplemental material: http://radiology.rsnajnls.org/cgi/content/full/243/1/112/DC1

© RSNA, 2007