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EXPERIMENTAL STUDY

Influence of injection site, microvascular pressureand ultrasound variables on microbubble-mediated delivery of microspheres to muscle

Ji Song, PhD^*, John C. Chappell, BS^*, Ming Qi, BS^*, Eric J. VanGieson, PhD^*, Sanjiv Kaul, MD, FACC and Richard J. Price, PhD^*,*

^* Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA
Cardiovascular Division, University of Virginia, Charlottesville, Virginia, USA

Manuscript received July 16, 2001; revised manuscript received November 9, 2001, accepted November 30, 2001.

^* Reprint requests and correspondence: Dr. Richard J. Price, Department of Biomedical Engineering, University of Virginia, Box 800759, Health System, Charlottesville, Virginia 22908, USA.
rprice{at}virginia.edu

OBJECTIVES: Our objective was to test the hypothesis that the ultrasound pulsing interval (PI), microbubble injection site and microvascular pressure significantly influence the transport of 100-nm microspheres to muscle through extravasation sites created by the destruction of microbubbles with ultrasound.

BACKGROUND: Microbubbles show promise as targeted drug and gene delivery agents; however, designing optimal microbubble-based therapies will require an understanding of the factors that influence the transport of microbubble-delivered, gene-bearing vehicles to tissue.

METHODS: Ultrasound at 1 MHz, with a peak negative pressure amplitude of 0.75 MPa, was applied to microbubbles and 100-nm microspheres in exteriorized rat spinotrapezius muscle. Ultrasound PIs of 1, 3, 5 and 10 s, arterial microsphere injection times of 10 or 40 s and arterial versus venous injection sites were tested.

RESULTS: Extravasation point creation and microsphere delivery were greatest when the ultrasound PI was 5 or 10 s. No significant differences in extravasation point creation or microsphere delivery were observed with arterial versus venous microbubble injection, but a trend toward increased microsphere delivery with arterial injection may exist. Decreasing the arterial injection time from 40 to 10 s increased microvascular pressure, which, in turn, substantially enhanced microsphere transport to tissue, without a concomitant increase in the number of extravasation points.

CONCLUSIONS: The ultrasound PI and microvascular pressure significantly influence the creation of extravasation points and the transport of microspheres to tissue. These factors may be important in designing and optimizing contrast ultrasound-based therapies.

Abbreviations and Acronyms   VEGF   MI   mechanical index   PI   pulsing interval   PM   polymer microsphere   VEGF   vascular endothelial growth factor

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