Ultrasonography is a safe, inexpensive and wide-spread diagnostic tool capable of producing real-time non-invasive images without significant biological effects. However, the propagation of higher energy, intensity and frequency ultrasound waves through living tissues can induce thermal, mechanical and chemical effects useful for a variety of therapeutic applications. With the recent development of clinically approved High Intensity Focused Ultrasound (HIFU) systems, therapeutic ultrasound is now a medical reality. Indeed, HIFU has been used for the thermal ablation of pathological lesions; localized, minimally invasive ultrasound-mediated drug delivery through the transient formation of pores on cell membranes; the temporary disruption of skin and the blood brain barrier; the ultrasound induced break-down of blood clots; and the targeted release of drugs using ultrasound and temperature sensitive drug carriers. This review seeks to engage the pharmaceutical research community by providing an overview on the biological effects of ultrasound as well as highlighting important therapeutic applications, current deficiencies and future directions.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
The development of novel MRI-guided therapeutic ultrasound methods including potentiated drug delivery and targeted thermal ablation requires extensive testing in small animals such as rats and mice due to the widespread use of these species as models of disease. An MRI-compatible, computer-controlled three-axis positioning system was constructed to deliver focused ultrasound exposures precisely to a target anatomy in small animals for high-throughput preclinical drug delivery studies. Each axis was constructed from custom-made nonmagnetic linear ball stages driven by piezoelectric actuators and optical encoders. A range of motion of 5 ϫ 5 ϫ 2.5 cm 3 was achieved, and initial bench top characterization demonstrated the ability to deliver ultrasound to the brain with a spatial accuracy of 0.3 mm. Operation of the positioning system within the bore of a clinical 3 T MR imager was feasible, and simultaneous motion and MR imaging did not result in any mutual interference. The system was evaluated in its ability to deliver precise sonications within the mouse brain, linear scanned exposures in a rat brain for blood barrier disruption, and circular scans for controlled heating under MR temperature feedback. Initial results suggest that this is a robust and precise apparatus for use in the investigation of novel ultrasound-based therapeutic strategies in small animal preclinical models.
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