The impact of standing wave effects on transcranial focused ultrasound disruption of the blood–brain barrier in a rat model

Abstract

Microbubble mediated disruption of the blood brain barrier (BBB) for targeted drug delivery using focused ultrasound shows great potential as a therapy for a wide range of brain disorders. This technique is currently at the pre-clinical stage and important work is being conducted in animal models. Measurements of standing waves in ex vivo rat skulls were conducted using an optical hydrophone and a geometry dependence was identified. Standing waves could not be eliminated through the use of swept frequencies, which have been suggested to eliminate standing waves. Definitive standing wave patterns were detected in over 25% of animals used in a single study. Standing waves were successfully eliminated using a wideband composite sharply focused transducer and a reduced duty cycle. The modified pulse parameters were used in vivo to disrupt the BBB in a rat indicating that, unlike some other bioeffects, BBB disruption is not dependant on standing wave conditions. Due to the high variability of standing waves and the inability to correctly estimate in situ pressures given standing wave conditions, attempts to minimize standing waves should be made in all future work in this field to ensure that results are clinically translatable.

The mechanism of interaction between focused ultrasound and microbubbles in blood-brain barrier opening in mice

“…Also, it has been shown that standing waves were not necessary in the BBB opening mechanism. 43,44 Therefore, the standing wave effect in this study was deemed insignificant.…”

Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

“…Preclinical investigation in this frequency range is important because the acoustic behavior of microbubbles and corresponding bioeffects may vary as a function of FUS frequency (23,37). However, such a low frequency is not typically adopted in rodent experiments due to the elongated focal area that exceeds the thickness of a rat brain, leading to internal reflections and standing waves (38). We therefore combined two spherically curved transducers to double the effective aperture size and provide significantly improved focusing in the axial direction.…”

“…The variability in the DOX measurements in the hippocampus could have been due to noisy data induced by autofluorescence. DOX fluorescence (excitation/emission: 480/575 nm 38 ) overlapped with the yellow/green autofluorescence of tissue. A two-wavelength excitation approach (see SI Methods for details) was thus applied in DOX imaging to remove the autofluorescence.…”

In vivo MR quantification of superparamagnetic iron oxide nanoparticle leakage during low‐frequency‐ultrasound‐induced blood–brain barrier opening in swine

“…The energy therefore has more room to generate complicated interference inside the cavity, and standing wave problems are a serious concern. In small animal cranial cavities, standing waves can be induced by a wide range of frequencies (0.26-2.5 MHz) when the cavity size is larger (i.e., within a few wavelength of the ultrasound wavelength) (29). Previous studies using a phantom similar in size to the human cranium showed that 28-kHz ultrasound produced a standing wave caused by constructive interference at the depth of its wavelength (i.e., $55 mm off the interface).…”