Rapid Short-pulse Ultrasound Delivers Drugs Uniformly across the Murine Blood-Brain Barrier with Negligible Disruption

Abstract

N oninvasively applied pulses of ultrasound and microbubbles can locally deliver molecules to the brain (1,2). Ultrasound has been shown to shrink brain tumors and improve cognitive function in animal models of Alzheimer disease (3-5). However, despite promising results, there remain concerns about potentially harmful effects from permeability changes to the blood-brain barrier (6,7). Focused ultrasound delivers molecules from the bloodstream to the brain by mechanically stimulating the vessels with acoustically active microbubbles. The microbubbles, composed of a lipid shell and stabilized gas core (1-10 µm), are administered intravenously (8). Pressure oscillations from the ultrasound drive the microbubbles to expand and contract, transporting molecules across the blood-brain barrier. In animals and in clinical trials, the most common method to drive microbubbles to disrupt the blood-brain barrier is with long-pulse sequencing (9-11), characterized by long pulses emitted in a slow sequence (6,12-14). Although parameters within this regimen attain the best performance-safety balance through thorough optimization, limitations exist. First, treatment is unequal within the beam (12,15), resulting in drugs delivered in some, but not all, targeted areas. Second, unwanted biologic responses can be triggered, such as neuronal damage, red blood cell extravasation, and hemorrhage (6,16,17). A recent clinical study has shown the presence of potential microhemorrhages (shown as hypointense areas on T2 MRI scans) using pulses that last in the range of milliseconds in humans (18). Third, it takes 4-48 hours for the permeability of the blood-brain barrier to return to normal (14,19),

A new safety index based on intrapulse monitoring of ultra-harmonic cavitation during ultrasound-induced blood-brain barrier opening procedures

“…On the contrary, in a recent study, Morse et al have suggested the use of multiple short bursts emitted at high pulse repetition frequency separated by off time in the range of microseconds to improve the safety of drug delivery 39 . The burst defined in this study was composed of 5-cycle short pulses (5 µs) repeated every 800 µs for 10 ms.…”

In vivo delivery of a fluorescent FPR2/ALX-targeted probe using focused ultrasound and microbubbles to image activated microglia

“…microglial activation. 31 To the best of our knowledge, this is the first time that a probe that targets activated microglia has been delivered to the brain in vivo using focused ultrasound.…”

“…2B), which had been treated using focused ultrasound to deliver the probe, was quantified via the normalised optical density (average fluorescence intensity in the targeted region subtracted by that of the control region). 30,31 In the right hemisphere (Fig. 2C), where no ultrasound treatment had occurred, no fluorescent signal was observed.…”

“…S1, n = 3, ESI †) with a heterogeneous distribution pattern, resulting in areas with high accumulation of the probe within the same treated region as areas with little or no probe. This uneven distribution is likely to be a result of the ms-long ultrasound pulses and the high pressure used, [30][31][32] parameters which were chosen to enable the probe to be delivered into the brain while inducing microglial activation. 29,33 In future work, low pressure short pulses of ultrasound will be used to deliver this probe homogenously, 31 as experiments will be performed on preclinical inflammatory models instead of (as performed here in this proof of principle study) using the ultrasound technique to induce the inflammation, i.e.…”

A Clinical System for Non-invasive Blood–Brain Barrier Opening Using a Neuronavigation-Guided Single-Element Focused Ultrasound Transducer

“…Such pulses have been reported to produce more uniform cavitation activity within the focal area by extending the microbubble lifetime (Pouliopoulos et al 2014), avoiding cluster formation and spreading the microbubble activity in space and time Pouliopoulos 2017). In vivo, rapid short-pulse sequences produce uniform BBB openings that last less than 10 min and do not allow extravasation of inflammation-inducing proteins, such as albumin, into the brain parenchyma (Morse et al 2019). On the other hand, it is more difficult to deliver large therapeutic molecules using short pulses (Choi et al 2011).…”