The Size of Blood–Brain Barrier Opening Induced by Focused Ultrasound is Dictated by the Acoustic Pressure

Abstract

Focused ultrasound (FUS) in combination with microbubbles (MBs) has been successfully used in the delivery of various-size therapeutic agents across the blood-brain barrier (BBB). This study revealed that FUS-induced BBB opening size, defined by the size of the largest molecule that can permeate through the BBB, can be controlled by the acoustic pressure as dictated by cavitational mechanisms. Focused ultrasound was applied onto the mouse hippocampus in the presence of systemically administered MBs for trans-BBB delivery of fluorescently labeled dextrans with molecular weights 3 to 2,000 kDa (hydrodynamic diameter: 2.3 to 54.4 nm). The dextran delivery outcomes were evaluated using ex vivo fluorescence imaging. Cavitation detection was employed to monitor the MB cavitation activity associated with the delivery of these agents. It was found that the BBB opening size was smaller than 3 kDa (2.3 nm) at 0.31 MPa, up to 70 kDa (10.2 nm) at 0.51 MPa, and up to 2,000 kDa (54.4 nm) at 0.84 MPa. Relatively smaller opening size (up to 70 kDa) was achieved with stable cavitation only; however, inertial cavitation was associated with relatively larger BBB opening size (above 500 kDa). These findings indicate that the BBB opening size can be controlled by the acoustic pressure and predicted using cavitation detection.

Ultrasound-Based Therapies for the Treatment of Cancer

“…less/greater than 10 min) and postulated that the fast and slow pathways were most likely paracellular (tight junction disruption) and transcellular (increased transcytosis and sonoporation), respectively 63 . Interestingly, 70kDa dextrans appeared to have a higher pressure threshold for BBB crossing than smaller 10kDa dextrans, in agreement with other studies indicating that the extent of BBBD (particularly the size of junctional clefts) is related to pressure 64 . Furthermore, smaller vessels (i.e.…”

The breakup of intravascular microbubbles and its impact on the endothelium

“…The stresses at the endothelial vessel interface before and after the breakup of the shell of an encapsulated MB with sizedependent shell characteristics are investigated. They are relevant to cavitation-induced damage and are hypothesized to play a key role in BBB opening (Chen and Konofagou 2014;McDannold et al 2008;Nyborg 2001;Wamel et al 2006). All studied setups comprise a single MB of equilibrium radius a 0 = 1 μm withã = 0.985 μm and shell properties κ s = 15 nN s m −1 , χ = 1.0 N m −1 and μ r = 0.4 μ s with a polytropic exponent of γ = 1.095, suitable for sulphur hexafluoride gas as employed in SonoVue UCAs (Marmottant et al 2005).…”

The use of transcranial focused ultrasound in CNS diseases

“…Авторы выявили следующие механиз-мы увеличения проницаемости стенки капилляров: уси-ление трансцитоза, формирование цитоплазматических каналов в клетках эндотелия, открытие части плотных со-единений, прямое прохождение через поврежденный эн-дотелий (при использовании большой мощности -более 3 Вт). Также было продемонстрировано, что чем большее акустическое давление создается в фокусе, тем более крупные молекулы могут проходить через ГЭБ [55].…”