Nonspherical ultrasound microbubbles.
Authors: Dasgupta A, Sun T, Palomba R, Rama E, Zhang Y, Power C, Moeckel D, Liu M, Sarode A, Weiler M, Motta A, Porte C, Magnuska Z, Said Elshafei A, Barmin R, Graham A, McClelland A, Rommel D, Stickeler E, Kiessling F, Pallares RM, De Laporte L, Decuzzi P, McDannold N, Mitragotri S, Lammers T
Surface tension provides microbubbles (MB) with a perfect spherical shape. Here, we demonstrate that MB can be engineered to be nonspherical, endowing them with unique features for biomedical applications. Anisotropic MB were generated via one-dimensionally stretching spherical poly(butyl cyanoacrylate) MB above their glass transition temperature. Compared to their spherical counterparts, nonspherical polymeric MB displayed superior performance in multiple ways, including i) increased margination behavior in blood vessel-like flow chambers, ii) reduced macrophage uptake in vitro, iii) prolonged circulation time in vivo, and iv) enhanced blood-brain barrier (BBB) permeation in vivo upon combination with transcranial focused ultrasound (FUS). Our studies identify shape as a design parameter in the MB landscape, and they provide a rational and robust framework for further exploring the application of anisotropic MB for ultrasound-enhanced drug delivery and imaging applications.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To create nonspherical poly(butyl cyanoacrylate) microbubbles and determine whether their anisotropic shape improves margination, circulation time, immune evasion, and focused-ultrasound–mediated blood–brain barrier permeabilization compared with spherical microbubbles.
Animal model / Human subject
Mouse (Mus musculus) BALB/c; strain not specified; age 6-8 weeks; sex not specified
Disease model
Healthy
Targeted brain region(s)
Striatum
Cargo name and characteristics
Trypan blue
Route of administration
Intravenous
Outcomes and Safety
Summary of Outcomes
Rod-shaped (anisotropic) polymer microbubbles marginated and tumbled more toward vessel walls, were taken up less by macrophages, had prolonged circulation in mice, and produced ~2-fold greater focused ultrasound–mediated blood–brain barrier permeation versus spherical microbubbles. Ultrasound parameters characterized included low-MI imaging (MI 0.03–0.07), high-MI destruction (MI 0.7), and transcranial FUS with pulse-ramped acoustic pressures chosen to yield equivalent cavitation (harmonic and broadband) — under these FUS settings the anisotropic MB gave superior BBB opening.
Duration of biological effect
1 h
Safety-related matter
Focused ultrasound combined with both anisotropic and spherical microbubbles caused some tissue damage in the sonicated brain region, evidenced by erythrocyte extravasation and microhemorrhages; the authors note that hard-shell microbubble destruction during FUS may result in vascular and tissue damage and suggest engineering softer-shell microbubbles to mitigate this risk.
Brain Region
Ultrasound Parameters
Ultrasound instrument
Air-backed spherically curved lead zirconate titanate transducer (diameter/radius of curvature: 10/8 cm)
FUS Frequency
835 kHz
FUS Pressure
1.29 Mpa (rod-shaped MB conditor for BBB opening); 0.91 Mpa (spherical MB threshold determination)
FUS Mode
pulsed
Pulse duration
10 ms
Duration of a single FUS session
100 s
Focal Characteristics
Focal depth: None; Focal length: 80 mm; Aperture size: 100 mm
Treatment frequency
single session
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