Nonspherical ultrasound microbubbles

Abstract

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.

Transferrin Receptor‐Targeted Nonspherical Microbubbles for Blood–Brain Barrier Sonopermeation

“…To this end, 18 MHz center frequency was used at varying mechanical indexes (MI), as this frequency has previously been shown to generate strong US responses with PBCA MB. [ 8,15,19 ] At an MI of 0.03, anti‐TfR‐modified rod‐shaped MB exhibited good brightness‐ and contrast‐mode US signals (Figure 2H), although the intensities generated were slightly lower than those observed for their spherical counterparts (Figure 2I). Similar findings were observed at an MI of 0.07 (Figure S3A–C, Supporting Information).…”

“…[5][6][7] We recently added shape as a novel design parameter, demonstrating that nonspherical rodlike MB possess several unique features. [8] First, anisotropic MB were found to exhibit enhanced tumbling and margination, i.e., propensity to flow closer to blood vessel walls. Second, anisotropic MB showed reduced phagocytosis and circulated longer in the bloodstream of mice.…”

Transformative Materials for Interfacial Drug Delivery

“…Recent efforts demonstrate that also non-spherical MB can be generated, which flows to blood vessel walls, thereby enabling enhancement of trans-BBB drug delivery upon transcranial-focused US. [102]…”

“…This approach resulted in the elimination of FAP-expressing fibrogenic cells, thereby reducing cardiac fibrosis and improving the function of the heart. [102] The in situ generation of CAR-T cells in vivo is highly attractive, [115] because it does not require ex vivo cell expansion under GMP conditions, thereby making it more cost-effective. Furthermore, the transient nature of in vivo-produced CAR-T cells may limit toxicity, allows for dose adjustment, and enables repeated administration.…”

Polymeric materials for ultrasound imaging and therapy

“…24,25 Their shape can be tuned, yielding anisotropic MB with better performance in drug delivery based on their increased margination behavior. 26 Moreover, their rigidity can be manipulated, improving their acoustic responses. 27 Beyond MB, polymers can facilitate the engineering of materials that stabilize the cavitation nucleus within their unique shape (as recently-demonstrated with nanocups, NC) 28 or present tailored composition with unique characteristics (as illustrated by rigid microcapsules, MC), 29,30 providing controlled acoustic responses ideally suited for US imaging and therapy.…”