title: Lipid shedding from single oscillating microbubbles.
abstract: Lipid-coated microbubbles are used clinically as contrast agents for ultrasound imaging and are being developed for a variety of therapeutic applications. The lipid encapsulation and shedding of the lipids by acoustic driving of the microbubble has a crucial role in microbubble stability and in ultrasound-triggered drug delivery; however, little is known about the dynamics of lipid shedding under ultrasound excitation. Here we describe a study that optically characterized the lipid shedding behavior of individual microbubbles on a time scale of nanoseconds to microseconds. A single ultrasound burst of 20 to 1000 cycles, with a frequency of 1 MHz and an acoustic pressure varying from 50 to 425 kPa, was applied. In the first step, high-speed fluorescence imaging was performed at 150,000 frames per second to capture the instantaneous dynamics of lipid shedding. Lipid detachment was observed within the first few cycles of ultrasound. Subsequently, the detached lipids were transported by the surrounding flow field, either parallel to the focal plane (in-plane shedding) or in a trajectory perpendicular to the focal plane (out-of-plane shedding). In the second step, the onset of lipid shedding was studied as a function of the acoustic driving parameters, for example, pressure, number of cycles, bubble size and oscillation amplitude. The latter was recorded with an ultrafast framing camera running at 10 million frames per second. A threshold for lipid shedding under ultrasound excitation was found for a relative bubble oscillation amplitude >30%. Lipid shedding was found to be reproducible, indicating that the shedding event can be controlled.
authors.affiliation: Biomedical Engineering Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: Y.luan@erasmusmc.nl.
authors.forename: Ying
authors.initials: Y
authors.lastname: Luan
authors.affiliation: Physics of Fluids Group and MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lajoinie
authors.affiliation: Physics of Fluids Group and MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Gelderblom
authors.affiliation: Biomedical Engineering Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ilya
authors.initials: I
authors.lastname: Skachkov
authors.affiliation: Biomedical Engineering Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands; Acoustical Wavefield Imaging, Delft University of Technology, Delft, The Netherlands.
authors.forename: Antonius F W
authors.initials: AF
authors.lastname: van der Steen
authors.affiliation: Biomedical Engineering Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands; Acoustical Wavefield Imaging, Delft University of Technology, Delft, The Netherlands.
authors.forename: Hendrik J
authors.initials: HJ
authors.lastname: Vos
authors.affiliation: Physics of Fluids Group and MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Michel
authors.initials: M
authors.lastname: Versluis
authors.affiliation: Biomedical Engineering Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands; Acoustical Wavefield Imaging, Delft University of Technology, Delft, The Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: De Jong
mesh_terms: D000162:Acoustics; D003287:Contrast Media / Q000032:analysis / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D008055:Lipids / Q000032:analysis / Q000737:chemistry*; D045423:Microbubbles; D013010:Sonication / Q000379:methods*
chemical_list: D003287:Contrast Media; D008055:Lipids
keywords: Controlled drug delivery; Fluorescence imaging; High-speed imaging; Lipid shedding; Microbubbles; Microstreaming