title: Stability of Monodisperse Phospholipid-Coated Microbubbles Formed by Flow-Focusing at High Production Rates.
abstract: Monodisperse microbubble ultrasound contrast agents may dramatically increase the sensitivity and efficiency in ultrasound imaging and therapy. They can be produced directly in a microfluidic flow-focusing device, but questions remain as to the interfacial chemistry, such as the formation and development of the phospholipid monolayer coating over time. Here, we demonstrate the synthesis of monodisperse bubbles with radii of 2-10 μm at production rates ranging from 10(4) to 10(6) bubbles/s. All bubbles were found to dissolve to a stable final radius 2.55 times smaller than their initial radius, independent of the nozzle size and shear rate, indicating that the monolayer self-assembles prior to leaving the nozzle. The corresponding decrease in surface area by a factor 6.6 reveals that lipid molecules are adsorbed to the gas-liquid interface in the disordered expanded state, and they become mechanically compressed by Laplace pressure-driven bubble dissolution to a more ordered condensed state with near zero surface tension. Acoustic characterization of the stabilized microbubbles revealed that their shell stiffness gradually increased from 0.8 to 2.5 N/m with increasing number of insonations through the selective loss of the more soluble lipopolymer molecules. This work therefore demonstrates high-throughput production of clinically relevant monodisperse contrast microbubbles with excellent control over phospholipid monolayer elasticity and microbubble resonance.
authors.affiliation: Physics of Fluids Group, MESA+ Institute for Nanotechnology, and MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , P. O. Box 217, 7500 AE Enschede, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Segers
authors.affiliation: Physics of Fluids Group, MESA+ Institute for Nanotechnology, and MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , P. O. Box 217, 7500 AE Enschede, The Netherlands.
authors.forename: Leonie
authors.initials: L
authors.lastname: de Rond
authors.affiliation: Department of Biomedical Engineering, Thoraxcenter, Erasmus MC , Wyternaweg 80 EE 2302, 3015 CN Rotterdam, The Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: de Jong
authors.affiliation: Department of Mechanical Engineering, University of Colorado , 1111 Engineering Drive, Boulder, Colorado 80309-0427, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Borden
authors.affiliation: Physics of Fluids Group, MESA+ Institute for Nanotechnology, and MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , P. O. Box 217, 7500 AE Enschede, The Netherlands.
authors.forename: Michel
authors.initials: M
authors.lastname: Versluis