TY - JOUR
T1 - Stability of Monodisperse Phospholipid-Coated Microbubbles Formed by Flow-Focusing at High Production Rates
AU - Segers, Tim
AU - De Rond, Leonie
AU - De Jong, Nico
AU - Borden, Mark
AU - Versluis, Michel
PY - 2016
Y1 - 2016
N2 - 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 104 to 106 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.
AB - 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 104 to 106 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.
UR - http://www.scopus.com/inward/record.url?scp=84967152794&partnerID=8YFLogxK
U2 - 10.1021/acs.langmuir.6b00616
DO - 10.1021/acs.langmuir.6b00616
M3 - Article
AN - SCOPUS:84967152794
SN - 0743-7463
VL - 32
SP - 3937
EP - 3944
JO - Langmuir: the ACS journal of surfaces and colloids
JF - Langmuir: the ACS journal of surfaces and colloids
IS - 16
ER -