Adhesion and ultrasound-induced delivery from monodisperse microbubbles in a parallel plate flow cell

Microbubbles, ultrasound contrast agents currently in development as ultrasonically activated drug delivery vehicles, were studied using a novel flow cell design. The flow cell combined ultrasound compatibility, a planar optical configuration, and a Cartesian orientation of buoyant, shear, and acoustic forces. The set-up enabled measurements of buoyant rise and adhesive sensitivity to shear forces for individual biotinylated, monodisperse, polymer-shelled microbubbles near a NeutrAvidin-coated polystyrene substrate. Analysis of the velocity history demonstrated that adhesion depended on the buoyant rise to the surface before attachment to the substrate: only when the distance parallel to the substrate in the flow direction was between 10 and 20 μm from the stopping position could specific molecular recognition events occur. Low intensity ultrasound caused strong two-dimensional mobility leading to reversible clustering of microbubbles, even though they interacted strongly with the substrate through biotin- NeutrAvidin bonds. At higher acoustic pressure, local gas release took place. With sufficient acoustic intensity, the agents demonstrate potential as large payload carriers for biomolecularly targeted therapeutic delivery. However, difficulties may limit the range of targeting applications: large sizes may render microbubbles susceptible to detachment at the shearing forces present in many regions of the vasculature and secondary radiation forces may reduce targeting effectiveness.