Localized and targeted
drug delivery can be achieved by the combined
action of ultrasound and microbubbles on the tumor microenvironment,
likely through sonoporation and other therapeutic mechanisms that
are not well understood. Here, we present a perfusable in vitro model
with a realistic 3D geometry to study the interactions between microbubbles
and the vascular endothelium in the presence of ultrasound. Specifically,
a three-dimensional, endothelial-cell-seeded in vitro microvascular
model was perfused with cell culture medium and microbubbles while
being sonicated by a single-element 1 MHz focused transducer. This
setup mimics the in vivo scenario in which ultrasound induces a therapeutic
effect in the tumor vasculature in the presence of flow. Fluorescence
and bright-field microscopy were employed to assess the microbubble–vessel
interactions and the extent of drug delivery and cell death both in
real time during treatment as well as after treatment. Propidium iodide
was used as the model drug while calcein AM was used to evaluate cell
viability. There were two acoustic parameter sets chosen for this
work: (1) acoustic pressure: 1.4 MPa, pulse length: 500 cycles, duty
cycle: 5% and (2) acoustic pressure: 0.4 MPa, pulse length: 1000 cycles,
duty cycle: 20%. Enhanced drug delivery and cell death were observed
in both cases while the higher pressure setting had a more pronounced
effect. By introducing physiological flow to the in vitro microvascular
model and examining the PECAM-1 expression of the endothelial cells
within it, we demonstrated that our model is a good mimic of the in
vivo vasculature and is therefore a viable platform to provide mechanistic
insights into ultrasound-mediated drug delivery.