Model drug delivery by transiently stable microbubbles produced by a microfluidic device

Ultrasound-mediated drug delivery using intravascular ultrasound (IVUS) and microbubbles holds promise as a potential therapy for diseases of the vasculature. In this work, we evaluate the therapeutic potential of an on-demand microbubble production framework using a flow-focusing microfluidic device to generate microbubbles at the tip of the IVUS catheter for direct administration into the bloodstream. Rat aortic smooth muscle cells were placed in a flow chamber, 8 μm diameter monodisperse microbubbles produced within the flow chamber by a flow-focusing microfluidic device, and ultrasound was applied to enhance uptake of a surrogate drug (calcein). Flow rates up to 18 mL/s and acoustic peak-negative-pressures up to 300 kPa were investigated. Microbubbles produced by the microfluidic device were stabilized with a polyethylene glycol-40-stearate shell and had either a perfluorbutane (PFB) or nitrogen gas core. Calcein delivery was observed at lower acoustic pressures with nitrogen microbubbles than with PFB microbubbles, and maximal delivery occurred at a flow rate of 9 mL/s. These results demonstrate the potential of transiently stable microbubbles produced by a microfluidic device for enhancing localized drug delivery.