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High-Rate Production, Size Control, and Destruction of Microfluidic Bubbles for Ultrasound and Drug Delivery

  • Author(s): Shih, Roger
  • Advisor(s): Lee, Abraham P
  • Chang, Kenneth J
  • et al.
Abstract

Ultrasound imaging often calls for the injection of contrast agents, micron-sized bubbles which echo strongly in blood and help distinguish vascularized tissue. Such microbubbles are also being augmented with surface receptors and therapeutic payloads for targeted treatment. Unfortunately, conventional production methods yield a polydisperse population, whose nonuniform resonance and drug-loading are less than ideal. An alternative technique, microfluidic flow-focusing, is able to produce highly monodisperse microbubbles with drug-carrying oil layers. However, the published production rate is very low compared to conventional methods, and must be improved for practical use. In addition, although production size is tunable by adjusting gas pressure and solution flow rate, other factors that can affect the final size and stability have not been closely examined. Ultrasonic destructibility of single- and dual-layer microfluidic bubbles has also not yet been verified. This dissertation thus sought to accelerate microfluidic production rates, investigate stabilization parameters, and confirm ultrasonic destruction of oil-carrying microbubbles.

Production of oil-layered lipid microbubbles was tested up to 300 kHz, with coalescence suppressed by high lipid concentrations or inclusion of Pluronic F68 surfactant in the lipid solution. The transition between geometry-controlled and dripping production regimes was analysed, and production scaling was found to be continuous, with a power trend of exponent ~5/12 similar to literature. Unlike prior studies with this trend, however, scaling curves here were found to be pressure-dependent, particularly at lower pressure-flow equilibria (e.g. <15 psi). Adjustments in oil flow rate were observed to have a similar effect, akin to a pressure change of 1-3 psi.

Solution parameters including lipid ratio, concentration, preparation temperature, and viscosity were tested for effects on bubble stabilization. Overall, stability roughly correlated with stable volume. Size, in turn, was strongly influenced by primary-lipid-to-emulsifier ratio, analogous to its effect on Langmuir collapse pressure and conventional bubble yield. Size also increased with lipid concentration, and varied with solution preparation temperature relative to the primary lipid's phase transition point. Viscosity, however, had no significant effect.

Finally, ultrasonic deflection and destruction of both single- and dual-layer bubbles was achieved with clinical ultrasound machines, confirming the bubbles' suitability for use with existing medical equipment.

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