Influence of lipid shell physicochemical properties on ultrasound-induced microbubble destruction

TLDR

The study investigates how lipid shell physicochemical properties influence the destruction of lipid‑coated microbubbles during single‑cycle 2.25 MHz insonification, with implications for ultrasound contrast agents and drug delivery. Shell cohesiveness was altered by varying phospholipid/emulsifier composition and post‑production processing, and individual 1–10 µm microbubbles were imaged during pulsing with brightfield and fluorescence microscopy. Destruction occurred via acoustic dissolution at 400–600 kPa and fragmentation at 800 kPa; shell composition affected dissolution rate, fragmentation, and lipid shedding, with less cohesive shells releasing small particles and more cohesive shells forming larger lipid aggregates that increased surface area and lability, while microbubbles stabilized in size at intermediate pressures.

Abstract

We present the first study of the effects of monolayer shell physicochemical properties on the destruction of lipid-coated microbubbles during insonification with single, one-cycle pulses at 2.25 MHz and low-duty cycles. Shell cohesiveness was changed by varying phospholipid and emulsifier composition, and shell microstructure was controlled by postproduction processing. Individual microbubbles with initial resting diameters between 1 and 10 /spl mu/m were isolated and recorded during pulsing with brightfield and fluorescence video microscopy. Microbubble destruction occurred through two modes: acoustic dissolution at 400 and 600 kPa and fragmentation at 800 kPa peak negative pressure. Lipid composition significantly impacted the acoustic dissolution rate, fragmentation propensity, and mechanism of excess lipid shedding. Less cohesive shells resulted in micron-scale or smaller particles of excess lipid material that shed either spontaneously or on the next pulse. Conversely, more cohesive shells resulted in the buildup of shell-associated lipid strands and globular aggregates of several microns in size; the latter showed a significant increase in total shell surface area and lability. Lipid-coated microbubbles were observed to reach a stable size over many pulses at intermediate acoustic pressures. Observations of shell microstructure between pulses allowed interpretation of the state of the shell during oscillation. We briefly discuss the implications of these results for therapeutic and diagnostic applications involving lipid-coated microbubbles as ultrasound contrast agents and drug/gene delivery vehicles.