Abstract
The production and stability of microbubbles (MBs) is enhanced by increasing the viscosity of both the formation and storage solution, respectively. Glycerol is a good candidate for biomedical applications of MBs, since it is biocompatible, although the exact molecular mechanisms of its action is not fully understood. Here, we investigate the influence glycerol has on lipid-shelled MB properties, using a range of techniques. Population lifetime and single bubble stability were studied using optical microscopy. Bubble stiffness measured by AFM compression is compared with lipid monolayer behavior in a Langmuir-Blodgett trough. We deduce that increasing glycerol concentrations enhances stability of MB populations through a 3-fold mechanism. First, binding of glycerol to lipid headgroups in the interfacial monolayer up to 10% glycerol increases MB stiffness but has limited impact on shell resistance to gas permeation and corresponding MB lifetime. Second, increased solution viscosity above 10% glycerol slows down the kinetics of gas transfer, markedly increasing MB stability. Third, above 10%, glycerol induces water structuring around the lipid monolayer, forming a glassy layer which also increases MB stiffness and resistance to gas loss. At 30% glycerol, the glassy layer is ablated, lowering the MB stiffness, but MB stability is further augmented. Although the molecular interactions of glycerol with the lipid monolayer modulate the MB lipid shell properties, MB lifetime continually increases from 0 to 30% glycerol, indicating that its viscosity is the dominant effect on MB solution stability. This three-fold action and biocompatibility makes glycerol ideal for therapeutic MB formation and storage and gives new insight into the action of glycerol on lipid monolayers at the gas-liquid interface.
Highlights
Microbubbles (MBs) for contrast enhanced ultrasound imaging are typically between 1 and 8 μm in diameter and consist of a biocompatible lipid, protein, or polymer shell encapsulating a gas core, which is usually a perfluorocarbon
We studied saturation of the surrounding medium with liquid PFC (C6F10) to increase the stability of MBs, and we showed that PFC molecules were incorporated in the shell lipid monolayer, which resulted in a 25% reduction in the surface tension that reduced the Laplace driving pressure for dissolution.[22]
Data are shown for the 1% solution, while histograms for the other solutions are presented in Figure S1 and show a slight reduction in the modal size and the fwhm (Figure 1b)
Summary
Microbubbles (MBs) for contrast enhanced ultrasound imaging are typically between 1 and 8 μm in diameter and consist of a biocompatible lipid, protein, or polymer shell encapsulating a gas core, which is usually a perfluorocarbon. For clinical and preclinical applications, control over MBs’ size distribution, stability, and mechanical response to US are key parameters typically considered when optimizing MB production. These are controlled by the gas type, the MB shell, and the properties of the solution phase. The MB shell introduces a resistance to gas permeation and together
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