Encapsulated microbubbles are well established as highly effective contrast agents for ultrasound imaging. There remain, however, some significant challenges to fully realize the potential of microbubbles in advanced applications such as perfusion mapping, targeted drug delivery, and gene therapy. A key requirement is accurate characterization of the viscoelastic surface properties of the microbubbles, but methods for independent, nondestructive quantification and mapping of these properties are currently lacking. We present here a strategy for performing these measurements that uses a small fluorophore termed a "molecular rotor" embedded in the microbubble surface, whose fluorescence lifetime is directly related to the viscosity of its surroundings. We apply fluorescence lifetime imaging to show that shell viscosities vary widely across the population of the microbubbles and are influenced by the shell composition and the manufacturing process. We also demonstrate that heterogeneous viscosity distributions exist within individual microbubble shells even with a single surfactant component.

Surfactant-coated microbubbles are utilized in a wide variety of applications, from wastewater purification to contrast agents in medical ultrasound imaging. In many of these applications, the stability of the microbubbles is crucial to their effectiveness. Controlling this, however, represents a considerable challenge. In this study, the potential for stabilizing microbubbles using solid nanoparticles adsorbed onto their surfaces was explored. A new theoretical model has been developed to describe the influence of interfacially adsorbed solid particles upon the dissolution of a gas bubble in a liquid. The aim of this work was to test experimentally the prediction of the model that the presence of the nanoparticles would inhibit gas diffusion and coalescence/disproportionation, thus increasing the life span of the bubbles. Near-monodisperse microbubbles (~100 μm diameter) were prepared using a microfluidic device and coated with a surfactant, with and without the addition of a suspension of spherical gold nanoparticles (~15 nm diameter). The experimental results confirmed the theoretical predictions that as the surface concentration of gold nanoparticles increased the bubbles underwent negligible changes in their size and size distribution over a period of 30 days at the ambient temperature and pressure. Under the same conditions, bubbles coated with the same surfactant but no nanoparticles survived only a matter of hours.

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Microbubbles have been used in ultrasound-assisted drug delivery to help target solid tumors via blood vessels in vivo; however, studies to understand the phenomena at the cellular level and to optimize parameters for ultrasound or microbubbles in vivo are challenging and expensive to perform. Here, we utilize microfluidic microvessels-on-a-chip that enable visualization of microbubble/ultrasound-dependent drug delivery to microvasculature. When exposed to pulsed ultrasound, microbubbles perfused through microvessels-on-a-chip were observed to stably oscillate. Minimal cellular damage was observed for both microbubbles and untargeted doxorubicin-encapsulating liposomes (DOX-liposomes) perfused through chip microvessels. In contrast, passive and ultrasound-assisted perfusion of integrin-targeted DOX-liposomes induced cytotoxicity, which was only significantly enhanced for ultrasound-assisted perfusion when microbubbles were coperfused. These results suggest that stably oscillating microbubbles enhance targeted DOX-liposome internalization/cytotoxicity largely by stimulating integrin receptor endocytosis. Furthermore, our study demonstrates the utility of our microvessels-on-a-chip as a screening platform for optimizing drug dosage, targeting ligands and drugs.

Recent work has shown that incorporating solid nanoparticles into the coatings of contrast agent microbubbles can be used to control their stability and to provide other functional characteristics for example in multimodality imaging. The aim of this study was to investigate the influence of nanoparticle characteristics and concentration on the response of the microbubbles to ultrasound excitation. Theoretical models were first derived to simulate the effects of adsorbing different types and concentrations of nanoparticle on to the surface of a bubble in both a monolayer and a layer of finite thickness. The results indicate that the particles modify the symmetry of the microbubble oscillations and enhance their nonlinear character. Experimentally, microbubbles coated with a surfactant and varying concentrations of gold nanoparticles of different sizes and surface properties were produced using either sonication or microfluidics. The attenuation and backscattering coefficients from the bubble suspensions and the scattered response from individual bubbles were measured for a range of frequencies (1-7.5MHz) and pressures (50-500kPa). The nanoparticles were found to enhance the nonlinear character of the bubble response in qualitative agreement with the theoretical results. Both the degree of enhancement and stability of the microbubbles was dependent upon the nanoparticle surface chemistry.

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Recent work has shown that incorporating solid nanoparticles into the coatings of contrast agent microbubbles can be used to control their stability and to provide other functional characteristics for example in multimodality imaging. The aim of this study was to investigate the influence of nanoparticle characteristics and concentration on the response of the microbubbles to ultrasound excitation. Theoretical models were first derived to simulate the effects of adsorbing different types and concentrations of nanoparticle on to the surface of a bubble in both a monolayer and a layer of finite thickness. The results indicate that the particles modify the symmetry of the microbubble oscillations and enhance their nonlinear character. Experimentally, microbubbles coated with a surfactant and varying concentrations of gold nanoparticles of different sizes and surface properties were produced using either sonication or microfluidics. The attenuation and backscattering coefficients from the bubble suspensions and the scattered response from individual bubbles were measured for a range of frequencies (1–7.5 MHz) and pressures (50–500 kPa). The nanoparticles were found to enhance the nonlinear character of the bubble response in agreement with the theoretical results. Both the degree of enhancement and stability of the microbubbles was dependent upon the nanoparticle surface chemistry.

Microbubbles stabilized by a surfactant or polymer coating are already in clinical use as ultrasound imaging contrast agents. They have also been widely investigated as vehicles for drug delivery and gene therapy that can be tracked and triggered using ultrasound. Extensive studies have been made of the effects of the coating material and gas core on microbubble characteristics but the influence of the fabrication method has received less attention. The aim of this study was to compare the behavior of microbubbles prepared using different techniques. Phospholipidcoated microbubbles were produced using sonication, electrospraying or in a specially designed microfluidic device. The microbubbles were observed using optical, electron and fluorescence lifetime imaging microscopy (FLIM) to interrogate their surface microstructure and stability over time. Their acoustic response was then determined in a flow chamber by detecting the pressure scattered from individual microbubbles as they passed through the focal region of a transducer (centre frequencies 1, 2.25 and 3.5 MHz; peak negative pressures 50-300kPa). The method of bubble generation was found to significantly affect the bubble surface characteristics, stability and acoustic response. The results demonstrate that the processing method affects not only the bubble size distribution but other characteristics important for biomedical applications.