Radial Dynamics of Pickering-stabilised Endoskeletal Antibubbles and Their Components in Pulsed Ultrasound

Abstract

Liquids containing microscopic antibubbles may have theranostic applications in harmonic diagnostic ultrasonic imaging and in ultrasound-assisted drug delivery. Presently there are no known agents available with the acoustic properties required for use in both of these applications. The Pickering-stabilised antibubble may possess the de- sired acoustic properties to be such a theranostic agent. An antibubble is a gas bubble containing at least one incompressible core. An antibubble is inherently unstable and thus needs to be stabilised to exist for longer than a moment. One such stabilising method, involving the adsorption of nanoparticles to gas–liquid interfaces, is called Pickering stabilisation. A Pickering-stabilised antibubble responds to an incident sound field by means of radial pulsation and other, more complicated, dynamics.

Despite the potential application of microscopic antibubbles in theranostics, their dynamic behaviour and the acoustic regimes in which this behaviour occurs are not known.

The purpose of this research was to predict the dynamic response of Pickering- stabilised antibubbles to pulsed ultrasound, and to identify and quantify the contribution of each of the Pickering-stabilised antibubble components to that behaviour. Radial excursions of antibubbles and their components during ultrasound exposure were extracted from high-speed footage. The applied ultrasound had a centre frequency of 1 MHz and pressure amplitudes between 0.20 MPa and 1.30 MPa. Moreover, damping coefficients, pulsation phases, and excursions of antibubbles and antibubble components were computed with equations describing a forced mass–spring–dashpot system and an adapted Rayleigh-Plesset equation. Over a range of driving pressure amplitudes, fragmentation thresholds were computed for antibubbles of varying size, core volume, shell stiffness, and driving frequency. In addition, the feasibility of an antibubble component for the disruption of cell walls was tested. From the experimental data, it was found that antibubble contractions and expansions were symmetrical and predictable at an acoustic amplitude of 0.20 MPa, whilst the pulsations were asymmetrical and less predictable at an acoustic amplitude of 1.00 MPa. These results show that the presence of the core inside of the antibubble hampers the contraction of a collapsing antibubble and ameliorates its stability. Consequently, Pickering-stabilised antibubbles appear to be feasible candidates for ultrasonic imaging, with greater stability than the agents currently in use.

Micron-sized antibubbles, much smaller than resonant size, were computed to have a pulsation phase difference of up to ^<u>1</u>₆^thof a cycle with respect to free gas bubbles. The difference in oscillation phase is a result of the increased damping coefficient caused by the friction of the internal components and shell of the antibubble. This indicates that altering the damping of the shell or skeletal material of minute antibubbles can alter the degree to which the particle’s oscillation is in phase with the sound field.

The shell stiffness of Pickering-stabilised microbubbles without incompressible contents was measured to be 7.6 N m−1 throughout low-amplitude sonication. Un- der high-amplitude sonication, the maximum expansions of microbubbles, measured from high-speed camera footage, were either agreeing with those computed for Pickering-stabilised microbubbles or corresponding to greater values. The differing oscillation amplitudes for similarly sized microbubbles is attributed to shell disruption of different severity.

For a 3-μm radius antibubble with a 90% core radius, subjected to a pulse of centre frequency 1 MHz, the fragmentation threshold was computed to drastically increase with shell stiffness. At a driving frequency of 13 MHz, the fragmentation threshold was computed to correspond to a mechanical index less than 0.4, irrespective of shell stiffness. Shell stiffness changes the resonance frequency, and thus the fragmentation threshold of antibubbles. This means that the resonance frequency of an extremely low concentration and quantity of homogeneous agent can be determined using microscopy. At driving frequencies above 1 MHz, the fragmentation threshold was computed to correspond to a mechanical index of less than 0.5, irrespective of shell stiffness.

Antibubbles exposed to high-amplitude ultrasound were found to have an exponential fragment size distribution. This brings us closer to understanding and controlling disruption and material release for these particles. If the pressure of the regime is known, the number of antibubble fragments produced can be theoretically determined.

Under low-amplitude ultrasound exposure, hydrophobic particles, a common component of antibubbles, were observed to jet through wood fibre cell walls, without causing visible internal structural damage to these cells. Hydrophobic particles can thus act as inertial cavitation nuclei which collapse asymmetrically close to solid boundaries such as wood pulp fibres. This indicates that hydrophobic particles on their own may be used for applications such as trans-dermal drug delivery.

The dynamic response of Pickering-stabilised antibubbles to ultrasound has been predicted. Furthermore the respective behaviour of Pickering-stabilised antibubble components under theranostic ultrasound conditions has been identified. This work has led to a straightforward way to determine the elasto-mechano properties of small samples of contrast agent.

Whilst possessing some theranostic properties, Pickering-stabilised antibubbles may be more suitable as replacements for current diagnostic agents. Hydrophobic particles, a current constituent of the Pickering-stabilised antibubble, may however, prove to be promising theranostic agents.