Multi-physics study of acoustofluidic delivery agents’ clustering behavior

Abstract

Acoustofluidicly manipulated microbubbles (MBs) and echogenic liposomes (ELIPs) have been suggested as drug delivery systems for the ‘on demand’ release of drug in target tissue. This requires a clear understanding of their behaviour during ultrasonication and after ultrasonication stops. The main focus of this study is to investigate the behaviour of MBs and ELIPs clusters after ultrasonication stops and the underlaying cause of cluster diffusion considering electrostatic repulsion, steric repulsion and Brownian motion. It also examines the capability of existing models used to predict MBs’ attraction velocity due to secondary radiation force, on predicting ELIPs’ attraction velocity. Tunable resistive pulse sensing (TRPS) and phase analysis light scattering (PALS) techniques were used to measure zeta potentials of the agents and the size distributions were measured using TRPS. The zeta potentials were found to be -2.43 mV and -0.62 mV for Definity™ MBs, and -3.62 mV and -2.35 mV for ELIPs using TRPS and PALS, respectively. Both agents were shown to have significant cluster formation at pressures as low as 6 kPa. Clusters of both agents were shown to diffuse as sonication stops at a rate that approximately equals the sum of the diffusion coefficients of the agents forming them. The de-clustering behaviours are due to Brownian motion as no sign of electrostatic repulsion was observed and particles movements were observed to be faster for smaller diameters. These findings are important to design and optimise effective drug delivery systems using acoustofluidically manipulated MBs and ELIPs.

Controlled Tempering of Lipid Concentration and Microbubble Shrinkage as a Possible Mechanism for Fine-Tuning Microbubble Size and Shell Properties

“…Microbubbles (MBs), gas-filled shell-encapsulated agents from ∼1 to 10 μm in diameter, are utilized in medical imaging and therapeutic applications. − The compressible core of MBs is typically composed of high-molecular-weight gases that have low solubility. ,, The encapsulation shell is usually made of lipids, proteins, or polymers and is used to stabilize the bubble against rapid dissolution of the gas from the MB core . In ultrasound imaging applications, MBs can be used to image blood perfusion and enhance blood–tissue contrast. − In therapeutic applications, MBs are used as targeted drug delivery vehicles whereby drugs are loaded on to the shells of MBs and are released when MBs are exposed to ultrasound through ultrasound-induced cavitation, − sonoporation-mediated applications (e.g., chemosensitization and noninvasive disruption of the blood–brain barrier). ,− The optimization of these applications significantly depends on the response of the MBs to ultrasound.…”