Multi-physics study of acoustofluidic delivery agents' clustering behavior

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.