Ultrasound-responsive droplets for therapy: A review

Abstract

The last two decades have seen the development of acoustically activated droplets, also known as phase-change emulsions, from a diagnostic tool to a therapeutic agent. Through bubble effects and triggered drug release, these superheated agents have found potential applications from oncology to neuromodulation. The aim of this review is to summarise the key developments in therapeutic droplet design and use, to discuss the current challenges slowing clinical translation, and to highlight the new frontiers progressing towards clinical implementation. The literature is summarised by addressing the droplet design criteria and by carrying out a multiparametric study of a range of droplet formulations and their associated vaporisation thresholds.

Keywords: Cavitation; Focused ultrasound; Phase-change emulsions.

Figure 1.

Schematic of acoustic droplet vaporisation with example 200 nm liquid droplet vaporising into a 1 μm gaseous microbubble when sonicated with focused ultrasound. Unique acoustic emissions are produced in each state, illustrated with example voltagetraces and frequency spectra detected with an ultrasound receiver.

Figure 2.

Schematic of the fabrication techniques, shell and core compositions - including perfluorohexane (PFH), dodecafluoropentane (DDFP), octafluoropropane (OFP) decafluorobutane (DFB) and perfluoro −15-crown-5-ether (PFCE) – and potential applications of droplets for therapy. By defining the design criteria, bespoke droplets may be fabricated with tech niques and materials most appropriate for the intended application.

Figure 3.

Summary of surface tension values at 20°C of various surfactants (●), albumin (◆), lipids (■) and polymers (▲).

Figure 4.

Vaporisation threshold of PFC droplets is reduced by increasing (a) droplet size and (b) burst length, as illustrated through studies by Sheeran et al. [80], Kripfgans et al.[55], Williams et al. [15] and Schad et al. [10].

Figure 5.

Vaporisation and inertial cavitation thresholds of PFC droplets at (a) 3.5 MHz (Fabiilli et al [59]), (b) 2.855 MHz (Schad et al. [10]) and (c) 1.736 MHz (Schad et al. [10]), where the separation between thresholds decreases with decreasing frequency.