Novel preparation techniques for controlling microbubble uniformity: a comparison

Abstract

In recent years, there has been increasing interest in the use of coated microbubbles as vehicles for ultrasound mediated targeted drug delivery. This application requires a high degree of control over the size and uniformity of microbubbles, in order to ensure accurate dosing of a given drug and to maximise delivery efficiency. Similarly, as more advanced imaging techniques are developed which exploit the complex nonlinear features of the microbubble signal and/or enable quantification of tissue perfusion, the ability to predetermine the acoustic response of a microbubble suspension is becoming increasingly important. Consequently, a number of new preparation technologies have been developed to meet the demand for improved control over microbubble characteristics. The aim of the work described in this paper was to compare a conventional microbubble preparation technique, sonication, with two more recent methods: coaxial electrohydrodynamic atomisation and microfluidic (T-junction) processing, in terms of their ability to produce bubbles which are sufficiently small and stable for in vivo use, microbubble uniformity, relative production rates and other practical and economic considerations.

Monodisperse Microbubbles as Drug Carrier Units Having the Olive Oil as the Coating Layer from Devices Manufactured by 3D Printing

“…A bottleneck process due to instability at the gas liquid interface forms the microbubbles [18]. The microfluidic device design was developed in the Solid Works environment with the SLDPRT extension, and manufactured from a 3D OBJET EDEN 250 printer using the Vero Clear RGD810 transparent resin.…”

“…The results presented show the capacity of the system proposed to generate microbubbles with mean diameter (D m ) of 18.76 µm and coefficient of variation (V c ) of 1.03% (Table 2), which characterizes the monodisperse character of the microbubble population produced [18]. This characteristic is very important because it is associated to the increase of the therapeutic action, since the frequency of the ultrasonic field has a near direct relation to the diameter of the microbubble and the homogeneous character of the population, considering that a narrow range of frequency potentiates the cavitation of the population of microbubbles and the consequent destruction of them, providing a greater release of the drug at the chosen site [18].…”

“…This characteristic is very important because it is associated to the increase of the therapeutic action, since the frequency of the ultrasonic field has a near direct relation to the diameter of the microbubble and the homogeneous character of the population, considering that a narrow range of frequency potentiates the cavitation of the population of microbubbles and the consequent destruction of them, providing a greater release of the drug at the chosen site [18]. The next step of the work consists of adding a biologically active compound from plants from the Brazilian Northeast semiarid to the microbubbles and studying the dynamic behavior of the generation process, besides the study of the stability of the microbubble population from the use of new lipid matrices.…”

Monodisperse bubbles and droplets for medical applications

“…Recent advances into the production of monodisperse UCA are promising, such as the use of flow-focusing devices to produce highly monodisperse bubble populations as reported by Hettiarachchi et al 65 . These methods are capable of producing highly monodisperse bubble populations at significant rates 64 , however, challenges remain in maintaining the monodispersity for extended periods of time 66,118 . Mechanical filtration is a widely used technique, where the microbubble sus- pension is forced through a filter 87 , acting as a low-pass filter.…”

“…Ultrasound contrast agents produced with conventional methods such as sonication and mechanical agitation 67,118 contain microbubbles in a size range from 1 to 10 µm in radius. The microbubbles are stabilized against dissolution and coalescence by a surfactant shell, typically consisting of biocompatible phospholipids.…”