Characterization of Contrast Agent Microbubbles for Ultrasound Imaging and Therapy Research

Abstract

The high efficiency with which gas microbubbles can scatter ultrasound compared with the surrounding blood pool or tissues has led to their widespread employment as contrast agents in ultrasound imaging. In recent years, their applications have been extended to include super-resolution imaging and the stimulation of localized bio-effects for therapy. The growing exploitation of contrast agents in ultrasound and in particular these recent developments have amplified the need to characterize and fully understand microbubble behavior. The aim in doing so is to more fully exploit their utility for both diagnostic imaging and potential future therapeutic applications. This paper presents the key characteristics of microbubbles that determine their efficacy in diagnostic and therapeutic applications and the corresponding techniques for their measurement. In each case, we have presented information regarding the methods available and their respective strengths and limitations, with the aim of presenting information relevant to the selection of appropriate characterization methods. First, we examine methods for determining the physical properties of microbubble suspensions and then techniques for acoustic characterization of both suspensions and single microbubbles. The next section covers characterization of microbubbles as therapeutic agents, including as drug carriers for which detailed understanding of their surface characteristics and drug loading capacity is required. Finally, we discuss the attempts that have been made to allow comparison across the methods employed by various groups to characterize and describe their microbubble suspensions and promote wider discussion and comparison of microbubble behavior.

Long-term physical evolution of an elastomeric ultrasound contrast microbubble

“…Undoubtedly, the understanding of ageing is pivotal for the optimisation of the acoustic properties, injectability, and biodistribution of UCAs [2,10,11]. To this end, valuable methodologies such as confocal [12] and near-field microscopies [13][14][15], together with acoustic spectroscopy [16,17], can be used and combined to detect morphological, structural, and, thus, functional fine alterations on the MB's wall at the liquid interface. Nevertheless, the literature has still been found to lack long-term studies in this respect.…”

Drug Delivery Strategies for Platinum-Based Chemotherapy

“…As permeability changes are temporary, it is essential that the drug and cavitation event are proximate. Cavitation nuclei typically consist of a gas bubble or phase change liquid encapsulated in a biocompatible shell, which can be surface functionalized to allow loading of drugs and/or nanoparticle drug carriers, [163][164][165] as reviewed in several publications. [166][167][168] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 24 muscle delivery in mice using fluorescent PLGA-based nanoparticles covalently attached to microbubbles compared to unbound co-injections of nanoparticle and microbubble, 169 highlighting the importance of localizing drug and cavitation.…”

Microbubble-Mediated Delivery for Cancer Therapy

“…In general, as permeability is only temporarily altered, colocalising the drug or nanocarrier to the site of microbubble activity promotes the delivery [131], effect [132], and release [133,134]. Finally, appropriate characterisation of the cavitation agent and drug loading is of vital importance to any drug delivery strategy (recently reviewed in [135]).…”