Invited Editorial – Sonoporation: Why Microbubbles Create Pores

 

Ultrasound contrast agents are commonly added to the blood stream in ultrasonic imaging: contrast-enhanced ultrasound (CEUS). They consist of microscopically small bubbles (microbubbles) encapsulated by elastic shells. The most common shell materials are phospholipids. During an ultrasound cycle microbubbles oscillate, i. e., they expand and subsequently contract. Depending on their elastic properties, on the local conditions, and on the acoustic settings, they move in the direction of the sound field, coalesce with other microbubbles, fragment, jet, cluster, release their contents, and dissolve in the surrounding liquid [1]. The diverse behaviour of encapsulated microbubbles in different acoustic regimes has triggered the idea to use them as ultrasound-controlled vehicles to facilitate the delivery of therapeutic agents to a site of interest. Such a noninvasive, localised, side-effect-free method would revolutionise drug delivery as we know it.

Cellular uptake of drugs and deoxyribonucleic acid (DNA) is increased when the region of interest is under sonication, and even more so when an ultrasound contrast agent is present [2]. This increased uptake has been attributed to the formation of transient porosities in the cell membrane that have diameters up to 0.1 µm, i. e., big enough for the transport of drugs into the cell. The pores reseal themselves within one minute. The ultrasound-assisted transient permeabilisation of a cell membrane is called sonoporation. Understanding the physics underlying sonoporation is of uttermost importance for the development of ultrasound-activated therapeutic agents.

There are five non-exclusive hypotheses for explaining the sonoporation phenomenon from a physics point of view [3]. These have been summarised in [Fig. 1]. It is noted that fragmenting microbubbles cannot create pores in cells, since fragmentation costs energy.

Fig. 1 Schematic representation of the five physical mechanisms supposedly involved in sonoporation.