Ultrasound contrast microbubbles in imaging and therapy: physical principles and engineering

Abstract

Microbubble contrast agents and the associated imaging systems have developed over the past twenty-five years, originating with manually-agitated fluids introduced for intra-coronary injection. Over this period, stabilizing shells and low diffusivity gas materials have been incorporated in microbubbles, extending stability in vitro and in vivo. Simultaneously, the interaction of these small gas bubbles with ultrasonic waves has been extensively studied, resulting in models for oscillation and increasingly sophisticated imaging strategies. Early studies recognized that echoes from microbubbles contained frequencies that are multiples of the microbubble resonance frequency. Although individual microbubble contrast agents cannot be resolved-given that their diameter is on the order of microns-nonlinear echoes from these agents are used to map regions of perfused tissue and to estimate the local microvascular flow rate. Such strategies overcome a fundamental limitation of previous ultrasound blood flow strategies; the previous Doppler-based strategies are insensitive to capillary flow. Further, the insonation of resonant bubbles results in interesting physical phenomena that have been widely studied for use in drug and gene delivery. Ultrasound pressure can enhance gas diffusion, rapidly fragment the agent into a set of smaller bubbles or displace the microbubble to a blood vessel wall. Insonation of a microbubble can also produce liquid jets and local shear stress that alter biological membranes and facilitate transport. In this review, we focus on the physical aspects of these agents, exploring microbubble imaging modes, models for microbubble oscillation and the interaction of the microbubble with the endothelium.

Assessment of tissue perfusion by contrast-enhanced ultrasound

“…Colour and power Doppler are limited by the low sensitivity to low-velocity flow in smaller vessels (<2 mm in diameter). Contrastenhanced ultrasound (CEUS) with microbubble contrast agents [6][7][8] has recently been proposed as a new imaging technique for quantifying tissue perfusion [9,10]. CEUS presents several advantages including low cost, portability, availability, lack of restrictions in performing serial examinations at short intervals, and absence of exposure to radiation or nuclear tracers.…”

Potential and problems in ultrasound-responsive drug delivery systems

“…48 Since the 1990s, a number of research groups have designed drugloaded microbubbles. As shown in Figure 2, their advantages include visualization of drug-loaded microbubbles with low acoustic pressures, ie, image-guided drug delivery; protection of biopharmaceuticals, such as proteins and nucleic acids, against being degraded on administration; targeted drug delivery to specific tissue (ie, tissue that is exposed to ultrasound) and thus reducing side effects; and enhanced uptake by cells via the cavitation effect upon exposure to ultrasound.…”

Ultrasound contrast agents : dynamics of coated bubbles

“…In contrast, its influence on the markedly unsteady translation in an ultrasound field has hardly been treated. Emerging applications of contrast agent microbubbles in drug delivery and targeted molecular imaging [8,9,131] demand a deeper understanding of the behavior on the time scale of competing phenomena, for instance the binding to target molecules or the interaction with the blood vessel walls. These applications ultimately require a detailed description of the instantaneous translation of coated microbubbles.…”