Physical Properties of Microbubble Ultrasound Contrast Agents

Microbubble Contrast Agents

A wide variety of ultrasound-enhancing agents (UEAs), or contrast agents, have been developed for use in diagnostic imaging. Agents that have been approved by regulatory agencies for routine diagnostic use in humans are composed of encapsulated microbubbles. Key considerations that have guided the design of these agents are that they must be safe, able to transit the pulmonary and systemic microcirculation unimpeded, and sufficiently stable after intravenous injection to reach the left ventricular cavity and the myocardium and to produce strong acoustic signals. To satisfy these requirements, microbubbles must be smaller than the effective diameter of the pulmonary and systemic capillary beds (<6–7 μm) and yet contain enough gas volume to undergo cavitation that can be readily be detected by ultrasound. The in vivo stability of microbubbles has been achieved by two strategies. Encapsulation of the microbubbles using lipid surfactant (arranged in a monolayer) or albumin “shells” has been used to reduce outward diffusion of the gas core and to reduce microbubble surface tension, which allows for the production of stable yet small microbubbles. Microbubble stability has been enhanced further by using biocompatible high-molecular-weight gases such as perfluorocarbons (octafluoropropane [C ₃ F ₈ ], decafluorobutane [C ₄ F ₁₀ ]) or sulfur hexafluoride (SF ₆ ). These gases have both low solubility (low Ostwald coefficient) and low diffusion coefficients, which, according to Epstein-Plesset modeling of the stability of free bubbles, markedly increase their life span. A partial list of microbubble agents approved for use in humans is provided in Fig. 19.1 .

The behavior of commercially produced microbubbles in the microcirculation, or their rheology, has been well characterized. This issue is of importance when considering their safety, their ability to transit to the peripheral circulation after intravenous injection, and their application as flow tracers when performing perfusion imaging. Rheology studies have relied on either (1) comparing microbubble transit rates on imaging with those of labeled erythrocytes or (2) intravital microscopy where microbubble transit can be directly visualized ( Fig. 19.2 ). These techniques have definitively demonstrated that microbubble behavior is similar to that of erythrocytes, and they transit the microcirculation of normal tissues unimpeded, with the exception of reticuloendothelial organs (e.g., the liver) where uptake occurs for many microbubbles as part of their normal clearance pathway. ^,

The acoustic detection of gas-filled microbubbles within the vascular compartment is based on their compressibility ( Fig. 19.3 ). The gases that have been used in microbubble contrast agents are several orders of magnitude more compressible than water or tissue. Because they are smaller than ultrasound wavelengths, they undergo volumetric oscillation, whereby they compress and expand during the pressure peaks and troughs of the ultrasound pulse. When imaging at low acoustic power, the degree of signal enhancement is governed by the magnitude of oscillation, also called stable cavitation . The mechanical index (MI), defined as the peak negative acoustic pressure divided by the square root of the transmit frequency, at which stable cavitation occurs, is less than 0.25 for most agents. At higher acoustic pressures (MI generally >0.5), exaggerated microbubble oscillation produces microbubble destruction, which is termed inertial cavitation . This activity produces very strong broadband ultrasound signals by a variety of mechanisms, the most important of which is the abrupt release of free gas microbubbles from the confines of their shell, which than can undergo nondamped exaggerated oscillation. The inertial cavitation phenomenon is also important for nullifying contrast signal when performing quantitative perfusion imaging, which is discussed elsewhere.

The schemes used clinically to augment microbubble signal relative to tissue rely on the detection of specific acoustic signatures produced by nonlinear oscillation. Nonlinear oscillation is defined by a variety of microbubble vibration behaviors in which the changes in microbubble volume are eccentric and not linearly related to the applied ultrasound pressure. The magnitude of oscillation and nonlinear behavior in turn depends on the compressibility and density of the gas, the viscosity and density of the surrounding medium, the frequency and power of ultrasound, and equilibrium radius of the microbubbles. Viscoelastic damping from the shell is a particularly important issue. Ideally, microbubbles should have “flexible” shells. With regard to frequency, there is an ideal resonant frequency at which all forms of radial oscillation become efficient and exaggerated. This “resonant frequency” is inversely related to the square of the microbubble’s radius and is also influenced by the viscoelastic and compressive properties of the shell and gas. When performing contrast echocardiography in patients, selection of the ideal frequency for microbubble resonance is generally not a major consideration because the range of frequencies used in clinical practice are generally close to the ideal resonant frequency for contrast agents approved for use in humans. This is not necessarily the case for high- and ultrahigh frequency probes that are used for intravascular and preclinical imaging in small animals.