The air-filled, cross-linked, human serum albumin (HSA) microcapsules (air-filled HSA microcapsules) is a stabilized mirobubble formulation that is being developed as an ultrasound (US) contrast agent for use in echocardiography to enhance US images (1) US contrast agents, or echopharmaceuticals, are designed to change the attenuation (absorption, reflection, and refraction) or impedance (resistance to sound propagation) of sound to enhance the differentiation of the signal (echo) of a target organ from that of the surrounding tissue (2-5). Gas-liquid emulsions (i.e., microbubbles or gaseous particles) are highly echogenic because of the nonlinear rarefaction and compression effects that lead to volume pulsations of microbubbles (3, 6, 7). HSA, synthetic polymers, and phospholipids have been used to construct the membranes of these bubbles. Microbubble preparations of various formulations have been developed, and their clinical usefulness depends very much on the size and stability of these bubbles . The current clinical application of these agents is in myocardial contrast echocardiography (MCE) (8). In addition to acoustic parameters, microbubble preparations must meet two other requirements in order to be useful for MCE applications. Microtubble preparations cannot be trapped significantly by the lung capillaries and they must be able to survive the high intracardiac pressure. Air-filled microbubbles stabilized within a galactose matrix were the first commercially available echopharmaceutical (9). However, these microbubbles are not stable enough to pass through the pulmonary capillary bed after a peripheral intravenous injection and can be used only to opacify the right heart chamber. Sonicated human serum microspheres (Sonicated HSM) were the first US contrast agent approved in the United States for cardiac applications. HSM consists of air-filled microbubbles stabilized in a thin shell of HSA with a mean diameter of 3.8 ± 2.5 μm (10). Although these air-filled microbubbles are very sensitive to pressure changes with an half-life () of <1 min, they can pass through the pulmonary capillary bed and reach the left heart chamber. The life-times of air-filled microbubbles can be prolonged by increasing the stiffness of the bubble shell (11). Air-filled HSA microcapsules have stabilized shells that can withstand pressures in excess of 300 mm Hg (1). Other microbubble preparations use perfluorocarbons which dissolve poorly in blood to increase the stability of the microbubbles (12). Serious cardiopulmonary reactions following the administration of ultrasound microbubble contrast agents have been reported (13). In 2007, the US FDA requested that warnings emphasizing the risk for serious cardiopulmonary reactions be added to the labeling of these agents. The uses of these agents are contraindicated in patients with unstable cardiopulmonary status.
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