Sonicated human serum microspheres

Sonicated human serum microspheres (HSM) is a preparation of air-filled HSM that was developed as an ultrasound (US) contrast agent for use in echocardiography to enhance US images (1). In the United States, sonicated HSM was approved by the Food and Drug Administration in 1994 for US contrast enhancement of cardiac ventricular chambers and improvement of endocardial border definition in patients with suboptimal echocardiograms undergoing ventricular function and regional wall motion studies (2). In 1997, sonicated HSM was also approved for use with transvaginal US to assess fallopian tube patency (2). However, it is currently not commercially available for clinical applications. 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 (3-6). Gas-liquid emulsions (microbubbles or gaseous particles) are highly echogenic because of the nonlinear rarefaction and compression effects that lead to volume pulsations of microbubbles (4, 7, 8). Human serum albumin (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) (9). Air-filled microbubbles stabilized within a galactose matrix were the first commercially available echopharmaceutical (10). 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 HSM was the first US contrast agent approved in the United States for cardiac applications. It consists of air-filled microbubbles stabilized in a thin shell of HSA with a mean diameter of 3.8 ± 2.5 μm (11). 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. In Europe, air-filled microbubbles stabilized by palmitic acid have been introduced. These air-filled microbubbles are considered the first-generation of echopharmaceuticals. Second-generation echopharmaceuticals use perfluorocarbons to increase the stability of the microbubbles (12). Sonicated HSM is composed of three protein fractions (1). The carrier protein fraction, which consists of 5% HSA into which the microspheres are dispersed, constitutes over 99.9% of the total protein. The microsphere shell comprises the other two protein fractions: a water-soluble fraction (shell protein 1) and a water-insoluble fraction (shell protein 2).