STRUCTURAL STUDIES ON STABILIZED MICROBUBBLES - DEVELOPMENT OF A NOVEL CONTRAST AGENT FOR DIAGNOSTIC ULTRASOUND

Ultrasound is a noninvasive tool with which the physician can gain ins ight into the state of the internal organs of the body. A contrast age nt is a substance which, when injected into the body improves the reso lution of an image. The use of diagnostic ultrasound is limited withou t development of such an agent. This paper describes the development o f a new class of contrast agent. The agent consists of microbubbles ge nerated in a solution by sonication, and stabilized by a layer of noni onic surfactant molecules. A single surfactant type alone does not pro duce stable bubbles, and only certain combinations of surfactants, one with a hydrophile-lipophile balance (HLB) greater than 10.5 and the o ther with an HLB less than 9, are successful. An agent prepared from S pan60 (R) and Tween80 (R) is described in detail. A Coulter analysis r evealed that 90% of the bubbles were less than 10 mu m in diameter. Th is is essential if the agent is to pass the pulmonary capillary bed. B -mode imaging of a sample of microbubbles indicated that these bubbles were highly echogenic (that is they produced a strong contrast). A La ngmuir trough study of the molecular arrangement of the surfactant mol ecules inside the microbubble skin suggested that there are 1.7 molecu les of Span to each Tween molecule. Detailed analysis of the pressure- area curves and area per molecule data lead to the hypothesis that the correct proportion of Span molecules can substantially reduce the hea d group repulsion found in the all-Tween situation, and this results i n the generation of stable microbubbles. A molecular arrangement of th ese surfactant molecules around the microbubble is proposed.