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Evidence that microbubbles are the main sources of ultrasound contrast in injected solutions has been largely indirect. To investigate this directly, we examined freshly agitated indocyanine green, freshly agitated water, commercially prepared precision microbubbles (diameter 75 +/- 25 mu) in gelatin, carbonated water, "degassed" indocyanine green solution, and "degassed" water in one or more of four different assay systems. Only fluids with microbubbles produced ultrasound contrast. Injected contrast material rose in a water bath at a rate that identified it as being caused by microbubbles. Indocyanine green and gelatin surface tensions were measured and found to be low (43 dynes/cm2), thus explaining their tendency to stabilize the microbubbles that cause ultrasound contrast effect when injected and to hold foam after agitation. The force of hand injections (force similar to that used clinically through catheters and 19-gauge or 23-gauge needles) was below the force needed to cause cavitation or ultrasound contrast effect. Microbubble content could be quantified by the decrease in amplitude of the echo from a structure distant to the microbubbles. We conclude that that the ultrasound contrast effect seen in peripherally injected fluids is caused by microbubbles present in the injectant. The contrast is not due to cavitation at needle tips, and it can be quantified over a limited range. Improved design for a peripheral contrast agent is suggest.

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We have developed novel adhesion molecule-targeted double-shelled microspheres which encapsulate nitrogen. We report in vitro targeting studies utilizing these microspheres conjugated to target-specific antibodies directed towards ICAM-1 and VCAM-1. In static adherence experiments, the adherence patterns of microspheres conjugated to three different monoclonal antibodies (two targeted to ICAM-1 and one to VCAM-1) to their target surfaces were very different. Maximum microsphere adherence at the lowest target and/or ligand densities was observed with the VCAM-1 system. Differences in target-specific adherence were also observed between anti-ICAM-1 and anti-VCAM-1 microsphere conjugates in flow adherence studies. Equilibrium binding studies of the target proteins in solution to the microsphere-bound ligands showed that the affinity constants of two microsphere-bound monoclonal antibodies for their target proteins are similar. Thus, ligand-target affinity is not the only determinant of microsphere adherence to the target surface in our systems. Shear stress was found to have an effect on the mean diameter of adhered microspheres; a decrease in the mean diameter with increasing shear was observed. The magnitude of this effect was dependent on both microsphere-bound ligand and target surface densities, with a more pronounced change at lower densities. Adhered microspheres were readily detectable using ultrasound at the lowest tested surface density of 40 mm(-2).

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