Although we have reported our attempts to actively control microbubbles in flow using acoustic radiation force for future drug delivery systems, the microbubbles we used are not applicable for in vivo experiments. Thus, we examined two types of nanobubble with a drug-retaining function. Because the nanobubbles are invisible in a conventional optical observation, we observed the behavior of nanobubbles using ultrasound images (echograms). First, we found the optimal settings of echography to guarantee the relationship between the brightness variation and lipid concentration of nanobubbles. Then, we derived the destructive coefficient using two types of path under continuous ultrasound exposure of 5 MHz. Results indicate that the controllability is related to the construction of nanobubbles and the spatial distribution of the ultrasound field. We realized that the design of the ultrasound field is important with Bubble A, whereas the frequency of ultrasound emission needs to be discussed with Bubble B.

Although we have already experimented on the bending of a thin catheter with acoustic radiation force using a single transducer, it is necessary to develop a method of bending a catheter in an arbitrary direction because the installation position of ultrasound transducers on a body surface is limited for application to various shapes of in vivo blood vessels. Therefore, we examined the bending of a thin catheter in the direction perpendicular to ultrasound propagation using a two-dimensional array transducer (1 MHz), which realizes not only the temporospatial design but also the dynamic variation of acoustic fields. Forming two focal points with opposite phases, where the amplitudes of the two points instantaneously have the positive and negative relationship, we confirmed the bending of a thin catheter in the direction perpendicular to ultrasound propagation. We used a thin catheter (diameter, 200 µm; length, 50 mm) to obtain the maximum displacement of 220 µm, where the displacement was proportional to the square of the maximum sound pressure and the duty ratio. From these results, the acoustic energy densities observed in front of and behind the catheter are dominant for the bending of the thin catheter independent of ultrasound propagation. We also found that the distance between two focal points may improve the bending performance without requiring a precise position setting.

No abstract

We have reported our attempts for active path selection of microbubbles by acoustic radiation forces, where we have investigated to control microbubbles by forming multiple focal points of continuous wave using a matrix array transducer. However, because those focal points were located to sweep microbubbles along the slope of sound pressure, it was difficult to concentrate microbubbles against the direction of flow. To produce attractive force to concentrate microbubbles in flow, we formed time-shared acoustic field of two focal points with phase variation. We have succeeded to concentrate microbubbles in water flow utilizing two focal points with opposite phase, where streamline of microbubbles was clearly confirmed in a thin channel. Also we confirmed induction performance using an artificial blood vessel with Y-form bifurcation, where induction rate to a desired path was calculated and varied according to the emission pattern of the focal points in time-shared acoustic fields.

Alhough the development of drug delivery system using microbubbles and ultrasound is expected, because microbubbles diffuse in bloodstream, we have so far reported our attempts for active control of the microbubbles in flow by acoustic radiation force in order to increase local concentration of the microbubbles. However, there was no evidence that in vivo microbubbles act as similar as in vitro experiments, because there were limitations for reproduction of in vivo conditions. In this study, we have elucidated the relationship between brightness variation and microbubbles concentration in the suspension to estimate the absolute concentration in an invisible condition considering in vivo experiment. Then we conducted an experiment of active induction of microbubbles in a Y-form bifurcation of artificial blood vessel, where experimental conditions were with focused ultrasound, the central frequency of 5 MHz, flow velocity of 30 mm/s, and maximum sound pressure of 300 kPa-pp, respectively. Then we applied the conditions for active induction of in vivo microbubbles to compare with in vitro experiments. We used a bifurcation of blood vessel in an ear of a rabbit because the bifurcation shape in its blood vessel is visible. As the results of the experiment, the microbubbles concentration in the induced path was almost two times higher than that in the other path, which agrees with the results from in vitro experiments.