Although various cellular immune therapies have been proposed and developed, because the therapeutic cells disperse upon injection into blood flow, there is a limitation on the accumulation of the cells to the target area. We previously reported our attempts to actively control microbubbles in artificial blood vessels, and here we propose a new method of carrying therapeutic cells for cellular therapy using microbubbles and ultrasound. When microbubbles and their aggregations attach to the surface of therapeutic cells, the acoustic force needed to propel the cells is increased because of the size expansion and the boundary in acoustic impedance on the cell surface. We fabricated a cylindrical chamber including two ultrasound transducers to emit a suspension of microbubbles (TF-BLs, transferrin-bubble liposomes) on the cells (Colon-26) to enhance the adhesion of microbubbles on the cells. We found that the optimum conditions for producing BL-surrounded cells were a sound pressure of 100 kPa-pp, an exposure time of 30 s, and a TF-BL concentration of 0.33 mg lipid/mL, when the cell concentration was constant at 0.77 ' 10 5 /mL in phosphate-buffered saline. Using these BL-surrounded cells, we confirmed the controllability of the cells under ultrasound exposure, where the displacement increased in proportion to the sound pressure and was not confirmed with the original cells.

We have developed a new matrix array transducer for controlling the behavior of microbubbles, which is different from that for high-intensity focused ultrasound (HIFU) therapy, in order to emit continuous wave by designing an acoustic field including multiple focal points. In the experiment using a thin-channel model, a wider acoustic field has an advantage for trapping microbubbles. In the experiment using a straight-path model, we have confirmed that a higher concentration of acoustic energy does not result in more aggregates. The dispersion of acoustic energy is important because the trapping performance is affected by the relationship between the shape of the acoustic field and the concentration of the suspension.

Bubble liposomes (BLs), which are gas-encapsulated liposomes several hundred nanometers in diameter, are expected to be developed as a novel tool for gene and drug delivery using ultrasound acoustic radiation force. However, since BLs are several hundred nanometers in diameter, difficulties exist in controlling their behaviors in blood flow under ultrasound exposure, since acoustic radiation forces have less effect on these small bubbles. In this study, we investigated the feasibility of active control of BLs in an artificial blood vessel under ultrasound exposure and attempted to evaluate the controllability. Then, we investigated the appropriate ultrasound conditions for active path selection of BLs in a bifurcated flow by applying acoustic radiation force. We prepared a single transducer to orient BLs toward one desired path. Two other transducers were targeted at the two paths after the bifurcation. We evaluated the areas of trapped BLs in the two paths after the bifurcation, to determine which path had increased BLs. The result showed a significant increase in area of trapped BLs in the desired path compared to the other path. Then, we defined the induction index of BLs by evaluating the area of trapped BLs, and changed the ultrasound conditions for active path selection of BLs by varying the sound pressure and frequency. We found that more BLs could be oriented to a desired path at higher sound pressure. For further study, we are aiming at active control of BLs in vivo.

In this study, the quantitative measurement of acoustic radiation force acting on a thin catheter has been carried out to develop endovascular therapy with microbubbles. First, it is elucidated that the force acting on a thin catheter made of perfluoroalkoxy (PFA) copolymer can be obtained from the cantilever equation in the effective range, where the displacement of the catheter divided by the cube of the length of the catheter is less than 1.0 ' 10 %5 mm %2 . Next, on the basis of the cantilever theory, the force acting on the catheter (diameter 400 µm, material PFA) is measured to be 24 µN under the continuous ultrasound (frequency 2 MHz, sound pressure 300 kPa) irradiation. Furthermore, it is observed that the force depends on the ultrasound frequency. Finally, we conclude that the force is obtained under practical conditions for the realization of endovascular therapy and suggest that thin catheter navigation using ultrasound is fully promising.

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