小井土 惇¹, 和田 洸¹, 保坂 直斗¹, 望月 剛¹, 桝田 晃司¹, 小田 雄介², 鈴木 亮², 丸山 一雄²

Jun KOIDO¹, Hikaru WADA¹, Naoto HOSAKA¹, Takashi MOCHIZUKI¹, Kohji MASUDA¹, Yusuke ODA², Ryo SUZUKI², Kazuo MARUYAMA²

¹東京農工大学大学院生物システム応用科学府, ²帝京大学薬学部

¹Graduate School of Bio-Applications and Systems Engineering, Tokyo University of Agriculture and Technology, ²Faculty of Pharma Sciences, Teikyo University

キーワード : microbubbles, bubble liposome, blood flow, controllability, echogram, brightness variation

目的：超音波と微小気泡との併用で超音波治療の効率向上が期待されているが，体内に注入後の微小気泡は血流と共に体内へ拡散してしまう．我々はこれまで，任意の箇所での微小気泡の濃度を高めることを目的として，流水中で超音波照射による微小気泡の誘導を行ってきた．この方法を，生体投与可能で様々な薬剤を包含できる微小気泡（バブルリポソーム，BLs）に応用する必要に迫られている一方，血流中での微小気泡の制御可能性については未確認であった．しかもBLsの平均直径は0.5 μmと小さく，従来の光学顕微鏡ではBLsの濃度を計測できない．対象と方法：そのため，超音波画像中の輝度変化からBLsの濃度を計測する校正法を確立し，生理食塩水とブタ血液の2種類の媒質を用いて実験を行った．まず超音波画像そのものによるBLsの破壊効果を調査し，BLsの濃度計測に影響を与えない超音波画像のMI値を検証した．さらにY字分岐を有する人工血管において，BLsを特定の経路に押し出す誘導実験を行った．ここでの実験条件は中心周波数5 MHz，最大音圧300 kPa-ppの集束波，流速30 mm/sとした．結果と考察：誘導実験の結果として，生理食塩水の場合に比べて，血流中ではBLsの破壊が軽減されることが今回の実験により初めて確認された．さらに誘導用音波の照射位置は，人工血管の分岐点で押し出すのでは無く，数mm離れた位置に設定した方が，誘導性能が向上することが分かった．結論：本研究の結果より，生体中におけるBLsの誘導の可能性を更に発展できる足がかりを確認できた．

Purpose: Though improvement in the efficiency of ultrasound treatment is expected in combination with microbubbles, because microbubbles disperse in the bloodstream, we have attempted to actively control microbubbles in blood flow by means of acoustic radiation force in order to increase the local concentration of the microbubbles. Bubble liposomes (BLs), which have a high potential to contain various kinds of drugs, are ready for in vivo applications, and investigation of the possibility of active control is needed. However, the controllability of microbubbles in blood flow has not been confirmed. Because the average diameter of BLs is 0.5 μm, their concentration cannot be measured with conventional optical observation. Subjects and Methods: Therefore, we established a method for identifying the concentration of BLs from the brightness variations in ultrasound images (echograms) with two kinds of suspension, i.e., normal saline and porcine blood. First, we derived an acceptable mechanical index at which the effect of BL destruction can be ignored when measuring the concentration. We then examined the active path selection of BLs using a Y-form bifurcation of artificial blood vessels with focused ultrasound with a central frequency of 5 MHz and a maximum sound pressure of 300 kPa-pp, in a flow velocity of 30 mm/s. Results and Discussion: The experiments confirmed less destruction of BLs with the medium of porcine blood as compared with normal saline. Furthermore, higher induction performance was confirmed when the focal point of ultrasound emission was several mm away from the bifurcation point versus the focal point corresponding to the bifurcation point. Conclusion: From these results there is a possibility to enhance the controllability of in vivo BLs.