Elucidation of mechanical and biological effects of oscillating microbubbles on capillary endothelial cells and extravasation

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H04542
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 90130:Medical systems-related
• Research Institution: Hokkaido University
• Principal Investigator: Kudo Nobuki 北海道大学, 情報科学研究院, 准教授 (30271638)
• Co-Investigator(Kenkyū-buntansha): 鈴木 亮 帝京大学, 薬学部, 教授 (90384784) ; 佐々木 東 北海道大学, 獣医学研究院, 講師 (00754532) ; 松崎 典弥 大阪大学, 大学院工学研究科, 教授 (00419467)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 超音波 / 微小気泡 / 薬物送達 / 血液脳関門・血液腫瘍関門開放 / 血管ファントム / 3次元培養 / 高速度・共焦点観察

Outline of Final Research Achievements

We conducted the following investigations to elucidate mechanical and physiological mechanisms in ultrasound-enhanced drug delivery. First, we prepared a vascular lumen phantom with a lumen diameter of 10 microns using a gel that mimicked the physical properties of cells and investigated the relationship between the lumen deformation caused by bubble dynamics and the gel stiffness. Next, extravasation of a drug through the endothelial cell layer created in the gel by the three-dimensional culture method and resulting cell damage were visualized using confocal fluorescence microscopy. Furthermore, ex vivo experiments using rat mesentery revealed microbubble dynamics in capillaries in biological tissues. Finally, the ability of ultrasound exposure to induce a mechanical sensation in dendritic cells demonstrates the potential of ultrasound to enhance dendritic cell function in immune cancer therapy.

Free Research Field

医用超音波

Academic Significance and Societal Importance of the Research Achievements

血管内の微小気泡への超音波照射による局所薬物送達は，実現に向けて多くの基礎的・臨床的研究が進められている．しかし，毛細血管内気泡のダイナミクスとそれが内皮細胞に与える影響の直接観察は難しく，薬物送達の根源的な作用機序は解明されていない．本研究では，ゲル，三次元培養細胞，腸間膜を用いて３種類の毛細血管ファントムを作成し，腔内における気泡ダイナミクスの高速度観察，血管外漏出の増加と細胞損傷の蛍光観察を実現する新手法を開発し，生体内で起きている現象の実像に迫った．本研究の成果は，超音波薬物送達の分野における全ての実験結果の統一的理解に重要な役割を果たし，応用の進展に大きく寄与するものと考えられる．