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研究者情報

マスター

アカウント（マスター）

  • 氏名

    工藤　信樹(クドウ　ノブキ), クドウ　ノブキ

所属（マスター）

  • 情報科学研究院　生命人間情報科学部門　バイオエンジニアリング分野

所属（マスター）

  • 情報科学研究院　生命人間情報科学部門　バイオエンジニアリング分野

researchmap

プロフィール情報

所属

  • 北海道大学, 大学院情報科学研究科 生命人間情報科学専攻 バイオエンジニアリング講座, 助教授・准教授

学位

  • 工学博士（北海道大学）
  • 工学修士（北海道大学）

プロフィール情報

  • 姓

    工藤, クドウ

  • 名

    信樹, ノブキ

  • ID各種

    200901019019923127

対象リソース

所属

  • 北海道大学, 大学院情報科学研究科 生命人間情報科学専攻 バイオエンジニアリング講座, 助教授・准教授

業績リスト

研究キーワード

  • 超音波   微小気泡   光イメージング   空間分解能   微弱光検出   光変調   透過光   減衰   屈折   パルス超音波   光パルス   ソノポレーション   ドプラ効果   タイムラプス観察   血管内皮細胞   遺伝子導入   シェル   干渉計   後方散乱光   光ピンセット   スペックル   血流計測   超音波造影剤   RF信号   粥腫   超音波診断   心筋細胞   心室筋細胞   音圧依存性減衰   ターゲティング気泡   医用超音波   医用光学   Biomedical UltrasoundBiomedical Optics   

研究分野

  • 人文・社会 / 教育工学
  • ライフサイエンス / 医用システム
  • ライフサイエンス / 生体材料学
  • ライフサイエンス / 生体医工学

経歴

  • 2009年 - 2013年 北海道大学 大学院・情報科学研究科 准教授
  • 2009年 - 北海道大学（大学院情報科学研究科) 准教授
  • 2004年 - 2007年 北海道大学助手（大学院情報科学研究科) 助手
  • 2004年 - 2007年 Research Associate
  • 1997年 - 2004年 北海道大学助手（大学院工学研究科) 助手
  • 1997年 - 2004年 Research Associate,Graduate School of Engineering, Hokkaido University
  • 1995年 - 1997年 北海道大学助手（工学部) 助手
  • 1995年 - 1997年 Research Associate,Faculty of Engineering, Hokkaido University
  • 1987年 - 1995年 (株)東芝医用機器技術研究所

学歴

  •         - 1987年   北海道大学
  •         - 1984年   北海道大学   生体工学専攻
  •         - 1984年   北海道大学
  •         - 1982年   北海道大学   工学部   電子工学科
  •         - 1982年   北海道大学

委員歴

  • 2017年04月 - 現在   日本生体医工学会   北海道支部長
  • 2013年09月 - 現在   IEEE   Area Editor
  • 2012年 - 現在   日本超音波医学会   理事   日本超音波医学会
  • 2012年 - 現在   日本超音波医学会機器及び安全に関する委員会   副委員長   日本超音波医学会機器及び安全に関する委員会
  • 2010年 - 現在   日本超音波医学会   北海道地方会運営委員長   日本超音波医学会
  • 2008年 - 現在   日本超音波医学会   Journal of Medical Ultrasonics, Area Editor   日本超音波医学会
  • 2004年 - 現在   日本生体医工学会   代議委員   日本生体医工学会

受賞

  • 2013年 日本超音波医学会 第２回新人賞
     
    受賞者: 内田和輝
  • 2012年 日本超音波医学会 第１回新人賞
     
    受賞者: 吉松幸里
  • 2010年 日本超音波医学会 第26回菊池賞（論文賞）
  • 2009年 日本超音波医学会 第25回菊池賞（論文賞）
  • 2007年 平成19年日本ソノケミストリー学会論文賞
  • 2005年 日本超音波医学会 第21回菊池賞（論文賞）
  • 2005年 日本超音波医学会 第７回奨励賞
  • 2005年 Best Presentation Award
  • 2004年 7th International Symposium on Ultrasound Contrast Imaging, Superb poster award
  • 2002年 6th International Symposium on Ultrasound Contrast Imaging, Poster session Silver Prize
  • 2002年 Asian Symposium on Biomedical Optics and Photomedicine Best Poster Award
  • 2002年 日本超音波医学会 第３回奨励賞（優秀発表賞）
  • 2002年 7th Ultrasound Contrast Research Symposium in Radiology Best Presentation Award
  • 1999年 日本超音波医学会第13回菊池賞（論文賞）
  • 1992年 日本エム・イー学会科学新聞賞新技術開発賞

論文

  • 超音波医学をどう広めるか?～医学教育と一般広報について～ 超音波医学をどう広めるか?
    小川 眞広, 秋山 いわき, 工藤 信樹, 紺野 啓, 長沼 裕子, 新田 尚隆, 水野 隆, 畠 二郎
    超音波医学 50 Suppl. S547 - S547 (公社)日本超音波医学会 2023年04月
  • マイクロバブルと超音波照射による固形がん組織の腫瘍微小環境変化を介した養子免疫療法の抗腫瘍効果増強に関する検討
    鈴木 亮, 丸山 保, 宗像 理紗, 鈴木 悠乃, 小俣 大樹, 工藤 信樹, 小山 正平, 岡田 欣晃
    Thermal Medicine 38 Suppl. 085 - 085 (一社)日本ハイパーサーミア学会 2022年08月
  • マイクロバブルと超音波照射による固形がん組織の腫瘍微小環境変化を介した養子免疫療法の抗腫瘍効果増強に関する検討
    鈴木 亮, 丸山 保, 宗像 理紗, 鈴木 悠乃, 小俣 大樹, 工藤 信樹, 小山 正平, 岡田 欣晃
    Thermal Medicine 38 Suppl. 085 - 085 (一社)日本ハイパーサーミア学会 2022年08月
  • 毛細血管ゲルファントムを用いた微小気泡ダイナミクスの高速度観察による弾性率の推定
    Hu Xinyue, 小俣 大樹, 鈴木 亮, 佐々木 東, 工藤 信樹
    超音波医学 49 Suppl. S802 - S802 (公社)日本超音波医学会 2022年04月
  • 抗がん剤付着型アルブミンナノ粒子と微小気泡を用いた超音波薬物送達の機序検討
    新里 美瑠, 胡 新げつ, 小俣 大樹, 鈴木 亮, 佐々木 東, 工藤 信樹
    超音波医学 49 Suppl. S803 - S803 (公社)日本超音波医学会 2022年04月
  • 気泡を貪食した樹状細胞への超音波照射による継続的なCa2+濃度変化誘導
    大竹 直幸, 鈴木 亮, 小俣 大樹, 工藤 信樹
    超音波医学 49 Suppl. S825 - S825 (公社)日本超音波医学会 2022年04月
  • 微小気泡を貪食した樹状細胞の超音波照射によるCa2+濃度変化誘導現象の高速度観察
    大竹 直幸, 鈴木 亮, 小俣 大樹, 工藤 信樹
    超音波医学 49 Suppl. S827 - S827 (公社)日本超音波医学会 2022年04月
  • 毛細血管ゲルファントムを用いた微小気泡ダイナミクスの高速度観察による弾性率の推定
    Hu Xinyue, 小俣 大樹, 鈴木 亮, 佐々木 東, 工藤 信樹
    超音波医学 49 Suppl. S802 - S802 (公社)日本超音波医学会 2022年04月
  • 抗がん剤付着型アルブミンナノ粒子と微小気泡を用いた超音波薬物送達の機序検討
    新里 美瑠, 胡 新げつ, 小俣 大樹, 鈴木 亮, 佐々木 東, 工藤 信樹
    超音波医学 49 Suppl. S803 - S803 (公社)日本超音波医学会 2022年04月
  • マイクロバブルと超音波併用による免疫微小環境の変化と養子免疫療法の抗腫瘍効果増強に関する基礎的検討
    丸山 保, 宗像 理紗, 小俣 大樹, 萩原 芙美子, 鈴木 悠乃, 小山 正平, 岡田 欣晃, 工藤 信樹, 鈴木 亮
    日本薬学会年会要旨集 142年会 28H - pm05S (公社)日本薬学会 2022年03月
  • マイクロバブルと超音波併用による免疫微小環境の変化と養子免疫療法の抗腫瘍効果増強に関する基礎的検討
    丸山 保, 宗像 理紗, 小俣 大樹, 萩原 芙美子, 鈴木 悠乃, 小山 正平, 岡田 欣晃, 工藤 信樹, 鈴木 亮
    日本薬学会年会要旨集 142年会 28H - pm05S (公社)日本薬学会 2022年03月
  • Naoyuki Otake, Ryo Suzuki, Daiki Omata, Nobuki Kudo
    IEEE International Ultrasonics Symposium, IUS 2022-October 2022年 
    The possibility of intracellular Ca2+ elevation being induced by short-pulsed ultrasound was investigated using cultured cells of the murine dendritic cell line DC2.4. Dendric cells (DCs) with phagocytosed microbubbles were irradiated by 3-cycle ultrasound of 0.2-0.6 MPa in peak-negative pressure to achieve safe and efficient mechanical stimulation. Two types of microbubbles, lipid-shell bubbles of about 1 μmn diameter and plastic-shell bubbles of 3-5 μm in diameter, were used to examine the effect of bubble dynamics on triggering Ca2+ elevation and cell damage generation. Experimental results showed that, in the presence of microbubbles, even pulsed ultrasound at diagnostic levels could induce Ca2+ elevation. It was also shown that the plastic-shell bubbles, which show contraction-only oscillation, can induce repetitive Ca2+ elevations under multiple exposures of pulsed ultrasound. The results indicate that ultrasonic irradiation can induce sustained mechanical sensation of DCs, enhancing their antigen-presenting ability through cell maturation.
  • Noboru Sasaki, Yoshinori Ikenaka, Keisuke Aoshima, Teiichiro Aoyagi, Nobuki Kudo, Kensuke Nakamura, Mitsuyoshi Takiguchi
    Frontiers in pharmacology 13 837754 - 837754 2022年 
    Intravesical chemotherapy after transurethral resection is a treatment option in patients with non-muscle invasive bladder cancer. The efficacy of intravesical chemotherapy is determined by the cellular uptake of intravesical drugs. Therefore, drug delivery technologies in the urinary bladder are promising tools for enhancing the efficacy of intravesical chemotherapy. Ultrasound-triggered microbubble cavitation may enhance the permeability of the urothelium, and thus may have potential as a drug delivery technology in the urinary bladder. Meanwhile, the enhanced permeability may increase systemic absorption of intravesical drugs, which may increase the adverse effects of the drug. The aim of this preliminary safety study was to assess the systemic absorption of an intravesical drug that was delivered by ultrasound-triggered microbubble cavitation in the urinary bladder of normal dogs. Pirarubicin, a derivative of doxorubicin, and an ultrasound contrast agent (Sonazoid) microbubbles were administered in the urinary bladder. Ultrasound (transmitting frequency 5 MHz; pulse duration 0.44 μsec; pulse repetition frequency 7.7 kHz; peak negative pressure -1.2 MPa) was exposed to the bladder using a diagnostic ultrasound probe (PLT-704SBT). The combination of ultrasound and microbubbles did not increase the plasma concentration of intravesical pirarubicin. In addition, hematoxylin and eosin staining showed that the combination of ultrasound and microbubble did not cause observable damages to the urothelium. Tissue pirarubicin concentration in the sonicated region was higher than that of the non-sonicated region in two of three dogs. The results of this pilot study demonstrate the safety of the combination of intravesical pirarubicin and ultrasound-triggered microbubble cavitation, that is, ultrasound-assisted intravesical chemotherapy.
  • Kazuhiro Nishida, Yuji Kato, Nobuki Kudo, Koichi Shimizu
    Japanese Journal of Applied Physics 60 7 2021年07月 
    For a practical technique of cross-sectional imaging of animal bodies, we developed a new method using spatially resolved backscattered light. This method is based on the solution of the one-dimensional nonlinear inverse problem, and on the lateral scan of the source-detector pair along the object surface. Using this method, unknown variables in inverse problems can be reduced more greatly than when using conventional methods. A stable solution for the inverse problem becomes possible. The possibility of using the proposed method was assessed using simulation analysis. The results verified that cross-sectional imaging from several to 10 millimeter depths is possible for animal tissue. This analysis clarified the specific spatial resolution and accuracy in the estimated absorption coefficient. Distortionless imaging was confirmed. Results suggest that the proposed method represents new options as a stable and practical method for biological cross-sectional imaging.
  • マイクロバブルの繰り返し投与における血流造影への影響に関する基礎的検討
    鈴木 亮, 島 忠光, 丸山 保, 小俣 大樹, 宗像 理紗, 工藤 信樹, 丸山 一雄
    超音波医学 48 Suppl. S648 - S648 (公社)日本超音波医学会 2021年04月
  • 超音波で生体の壁を超える 超音波と気泡を併用する膀胱内注入療法の犬における安全性検討
    佐々木 東, 青柳 貞一郎, 池中 良徳, 工藤 信樹, 中村 健介, 滝口 満喜
    超音波医学 48 Suppl. S195 - S195 (公社)日本超音波医学会 2021年04月
  • Ri Ichiro Shimizu, Ryo Suzuki, Nobuki Kudo
    IEEE International Ultrasonics Symposium, IUS 2020-September 2020年09月07日 
    Mechanisms of BBB opening were investigated using a capillary model created by a three-dimensional cell culture technique. The model was made using human umbilical vein endothelial cells (HUVECs) suspended in collagen gel. Incubation with endothelial growth factor for one week resulted in the creation of capillary lumens, and a suspension of microbubbles supplemented with FITC-dextran, SYTOX Blue, and Calcein-AM was introduced inside the lumens. Bubble-cell interaction under exposure to short pulsed ultrasound of 1.0 MHz in center frequency and 0.4 MPa in peak negative pressure was captured using a high-speed camera, and lumen and endothelial cell damage was visualized using fluorescence microscopy. High-speed observation showed that non-uniform contraction of a bubble caused significant local deformation of the lumen beside the bubble, and strong extravasation from the lumen (FITC-dextran) and significant membrane damage of the endothelial cells (SYTOX Blue) were confirmed at this location. Lethal damage was also observed frequently (Calcein). On the other hand, cells on the opposite side of the lumen received stretching force during bubble expansion, and smaller extravasation and cell damage maintained the integrity of endothelial cells. These suggested the presence of different mechanisms of BBB opening.
  • Antoine Presset, Corentin Bonneau, Sasaoka Kazuyoshi, Lydie Nadal-Desbarats, Takigucho Mitsuyoshi, Ayache Bouakaz, Nobuki Kudo, Jean-Michel Escoffre, Noboru Sasaki
    Ultrasound in medicine & biology 46 7 1565 - 1583 2020年04月21日 [査読有り][通常論文]
     
    Microbubble-assisted ultrasound has emerged as a promising method for local drug delivery. Microbubbles are intravenously injected and locally activated by ultrasound, thus increasing the permeability of vascular endothelium for facilitating extravasation and drug uptake into the treated tissue. Thereby, endothelial cells are the first target of the effects of ultrasound-driven microbubbles. In this review, the in vitro and in vivo bioeffects of this method on endothelial cells are described and discussed, including aspects on the permeabilization of biologic barriers (endothelial cell plasma membranes and endothelial barriers), the restoration of their integrity, the molecular and cellular mechanisms involved in both these processes, and the resulting intracellular and intercellular consequences. Finally, the influence of the acoustic settings, microbubble parameters, treatment schedules and flow parameters on these bioeffects are also reviewed.
  • Kazuhiro Nishida, Yuji Kato, Nobuki Kudo, Koichi Shimizu
    Optics and Lasers in Engineering 126 1 - 11 2020年03月 [査読有り][通常論文]
     
    This report presents a proposal of a new technique to estimate the cross-sectional absorption distribution of turbid media from backscattered light by solving a nonlinear inverse problem. After illuminating a beam of light on the surface of a turbid object and measuring the backscattered light as a function of distance from the light incident point, we divide the object into multiple virtual layers to estimate the absorption distribution. The path lengths of photon propagation in the respective layers are calculated using Monte Carlo simulation. The absorption coefficient of each virtual layer can be estimated from the backscattered intensity and the path length distribution in a depth direction. For solving this inverse problem, the linear calculation results are useful as initial solutions. Then the final solutions are obtained from iteration of the nonlinear calculation. Convergence into a unique solution and robustness of the solution against the measurement noise were confirmed. The effectiveness of the proposed technique was verified through simulation and measurement. By lateral scanning of a source detector pair, we can reconstruct a cross-sectional image of the turbid medium to the depth to which the detected light reaches.
  • Johan Unga, Daiki Omata, Nobuki Kudo, Soki Ueno, Lisa Munakata, Tadamitsu Shima, Ryo Suzuki, Kazuo Maruyama
    Journal of liposome research 29 4 368 - 374 2019年12月 [査読有り][通常論文]
     
    It is known that Phosphatidyl choline-Phosphatidyl glycerol mixtures can be used for liposome formulations, making them less leaky than liposomes with only one lipid. We hypothesized that this might also be the case for bubbles, which can be used as ultrasound (US) contrast agents. Therefore, we have compared a series of mixed distearoyl phosphatidylcholine-distearoyl phosphatidylglycerol (DSPC-DPSG) bubbles and with bubbles containing either DSPC or DSPG (and distearoyl ethanolamine-polyethyleneglycol 2000, DSPE-PEG2k). Here, we describe the development, examination of stability in vitro and attenuation of broad frequency US pulses. Novel lipid-stabilized freeze-dried formulations for US applications, using the phospholipids DSPC, DSPG, and PEGylated DSPE-PEG2k and perfluoropropane gas were developed. It was found that the bubbles could effectively be preserved by freeze-drying and then re-constituted by addition of water. Average bubble sizes were around 2 µm for all bubbles after re-constitution. Bubble stability was assessed by evaluating the decay of the US backscattering signal in vitro. Bubbles containing DSPG were more stable than bubbles with only DSPC. The composition DSPC:DSPG:DSPE-PEG2k 30:60:10 (molar ratio) was the most stable with an effective half-life of 9.12 min, compared to bubbles without DSPG, which had half-life of 2.05 min. Bubble attenuation of US depended highly on the compositions. Bubbles without DSPG had the highest attenuation indicating higher oscillation the most but were also destroyed by higher energy US. No bubbles with DSPG showed any indication of destruction but all had increased attenuations to varying degrees, DSPC:DSPG:DSPE-PEG2k 45:45:10 showed the least attenuation.
  • Sogo Toda, Yuji Kato, Nobuki Kudo, Koichi Shimizu
    Japanese Journal of Applied Physics 58 3 1 - 4 Japan Society of Applied Physics 2019年03月 [査読有り][通常論文]
     
    Far transillumination imaging of animal tissue, we have developed a technique to suppress the scattering effect in a turbid medium using the time-reversal principle of phase-conjugate light. In biomedical applications of this technique, the effects of absorption variation and the applicable tissue thickness must be clarified. Analysis of experimental data revealed that the scattering suppression capablity of the, proposed technique is independent of the absorption change of a turbid medium. Results also verified that the applicable thickness of animal tissue can be extended using a light source with greater coherence length. (C) 2019 The Japan Society of Applied Physics
  • Sogo Toda, Yuji Kato, Nobuki Kudo, Koichi Shimizu
    ADAPTIVE OPTICS AND WAVEFRONT CONTROL FOR BIOLOGICAL SYSTEMS V 10886 2019年
  • Noboru Sasaki, Nobuki Kudo, Hiroshi Ohta, Mitsuyoshi Takiguchi
    2019 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) 1308 - 1310 2019年 
    Axon regeneration is crucial for the functional recovery after spinal cord injury. Myelin-related growth inhibitors, such as Nogo-A, inhibit neurites regrowth and elongation. Low-intensity pulsed ultrasound (LIPUS) is known to show neuroprotective effects in neurodegenerative diseases. In the present study, we evaluated the feasibility of LIPUS for enhancing axon regeneration in the presence of Nogo-A. Low-intensity pulsed ultrasound was exposed to rat cortical neurons in vitro after Nogo-A treatment. The total length of neurites per cell in LIPUS group was significantly larger than that of non-LIPUS group. There was no significant difference in the number of neurites. The results suggest that LIPUS may enhance the elongation of neurites in the presence of Nogo-A while may not affect on neurites sprouting and branching. This preliminary study implies the feasibility of LIPUS for axonal regeneration.
  • Iwaki Akiyama, Pak Kon Choi, Hiroyuki Hachiya, Akira Harata, Hideyuki Hasegawa, Kenya Hashimoto, Shoji Kakio, Nobuki Kudo, Subaru Kudo, Mami Matsukawa, Tatsuro Matsuoka, Koichi Mizutani, Kentaro Nakamura, Hirotsugu Ogi, Shinichi Takeuchi, Takao Tsuchiya, Shin ichiro Umemura, Yasuaki Watanabe, Ken Yamada, Kyuichi Yasui
    Japanese Journal of Applied Physics 57 7 2018年07月 [査読有り][通常論文]
  • Sogo Toda, Yuji Kato, Nobuki Kudo, Koichi Shimizu
    Biomedical Optics Express 9 4 1570 - 1581 2018年04月01日 [査読有り][通常論文]
     
    For transillumination imaging of animal tissues, we have attempted to suppress the scattering effect in a turbid medium using the time-reversal principle of phase-conjugate light. We constructed a digital phase-conjugate system to enable intensity modulation and phase modulation. Using this system, we clarified the effectiveness of the intensity information for restoration of the original light distribution through a turbid medium. By varying the scattering coefficient of the medium, we clarified the limit of time-reversal ability with intensity information of the phase-conjugate light. Experiment results demonstrated the applicability of the proposed technique to animal tissue.
  • Noboru Sasaki, Kazuhiro Ishi, Nobuki Kudo, Shouta M. M. Nakayama, Kensuke Nakamura, Keitaro Morishita, Hiroshi Ohta, Mayumi Ishizuka, Mitsuyoshi Takiguchi
    PLOS ONE 12 11 e0188093  2017年11月 [査読有り][通常論文]
     
    Non-muscle invasive bladder cancer is one of the most common tumors of the urinary tract. Despite the current multimodal therapy, recurrence and progression of disease have been challenging problems. We hereby introduced a new approach, ultrasound-assisted intravesical chemotherapy, intravesical instillation of chemotherapeutic agents and microbubbles followed by ultrasound exposure. We investigated the feasibility of the treatment for nonmuscle invasive bladder cancer. In order to evaluate intracellular delivery and cytotoxic effect as a function to the thickness, we performed all experiments using a bladder cancer mimicking 3D culture model. Ultrasound-triggered microbubble cavitation increased both the intracellular platinum concentration and the cytotoxic effect of cisplatin at the thickness of 70 and 122 mu m of the culture model. The duration of enhanced cytotoxic effect of cisplatin by ultrasound-triggered microbubble cavitation was approximately 1 hr. Based on the distance and duration of delivery, we further tested the feasibility of repetition of the treatment. Triple treatment increased the effective distance by 1.6-fold. Our results clearly showed spatial and temporal profile of delivery by ultrasound-triggered microbubble cavitation in a tumor-mimicking structure. Furthermore, we demonstrated that the increase in intracellular concentration results in the enhancement of the cytotoxic effect in a structure with the certain thickness. Repetition of ultrasound exposure would be treatment of choice in future clinical application. Our results suggest ultrasound-triggered microbubble cavitation can be repeatable and is promising for the local control of non-muscle invasive bladder cancer.
  • Akane Isono, Nobuki Kudo
    IEEE International Ultrasonics Symposium, IUS 2017年10月31日 [査読有り][通常論文]
     
    It is widely accepted that cell membrane rupture induced by bubbles oscillating beside the cells is a maj or mechanism of sonoporation however, elucidation of bubble dynamics by high-speed observation is still important because the behavior is highly dependent on their surrounding conditions. In this study, a new observation chamber was developed. The observation chamber allows observation of bubble-cell interaction from a lateral direction without obstruction of the view by the oscillating bubbles themselves. Dynamics of bubbles beside cells cultured on a soft scaffold was investigated.
  • Akane Isono, Nobuki Kudo
    IEEE International Ultrasonics Symposium, IUS 2017年10月31日 [査読有り][通常論文]
     
    A high-speed observation system for sonoporation study was improved for observation of bubble and cell dynamics under ultrasound exposure from a lateral direction. The effect of the presence of a scaffold mimicking an in vivo situation on the dynamics was investigated to study the mechanisms by which bubbles cause cell membrane damage. Observations showed that the stiffness of the scaffold has a significant effect on bubble dynamics: a microbubble on a hard scaffold remains on its hard surface, but a bubble on a soft scaffold make a translational movement in a direction away from the soft surface. The same movement was observed for bubbles adhering to cell membranes, and bubble-cell interaction was classified into four phenomena. Higher frequencies of cell membrane damage were found in two phenomena: a phenomenon in which a bubble moving in a separating direction drags the cell membrane, resulting in membrane damage, and a phenomenon in which a jet flow generated by bubble-bubble interaction causes local deformation of a cell, resulting in membrane damage. The results suggest that the efficiency of in vivo sonoporation can be improved by utilizing the mechanisms observed in the two phenomena.
  • Nobuki Kudo
    The Micro-World Observed by Ultra High-Speed Cameras: We See What You Don't See 391 - 405 2017年08月30日 [査読有り][通常論文]
     
    Cavitation is an important phenomenon that has been intensively studied in the field of fluid dynamics. The formation of cavitation bubbles is induced under the condition of pressure fluctuations in a fluid, and the collapse of bubbles elicits strong effects in their surroundings. Normally, cavitation does not occur inside a biological body however, the use of an artificial organ and irradiation of acoustic energy may induce the formation of cavitation bubbles inside the body. In this chapter, medical equipment is introduced, that induces or utilizes cavitation phenomena. A mechanical heart valve is known to generate bubbles that may cause thrombosis and valve failure, and various types of ultrasound exposure are used for medical purposes such as surgical equipment, non-invasive therapy, and drug delivery. High-speed observation plays an important role in visualizing cavitation activities generated in various applications. Results of observations provide valuable insights into the mechanisms by which cavitation bubbles elicit effects and also insights into how the effects can be minimized or maximized.
  • Mami Matsukawa, Jun Kondoh, Keiji Sakai, Iwaki Akiyama, Pak Kon Choi, Hiroyuki Hachiya, Akira Harata, Hideyuki Hasegawa, Kenya Hashimoto, Shoji Kakio, Nobuki Kudo, Subaru Kudo, Tatsuro Matsuoka, Koichi Mizutani, Kentaro Nakamura, Hirotugu Ogi, Sinichi Takeuchi, Takao Tsuchiya, Shinichiro Umemura, Yasuaki Watanabe, Ken Yamada, Kyuichi Yasui
    Japanese Journal of Applied Physics 56 7 2017年07月 [査読有り][通常論文]
  • Yukina Iijima, Nobuki Kudo
    JAPANESE JOURNAL OF APPLIED PHYSICS 56 7 2017年07月 [査読有り][通常論文]
     
    Acoustic fields of a short-pulsed ultrasound propagating through a transparent medium with ultrasound attenuation were visualized by the focused shadowgraph technique. A brightness waveform and its spatial integrations were derived from a visualized field image and compared with a pressure waveform measured by a membrane hydrophone. The experimental results showed that first-order integration of the brightness wave has good agreement with the pressure waveforms. Frequency-dependent attenuation of the pulse propagating through castor oil was derived from brightness and pressure waveforms, and attenuation coefficients determined from focused shadowgraphy and hydrophone techniques showed good agreement. The results suggest the usefulness of the shadowgraph technique not only for the visualization of ultrasound fields but also for noncontact estimation of rough pressure waveforms and correct ultrasound attenuation. (C) 2017 The Japan Society of Applied Physics
  • 近藤 隆, 工藤 信樹
    超音波医学 一般社団法人 日本超音波医学会 2017年
  • 工藤 信樹
    超音波医学 44 1 37 - 39 一般社団法人 日本超音波医学会 2017年
  • 今井 慎司, 工藤 信樹
    生体医工学 55 5 405 - 405 公益社団法人 日本生体医工学会 2017年 

    我々は微小気泡とパルス超音波を用いた細胞への薬物・遺伝子導入技術であるソノポレーションについて基礎的な検討を行っている．なかでも，薬物を付加した微小気泡を用いて目的の部位のみに薬物を直接導入する技術は，使用薬物量の抑制が期待され盛んに検討されているが，導入率が低いことが問題となっている．本研究では，異なる膜損傷のメカニズムを誘導するために，薬物を模擬する蛍光物質を付加した微小気泡に種々の条件で超音波を照射し，細胞内への模擬薬物の導入効果を共焦点顕微鏡により観察した．ヒト前立腺がん細胞を培養したカバーガラスを水槽の底面に設けた観察チャンバに設置した．顕微鏡観察下で模擬薬物付加気泡が付着した細胞に3種類の条件で超音波を照射し（連続波，繰り返し波，パルス波），照射前後および照射中の共焦点観察により膜損傷の様子と模擬薬物の細胞内導入の発生を調べた．その結果，パルス超音波では，気泡の崩壊に伴う微小な水流による膜損傷が，連続波ではマイクロストリーミングによる膜損傷が観察された．しかし，模擬薬物の細胞内への導入は，パルス超音波照射で1例確認されただけで導入効率は3%と低かった．観察例の多くで照射後，細胞膜上に模擬薬物が付着していたことから、低効率は細胞膜と気泡の脂質膜が付着して模擬薬物が膜から離れなかったためと推測され、気泡と細胞の付着状態を制御することによる導入効率向上の可能性が示唆された．

  • 門田 智明, 工藤 信樹
    生体医工学 55 5 403 - 403 公益社団法人 日本生体医工学会 2017年 

    我々は簡便な超音波音場可視化法としてフォーカストシャドウグラフ法を提案し，その有用性を検証してきた．従来の実験装置では光源にレーザダイオード（LD）を使用していたが，音場画像に光の干渉によるノイズが重畳するという問題があった．そこで本報告では光源にコヒーレンシーの低いLEDを用いて音場像のノイズ低減および，音圧波形の再現可能性について検討した結果を述べる．光源として波長850 nm，パルス幅5 nsのLDと波長610 nm，パルス幅35 nsのLEDを用い，超音波診断装置用プローブが発生する中心周波数2.5 MHzのパルス音場を可視化した．また，光源の点光源性が音場像に与える影響を調べるため，LED光源のコリメート光学系に200 μmのピンホールを挿入した条件でも可視化を行った．その結果LED光源（ピンホールなし）の条件ではLD光源に比べて音場像上の干渉ノイズが軽減されたが，ピンホールを入れると干渉ノイズが再発した．また音場像から求めた焦点近傍の輝度分布を1階空間積分してハイドロホンで測定した音圧波形と比較した．その結果，1階積分波形には音圧波形特有の急峻な圧力の立ち上がりが見られなかったが，ピンホールを入れることで立ち上がり特性が改善され，音圧波形と良い一致を示した．これよりフォーカストシャドウグラフ法の光源にLEDを使用することで画質が向上した音場像が取得可能であり，音圧波形の再現には光源の点光源性が重要であることが示された．

  • 根岸 聖太, 工藤 信樹
    生体医工学 55 5 445 - 445 公益社団法人 日本生体医工学会 2017年 

    我々は医用超音波機器の安全性検討の一環として，ラットから単離培養した心筋細胞への超音波照射を行い，超音波照射により拍動異常が誘導されることを示してきた．しかし，これまでの検討はガラス上に培養した心筋細胞で行われたものであり，その細胞形態は生体内と大きく異なる．そこで，本研究では生体を模擬した柔軟な足場層上に心筋細胞を培養し，細胞骨格を生体内の状態に近づけ，機械受容感度の変化を調べた．実験には生後2~3日のラット新生仔から単離培養した心筋細胞を用いた．柔軟な足場としては、アクリルアミドゲルを用い、対照条件としてカバーガラス上に培養した試料も作製した．ゲル上とカバーガラス上で拍動する培養心筋細胞の機械刺激受容感度の差を調べるために，音圧と波数が異なる超音波パルスを一回のみ照射し，拍動異常が誘導される閾値を調べた．拍動観察には倒立型光学顕微鏡を用い，拍動異常の判定は目視により行った．細胞の円形度を表すShape indexはゲル上で0.29±0.08，ガラス上で0.11±0.04であり，ゲル上の細胞は細胞骨格が未発達であることが示された．また，拍動異常が生じる波数閾値はゲル上の細胞が約10倍高かった（音圧13.5 MPa）．これらの結果は，心筋細胞の機械刺激受容感度が細胞骨格の発達程度に依存して変化することを示唆するものと考えられた．

  • 近藤 隆, 工藤 信樹
    超音波医学 44 6 525 - 528 公益社団法人 日本超音波医学会 2017年
  • Nobuki Kudo
    IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL 64 1 273 - 280 2017年01月 [査読有り][通常論文]
     
    A high-speed in situ microscopic observation system developed for basic studies on mechanisms of sonoporation is introduced in this paper. The main part of the system is an inverted-type fluorescence microscope, and a high-speed camera of 20 MHz in a maximum framing rate was used to visualize the dynamics of cavitation bubbles that causes a sonoporation effect. Differential interference contrast and fluorescence techniques were used for sensitive visualization of cell changes during sonoporation. The system is also equipped with optical tweezers that can move a microbubble of several microns in size by using a donut-shaped light beam. In situ microscopic observation of sonoporation was carried out using a cell with a size-and position-controlled microbubble. The experimental results showed that the ability of cells to repair sonoporation-induced damage depends on their membrane tension, indicating the usefulness of the observation system as a basic tool for the investigation of sonoporation phenomena.
  • Norio Kato, Toshiaki Tanaka, Shunichi Sugihara, Koichi Shimizu, Nobuki Kudo
    ICCSE 2016 - 11th International Conference on Computer Science and Education 285 - 290 2016年10月03日 [査読有り][通常論文]
     
    We developed a tele-rehabilitation system to improve community rehabilitation for patients who are discharged early from hospital. The developed tele-rehabilitation system consists of devices designed to reduce the physical and economic burden on users while promoting optimum user movement. A Backend-as-a-Service cloud computing service was used for the communication between terminals. A non-contact sensor, Kinect, was used to measure movement. In addition, we used a three-dimensional (3D) display to present 3D images using binocular parallax, to encourage smooth movement of patients. We used this system for stroke patients and found improvements in task-performance time, smoothness of movements, and range of motion in all patients. No major issues occurred during the tele-rehabilitation. These results demonstrated the high operability and efficacy of our cloud service-based 3D virtual reality tele-rehabilitation system.
  • Norio Kato, Toshiaki Tanaka, Syunichi Sugihara, Koichi Shimizu, Nobuki Kudo
    Journal of Physical Therapy Science 28 4 1134 - 1141 2016年04月01日 [査読有り][通常論文]
     
    [Purpose] This study verified that the smoothness of reaching movements is able to quantitatively evaluate the effects of two- and three-dimensional images on movement in healthy people. In addition, clinical data of cerebrovascular accident patients were also analyzed by the same method. [Subjects] Ten healthy adult volunteers and two male patients with previous cerebrovascular accidents participated. [Methods] The subjects were tasked with reaching for objects shown on a display. The target and virtual limb, rendered with computer graphics, were shown on the display. Movements of the virtual limb were synchronized with those of the subject. Healthy subjects reached for targets with their dominant arm, and cerebrovascular accident patients used their paretic arm. A polarized display and polarized glasses were used when the subjects were shown three-dimensional images. In the present study, jerk cost was used to quantify the smoothness of movement. [Results] Six of the 10 healthy subjects had significantly smoother reaching movements when viewing the three-dimensional images. The two cerebrovascular accident patients tended to have smoother movements in response to the three-dimensional images. [Conclusion] Analysis of the smoothness of movement was able to detect the influence of the depth cue in vision on movement quantitatively for the healthy subjects and cerebrovascular accident patients.
  • 工藤 信樹
    超音波医学 43 5 637 - 638 一般社団法人 日本超音波医学会 2016年
  • 工藤 信樹, 木下 勇人
    超音波医学 43 2 279 - 289 一般社団法人 日本超音波医学会 2016年 
    目的：In vivoソノポレーションに向けた基礎研究として，硬さが異なる足場上に単層培養した細胞のソノポレーションにより生じる細胞膜損傷率を検討した．方法：コラーゲンゲル，10％，30％アクリルアミドゲル，およびカバーガラスを用いて作成した4種類の細胞培養足場を単層細胞の培養に用いた．原子間力顕微鏡を用いて測定したヤング率はゲル足場では0.09‐8.6 kPa，生細胞では4.5 kPaであった．波数3，100および10,000波でピーク正圧/負圧が8.0/-1.3 MPaのパルス超音波を微小気泡が付着した細胞に1回のみ照射した．結果：Propidium iodideを用いて細胞膜損傷を蛍光顕微鏡により可視化した．波数3波の超音波パルスでは有意な変化は見られなかったが，波数100および10,000波のパルスではヤング率の増加に伴い損傷が増加する明確な傾向が確認された．結論：実験結果より，接着細胞の下層にある足場層の硬さをソノポレーション条件の重要なパラメータとして考慮に入れる必要があること，またin vivoソノポレーションに対する最適照射条件は生体組織の物理的特性を考慮して決定すべきであることが示唆された．
  • 梅村 晋一郎, 工藤 信樹
    超音波医学 43 2 255 - 263 一般社団法人 日本超音波医学会 2016年 
    本論文では，光学的手法を用いて医用超音波の音場を可視化する3つの手法について述べる．1つは光源とカメラのみからなる単純な光学系で可視化を実現するシャドーグラフ法である．本手法で取得した音場可視化像を従来のシュリーレン法と比較するとともに，超音波診断用の短いパルス超音波の音場可視化における有用性を示す．続く2つの手法は，ハイドロホンによる音場測定の置き換えを目指して開発した定量化シャドーグラフ法と位相コントラスト法である．各手法の原理を解説するとともに，超音波治療に用いられる連続超音波の集束音場を可視化する実験を行い，ハイドロホン計測との比較を通じて3次元音場の精密計測における有用性を示す．
  • 任田 崇吾, 加藤 祐次, 工藤 信樹, 清水 孝一
    生体医工学 54 1T3 - 4-6-1-1T3-4-6-2 一般社団法人 日本生体医工学会 2016年 

    The scattering effect in light propagation through random media can be suppressed with the phase-conjugate optics. We have applied this technique to the transillumination imaging of animal body using a digital phase-conjugate system. In the experiment, we attempted to restore various incident light patterns through a scattering medium. As a result, the feasibility of scattering suppression using digital phase-conjugate light was verified.

  • 榊 飛翔, 工藤 信樹
    生体医工学 54 1T3 - 4-1-1-1T3-4-1-2 一般社団法人 日本生体医工学会 2016年 

    A high intensity focused ultrasound (HIFU) field of a transducer for ultrasound therapy was visualized using an image subtraction Schlieren technique. The transducer of 110 mm in diameter and 100 mm in focal length was driven by a burst pulse of 1.58 MHz in center frequency and of 10 W or 100 W in input electric power. 10 instantaneous HIFU fields were visualized at 10 different phases, and a beam profile was determined by superimposing the fields. FWHMs of the beam were 5.8 mm in a visualized field but was 7.3 mm in a field determined by hydrophone measurement.

  • 工藤 信樹
    超音波医学 43 6 719 - 721 一般社団法人 日本超音波医学会 2016年
  • Nobuki Kudo
    Handbook of Ultrasonics and Sonochemistry 207 - 238 2016年01月01日 [査読有り][通常論文]
     
    In this section, optical techniques used for experimental observation of acoustic fields are reviewed. Acousto-optic interaction is discussed as a basic principle for visualizing inhomogeneity in refractive index fields. Light deflection and diffraction are also discussed as typical phenomena, especially in visualization of ultrasound fields. Three techniques, phase detection, Schlieren, and shadowgraph techniques, are mainly reviewed with discussion of the differences in the principles, optical systems, and acquired images. Background-oriented Schlieren technique, scanning laser Doppler vibrometry, and photoelastic techniques are also discussed as relatively new techniques for visualization of ultrasound fields. A technique that visualizes a distribution of temperature rise generated by ultrasound exposure is also introduced.
  • Aya Miwa, Nobuki Kudo
    2016 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) 2016年 [査読有り][通常論文]
     
    We have been studying experimental methods using cultured cardiomyocytes to evaluate the effect of short-pulsed ultrasound for generating disruption in pulsation such as premature contractions. In this study, we focused on the effect of ultrasound pulses with longer duration for a basic study on the safety of acoustic radiation force impulse (ARFI) imaging. Cardiomyocytes isolated from neonatal rats and cultured on a coverslip were used for this study. Pulsation of cardiomyocytes was controlled by an electric pacing signal, and the effect of ultrasound exposure on the pulsation was investigated by microscopic observation. Hanks' balanced salt solution degassed by using a vacuum chamber was used to eliminate cell damage caused by cavitation. To determine the parameter responsible for the induction of pulsation disruption, the effect of ultrasound exposure on cardiomyocyte pulsation was studied under exposure conditions combining different ultrasound pressures and pulse energies. The results indicated that the adverse effect of long duration pulses on cardiac pulsation is more dependent on ultrasound pressure, which determines the acoustic radiation force, than on pulse energy, which determines the temperature elevation of tissues.
  • Nobuki Kudo, Tomoaki Kadota, Yukina Iijima
    2016 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) 2016年 [査読有り][通常論文]
     
    We have proposed a simple optical technique for visualization of ultrasound fields using the focused shadowgraph technique. To improve the quality of field images, effects of coherency in the illuminating light source were investigated using a laser diode (LD) and a light-emitting diode (LED). An experimental system with the two light sources was developed, and an acoustic field of a 2.5-MHz ultrasound pulse was visualized. Two images were taken with and without ultrasound exposure, and the image taken without ultrasound exposure was subtracted from that with ultrasound exposure for sensitive detection and noise reduction. The results show that the effect of noise in the LD beam, which was generated by interference of light diffraction, was not removed by the image subtraction, while the effect of noise in LED beam containing no interference noise was successfully removed. Sharpness of the LED image was degraded, but its spatial resolution was still higher than one-tenth of the ultrasound wavelength, indicating the usefulness of an LED illuminating light source for improving the quality of acoustic field images acquired by using the focused shadowgraph technique.
  • Shogo Endo, Nobuki Kudo, Shigeru Yamaguchi, Koki Sumiyoshi, Hiroaki Motegi, Hiroyuki Kobayashi, Shunsuke Terasaka, Kiyohiro Houkin
    ULTRASOUND IN MEDICINE AND BIOLOGY 41 9 2458 - 2465 2015年09月 [査読有り][通常論文]
     
    Because it is highly infiltrative, malignant glioma is a cancer with a poor prognosis despite multidisciplinary treatment strategies, such as aggressive surgery and chemoradiotherapy, necessitating new therapeutic approaches to control migration of tumor cells. In our study, we investigated the efficacy of sonodynamic therapy of glioma cells in vitro using porphyrin derivatives, including 5-aminolevulinic acid, protoporphyrin IX and talaporfin sodium, as sonosensitizers. These substances have been known to accumulate in glioma cells and are expected to have cytotoxic effects on sonication. Our study found that the cytotoxicity of sonication of glioma cells is enhanced by each sonosensitizer and that the efficacy of sonodynamic therapy may depend on the degree of intracellular accumulation of sonosensitizer. Also, the study suggests that induction of apoptosis is a major mechanism underlying cell death. Though further investigations are necessary, our preliminary result indicates a potential for sonodynamic therapy with sonosensitizers in glioma treatment. (C) 2015 World Federation for Ultrasound in Medicine & Biology.
  • Nobuki Kudo
    ULTRASOUND IN MEDICINE AND BIOLOGY 41 7 2071 - 2081 2015年07月 [査読有り][通常論文]
     
    A simple technique designed for visualization of ultrasound fields without Schlieren optics is introduced. An optical system of direct shadowgraphy with diverging light, which consists of a point light source and a shadow screen, constituted the basic system, but the screen was replaced by focusing optics: a camera that makes a virtual screen at its focus plane. The proposed technique visualizes displacement of light deflected by ultrasound, and the use of focusing optics enables flexible settings of the virtual screen position and optical magnification. Insufficient sensitivity of shadowgraphy was overcome by elimination of non-deflecting light using image subtraction of shadowgrams taken with and without ultrasound exposure. A 1-MHz focused transducer for ultrasound therapy and a 20-MHz miniature transducer for intravascular imaging were used for experiments, and alternate pressure change in short-pulsed ultrasound was visualized, indicating the usefulness of the proposed technique for evaluation of medical ultrasound fields. (C) 2015 World Federation for Ultrasound in Medicine & Biology.
  • Nobuki Kudo
    JAPANESE JOURNAL OF APPLIED PHYSICS 54 7 07HA01  2015年07月 [査読有り][通常論文]
     
    A brief review of optical techniques for visualizing ultrasound fields is given. Acousto-optic interaction is discussed as a basic principle for visualizing inhomogeneity in refractive index fields. Light diffraction and deflection are also discussed as important phenomena, especially for visualization of ultrasound fields. Three techniques, Schlieren, phase contrast, and shadowgraph techniques, used for visualization of ultrasound fields are reviewed with discussion of the differences in optical systems and visualized field images. A newly developed focused shadowgraph technique that achieves sensitive detection with simple optics is introduced, and its usefulness for visualization of very short pulses of diagnostic ultrasound equipment is shown. (C) 2015 The Japan Society of Applied Physics
  • 画像差分型シュリーレン法を用いた故障プローブ音場の定量評価
    関根 大輝, 西田 睦, 工藤 信樹
    超音波医学 42 1 93 - 94 (公社)日本超音波医学会 2015年01月
  • Nobuki Kudo, Yuto Kinoshita
    JOURNAL OF MEDICAL ULTRASONICS 41 4 411 - 420 2014年10月 [査読有り][通常論文]
     
    Purpose As basic studies to realize in vivo sonoporation, rates of cell membrane damage during sonoporation were evaluated using monolayer cells cultured on scaffolds with different degrees of stiffness. Methods Four types of scaffolds, constructed using collagen gel, 10 and 30 % acrylamide gels, and a coverslip, were used for cultivation of monolayer cells. Young's moduli measured using an atomic force microscope were in the range 0.09-8.6 kPa for the gel scaffolds, whereas Young's modulus for living cells was 4.5 kPa. Cells with attached microbubbles were exposed to one-shot pulsed ultrasound of 8.0/-1.3 MPa in peak positive/negative pressures with durations of 3, 100, and 10,000 cycles. Results Cell membrane damage was visualized by fluorescence microscopy using propidium iodide. The 3-cycle ultrasound pulse had no significant effect; however, the rates of damage caused by 100-cycle and 10,000-cycle pulses showed a strong tendency for higher rates of damage with a higher Young's modulus. Conclusion The experimental results indicate that the stiffness of the underlying layer of adherent cells should be considered as an essential parameter of the sonoporation condition and that the optimum exposure conditions for in vivo sonoporation should be determined with consideration of the physical properties of underlying tissues.
  • Koki Sumiyoshi, Daiki Sekine, Nobuki Kudo, Koichi Shimizu
    Transactions of Japanese Society for Medical and Biological Engineering 52 343 - O-344 2014年08月17日 [査読有り][通常論文]
     
    We have been studying usefulness of image subtraction Schlieren technique that visualizes ultrasound fields. Also, in studies of the adverse effect of ultrasound exposure on cells, a culture dish is used as an exposure chamber with an ultrasound transducer placed beneath the dish. In this exposure setup, a standing wave field is produced inside the chamber, and change in shape of the chamber causes change in the standing wave fields. In this study, standing wave fields generated inside small chambers with different shapes were visualized using our technique, and the relation between acoustic fields and production of free radicals that cause cell damage was investigated.
  • Yasunobu Igarashi, Nobuki Kudo
    Transactions of Japanese Society for Medical and Biological Engineering 52 335 - O-336 2014年08月17日 [査読有り][通常論文]
     
    It is widely accepted that the presence of microbubbles improves efficiency of sonoporation. We have been studying the mechanisms by using high-speed observation of bubble behavior. In this study, an observation chamber was improved to observe bubble behavior from a lateral direction. A pair of miniature mirrors was added to the chamber, and one mirror was used to illuminate bubbles from the lateral direction, and another was used to guide the lateral image to an objective lens. Observation results showed that the presence of a rigid wall or other bubble causes a bubbles to make non-spherical deformation that might induce cell membrane perforation.
  • Ryo Takada, Nobuki Kudo, Ryo Suzuki
    Transactions of Japanese Society for Medical and Biological Engineering 52 339 - O-340 2014年08月17日 [査読有り][通常論文]
     
    Recently, much attention has been paid to dendritic cell (DC)-based cancer immunotherapy. Antigen delivery by sonoporation has been examined using microbubbles (MBs) loaded with antigen however, its mechanisms are not revealed yet. In this study, sonoporation effect was compared in three typical locations of MBs: (1) MBs in the vicinity of a cell, (2) MBs on a cell membrane, and (3) MBs endocytosed inside a cell, by using MBs conjugated with fluorescent dye. The results showed that antigen was transduced by ultrasound exposure in the cases (1) and (2) but not in the case (3), indicating that the positional relation between MBs and the cells strongly affects efficiency of antigen transduction.
  • Yuya Kudo, Nobuki Kudo
    Transactions of Japanese Society for Medical and Biological Engineering 52 347 - O-348 2014年08月17日 [査読有り][通常論文]
     
    Membrane damage produced by sonicated bubbles is the mechanism of sonoporation for drug delivery. The low transduction efficacy is the main problem however, improvement can be expected by controlling a force that works between oscillating bubbles. High-speed observation was carried out in this study to elucidate interaction of oscillating two microbubbles. Two several -micron bubbles were trapped using optical tweezers and photographed under exposure to pulsed ultrasound at 4×10< sup> 6< /sup> fps. Generation of an attractive force between the bubbles and jetting to cause the bubbles to be fragmented were confirmed, indicating the possibility to control jetting and cell membrane damage.
  • Nobuki Kudo
    Journal of Medical Ultrasonics 41 2 137 - 138 2014年04月01日 [査読有り][通常論文]
  • 画像差分シュリーレン装置を用いた故障プローブの音場可視化
    関根 大輝, 西田 睦, 清水 孝一, 工藤 信樹
    超音波医学 41 1 56 - 56 (公社)日本超音波医学会 2014年01月
  • Noboru Sasaki, Nobuki Kudo, Kensuke Nakamura, Sue Yee Lim, Masahiro Murakami, W R Bandula Kumara, Yu Tamura, Hiroshi Ohta, Masahiro Yamasaki, Mitsuyoshi Takiguchi
    Journal of medical ultrasonics (2001) 41 1 11 - 21 2014年01月 [査読有り][通常論文]
     
    PURPOSE: The aim of this study was to clarify whether ultrasound image-guided cisplatin delivery with an intratumor microbubble injection enhances the antitumor effect in a xenograft mouse model. METHODS: Canine thyroid adenocarcinoma cells were used for all experiments. Before in vivo experiments, the cisplatin and microbubble concentration and ultrasound exposure time were optimized in vitro. For in vivo experiments, cells were implanted into the back of nude mice. Observed by a diagnostic ultrasound machine, a mixture of cisplatin and ultrasound contrast agent, Sonazoid, microbubbles was injected directly into tumors. The amount of injected cisplatin and microbubbles was 1 μg/tumor and 1.2 × 10(7) microbubbles/tumor, respectively, with a total injected volume of 20 μl. Using the same diagnostic machine, tumors were exposed to ultrasound for 15 s. The treatment was repeated four times. RESULTS: The combination of cisplatin, microbubbles, and ultrasound significantly delayed tumor growth as compared with no treatment (after 18 days, 157 ± 55 vs. 398 ± 49 mm(3), P = 0.049). Neither cisplatin alone nor the combination of cisplatin and ultrasound delayed tumor growth. The treatment did not decrease the body weight of mice. CONCLUSION: Ultrasound image-guided anticancer drug delivery may enhance the antitumor effects of drugs without obvious side effects.
  • Naotaka Nitta, Nobuki Kudo, Tomoo Kamakura, Yasunao Ishiguro, Hideki Sasanuma, Nobuyuki Taniguchi, Iwaki Akiyama
    IEEE International Ultrasonics Symposium, IUS 386 - 389 2013年 [査読有り][通常論文]
     
    Acoustic radiation force (ARF) has been recently used for the tissue elasticity measurement and imaging. On the other hand, it is predicted that the higher temperature rises occur. In vivo measurement of temperature rise in animal experiments is important, whereas the measurement using thermocouples have some problems such as position mismatch of a temperature measuring junction of thermocouple and a focal point of ultrasound and so on. Therefore, in vivo measurement system for solving the above problems was developed in this study. The feasibility of the developed system was verified by the experiments using a tissue mimicking materials (TMM), TMM with a bone mode, an extracted porcine liver and a bone of chicken. Moreover, relations between conditions of ultrasound irradiation and temperature rises were investigated using the system. These results showed that temperature rises at focus on the surface of bone may exceed an allowable temperature rise which WFUMB guideline recommends, even though the acoustic intensity is within the limits of acoustic output regulation in diagnostic ultrasound devices. © 2013 IEEE.
  • Nobuki Kudo, Yuto Tanaka, Kazuaki Uchida
    2013 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS) 53 - 56 2013年 [査読有り][通常論文]
     
    We have been studying a sonoporation technique that uses one-shot exposure of short-pulsed ultrasound to cells with attached microbubbles. Here, we introduce a new observation system developed for elucidation of sonoporation mechanisms. An inverted-type microscope was equipped with optical tweezers that enable position control of a microbubble. A Laguerre-Gaussian (LG) beam, a Gaussian beam with a dark spot at the center, was used to trap a microbubble with a refractive index lower than that of the surrounding water. The LG beam was produced using a phase-only spatial light modulator and 1,065-nm laser light. Results of basic experiments showed that the tweezers can trap bubbles of 1-30 mu m in diameter suspended in water, and the minimum optical power for trapping bubbles of 5 m in diameter was around 10 mW. Sonoporation experiments were carried out using size-and position-controlled bubbles placed on cell membranes or placed at separated positions from cells, and the results indicated the importance of the newly developed system for elucidation of sonoporation mechanisms.
  • Yuto Tanaka, Nobuki Kudo
    IEEE International Ultrasonics Symposium, IUS 1777 - 1780 2013年 [査読有り][通常論文]
     
    We have been studying a sonoporation technique and have reported that one-shot exposure of short-pulsed ultrasound can elicit a sonoporation effect in the presence of a microbubble attached to a cell. It is generally thought that sonoporation causes more severe damage to cells cultured on a rigid scaffold than to cells suspended in a medium or to cells of in vivo tissue. One possible explanation is that a higher damage rate is caused by higher membrane tension. Since the ability of cells to rescue themselves from membrane damage is strongly dependent on their membrane tension, cells cultured on a rigid scaffold, which have higher membrane tension, may have more severe sonoporation damage. In this study, cell membrane tension was controlled by changing osmolality of the culture medium and selecting shapes of cells cultured on a coverslip, and the effect of membrane tension on ability for membrane repair was investigated by fluorescence microscopic observation that visualizes severity of sonoporation-induced cell damage. Repair rates of cells treated under isotonic and hypertonic conditions of osmolality were 55±8%and 75±14% (means ± S.D.), respectively, indicating that lower membrane tension causes higher repair rate. The repair ability was also studied using cells with different shapes. The results showed that spherical-shaped cells, which have lower membrane tension, have a minimum lethal damage level five-times higher than that of spindle-shaped cells, also suggesting that lower membrane tension can increase the ability of cells to repair sonoporation-induced membrane damage. © 2013 IEEE.
  • Etsuo Takada, Nobuki Kudo, Nobuyuki Endoh, Hiroyuki Hachiya, Shin-ichi Takeuchi, Takenobu Tsuchiya, Michiya Natori
    JOURNAL OF MEDICAL ULTRASONICS 39 3 107 - 113 2012年07月 [査読無し][通常論文]
     
    The Ultrasound Equipment and Safety Committee of The Japan Society of Ultrasonics in Medicine performed experiments to confirm whether contrast-enhanced ultrasonography damages liver cells. Rats were injected with 0.1 ml of 300 mg/ml ultrasound contrast agent (UCA). Diagnostic ultrasound pulses with a center frequency of 6 MHz and a mechanical index of 1.9 were applied to rat livers with a water bag as a coupler to maintain a distance of 2-6 cm between the ultrasound probe surface and the liver. Contrast-enhanced ultrasonography was carried out for 10 s to visualize the entire liver. Then, specimens of liver tissue were fixed using two types of fixation: immersion and perfusion fixation. Although some variations were found in electron micrographs of liver tissue fixed using immersion fixation, none of three blinded readers found any significant differences between micrographs of liver tissue from rats receiving UCA with sonication and those from sham-treated control rats. Changes observed were not thought to be group-specific but instead due to differences between individual rats. When the livers were fixed using perfusion fixation and the hepatic vein was cut after injection of physiological saline for perfusion, a large number of vacuoles a parts per thousand yen2 mu m in diameter were observed. This finding suggested that hepatic cell damage observed in this study was caused by high perfusion pressure during the liver fixation process rather than by sonication with UCA. Blinded readings of electron micrographs showed no clear evidence that the use of Levovist in ADI mode ultrasonography causes significant damage to liver tissue.
  • Yusuke Oda, Ryo Suzuki, Shota Otake, Norihito Nishiie, Keiichi Hirata, Risa Koshima, Tetsuya Nomura, Naoki Utoguchi, Nobuki Kudo, Katsuro Tachibana, Kazuo Maruyama
    JOURNAL OF CONTROLLED RELEASE 160 2 362 - 366 2012年06月 [査読有り][通常論文]
     
    Melanoma has an early tendency to metastasize, and the majority of the resulting deaths are caused by metastatic melanoma. It is therefore important to develop effective therapies for metastasis. Dendritic cell (DC)-based cancer immunotherapy has been proposed as an effective therapeutic strategy for metastasis and recurrence due to prime tumor-specific cytotoxic T lymphocytes. In this therapy, it is important that DCs present peptides derived from tumor-associated antigens on MHC class I molecules. Previously, we developed an innovative approach capable of directly delivering exogenous antigens into the cytosol of DCs using perfluoropropane gas-entrapping liposomes (Bubble liposomes, BLs) and ultrasound. In the present study, we investigated the prevention of melanoma lung metastasis via DC-based immunotherapy. Specifically, antigens were extracted from melanoma cells and used to treat DCs by BL and ultrasound. Delivery into the DCs by this route did not require the endocytic pathway. The delivery efficiency was approximately 74.1%. DCs treated with melanoma-derived antigens were assessed for in vivo efficacy in a mouse model of lung metastasis. Prophylactic immunization with BL/ultrasound-treated DCs provided a four-fold decrease in the frequency of melanoma lung metastases. These in vitro and in vivo results demonstrate that the combination of BLs and ultrasound is a promising method for antigen delivery system into DCs. Crown Copyright (C) 2011 Published by Elsevier B. V. All rights reserved.
  • Yusuke Oda, Ryo Suzuki, Shota Otake, Norihito Nishiie, Keiichi Hirata, Risa Koshima, Tetsuya Nomura, Naoki Utoguchi, Nobuki Kudo, Katsuro Tachibana, Kazuo Maruyama
    JOURNAL OF CONTROLLED RELEASE 160 2 362 - 366 2012年06月 [査読無し][通常論文]
     
    Melanoma has an early tendency to metastasize, and the majority of the resulting deaths are caused by metastatic melanoma. It is therefore important to develop effective therapies for metastasis. Dendritic cell (DC)-based cancer immunotherapy has been proposed as an effective therapeutic strategy for metastasis and recurrence due to prime tumor-specific cytotoxic T lymphocytes. In this therapy, it is important that DCs present peptides derived from tumor-associated antigens on MHC class I molecules. Previously, we developed an innovative approach capable of directly delivering exogenous antigens into the cytosol of DCs using perfluoropropane gas-entrapping liposomes (Bubble liposomes, BLs) and ultrasound. In the present study, we investigated the prevention of melanoma lung metastasis via DC-based immunotherapy. Specifically, antigens were extracted from melanoma cells and used to treat DCs by BL and ultrasound. Delivery into the DCs by this route did not require the endocytic pathway. The delivery efficiency was approximately 74.1%. DCs treated with melanoma-derived antigens were assessed for in vivo efficacy in a mouse model of lung metastasis. Prophylactic immunization with BL/ultrasound-treated DCs provided a four-fold decrease in the frequency of melanoma lung metastases. These in vitro and in vivo results demonstrate that the combination of BLs and ultrasound is a promising method for antigen delivery system into DCs. Crown Copyright (C) 2011 Published by Elsevier B. V. All rights reserved.
  • Noboru Sasaki, Nobuki Kudo, Kensuke Nakamura, Sue Yee Lim, Masahiro Murakami, W. R. Bandula Kumara, Yu Tamura, Hiroshi Ohta, Masahiro Yamasaki, Mitsuyoshi Takiguchi
    ULTRASOUND IN MEDICINE AND BIOLOGY 38 1 109 - 118 2012年01月 [査読有り][通常論文]
     
    Ultrasound targeted microbubble destruction has succeeded in delivering drugs and genes. This study was designed to explore characteristics of ultrasound targeted microbubble destruction using short-pulsed diagnostic ultrasound. Canine thyroid adenocarcinoma cells were exposed to short-pulsed diagnostic ultrasound in the presence of cis-diamminedichloroplatinum (II) (cisplatin) and ultrasound contrast agent Sonazoid (R) microbubbles. The cytotoxic effect of cisplatin was enhanced by short-pulsed diagnostic ultrasound and microbubbles. Incubation time with microbubbles influenced the cytotoxic effect of cisplatin. However, exposure duration did not affect the cytotoxic effect of cisplatin. Therefore, short-pulsed diagnostic ultrasound may activate microbubbles near cells and deliver cisplatin into cells. In addition, activation of microbubbles may be concluded in a short time. Our results suggest that short exposure duration could be potentially sufficient to induce efficient drug delivery by ultrasound targeted microbubble destruction using short-pulsed diagnostic ultrasound. (E-mail: mtaki@vetmed.hokudai.ac.jp) (C) 2012 World Federation for Ultrasound in Medicine & Biology.
  • Naotaka Nitta, Nobuki Kudo, Iwaki Akiyama
    NONLINEAR ACOUSTICS: STATE-OF-THE-ART AND PERSPECTIVES (ISNA 19) 1474 264 - 267 2012年 [査読有り][通常論文]
     
    Focused ultrasound with acoustic radiation force (ARF) is beginning to be used for imaging and measuring tissue elasticity. On the other hand, it was suggested that the temperature elevation near bone at focus may be significant within the limits of acoustic output regulation in diagnostic ultrasound devices (Herman; 2002). In this study, with the aim of obtaining the relationships between temperature elevations and parameters of ultrasound exposure with ARF, temperature elevations in two kinds of tissue models with or without bone were numerically evaluated. The results showed that the temperature elevation at focus on the surface of bone may exceed an allowable temperature elevation which WFUMB guideline recommends, even though the acoustic intensity is within the limits of acoustic output regulation in diagnostic ultrasound devices.
  • Nobuki Kudo, Yuto Kinoshita
    12TH INTERNATIONAL SYMPOSIUM ON THERAPEUTIC ULTRASOUND 1503 61 - 64 2012年 [査読有り][通常論文]
     
    Efficiencies of sonoporation were investigated using four types of monolayer-cell samples: cells cultured directly on a cover slip, cells cultured on a cover slip coated with collagen gel of several mu m in thickness, and cells cultured on collagen gel scaffolds of 0.4 and 1.0 mm in thicknesses. Cell samples attached with Levovist microbubbles were irradiated by one shot of a three-or 10,000-cycle ultrasound pulse, and cell detachment and membrane perforation were investigated. Experimental results showed that rates of cell detachment and membrane damage were markedly decreased in the presence of soft gel layer of 0.4 and 1.0 mm in thicknesses under the cells and that these rates were inversely proportional to the thickness of the gel layer. These results indicate that optimum conditions of sonoporation in vitro should be carefully translated into those in vivo.
  • Shigeru Yamaguchi, Hiroyuki Kobayashi, Takuhito Narita, Koki Kanehira, Shuji Sonezaki, Nobuki Kudo, Yoshinobu Kubota, Shunsuke Terasaka, Kiyohiro Houkin
    ULTRASONICS SONOCHEMISTRY 18 5 1197 - 1204 2011年09月 [査読有り][通常論文]
     
    Sonodynamic therapy is expected to be a novel therapeutic strategy for malignant gliomas. The titanium dioxide (TiO2) nanoparticle, a photosensitizer, can be activated by ultrasound. In this study, by using water-dispersed TiO2 nanoparticles, an in vitro comparison was made between the photodynamic and sonodynamic damages on U251 human glioblastoma cell lines. Water-dispersed TiO2 nanoparticles were constructed by the adsorption of chemically modified polyethylene glycole (PEG) on the TiO2 surface (TiO2/PEG). To evaluate cytotoxicity, U251 monolayer cells were incubated in culture medium including 100 mu g/ml of TiO2/PEG for 3 h and subsequently irradiated by ultraviolet light (5.0 mW/cm(2)) or 1.0 MHz ultrasound (1.0 W/cm(2)). Cell survival was estimated by MTT assay 24 h after irradiation. In the presence of TiO2/PEG, the photodynamic cytotoxic effect was not observed after 20 min of an ultraviolet light exposure, while the sonodynamic cytotoxicity effect was almost proportional to the time of sonication. In addition, photodynamic cytotoxicity of TiO2/PEG was almost completely inhibited by radical scavenger, while suppression of the sonodynamic cytotoxic effect was not significant. Results of various fluorescent stains showed that ultrasound-treated cells lost their viability immediately after irradiation, and cell membranes were especially damaged in comparison with ultraviolet-treated cells. These findings showed a potential application of TiO2/PEG to sonodynamic therapy as a new treatment of malignant gliomas and suggested that the mechanism of TiO2/PEG mediated sonodynamic cytotoxicity differs from that of photodynamic cytotoxicity. (C) 2011 Elsevier B.V. All rights reserved.
  • Shigeru Yamaguchi, Hiroyuki Kobayashi, Takuhito Narita, Koki Kanehira, Shuji Sonezaki, Nobuki Kudo, Yoshinobu Kubota, Shunsuke Terasaka, Kiyohiro Houkin
    ULTRASONICS SONOCHEMISTRY 18 5 1197 - 1204 2011年09月 [査読無し][通常論文]
     
    Sonodynamic therapy is expected to be a novel therapeutic strategy for malignant gliomas. The titanium dioxide (TiO2) nanoparticle, a photosensitizer, can be activated by ultrasound. In this study, by using water-dispersed TiO2 nanoparticles, an in vitro comparison was made between the photodynamic and sonodynamic damages on U251 human glioblastoma cell lines. Water-dispersed TiO2 nanoparticles were constructed by the adsorption of chemically modified polyethylene glycole (PEG) on the TiO2 surface (TiO2/PEG). To evaluate cytotoxicity, U251 monolayer cells were incubated in culture medium including 100 mu g/ml of TiO2/PEG for 3 h and subsequently irradiated by ultraviolet light (5.0 mW/cm(2)) or 1.0 MHz ultrasound (1.0 W/cm(2)). Cell survival was estimated by MTT assay 24 h after irradiation. In the presence of TiO2/PEG, the photodynamic cytotoxic effect was not observed after 20 min of an ultraviolet light exposure, while the sonodynamic cytotoxicity effect was almost proportional to the time of sonication. In addition, photodynamic cytotoxicity of TiO2/PEG was almost completely inhibited by radical scavenger, while suppression of the sonodynamic cytotoxic effect was not significant. Results of various fluorescent stains showed that ultrasound-treated cells lost their viability immediately after irradiation, and cell membranes were especially damaged in comparison with ultraviolet-treated cells. These findings showed a potential application of TiO2/PEG to sonodynamic therapy as a new treatment of malignant gliomas and suggested that the mechanism of TiO2/PEG mediated sonodynamic cytotoxicity differs from that of photodynamic cytotoxicity. (C) 2011 Elsevier B.V. All rights reserved.
  • Mariame A. Hassan, Yukihiro Furusawa, Qing-Li Zhao, Ichiro Takasaki, Loreto B. Feril, Katsuro Tachibana, Nobuki Kudo, Masami Minemura, Toshiro Sugiyama, Takashi Kondo
    JOURNAL OF MEDICAL ULTRASONICS 38 2 65 - 72 2011年04月 [査読無し][通常論文]
     
    Although sanazole has been used as a hypoxic radiosensitizer, we recently reported on its ability to sensitize U937 cells to hyperthermia and X-irradiation under aerobic conditions, enhancing apoptotic cell death following the combined treatment. The current study was undertaken to evaluate the effect of sanazole as a sonosensitizer under previously studied acoustic conditions of different pulse repetition frequencies, using two cell lines representative of solid tumours and haematopoietic cancers. Cells were treated with different doses of sanazole. Flow-cytometric analysis and DNA fragmentation assay were carried out at different times, and morphological features were also inspected. For ultrasound treatment, cells were pre-incubated with a non-cytotoxic dose of sanazole for 30 min before exposure. Evaluation of cell killing and a parallel examination of intracellular oxidative stress levels in both cell lines were performed using flow cytometry. Sanazole alone displayed selective cytotoxic effects towards solid tumour-derived cancer cells, resulting in complete cell death after 24 h of treatment, and enhanced the ultrasound-induced cell killing 6 h post-treatment. The enhancement seemed to be mediated by an additive increase in intracellular oxidative stress levels. Sanazole seems to be an efficient cytotoxic agent for the treatment of solid tumours and a promising sonosensitizer under aerobic conditions.
  • 工藤 信樹, 清水 孝一
    Japanese journal of medical ultrasonics = 超音波医学 38 1 25 - 26 2011年 [査読無し][通常論文]
  • 工藤 信樹, 清水 孝一
    超音波医学 38 1 25 - 26 2011年 [査読無し][通常論文]
  • Risa Koshima, Ryo Suzuki, Yusuke Oda, Keiichi Hirata, Tetsuya Nomura, Yoichi Negishi, Naoki Utoguchi, Nobuki Kudo, Kazuo Maruyama
    10TH INTERNATIONAL SYMPOSIUM ON THERAPEUTIC ULTRASOUND (ISTU 2010) 1359 330 - + 2011年 [査読有り][通常論文]
     
    The combination of nano/microbubbles and ultrasound is a novel technique for a non-viral gene deliver. We have previously developed novel ultrasound sensitive liposomes (Bubble liposomes) which contain the ultrasound imaging gas perfluoropropane. In this study, Bubble liposomes were compared with cationic lipid (CL)-DNA complexes as potential gene delivery carriers into tumors in vivo. The delivery of genes by bubble liposomes depended on the intensity of the applied ultrasound. The transfection efficiency plateaued at 0.7 W/cm(2) ultrasound intensity. Bubble liposomes efficiently transferred genes into cultured cells even when the cells were exposed to ultrasound for only 1 s. In addition, bubble liposomes were able to introduce the luciferase gene more effectively than CL-DNA complexes into mouse ascites tumor cells. We conclude that the combination of Bubble liposomes and ultrasound is a good method for gene transfer in vivo.
  • 貴田岡 正史, 熊田 卓, 松田 康雄, 飯島 尋子, 小川 眞広, 工藤 信樹, 小原 和史, 紺野 啓, 高倉 玲奈, 西田 睦, 南 康範, 森 秀明, 山田 昌彦
    Japanese journal of medical ultrasonics = 超音波医学 37 2 157 - 166 2010年03月15日 [査読無し][通常論文]
  • Mariame A. Hassan, Mikhail A. Buldakov, Ryohei Ogawa, Qing-Li Zhao, Yukihiro Furusawa, Nobuki Kudo, Takashi Kondo, Peter Riesz
    JOURNAL OF CONTROLLED RELEASE 141 1 70 - 76 2010年01月 [査読有り][通常論文]
     
    Low modulation frequencies from 0.5 to 100 Hz were shown to alter the characteristics of the ultrasound field producing solution agitation (<5 Hz; region of "ultrasound streaming" prevalence) or stagnancy (>5 Hz; region of standing waves establishment) (Buldakov et al., Ultrason. Sonochem., 2009). In this study, the same conditions were used to depict the changes in exogenous DNA delivery in these regions. The luciferase expression data revealed that lower modulations were more capable of enhancing delivery at the expense of viability. On the contrary, the viability was conserved at higher modulations whereas delivery was found to be null. Cavitational activity and acoustic streaming were the effecters beyond the observed pattern and delivery enhancement was shown to be mediated mainly through sonopermeation. To promote transfection, the addition of calcium ions or an echo contrast agent (Levovist (R)) was proposed. Depending on the mechanism involved in each approach, differential enhancement was observed in both regions and at the interim zone (5 Hz). In both cases, enhancement in standing waves field was significant reaching 16.0 and 3.3 folds increase, respectively. Therefore, it is concluded that although the establishment of standing waves is not the only prerequisite for high transfection rates, yet, it is a key element in optimization when other factors such as proximity and cavitation are considered. (C) 2009 Elsevier B.V. All rights reserved.
  • Khai Jun Kek, Nobuki Kudo, Katsuyuki Yamamoto
    OXYGEN TRANSPORT TO TISSUE XXXI 662 199 - 204 2010年 [査読有り][通常論文]
     
    Near-infrared spectroscopy (NIRS) enables noninvasive measurement of muscle oxygenation. However, since NIRS does not enable direct measurement of muscle metabolism, it is necessary to analyze the dynamic changes in metabolism during exercise using other methods in order to understand the relationship between NIRS measurements and muscle metabolism. A model of muscle metabolism that is composed of aerobic and anaerobic metabolic systems and 02 transport to tissue system was developed. Using the model, the temporal profiles of muscle oxygenation during exercise with different intensities (20, 40 and 70% maximum voluntary contraction), measured using NIRS in a single subject, were sufficiently reproduced. In addition, analyses of simulation results of (i) aerobic and anaerobic metabolic systems and (ii) O(2) consumption were performed, and the intensity-dependent differences in the temporal responses during exercise and recovery periods were estimated. The initial results show the usefulness of the model for simulating the kinetics of NIRS measurement data and for systematic interpretation of the relationship between NIRS data and muscle metabolism.
  • Khai Jun Kek, Nobuki Kudo, Katsuyuki Yamamoto
    OXYGEN TRANSPORT TO TISSUE XXXI 662 199 - 204 2010年 [査読無し][通常論文]
     
    Near-infrared spectroscopy (NIRS) enables noninvasive measurement of muscle oxygenation. However, since NIRS does not enable direct measurement of muscle metabolism, it is necessary to analyze the dynamic changes in metabolism during exercise using other methods in order to understand the relationship between NIRS measurements and muscle metabolism. A model of muscle metabolism that is composed of aerobic and anaerobic metabolic systems and 02 transport to tissue system was developed. Using the model, the temporal profiles of muscle oxygenation during exercise with different intensities (20, 40 and 70% maximum voluntary contraction), measured using NIRS in a single subject, were sufficiently reproduced. In addition, analyses of simulation results of (i) aerobic and anaerobic metabolic systems and (ii) O(2) consumption were performed, and the intensity-dependent differences in the temporal responses during exercise and recovery periods were estimated. The initial results show the usefulness of the model for simulating the kinetics of NIRS measurement data and for systematic interpretation of the relationship between NIRS data and muscle metabolism.
  • Mariame A. Hassan, Mikhail A. Buldakov, Ryohei Ogawa, Qing-Li Zhao, Yukihiro Furusawa, Nobuki Kudo, Takashi Kondo, Peter Riesz
    JOURNAL OF CONTROLLED RELEASE 141 1 70 - 76 2010年01月 [査読無し][通常論文]
     
    Low modulation frequencies from 0.5 to 100 Hz were shown to alter the characteristics of the ultrasound field producing solution agitation (<5 Hz; region of "ultrasound streaming" prevalence) or stagnancy (>5 Hz; region of standing waves establishment) (Buldakov et al., Ultrason. Sonochem., 2009). In this study, the same conditions were used to depict the changes in exogenous DNA delivery in these regions. The luciferase expression data revealed that lower modulations were more capable of enhancing delivery at the expense of viability. On the contrary, the viability was conserved at higher modulations whereas delivery was found to be null. Cavitational activity and acoustic streaming were the effecters beyond the observed pattern and delivery enhancement was shown to be mediated mainly through sonopermeation. To promote transfection, the addition of calcium ions or an echo contrast agent (Levovist (R)) was proposed. Depending on the mechanism involved in each approach, differential enhancement was observed in both regions and at the interim zone (5 Hz). In both cases, enhancement in standing waves field was significant reaching 16.0 and 3.3 folds increase, respectively. Therefore, it is concluded that although the establishment of standing waves is not the only prerequisite for high transfection rates, yet, it is a key element in optimization when other factors such as proximity and cavitation are considered. (C) 2009 Elsevier B.V. All rights reserved.
  • アリ ハッサン マリアム, 古澤 之裕, Zhao Qing-Li, Takasaki Ichiro, Feril Loreto B., Tachibana Katsuro, Kudo Nobuki, Minemura Masami, Sugiyama Toshiro, 近藤 隆
    ソノケミストリー討論会講演論文集 19 7 - 8 日本ソノケミストリー学会 2010年 
    The current study was undertaken to evaluate the effect of sanazole as a sonosensitizer at previously studied acoustic conditions of different pulse repetition frequencies using two cell lines representatives of solid tumors and hematopoietic cancers. Sanazole alone displayed selective cytotoxic effects towards solid tumor-derived cancer cells resulting in complete cell death after 24 hr treatment and enhanced the ultrasound-induced cell killing after 6 hr post-treatment. The enhancement seemed to be mediated by an additive increase in intracellular oxidative stress levels. Sanazole seems to be an efficient cytotoxic agent for the treatment of solid tumors and a promising sonosensitizer under aerobic conditions.
  • Mariame A. Hassan, Loreto B. Feril, Nobuki Kudo, Katsuro Tachibana, Takashi Kondo, Peter Riesz
    JAPANESE JOURNAL OF APPLIED PHYSICS 49 7 2010年 [査読有り][通常論文]
     
    The encapsulation of gas bubbles has resulted in improved stability and added a binding capacity to shells for ultrasound-guided targeted delivery. However, this has also changed the physical and acoustical properties of the final formulation. In this study, we have evaluated three clinically-used contrast agents of different compositions, namely, Levovist, Sonazoid, and SonoVue, with respect to their sonochemical and biological effects at different concentrations. The results showed that both shell elasticity and reactivity played a role in modulating both effects influencing the extent of ultrasound-induced free-radical formation. Microbubbles with elastic shells were found to be more capable of inducing delayed symptoms of cell killing, whereas the combined use of chemically reactive robust shells and high-density gases, such as perfluorocarbons, could exert a protective effect on cells. These conclusions offer new perspectives on how microbubbles interact with biological systems and might be useful in tailoring novel microbubbles in the future. (C) 2010 The Japan Society of Applied Physics
  • Naoki Hirokawa, Kazumitsu Koito, Futoshi Okada, Nobuki Kudo, Katsuyuki Yamamoto, Katsuhiko Fujimoto, Mutsumi Nishida, Takeshi Ichimura, Masakazu Hori, Taishi Satoh, Masato Hareyama
    JOURNAL OF MEDICAL ULTRASONICS 36 4 177 - 185 2009年12月 [査読無し][通常論文]
     
    The purpose of the present study is to investigate anticancer efficacy and apoptosis confirmed by caspase under several exposure conditions of high-intensity focused ultrasound (HIFU). Twenty-five rats with KDH-8 hepatoma were treated by HIFU at several acoustic energies to evaluate treatment efficacy. Apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and Hoechst 33258 staining, and caspase 3, 8, and 9/6 activity was respectively assayed. The KDH-8 subcutaneous tumors were reduced by HIFU, and these rats survived longer than the nontreatment rats (P < 0.01). The minimal threshold of HIFU energy was 30 W x 1.0 s for tumor control and long-term survival. The tumors exposed to HIFU exhibited marked apoptotic features under conditions of less than 10 W x 1.0 s. In cultured KDH-8 cells, apoptosis was caused at less than 30 W x 1.0 s (P < 0.01), and more was induced as the energy went down. Caspase 3, 8, and 9/6 were more activated at low energy under 10 W x 1.0 s (P < 0.01), and caspase 8, which is death receptor dependent, was significantly more activated than caspase 9/6, which is mitochondria dependent (P < 0.01). HIFU-induced apoptosis in vivo and in vitro is one of the mechanisms for tumor control and is mediated by caspase 3, 8, and 9/6. The significantly greater activation of caspase 8 than of caspase 9/6 suggests that the apoptosis pathway induced by HIFU might be more mitochondria dependent than death receptor dependent. However, further examination will be needed.
  • Takashi Kondo, Toru Yoshida, Ryohei Ogawa, Mariame A. Hassan, Yukihiro Furusawa, Qing-Li Zhao, Akihiko Watanabe, Akihiro Morii, Loreto B. Feril, Katsuro Tachibana, Hiroshi Kitagawa, Yoshiaki Tabuchi, Ichiro Takasaki, Mohammad H. Shehata, Nobuki Kudo, Kazuhiro Tsukada
    JOURNAL OF MEDICAL ULTRASONICS 36 2 61 - 68 2009年06月 [査読無し][通常論文]
     
    In this study, the effects of low-intensity pulsed ultrasound (LIU) as an adjuvant to doxorubicin (DOX) treatment was further investigated in comparison to hyperthermia as another widely used adjuvant. The effects were compared with respect to cell killing and apoptosis induction in U937 cells. Human primary liver cancer (PLC) cells were also used to evaluate the effects of the combinations. The use of an echo contrast agent was investigated for further enhancement of cytotoxicity. Finally, the acoustic mechanisms involved were investigated. The effects of different treatment regimens on cell viability were determined using the Trypan blue dye-exclusion test. Apoptosis induction was detected by flow cytometry using fluorescein isothiocyanate-annexin V and propidium iodide staining. The mechanistic study involved electron paramagnetic spin trapping for detecting free radical formation as an indicator of the occurrence of inertial cavitation and spectrophotometry for sucrose hydrolysis as an indicator for noncavitational effects. The combination treatments exerted synergistic effects on cytotoxicity depending on the acoustic conditions used. The use of LIU as an adjuvant to DOX treatment was shown to be superior to the use of hyperthermia as an adjuvant. Moreover, the combination seems to be promising for other cancer types provided that the acoustic conditions are properly selected with respect to drug concentration. The key ultrasound mechanism responsible for the synergism observed was shown to be the production of free radicals by inertial cavitation. Non-cavitational forces were also shown to contribute to the effect. This study is motivating to engage in in vivo research with various cancer types as a step toward clinical applicability and is emphasizing on the importance of developing therapeutic protocols for setting LIU parameters with respect to other therapeutic conditions.
  • Nobuki Kudo, Kengo Okada, Katsuyuki Yamamoto
    BIOPHYSICAL JOURNAL 96 12 4866 - 4876 2009年06月 [査読有り][通常論文]
     
    In this article, membrane perforation of endothelial cells with attached microbubbles caused by exposure to single-shot short pulsed ultrasound is described, and the mechanisms of membrane damage and repair are discussed. Real-time optical observations of cell-bubble interaction during sonoporation and successive scanning electron microscope observations of the membrane damage with knowledge of bubble locations revealed production of micron-sized membrane perforations at the bubble locations. High-speed observations of the microbubbles visualized production of liquid microjets during nonuniform contraction of bubbles, indicating that the jets are responsible for cell membrane damage. The resealing process of sonoporated cells visualized using fluorescence microscopy suggested that Ca(2+)-independent and Ca(2+)-triggered resealing mechanisms were involved in the rapid resealing process. In an experimental condition in which almost all cells have one adjacent bubble, 25.4% of the cells were damaged by exposure to single-shot pulsed ultrasound, and 15.9% (similar to 60% of the damaged cells) were resealed within 5 s. These results demonstrate that single-shot pulsed ultrasound is sufficient to achieve sonoporation when microbubbles are attached to cells.
  • Takashi Kondo, Toru Yoshida, Ryohei Ogawa, Mariame A. Hassan, Yukihiro Furusawa, Qing-Li Zhao, Akihiko Watanabe, Akihiro Morii, Loreto B. Feril, Katsuro Tachibana, Hiroshi Kitagawa, Yoshiaki Tabuchi, Ichiro Takasaki, Mohammad H. Shehata, Nobuki Kudo, Kazuhiro Tsukada
    JOURNAL OF MEDICAL ULTRASONICS 36 2 61 - 68 2009年06月 [査読無し][通常論文]
     
    In this study, the effects of low-intensity pulsed ultrasound (LIU) as an adjuvant to doxorubicin (DOX) treatment was further investigated in comparison to hyperthermia as another widely used adjuvant. The effects were compared with respect to cell killing and apoptosis induction in U937 cells. Human primary liver cancer (PLC) cells were also used to evaluate the effects of the combinations. The use of an echo contrast agent was investigated for further enhancement of cytotoxicity. Finally, the acoustic mechanisms involved were investigated. The effects of different treatment regimens on cell viability were determined using the Trypan blue dye-exclusion test. Apoptosis induction was detected by flow cytometry using fluorescein isothiocyanate-annexin V and propidium iodide staining. The mechanistic study involved electron paramagnetic spin trapping for detecting free radical formation as an indicator of the occurrence of inertial cavitation and spectrophotometry for sucrose hydrolysis as an indicator for noncavitational effects. The combination treatments exerted synergistic effects on cytotoxicity depending on the acoustic conditions used. The use of LIU as an adjuvant to DOX treatment was shown to be superior to the use of hyperthermia as an adjuvant. Moreover, the combination seems to be promising for other cancer types provided that the acoustic conditions are properly selected with respect to drug concentration. The key ultrasound mechanism responsible for the synergism observed was shown to be the production of free radicals by inertial cavitation. Non-cavitational forces were also shown to contribute to the effect. This study is motivating to engage in in vivo research with various cancer types as a step toward clinical applicability and is emphasizing on the importance of developing therapeutic protocols for setting LIU parameters with respect to other therapeutic conditions.
  • Nobuki Kudo, Kengo Okada, Katsuyuki Yamamoto
    BIOPHYSICAL JOURNAL 96 12 4866 - 4876 2009年06月 [査読無し][通常論文]
     
    In this article, membrane perforation of endothelial cells with attached microbubbles caused by exposure to single-shot short pulsed ultrasound is described, and the mechanisms of membrane damage and repair are discussed. Real-time optical observations of cell-bubble interaction during sonoporation and successive scanning electron microscope observations of the membrane damage with knowledge of bubble locations revealed production of micron-sized membrane perforations at the bubble locations. High-speed observations of the microbubbles visualized production of liquid microjets during nonuniform contraction of bubbles, indicating that the jets are responsible for cell membrane damage. The resealing process of sonoporated cells visualized using fluorescence microscopy suggested that Ca(2+)-independent and Ca(2+)-triggered resealing mechanisms were involved in the rapid resealing process. In an experimental condition in which almost all cells have one adjacent bubble, 25.4% of the cells were damaged by exposure to single-shot pulsed ultrasound, and 15.9% (similar to 60% of the damaged cells) were resealed within 5 s. These results demonstrate that single-shot pulsed ultrasound is sufficient to achieve sonoporation when microbubbles are attached to cells.
  • Kengo Okada, Nobuki Kudo, Mariame A. Hassan, Takashi Kondo, Katsuyuki Yamamoto
    ULTRASONICS SONOCHEMISTRY 16 4 512 - 518 2009年04月 [査読有り][通常論文]
     
    To understand the underlying concepts required for the determination of thresholds for free radical generation, effects of gas dissolution in and microbubble addition to sonicated solutions were investigated. Four solutions with different gaseous conditions, air-saturated and degassed solutions with and without microbubbles of 20 pm in diameter with shells, were studied in the presence of an air-liquid interface. These test solutions were exposed to 1 MHz ultrasound of 0.06 MPa(p-p) at various pulse durations (PDs) from 0.1 to 5 ms and pulse repetition frequencies from 0.1 to 2 kHz. Generation of free radicals was evaluated using the electron spin resonance (ESR) spin trapping method and starch-iodine method. Thresholds of duty ratio (DR) corresponding to temporal average intensity of ultrasound for free radical generation were significantly greater in degassed solutions than in air-saturated solutions. Microbubbles had no significant effects in air-saturated solutions but caused a slight decrease in the threshold in degassed solutions. In all of these results, the DR of a threshold curve against pulse repetition period (PRP) was not constant but linearly decreased with it, suggesting that a balance between bubble growth and shrinkage during the ON and OFF times of burst ultrasound is the primary parameter for the interpretation of thresholds. The effect of an air-liquid interface of the solution was also examined, and it was revealed that gas transport from the air is a predominant factor determining the amount of free radicals. (c) 2008 Elsevier B.V. All rights reserved.
  • OKADA Kengo, KUDO Nobuki, HASSAN Mariame A, KONDO Takashi, YAMAMOTO Katsuyuki
    Ultrasonics Sonochemistry 16 4 512 - 518 2009年04月 [査読無し][通常論文]
     
    To understand the underlying concepts required for the determination of thresholds for free radical generation, effects of gas dissolution in and microbubble addition to sonicated solutions were investigated. Four solutions with different gaseous conditions, air-saturated and degassed solutions with and without microbubbles of 20 pm in diameter with shells, were studied in the presence of an air-liquid interface. These test solutions were exposed to 1 MHz ultrasound of 0.06 MPa(p-p) at various pulse durations (PDs) from 0.1 to 5 ms and pulse repetition frequencies from 0.1 to 2 kHz. Generation of free radicals was evaluated using the electron spin resonance (ESR) spin trapping method and starch-iodine method. Thresholds of duty ratio (DR) corresponding to temporal average intensity of ultrasound for free radical generation were significantly greater in degassed solutions than in air-saturated solutions. Microbubbles had no significant effects in air-saturated solutions but caused a slight decrease in the threshold in degassed solutions. In all of these results, the DR of a threshold curve against pulse repetition period (PRP) was not constant but linearly decreased with it, suggesting that a balance between bubble growth and shrinkage during the ON and OFF times of burst ultrasound is the primary parameter for the interpretation of thresholds. The effect of an air-liquid interface of the solution was also examined, and it was revealed that gas transport from the air is a predominant factor determining the amount of free radicals. (c) 2008 Elsevier B.V. All rights reserved.
  • Mariame A. Hassan, Loreto B. Feril, Kosho Suzuki, Nobuki Kudo, Katsuro Tachibana, Takashi Kondo
    ULTRASONICS SONOCHEMISTRY 16 3 372 - 378 2009年03月 [査読有り][通常論文]
     
    Three novel lipid-shell-type microbubbles (MBs), AS-0100, BG6356A and BG6356B, have been evaluated for their impact on ultrasound (US)-induced cell death and free radicals production. Previously studied and well-characterized US exposure conditions were employed in which human myelomonocytic lymphoma U937 cells were exposed to 1 MHz pulsed US beam (0.3 W/cm(2), 10% duty factor) for 1 min with or without MBs. Three different concentrations of each MB were used. Apoptosis and cell lysis were assessed by examining phosphatidylserine externalization and by counting viable cells, respectively, 6 h post-exposure. Free radicals production and scavenging activities were evaluated using electron paramagnetic resonance (EPR)-spin trapping. The results showed that only AS-0100 and BG6356A were able to enhance the US-induced apoptosis, mainly by increasing the secondary necrosis. Apoptosis and cell lysis seemed to depend more on mechanical forces exerted by oscillating MBs while free radicals played a trivial role. BG series MBs exhibited pronounced scavenging activities. Generally, despite the need for further optimization, AS-0100 and BG6356A appear to be promising as adjuncts in cases where US-induced cell death is required. (c) 2008 Published by Elsevier B.V.
  • Mikhail A. Buldakov, Mariame A. Hassan, Qing-Li Zhao, Loreto B. Feril, Nobuki Kudo, Takashi Kondo, Nikolai V. Litvyakov, Mikhail A. Bolshakov, Vladislav V. Rostov, Nadejda V. Cherdyntseva, Peter Riesz
    ULTRASONICS SONOCHEMISTRY 16 3 392 - 397 2009年03月 [査読有り][通常論文]
     
    This study was undertaken to examine ultrasound (US) mechanisms and their impact on chemical and biological effects in vitro as a function of changing pulse repetition frequency (PRF) from 0.5 to 100 Hz using a 1 MHz-generator at low-intensities and 50% duty factor (DF). The presence of inertial cavitation was detected by electron paramagnetic resonance (EPR) spin-trapping of hydroxyl radicals resulting from sonolysis of water. Non-cavitational effects were evaluated by studying the extent of sucrose hydrolysis measured by UV spectrophotometry. Biological effects were assessed by measuring the extent of cell killing and apoptosis induction in U937 cells using Trypan blue dye exclusion test and flow cytometry, respectively. The results indicate significant PRF dependence with respect to hydroxyl radical formation, cell killing and apoptosis induction. The lowest free radical formation and cell killing and the highest cell viability were found at 5 Hz (100 ms pulse duration). On the other hand, no correlation was found between sucrose hydrolysis and PRF. To our knowledge, this is the first report to be devoted to study the impact of low PRFs at low-intensities on US-induced chemical and biological effects and the mechanisms involved. This study has introduced the role of "US streaming" (convection); a forgotten factor in optimization studies, and explored its importance in comparison to standing waves. (c) 2008 Published by Elsevier B.V.
  • Mikhail A. Buldakov, Mariame A. Hassan, Qing-Li Zhao, Loreto B. Feril, Nobuki Kudo, Takashi Kondo, Nikolai V. Litvyakov, Mikhail A. Bolshakov, Vladislav V. Rostov, Nadejda V. Cherdyntseva, Peter Riesz
    ULTRASONICS SONOCHEMISTRY 16 3 392 - 397 2009年03月 [査読無し][通常論文]
     
    This study was undertaken to examine ultrasound (US) mechanisms and their impact on chemical and biological effects in vitro as a function of changing pulse repetition frequency (PRF) from 0.5 to 100 Hz using a 1 MHz-generator at low-intensities and 50% duty factor (DF). The presence of inertial cavitation was detected by electron paramagnetic resonance (EPR) spin-trapping of hydroxyl radicals resulting from sonolysis of water. Non-cavitational effects were evaluated by studying the extent of sucrose hydrolysis measured by UV spectrophotometry. Biological effects were assessed by measuring the extent of cell killing and apoptosis induction in U937 cells using Trypan blue dye exclusion test and flow cytometry, respectively. The results indicate significant PRF dependence with respect to hydroxyl radical formation, cell killing and apoptosis induction. The lowest free radical formation and cell killing and the highest cell viability were found at 5 Hz (100 ms pulse duration). On the other hand, no correlation was found between sucrose hydrolysis and PRF. To our knowledge, this is the first report to be devoted to study the impact of low PRFs at low-intensities on US-induced chemical and biological effects and the mechanisms involved. This study has introduced the role of "US streaming" (convection); a forgotten factor in optimization studies, and explored its importance in comparison to standing waves. (c) 2008 Published by Elsevier B.V.
  • Mariame A. Hassan, Loreto B. Feril, Kosho Suzuki, Nobuki Kudo, Katsuro Tachibana, Takashi Kondo
    ULTRASONICS SONOCHEMISTRY 16 3 372 - 378 2009年03月 [査読無し][通常論文]
     
    Three novel lipid-shell-type microbubbles (MBs), AS-0100, BG6356A and BG6356B, have been evaluated for their impact on ultrasound (US)-induced cell death and free radicals production. Previously studied and well-characterized US exposure conditions were employed in which human myelomonocytic lymphoma U937 cells were exposed to 1 MHz pulsed US beam (0.3 W/cm(2), 10% duty factor) for 1 min with or without MBs. Three different concentrations of each MB were used. Apoptosis and cell lysis were assessed by examining phosphatidylserine externalization and by counting viable cells, respectively, 6 h post-exposure. Free radicals production and scavenging activities were evaluated using electron paramagnetic resonance (EPR)-spin trapping. The results showed that only AS-0100 and BG6356A were able to enhance the US-induced apoptosis, mainly by increasing the secondary necrosis. Apoptosis and cell lysis seemed to depend more on mechanical forces exerted by oscillating MBs while free radicals played a trivial role. BG series MBs exhibited pronounced scavenging activities. Generally, despite the need for further optimization, AS-0100 and BG6356A appear to be promising as adjuncts in cases where US-induced cell death is required. (c) 2008 Published by Elsevier B.V.
  • Kengo Okada, Nobuki Kudo, Takashi Kondo, Katsuyuki Yamamoto
    JOURNAL OF MEDICAL ULTRASONICS 35 4 169 - 176 2008年12月 [査読無し][通常論文]
     
    The objective was to investigate the contributions of mechanical effects due to kinetic force induced by the dynamic behavior of microbubbles and sonochemical effects due to free radicals produced by inertial cavitation to cell membrane damage under sonoporation conditions in which cells with adjacent microbubbles were irradiated with single-shot pulsed ultrasound. The free radical scavenger cysteamine was used to control the occurrence of sonochemical effects, and the ratios of cells with membrane damage to intact cells were compared in the presence and absence of cysteamine. To determine the optimal dose of cysteamine, free radical production on exposure to burst pulse ultrasound was investigated using KI-starch solutions with different concentrations (0-5 mM) of cysteamine. High-speed observation of the dynamic behavior of Levovist microbubbles during ultrasound exposure was also carried out in the presence and absence of cysteamine, and the difference in the ratios of the maximum bubble diameter to the initial diameter was evaluated. Next, human prostate cancer cells with adjacent Levovist microbubbles were exposed to single-shot pulsed ultrasound with a center frequency of 1 MHz, a peak negative pressure of 1.1 MPa, and a pulse width of 3 mu s, and the percentages of cells with membrane damage were evaluated by fluorescent microscopy using propidium iodide in the presence and absence of cysteamine. It was confirmed that cysteamine at a concentration of 5 mM completely suppressed sonochemical effects without causing a change in the dynamic response of microbubbles to pulsed ultrasound. The percentages of cells with membrane damage in the presence and absence of cysteamine (5 mM) were 10.3% +/- 4.1% (n = 13) and 8.7% +/- 3.9% (n = 9), respectively. No significant difference was found (P = 0.36). The results indicate that cell membrane damage induced by single-shot pulsed ultrasound with adjacent microbubbles was due mainly to mechanical effects, not to sonochemical effects.
  • 工藤 信樹, 山本 克之
    Japanese journal of medical ultrasonics = 超音波医学 35 6 623 - 629 2008年11月15日 [査読無し][通常論文]
  • Khai Jun Kek, Ryuta Kibe, Masatsugu Niwayama, Nobuki Kudo, Katsuyuki Yamamoto
    OPTICS EXPRESS 16 22 18173 - 18187 2008年10月 [査読有り][通常論文]
     
    An imaging instrument based on spatially resolved spectroscopy that enables temporal and spatial analyses of muscle oxygenation was designed. The instrument is portable and can be connected to 32 compact and separate-type optical probes. Its measurement accuracy of O-2 saturation and hemoglobin concentration was evaluated using a tissue-equivalent phantom. Imaging and multi-point measurements of tissue oxygen saturation (StO2) in the quadriceps muscle were also performed, and dynamic changes in StO2 in response to increase in exercise intensity (within the rectus femoris region) and variation in exercise protocol (among the rectus femoris, vastus lateralis and vastus medialis) were clearly shown. (C) 2008 Optical Society of America
  • Khai Jun Kek, Ryuta Kibe, Masatsugu Niwayama, Nobuki Kudo, Katsuyuki Yamamoto
    OPTICS EXPRESS 16 22 18173 - 18187 2008年10月 [査読無し][通常論文]
     
    An imaging instrument based on spatially resolved spectroscopy that enables temporal and spatial analyses of muscle oxygenation was designed. The instrument is portable and can be connected to 32 compact and separate-type optical probes. Its measurement accuracy of O-2 saturation and hemoglobin concentration was evaluated using a tissue-equivalent phantom. Imaging and multi-point measurements of tissue oxygen saturation (StO2) in the quadriceps muscle were also performed, and dynamic changes in StO2 in response to increase in exercise intensity (within the rectus femoris region) and variation in exercise protocol (among the rectus femoris, vastus lateralis and vastus medialis) were clearly shown. (C) 2008 Optical Society of America
  • 吉田 徹, 近藤 隆, 小川 良平, ZHAO QING-LI, HASSAN MARIAME A, 渡部 明彦, 高崎 一朗, 田渕 圭章, 庄司 美樹, 工藤 信樹, FERIL LORETO B. JR, 立花 克郎, BULDAKOV MIKHAIL A, 本田 昂, 塚田 一博, RIESZ PETER
    日本ハイパーサーミア学会誌 = Japanese journal of hyperthermic oncology 23 3 113 - 122 Japanese Society for Thermal Medicine 2007年09月20日 [査読無し][通常論文]
     
    がん治療における分子イメージング技術や分子標的治療法が注目されている. 超音波は診断のみならず, がん治療への応用も進んできており, さらに分子レベルでの生物作用の解明が必要とされる. 本稿では特に分子生物学的見地から超音波によるアポトーシス誘導, 遺伝子発現の変化および遺伝子導入について概説した. また, 抗がん剤であるドキソルビシンの増強作用についても触れた. これらの生物作用は高い強度の超音波照射で認められることはわかっていたが, 最近の研究で低強度のパルス波でも認められることが判明した. 低強度のパルス波でもキャビテーション発生が認められ, これによる機械的作用と生体膜との相互作用が分子レベルの生物作用を考える上で重要となる. そのため, キャビテーションの発生を促進する微小気泡や生体膜を修飾する手法が超音波を利用した治療に考慮されるべきである.
    最近の研究の進歩により, 超音波により細胞内へ遺伝子導入ができること, 遺伝子制御された細胞死であるアポトーシスが誘導されること, 照射された細胞での遺伝子発現が変化することが明らかとなった. 機械的エネルギーの代表とも言える超音波が遺伝子の発現および制御にも大きく関わることがわかり, 今後の治療応用が期待される.
  • Loreto B. Feril, Takashi Kondo, Yoshiaki Tabuchi, Ryohei Ogawa, Qing-Li Zhao, Tetsuo Nozaki, Toru Yoshida, Nobuki Kudo, Katsuro Tachibana
    JAPANESE JOURNAL OF APPLIED PHYSICS PART 1-REGULAR PAPERS BRIEF COMMUNICATIONS & REVIEW PAPERS 46 7B 4435 - 4440 2007年07月 [査読有り][通常論文]
     
    Biological effects of low-intensity ultrasound (US) focusing on US-induced programmed cell death (apoptosis), regulation of gene expression, and US-mediated gene transfection (sonotransfection) are reviewed. Studies have shown that US can induce apoptosis and that certain conditions can provide an optimal apoptosis induction. Sonotransfection of different cell lines in vitro and target tissues in vivo have been reported. Several genes can also be up-regulated or down-regulated by sonication. As to the potential therapeutic applications, apoptosis induction by US may induce direct and fast ways of treating tumor or cancer tissues. Systemic or local sonotransfection might also be a safe and effective gene therapy method in effecting the cure of local and systemic disorders. Gene regulation of target cells may be utilized in modifying cellular response to a treatment, such as increasing the sensitivity of diseased cells while making normal cells resistant to the side effects of the treatment. In addition, gene regulation by US may also play an important part in the enhanced healing of damaged tissues.
  • Yoshiaki Tabuchi, Hidetaka Ando, Ichiro Takasaki, Loreto B. Feril, Qing-Li Zhao, Ryohei Ogawa, Nobuki Kudo, Katsuro Tachibana, Takashi Kondo
    CANCER LETTERS 246 1-2 149 - 156 2007年02月 [査読有り][通常論文]
     
    We examined the gene expression of human leukemia Molt-4 cells treated with non-thermal low intensity pulsed ultrasound. Six hours after 0.3 W/cm(2) pulsed ultrasound treatment, apoptosis (24 +/- 3.3%, mean +/- SD) with minimal cell lysis was observed. Of approximately 16,600 genes analyzed, BCL2-associated athanogene 3 (BAG3), Dual (Hsp40) homolog, subfamily B, member I (DNAJB1), heat shock 70 kDa protein 113 (HSPA1B), and heat shock 70 kDa protein 6 (HSPA6) showed increased levels of expression while isopentenyl-diphosphate delta isomerase (IDII) and 3-hydroxy-3-methylglutaryl-coenzyme A synthase I (HMGCS1) showed decreased levels in the cells 3 h after the ultrasound treatment. The expression levels of these six genes were confirmed by a real-time quantitative polymerase chain reaction. To our knowledge, this is the first report of DNA microarray analysis of genes that are differentially expressed in response to apoptosis induced by non-thermal low intensity pulsed ultrasound in human leukemia cells. The present results will provide a basis for further understanding of the molecular mechanisms of effects of not only low intensity pulsed ultrasound but also that of mechanical shear stress in the cells. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
  • Yoshiaki Tabuchi, Hidetaka Ando, Ichiro Takasaki, Loreto B. Feril, Qing-Li Zhao, Ryohei Ogawa, Nobuki Kudo, Katsuro Tachibana, Takashi Kondo
    CANCER LETTERS 246 1-2 149 - 156 2007年02月 [査読無し][通常論文]
     
    We examined the gene expression of human leukemia Molt-4 cells treated with non-thermal low intensity pulsed ultrasound. Six hours after 0.3 W/cm(2) pulsed ultrasound treatment, apoptosis (24 +/- 3.3%, mean +/- SD) with minimal cell lysis was observed. Of approximately 16,600 genes analyzed, BCL2-associated athanogene 3 (BAG3), Dual (Hsp40) homolog, subfamily B, member I (DNAJB1), heat shock 70 kDa protein 113 (HSPA1B), and heat shock 70 kDa protein 6 (HSPA6) showed increased levels of expression while isopentenyl-diphosphate delta isomerase (IDII) and 3-hydroxy-3-methylglutaryl-coenzyme A synthase I (HMGCS1) showed decreased levels in the cells 3 h after the ultrasound treatment. The expression levels of these six genes were confirmed by a real-time quantitative polymerase chain reaction. To our knowledge, this is the first report of DNA microarray analysis of genes that are differentially expressed in response to apoptosis induced by non-thermal low intensity pulsed ultrasound in human leukemia cells. The present results will provide a basis for further understanding of the molecular mechanisms of effects of not only low intensity pulsed ultrasound but also that of mechanical shear stress in the cells. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
  • Kudo Nobuki, Yamamoto Katsuyuki
    ソノケミストリー討論会講演論文集 2007 41 - 41 日本ソノケミストリー学会 2007年
  • Kondo Takashi, Tabuchi Yoshiaki, Takasaki Ichiro, Feril Loreto B. Jr., Tachibana Katsuro, Kudo Nobuki, Zhao Qing-Li, Ogawa Ryohei
    ソノケミストリー討論会講演論文集 2007 48 - 48 日本ソノケミストリー学会 2007年
  • Khai Jun Kek, Takahiro Miyakawa, Nobuki Kudo, Katsuyuki Yamamoto
    Progress in Biomedical Optics and Imaging - Proceedings of SPIE 6434 2007年 [査読有り][通常論文]
     
    In this study, we showed that exercise type- and intensity-dependent regional differences in muscle oxygenation and oxygen consumption rate (V̇o2) of the knee extensor muscles could be imaged in real time with a multi-channel spatially resolved near-infrared spectroscopy (SR-NIRS) imaging device. Healthy subjects performed isometric knee extension exercise for 30 s (without- or with-leg-press action) at different exercise intensities [10%, 40% and 70% of maximum voluntary contraction (MVC)]. "Separation- type" probes were attached to the skin over the major knee extensor muscles: vastus lateralis (VL), rectus femoris (RF) and vastus medialis (VM). Placement of the probes enabled simultaneously measurement of 12 sites over a skin area of about 30 cm2 (temporal resolution = 0.25 s). Local V̇o2 of each muscle, resting V̇o2 (V̇o 2,rest) and recovery V̇o2 (V̇o2,rec ), were determined with arterial occlusion before the start and after the end of contraction, respectively. There was no significant difference between the values of V̇o2,rest in the muscles. However, during knee extension exercise without-leg-press action, V̇o2,rec value of the RF was significantly greater than the values of the VL and VM at all exercise intensities. In contrast, during exercise with-leg-press action, V̇o2,rec values of the RF and VM were greater than those of the VL, especially during exercise at 40% and 70% MVC. In summary, the regional differences in muscle oxygenation and V̇o2 of the knee extensor muscles, probably due to the differences in relative contributions of muscles to exercise and in muscle architecture, were imaged using SR-NIRS.
  • Khai Jun Kek, Takahiro Miyakawa, Nobuki Kudo, Katsuyuki Yamamoto
    OPTICAL TOMOGRAPHY AND SPECTROSCOPY OF TISSUE VII 6434 2007年 [査読有り][通常論文]
     
    In this study, we showed that exercise type- and intensity-dependent regional differences in muscle oxygenation and oxygen consumption rate ((V) over dotO(2)) of the knee extensor muscles could be imaged in real time with a multi-channel spatially resolved near-infrared spectroscopy (SR-NIRS) imaging device. Healthy subjects performed isometric knee extension exercise for 30 s (without- or with-leg-press action) at different exercise intensities [10%, 40% and 70% of maximum voluntary contraction (MVC)]. "Separation-type" probes were attached to the skin over the major knee extensor muscles: vastus lateralis (VL), rectus femoris (RF) and vastus medialis (VM). Placement of the probes enabled simultaneously measurement of 12 sites over a skin area of about 30 cm(2) (temporal resolution = 0.25 s). Local (V) over dotO(2) of each muscle, resting (V) over dotO(2) ((V) over dotO(2), rest) and recovery (V) over dotO(2) ((V) over dotO(2), rec), were determined with arterial occlusion before the start and after the end of contraction, respectively. There was no significant difference between the values of (V) over dotO(2),rest in the muscles. However, during knee extension exercise without-leg-press action, (V) over dotO(2),rec value of the RF was significantly greater than the values of the VL and VM at all exercise intensities. In contrast, during exercise with-leg-press action, (V) over dotO(2),rec values of the RF and VM were greater than those of the VL, especially during exercise at 40% and 70% MVC. In summary, the regional differences in muscle oxygenation and (V) over dotO(2) of the knee extensor muscles, probably due to the differences in relative contributions of muscles to exercise and in muscle architecture, were imaged using SR-NIRS.
  • Wakako Hiraoka, Hidemi Honda, Loreto B. Feril, Nobuki Kudo, Takashi Kondo
    ULTRASONICS SONOCHEMISTRY 13 6 535 - 542 2006年09月 [査読有り][通常論文]
     
    Although enhancement of ultrasound-induced cell killing by photodynamic reagents has been shown, the sonochemical mechanism in detail is still not clear. Here, comparison between sonodynamic effect and photodynamic effect with photosensitizers at a concentration of 10 mu M on free radical formation and cell killing was made. When electron paramagnetic-resonance spectroscopy (EPR) was used to detect 2,2,6,6-tetramethyl-4-piperidone-N-oxyl (TAN) after photo-irradiation or sonication with 2,2,6,6-tetramethyl-4-piperidone (TMPD), the order of TAN formation in the photo-irradiated samples was as follows: thodamine 6G (R6) > sulforhodamine B (SR) > hematoporphyrin (Hp) > rhodamine 123 (R 123) > rose bengal (RB) > erythrosine B (Er) = 0; although there was time-dependent TAN formation when the samples were sonicated, no significant difference among these agents were observed. All these agents suppressed ultrasound-induced OH radical formation detected by EPR-spin trapping. Sensitizer-derived free radicals were markedly observed in SR, RB and Er, while trace level of radicals derived from R6 and R123 were observed. Enhancement of ultrasound-induced decrease of survival in human lymphoma U937 cells was observed at 1.5 W/cm(2) (less than inertial cavitation threshold) for R6, R123, SR and Er, and at 2.3 W/cm(2) for R6, R123, Er, RB and SR. On the other hand, photo-induced decrease of survival was observed for R6, Hp and RB at the same concentration (10 mu M). These comparative results suggest that (1) O-1(2) is not involved in the enhancement of ultrasound-induced loss of cell survival, (2) OH radicals and sensitizer-derived free radicals do not take part in the enhancement, and (3) the mechanism is mainly due to certain mechanical stress such as augmentation of physical disruption of cellular membrane by sensitizers in the close vicinity of cells and/or cavitation bubbles. (C) 2005 Elsevier B.V. All rights reserved.
  • 工藤 信樹, 平尾 紀文, 岡田 健吾, 山本 克之
    電子情報通信学会論文誌. A, 基礎・境界 89 9 746 - 753 一般社団法人電子情報通信学会 2006年09月01日 [査読無し][通常論文]
     
    超音波造影法では,造影剤の種類によって最適な造影効果を得るための超音波照射条件が異なることが知られている.このような特徴は,造影剤の微小気泡を包むシェルの力学的な特性に強く影響されると考えられている.そこで本論文では,音圧振幅が異なる超音波パルス列を一つの微小気泡に連続的に照射し,気泡の振舞いを高速度撮影することによりシェル特性を可視化する手法について検討した.更に,これを実現するシステムを開発して2種類の造影剤気泡の高速度観察を行い,本手法によりシェルの力学的特性の違いが可視化できることを確認した.また,広帯域超音波パルスを用いて微小気泡懸濁液の消失係数の音圧依存性を測定し,高速度カメラで可視化されたシェル特性の違いが音響計測でも確認できることを確認した.これらの評価によって明らかにされた各造影剤気泡の特徴は,臨床で報告されている特徴と一致しており,開発したシェル特性評価手法の有用性が確認された.
  • Wakako Hiraoka, Hidemi Honda, Loreto B. Feril, Nobuki Kudo, Takashi Kondo
    ULTRASONICS SONOCHEMISTRY 13 6 535 - 542 2006年09月 [査読無し][通常論文]
     
    Although enhancement of ultrasound-induced cell killing by photodynamic reagents has been shown, the sonochemical mechanism in detail is still not clear. Here, comparison between sonodynamic effect and photodynamic effect with photosensitizers at a concentration of 10 mu M on free radical formation and cell killing was made. When electron paramagnetic-resonance spectroscopy (EPR) was used to detect 2,2,6,6-tetramethyl-4-piperidone-N-oxyl (TAN) after photo-irradiation or sonication with 2,2,6,6-tetramethyl-4-piperidone (TMPD), the order of TAN formation in the photo-irradiated samples was as follows: thodamine 6G (R6) > sulforhodamine B (SR) > hematoporphyrin (Hp) > rhodamine 123 (R 123) > rose bengal (RB) > erythrosine B (Er) = 0; although there was time-dependent TAN formation when the samples were sonicated, no significant difference among these agents were observed. All these agents suppressed ultrasound-induced OH radical formation detected by EPR-spin trapping. Sensitizer-derived free radicals were markedly observed in SR, RB and Er, while trace level of radicals derived from R6 and R123 were observed. Enhancement of ultrasound-induced decrease of survival in human lymphoma U937 cells was observed at 1.5 W/cm(2) (less than inertial cavitation threshold) for R6, R123, SR and Er, and at 2.3 W/cm(2) for R6, R123, Er, RB and SR. On the other hand, photo-induced decrease of survival was observed for R6, Hp and RB at the same concentration (10 mu M). These comparative results suggest that (1) O-1(2) is not involved in the enhancement of ultrasound-induced loss of cell survival, (2) OH radicals and sensitizer-derived free radicals do not take part in the enhancement, and (3) the mechanism is mainly due to certain mechanical stress such as augmentation of physical disruption of cellular membrane by sensitizers in the close vicinity of cells and/or cavitation bubbles. (C) 2005 Elsevier B.V. All rights reserved.
  • Go Kagiya, Yoshiaki Tabuchi, Loreto B Feril Jr, Ryohei Ogawa, Qing-Li Zhao, Nobuki Kudo, Wakako Hiraoka, Katsuro Tachibana, Shin-Ichiro Umemura, Takashi Kondo
    Journal of medical ultrasonics (2001) 33 1 3 - 10 2006年03月 [査読無し][通常論文]
     
    PURPOSE: The present study was undertaken to reconfirm heme oxygenase-1 (HO-1) induction by ultrasound, and elucidate the mechanism by which this occurs. METHODS: After exposure of human lymphoma U937 cells to 1 MHz continuous ultrasound (US), gene profiling by using cDNA microarray analysis, cell viability by using the trypan blue dye exclusion test, mRNA expression by using real-time quantitative polymerase chain reaction, and protein expression by using Western blotting were examined. As an indicator of cavitation, hydroxyl radical formation was studied by using electron paramagnetic resonance-spin trapping. RESULTS: The cDNA microarray analysis reconfirmed HO-1 induction in human lymphoma U937 cells after exposure to US, and further identified one upregulated and two downregulated genes. When U937 cells were exposed to US for 1 min, HO-1 induction, as examined by real-time quantitative polymerase chain reaction and Western blotting, was observed at intensities higher than the cavitational threshold. When a potent antioxidant, N-acetyl-L-cysteine, was added to the culture medium before or after sonication, the induction was attenuated, indicating that reactive oxygen species are involved in HO-1 induction. A decrease in mitochondrial membrane potential and generation of superoxide anion radicals were also observed in the cells exposed to US. CONCLUSION: We used a cDNA microarray system to confirm upregulation of the HO-1 gene and to discover new genes that respond to ultrasonic cavitation. Increased intracellular oxidative stress secondary to the sonomechanical effects arising from ultrasonic cavitation is suggested to be the mechanism of enhancement of HO-1 expression.
  • 光学的高速度観測による超音波造影剤気泡のシェル特性の評価
    電子情報通信学会和文誌 J89-A 9 746 - 753 2006年 [査読無し][通常論文]
  • Nobuki Kudo, Hideki Miyashita, Katsuyuki Yamamoto
    THERAPEUTIC ULTRASOUND 829 829 614 - + 2006年 [査読無し][通常論文]
     
    We have proposed a new simple Schlieren method for visualizing an acoustic field without the requirement of a complex optical system. In this study, we developed an experimental system of the simple Schlieren method and investigated the possibility of applying this technique to visualization of an acoustic field of a HIFU transducer. Since visualized acoustic fields showed typical non-linear distortion of high-intensity ultrasound, we concluded that the proposed simple Schlieren method is useful for evaluating a HIFU field.
  • 工藤 信樹
    ソノケミストリー討論会講演論文集 15 9 - 10 日本ソノケミストリー学会 2006年 
    Single bubble sonoluminescence was discovered in 1989, and the following studies on this phenomenon greatly contributed to elucidate the mechanisms of cavitation phenomena. However, several important problems of the phenomenon are still under investigation. Non-spherical behavior of a single or multi bubbles is one of the unsettled problem. As part of our studies on the safety of diagnostic ultrasound using an ultrasound contrast agent, dynamics of microbubbles of several microns in diameter have been studied using high-speed photography method. This paper introduces our observation system and a collection of high-speed photos especially focusing on non-spherical bubble behavior.
  • K. J. Kek, T. Miyakawa, S. Yoneyama, N. Kudo, K. Yamamoto
    Annual International Conference of the IEEE Engineering in Medicine and Biology - Proceedings 5101 - 5104 2006年 [査読有り][通常論文]
     
    Near-infrared spectroscopy (NIRS) is a useful technique for noninvasive measurement of muscle oxygenation. However, analyses of the dynamic changes in muscle metabolism based only on experimental observations of NIRS are difficult. Therefore, we constructed a mathematical model of muscle metabolism, comprising of the ATP synthesizing systems and O2 diffusion system, to identify the mechanisms responsible for those observations. A customized NIRS instrument was used to measure the changes in muscle oxygenation of the forearm flexor muscles during intermittent and continuous isometric flexion exercises when healthy male subjects participated in exercises tests. The exercise-dependent difference in changes could be distinguished and the simulated results agreed well with that measured experimentally. Although the contraction intensity for both exercises was identical, the magnitude of energy needed to perform the respective exercises was different This difference was reflected by the changes in the ATP synthesizing systems, in which the energy needed during the latter-half of continuous exercise was mostly supplied by anaerobic system, whereas that during intermittent exercise was supplied by the aerobic and anaerobic systems that operated synergisti-cally. From the results, we conclude that the model could be a useful tool for the elucidation of the relationship between experimental observations of NIRS and muscle metabolism. © 2006 IEEE.
  • 岡田 健吾, 工藤 信樹, 丹羽 光一, 山本 克之
    Japanese journal of medical ultrasonics = 超音波医学 32 5 461 - 470 2005年09月15日 [査読無し][通常論文]
  • 岡田 健吾, 工藤 信樹, 丹羽 光一, 山本 克之
    Journal of medical ultrasonics = 超音波医学 32 5 461 - 470 2005年09月15日 [査読無し][通常論文]
  • 工藤 信樹, 山本 克之
    生体医工学 : 日本エム・イー学会誌 43 2 231 - 237 社団法人日本生体医工学会 2005年06月10日 [査読無し][通常論文]
  • Kengo Okada, Nobuki Kudo, Koichi Niwa, Katsuyuki Yamamoto
    Journal of Medical Ultrasonics 32 1 3 - 11 2005年03月 [査読無し][通常論文]
     
    Purpose. Sonoporation is an ultrasound technique that enables large molecules that normally do not penetrate the cell membrane to pass through it. Recent studies show that pulsed ultrasound in the presence of microbubbles increases the permeability of the cell membrane. However, the mechanism and basic properties of this sonoporation remain unclear. We thus investigated the mechanism of generation and frequency of occurrence of sonoporation, as well as the repair of a cell membrane damaged by microbubbles. Methods. The spatial relationship between microbubbles and cells was observed microscopically when cells were sonicated with pulsed ultrasound. Effects of microbubbles on the cells were observed with a high-speed camera, and the ratio of cell membrane damage and repair was examined using fluorescent microscopy. Results. Damage to the cell membrane, caused mainly by mechanical effects of the expansion and contraction of microbubbles, significantly increased the permeability of the cell membrane. The frequency of cell membrane damage was closely associated with the presence of microbubbles and increased with increase in acoustic pressure. The ratio of repair of damaged cells was about 70% during 3 min after a single shot of pulsed ultrasound, indicating that repair of damaged cell membranes requires little time. Conclusion. We examined the frequency of occurrence of cell membrane damage and repair in sonoporation using pulsed ultrasound and microbubbles. Our results should prove useful for improving pulsed-ultrasound sonoporation. © The Japan Society of Ultrasonics in Medicine 2005.
  • S Yamada, K Komuro, T Mikami, N Kudo, H Onozuka, K Goto, S Fujii, K Yamamoto, A Kitabatake
    HEART 91 2 183 - 188 2005年02月 [査読無し][通常論文]
     
    Objective: To test the hypothesis that the power of the received signal of harmonic power Doppler imaging ( HPDI) is proportional to the bubble concentration under conditions of constant applied acoustic pressure, and to determine whether a new quantitative method can overcome the acoustic field inhomogeneity during myocardial contrast echocardiography (MCE) and identify perfusion abnormalities caused by myocardial infarction. Methods: The relation between Levovist concentration and contrast signal intensity (CI) of HPDI was investigated in vitro under conditions of constant acoustic pressure. MCE was performed during continuous infusion of Levovist with intermittent HPDI every sixth cardiac cycle in 11 healthy subjects and 25 patients with previous myocardial infarction. In the apical views myocardial CI (CImyo) was quantified in five myocardial segments. The CI from the left ventricular blood pool adjacent to the segment was also measured in dB and subtracted from the CImyo ( relative CI (RelCI)). Results: CI had a logarithmic correlation and the calculated signal power a strong linear correlation with Levovist concentration in vitro. Thus, a difference in CI of X dB indicates a microbubble concentration ratio of 10(X/10). In normal control subjects, CImyo differed between the five segments (p< 0.0001), with a lower CImyo in deeper segments. However, RelCI did not differ significantly between segments ( p = 0.083). RelCI was lower ( p, 0.0001) in the 39 infarct segments (mean (SD) -18.6 (2.8) dB) than in the 55 normal segments (mean (SD) -15.1 (1.6) dB). RelCI differed more than CImyo between groups. Conclusions: The new quantitative method described can overcome the acoustic field inhomogeneity in evaluation of myocardial perfusion during MCE. RelCI represents the ratio of myocardium to blood microbubble concentrations and may correctly reflect myocardial blood volume fraction.
  • パルス超音波による微小気泡存在下でのsonoporationに関する基礎的検討
    超音波医学 32 461 - 470 2005年 [査読無し][通常論文]
  • N Kobayashi, T Yasu, S Yamada, N Kudo, M Kuroki, K Miyatake, M Kawakami, M Saito
    CIRCULATION JOURNAL 67 7 630 - 636 2003年07月 [査読無し][通常論文]
     
    Microbubbles have been reported to enhance ultrasound (US)-related side effects in animal systems. The present study investigated the influence of contrast ultrasonography (US) with perflutren lipid microspheres, a recently developed second-generation contrast agent, on microvessels. Rat mesentery was exposed to 1.8-MHz pulsed US with intravenous injection of perflutren (0.1 or 1.0ml/kg) or Levovist(R) (300mg/kg), and the microvessel bleeding and endothelial cell injury was examined. Impaired endothelial cells were identified by the fluorescence of propidium iodide. Microvessel bleeding was examined also in the rat myocardium. The interaction between 0.1 ml/kg of perflutren and US exposure did not cause microvessel bleeding, and did not increase endothelial cell injury compared with the sham operation, unless frequent, strong US exposure occurred. When the dose was increased to 1.0ml/kg, the combination of perflutren and US exposure resulted in capillary bleeding and increased endothelial cell injury in capillaries and venules (p<0.01). However, the incidence of microvessel bleeding and endothelial cell injury did not exceed that with Levovist(R) microbubbles. In the myocardium, microvessel bleeding was not observed under any conditions. In conclusion, perflutren lipid microspheres enhanced US-related microvessel injury as with other contrast agents at the dose of 1.0 ml/kg, but not with 0.1 ml/kg and the appropriate US setting.
  • Loreto B. Feril Jr., Takashi Kondo, Qing-Li Zhao, Ryohei Ogawa, Katsuro Tachibana, Nobuki Kudo, Shinichi Fujimoto, Shinobu Nakamura
    Ultrasound in Medicine and Biology 29 2 331 - 337 2003年02月01日 [査読有り][通常論文]
     
    To determine the effects of echo-contrast agents (ECAs) on ultrasound (US)-induced apoptosis and cell lysis, human myelomonocytic lymphoma U937 cells in suspension were exposed to 1 MHz continuous waves US for 1 min at an intensity of 0.5, 1.0, 2.0 or 4.0 W/cm2 with or without non-shell type ECA, Levovist™ (2 mg/ml), and shell type, Optison™ (1 μl/ml) or YM454 (1 μl/ml). Levovist™ minimally enhanced the US-induced apoptosis at 1.0 W/cm2 while Optison™ and YM454 did at 2.0 and 4.0 W/cm2, as detected by flow cytometry. Cell lysis was also augmented when Levovist™ was combined with US at 2.0 W/cm2, and when Optison™ was combined with US at 2.0 and 4.0 W/cm2. YM454 showed the highest rate of enhanced cell lysis at 1.0, 2.0 and 4.0 W/cm2. Therefore, this study shows that Optison™ and YM454 are effective in augmenting the US-induced cell killing, but not Levovist™. Another result indicates that cavitation plays a role in the augmented effects and that inertial cavitation appears necessary for Optison™ and YM454 to effect their actions. In addition, results show that the rate of apoptosis is lower in the presence of ECAs with higher free radical scavenging activity, suggesting a possible role for free radicals in apoptosis. These findings suggest that some ECAs have potential to be adjuncts in cases wherein augmented US-induced cell killing is needed, such as in cancer therapy with US. © 2003 World Federation for Ultrasound in Medicine & Biology.
  • N Kobayashi, T Yasu, S Yamada, N Kudo, M Kuroki, M Kawakami, K Miyatake, M Saito
    ULTRASOUND IN MEDICINE AND BIOLOGY 28 7 949 - 956 2002年07月 [査読無し][通常論文]
     
    The aim of the present study was to test the hypothesis that microvascular endothelial cells (EC) are subject to the bioeffects induced by contrast ultrasound (US) because of their proximity to the circulating microbubbles. We examined EC injury in each microvessel section (arteriole, capillary or venule) in rat mesenteries among the following five groups: three controls (sham operation, microbubble injection alone, US exposure with saline injection), and two contrast-US groups (US exposure at a 1-Hz or 30-Hz frame rate with microbubble injection). Propidium iodide (PI), a fluorescent indicator of cell injury, was employed to visualize impaired EC. PI-positive nuclei were equally few among the three controls. Contrast-US increased PI-positive cells in capillaries (1-Hz frame rate, 2.4 +/- 2.2 cells per 0.1-mm vessel length, p = 0.09; 30-Hz frame rate, 4.3 +/- 1.8 cells, p < 0.01) and in venules (1-Hz frame rate, 4.1 +/- 2.5 cells, p < 0.05; 30-Hz frame rate, 13.8 +/- 3.6 cells, p < 0.01) compared with sham operation (0.10 +/- 0.22 cells). The finding indicates that diagnostic contrast US potentially causes EC injury, particularly in venules and capillaries. (E-mail: tyasu@omiya.jichi.ac.jp) (C) 2002 World Federation for Ultrasound in Medicine Biology.
  • M Niwayama, K Yamamoto, D Kohata, K Hirai, N Kudo, T Hamaoka, R Kime, T Katsumura
    IEICE TRANSACTIONS ON INFORMATION AND SYSTEMS E85D 1 115 - 123 2002年01月 [査読無し][通常論文]
     
    We have developed a 200-channel imaging system that enables measurement of changes in oxygenation and blood volume and that covers a wider area (45 cm x 15 cm) than that covered by conventional systems. This system consisted of 10 probes of five channels, a light-emitting diode (LED) driver, multiplexers and a personal computer. Each probe was cross-shaped and consisted of an LED, five photo diodes, and a current-to-volt age (I-V) converter. Lighting of the LEDs and acquisition of 200-channel data were time-multiplexed. The minimum data acquisition time for 200 channels, including the time required for calculation of oxygenation and monitoring of a few traces of oxygenation on a computer display, was about 0.2 s. We carried out exercise tests and measured the changes in oxy- and deoxy-hemoglobin concentrations in the thigh. Working muscles in exercises could be clearly imaged, and spatio-temporal changes in muscle oxygenation during exercise and recovery were also shown. These results demonstrated that the 200-channel imaging system enables observation of the distribution of muscle metabolism and localization of muscle function.
  • H. Lee, K. Yamamoto, N. Kudo, T. Shimooka, Y. Mitamura, T. Yuhta
    Journal of Artificial Organs 5 3 193 - 199 2002年 [査読無し][通常論文]
     
    Recently, cavitation on the surface of mechanical heart valves has been studied as a cause of fractures that occur in implanted mechanical heart valves. Several factors, including peak dp/dt of the ventricular pressure, maximum closing velocity of the leaflet, and squeeze flow, have been studied as indices of the cavitation threshold. In the present study, cavitation erosion on the surface of a mechanical valve was examined by focusing on squeeze flow and the water-hammer phenomenon during the closing period of the valve. A simple solenoid-actuated test device that can directly control the valve closing velocity was developed, and opening - closing tests of 3000 and 40000 cycles were performed at various closing velocities. The results showed that there was a closing velocity threshold above which erosion pitting was induced and that the threshold was about 0.4m/s in the valves used in this study. Cavitation-induced erosion pits were observed only in regions where squeeze flow occurred immediately before valve closure. On the other hand, the number of the pits was found to be closely related to the area of the water hammer-induced pressure were below the critical pressure defined by water vapor pressure. Therefore, it was concluded that cavitation is initiated and augmented by the two pressure drops due to squeeze flow and the water-hammer phenomenon, respectively.
  • J Shao, L Lin, M Niwayama, N Kudo, K Yamamoto
    OPTICAL ENGINEERING 40 10 2293 - 2301 2001年10月 [査読無し][通常論文]
     
    In spite of the usefulness of continuous-wave near-infrared spectroscopy (CW-NIRS) for noninvasive measurement of oxygenation of the brain and muscle, no theoretically derived algorithms for this technique have yet been presented, although an algorithm can be theoretically determined on the basis of diffusion. We derive the theoretical mean optical pathlength based on diffusion theory, and we develop linear and nonlinear algorithms for CW-NIRS. Both algorithms are validated by the results of experiments using a phantom consisting of Intralipid and hemoglobin solutions. An extra absorber is also used to examine the effects of background absorption in tissues, except for blood. The changes in concentrations of oxy- and deoxyhemoglobin, calculated using both algorithms, agree well with those obtained by experiments around an operating point determined by the optical pathlength. The results of the phantom experiments and theoretical analyses show that the nonlinear algorithm can be used in a wider range of variation in absorption than the linear algorithm. The results also suggest that if the operating point is inappropriately given, the accuracy of both algorithms is greatly reduced. The errors in actual measurements of muscle oxygenation using the linear and nonlinear algorithms are also estimated, assuming a variation of +/-50% in blood volume, and are found to be less than 12 and 6%, respectively, if the operating point is set appropriately. (C) 2001 Society of Photo-Optical Instrumentation Engineers.
  • 超音波照射下における微小気泡のふるまいの高速度カメラによる観察
    電子情報通信学会論文誌Ａ J84-A 1492 - 1499 2001年 [査読無し][通常論文]
  • 超音波変調光による生体の光イメージングに関する基礎的検討 ‐スペックルパターンの変動を利用した変調光の検出‐
    電子情報通信学会論文誌Ａ J84-A 2293 - 2301 2001年 [査読無し][通常論文]
  • M Niwayama, L Lin, J Shao, N Kudo, K Yamamoto
    REVIEW OF SCIENTIFIC INSTRUMENTS 71 12 4571 - 4575 2000年12月 [査読無し][通常論文]
     
    The inhomogeneity of tissue structure greatly affects the sensitivity of tissue oxygenation measurement by reflectance near-infrared spectroscopy. In this study, we investigated the influence of a fat layer on muscle oxygenation measurement by in vivo tests and Monte Carlo simulation, and we propose a method for correcting the influence. In the simulation, a three-dimensional model consisting of the epidermis, dermis, fat, and muscle layers was used. In in vivo tests, measurement sensitivity was examined by measuring oxygen consumption of the forearm muscle and the peak-to-peak variation of oxygenation in periodic exercise tests on the vastus lateralis using a newly developed multisensor type of tissue oximeter. Fat layer thickness was also measured by ultrasonography. The correction curve of measurement sensitivity against fat layer thickness was obtained from the results of simulation and in vivo tests. The values of corrected oxygen consumption were almost the same and had less variation between individuals (0.13 +/-0.02 ml 100 g(-1) min(-1)) than did the uncorrected values (0.08 +/-0.04 ml 100 g(-1) min(-1)). (C) 2000 American Institute of Physics. [S0034-6748(00)02812-4].
  • NIRSによる筋組織酸素計測における脂肪層の影響補正 ‐ 31P-NMRお よびPETによる筋酸素消費量との比較‐
    セラピューティックリサーチ 21 6 1520 - 1523 2000年 [査読無し][通常論文]
  • Influence of a fat layer on muscle oxygenation measurement using near-IR spectroscopy: quantitative analysis based on two-layered phantom experiments and Monte Carlo simulation
    Frontiers Med. Biol. Eng. 10 43 - 58 2000年 [査読無し][通常論文]
  • 李 桓成, 工藤 信樹, 下岡 聡行, 三田村 好矩, 山本 克之
    人工臓器 28 2 436 - 441 JAPANESE SOCIETY FOR ARTIFICIAL ORGANS 1999年04月15日 [査読無し][通常論文]
     
    1980年代に動物やヒトに埋植された人工弁に壊食ピットが発見されて以来, その原因としてキャビテーションが注目されている.我々は人工弁の加速耐久試験を行い, 弁付近の管壁のコンプライアンスが大きくなるとキャビテーションによる壊食ピット数やピットの直径が増加することを示してきた. 本研究では, 自然心に近い圧力条件で剛体ホルダーとコンプライアンス付加ホルダーを用いてディスクの閉鎖運動および弁近傍の圧力変化を計測した. 計測の結果, コンプライアンス付加ホルダーでは, 剛体ホルダーよりも弁近傍の負圧のピークは小さいが, その持続時間は長くなっていた. 剛体ホルダーでは閉鎖直前の速度が速くなり, 表面壊食も増加することがわかった. 閉鎖直前のディスクの速度は表面壊食に大きな影響を与えると考えられる.
  • 張旭
    超音波医学 25 167 - 178 1998年 [査読無し][通常論文]
  • 超音波ＲＦエコー解析による頸動脈壁厚計測に関する検討
    超音波医学 25 155 - 166 1998年 [査読無し][通常論文]
  • 庭山 雅嗣, 志賀 利一, 林 凌, 工藤 信樹, 高橋 誠, 山本 克之
    医用電子と生体工学 36 1 41 - 48 1998年 [査読無し][通常論文]
  • N Kudo, M Yoshida, K Yamamoto, T Mikami, A Kitabatake, Y Ito
    1998 IEEE ULTRASONICS SYMPOSIUM - PROCEEDINGS, VOLS 1 AND 2 1479 - 1482 1998年 [査読有り][通常論文]
     
    To investigate the effects of a myofibrous structure of biological tissue on ultrasound attenuation, the frequency-dependence of attenuation in bovine muscle tissue was measured in the frequency range of 10-40 MHz. The frequency-dependence of attenuation was approximated by a power-low, af(b), in the measured frequency range. The exponent value 'b' of the sliced samples was 1.2 for parallel insonification with respect to the direction of myofibers and 1.9 for normal insonification, while it was 1.5 for the supernatant liquid extracted from the homogenized tissue suspension. These results suggest that the exponent value 'b' of fibrous structure is changed by the angle of insonification. It is well known that ultrasound attenuation of fibrous tissue at frequencies below 10 MHz depends on the direction of the fibrous structure. Our results suggest that this angular dependence of attenuation is caused by a change in the exponent value of frequency-dependent attenuation.
  • M Niwayama, T Shiga, L Lin, N Kudo, M Takahashi, K Yamamoto
    PROCEEDINGS OF THE 20TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOL 20, PTS 1-6 20 1849 - 1850 1998年 [査読有り][通常論文]
     
    The inhomogeneity of tissue structure greatly affects the sensitivity of tissue oxygenation measurement by reflectance NIRS. We have proposed a method for correcting the influence of a subcutaneous fat layer on muscle oxygenation measurement. The correction is based on an inverse realtionship between the measurement sensitivity and detected light intensity. In this study, this method was validated by measuring the peak-to-peak variation of muscle oxygenation in periodic exercise tests on the vastus lateralis. A multisensor probe consisting of a light source and four photodiodes with source-detector distances of 7-40 mm was newly developed. A proximal detector with a 7-mm separation was used to eliminate the effect of skin. The fat layer thickness was also measured by ultrasonography. Results of the tests clearly showed that the presence of a fat layer greatly decreases the sensitivity of measurement and increases the light intensity at the detectors. Sensitivity correction by detected light intensity resulted in almost the same changes in muscle oxygention due to periodic exercise among subjects regardless of different fat layer thicknesses. The proximal detector was also effective for reducing the effect of skin.
  • M OYANAGI, N KUDO, Y YANAGIDA, N IWAMA, K OKAZAKI
    Jpn. J. Appl. Phys 33 5B 3155 - 3158 1994年05月 [査読無し][通常論文]
     
    A new, method for evaluating shock wave pressure distribution of extracorporeal shock wave lithotripters, using pressure-sensitive paper has been developed. It is a simple method to visualize the shock wave pressure distribution and has a better spatial resolution than the hydrophone. The pressure-sensitive paper can be used to visually detect whether the focal point is on the correct position, and to detect changes of pressure distribution. Additionally, the relationship between lithotripter power and integrated density, as a new evaluating value shows linearity. Therefore, this method is useful for quality assurance of lithotripters at hospitals.
  • Development of the robust hydrophone for extracorporeal shock wave lithotripters
    Jpn. J. Endourology and ESWL 7 2 153 - 158 1994年 [査読無し][通常論文]
  • KUDO N.
    Frontiers of Medical and Biological Engineering 1 1 19 - 28 1988年 [査読無し][通常論文]
  • Nobuki Kudo, Koichi Shimizu, Goro Matsumoto
    医用電子と生体工学 25 2 91 - 98 1987年 [査読無し][通常論文]
     
    The optical biotelemetry using free-space light transmission in a closed space has many advantages over the conventional telemetry techniques using radio waves. There are some reports on the optical telemeters using direct light transmission, but few are found which use the indirect light scattered from a ceiling, a floor and walls. Since the latter technique does not require the line-of-sight transmission, it enables us to realize the non-restraint measurement of biological signals. In order to examine the possibility of this technique, the distribution of the indirect light in a room was calculated by a computer simulation. The distribution is uniform enough to carry out the telemetry with one receiver in the room with the dimension of W4.2XL6.4XH2.7m. The minimum received power was -28.0dBm with the transmitter power of 1 watt, which was about a half of the maximum power. To verify the possibility shown in the theoretical analysis, an optical biotelemetry system using the indirect light transmission was developed. 3 ECG's and a body temperature are multiplexed in time domain and modulated into a PIM pulse sequence. Light emitters placed on both shoulders emit the light of about 1 watt when the pulse is on. The system can be operated over 100 hours without replacing batteries. To examine the practical usefulness of this technique in clinical application, the optical biotelemetry from a freely moving subject is carried out with the developed system. A stable data acquisition was demonstrated even from the subject in exercise. © 1987, Japanese Society for Medical and Biological Engineering. All rights reserved.
  • Optical biotelemetry using indirect light transmission
    Biotelemetry IX 55 - 58 1987年 [査読無し][通常論文]
  • 工藤 信樹, 清水 孝一, 松本 伍良
    医用電子と生体工学 23 3 194 - 198 1985年 [査読無し][通常論文]
     
    A new method of biotelemetry is proposed, which realizes nonrestrained acquisition of biological signals using the infrared light diffused out from animal skin. This technique is fundamentally different from conventional telemetry techniques which use radio-frequency electromagnetic waves. An optical transmitter which consists of some LED's is implanted beneath the skin. Biological information such as ECO signal is collected in vivo and the light emitted from the LED's is modulated by the signal. The light transmitted through the skin is strongly diffused and spread out in a wide angle. The light is collected by the remotely located optical receivers and the biological information is obtained by demodulating the signal. Thus, the biological information in vivo is obtained without restraining the object with cables or optical fibers. In order to verify the possibility of the above technique, a system, which obtains an ECG from laboratory animals, has been developed. An infrared light was chosen due to its invisibility and high transmittance through the skin. Considering the stability of the communication link and the power consumption of the implanted transmitter, PFM (Pulse Frequency Modulation) technique was used. Using the system, the transcutaneous ECG telemetry was performed successfully. In the experiment, the indirect light reflected and scattered by the walls, the ceiling and the floor was shown to be useful in the optical telemetry. Light transmission patterns through the skin of a mouse were measured. The results suggest the possibility of telemetry even from the deep part of the body cavity. It is concluded that recent progress of optical and electronic technologies have reached the point, where transcutaneous optical telemetry of biological signals has become practically possible. © 1985, Japanese Society for Medical and Biological Engineering. All rights reserved.

MISC

  • 超音波で生体の壁を超える 超音波と気泡を併用する膀胱内注入療法の犬における安全性検討
    佐々木 東, 青柳 貞一郎, 池中 良徳, 工藤 信樹, 中村 健介, 滝口 満喜 超音波医学 48 (Suppl.) S195 -S195 2021年04月
  • 鈴木亮, 島忠光, 丸山保, 小俣大樹, 宗像理紗, 工藤信樹, 丸山一雄 超音波医学 Supplement 48 2021年
  • 佐々木東, 青柳貞一郎, 池中良徳, 工藤信樹, 中村健介, 滝口満喜 超音波医学 Supplement 48 2021年
  • 低強度パルス超音波照射による毛髪細胞刺激
    佐々木 東, 工藤 信樹, 大田 寛, 滝口 満喜 超音波医学 46 (Suppl.) S579 -S579 2019年04月 [査読無し][通常論文]
  • 今井慎司, UNGA Johan, 鈴木亮, 丸山一雄, 工藤信樹 超音波医学 46 (Supplement (CD-ROM)) 2019年
  • 佐々木 東, 工藤 信樹, 大田 寛, 滝口 満喜 超音波医学 45 (Suppl.) S575 -S575 2018年04月 [査読無し][通常論文]
  • 佐々木 東, 工藤 信樹, 中山 翔太, 滝口 満喜 超音波techno 29 (4) 27 -30 2017年07月 [査読無し][通常論文]
  • 佐々木東, 工藤信樹, 中村健介, 森下啓太郎, 大田寛, 滝口満喜 再生医療 16 348 2017年02月01日 [査読無し][通常論文]
  • 佐々木東, 工藤信樹, 森下啓太郎, 大田寛, 滝口満喜 日本超音波医学会光超音波画像研究会プログラム・抄録集 2017 (2nd) 66‐67 2017年 [査読無し][通常論文]
  • Sogo Toda, Yuji Kato, Nobuki Kudo, Koichi Shimizu Proceedings of SPIE - The International Society for Optical Engineering 10251 2017年01月01日 [査読無し][通常論文]
     
    © 2017 SPIE. For transillumination imaging of an animal body, we have attempted to suppress the scattering effect in a turbid medium. It is possible to restore the optical image before scattering using phase-conjugate light. We examined the effect of intensity information as well as the phase information for the restoration of the original light distribution. In an experimental analysis using animal tissue, the contributions of the phase-and the intensity-information to the image restoration through turbid medium were demonstrated.
  • 工藤 信樹 光アライアンス 27 (9) 6 -10 2016年09月
  • 超音波による細胞周期変動を利用した増感放射線療法の可能性
    藤沢 眞代, 佐々木 東, 安井 博宣, 工藤 信樹, 滝口 満喜 超音波医学 43 (5) 679 -679 2016年09月 [査読無し][通常論文]
  • 膀胱癌を模した3次元培養系でのシスプラチンデリバリー
    佐々木 東, 工藤 信樹, 滝口 満喜 超音波医学 43 (5) 679 -679 2016年09月 [査読無し][通常論文]
  • 佐々木 東, 工藤 信樹, 中村 健介, 森下 啓太郎, 大田 寛, 滝口 満喜 超音波医学 43 (Suppl.) S544 -S544 2016年04月 [査読無し][通常論文]
  • 髙田 亮, 小田 雄介, 鈴木 亮, 工藤 信樹 電子情報通信学会技術研究報告 = IEICE technical report : 信学技報 115 (513) 33 -38 2016年03月22日
  • 佐々木東, 工藤信樹, 中山翔太, 滝口満喜 日本超音波医学会光超音波画像研究会プログラム・抄録集 2016 (2nd) 22‐24 2016年 [査読無し][通常論文]
  • 五十嵐 康信, 工藤 信樹 超音波エレクトロニクスの基礎と応用に関するシンポジウム講演論文集 36 "1J2 -2-1"-"1J2-2-2" 2015年11月05日
  • 住吉 洸城, 工藤 信樹 電子情報通信学会技術研究報告 = IEICE technical report : 信学技報 115 (116) 1 -6 2015年06月26日
  • 白幡 陽, 繁富(栗林) 香織, 工藤 信樹 電子情報通信学会技術研究報告 = IEICE technical report : 信学技報 114 (514) 19 -23 2015年03月16日 
    これまで我々は,微小気泡が接着した細胞にパルス超音波を照射することによって膜損傷を生じさせ,細胞内に薬物を導入するソノポレーション技術に関し検討を行なってきた.その研究の過程で,細胞膜の張力が膜修復に影響を与える可能性が見出された.そこで,本研究では細胞膜の張力制御を細胞の伸展状態を制御することによって実現することを考え,数個から数十個の単位で細胞培養が可能な微小培養ウェルの開発を行った.ウェルは厚膜フォトレジストSU-8により作製した.ウェル径は15〜200μm,深さは40μmとし,1週間程度の培養が可能であることを確認した.また,開発したウェルを用いて実際に培養を行ない,ウェル内の細胞数により細胞伸展の程度を2倍程度制御できることを確認した.このことから本培養ウェルは生体内を想定したソノポレーション検討に有用と考えられる.
  • 遠藤将吾, 工藤信樹, 山口秀, 住吉洸城, 茂木洋晃, 金子貞洋, 小林浩之, 寺坂俊介, 寳金清博 日本超音波医学会光超音波画像研究会プログラム・抄録集 2015 (2nd) 25 -26 2015年 [査読無し][通常論文]
  • 工藤 信樹 超音波エレクトロニクスの基礎と応用に関するシンポジウム講演論文集 35 397 -398 2014年12月03日
  • 吉松幸里, 工藤信樹, 鈴木亮, 丸山一雄 超音波医学 40 (4) 427 2013年07月15日 [査読無し][通常論文]
  • 関根 大輝, 工藤 信樹, 清水 孝一 電子情報通信学会技術研究報告 = IEICE technical report : 信学技報 113 (103) 39 -44 2013年06月21日 
    我々は,超音波音場計測の新たな手法として画像差分シュリーレン法を提案し,その有用性を検討してきた.本手法では,超音波照射有無の2条件で撮影したシャドウグラフを計算機上で処理することにより,シュリーレン法と類似の画像を取得する.本報告では,提案手法を超音波診断装置に応用するために装置を改良し,可視化を行なった結果について述べる.本手法では,超音波の瞬時音場を可視化するために超音波の照射と同期したストロボ撮影を行なっており,同期信号が必要となる.臨床用の診断装置ではこのような信号を得ることが難しいため,これまでは診断装置を改造して同期信号を取得していた.今回,可視化装置に音圧測定素子を組み込み,この信号を同期信号として用いることとした.改良装置を用いて超音波診断装置のパルス音場を可視化した.その結果,近距離から焦点まで広範囲の音場が可視化でき,超音波診断装置のモードの違いによる音場の変化も明確に捉えられた.さらに,可視化像の輝度と音圧,パルス平均強度との間には相関が見られたことから,本システムは超音波診断用プローブの経年劣化や故障の検出,さらには超音波出力の評価にも有用と考えられた.
  • 吉松幸里, 工藤信樹, 鈴木亮, 丸山一雄 超音波医学 40 (2) 230 2013年03月15日 [査読無し][通常論文]
  • 工藤 信樹 Japanese journal of medical ultrasonics = 超音波医学 39 (6) 567 -568 2012年11月15日 [査読無し][通常論文]
  • 小原 浩貴, 工藤 信樹, 清水 孝一 超音波エレクトロニクスの基礎と応用に関するシンポジウム講演論文集 33 249 -250 2012年11月13日
  • 吉松幸里, 工藤信樹, 鈴木亮, 丸山一雄 日本DDS学会学術集会プログラム予稿集 28th 143 2012年06月05日 [査読無し][通常論文]
  • 熊田 卓, 松田 康雄, 飯島 尋子, 小川 眞広, 工藤 信樹, 小原 和史, 紺野 啓, 高倉 玲奈, 西田 睦, 南 康範, 森 秀明, 山田 昌彦 Japanese journal of medical ultrasonics = 超音波医学 39 (3) 317 -326 2012年05月15日 [査読無し][通常論文]
  • 工藤信樹, 佐々木東, 滝口満喜 超音波医学 39 (Suppl.) S174 -S174 2012年04月15日 [査読無し][通常論文]
  • 佐々木東, 中村健介, 工藤信樹, 滝口満喜 超音波医学 39 (2) 226 -227 2012年03月15日 [査読無し][通常論文]
  • 宇留賀仁史, 鈴木亮, 小田雄介, 工藤信樹, 根岸洋一, 平田圭一, 野村鉄也, 宇都口直樹, 丸山一雄 日本薬学会年会要旨集 132nd (4) 321 2012年03月05日 [査読無し][通常論文]
  • 佐々木東, 中村健介, 工藤信樹, 滝口満喜 超音波医学 38 (6) 674 -674 2011年11月15日 [査読無し][通常論文]
  • 吉松幸里, 工藤信樹, 鈴木亮, 丸山一雄 超音波医学 38 (6) 671 2011年11月15日 [査読無し][通常論文]
  • 工藤 信樹 Japanese journal of medical ultrasonics = 超音波医学 38 (6) 623 -624 2011年11月15日 [査読無し][通常論文]
  • 小原 浩貴, 工藤 信樹, 清水 孝一 電子情報通信学会技術研究報告. US, 超音波 111 (88) 31 -35 2011年06月16日 [査読無し][通常論文]
     
    現在,超音波の治療応用として,通常は細胞内に入らない薬物や遺伝子を超音波照射によって細胞内に取り込ませるsonoporationが注目されている.培養細胞にsonoporationを行う際には,細胞と微小気泡を懸濁した培養液をシャーレに入れ,下方から連続超音波を照射する方法が多く用いられている.この際,シャーレ内部では様々な反射によって定在波が発生し,内部の超音波音場は非常に複雑になる.そこで本報告では,我々が提案する画像差分シュリーレン法を用いてシャーレのような小さな容器内の複雑な音場を可視化した結果について述べる.この手法は,簡易な光学系で超音波の瞬時音場を可視化できる点で従来の方法よりも優れている.実験の結果,定在波音場像の輝度が進行波に比べて約2倍増加すること,また壁面の近傍では輝度の低下が生じることが示された.さらに,超音波の照射圧によって生じる水面の波立ちにより,定在波の腹の位置における振幅が大きく変化することが確認された.可視化画像の輝度と超音波圧力の関係には比較的良い線形性が確認されたことから,画像差分シュリーレン法は小容器内の複雑な音場の定量化に有用と考えられる.
  • 奥山 学, 工藤 信樹, 清水 孝一 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 111 (84) 7 -12 2011年06月10日 [査読無し][通常論文]
     
    超音波を照射することにより一時的に細胞膜の透過性を向上させるソノポレーションが注目されている.我々は,微小気泡が細胞に付着した状態で超音波を照射すると,一般的にはソノポレーションに用いられない短いパルス超音波でもソノポレーションが起きることを世界に先駆けて見いだし,ソノポレーションにおいて気泡が果たす役割について検討を行っている.微小気泡が細胞に与える作用と機序を明らかにするためには,気泡の大きさや細胞に付着する部位を制御して実験を行う必要がある.しかし,直径数ミクロンの微小気泡の位置を制御することは難しく,これまで十分な検討を行うことができなかった.そこで本研究では,気泡を光ビームで捕捉する光ピンセット装置の開発を行った.周囲の水よりも屈折率が小さな気泡を捕捉するため,空間位相変調器で作成したホログラムを用いてドーナツ形状の光ビーム(ラゲールガウシアンビーム)を発生した.その結果,光パワー1Wのとき半径2.5μmの気泡に対しておよそ20 pNの捕捉力が得られ,現在ソノポレーション研究に広く用いられている半径0.5-2.5μmの気泡位置の制御が十分可能であることを確認した.
  • 佐々木東, 中村健介, 村上正紘, 大田寛, 山崎真大, 工藤信樹, 滝口満喜 超音波医学 38 (3) 338 -338 2011年05月15日 [査読無し][通常論文]
  • 佐々木東, 中村健介, 村上正紘, KUMARA Badula, 大田寛, 山崎真大, 工藤信樹, 滝口満喜 超音波医学 38 (Suppl.) S316 -S316 2011年04月15日 [査読無し][通常論文]
  • 李 〓, 工藤 信樹, 清水 孝一, 栗城 眞也 電気学会研究会資料. MBE, 医用・生体工学研究会 2011 (1) 71 -76 2011年01月27日 [査読無し][通常論文]
  • 李 〓, 工藤 信樹, 清水 孝一, 栗城 眞也 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 110 (399) 71 -76 2011年01月20日 [査読無し][通常論文]
     
    経口摂取が難しい患者に使われる経鼻栄養チューブの先端位置を常に無侵襲計測することを目指し,磁気的検出法を考案した.これを実現するため,励磁コイルと差動型磁気検出コイルより成る交流帯磁率計測システムを設計した.実用感度を得るため,体内の特定深さで励起磁界を最大化するコイルの設計法を新たに考案した.実験をとおし,コイル設計法の有効性を実証した.
  • Nobuki Kudo, Masaya Yamamoto 10TH INTERNATIONAL SYMPOSIUM ON THERAPEUTIC ULTRASOUND (ISTU 2010) 1359 318 -321 2011年 [査読無し][通常論文]
     
    It is known that use of a contrast agents in echocardiography increases the probability of generation of premature ventricular contractions (PVCs). As a basic study to elucidate the mechanisms and to reduce adverse effects, the generation of PVCs was investigated using cultured cardiac myocytes instead of the intact heart in vivo. Cardiac myocytes were isolated from neonatal rats and cultured on a cover slip. The myocyte sample was exposed to pulsed ultrasound with microbubbles adjacent to the myocytes, and generation of PVCs was examined with ultrasound exposure at various delay times after onset of myocyte contraction. The experimental results showed that generation of PVCs had a stable threshold delay time and that PVCs were generated only when myocytes were exposed to ultrasound with delay times longer than the threshold. The results indicate that the model used in this study is useful for revealing the mechanisms by which PVCs are induced by ultrasound exposure.
  • 佐々木東, 中村健介, 村上正紘, BANDULA Kumara, 田村悠, 大田寛, 山崎真大, 工藤信樹, 滝口満喜 日本獣医学会学術集会講演要旨集 150th 297 -297 2010年09月01日 [査読無し][通常論文]
  • 工藤 信樹, 清水 孝一 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 110 (111) 13 -16 2010年06月23日 [査読無し][通常論文]
     
    直径1ミクロン程度の微小気泡を血管内に注射し,超音波診断の造影剤や,超音波治療の効果促進剤として用いる研究が盛んに行われている.我々は,このような用途に用いる微小気泡の超音波照射下におけるダイナミクスに関して検討を行ってきた.本報告では,膜の材質が異なる5種類の微小気泡を作成し,その安定性について検討を行った結果を報告する.気泡の材料となるリポソームには,ゲル相と液晶層の相転移温度が-22℃から+55℃の範囲に存在する5種類のリン脂質(DOPC,POPC,DMPC,DPPC,DSPC)を用い,これらを用いて作成した気泡の静的および動的な安定性を調べた.静的な安定性は気泡懸濁液の濁度を観察することにより評価し,動的な安定性は音圧に応じて変化する気泡懸濁液の超音波透過率を測定することにより評価した.その結果,両安定性とも気泡懸濁液の温度に強く依存することが確認され,気泡のシェルを構成する脂質膜の相が気泡の安定性に大きな影響を与えることが示された.ゲル相にあるシェルを持つ気泡は超音波の照射下でも比較的壊れにくい傾向があったことから,比較的流動性が低いゲル相のリン脂質膜でも,気泡の膨張・収縮によって分断された後に速やかに修復されるものと考えられた.
  • 工藤信樹, 八木智史, 萩沢康介, 鈴木亮, 丸山一雄, 山本克之 超音波医学 37 (3) 368 2010年05月15日 [査読無し][通常論文]
  • 八木智史, 工藤信樹, 鈴木亮, 丸山一雄 超音波医学 37 (3) 372 -373 2010年05月15日 [査読無し][通常論文]
  • 佐々木東, 中村健介, 村上正紘, KUMARA Bandula, 大田寛, 山崎真大, 工藤信樹, 滝口満喜 超音波医学 37 (Suppl.) S322 -S322 2010年04月15日 [査読無し][通常論文]
  • 八木智史, 工藤信樹, 鈴木亮, 丸山一雄 超音波医学 37 (1) 45 2010年01月15日 [査読無し][通常論文]
  • Nobuki Kudo JOURNAL OF MEDICAL ULTRASONICS 37 (1) 1 -2 2010年01月 [査読無し][通常論文]
  • Nobuki Kudo, Yoshiaki Sanbonmatsu, Koichi Shimizu Proceedings - IEEE Ultrasonics Symposium 829 -832 2010年 [査読無し][通常論文]
     
    We have proposed a new technique for visualization of an ultrasound fieldthat enables acquisition of Schlieren images by subtraction of two shadowgraphstaken in the presence and absence of ultrasound exposure. This technique can beeasily applied to other optical methods because there is no need to use aconventional Schlieren optics. This paper shows the possibility of applying thetechnique to microscopic observation of high-frequency ultrasound fields. Alight source of short pulsed light of 0.11 ns and a CCD camera with a 15 bitdynamic range were installed in an inverted-type microscope. High-frequencyultrasound fields of a miniature 20-MHz transducer for intravascular ultrasoundimaging and a 50-MHz wideband transducer were visualized using 4 and 10objective lenses. Observation results showed that the high-frequency fields weresuccessfully visualized at the maximum spatial resolution of 0.93 m.Transmission and reflection of pulsed ultrasound at a water-Plexiglas interfacewere also observed, and the acquired movie image of ultrasound propagationdemonstrated the importance of this technique for direct understanding ofcomplex acoustic fields. © 2010 IEEE.
  • 坂口克至, 工藤信樹, 鈴木亮, 丸山一雄, 山本克之 超音波医学 36 (3) 384 2009年05月15日 [査読無し][通常論文]
  • 八木智史, 岡田健吾, 工藤信樹, 萩沢康介, 鈴木亮, 丸山一雄, 山本克之 超音波医学 36 S315 2009年04月15日 [査読無し][通常論文]
  • 八木智史, 岡田健吾, 工藤信樹, 萩沢康介, 鈴木亮, 丸山一雄, 山本克之 超音波医学 36 (1) 67 -68 2009年01月15日 [査読無し][通常論文]
  • Nobuki Kudo, Katsuji Sakaguchi, Ryo Suzuki, Kazuo Maruyama Proceedings - IEEE Ultrasonics Symposium 1255 -1258 2009年 [査読無し][通常論文]
     
    Five types of gas-encapsulated liposomes (bubble liposomes) were produced and their stability was studied under static pressure and dynamic pressure conditions. Five types of phosphatidylcholine, DOPC, POPC, DMPC DPPC and DSPC, with different transition temperatures between liquid-crystalline and gel phases in the range from ! 22°C to +55°C were used as a main component of the liposomes. Static stability of these BLs was evaluated by observations of turbidity of their suspension, and dynamic stability was evaluated by measurements of pressure-dependent ultrasound transmission. The results showed that both stabilities have strong dependence on temperature of bubble suspensions, suggesting that the phase of the shell material is one of the main parameters to determine bubble stabilities. Bubbles with shells in gel phase have higher stability under exposure to ultrasound, suggesting that the intact shell in this phase can be restored immediately after bubble oscillation. ©2009 IEEE.
  • 岡田 健吾, 工藤 信樹, ハッサン マリアム アリ, 近藤 隆, 山本 克之 超音波エレクトロニクスの基礎と応用に関するシンポジウム講演論文集 29 (29) 419 -420 2008年11月11日 [査読無し][通常論文]
  • 鈴木 良輔, 工藤 信樹, 山本 克之 Japanese journal of medical ultrasonics = 超音波医学 35 S280 2008年04月15日
  • 工藤 信樹, 渡辺 大士, 後藤 慎吾, 岡田 健吾, 山本 克之 Japanese journal of medical ultrasonics = 超音波医学 35 S289 2008年04月15日
  • 工藤 信樹, 山本 克之 Japanese journal of medical ultrasonics = 超音波医学 35 S181 2008年04月15日
  • 坂口克至, 工藤信樹, 鈴木亮, 丸山一雄, 山本克之 超音波医学 35 S555 2008年04月15日 [査読無し][通常論文]
  • 八木智史, 岡田健吾, 工藤信樹, 鈴木亮, 丸山一雄, 山本克之 超音波医学 35 S560 2008年04月15日 [査読無し][通常論文]
  • Katsuji Sakaguchi, Nobuki Kudo, Katsuyuki Yamamoto, Ryo Suzuki, Kazuo Maruyama 2008 IEEE Ultrasonics Symposium Proceedings 1675 -1678 2008年 [査読無し][通常論文]
     
    Two types of gas-encapsulated liposomes (Bubble liposomes) with different shell compositions were evaluated by measurements of pressure-dependent ultrasound attenuation of bubble suspensions and by high-speed observations of bubble behaviors under exposure to pulsed ultrasound. Attenuation peaks were observed at the frequency range\\ of 16-19 MHz, suggesting that the size of Bubble liposomes is around 400 nm. There was a large difference between threshold pressures of bubble collapse in the two types of Bubble liposomes, indicating that decrease in shell fluidity by addition of cholesterol to a lipid bilayer and increase in surface area by bubble fragmentation have strong effects for facilitating bubble disappearance. ©2008 IEEE.
  • N. Kudo, N. Hirao, K. Okada, K. Yamamoto ACOUSTICAL IMAGING, VOL 29 29 107 -+ 2008年 [査読無し][通常論文]
     
    This paper describes a method for measuring extinction coefficients of a microbubble suspension at different probing pulse pressures. The experimental results demonstrated the usefulness of this method for evaluating acoustic properties of microbubbles of ultrasound contrast agents and also for finding the optimum exposure conditions of ultrasound.
  • 木部 龍太, 郭 凱俊, 工藤 信樹, 山本 克之 電気学会研究会資料. MBE, 医用・生体工学研究会 2007 (36) 13 -16 2007年06月29日 [査読無し][通常論文]
     
    われわれは,近赤外分光法(NIRS)の手法の一つである,空間分解法(spatially resolved spectroscopy, SRS)を用いた筋組織酸素濃度のイメージング装置の開発を行っており,その計測精度の検証には赤血球を使った液体ファントムを用いてきた.しかしその特性は不安定で,再現性に乏しいため十分な検証ができていなかった.そこで本研究では,計測誤差に関する安定な評価基準の実現を目標として,筋組織の光後方散乱特性を模擬したプラスチックファントムの作製を行った.透明プラスチックを主剤として,生体組織の吸収と散乱を,加える吸収体と散乱体の濃度で調整してファントムを作製したところ,時間分解法(time-resolved spectroscopy, TRS)で計測した吸収および等価散乱係数は,筋組織ファントムでμ_a=0.019-0.047 mm^<-1>, μ'_s=0.53-0.68 mm^<-1>,脂肪組織ファントムでμ_a=0.0002-0.0052 mm^<-1>,μ'_s=0.83-1.05 mm^<-1>となり,実際の組織の光学特性とほぼ一致した.
  • 鈴木 良輔, SOSEKHA Ly, 工藤 信樹, 山本 克之 電気学会研究会資料. MBE, 医用・生体工学研究会 2007 (36) 17 -20 2007年06月29日 [査読無し][通常論文]
     
    これまで,我々は超音波診断で用いられるパルス超音波の音場を可視化する手法として,複雑な光学系を用いずに従来のシュリーレン法とほぼ等価な画像を取得できる新しい音場可視化手法を提案し,その有用性の検討を行ってきた.本報告では,撮像装置を民生用ディジタルカメラで,光源を低価格な高出力レーザダイオードで代用した新システムを構築し,その性能を検討した結果について述べる.超音波診断装置のプローブのパルス超音波音場を可視化した結果,従来のシステムと遜色ない画像を得られることが確認されたことから,医療の現場でプローブの性能を評価できる簡便な装置を実現する見通しを得た.
  • 木部 龍太, 郭 凱俊, 工藤 信樹, 山本 克之, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 107 (126) 13 -16 2007年06月22日 [査読無し][通常論文]
     
    われわれは,近赤外分光法(NIRS)の手法の一つである,空間分解法(spatially resolved spectroscopy, SRS)を用いた筋組織酸素濃度のイメージング装置の開発を行っており,その計測精度の検証には赤血球を使った液体ファントムを用いてきた.しかしその特性は不安定で,再現性に乏しいため十分な検証ができていなかった.そこで本研究では,計測誤差に関する安定な評価基準の実現を目標として,筋組織の光後方散乱特性を模擬したプラスチックファントムの作製を行った.透明プラスチックを主剤として,生体組織の吸収と散乱を,加える吸収体と散乱体の濃度で調整してファントムを作製したところ,時間分解法(time-resolved spectroscopy, TRS)で計測した吸収および等価散乱係数は,筋組織ファントムでμ_a=0.019-0.047 mm^<-1>, μ'_s=0.53-0.68 mm^<-1>,脂肪組織ファントムでμ_a=0.0002-0.0052 mm^<-1>,μ'_s=0.83-1.05 mm^<-1>となり,実際の組織の光学特性とほぼ一致した.
  • 鈴木 良輔, Sosekha Ly, 工藤 信樹, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 107 (126) 17 -20 2007年06月22日 [査読無し][通常論文]
     
    これまで,我々は超音波診断で用いられるパルス超音波の音場を可視化する手法として,複雑な光学系を用いずに従来のシュリーレン法とほぼ等価な画像を取得できる新しい音場可視化手法を提案し,その有用性の検討を行ってきた.本報告では,撮像装置を民生用ディジタルカメラで,光源を低価格な高出力レーザダイオードで代用した新システムを構築し,その性能を検討した結果について述べる.超音波診断装置のプローブのパルス超音波音場を可視化した結果,従来のシステムと遜色ない画像を得られることが確認されたことから,医療の現場でプローブの性能を評価できる簡便な装置を実現する見通しを得た.
  • 後藤 慎吾, 岡田 健吾, 工藤 信樹, 山本 克之 Journal of medical ultrasonics = 超音波医学 34 S272 2007年04月15日
  • 江本 精, 工藤 信樹 Journal of medical ultrasonics = 超音波医学 34 S164 2007年04月15日
  • 渡辺 大士, 後藤 慎吾, 岡田 健吾, 工藤 信樹, 山本 克之 Journal of medical ultrasonics = 超音波医学 34 S167 2007年04月15日
  • 岡田 健吾, 工藤 信樹, 山本 克之 Journal of medical ultrasonics = 超音波医学 34 S333 2007年04月15日
  • 鈴木 亮, 滝澤 知子, 根岸 洋一, 宇都口 直樹, 門脇 則光, 工藤 信樹, 立花 克郎, 丸山 一雄 Journal of medical ultrasonics = 超音波医学 34 2007年04月15日 [査読無し][通常論文]
  • Kek Khai Jun, Yoneyama Satoko, Miyakawa Takahiro, KUDO Nobuki, YAMAMOTO Katsuyuki 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 106 (127) 25 -28 2006年06月16日 
    Near-infrared spectroscopy (NIRS) is a technique for noninvasive measurement of muscle oxygenation. However, analyses of the dynamic changes in metabolism based only on NIRS measurements are difficult because the changes in muscle oxygenation could be affected by different factors of the complex metabolic system. Therefore, we constructed a model of muscle metabolism to identify the mechanisms responsible for experimental observation of NIRS measurements. Simulations that were performed with the model sufficiently reproduced the characteristic temporal changes of NIRS measurements. The results demonstrate the usefulness of the model for elucidation of the relationship between muscle metabolism and NIRS measurements.
  • 宮川 崇拓, 郭 凱俊, 工藤 信樹, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 106 (127) 21 -24 2006年06月16日 [査読無し][通常論文]
     
    近赤外分光法は組織酸素濃度を無侵襲・実時間的に計測可能な有用な手法であり,臨床やスポーツ医学などに幅広く利用されている.しかし,組織酸素濃度だけでなく,酸素消費量を同時に計測できれば,その有用性はより高まると考えられる.本研究では,連続光法による高速測定可能な装置を試作し,運動中の局所的な筋酸素消費量を短時間阻血法で測定し,運動負荷や測定部位による差異について検討した.運動時の局所的な酸素消費量をほぼ実時間で測定でき,運動負荷や部位による酸素消費量の経時変化の違いを明瞭に把握できることを確認した.
  • 宮下 英樹, 工藤 信樹, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 106 (127) 5 -8 2006年06月16日 [査読無し][通常論文]
     
    これまで,我々は超音波診断で用いられるパルス超音波の音場を可視化する手法として,複雑な光学系を用いずに従来のシュリーレン法と同等の画像を取得できる新しい音場可視化手法を提案し,有用性の確認を行ってきた.本報告では,我々が提案する簡易型シュリーレン法を用いて強力集束超音波(HIFU, high-intensity focused ultrasound)の音場可視化を行った結果について述べる.集束型超音波振動子への投入電力を10Wから100Wまで変化させて計測を行った結果,より高い音圧において超音波の非線形伝搬の影響と考えられる音場の変化が可視化されたことから,本手法は強力集束超音波の音場評価に有用と考えられた.
  • 宮下 英樹, 工藤 信樹, 山本 克之 生体医工学 : 日本エム・イー学会誌 44 (2) 315 -316 2006年06月10日
  • 郭 凱俊, 宮川 崇拓, 佐溝 正輝, 工藤 信樹, 山本 克之 生体医工学 : 日本エム・イー学会誌 44 (2) 315 -315 2006年06月10日
  • 岡田 健吾, 工藤 信樹, 山本 克之 生体医工学 : 日本エム・イー学会誌 44 (2) 311 -311 2006年06月10日
  • 岡田健吾, 工藤信樹, 鈴木亮, 滝澤知子, 丸山一雄, 山本克之 日本生体医工学会大会プログラム・論文集 45th 528 2006年05月15日 [査読無し][通常論文]
  • 工藤 信樹, 山本 克之 細胞 38 (4) 129 -132 2006年04月
  • 横山 剛也, 岡田 健吾, 工藤 信樹, 河原 剛一, 山本 克之 電気学会研究会資料. MBE, 医用・生体工学研究会 2005 (7) 21 -24 2005年06月17日 [査読無し][通常論文]
  • 池淵 正康, 岡田 健吾, 工藤 信樹, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 105 (122) 25 -28 2005年06月10日 [査読無し][通常論文]
     
    Sonoporationとは, 超音波の照射に伴い細胞膜の膜透過性が一時的に向上することを利用して, 通常の状態では入らない薬物を細胞内に導入する技術を言う.この技術に関して微小気泡を付加することにより, 薬物の導入効率が向上することが知られているが, そのメカニズムや基本的性質は明らかになっていない.そこで本研究では, 微小気泡存在下でのパルス超音波によるsonoporationに関して, 蛍光観察および電子顕微鏡観察を用いて, 細胞膜損傷・修復に関する基礎的な検討を行った.その結果, パルス超音波照射が引き起こした微小気泡のふるまいにより細胞膜に穿孔が生じることが膜の透過性向上の原因と考えられること, またその損傷は20秒以内に修復されることが確認された.
  • 横山 剛也, 岡田 健吾, 工藤 信樹, 河原 剛一, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 105 (122) 21 -24 2005年06月10日 [査読無し][通常論文]
     
    近年, 超音波造影剤を用いた心臓の超音波診断で心室性期外収縮(PVCs)を発生させる可能性があることがヒトボランティア試験によって示された.本研究では, そのメカニズムを探ることを目的として培養心筋細胞を用いた実験を行い, 期外収縮の発生と超音波照射時相の関係, および微小気泡の存在による期外収縮の発生音圧の閾値を微小気泡の有無の2条件で調べた.その結果, 期外収縮は心筋収縮期以降の時相でのみ観察され, これより期外収縮発生の超音波照射時相の依存性は不応期に起因するものと考えられた.また, 微小気泡を加えて超音波を照射した場合, 微小気泡を加えない場合に比べて期外収縮発生の音圧閾値が低下した.これは超音波照射を受けた気泡のふるまいが気泡がない場合より大きな機械的作用を心筋細胞に与えるためと考えられた.
  • 池淵 正康, 岡田 健吾, 工藤 信樹, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 105 (122) 25 -28 2005年06月10日 [査読無し][通常論文]
  • 横山 剛也, 岡田 健吾, 工藤 信樹, 山本 克之 Japanese journal of medical ultrasonics = 超音波医学 32 S286 2005年04月15日
  • 岡田 健吾, 工藤 信樹, 丹羽 光一, 山本 克之 Japanese journal of medical ultrasonics = 超音波医学 32 S284 2005年04月15日
  • 工藤 信樹, 岡田 健吾, 山本 克之 Japanese journal of medical ultrasonics = 超音波医学 32 S285 2005年04月15日
  • 工藤 信樹, 宮下 英樹, 大内 啓之, 山本 克之, 関水 英正 Japanese journal of medical ultrasonics = 超音波医学 32 S250 2005年04月15日
  • 池淵 正康, 岡田 健吾, 工藤 信樹, 山本 克之 Japanese journal of medical ultrasonics = 超音波医学 32 S210 2005年04月15日
  • 廣川 直樹, 小井戸 一光, 西田 睦, 佐藤 大志, 河合 有里子, 染谷 正則, 庄内 孝春, 山 直也, 兵頭 秀樹, 工藤 信樹, 山本 克之, 晴山 雅人 Japanese journal of medical ultrasonics = 超音波医学 32 S242 2005年04月15日 [査読無し][通常論文]
  • 工藤 信樹, 山本 克之 超音波techno 17 (1) 13 -16 2005年01月 [査読無し][通常論文]
  • N Kudo, K Yamamoto 4th International Symposium on Therapeutic Ultrasound 754 (754) 211 -213 2005年 [査読無し][通常論文]
     
    To study the mechanisms of sonoporation caused by exposure of cells to pulsed ultrasound in the presence of microbubbles, microscopic observations of bubble behaviour and cell-bubble interaction were carried out using a high-speed camera and a video camera. In the highspeed observation of bubble behaviour, symmetric radial oscillation of bubbles with spherical shape was mainly observed at lower pressure-amplitudes of ultrasound, but asymmetric contraction was frequently observed at higher pressure-amplitudes. The asymmetric contraction of a microbubble generates a small stream in the surrounding liquid, resulting in bubble fragmentation. In the next series of experiments, interactions with bubbles with cells exposed to pulsed ultrasound were observed using bovine endothelial cells with microbubbles attached to the cell membranes, and the repair of cell membrane damage caused by the small streams was investigated. Damage to the membrane was found at the locations where bubble collapse was observed. Using fluorescence microscopy, repair of the membrane was observed in about 70% of damaged cells within three minutes. These observational results suggest that the mechanical stress from a small liquid stream caused by asymmetric contraction of a bubble is responsible for membrane damage in our experimental conditions and that most damaged cells are repaired in a few minutes.
  • 大内 啓之, 工藤 信樹, 山本 克之, 関水 英正 電子情報通信学会技術研究報告. US, 超音波 104 (142) 9 -12 2004年06月18日 [査読無し][通常論文]
     
    超音波診断で用いられる周波数帯域のパルス超音波の音場を可視化する手法として,シュリーレン法と同じ画像を取得できる新しい音場可視化手法を提案する.本手法を実現するシステムは,短パルスレーザとCCDカメラ,およびCCDカメラで撮影した画像を処理するためのPCから成り,従来のシュリーレン法では光学系を用いて行っていた超音波屈折光の抽出を,超音波照射有・無の2条件で撮影した画像の差分を取ることにより実現する.さらに本報告では,5MHzの集束型振動子および20MHzの小型高周波振動子の音場分布の可視化実験を行い,本手法の有用性に関して検討を行った結果についても述べる.
  • 米山 聡子, 工藤 信樹, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 104 (129) 5 -8 2004年06月11日 [査読無し][通常論文]
     
    近年,近赤外分光法(near-infrared spectroscopy,NIRS)による筋組織酸素濃度計測に関する研究が盛んになされているが,筋組織における代謝動態は様々な要因で変化するため,NIRS測定波形のみから組織でのエネルギー代謝動態を推測することは困難である.そこで,本研究ではNIRS測定波形解釈を目的とし,有酸素系,クレアチンリン酸系,解糖系からなるATP生成系と,組織相,血液相からなる酸素拡散系で構成された筋代謝モデルを作成し,実測値と比較検討することとした.運動負荷応答のシミュレーションを行い,実測値と比較検討したところ,NIRS測定波形は,筋組織の酸素化レベルが高いときにはヘモグロビンの影響を強く受け,低いときにはミオグロビンの影響を強く反映していることが示唆された.
  • 前川 耕太, 工藤 信樹, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 104 (129) 9 -12 2004年06月11日 [査読無し][通常論文]
     
    近赤外分光法(near-infrared spectroscopy,NIRS)は組織酸素濃度を無侵襲かつリアルタイムに計測できる非常に有用な手法である.しかし,その測定原理からヘモグロビン(Hb)とミオグロビン(Mb)の酸素濃度を分離して測定することはできない.そこで,本研究では小動物の骨格筋を対象に顕微分光法を用いた組織酸素濃度計測を行い,NIRS測定値へのHbとMbの寄与率を解明することを最終目的とし,基礎的検討を行った.マウス腸開腹,ラット挙睾筋を対象とした微小循環の酸素飽和度計測では,径が30μm程度の血管までイメージング可能なことが確認された.しかし,透過光源を用いており,厚い骨格筋を対象とした計測には不向きであるため,反射鏡と落射光源を組み合わせた照明系についても検討を加えた.
  • 米山 聡子, 工藤 信樹, 山本 克之 生体医工学 : 日本エム・イー学会誌 42 (2) 133 -133 2004年06月10日
  • 大内 啓之, 工藤 信樹, 山本 克之, 関水 英正 Journal of medical ultrasonics = 超音波医学 31 S104 2004年04月15日
  • 工藤 信樹, 池淵 正康, 岡田 健吾, 山本 克之, 谷山 義明 Journal of medical ultrasonics = 超音波医学 31 S127 2004年04月15日
  • N Kudo, H Ouchi, K Yamamoto, H Sekimizu AMUM 2004: ADVANCED METROLOGY FOR ULTRASOUND IN MEDICINE 2004 1 (1) 146 -149 2004年 [査読無し][通常論文]
     
    A new Schlieren method for visualizing an acoustic field of pulsed ultrasound was proposed, and a system was developed to evaluate the validity of the proposed method by visualizing an acoustic field of a focused ultrasound field of diagnostic frequency range. A conventional Schlieren optical system is not used in the developed system. The system uses a short-pulsed laser, a CCD camera with a wide dynamic range, and a PC that processes images captured by the CCD camera. In the proposed method, extraction of light diffracted by ultrasound is carried out by subtraction of images captured with and without ultrasound exposure. The usefulness of the developed system was confirmed by an experiment in which acoustic fields of a 5-MHz focused transducer were visualized. Good agreement was found between the visualized and simulated ultrasound fields.
  • N Kudo, G Yokoyama, M Ikebuchi, K Okada, K Kawahara, K Yamamoto AMUM 2004: Advanced Metrology for Ultrasound in Medicine 2004 1 (1) 118 -121 2004年 [査読無し][通常論文]
     
    It has been shown that diagnostic ultrasound examination using a contrast agent can cause premature ventricular contractions (PVCs). In this study, we investigated a usefulness of a new technique using cultured cardiac myocytes to study mechanisms of PVC production. Cardiac myocytes were isolated from neonatal rats and cultured on a cover glass. The cover glass was attached to an observation chamber in which it was possible to observe changes in myocytes during ultrasound exposure. In the experiments, cardiac myocytes were exposed to pulsed ultrasound in the presence and absence of microbubbles. The pressure amplitudes (peak-negative pressures) were set at 5 steps, -0.28, -0.55, -0.73, -0.92 and -1.1 MPa, and threshold pressure to produce a PVC was recorded. The results showed that the presence of microbubbles attached to a cell reduces threshold pressure for producing PVCs, and it was concluded that our method is useful for studying the mechanisms of PVC production.
  • N Kudo, K Yamamoto STATE OF THE ART: ULTRASONICS IN MEDICINE 1274 (1274) 129 -132 2004年 [査読無し][通常論文]
     
    Microbubbles in a medium function to concentrate the energy of the ultrasound to which it is exposed, and the focused energy has thermal, chemical and mechanical effects on surrounding biological tissue. Thermal effects: When a microbubble vibrates. it extracts energy from the ultrasound to which it is exposed. Part of this power is used for re-radiation of acoustic waves, but most of the extracted power is converted into heat due to adiabatic compression of encapsulated gas, viscosity of surrounding water and friction of the shell. Generated heat can cause an additional temperature rise in biological tissue. Chemical effects: The presence of microbubbles reduces the pressure threshold to produce inertial cavitation bubbles. Symmetrical contraction of an inertial cavitation bubble will result in very high temperature and pressure inside the bubble and generate highly reactive sonochemicals. Mechanical effects: Behavior of microbubbles exposed to ultrasound can cause mechanical stress to the surrounding tissue. Asymmetric contraction of an inertial cavitation bubble generates a microjet-like small stream that has a localized but unfavorable mechanical effect, such as membrane damage of a cell. (C) 2004 Elsevier B.V. All rights reserved.
  • AE Takada, N Kudo, N Endoh, H Hachiya, S Takeuchi, T Tuchiya, M Natori, K Yamaguchi STATE OF THE ART: ULTRASONICS IN MEDICINE 1274 (1274) 147 -150 2004年 [査読無し][通常論文]
     
    To confirm whether the microbubble activated by sonication causes liver damage. the authors performed two experiments. Experiment 1 followed Shigeta's experiment As an ultrasound contrast agent (UCA), Levovist was used and sonicated by Acuson Sequoia(TM) 512 by Siemens. Wister rats of 300 g were divided into four groups: (A) administration of ultrasonic contrast agent (UCA) and ultrasonic exposure, (B) administration of UCA, (C) ultrasonic exposure, and (D) control. Experiment 1 did not show the evidence of hepatic damage such as Shigeta et al. reported. Hence, we conducted Experiment 2 with a much higher acoustic output. But no clear damage was observed in both optical and electron microscopic specimens. (C) 2004 Elsevier B.V. All rights reserved.
  • N Kudo, G Yokoyama, M Ikebuchi, K Okada, K Kawahara, K Yamamoto 2004 IEEE Ultrasonics Symposium, Vols 1-3 1820 -1823 2004年 [査読無し][通常論文]
     
    It has been shown that diagnostic ultrasound examination using a contrast agent can cause premature ventricular contractions (PVCs). In this study, we investigated the usefulness of a new technique using cultured cardiac myocytes to study mechanisms of PVC production. Cardiac myocytes isolated from neonatal rats were cultured on a cover glass. Synchronized autonomous pulsation of myocytes started after incubation for one week. The cover glass was then attached to an observation chamber so that it was possible to observe changes in myocytes during exposure to ultrasound. In the experiments, cardiac myocytes were exposed to pulsed ultrasound with and without microbubbles. The peak negative pressure amplitudes were set at five steps (-0.28, -0.55, -0.73, -0.92 and -1.1 MPa), and threshold pressure to produce a PVC was recorded. The results showed that the presence of microbubbles attached to a cell reduces the threshold pressure for producing PVCs, and it was concluded that our method is useful for studying the mechanisms of PVC production.
  • N Kudo, K Yamamoto STATE OF THE ART: ULTRASONICS IN MEDICINE 1274 (1274) 49 -52 2004年 [査読無し][通常論文]
     
    It has recently been shown that the new generation of contrast agents has suitable pressure ranges and driving pulse sequences for optimal imaging. Differences in imagine conditions are due to differences in physical properties of microbubbles of the ultrasound contrast agents: mechanical properties of shell materials and diffusion of encapsulated gases. In this study, bubble behaviors of two types of contrast agents were observed using a high-speed camera and differences in mechanical properties of the shells and diffusion of the encapsulated gases were investigated. A microbubble was exposed to five ultrasound pulses with constant or increasing pressures with a pulse interval of 20 us, and the bubbles exposed to each pulse were photographed using a high-speed camera. Definity(R) and Levovist(R) were used in the experiments. In the case of Definity(R), amplitude of bubble oscillation increased with an increase in pulse pressure. In the case of Levovist(R), discontinuous expansion of the bubble was observed during exposure to five pulses with increasing pressure, and it is thought that the strong non-linear relationship between oscillation amplitude and ultrasound pressure in the case of Levovist(R) is caused by the presence of bubble shells, which cannot be treated with a simple elastic model. Furthermore, shrinkage of bubble fragments seas observed in the case of Levovist(R), and it is thought that diffusion of encapsulated gas is accelerated by exposure to pulsed ultrasound. (C) 2004 Elsevier B.V. All rights reserved.
  • 広川直樹, 小井戸一光, 市村健, 西田睦, 晴山雅人, 岡田太, 工藤信樹, 藤本克彦 超音波医学 30 (6) J809 -J809 2003年11月 [査読無し][通常論文]
  • 工藤 信樹, 山本 克之 超音波techno 15 (5) 61 -64 2003年09月 [査読無し][通常論文]
  • 工藤 信樹, 山本 克之 超音波techno 15 (5) 65 -68 2003年09月 [査読無し][通常論文]
  • 岡田 健吾, 工藤 信樹, 丹羽 光一, 和田 成生, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 103 (133) 49 -54 2003年06月13日 [査読無し][通常論文]
     
    Sonoporationとは,超音波を細胞に照射することで細胞膜の透過性を一時的に向上させることにより,細胞内への薬物の取り込みを促進する技術である.Sonoporationでは主として連続超音波が用いられるが,超音波造影剤の微小気泡を付加することでsonoporationの効果が促進されることが知られるようになってきている.さらにこの場合にはパルス超音波でもsonoporationが生じることが最近報告されたが,そのメカニズムや基本的性質は明らかになっていない.そこで本研究では微小気泡存在下の細胞に超音波パルスを照射し,気泡のふるまいや細胞との相互作用を高速度カメラと蛍光顕微鏡によって観察し,細胞への作用が発生するメカニズムについて検討した.その結果,超音波パルス照射時に,細胞近傍の微小気泡が膨張・収縮することにより細胞が機械的ストレスを受け,細胞膜に損傷が生じていることが確認された.また,超音波照射により細胞が受ける損傷を生存率で評価する実験を行い,気泡の存在に強く依存すること,音圧の増加とともに損傷を受ける細胞の割合が増加することを示した.
  • 平井 甲亮, 工藤 信樹, 山本 克之 生体医工学 : 日本エム・イー学会誌 41 (1) 63 -63 2003年03月10日
  • N Kudo, K Okada, K Yamamoto 2003 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1 AND 2 1507 -1510 2003年 [査読無し][通常論文]
     
    New methods for ultrasound contrast imaging that use amplitude-encoded ultrasound pulses have recently been developed. An understanding of various behaviors of bubbles exposed to ultrasound pulses with different pressures is important for using these methods. In order to study the dependence of bubble behavior on pressure, a high-speed observation system was improved to generate pulses that have various pressures at pulse intervals of several tens of microseconds. A microbubble was exposed to five ultrasound pulses with increasing pressures (normalized pressures of 1.0, 1.2, 1.4, 1.6 and 1.8 at pulse intervals of 20 mus). The total frame number of the high-speed camera is 24, and 5 frames were assigned to the first 4 pulses and 4 frames were assigned to the last pulse. The ultrasound contrast agents Definity and Levovist were used in the experiments, and the center frequency of ultrasound pulses was set at 1 MHz. It was found that the amplitude of bubble oscillation generally increased with increase in pulse pressure, though discontinuous increase in oscillation amplitude was frequently observed in the results obtained using Levovist. This strong nonlinear relationship between pressure of ultrasound pulse and amplitude of radial oscillation should be considered in amplitude-encoded contrast imaging methods.
  • 平井 甲亮, 前川 和也, 木幡 大輔, 工藤 信樹, 山本 克之 生体・生理工学シンポジウム論文集 17 341 -344 2002年09月09日 [査読無し][通常論文]
  • 荻原 誠, 工藤 信樹, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 102 (137) 13 -16 2002年06月14日 [査読無し][通常論文]
     
    超音波診断装置は無侵襲で安全な診断装置として広く臨床で使用されているが,近年の性能向上に伴い局所的な超音波強度が増大する傾向にあり,生体への熱的作用が再び関心を集めている.そこで本報告では,超音波照射による生体組織の温度上昇と血液の潅流量との関連をin vivoに近い条件で調べることを目的として,摘出したブタ肝臓を用いて温度上昇計測を行った結果について述べる.実験では,屠殺場より入手した新鮮なブタ肝臓の門脈から送液ポンプを用いて直接生理食塩水を灌流させる循環系を作成し,潅流量をパラメータとして超音波照射による温度上昇を超音波焦点およびその近傍にて測定した.この結果,潅流のない状態に比べ,潅流量0.30 l/min,0.68 l/minでは,それぞれ25%,55%,温度上昇の最大値が軽減された.このことから,生体組織の温度上昇の検討において組織潅流の影響を充分考慮する必要があることが確認された.
  • 工藤 信樹, 山本 克之 映像情報medical 34 (6) 572 -574 2002年05月 [査読無し][通常論文]
  • 中村 和明, 北間 正崇, 三澤 顕次, 有澤 準二, 邵 軍, 工藤 信樹, 山本 克之 北海道工業大学研究紀要 30 261 -266 2002年03月 [査読無し][通常論文]
  • N Kudo, T Miyaoka, K Okada, K Yamamoto, K Niwa 2002 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1 AND 2 1383 -1386 2002年 [査読無し][通常論文]
     
    To elucidate the mechanisms of cell damage caused by microbubbles exposed to ultrasound, two series of experiments were carried out. In one series of experiments, microbubbles and cells were exposed to 1-MHz pulsed ultrasound and observed using a high-speed camera. In another series of experiments, endothelial cells were exposed to ultrasound with and without microbubbles, and the viabilities of the cells were evaluated by fluorescent staining. In the high-speed images, generation of a small stream of the surrounding liquid caused by non-uniform contraction of a microbubble and deformation of a cell beside the bubble were observed. In the cell viability test, the percentage of damaged cells in the presence of microbubbles that had been exposed to ultrasound was significantly higher than that of cells without microbubbles that had been exposed to ultrasound. These results indicated that bubbles exposed to ultrasound causes mechanical stress to act on cells and that this mechanical stress may cause cell injury.
  • 工藤 信樹, 栗林 香織, 名取 道也, 森安 史典, 山本 克之 電子情報通信学会論文誌. A, 基礎・境界 84 (12) 1492 -1499 2001年12月01日 [査読無し][通常論文]
     
    超音波照射下での超音波造影剤の振舞いの解明を目的として, 高速度カメラを用いた観察システムを開発し, キャビテーション気泡と, 20〜100μmの含気気泡の振舞いを観察した.キャビテーション気泡では, 収縮時に気泡の崩壊と考えられる現象が観察され, 高温高圧状態が発生していることが示唆された.これに対し, 含気気泡では収縮時にもある程度の大きさが保たれており, 気泡の崩壊現象は起きていないと考えられたが, 気泡の分割が観察されており, これは気泡の非等方的な収縮により生じた微小な流れによるものと考えられた.
  • 中村 和明, 邵 軍, 工藤 信樹, 北間 正崇, 三澤 顕次, 有澤 準二, 山本 克之 電子情報通信学会論文誌. A, 基礎・境界 84 (12) 1525 -1532 2001年12月01日 [査読無し][通常論文]
     
    近年, 生体の光イメージングの空間分解能の向上を目指して, 超音波変調光を利用する方法が検討されている.本論文では, 光のスペックルパターンの変動に着目した超音波変調光の検出方法について基礎的検討を行った.まず, パルスレーザ光を散乱体に入射させ, 連続集束超音波を用いて局所的に光を変調し, スペックルパターンの変動をCCDカメラで検出した.パスル光を超音波の位相と同期させることにより, 変調成分を一般的なCCDカメラで検出可能とした.更に, 超音波のパルス化により空間分解能を向上させる手法についても検討し, 提案手法により, 連続及びパルス超音波を用いて散乱光から超音波変調成分を効率的に検出できることを確認した.
  • 中村 和朗, 邵 軍, 工藤 信樹, 北間 正崇, 三澤 顕次, 有澤 準二, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 101 (478) 87 -92 2001年11月22日 [査読無し][通常論文]
     
    近年, 生体の光イメージングの空間分解能向上を目指して, 超音波変調光を利用する方法が検討されている.本報告では, 光のスペックルパターンの変動に着目して超音波によって変調された光を高感度で検出する方法について基礎的検討を行った.まず, パルスレーザ光を散乱体に入射させ, 集束したパルス超音波を用いて局所的に光を変調し, スペックルパターンの変動をCCDカメラで検出した.パルス光を超音波の位相と同期させることにより, 一般的なCCDカメラを用いて超音波で変調された成分のみを検出することを可能とした.さらに, 超音波のパルス化による空間分解能の評価を行うため, 透過および後方散乱光を用いた場合において散乱体中の吸収物質の1次元イメージングを行い, 本手法の有効性を確認した.
  • 平井 甲亮, 庭山 雅嗣, 木幡 大輔, 前川 和也, 工藤 信樹, 浜岡 隆文, 勝村 俊仁, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 101 (130) 1 -8 2001年06月15日 [査読無し][通常論文]
     
    近年, 近赤外分光法による組織酸素計測を多チャネル化し, 酸素濃度変化の空間分布を観測しようとする研究がなされている. 我々はこれまでに, 200チャネルの受光系を有する筋組織酸素濃度イメージングシステムを開発してきた. しかし, 本システムでは, 画像表示がデータ取得後のオフライン処理であり, 臨床での実用性を考慮すると, リアルタイムイメージングが必須となる. そこで本研究では, リアルタイムに酸素化及び脱酸素化ヘモグロビン濃度, 血液量変化の3測定量をイメージング可能なシステムを開発した. 実測として運動負荷試験時の大腿部のイメージングを行った結果, 筋の使い分け, 及び筋の収縮, 弛緩に伴う血液量の速い変化を観測可能であった. また活動部位での脱酸素化も観測可能であり臨床への適応性を向上させることができた.
  • 宮岡 武洋, 古谷 淳二, 工藤 信樹, 丹羽 光一, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 101 (130) 83 -89 2001年06月15日 [査読無し][通常論文]
     
    近年, 超音波照射を受けた超音波造影剤の微小気泡が細胞膜に作用を与えることが報告されている. そこで本研究では, そのメカニズムに関する検討を目的として, 新しい高速度カメラと倒立型顕微鏡を用いて高速・高倍率観察システムを改良し, 250kHzおよび1MHzの超音波照射下における直径約3μmから数十μmの微小気泡のふるまいを連続24コマ, 最大800万コマ毎秒で撮影した. その結果, 気泡の収縮に伴う気泡の分割や, 気泡の非等方的な収縮による微小な流れの発生が観察された. また, これらの気泡のふるまいが細胞に与える機械的な作用について検討するため, ウシ血管内皮細胞周辺に微小気泡が存在する条件で観察を行った. その結果, 微小気泡の非等方的な収縮により細胞が変形する様子が観察され, 気泡の非等方的収縮に伴って発生する微小な流れが細胞に機械的な作用を与える可能性があることが示唆された.
  • 工藤 信樹, 宮岡 武洋, 萩原 誠, 名取 道也, 山本 克之 Journal of medical ultrasonics = 超音波医学 28 (3) J363 2001年04月15日 [査読無し][通常論文]
  • 宮岡 武洋, 古谷 淳二, 工藤 信樹, 名取 道也, 山本 克之 Journal of medical ultrasonics = 超音波医学 28 (3) J411 2001年04月15日 [査読無し][通常論文]
  • 中村 和明, 北間 正崇, 三澤 顕次, 有澤 準二, 柴山 佳一郎, 邵 軍, 工藤 信樹, 山本 克之 北海道工業大学研究紀要 29 217 -223 2001年03月26日 [査読無し][通常論文]
  • K Yamamoto, M Niwayama, D Kohata, N Kudo, T Hamaoka, R Kime, T Katsumura OPTICAL TOMOGRAPHY AND SPECTROSCOPY OF TISSUE IV 4250 (4250) 142 -152 2001年 [査読無し][通常論文]
     
    Functional imaging of muscle oxy enation using NIRS is a promising technique for evaluation of the heterogeneity of muscle function and diagnosis of peripheral vascular disease or muscle injury. We have developed a 200-channel imaging system that can measure the changes in oxygenation and blood volume of muscles and that covers a wider area than do previously reported systems. Our system consists of 40 probes, a multiplexer for switching signals to and from the probes, and a personal computer for obtaining images. In each probe, one two-wavelength light-emitting diode (770 and 830 mn) and five photodiodes were mounted on a flexible substrate. In order to eliminate the influence of a subcutaneous fat layer, a correction method, which we previously developed, was also used in imaging. Thus, quantitative changes in concentrations of oxy- and deoxy-hemoglobin were obtained. Temporal resolution was 1.5 s and spatial resolution was about 20 mm, depending on probe separations. Exercise tests (isometric contraction of 50% MVC) on the thigh with and without arterial occlusion were conducted. and changes in muscle oxygenation were imaged using our system. Results showed that the heterogeneity of deoxygenation and reoxygenation during exercise and recovery periods, respectively, were clearly observed. These results suggest that optical imaging of dynamic change in muscle oxygenation using MRS would be useful not only for basic physiological studies but also for clinical applications with respect to muscle functions.
  • 工藤 信樹, 有田 直樹, 山本 克之 超音波エレクトロニクスの基礎と応用に関するシンポジウム講演予稿集 (21) 347 -348 2000年11月06日 [査読無し][通常論文]
  • 山本 克之, 庭山 雅嗣, 工藤 信樹 電子情報通信学会技術研究報告. MI, 医用画像 100 (287) 19 -23 2000年09月07日 [査読無し][通常論文]
     
    超音波や光を用いた新しい生体機能イメージングの試みについて, いくつか紹介する.高分解能イメージングを目的とした穿刺型マイクロプローブによる組織と血流のイメージングは, 侵襲的ではあるが穿刺生検時や術中の検査法として有望である.超音波造影剤マイクロバブルの振動・崩壊過程の高速イメージングは, 超音波照射時の気泡崩壊のメカニズムを解明し, 超音波造影剤の高性能化と安全性を確立するために必須の基礎資料となろう.近赤外光による筋組織酸素濃度のイメージングは, リハビリテーションにおける筋力回復診断, スポーツ医学・運動生理学などへの活用が期待できる.
  • 木幡 大輔, 庭山 雅嗣, 邵 軍, 工藤 信樹, 浜岡 隆文, 勝村 俊仁, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 100 (163) 33 -38 2000年06月23日 [査読無し][通常論文]
     
    近年, 近赤外分光法による組織酸素計測を多チャネル化し, 酸素濃度変化の空間分布を観測しようとする研究がなされている.しかし, 従来のシステムでは, プローブの面積や構造により測定領域が制限され, 複数の筋組織を同時に観測することは困難であり, 定量性の面でも問題があった.そこで本研究では200チャネルの受光系を有する筋組織酸素濃度システムを試作し, 筋収縮に伴う体表の形状変化にも対応できるようプローブを40個に分割するとともに, 脂肪層の影響補正法を組み込むことで定量計測も可能とした.本システムを用いた大腿部全体の酸素濃度分布を画像化し, 2種の運動負荷試験を行った結果, 各筋における酸素濃度及び血液量変化の差異を明確に観測することができた.
  • 前川 和也, 庭山 雅嗣, 邵 軍, 工藤 信樹, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 100 (163) 39 -44 2000年06月23日 [査読無し][通常論文]
     
    空間分解近赤外分光法(SRS)は, 後方散乱光強度の空間分布から媒質の光学定数の絶対値を算出する手法であり, 連続光を用いて実時間的かつ定量的に組織酸素濃度を計測する上で有用である.しかし, 従来の計測法は均質な媒質を仮定しており, 不均質構造を有する実際の生体組織においては大きな誤差が生じると考えられる.そこで本研究ではSRSを用いた筋組織酸素濃度計測における介在組織の影響を4層モデルモンテカルロシミュレーションにより検討し, その影響の補正法を考案した.さらに, 本手法を用いて実測を行った結果, 従来の均質モデルでの結果と大きな差異が認められSRS筋組織酸素計測における介在組織の影響補正の重要性が示された.
  • 工藤 信樹, 栗林 香織, 名取 道也, 森安 史典, 山本 克之 Journal of medical ultrasonics = 超音波医学 27 (4) 416 -416 2000年04月15日 [査読無し][通常論文]
  • 工藤 信樹, 栗林 香織, 山本 克之, 名取 道也, 森安 史典 Journal of medical ultrasonics = 超音波医学 27 (4) 517 -517 2000年04月15日 [査読無し][通常論文]
  • 山本 克之, 庭山 雅嗣, 工藤 信樹, 川初 清典 計測と制御 = Journal of the Society of Instrument and Control Engineers 39 (4) 283 -286 2000年04月10日 [査読無し][通常論文]
  • 工藤 信樹, 栗林 香織, 山本 克之, 名取 道也, 森安 史典 日本音響学会研究発表会講演論文集 2000 (1) 1057 -1058 2000年03月01日 [査読無し][通常論文]
  • M Niwayama, D Kohata, J Shao, N Kudo, T Hamaoka, T Katsumura, K Yamamoto OPTICAL SENSING, IMAGING, AND MANIPULATION FOR BIOLOGICAL AND BIOMEDICAL APPLICATIONS 4082 (4082) 48 -56 2000年 [査読無し][通常論文]
     
    Near-infrared spectroscopy (NIRS) is a very useful technique for noninvasive measurement of tissue oxygenation. Among various methods of NIRS, continuous wave near-infrared spectroscopy (CW-NIRS) is especially suitable for real-time measurement and for practical use. CW-NIRS has recently been applied to in vivo reflectance imaging of muscle oxygenation and brain activity. However, conventional mapping systems do not have a sufficient mapping area at present. Moreover, they do not enable quantitative measurement of tissue oxygenation because conventional MRS is based on the inappropriate assumption that tissue is homogeneous. In this study we developed a 200-channel mapping system that enables measurement of changes in oxygenation and blood volume and that covers a wider area (30 cm x 20 cm) than do conventional systems. The spatial resolution (source-detector separation) of this system is 15 mm. As for the effects of tissue inhomogeneity on muscle oxygenation measurement, subcutaneous adipose tissue greatly reduces measurement sensitivity. Therefore, we also used a correction method for the influence of the subcutaneous fat layer so that we could obtain quantitative changes in concentrations of oxy- and deoxy-hemoglobin. We conducted exercise tests and measured the changes in hemoglobin concentration in the thigh using the new system. The working muscles in the exercises could be imaged, and the heterogeneity of the muscles was shown. These results demonstrated the new 200-channel mapping system enables observation of the distribution of muscle metabolism and localization of muscle function.
  • M Niwayama, T Hamaoka, L Lin, J Shao, N Kudo, C Katoh, K Yamamoto BIOMEDICAL DIAGNOSTIC, GUIDANCE, AND SURGICAL-ASSIST SYSTEMS II 3911 (3911) 256 -265 2000年 [査読無し][通常論文]
     
    The inhomogeneity of tissue structure greatly affects the sensitivity of tissue oxygenation measurement by near-infrared spectroscopy (NIRS). We have proposed a method for correcting the influence of a subcutaneous fat layer on muscle oxygenation measurements. In this study, we validated our correction method by measuring oxygen consumption rates of the forearm muscle (Vo(2)mus) and comparing the measurements with those obtained by other techniques: P-31-magnetic resonance spectroscopy (P-31-NMR) and positron emission tomography (PET). In NIRS, Vo2mus was obtained from the falling rate of oxygenation in ischemia tests. The values of Vo(2)mus were corrected using a curve of measurement sensitivity against fat layer thicknesses, which were measured by ultrasonography. The corrected Vo(2)mus showed greater values and less variation between individuals (0.21 +/-0.03 ml 100g(-1) min(-1)) than did the uncorrected one (0.17+/-0.04 ml 1000g(-1) min(-1)). In the P-31-NMR measurements on 10 subjects, Vo(2)mus was estimated from changes in phosphocreatine (PCr). The corrected Vo(2)mus in NIRS correlated well with the measurements by P-31-NMR (r = 0.61), compared to the uncorrected Vo(2)mus (r=-0.26). This result suggested that our correction method is valid. Vo2mus was also measured using PET in one of the authors. The measured values by NIRS (with correction), P-31-NMMR, and PET were 0.22, 0.17, 0.24 ml 100g(-1) min(-1) respectively. The measurement by NIRS using our correction method was in an acceptable range.
  • J Shao, L Lin, M Niwayama, N Kudo, K Yamamoto Proceedings of SPIE 4082 (4082) 76 -86 2000年 [査読無し][通常論文]
     
    Near-infrared spectroscopy (NIRS) is a useful technique for noninvasive measurement of oxygenation of the brain and muscle. However, no accurate, quantitative algorithms for continuous wave NIRS (CW-NIRS) have yet been presented dute to the following two problems. The first is that inhomogeneous tissue structure greatly affects measurement sensitivity. We previously reported on the influence of a fat layer on muscle oxygenation measurement and proposed a method for correcting the sensitivity. The second problem is that almost all algorithms for CW-NIRS have been experimentally determined, although an algorithm can be theoretically determined on the basis of diffusion theory if the mean optical pathlength in muscle in an in vivo state is known. In this study, we derived basic equations for a CW-NIRS algorithm based on diffusion theory, and we determined linear and nonlinear algorithms from mean optical pathlengths and validated them by results obtained from phantom experiments. For the determination of pathlength, the absorption and scattering coefficients of the muscle must be obtained by taking into account the influence of a fat layer. Laser pulses of 752 and 871 nm were applied to the forearms of subjects, and the temporal point spread function (TPSF) was obtained by using a streak camera. The absorption and scattering coefficients of the muscle were determined by fitting the measured TPSF with that obtained by a Monte Carlo model consisting of skin, fat and muscle layers. From these coefficients, the mean optical pathlengths at two wavelengths were obtained and the algorithms were determined.
  • 池田 剛史, 工藤 信樹, 山本 克之 電気学会研究会資料. MBE, 医用・生体工学研究会 1999 (21) 31 -35 1999年06月26日 [査読無し][通常論文]
  • 工藤 信樹, 柴山 佳一郎, 邵 軍, 山本 克之 電気学会研究会資料. MBE, 医用・生体工学研究会 1999 (21) 37 -42 1999年06月26日 [査読無し][通常論文]
  • 邵 軍, 林 凌, 庭山 雅嗣, 工藤 信樹, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 99 (138) 15 -22 1999年06月24日 
    近赤外光を用いた組織酸素計測法は組織酸素濃度を無侵襲的に連続計測できるため,様々な領域において多くの研究がなされている.しかし,連続定常光を用いた酸素濃度の基本算出式に関しては,まだ明確な決定法がなく,測定値が算出アルゴリズムにより大きく異なることが指摘されている.我々は光拡散方程式を用いた酸素濃度算出式を導出し,その妥当性をファントム実験で確認した.吸収係数の変化があまり大きくなければ,導出した理論式により実測した吸光度変化から酸素濃度を正確に算出できることが明らかになった.
  • 李 桓成, 工藤 信樹, 下岡 聡行, 三田村 好矩, 勇田 敏夫, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 99 (138) 7 -13 1999年06月24日 
    動物やヒトに埋植された人工弁の破損の原因としてキャビテーションが注目され,研究が進められてきている.従来,キャビテーション発生の閾値を与える指標としてはdp/dtや弁の平均閉鎖速度が用いられてきたが,我々は以前の実験結果から,これらの指標よりも閉鎖直前のディスクの速度が表面壊食に大きな影響を与えることを示してきた.本研究では閉鎖直前のディスクの速度とディスク表面の壊食の関係について検討した.その結果,キャビテーション発生にはディスクの閉鎖速度に関する閾値が存在することが示され,本研究で用いた人工弁では約0.4m/sであった.
  • 池田 剛史, 工藤 信樹, 山本 克之 Journal of medical ultrasonics = 超音波医学 26 (4) 693 -693 1999年04月15日 [査読無し][通常論文]
  • 栗林 香織, 工藤 信樹, 名取 道也, 山本 克之 Journal of medical ultrasonics = 超音波医学 26 (4) 695 -695 1999年04月15日 [査読無し][通常論文]
  • M Niwayama, L Lin, J Shao, T Shiga, N Kudo, K Yamamoto OPTICAL TOMOGRAPHY AND SPECTROSCOPY OF TISSUE III, PROCEEDINGS OF 3597 (3597) 291 -299 1999年 [査読無し][通常論文]
     
    The inhomogeneity of tissue structure greatly affects the sensitivity of tissue oxygenation measurement by reflectance NIRS. We have examined the influence of a subcutaneous fat layer on muscle oxygenation measurements. In this study, the influences of a fat layer and skin on muscle oxygenation measurement were investigated using Monte Carlo simulation and in vivo tests. Based on the experimental results, a correction curve for measurement sensitivity was determined. In the simulation, a 3-D model consisting of the epidermis, dermis, fat and muscle layers was used. In in vivo tests, measurement sensitivity was examined by measuring the falling rate of oxygenation in ischemia tests on the forearm using a newly developed multisensor type of oximeter with source-detector distances of 3-40 mm. Fat layer thickness was also measured by ultrasonography. The correction curve of measurement sensitivity against fat layer thickness was obtained from the results of simulation and in vivo tests. The measurements of oxygen consumption, calculated from the falling rates of oxygenation without correction, varied widely due to different thicknesses of fat layers. In contrast, the measurements of oxygen consumption with correction were almost the same (0.21 +/- 0.03 ml 100g(-1) min(-1)). In this correction, the effect of skin on change in optical density was also taken into account using a detector with a short separation.
  • K Kuribayashi, N Kudo, M Natori, K Yamamoto 1999 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1 AND 2 1755 -1758 1999年 [査読無し][通常論文]
     
    Clinical applications of ultrasound contrast agent (UCA) have been widely studied in recent years, but the behavior of microbubbles exposed to ultrasound is not fully understood yet. We developed a high-magnification and high-speed observation system, and we studied the dynamic behavior of cavitation bubbles, air-contained microbubbles, and UCA under ultrasound exposure. The dynamic behavior of cavitation was observed at the frame rate of 2 x 10(6) frames/s with magnification of x 15, and periodic expansion and shrinkage due to exposure to ultrasound were observed. The maximum diameter of a bubble was around 10 mu m in the expansion phase, and it was too small to observe in the compression phase. Air-contained microbubbles of 20-100 mu m in diameter and UCA of 3-5 mu m in diameter were also observed at the maximum imaging rate of 1 x 10(7) frames/s and maximum magnification of x 100. Typically, microbubbles exposed to ultrasound pressure undergo repeated expansion and shrinkage and reach a critical size, then collapse.
  • K Nakajima, N Kudo, K Yamamoto, T Mikami, A Kitabatake 1999 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1 AND 2 1381 -1384 1999年 [査読無し][通常論文]
     
    We have been measuring ultrasound attenuation of biological tissues in the frequency range of 2.5-40 MHz using a multi-resonance transducer [1, 2]. In this study, we used two additional wide-band transducers of 5 and 10 MHz, and we measured liquid-type samples to improve the accuracy of the measurement, especially at frequencies below 10 MHz. Homogenized swine liver tissue was centrifuged to separate it into two samples: a supernatant liquid sample containing water-soluble proteins of liver cells and a sediment sample containing the constituents of the tissue structure. Specific attenuations of both samples were almost the same at frequencies around 10 MHz. However, the exponent values of the two samples were clearly different; the exponent value of the supernatant liquid sample was 1.3 in the entire frequency range of 2-40 MHz, while the exponent value of the sediment sample was 0.7. This result suggests that there is a turning point of the exponent value of the whole liver tissue at about 10 MHz.
  • 吉田 誠, 工藤 信樹, 山本 克之, 三神 大世, 北畠 顕 電気学会研究会資料. MBE, 医用・生体工学研究会 1998 (5) 75 -80 1998年06月19日 [査読無し][通常論文]
     
    我々は, 生体組織の線維構造が超音波減衰に与える影響について検討するため10〜40MHz帯の超音波を発生する振動子を用いて, ウシ骨格筋の超音波減衰特性を測定した.試料には, ホモナイズした試料と切片試料を用いた.ホモジナイズした試料は, 粉砕した骨格筋組織に生理食塩水を加えた上澄み液を用いた.切片試料は, 線維構造に対し平行および, 垂直に切り出した.その結果上澄み液試料の減衰係数は周波数の1.5乗に比例して増加し, 切片試料では, 超音波の入射方向と線維の向きが垂直の場合には1.9乗に, 平行の場合には1.2乗に比例した.10MHz以下の帯域で線維性組織の超音波減衰が線維方向に依存することは良く知られている.我々の結果によれば, 線維方向による減衰の変化は, この累乗値の違いに起因するもとの考えられた.
  • 庭山 雅嗣, 志賀 利一, 林 凌, 工藤 信樹, 高橋 誠, 山本 克之 電気学会研究会資料. MBE, 医用・生体工学研究会 1998 (5) 81 -88 1998年06月19日 [査読無し][通常論文]
     
    近赤外光を用いた組織酸素モニタは, 生体組織が不均質な構造であることにより, 測定感度が大きく変化する問題がある.我々はこれまでに, 筋組織酸素計測における脂肪層の影響を検証し, その影響を受光量を用いて補正する手法を提案してきた.本研究では, 脂肪層の影響補正法の有効性を確認するとともに, 補正精度の向上を目的とし, 送光器に近接した受光器を付加した組織酸素モニタを試作し, 皮膚の影響を検討した.運動負荷試験における大腿部外側広筋の酸素濃度変化の測定感度を補正した結果, 脂肪厚の増加で測定感度が減少する傾向を除去することができた.また, 送光器に近接した受光器により, 皮膚の影響を除去することで, 補正精度が向上することが示された.
  • 吉田 誠, 工藤 信樹, 山本 克之, 三神 大世, 北畠 顕 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 98 (135) 75 -80 1998年06月19日 [査読無し][通常論文]
     
    我々は, 生体組織の線維構造が超音波減衰に与える影響について検討するため10〜40MHz帯の超音波を発生する振動子を用いて, ウシ骨格筋の超音波減衰特性を測定した.試料には, ホモナイズした試料と切片試料を用いた.ホモジナイズした試料は, 粉砕した骨格筋組織に生理食塩水を加えた上澄み液を用いた.切片試料は, 線維構造に対し平行および, 垂直に切り出した.その結果上澄み液試料の減衰係数は周波数の1.5乗に比例して増加し, 切片試料では, 超音波の入射方向と線維の向きが垂直の場合には1.9乗に, 平行の場合には1.2乗に比例した.10MHz以下の帯域で線維性組織の超音波減衰が線維方向に依存することは良く知られている.我々の結果によれば, 線維方向による減衰の変化は, この累乗値の違いに起因するもとの考えられた.
  • 庭山 雅嗣, 志賀 利一, 林 凌, 工藤 信樹, 高橋 誠, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 98 (135) 81 -88 1998年06月19日 [査読無し][通常論文]
     
    近赤外光を用いた組織酸素モニタは, 生体組織が不均質な構造であることにより, 測定感度が大きく変化する問題がある.我々はこれまでに, 筋組織酸素計測における脂肪層の影響を検証し, その影響を受光量を用いて補正する手法を提案してきた.本研究では, 脂肪層の影響補正法の有効性を確認するとともに, 補正精度の向上を目的とし, 送光器に近接した受光器を付加した組織酸素モニタを試作し, 皮膚の影響を検討した.運動負荷試験における大腿部外側広筋の酸素濃度変化の測定感度を補正した結果, 脂肪厚の増加で測定感度が減少する傾向を除去することができた.また, 送光器に近接した受光器により, 皮膚の影響を除去することで, 補正精度が向上することが示された.
  • 工藤 信樹, 吉田 誠, 山本 克之, 三神 大世, 北畠 顕, 伊藤 由喜男, 神田 浩 Journal of medical ultrasonics = 超音波医学 25 (4) 495 -495 1998年04月15日 [査読無し][通常論文]
  • 工藤 信樹, 張 旭, 山本 克之 Journal of medical ultrasonics = 超音波医学 25 (3) 1 -12 1998年03月15日 [査読無し][通常論文]
  • 張 旭, 工藤 信樹, 山本 克之 Journal of medical ultrasonics = 超音波医学 25 (3) 13 -24 1998年03月15日 [査読無し][通常論文]
  • 庭山 雅嗣, 志賀 利一, 林 凌, 工藤 信樹, 高橋 誠, 山本 克之 医用電子と生体工学 : 日本ME学会雑誌 = Japanese journal of medical electronics and biological engineering : JJME 36 (1) 41 -48 1998年03月10日 [査読無し][通常論文]
  • K Yamamoto, M Niwayama, L Lin, T Shiga, N Kudo, M Takahashi INFRARED SPECTROSCOPY: NEW TOOL IN MEDICINE, PROCEEDINGS OF 3257 (3257) 146 -155 1998年 [査読無し][通常論文]
     
    The inhomogeneity of tissue structure greatly affects the sensitivity of tissue oxygenation measurement by reflectance NIRS. We have proposed a method for correcting the influence of a subcutaneous fat layer an muscle oxygenation measurement. In this study, this method was validated by measuring the peak-to-peak variation of muscle oxygenation in periodic exercise tests an the vastus lateralis and the ailing rate of oxygenation in ischemia tests on the forearm. A newly developed multisensor probe with source-detector distances of 7-40 mm was used. The probe, consisting of a two-wavelength LED and four photodiodes, was connected to a 4-channel tissue oxygen monitor. The fat layer thickness was also measured by ultrasonography. Results of the tests clearly showed that the presence of a fat layer greatly decreases the sensitivity of measurement and increases the light intensity at a detector. The correction factors of sensitivity were determined from this relationship and Monte Carlo simulation. The corrected oxygenation levels were quantitatively compared among subjects in spite of different fat layer thicknesses.
  • K Yamamoto, M Niwayama, L Lin, T Shiga, N Kudo, M Takahashi PHOTON PROPAGATION IN TISSUES III, PROCEEDINGS OF 3194 (3194) 166 -173 1998年 [査読無し][通常論文]
     
    Although the inhomogeneity of tissue structure affects the sensitivity of tissue oxygenation measurement by reflectance near-infrared spectroscopy (NIRS), few analyses of this effect have been reported. In this study, the influence of a subcutaneous fat layer on muscle oxygenation measurement was investigated by Monte Carlo simulation and experimental studies. In the experiments, measurement sensitivity was examined by measuring the falling rate of oxygenation in occlusion tests on the forearm using a tissue oxygen monitor. The fat layer thickness was measured by ultrasonography. Results of the simulation and occlusion tests clearly showed that the presence of a fat layer greatly decreases the measurement sensitivity and increases the light intensity at the detector. The correction factors of sensitivity were obtained from this relationship and were successfully validated by experiments on 12 subjects whose fat layer thickness ranged from 3.5 to 8 mm.
  • L Lin, M Niwayama, T Shiga, N Kudo, M Takahashi, K Yamamoto INFRARED SPECTROSCOPY: NEW TOOL IN MEDICINE, PROCEEDINGS OF 3257 (3257) 156 -166 1998年 [査読無し][通常論文]
     
    Two-layered phantom experiments were performed to examine the influence of a Eat layer on measurement of muscle oxygenation using near-infrared spectroscopy (NIRS). Tire phantom consisted of a fat-like layer and a muscle-like layer which were a mixture of agar and TiO2 powder and a suspension of washed bovine blood into 0.55% Intralipid solution. An LED including 760 and 840 nm elements was used as the optical source,( )and the reflectance light was detected by photodiodes at source-detector distances of 20, 30 and 40 mm, Curves of optical density changes versus blood volume ratio were obtained with fat-like layer thickness of 0, 5, 10, and 15 mm. It was found that the change in optical density is significantly decreased and that the linearity of measurement characteristics clearly deteriorated by the presence of a fat layer. This strongly suggests that a new algorithm is needed for muscle oxygenation measurement to eliminate the influence of a fat layer. In addition to the phantom experiments, Monte Carlo simulations corresponding to the experiments were performed. Although the simulations showed similar results concerning the influence of a fat layer, it was noted that the changes in optical density obtained from simulations were lower than those of the phantom experiments. This discrepancy was thought to be due to the light scattering caused by blood cells.
  • M Natori, T Tsuchiya, S Umemura, T Shiina, Y Takeuchi, N Kudo 1998 IEEE ULTRASONICS SYMPOSIUM - PROCEEDINGS, VOLS 1 AND 2 1435 -1438 1998年 [査読無し][通常論文]
     
    Echo enhancers are consisted of microballoons and we aimed to investigate the thresholds of microballoon collapse of two different shell types. PVC-AN microballoon is a mimicking echo enhancer with a hard shell and Albunex(R) that is a commercially available albumin shelled echo enhancer. The thresholds of the microballoon collapse were analyzed by detecting subharmonic wave production. Scattered waveforms by PVC-AN that was diluted to 1/1000 with normal saline. The scattered waves from the microballoon were detected by the hydrophone and analyzed by the digital oscilloscope with 10 bit A/D conversion rate. The spectrum was calculated with Fast Fourier Transform applied to the leading 5 microseconds of the waveform. We concluded that the threshold of PVC-AN collapse exists between 1.5 to 2.25 W/cm(2) of ultrasound intensity. We however, could not determine the threshold of Albunex(R) that was diluted to 1/100 with normal saline, since subharmonics were recognized even by 0.1 W/cm(2) irradiation which was the lowest intensity in our system.
  • Ultrasound attenuation measurement of tissue in frequency range 2.5-40 MHz using a multi-resonance transducer
    1998 IEEE UFFC Ultrasound Symposium Proc. 1479 -1482 1998年 [査読無し][通常論文]
  • 工藤 信樹, 山本 克之, 小野塚 久夫, 三神 大世, 北畠 顕 Journal of medical ultrasonics = 超音波医学 24 (9) 148 -148 1997年09月15日 [査読無し][通常論文]
  • 工藤 信樹, 兼成 哲也, 張 旭, 山本 克之 Journal of medical ultrasonics = 超音波医学 24 (9) 291 -291 1997年09月15日 [査読無し][通常論文]
  • 工藤 信樹, 吉田 誠, 山本 克之, 三神 大世, 北畠 顕, 伊藤 由喜男, 神田 浩 Journal of medical ultrasonics = 超音波医学 24 (9) 425 -425 1997年09月15日 [査読無し][通常論文]
  • 八久保 敬弘, 工藤 信樹, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 97 (124) 1 -8 1997年06月20日 
    超音波診断装置は無侵襲で体内の断層像を得ることができることから, 臨床において重要な位置を占めている. しかし, 一般の装置では超音波の周波数が3〜5MHz程度で, 体内での超音波パルス長が1〜1.5 mm程度であるため, 空間分解能がCTやMRIに比べて劣る. 周波数を高くすることで空間分解能を高くできるが, 生体組織での減衰が大きくなるために観察範囲が表層に限定される. 本研究では, 高い空間分解能と深部組織の画像化を実現できる, 深部組織に穿刺する針型のマイクロプローブを用いた新しい手法を提案する. 我々はこのマイクロプローブとリニアスキャンのBモード画像を取得するシステムを試作し, 本手法の有用性について検討した. 試作したプローブは0.8×1.2×0.3mmの大きさの振動子を持ち, 18ゲージの留置針に挿入可能である. その基本性能は, 超音波の中心周波数23MHz, 距離分解能0.15 mm, 方位分解能0.9 mmである. in vitro実験においてブタ肝臓の鮮明なBモード画像を得ることができた.
  • 兼成 哲也, 工藤 信樹, 張 旭, 高橋 誠, 山本 克之 電気学会研究会資料. MBE, 医用・生体工学研究会 1997 (16) 9 -16 1997年06月20日 [査読無し][通常論文]
     
    近年, 血管内超音波エコー法(IVUS)は臨床において重要な検査法になりつつある. IVUSを用いて血管内腔を描出することは血管狭窄の定量的評価を行う上で重要ではあるが, 血液のと粥腫の音響インピーダンスの差が小さいことから, 両者を見分けることが困難なことも多い. そこで, 本研究では血流や粥腫の動きを検出することにより血管内腔を明瞭に描出する新しいIVUSを提案する. IVUSにでは超音波の伝搬方向と血流方向が直交するために, ドプラ法では血流を検出できない. それゆえ, 本研究では血流を検出する方法として相関法を用いた. 本手法を実現するシステムを試作し, 血管ファントムを用いて評価を行った. その結果, 本手法を用いることにより従来のMモード像やBモード像では見分けることが困難であった血流と粥腫を明瞭に分離することができた.
  • 兼成 哲也, 工藤 信樹, 張 旭, 高橋 誠, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 97 (124) 9 -16 1997年06月20日 [査読無し][通常論文]
     
    近年, 血管内超音波エコー法(IVUS)は臨床において重要な検査法になりつつある. IVUSを用いて血管内腔を描出することは血管狭窄の定量的評価を行う上で重要ではあるが, 血液のと粥腫の音響インピーダンスの差が小さいことから, 両者を見分けることが困難なことも多い. そこで, 本研究では血流や粥腫の動きを検出することにより血管内腔を明瞭に描出する新しいIVUSを提案する. IVUSにでは超音波の伝搬方向と血流方向が直交するために, ドプラ法では血流を検出できない. それゆえ, 本研究では血流を検出する方法として相関法を用いた. 本手法を実現するシステムを試作し, 血管ファントムを用いて評価を行った. その結果, 本手法を用いることにより従来のMモード像やBモード像では見分けることが困難であった血流と粥腫を明瞭に分離することができた.
  • 工藤 信樹, 鎌滝 崇央, 山本 克之, 小野塚 久夫, 三神 大世, 北畠 顕, 伊藤 由喜男, 神田 浩 Journal of medical ultrasonics = 超音波医学 24 (3) 567 -567 1997年03月15日 [査読無し][通常論文]
  • N Kudo, T Kamataki, K Yamamoto, H Onozuka, T Mikami, A Kitabatake, Y Ito, H Kanda 1997 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1 & 2 1181 -1184 1997年 [査読無し][通常論文]
     
    We developed a measurement system of ultrasound attenuation in the frequency range of 2.5 to 40 MHz and measured the ultrasound attenuation coefficients of normal, infarcted, and dilated cardiomyopathy samples of a human formalized myocardium. Results of attenuation measurements showed that the attenuation coefficients increased proportionally to the n-th power of frequency in the measured frequency range. Attenuation coefficients in the myocardium specimens increased proportionally to the 1.3 power for the infarction and 1.2 power for the dilated cardiomyopathy of frequency, respectively, while the attenuation coefficient increased proportionally to the 1.6 power for the normal myocardium. These results suggest that an exponent of frequency-dependent attenuation could be used as an index of tissue characterization.
  • 山本 克之, 工藤 信樹 精密工学会誌 62 (11) 1541 -1544 1996年11月05日 [査読無し][通常論文]
  • 鎌滝 崇央, 工藤 信樹, 高橋 誠, 山本 克之, 小野塚 久夫, 三神 大世, 北畠 顕 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 96 (114) 65 -70 1996年06月21日 
    従来報告の少ない,5-40MHzの周波数帯での超音波減衰率を測定するシステムを試作し,システムの基本特性の確認を行った.また, ヒト心筋の正常部位と梗塞部位における減衰率の周波数依存性を計測した.基礎実験ではシステムの測定精度を確認すると共に,ホルマリン固定によるブタ心筋の減衰率の周波数依存性が経時的に変化することを確認した.ヒト心筋に関する測定では,従来報告されているように,梗塞部位の減衰率が正常部位より大きいことを確認した.さらに,減衰率の周波数依存性に差異があり周波数の増加に伴い,正常部位の減衰が急速に増加することより,高い周波数領域で両者の減衰量が逆転することが予想された.
  • 庭山 雅嗣, 志賀 利一, 林 凌, 工藤 信樹, 高橋 誠, 山本 克之 電子情報通信学会技術研究報告. MBE, MEとバイオサイバネティックス 96 (114) 51 -56 1996年06月21日 [査読無し][通常論文]
     
    近赤外光を用いた組織酸素モニタは,脳活動や筋組織代謝の時間変化を知る上で極めて有用な装置として普及しつつある.しかし,測定部位の解剖学的不均一構造が測定値にどの様に影響するかについては,系統的検証はほとんどなされていない.本研究では,筋組織を対象にした酸素濃度計測における脂肪層の影響を,モンテカルロシミュレーションと実測により検討した.シミュレーション結果より,脂肪層の介在により測定感度は大きく減少することが示された.さらに前腕での動静脈閉塞試験,大腿部での運動負荷試験を行い,超音波診断装置で得た脂肪層の厚みと測定感度の相関を検討したところ,シミュレーションと同様の傾向が得られた.
  • 川上 芳明, 志村 尚宣, 郷 秀人, 武田 正之, 工藤 信樹 日本泌尿器科學會雜誌 86 (1) 237 -237 1995年01月20日 [査読無し][通常論文]
  • 小柳 正道, 工藤 信樹, 柳田 祐司, 岩間 信行, 岡崎 清 超音波エレクトロニクスの基礎と応用に関するシンポジウム講演予稿集 (14) 165 -166 1993年12月07日 [査読無し][通常論文]
  • 工藤 信樹, 清水 孝一, 松本 伍良 医用電子と生体工学 25 (2) 91 -98 1987年 [査読無し][通常論文]
     
    The optical biotelemetry using free-space light transmission in a closed space has many advantages over the conventional telemetry techniques using radio waves. There are some reports on the optical telemeters using direct light transmission, but few are found which use the indirect light scattered from a ceiling, a floor and walls. Since the latter technique does not require the line-of-sight transmission, it enables us to realize the non-restraint measurement of biological signals. In order to examine the possibility of this technique, the distribution of the indirect light in a room was calculated by a computer simulation. The distribution is uniform enough to carry out the telemetry with one receiver in the room with the dimension of W4.2XL6.4XH2.7m. The minimum received power was -28.0dBm with the transmitter power of 1 watt, which was about a half of the maximum power. To verify the possibility shown in the theoretical analysis, an optical biotelemetry system using the indirect light transmission was developed. 3 ECG's and a body temperature are multiplexed in time domain and modulated into a PIM pulse sequence. Light emitters placed on both shoulders emit the light of about 1 watt when the pulse is on. The system can be operated over 100 hours without replacing batteries. To examine the practical usefulness of this technique in clinical application, the optical biotelemetry from a freely moving subject is carried out with the developed system. A stable data acquisition was demonstrated even from the subject in exercise. © 1987, Japanese Society for Medical and Biological Engineering. All rights reserved.

書籍等出版物

  • 放射線医科学
    学会出版センター 2007年
  • 別冊・医学の歩み 超音波医学最前線ー新技術と臨床応用
    医歯薬出版 2004年
  • 超音波造影剤ガイドブック <森安史典，別府慎太郎，久 直史>
    金原出版 2003年
  • 『新超音波医学』<日本超音波医学会>
    医学書院 2000年

講演・口頭発表等

担当経験のある科目（授業）

  • バイオメカニクス特論北海道大学大学院情報科学研究科
  • 科学計測北海道大学工学部
  • 応用電気回路北海道大学工学部

所属学協会

  • 日本音響学会   電子情報通信学会   IEEE   日本生体医工学会   日本超音波医学会   IEEE   

共同研究・競争的資金等の研究課題

  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2022年06月 -2025年03月 
    代表者 : 橋本 守, 工藤 信樹, 加藤 祐次
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2020年04月 -2023年03月 
    代表者 : 工藤 信樹, 鈴木 亮, 佐々木 東, 松崎 典弥
     
    血管内に投与した薬剤を超音波の照射により血管外の組織に漏出させる超音波薬物送達法では，薬剤とともに投与される微小気泡が超音波の照射下で血管に与える作用を明らかにする必要がある．本年度は主に２つの方法により解明に向けた準備作業を行った． ①血管の物理特性を模擬するゲルファントムの開発 微細径のタングステンワイヤを張った型にアクリルアミドゲルを流し込み，ゲル硬化後にワイヤを引き抜くことにより最小直径約10ミクロンの内腔を有する毛細血管ファントムを作成する技術を開発した．微細管腔への微小気泡導入は，初期的にはゲルからワイヤを引き抜く作業を微小気泡の懸濁液内で行うことにより実現できる．また，ゲルの浸透圧を気泡懸濁液の浸透圧よりも低く設定することにより持続的に管腔内に気泡を引き込む流れが形成できることを発見した．これにより，超音波照射により気泡が壊れても新たな気泡が自動的に導入され，繰り返し実験できるようになった． ②生体の組織構造を模擬する3次元培養細胞血管ファントムの開発 コラーゲンゲルに懸濁した血管内皮細胞（HUVEC）を血管内皮増殖因子（VEGF）を加えた培地内で3次元培養することにより毛細血管ファントムを作成する手法を開発し，安定な作成プロセスを検討した．血管内腔に取り込んだ気泡が超音波照射下で生じるダイナミクスを高速度観察する手法，薬剤の漏出や内皮細胞に生じる損傷を可視化する蛍光観察手法を開発した．さらに，血管内に模擬薬剤を導入し，超音波を照射していない状態での漏出が薬剤の分子量によってどのように変化するかを調べた． さらに，次年度以降に向けた準備作業として，生体内の毛細血管を用いて超音波照射下での気泡のダイナミクスを観察する手法について文献調査を行い，ラットなどの腸間膜を使う手法について検討した．
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2020年04月 -2023年03月 
    代表者 : 鈴木 亮, 工藤 信樹, 岡田 欣晃, 小山 正平
     
    現在、T 細胞療法に代表される養子免疫療法によるがん治療が行われており、血液系がんに対して良好な臨床成績をあげている。しかし、固形がんにおいては期待するほどの結果が得られていない。この要因として、移入した T 細胞の腫瘍組織への低浸潤性や腫瘍組織内の免疫抑制的環境による T 細胞の不活性化などが挙げられる。そこで本研究では、超音波照射によるマイクロバブルの収縮・膨張や圧壊といった機械的作用に着目し、固形がん組織内の血管透過性の促進や腫瘍組織の傷害に伴う腫瘍内環境の変化の誘導による、養子免疫療法の治療効果の増強を検討した。乳がん細胞株移植マウスにマイクロバブルを静脈内投与し、腫瘍組織へ超音波を照射した。その 1 日後に CD8 陽性 T 細胞を静脈内から移入する養子免疫療法を行った。その結果、未治療群と比較して、マイクロバブルと超音波照射群において、抗腫瘍効果は認められなかった。一方、CD8 陽性 T 細胞移入群において、わずかな抗腫瘍効果が認められた。さらに、マイクロバブルと超音波照射後に CD8 陽性 T 細胞を移入した群では、顕著な抗腫瘍効果が認められた。このことから、マイクロバブルと超音波照射が、腫瘍内環境の変化を誘導し、養子免疫療法の効果を増強したものと考えられた。今後は、マイクロバブルと超音波照射による腫瘍内環境の変化を免疫学的に解析し、抗腫瘍効果の増強メカニズムに関して検討を進める予定である。また、本治療効果の最適化を図るため、マイクロバブルの投与量や超音波照射条件の最適化を進める。
  • 細胞・微小気泡間相互作用のその場観察によるソノポレーションの機序解明と応用拡大
    文部科学省：科学研究費補助金（基盤研究（A））
    研究期間 : 2017年 -2021年 
    代表者 : 工藤 信樹
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2016年04月 -2019年03月 
    代表者 : 松本 成史, 竹内 康人, 工藤 信樹, 原 量宏
     
    本研究課題は膀胱内圧リアルタイム連続監視が可能なカプセル型テレメーターの開発である。ダイヤフラム構造で樹脂カプセル外径6mm、肉圧0.2mm、端部に3mm径x3mm長ソフトフェライトコア、12.5μm厚ポリエステル膜を同軸的接着、発振コイルは膜4mm程奧に、カプセルは奥から電池、発振回路集積回路、発振コイル、ダイヤフラムを順に配置。試作例では発振コイルのインダクタンスは140μH、発振周波数2.06MHz、電池寿命約10日、in vitroで10mmHg毎に500Hzの発振周波数変移が得られ、100mmHgまで良好な直線性と再現性を確認出来、畜尿排尿過程の膀胱内圧観測には十分な観測域であった。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2016年04月 -2018年03月 
    代表者 : 清水 孝一, 加藤 祐次, 工藤 信樹, 北間 正崇, 犬島 浩
     
    本研究では、位相共役波による時間反転という新原理を散乱分光の分野に新たに導入し、これまで実現が困難であった拡散性散乱体内部局所領域の選択的分光実現の道を拓くことをめざして、次の成果を得た。 1. 理論解析により、着想を具現化するための基本的計測方法を明確化した。2. シミュレーションを通し、提案手法の機能最適化を図った。3. 位相共役波による時間反転原理を実現する散乱体計測システムを開発した。4. 生体模擬試料を用い開発システムの性能を明らかにした。5. トリささみ肉の実験により生体組織への適用可能性を実証した。6. OSAのBiomedical Optics Express誌に採択掲載された。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2014年04月 -2017年03月 
    代表者 : 滝口 満喜, 中村 健介, 佐々木 東, 工藤 信樹
     
    超音波による診断と治療の融合の確立に向けた基盤を形成し、臨床応用へと発展させることを目的とし、犬の甲状腺癌および膀胱癌に対する超音波とマイクロバブルを用いた実用的な新規がん治療法「ソノポレーション」に関する前臨床段階の知見を得た。また、ソノポレーションの新たなメカニズムを明らかにすることで、臨床応用の基盤を構築した。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2014年04月 -2016年03月 
    代表者 : 小林 浩之, 寺坂 俊介, 工藤 信樹, 志賀 哲
     
    悪性神経膠腫は難治性悪性腫瘍で手術や放射線化学療法を行っても予後は不良である。そこでこれまでとは異なる治療法の開発が必要とされてきた。今回我々の研究グループは超音波とそれに反応する音響感受性物質を組み合わせた音響力学療法の効果を悪性神経膠腫細胞株を用いて行った。音響感受性物質としてアミノレブリン酸などのポルフィリン関連物質を用いた。結果、神経膠腫細胞に対して音響力学療法に殺細胞効果があることが証明され、さらにアポトーシス誘導がその細胞障害のメカニズムであり、その程度はポルフィリン製剤の細胞取り込みの量に依存することが確認された。本結果から音響力学療法が新規治療として有望であることが示唆された。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2013年04月 -2016年03月 
    代表者 : 清水 孝一, 工藤 信樹, 加藤 祐次, 北間 正崇, 千葉 仁志
     
    生体内部のマクロな構造を光により３次元的に透視イメージングすることをめざし、新原理を集約した手法を創出した。シミュレーション解析による最適化の後、計測システムを開発した。開発システムの特性を解析し、必要な改良を図った。動物実験により、放射線被曝のない安全な近赤外光を用い、実験用小動物の内部構造をイメージングできる可能性を実証した。また、臓器形状だけではなく、組織酸素化状態などの機能情報もイメージングできる可能性が確かめられた。
  • 文部科学省：科学研究費補助金(挑戦的萌芽研究)
    研究期間 : 2013年 -2014年 
    代表者 : 工藤 信樹
     
    本研究では，微小気泡を付着させた細胞への超音波照射により細胞内に遺伝子や薬剤を導入する手法に関する実験的検討に必要となる２つの要素技術について検討した．気泡による導入はその付着位置に起きるため，気泡の大きさや位置の制御により導入を制御することができる．そこで本検討では，気泡捕捉用光ピンセットの捕捉力を改善し，従来困難であった細胞核上への気泡の移動を実現した．また，細胞膜の張力が低く損傷細胞の修復力が高い生体内に近い状態での実験を実現することを目的に直径１００ミクロン程度の微小細胞培養ウエルを開発した．さらに，これを用いた細胞内導入実験を行い，容器の有用性を確認した．
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2011年 -2012年 
    代表者 : 清水 孝一, 工藤 信樹, 加藤 祐次, 浪田 健
     
    生体組織への適用を念頭に、これまで困難であった強散乱体内部局所領域の選択的分光の実現をめざし研究を行った。2年間にわたる研究の結果、実用性の高い後方散乱光計測システムにより体内局所領域の吸光度を定量計測する手法を開発した。これにより、体表からの正確な無侵襲吸光度計測、および介在組織の影響を排除した体表からの組織スペクトル計測の可能性が拓かれた。この成果を、学術誌や国内外の会議において発表した。また本研究の成果を含む特許を出願した。
  • 文部科学省：科学研究費補助金(基盤研究(B))
    研究期間 : 2011年 -2012年 
    代表者 : 工藤 信樹
     
    超音波の利用が診断と治療の両面において飛躍的に進展し，これに伴なって超音波音場を正しく評価する技術にも改善が求められている．我々は，音場を光学的な手法により音場を可視化する簡便な手法を提案してきた．今回の研究では，光学機器の開発経験を持つ企業の協力を得て，我々が提案する画像差分型シュリーレン法で音場を可視化する装置を新規開発した．さらに，臨床で実用されている複数の診断装置の音場の比較や故障プローブの音場評価に有用であること，従来の音場計測法では測定が難しい治療装置の音場可視化にも有用であることを実験を通じて明らかにした．以上より，本手法は医用超音波の更なる進展の基盤技術として重要と結論した．
  • 文部科学省：科学研究費補助金(挑戦的萌芽研究)
    研究期間 : 2011年 -2012年 
    代表者 : 工藤 信樹
     
    細胞のメカノトランスダクション研究への応用を目的に,細胞局所を機械的に刺激する新しい手法を提案した.この方法では,大きさ数ミクロンの微小気泡を細胞に接触させた状態で超音波を照射することにより,気泡が細胞よりも強い音響放射力を受けることを利用して局所刺激を実現する.微小気泡の位置制御は光ピンセットで実現した.刺激対象としてラットから単離・培養した心室筋細胞を用いることとし,拍動の電気的ペーシングと気泡付着状態での超音波照射を顕微鏡観察下で行える観察チャンバを開発した.手法の有用性を確認するため,気泡を付着した培養心筋細胞に超音波を照射する実験を行い,機械刺激による期外収縮を誘導できることを確認した.さらに,心筋細胞の不応期を求める実験を通じて拍動周期に依存して不応期が変化することを確認し,機械的刺激に対する細胞の反応を調べる上での本刺激手法の有用性を確認した.
  • 文部科学省：科学研究費補助金(基盤研究(A))
    研究期間 : 2009年 -2012年 
    代表者 : 清水 孝一, 加藤 祐次, 工藤 信樹, 北間 正崇, 千葉 仁志
     
    本研究は、生体内部の構造情報および機能情報を光により3次元的に透視イメージングすることをめざし、新原理に基づく新たな手法を創出するとともに、それを具現化するシステムを開発しようとするものである。第二年度は、初年度の基礎的検討の成果を受け、3次元光透視原理を具現化するシステムの基本構成を設計した。具体的内容は、次のとおりである。1.生体に対する光入射部分の設計と改良を繰り返し、透視可能な生体の厚みを大きく増加させた。これにより、従来は手掌程度の厚さにとどまっていた透過型透視を、成人上腕部全域にまで拡大することに成功した。2.静脈認証と言われるように、光で透視できる血管は体表近くの静脈とされてきた。これに対し、透視システムの改良により、これまで不可能と思われてきた動脈の透視を、成人前腕部において初めて可能とした。この成果は、現在のところ世界初のものと考えられる。3.透過光方式CTのシミュレーションを繰り返し、光CTによる3次元構造再構成を可能とするシステム条件を明らかにした。4.マウスやラット胴体を模擬する実験ファントムを作成し、体内吸光構造の3次元光透視の可能性を実証した。研究成果の発表:学術誌(Ann.Clin.Biochem.,超音波医学)、国際会議、国内会議(invited talk 2件、シンポジスト2件を含む)において、本研究の成果を発表した。
  • 文部科学省：科学研究費補助金(基盤研究(A))
    研究期間 : 2008年 -2010年 
    代表者 : 工藤 信樹, 山本 克之, 鈴木 亮, 山本 克之, 岡田 健吾, 坂口 克至, 八木 智史, 渡辺 典子, 千田 裕樹, 奥山 学, 松井 智子, 吉松 幸里
     
    本研究の最終的な目的は,パルス超音波と微小気泡を用いることにより,効率が良く生体に対する安全性が高いin vivoソノポレーション手法を開発することにある.今回の研究では,手法の効率向上を主な目的として,ソノポレーションに伴う細胞変化をタイムラプス観察する光学顕微鏡システムを開発した.また,気泡位置を制御できる光ピンセット装置も開発し,細胞膜損傷の程度や発生部位の制御を実現した.開発した装置を用いて,数10分間の比較的早い時間内に起きる細胞の損傷と修復を観察し,その発生機序について検討した.また,気泡に取り込まれた薬剤の効果発現をとらえるために観察チャンバを改良し,最大20時間程度にわたって細胞に生じる変化を連続観察する手法を確立した.さらに,特定の細胞にのみ付着するターゲティング気泡とシェルに薬剤を付着した気泡を作製し,提案するソノポレーションにおけるこれらの気泡の有用性を確認した.
  • 文部科学省：科学研究費補助金(基盤研究(C))
    研究期間 : 2007年 -2008年 
    代表者 : 山本 克之, 工藤 信樹, 川初 清典, 郭 凱俊, 三枝 俊, 木部 龍太
     
    本研究では,近赤外分光法(NIRS)を用いた絶対値計測可能な筋組織酸素濃度のイメージング装置を開発し,運動時における同一筋内や異なる筋について筋組織酸素濃度分布の計測を行い,運動強度や運動様式の違いによる酸素濃度分布の変化を把握できることを明らかにした.また,一般成人と運動選手を対象に足踏み込み運動時に協調して動作する3種類の筋の酸素濃度を計測し,装置が運動時における複数の筋の同時比較や練習効果の定量的評価に有用であることも明らかにした.さらに,実測とシミュレーションによる解析との比較により,NIRS計測波形を解釈する上で筋代謝モデルを用いた解析の有用性を明らかにした.
  • 文部科学省：科学研究費補助金(萌芽研究)
    研究期間 : 2006年 -2007年 
    代表者 : 工藤 信樹, 山本 克之
     
    ○パルス超音波による遺伝子導入の実証従来,連続波もしくは波数の多いバースト波を用いて行われてきたソノポレーションが,波数3波程度の短い超音波パルスを1回照射するだけでも実現できることを,GFP遺伝子の導入と発現のタイムラプス観察を通じて実証した.しかしその導入効率は低く,パルス超音波が撹拌効果を持たないことが原因の一つと考えられた○遺伝子付着気泡の作成撹拌効果を持たないペルス超音波でも効率が高いソノポレーションを実現するための方法として,細胞に穿孔をもたらす微小気泡自体に遺伝子を付着させる方法について検討した.その結果,アルブミンとGFP遺伝子を混入した生理食塩水を撹拌することで,遺伝子が付着した直径数ミクロンの微小気泡を再現性良く作成できることを確認した.○導入効率の向上上記で作成した気泡を用いて,遺伝子導入効率の向上効果を調べた.GFT遺伝子を培養液中に懸濁させた条件と気泡に付着させた条件で発現効率を調べた結果,気泡に付着させることによって導入効率が,培養駅に懸濁させた場合の約4倍に向上することを確認した.○気泡の種類による膜損傷の違い種々の気泡を用いてパルス超音波を用いたソノポレーションを行い,細胞の損傷率と修復率が気泡の種類によってどのように変化をするかを調べた.その結果,気泡の種類に依存して修復率が60%から100%近くまで変化することが確認され,ソノポレーションに...
  • 文部科学省：科学研究費補助金(基盤研究(B))
    研究期間 : 2004年 -2006年 
    代表者 : 工藤 信樹, 山本 克之
     
    ○高速度顕微観察システムの改良時間・空間分解能の向上を目指し,微弱光増幅装置の利用や照明用アーク放電型光源の集光光学系の改良に関して検討した.その結果,対物倍率40倍では最小露光時間は200nsから20nsに向上し,最大撮影速度は毎秒400万コマから1,600万コマに向上した.○減衰特性計測装置の開発我々が以前生体組織の減衰特性の測定で開発した技術を基に,微小気泡懸濁液の減衰特性を高精度に計測する装置を開発した.中心周波数10MHzの広帯域パルスを用いることにより3から14MHz程度の帯域で微小気泡懸濁液の減衰の周波数特性が計測でき,計測の半自動化により精度向上を図った.○微小気泡のふるまいの高速度観察によるシェルの機械的特性の検討1つの微小気泡に音圧が増加する超音波パルス列を照射して気泡の径振動を高速度観察し,超音波の音圧と径振動振幅の変化の関連からシェルの機械的特性を調べた.観察対象としては,7種類の超音波造影剤と1種類のサブミクロン気泡,1種類のプラスチック気泡を用いた.観察の結果,リン脂質系のシェルでは,低音圧から音圧に応じて膨張・収縮が増強する様子が,バルミチン酸やアルブミンシェルの気泡では,ある音圧閾値を越えて初めて振動を始める特性が確認され,その違いは臨床で用いられている超音波照射条件の違いに対応していた.○気泡懸濁液の音圧依存性減衰の計測によるシェルの機械的特...
  • 文部科学省：科学研究費補助金(基盤研究(B))
    研究期間 : 2004年 -2006年 
    代表者 : 山本 克之, 工藤 信樹, 川初 清典, 河原 剛一, 高橋 英嗣
     
    本研究では,近赤外分光法(NIRS)を用いた筋組織酸素濃度分布のイメージング装置を開発し,運動負荷時の筋組織酸素濃度・飽和度・消費量などの時空間解析を行うことにより筋組織酸素濃度変化と筋代謝機構の因果関係を解明し,筋を対象とするNIRSイメージング法の確立を目指した.1.空間分解法を用いた筋組織酸素濃度イメージング装置の開発小型化とS/Nを両立する最適な光プローブの設計・試作を行い,ファントムを用いて試作プローブの性能を確認した.データの取得,筋組織酸素濃度のイメージングを行うシステムを作成し,32プローブ(96チャンネル)で毎秒2フレームのイメージングを実現した.2.ヒト運動負荷試験の時空間応答解析試作した時空間解析装置を用いて,種々の運動負荷に対する筋組織酸素飽和度分布の時空間応答を解析した.特に大腿部筋群,前脛骨筋について組織酸素飽和度の時空間応答を解析し,わずかな運動様式の違いを酸素飽和度の時空間解析により明瞭に把握できることを示した.また,運動プロトコルを2回繰り返して酸素消費量の時間応答を比較し,酸素飽和度が著しく低下しなければ,運動負荷による酸素負債が局所な酸素消費量に単純に加算されることを明らかにした.3.顕微分光による筋組織酸素飽和度の測定波長400〜850nm帯の波長を用いて吸光度を測定し,重回帰により散乱成分を除去して酸素飽和度を求める顕微分光システムを...
  • 文部科学省：科学研究費補助金(萌芽研究)
    研究期間 : 2004年 -2005年 
    代表者 : 工藤 信樹, 山本 克之, 河原 剛一
     
    ○超音波パルス照射による期外収縮の発生自律拍動する培養心筋細胞に,直径数ミクロンの微小気泡を接触させた状態とさせない状態で超音波パルスを照射し,心筋細胞に生じる拍動リズムの変化を観察した.その結果,超音波診断装置に準じたパルス超音波の照射でも,以下に述べる特定の音圧と照射タイミングにおいて,超音波照射と同期して期外収縮が発生することを確認した.また,蛍光試薬を用いて細胞損傷を調べた結果,細胞膜に損傷が無くても期外収縮が起き得ることが示された.○音圧閾値超音波パルスの音圧と期外収縮の発生頻度の関連を,培養心筋細胞を用いて調べた.この検討では,昨年開発した心筋拍動非接触計測装置を用いて,心筋の収縮開始から超音波照射までのディレイを一定(350-400ms)に制御した.実験の結果,期外収縮の発生には音圧閾値があること,その値は気泡が細胞に接触した条件では明らかに低下することを確認した.これは,気泡が細胞近傍に存在する場合,より強い放射圧を受けた気泡が2次的に細胞に機械的作用をおよぼすためと考えられた.○照射時相の影響音圧を一定として,超音波を照射するタイミングを変えながら期外収縮発生の頻度を調べた.その結果,超音波パルスを心筋の収縮開始直後から約200msまでの間に照射した場合には期外収縮がまったく発生せず,これを超えると発生したことから,期外収縮の発生には時間的な閾値も存在するこ...
  • 文部科学省：科学研究費補助金(基盤研究(B))
    研究期間 : 2001年 -2003年 
    代表者 : 山本 克之, 河原 剛一, 浜岡 隆文, 工藤 信樹
     
    本研究は,近赤外分光法(NIRS)による筋組織酸素濃度測定値が組織酸素運搬機構といかなる因果関係にあるかを,実測,計算機シミュレーション,顕微分光法で明らかにし,NIRS測定値に対するヘモグロビン(Hb)とミオグロビン(Mb)の寄与率など,NIRS測定波形を解釈する上で不可欠な基礎資料を得ることを目的とした.(1)筋組織酸素濃度イメージングによる筋代謝の時空間解析:絶対値計測が可能な空間分解法を導入し,組織酸素飽和度を画像化できるイメージング装置を試作した.運動時と回復期の組織酸素飽和度は,運動負荷の様式や酸素負債を反映した特徴的な変化を示し,本法の有用性を実証できた.(2)運動時の筋酸素消費量の時間応答:高強度収縮時の筋血流遮断を利用し,筋収縮時の酸素濃度低下率から局所的筋酸素消費量を測定する新たな測定法を開発した.装置の時間分解能を約0.1sと高速化することにより,動脈阻血などを行うことなく筋収縮時の酸素消費量をほぼ瞬時に推定することが可能になった.(3)筋組織酸酸素運搬モデルによるNIRS測定値の解析:好・嫌気性代謝系,クレアチンリン酸系,および組織酸素運搬系からなる筋代謝モデルを作成し,ヒト実測結果とモデル・シミュレーションの結果を比較検討した.その結果,HbとミオグロビンMbの測定値への寄与率に関しては,HbとMbの酸素解離曲線の違いを反映し,組織の酸素化レベルによ...
  • 文部科学省：科学研究費補助金(基盤研究(C))
    研究期間 : 2001年 -2002年 
    代表者 : 工藤 信樹, 山本 克之
     
    光が超音波によって変調される現象を利用し,超音波の分解能で生体内の構造や代謝情報を可視化する超音波変調型光イメージングの実現を目指して,スペックルパターンの強度変化に着目した手法を提案した.また手法の実現を目指して実験的検討を行い,以下に述べる結論を得た.・手法の提案と実験システムの開発 ストロボスコープの原理により,超音波の周波数で変調されたスペックルパターンを一般的なCCDカメラを用いて検出する手法を提案し.これを実現する観察システムを開発した.本手法では,超音波の照射条件を変えて2枚のスペックル画像を取得し,その差分をとることにより無変調光成分を打ち消して,微弱変調光の高感度な検出を実現する.・透過光イメージング ファントムを透過して出射側に発生したスペックルパターンを用いる透過光イメージングの可能性について検討した.散乱体中心にヒト乳ガンと同じ光学特性を持つ吸収体を埋め込み,これを透過光により可視化する実験(1次元イメージング)を行なった.その結果,散乱体中の吸収体の位置を従来法よりも高い空間分解能で検出できることが確認された.・反射光イメージング 透過光の強度は,散乱体の厚さの増加に伴い急激に減衰するため,光源とCCDを対向させる必要がある透過光イメージングのみでは本法の適用可能部位は乳房や頬などに限定されてしまうが,反射光も利用できればほとんどの表在臓器が適用の対...
  • 文部科学省：科学研究費補助金(萌芽的研究, 萌芽研究)
    研究期間 : 2001年 -2002年 
    代表者 : 山本 克之, 工藤 信樹
     
    マイクロカプセルを用いたDDSにおいて,カプセルに付加した薬剤が効率よく細胞内に取り込まれるよう超音波の照射条件を最適化し,カプセルの破壊を制御するには,マイクロカプセルなどの微小気泡の存在が細胞への薬剤取り込みを促進するメカニズムを明らかにする必要がある.そこで本年度は,下記の2点に関する検討を行った.1.細胞と気泡の相互作用の高速度観察前年度に行った高速度観察から,気泡が急速に収縮する際に微小な流れが発生し,これが気泡の崩壊の原因になっていることが示された.そこで本年度は,このような気泡のふるまいが細胞に作用を与える可能性に関する検討を行うために,培養した血管内皮細胞を用いて,細胞と微小気泡の相互作用の高速度撮影を行った.その結果,細胞の近傍に気泡が存在する場合に,明らかに気泡のふるまいに同期した細胞の変形が観察された.これは,気泡が存在しない場合には,超音波のエネルギは細胞にほとんど作用を及ぼさずに透過してしまうが,気泡が存在する場合には,超音波のエネルギが一旦気泡の運動エネルギに変換され.気泡のふるまいにより2次的に細胞が作用を受けているものと考えられた.2.Sonoporation(細胞穿孔)のメカニズムの解明高速度観察では,細胞の変形は観察できるものの画質が低く,細胞が受ける作用を詳細に観察することができなかった.そこで,パルス超音波照射下において気泡のふるまいが...
  • 文部科学省：科学研究費補助金(基盤研究(B))
    研究期間 : 1999年 -2001年 
    代表者 : 山本 克之, 清水 孝一, 川初 清典, 工藤 信樹, 浜岡 隆文
     
    本研究は,筋組織酸素濃度計測における皮下脂肪層の影響を系統的に解析し,その影響を除去し得る絶対値計測可能な近赤外分光(NIRS)組織酸素モニタを開発して,本装置の最も効果的な適用分野と考えられるスポーツ医学の分野で,その有効性を実証することを目的とした.1.時間分解法を用いたin vivo計測と多層モンテカルロシミュレーションにより,組織の不均一性を考慮して,筋および脂肪層の平均的な光学特性(吸収係数,散乱係数)を決定した.2.光拡散理論を適用し,吸光度変化と吸収係数の非直線的関係をも考慮した組織酸素濃度算出式を理論的に導出し,その具体的な係数を上記光学特性から決定した.3.脂肪層の影響で近赤外分光法の測定感度が大きく減少するので,測定感度を脂肪厚で補正することにより,均質な系を仮定した上記理論式に適用可能な補正式を決定した.また,安静時の筋酸素消費量を磁気共鳴スペクトル法と試作装置で計測・比較し,補正法の妥当性を確認した.4.NIRSの運動能力の評価法として,トップレベルの選手(ノルディック複合ナショナルチーム,13名)を対象に測定を実施し,高地トレーニングにより筋組織酸素濃度回復速度が6日後で11%,11日後で20%程度増加することを見出した.5.NIRSの筋代謝の評価法として,筋収縮・弛緩に伴う血液量変化から局所的血液酸素飽和度を,筋収縮時の酸素濃度低下率から局所的筋酸...
  • 文部科学省：科学研究費補助金(基盤研究(B))
    研究期間 : 1998年 -2000年 
    代表者 : 工藤 信樹, 清水 匡, 三神 大世, 山本 克之
     
    本研究では,穿刺型超音波マイクロプローブと,これを用いて生体深部組織の超音波断層像を取得するシステムを開発するとともに,生体組織の超音波減衰を測定することによる組織性状診断の可能性について検討し,以下の成果を得た.・穿刺型超音波マイクロプローブと画像取得システムの開発:16-20ゲージの留置針の先端に,0.8-1.0mm×1.2mm,中心周波数20MHz程度の超音波振動子を搭載したマイクロプローブを開発し,さらにこのプローブを機械的にスキャンして約6秒で2次元の超音波画像を取得できる画像取得システムを開発した.また,これを用いてウサギ肝臓の断層像を取得するin vivo実験を行い,本手法の有用性を確認した.・相関法による組織血流計測法に関する検討:生体深部の微小組織血流の検出を目的として,本研究室で従来から検討を行ってきた相関法の本手法への適用について検討し,微小血管ファントムおよびブタ腎臓を用いたin vitro実験を通じて,0.35mm程度の微小な流れを検出できることを確認した.また,ウサギを用いたin vivo実験でも,血流検出可能性を検討した.・複合共振型振動子を用いた減衰計測と生体組織の減衰機序の検討:生体組織の減衰特性から組織性状の変化を診断することを目的として,複合共振型振動子を用いて,5-40MHzの広い帯域で生体組織の減衰を計測するシステムを開発し,種々の生...
  • 文部科学省：科学研究費補助金(基盤研究(B))
    研究期間 : 1998年 -2000年 
    代表者 : 山本 克之, 工藤 信樹, 清水 孝一
     
    本研究では,超音波で光を変調することにより生体の光イメージングの分解能を向上させる手法について検討し,以下の成果を得た.・超音波による光の変調機序に関する検討 冷却光電子増倍管とロックインアンプを用いた微弱光検出システム,およびマッハツェンダ型干渉計を用いた光周波数のドプラシフト計測システムを作成し,超音波音場による光の屈折,散乱体粒子の振動による光の位相変調,超音波による光周波数のドプラシフトなどの光変調機序に関して検討し,媒質の散乱係数と変調光強度の関係を求めた.・後方散乱光によるイメージングの可能性 生体を透過する光を用いてイメージングを行う方法では,送受光器を対向させる必要があるとともに,超音波で変調された光が強い減衰を受けるため,イメージング可能な組織の厚さには強い制約があり,計測対象が頬や乳房などに限定される.そこで後方散乱光の利用可能性について検討を行い,散乱体振動による光の位相変調を干渉光学系で検出する方式を用いることにより,変調成分の検出が可能であることを見いだした.・2次元センサを用いた微弱変調光検出法の提案と有用性の確認 超音波変調光の検出感度の向上を目的として,スペックルパターンの変調を2次元センサで計測する手法について検討した.本手法の特徴は,光をパルス化することにより,通常のCCDカメラを用いた変調成分の検出を可能としていることである.実験により本...
  • 文部科学省：科学研究費補助金(基盤研究(B))
    研究期間 : 1998年 -2000年 
    代表者 : 高橋 誠, 村田 和香, 工藤 信樹, 山本 克之, 水戸部 一孝
     
    本研究では、健常成人とLD児による到達運動の軌跡を計測し、視覚情報を回転した環境に対する適応について分析した.被験者は健常成人2名(19歳と24歳,男)とLD児2名(13歳,男)の計4名.被験者の胸の高さに設置した水平なスクリーンの下面で,正中線上のスタート地点を出発し,もう1点の視標までの到達運動を行った.各被験者それぞれ4種類の視標について各30試行を計測した.Exposure period(Trials11〜20)でのみ,カーソルはスタート地点に対して30°回転移動した手先位置を呈示する.到達運動では,はじめに素早い運動(弾道運動)が生じる.このときの運動方向と到達運動のゴールである指標の方向がなす角度を初期ずれ角θ,その後に続く修正運動も含め,軌道全体とスタート-ゴールを結ぶ直線で囲まれる面積をずれ面積Aとし,これらを適応の評価に用いた.Exposure periodの最初の試行(Trial11)において,初期ずれ角θは,健常成人,LD児ともに約-30°を示したが,ずれ面積Aについては,LD児の値が健常成人よりやや大きくなった.LD児が修正運動を不得意とした結果であると考えられる.次に,Exposure periodにおいて,試行を繰り返すにしたがって適応が生じ,ずれが減少した.減少速度は,ずれ面積Aに比べ,初期ずれ角θにおいて健常成人とLD児の差が顕著となった.Ex...
  • 文部科学省：科学研究費補助金(萌芽的研究)
    研究期間 : 1998年 -1999年 
    代表者 : 工藤 信樹, 山本 克之
     
    超音波で変調した光を用いて,強散乱体である生体の断層像を比較的高い空間分解能で画像化する手法に関し,平成11年度において以下に述べる検討を行った.・微弱光検出システムの改良 昨年度作成した微弱変調光検出システムの改良を行った.ロックインアンプの参照周波数の取得法を変更することなどにより,計測系のノイズレベルを50dB程度低減することができた.・透過光に含まれる変調成分の検出 超音波と光の進行方向を直交させた配置では,超音波による強度変調,位相変調ともに検出が可能であったが,散乱体の濃度が大きくなるとともにレーザ光のコヒーレンシィが低下し,強度変調のみが検出された.散乱体厚が35mmの場合,散乱係数が0.1mm^<-1>増加すると変調強度は約100dB低下した.これをもとに推測すると,超音波とレーザ光の強度の向上を合計80dB見込んだ上で,生体での観察可能な厚さは約10mmと考えられた.・後方散乱した変調光の検出 後方散乱光に含まれる変調光成分は,超音波と光を直交させた配置では検出できなかったが,光と超音波を対向させ,超音波による散乱体振動にもとづく光の位相変調を干渉光学系で検出する方式では検出できた.観察可能な深さは約5mmであり,後方散乱した超音波変調光を用いる手法の有用性が確認された.
  • 文部科学省：科学研究費補助金(基盤研究(A))
    研究期間 : 1996年 -1998年 
    代表者 : 山本 克之, 志賀 利一, 工藤 信樹, 高橋 誠, 清水 孝一
     
    マルチセンサ方式を導入し,2波長近赤外分光法を用いた携帯型組織酸素モニタを開発し,その実用性を確認した.本酸素モニタでは,筋代謝動態を無拘束,実時間で定量計測可能であり,筋生理学,スポーツ・リハビリテーション医学の分野に有用な評価手段となる.本研究の主要な成果を以下にまとめる.・ 携帯型組織酸素モニタの開発:携帯可能な小型の装置とするために光源として発光ダイオードを採用し,送受光器間隔が20,30,40mmのマルチセンサ方式の組織酸素モニタを試作し,光拡散理論に基づく反射光強度の理論式と筋組織を模擬したファントム実験により算出アルゴリズムを決定した.・ 皮下脂肪,皮膚の影響の補正:筋組織酸素計測に及ぼす皮下脂肪層の影響をモンテカルロシミュレーション,実測,ファントム実験の3種の方法で系統的に解析し,脂肪層の影響の補正法を確立した.また、皮膚および皮膚血流の影響補正について検討し,送光器から3mmの位置に設置した近接受光器により,皮膚および皮膚血流の影響が除去可能であることを見い出した.・ 近赤外組織酸素モニタの有用性確認:実用性確認のためにノルディック複合オリンピック候補選手の筋組織酸素供給能力を測定し,一流選手の酸素供給能が一般成人と比較して明らかに高いことを定量化できた.・ 生体組織の光学特性の計測:酸素濃度変化の絶対量計測のための基礎的データとして,ストリークカメラを用...
  • 文部科学省：科学研究費補助金(基盤研究(C))
    研究期間 : 1996年 -1998年 
    代表者 : 高橋 誠, 村田 和香, 工藤 信樹, 山本 克之
     
    本研究では,ヒトの内部空間の構成過程を調べることを目的とし,視聴覚刺激の時間をいろいろ変化させ,姿勢を変化させることにより時間的に内部空間がどのように構成されるかを調べた.これまで指示運動時の学習障害児の頭部および体幹の位置変化を計測してきたが,体動の指標としてさらに重心動揺計を用いて重心を計測した.これにより床近傍で磁気に乱れが生じるため計測できなかった下肢などの動きや全体的な体動を調べることができた.被験者として健常者および学習障害児を用い,得られたデータから内部空間の時間的形成過程,刺激の種類による差異および刺激ごとの内部空間の存在の有無を調べた.平成8年度は本年度の設備備品費で重心動揺計を購入し,これまで計測してきた頭部,上肢および体幹部以外に重心や下肢などの動きの計測を行うことを中心に以下の手順で行った.平成9年度には,学習障害児の計測を重点的に行い,健常者のデータと比較を行った.また,指示運動は3次元的に行われることから,その表示に適した高速処理ができるパーソナルコンピュータを購入し,データ処理を行った.平成10年度は,内部空間の構造および形成過程について検討した.
  • 文部科学省：科学研究費補助金(基盤研究(C))
    研究期間 : 1996年 -1997年 
    代表者 : 工藤 信樹, 高橋 誠, 山本 克之
     
    本研究では,IVUSへの相関法の応用として,血管内の血流計測および血管内腔の明瞭な描出を目的に検討を行なった.具体的内容は以下の通り.1.相関法に関する理論解析◯相関法による血管血流計測法の理論解析を行い,振動子寸法や集束の有無等,種々の計測条件下での血流速と相関値の関係を定式化した.2.計測システムの開発◯血管内超音波トランスデューサ 血管内に導入可能な微小振動子(1.2mmchi0.8mm)を作成した.よりS/Nの高いRF信号の取得を目的として,空間分解能の向上およびスペックルノイズの軽減について検討した.◯データ収集・相関処理システム 連続した16枚の断層像のRFエコーデータ(4MByte)をサンプリング周波数50MHzで収集,相関処理し,結果を表示する計測システムを開発した.◯血流ファントム 血管内での血流を模擬するファントムを作成し,in vitroでの評価実験に用いた.3.実用性の確認◯血流速計測(1次元分布) 上記計測システムを用い,従来のドプラ法では原理的に測定不可能であったIVUSでの流速計測が,本手法では可能であることを確認した.◯血管内腔描出(2次元像) IVUSで一般的なラジアルスキャン画像に対して相関法を適用する手法を考案し,血流と粥腫・血管壁の動きの違いを画像化することにより,血管内腔が明瞭に描出できることを実験的に確認した.相関法は,超音波に直交...
  • 文部科学省：科学研究費補助金(基盤研究(B))
    研究期間 : 1996年 -1997年 
    代表者 : 清水 孝一, 福島 菊郎, 工藤 信樹, 加藤 祐次, 山本 克之
     
    光による生体内機能の透視および光CTの実現をめざし、多波長・短パルス光技術を用いたイメージング技術の開発に関する基礎的研究を行った。その結果、以下の成果が得られた。1.近赤外領域の多波長光源を用いて生体透視を行うことにより、体内機能情報をイメージングできることを示した。2.本原理に基づく生体透視イメージングシステムを開発した。本システムにより小型実験動物の脳機能のイメージングを試みた。その結果、体性感覚刺激により大脳体性感覚野に局在した血流変化を描出することに成功した。この結果は、生体透視による脳機能イメージングの可能性を実証した世界初の結果と考えられる。3.生体断層イメージングシステムを開発し、本原理により体内機能をCT像中に描出することを試みた。その結果、マウス腹部の局所的血流変化に伴う体内臓器(腎臓)の酸素化状態変化をCT像中にイメージングすることができた。4.フェムト秒レーザとストリークカメラを中心とする短パルス光実験装置を構築し、散乱体を透過したインパルス光の時間分解解析を可能とした。5.後方散乱光の時間分解波形を用いた断層像再構成手法を、新たに開発した。シミュレーションとファントム実験を通し、本手法の有効性を実証した。6.短パルス光の時間分解解析により、透過光中の散乱成分を調べ、入射光軸に沿って伝搬する近軸散乱光(snake photon)の挙動や特性を明らかにし...
  • 文部科学省：科学研究費補助金(基盤研究(C))
    研究期間 : 1996年 -1997年 
    代表者 : 山本 克之, 森川 一, 工藤 信樹, 佐藤 嘉晃
     
    生体組織の適応現象の中でも,歯科矯正時の歯槽骨のリモデリングは,特に顕著であり,かつ力学条件を明確に設定できるため,骨リモデリングの機序を解明する最適な研究対象のひとつである.本研究は,歯科矯正における歯槽骨リモデリングと力学的刺激との因果関係を,歯根部力学条件・血流・破骨細胞出現の相互関係から,生体力学的に明らかにすることを目標とした.歯周組織内の応力解析には歯根膜の材料定数が必須であるが、実測値は皆無に近い。そこでまず,ネコ歯根膜を対象に,歯根膜の材料定数を測定した.微小組織を実体顕微鏡下で測定の可能な小型の圧縮・引張試験機を開発し,応力・ひずみ特性を求めたところ,引張では速度依存性が見られないのに対し,圧縮では大きく速度に依存することが明らかになった.応力・ひずみ特性から求めた準静的状態での歯根膜の弾性率は,引張では0.37±0.11MPa,圧縮では0.079±0.017MPaであった.歯科矯正圧迫側で生じる変性組織の圧縮弾性率は,0.143±0.035MPaと有意に高値を示した.また,荷重試験中の歯根膜の体積変化からポアソン比を測定したところ,圧縮では引張に比し有意に低値を示した.次に,ネコ犬歯を対象に実験的歯科矯正を実施し,各組織切片に対応する有限要素モデルを作成して,破骨細胞出現部位の応力値を求めた.その結果,破骨細胞は,固体,矯正条件によらず,歯根膜内の最小主応...
  • 光および超音波による生体計測
    研究期間 : 1995年
  • Measurements of biomedical parameters using optical and ultrasonic techniques
    研究期間 : 1995年

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