公开(公告)号：US08058610B2

公开(公告)日：2011-11-15

申请号：US12515674

申请日：2006-12-05

申请人： Takahiro Harada ,  Sadao Takeuchi ,  Kiyoshi Ogawa ,  Mitsutoshi Setou

发明人： Takahiro Harada ,  Sadao Takeuchi ,  Kiyoshi Ogawa ,  Mitsutoshi Setou

IPC分类号： H01J49/04 ,  H01J49/00

CPC分类号： H01J49/164

摘要： A sample plate 3 with a sample 4 placed thereon is initially set on a stage 2, and a visual image of the sample is taken with a CCD camera 14. This image is stored in an image data memory 23. Then, an operator removes the sample plate 3, sprays a matrix for a MALDI process onto the sample 4 and replaces the plate onto the stage 2. After that, when a predetermined operation is made, a clear image of the sample taken before the application of the matrix is shown on a display unit 24. On this image, the operator specifies a point or area for the analysis. The sample 4 may have been displaced due to the removal and replacement of the plate 3. Accordingly, an image analyzer 44 calculates the direction and magnitude of the displacement, for example, by recognizing the position of the markings provided on the sample plate 3. A displacement corrector 42 computes coordinate values in which the displacement is corrected. Thus, even if a displacement occurs, the mass analysis can be accurately performed on the point or area of the actual sample as specified on the clear visual image taken before the application of the matrix.

摘要翻译： 将样品4放置在其上的样品板3初始设置在载物台2上，用CCD照相机14拍摄样品的视觉图像。该图像存储在图像数据存储器23中。然后，操作者将 样品板3将MALDI工艺的矩阵喷射到样品4上，并将该板替换到载物台2上。之后，当进行预定的操作时，在施加矩阵之前拍摄的样品的清晰图像显示在 在该图像上，操作者指定用于分析的点或区域。 样品4可能由于板3的移除和更换而被移动。因此，图像分析器44例如通过识别设置在样品板3上的标记的位置来计算位移的方向和大小。 位移校正器42计算校正位移的坐标值。 因此，即使发生位移，也可以在施加矩阵之前在清晰的视觉图像上指定的实际样品的点或面积上精确地进行质量分析。

公开(公告)号：US08395116B2

公开(公告)日：2013-03-12

申请号：US13094659

申请日：2011-04-26

申请人： Takahiro Harada ,  Kiyoshi Ogawa ,  Mitsutoshi Setou

发明人： Takahiro Harada ,  Kiyoshi Ogawa ,  Mitsutoshi Setou

IPC分类号： H01J49/00

CPC分类号： H01J49/0004

摘要： A mass spectrometer capable of obtaining a clear microscopic observation image with high spatial resolution in real time, even during a mass analysis, without affecting the analysis is provided. An aperture 1a is formed in a stage 1 on which a sample plate 2 to be placed. The sample plate 2 is transparent or translucent. A microscopic observation unit, including an observation optical system 20 and a CCD camera 21, is provided below the stage 1 to observe the reverse side of the sample 3 through the aperture 1a of the stage 1 as well as the transparent sample plate 2. The observed image is displayed on the screen of a display unit 27. If the sample 3 is a slice of biological tissue, the sample image taken from the reverse side will be substantially the same as an image taken from the obverse side.

摘要翻译： 提供了即使在质量分析期间也能够实时获得具有高空间分辨率的清晰显微镜观察图像的质谱仪，而不影响分析。 孔1a形成在载置样品板2的台1上。 样品板2是透明或半透明的。 包括观察光学系统20和CCD照相机21的显微镜观察单元设置在平台1的下方，通过台1的孔1a以及透明样板2观察样品3的反面。 观察到的图像显示在显示单元27的屏幕上。如果样品3是生物组织的切片，则从背面拍摄的样本图像将与从正面获取的图像基本相同。

公开(公告)号：US20100044563A1

公开(公告)日：2010-02-25

申请号：US12515674

申请日：2006-12-05

申请人： Takahiro Harada ,  Sadao Takeuchi ,  Kiyoshi Ogawa ,  Mitsutoshi Setou

发明人： Takahiro Harada ,  Sadao Takeuchi ,  Kiyoshi Ogawa ,  Mitsutoshi Setou

IPC分类号： H01J49/26

CPC分类号： H01J49/164

摘要： A sample plate 3 with a sample 4 placed thereon is initially set on a stage 2, and a visual image of the sample is taken with a CCD camera 14. This image is stored in an image data memory 23. Then, an operator removes the sample plate 3, sprays a matrix for a MALDI process onto the sample 4 and replaces the plate onto the stage 2. After that, when a predetermined operation is made, a clear image of the sample taken before the application of the matrix is shown on a display unit 24. On this image, the operator specifies a point or area for the analysis. The sample 4 may have been displaced due to the removal and replacement of the plate 3. Accordingly, an image analyzer 44 calculates the direction and magnitude of the displacement, for example, by recognizing the position of the markings provided on the sample plate 3. A displacement corrector 42 computes coordinate values in which the displacement is corrected. Thus, even if a displacement occurs, the mass analysis can be accurately performed on the point or area of the actual sample as specified on the clear visual image taken before the application of the matrix.

摘要翻译： 将样品4放置在其上的样品板3初始设置在载物台2上，用CCD照相机14拍摄样品的视觉图像。该图像存储在图像数据存储器23中。然后，操作者将 样品板3将MALDI工艺的矩阵喷射到样品4上，并将该板替换到载物台2上。之后，当进行预定的操作时，在施加矩阵之前拍摄的样品的清晰图像显示在 在该图像上，操作者指定用于分析的点或区域。 样品4可能由于板3的移除和更换而被移动。因此，图像分析器44例如通过识别设置在样品板3上的标记的位置来计算位移的方向和大小。 位移校正器42计算校正位移的坐标值。 因此，即使发生位移，也可以在施加矩阵之前在清晰的视觉图像上指定的实际样品的点或面积上精确地进行质量分析。

公开(公告)号：US20090146053A1

公开(公告)日：2009-06-11

申请号：US12063625

申请日：2006-08-10

申请人： Mitsutoshi Setou ,  Shuichi Shimma ,  Takahiro Harada ,  Sadao Takeuchi ,  Osamu Furuhashi ,  Kiyoshi Ogawa ,  Yoshikazu Yoshida

发明人： Mitsutoshi Setou ,  Shuichi Shimma ,  Takahiro Harada ,  Sadao Takeuchi ,  Osamu Furuhashi ,  Kiyoshi Ogawa ,  Yoshikazu Yoshida

IPC分类号： H01J49/26

CPC分类号： H01J49/0413 ,  H01J49/164

摘要： In a mass spectrometer for carrying out mass analysis while microscopically observing a two-dimensional area of a sample 15, the observation position for selecting a target portion while observing an image of the sample 15 captured with a CCD camera 23 is separated from the analysis position for carrying out the mass analysis of the sample 15 by delivering laser light from the laser-delivering unit 20 onto the sample 15. The sample 15 is placed on a stage 13, which can be precisely moved between the observation position and the analysis position by a stage-driving mechanism 30. An observation optical system 24 can be set close to the sample 15 at the observation position, without impeding the flight of the ions generated from the sample 15 during the analysis or interfering with a laser-condensing optical system 22. Thus, the spatial resolution for observation is improved without deteriorating the ion-detecting efficiency.

摘要翻译： 在微观观察样品15的二维区域的质谱分析仪中，在用CCD摄像机23拍摄的样本15的图像上选择目标部位的观察位置与分析位置分离 用于通过将来自激光输送单元20的激光输送到样品15上来对样品15进行质量分析。将样品15放置在台13上，台13可以在观察位置和分析位置之间精确地移动， 阶段驱动机构30.观察光学系统24可以在观察位置处靠近样本15设置，而不会在分析期间产生的样本15的离子的飞行或与激光聚光光学系统22干涉 因此，不会降低离子检测效率，可以提高观察用的空间分辨率。

公开(公告)号：US07759640B2

公开(公告)日：2010-07-20

申请号：US12063625

申请日：2006-08-10

申请人： Mitsutoshi Setou ,  Shuichi Shimma ,  Takahiro Harada ,  Sadao Takeuchi ,  Osamu Furuhashi ,  Kiyoshi Ogawa ,  Yoshikazu Yoshida

发明人： Mitsutoshi Setou ,  Shuichi Shimma ,  Takahiro Harada ,  Sadao Takeuchi ,  Osamu Furuhashi ,  Kiyoshi Ogawa ,  Yoshikazu Yoshida

IPC分类号： H01J49/04

CPC分类号： H01J49/0413 ,  H01J49/164

摘要： In a mass spectrometer for carrying out mass analysis while microscopically observing a two-dimensional area of a sample 15, the observation position for selecting a target portion while observing an image of the sample 15 captured with a CCD camera 23 is separated from the analysis position for carrying out the mass analysis of the sample 15 by delivering laser light from the laser-delivering unit 20 onto the sample 15. The sample 15 is placed on a stage 13, which can be precisely moved between the observation position and the analysis position by a stage-driving mechanism 30. An observation optical system 24 can be set close to the sample 15 at the observation position, without impeding the flight of the ions generated from the sample 15 during the analysis or interfering with a laser-condensing optical system 22. Thus, the spatial resolution for observation is improved without deteriorating the ion-detecting efficiency.

摘要翻译： 在微观观察样品15的二维区域的质谱分析仪中，在用CCD摄像机23拍摄的样本15的图像上选择目标部位的观察位置与分析位置分离 用于通过将来自激光输送单元20的激光输送到样品15上来对样品15进行质量分析。将样品15放置在台13上，台13可以在观察位置和分析位置之间精确地移动， 阶段驱动机构30.观察光学系统24可以在观察位置处靠近样本15设置，而不会在分析期间产生的样本15的离子的飞行或与激光聚光光学系统22干涉 因此，不会降低离子检测效率，可以提高观察用的空间分辨率。

公开(公告)号：US20070114388A1

公开(公告)日：2007-05-24

申请号：US11590802

申请日：2006-11-01

申请人： Kiyoshi Ogawa ,  Sadao Takeuchi ,  Takahiro Harada ,  Yoshihiro Ueno ,  Fujio Inoue ,  Mitsutoshi Setou

发明人： Kiyoshi Ogawa ,  Sadao Takeuchi ,  Takahiro Harada ,  Yoshihiro Ueno ,  Fujio Inoue ,  Mitsutoshi Setou

IPC分类号： H01J49/00

CPC分类号： H01J49/161 ,  H01J49/0004

摘要： An imaging mass spectrometer, an image of a sample is generated, and a region in the image is selected in accordance with predetermined criteria. Then, a mass analysis of the region is performed while scanning the sample in the selected region with a laser beam spot. By computing the total or average of the results in the region, a high precision analytical value in the region can be obtained. In a biological sample, by preliminarily performing a staining process on the biological sample using a certain dye, only the objective tissues can be analyzed. Also, a fluorescence microscope can be used.

摘要翻译： 产生成像质谱仪，样品的图像，并且根据预定标准选择图像中的区域。 然后，利用激光束点扫描所选择的区域中的样品，进行该区域的质量分析。 通过计算该区域的结果的总体或平均值，可以获得该区域的高精度分析值。 在生物样品中，通过使用某种染料预先对生物样品进行染色处理，只能分析目标组织。 此外，可以使用荧光显微镜。

公开(公告)号：US10012572B2

公开(公告)日：2018-07-03

申请号：US13458850

申请日：2012-04-27

申请人： Masaaki Matsuura ,  Masaru Ushijima ,  Masatoshi Wakui ,  Mitsutoshi Setou ,  Shigeki Kajihara ,  Kiyoshi Ogawa

发明人： Masaaki Matsuura ,  Masaru Ushijima ,  Masatoshi Wakui ,  Mitsutoshi Setou ,  Shigeki Kajihara ,  Kiyoshi Ogawa

IPC分类号： G01N1/28 ,  G06F15/00 ,  H01J49/00

CPC分类号： G01N1/28 ,  G06F15/00 ,  H01J49/0004 ,  H01J49/0027

摘要： Provided is a technique for using an optical microscope image of an area on a sample to collect area-specific information characterizing each kind of biological tissue from imaging mass analysis data. On an optical image of a two-dimensional target area on a sample, a difference is examined in the kind of tissue or other features and areas are specified, each regarded as the same kind of tissue. When data processing is initiated, peak information is extracted, for each specified area, from mass spectrum data of all the measurement points. A peak method is applied to each area to extract peak information. Then, when a command to compare a set of areas is given, the peak information of those areas is collected. By comparing the peak information of different areas by a machine learning algorithm or similar judging technique, area-specific peak information is obtained, and this information is stored in memory.

公开(公告)号：US20120132799A1

公开(公告)日：2012-05-31

申请号：US13260061

申请日：2009-03-31

申请人： Kazuteru Takahashi ,  Kiyoshi Ogawa ,  Mitsutoshi Setou

发明人： Kazuteru Takahashi ,  Kiyoshi Ogawa ,  Mitsutoshi Setou

IPC分类号： H01J49/26

CPC分类号： H01J49/0004 ,  G01N2001/045

摘要： A samples stage (2) on which a sample (4) is placed can reciprocally move along a guide (5) by a driving mechanism. An image taken by an imaging unit (7) when the sample stage (2) is at an observation position (A) is processed by an image processor (34) and is displayed on a window of a display unit (38). When an analysis operator specifies a measurement area by an operation unit (37), a controller (3) moves, through a stage driver (33), the stage (2) to a sample operation position (B) and a matrix is applied to the specified measurement area by an ejector (9). After that, the stage (2) is moved to an analysis position (C) and a laser light is delivered onto the measurement area on the sample (4) to which the matrix was applied, and the ionization by the MALDI method is performed. This eliminates the need to take out the sample from the apparatus to apply the matrix after the measurement point or measurement area is determined based on a microscopic observation of the sample. Accordingly, the efficiency of the measurement can be increased, and since no positional error of the sample occurs, it is possible to perform an imaging mass analysis for a measurement area of interest with high positional accuracy.

摘要翻译： 其上放置有样品（4）的样品台（2）可以通过驱动机构沿引导件（5）往复运动。 当样本台（2）处于观察位置（A）时由成像单元（7）拍摄的图像由图像处理器（34）处理并显示在显示单元（38）的窗口上。 当分析操作者通过操作单元（37）指定测量区域时，控制器（3）通过平台驱动器（33）将平台（2）移动到采样操作位置（B），并将矩阵应用于 由喷射器（9）指定的测量区域。 之后，将阶段（2）移动到分析位置（C），并将激光输送到施加了矩阵的样品（4）的测量区域上，并通过MALDI方法进行电离。 这消除了在基于样品的显微镜观察确定测量点或测量区域之后，从设备中取出样品以施加基质的需要。 因此，可以提高测量效率，并且由于不发生样本的位置误差，因此可以以高位置精度对感兴趣的测量区域进行成像质量分析。

公开(公告)号：US20120104247A1

公开(公告)日：2012-05-03

申请号：US13262217

申请日：2009-03-31

申请人： Kiyoshi Ogawa ,  Mitsutoshi Setou

发明人： Kiyoshi Ogawa ,  Mitsutoshi Setou

IPC分类号： H01J49/26

CPC分类号： H01J49/0004 ,  G01N1/06 ,  G01N1/286 ,  H01J49/0459

摘要： A sample stage (2) on which a sample (4) is placed can be reciprocally moved along a guide (5) by a driving mechanism (6). A cutter (9) which is moved in an X-Y plane by a driving mechanism (10) is placed at a sample cutting position (B). When the sample stage (2) is moved to the sample cutting position (B) and the cutter is driven with the height of the sample stage (2) being appropriately adjusted, an upper portion of the sample 4 is horizontally cut off with a predetermined thickness and a new sample analysis surface which was inside the sample 4 is exposed. Hence, by repeating a mass analysis for a predetermined measurement area at an analysis position (C) and a partial cutting of the sample 4 at the sample cutting position (B), it is possible to achieve a three-dimensional mass analysis imaging of the sample (4) without removing the sample (4) from the sample stage (2).

摘要翻译： 其上放置有样品（4）的样品台（2）可以通过驱动机构（6）沿引导件（5）往复运动。 通过驱动机构（10）在X-Y平面中移动的切割器（9）被放置在样品切割位置（B）。 当样品台（2）移动到样品切割位置（B）并且在适当调节样品台（2）的高度的情况下驱动切割器时，样品4的上部以预定的 厚度和样品4内部的新的样品分析表面露出。 因此，通过在样本切断位置（B）的分析位置（C）和样本4的部分切割重复对于预定测量区域的质量分析，可以实现三维质量分析成像 样品（4），而不从样品台（2）中移除样品（4）。

公开(公告)号：US20070045527A1

公开(公告)日：2007-03-01

申请号：US11362526

申请日：2006-02-27

申请人： Kiyoshi Ogawa ,  Yoshikazu Yoshida ,  Kozo Shimazu ,  Mitsutoshi Setou ,  Shuichi Shimma ,  Michisato Toyoda

发明人： Kiyoshi Ogawa ,  Yoshikazu Yoshida ,  Kozo Shimazu ,  Mitsutoshi Setou ,  Shuichi Shimma ,  Michisato Toyoda

IPC分类号： H01J49/26

CPC分类号： H01J49/40 ,  H01J49/0004 ,  H01J49/004 ,  H01J49/164 ,  H01J49/424

摘要： The present invention provides a laser irradiation mass spectrometer capable of analyzing components of living tissue or living cells with high accuracy. It includes a laser unit for irradiating a sample with a beam of laser light and controlling the irradiation spot of the laser beam on the sample; and a mass analyzer for performing a mass analysis of the ions generated at the irradiation spot, where the mass analyzer uses a frequency-driven ion trap and a time-of-flight mass spectrometer to carry out the mass analysis. The ion trap of this system assuredly traps ions having large mass to charge ratios, and enables the system to carry out analyses on samples of large molecules. Preferably, a digital driving method is used to drive the aforementioned frequency-driven ion trap. Also, a multi-turn time-of-flight mass spectrometer may preferably be used as the aforementioned time-of-flight mass spectrometer.

摘要翻译： 本发明提供能够高精度地分析活体组织或活细胞的成分的激光照射质谱仪。 它包括用激光束照射样品的激光单元，并将激光束的照射点控制在样品上; 以及质量分析器，用于对照射点产生的离子进行质量分析，质量分析仪使用频率驱动离子阱和飞行时间质谱仪进行质量分析。 该系统的离子阱确实捕获具有大质量与电荷比的离子，并使系统能够对大分子样品进行分析。 优选地，使用数字驱动方法来驱动上述频率驱动的离子阱。 此外，可以优选使用多匝飞行时间质谱仪作为上述飞行时间质谱仪。