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1. 发明授权

US06511817B1 Methods and device for in vitro detection and characterization of psychoactives using analysis of repetitive electrical activity in a neuronal sample 失效
标题翻译：使用分析神经元样本中重复性电活动的心理活体的体外检测和表征的方法和装置
公开(公告)号：US06511817B1
公开(公告)日：2003-01-28
申请号：US09602629
申请日：2000-06-21
申请人： Gary Lynch , Makoto Taketani , Ken Shimono , Hirokazu Sugihara
发明人： Gary Lynch , Makoto Taketani , Ken Shimono , Hirokazu Sugihara
IPC分类号： C12Q102
CPC分类号： G01N33/48714 , G01N33/48707 , G01N33/5088 , G01N33/94
摘要： This relates to methods for the detection of psychoactive compounds in an in vitro neuronal tissue sample by detecting oscillations of extracellular voltage desirably before and after the introduction of a candidate sample onto an in vitro neuronal tissue sample and for devices useful in practicing the methods. Analysis of the extracellular voltage parameters leads to indication of the presence of psychoactive material in the candidate sample and information as to its pharmacological activity and/or composition. Further, it relates to a process of initiating and maintaining the presence of repetitive neuronal activity within the in vitro sample. Additionally, this includes a method for the stimulation of or initiation of repetitive neuronal activity, e.g., EEG, in an in vitro neuronal tissue sample by introducing a stimulating composition comprising compounds that facilitate or mimic the actions of acetylcholine, serotonin, or catecholamines, such as carbachol, or by subjecting the in vitro neuronal sample to electrical stimulation parameters.
摘要翻译：这涉及通过在候选样品引入体外神经元组织样品之前和之后检测细胞外电压的振荡以及用于实施该方法的装置来检测体外神经元组织样品中精神活性化合物的方法。细胞外电压参数的分析导致候选样品中存在精神活性物质的迹象以及关于其药理活性和/或组成的信息。此外，它涉及启动和维持体外样品中重复性神经元活性的存在的过程。另外，这包括通过引入促进或模拟乙酰胆碱，5-羟色胺或儿茶酚胺的作用的刺激性组合物刺激或起始体外神经元组织样品中的重复性神经元活动（例如EEG）的方法，作为卡巴胆碱，或通过使体外神经元样品经受电刺激参数。

2. 再颁专利

USRE37977E1 Cell potential measuring electrode and measuring apparatus using the same 有权
标题翻译：电池电位测量电极及使用其的测量装置
公开(公告)号：USRE37977E1
公开(公告)日：2003-02-04
申请号：US09953412
申请日：2001-09-11
申请人： Hirokazu Sugihara , Hiroaki Oka , Ken Shimono , Ryuta Ogawa , Makoto Taketani
发明人： Hirokazu Sugihara , Hiroaki Oka , Ken Shimono , Ryuta Ogawa , Makoto Taketani
IPC分类号： G01N2700
CPC分类号： G01N33/4836 , C12M41/46
摘要： This invention relates to a low impedance cell potential measuring electrode assembly typically having a number of microelectrodes on an insulating substrate and having a wall enclosing the region including the microelectrodes. The device is capable of measuring electrophysiological activities of a monitored sample using the microelectrodes while cultivating those cells or tissues in the in the region of the microelectrodes. The invention utilizes independent reference electrodes to lower the impedance of the overall system and to therefore lower the noise often inherent in the measured data. Optimally the microelectrodes are enclosed by a physical wall used for controlling the atmosphere around the monitored sample.
摘要翻译：本发明涉及一种低阻抗电池电位测量电极组件，通常在绝缘衬底上具有许多微电极，并且具有围绕包括微电极的区域的壁。该装置能够在微电极区域中培养那些细胞或组织的同时使用微电极测量被监测样品的电生理活性。本发明利用独立的参考电极来降低整个系统的阻抗并因此降低测量数据中常常固有的噪声。最佳地，微电极由用于控制被监测样品周围大气的物理壁包围。

3. 发明授权

US6132683A Cell potential measuring electrode and measuring apparatus using the same 有权
公开(公告)号：US6132683A
公开(公告)日：2000-10-17
申请号：US220981
申请日：1998-12-23
申请人： Hirokazu Sugihara , Hiroaki Oka , Ken Shimono , Ryuta Ogawa , Makoto Taketani
发明人： Hirokazu Sugihara , Hiroaki Oka , Ken Shimono , Ryuta Ogawa , Makoto Taketani
IPC分类号： C12M1/34 , G01N33/487 , G01N27/26
CPC分类号： C12M41/46 , G01N33/4836
摘要： This invention relates to a low impedance cell potential measuring electrode assembly typically having a number of microelectrodes on an insulating substrate and having a wall enclosing the region including the microelectrodes. The device is capable of measuring electrophysiological activities of a monitored sample using the microelectrodes while cultivating those cells or tissues in the in the region of the microelectrodes. The invention utilizes independent reference electrodes to lower the impedance of the overall system and to therefore lower the noise often inherent in the measured data. Optimally the microelectrodes are enclosed by a physical wall used for controlling the atmosphere around the monitored sample.

4. 发明申请

US20050118565A1 Systems and methods for assessing neuronal degeneration 审中-公开
标题翻译：用于评估神经元变性的系统和方法
公开(公告)号：US20050118565A1
公开(公告)日：2005-06-02
申请号：US10966405
申请日：2004-10-15
申请人： Ken Shimono , Victor Panchenko , Makoto Taketani , Michael Krause
发明人： Ken Shimono , Victor Panchenko , Makoto Taketani , Michael Krause
IPC分类号： A61K31/42 , A61K31/55 , A61K33/00 , A61K33/40 , C12Q1/00 , G01N33/487 , G01N33/543
CPC分类号： A61K33/00 , A61K33/40 , G01N33/48707 , G01N33/5438 , G01N2500/00
摘要： The invention relates to systems and methods for assessing neuronal degeneration in vitro. A multielectrode probe is used to culture and measure synaptic transmission of a neuronal sample in the presence of various compounds and culturing conditions capable of inducing or protecting against neuronal damage.
摘要翻译：本发明涉及用于评估体外神经元变性的系统和方法。多电极探针用于在存在各种化合物和能够诱导或保护免受神经损伤的培养条件下培养和测量神经元样品的突触传递。

5. 再颁专利

USRE38323E1 Cell potential measurement apparatus having a plurality of microelectrodes 有权
标题翻译：具有多个微电极的电池电位测量装置
公开(公告)号：USRE38323E1
公开(公告)日：2003-11-18
申请号：US09169188
申请日：1998-10-08
申请人： Hirokazu Sugihara , Akihito Kamei , Yasushi Kobayashi , Makoto Taketani , Tadayasu Mitsumata
发明人： Hirokazu Sugihara , Akihito Kamei , Yasushi Kobayashi , Makoto Taketani , Tadayasu Mitsumata
IPC分类号： C12M134
CPC分类号： G01N33/4836 , C12M41/46
摘要： A cell potential measurement apparatus, which uses a planar electrode enabling a multi-point simultaneous measurement of potential change arising from cell activities, is provided which can conduct measurements accurately and efficiently as well as can improve convenience of arranging measurement results. According to the configuration of the cell potential measurement apparatus of this invention, it includes an integrated cell holding instrument, which includes a planar electrode provided with a plurality of microelectrodes arranged in a matrix form on the surface of a substrate, a cell holding part for placing cells thereon, drawer patterns from the microelectrodes, and electric contact points for outside connections; an optical observation means for optical observations of cells; a stimulation signal supply means to be connected to the cell holding instrument for providing electric stimulation to the cells; and a signal processing means to be connected to the cell holding instrument for processing an output signal arising from electric physiological activities of the cells. It is preferable that a cell culturing means is also provided for maintaining a culture atmosphere of the cells placed on the integrated cell holding instrument.

6. 发明授权

US5810725A Planar electrode 失效
标题翻译：平面电极
公开(公告)号：US5810725A
公开(公告)日：1998-09-22
申请号：US481149
申请日：1995-06-07
申请人： Hirokazu Sugihara , Makoto Taketani , Tadayasu Mitsumata
发明人： Hirokazu Sugihara , Makoto Taketani , Tadayasu Mitsumata
IPC分类号： A61N1/04 , A61N1/05 , G01N33/483 , G01N33/487 , A61B5/04
CPC分类号： G01N33/48728 , A61N1/0456 , A61N1/0476 , A61N1/0496 , A61N1/0551 , A61N1/0464 , A61N1/0488 , A61N1/0553
摘要： A planar electrode which enables multi-point simultaneous stimulation and recording of nerve cells over a long time is provided, which also has excellent response property. An ITO film is evaporated on the whole surface of an insulating substrate of the hard glass, and the ITO film is etched so that the central portion of each electrode is located on each intersection of 8.times.8 lattices, the center-to-center distances of nearest electrodes of each electrode are equal, and a lead wire is stretched radially. Then, for an insulating layer, negative photo-sensitive polyimide is spin-coated, and an insulating layer pattern is exposure-formed so that a 50 .mu.ms square hole is produced at the center of each electrode. Furthermore, to the exposed portion of each electrode (that is, the inside of the 50 .mu.ms square), Ni is evaporated in a film thickness of 500 nm, which is followed by evaporating gold (50 nm) and platinum black (about 1 .mu.m ). The contact with the external circuit of the section near the end opposite to the electrode of the lead wire was coated with gold and nickel.
摘要翻译：提供了能够长时间多点同时刺激和记录神经细胞的平面电极，其也具有优异的响应特性。在硬质玻璃的绝缘基板的整个表面上蒸发ITO膜，蚀刻ITO膜，使得每个电极的中心部分位于8×8晶格的每个交点上，中心距离最近每个电极的电极相等，引线径向拉伸。然后，对于绝缘层，旋转涂覆负光敏聚酰亚胺，并且将曝光形成绝缘层图案，使得在每个电极的中心处产生50微米的方孔。此外，对于每个电极的曝光部分（即，50μs均方的内部），以500nm的膜厚度蒸发Ni，然后蒸发金（50nm）和铂黑（约1 亩）。与导线的电极相对的端部附近的部分的外部电路的接触涂覆有金和镍。

7. 发明授权

US06297025B1 Measurement of complete electrical waveforms of tissue or cells 失效
标题翻译：测量组织或细胞的完整电波形
公开(公告)号：US06297025B1
公开(公告)日：2001-10-02
申请号：US08662629
申请日：1996-06-13
申请人： Hirokazu Sugihara , Akihito Kamei , Yasushi Kobayashi , Makoto Taketani , Tadayasu Mitsumata
发明人： Hirokazu Sugihara , Akihito Kamei , Yasushi Kobayashi , Makoto Taketani , Tadayasu Mitsumata
IPC分类号： C12Q102
CPC分类号： G01N33/4836 , C12M21/08 , C12M41/00 , C12M41/46
摘要： A method of observing a physical and chemical property of a tissue or cell by using an apparatus which comprises at least a cell culturing means, an environment conditioning means, an observing means and a comparing means, comprising the steps of (A) culturing the tissue or cell by the cell culturing means, (B) maintaining a first physical and chemical environment around the tissue or cell by the cell culturing means, (C) observing a first physical and chemical property of the tissue or cell in the first physical and chemical environment by the observing means, (D) changing the first physical and chemical environment to a second physical and chemical environment by the environment conditioning means, (E) observing a second physical and chemical property of the tissue or cell in the second physical and chemical environment by the observing means, and (F) comparing the first physical and chemical property of the tissue or cell with the second physical and chemical property of the tissue or cell by the comparing means.
摘要翻译：通过使用至少包含细胞培养装置，环境调节装置，观察装置和比较装置的装置观察组织或细胞的物理和化学性质的方法，包括以下步骤：（A）培养组织或细胞，（B）通过细胞培养装置保持组织或细胞周围的第一物理和化学环境;（C）观察第一物理和化学物质中组织或细胞的第一物理和化学性质环境，（D）通过环境调节装置将第一物理化学环境改变为第二物理化学环境;（E）观察第二物理和化学中组织或细胞的第二物理和化学性质环境，以及（F）将组织或细胞的第一物理和化学性质与组织的第二物理和化学性质进行比较或细胞。

8. 发明授权

US6151519A Planar electrode 有权
标题翻译：平面电极
公开(公告)号：US6151519A
公开(公告)日：2000-11-21
申请号：US160252
申请日：1998-09-22
申请人： Hirokazu Sugihara , Makoto Taketani , Tadayasu Mitsumata
发明人： Hirokazu Sugihara , Makoto Taketani , Tadayasu Mitsumata
IPC分类号： A61N1/04 , A61N1/05 , G01N33/483 , G01N33/487 , A61B5/04
CPC分类号： G01N33/48728 , A61N1/0456 , A61N1/0476 , A61N1/0496 , A61N1/0551 , A61N1/0464 , A61N1/0488 , A61N1/0553
摘要： A planar electrode which enables multi-point simultaneous stimulation and recording of nerve cells over a long time is provided, which also has excellent response property. An ITO film is evaporated on the whole surface of an insulating substrate of the hard glass, and the ITO film is etched so that the central portion of each electrode is located on each intersection of 8.times.8 lattices, the center-to-center distances of nearest electrodes of each electrode are equal, and a lead wire is stretched radially. Then, for an insulating layer, negative photo-sensitive polyimide is spin-coated, and an insulating layer pattern is exposure-formed so that a 50 .mu.ms square hole is produced at the center of each electrode. Furthermore, to the exposed portion of each electrode (that is, the inside of the 50 .mu.ms square), Ni is evaporated in a film thickness of 500 nm, which is followed by evaporating gold (50 nm) and platinum black (about 1 .mu.m). The contact with the external circuit of the section near the end opposite to the electrode of the lead wire was coated with gold and nickel.
摘要翻译：提供了能够长时间多点同时刺激和记录神经细胞的平面电极，其也具有优异的响应特性。在硬质玻璃的绝缘基板的整个表面上蒸发ITO膜，蚀刻ITO膜，使得每个电极的中心部分位于8×8晶格的每个交点处，最近的中心距离每个电极的电极相等，引线径向拉伸。然后，对于绝缘层，旋转涂覆负光敏聚酰亚胺，并且将曝光形成绝缘层图案，使得在每个电极的中心处产生50微米的方孔。此外，对于每个电极的曝光部分（即，50μs均方的内部），以500nm的膜厚度蒸发Ni，然后蒸发金（50nm）和铂黑（约1 亩）。与导线的电极相对的端部附近的部分的外部电路的接触涂覆有金和镍。

9. 再颁专利

USRE40209E1 Cell potential measurement apparatus having a plurality of microelectrodes 有权
标题翻译：具有多个微电极的电池电位测量装置
公开(公告)号：USRE40209E1
公开(公告)日：2008-04-01
申请号：US09688077
申请日：2000-10-13
申请人： Hirokazu Sugihara , Akihito Kamei , Yasushi Kobayashi , Makoto Taketani , Tadayasu Mitsumata
发明人： Hirokazu Sugihara , Akihito Kamei , Yasushi Kobayashi , Makoto Taketani , Tadayasu Mitsumata
IPC分类号： C12M1/34
CPC分类号： C12M41/46 , G01N33/48728
摘要： A cell potential measurement apparatus, which uses a planar electrode enabling a multi-point simultaneous measurement of potential change arising from cell activities, is provided which can conduct measurements accurately and efficiently as well as can improve convenience of arranging measurement results. According to the configuration of the cell potential measurement apparatus of this invention, it includes an integrated cell holding instrument, which includes a planar electrode provided with a plurality of microelectrodes arranged in a matrix form on the surface of a substrate, a cell holding part for placing cells thereon, drawer patterns from the microelectrodes, and electric contact points for outside connections; an optical observation means for optical observations of cells; a stimulation signal supply means to be connected to the cell holding instrument for providing electric stimulation to the cells; and a signal processing means to be connected to the cell holding instrument for processing an output signal arising from electric physiological activities of the cells. It is preferable that a cell culturing means is also provided for maintaining a culture atmosphere of the cells placed on the integrated cell holding instrument.
摘要翻译：提供一种电池电位测量装置，其使用能够进行多点同时测量由电池活动引起的电位变化的平面电极，其可以精确且有效地进行测量，并且可以提高排列测量结果的便利性。根据本发明的电池电位测量装置的结构，它包括一个集成的电池保持仪器，它包括一个平面电极，该平面电极设置有以矩阵形式布置在基片表面上的多个微电极，在其上放置电池，来自微电极的抽屉图案和用于外部连接的电接触点; 用于细胞光学观察的光学观察装置; 刺激信号提供装置，连接到用于向细胞提供电刺激的细胞保持仪器; 以及信号处理装置，其连接到用于处理由电池的电生理活动引起的输出信号的电池保持装置。还优选还设置有用于维持放置在集成电池保持器具上的电池的培养气氛的细胞培养装置。

10. 发明授权

US06890762B1 Method for measuring physiocochemical properties of tissues of cells, method for examining chemicals, and apparatus therefor 失效
标题翻译：用于测量细胞组织的生理化学性质的方法，用于检查化学品的方法及其装置
公开(公告)号：US06890762B1
公开(公告)日：2005-05-10
申请号：US08913811
申请日：1997-01-24
申请人： Hirokazu Sugihara , Yasushi Kobayashi , Hiroaki Oka , Ryuta Ogawa , Makoto Taketani
发明人： Hirokazu Sugihara , Yasushi Kobayashi , Hiroaki Oka , Ryuta Ogawa , Makoto Taketani
IPC分类号： C12Q1/02 , G01N33/50 , G01N33/567 , C12Q1/04 , G01N33/48 , G01N33/53 , C12N27/00
CPC分类号： G01N33/5005 , C12Q1/02 , Y10S436/806 , Y10S436/807
摘要： A method of measuring the physical and chemical properties of tissue or cells and a device for the same is provided, with which the physical and chemical environment of the tissue or cells can be changed arbitrarily corresponding to experimental necessities. The device comprises a system 40 for keeping the physical and chemical environment surrounding the biological tissue or cells constant, a system 50 for arbitrarily changing the physical and chemical environment, observation systems 10 and 20 for observing the physical and chemical properties of the tissue or cells, and a system 30 for comparing the change of the physical and chemical properties of the tissue or cells before and after changing the physical and chemical environment. The observation system 10 is a potential measurement device for measuring the electrophysiological properties of the tissue or cells. This device comprises an integrated cell placement device 1 provided with a plurality of microelectrodes 11 on a substrate, a cell placement portion 6 for placing the tissue or cells on the microelectrodes 11, and a wiring pattern 12 for applying an electrical signal to the microelectrodes 11 and extracting an electrical signal from the microelectrodes 11.
摘要翻译：提供了一种测量组织或细胞的物理和化学性质的方法及其装置，通过该方法可以根据实验需要任意改变组织或细胞的物理和化学环境。该装置包括用于保持生物组织或细胞周围的物理和化学环境恒定的系统40，用于任意改变物理和化学环境的系统50，用于观察组织或细胞的物理化学性质的观察系统10和20 以及用于比较在改变物理和化学环境之前和之后组织或细胞的物理和化学性质的变化的系统30。观察系统10是用于测量组织或细胞的电生理特性的电位测量装置。该装置包括在基板上设置有多个微电极11的集成电池放置装置1，用于将组织或电池放置在微电极11上的电池放置部分6以及用于向微电极11施加电信号的布线图案12 以及从微电极11提取电信号。

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