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- 238000012544 monitoring process Methods 0.000 claims description 45
- 238000012634 optical imaging Methods 0.000 claims description 31
- 238000005286 illumination Methods 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 21
- 239000000758 substrate Substances 0.000 claims description 17
- 239000012472 biological sample Substances 0.000 claims description 9
- 230000005284 excitation Effects 0.000 claims description 6
- 238000002073 fluorescence micrograph Methods 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 6
- 238000004458 analytical method Methods 0.000 claims description 4
- 239000003086 colorant Substances 0.000 claims description 4
- 238000004891 communication Methods 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 238000005259 measurement Methods 0.000 claims description 2
- 239000013553 cell monolayer Substances 0.000 claims 2
- 238000003384 imaging method Methods 0.000 claims 2
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002952 image-based readout Methods 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
Description
［実施例４］
［細胞基質インピーダンスと光学撮像の同時監視による薬効の定量化］
実施例ＩＩ～ＩＶに提示されたインピーダンスおよび画像ベースの読み出しを使用して、ＭＧ１３２のＥＣ５０を計算した。薬剤添加時から薬剤添加後６０時間までにわたる曲線下面積をＭＧ１３２濃度の関数としてプロットし、図１６に見られる用量応答曲線を得た。Ｒ２値が０．９６～０．９８の範囲で、４つの異なる読み取り値のフィッティングの質は非常に良好である。計算されたＥＣ５０値は０．８６～３．０μｍの範囲であり、文献で報告されている値と一致している。Han, Y. H.他、The Effect of MG132, a Proteasome Inhibitor on HeLa Cells in Relation to Cell Growth, Reactive Oxygen Species and GSH. Oncol. Rep. 2009, 22(1), 215-21を参照されたい。
なお、出願当初の特許請求の範囲の記載は以下の通りである。
請求項１：
複数の生物学的サンプルを受容するように構成された複数のウェルを有するマルチウェルプレートであって、前記ウェルのそれぞれが一組の電極、電極のない前記ウェルの底面上の透明窓とを含むマルチウェルプレートと、
前記ウェルを照明するように構成された照明モジュールと、
前記ウェルの前記透明窓を露出させるように構成された前記底部に開口部を有し、前記マルチウェルプレートを受け入れるように構成されたクレードルと、
前記露出した窓を通して画像を取り込むために、同じマルチウェルプレートの異なるウェル間で移動可能な光学撮像モジュールと
を備える、生物学的サンプルを電子的および光学的に監視するためのシステム。
請求項２：
前記生物学的サンプルが細胞、任意選択的に癌細胞を含む、請求項１に記載のシステム。
請求項３：
前記照明モジュールが、前記ウェルのうちの１つまたは複数を独立して照明するように構成された複数のライトを備える、請求項１に記載のシステム。
請求項４：
前記照明モジュールが発光ダイオード（ＬＥＤ）アレイを備え、各ＬＥＤが単一のウェルを照明するように配置される、請求項１に記載のシステム。
請求項５：
前記照明モジュールが明視野照明モジュールである、請求項１に記載のシステム。
請求項６：
前記クレードルがヒンジ付きカバーをさらに備え、前記照明モジュールが前記カバーに接合される、請求項１に記載のシステム。
請求項７：
前記クレードルは、前記一組の電極と電子的に通信するための前記マルチウェルプレートと、照明命令を通信するための前記照明モジュールとの両方に電気的に係合する、請求項１に記載のシステム。
請求項８：
前記光学撮像モジュールが、一度に単一のウェルから１つまたは複数の画像を取り込むように構成されている、請求項１に記載のシステム。
請求項９：
前記光学撮像モジュールが前記クレードルの下にある、請求項１に記載のシステム。
請求項１０：
前記光学撮像システムは、１つまたは複数の分子を励起するように構成された励起光源をさらに含み、前記励起光源は、紫外光、紫光、青色光、緑色光、黄色光、橙色光、および赤色光からなる群から選択される１つまたは複数の光を任意選択的に含む、請求項１に記載のシステム。
請求項１１：
前記光学撮像モジュールがカメラを含む、請求項１に記載のシステム。
請求項１２：
前記光学撮像モジュールが、カメラと、バンドパスフィルタと、チューブレンズと、対物レンズとを備える、請求項１に記載のシステム。
請求項１３：
１つまたは複数のウェル内の細胞基質インピーダンスを電子的に監視するための前記一組の電極セットのそれぞれを選択的に操作するための前記クレードルと、
前記１つまたは複数のウェルを選択的に照明するための前記照明モジュールと、
前記１つまたは複数のウェルからの画像の取り込みおよび受信と選択的な動きのための前記光学撮像モジュールと
に通信可能に結合されたコンピュータプロセッサをさらに備える、請求項１に記載のシステム。
請求項１４：
前記コンピュータプロセッサは、前記１つまたは複数のウェルが電子的監視から設定されたインピーダンスベースの値またはインピーダンスベースのパラメータに到達または追従することに応答して、前記光学撮像モジュールを介して前記１つまたは複数のウェルから画像を取り込むようにプログラムされている、請求項１３に記載のシステム。
請求項１５：
前記プロセッサが、細胞基質インピーダンスを電子的に監視し、同じウェルを光学的に監視するようにプログラムされ、表示または分析のためにインピーダンスと光学データとを対にするように構成されている、請求項１３に記載のシステム。
請求項１６：
それぞれが複数のサンプルを受け取るように構成された複数のウェルを有し、前記ウェルのそれぞれが一組の電極と、電極のない前記ウェルの底面上の透明窓とを含む２つの追加のマルチウェルプレートと、
前記２つの追加のマルチウェルプレートの前記ウェルを照明するように構成された２つの追加の照明モジュールと、
それぞれが前記ウェルの前記透明窓を露出させる開放底を有し、前記２つの追加のマルチウェルプレートを受け入れるように構成された２つの追加のクレードルと
をさらに備え、
前記光学撮像モジュールは、すべての窓を通して画像を取り込むために、すべてのウェルにわたって移動可能である、請求項１に記載のシステム。
請求項１７：
電子監視用に構成されていない細胞または組織培養容器をさらに備え、前記光学撮像モジュールは、前記細胞または組織培養容器内の画像を取り込むように構成されている、請求項１に記載のシステム。
請求項１８：
マルチウェルプレートのウェル内の細胞を、連続監視間の特定の時間間隔で、ある期間にわたって連続的に電子的に監視するステップであって、前記ウェルのそれぞれが、一組の細胞基質インピーダンス監視電極と、電極のない前記ウェルの底面上の透明窓とを含むステップと、
電子的に監視されている少なくとも１つのウェルから前記透明窓を通して画像を取り込むステップと
を含む、細胞を監視する方法。
請求項１９：
前記画像は、前記電子監視期間内の期間にわたって定期的または不定期に取り込まれ、前記方法は、前記細胞の電子測定を実行すると同時に前記画像を取り込むステップを任意選択的に含む、請求項１８に記載の方法。
請求項２０：
前記少なくとも１つのウェルから画像を取り込む前記ステップの前に、前記電子監視ステップが、設定値を満たす前記少なくとも１つのウェルからの結果を出力し、前記光学撮像モジュールに前記少なくとも１つのウェルから前記画像を取り込むように指示する、請求項１８に記載の方法。
請求項２１：
前記取得される画像が細胞の明視野画像を含み、前記明視野画像から細胞コンフルエンス数またはパラメータを決定し、任意選択的に細胞を計数するステップをさらに含む請求項１８に記載の方法。
請求項２２：
前記取り込まれた画像が細胞の蛍光画像を含み、総蛍光計数と、総蛍光強度と、平均蛍光強度とからなる群のうちの１つまたは複数から任意選択的に選択される画像から蛍光パラメータを決定するステップをさらに含む請求項１８に記載の方法。
請求項２３：
前記取得された画像は、前記細胞の明視野画像および前記細胞の蛍光画像を含み、
前記明視野画像から細胞コンフルエンス数またはパラメータを導出し、任意選択的に前記明視野画像から細胞を計数するステップと、
総蛍光計数と、総蛍光強度と、平均蛍光強度とからなる群のうちの１つまたは複数から任意選択的に選択される、蛍光画像からの蛍光パラメータを決定するステップと、
任意選択的に、前記明視野画像および蛍光画像、または同じウェルの１つまたは複数の色を重ね合わせるステップと
をさらに含む請求項１８に記載の方法。
請求項２４：
ある期間にわたってマルチウェルプレートのウェル内の細胞を電子的に監視するステップであって、前記ウェルのそれぞれが、一組の細胞基質インピーダンス監視電極と、電極のない前記ウェルの底面上の透明窓とを構成するステップと、
前記マルチウェルプレートの少なくとも１つのウェルから、前記透明窓を通して、電子的監視の前記期間内の期間にわたって画像を取り込むステップと
を含む細胞を監視する方法。
請求項２５：
前記取得される画像は前記細胞の明視野画像であり、前記明視野画像から細胞を計数するステップ、または細胞コンフルエンス数またはパラメータを決定するステップを任意選択的に含み、
前記取得される画像は、前記細胞の蛍光画像であり、総蛍光計数と、総蛍光強度と、平均蛍光強度とからなる群のうちの１つまたは複数から任意選択的に選択される、前記画像からある蛍光パラメータを任意選択的に決定するステップを含み、
前記取得される画像は、前記細胞の明視野画像と前記細胞の蛍光画像とを含むもので、
前記明視野画像から細胞を計数することと、任意選択的に前記明視野画像から細胞コンフルエンス数またはパラメータを導き出すことと、任意選択的に、総蛍光計数と、総蛍光強度と、平均蛍光強度とからなる群のうちの１つまたは複数から選択される、前記蛍光画像からの蛍光パラメータを決定することと、任意選択的に、１つまたは複数の前記ウェルについて、１つまたは複数の色の前記明視野画像と蛍光画像とを重ね合わせることとをさらに含む請求項２４に記載の方法。
[Example 4]
Quantifying drug efficacy by simultaneous monitoring of cell-substrate impedance and optical imaging
Using the impedance and image-based readouts presented in Examples II-IV, the EC50 of MG132 was calculated. The area under the curve from the time of drug addition to 60 hours after drug addition was plotted as a function of MG132 concentration, resulting in the dose-response curve seen in FIG. 16. The quality of the fit of the four different readouts is very good, with R2 values ranging from 0.96 to 0.98. The calculated EC50 values range from 0.86 to 3.0 μm, which is consistent with values reported in the literature. See Han, YH et al., The Effect of MG132, a Proteasome Inhibitor on HeLa Cells in Relation to Cell Growth, Reactive Oxygen Species and GSH. Oncol. Rep. 2009, 22(1), 215-21.
The claims as originally filed are as follows:
Claim 1:
a multiwell plate having a plurality of wells configured to receive a plurality of biological samples, each of the wells including a set of electrodes, a transparent window on a bottom surface of the well that is free of electrodes;
an illumination module configured to illuminate the well;
a cradle configured to receive the multiwell plate, the cradle having an opening at the bottom configured to expose the transparent windows of the wells;
an optical imaging module movable between different wells of the same multiwell plate to capture images through the exposed windows;
A system for electronically and optically monitoring a biological sample comprising:
Claim 2:
The system of claim 1 , wherein the biological sample comprises cells, optionally cancer cells.
Claim 3:
The system of claim 1 , wherein the illumination module comprises a plurality of lights configured to independently illuminate one or more of the wells.
Claim 4:
10. The system of claim 1, wherein the illumination module comprises an array of light emitting diodes (LEDs), each LED positioned to illuminate a single well.
Claim 5:
The system of claim 1 , wherein the illumination module is a bright field illumination module.
Claim 6:
The system of claim 1 , wherein the cradle further comprises a hinged cover, the lighting module being joined to the cover.
Claim 7:
10. The system of claim 1, wherein the cradle electrically engages both the multiwell plate for electronic communication with the set of electrodes and the illumination module for communicating illumination commands.
Claim 8:
The system of claim 1 , wherein the optical imaging module is configured to capture one or more images from a single well at a time.
Claim 9:
The system of claim 1 , wherein the optical imaging module is located below the cradle.
Claim 10:
10. The system of claim 1, wherein the optical imaging system further comprises an excitation light source configured to excite one or more molecules, the excitation light source optionally comprising one or more lights selected from the group consisting of ultraviolet light, violet light, blue light, green light, yellow light, orange light, and red light.
Claim 11:
The system of claim 1 , wherein the optical imaging module comprises a camera.
Claim 12:
The system of claim 1 , wherein the optical imaging module comprises a camera, a bandpass filter, a tube lens, and an objective lens.
Claim 13:
the cradle for selectively manipulating each of the set of electrodes for electronically monitoring cell-substrate impedance in one or more wells;
the illumination module for selectively illuminating the one or more wells;
said optical imaging module for selective movement and capture and reception of images from said one or more wells;
The system of claim 1 , further comprising a computer processor communicatively coupled to the
Claim 14:
14. The system of claim 13, wherein the computer processor is programmed to capture images from the one or more wells via the optical imaging module in response to the one or more wells reaching or following a set impedance-based value or impedance-based parameter from electronic monitoring.
Claim 15:
14. The system of claim 13, wherein the processor is programmed to electronically monitor cell substrate impedance and optically monitor the same wells and configured to pair impedance and optical data for display or analysis.
Claim 16:
two additional multi-well plates each having a plurality of wells configured to receive a plurality of samples, each of the wells including a set of electrodes and a transparent window on a bottom surface of the well that does not include electrodes;
two additional illumination modules configured to illuminate the wells of the two additional multiwell plates;
two additional cradles, each having an open bottom exposing the transparent windows of the wells, configured to receive the two additional multiwell plates;
Further equipped with
The system of claim 1 , wherein the optical imaging module is movable across all wells to capture images through all windows.
Claim 17:
10. The system of claim 1, further comprising a cell or tissue culture vessel not configured for electronic monitoring, wherein the optical imaging module is configured to capture images within the cell or tissue culture vessel.
Claim 18:
Continuously electronically monitoring cells in wells of a multi-well plate over a period of time with specific time intervals between successive monitoring, each of said wells containing a set of cell substrate impedance monitoring electrodes and a transparent window on the bottom of said well that is devoid of electrodes;
capturing an image through said transparent window from at least one well being electronically monitored;
A method for monitoring a cell, comprising:
Claim 19:
20. The method of claim 18, wherein the images are captured periodically or irregularly over a period of time within the electronic monitoring period, the method optionally including the step of capturing the images simultaneously with performing electronic measurements of the cells.
Claim 20:
20. The method of claim 18, wherein prior to the step of capturing an image from the at least one well, the electronic monitoring step outputs a result from the at least one well that meets a set value and instructs the optical imaging module to capture the image from the at least one well.
Claim 21:
20. The method of claim 18, wherein the acquired images include brightfield images of cells, further comprising determining a cell confluence number or parameter from the brightfield images and optionally counting cells.
Claim 22:
20. The method of claim 18, wherein the captured images include fluorescent images of cells, further comprising determining a fluorescent parameter from the images optionally selected from one or more of the group consisting of: total fluorescent count, total fluorescent intensity, and mean fluorescent intensity.
Claim 23:
the acquired images include a bright field image of the cell and a fluorescent image of the cell;
Deriving a cell confluence number or parameter from said brightfield image and optionally counting cells from said brightfield image;
determining a fluorescence parameter from the fluorescence image, optionally selected from one or more of the group consisting of: total fluorescence count, total fluorescence intensity, and mean fluorescence intensity;
Optionally, overlaying the bright field image and the fluorescent image, or one or more colors, of the same well.
20. The method of claim 18 further comprising:
Claim 24:
electronically monitoring cells in wells of a multi-well plate over a period of time, each of said wells comprising a set of cell substrate impedance monitoring electrodes and a transparent window on the bottom of said well that is devoid of electrodes;
capturing images from at least one well of said multi-well plate through said transparent window for a period within said period of electronic monitoring;
A method for monitoring cells comprising:
Claim 25:
the acquired image is a brightfield image of the cells, optionally comprising counting cells or determining a cell confluence number or parameter from the brightfield image;
the acquired image is a fluorescent image of the cells, optionally comprising determining a fluorescent parameter from the image, optionally selected from one or more of the group consisting of: total fluorescent count, total fluorescent intensity, and mean fluorescent intensity;
the acquired images include a bright field image of the cell and a fluorescent image of the cell;
25. The method of claim 24, further comprising counting cells from the brightfield image, optionally deriving a cell confluence number or parameter from the brightfield image, optionally determining a fluorescence parameter from the fluorescence image selected from one or more of the group consisting of total fluorescence count, total fluorescence intensity, and mean fluorescence intensity, and optionally overlaying the brightfield image and fluorescence image of one or more colors for one or more of the wells.
Claims (35)
前記ウェルを照明するように構成された照明モジュールと、
前記ウェルの前記透明窓を露出させるように構成された前記底部に開口部を有し、前記マルチウェルプレートを受け入れるように構成されたクレードルと、
前記露出した窓を通して画像を取り込むために、同じマルチウェルプレートの異なるウェル間で移動可能な光学撮像モジュールと、
１つまたは複数のウェル内の細胞基質インピーダンスを電子的に監視する前記一組の電極のそれぞれを選択的に操作するコンピュータプロセッサと
を備え、
前記照明モジュールは、１つまたは複数のウェルを選択的に照明するためであり、前記光学撮像モジュールは、選択的な動きならびに１つまたは複数のウェルからの画像の取り込みおよび受信のためであり、
前記コンピュータプロセッサは、１つまたは複数のウェルが電子的監視から設定されたインピーダンスベースの値またはパラメータに到達または追従することに応答して、光学撮像モジュールを介して１つまたは複数のウェルから画像を取り込むようにプログラムされている、生物学的サンプルを電子的および光学的に監視するためのシステム。 a multiwell plate having a plurality of wells configured to receive a plurality of biological samples, each of the wells including a set of electrodes, a transparent window on a bottom surface of the well that is free of electrodes;
an illumination module configured to illuminate the well;
a cradle configured to receive the multiwell plate, the cradle having an opening at the bottom configured to expose the transparent windows of the wells;
an optical imaging module movable between different wells of the same multi-well plate to capture images through the exposed windows ;
a computer processor for selectively operating each of said set of electrodes to electronically monitor cell-substrate impedance within one or more wells;
Equipped with
the illumination module is for selectively illuminating one or more wells, and the optical imaging module is for selectively moving and capturing and receiving images from one or more wells;
A system for electronically and optically monitoring a biological sample, wherein the computer processor is programmed to capture images from one or more wells via the optical imaging module in response to the one or more wells reaching or following a set impedance-based value or parameter from the electronic monitoring.
前記１つまたは複数のウェルを選択的に照明するための前記照明モジュールと、
前記１つまたは複数のウェルからの画像の取り込みおよび受信と選択的な動きのための前記光学撮像モジュールと
に通信可能に結合されたコンピュータプロセッサをさらに備える、請求項１に記載のシステム。 the cradle for selectively manipulating each of the set of electrodes for electronically monitoring cell-substrate impedance in one or more wells;
the illumination module for selectively illuminating the one or more wells;
10. The system of claim 1, further comprising a computer processor communicatively coupled to the optical imaging module for selective movement and for capturing and receiving images from the one or more wells.
前記２つの追加のマルチウェルプレートの前記ウェルを照明するように構成された２つの追加の照明モジュールと、
それぞれが前記ウェルの前記透明窓を露出させる開放底を有し、前記２つの追加のマルチウェルプレートを受け入れるように構成された２つの追加のクレードルと
をさらに備え、
前記光学撮像モジュールは、すべての窓を通して画像を取り込むために、すべてのウェルにわたって移動可能である、請求項１に記載のシステム。 two additional multi-well plates each having a plurality of wells configured to receive a plurality of samples, each of the wells including a set of electrodes and a transparent window on a bottom surface of the well that does not include electrodes;
two additional illumination modules configured to illuminate the wells of the two additional multiwell plates;
and two additional cradles, each having an open bottom exposing the transparent windows of the wells, configured to receive the two additional multiwell plates;
The system of claim 1 , wherein the optical imaging module is movable across all wells to capture images through all windows.
電子的に監視されている少なくとも１つのウェルから前記透明窓を通して画像を取り込むステップであって、前記少なくとも１つのウェルから画像を取り込む前記ステップの前に、前記電子監視ステップが、設定値を満たす前記少なくとも１つのウェルからの結果を出力し、前記光学撮像モジュールに前記少なくとも１つのウェルから前記画像を取り込むように指示する、画像を取り込むステップと
を含む、細胞を監視する方法。 Continuously electronically monitoring cells in wells of a multi-well plate over a period of time with specific time intervals between successive monitoring, each of said wells containing a set of cell substrate impedance monitoring electrodes and a transparent window on the bottom of said well that is devoid of electrodes;
and capturing an image through the transparent window from at least one well that is being electronically monitored , wherein prior to the step of capturing an image from the at least one well, the electronic monitoring step outputs a result from the at least one well that meets a set value and instructs the optical imaging module to capture the image from the at least one well .
前記明視野画像から細胞コンフルエンス数またはパラメータを導出し、任意選択的に前記明視野画像から細胞を計数するステップと、
総蛍光計数と、総蛍光強度と、平均蛍光強度とからなる群のうちの１つまたは複数から任意選択的に選択される、前記蛍光画像からの蛍光パラメータを決定するステップと、
任意選択的に、前記明視野画像および蛍光画像、または同じウェルの１つまたは複数の色を重ね合わせるステップと
をさらに含む請求項１８に記載の方法。 the acquired images include a bright field image of the cell and a fluorescent image of the cell;
Deriving a cell confluence number or parameter from said brightfield image and optionally counting cells from said brightfield image;
determining a fluorescence parameter from the fluorescence image, optionally selected from one or more of the group consisting of: total fluorescence count, total fluorescence intensity, and mean fluorescence intensity;
20. The method of claim 18, further comprising optionally overlaying the bright field image and the fluorescent image, or one or more colors, of the same well.
前記マルチウェルプレートの少なくとも１つのウェルから、前記透明窓を通して、電子的監視の前記期間内または前記期間外の期間にわたって画像を取り込むステップと
を含み、
細胞を電子的に監視する前記ステップおよび画像を取り込む前記ステップは、
ｉ）細胞基質インピーダンスを電子的に監視し、前記同じウェルの画像を取り込み、表示または分析のためにインピーダンスと光学データを対にすることと、
ｉｉ）１つまたは複数のウェルが前記電子的監視から設定されたインピーダンスベースの値またはパラメータに到達または追従することに応答して、前記少なくとも１つのウェルから画像を取り込むことと、
ｉｉｉ）２つの連続する電子インピーダンス監視間の特定の時間間隔を含む期間にわたって細胞基質インピーダンスを電子的に監視し、電子的監視の前記期間内の期間、または電子的監視とは異なる期間にわたって前記同じウェルの画像を取り込むことと
のうちの１つまたは複数により結合される、細胞を監視する方法。 electronically monitoring cells in wells of a multi-well plate over a period of time, each of said wells comprising a set of cell substrate impedance monitoring electrodes and a transparent window on the bottom of said well that is devoid of electrodes;
capturing images from at least one well of said multi-well plate through said transparent window for periods during and outside said period of electronic monitoring ;
The steps of electronically monitoring the cells and capturing images include:
i) electronically monitoring cell-substrate impedance and capturing images of the same wells and pairing impedance and optical data for display or analysis;
ii) capturing an image from one or more wells in response to said at least one well reaching or following a set impedance-based value or parameter from said electronic monitoring;
iii) electronically monitoring cell substrate impedance over a period of time that includes a specific time interval between two successive electronic impedance monitors, and capturing images of the same well over a period of time within the period of electronic monitoring or over a period of time that is different from the electronic monitoring.
The method of claim 1, wherein the cell is bound by one or more of the following :
前記取得される画像は、前記細胞の蛍光画像であり、総蛍光計数と、総蛍光強度と、平均蛍光強度とからなる群のうちの１つまたは複数から任意選択的に選択される、前記画像からある蛍光パラメータを任意選択的に決定するステップを含み、
前記取得される画像は、前記細胞の明視野画像と前記細胞の蛍光画像とを含むもので、
前記明視野画像から細胞を計数し、任意選択的に前記明視野画像から細胞コンフルエンス数またはパラメータを導き出すことと、任意選択的に、総蛍光計数と、総蛍光強度と、平均蛍光強度とからなる群のうちの１つまたは複数から選択される前記蛍光画像からの蛍光パラメータを決定することと、任意選択的に、１つまたは複数の前記ウェルについて、１つまたは複数の色の前記明視野画像と蛍光画像とを重ね合わせることとをさらに含む請求項２３に記載の方法。 the acquired image is a brightfield image of the cells, optionally comprising counting cells or determining a cell confluence number or parameter from the brightfield image;
the acquired image is a fluorescent image of the cells, optionally comprising determining a fluorescent parameter from the image, optionally selected from one or more of the group consisting of: total fluorescent count, total fluorescent intensity, and mean fluorescent intensity;
the acquired images include a bright field image of the cell and a fluorescent image of the cell;
24. The method of claim 23, further comprising counting cells from the brightfield image, and optionally deriving a cell confluence number or parameter from the brightfield image, optionally determining a fluorescence parameter from the fluorescence image selected from one or more of the group consisting of total fluorescence count, total fluorescence intensity, and mean fluorescence intensity, and optionally overlaying the brightfield image and fluorescence image of one or more colors for one or more of the wells.
前記ウェルを撮像する光学撮像モジュールと、an optical imaging module for imaging the well;
前記ウェルを照明するように構成された照明モジュールと、an illumination module configured to illuminate the well;
細胞基質インピーダンスを電子的に監視し、同じウェルを光学的に監視するようにプログラムされるコンピュータプロセッサであって、a computer processor programmed to electronically monitor cell substrate impedance and optically monitor the same wells,
ｉ）細胞基質インピーダンスを電子的に監視し、前記同じウェルの画像を取り込み、表示または分析のためにインピーダンスと光学データを対にすることと、i) electronically monitoring cell-substrate impedance and capturing images of the same wells and pairing impedance and optical data for display or analysis;
ｉｉ）１つまたは複数のウェルが前記電子的監視から設定されたインピーダンスベースの値またはパラメータに到達または追従することに応答して、前記少なくとも１つのウェルから画像を取り込むことと、ii) capturing an image from one or more wells in response to said at least one well reaching or following a set impedance-based value or parameter from said electronic monitoring;
ｉｉｉ）２つの連続する電子インピーダンス監視間の特定の時間間隔を含む期間にわたって細胞基質インピーダンスを電子的に監視し、電子的監視の前記期間内の期間、または電子的監視とは異なる期間にわたって前記同じウェルの画像を取り込むこととiii) electronically monitoring cell substrate impedance over a period of time that includes a specific time interval between two successive electronic impedance monitors, and capturing images of the same well over a period of time within the period of electronic monitoring or over a period of time that is different from the electronic monitoring.
のうちの１つまたは複数により結合されるように、インピーダンスと光学データとを結合するように構成されている、コンピュータプロセッサとa computer processor configured to combine the impedance and optical data such that the impedance and optical data are coupled by one or more of the following:
を備える、生物学的サンプルを電子的および光学的に監視するためのシステム。A system for electronically and optically monitoring a biological sample comprising:
前記コンピュータプロセッサは、前記光学撮像モジュールと前記照明モジュールとに通信可能に結合されて、１つまたは複数のウェル内の細胞基質インピーダンスを電子的に監視するための前記一組の電極セットのそれぞれを選択的に操作し、前記１つまたは複数のウェルを選択的に照明し、１つまたは複数のウェルからの画像の取り込みおよび受信のための前記光学撮像モジュールを選択的に操作する、請求項３０に記載のシステム。31. The system of claim 30, wherein the computer processor is communicatively coupled to the optical imaging module and the illumination module to selectively operate each of the sets of electrodes for electronically monitoring cell substrate impedance in one or more wells, selectively illuminate the one or more wells, and selectively operate the optical imaging module for capturing and receiving images from one or more wells.
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