CA2324262A1 - Confocal microscopy imaging system - Google Patents
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- CA2324262A1 CA2324262A1 CA002324262A CA2324262A CA2324262A1 CA 2324262 A1 CA2324262 A1 CA 2324262A1 CA 002324262 A CA002324262 A CA 002324262A CA 2324262 A CA2324262 A CA 2324262A CA 2324262 A1 CA2324262 A1 CA 2324262A1
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- 238000004624 confocal microscopy Methods 0.000 title 1
- 238000003384 imaging method Methods 0.000 title 1
- 238000010226 confocal imaging Methods 0.000 claims abstract 24
- 238000000034 method Methods 0.000 claims 54
- 230000005670 electromagnetic radiation Effects 0.000 claims 52
- 239000000758 substrate Substances 0.000 claims 50
- 238000003556 assay Methods 0.000 claims 45
- 238000001514 detection method Methods 0.000 claims 26
- 230000005855 radiation Effects 0.000 claims 19
- 238000004166 bioassay Methods 0.000 claims 13
- 238000002714 localization assay Methods 0.000 claims 10
- 238000000159 protein binding assay Methods 0.000 claims 10
- 230000009087 cell motility Effects 0.000 claims 5
- 150000001875 compounds Chemical class 0.000 claims 5
- 238000001952 enzyme assay Methods 0.000 claims 5
- 238000002866 fluorescence resonance energy transfer Methods 0.000 claims 5
- 208000015181 infectious disease Diseases 0.000 claims 5
- 238000003367 kinetic assay Methods 0.000 claims 5
- 230000033001 locomotion Effects 0.000 claims 5
- 238000007826 nucleic acid assay Methods 0.000 claims 5
- 210000003463 organelle Anatomy 0.000 claims 5
- 230000026447 protein localization Effects 0.000 claims 5
- 230000007398 protein translocation Effects 0.000 claims 5
- 239000003642 reactive oxygen metabolite Substances 0.000 claims 5
- 238000007423 screening assay Methods 0.000 claims 5
- 238000001890 transfection Methods 0.000 claims 5
- 238000012544 monitoring process Methods 0.000 claims 4
- 230000003287 optical effect Effects 0.000 claims 3
- 239000003153 chemical reaction reagent Substances 0.000 claims 2
- 238000001914 filtration Methods 0.000 claims 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5002—Partitioning blood components
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B21/00—Microscopes
- G02B21/0004—Microscopes specially adapted for specific applications
- G02B21/002—Scanning microscopes
- G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
- G02B21/0028—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders specially adapted for specific applications, e.g. for endoscopes, ophthalmoscopes, attachments to conventional microscopes
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B21/00—Microscopes
- G02B21/0004—Microscopes specially adapted for specific applications
- G02B21/002—Scanning microscopes
- G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
- G02B21/0052—Optical details of the image generation
- G02B21/006—Optical details of the image generation focusing arrangements; selection of the plane to be imaged
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B21/00—Microscopes
- G02B21/0004—Microscopes specially adapted for specific applications
- G02B21/002—Scanning microscopes
- G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
- G02B21/0052—Optical details of the image generation
- G02B21/0064—Optical details of the image generation multi-spectral or wavelength-selective arrangements, e.g. wavelength fan-out, chromatic profiling
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B21/00—Microscopes
- G02B21/0004—Microscopes specially adapted for specific applications
- G02B21/002—Scanning microscopes
- G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
- G02B21/0052—Optical details of the image generation
- G02B21/0072—Optical details of the image generation details concerning resolution or correction, including general design of CSOM objectives
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B21/00—Microscopes
- G02B21/0004—Microscopes specially adapted for specific applications
- G02B21/002—Scanning microscopes
- G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
- G02B21/0052—Optical details of the image generation
- G02B21/0076—Optical details of the image generation arrangements using fluorescence or luminescence
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B21/00—Microscopes
- G02B21/0004—Microscopes specially adapted for specific applications
- G02B21/002—Scanning microscopes
- G02B21/0024—Confocal scanning microscopes (CSOMs) or confocal "macroscopes"; Accessories which are not restricted to use with CSOMs, e.g. sample holders
- G02B21/008—Details of detection or image processing, including general computer control
- G02B21/0084—Details of detection or image processing, including general computer control time-scale detection, e.g. strobed, ultra-fast, heterodyne detection
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
- G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/645—Specially adapted constructive features of fluorimeters
- G01N21/6456—Spatial resolved fluorescence measurements; Imaging
- G01N21/6458—Fluorescence microscopy
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Abstract
A confocal imaging system utilizing an elongated beam. Specific embodiments are directed to the apparatus with charged couple devices (CCD) and those in which the apparatus is used in fluorescent object observation.
Claims (66)
1. A confocal imaging system comprising:
a) a means for forming an elongated beam of electromagnetic radiation extending transverse to an optical axis along which the radiation propagates;
b) a means for directing and focusing the elongated beam onto a first elongated region in a first plane where an object is located and for directing electromagnetic radiation emitted from the object onto one or more second elongated regions, wherein each second elongated region is on a different second plane conjugate to the first plane;
c) in at least one of the second conjugate planes, or in a third plane conjugate to at least one of the second conjugate planes, a detection device comprising a rectangular array of detection elements on which the electromagnetic radiation emitted from the object is coincident; and d) a means for scanning the object by moving the elongated beam relative to the object or by moving the object relative to the elongated beam such that the emitted electromagnetic radiation is delivered to the rectangular array of detection elements and is converted by the detection device into a plurality of electrical signals representative of the emitted electromagnetic radiation synchronously with said scanning.
a) a means for forming an elongated beam of electromagnetic radiation extending transverse to an optical axis along which the radiation propagates;
b) a means for directing and focusing the elongated beam onto a first elongated region in a first plane where an object is located and for directing electromagnetic radiation emitted from the object onto one or more second elongated regions, wherein each second elongated region is on a different second plane conjugate to the first plane;
c) in at least one of the second conjugate planes, or in a third plane conjugate to at least one of the second conjugate planes, a detection device comprising a rectangular array of detection elements on which the electromagnetic radiation emitted from the object is coincident; and d) a means for scanning the object by moving the elongated beam relative to the object or by moving the object relative to the elongated beam such that the emitted electromagnetic radiation is delivered to the rectangular array of detection elements and is converted by the detection device into a plurality of electrical signals representative of the emitted electromagnetic radiation synchronously with said scanning.
2. The confocal imaging system according to claim 1 further comprising:
a) an elongated spatial filter having a long axis which is aligned with the second elongated region; and b) a means for forming, on the detection device, an image of the second conjugate plane.
a) an elongated spatial filter having a long axis which is aligned with the second elongated region; and b) a means for forming, on the detection device, an image of the second conjugate plane.
3. The confocal imaging system according to claim 1, wherein the elongated beam of electromagnetic radiation directed onto the object comprises two or more wavelengths.
4. The confocal imaging system according to claim 2, wherein the spatial filter has a variable width.
5. The confocal imaging system according to claim 1, wherein the detection device comprises an m x n array of detector elements wherein m is the number of detector elements in a first dimension of the array and n is the number of detector elements in a second dimension of the array and n is greater than m.
6. The confocal imaging system according to claim 5, wherein the elongated region on which the emitted electromagnetic radiation is directed has a long axis that is aligned with the array of the detection device, so that the long axis extends in the same direction as the second dimension.
7. The confocal imaging system according to claim 5, wherein at least two detector elements forming a column extending in the first dimension of the array are binned together.
8. The confocal imaging system according to claim 5, wherein a plurality of detector elements of the array are binned together.
9. The confocal imaging system according to claim 5, wherein the detection device is a CCD array.
10. The confocal imaging system according to claim 1, wherein the detection device is a rectangular format CCD array.
11. The confocal imaging system according to claim 1, wherein the radiation emitted from the object is fluorescent radiation.
12. The confocal imaging system according to claim 1, wherein the object is located on a discontinuous surface of a substrate that has a continuous surface extending in the same direction as the discontinuous surface, said system further comprising a focus system comprising:
a) a first focusing beam of electromagnetic radiation having a first wavelength, said first beam being directed through the objective lens to the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
b) a second focusing beam of electromagnetic radiation having a second wavelength, said second beam being directed through the objective lens to the continuous surface and reflected by said continuous surface back through the objective lens;
c) a means for separating the radiation of the first wavelength from the radiation of the second wavelength that is reflected back through the objective lens;
d) a first detector for detecting the first focusing beam reflected by the discontinuous surface back through the objective lens;
e) a second detector for detecting the second focusing beam reflected by the continuous surface back through the objective lens;
f) a moving means for moving the objective lens relative to the substrate or the substrate relative to the objective lens; and g) a controller connected to the first and second detectors and the moving means, wherein the controller operates the moving means in response to a signal from the first detector or the second detector according to the position of the first focusing beam or the second focusing beam on the substrate.
a) a first focusing beam of electromagnetic radiation having a first wavelength, said first beam being directed through the objective lens to the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
b) a second focusing beam of electromagnetic radiation having a second wavelength, said second beam being directed through the objective lens to the continuous surface and reflected by said continuous surface back through the objective lens;
c) a means for separating the radiation of the first wavelength from the radiation of the second wavelength that is reflected back through the objective lens;
d) a first detector for detecting the first focusing beam reflected by the discontinuous surface back through the objective lens;
e) a second detector for detecting the second focusing beam reflected by the continuous surface back through the objective lens;
f) a moving means for moving the objective lens relative to the substrate or the substrate relative to the objective lens; and g) a controller connected to the first and second detectors and the moving means, wherein the controller operates the moving means in response to a signal from the first detector or the second detector according to the position of the first focusing beam or the second focusing beam on the substrate.
13. The confocal image system according to claim 1, wherein the scanning means comprises a rotating optical element for moving the elongated beam across the object.
14. The confocal image system according to claim l, wherein the scanning means comprises a movable stage on which the object is located.
15. The confocal image system according to claim 1 further comprising a means for dispensing a reagent into the first plane where the object is located.
16. The confocal image system according to claim 1 further comprising a means for controlling the temperature of the object.
17. The confocal imaging system according to claim 2, wherein the elongated beam of the electromagnetic radiation directed onto the object comprises one or more wavelengths and wherein the second plane is singular.
18. The confocal imaging system according to any one of claims 1, 3 or 17 wherein two or more wavelengths of electromagnetic radiation are emitted from the object in the first elongated region in the first plane, said system further comprising a means for separating the emitted wavelengths to detect at least one of the separated wavelengths by one or more detection devices.
19. The confocal imaging system according to claim 1, wherein the object is located on a discontinuous surface of a substrate comprising a continuous surface extending in the same direction as the discontinuous surface, said system further comprising a focusing system comprising:
a) a focusing beam of electromagnetic radiation directed through the objective lens to the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
b) a focus detector for detecting the focusing beam reflected by the discontinuous surface back through the objective lens;
c) a moving means for moving the objective lens relative to the substrate or the substrate relative to the objective lens; and d) a controller connected to the focus detector and the moving means, wherein the controller adjusts the moving means in response to a signal from the focus detector according to the position of the focusing beam on the substrate.
a) a focusing beam of electromagnetic radiation directed through the objective lens to the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
b) a focus detector for detecting the focusing beam reflected by the discontinuous surface back through the objective lens;
c) a moving means for moving the objective lens relative to the substrate or the substrate relative to the objective lens; and d) a controller connected to the focus detector and the moving means, wherein the controller adjusts the moving means in response to a signal from the focus detector according to the position of the focusing beam on the substrate.
20. The confocal imaging system according to claim 12, wherein the first and second wavelengths are the same.
21. The confocal imaging system according to claim 12 or 19, wherein the controller comprises a computer.
22. The confocal imaging system according to claim 12 or 19, wherein the substrate is a microtiter plate and the discontinuous surface is a bottom of a well in the microtiter plate.
23. The confocal imaging system according to claim 18, wherein the object is located on a discontinuous surface of a substrate comprising a continuous surface extending in the same direction as the discontinuous surface and wherein two or more wavelengths of electromagnetic radiation are emitted from the object, said system further comprising a focus system comprising:
a) a first focusing beam of electromagnetic radiation having a first wavelength, said first beam being directed through the objective lens to the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
b) a second focusing beam of electromagnetic radiation having a second wavelength, said second beam being directed through the objective lens to the continuous surface and reflected by said continuous surface back through the objective lens;
c) a means for separating the radiation of the first wavelength from the radiation of the second wavelength that is reflected back through the objective lens;
d) a first detector for detecting the first focusing beam reflected by the discontinuous surface back through the objective lens;
e) a second detector for detecting the second focusing beam reflected by the continuous surface back through the objective lens;
f) a moving means for moving the objective lens relative to the substrate or the substrate relative to the objective lens; and g) a controller connected to the first and second detectors and the moving means, wherein the controller operates the moving means in response to a signal from the first detector or the second detector according to the position of the first focusing beam or the second focusing beam on the substrate.
a) a first focusing beam of electromagnetic radiation having a first wavelength, said first beam being directed through the objective lens to the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
b) a second focusing beam of electromagnetic radiation having a second wavelength, said second beam being directed through the objective lens to the continuous surface and reflected by said continuous surface back through the objective lens;
c) a means for separating the radiation of the first wavelength from the radiation of the second wavelength that is reflected back through the objective lens;
d) a first detector for detecting the first focusing beam reflected by the discontinuous surface back through the objective lens;
e) a second detector for detecting the second focusing beam reflected by the continuous surface back through the objective lens;
f) a moving means for moving the objective lens relative to the substrate or the substrate relative to the objective lens; and g) a controller connected to the first and second detectors and the moving means, wherein the controller operates the moving means in response to a signal from the first detector or the second detector according to the position of the first focusing beam or the second focusing beam on the substrate.
24. The confocal imaging system according to claim 18, wherein the object is located on a discontinuous surface of a substrate comprising a continuous surface extending in the same direction as the discontinuous surface and wherein two or more wavelengths of electromagnetic radiation are emitted from the object, said system further comprising a focusing system comprising:
a) a focusing beam of electromagnetic radiation directed through the objective lens to the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
b) a focus detector for detecting the focusing beam reflected by the discontinuous surface back through the objective lens;
c) a moving means for moving the objective lens relative to the substrate or the substrate relative to the objective lens; and d) a controller connected to the focus detector and the moving means, wherein the controller adjusts the moving means in response to a signal from the focus detector according to the position of the focusing beam on the substrate.
a) a focusing beam of electromagnetic radiation directed through the objective lens to the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
b) a focus detector for detecting the focusing beam reflected by the discontinuous surface back through the objective lens;
c) a moving means for moving the objective lens relative to the substrate or the substrate relative to the objective lens; and d) a controller connected to the focus detector and the moving means, wherein the controller adjusts the moving means in response to a signal from the focus detector according to the position of the focusing beam on the substrate.
25. A focusing system for use with a substrate comprising a discontinuous surface and a continuous surface extending in the same direction as the discontinuous surface, said system comprising:
a) an objective lens through which is directed a first beam of electromagnetic radiation that is to be focused on the discontinuous surface or on an object located on the discontinuous surface;
b) a second beam of electromagnetic radiation having a first wavelength, said second beam being directed through said objective lens to a focus on the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
c) a third beam of electromagnetic radiation having a second wavelength, said third beam being directed through said objective lens to a focus on the continuous surface and reflected by said continuous surface back through the objective lens;
d) a means for separating the radiation of the first wavelength from the radiation of the second wavelength that is reflected back through the objective lens;
e) a first detector for detecting the second beam reflected by the discontinuous surface back through the objective lens;
f) a second detector for detecting the third beam reflected by the continuous surface back through the objective lens;
g) a moving means for moving the objective lens relative to the substrate or the substrate relative to the objective lens so as to control the focus of the beams reflected back through the objective lens; and h) a controller connected to the first and second detectors and the moving means, wherein the controller operates the moving means in response to a signal from the first detector or the second detector according to the position of the first focusing beam or the second focusing beam on the substrate.
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a) an objective lens through which is directed a first beam of electromagnetic radiation that is to be focused on the discontinuous surface or on an object located on the discontinuous surface;
b) a second beam of electromagnetic radiation having a first wavelength, said second beam being directed through said objective lens to a focus on the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
c) a third beam of electromagnetic radiation having a second wavelength, said third beam being directed through said objective lens to a focus on the continuous surface and reflected by said continuous surface back through the objective lens;
d) a means for separating the radiation of the first wavelength from the radiation of the second wavelength that is reflected back through the objective lens;
e) a first detector for detecting the second beam reflected by the discontinuous surface back through the objective lens;
f) a second detector for detecting the third beam reflected by the continuous surface back through the objective lens;
g) a moving means for moving the objective lens relative to the substrate or the substrate relative to the objective lens so as to control the focus of the beams reflected back through the objective lens; and h) a controller connected to the first and second detectors and the moving means, wherein the controller operates the moving means in response to a signal from the first detector or the second detector according to the position of the first focusing beam or the second focusing beam on the substrate.
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26. A focusing system for use with a substrate comprising a discontinuous surface and a continuous surface extending in the same direction as the discontinuous surface, said system comprising:
a) an objective lens through which is directed a first beam of electromagnetic radiation that is to be focused on the discontinuous surface or on an object located on the discontinuous surface;
b) a focusing beam of electromagnetic radiation directed through the objective lens to the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
c) a focus detector for detecting the focusing beam reflected by the discontinuous surface back through the objective lens;
d) a moving means for moving the objective lens relative to the substrate or the substrate relative to the objective lens so as to control the focus of the focusing beam reflected back through the objective lens; and e) a controller connected to the focus detector and the moving means, wherein the controller operates the moving means in response to a signal from the focus detector according to the position of the focusing beam on the substrate.
a) an objective lens through which is directed a first beam of electromagnetic radiation that is to be focused on the discontinuous surface or on an object located on the discontinuous surface;
b) a focusing beam of electromagnetic radiation directed through the objective lens to the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
c) a focus detector for detecting the focusing beam reflected by the discontinuous surface back through the objective lens;
d) a moving means for moving the objective lens relative to the substrate or the substrate relative to the objective lens so as to control the focus of the focusing beam reflected back through the objective lens; and e) a controller connected to the focus detector and the moving means, wherein the controller operates the moving means in response to a signal from the focus detector according to the position of the focusing beam on the substrate.
27. The focusing system according to claim 25, wherein the first and second wavelengths are the same.
28. The focusing system according to claim 25 or 26, wherein the controller comprises a computer.
29. The focusing system according to claim 25 or 26, wherein the substrate is a microtiter plate and the discontinuous surface is a bottom of a well in the microtiter plate.
30. A method for monitoring a biological assay comprising the step of measuring electromagnetic radiation emitted from an object in the biological assay using a confocal imaging system according to claim 1.
31. A method for monitoring a biological assay comprising the step of measuring electromagnetic radiation emitted from an object in the biological assay using a microscope with a focusing system according to claim 25 or 26.
32. A method for monitoring a biological assay comprising the step of measuring electromagnetic radiation emitted from an object in the biological assay using a confocal imaging system according to claim 12 or 19.
33. The method according to claim 30, wherein the biological assay is a transfection efficiency assay, an infection assay, a FRET assay, protein translocation assay, a protein localization assay, an ion localization assay, pH
differential assay, a cellular movement assay, an organelle movement assay, a morphology assay, a chemical compound screening assay, a ligand-protein binding assay, a protein-protein binding assay, a nucleic acid assay, an assay for reactive oxygen species, an enzyme activity assay, or a kinetic assay.
differential assay, a cellular movement assay, an organelle movement assay, a morphology assay, a chemical compound screening assay, a ligand-protein binding assay, a protein-protein binding assay, a nucleic acid assay, an assay for reactive oxygen species, an enzyme activity assay, or a kinetic assay.
34. The method according to claim 31, wherein the biological assay is a transfection efficiency assay, an infection assay, a FRET assay, protein translocation assay, a protein localization assay, an ion localization assay, pH
differential assay, a cellular movement assay, an organelle movement assay, a morphology assay, a chemical compound screening assay, a ligand-protein binding assay, a protein-protein binding assay, a nucleic acid assay, an assay for reactive oxygen species, an enzyme activity assay, or a kinetic assay.
differential assay, a cellular movement assay, an organelle movement assay, a morphology assay, a chemical compound screening assay, a ligand-protein binding assay, a protein-protein binding assay, a nucleic acid assay, an assay for reactive oxygen species, an enzyme activity assay, or a kinetic assay.
35. The method according to claim 32, wherein the biological assay is a transfection efficiency assay, an infection assay, a FRET assay, protein translocation assay, a protein localization assay, an ion localization assay, pH
differential assay, a cellular movement assay, an organelle movement assay, a morphology assay, a chemical compound screening assay, a ligand-protein binding assay, a protein-protein binding assay, a nucleic acid assay, an assay for reactive oxygen species, an enzyme activity assay, or a kinetic assay.
differential assay, a cellular movement assay, an organelle movement assay, a morphology assay, a chemical compound screening assay, a ligand-protein binding assay, a protein-protein binding assay, a nucleic acid assay, an assay for reactive oxygen species, an enzyme activity assay, or a kinetic assay.
36. A method for examining an object comprising the steps of:
a) measuring electromagnetic radiation emitted from the object using a confocal imaging system according to claim 1, and b) grouping a plurality of the electrical signals produced by the detection device, using a process which comprises:
receiving the plurality of signals;
comparing the plurality of signals to a threshold;
creating a set of reduced data values corresponding to the plurality of signals based upon the comparing of the plurality of signals to the threshold; and grouping the set of reduced data values into at least two groups based upon a spatial relationship of a portion of the plurality of regions of the object corresponding to the set of reduced data values.
a) measuring electromagnetic radiation emitted from the object using a confocal imaging system according to claim 1, and b) grouping a plurality of the electrical signals produced by the detection device, using a process which comprises:
receiving the plurality of signals;
comparing the plurality of signals to a threshold;
creating a set of reduced data values corresponding to the plurality of signals based upon the comparing of the plurality of signals to the threshold; and grouping the set of reduced data values into at least two groups based upon a spatial relationship of a portion of the plurality of regions of the object corresponding to the set of reduced data values.
37. A method for examining an object comprising the steps of:
a) measuring electromagnetic radiation emitted from the object using a microscope with the focusing system according to claim 25 or 26, wherein electromagnetic radiation emitted from the object is delivered to a detection device and converted into a plurality of electrical signals; and b) grouping a plurality of the electrical signals produced by the detection device, using a process which comprises:
receiving the plurality of signals;
comparing the plurality of signals to a threshold;
creating a set of reduced data values corresponding to the plurality of signals based upon the comparing of the plurality of signals to the threshold; and grouping the set of reduced data values into at least two groups based upon a spatial relationship of a portion of the plurality of regions of the object corresponding to the set of reduced data values.
a) measuring electromagnetic radiation emitted from the object using a microscope with the focusing system according to claim 25 or 26, wherein electromagnetic radiation emitted from the object is delivered to a detection device and converted into a plurality of electrical signals; and b) grouping a plurality of the electrical signals produced by the detection device, using a process which comprises:
receiving the plurality of signals;
comparing the plurality of signals to a threshold;
creating a set of reduced data values corresponding to the plurality of signals based upon the comparing of the plurality of signals to the threshold; and grouping the set of reduced data values into at least two groups based upon a spatial relationship of a portion of the plurality of regions of the object corresponding to the set of reduced data values.
38. A method of examining an object comprising the steps of:
a) forming an elongated beam of electromagnetic radiation extending transverse to an optical axis along which the radiation propagates;
b) directing and focusing the elongated beam onto a first elongated region in a first plane where the object is located and directing electromagnetic radiation emitted from the object onto one or more second elongated regions, wherein each second elongated region is on a different second plane conjugate to the first plane;
c) placing in at least one of the second conjugate planes, or in a third plane conjugate to at least one of the second conjugate planes, a detection device comprising a rectangular array of detection elements on which the electromagnetic radiation emitted from the object is coincident; and d) scanning the object by moving the elongated beam relative to the object or by moving the object relative to the elongated beam such that the emitted electromagnetic radiation is delivered to the rectangular array of detection elements and is converted by the detection device into a plurality of electrical signals representative of the emitted electromagnetic radiation synchronously with said scanning.
a) forming an elongated beam of electromagnetic radiation extending transverse to an optical axis along which the radiation propagates;
b) directing and focusing the elongated beam onto a first elongated region in a first plane where the object is located and directing electromagnetic radiation emitted from the object onto one or more second elongated regions, wherein each second elongated region is on a different second plane conjugate to the first plane;
c) placing in at least one of the second conjugate planes, or in a third plane conjugate to at least one of the second conjugate planes, a detection device comprising a rectangular array of detection elements on which the electromagnetic radiation emitted from the object is coincident; and d) scanning the object by moving the elongated beam relative to the object or by moving the object relative to the elongated beam such that the emitted electromagnetic radiation is delivered to the rectangular array of detection elements and is converted by the detection device into a plurality of electrical signals representative of the emitted electromagnetic radiation synchronously with said scanning.
39. The method of examining an object according to claim 38 further comprising the steps of:
a) spatially filtering the emitted electromagnetic radiation with an elongated spatial filter having a long axis which is aligned with the second elongated region; and b) forming, on the detection device, an image of the second conjugate plane.
a) spatially filtering the emitted electromagnetic radiation with an elongated spatial filter having a long axis which is aligned with the second elongated region; and b) forming, on the detection device, an image of the second conjugate plane.
40. The method of examining an object according to claim 38, wherein two or more wavelengths of electromagnetic radiation are directed onto the object.
41. The method of examining an object according to claim 39, wherein the spatial filter has a variable width.
42. The method of examining an object according to claim 38, wherein the detection device comprises an m x n array of detector elements, wherein m is the number of detector elements in a first dimension of the array and n is the number of detector elements in a second dimension of the array and n is greater than m.
43. The method of examining an object according to claim 42, wherein the elongated region on which the emitted electromagnetic radiation is directed has a long axis that is aligned with the array of the detection device, so that the long axis extends in the same direction as the second dimension.
44. The method of examining an object according to claim 42, wherein at least two detector elements forming a column extending in the first dimension of the array are binned together.
45. The method of examining an object according claim 42, wherein a plurality of detector elements of the array are binned together.
46. The method of examining an object according claim 42, wherein the detection device is a CCD array.
47. The method of examining an object according to claim 38, wherein the detection device is a rectangular format CCD array.
48. The method of examining an object according claim 38, wherein the radiation emitted from the object is fluorescent radiation.
49. The method of examining an object according to claim 38, wherein the object is located on a discontinuous surface of a substrate that has a continuous surface extending in the same direction as the discontinuous surface, said method further comprising a method of focusing comprising the steps of:
a) directing a first focusing beam of electromagnetic radiation having a first wavelength through the objective lens to the discontinuous surface such that the first focusing beam is reflected by said discontinuous surface back through the objective lens;
b) directing a second focusing beam of electromagnetic radiation having a second wavelength through the objective lens to the continuous surface such that the second focusing beam is reflected by said continuous surface back through the objective lens;
c) separating the radiation of the first wavelength from the radiation of the second wavelength that is reflected back through the objective lens;
d) detecting the first focusing beam reflected by the discontinuous surface back through the objective lens with a first detector;
e) detecting the second focusing beam reflected by the continuous surface back through the objective lens with a second detector; and f) moving the objective lens relative to the substrate or the substrate relative to the objective lens in response to a signal from the first or second detector according to the position of the first focusing beam or the second focusing beam on the substrate.
a) directing a first focusing beam of electromagnetic radiation having a first wavelength through the objective lens to the discontinuous surface such that the first focusing beam is reflected by said discontinuous surface back through the objective lens;
b) directing a second focusing beam of electromagnetic radiation having a second wavelength through the objective lens to the continuous surface such that the second focusing beam is reflected by said continuous surface back through the objective lens;
c) separating the radiation of the first wavelength from the radiation of the second wavelength that is reflected back through the objective lens;
d) detecting the first focusing beam reflected by the discontinuous surface back through the objective lens with a first detector;
e) detecting the second focusing beam reflected by the continuous surface back through the objective lens with a second detector; and f) moving the objective lens relative to the substrate or the substrate relative to the objective lens in response to a signal from the first or second detector according to the position of the first focusing beam or the second focusing beam on the substrate.
50. The method of examining an object according to claim 38 further comprising the step of dispensing a reagent into the first plane where the object is located.
51. The method of examining an object according to claim 38 further comprising the step of controlling the temperature of the object.
52. The method of examining an object according to claim 39, wherein two or more wavelengths of electromagnetic radiation are directed onto the object and wherein the second plane is singular.
53. The method of examining an object according to any one of claims 38, 40 or 52 wherein two or more wavelengths of electromagnetic radiation are emitted from the object in the first elongated region in the first plane, said method further comprising the steps of:
a) separating the emitted wavelengths; and b) detecting at least one of the separated wavelengths by one or more detection devices.
a) separating the emitted wavelengths; and b) detecting at least one of the separated wavelengths by one or more detection devices.
54. The method of examining an object according to claim 38, wherein the object is located on a discontinuous surface of a substrate comprising a continuous surface extending in the same direction as the discontinuous surface, said method further comprising a method of focusing comprising the steps of:
a) directing a focusing beam of electromagnetic radiation through the objective lens to the discontinuous surface such that it is reflected by said discontinuous surface back through the objective lens;
b) detecting the focusing beam reflected by the discontinuous surface back through the objective lens with a focus detector;
and c) moving the objective lens relative to the substrate or the substrate relative to the objective lens in response to a signal from the focus detector according to the position of the focusing beam on the substrate.
a) directing a focusing beam of electromagnetic radiation through the objective lens to the discontinuous surface such that it is reflected by said discontinuous surface back through the objective lens;
b) detecting the focusing beam reflected by the discontinuous surface back through the objective lens with a focus detector;
and c) moving the objective lens relative to the substrate or the substrate relative to the objective lens in response to a signal from the focus detector according to the position of the focusing beam on the substrate.
55. The method of examining an object according to claim 49, wherein the first and second wavelengths are the same.
56. The method of examining an object according to claim 53, wherein the object is located on a discontinuous surface of a substrate comprising a continuous surface extending in the same direction as the discontinuous surface and wherein two or more wavelengths of electromagnetic radiation are emitted from the object, said method further comprising a method of focusing comprising the steps of:
a) directing a first focusing beam of electromagnetic radiation, having a first wavelength, through the objective lens to the discontinuous surface such that it is reflected by said discontinuous surface back through the objective lens;
b) directing a second focusing beam of electromagnetic radiation, having a second wavelength, through the objective lens to the continuous surface such that it is reflected by said continuous surface back through the objective lens;
c) separating the radiation of the first wavelength from the radiation of the second wavelength that is reflected back through the objective lens;
d) detecting the first focusing beam reflected by the discontinuous surface back through the objective lens with a first detector;
e) detecting the second focusing beam reflected by the continuous surface back through the objective lens with a second detector; and f) moving the objective lens relative to the substrate or the substrate relative to the objective lens in response to a signal from the first detector or the second detector according to the position of the first focusing beam or the second focusing beam on the substrate.
a) directing a first focusing beam of electromagnetic radiation, having a first wavelength, through the objective lens to the discontinuous surface such that it is reflected by said discontinuous surface back through the objective lens;
b) directing a second focusing beam of electromagnetic radiation, having a second wavelength, through the objective lens to the continuous surface such that it is reflected by said continuous surface back through the objective lens;
c) separating the radiation of the first wavelength from the radiation of the second wavelength that is reflected back through the objective lens;
d) detecting the first focusing beam reflected by the discontinuous surface back through the objective lens with a first detector;
e) detecting the second focusing beam reflected by the continuous surface back through the objective lens with a second detector; and f) moving the objective lens relative to the substrate or the substrate relative to the objective lens in response to a signal from the first detector or the second detector according to the position of the first focusing beam or the second focusing beam on the substrate.
57. The method of examining an object according to claim 53, wherein the object is located on a discontinuous surface of a substrate comprising a continuous surface extending in the same direction as the discontinuous surface and wherein two or more wavelengths of electromagnetic radiation are emitted from the object, said method further comprising a method of focusing comprising the steps of:
a) directing a focusing beam of electromagnetic radiation through the objective lens to the discontinuous surface such that it is reflected by said discontinuous surface back through the objective lens;
b) detecting the focusing beam reflected by the discontinuous surface back through the objective lens with a focus detector;
and c) moving the objective lens relative to the substrate or the substrate relative to the objective lens in response to a signal from the focus detector according to the position of the focusing beam on the substrate.
a) directing a focusing beam of electromagnetic radiation through the objective lens to the discontinuous surface such that it is reflected by said discontinuous surface back through the objective lens;
b) detecting the focusing beam reflected by the discontinuous surface back through the objective lens with a focus detector;
and c) moving the objective lens relative to the substrate or the substrate relative to the objective lens in response to a signal from the focus detector according to the position of the focusing beam on the substrate.
58. A method of focusing for use with a substrate comprising a discontinuous surface and a continuous surface extending in the same direction as the discontinuous surface, said method comprising the steps of a) directing a first beam of electromagnetic radiation through an objective lens to be focused on the discontinuous surface or on an object located on the discontinuous surface;
b) directing a second beam of electromagnetic radiation, having a first wavelength, through the objective lens to be focused on the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
c) directing a third beam of electromagnetic radiation, having a second wavelength, through the objective lens to be focused on the continuous surface and reflected by said continuous surface back through the objective lens;
d) separating the radiation of the first wavelength from the radiation of the second wavelength that is reflected back through the objective lens;
e) detecting the second beam reflected by the discontinuous surface back through the objective lens with a first detector;
f) detecting the third beam reflected by the continuous surface back through the objective lens with a second detector; and g) moving the objective lens relative to the substrate or the substrate relative to the objective lens in response to a signal from the first detector or the second detector according to the position of the first focusing beam or the second focusing beam on the substrate so as to control the focus of the beams reflected back through the objective lens.
b) directing a second beam of electromagnetic radiation, having a first wavelength, through the objective lens to be focused on the discontinuous surface and reflected by said discontinuous surface back through the objective lens;
c) directing a third beam of electromagnetic radiation, having a second wavelength, through the objective lens to be focused on the continuous surface and reflected by said continuous surface back through the objective lens;
d) separating the radiation of the first wavelength from the radiation of the second wavelength that is reflected back through the objective lens;
e) detecting the second beam reflected by the discontinuous surface back through the objective lens with a first detector;
f) detecting the third beam reflected by the continuous surface back through the objective lens with a second detector; and g) moving the objective lens relative to the substrate or the substrate relative to the objective lens in response to a signal from the first detector or the second detector according to the position of the first focusing beam or the second focusing beam on the substrate so as to control the focus of the beams reflected back through the objective lens.
59. A method of focusing for use with a substrate comprising a discontinuous surface and a continuous surface extending in the same direction as the discontinuous surface, said method comprising the steps of:
a) directing a first beam of electromagnetic radiation through an objective lens to be focused on the discontinuous surface or on an object located on the discontinuous surface;
b) directing a focusing beam of electromagnetic radiation through the objective lens to the discontinuous surface such that it is reflected by said discontinuous surface back through the objective lens;
c) detecting the focusing beam reflected by the discontinuous surface back through the objective lens with a focus detector;
and d) moving the objective lens relative to the substrate or the substrate relative to the objective lens in response to a signal from the focus detector according to the position of the focusing beam on the substrate so as to control the focus of the focusing beam reflected back through the objective lens.
a) directing a first beam of electromagnetic radiation through an objective lens to be focused on the discontinuous surface or on an object located on the discontinuous surface;
b) directing a focusing beam of electromagnetic radiation through the objective lens to the discontinuous surface such that it is reflected by said discontinuous surface back through the objective lens;
c) detecting the focusing beam reflected by the discontinuous surface back through the objective lens with a focus detector;
and d) moving the objective lens relative to the substrate or the substrate relative to the objective lens in response to a signal from the focus detector according to the position of the focusing beam on the substrate so as to control the focus of the focusing beam reflected back through the objective lens.
60. The method of focusing according to claim 58, wherein the first and second wavelengths are the same.
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61. A method for examining an object according to claim 38 further comprising the step of grouping a plurality of the electrical signals produced by the detection device, using a process which comprises:
a) receiving the plurality of signals;
b) comparing the plurality of signals to a threshold;
c) creating a set of reduced data values corresponding to the plurality of signals based upon the comparing of the plurality of signals to the threshold; and d) grouping the set of reduced data values into at least two groups based upon a spatial relationship of a portion of the plurality of regions of the object corresponding to the set of reduced data values.
a) receiving the plurality of signals;
b) comparing the plurality of signals to a threshold;
c) creating a set of reduced data values corresponding to the plurality of signals based upon the comparing of the plurality of signals to the threshold; and d) grouping the set of reduced data values into at least two groups based upon a spatial relationship of a portion of the plurality of regions of the object corresponding to the set of reduced data values.
62. A method for examining an object comprising the steps of:
a) using a method of focusing according to claims 58 or 59;
b) measuring electromagnetic radiation emitted from the object by delivering the emitted radiation to a detection device where it is converted into a plurality of electrical signals;
c) grouping the plurality of the electrical signals produced by the detection device, using a process which comprises:
receiving the plurality of signals;
comparing the plurality of signals to a threshold;
creating a set of reduced data values corresponding to the plurality of signals based upon the comparing of the plurality of signals to the threshold; and grouping the set of reduced data values into at least two groups based upon a spatial relationship of a portion of the plurality of regions of the object corresponding to the set of reduced data values.
a) using a method of focusing according to claims 58 or 59;
b) measuring electromagnetic radiation emitted from the object by delivering the emitted radiation to a detection device where it is converted into a plurality of electrical signals;
c) grouping the plurality of the electrical signals produced by the detection device, using a process which comprises:
receiving the plurality of signals;
comparing the plurality of signals to a threshold;
creating a set of reduced data values corresponding to the plurality of signals based upon the comparing of the plurality of signals to the threshold; and grouping the set of reduced data values into at least two groups based upon a spatial relationship of a portion of the plurality of regions of the object corresponding to the set of reduced data values.
63. A method of examining an object according to claims 38, 49 or 54 wherein the object is in a biological assay.
64. A method for monitoring a biological assay comprising the step of using a method of focusing according to claims 58 or 59.
65. The method according to claim 63, wherein the biological assay is a transfection efficiency assay, an infection assay, a FRET assay, protein translocation assay, a protein localization assay, an ion localization assay, pH
differential assay, a cellular movement assay, an organelle movement assay, a morphology assay, a chemical compound screening assay, a ligand-protein binding assay, a protein-protein binding assay, a nucleic acid assay, an assay for reactive oxygen species, an enzyme activity assay, or a kinetic assay.
differential assay, a cellular movement assay, an organelle movement assay, a morphology assay, a chemical compound screening assay, a ligand-protein binding assay, a protein-protein binding assay, a nucleic acid assay, an assay for reactive oxygen species, an enzyme activity assay, or a kinetic assay.
66. The method according to claim 64, wherein the biological assay is a transfection efficiency assay, an infection assay, a FRET assay, protein translocation assay, a protein localization assay, an ion localization assay, pH
differential assay, a cellular movement assay, an organelle movement assay, a morphology assay, a chemical compound screening assay, a ligand-protein binding assay, a protein-protein binding assay, a nucleic acid assay, an assay for reactive oxygen species, an enzyme activity assay, or a kinetic assay.
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differential assay, a cellular movement assay, an organelle movement assay, a morphology assay, a chemical compound screening assay, a ligand-protein binding assay, a protein-protein binding assay, a nucleic acid assay, an assay for reactive oxygen species, an enzyme activity assay, or a kinetic assay.
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1999
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- 1999-03-16 JP JP2000537103A patent/JP4812937B2/en not_active Expired - Fee Related
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| CA2324262C (en) | 2010-05-25 |
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| AU758571B2 (en) | 2003-03-27 |
| KR100560588B1 (en) | 2006-03-16 |
| CN1301357A (en) | 2001-06-27 |
| JP4812937B2 (en) | 2011-11-09 |
| CN100380160C (en) | 2008-04-09 |
| KR20010041945A (en) | 2001-05-25 |
| EP1064579A4 (en) | 2007-11-07 |
| JP2002507762A (en) | 2002-03-12 |
| BR9908767B1 (en) | 2011-09-06 |
| WO1999047963A8 (en) | 1999-11-18 |
| NO20004601L (en) | 2000-11-10 |
| KR20050088500A (en) | 2005-09-06 |
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