EP1384104A2 - Dispositif et procede de mesure optique d'echantillons chimiques et/ou biologiques - Google Patents

Dispositif et procede de mesure optique d'echantillons chimiques et/ou biologiques

Info

Publication number
EP1384104A2
EP1384104A2 EP02738002A EP02738002A EP1384104A2 EP 1384104 A2 EP1384104 A2 EP 1384104A2 EP 02738002 A EP02738002 A EP 02738002A EP 02738002 A EP02738002 A EP 02738002A EP 1384104 A2 EP1384104 A2 EP 1384104A2
Authority
EP
European Patent Office
Prior art keywords
sample
image field
detector
measuring device
focusing
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02738002A
Other languages
German (de)
English (en)
Inventor
Achim Kirsch
Roland Stange
Jürgen Müller
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Evotec OAI AG
Original Assignee
Evotec OAI AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Evotec OAI AG filed Critical Evotec OAI AG
Publication of EP1384104A2 publication Critical patent/EP1384104A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/18—Arrangements with more than one light path, e.g. for comparing two specimens
    • 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
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00—Microscopes
    • G02B21/0096—Microscopes with photometer devices

Definitions

  • the invention relates to a device and a method for the optical measurement of chemical and / or biological samples.
  • the device according to the invention and the method according to the invention are particularly suitable for use in high and medium throughput screening systems.
  • image measurement methods examples include: bright field, dark field, total internal reflection, fluorescence, 2-photon fluorescence, fluorescence lifetime, fluorescence emission spectroscopy, polarization and fluorescence polarization microscopy.
  • these methods can be carried out with different detectors, such as line or area cameras and there is also the possibility to use them in both conventional and confocal arrangements.
  • the measurement is only carried out at a single location in the sample, the location information is not evaluated or it is averaged over a large number of measurement locations at the same time (conventional measurement with a large-area detector). Accordingly, the single measurement can be both complex and time consuming.
  • the complexity can relate to both the measuring apparatus and the resulting data (e.g. entire spectra).
  • FCS fluorescence correlation spectroscopy
  • FCS records the fluctuation of a fluorescence signal coming from a small volume over a longer period of time and derives information about the photophysical, chemical and physical properties of fluorescent particles and molecules in this volume.
  • Possible point measuring methods include but not exclusively FCS, FIDA, fluorescence emission, fluorescence excitation and absorption spectroscopy, fluorescence lifetime spectroscopy and fluorescence anisotropy measurements as described in many scientific and technical publications. The measurements can often be carried out in a conventional as well as in a confocal arrangement.
  • FCS instrument for intracellular FCS from Brock (see e.g. Brock, "Fluorescence Correlation Microscopy and Quantitative Microsphere Recruitment Assay", Dissertation, 1999) can be mentioned as devices that combine image measurement methods with point measurement methods.
  • This device consists of a fluorescence microscope, which has been supplemented with the parts necessary for FCS.
  • the choice between the measurement methods of microscopy or FCS is made by a folding mirror arranged in the beam path.
  • LSM laser scanning microscopes
  • optical filters In order to distinguish several fluorophores in a microscope based on their excitation and emission spectra, special optical filters, color cameras and imaging spectrographs are used in multi-channel microscopes. If optical filters are used, at least three filters are usually used. The first filter defines the excitation wavelength range, the second filter is a dichromatic mirror that reflects the excitation light and transmits the emission light (or vice versa). Another filter is inserted in front of the detector, which only allows the emission area to pass. For the detection of different fluorophores, there is the possibility to replace all three filters, as is done as standard in the commercially available microscopes.
  • a single filter set can be built up for several dyes if the excitation and emission wavelengths are far enough apart, as is the case, for example, for the dyes DAPI, FITC and TRITC. If these dyes are to be recorded separately, a color film or a color CCD camera can be used. A black and white camera can also be used in combination with a selectable excitation spectrum, as is also done, for example, in the so-called Pinkel filter sets. With filter sets, it is also possible to differentiate dyes based on their Stokes shift. Different dyes can be excited with the same wavelength and differ in the different shift of the emission spectrum.
  • the object of the invention is to provide a device and a method for measuring chemical and / or biological samples, with which or with which different measurements of a sample, in particular an image measuring method and a point measuring method, can be carried out in a simple manner.
  • the invention is based on the finding that when imaging a sample area in an image field, part of the image field is always not used for the examination.
  • a round image field 10 (FIG. 1) is generated.
  • the field of a CCD camera is arranged within the image field, for example in a first partial area 12 of the image field 10.
  • the part of the image area 10 surrounding the first partial area 12 is thus not used for the detection of reactions occurring in the sample.
  • the essence of the invention is to detect a second partial area of the image field in the unused area of the image field by means of a second detector.
  • the optical measuring device which is particularly suitable for use in high-throughput screening systems, can have an illumination unit for illuminating the sample to be measured. Furthermore, an optical device is provided for imaging a sample area in the image field. Furthermore, a first detector is provided which covers a first partial area of the Image field captured. According to the invention, a second detector is provided which detects a second partial area of the image field.
  • At least two detectors each of which detects a partial area of the image field, it is possible to carry out different measurements simultaneously on a sample.
  • a CCD camera as the first detector with which one of the image measurement methods described above is carried out.
  • a point measurement method can then preferably be used, by means of which e.g. the time course of a signal can be recorded.
  • a spatially limited decoupling of at least a partial area of the image field thus takes place.
  • This decoupling is preferably carried out by a totally reflecting mirror, the decoupled one Partial area is detected by a point detector, such as a fiber end.
  • a point detector such as a fiber end.
  • the device according to the invention is particularly suitable for use in medium and high-throughput screening methods, individual wells of sample carriers, such as titer plates or the like, are preferably observed with the aid of the device. A part of the liquid in a well is thus preferably imaged by the device in an image, a partial region of this well image being coupled out.
  • Multi-channel microscopy can also be carried out in a simple manner with the device according to the invention. Since the different partial areas of the image field can be deflected, for example by providing mirrors, it is possible to arrange different filters in the individual beam paths. There is no need to change the filters. Likewise, filters that are specifically tailored to the requirements can then be used in the two beam paths. The provision of expensive combination filters and the like. not necessary. Likewise, the number of dyes that can be used is considerably larger, since these are no longer the same on a special filter system. must be coordinated.
  • the separation of the two partial areas does not take place via spectral differences due to dichromatic mirrors or sequentially in time by pivoting a mirror in and out.
  • the first detector is located on the optical axis of a lens of the optical unit. Furthermore, there is a mirror in the edge region of the beam path generating the image field, via which the second partial region is coupled out and directed onto the second detector.
  • This has the advantage that the second detector does not have to be arranged directly next to the first detector.
  • different detectors can be used, in which it may not be possible to arrange two detectors directly next to one another, since control elements of the detector or the like are arranged next to the detector surface.
  • the first detector directly on the axis of the objective, but also to deflect the beam path by means of a mirror.
  • a mirror coupling out the second partial region is arranged in the beam path generating the image field.
  • the mirror is preferably arranged such that it lies outside the beam path that is detected by the first detector. An overlap of the individual subareas is preferably avoided. Since the position of the mirror coupling out the second partial area ensures that it does not protrude into the beam path that strikes the first detector, a totally reflecting mirror can preferably be used. This has the advantage that the mirror does not influence the radiation perceived by the second detector.
  • the remaining image field can be used by several detectors.
  • the image field is thus divided into a number of two, three, four or more partial areas. Each of these sub-areas can in turn have one Mirror can be coupled out. This avoids space problems in the area of the image field.
  • the further detectors or the further mirrors, which couple out corresponding partial areas for these detectors, are preferably arranged such that an overlap of the partial areas is excluded.
  • At least one of the detectors is designed as a point detector.
  • This can be, for example, the open fiber end of an optical fiber.
  • a point detector for example, temporal courses of the fluorescence of a substance can be measured.
  • the device according to the invention design one of the detectors as a focusing device for the axial detection of the sample area depicted in the image field.
  • One of the detectors on which a partial area of the image field is imaged can thus be used for focusing. This has the advantage that none additional focusing devices are required, which generally require a separate light source, by which the measurement results are influenced, since this light source also introduces light into the sample.
  • active focusing devices can also be used, which then have, for example, their own light source in order to introduce light into the sample for focusing.
  • a light beam incident obliquely into the sample can be used, which generates a fluorescence line in the fluorescent sample.
  • the reflection of this obliquely incident light beam can be used for focusing.
  • a corresponding device is described for example in US 6 025 601.
  • Such focusing by means of a line appearing in the sample is particularly unsuitable for brightly fluorescent samples.
  • the lowest possible excitation power should be used in these samples in order to avoid bleaching of the sample and possibly damage to any living cells present in the sample. In this autofocus system, however, a reduction in the excitation power also results in the height signal being weakened. This will make the focus setting worse.
  • such a focusing device can only be used with relatively small numerical apertures, since the light is irradiated at an angle to the optical axis. This increases the excitation focus, so that the axial resolution is lower.
  • a focusing device with an aperture diaphragm is used.
  • the smallest possible point in the sample is illuminated with the aid of the aperture diaphragm.
  • the light reflected from this point reaches a suitable detector through the same aperture diaphragm. Due to the confocality of the arrangement, focusing has only taken place if there is a reflecting surface in the position corresponding to the aperture in the sample. For example, the reflection occurs on a glass bottom of the sample holder in which the samples are are arranged, simple focusing on the glass bottom is possible with the device according to the invention.
  • the thickness of the glass bottom and the optimal distance between measuring points in the sample and the sample bottom are known, after focusing on the glass bottom, a corresponding relative displacement between the sample carrier and the objective can ensure that the measurement within the sample is at a predetermined distance from the sample bottom he follows. Furthermore, it is possible to select the plane in which the aperture diaphragm is located so that in the event of a reflection signal from the glass bottom through the aperture, the other detectors are arranged in such a way that their focus lies in the sample area of interest.
  • the invention thus further relates to an optical measuring device with an illumination unit and an optical unit as described above.
  • a first partial area of the image field is detected by a first detector.
  • a focusing device is provided for axially fixing the sample area depicted in the image field.
  • the focusing device has a light source generating a focusing beam, the focusing beam running at least partially within the beam path generating the image field.
  • a focusing mirror is preferably provided, which is arranged in the image field beam path in accordance with the above mirror. The arrangement of the mirror is in turn preferably such that the mirror does not overlap the portion of the image field perceived by the first detector, i.e. does not cast a shadow on the first detector.
  • the focusing device is arranged, if necessary using a correspondingly arranged focusing mirror, in such a way that the optical device directs the focusing beam in the direction of the sample.
  • the focusing beam reflected by the sample or an interface of a sample carrier is likewise directed in the direction of the optical device Focusing device or directed in the direction of the focusing mirror.
  • the reflection of the focusing beam can take place at different interfaces.
  • the reflection of the outer surface of the sample holder, on the bottom surface of the sample holder, ie the inside of the sample holder bottom on which the sample liquid is applied, or also on the surface of the sample itself, ie on the interface between the sample and the surrounding medium can generally be air , be reflected.
  • the lens device must be appropriately adjusted so that it is ensured that the measurement within the sample takes place at a corresponding distance from the interfaces. This ensures an optimal measurement result.
  • a combination of the two devices described above is possible, so that several detectors are provided which detect different sub-areas of the image field, and a focusing device is additionally provided which preferably does not cover any of the sub-areas of the image field, but uses the optical device for guiding the focusing beam.
  • the invention further relates to a method for the optical measurement of chemical and / or biological samples, in particular by means of high-throughput screening systems.
  • the sample to be measured can be illuminated.
  • a sample area is then imaged in an image field with the aid of an optical device.
  • Both the sample area and the image field are each a spatially limited area.
  • the image depicted in the partial area is detected by means of a first detector.
  • a second partial area of the image field is detected by means of a second detector.
  • the method according to the invention preferably not only captures two, but three, four, five or more sub-areas of the image field.
  • the individual partial areas preferably do not overlap.
  • Fig. 2 is a schematic representation of a preferred embodiment
  • Embodiment of the invention with three detectors Embodiment of the invention with three detectors
  • FIGS. 3-5 schematic representations of possible arrangements of the second detector
  • FIGS. 6-8 schematic representations of design options of the first detector together with an illumination device
  • Fig. 9 is a schematic representation of another preferred embodiment
  • Embodiment of the invention in combination with a focusing device.
  • an image field 10 is shown, which is usually from a microscope and the like. used optical device is generated.
  • the image field 10 is usually a circular two-dimensional one Area.
  • a first partial area 12 is provided within the image field 10.
  • the first partial area 12 is a rectangular partial area, for example a camera field of a CCD camera.
  • a second partial area 14 is also arranged within the image field 10.
  • the second partial area 14 is shown as a circle.
  • it is a sub-area in which a point measurement is carried out.
  • this is a detector designed as an optical fiber, so that a fiber end of an optical fiber is arranged in the partial region 14.
  • FIG. 2 The schematic structure of an optical measuring device according to the invention (FIG. 2) has an illumination device 16 which illuminates a sample 20 arranged, for example, in a titer plate 18.
  • the light emitted by the sample 20 or the radiation emitted by the sample 20 is directed in the direction of a first detector 28 with the aid of an optical device 22 which has an objective 24 and at least one tube lens 26.
  • the image field 10 (FIG. 1) is generated in an image plane located at the level of the detector 28.
  • the image field is generated by a beam path 30 shown in dashed lines.
  • the first detector 28 detects the first partial area 12 (FIG. 1). This is delimited by a first beam path 32, which is part of the image field beam path 30.
  • a second detector 34 which serves to detect the second partial area 14 of the image field 10 (FIG. 1), is arranged rotated through 90 ° to an optical axis 36.
  • a totally reflecting mirror 38 is provided in order to steer the relevant part of the image field beam path 30 in the direction of the second detector 34. The mirror 38 couples out a part 40 of the image field beam path 30 and directs it onto the second detector 34.
  • a further, third detector 42 can be arranged opposite the second detector 34. This is perpendicular to the second detector 34 the optical axis 36 is arranged.
  • the third partial area of the image field 10 imaged on the third detector 42 is coupled out of the image field beam path 30 by a mirror 44.
  • the third detector 42 can also be arranged in a different position together with the mirror 44 and can detect a different partial area of the image field 10.
  • the partial region 12 imaged on the first detector 28, which is generated by an optical path 46, is not influenced by the second and third detectors 34, 42. 2, the beam path 46 runs between the two mirrors 38, 44, so that neither of the two mirrors 38, 44 protrude into the beam path 46 and would thereby impair the part of the sample 20 imaged on the first detector 28.
  • the lighting device 16 has a light source 50 and a lens arrangement 52.
  • the lens arrangement 52 bundles the light emitted by the light source 50 onto the sample so that the light is concentrated in the sample 20.
  • the illuminating device 16 is arranged opposite the objective device 22, so that the sample is illuminated from the side opposite the objective device 22. This is the so-called transmission lighting. It is also possible to illuminate the sample 20 by incident light illumination. For this purpose, a light emitted by a light source is coupled into the lens 24 via a corresponding lens and mirror arrangement and is guided by the latter into the sample.
  • the first detector 28 is, for example, a CCD or CMOS camera. In combination with a suitable line illumination, the first detector 28 can also be a line camera. A spectrograph can also be used as a detector. A detector corresponding to the first detector or a combination of the detectors mentioned above can be provided as the second detector. There is also the possibility of providing one or more of the detectors 28, 34, 42, for example as a fluorescence emission spectroscope, possibly in combination with suitable filters. The detectors can also be designed as FCS or FIDA detectors.
  • FIGs. 3-5 different arrangement options of the second detector 34 are shown.
  • the lighting device 16 is not shown in each of these figures.
  • the mirror 38 is arranged in front of an image plane 54 in which the image field 10 is located.
  • a beam 40 is deflected as described above with reference to FIG. 2.
  • the second detector 34 is arranged in an image plane 56, which is part of the image plane 54, which has been deflected by the mirror 38.
  • the mirror 38 it is also possible to arrange the mirror 38 in an intermediate image plane 58 (FIG. 4).
  • a lens 60 is provided between the mirror 38 and the detector 34.
  • a further lens 62 is provided between the intermediate image plane 58 and the image plane 54, through which the first partial region 10 is imaged on the detector 28. If the detectors 28, 34 do not require imaging of the sample (e.g. point intensity measurements or direct coupling into a spectrograph), the lenses 60, 62 can also be dispensed with.
  • the mirror 38 behind the intermediate image plane 58 in relation to the beam path. 4 is again between the mirror 38 and the image plane 56 of the detector 34, the lens 60 is arranged. Likewise, the lens 62 is provided between the intermediate image plane 58 and the image plane 54 of the detector 28.
  • the lighting device 16 is arranged between the intermediate image plane 58 and the image plane 54.
  • the lighting device has a lens or lens arrangement 52.
  • the light emitted by the light source 50 which can also be a line illumination 64 (FIGS. 7 and 8), is coupled into the beam path running between the objective 24 and the first detector unit 28 via a partially transparent or dichromatic mirror 66.
  • the second detector 34 is together with the mirror 38 in the in FIGS. 6-8 illustrated embodiments each arranged in front of the intermediate image plane 58.
  • the line lighting 64 is provided, which is combined with a line detector as the first detector 28.
  • the line must be moved relative to sample 20. This is done either by moving the sample or by moving the light beam incident on the sample, e.g. over an oscillating mirror.
  • an imaging spectrograph can also be used as the first detector 28 (FIG. 8).
  • the latter has a mirror arrangement comprising two planar mirrors 69 and a concave mirror 71. The planar mirrors 69 can be tilted against one another.
  • a focusing device 70 is arranged instead of the second detector 34.
  • one or more detectors 34, 42 can be arranged in addition to the focusing device 70.
  • the mirror 38 is arranged as described above and in particular as can be seen in FIG. 2.
  • a light source 72 directs light through a lens 74 onto a partially transparent mirror 76. Of the light is deflected towards an aperture diaphragm 78.
  • the aperture diaphragm is located in or near an image plane. This illuminates a point in the sample. The light reflected from this point in the sample likewise arrives in the direction of the aperture diaphragm 78 via the mirror 38.
  • the light returning from the sample 20 is transmitted through the partially transparent mirror 76 and via a lens 80 to a detector 82 steered.
  • a reflecting surface of the sample for example an interface of the titer plate or a surface of the sample.
  • a maximum of light reflected from the sample reaches the detector 82 through the aperture diaphragm.
  • the optical unit can subsequently be shifted by a certain amount, so that in the Image area 10, an area lying within the sample is imaged.
  • the aperture diaphragm 78 can also be shifted so far out of the image plane 56 that a signal at the detector 82 is accompanied by a focusing of the sample region of interest on the detector 28.
  • focusing devices are also possible in which the focusing takes place, for example, via the contrast or via a fluorescence line generated in the sample.
  • 2x2 phase couplers can be used as focusing sensors.
  • the fiber itself is then used as the aperture determining the autofocal measuring location.
  • an additional aperture diaphragm For example, in scanning systems such as line detectors, the measuring point for the autofocus can also lie in front of the line in the scanning direction. In this case, it is possible to carry out the height control in the control loop without a phase offset, since the measuring point records the measured value in a position which the actual detector will only reach later. There If the autofocus measuring point is located next to the area captured by the image detector, it makes sense to use a correction of the height according to the skew of the sample. Such a correction is always useful if there is a lateral offset of measuring points.
  • the decoupling mirror or the detectors i.e. the fiber or other point detectors are arranged in front of, in or behind the image plane.
  • the detectors are arranged near the image plane.

Landscapes

  • Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)

Abstract

L'invention concerne un dispositif de mesure, destiné à mesurer des échantillons chimiques et/ou biologiques et comprenant un dispositif d'éclairage (16) pour éclairer l'échantillon (20) à mesurer. En outre, un dispositif optique (22) sert à reproduire une zone de l'échantillon dans un champ d'image (10). Selon l'invention, une première zone partielle (12) du champ d'image est balayée par un premier détecteur (28) et une deuxième zone partielle (14) du champ d'image (10) est balayée par un deuxième détecteur (34). Il est ainsi possible de sélectionner entre deux procédés de mesure sans avoir à effectuer de commutation ou bien d'effectuer simultanément deux mesures sur un échantillon.
EP02738002A 2001-04-28 2002-04-26 Dispositif et procede de mesure optique d'echantillons chimiques et/ou biologiques Withdrawn EP1384104A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10121064A DE10121064A1 (de) 2001-04-28 2001-04-28 Vorrichtung und Verfahren zur optischen Messung von chemischen und/oder biologischen Proben
DE10121064 2001-04-28
PCT/EP2002/004623 WO2002088819A2 (fr) 2001-04-28 2002-04-26 Dispositif et procede de mesure optique d'echantillons chimiques et/ou biologiques

Publications (1)

Publication Number Publication Date
EP1384104A2 true EP1384104A2 (fr) 2004-01-28

Family

ID=7683202

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02738002A Withdrawn EP1384104A2 (fr) 2001-04-28 2002-04-26 Dispositif et procede de mesure optique d'echantillons chimiques et/ou biologiques

Country Status (5)

Country Link
US (1) US7474777B2 (fr)
EP (1) EP1384104A2 (fr)
AU (1) AU2002312858A1 (fr)
DE (1) DE10121064A1 (fr)
WO (1) WO2002088819A2 (fr)

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6937330B2 (en) 1999-04-23 2005-08-30 Ppd Biomarker Discovery Sciences, Llc Disposable optical cuvette cartridge with low fluorescence material
US6687395B1 (en) 1999-07-21 2004-02-03 Surromed, Inc. System for microvolume laser scanning cytometry
US6787761B2 (en) 2000-11-27 2004-09-07 Surromed, Inc. Median filter for liquid chromatography-mass spectrometry data
US6873915B2 (en) 2001-08-24 2005-03-29 Surromed, Inc. Peak selection in multidimensional data
WO2003095978A2 (fr) 2002-05-09 2003-11-20 Surromed, Inc. Procedes d'alignement temporel de donnees obtenues par chromatographie liquide ou par spectrometrie de masse
DE102004005878A1 (de) * 2004-02-05 2005-09-01 Rina-Netzwerk Rna Technologien Gmbh Verfahren zur Überwachung der Herstellung von Biomolekülkristallen
US7248360B2 (en) * 2004-04-02 2007-07-24 Ppd Biomarker Discovery Sciences, Llc Polychronic laser scanning system and method of use
US7276720B2 (en) * 2004-07-19 2007-10-02 Helicos Biosciences Corporation Apparatus and methods for analyzing samples
US20070070349A1 (en) * 2005-09-23 2007-03-29 Helicos Biosciences Corporation Optical train and method for TIRF single molecule detection and analysis
JP2007293210A (ja) * 2006-04-27 2007-11-08 Olympus Corp イメージング装置
WO2008143849A2 (fr) 2007-05-14 2008-11-27 Historx, Inc. Séparation en compartiments par caractérisation de pixel utilisant le regroupement de données d'image
WO2008156669A1 (fr) 2007-06-15 2008-12-24 Historx, Inc. Procédé et système pour normaliser des instruments de microscope
GB2451442B (en) * 2007-07-30 2013-03-06 Lein Applied Diagnostics Ltd Optical measurement apparatus and method therefor
CA2604317C (fr) * 2007-08-06 2017-02-28 Historx, Inc. Methodes et systeme permettant de valider des echantillons d'images pour dosages immunologiques quantitatifs
EP2335221B8 (fr) * 2008-09-16 2016-05-25 Novartis AG Quantification reproductible de l'expression de biomarqueurs
US8331751B2 (en) * 2009-03-02 2012-12-11 mBio Diagnositcs, Inc. Planar optical waveguide with core of low-index-of-refraction interrogation medium
US9212995B2 (en) 2009-03-02 2015-12-15 Mbio Diagnostics, Inc. System and method for detecting multiple molecules in one assay
US9658222B2 (en) 2009-03-02 2017-05-23 Mbio Diagnostics, Inc. Planar waveguide based cartridges and associated methods for detecting target analyte
DE102010015915A1 (de) * 2010-03-11 2011-09-15 Leica Microsystems Cms Gmbh Verfahren für einen beschleunigten Anregungswellenlängen-Scan bei einem Fluoreszenzmikroskop
DE102010035003B4 (de) * 2010-08-20 2015-08-06 PicoQuant GmbH. Unternehmen für optoelektronische Forschung und Entwicklung Räumlich und zeitlich hochauflösende Mikroskopie
JP6286863B2 (ja) * 2013-05-09 2018-03-07 ソニー株式会社 光学系、及びテラヘルツ放射顕微鏡

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5913206A (ja) * 1982-07-15 1984-01-24 Hitachi Denshi Ltd 合焦制御装置

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4283112A (en) * 1979-04-24 1981-08-11 Venable Thomas C Telescope guiding system
DE3328821C2 (de) * 1983-08-10 1986-10-02 Fa. Carl Zeiss, 7920 Heidenheim Autofokus für Mikroskope
GB8524776D0 (en) * 1985-10-08 1985-11-13 Iravani M V M v saw detector & pc microscope
US4844617A (en) * 1988-01-20 1989-07-04 Tencor Instruments Confocal measuring microscope with automatic focusing
ATE158659T1 (de) * 1988-07-13 1997-10-15 Optiscan Pty Ltd Confokales abtast-endoskop
US5635402A (en) * 1992-03-05 1997-06-03 Alfano; Robert R. Technique for determining whether a cell is malignant as opposed to non-malignant using extrinsic fluorescence spectroscopy
WO1994010595A1 (fr) * 1992-10-23 1994-05-11 Monash University Endoscope et microscope confocaux
JP2750987B2 (ja) * 1992-12-04 1998-05-18 東京航空計器株式会社 微小円筒形部品寸法測定システム
US5384455A (en) * 1993-04-12 1995-01-24 Environmental Research Institute Of Michigan Measurement-diverse speckle imaging
DE4330347C2 (de) * 1993-09-08 1998-04-09 Leica Lasertechnik Verwendung einer Vorrichtung zur Selektion und Detektion mindestens zweier Spektralbereiche eines Lichtstrahls
US5578832A (en) * 1994-09-02 1996-11-26 Affymetrix, Inc. Method and apparatus for imaging a sample on a device
JP3404134B2 (ja) * 1994-06-21 2003-05-06 株式会社ニュークリエイション 検査装置
US5508844A (en) * 1994-09-01 1996-04-16 Blake, Sr.; Roger A. Telescope tracker
US5813987A (en) * 1995-08-01 1998-09-29 Medispectra, Inc. Spectral volume microprobe for analysis of materials
JP2000512744A (ja) * 1996-05-16 2000-09-26 アフィメトリックス，インコーポレイテッド 標識材料を検出するシステムおよび方法
US6084670A (en) * 1997-03-11 2000-07-04 Nihon Kohden Corporation Particle analyzer and composite lens formed by integrally joining plural lens elements of different focal points
DE19728966C2 (de) * 1997-03-25 1999-03-18 Optomed Optomedical Systems Gmbh Bildgebendes Spektrometer
JPH10307252A (ja) * 1997-05-07 1998-11-17 Hitachi Denshi Ltd 自動合焦点光学式テレビカメラ顕微鏡
DE19748211A1 (de) * 1997-10-31 1999-05-06 Zeiss Carl Fa Optisches Array-System und Reader für Mikrotiterplatten
DE19919092A1 (de) * 1999-04-27 2000-11-02 Zeiss Carl Jena Gmbh Anordnung zur optischen Auswertung eines Gegenstandsarrays
DE19936999C2 (de) * 1999-08-02 2002-03-14 Jena Optronik Gmbh Anordnung zum Erfassen der Fluoreszenzstrahlung von matrixförmigen Probenträgern

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5913206A (ja) * 1982-07-15 1984-01-24 Hitachi Denshi Ltd 合焦制御装置

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO02088819A3 *

Also Published As

Publication number Publication date
US20040257576A1 (en) 2004-12-23
US7474777B2 (en) 2009-01-06
WO2002088819A2 (fr) 2002-11-07
DE10121064A1 (de) 2002-10-31
WO2002088819A3 (fr) 2003-09-25
AU2002312858A1 (en) 2002-11-11

Similar Documents

Publication Publication Date Title
DE10004191B4 (de) Fluoreszenz-Scanmikroskop
EP1384104A2 (fr) Dispositif et procede de mesure optique d'echantillons chimiques et/ou biologiques
EP3206070B1 (fr) Microscopie combinée
DE3037983C2 (de) Verfahren und Vorrichtung zur lichtinduzierten rastermikroskopischen Darstellung von Probenparametern in ihrer räumlichen Verteilung
DE68919892T2 (de) Fluoreszenz-Mikroskopvorrichtung.
EP1396739B1 (fr) Méthode et arrangement pour la modulation ajustable de la constitution spectrale et/ou de l'intensité de lumière de l'éclairage et/ou de lumière sonde
EP2195697B1 (fr) Procédé pour l'analyse d'un échantillon
EP2097781B1 (fr) Microscope laser a diviseur spatial de faisceau
DE10038526B4 (de) Verfahren und Anordnung zur Erfassung des wellenlängenabhängigen Verhaltens einer beleuchteten Probe
DE10033180B4 (de) Verfahren zur Detektion von Farbstoffen in der Fluoreszenzmikroskopie
EP1121581B1 (fr) Systeme d'imagerie comportant un ensemble de lentilles cylindriques
DE10038528A1 (de) Verfahren und Anordnung zur Erhöhung der spektralen und räumlichen Detektorauflösung
DE10257237A1 (de) Anordnung zur optischen Erfassung von in einer Probe angeregter und/oder rückgestreuter Lichtstrahlung
WO2012034852A1 (fr) Système d'imagerie optique pour l'imagerie multispectrale
DE102012205311A1 (de) Optische Vorrichtung, insbesondere Polarimeter, zur Detektion von Inhomogenitäten in einer Probe
DE69937531T2 (de) Elektronenmikroskop und spektroskopisches system
EP1678547B1 (fr) Dispositif et procede de mesure des proprietes optiques d'un objet
DE102015001032A1 (de) Raman-Spektroskopie-Beleuchtungs- und Auslesesystem
WO2024153476A1 (fr) Microscope
DE60205406T2 (de) Optisches zweiwellenlängen-fluoreszenzanalysegerät
EP1720054A2 (fr) Procédé et dispositif destinés à la modification réglable de la lumière
EP1273951B1 (fr) Microscope à balayage et méthode de detection dependant de la longueur d'onde
EP1523667B1 (fr) Systeme d'imagerie en fond noir destine a l'imagerie en fond noir a resolution spatiale d'un echantillon et methode d'examen
WO2000068667A1 (fr) Systemes microscopiques utilises pour le balayage optique d'objets microscopiques
DE10012641A1 (de) Objektivanordnung

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20031029

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

RIC1 Information provided on ipc code assigned before grant

Ipc: 7G 02B 27/14 B

Ipc: 7G 01N 21/00 B

Ipc: 7G 02B 21/18 A

17Q First examination report despatched

Effective date: 20041027

RIN1 Information on inventor provided before grant (corrected)

Inventor name: MUELLER, JUERGEN

Inventor name: STANGE, ROLAND

Inventor name: KIRSCH, ACHIM

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20091201