CA2347184C - Imaging system with a cylindrical lens array - Google Patents
Imaging system with a cylindrical lens array Download PDFInfo
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- CA2347184C CA2347184C CA002347184A CA2347184A CA2347184C CA 2347184 C CA2347184 C CA 2347184C CA 002347184 A CA002347184 A CA 002347184A CA 2347184 A CA2347184 A CA 2347184A CA 2347184 C CA2347184 C CA 2347184C
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- 238000003384 imaging method Methods 0.000 title claims abstract description 37
- 230000003287 optical effect Effects 0.000 claims abstract description 22
- 230000000694 effects Effects 0.000 claims abstract description 14
- 238000011144 upstream manufacturing Methods 0.000 claims abstract 2
- 238000011156 evaluation Methods 0.000 claims description 8
- 238000010276 construction Methods 0.000 claims description 6
- 230000003247 decreasing effect Effects 0.000 claims description 2
- 238000012634 optical imaging Methods 0.000 claims description 2
- 238000001514 detection method Methods 0.000 abstract description 11
- 238000004458 analytical method Methods 0.000 abstract description 4
- 230000005855 radiation Effects 0.000 abstract description 4
- 230000035945 sensitivity Effects 0.000 abstract description 4
- 238000005259 measurement Methods 0.000 description 19
- 230000005284 excitation Effects 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 5
- 238000006073 displacement reaction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000005540 biological transmission Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000003491 array Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000009304 pastoral farming Methods 0.000 description 2
- 101150034533 ATIC gene Proteins 0.000 description 1
- 241000518994 Conta Species 0.000 description 1
- 241001517310 Eria Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000012921 fluorescence analysis Methods 0.000 description 1
- 238000001917 fluorescence detection Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000001747 pupil Anatomy 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
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Classifications
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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
- G01N21/6452—Individual samples arranged in a regular 2D-array, e.g. multiwell plates
-
- 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
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/251—Colorimeters; Construction thereof
- G01N21/253—Colorimeters; Construction thereof for batch operation, i.e. multisample apparatus
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B3/00—Simple or compound lenses
- G02B3/0006—Arrays
- G02B3/0037—Arrays characterized by the distribution or form of lenses
- G02B3/005—Arrays characterized by the distribution or form of lenses arranged along a single direction only, e.g. lenticular sheets
-
- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B3/00—Simple or compound lenses
- G02B3/0006—Arrays
- G02B3/0037—Arrays characterized by the distribution or form of lenses
- G02B3/0062—Stacked lens arrays, i.e. refractive surfaces arranged in at least two planes, without structurally separate optical elements in-between
- G02B3/0068—Stacked lens arrays, i.e. refractive surfaces arranged in at least two planes, without structurally separate optical elements in-between arranged in a single integral body or plate, e.g. laminates or hybrid structures with other optical elements
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B5/00—Optical elements other than lenses
- G02B5/04—Prisms
- G02B5/045—Prism arrays
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2201/00—Features of devices classified in G01N21/00
- G01N2201/02—Mechanical
- G01N2201/024—Modular construction
Abstract
The invention relates to an imaging system for optical automatic analysers, especially fluorescence readers. On the sample side, the imaging system contains a cylindrical lens array (6) and a prism array (7), which is arranged upstream of the cylindric al lens array. The prismatic effect of the prisms (7a-7c) of the prism array (7) lies in th e direction of the cylinder axes of the cylindrical lenses (6a-6c). Together with a telescopic imaging system (8, 11), the inventive imaging system creates a number of parallel cylindrical focussing volumes between the cylindrical lens array (6) and a detector array (10), these focussing volumes being slanted towards the optical axis of the telescopic system in relation to the vertical. The arrangement enables the detection of fluorescence with a large aperture in one direction, and at the same time enables depth selective analysis of the fluorescence signal, especially the discrimination of the fluorescent radiation originating from the areas around the bases of the sample containers from the fluorescent radiation originating from the solution above. With the focussing volumes that are slanted towards the bases of the sample containers, the imaging system ensures that the fluorescence from the areas around the bases of the sample containers (5a-5c) is detected with the same sensitivity even when the heigh ts of the bases vary in the individual sample containers.
Description
~
jMaging System With aj( yidrical Lens Airay The invention relates to an imagi.ng syst.em, in part:ir,ular for automatic analyzers with a luigh sample tluoughput, Such automatic analyzers are freqr.tently tCrXned "readers" or "fluorescence readers" for microtiter plates. Such-"reA,ders" are used, for example, in the development of pharmaceutically active materials or in nidlecular medical diagnoses, and thus in applications in which tluorescence, luminescence, and absorption investigations of large sample numbers and very small sample quantities are required. Consequently a high sample throu,ghput is of &reat itnportance in these applications, On the other hand, measurements of reaotion kinetics are frequently required, the time constonts. of which are an obstacle -to a high sample throughput.
In these applications, tzaicrotiter plates are used, with very small sample containers arranged in an array, in stapdardized embodimeiits wztb, e.g., 96 or a multiple thereof, for example, 384 or h 536, sample containers. As an alternaCive, so-called substance chips are also in 4se as salnple containers.
In a few applications, the actual task of the meastu'ement is to dete-muine the fraction, or ttae change with time of the fraction, of a substance which has.
penetrated from the solution into the interior of aicel] or wlt.i,ch is bound to the cell surface. The substance con.cerned is as a rule mark~d with a fluorescing dye. In this measurement task, it is required to discriminate the fluorescence signal of the dye taken up by, or bound to, the cell frotn the fluorescence signal of the substance styll present in the solution. Since the Geils concerned are as a rule situated on the floor of the microtiter plate, a fluorescence reader is consequently required which operates floor-selectively.
A corresponding floor-selective fluorescence reader is offered, for example, by the Molecular Devices Corporation, USA under the name Fluorometric Imaging Plate Reader. In this device, the fluorescence excitation takes place from below through the floor of the microtiter plate at a strongly grazing incidence through a slit mask. The fluorescence light is then detected from that lateral region of the microtiter plate into which the excitation light has penetrated to only a small depth into the sample container, due to the grazing incidence. However, the fluorescence excitation is very ineffective with this device, since only a small fraction of the excited fluorescence is used for the detection. Furthermore, only the fluorescence of a very small lateral region of the sample space floor is used, so that only the cells situated in this small lateral region contribute to the measurement signal.
In the Applicant's published German patent application DE 197 48 211 Al, an optical system for a corresponding analytical device is described, in which a lens array with a lens allocated to each sample container is provided on the sample space side. Together with a telescope with a field lens, arranged after the lens array on the detection side, the foci of the individual lenses of the lens array are imaged on a detector array for the production of the desired measurement signal.
Signal acquisition here takes place in parallel and simultaneously for all the sample containers, so that a high throughput can be realized with this optical arrangement.
Since the measurement signal, for example the detected fluorescence light, originates almost exclusively from the focal volumes of the individual lenses of the lens array, a very depth-selective fluorescence detection is possible with this optical arrangement. Here also, the lateral cross section, that is, perpendicular to the optical axes of the lenses of the lens array, of the detection volume is of course very small. Furthermore, the detection of the fluorescence or of another measurement signal from the region of the floor of the sample container requires in practice a depth scan, and thus several measurements with different distances between the microtiter plate and the optical arrangement in the direction of the optical axis, since the individual floors of the sample containers of the microtiter plate have different heights, due to production conditions. The time required for a depth scan is however contrary to the aim of a high sample throughput.
A line-form imagirig systern is known from JP 7013101-A in whicb an array of perntaprisms is arxanged betv++een two lens arrays. The Icns arrays respectively have a oylindrical lens surface on the side toward the pentaprisJxls.
The pentapiisms then bring gbout a lateral interchan$e of the Image effectetl by the whole systemt in the direction of the axes of the cylindrical lenses.
The present invention has as its object.to provide an imaging system which makes possible measurements in pargllel in plural sainple containers, The measurement signals acquired in parallel are to have an identical sensitivity, in all the sample containers, even when the floor height of the sample containers is different, and to make possible a discrimination of th.e roeasu.remeiit sig,naJs originating from the region near the floor. and a high sample througliput.
The imaging system according to one aspect of the invention consequently has an array of cylindrical lenses. A prism array is arranged before this cylindrical lens array on the sample side, the prism array being oriented relative to the cylindrical lens array such that the prismatic effect of the prisms is in the direction of the cylinder axes of the cylindrical lenses. The cylindrical lens array and the prism array can be constituted here as two separate components or as a single component. In the latter case, the combined array has, on a common support, a constitution as a prism array on the sample side and the cylindrical lenses on the side remote from the sample. Due to the cylindrical lenses, a substantially cylindrical detection volume results in each of the sample containers. Due to the prisms arranged on the sample side in front of the aylindrical lenses, the cylinder axes of the focal volume receive an inclination -relative to the cylinder axes of the cylindrical lenses. If ihe cylindrical lens array is 3a combined array has, on a common support, a cotistitution as a prisin array on the sample si.de and the cylindrical lenses, on the side remote from the sample.
Due to the cyli,ndnical lenses, a substanta.al y cylindrical detection volume results. in each of the sample containers. Due to the risms arranged on the sample side in front of AMDENDED SHEET
jMaging System With aj( yidrical Lens Airay The invention relates to an imagi.ng syst.em, in part:ir,ular for automatic analyzers with a luigh sample tluoughput, Such automatic analyzers are freqr.tently tCrXned "readers" or "fluorescence readers" for microtiter plates. Such-"reA,ders" are used, for example, in the development of pharmaceutically active materials or in nidlecular medical diagnoses, and thus in applications in which tluorescence, luminescence, and absorption investigations of large sample numbers and very small sample quantities are required. Consequently a high sample throu,ghput is of &reat itnportance in these applications, On the other hand, measurements of reaotion kinetics are frequently required, the time constonts. of which are an obstacle -to a high sample throughput.
In these applications, tzaicrotiter plates are used, with very small sample containers arranged in an array, in stapdardized embodimeiits wztb, e.g., 96 or a multiple thereof, for example, 384 or h 536, sample containers. As an alternaCive, so-called substance chips are also in 4se as salnple containers.
In a few applications, the actual task of the meastu'ement is to dete-muine the fraction, or ttae change with time of the fraction, of a substance which has.
penetrated from the solution into the interior of aicel] or wlt.i,ch is bound to the cell surface. The substance con.cerned is as a rule mark~d with a fluorescing dye. In this measurement task, it is required to discriminate the fluorescence signal of the dye taken up by, or bound to, the cell frotn the fluorescence signal of the substance styll present in the solution. Since the Geils concerned are as a rule situated on the floor of the microtiter plate, a fluorescence reader is consequently required which operates floor-selectively.
A corresponding floor-selective fluorescence reader is offered, for example, by the Molecular Devices Corporation, USA under the name Fluorometric Imaging Plate Reader. In this device, the fluorescence excitation takes place from below through the floor of the microtiter plate at a strongly grazing incidence through a slit mask. The fluorescence light is then detected from that lateral region of the microtiter plate into which the excitation light has penetrated to only a small depth into the sample container, due to the grazing incidence. However, the fluorescence excitation is very ineffective with this device, since only a small fraction of the excited fluorescence is used for the detection. Furthermore, only the fluorescence of a very small lateral region of the sample space floor is used, so that only the cells situated in this small lateral region contribute to the measurement signal.
In the Applicant's published German patent application DE 197 48 211 Al, an optical system for a corresponding analytical device is described, in which a lens array with a lens allocated to each sample container is provided on the sample space side. Together with a telescope with a field lens, arranged after the lens array on the detection side, the foci of the individual lenses of the lens array are imaged on a detector array for the production of the desired measurement signal.
Signal acquisition here takes place in parallel and simultaneously for all the sample containers, so that a high throughput can be realized with this optical arrangement.
Since the measurement signal, for example the detected fluorescence light, originates almost exclusively from the focal volumes of the individual lenses of the lens array, a very depth-selective fluorescence detection is possible with this optical arrangement. Here also, the lateral cross section, that is, perpendicular to the optical axes of the lenses of the lens array, of the detection volume is of course very small. Furthermore, the detection of the fluorescence or of another measurement signal from the region of the floor of the sample container requires in practice a depth scan, and thus several measurements with different distances between the microtiter plate and the optical arrangement in the direction of the optical axis, since the individual floors of the sample containers of the microtiter plate have different heights, due to production conditions. The time required for a depth scan is however contrary to the aim of a high sample throughput.
A line-form imagirig systern is known from JP 7013101-A in whicb an array of perntaprisms is arxanged betv++een two lens arrays. The Icns arrays respectively have a oylindrical lens surface on the side toward the pentaprisJxls.
The pentapiisms then bring gbout a lateral interchan$e of the Image effectetl by the whole systemt in the direction of the axes of the cylindrical lenses.
The present invention has as its object.to provide an imaging system which makes possible measurements in pargllel in plural sainple containers, The measurement signals acquired in parallel are to have an identical sensitivity, in all the sample containers, even when the floor height of the sample containers is different, and to make possible a discrimination of th.e roeasu.remeiit sig,naJs originating from the region near the floor. and a high sample througliput.
The imaging system according to one aspect of the invention consequently has an array of cylindrical lenses. A prism array is arranged before this cylindrical lens array on the sample side, the prism array being oriented relative to the cylindrical lens array such that the prismatic effect of the prisms is in the direction of the cylinder axes of the cylindrical lenses. The cylindrical lens array and the prism array can be constituted here as two separate components or as a single component. In the latter case, the combined array has, on a common support, a constitution as a prism array on the sample side and the cylindrical lenses on the side remote from the sample. Due to the cylindrical lenses, a substantially cylindrical detection volume results in each of the sample containers. Due to the prisms arranged on the sample side in front of the aylindrical lenses, the cylinder axes of the focal volume receive an inclination -relative to the cylinder axes of the cylindrical lenses. If ihe cylindrical lens array is 3a combined array has, on a common support, a cotistitution as a prisin array on the sample si.de and the cylindrical lenses, on the side remote from the sample.
Due to the cyli,ndnical lenses, a substanta.al y cylindrical detection volume results. in each of the sample containers. Due to the risms arranged on the sample side in front of AMDENDED SHEET
arranged substantially parallel to the mictotiter plate, cylindrieal detection volumes thereby result which are inclined to the floors of the sample oontainers.
Since the cross sectional surfaeos through the detection volumes are identical for parallel sections through these detection volumes, the detection of ttie measurez ent saignai.
from different depths of the sample v lume takes :plaee with identical sensitivity.
Consequently even different floor hei ts in the different sample eontainers do not give rise to different measurement sensitivities.
It should be mentioned at this point that an imaging system for the projeotion of color 1.CD displays as the object to be imaged is already k-nown from U.S.
Patent 5,602,679, in which a lens array with a superposed prismatic effcct is used.
Cylindrical lenses are also stated there as a possible lens form of the lens array, Although no specific data are given, it is to be concluded therefrom that the prisin action of the prisma has to be oriente4 perpendicular to the cylinder axes of the cylindrical lenses, so that the desired pi.iperposition of the, color pixels is attained.
Apart from this, the statement of objdcts given there completely departs from the statement o object of the present invfntion.
The imaging system according rto the invention is preferably used, similarly to that of the German Patent Application DE 197 48 211 Al mentioned hereinabove, together with a telescopic imaging system, the long-focus lens of the telescopic imaging system being oriented in the direction toward the cylindrical lens array, and overlapping with its diameter plural, preferably all the, cylindrical lenses.
A-detector array is then preferably arranged after the imaging system or the telescopic imaging system, and with it the measiFe.ment light for the different parallef channels of the imaging system is detected in parallel. The detector arra.y is then fiuthermore preferably arranged behind the exit-side focal plane of the telescope lens remote from the cylindrical lens anray, the said focal plane being remote from the long-focus telescope lens and the cylindxical lens array. With sttch an optical arrangement, different lateral displacements of the intensity distribution of the measurement light on the detector array result from different heights of the floor of the microtit,atr plate.
Since as a nile the maximum measurement signal, for example, the maximum fluorescence intensity, originates from the transition region from the sample space floor into the solution, the measurement signal resulting from this region can ther4by be easily disciiminated from the xemadning measurement signal in that only the regions of the detector array with maycimum signal strengths- are made use of for fauther evaluation. In this manner, the measuroment signal originating from the floor re.gion can quickly and easily be disctiminatsd from the measurement originating from the solution.
The iinaging system according to the invention can in principle be combined with the telescopio imaging systern and the detector earay into a single constructional unit. However, a modplar construction is partioularl.y advantageous, in w}uioh the cylindrical lens array and the prism array form their own constnlctional unit. This constructional unit can then be easily exchanged for the lens arrax from from the abovecited patent application DE 197 48 211 Al, so that the functionality of the reader described there can be correspondingly enlarged. Alternatively, a reader constructed according to the present invention can easily be changed to a reader according to DE 197 48 211 by exchange of the constructional unit with the lens array on the sample side, and by insertion or exchange of a spacing ring for a constructional unit with a field lens between the two telescope lenses.
In the present invention, the alpertures of the cylindrical lenses are imaged on the detector array by the telescopic imaging syst:eria.
.6_ For the excitation of fluorescence or luminescence, a vertical illuminator is to be provided, light from which is reflected into the measurement beam path, preferably between the detector array and the short-focus teloscope lens.
In a completely atitomatic analyzer with an optical imaging system according to the invention, an evaluation computer for the evaluation of the light signals detected with. the detector array is to be provided. This eval-,attion conlputer can carry out an integration of the light signals belonging to each sample container, in the direction perpendieular to the cylinder axes of the cylindrical lens arra.y, and then, by means of software, deterxnine solely the- maximum value of the integrated light intensity or the other characteristic signal change in the direction of the cylinder axes of the cylindrical lenses7 in order to thereby discriminate the -measurement signal originating from the iloor region of the sample voluumcs:.
Details of the invention are described in more detail hereinbelow with reference t.o the embodiment examples shown in the Figures.
Fig. 1 shows an outline of principles of the.optical construction of an analysis system with an imaging system according to the inventXon, Figs. 2a show the bevn paths in the analysis systeirt of. Fig. 1, in and 2b two mutually perpendicular sectional directions, Figs. 3a show details from perspeotive illustration-s of the and 3b cylindrical lens array (E4. 3a) and of the prisni array (Fig. 3b).
Flg. 3c shows a detail from an atT~,y with combined cyXindrical lenses and prisms, in section.;
Figs. 4a show graphical illustrations of two cylindrical focus and 4b volumes relative to two qarrlple space floors with differetit floor heights;
Figs. 5a show graphical illustrations of the intanaity distri-and 5b butions on the detector array with the different floor heights according to Figs. 4a and 4b;
Fig. 6a shows ainodule with a lens array with rotationally symmetrical lenses, which module can be exchanged for the imaging system accoarding to the invantion, in a modular type of construction. and Fig. 6b shows, in a modular type of construction, a module with afield lens wh.ich. can be inserted. between the telescope lenses.
The measuring and evaluation system shown in Fig.. I consists of a total of four modules (1 -4), three of which cQntain optical components. It serves for the analysis, particularly fluorescence analysis, of the saynples situated in sample containers (5a-5c) of a microtiter plate (5), as a rule cells lying on the floor.of the' sample containers (5a-5c) and surrounded by a nut'rient solution.
The module (1) next adjacent to the miaroCiter pla.te (5) contains a lens.array (6) with plural cylindrical lenses (6a-6c) and a prism array (7) with prisms (7a-7C), The prism array (7) is arranged on the sample side of the lens array (6), so that the prisrns (7a-7c) are situated between the cylindrical. leiises (6a-6c) and the sample containers (5a-5c). The prism array (7) or the prisms (7a-7c) of the prisrn array are - O -then oriented relative to the cylindrical lens array (6) sucli that the priarnatic effect of the prisms is in the direction of the cylinder axes of the cylindrical lenses (6a-6c).
A nmodule (2) which contains a long-focus telescope lens (8) a.djoins the side of the module (1) remote from the nzicrotiiter plate (5). The opening diameter, or more precisely the usable aperttare, of the long-focu.s telescope lens (8) is then chosen such that this aperture overlaps the su.rfaco of all the apertures of the -cylindrical lenses (6a-6c) of the cylindrical lens atra,y. It should be mentioned at this point that for the sake of clarity, in Fig. l and the otlie.r Figures, respectively only a small section of the microtiter plate (5) with llaree sample containers is shown. 'in reality, 96, or an integral multiple thereof, 384 or 1536, corresponding sarnple containers are present, and there is a corresponding nuznber of optical channels, whieb is determined by the number of microlenses (6a-6c) and of prisms (7a-7c).
Correspondin8ly, the aperture of the long-focus telescope -lens (8) overlaps-all the optlcal. channels.
In the region of the focal plane of the long-focus telescope lens (8), an intermediate module (3) follows the module (2) containing the long-focus tele'scope lens, and primarily serves as a spacer; with the exception of a diaphragm (9), it contains no optics. The diaphragm (9) forms an,aperture stop in the direction of the cylinder axes of the cylindrical lenses (6a-6c), which in p'iS. 1 stand perpendiieular to the plane of the drawing. In the direction perpendicular thereto, and thus in the plane of the drawing of F'ig. l, the dya,phragm. (9) forms a field stop, In this ' direction, the diapluagm (9) has the e$fect that meastirement light, for example fluorescence light, from. the lateral edges of the sample holder (5a-5c) is scxcened off by the diaphragm (9) fi-onct the detector array (10).
Finally, the illumination and detector module (4) follows the intermediate module (3). It contains a short-focus telescope lens (11) which together with the lAng-focus telescope lens (8) forms an afocal syste.na; the detector array (10); th.e vertical ylluminator (12); and also an incident light reflector (13) arranged between the s.laort-focus telescope lens (11) and the detector array (10). A
fluorescence ftlter, (14) with high transmission in the wavelength region of the fluorescence light or luminescence light and low transmission in the wavelength region of the excitation light of the vertical illwninator (12) is also arranged between the incident light reflector (13) and the detector array (10). Axternatively to this, the incident light rcflecto.r can also be constituted as a corresponding dichroic beamsplitter.
The vertical illuminator (] 2) produces a collimated illuminating beam path, the diameter of which corresponds to the aperture of the short-focus telescope lens (1, 1). This illuminating pencil of rays is eXpanded to the aperture of the long-focus telescope lens (8) by the telescope fornned by the lep.ses (8 and 11), and correspondingly illuzninates all the apertures of the cylindrical lenses (6A) of the cylindrical lens array (6). A focusing of the excitation light by the Gylindrical, lenses (6a-6c) thus takes place in the direction perpendicular to the cylinder axes of the cylindrical lenses (6a-6c), and thus in the plane of the drawing of Fig. 1. In the direction perpendicular to this, on the other hand, the excitation light rexnains coUina.a.ted, a defleotion taking place d e to the prismatic effect of the priSams (7a-7c), so that a number of line foci arise Inear the floors of the.-sam,ple containers (5a-5c), and are inclined to the floors of the sample conta,iners (Sa-5c). The width of the.
line foci is then detenmined by the latc;al dimensions of the effectively active light source, the exit. $ucface (15a) of an opocal fiber (1 S) in the vertical illuminator (12).
The dimensions of this effectively active light source are then chosen so that a sufficiontly large focal, volume, and thus excitation volume, arises in the sample containers (5a-Sc).
The transmission relationships on the imaging side are shown in Figs. 2a and `1p.
2b for the two mutually perpendicullir directions. The plar-e,of the drawing in Fig. 2a then corresponds to the plane of the drawiytg in Fig. l. The prism array (7) plays no ,part in the imaging relationships in this direction, since the pristnatic effect of the prisms (7b. 7c) lies in the direction perpendicular to this. Since the cylindrical l.nses (6b, 6c) have their effect in this direction, fluoresGence radiation arising. in the sample containers (5b, 5c) in the focal volume of the cylindrical lenses (6b, 6c) is, collected with high aperture by the cylindr.ical lenses (6b, 6c) and is imaged by the long-focus telescope lens (8) in tlio focal plane of this long-focus telescope lens (8), and thus in the plane of the diaphragrrl (9), Superposed astigmatic intermediate images arise here, and are then imaged to infinity by the short-focus telescope lens (11.). The fluorescence light is then detected by separate regions (10b, l0c) of the detector array (10). The pupils of the;cylindrical lenses (6b, 6c) are thus imaged in the plane of the detector array, on separate regions of -the detector anray (:l Ob, lOc)s by. the telescope formed by the two lenses (8, 11 ).
In the direction of the cylinder axes of the cyliadrical lenses (6b) (Fig.
2b), on the contrary, the cylindrical lenscs have no effect. In this direction, the prisms (7b, 7d) of the prism array (7) of course have a prisnzatic effect. In this direction, the long-focus telescope lens (8) acts as the objective wlaioh oollects the fluorescence light wit.lx relatively small aperture from the sample containers (5b, 5d). A
deflection additionally takes place duO to the prismatic effect of the prisms (7b, 7d), so that in this direction the foei of the individual Ghannnels are inclined to the focal plane of the long-focus telescope lens (8) and are il,us inclined to the floors of the sample containers (Sb, 5d). The smnmple containers (Sb, 'Sd), and thus the rnicrotiter plate, are arranged with the floors of the sample containers in the focal plane of the long^foaus telescope lens (8). The fluqrescence light collected by the long-focus telescope lens (8) is collimated by this, so that in this direction the diaplaragm (9) -ll-acts as an aperture stop. hltermediatc images of the foci of the long-f.ocus telescopo lens (8) arise in tlie rear focal plan of the short-foGt1s telescope lens (11). The detector array with the regions (lOb, lOd) is arranged 9lightly behind this focal plane.
The structure of the eylindrical lens array (6) is shown in Fig. 3a as a detail of the cylindrieal lens a ray (6). The eylindrical lens array contains plural eylindrical lenses (6a, 6b, 6c), anranged mutually parallel and respectivtly able to extend over' the whole length of the array in the direction of the cylinder axes. The regions (17) between thC cylindrical lenses are preferably made opaqup, for channel=
separation.
A corresponding detail of the prism array (7) is.shovvn in perspective in Fig.
3b; It contains a strip-shaped arrangement of prisms (7a.,.?b, 7c), with respective prismatir effect in the direction of die oyluider axes of the cyl'in.drical=lenses (6a, 6b, 6c). In other words, each prism (7a, 7b, 7o) has an increasing or decreasing thiclrness in tho direction of the cylinder axes. The prisms (7a, 7b, 7c) can exteiid over the whole length of the prism array (7) in the direction perpendicular to the cylinder axes of=the cyaindrical lenses (6a, 6b, 6c). ThG regions (18) between the prisma (7a, 7b, 7c) are again made opaque, for channel separation. .
A two-dimensional artay of optical channels, the number of which.
corresponds to the product of the numbor of cylindrical lens.es and the number of prisms, arises by the superposition of t$te telescope lens array (6) a d the'prism array (7), and the opaque constitution ~f the interspaces (17, 18) betweeli .the cylindrical lenses or between the priams.
Altexnatively to the constitution according to Figs. 31 and 3b, it is however also conceivable to provide, for each optical channea, its ovAi prism on the prism array and its own cylindrical lens on. the cylindrical lens array. In this case, both the Gylindrica,l lens array and the prism array are constituted as a two-dimensional array.
A. slightly better channel separation results from a corresponding opaque -const.itution of the interspaces; that is, crosstalk between the optical channels is reduced, A'section through a coztibined cylindrical lens and prism array (19), whicli is achromatic over an extended spectral region, is shown in Fig. 3c. lt contains, on a common support, a cylindrical lens sind prism combination (] 9a, 19b, 19c) for each optical channel respectively consisting of three lenses (20s,-20c, 21 a-21 c, 22a-22c) and prisans (23a-23c) following the lenses. In a mairner known pg-r so, the individual components of each cylindricsl lens system consist of differ nt materials, by means of which an achromatic correction i.s attained for a waveleugffi region of 35 0 nm -700 nm. The prisms (23a, 23b, 23c) again have a different thickness, from which the prismatic effect results, perpendicular to the plan-e of the drawing in.Fig. 3, and thus in the direction of the cylinder axes of the cylindrical 'lenses, The effect produced by the above-described arrangement in the region of the sample space floor can be seen from Figs. 4a and 4b. The sample space floors (24a, 24b) are shown there for two exernplary adjacent cella of the microtiter plato. Tt is i;o be assumed here that the two sample space floors are mutually displaced'by a small distance (h). The focal volumes of the relevent optical channels in the two sample spaces are deiaoted by (25a, 25b). These focus volumes are circular cylinders, the cylinder axis being respectively inclined to the plane of the saia-ple space floor. The inclination between the plane of the sample space floor and the, cylinder axes of the focus volumes (25a, 25b) is then. determined by the prism,atic effect of the priszn.s. 'T1ie diameter of the cylindrical focus volumes is substantially determined by the numerical aperture of the whole arrangement, primarily the numerical aperture of the cylindrical lenses being considerable here.
Numerical apertures in this direction of 0.5 or more can be attained without problems.
-].3-As can be .recognized froni a comparison of Figs. 4a and 4b, a lateral displacement of the relevant sectional plane between the cylindrical focus volume and the surface of the sample space floor results frorn different floor.height,a in the dr,fFexent cells of the microtite.r plate, because of the inclanation of the focus volumes to the plane of the sample space .floo,r, The different intensity distributions of the fluorescence radiation thereby arising in the regions (10a=10c) on the deteotor array are correspondyngly shown in Figs. 5a and 5b. By a displacement of the sectional plane between the focus vohume and the sample space floor, there resulta' a.
corresponding displacement of the intensity distribution in the direction of the cylinder axes of the cylindrical lens array, since the fluorescence intensity is as a rule maximum in the iaunediatC neighborhood of the sample space floor_ For signal 'evaluation, in an evaluation computer (16), the intensity signals of the pixels of the detector array belonging to each sample space or each optical channel are first integrated in a direction perpendicu.lar to the cylinder axes of the cylindr:ical lenses, and subsequently the characteristic signal change. in the direction of the cylinder axes, as a rule the maximum, of the integrated fluorescence intensity is determined axld evaluated. In measurements of reaction k;inetias or of the time course of the fluorescence signal, the fluorescence measurement takes place repeatedly over plural receiving and readout cycles of the detector array.
.lt has been found to be approptiate to dimension the prisms of the prism array such that the cylindrical focus volumqs (25a, 25b) cover a region of 03-0.5 mm in.
the direction of the optical axis of the' whole arrangement. The len,gth.,of the eylindrical focus volume preferably extends over the whole corresponding length of the sample space, which corresponds to about 3 mm for a 384-we11 microtiter plate.
A substantially elliptical intersectioai surface between the sample space floor and the focus volume then results due to the inclinatiori of the cylindrical focus volume, and has a major axis of about 1 mm and a minor axis of about 0.13 mm.
Fig. 6a shows an interchange module or supplementary module (31) for interchange with a module (1) in the arrangement according to Fig. 1. The interchange module (31) contains a lens array with rotationally symmetrical lenses (32a-32c). A further interchange module (33) (Fig. 6b) for interchange with the module (3) contains a field lens (34). Interchange of the modules (31) and (33) with the modules (1) and (3) in Fig. 1 results in an optical arrangement which corresponds to the optics according to the above-cited patent application DE
48 211 Al. Compatibility with the optical arrangement described in the older application is thus ensured by corresponding additional modules.
Since the cross sectional surfaeos through the detection volumes are identical for parallel sections through these detection volumes, the detection of ttie measurez ent saignai.
from different depths of the sample v lume takes :plaee with identical sensitivity.
Consequently even different floor hei ts in the different sample eontainers do not give rise to different measurement sensitivities.
It should be mentioned at this point that an imaging system for the projeotion of color 1.CD displays as the object to be imaged is already k-nown from U.S.
Patent 5,602,679, in which a lens array with a superposed prismatic effcct is used.
Cylindrical lenses are also stated there as a possible lens form of the lens array, Although no specific data are given, it is to be concluded therefrom that the prisin action of the prisma has to be oriente4 perpendicular to the cylinder axes of the cylindrical lenses, so that the desired pi.iperposition of the, color pixels is attained.
Apart from this, the statement of objdcts given there completely departs from the statement o object of the present invfntion.
The imaging system according rto the invention is preferably used, similarly to that of the German Patent Application DE 197 48 211 Al mentioned hereinabove, together with a telescopic imaging system, the long-focus lens of the telescopic imaging system being oriented in the direction toward the cylindrical lens array, and overlapping with its diameter plural, preferably all the, cylindrical lenses.
A-detector array is then preferably arranged after the imaging system or the telescopic imaging system, and with it the measiFe.ment light for the different parallef channels of the imaging system is detected in parallel. The detector arra.y is then fiuthermore preferably arranged behind the exit-side focal plane of the telescope lens remote from the cylindrical lens anray, the said focal plane being remote from the long-focus telescope lens and the cylindxical lens array. With sttch an optical arrangement, different lateral displacements of the intensity distribution of the measurement light on the detector array result from different heights of the floor of the microtit,atr plate.
Since as a nile the maximum measurement signal, for example, the maximum fluorescence intensity, originates from the transition region from the sample space floor into the solution, the measurement signal resulting from this region can ther4by be easily disciiminated from the xemadning measurement signal in that only the regions of the detector array with maycimum signal strengths- are made use of for fauther evaluation. In this manner, the measuroment signal originating from the floor re.gion can quickly and easily be disctiminatsd from the measurement originating from the solution.
The iinaging system according to the invention can in principle be combined with the telescopio imaging systern and the detector earay into a single constructional unit. However, a modplar construction is partioularl.y advantageous, in w}uioh the cylindrical lens array and the prism array form their own constnlctional unit. This constructional unit can then be easily exchanged for the lens arrax from from the abovecited patent application DE 197 48 211 Al, so that the functionality of the reader described there can be correspondingly enlarged. Alternatively, a reader constructed according to the present invention can easily be changed to a reader according to DE 197 48 211 by exchange of the constructional unit with the lens array on the sample side, and by insertion or exchange of a spacing ring for a constructional unit with a field lens between the two telescope lenses.
In the present invention, the alpertures of the cylindrical lenses are imaged on the detector array by the telescopic imaging syst:eria.
.6_ For the excitation of fluorescence or luminescence, a vertical illuminator is to be provided, light from which is reflected into the measurement beam path, preferably between the detector array and the short-focus teloscope lens.
In a completely atitomatic analyzer with an optical imaging system according to the invention, an evaluation computer for the evaluation of the light signals detected with. the detector array is to be provided. This eval-,attion conlputer can carry out an integration of the light signals belonging to each sample container, in the direction perpendieular to the cylinder axes of the cylindrical lens arra.y, and then, by means of software, deterxnine solely the- maximum value of the integrated light intensity or the other characteristic signal change in the direction of the cylinder axes of the cylindrical lenses7 in order to thereby discriminate the -measurement signal originating from the iloor region of the sample voluumcs:.
Details of the invention are described in more detail hereinbelow with reference t.o the embodiment examples shown in the Figures.
Fig. 1 shows an outline of principles of the.optical construction of an analysis system with an imaging system according to the inventXon, Figs. 2a show the bevn paths in the analysis systeirt of. Fig. 1, in and 2b two mutually perpendicular sectional directions, Figs. 3a show details from perspeotive illustration-s of the and 3b cylindrical lens array (E4. 3a) and of the prisni array (Fig. 3b).
Flg. 3c shows a detail from an atT~,y with combined cyXindrical lenses and prisms, in section.;
Figs. 4a show graphical illustrations of two cylindrical focus and 4b volumes relative to two qarrlple space floors with differetit floor heights;
Figs. 5a show graphical illustrations of the intanaity distri-and 5b butions on the detector array with the different floor heights according to Figs. 4a and 4b;
Fig. 6a shows ainodule with a lens array with rotationally symmetrical lenses, which module can be exchanged for the imaging system accoarding to the invantion, in a modular type of construction. and Fig. 6b shows, in a modular type of construction, a module with afield lens wh.ich. can be inserted. between the telescope lenses.
The measuring and evaluation system shown in Fig.. I consists of a total of four modules (1 -4), three of which cQntain optical components. It serves for the analysis, particularly fluorescence analysis, of the saynples situated in sample containers (5a-5c) of a microtiter plate (5), as a rule cells lying on the floor.of the' sample containers (5a-5c) and surrounded by a nut'rient solution.
The module (1) next adjacent to the miaroCiter pla.te (5) contains a lens.array (6) with plural cylindrical lenses (6a-6c) and a prism array (7) with prisms (7a-7C), The prism array (7) is arranged on the sample side of the lens array (6), so that the prisrns (7a-7c) are situated between the cylindrical. leiises (6a-6c) and the sample containers (5a-5c). The prism array (7) or the prisms (7a-7c) of the prisrn array are - O -then oriented relative to the cylindrical lens array (6) sucli that the priarnatic effect of the prisms is in the direction of the cylinder axes of the cylindrical lenses (6a-6c).
A nmodule (2) which contains a long-focus telescope lens (8) a.djoins the side of the module (1) remote from the nzicrotiiter plate (5). The opening diameter, or more precisely the usable aperttare, of the long-focu.s telescope lens (8) is then chosen such that this aperture overlaps the su.rfaco of all the apertures of the -cylindrical lenses (6a-6c) of the cylindrical lens atra,y. It should be mentioned at this point that for the sake of clarity, in Fig. l and the otlie.r Figures, respectively only a small section of the microtiter plate (5) with llaree sample containers is shown. 'in reality, 96, or an integral multiple thereof, 384 or 1536, corresponding sarnple containers are present, and there is a corresponding nuznber of optical channels, whieb is determined by the number of microlenses (6a-6c) and of prisms (7a-7c).
Correspondin8ly, the aperture of the long-focus telescope -lens (8) overlaps-all the optlcal. channels.
In the region of the focal plane of the long-focus telescope lens (8), an intermediate module (3) follows the module (2) containing the long-focus tele'scope lens, and primarily serves as a spacer; with the exception of a diaphragm (9), it contains no optics. The diaphragm (9) forms an,aperture stop in the direction of the cylinder axes of the cylindrical lenses (6a-6c), which in p'iS. 1 stand perpendiieular to the plane of the drawing. In the direction perpendicular thereto, and thus in the plane of the drawing of F'ig. l, the dya,phragm. (9) forms a field stop, In this ' direction, the diapluagm (9) has the e$fect that meastirement light, for example fluorescence light, from. the lateral edges of the sample holder (5a-5c) is scxcened off by the diaphragm (9) fi-onct the detector array (10).
Finally, the illumination and detector module (4) follows the intermediate module (3). It contains a short-focus telescope lens (11) which together with the lAng-focus telescope lens (8) forms an afocal syste.na; the detector array (10); th.e vertical ylluminator (12); and also an incident light reflector (13) arranged between the s.laort-focus telescope lens (11) and the detector array (10). A
fluorescence ftlter, (14) with high transmission in the wavelength region of the fluorescence light or luminescence light and low transmission in the wavelength region of the excitation light of the vertical illwninator (12) is also arranged between the incident light reflector (13) and the detector array (10). Axternatively to this, the incident light rcflecto.r can also be constituted as a corresponding dichroic beamsplitter.
The vertical illuminator (] 2) produces a collimated illuminating beam path, the diameter of which corresponds to the aperture of the short-focus telescope lens (1, 1). This illuminating pencil of rays is eXpanded to the aperture of the long-focus telescope lens (8) by the telescope fornned by the lep.ses (8 and 11), and correspondingly illuzninates all the apertures of the cylindrical lenses (6A) of the cylindrical lens array (6). A focusing of the excitation light by the Gylindrical, lenses (6a-6c) thus takes place in the direction perpendicular to the cylinder axes of the cylindrical lenses (6a-6c), and thus in the plane of the drawing of Fig. 1. In the direction perpendicular to this, on the other hand, the excitation light rexnains coUina.a.ted, a defleotion taking place d e to the prismatic effect of the priSams (7a-7c), so that a number of line foci arise Inear the floors of the.-sam,ple containers (5a-5c), and are inclined to the floors of the sample conta,iners (Sa-5c). The width of the.
line foci is then detenmined by the latc;al dimensions of the effectively active light source, the exit. $ucface (15a) of an opocal fiber (1 S) in the vertical illuminator (12).
The dimensions of this effectively active light source are then chosen so that a sufficiontly large focal, volume, and thus excitation volume, arises in the sample containers (5a-Sc).
The transmission relationships on the imaging side are shown in Figs. 2a and `1p.
2b for the two mutually perpendicullir directions. The plar-e,of the drawing in Fig. 2a then corresponds to the plane of the drawiytg in Fig. l. The prism array (7) plays no ,part in the imaging relationships in this direction, since the pristnatic effect of the prisms (7b. 7c) lies in the direction perpendicular to this. Since the cylindrical l.nses (6b, 6c) have their effect in this direction, fluoresGence radiation arising. in the sample containers (5b, 5c) in the focal volume of the cylindrical lenses (6b, 6c) is, collected with high aperture by the cylindr.ical lenses (6b, 6c) and is imaged by the long-focus telescope lens (8) in tlio focal plane of this long-focus telescope lens (8), and thus in the plane of the diaphragrrl (9), Superposed astigmatic intermediate images arise here, and are then imaged to infinity by the short-focus telescope lens (11.). The fluorescence light is then detected by separate regions (10b, l0c) of the detector array (10). The pupils of the;cylindrical lenses (6b, 6c) are thus imaged in the plane of the detector array, on separate regions of -the detector anray (:l Ob, lOc)s by. the telescope formed by the two lenses (8, 11 ).
In the direction of the cylinder axes of the cyliadrical lenses (6b) (Fig.
2b), on the contrary, the cylindrical lenscs have no effect. In this direction, the prisms (7b, 7d) of the prism array (7) of course have a prisnzatic effect. In this direction, the long-focus telescope lens (8) acts as the objective wlaioh oollects the fluorescence light wit.lx relatively small aperture from the sample containers (5b, 5d). A
deflection additionally takes place duO to the prismatic effect of the prisms (7b, 7d), so that in this direction the foei of the individual Ghannnels are inclined to the focal plane of the long-focus telescope lens (8) and are il,us inclined to the floors of the sample containers (Sb, 5d). The smnmple containers (Sb, 'Sd), and thus the rnicrotiter plate, are arranged with the floors of the sample containers in the focal plane of the long^foaus telescope lens (8). The fluqrescence light collected by the long-focus telescope lens (8) is collimated by this, so that in this direction the diaplaragm (9) -ll-acts as an aperture stop. hltermediatc images of the foci of the long-f.ocus telescopo lens (8) arise in tlie rear focal plan of the short-foGt1s telescope lens (11). The detector array with the regions (lOb, lOd) is arranged 9lightly behind this focal plane.
The structure of the eylindrical lens array (6) is shown in Fig. 3a as a detail of the cylindrieal lens a ray (6). The eylindrical lens array contains plural eylindrical lenses (6a, 6b, 6c), anranged mutually parallel and respectivtly able to extend over' the whole length of the array in the direction of the cylinder axes. The regions (17) between thC cylindrical lenses are preferably made opaqup, for channel=
separation.
A corresponding detail of the prism array (7) is.shovvn in perspective in Fig.
3b; It contains a strip-shaped arrangement of prisms (7a.,.?b, 7c), with respective prismatir effect in the direction of die oyluider axes of the cyl'in.drical=lenses (6a, 6b, 6c). In other words, each prism (7a, 7b, 7o) has an increasing or decreasing thiclrness in tho direction of the cylinder axes. The prisms (7a, 7b, 7c) can exteiid over the whole length of the prism array (7) in the direction perpendicular to the cylinder axes of=the cyaindrical lenses (6a, 6b, 6c). ThG regions (18) between the prisma (7a, 7b, 7c) are again made opaque, for channel separation. .
A two-dimensional artay of optical channels, the number of which.
corresponds to the product of the numbor of cylindrical lens.es and the number of prisms, arises by the superposition of t$te telescope lens array (6) a d the'prism array (7), and the opaque constitution ~f the interspaces (17, 18) betweeli .the cylindrical lenses or between the priams.
Altexnatively to the constitution according to Figs. 31 and 3b, it is however also conceivable to provide, for each optical channea, its ovAi prism on the prism array and its own cylindrical lens on. the cylindrical lens array. In this case, both the Gylindrica,l lens array and the prism array are constituted as a two-dimensional array.
A. slightly better channel separation results from a corresponding opaque -const.itution of the interspaces; that is, crosstalk between the optical channels is reduced, A'section through a coztibined cylindrical lens and prism array (19), whicli is achromatic over an extended spectral region, is shown in Fig. 3c. lt contains, on a common support, a cylindrical lens sind prism combination (] 9a, 19b, 19c) for each optical channel respectively consisting of three lenses (20s,-20c, 21 a-21 c, 22a-22c) and prisans (23a-23c) following the lenses. In a mairner known pg-r so, the individual components of each cylindricsl lens system consist of differ nt materials, by means of which an achromatic correction i.s attained for a waveleugffi region of 35 0 nm -700 nm. The prisms (23a, 23b, 23c) again have a different thickness, from which the prismatic effect results, perpendicular to the plan-e of the drawing in.Fig. 3, and thus in the direction of the cylinder axes of the cylindrical 'lenses, The effect produced by the above-described arrangement in the region of the sample space floor can be seen from Figs. 4a and 4b. The sample space floors (24a, 24b) are shown there for two exernplary adjacent cella of the microtiter plato. Tt is i;o be assumed here that the two sample space floors are mutually displaced'by a small distance (h). The focal volumes of the relevent optical channels in the two sample spaces are deiaoted by (25a, 25b). These focus volumes are circular cylinders, the cylinder axis being respectively inclined to the plane of the saia-ple space floor. The inclination between the plane of the sample space floor and the, cylinder axes of the focus volumes (25a, 25b) is then. determined by the prism,atic effect of the priszn.s. 'T1ie diameter of the cylindrical focus volumes is substantially determined by the numerical aperture of the whole arrangement, primarily the numerical aperture of the cylindrical lenses being considerable here.
Numerical apertures in this direction of 0.5 or more can be attained without problems.
-].3-As can be .recognized froni a comparison of Figs. 4a and 4b, a lateral displacement of the relevant sectional plane between the cylindrical focus volume and the surface of the sample space floor results frorn different floor.height,a in the dr,fFexent cells of the microtite.r plate, because of the inclanation of the focus volumes to the plane of the sample space .floo,r, The different intensity distributions of the fluorescence radiation thereby arising in the regions (10a=10c) on the deteotor array are correspondyngly shown in Figs. 5a and 5b. By a displacement of the sectional plane between the focus vohume and the sample space floor, there resulta' a.
corresponding displacement of the intensity distribution in the direction of the cylinder axes of the cylindrical lens array, since the fluorescence intensity is as a rule maximum in the iaunediatC neighborhood of the sample space floor_ For signal 'evaluation, in an evaluation computer (16), the intensity signals of the pixels of the detector array belonging to each sample space or each optical channel are first integrated in a direction perpendicu.lar to the cylinder axes of the cylindr:ical lenses, and subsequently the characteristic signal change. in the direction of the cylinder axes, as a rule the maximum, of the integrated fluorescence intensity is determined axld evaluated. In measurements of reaction k;inetias or of the time course of the fluorescence signal, the fluorescence measurement takes place repeatedly over plural receiving and readout cycles of the detector array.
.lt has been found to be approptiate to dimension the prisms of the prism array such that the cylindrical focus volumqs (25a, 25b) cover a region of 03-0.5 mm in.
the direction of the optical axis of the' whole arrangement. The len,gth.,of the eylindrical focus volume preferably extends over the whole corresponding length of the sample space, which corresponds to about 3 mm for a 384-we11 microtiter plate.
A substantially elliptical intersectioai surface between the sample space floor and the focus volume then results due to the inclinatiori of the cylindrical focus volume, and has a major axis of about 1 mm and a minor axis of about 0.13 mm.
Fig. 6a shows an interchange module or supplementary module (31) for interchange with a module (1) in the arrangement according to Fig. 1. The interchange module (31) contains a lens array with rotationally symmetrical lenses (32a-32c). A further interchange module (33) (Fig. 6b) for interchange with the module (3) contains a field lens (34). Interchange of the modules (31) and (33) with the modules (1) and (3) in Fig. 1 results in an optical arrangement which corresponds to the optics according to the above-cited patent application DE
48 211 Al. Compatibility with the optical arrangement described in the older application is thus ensured by corresponding additional modules.
Claims (10)
1. Imaging system with an array (6) of cylindrical lenses (6a, 6b. 6c) and a prism array (7) which is combined with the array of cylindrical lenses or placed upstream thereof, in which the prisms of the prism array (7) have an increasing or decreasing thickness in the direction of the cylinder axes of the cylindrical lenses (6a, 6b 6c), the result of which is a prismatic action of the prisms (7a, 7b, 7c) in the direction of the cylinder axes of the cylindrical lenses (6a, 6b, 6c) such that the cylinder axes of the substantially cylindrical focus volumes of the cylindrical lenses acquire an inclination relative to the cylinder axes of the cylindrical lenses.
2. Imaging system according to claim 1, wherein a detector array (10) and a telescopic imaging system are provided, wherein the telescopic imaging system is arranged between the array (6) of cylindrical lenses (6a, 6b, 6c) and the detector array (10) and wherein the prism array (7) is arranged on the side of the array (6) of cylindrical lenses (6a, 6b, 6c) remote from the telescopic imaging system.
3. Imaging system according to claim 2, wherein a long-focus lens (8) of the telescopic imaging system is arranged adjoining the array (6) of cylindrical lenses (6a, 6b, 6c), and wherein the diameter of the long-focus lens overlaps several cylindrical lenses (6a, 6b, 6c).
4. Imaging system according to claim 2 or 3, wherein the detector array (10) is arranged behind the exit-side focal plane of a telescope lens (11) remote from the cylindrical lens array (6).
5. Imaging system according to one of claims 2 to 4, wherein the apertures of the cylindrical lenses (6a, 6b, 6c) are imaged on the detector array (10) by means of the telescopic imaging system (8, 11).
6. Imaging system according one of claims 1 to 5, wherein the cylindrical lens array (6) or the prism array (7) or both are strip-shaped.
7. Imaging system according to one of claim 2 to 6, wherein a vertical illuminator (12) is provided which is reflected between the detector array (10) and a short-focus lens of the telescopic imaging system into the beam path leading into the array (6) of cylindrical lenses (6a, 6b, 6c).
8. Automatic analyser with an optical imaging system according to one of claims 2 to 7, wherein an evaluation computer (16) is provided for the evaluation of the optical signals detected with the detector array (10).
9. Imaging system of modular construction, consisting of:
- a first constructional unit (1) with an array of cylindrical lenses and a prism array combined with, or arranged before, the array of cylindrical lenses, wherein the prismatic effect of the prisms (7a, 7b, 7c) is in the direction of the cylinder axes of the cylindrical lenses (6a, 6b, 6c), - a second constructional unit with a long-focus optics (8), the free usable aperture diameter of which overlaps diameter of the cylindrical lens array (6), - a third constructional unit (4) with a short-focus optics (11), which in common with the long-focus optics (8) of the second constructional unit forms an afocal system, and - a fourth constructional unit (3) including only a diaphragm, arranged between the second constructional unit (2) and the third constructional unit (4).
- a first constructional unit (1) with an array of cylindrical lenses and a prism array combined with, or arranged before, the array of cylindrical lenses, wherein the prismatic effect of the prisms (7a, 7b, 7c) is in the direction of the cylinder axes of the cylindrical lenses (6a, 6b, 6c), - a second constructional unit with a long-focus optics (8), the free usable aperture diameter of which overlaps diameter of the cylindrical lens array (6), - a third constructional unit (4) with a short-focus optics (11), which in common with the long-focus optics (8) of the second constructional unit forms an afocal system, and - a fourth constructional unit (3) including only a diaphragm, arranged between the second constructional unit (2) and the third constructional unit (4).
10. Imaging system of modular construction according to claim 9, wherein two further constructional units (31, 33) are provided, of which the one is an array (32) with rotationally symmetrical individual lenses (32a-32c) for interchange with the first constructional unit (1), and the second additional constructional unit (33) has a field lens (34) and is interchangeable with the fourth constructional unit.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19846928A DE19846928A1 (en) | 1998-10-12 | 1998-10-12 | Imaging system, especially in a high throughput automatic analyzer useful for drug development or medical diagnosis, has a cylindrical lens array combined with or preceded by a prism array |
| DE19846928.4 | 1998-10-12 | ||
| PCT/EP1999/006925 WO2000022417A1 (en) | 1998-10-12 | 1999-09-18 | Imaging system with a cylindrical lens array |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2347184A1 CA2347184A1 (en) | 2000-04-20 |
| CA2347184C true CA2347184C (en) | 2009-12-15 |
Family
ID=7884169
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002347184A Expired - Fee Related CA2347184C (en) | 1998-10-12 | 1999-09-18 | Imaging system with a cylindrical lens array |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US6473239B2 (en) |
| EP (1) | EP1121581B8 (en) |
| JP (1) | JP4468583B2 (en) |
| AU (1) | AU759896B2 (en) |
| CA (1) | CA2347184C (en) |
| DE (2) | DE19846928A1 (en) |
| WO (1) | WO2000022417A1 (en) |
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| WO2001007896A1 (en) * | 1999-07-21 | 2001-02-01 | Tropix, Inc. | Luminescence detection workstation |
| US7158224B2 (en) * | 2000-06-25 | 2007-01-02 | Affymetrix, Inc. | Optically active substrates |
| FR2813121A1 (en) * | 2000-08-21 | 2002-02-22 | Claude Weisbuch | PERFECTED DEVICE FOR SUPPORTING CHROMOPHORIC ELEMENTS |
| US6839179B2 (en) * | 2002-05-10 | 2005-01-04 | Applera Corporation | Imaging system and method for reduction of interstitial images |
| US6982166B2 (en) | 2002-05-16 | 2006-01-03 | Applera Corporation | Lens assembly for biological testing |
| US9157860B2 (en) | 2002-05-16 | 2015-10-13 | Applied Biosystems, Llc | Achromatic lens array |
| JP3747890B2 (en) * | 2002-07-08 | 2006-02-22 | オムロン株式会社 | OPTICAL COMPONENT, OPTICAL DETECTOR USING THE OPTICAL COMPONENT, OPTICAL DETECTING METHOD, AND ANALYSIS METHOD |
| US20050112703A1 (en) | 2003-11-21 | 2005-05-26 | Kimberly-Clark Worldwide, Inc. | Membrane-based lateral flow assay devices that utilize phosphorescent detection |
| US7943395B2 (en) | 2003-11-21 | 2011-05-17 | Kimberly-Clark Worldwide, Inc. | Extension of the dynamic detection range of assay devices |
| US7038863B2 (en) * | 2004-06-02 | 2006-05-02 | Raytheon Company | Compact, wide-field-of-view imaging optical system |
| JP2006058044A (en) | 2004-08-18 | 2006-03-02 | Yokogawa Electric Corp | Cartridge for biochip and biochip reading apparatus |
| DE102004047448A1 (en) * | 2004-09-30 | 2006-04-06 | Hentze-Lissotschenko Patentverwaltungs Gmbh & Co. Kg | Imaging apparatus and method of making the same |
| FI20055043A0 (en) * | 2005-01-31 | 2005-01-31 | Wallac Oy | Arrangements at an imaging device for microtiter wells |
| JP2007110588A (en) * | 2005-10-17 | 2007-04-26 | Funai Electric Co Ltd | Compound-eye imaging apparatus |
| US20100167413A1 (en) * | 2007-05-10 | 2010-07-01 | Paul Lundquist | Methods and systems for analyzing fluorescent materials with reduced autofluorescence |
| DE102007051669A1 (en) * | 2007-10-26 | 2009-04-30 | Carl Zeiss Smt Ag | Imaging optics, projection exposure apparatus for microlithography with such an imaging optical system and method for producing a microstructured component with such a projection exposure apparatus |
| DE102008010382A1 (en) * | 2008-02-21 | 2009-08-27 | Limo Patentverwaltung Gmbh & Co. Kg | Device for splitting a light beam |
| DE102008001322A1 (en) * | 2008-04-22 | 2009-10-29 | Linos Photonics Gmbh & Co. Kg | Sample array analysis system for use in e.g. pharma research, has detector detecting luminescence radiation emitted by samples, and light conductor array arranged in front of sample plate for conducting light on samples |
| GB2473636A (en) * | 2009-09-18 | 2011-03-23 | Sharp Kk | Multiple view display comprising lenticular lens having regions corresponding to two different centres of curvature |
| DE102010016382B4 (en) * | 2010-04-09 | 2022-06-02 | Leica Microsystems Cms Gmbh | Fluorescence microscope and method for carrying out multi-positioning in a screening application |
| DE202011001569U1 (en) * | 2011-01-14 | 2012-03-01 | Berthold Technologies Gmbh & Co. Kg | Device for measuring optical properties in microplates |
| WO2013185621A1 (en) * | 2012-06-14 | 2013-12-19 | 南京拓鉒医药科技有限公司 | Endotoxin detection systems and detection methods thereof |
| JP6189666B2 (en) * | 2012-08-02 | 2017-08-30 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | Array optics |
| US9989534B2 (en) * | 2014-06-30 | 2018-06-05 | Biodesy, Inc. | Systems and methods for high throughput analysis of conformation in biological entities |
| WO2016106286A1 (en) | 2014-12-23 | 2016-06-30 | Biodesy, Inc. | Attachment of proteins to interfaces for use in nonlinear optical detection |
| FR3057662B1 (en) * | 2016-10-13 | 2018-11-16 | Airbus Defence And Space Sas | SPECTROPHOTOMETRIC DEVICE WITH MULTIPLE SPECTRAL MEASURING BANDS |
| DE102017115661A1 (en) * | 2017-07-12 | 2019-01-17 | Endress+Hauser Conducta Gmbh+Co. Kg | Optical sensor |
| DE112019002269T5 (en) | 2018-05-31 | 2021-01-21 | Phoseon Technology, Inc. | RADIATION SYSTEM FOR MULTIWELL INACTIVATION |
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| US4642526A (en) * | 1984-09-14 | 1987-02-10 | Angstrom Robotics & Technologies, Inc. | Fluorescent object recognition system having self-modulated light source |
| US5602679A (en) | 1987-12-31 | 1997-02-11 | Projectavision, Inc. | High efficiency light valve projection system |
| US5150259A (en) * | 1990-07-30 | 1992-09-22 | Mitsubishi Rayon Company Ltd. | Optical imaging device |
| TW281734B (en) * | 1993-06-20 | 1996-07-21 | Unic View Ltd | |
| JPH0713101A (en) * | 1993-06-24 | 1995-01-17 | Mitsubishi Rayon Co Ltd | Line image forming element |
| US5574790A (en) * | 1993-09-27 | 1996-11-12 | Angstrom Technologies, Inc. | Fluorescence authentication reader with coaxial optics |
| US5808784A (en) * | 1994-09-06 | 1998-09-15 | Dai Nippon Printing Co., Ltd. | Lens array sheet surface light source, and transmission type display device |
| JPH09113858A (en) * | 1995-10-17 | 1997-05-02 | Fuji Photo Optical Co Ltd | Projection device |
| WO1997034171A2 (en) * | 1996-02-28 | 1997-09-18 | Johnson Kenneth C | Microlens scanner for microlithography and wide-field confocal microscopy |
| US5723294A (en) * | 1996-03-05 | 1998-03-03 | Gull Laboratories | Methods for detection and discrimination of multiple analytes using fluorescent technology |
| US6177667B1 (en) * | 1997-10-03 | 2001-01-23 | Ricoh Company, Ltd. | Imaging device |
| DE19748211A1 (en) | 1997-10-31 | 1999-05-06 | Zeiss Carl Fa | Optical array system and reader for microtiter plates |
-
1998
- 1998-10-12 DE DE19846928A patent/DE19846928A1/en not_active Ceased
-
1999
- 1999-09-18 WO PCT/EP1999/006925 patent/WO2000022417A1/en active IP Right Grant
- 1999-09-18 AU AU60854/99A patent/AU759896B2/en not_active Ceased
- 1999-09-18 EP EP99947384A patent/EP1121581B8/en not_active Expired - Lifetime
- 1999-09-18 CA CA002347184A patent/CA2347184C/en not_active Expired - Fee Related
- 1999-09-18 JP JP2000576266A patent/JP4468583B2/en not_active Expired - Fee Related
- 1999-09-18 DE DE59913131T patent/DE59913131D1/en not_active Expired - Lifetime
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2001
- 2001-04-12 US US09/835,172 patent/US6473239B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US6473239B2 (en) | 2002-10-29 |
| DE19846928A1 (en) | 2000-04-13 |
| JP4468583B2 (en) | 2010-05-26 |
| EP1121581A1 (en) | 2001-08-08 |
| WO2000022417A1 (en) | 2000-04-20 |
| CA2347184A1 (en) | 2000-04-20 |
| EP1121581B8 (en) | 2006-06-21 |
| JP2002527743A (en) | 2002-08-27 |
| US20020030894A1 (en) | 2002-03-14 |
| AU759896B2 (en) | 2003-05-01 |
| AU6085499A (en) | 2000-05-01 |
| DE59913131D1 (en) | 2006-04-20 |
| EP1121581B1 (en) | 2006-02-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20140918 |