WO2011058488A1 - A chip holder kit for a wire-gird sensor. - Google Patents

A chip holder kit for a wire-gird sensor. Download PDF

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Publication number
WO2011058488A1
WO2011058488A1 PCT/IB2010/055032 IB2010055032W WO2011058488A1 WO 2011058488 A1 WO2011058488 A1 WO 2011058488A1 IB 2010055032 W IB2010055032 W IB 2010055032W WO 2011058488 A1 WO2011058488 A1 WO 2011058488A1
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WO
WIPO (PCT)
Prior art keywords
wire
polarizer
chip holder
aperture
grid sensor
Prior art date
Application number
PCT/IB2010/055032
Other languages
French (fr)
Inventor
Ruth W. I. De Boer
Derk J. W. Klunder
Maarten M. J. W. Van Herpen
Roel Penterman
Johan Lub
Christianne R. M. De Witz
Original Assignee
Koninklijke Philips Electronics N.V.
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 Koninklijke Philips Electronics N.V. filed Critical Koninklijke Philips Electronics N.V.
Publication of WO2011058488A1 publication Critical patent/WO2011058488A1/en

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Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64Fluorescence; Phosphorescence
    • G01N21/645Specially adapted constructive features of fluorimeters
    • G01N21/648Specially adapted constructive features of fluorimeters using evanescent coupling or surface plasmon coupling for the excitation of fluorescence
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L9/00Supporting devices; Holding devices
    • B01L9/52Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366Apparatus specially adapted for solid-phase testing
    • G01N33/54373Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • GPHYSICS
    • G02OPTICS
    • G02BOPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00Microscopes
    • G02B21/24Base structure
    • G02B21/26Stages; Adjusting means therefor
    • GPHYSICS
    • G02OPTICS
    • G02BOPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B21/00Microscopes
    • G02B21/34Microscope slides, e.g. mounting specimens on microscope slides
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/06Auxiliary integrated devices, integrated components
    • B01L2300/0627Sensor or part of a sensor is integrated
    • B01L2300/0654Lenses; Optical fibres
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0809Geometry, shape and general structure rectangular shaped
    • B01L2300/0819Microarrays; Biochips
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0809Geometry, shape and general structure rectangular shaped
    • B01L2300/0822Slides
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03Cuvette constructions
    • G01N2021/0367Supports of cells, e.g. pivotable
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00Features of devices classified in G01N21/00
    • G01N2201/02Mechanical
    • G01N2201/024Modular construction
    • G01N2201/0245Modular construction with insertable-removable part

Definitions

  • the present invention relates to a chip holder kit for a wire-grid sensor and a chip holder system.
  • FIG. 1(a) illustrates an operation principle of this concept showing a cross-sectional view of a wire-grid sensor or biosensor 100 including wire grid substrate 104 where wires 101 at the substrate 104 are covered with a fluid 102
  • FIG. 1(b) shows a finite element simulation of the intensity distribution for a wire grid structure illuminated with TE polarized light.
  • FIG.1(c) shows a scanning electron microscope (SEM) picture of a fabricated wire grid substrate with aluminum wires 108 as viewed from the top.
  • the dimensions of the wire grid depend critically on the used wavelength of the excitation light (for the detection of the fluorescently labeled molecules).
  • Evanescent detection in the space between the wires requires that the space between the wires (pitch- width) is below the diffraction limit in the medium that fills the space between the wires, which may be bodily fluid e.g. a water-like substance.
  • n refractive index
  • Typical dimensions of the wires are: width below 100 nm (typically 70 nm); pitch below 200 nm (typically 140 nm) and height of about 160 nm. This results in a width of the space between the wires of 70 nm, which is well below the diffraction limited width.
  • the wire grid sensor concept utilizes the strong polarization dependence of a wire grid.
  • Said evanescent detection can be achieved in two ways. One way is by illuminating the wire grid with TE polarized light. The other way is, in case of luminescence detection where there the luminescent light is a mixture of both TE and transverse magnetic mode (TM) polarized light, by filtering the luminescent light with a polarizer that transmits TM polarized light.
  • TM transverse magnetic mode
  • the invention preferably seeks to mitigate, alleviate or eliminate one or more of the above mentioned disadvantages singly or in any combination.
  • a chip holder kit comprising:
  • a base plate having a first aperture formed at the front side and a second aperture formed at the rear side such that an overlapping region is formed where the first and the second apertures overlap
  • polarization structure including a polarizer
  • the second aperture has an area that substantially matches the area of the wire- grid sensor and is adapted to removably receive the wire-grid sensor
  • the first aperture is adapted to removably receive the polarization structure and wherein the first and second apertures are arranged such that when the wire-grid sensor and the polarizer are received in the overlapping region the polarizer filters any incoming excitation light to a transverse electric mode (TE) polarized excitation light before the wire-grid sensor is illuminated.
  • TE transverse electric mode
  • a chip holder kit which enables an easy, quick and simple way to integrate correctly the wire-grid sensor into any commercially available scanner as the chip holder itself can be used as microscope slide.
  • the polarizer is moveable along the first aperture between a first and a second state, the first state being the state where the polarizer is received in the overlapping region. It is thus possible to move the between an evanescent and non- evanescent detection states.
  • the first aperture and the second aperture are designed so as to ensure a fixed orientation of the transmission axis of the polarizer and the wire-grid sensor, forming an angle of 90 degrees with respect to one another. In that way, a proper orientation of the transmission axis of the polarizer and the wire-grid sensor and therefore it is ensured that the polarization control becomes accurate.
  • the polarization structure is a slider in which the polarizer is mounted.
  • the polarizer comprises at least a first and a second sub-polarizers, said first state being the state where the first and the at least second sub-polarizer overlap with the first aperture and thus with the wire-grid sensor when it is in place of the first aperture.
  • the polarizer is formed by a number of parallel arranged wires where the distance between two adjacent wires is below the diffraction of the medium that fills the space between the wires.
  • the chip holder kit further comprises a quarter wave plate mounted at the front side of the base plate and in front of said polarizer.
  • a quarter-wave plate turns linearly polarized light that enter the quarter wave plate into circularly polarized light.
  • the quarter wave plate causes a homogeneous spreading of the light intensity of the incoming light over all polarization angles, independent of the polarization state of the incoming light, assuming that one integrates over a long time frame (i.e. a multiple of one over the frequency of the light). The reason for doing this is that, in any orientation of the polarizer, the same light intensity goes through the wire-grid chip.
  • any type of polarization can be used in the excitation source while always ensuring an optimal polarization alignment control. Therefore, the possibility to use the chip holder kit in a scanner does not depend on the type of polarization used in the latter and the wire-grid technology can thus be adapted to various kinds of commercially available scanners.
  • the chip holder kit further comprises hybridization chamber mounted at the rear side of the base plate adapted to be filled with hybridization medium including target molecules such that said wire-grid sensor becomes covered with the hybridization medium.
  • the chip holder kit further comprises a replaceable power source arranged with said housing adapted to act as a power source for the fluidics and/or to be coupled to a heating element for heating said hybridization medium. It is namely so that specific binding means that target molecules hybridize to the matching capture probes. Aspecific binding is the undesired binding of non-targeted molecules to the capture probes or other parts of the biosensor surface. Thus, heating said hybridization medium during hybridization reduces this aspecific binding.
  • the chip holder kit further comprises housing for hosting said quarter wave plate, said hybridization chamber, said replaceable power source, said fluidics and/or said heating element.
  • the base plate is made, partially or entirely, of transparent material.
  • first and the second apertures are cut into the base plate and where the overlapping region where the first and the second apertures overlap is either an opening throughout the base plate, or a slide of a said base plate.
  • surface spots including capture probes are arranged at the surface of the polarizer, the chip holder kit further comprising fluidics adapted to transport hybridization medium including target molecules to and from the wire-grid sensor. Since such capture probes are molecules with high affinity for certain target molecules, i.e. said target molecules, it becomes possible to detect the target molecules at certain localized areas, namely at said capture probes, whereby it is simultaneously possible to monitor other processes that occur in the hybridization medium.
  • the polarization structure comprises at least a first and a second polarizers with perpendicular orientation placed side by side in the polarization structure, where the first polarizer has a transmission axis oriented at 90 degrees with respect to the transmission axis of the wire-grid sensor and the second polarizer has its transmission axis parallel to the wire-grid.
  • the second polarizer might as an example transmit only TM polarized light but both polarizers might be constructed so as to transmit the same light intensity.
  • the first polarizer may result in a purely evanescent measurement, whereas the second one may result in a purely non-evanescent measurement.
  • a chip holder system comprising: - a base plate having a first aperture formed at the front side and a second aperture formed at the rear side such that an overlapping region is formed where the first and the second apertures overlap,
  • polarization structure including a polarizer
  • the second aperture has an area that substantially matches the area of the wire- grid sensor and is adapted to removably receive the wire-grid sensor
  • the first aperture is adapted to removably receive the polarization structure and wherein the first and second apertures are arranged such that when the wire-grid sensor and the polarizer are received in the overlapping region the polarizer filters any incoming excitation light emitted from said light source to a transverse electric mode (TE) polarized excitation light before the wire-grid sensor is illuminated
  • TE transverse electric mode
  • the system further comprises a detector for detecting the light reflected from the wire-grid sensor.
  • FIG. l(a)-(c) illustrates an operation principle of a wire grid biosensor
  • FIG. 1(a) a cross-sectional view of a wire grid biosensor including wire grid substrate where wires are covered with a fluid
  • FIG. 1(b) shows a finite element simulation of the intensity distribution for a wire grid structure illuminated with TE polarized light
  • FIG.1(c) shows a scanning electron microscope (SEM) picture of a fabricated wire grid substrate with aluminum wires as viewed from the top
  • SEM scanning electron microscope
  • FIG. 2 shows a plan view of an embodiment of a base plate from a chip holder kit according to the present invention
  • FIG. 3 shows a cross sectional view along the line AA of the base plate in FIG. 2,
  • FIGS. 4 and 5 shows one embodiment of a chip holder kit according to the present invention
  • FIG. 6 shows another embodiment of a chip holder kit according to the present invention
  • FIG. 7 shows still another embodiment of a chip holder kit according to the present invention.
  • FIG. la shows a cross-sectional view of a wire-grid sensor 100 comprising a transparent substrate 104 with metal wires 101 which during use are covered with hybridization medium 102 including target molecules 103 (for illustration purposes, depicted within the box shown).
  • hybridization medium 102 including target molecules 103 (for illustration purposes, depicted within the box shown).
  • the interface between the substrate 104 and the fluid 102 is functionalized with capture molecules 105 that can bind with the labeled target molecules 103.
  • TE transverse electric mode
  • FIG.1(b) shows a finite element simulation of the intensity distribution for a wire grid structure illuminated with TE polarized light, where the intensity in the space between the wires decays rapidly away from the interface between the carrier and the fluid.
  • FIG.1(c) shows a scanning electron microscope (SEM) picture of a fabricated wire grid substrate with aluminum wires 108 as viewed from the top. Further details regarding such wire-grid sensor and the functioning of such wire-grid sensor may be found in WO2006136991 and
  • FIG. 2 shows a plan view of an embodiment of a base plate 201 from a chip holder kit 200 according to the present invention, where the base plate 201 is in one embodiment partially or entirely made of a transparent material such as a glass or any type of plastic material.
  • a first aperture 203 is formed at the front side of the base plate 201 and a second aperture 202 formed at the rear side of the base plate such that an overlapping region where the first and the second apertures overlap is formed 204.
  • the second aperture 202 has an area that is approximately the same as the area of the wire-grid sensor and is adapted to removable receive the wire-grid sensor so that the wire-grid sensor becomes easily replaceable.
  • the first aperture 203 is adapted to receive a polarization structure including a polarizer in the overlapping region such that the polarizer filters any incoming excitation light to a transverse electric mode (TE) polarized excitation light before the wire-grid sensor is illuminated.
  • a polarization structure including a polarizer in the overlapping region such that the polarizer filters any incoming excitation light to a transverse electric mode (TE) polarized excitation light before the wire-grid sensor is illuminated.
  • TE transverse electric mode
  • FIG. 3 shows a cross sectional view along the line AA of the base plate in FIG. 2, where as shown here the overlapping region 204 where the first 203 and the second 202 apertures overlap is an opening throughout the base plate.
  • the base material may be a transparent material the overlapping region may just as well be a slide of the base plate (not shown here), e.g. in case the base plate is glass a slide of glass.
  • FIGS. 4 and 5 show a chip holder kit 200 according to the present invention 201 where a polarization structure 302 including a polarizer 303 and a wire-grid sensor 301, e.g. similar as the one discussed in relation to FIG. 1, have been placed in the first 203 and the second 202 apertures in said base plate 201, respectively.
  • the polarizer is moveable along the first aperture between a first and a second state, the first state being the state where the polarizer is received in the overlapping region.
  • the first aperture and the second aperture are preferably designed so as to ensure a fixed orientation of the transmission axis of the polarizer and the wire-grid sensor, forming an angle of 90 degrees with respect to one another.
  • FIG. 4 shows where the structure 302 and the polarizer 303 are in a first state, namely an evanescent detection state, where the polarizer 303 overlaps with the overlapping region 204 and thus with the wire-grid sensor 301 such that during use an incoming light emitted from a light source at a scanner being used goes through the polarizer 303 to the wire-grid sensor 301.
  • an evanescent detection can be achieved in two ways; by illuminating the wire grid with transverse electric mode (TE) polarized excitation light, or, in case of luminescence detection where there the luminescent light is a mixture of both TE and transverse magnetic mode (TM) polarized light, by filtering the luminescent light with a polarizer that transmits TM polarized light.
  • TE transverse electric mode
  • TM transverse magnetic mode
  • FIG. 5 depicts the scenario where the polarizer has been moved towards right as indicated by the arrow to a second state, i.e. a non-evanescent detection state.
  • the polarizer is preferably formed by a number of parallel arranged wires 501 such as metal wires, where the distance between two adjacent wires (pitch- width) is below the diffraction of the medium that fills the space between the wires.
  • Evanescent detection in the space between the wires requires that the space between the wires is below the diffraction limit in the medium that fills the space between the wires, which may be bodily fluid e.g. a water-like substance.
  • n ⁇ l .33 For water (refractive index: n ⁇ l .33) this results in a diffraction limited width of the space between the wires of ⁇ /(2 ⁇ ) ⁇ -0.38* ⁇ or for a wavelength of the incident light of ⁇ 633 nm in a diffraction limited width of the space between the wires of 238 nm.
  • An example of dimensions of the wires is: width below 100 nm (typically 70 nm); pitch below 200 nm (typically 140 nm) and height of about 160 nm. This results in a width of the space between the wires of 70 nm, which is well below the diffraction limited width.
  • FIG. 6 shows another embodiment of a chip holder kit according to the present invention, showing a wire-grid sensor 607 and a polarizer made of four sub-polarizers 601-604, which as depicted here overlap with said overlapping region 204.
  • the sub-polarizers include on the detection surface an array of spots 605 with capture probes, i.e. molecules with a high affinity for certain target molecules and fluidics (not shown) adapted to transport hybridization medium, e.g. fluid such as water- like substance including target molecules, to and from the wire-grid sensor.
  • hybridization medium e.g. fluid such as water- like substance including target molecules
  • the evanescent detection is most relevant at the locations of the spots so one could also follow another approach where evanescent detection is performed locally where the spots are and that non-evanescent imaging is performed in regions where there are no spots. This way one can use the same camera system for simultaneous evanescent and non-evanescent imaging. In this case the user has to properly slide the polarizer to ensure evanescent detection where spots are located.
  • the distance between the spots is as an example few 100 microns and the spots can as an example be around 100 microns in diameter.
  • the polarization structure includes two polarizers, namely said polarizer 303 and a second polarizer, with perpendicular orientation and placed side by side in the polarization structure.
  • the polarizer 303 is as defined before, with transmission axis oriented at 90 degrees with respect to the transmission axis of the wire-grid sensor.
  • the second polarizer (not shown) has its transmission axis parallel to the wire-grid, and transmits only TM polarized light. Both polarizers transmit the same light intensity, but the first polarizer results in a purely evanescent measurement, whereas the second polarizer results in a purely non-evanescent measurement. It can be advantageous to have a direct comparison between these two measurements, for example if one wants to compare the non-evanescent measurement with the more conventional method of non-evanescent imaging.
  • FIG. 6 depicts a scenario where the sub-polarizers are covered with hybridization medium, and where there is an air bubble 606 in the hybridization medium. This bubble is not visible in the regions where evanescent detection is performed, but can be recognized/ detected by looking at the regions where non-evanescent detection is performed.
  • FIG. 7 shows a cross-sectional view of still another embodiment of a chip holder kit 700 according to the present invention, where the chip holder kit further comprises a quarter wave plate 701 mounted at the front side of the base plate 701 and in front of a polarizer 702, 303, a base plate 703, 201, a wire-grid sensor with parallel arranged wires 704, a hybridization chamber 705 mounted at the rear side of the base plate adapted to be filled with hybridization medium including target molecules such that said wire-grid sensor becomes covered with the hybridization medium (typically water) containing fluorescently labeled target bio-molecules 103.
  • the hybridization medium typically water
  • the chip holder kit further comprises a power source 707 such as a battery which is preferably replaceable that is adapted to be coupled to a heating element 706 for heating the hybridization medium 705 and which may further be adapted to supply said fluidics with energy.
  • a power source 707 such as a battery which is preferably replaceable that is adapted to be coupled to a heating element 706 for heating the hybridization medium 705 and which may further be adapted to supply said fluidics with energy.
  • the chip holder kit shown in FIG. 7 comprises a housing 708 for the chip holder 700 kit which may as an example be fabricated of a heat-resistant plastic or any other types of materials, it is preferably designed such that the wire-grid chip can easily be inserted and aligned to the polarizer in the chip-holder kit.
  • a suitable medium such as an optical storage medium or a solid- state medium supplied together with or as part of other hardware, but may also be distributed in other forms, such as via the Internet or other wired or wireless

Abstract

This invention relates to a chip holder kit for a wire-grid sensor, where the chip holder kit includes a base plate, where a first aperture is formed at the front side of the base plate, a second aperture is formed at the rear side of the base plate, and an overlapping region where the first and the second apertures overlap. The second aperture has an area that substantially matches the area of the wire-grid sensor and is adapted to removable receive the wire-grid sensor. The first aperture is adapted to removably receive the polarization structure and the first and second apertures are arranged such that when the wire-grid sensor and the polarizer are received in the overlapping region the polarizer filters any incoming excitation light to a transverse electric mode (TE) polarized excitation light before the wire-grid sensor is illuminated.

Description

A CHIP HOLDER KIT FOR A WIRE-GRID SENSOR
FIELD OF THE INVENTION
The present invention relates to a chip holder kit for a wire-grid sensor and a chip holder system. BACKGROUND OF THE INVENTION
The wire-grid biosensor concept concerns the surface specific detection of the binding of biomolecules in the space between the wires of the wire grid. For further clarification, FIG. 1(a) illustrates an operation principle of this concept showing a cross-sectional view of a wire-grid sensor or biosensor 100 including wire grid substrate 104 where wires 101 at the substrate 104 are covered with a fluid 102
(typically water) containing fluorescently labeled target bio-molecules 103. The interface between the substrate 104 and the fluid 102 is functionalized with capture molecules 105 that can bind with the labeled target molecules 103. The wire grid is illuminated from the bottom with transverse electric mode (TE) polarized excitation light 106 (i.e. light with an electric field that is parallel to the plane normal to the paper) that is substantially reflected 107 and generates an evanescent wave in the space between the wires with an intensity that decays exponentially away from the carrier. FIG. 1(b) shows a finite element simulation of the intensity distribution for a wire grid structure illuminated with TE polarized light. As shown here the intensity in the space between the wires decays rapidly away from the interface between the carrier and the fluid. FIG.1(c) shows a scanning electron microscope (SEM) picture of a fabricated wire grid substrate with aluminum wires 108 as viewed from the top.
The dimensions of the wire grid depend critically on the used wavelength of the excitation light (for the detection of the fluorescently labeled molecules). Evanescent detection in the space between the wires requires that the space between the wires (pitch- width) is below the diffraction limit in the medium that fills the space between the wires, which may be bodily fluid e.g. a water-like substance. As an example, for water (refractive index: n~1.33) this results in a diffraction limited width of the space between the wires of λ/(2η)~-0.38* λ or for a wavelength of the incident light of λ~633 nm in a diffraction limited width of the space between the wires of 238 nm. Typical dimensions of the wires are: width below 100 nm (typically 70 nm); pitch below 200 nm (typically 140 nm) and height of about 160 nm. This results in a width of the space between the wires of 70 nm, which is well below the diffraction limited width.
The wire grid sensor concept utilizes the strong polarization dependence of a wire grid. Said evanescent detection can be achieved in two ways. One way is by illuminating the wire grid with TE polarized light. The other way is, in case of luminescence detection where there the luminescent light is a mixture of both TE and transverse magnetic mode (TM) polarized light, by filtering the luminescent light with a polarizer that transmits TM polarized light.
In both cases accurate control of the polarization state is important. From experiments, it has been found that an accuracy of +/- 1 degree in the polarization angle is needed. If it is assumed that the wire grid has an infinite extinction (ratio between the transmission for TM and TE polarized light) an error in the polarization angle of 1 degree already results in a significantly reduced, but still reasonable, extinction of (l/sin(l degree)) 2~3300.
Although it may not be too difficult to achieve an accurate polarization control in a lab set up installation, this may become more a problem when the wire grid biosensor is to be used in a commercial available scanner because integrating such wire grid biosensor in a commercial optical setup such as in a commercial microscope is very difficult. For instance, the optical elements used for e.g. polarization control, may have to be installed all around the microscope and the latter can vary upon the company name. This approach thus may lead to a bulky set up and a time consuming installation with the need of as many adaptations as type of commercial scanner available. The inventor of the present invention has appreciated that there is thus a need for an installation that makes it possible to use such wire-grid biosensor in all types of available scanners and has in consequence devised the present invention. SUMMARY OF THE INVENTION
It would be advantageous to achieve a setup that makes it possible to use wire-grid biosensor in all types of available scanners. In general, the invention preferably seeks to mitigate, alleviate or eliminate one or more of the above mentioned disadvantages singly or in any combination. In particular, it may be seen as an object of the present invention to provide a chip holder kit that solves the above mentioned problems, or other problems, of the prior art.
To better address one or more of these concerns, in a first aspect of the invention a chip holder kit is provided, comprising:
- a base plate having a first aperture formed at the front side and a second aperture formed at the rear side such that an overlapping region is formed where the first and the second apertures overlap,
- a wire-grid sensor, and
- a polarization structure including a polarizer,
wherein the second aperture has an area that substantially matches the area of the wire- grid sensor and is adapted to removably receive the wire-grid sensor, wherein the first aperture is adapted to removably receive the polarization structure and wherein the first and second apertures are arranged such that when the wire-grid sensor and the polarizer are received in the overlapping region the polarizer filters any incoming excitation light to a transverse electric mode (TE) polarized excitation light before the wire-grid sensor is illuminated.
Thus, a chip holder kit is provided which enables an easy, quick and simple way to integrate correctly the wire-grid sensor into any commercially available scanner as the chip holder itself can be used as microscope slide. In one embodiment, the polarizer is moveable along the first aperture between a first and a second state, the first state being the state where the polarizer is received in the overlapping region. It is thus possible to move the between an evanescent and non- evanescent detection states.
In one embodiment, the first aperture and the second aperture are designed so as to ensure a fixed orientation of the transmission axis of the polarizer and the wire-grid sensor, forming an angle of 90 degrees with respect to one another. In that way, a proper orientation of the transmission axis of the polarizer and the wire-grid sensor and therefore it is ensured that the polarization control becomes accurate.
In one embodiment, the polarization structure is a slider in which the polarizer is mounted. Thus, it is possible in a very convenient and user friendly way to switch between an evanescent and non-evanescent detection as the relative orientation between the wire grid and the polarizer remains unchanged.
In one embodiment, the polarizer comprises at least a first and a second sub-polarizers, said first state being the state where the first and the at least second sub-polarizer overlap with the first aperture and thus with the wire-grid sensor when it is in place of the first aperture. In that way, both an evanescent and propagating detection can be performed simultaneously and thus it is possible to monitor, in addition to detecting whether target molecules are present in a hybridization medium which covers the polarizer, other processes such as verifying if the chip holder is ok (e.g. still intact), and whether the hybridization medium has actually reached the polarizer.
In one embodiment, the polarizer is formed by a number of parallel arranged wires where the distance between two adjacent wires is below the diffraction of the medium that fills the space between the wires. By using such wires the background of the fluorescence of the biological material under investigation in the hybridization medium is strongly reduced. Further, when the distance between adjacent wires is below the diffraction of the medium that fills the space between the wires the resolution of the detection will be greatly enhanced.
In one embodiment, the chip holder kit further comprises a quarter wave plate mounted at the front side of the base plate and in front of said polarizer. Such a quarter-wave plate turns linearly polarized light that enter the quarter wave plate into circularly polarized light. As such, the quarter wave plate causes a homogeneous spreading of the light intensity of the incoming light over all polarization angles, independent of the polarization state of the incoming light, assuming that one integrates over a long time frame (i.e. a multiple of one over the frequency of the light). The reason for doing this is that, in any orientation of the polarizer, the same light intensity goes through the wire-grid chip. Accordingly, any type of polarization can be used in the excitation source while always ensuring an optimal polarization alignment control. Therefore, the possibility to use the chip holder kit in a scanner does not depend on the type of polarization used in the latter and the wire-grid technology can thus be adapted to various kinds of commercially available scanners.
In one embodiment, the chip holder kit further comprises hybridization chamber mounted at the rear side of the base plate adapted to be filled with hybridization medium including target molecules such that said wire-grid sensor becomes covered with the hybridization medium.
In one embodiment, the chip holder kit further comprises a replaceable power source arranged with said housing adapted to act as a power source for the fluidics and/or to be coupled to a heating element for heating said hybridization medium. It is namely so that specific binding means that target molecules hybridize to the matching capture probes. Aspecific binding is the undesired binding of non-targeted molecules to the capture probes or other parts of the biosensor surface. Thus, heating said hybridization medium during hybridization reduces this aspecific binding. In one embodiment, the chip holder kit further comprises housing for hosting said quarter wave plate, said hybridization chamber, said replaceable power source, said fluidics and/or said heating element. In one embodiment, the base plate is made, partially or entirely, of transparent material. In another embodiment, the first and the second apertures are cut into the base plate and where the overlapping region where the first and the second apertures overlap is either an opening throughout the base plate, or a slide of a said base plate. In one embodiment, surface spots including capture probes are arranged at the surface of the polarizer, the chip holder kit further comprising fluidics adapted to transport hybridization medium including target molecules to and from the wire-grid sensor. Since such capture probes are molecules with high affinity for certain target molecules, i.e. said target molecules, it becomes possible to detect the target molecules at certain localized areas, namely at said capture probes, whereby it is simultaneously possible to monitor other processes that occur in the hybridization medium.
In one embodiment, the polarization structure comprises at least a first and a second polarizers with perpendicular orientation placed side by side in the polarization structure, where the first polarizer has a transmission axis oriented at 90 degrees with respect to the transmission axis of the wire-grid sensor and the second polarizer has its transmission axis parallel to the wire-grid. The second polarizer might as an example transmit only TM polarized light but both polarizers might be constructed so as to transmit the same light intensity. The first polarizer may result in a purely evanescent measurement, whereas the second one may result in a purely non-evanescent measurement. It can namely be advantageous to have a direct comparison between these two measurements, for example if one wants to compare the non-evanescent measurement with the more conventional method of non-evanescent imaging. In a second aspect of the invention a chip holder system is provided, comprising: - a base plate having a first aperture formed at the front side and a second aperture formed at the rear side such that an overlapping region is formed where the first and the second apertures overlap,
- a wire-grid sensor,
- a polarization structure including a polarizer, and
- a light source,
wherein the second aperture has an area that substantially matches the area of the wire- grid sensor and is adapted to removably receive the wire-grid sensor, wherein the first aperture is adapted to removably receive the polarization structure and wherein the first and second apertures are arranged such that when the wire-grid sensor and the polarizer are received in the overlapping region the polarizer filters any incoming excitation light emitted from said light source to a transverse electric mode (TE) polarized excitation light before the wire-grid sensor is illuminated
In one embodiment, the system further comprises a detector for detecting the light reflected from the wire-grid sensor.
In general the various aspects of the invention may be combined and coupled in any way possible within the scope of the invention. These and other aspects, features and/or advantages of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
Embodiments of the invention will be described, by way of example only, with reference to the drawings, in which
FIG. l(a)-(c) illustrates an operation principle of a wire grid biosensor, where FIG. 1(a) a cross-sectional view of a wire grid biosensor including wire grid substrate where wires are covered with a fluid, FIG. 1(b) shows a finite element simulation of the intensity distribution for a wire grid structure illuminated with TE polarized light and FIG.1(c) shows a scanning electron microscope (SEM) picture of a fabricated wire grid substrate with aluminum wires as viewed from the top,
FIG. 2 shows a plan view of an embodiment of a base plate from a chip holder kit according to the present invention,
FIG. 3 shows a cross sectional view along the line AA of the base plate in FIG. 2,
FIGS. 4 and 5 shows one embodiment of a chip holder kit according to the present invention,
FIG. 6 shows another embodiment of a chip holder kit according to the present invention, and FIG. 7 shows still another embodiment of a chip holder kit according to the present invention.
DESCRIPTION OF EMBODIMENTS
FIG. la shows a cross-sectional view of a wire-grid sensor 100 comprising a transparent substrate 104 with metal wires 101 which during use are covered with hybridization medium 102 including target molecules 103 (for illustration purposes, depicted within the box shown). The interface between the substrate 104 and the fluid 102 is functionalized with capture molecules 105 that can bind with the labeled target molecules 103. When the wire grid is illuminated from the bottom with transverse electric mode (TE) polarized excitation light 106 it becomes partly reflected 107 and generates an evanescent wave in the space between the wires with an intensity that decays exponentially away from the carrier. FIG. 1(b) shows a finite element simulation of the intensity distribution for a wire grid structure illuminated with TE polarized light, where the intensity in the space between the wires decays rapidly away from the interface between the carrier and the fluid. FIG.1(c) shows a scanning electron microscope (SEM) picture of a fabricated wire grid substrate with aluminum wires 108 as viewed from the top. Further details regarding such wire-grid sensor and the functioning of such wire-grid sensor may be found in WO2006136991 and
WO2007072415, hereby incorporated in whole by reference. FIG. 2 shows a plan view of an embodiment of a base plate 201 from a chip holder kit 200 according to the present invention, where the base plate 201 is in one embodiment partially or entirely made of a transparent material such as a glass or any type of plastic material. A first aperture 203 is formed at the front side of the base plate 201 and a second aperture 202 formed at the rear side of the base plate such that an overlapping region where the first and the second apertures overlap is formed 204. The second aperture 202 has an area that is approximately the same as the area of the wire-grid sensor and is adapted to removable receive the wire-grid sensor so that the wire-grid sensor becomes easily replaceable. The first aperture 203 is adapted to receive a polarization structure including a polarizer in the overlapping region such that the polarizer filters any incoming excitation light to a transverse electric mode (TE) polarized excitation light before the wire-grid sensor is illuminated.
FIG. 3 shows a cross sectional view along the line AA of the base plate in FIG. 2, where as shown here the overlapping region 204 where the first 203 and the second 202 apertures overlap is an opening throughout the base plate. However, since the base material may be a transparent material the overlapping region may just as well be a slide of the base plate (not shown here), e.g. in case the base plate is glass a slide of glass.
FIGS. 4 and 5 show a chip holder kit 200 according to the present invention 201 where a polarization structure 302 including a polarizer 303 and a wire-grid sensor 301, e.g. similar as the one discussed in relation to FIG. 1, have been placed in the first 203 and the second 202 apertures in said base plate 201, respectively. As depicted here, the polarizer is moveable along the first aperture between a first and a second state, the first state being the state where the polarizer is received in the overlapping region. The first aperture and the second aperture are preferably designed so as to ensure a fixed orientation of the transmission axis of the polarizer and the wire-grid sensor, forming an angle of 90 degrees with respect to one another.
FIG. 4 shows where the structure 302 and the polarizer 303 are in a first state, namely an evanescent detection state, where the polarizer 303 overlaps with the overlapping region 204 and thus with the wire-grid sensor 301 such that during use an incoming light emitted from a light source at a scanner being used goes through the polarizer 303 to the wire-grid sensor 301. Generally, an evanescent detection can be achieved in two ways; by illuminating the wire grid with transverse electric mode (TE) polarized excitation light, or, in case of luminescence detection where there the luminescent light is a mixture of both TE and transverse magnetic mode (TM) polarized light, by filtering the luminescent light with a polarizer that transmits TM polarized light.
FIG. 5 depicts the scenario where the polarizer has been moved towards right as indicated by the arrow to a second state, i.e. a non-evanescent detection state.
Accordingly, by sliding the polarization structure 302 in this way one can easily switch between evanescent and non-evanescent detection while ensuring that the orientation of the transmission axis of the polarizer on the polarizing element and the wire grid chip remains the same.
The polarizer is preferably formed by a number of parallel arranged wires 501 such as metal wires, where the distance between two adjacent wires (pitch- width) is below the diffraction of the medium that fills the space between the wires. Evanescent detection in the space between the wires requires that the space between the wires is below the diffraction limit in the medium that fills the space between the wires, which may be bodily fluid e.g. a water-like substance. As an example, for water (refractive index: n~l .33) this results in a diffraction limited width of the space between the wires of λ/(2η)~-0.38* λ or for a wavelength of the incident light of λ~633 nm in a diffraction limited width of the space between the wires of 238 nm. An example of dimensions of the wires is: width below 100 nm (typically 70 nm); pitch below 200 nm (typically 140 nm) and height of about 160 nm. This results in a width of the space between the wires of 70 nm, which is well below the diffraction limited width.
FIG. 6 shows another embodiment of a chip holder kit according to the present invention, showing a wire-grid sensor 607 and a polarizer made of four sub-polarizers 601-604, which as depicted here overlap with said overlapping region 204. This results in evanescent detection for areas where the sub-polarizers 601-604 and the wire-grid sensor 607 overlap and a propagating detection where only the wire-grind sensor 607 is present. In this embodiment, the sub-polarizers include on the detection surface an array of spots 605 with capture probes, i.e. molecules with a high affinity for certain target molecules and fluidics (not shown) adapted to transport hybridization medium, e.g. fluid such as water- like substance including target molecules, to and from the wire-grid sensor. Besides detecting the presence of the target molecules, one also often wants (e.g., for quality checks in a diagnostic test) to verify if the chip holder kit is
functioning properly (i.e., still intact), whether the fluid has actually reached the wire grid etc. The evanescent detection is most relevant at the locations of the spots so one could also follow another approach where evanescent detection is performed locally where the spots are and that non-evanescent imaging is performed in regions where there are no spots. This way one can use the same camera system for simultaneous evanescent and non-evanescent imaging. In this case the user has to properly slide the polarizer to ensure evanescent detection where spots are located. The distance between the spots is as an example few 100 microns and the spots can as an example be around 100 microns in diameter. In one embodiment, the polarization structure includes two polarizers, namely said polarizer 303 and a second polarizer, with perpendicular orientation and placed side by side in the polarization structure. In this embodiment, the polarizer 303 is as defined before, with transmission axis oriented at 90 degrees with respect to the transmission axis of the wire-grid sensor. The second polarizer (not shown) has its transmission axis parallel to the wire-grid, and transmits only TM polarized light. Both polarizers transmit the same light intensity, but the first polarizer results in a purely evanescent measurement, whereas the second polarizer results in a purely non-evanescent measurement. It can be advantageous to have a direct comparison between these two measurements, for example if one wants to compare the non-evanescent measurement with the more conventional method of non-evanescent imaging.
In another embodiment, it may even be favorable to use no polarizer at all, however, this results in TE plus TM polarized light, and is therefore a mixture of evanescent and non-evanescent measurement. FIG. 6 depicts a scenario where the sub-polarizers are covered with hybridization medium, and where there is an air bubble 606 in the hybridization medium. This bubble is not visible in the regions where evanescent detection is performed, but can be recognized/ detected by looking at the regions where non-evanescent detection is performed.
For propagating detection, a significantly larger volume (limited by the lens system for imaging on the camera/detector and is typically a few 100 μιη in height) is probed than for evanescent detection (height of measurement volume of only 20-30 nm) and therefore a camera with a large dynamic range is preferred. For too low dynamic range either the evanescent signal cannot be measured accurately or the pixels of the camera that detect the propagating signal are over-exposured. This problem can be solved using either a patterned neutral density filter that can either be integrated with the polarizing element in the chip holder kit, in which case sections without a polarizing element contain a neutral density filter.
FIG. 7 shows a cross-sectional view of still another embodiment of a chip holder kit 700 according to the present invention, where the chip holder kit further comprises a quarter wave plate 701 mounted at the front side of the base plate 701 and in front of a polarizer 702, 303, a base plate 703, 201, a wire-grid sensor with parallel arranged wires 704, a hybridization chamber 705 mounted at the rear side of the base plate adapted to be filled with hybridization medium including target molecules such that said wire-grid sensor becomes covered with the hybridization medium (typically water) containing fluorescently labeled target bio-molecules 103. The chip holder kit further comprises a power source 707 such as a battery which is preferably replaceable that is adapted to be coupled to a heating element 706 for heating the hybridization medium 705 and which may further be adapted to supply said fluidics with energy. Finally, the chip holder kit shown in FIG. 7 comprises a housing 708 for the chip holder 700 kit which may as an example be fabricated of a heat-resistant plastic or any other types of materials, it is preferably designed such that the wire-grid chip can easily be inserted and aligned to the polarizer in the chip-holder kit.
While the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive; the invention is not limited to the disclosed embodiments. Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used to advantage. A computer program may be
stored/distributed on a suitable medium, such as an optical storage medium or a solid- state medium supplied together with or as part of other hardware, but may also be distributed in other forms, such as via the Internet or other wired or wireless
telecommunication systems. Any reference signs in the claims should not be construed as limiting the scope.

Claims

1. A chip holder kit (200), comprising:
- a base plate (201) having a first aperture (203) formed at the front side and a second aperture (202) formed at the rear side such that an overlapping region (204) is formed where the first and the second apertures overlap,
- a wire-grid sensor (100), and
- a polarization structure (302) including a polarizer (303),
wherein the second aperture has an area that substantially matches the area of the wire- grid sensor and is adapted to removably receive the wire-grid sensor, wherein the first aperture is adapted to removably receive the polarization structure and wherein the first and second apertures are arranged such that when the wire-grid sensor and the polarizer are received in the overlapping region the polarizer (303) filters any incoming excitation light to a transverse electric mode (TE) polarized excitation light before the wire-grid sensor is illuminated.
2. A chip holder kit according to claim 1, wherein the polarizer is moveable along the first aperture (203) between a first and a second state, the first state being the state where the polarizer is received in the overlapping region.
3. A chip holder kit according to claim 2, where the first aperture (203) and the second aperture (202) are designed so as to ensure a fixed orientation of the transmission axis of the polarizer (303) and the wire-grid sensor (100), forming an angle of 90 degrees with respect to one another.
4. A chip holder kit according to claim 1, wherein the polarization structure (303) is a slider in which the polarizer is mounted.
5. A chip holder kit according to claim 1, wherein the polarizer (303) comprises at least a first and a second sub-polarizers (601-604), said first state being the state where the first and the at least second sub-polarizer overlap with the first aperture and thus with the wire-grid sensor when it is in place of the first aperture.
6. A chip holder kit according to claim 1 or 5, wherein the polarizer (303) is formed by a number of parallel arranged wires (501) where the distance between two adjacent wires is below the diffraction of the medium that fills the space between the wires.
7. A chip holder kit according to claim 1, further comprising a quarter wave plate (701) mounted at the front side of the base plate (703) in front of the polarizer (303).
8. A chip holder kit according to claim 1 or 7, further comprising hybridization chamber (705) mounted at the rear side of the base plate (201, 703) adapted to be filled with hybridization medium including target molecules such that said wire-grid sensor becomes covered with the hybridization medium.
9. A chip holder kit according to claim 8, further comprising a replaceable power source (707) arranged with said housing adapted to act as a power source for the fluidics and/or to be coupled to a heating element (706) for heating said hybridization medium.
10. A chip holder kit according to claim 9, further comprising housing for hosting said quarter wave plate (701), said hybridization chamber (705), said replaceable power source (707), said fluidics and/or said heating element (706).
11. A chip holder kit according to claim 1, wherein surface spots (605) including capture probes are arranged at the surface of the polarizer (303), the chip holder kit further comprising fluidics adapted to transport hybridization medium including target molecules to and from the wire-grid sensor.
12. A chip holder kit according to claim 1, wherein the base plate (201) is made, partially or entirely, of transparent material.
13. A chip holder kit according to claim 12, wherein the first and the second apertures are cut into the base plate and where the overlapping region where the first and the second apertures overlap is either an opening throughout the base plate, or a slide of a said base plate.
14. A chip holder kit according to claim 1, wherein the polarization structure (302) comprises at least a first and a second polarizers with perpendicular orientation placed side by side in the polarization structure (302), where the first polarizer has a transmission axis oriented at 90 degrees with respect to the transmission axis of the wire-grid sensor and the second polarizer has its transmission axis parallel to the wire- grid.
15. A chip holder system, comprising:
- a base plate (201) having a first aperture formed at the front side and a second
aperture formed at the rear side such that an overlapping region is formed where the first and the second apertures overlap,
- a wire-grid sensor (100),
- a polarization structure (302) including a polarizer (303), and
- a light source,
wherein the second aperture has an area that substantially matches the area of the wire- grid sensor and is adapted to removably receive the wire-grid sensor, wherein the first aperture is adapted to removably receive the polarization structure and wherein the first and second apertures are arranged such that when the wire-grid sensor and the polarizer are received in the overlapping region the polarizer filters any incoming excitation light emitted from said light source to a transverse electric mode (TE) polarized excitation light before the wire-grid sensor is illuminated.
PCT/IB2010/055032 2009-11-12 2010-11-05 A chip holder kit for a wire-gird sensor. WO2011058488A1 (en)

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EP09306086 2009-11-12

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Citations (8)

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Publication number Priority date Publication date Assignee Title
GB612780A (en) * 1946-06-03 1948-11-17 Charles Stuart Pyser Improvements in or relating to stages for microscopes
US20020044347A1 (en) * 2000-04-03 2002-04-18 Steenblik Richard A. Lenses and uses, including microscopes
WO2006136991A1 (en) 2005-06-23 2006-12-28 Koninklijke Philips Electronics N.V. Luminescence sensors using sub-wavelength apertures or slits
US20070042505A1 (en) * 2005-05-06 2007-02-22 Platypus Technologies, Llc Liquid crystal based analyte detection
WO2007072293A2 (en) * 2005-12-20 2007-06-28 Koninklijke Philips Electronics, N.V. Biosensor with one-dimensional sub-diffraction-limited apertures composed of a grid and a polarizer
WO2007072415A2 (en) 2005-12-22 2007-06-28 Koninklijke Philips Electronics N.V. Luminescence sensor operating in reflection mode
US20070206187A1 (en) * 2006-02-13 2007-09-06 Pacific Biosciences Of California, Inc. Methods and systems for simultaneous real-time monitoring of optical signals from multiple sources
WO2008099339A1 (en) * 2007-02-12 2008-08-21 Koninklijke Philips Electronics N.V. Wiregrid monitor device

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB612780A (en) * 1946-06-03 1948-11-17 Charles Stuart Pyser Improvements in or relating to stages for microscopes
US20020044347A1 (en) * 2000-04-03 2002-04-18 Steenblik Richard A. Lenses and uses, including microscopes
US20070042505A1 (en) * 2005-05-06 2007-02-22 Platypus Technologies, Llc Liquid crystal based analyte detection
WO2006136991A1 (en) 2005-06-23 2006-12-28 Koninklijke Philips Electronics N.V. Luminescence sensors using sub-wavelength apertures or slits
WO2007072293A2 (en) * 2005-12-20 2007-06-28 Koninklijke Philips Electronics, N.V. Biosensor with one-dimensional sub-diffraction-limited apertures composed of a grid and a polarizer
WO2007072415A2 (en) 2005-12-22 2007-06-28 Koninklijke Philips Electronics N.V. Luminescence sensor operating in reflection mode
US20070206187A1 (en) * 2006-02-13 2007-09-06 Pacific Biosciences Of California, Inc. Methods and systems for simultaneous real-time monitoring of optical signals from multiple sources
WO2008099339A1 (en) * 2007-02-12 2008-08-21 Koninklijke Philips Electronics N.V. Wiregrid monitor device

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