EP1896833A2 - Integrated waveguide laser for lab-on-a-chip diagnostics - Google Patents

Integrated waveguide laser for lab-on-a-chip diagnostics

Info

Publication number
EP1896833A2
EP1896833A2 EP06765778A EP06765778A EP1896833A2 EP 1896833 A2 EP1896833 A2 EP 1896833A2 EP 06765778 A EP06765778 A EP 06765778A EP 06765778 A EP06765778 A EP 06765778A EP 1896833 A2 EP1896833 A2 EP 1896833A2
Authority
EP
European Patent Office
Prior art keywords
laser
detection device
waveguide
substrate
lasers
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06765778A
Other languages
German (de)
French (fr)
Inventor
Holger Philips IP &Standards GmbH MOENCH
Gero Philips IP &Standards GmbH HEUSLER
Ulrich Philips IP &Standards GmbH WEICHMANN
Jens Philips IP &Standards GmbH GOTTMANN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV
Original Assignee
Philips Intellectual Property and Standards GmbH
Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV
Koninklijke Philips Electronics NV
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 Philips Intellectual Property and Standards GmbH, Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV, Koninklijke Philips Electronics NV filed Critical Philips Intellectual Property and Standards GmbH
Priority to EP06765778A priority Critical patent/EP1896833A2/en
Publication of EP1896833A2 publication Critical patent/EP1896833A2/en
Withdrawn legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • 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
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • 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
    • 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
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    • 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
    • G01N21/648—Specially adapted constructive features of fluorimeters using evanescent coupling or surface plasmon coupling for the excitation of fluorescence
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    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/7703—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
    • H—ELECTRICITY
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    • H01S3/10—Controlling the intensity, frequency, phase, polarisation or direction of the emitted radiation, e.g. switching, gating, modulating or demodulating
    • H01S3/102—Controlling the intensity, frequency, phase, polarisation or direction of the emitted radiation, e.g. switching, gating, modulating or demodulating by controlling the active medium, e.g. by controlling the processes or apparatus for excitation
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    • 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
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/39—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using tunable lasers
    • G01N2021/392—Measuring reradiation, e.g. fluorescence, backscatter
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    • 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
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    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks
    • G01N2021/6441—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks with two or more labels
    • 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
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N2021/7769—Measurement method of reaction-produced change in sensor
    • G01N2021/7786—Fluorescence
    • 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
    • G01N21/55—Specular reflectivity
    • G01N21/552—Attenuated total reflection
    • 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
    • G01N21/6402—Atomic fluorescence; Laser induced fluorescence
    • 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
    • G01N2201/06—Illumination; Optics
    • G01N2201/061—Sources
    • G01N2201/06113—Coherent sources; lasers
    • G—PHYSICS
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/08—Optical fibres; light guides
    • G01N2201/0873—Using optically integrated constructions
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01S—DEVICES USING THE PROCESS OF LIGHT AMPLIFICATION BY STIMULATED EMISSION OF RADIATION [LASER] TO AMPLIFY OR GENERATE LIGHT; DEVICES USING STIMULATED EMISSION OF ELECTROMAGNETIC RADIATION IN WAVE RANGES OTHER THAN OPTICAL
    • H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
    • H01S3/05—Construction or shape of optical resonators; Accommodation of active medium therein; Shape of active medium
    • H01S3/06—Construction or shape of active medium
    • H01S3/063—Waveguide lasers, i.e. whereby the dimensions of the waveguide are of the order of the light wavelength
    • H01S3/0632—Thin film lasers in which light propagates in the plane of the thin film
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01S—DEVICES USING THE PROCESS OF LIGHT AMPLIFICATION BY STIMULATED EMISSION OF RADIATION [LASER] TO AMPLIFY OR GENERATE LIGHT; DEVICES USING STIMULATED EMISSION OF ELECTROMAGNETIC RADIATION IN WAVE RANGES OTHER THAN OPTICAL
    • H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
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    • H01S3/06—Construction or shape of active medium
    • H01S3/063—Waveguide lasers, i.e. whereby the dimensions of the waveguide are of the order of the light wavelength
    • H01S3/0632—Thin film lasers in which light propagates in the plane of the thin film
    • H01S3/0637—Integrated lateral waveguide, e.g. the active waveguide is integrated on a substrate made by Si on insulator technology (Si/SiO2)
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    • H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
    • H01S3/09—Processes or apparatus for excitation, e.g. pumping
    • H01S3/091—Processes or apparatus for excitation, e.g. pumping using optical pumping
    • H01S3/094—Processes or apparatus for excitation, e.g. pumping using optical pumping by coherent light
    • H01S3/094084—Processes or apparatus for excitation, e.g. pumping using optical pumping by coherent light with pump light recycling, i.e. with reinjection of the unused pump light, e.g. by reflectors or circulators
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    • H01S—DEVICES USING THE PROCESS OF LIGHT AMPLIFICATION BY STIMULATED EMISSION OF RADIATION [LASER] TO AMPLIFY OR GENERATE LIGHT; DEVICES USING STIMULATED EMISSION OF ELECTROMAGNETIC RADIATION IN WAVE RANGES OTHER THAN OPTICAL
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    • H01S3/09—Processes or apparatus for excitation, e.g. pumping
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    • H01S3/094—Processes or apparatus for excitation, e.g. pumping using optical pumping by coherent light
    • H01S3/0941—Processes or apparatus for excitation, e.g. pumping using optical pumping by coherent light of a laser diode
    • H01S3/09415—Processes or apparatus for excitation, e.g. pumping using optical pumping by coherent light of a laser diode the pumping beam being parallel to the lasing mode of the pumped medium, e.g. end-pumping
    • H—ELECTRICITY
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    • H01S—DEVICES USING THE PROCESS OF LIGHT AMPLIFICATION BY STIMULATED EMISSION OF RADIATION [LASER] TO AMPLIFY OR GENERATE LIGHT; DEVICES USING STIMULATED EMISSION OF ELECTROMAGNETIC RADIATION IN WAVE RANGES OTHER THAN OPTICAL
    • H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
    • H01S3/14—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range characterised by the material used as the active medium
    • H01S3/16—Solid materials
    • H01S3/1601—Solid materials characterised by an active (lasing) ion
    • H01S3/1603—Solid materials characterised by an active (lasing) ion rare earth
    • H01S3/1608—Solid materials characterised by an active (lasing) ion rare earth erbium
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    • H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
    • H01S3/14—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range characterised by the material used as the active medium
    • H01S3/16—Solid materials
    • H01S3/17—Solid materials amorphous, e.g. glass
    • H01S3/173—Solid materials amorphous, e.g. glass fluoride glass, e.g. fluorozirconate or ZBLAN [ ZrF4-BaF2-LaF3-AlF3-NaF]
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    • H01S—DEVICES USING THE PROCESS OF LIGHT AMPLIFICATION BY STIMULATED EMISSION OF RADIATION [LASER] TO AMPLIFY OR GENERATE LIGHT; DEVICES USING STIMULATED EMISSION OF ELECTROMAGNETIC RADIATION IN WAVE RANGES OTHER THAN OPTICAL
    • H01S3/00—Lasers, i.e. devices using stimulated emission of electromagnetic radiation in the infrared, visible or ultraviolet wave range
    • H01S3/23—Arrangements of two or more lasers not provided for in groups H01S3/02 - H01S3/22, e.g. tandem arrangements of separate active media
    • H01S3/2383—Parallel arrangements

Definitions

  • the present invention relates to a detection device for detecting target substances in samples by means of an evanescent wave formed in said samples.
  • micro-arrays allow for the investigation of very small sample quantities on many characteristics in parallel.
  • a micro-array consists of different probes arranged on a substrate.
  • a sample containing one or several target substances is applied to the micro-array, where reactions with the different probes can occur.
  • the target substances or the probes are fluorescently labeled.
  • the corresponding probe will then exhibit fluorescence or not.
  • the present invention refers to an optical readout using laser-induced fluorescence. In that case the micro-arrays are irradiated by laser light and the fluorescence signal from each probe is detected.
  • An apparatus for detecting a target substance in a sample using such a detection of fluorescence is known for example from EP 0 677 734 A2.
  • This apparatus comprises a light source and an optical resonator including a resonance cavity for light generated by the light source.
  • a total internal reflection member is located within the resonance cavity in order to provide a total internal reflection surface with an angle of incidence greater than a critical angle.
  • This surface includes an evanescent field region in which a sample is positioned. The evanescent field excites the fluorescence in the sample which can then be detected by an appropriate optical detector.
  • the internal reflection member may be a passive device such as a prism, a waveguide or a fiber, or an active gain element such as a doped optical fiber.
  • the resonator comprises a fiber laser as a gain medium in which the total internal reflecting surface is created by removing a portion of cladding that typically surrounds the optical fiber.
  • the sample has to be applied directly to the region of the optical fiber, where the cladding has been removed.
  • the proposed detection device comprises a substrate with at least one planar waveguide laser in or on said substrate, said waveguide laser having a gain medium for up-conversion or for down-conversion.
  • a top layer of said waveguide laser forms at least part of a surface of said substrate and allows formation of an evanescent wave in a sample contacting said surface.
  • a structure is applied to said top layer to define an array of probe regions on said top layer, said probe regions consisting of a coating of probe materials for sensing said target substances to be detected.
  • the laser for exciting the fluorescence is arranged as a planar waveguide laser in or on the substrate defining the array or micro- array, instead of using separate waveguides or fibers as in the prior art.
  • the substrate of the proposed detection device one or several planar waveguide lasers are incorporated underneath an array of probe regions for parallel detection of different target substances in one or several samples.
  • the laser radiation in this one or several waveguide lasers excites the fluorescent markers of the fluorescently labeled samples, which are in contact with the probe regions on the surface of the substrate, via the evanescent electromagnetic wave leaking out of the waveguide.
  • the fluorescent light emitted in the presence of the target substances can be detected in a known manner, for example by means of a CCD camera which monitors the surface of the substrate. Due to the definition of several probe regions and the integration of the planar waveguide laser(s) a high level of integration is reached. A further advantage of the proposed detection device is the high photon density inside the laser cavity resulting in a higher in density of the evanescent wave to excite the fluorescence.
  • the gain medium for the waveguide laser(s) is preferably a rare earth doped material.
  • Suitable dopants can be e.g. Er, Yb, Tm, Ho, Sm, Pr, Dy, Nd, Pm, Eu, Gd or Tb.
  • Suitable host materials for the doping include heavy-metal fluoride glasses, as for example ZBLAN, heavy metal oxide glasses, as for example telluride glass, or crystalline hosts, as for example LiLuF, YAG, YLF or YVO.
  • the gain medium of such a waveguide laser is embedded in a material of a lower refractive index than the gain medium.
  • the top layer formed of said material has a thickness at least in the probe regions which is less than or equal to the laser wavelength of the waveguide laser in order to allow an evanescent wave to form in the sample.
  • the top layer of the waveguide laser can have such a small thickness over the entire length of the waveguide laser, or in an alternative embodiment, only in the defined probe regions.
  • the waveguide laser is only embedded on two or three sides in said material of low refractive index, or is attached on one side on the substrate with such a low refractive index, so that the upper side of the gain medium forms the top layer.
  • the evanescent wave has a maximum penetration depth in said sample.
  • the waveguide laser of the proposed detection device has two end mirrors on the end facets of the waveguide, said end mirrors being preferably formed on side surfaces of said substrate. Both end mirrors are highly reflective for the wavelength of said waveguide laser, preferably with a reflectivity of R > 99.9 %.
  • the pump light of one or several pump lasers is preferably coupled from one end side of the waveguide laser(s) to the gain medium. This pump laser is preferably a semiconductor laser or, in the case of several parallel waveguide lasers, a semiconductor laser bar.
  • the end mirrors are formed of a dielectric coating, wherein one end mirror, on the incoupling side for the pump laser, has a high transmission for the wavelength of the pump laser and a high reflectivity, preferably of R > 99.9 %, for the waveguide laser wavelength.
  • the end mirror of the other side should also have such a high reflectivity for the waveguide laser wavelength and preferably also a high reflectivity for the pump laser wavelength.
  • the skilled person in the field of laser technology is familiar with different dielectric coatings fulfilling the above requirements. With such a design a high photon density inside the laser cavity of the waveguide laser is achieved. Ideally the only losses of this resonator are due to the evanescent wave, thus enhancing the amount of light coupled into the samples.
  • the gain medium of the waveguide laser(s) can be based on an up-conversion or down-conversion material, depending on the wavelength of the pump laser used and the wavelength required for exciting the fluorescence of the target substances.
  • the one or several pump lasers are arranged on a heat sink which is mounted on a carrier plate.
  • fixation and/or positioning means are arranged for mounting said substrate in a predefined position with respect to the pump laser(s) on said carrier plate.
  • This fixation and/or positioning means can also be designed to adjust the alignment of the substrate relative to the pump laser(s).
  • these adjustment means are for example piezoelectric transducers which are connected to a feedback loop to properly align the substrate to the pump laser(s).
  • the feedback loop can be designed, for example, to detect laser light of the waveguide laser(s) emitted by one of its end mirrors, wherein the piezoelectric transducers are driven to achieve a maximum intensity of the detected laser light.
  • Another possibility is to detect fluorescent light of an applied sample, in which case the substrate is also adjusted to achieve a maximum of the fluorescence intensity.
  • Such a feedback loop is especially of advantage in cases where the substrate with the waveguide lasers has to be changed and is a disposable.
  • several waveguide lasers are arranged in or on said substrate, preferably in a parallel manner. At least two of these waveguide lasers, comprise different dielectric coatings as end mirrors resulting in a different laser wavelength of the waveguide lasers. In the same manner more than two waveguide lasers emitting different wavelengths can be provided in the proposed detection device. This allows the use of different fluorescently labeled targets expanding the application of the present detection device to the parallel detection of even more characteristics of applied samples.
  • the top layer of the waveguide laser(s) is additionally structured in order to enhance the intensity of laser light coupled into the sample.
  • a structuring can be done for example by embedding scattering particles in the top layer or by forming scattering structures or micro prisms in the upper surface. Several such techniques are well known in the field of LCD-backlighting.
  • additional light of the waveguide laser is deflected, diffracted or scattered out of the laser cavity.
  • the dimensions of the waveguide laser(s) used in the proposed detection device are preferably adapted to the dimensions of the pump laser diode. Typical dimensions are as follows: height of the waveguide 1 to 10 ⁇ m, width 5 to 200 ⁇ m and length 1 to 10 cm.
  • Fig. 1 a schematic side view of the proposed substrate together with the pump laser on a carrier plate;
  • Fig. 2 a further schematic view of a substrate of the present detection device; and Fig. 3 a schematic view of the substrate of figure 2 with different probe regions indicated.
  • Fig. 1 shows an example of the present detection device in which the substrate 1 is mounted on a carrier plate 9 together with a laser diode 7 on a heat sink 8.
  • Laser diode 7 is used as a pump laser for the waveguide laser 2 integrated in said substrate 1.
  • a probe region 4 is formed by a coating of a probe material, which may be fluorescently labeled.
  • an evanescent electromagnetic wave of the laser light of the waveguide laser 2 is formed in a thin region adjacent to the surface of said sample. This evanescent electromagnetic wave excites the fluorescent light of target substances which are bound by said probe materials.
  • the probe materials may be any materials which are able to bind the target substances. Typical materials include binding agents as for example nucleid acid, DNA or proteins.
  • the end mirrors 6 of the waveguide laser 2 are applied to the side faces of the substrate 1.
  • the substrate 1 comprising the micro-array of probes can be a disposable.
  • means have to be taken to align the substrate 1 with respect to the pump laser diode 7 in case of replacing the micro-array substrate 1.
  • These means can be simple fixation and position pins which allow a very exact positioning and fixation of the substrate relative to the pump laser diode 7.
  • the adjustment means 10 are arranged on the carrier plate 9 which exactly define a lateral position of the substrate 1 with respect to the pump laser 7 on the one hand, and allow for an adjustment with respect to the vertical position of the substrate 1 in order to exactly align the waveguide laser 2 to the pump laser diode 7 on the other hand.
  • the adjustment means 10 can be formed of a stack of piezoelectric transducers allowing the vertical movement of the substrate 1 by applying an electrical voltage to the stack.
  • the adjustment is controlled by a feedback loop comprising a photo detector 12 and a control circuit 11 connected to the adjustment means 10 and the photo detector 12.
  • the laser light of the waveguide laser 2 emitted on the right hand side end mirror 6 is monitored by the photo detector 12.
  • the control circuit 11 drives the adjustment means 10 to achieve a maximum intensity detected with said photo detector 12. When this maximum intensity is achieved, the substrate 1 is optimally aligned with respect to the pump laser diode 7.
  • the waveguide has dimensions preferably adapted to the dimensions of the pump laser diode 7. Typical dimensions are indicated in the example of figure 2 showing a substrate 1 with six waveguide lasers 2 arranged in parallel on said substrate 1. These waveguide lasers 2 may be pumped by several diode lasers that may be arranged in a laser diode bar. To form the waveguides, the rare earth doped gain medium 5 of this example is embedded in a material with a lower refractive index. For an efficient formation of the evanescent wave the top layer 3 of this enclosing material should have a small thickness not exceeding the wavelength of the waveguide laser light.
  • Figure 2 indicates with different hatching waveguide lasers 2 having different laser wavelengths on the same substrate 1. Every two of these waveguide lasers 2 provide the same wavelength.
  • the waveguide lasers 2 comprise an Er-doped waveguide layer (gain medium 5) of ZBLAN pumped by an infrared diode around 970 nm.
  • the emission wavelength of the waveguide laser 2 is around 544 nm.
  • the waveguide layer is placed on a MgF 2 substrate and covered by a thin MgF 2 layer of approximately 100 nm thickness as the top layer.
  • waveguide lasers made of a Pr/Yb-doped ZBLAN gain material can be used, for example. Lasers with different wavelengths can then be realized in this material system by choosing appropriate dielectric coatings, having their maximum reflectivity at the different wavelengths, as the resonator mirrors.
  • Figure 3 shows such a substrate 1 with waveguide lasers 2 of different wavelengths with the structured probe regions 4 on the surface of the substrate 1.
  • This detection device provides an array of probe regions 4 having different probes for sensing different target substances of a sample.
  • Probe regions 4 of waveguide lasers 2 emitting different wavelengths enhance the possibilities of parallel testing of a sample for different target substances.
  • the arrangement of the waveguide lasers on the substrate is not limited to the above examples.
  • the waveguide lasers can also be arranged in another than a parallel arrangement.
  • one or several waveguide lasers may extend not in a straight but in a curved manner, for example in a sinusoidal manner.
  • the detection device With the present detection device a highly integrated design for parallel testing as well as a high photon density for excitation of fluorescence is achieved.
  • the detection device is in particular advantageous for diagnostic applications, for example in the field of biometrical diagnostics. Nevertheless, it is also possible to use the present detection device for other applications, in which a target substance in a sample has to be excited by laser light in order to detect the target substance.

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Abstract

The present invention relates to a detection device for detecting target substances in samples. The device comprises a substrate (1) with at least one planar waveguide laser (2) in or on said substrate (1), said waveguide laser (2) having a gain medium (5) for up-conversion or for down-conversion. A top layer (3) of said waveguide laser (2) forms at least part of a surface of said substrate (1) and allows formation of an evanescent wave in a sample contacting said surface. A structure is applied on said top layer (3) to define an array of probe regions (4) on said top layer (3), said probe regions (4) consisting of a coating of probe materials for sensing said target substances to be detected. The present detection device allows a parallel detection of target substances with a highly integrated design.

Description

Integrated waveguide laser for lab-on-a-chip diagnostics
The present invention relates to a detection device for detecting target substances in samples by means of an evanescent wave formed in said samples.
Many branches of medicine, chemistry and biology depend on an ability to assay chemical, biochemical or biological samples or to determine changes in the chemical composition of such samples. The diagnosis of many diseases, for example, often relies on the ability to detect the presence of antibodies in the blood.
In biomedical applications micro-arrays allow for the investigation of very small sample quantities on many characteristics in parallel. Experimentally, such a micro-array consists of different probes arranged on a substrate. A sample containing one or several target substances is applied to the micro-array, where reactions with the different probes can occur. In fluorometric analysis, a preferred application of the detection device of the present invention, the target substances or the probes are fluorescently labeled. Depending on whether a reaction with the different probes occurred, the corresponding probe will then exhibit fluorescence or not. Several techniques are known for the readout of the micro-array. The present invention refers to an optical readout using laser-induced fluorescence. In that case the micro-arrays are irradiated by laser light and the fluorescence signal from each probe is detected.
An apparatus for detecting a target substance in a sample using such a detection of fluorescence is known for example from EP 0 677 734 A2. This apparatus comprises a light source and an optical resonator including a resonance cavity for light generated by the light source. A total internal reflection member is located within the resonance cavity in order to provide a total internal reflection surface with an angle of incidence greater than a critical angle. This surface includes an evanescent field region in which a sample is positioned. The evanescent field excites the fluorescence in the sample which can then be detected by an appropriate optical detector. The internal reflection member may be a passive device such as a prism, a waveguide or a fiber, or an active gain element such as a doped optical fiber. In one of the embodiments of this document, the resonator comprises a fiber laser as a gain medium in which the total internal reflecting surface is created by removing a portion of cladding that typically surrounds the optical fiber. In such a case the sample has to be applied directly to the region of the optical fiber, where the cladding has been removed.
It is an object of the present invention to provide a detection device for detecting target substances in samples allowing a parallel detection of several substances at a high level of integration.
The object is achieved with the detection device according to claim 1. Advantageous embodiments of the detection device are subject matter of the dependent claims or are disclosed in the subsequent description.
The proposed detection device comprises a substrate with at least one planar waveguide laser in or on said substrate, said waveguide laser having a gain medium for up-conversion or for down-conversion. A top layer of said waveguide laser forms at least part of a surface of said substrate and allows formation of an evanescent wave in a sample contacting said surface. A structure is applied to said top layer to define an array of probe regions on said top layer, said probe regions consisting of a coating of probe materials for sensing said target substances to be detected.
In the present invention the laser for exciting the fluorescence is arranged as a planar waveguide laser in or on the substrate defining the array or micro- array, instead of using separate waveguides or fibers as in the prior art. This means that in the substrate of the proposed detection device one or several planar waveguide lasers are incorporated underneath an array of probe regions for parallel detection of different target substances in one or several samples. The laser radiation in this one or several waveguide lasers excites the fluorescent markers of the fluorescently labeled samples, which are in contact with the probe regions on the surface of the substrate, via the evanescent electromagnetic wave leaking out of the waveguide. The fluorescent light emitted in the presence of the target substances can be detected in a known manner, for example by means of a CCD camera which monitors the surface of the substrate. Due to the definition of several probe regions and the integration of the planar waveguide laser(s) a high level of integration is reached. A further advantage of the proposed detection device is the high photon density inside the laser cavity resulting in a higher in density of the evanescent wave to excite the fluorescence.
The gain medium for the waveguide laser(s) is preferably a rare earth doped material. Suitable dopants can be e.g. Er, Yb, Tm, Ho, Sm, Pr, Dy, Nd, Pm, Eu, Gd or Tb. Suitable host materials for the doping include heavy-metal fluoride glasses, as for example ZBLAN, heavy metal oxide glasses, as for example telluride glass, or crystalline hosts, as for example LiLuF, YAG, YLF or YVO.
The gain medium of such a waveguide laser is embedded in a material of a lower refractive index than the gain medium. In the present detection device, the top layer formed of said material has a thickness at least in the probe regions which is less than or equal to the laser wavelength of the waveguide laser in order to allow an evanescent wave to form in the sample. This means that the top layer of the waveguide laser can have such a small thickness over the entire length of the waveguide laser, or in an alternative embodiment, only in the defined probe regions. Nevertheless it is also possible that the waveguide laser is only embedded on two or three sides in said material of low refractive index, or is attached on one side on the substrate with such a low refractive index, so that the upper side of the gain medium forms the top layer. In this case the evanescent wave has a maximum penetration depth in said sample.
The waveguide laser of the proposed detection device has two end mirrors on the end facets of the waveguide, said end mirrors being preferably formed on side surfaces of said substrate. Both end mirrors are highly reflective for the wavelength of said waveguide laser, preferably with a reflectivity of R > 99.9 %. The pump light of one or several pump lasers is preferably coupled from one end side of the waveguide laser(s) to the gain medium. This pump laser is preferably a semiconductor laser or, in the case of several parallel waveguide lasers, a semiconductor laser bar.
In a further preferred embodiment, the end mirrors are formed of a dielectric coating, wherein one end mirror, on the incoupling side for the pump laser, has a high transmission for the wavelength of the pump laser and a high reflectivity, preferably of R > 99.9 %, for the waveguide laser wavelength. The end mirror of the other side should also have such a high reflectivity for the waveguide laser wavelength and preferably also a high reflectivity for the pump laser wavelength. The skilled person in the field of laser technology is familiar with different dielectric coatings fulfilling the above requirements. With such a design a high photon density inside the laser cavity of the waveguide laser is achieved. Ideally the only losses of this resonator are due to the evanescent wave, thus enhancing the amount of light coupled into the samples. The gain medium of the waveguide laser(s) can be based on an up-conversion or down-conversion material, depending on the wavelength of the pump laser used and the wavelength required for exciting the fluorescence of the target substances. In one embodiment of the present detection device, the one or several pump lasers are arranged on a heat sink which is mounted on a carrier plate. On this carrier plate fixation and/or positioning means are arranged for mounting said substrate in a predefined position with respect to the pump laser(s) on said carrier plate. This fixation and/or positioning means can also be designed to adjust the alignment of the substrate relative to the pump laser(s). In this case these adjustment means are for example piezoelectric transducers which are connected to a feedback loop to properly align the substrate to the pump laser(s). The feedback loop can be designed, for example, to detect laser light of the waveguide laser(s) emitted by one of its end mirrors, wherein the piezoelectric transducers are driven to achieve a maximum intensity of the detected laser light. Another possibility is to detect fluorescent light of an applied sample, in which case the substrate is also adjusted to achieve a maximum of the fluorescence intensity. Such a feedback loop is especially of advantage in cases where the substrate with the waveguide lasers has to be changed and is a disposable. In a further preferred embodiment of the proposed detection device, several waveguide lasers are arranged in or on said substrate, preferably in a parallel manner. At least two of these waveguide lasers, comprise different dielectric coatings as end mirrors resulting in a different laser wavelength of the waveguide lasers. In the same manner more than two waveguide lasers emitting different wavelengths can be provided in the proposed detection device. This allows the use of different fluorescently labeled targets expanding the application of the present detection device to the parallel detection of even more characteristics of applied samples.
In a further embodiment of the present detection device, the top layer of the waveguide laser(s) is additionally structured in order to enhance the intensity of laser light coupled into the sample. Such a structuring can be done for example by embedding scattering particles in the top layer or by forming scattering structures or micro prisms in the upper surface. Several such techniques are well known in the field of LCD-backlighting. In this embodiment additional light of the waveguide laser is deflected, diffracted or scattered out of the laser cavity.
The dimensions of the waveguide laser(s) used in the proposed detection device are preferably adapted to the dimensions of the pump laser diode. Typical dimensions are as follows: height of the waveguide 1 to 10 μm, width 5 to 200 μm and length 1 to 10 cm.
It is obvious for the skilled person that the different embodiments disclosed in the present description can be combined in any reasonable manner. In the present description and claims the word "comprising" does not exclude other elements or steps and neither does "a" or "an" exclude a plurality. Also any reference signs in the claims shall not be construed as limiting the scope of these claims.
The present detection device is also described in connection with the following drawings in some exemplary embodiments without limiting the scope of the claims. The figures show:
Fig. 1 a schematic side view of the proposed substrate together with the pump laser on a carrier plate;
Fig. 2 a further schematic view of a substrate of the present detection device; and Fig. 3 a schematic view of the substrate of figure 2 with different probe regions indicated.
Fig. 1 shows an example of the present detection device in which the substrate 1 is mounted on a carrier plate 9 together with a laser diode 7 on a heat sink 8. Laser diode 7 is used as a pump laser for the waveguide laser 2 integrated in said substrate 1. On the top layer 3 of the waveguide laser 2 a probe region 4 is formed by a coating of a probe material, which may be fluorescently labeled. When applying a sample to this probe region 4, an evanescent electromagnetic wave of the laser light of the waveguide laser 2 is formed in a thin region adjacent to the surface of said sample. This evanescent electromagnetic wave excites the fluorescent light of target substances which are bound by said probe materials.
The probe materials may be any materials which are able to bind the target substances. Typical materials include binding agents as for example nucleid acid, DNA or proteins.
In the example of figure 1 the end mirrors 6 of the waveguide laser 2 are applied to the side faces of the substrate 1. In such a lab-on-a-chip setup as that of figure 1 the substrate 1 comprising the micro-array of probes can be a disposable. In this case means have to be taken to align the substrate 1 with respect to the pump laser diode 7 in case of replacing the micro-array substrate 1. These means can be simple fixation and position pins which allow a very exact positioning and fixation of the substrate relative to the pump laser diode 7. In the present example adjustment means 10 are arranged on the carrier plate 9 which exactly define a lateral position of the substrate 1 with respect to the pump laser 7 on the one hand, and allow for an adjustment with respect to the vertical position of the substrate 1 in order to exactly align the waveguide laser 2 to the pump laser diode 7 on the other hand. To this end, the adjustment means 10 can be formed of a stack of piezoelectric transducers allowing the vertical movement of the substrate 1 by applying an electrical voltage to the stack. The adjustment is controlled by a feedback loop comprising a photo detector 12 and a control circuit 11 connected to the adjustment means 10 and the photo detector 12. The laser light of the waveguide laser 2 emitted on the right hand side end mirror 6 is monitored by the photo detector 12. The control circuit 11 drives the adjustment means 10 to achieve a maximum intensity detected with said photo detector 12. When this maximum intensity is achieved, the substrate 1 is optimally aligned with respect to the pump laser diode 7.
The waveguide has dimensions preferably adapted to the dimensions of the pump laser diode 7. Typical dimensions are indicated in the example of figure 2 showing a substrate 1 with six waveguide lasers 2 arranged in parallel on said substrate 1. These waveguide lasers 2 may be pumped by several diode lasers that may be arranged in a laser diode bar. To form the waveguides, the rare earth doped gain medium 5 of this example is embedded in a material with a lower refractive index. For an efficient formation of the evanescent wave the top layer 3 of this enclosing material should have a small thickness not exceeding the wavelength of the waveguide laser light.
Using different dielectric coatings for at least two different waveguide lasers, different colors of these waveguide lasers can be achieved. Figure 2 indicates with different hatching waveguide lasers 2 having different laser wavelengths on the same substrate 1. Every two of these waveguide lasers 2 provide the same wavelength. In one example the waveguide lasers 2 comprise an Er-doped waveguide layer (gain medium 5) of ZBLAN pumped by an infrared diode around 970 nm. The emission wavelength of the waveguide laser 2 is around 544 nm. The waveguide layer is placed on a MgF2 substrate and covered by a thin MgF2 layer of approximately 100 nm thickness as the top layer. In order to provide waveguide lasers with different emission wavelengths allowing the use of different fluorescent label targets, waveguide lasers made of a Pr/Yb-doped ZBLAN gain material can be used, for example. Lasers with different wavelengths can then be realized in this material system by choosing appropriate dielectric coatings, having their maximum reflectivity at the different wavelengths, as the resonator mirrors.
Figure 3 shows such a substrate 1 with waveguide lasers 2 of different wavelengths with the structured probe regions 4 on the surface of the substrate 1. This detection device provides an array of probe regions 4 having different probes for sensing different target substances of a sample. Probe regions 4 of waveguide lasers 2 emitting different wavelengths enhance the possibilities of parallel testing of a sample for different target substances.
It is obvious to the skilled person that the arrangement of the waveguide lasers on the substrate is not limited to the above examples. The waveguide lasers can also be arranged in another than a parallel arrangement. Furthermore, one or several waveguide lasers may extend not in a straight but in a curved manner, for example in a sinusoidal manner.
With the present detection device a highly integrated design for parallel testing as well as a high photon density for excitation of fluorescence is achieved. The detection device is in particular advantageous for diagnostic applications, for example in the field of biometrical diagnostics. Nevertheless, it is also possible to use the present detection device for other applications, in which a target substance in a sample has to be excited by laser light in order to detect the target substance.
LIST OF REFERENCE SIGNS
1 substrate
2 waveguide laser
3 top layer
4 probe region
5 gain medium
6 resonator mirror
7 pump laser diode
8 heat sink
9 carrier plate
10 adjustment means
11 control circuit
12 photo detector

Claims

CLAIMS:
1. Detection device for detecting target substances in samples, said device comprising a substrate (1) with at least one planar waveguide laser (2) in or on said substrate (1), said waveguide laser (2) having a gain medium (5) for up-conversion or for down-conversion, wherein a top layer (3) of said waveguide laser (2) forms at least part of a surface of said substrate (1) and allows formation of an evanescent wave in a sample contacting said surface, and wherein a structure is applied on said top layer (3) to define an array of probe regions (4) on said top layer (3), said probe regions (4) consisting of a coating of probe materials for sensing said target substances to be detected.
2. Detection device according to claim 1, characterized in that said gain medium (5) is embedded in a material of a lower refractive index than the gain medium (5), wherein said top layer (3) is formed of said material and has a thickness in the probe regions (4) which is less than or equal to a laser wavelength of the waveguide laser (2).
3. Detection device according to claim 1 or 2, characterized in that said gain medium (5) is a rare earth doped material.
4. Detection device according to claim 1 or 2, characterized in that said waveguide laser (2) comprises two end mirrors (6) that are both highly reflective for the wavelength of said waveguide laser, thus forming a resonator, wherein one of said end mirrors (6) is at least partially transparent for radiation of a pump laser (7).
5. Detection device according to claim 4, characterized in that the end mirrors (6) are formed on side faces of said substrate (1).
6. Detection device according to claim 4 or 5, characterized in that the end mirrors (6) are formed of a dielectric coating.
7. Detection device according to claim 6, characterized in that at least two waveguide lasers (2) comprise end mirrors (6) of different dielectric coatings and/or comprise different gain media resulting in different laser wavelengths of the at least two waveguide lasers (2).
8. Detection device according to claim 1 or 2, characterized in that at least two waveguide lasers (2) are designed such that one of these at least two waveguide lasers (2) produces a laser wavelength different from a laser wavelength of the other of these at least two waveguide lasers (2) .
9. Detection device according to any one of claims 1 to 8, characterized in that several waveguide lasers (2) are arranged in parallel in or on said substrate (1).
10. Detection device according to any one of claims 1 to 9, characterized in that one or several pump lasers (7) are arranged on a carrier element (9), wherein fixation and/or positioning means (10) are arranged on said carrier element (9) for mounting said substrate (1) in a proper position and alignment on said carrier element (9).
11. Detection device according to claim 10, characterized in that said fixation and/or positioning means (10) allow an active alignment of said substrate (1) on said carrier element (9) by a feedback circuit (11, 12) which is connected to said fixation and/or positioning means (10).
12. Detection device according to claim 11, characterized in that said feedback circuit (11, 12) comprises a photodetector (12) for detecting laser light of said waveguide laser(s) (2) or fluorescent light of a sample applied to said substrate (1), and a control circuit (11) driving said fixation and/or positioning means (10) until a maximum intensity of said laser or fluorescent light is detected by said photodetector (12).
13. Detection device according to any one of claims 10 to 12, characterized in that said one or several pump lasers (7) are semiconductor lasers or a semiconductor laser bar.
14. Detection device according to any one of claims 1 to 13, characterized in that said top layer (3) is structured to enhance an amount of laser light of said waveguide laser(s) (2) coupling in said sample.
15. Detection device according to any one of claims 1 to 14, characterized in that different probe regions (4) or at least some of said different probe regions (4) are coated with different probe materials.
16. A diagnostic apparatus using the detection device according to any one of claims Itol5.
EP06765778A 2005-06-24 2006-06-19 Integrated waveguide laser for lab-on-a-chip diagnostics Withdrawn EP1896833A2 (en)

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