WO2006136998A2 - Integrated waveguide laser for lab-on-a-chip diagnostics - Google Patents
Integrated waveguide laser for lab-on-a-chip diagnostics Download PDFInfo
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- WO2006136998A2 WO2006136998A2 PCT/IB2006/051957 IB2006051957W WO2006136998A2 WO 2006136998 A2 WO2006136998 A2 WO 2006136998A2 IB 2006051957 W IB2006051957 W IB 2006051957W WO 2006136998 A2 WO2006136998 A2 WO 2006136998A2
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- 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"
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- G01N21/64—Fluorescence; Phosphorescence
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- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
- G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks
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- 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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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.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06765778A EP1896833A2 (en) | 2005-06-24 | 2006-06-19 | Integrated waveguide laser for lab-on-a-chip diagnostics |
JP2008517660A JP2008544278A (en) | 2005-06-24 | 2006-06-19 | Integrated waveguide laser for experimental chip diagnostics |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05105676.0 | 2005-06-24 | ||
EP05105676 | 2005-06-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2006136998A2 true WO2006136998A2 (en) | 2006-12-28 |
WO2006136998A3 WO2006136998A3 (en) | 2007-03-15 |
Family
ID=37065525
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2006/051957 WO2006136998A2 (en) | 2005-06-24 | 2006-06-19 | Integrated waveguide laser for lab-on-a-chip diagnostics |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1896833A2 (en) |
JP (1) | JP2008544278A (en) |
KR (1) | KR20080031750A (en) |
CN (1) | CN101203745A (en) |
WO (1) | WO2006136998A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT504669B1 (en) * | 2007-05-15 | 2008-07-15 | Arc Austrian Res Centers Gmbh | Sample support for use in recording unit during analyzing of hybridization reactions, has plano-convex cylinder lens provided for collimation and formation of laser band, which is irradiated through side surface in support |
WO2011042673A3 (en) * | 2009-10-08 | 2011-06-03 | Universite De Technologies De Troyes | Optical detection system having an active substrate and method for manufacturing such a system |
EP2782196A4 (en) * | 2011-11-16 | 2015-09-02 | Mitsubishi Electric Corp | Semiconductor laser-excitation solid-state laser |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5591407A (en) * | 1995-04-21 | 1997-01-07 | American Research Corporation Of Virginia | Laser diode sensor |
US5766956A (en) * | 1997-05-27 | 1998-06-16 | American Research Corporation | Diode laser-based chemical and biological sensor |
WO2002010719A2 (en) * | 2000-07-28 | 2002-02-07 | The Regents Of The University Of California | Integrated sensor |
US6493090B1 (en) * | 1998-01-23 | 2002-12-10 | Torsana A/S | Detection of a substance by refractive index change |
US20030030067A1 (en) * | 2001-06-06 | 2003-02-13 | Wei Chen | Upconversion luminescence materials and methods of making and using same |
WO2005022708A1 (en) * | 2003-08-29 | 2005-03-10 | Philips Intellectual Property & Standards Gmbh | Waveguide laser light source suitable for projection displays |
GB2408796A (en) * | 2003-12-01 | 2005-06-08 | Stephen Richard Elliott | Raman gain or loss effect optical sensor chip |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7444045B2 (en) * | 2003-10-14 | 2008-10-28 | 3M Innovative Properties Company | Hybrid sphere-waveguide resonators |
-
2006
- 2006-06-19 KR KR1020087001743A patent/KR20080031750A/en not_active Application Discontinuation
- 2006-06-19 EP EP06765778A patent/EP1896833A2/en not_active Withdrawn
- 2006-06-19 JP JP2008517660A patent/JP2008544278A/en not_active Withdrawn
- 2006-06-19 CN CNA2006800226020A patent/CN101203745A/en active Pending
- 2006-06-19 WO PCT/IB2006/051957 patent/WO2006136998A2/en active Application Filing
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5591407A (en) * | 1995-04-21 | 1997-01-07 | American Research Corporation Of Virginia | Laser diode sensor |
US5766956A (en) * | 1997-05-27 | 1998-06-16 | American Research Corporation | Diode laser-based chemical and biological sensor |
US6493090B1 (en) * | 1998-01-23 | 2002-12-10 | Torsana A/S | Detection of a substance by refractive index change |
WO2002010719A2 (en) * | 2000-07-28 | 2002-02-07 | The Regents Of The University Of California | Integrated sensor |
US20030030067A1 (en) * | 2001-06-06 | 2003-02-13 | Wei Chen | Upconversion luminescence materials and methods of making and using same |
WO2005022708A1 (en) * | 2003-08-29 | 2005-03-10 | Philips Intellectual Property & Standards Gmbh | Waveguide laser light source suitable for projection displays |
GB2408796A (en) * | 2003-12-01 | 2005-06-08 | Stephen Richard Elliott | Raman gain or loss effect optical sensor chip |
Non-Patent Citations (1)
Title |
---|
See also references of EP1896833A2 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT504669B1 (en) * | 2007-05-15 | 2008-07-15 | Arc Austrian Res Centers Gmbh | Sample support for use in recording unit during analyzing of hybridization reactions, has plano-convex cylinder lens provided for collimation and formation of laser band, which is irradiated through side surface in support |
WO2011042673A3 (en) * | 2009-10-08 | 2011-06-03 | Universite De Technologies De Troyes | Optical detection system having an active substrate and method for manufacturing such a system |
EP2782196A4 (en) * | 2011-11-16 | 2015-09-02 | Mitsubishi Electric Corp | Semiconductor laser-excitation solid-state laser |
Also Published As
Publication number | Publication date |
---|---|
CN101203745A (en) | 2008-06-18 |
WO2006136998A3 (en) | 2007-03-15 |
KR20080031750A (en) | 2008-04-10 |
EP1896833A2 (en) | 2008-03-12 |
JP2008544278A (en) | 2008-12-04 |
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