WO2019106056A1 - Appareil compact et procédé pour poser des diagnostics dans le cadre d'examens pratiqués en dehors des lieux de service, par diffusion raman exaltée de surface (sers) - Google Patents

Appareil compact et procédé pour poser des diagnostics dans le cadre d'examens pratiqués en dehors des lieux de service, par diffusion raman exaltée de surface (sers) Download PDF

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Publication number
WO2019106056A1
WO2019106056A1 PCT/EP2018/082911 EP2018082911W WO2019106056A1 WO 2019106056 A1 WO2019106056 A1 WO 2019106056A1 EP 2018082911 W EP2018082911 W EP 2018082911W WO 2019106056 A1 WO2019106056 A1 WO 2019106056A1
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Prior art keywords
sample
light
raman
scattered light
band
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PCT/EP2018/082911
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German (de)
English (en)
Inventor
Bernd WALKENFORT
Sebastian Schlücker
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Universität Duisburg-Essen
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Publication of WO2019106056A1 publication Critical patent/WO2019106056A1/fr

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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
    • G01N21/65—Raman scattering
    • G01N21/658—Raman scattering enhancement Raman, e.g. surface plasmons
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G01J3/0205—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows
    • G01J3/0208—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows using focussing or collimating elements, e.g. lenses or mirrors; performing aberration correction
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G01J3/0205—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows
    • G01J3/021—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows using plane or convex mirrors, parallel phase plates, or particular reflectors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G01J3/0205—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows
    • G01J3/0218—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows using optical fibers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G01J3/0205—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows
    • G01J3/024—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows using means for illuminating a slit efficiently (e.g. entrance slit of a spectrometer or entrance face of fiber)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G01J3/0256—Compact construction
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G01J3/0291—Housings; Spectrometer accessories; Spatial arrangement of elements, e.g. folded path arrangements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G01J3/0297—Constructional arrangements for removing other types of optical noise or for performing calibration
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/28—Investigating the spectrum
    • G01J3/44—Raman spectrometry; Scattering spectrometry ; Fluorescence spectrometry
    • 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
    • G01N21/84—Systems specially adapted for particular applications
    • G01N21/8483—Investigating reagent band
    • 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
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/4738—Diffuse reflection, e.g. also for testing fluids, fibrous materials
    • G01N21/474—Details of optical heads therefor, e.g. using optical fibres
    • G01N2021/4742—Details of optical heads therefor, e.g. using optical fibres comprising optical fibres
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/02—Mechanical
    • G01N2201/022—Casings
    • G01N2201/0221—Portable; cableless; compact; hand-held

Definitions

  • the present invention relates to a readout device and a method for quantitative pati gene near diagnostic, for example in the context of so-called POC (Point Of Care Test) by means of surfaces enhanced Raman scattering (SERS, surface-enhanced Raman scattering) of Raman reporters molecularly functionalized SERS labeling particles (SERS labels / nanotags), preferably noble metal nanoparticles.
  • SERS surface enhanced Raman scattering
  • SERS labels / nanotags molecularly functionalized SERS labeling particles
  • a device for diagnostics in particular for quantitative diagnosis, of a sample comprising at least one kind / type of SERS-active particles, each with a specific Raman band, by means of surface-enhanced Raman scattering, the device being a light source for substantially monochromatic light, an optical probe for illuminating the sample to be examined with light from the light source and for collecting light scattered from the sample, and a photodetector for detecting the light collected by the probe and scattered by the sample.
  • It also relates to a method for diagnostics, in particular for quantitative diagnostics, of a sample comprising at least one species / type of SERS-active particles, each with a specific Raman band, by means of surface-enhanced Raman scattering, wherein substantially monochromatic light is transformed into an optical one Probe is irradiated, which illuminates the sample to be examined with light from the light source and collects the light scattered by the sample, wherein scattered light from the sample is passed to a photodetector for detecting the light collected by the probe and scattered by the sample.
  • test strips also referred to as LEA (lateral flow assay)
  • LEA lateral flow assay
  • Raman spectroscopy samples can be analyzed by studying the inelastic scattering of light on molecules of a sample (Raman scattering).
  • the state of the art is inter alia the so-called Raman microscopy, in optical microscopy, For example, using a light microscope, combined with Raman spectroscopy, for example, using a Raman spectrometer.
  • Raman microscopy a sample to be examined is irradiated with monochromatic light, for example in the form of a laser beam.
  • a laser can be focused with a microscope on the sample to be analyzed.
  • SERS nanoparticles each have certain specific spectral signatures, that is, Raman bands or Raman spectra due to inelastic scattering, which are known.
  • spectral signatures that is, Raman bands or Raman spectra due to inelastic scattering, which are known.
  • reader For reading and analyzing a suitable reader (reader) is used.
  • a device and a method for surface-enhanced Raman spectroscopy are known, for example, from US Pat. No. 7,688,440.
  • SERS surface-enhanced Raman spectroscopy
  • an excitation and a collection of Raman scattered light with a fiber-optic probe.
  • a spectrally resolving detection of the Raman scattered light is carried out by means of a grating spectrometer (also referred to as a CCD system).
  • the probe is placed appropriately over the sample to be examined.
  • the size of the examined section depends on the focus of the lens used and a spatially resolved detection is possible only by screening the entire area of the sample to be examined with a positionable microscope stage and a plurality of individual examinations. Due to the use of the grating spectrometer, the entire frequency range of the scattered light of the sample is examined.
  • the disadvantage here is that the use of a lattice Raman spectrometer with multi-channel detection (CCD) is more expensive and expensive.
  • the object of the invention is based on the object to reduce or avoid the disadvantages mentioned, in particular to provide a device and a method in which samples in particular with LFA test strips quantitatively and also more sensitive, faster and cost-effective than can be studied and analyzed in the prior art.
  • This object is solved by the subject matters of the independent claims. Before ferred developments of the invention are described in the subclaims.
  • a device for diagnostics, in particular for quantitative diagnosis, of a sample which comprises at least one type of SERS-active particle, each with a specific Raman band, by means of surface-enhanced Raman scattering (SESR), the device being a light source for substantially monochromatic light, an optical probe for illuminating the sample to be examined with light from the light source and for collecting scattered light from the sample and a reference photodetector and a Raman photodetector for detecting the collected by the probe and the Sample scattered light has, wherein in the beam path of the light scattered by the sample, an optical Lilterelement for separating elastic scattered light of inelastic scattered light of the speci fied Raman band is arranged, wherein passed from the optical Lilterelement the unelasti cal scattered light and blocked the elastic scattered light is, and in the beam path hinte the Lilterelement for separating elastic scattered light from inelastic scattering light, another Lilter- and reflection element for separating a sample
  • SESR surface-enh
  • the above-mentioned optical filter element for separating stray elastic light from inelastic stray light of the specific Raman band is also referred to as Rayleigh filter element for the sake of simplicity and preferably has a high optical density in the wavelength range of the used monochromatic light.
  • the light source for monochromatic light is preferably a laser.
  • Under a sample according to the invention is to be analyzed material. This is preferably applied to a substrate or sample holder, for example an LLA test strip.
  • the term of the scattered light scattered by the sample therefore also includes such scattered light, the not directly from the material to be analyzed, but from the substrate / sample carrier was scattered.
  • the analysis and evaluation of the light emitted by the sample can be limited in a particularly advantageous manner to the proportion of inelastic scattered light. Since the elastic cal fraction of the scattered light is separated from the inelastic portion, the units used for the evaluation of the device can be designed simpler than in the prior art. In particular, no use of a lattice Raman spectrometer with expensive and time-consuming multi-channel detection (CCD) is required.
  • CCD multi-channel detection
  • the use of the Rayleigh filter element makes it possible, in particular, to evaluate the inelastic scattered light originating from the sample by means of inexpensive single-channel detectors.
  • the evaluation can be carried out limited to the known specific Raman bands of the SERS nanoparticles used and present in the sample, ie to inelastic scattered radiation.
  • the evaluation of the light scattered by the sample is facilitated, since not as in the initially described prior art, the entire frequency spectrum of the sample stam menden scattered light is evaluated.
  • the Rayleigh filter element for separating elastic and inelastic scattered light is designed to filter out stray elastic light and to transmit inelastic scattering light of the specific Raman band. It is preferably designed as a long-pass filter element such that the Rayleigh scattering, that is, elastically scattered light, is blocked. Preferably, it is in the beam path of the light emitted by the sample between the Probe and the photodetector arranged. Alternatively, it may be net before or in the probe.
  • the filter element for separating elastic scattered light of inelastic scattered light another filter and reflection element for Tren nen a specific reference to a substrate of the sample reference band of the specific Raman band of SERS active particles arranged.
  • This filter and reflection element is designed and arranged in such a way that the reference band is reflected and directed onto the reference photodetector and the Raman band is passed through and directed onto the Raman photodetector.
  • the filter and reflection element thus acts practically as a bandpass for the reference band, while the filter and reflection element in Transmis sion acts as a notch filter for the other frequencies.
  • several filter and reflection elements of the type described above are arranged in the beam path of the scattered light of the sample behind the filter element for separating elastic scattered light from inelastic scattered light of the specific Raman band and in front of the photodetector.
  • At least the first filter and reflection element in the beam path, several or all filter and reflection elements is or are designed and arranged for separating a reference band specific for a substrate of the sample from a Raman specific for one type of SERS-active particle - gang.
  • antibodies matching a first type of target molecule are associated with a signature Fl-type SERS nanoparticle and antibodies suitable for a second type of target molecule a signature F2 SERS nanoparticle.
  • the two filter and reflection elements required for simultaneous detection are such that the one on the Raman band of the signature Fl and the other on the Raman band of the signature F2 is true ask. Since the respective Raman bands Fl and F2 are known, it can be concluded from a detection of signals in the corresponding Raman bands on the presence of corresponding target molecules. Under a target molecule is in the context of the invention, in principle, a target atom to understand.
  • the device has at least one reference photodetector, to which the reference band specific for the substrate of the sample is directed in order to provide a reference signal for evaluating the detected inelastic scattered light.
  • the signal of this reference photodetector can be used, for example, by means of evaluation electronics for correction of other signals, in particular for correction of the detected Raman bands, in order to obtain e.g. Fluctuations in fiber performance, fluorescence of the substrate or deviations of the focusing of the fiber beam on the sample compensate.
  • the device comprises a positioning device for in particular automatic one-, two- or multi-dimensional positioning of the sample relative to the optical probe, in particular orthogonal to its beam axis.
  • the positioning device can receive and hold a sample carrier or a substrate in such a positionable manner. The sample can thus be moved relative to the probe so that it is particularly easy to perform a surface or area scan of sections of the sample or the sample carrier or even the entire surface.
  • the Po sitionier coupled is coupled to a control and evaluation of the device, so that an automatic vote of sample position and detected Raman bands made and can be taken into account in the evaluation.
  • the optical probe according to the invention may comprise a filter element which is angeord net and formed so that the sample with a divergent beam which strikes with an oblique angle of incidence (not equal to 0 ° and 90 °) to the sample is illuminated.
  • the optical probe can have a collection array for scattered light emitted by the sample, which is aligned and arranged in a coordinated manner to the angle of incidence. Collection array and Filterele element are preferably positioned and aligned so that there is a maximum overlap between lighting and detection area.
  • the former filter element may in particular be a bandpass filter.
  • a further embodiment of the invention is characterized in that the device has a linear fiber bundle for coupling light from the light source into the optical probe.
  • the optical probe may have a linear fiber bundle for coupling stray light from the sample into the probe.
  • the optical probe may comprise an optical element, in particular a lens, which produces an image of the fiber bundle at infinity. This image illuminates the sample.
  • the optical probe may have a dichroic ele ment passed over the sample passed to the light as well as scattered light from the sample.
  • the optical probe may comprise an optical system or element, for example a cylindrical lens, for producing a substantially line-shaped illumination region on the sample.
  • the abovementioned object is also achieved by a method for diagnostics, in particular for quantitative diagnostics, of a sample comprising at least one type of SERS-active particle, each with a specific Raman band, by means of surface-enhanced Raman scattering (SESR).
  • SESR surface-enhanced Raman scattering
  • the complete sample surface to be examined is tailor-made and the un elastic scattered radiation emitted thereby can be evaluated in a particularly simple and effective manner.
  • the sample-derived Raman scattered light can be analyzed by a series of selectively selected long-pass filters or bandpass filters tuned to the known Raman signatures of the SERS gold nanoparticles used in the sample and conveniently imaged on inexpensive single-channel detectors.
  • the inven tion thus provides a possibility for rapid quantitative and highly sensitive pa tientennahe diagnostics using surface-enhanced Raman scattering and can be particularly advantageous in a so-called POCT (point of care testing) can be used.
  • An advantage of section-wise planar or even complete illumination of the sample to be analyzed is that measurements, in particular spatially resolved measurements, can be carried out particularly quickly and sensitively.
  • the inventive use of long-pass filters / Bandpassfiltem and Einkanaldetek factors favors a lower cost compared to the prior art measurement.
  • the invention is particularly suitable for use by hospitals, medical practices, laboratory physicians, veterinarians and pharmaceutical companies. In laboratory medicine, using SERS technology, for example, a fast measuring procedure can be applied directly on-site to the patient or animal, which even allows for absolute quantification through the use of internal standards.
  • the invention is also particularly suitable for use by public authorities of internal and external security (Bundeswehr, police, etc.), for example, for a safety-relevant hazardous substance analysis for the identification of chemical and biological weapons. Another aspect of the invention may be closing investigations in water and food analysis.
  • Fig. 1 is a schematic representation of a device according to the invention in a first
  • FIG. 2 shows a position-voltage diagram for the sample shown in FIG. 1,
  • FIG. 3 shows a frequency-intensity diagram as an example of a Raman spectrum acquired in relation to the sample shown in FIG. 1,
  • Fig. 4 is a schematic representation of a device according to the invention in a second
  • FIG. 5 shows a position-voltage diagram for the sample shown in FIG. 4,
  • FIG. 6 shows a frequency-intensity diagram as an example of three Raman spectra recorded for the sample shown in FIG. 3, FIG.
  • Fig. 7 is a schematic representation of a device according to the invention in a third
  • FIG. 8 a position-voltage diagram for the sample shown in FIG. 7, FIG.
  • FIG. 9 is a frequency-intensity diagram as an example of that shown in FIG.
  • FIG. 10 shows a schematic representation of a first embodiment of an optical probe for a device according to the invention
  • Fig. 11 is a schematic representation of a second embodiment of an optical system
  • Fig. 12 is a schematic representation of a third embodiment of an optical
  • Fig. 13 is a further schematic representation of an apparatus according to the invention.
  • FIG. 1 shows a schematic representation of a device 1 according to the invention for the quantitative diagnosis of a sample 2 with a single sort of SERS nanoparticles in several Measuring lines I, II, III and IV.
  • the sample 2 is applied to a known LFA test strip 13 as a sample substrate (lateral flow essay), whose operation is well known and therefore will not be described here.
  • the test strip 13 has four test lines I, II, III and IV, at which each - if any - target proteins to be detected on SERS nanogold particles labeled antibodies accumulate.
  • the immobilization of Desingeranti body on the LFA membrane (often nitrocellulose) is carried out with established methods.
  • the corresponding SERS nanoparticle detection antibody conjugates occur.
  • the test strip 13 is mounted on a positioning device (not shown in detail in the figures) 14, which permits linear positioning in the direction of the arrow 15 shown in FIG. 1 (and subsequently back again) during a measurement of the sample.
  • the sample 2 to be measured is placed with the test strip 13 in the plane of the focus of the measuring probe 4 and moved in the direction 15 perpendicular to the axis of the focus.
  • the signal of a Raman photodetector 5 or of a reference photodetector 11 is detected and processed by evaluation electronics 12.
  • Figure 13 shows an embodiment in which the positioning device 14 is shown in more detail. It comprises a stepping motor 33, a linear guide 34 and a sample holder 35, which holds a sample applied to a test strip 13 as a substrate.
  • stepping motor 33 By means of the stepping motor 33 and the linear guide 34 is the sample holder together with the therein received
  • Probe 2 in the direction of arrow 15 relative to the probe 4 positionable.
  • a reference photodetector 11 and a total of four Raman photodetectors 5a, 5b, 5c, 5d, four filter and reflection elements 9a, 9b, 9c, 9d, which as described above act as a dielectric bandpass or notch filter, and a deflection mirror 36 is used.
  • the device 1 has a light source 3, which he essentially testifies monochromatic light, in the present case, a laser 3. It further comprises an optical probe 4 to the sample to be examined 2 on the substrate 13 with light of the laser 3 light and to collect stray light from the sample 2 and the substrate 13.
  • the device 1 has a photodetector 5 for detecting inelastic scattered light from the sample 2, that is, from an emitted Raman band of the scattered light.
  • a laser beam generated in the laser 3 is conducted to the probe 4 via a first optical waveguide 6.
  • Light collected by the probe 4 is coupled into a second optical waveguide 7.
  • the light emitted from the second optical waveguide 7 at the end opposite the probe 4 is collimated by an optical system and directed to a filter element 8 in the form of a longpass filter 8.
  • the long-pass filter 8 has a high optical density in the range of the laser wavelength and is designed and arranged such that the largest possible proportion of elastic scattered light, preferably substantially the entire proportion of the elas tical scattered light is blocked. It can therefore be said that the long-pass filter 8 separates elastic scattered light from inelastic scattered light.
  • the long-pass filter 8 passes inelastic scattered light and reflects and blocks elas table stray light. In the beam path after the long-pass filter 8 is therefore only unelasti cal scattered light before.
  • the long-pass filter 8 is also referred to as Rayleigh filter element 8 in the context of the invention.
  • a Lilter- and reflection elements 9 is arranged after the long-pass filter 8. This reflects from the inelastic scattered light guided through the Rayleigh filter element 8 the respective Raman signals onto the associated detector elements 5
  • the spectral components around a substrate-specific reference band 10 are transmitted through the reflection elements 9 and then pass directly or via the mirror 36 to the reference detector 11.
  • the signal of the reference photodetector 11 is represented by an evaluation electronics 12 of the device, shown schematically in FIGS 1 used for a correction of the other signals, for example, to compensate for fluctuations in the power of the laser 3, a fluorescence of the substrate or deviations of the focusing of the laser beam on the sample.
  • the evaluation and control unit 12 amplifies and processes signals originating from the photodetectors 5 and 11 (shown in FIG. 2 in a position-voltage diagram). For putting in, it is control technology connected to the positioning device 14 for the test strip 13. The interaction with a user via the evaluation and Steuerein unit 12.
  • FIG. 3 shows the Raman spectrum recorded with the device 1 of FIG. 1 for the test strip 13 shown there. Shown is the intensity peak of the reference band 10 and the SERS signature 16 of the nanoparticle type used in the sample 2 on the lines I, II, III and IV.
  • FIG. 4 shows a schematic representation of a device 1 according to the invention for quantitatively diagnosing a sample 2 with three different types of SERS nanoparticles on a plurality of measurement lines I, II, III and IV.
  • Each of the measuring lines I, II and III each have a different type of SERS nanoparticles, for example on the measuring line I SERSl nanoparticles, on the measuring line II SERS2 nanoparticles and on the measuring line III SERS3 nanoparticles.
  • On line IV are all three different SERS nanoparticles.
  • the device 1 corresponds wesentli chen the embodiment shown in Figure 1, so that in the following only the differences are listed.
  • the filter and reflection elements 9a, 9b, 9c are now each true ist on the specific Raman band of one of the three SERS nanoparticles used.
  • the filter and reflection element 9a is matched, for example, to SERSl nanoparticles, the filter and reflection element 9b to SERS2 nanoparticles and the filter and reflection element 9a to SERS3 nanoparticles.
  • the filter and reflection element 9a is associated with a detector 5a, the filter and reflection element 9b, a detector 5b, and the filter and reflection element 9c with a detector 5c.
  • FIG. 5 shows a position-voltage diagram for the sample shown in FIG. Since the signal of the detector 5a by means of the graph 17, the signal of the detector 5b by means of the graph 18 and the signal of the detector 5c by means of the graph 19 is shown.
  • FIG. 6 shows the Raman spectrum recorded with the device 1 of FIG. 4 for the test strip 13 shown there. Shown are the intensity peaks of the reference band 10 as well as the SERS 1 signature 20, the SERS2 signature 21 and the SERS3 signature 22 of the three different nanoparticle types used in the sample 2 on the fi les I, II, III and IV.
  • FIG. 7 shows a schematic representation of a device 1 according to the invention for the quantitative diagnosis of a sample 2 with three different types of SERS nanoparticles on a single measurement line I.
  • each is here Measurement line I and IV three different types of SERS nanoparticles, namely on the measurement line I as well as on the measurement line IV SERSl nanoparticles, SERS2 nanoparticles and SERS3 nanoparticles.
  • FIG. 8 shows a position-voltage diagram for the sample shown in FIG. Since the signal of the detector 5a by means of the graph 17, the signal of the detector 5b by means of the graph 18 and the signal of the detector 5c by means of the graph 19 is shown.
  • FIG. 1 shows a schematic representation of a device 1 according to the invention for the quantitative diagnosis of a sample 2 with three different types of SERS nanoparticles on a single measurement line I.
  • each is here Measurement line I and IV three different types of SERS nanoparticles, namely on the measurement line I as well as on the measurement line IV
  • FIGS. 10, 11 and 12 show Embodiments of the probe 4.
  • Figure 10 shows an embodiment of the probe 4, in which the laser is coupled into a linear fiber bundle 6, at the end of which a bandpass filter 23 is located, which passes only a narrow spectral range around the laser line.
  • the fiber bundle 6 and the notch filter 23 are arranged and aligned such that the outgoing beam is divergent and hits the sample at an oblique angle of incidence.
  • the light scattered on the sample 2 as well as on the substrate 13 is collected via a linear array 24 which is attached to the sample surface so that there is a maximum overlap between illumination and detection range.
  • a long-pass filter 25 is mounted, which blocks elastically scattered light. This represents an alternative embodiment to the fact that such a filter is provided as a Rayleigh filter element 8 after the probe, as shown for example in Fig. 1.
  • FIG. 11 shows a further embodiment of the probe 4.
  • the laser is coupled into a linear fiber bundle 6, at the end of which there is a notch filter 23.
  • a lens 26 Through a lens 26, an image of the fiber bundle 6 is generated at infinity.
  • a mirror 27 and a dichroic 28 which only reflects light of the laser wavelength, an image of the light emerging from the fiber bundle is generated via an objective lens 29.
  • the scattered light is collected by the objective lens 29 or detil detil the infinite.
  • the elastic scattering components are filtered out by a longpass filter 30.
  • the image of the fiber input bundle is mapped congruent to the Faserausgangsbün del 7
  • FIG. 12 shows a further embodiment of the probe 4.
  • a linear fiber bundle is not used here for illumination, but instead a cylindrical lens 32 or a more complex optical system for producing a linear illumination. and detection range on the sample 2.
  • the coupling is done by simple optical waveguides 6, 7.

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  • Spectroscopy & Molecular Physics (AREA)
  • General Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
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  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

L'invention concerne un appareil (1) permettant de poser un diagnostic, en particulier un diagnostic quantitatif, d'un échantillon (2), lequel comprend au moins un type de particules à activité SERS présentant respectivement une bande Raman (16, 20, 21, 22) spécifique, par diffusion Raman exaltée de surface, ledit appareil (1) présentant une source lumineuse (3) pour une lumière sensiblement monochromatique, une sonde optique (4) destinée à éclairer l'échantillon (2) à examiner avec de la lumière de la source lumineuse (3) et à collecter la lumière diffusée émanant de l'échantillon (2) et un photodétecteur Raman (5, 5a, 5b, 5c, 5d) ainsi qu'un photodétecteur de référence (11) pour détecter la lumière collectée par la sonde (4) et diffusée par l'échantillon (2), un élément filtrant (8) optique étant monté dans le chemin optique de la lumière diffusée par l'échantillon (2), et étant destiné à séparer la lumière diffusée élastique de la lumière diffusée non élastique de la bande Raman (16, 20, 21, 22) spécifique, la lumière diffusée non élastique étant traversée par l'élément filtrant (8) optique et la lumière élastique étant bloquée par ledit élément filtrant optique, et un autre élément filtrant et réflecteur (9, 9a, 9b, 9c, 9d, 9 e) destiné à séparer une bande de référence (10) spécifique d'un substrat de l'échantillon de la bande Raman spécifique (16, 20, 21, 22) des particules à activité SERS est monté dans le chemin optique derrière l'élément filtrant (8) destiné à séparer la lumière diffusée élastique de la lumière diffusée non élastique, la bande de référence étant réfléchie et guidée sur le photodétecteur Raman (5, 5a, 5b, 5c, 5d) et la bande de référence étant transmise et guidée sur le photodétecteur de référence (1). L'invention concerne également un procédé correspondant.
PCT/EP2018/082911 2017-11-30 2018-11-28 Appareil compact et procédé pour poser des diagnostics dans le cadre d'examens pratiqués en dehors des lieux de service, par diffusion raman exaltée de surface (sers) WO2019106056A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102017128443.5A DE102017128443A1 (de) 2017-11-30 2017-11-30 Kompaktes Gerät und Verfahren für POCT-Diagnostik mittels SERS
DE102017128443.5 2017-11-30

Publications (1)

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WO2019106056A1 true WO2019106056A1 (fr) 2019-06-06

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PCT/EP2018/082911 WO2019106056A1 (fr) 2017-11-30 2018-11-28 Appareil compact et procédé pour poser des diagnostics dans le cadre d'examens pratiqués en dehors des lieux de service, par diffusion raman exaltée de surface (sers)

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DE (1) DE102017128443A1 (fr)
WO (1) WO2019106056A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009093050A1 (fr) * 2008-01-25 2009-07-30 Renishaw Plc Appareil de spectroscopie raman à balayage linéaire
US7688440B2 (en) 2005-01-27 2010-03-30 Prescient Medical, Inc. Raman spectroscopic test strip systems
US20130182247A1 (en) * 2006-10-24 2013-07-18 Pd-Ld, Inc. Compact, Low Cost Raman Monitor For Single Substances
US9599507B2 (en) * 2013-02-05 2017-03-21 Rafal Pawluczyk Fiber optic probe for remote spectroscopy

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7688440B2 (en) 2005-01-27 2010-03-30 Prescient Medical, Inc. Raman spectroscopic test strip systems
US20130182247A1 (en) * 2006-10-24 2013-07-18 Pd-Ld, Inc. Compact, Low Cost Raman Monitor For Single Substances
WO2009093050A1 (fr) * 2008-01-25 2009-07-30 Renishaw Plc Appareil de spectroscopie raman à balayage linéaire
US9599507B2 (en) * 2013-02-05 2017-03-21 Rafal Pawluczyk Fiber optic probe for remote spectroscopy

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