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WO1999041594A1 - Determination de la resonance de plasmons superficiels a l'aide de couches a modifications locales et temporelles - Google Patents

Determination de la resonance de plasmons superficiels a l'aide de couches a modifications locales et temporelles Download PDF

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Publication number
WO1999041594A1
WO1999041594A1 PCT/EP1999/000895 EP9900895W WO9941594A1 WO 1999041594 A1 WO1999041594 A1 WO 1999041594A1 EP 9900895 W EP9900895 W EP 9900895W WO 9941594 A1 WO9941594 A1 WO 9941594A1
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WO
WIPO (PCT)
Prior art keywords
transducer
layer
optical sensor
light
surface plasmon
Prior art date
Application number
PCT/EP1999/000895
Other languages
German (de)
English (en)
Inventor
Gunnar Brink
Henning Groll
Original Assignee
Biotul Ag
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
Priority claimed from DE19805809A external-priority patent/DE19805809C2/de
Application filed by Biotul Ag filed Critical Biotul Ag
Priority to AU26232/99A priority Critical patent/AU2623299A/en
Priority to EP99906225A priority patent/EP1161676A1/fr
Publication of WO1999041594A1 publication Critical patent/WO1999041594A1/fr

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Classifications

    • 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
    • G01N21/553—Attenuated total reflection and using surface plasmons

Definitions

  • the invention relates to a device and a method for measuring surface plasmons.
  • SPR Surface plasmon resonance
  • the position of the SPR in the spectrum does not depend solely on the properties of the plasmon-bearing layer of the free electron metal.
  • the position of the SPR and also its shape depend on the optical properties of the medium adjacent to the surface. This property is used for the use of the SPR in sensors. Particularly in biosensors, the adjacent medium is designed so that its optical properties (thickness and refractive index) are modified by specific adsorption of analyte molecules. This is typically done by firmly binding special ligand molecules in a thin layer that prevents unspecific adsorption. These ligands are specific binding partners for the molecules to be analyzed. For example, such a typical pair is an antibody (ligand) and the corresponding antigen (analyte).
  • the sensors described in the prior art and the underlying methods are based on observing the displacement of the SPR either in the spectrum of the incident light or in the excitation angle.
  • the use of a method that is based on the spectral measurement of the SPR has the advantage that the location space is available for obtaining additional information. If the wavelength-resolved measurement is linked to a spatially resolved measurement, the information density can be increased significantly. The difference corresponds to that between a black and white screen and a color screen.
  • Both the angular and the wavelength-resolved measurement of SPR use the controlled change (tuning) of an external variable across the width of the resonance or the irradiation of light with the width of the resonance - spectrally, approx. 100 nm or more, angularly resolved , a few degrees - to measure changes in SPR.
  • These methods have the disadvantage that they either cannot provide an optimal time resolution, an optimal energy density or neither of the two.
  • the invention has for its object to provide a device and a method for measuring surface plasmons, which enables better time resolution and / or energy density.
  • Measuring the SPR with a spectrally narrow-band, parallel, constant light beam of high intensity is ideal in terms of time resolution and sensitivity. This means that both the temporal and the resolution when measuring intensities and thus the sensitivity can be optimized.
  • the invention is based on the basic idea that the material properties of those areas which adjoin the surface of the SPR sensor (transducer) carrying the SPR, 4
  • These layers can be the free electron metal (metal layer) or a first layer on the light coupling side or a second (dielectric) layer on the sample side.
  • the first and second layers can directly adjoin the metal layer.
  • the first or second layer can be separated from the metal layer by a first or second intermediate layer or a plurality of intermediate layers.
  • the second layer can also directly adjoin the sample volume.
  • the form and location of the SPR are primarily influenced either spatially or temporally.
  • the invention enables the above-mentioned determination of the SPR both with an optimal temporal (only with spatially resolved determination) and with an optimal intensity resolution. It also has the advantage that the other spatial axes can optionally be used to obtain further information. This is made clear in the exemplary embodiments.
  • the invention also allows the combination of spatially or temporally resolved measurements and narrow-band spectral modulation of the light source to suppress external disturbance variables and to achieve an optimal signal-to-noise ratio.
  • Various methods are available for spatial modification of the transducer surface - more precisely: of complex refractive index n, thickness d or the product n * d.
  • the thin layer of the free electron metal can be produced or modified in a correspondingly structured manner, or one or more layers which directly or indirectly adjoin the metal layer.
  • Techniques available for modification are based on the spatially resolved application of material, such as spatially resolved sputtering of material on surfaces, or by printing, by directional diffusion of foreign materials, by spatially resolved ion implantation, by spatially resolved photo-induced binding or also by deliberately removing material from the surface, for example by sputtering or lithographic techniques, plasma etching etc.
  • a further possibility for the spatial modification according to the invention is the generation of a standing wave - for example as a density modification in an acoustic way - in the area of the transducer which adjoins the SPR-bearing surface.
  • a material at the interface whose refractive index can be modified in a spatially or time-resolved manner by irradiation with a further light field.
  • a material is, for example, a dye.
  • time-resolved modification is understood here to mean the change in the properties of one or more layers in an SPR transducer, which are suitable for changing the shape and position of the SPR, in such a way that these changes are reversible and by changing a time external size come about.
  • one or more of the layers described or the entire transducer can be compressed or expanded, or the temperature of corresponding areas can be changed or a light field as described above can be irradiated.
  • Figure la a schematic structure of a device for
  • Figure lb a schematic structure of an SPR sensor with a configuration according to Kretschmann for excitation of SPR
  • Figure lc a schematic diagram of a section of a
  • FIG. 1d shows a diagram of the strength of the electric field E in the border area free electron metal 5 / sample 6
  • Figure le a schematic representation of a layer structure of the transducer area acting on the shape and position of the SPR
  • FIG. 2a a schematic representation of a variation of the layer thickness d of the free electron metal 5 in an SPR sensor according to a first embodiment of the invention
  • FIG. 2b a schematic representation of a variation in the layer thickness of an additional dielectric layer 7 between free electron metal 5 and sample 6;
  • FIG. 3 shows a basic illustration of a variation of the refractive index n of the free electron metal 5 or of a layer 7, 8;
  • FIG. 4 shows a basic illustration of a cyclic variation of the optical properties of the free electron metal 5 or a layer 7, 8;
  • FIG. 5a a top view of a circular transducer 2 according to a further embodiment of the invention;
  • FIG. 5b a schematic arrangement of different sample channels 10 along the radius r of the circular transducer according to FIG. 5a;
  • FIG. 5c a basic representation of an SPR signal as a function of the angle of rotation in a transducer according to FIG. 5a;
  • FIG. 6a a perspective view of a sensor based on the rotationally resolved measurement of an SPR signal according to an alternative embodiment of the invention;
  • Figure 6b a schematic structure of a device for
  • FIG. 7a shows a perspective view of a sensor with a linear arrangement for determining analyte concentrations with the aid of spatially resolved measurement of an SPR signal
  • FIG. 7b shows a basic illustration of an SPR signal as a function of the location in a transducer according to FIG. 7a.
  • FIG. 1 A parallel light beam of constant wavelength is emitted from a light source 1, preferably a laser, e.g. a diode laser, irradiated onto an SPR transducer 2.
  • the light emitted by the transducer is detected by a detector 3 and then evaluated by an evaluation unit (not shown).
  • the transducer 2 is used, for example, as shown in FIG. 1b in a Kretschmann configuration.
  • the transducer consists of a free electron metal layer 5 on the light-coupling side of which a glass prism 4 is arranged.
  • a sample 6 is arranged on the sample side of the metal layer 5.
  • the light beam is emitted from one side of the glass prism 8th
  • FIG. 1c which shows a section of FIG. 1b, there is a total reflection of the light on the metal layer 5.
  • An evanescent field is formed in the metal layer 5 and the adjacent sample, which excites surface plasmons on the opposite side of the metal layer.
  • the corresponding field course of the surface plasmons is shown in FIG. 1d.
  • SPR Surface plasmon resonance
  • the transducer 2 can consist of several layers arranged one above the other.
  • a first dielectric layer 7 is arranged on the light-coupling side, and adjoins the metal layer 5 directly or as shown via one or more first intermediate layers 7a.
  • a second layer 8 is arranged directly adjacent to the sample side or separated by one or more second intermediate layers 8a.
  • the structure or the surface of the transducer according to the invention is such that the thickness of at least one of the layers varies along at least one of its axes.
  • the remaining layers are equally thick.
  • the refractive index varies in at least one of the layers mentioned.
  • Figure 2a shows a preferred embodiment of a transducer according to the present invention.
  • the thickness of the layer of free electron metal 5 varies in the y direction. In the example, the thickness increases linearly from 40 to 50 nm from the left (from the first side of the prism) to the right (to the second side of the prism). Gold or silver, for example, is used as the free electron metal.
  • the thickness of a thin glass layer 8 located on the sample side of a gold layer 5 varies in the y-direction of the transducer. In the example, the thickness changes linearly from 20 to 100 nm. The thickness of the gold layer 5 is uniform in this example. Alternatively, the thickness of the gold layer can also vary.
  • the intensity of the light reflected from the transducer surface is measured with a detector 3, which is designed in such a way that it permits measurements with spatial resolution in at least one dimension.
  • the detector is, for example, a photodiode array that is arranged in the y direction.
  • the resulting signal is a spatially resolved SPR. If the optical properties of the layer 6 adjoining the gold layer (FIG. 2a) or the glass layer (FIG. 2b) change, the SPR shifts as shown schematically in FIG. 2c. The shift is, for example, a measure of the analyte atoms bound in the adjacent layer.
  • Figure 3 shows a further embodiment of the invention.
  • the optical structure corresponds to the exemplary embodiment in FIG. 1b.
  • the transducer surface is designed such that the refractive index n of the layer of free electron metal 5 or another layer 7, 8 increases along a transducer axis, as shown in the diagram.
  • the resulting signal is a spatially resolved SPR.
  • the optical properties d * n of the plasmon-bearing layer 5 or another layer 7, 8 are varied cyclically.
  • the product n * d indicates the variation in the thickness d and / or the refractive index n that is present in the y-direction of the transducer.
  • the amplitude of the cyclic modification of the optical properties is preferably just large enough to sweep the entire SPR in one period.
  • This cyclic variation can e.g. corresponding to a sawtooth-shaped function, a triangular function, a sine function or, for example, a function which maps the surface plasmon to one of the functions mentioned.
  • the underlying coordinate system is not necessarily a rectangular one, as shown in Figures 1 to 4.
  • a circular transducer can also be used - FIG. 5a.
  • the corresponding coordinate in the exemplary embodiments described above is no longer y but the angle of rotation and the spatially resolved measurement of the intensity with the aid of a diode line or a camera can be carried out by detection with a photodiode and simultaneous rotation of the circular transducer.
  • the rotation can be uniform or stepwise.
  • the signal 'of the photodiode can be read out just when the rotation frequency.
  • a shift in the SPR can then be measured, for example, as a phase shift.
  • a reference signal of constant phase is preferably recorded simultaneously with the actual measurement signal and a comparison is carried out with the aid of a PLL circuit (phase locked loop).
  • the second dimension of the transducer surface can be used to provide further information about the sample to be examined.
  • Different ligands for different analytes or ligands of different affinity for one or more analytes can be applied in a affinity sensor along the x-axis (see FIG. 1b) or the radius r (see FIG. 5b).
  • concentration of the ligands on the surface can also be varied along the x-axis or from r.
  • a number of different sample channels, which run correspondingly can be used with different samples.
  • affinity sensors can be implemented.
  • completely new devices can be implemented for use as diagnostic affinity sensors. Two of these devices are described below as preferred embodiments of the invention with reference to FIGS. 6 and 7.
  • the device described here and shown schematically in FIG. 6 is based on the use of a circular transducer surface with concentric semicircular sample channels 10.
  • a laser diode or, for example, a light-emitting diode serves as light source 1, the spectral width of which is restricted by the use of an optical filter or any other another light source with a spectral width that is small compared to the spectral width of the surface plasmon with a constant angle of incidence of the exciting light, or a light source that is provided with a spectral filter, such as a monochromator.
  • the SPR is approx. 100 nm wide (2 * FWHM - Fill Width Half Minimum).
  • An LED in this wavelength range with a spectral width of the emitted light of approx. 15 nm - 30 nm is already small enough 12
  • a much narrower band light source is preferably used.
  • a light source is a laser diode that shines at the wavelength mentioned with a spectral width of approximately 1 pm or less.
  • the incident light is applied as parallel as possible.
  • the measure for a tolerable deviation from parallelism is preferably the width of the SPR in the angular space at a constant wavelength of the incident light. Under the above conditions, this width is approximately 2 degrees, so that a light beam should have a convergence or divergence angle of approximately 0.5 ° or less.
  • the required parallelism relates to the angle of incidence in the reflection plane.
  • This parallel, monochromatic light beam is widened, for example by means of a beam forming optics 11 of cylindrical lenses in the direction perpendicular to the reflection plane, ⁇ so that a "light curtain" is formed.
  • the light beam designed in this way is coupled into a cylindrical prism 12, for example made of BK7 glass.
  • This cylindrical prism is arranged in such a way that a disc, for example also with a BK7 surface, rotates past as a coupling layer 13 at its base.
  • a layer for refractive index adjustment 14 for example silicone oil, is placed between the base of the prism and the rotating disk.
  • a cushion made of silicone rubber between the prism and the rotating disk can also be used to adjust the refractive index.
  • the disk On the side which is arranged opposite the prism, the disk carries a layer of a free electron metal 5, for example gold, and possibly one or more further layers 7, 8, for example glass and dextran. These are modified in accordance with the above statements so that the SPR is a function of the angle of rotation.
  • a free electron metal for example gold
  • further layers 7, 8, for example glass and dextran for example glass and dextran.
  • channels can be extended over a wide angular range. They first serve to functionalize the sensor surface, ie. H. With the help of a certain sequence of chemical reactions, ligands are immobilized on the sensor surface. The samples to be examined can then be applied. As already said, the channels can be extended over a large range of the rotation angle ⁇ . A sequence of different chambers, for example with a sample and buffer solution, is also useful. Where u. U. The arrangement of the complete system can be such that the actual intensity measurement always takes place in an area with buffer solution, since the SPR signal in affinity sensors is always dependent on the optical properties of the medium that is adjacent to the sensitive surface.
  • the reflected light is detected with spatial resolution along the radius r of the rotation, for example with the aid of a photodiode array, a CCD line or a camera.
  • the information on shape and position is now obtained for each individual channel in a time-resolved manner, corresponding to the rotation of the transducer disc. If you are only interested in the position of the SPR, the appropriate determination of the phase (exemplary embodiment according to FIG. 4), the determination of the phase of a periodic SPR signal is sufficient. If enough time is available for the measurement, a step-by-step sampling of the SPR signals from the individual channels is also conceivable. In this way, the synergy with the modern CD player technology is extensive.
  • the exemplary embodiment of an SPR system described with reference to FIG. 6 is suitable for the simultaneous determination of a large number of analytes and, for example, their concentrations.
  • the number of information that can be determined independently depends only on the possibility of generating systems for handling the samples with a sufficient packing density and modifying the surface with a corresponding resolution 14
  • FIG. 7 shows an alternative system which, similar to that from the exemplary embodiment in FIG. 6, obtains the spatial resolution required for the SPR measurement technology according to the invention from the movement of the transducer chip or the transducer disk.
  • This system is particularly characterized by a simple structure.
  • the energy required to move the transducer is low. Low energy is also required to operate the light source 1, the detector 3 and the evaluation and display units.
  • the system can be operated with a battery.
  • the energy can preferably be obtained from the conversion of mechanical energy or from light energy. This enables the device to be operated independently of the mains. Only a few parallel channels are used.
  • the possible movement form here is in particular the linear displacement of the transducer in the direction of the SPR axis, which queries the status of a reaction after a certain time - for example after the equilibrium of the corresponding reaction has been reached.
  • a system can be used, for example, for self-monitoring of patients with diseases in which crisis-related complications can be predicted by monitoring (monitors) certain factors, for example in the serum. This enables the patient to take countermeasures at an early stage.
  • the system includes, in particular, an optical structure in accordance with the exemplary embodiment in FIG. 1. The transducer chip is moved along the y axis.
  • the movement takes place, for example, driven by a spring that is simply tensioned, for example by rotation (restlessness) or by pulling apart or compressing it.
  • a further spring is tensioned, which uses the energy to operate the light sources, the detector and the electronic ones 15
  • the electrical energy for operating the detection system is made available with the aid of a photovoltaic system, a battery or an accumulator for charging via the electrical network.
  • the measurement in different channels is carried out either by multiplying the optical and / or the electrical measuring system or by time-delayed observation of the different channels, or by using a light source which is imaged in a light curtain along the y-axis in accordance with the exemplary embodiment of FIG. 6 and then either time-shifted with a photodetector or simultaneously with the aid of several photodiodes, a photodiode line, a CCD line or an adapted arrangement of photodetectors.
  • the modification of the surface can follow certain continuous functions, as suggested in the previous examples, but can also be step-like. The latter surface modification is particularly useful when a YES / NO answer is required, as is often the case in diagnostic systems.
  • FIGS. 1 to 7 describe the spatially resolved measurement of SPR or technical devices based thereon.
  • the necessary local variations of layers 5, 7 and 8 can be replaced by corresponding reversible temporal modifications.
  • Options for this are, in particular, variations in the refractive index of one or more appropriately designed layers 5, 7 and 8 16
  • the resulting SPR signal is measured in a temporally resolved manner and its shape and position when irradiated with parallel, monochromatic light is determined with respect to the time axis and used as information in corresponding sensor systems.

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  • 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)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)

Abstract

L'invention concerne un transducteur de résonance de plasmons superficiels dans lequel les propriétés de la surface (5) où se produit la résonance des plasmons superficiels et/ou les propriétés d'au moins une zone (7, 8) voisine se présentent et/ou peuvent être modifiées de façon telle qu'il est possible de mesurer la résonance des plasmons superficiels par détermination, avec résolution spatiale et/ou temporelle, de l'intensité du rayonnement réfléchi par la surface.
PCT/EP1999/000895 1998-02-12 1999-02-11 Determination de la resonance de plasmons superficiels a l'aide de couches a modifications locales et temporelles WO1999041594A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU26232/99A AU2623299A (en) 1998-02-12 1999-02-11 Determining surface plasmon resonance using spatially or time-modified layers
EP99906225A EP1161676A1 (fr) 1998-02-12 1999-02-11 Determination de la resonance de plasmons superficiels a l'aide de couches a modifications locales et temporelles

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
DE19805806 1998-02-12
DE19805806.3 1998-02-12
DE19805807 1998-02-12
DE19805807.1 1998-02-12
DE19805809A DE19805809C2 (de) 1998-02-12 1998-02-12 Bestimmung der Oberflächenplasmonen-Resonanz mit Hilfe von örtlich oder zeitlich modifizierten Schichten
DE19805809.8 1998-02-12

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10008006A1 (de) * 2000-02-22 2001-09-13 Graffinity Pharm Design Gmbh SPR-Sensor und SPR-Sensoranordnung
US6752963B2 (en) 2000-02-22 2004-06-22 Graffinity Pharmaceutical Design Gmbh SPR sensor system
DE10327399A1 (de) * 2003-06-18 2005-01-05 Carl Zeiss Jena Gmbh Verfahren und Messanordnung zur markierungsfreien Detektion von Bindungsereignissen zwischen Proteinen und oberflächengebundenen Antikörpern
CN101556248B (zh) * 2009-05-18 2011-03-30 中国科学院长春应用化学研究所 一种表面等离子共振光谱的时间分辨率检测方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3720387C1 (en) * 1987-06-19 1988-11-24 Benno Rothenhaeusler Method and device for examining the physical properties of thin layers by means of polarised light
EP0577285A1 (fr) * 1992-06-17 1994-01-05 Hewlett-Packard Company Instruments de mesure utilisant la résonance plasmonique de surface

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3720387C1 (en) * 1987-06-19 1988-11-24 Benno Rothenhaeusler Method and device for examining the physical properties of thin layers by means of polarised light
EP0577285A1 (fr) * 1992-06-17 1994-01-05 Hewlett-Packard Company Instruments de mesure utilisant la résonance plasmonique de surface

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HICKEL W ET AL: "SURFACE PLASMON MICROSCOPIC CHARACTERIZATION OF EXTERNAL SURFACES", JOURNAL OF APPLIED PHYSICS, vol. 66, no. 10, 15 November 1989 (1989-11-15), pages 4832 - 4836, XP000105131 *
MADDALENA P ET AL: "EXPERIMENTAL INVESTIGATION OF LATERAL WAVE CONTRIBUTION TO THE SHIFT OF A REFLECTED BEAM AT SURFACE PLASMON RESONANCE", OPTICS COMMUNICATIONS, vol. 96, no. 4 / 05 / 06, 15 February 1993 (1993-02-15), pages 221 - 224, XP000336860 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10008006A1 (de) * 2000-02-22 2001-09-13 Graffinity Pharm Design Gmbh SPR-Sensor und SPR-Sensoranordnung
DE10008006C2 (de) * 2000-02-22 2003-10-16 Graffinity Pharm Design Gmbh SPR-Sensor und SPR-Sensoranordnung
US6752963B2 (en) 2000-02-22 2004-06-22 Graffinity Pharmaceutical Design Gmbh SPR sensor system
US6795192B2 (en) 2000-02-22 2004-09-21 Graffinity Pharmaceutical Design Gmbh SPR sensor and SPR sensor array
DE10327399A1 (de) * 2003-06-18 2005-01-05 Carl Zeiss Jena Gmbh Verfahren und Messanordnung zur markierungsfreien Detektion von Bindungsereignissen zwischen Proteinen und oberflächengebundenen Antikörpern
CN101556248B (zh) * 2009-05-18 2011-03-30 中国科学院长春应用化学研究所 一种表面等离子共振光谱的时间分辨率检测方法

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AU2623299A (en) 1999-08-30

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