EP1212582A1 - Dispositif et procede pour la determination de distances, et systeme de nanodosage associe - Google Patents

Dispositif et procede pour la determination de distances, et systeme de nanodosage associe

Info

Publication number
EP1212582A1
EP1212582A1 EP99941606A EP99941606A EP1212582A1 EP 1212582 A1 EP1212582 A1 EP 1212582A1 EP 99941606 A EP99941606 A EP 99941606A EP 99941606 A EP99941606 A EP 99941606A EP 1212582 A1 EP1212582 A1 EP 1212582A1
Authority
EP
European Patent Office
Prior art keywords
transducer
refractive index
transducer surface
nanodosing
volume
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Withdrawn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
EP99941606A
Other languages
German (de)
English (en)
Inventor
Henning Groll
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.)
Jandratek GmbH
Original Assignee
Jandratek GmbH
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 Jandratek GmbH filed Critical Jandratek GmbH
Publication of EP1212582A1 publication Critical patent/EP1212582A1/fr
Withdrawn legal-status Critical Current

Links

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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01B—MEASURING LENGTH, THICKNESS OR SIMILAR LINEAR DIMENSIONS; MEASURING ANGLES; MEASURING AREAS; MEASURING IRREGULARITIES OF SURFACES OR CONTOURS
    • G01B11/00—Measuring arrangements characterised by the use of optical techniques
    • G01B11/14—Measuring arrangements characterised by the use of optical techniques for measuring distance or clearance between spaced objects or spaced apertures
    • 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

Definitions

  • the present invention relates to a device and a method for determining distances, the device being usable in particular as a proximity sensor.
  • the invention further relates to a nanodosing system which has a device for determining distances in the nanometer range or uses a corresponding method.
  • the present invention relates in particular to the field of biosensors with optical transducers.
  • Optical biosensors are generally based on the fact that particles such as molecules, bacteria, viruses and the like are bound to an optical measuring surface.
  • the binding takes place via a ligand-receptor interaction, the optical layer thickness, in particular the refractive index of a thin film on the measuring surface, being changed.
  • This change is detected using an optical method, the optical signal corresponding to the number of analyte particles bound to the surface. In this way it is possible to change the association speed and the To show dissociation speed, the strength of the bond and the concentration of the binding partner.
  • a first method relates to a cuvette system in which a chamber or a pot is used in which a side wall or the bottom forms the sensor surface.
  • a second method relates to a flow system in which the liquid is pumped past the measurement surface via flow channels.
  • a flow injection analysis method is frequently used here, and the liquid is frequently passed over the measurement surface in a liquid loop.
  • a surface binding reaction is used as a sensory response.
  • the extent of the bond in the vicinity of the surface depends on the concentration of the binding molecules that are available for binding within the binding range of the functional groups that are immobilized on the sensor system. If molecules or larger particles from the liquid have already bound to the surface due to previous binding events, depletion or a concentration gradient occurs locally in the immediate vicinity of the surface (up to 1-10 ⁇ m), which falsifies the further measurement.
  • kinetic phenomena are to be measured, it is not the reaction rates but the diffusion or the mass transport limited binding kinetics (“mass transport limited diffusion”) that are measured.
  • the kinetic constant and affinity measured by the sensor will not reflect the actual conditions at which binding occurs between molecules that are well mixed in a liquid.
  • conventional mixing such as stirring or a micro flow system, there is usually a laminar liquid flow in the vicinity of the measuring surface and due to Newton friction there is insufficient mixing instead to avoid impoverishment.
  • the measurement is limited to mass transport kinetics.
  • the object of the present invention is to provide a device and a method with which distances between an object and the measurement surface can be determined and to provide a nanodosing system system in which the formation of depletion zones is avoided.
  • the invention is based on the basic idea of using a sensor unit in the case of surface-bound analysis systems to determine a measured variable in the area of the test field which corresponds to the average refractive index.
  • This average refractive index results on the one hand from the refractive index of the medium which is adjacent to the transducer surface and on the other hand from an object arranged in the vicinity of the transducer surface which consists of a material whose refractive index is different from the refractive index of the medium.
  • An evaluation device which is connected to the sensor unit, detects a change in the measurement variable corresponding to the average refractive index, which is caused by the object approaching the transducer surface.
  • the invention is applicable to all optical measuring principles in which a change in refractive index occurs adjacent to a transducer surface when an object is arranged adjacent to the transducer surface.
  • the measured variable obtained can be used to determine the numerical value of the average refractive index, for example by calibrating the measured variable.
  • the present invention relates on the one hand to an apparatus and a method for determining distances of an object from a transducer surface in the nano range.
  • the determination of distances in the range of about 0 to 500 nm is possible.
  • this distance is correspondingly larger.
  • Evanescent optical fields are preferably used to measure average calculation indices in the space above a measurement surface in which the evanescent field is sufficiently sensitive to changes in the refractive index. Methods such as surface plasmon resonance (SPR), the measuring principle of attenuated total reflection (attenuated total reflectance, ATR) and interference contrast are preferred.
  • SPR surface plasmon resonance
  • ATR attenuated total reflectance
  • the present invention furthermore relates to the use of the device or the method for determining the distance when forming very small volumes in systems in which evanescent fields or other detection principles, such as, in particular, reflection interference, are used for surface-bound analysis of samples.
  • the volume is controlled in one dimension perpendicular to the sensor surface by using the principle according to the invention for distance measurement and can thus be adjusted.
  • the smallest distances or optimal distances in the nano range can be set.
  • Nanodosing systems can be implemented with the invention.
  • a central advantage of the nanodosing system according to the invention is that it consists of moving parts that can be easily removed from one another, in particular for the purpose of cleaning, and then subsequently moved back into the desired position.
  • a nano-dosing volume is formed in which an object: which is preferably plate-shaped, or an object with a surface which faces the sensor surface, and with a view to optimal analyte transport to the sensor surface or to the measuring point was molded on the surface of the sensor to optimize the flow characteristics near the Transducer surface is arranged such that a volume is created through which the liquid to be examined is passed.
  • the smallest distances and thus low volume heights can be set in the nanometer range.
  • This nanodosing volume is preferably delimited by side walls, so that an inlet and an outlet are provided for the liquid to be examined.
  • the nanodosing system is implemented by a metering device, preferably in the form of a pipette tip, the metering device being able to be arranged close to the transducer surface.
  • a metering device preferably in the form of a pipette tip
  • the metering device being able to be arranged close to the transducer surface.
  • the drive device for moving the parts preferably has systems with which movements with a sufficiently high resolution are possible.
  • stepper motors using microsteps and / or piezotranslators are used.
  • a combination of a stepper motor for a fine drive and a piezo translator for a fine drive can be used.
  • depletion zones result from the fact that the molecules to be analyzed are bound from the sample to the sensor surface, so that they are removed from a layer of the sample close to the surface and transport of further molecules from more distant areas of the sample by diffusion does not take place so quickly how the bond to the surface.
  • This problem occurs with "stationary" sample delivery systems such as cuvettes but also with microflow systems if the dimension of the microflow chamber right to the surface is in the micrometer range and the flows are aligned parallel to the surface.
  • it can it be overcome by metering the sample with a velocity vector perpendicular to the surface when the metering opening is in the micrometer range above the surface. Only the use of the nanodosing volume according to the invention or the dosing from a dosing system, the dosing opening of which is less than 1 ⁇ m from the surface, overcomes the depletion problem.
  • the device according to the invention for determining distances and the associated method can be used in a further preferred embodiment of the invention when mixing a liquid with the aid of mixing bodies.
  • These mixing bodies can be moved above the transducer surface by applying an external field, in particular a magnetic field.
  • the movements of the mixing bodies, in particular the distance of the mixing bodies from the transducer surface, can be determined with the aid of the detector system according to the invention.
  • Mixing beads are preferably used as the mixing body.
  • a mesh (or membrane) is used as the mixing body.
  • Fig. 2 is a schematic view of part of a first preferred embodiment of the invention.
  • Fig. 3 is a schematic view of part of a second preferred embodiment of the invention.
  • 1 shows the basic structure of a biosensor with an optical transducer, which is designed as a surface plasmon resonance sensor in the present example.
  • the measuring arrangement has an optical transducer 10, which in the example shown is designed as a prism with a transducer surface 12.
  • Light is introduced into the prism from a light source 14 and surface plasmon resonance is excited in the region of the transducer surface, the reflected light being received by a detector arrangement 16.
  • the output signal of the detector device is sent to an evaluation device 40.
  • a cuvette arrangement 20 with at least one cuvette for holding a liquid to be examined is arranged on the transducer surface.
  • the bottom 22 of the cuvette is formed by part of the transducer surface 12. 1 also shows an object 32 arranged at a distance from the transducer surface.
  • the object 32 is arranged on a holder 34 which is connected to a drive device 36. With the help of the drive device, the object 32 can be adjusted in height and can be moved up to the transducer surface with high precision.
  • the refractive index of a medium which is adjacent to the transducer surface is determined with the aid of the sensor unit, which is formed from the light source 14, the optical transducer 10 and the detector arrangement 16.
  • An average refractive index is determined within the range of the evanescent field, which extends from the transducer surface into the space inside the cuvette.
  • the device shown in FIG. 1 can be used as a proximity sensor, whereby an object approaches Transducer surface causes a signal change that is detected by the evaluation device.
  • calibrating the measuring device ie correspondingly evaluating a measuring signal depending on the position of the object with respect to the transducer surface, distances can be determined with the device.
  • a precise high-resolution drive device 36 for example a stepper motor with micro steps, the holder 34 with the object 32 arranged thereon can be arranged with high precision relative to the transducer surface 12.
  • the first preferred embodiment of FIG. 2 shows the schematic structure of a nanodosing volume 50.
  • the nanodosing volume 50 is formed in the space between the transducer surface 12 or the cuvette bottom 22 and the object 32.
  • a plate-shaped object 32 is shown, the underside of which is arranged essentially parallel to the transducer surface 12.
  • the plate-shaped object is selectively adjusted in height with the aid of three drives and three holders which hold the plate at spaced apart locations.
  • the respective distances between reference points on the underside of the object and the transducer surface 12 are determined at preferably three measuring spots. This has the advantage that the underside of the plate can be aligned, for example, parallel to the transducer surface.
  • the nanodosing volume 50 has an inlet 52 and an outlet 54.
  • the nanodosing volume is also delimited by two side walls 56, only the rear side wall 56 being shown in FIG. 2.
  • the nanodosing volume 50 can be formed with a height in the range from 0 to approximately 500 nm.
  • the object is a pipette tip 62 which, like the object 32, is height-adjustable with a drive device 36.
  • a space 60 is formed between the end of the pipette tip and the transducer surface, in which liquid with sample material can be introduced via a metering device, sample material being applied directly to the detector surface with the aid of the metering device.
  • This arrangement forms a special case of a nanodosing system.
  • the position of mixing bodies in a cuvette can be determined with the aid of the device according to the invention for determining distances.
  • mixing bodies such as mixing balls or nets, these are introduced into the cuvette and their position is detected by determining the average refractive index.

Landscapes

  • Physics & Mathematics (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)
  • Pathology (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)
  • Optical Measuring Cells (AREA)

Abstract

L'invention concerne un dispositif destiné, en particulier, à être utilisé en tant que capteur de proximité, comprenant une unité de détection qui comporte un transducteur optique et un objet qui peut être rapproché de la surface du transducteur, l'indice de réfraction moyen étant déterminé au moyen d'un dispositif d'évaluation. La distance séparant un objet de la surface du transducteur peut être déterminée par détection d'une modification de l'indice de diffraction.
EP99941606A 1998-08-18 1999-08-13 Dispositif et procede pour la determination de distances, et systeme de nanodosage associe Withdrawn EP1212582A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19837437 1998-08-18
DE19837437A DE19837437C2 (de) 1998-08-18 1998-08-18 Abstandsmessende Vorrichtung zur Nanodosierung und Verfahren zum Einstellen eines Nano-Dosiersystems
PCT/EP1999/005931 WO2000011432A1 (fr) 1998-08-18 1999-08-13 Dispositif et procede pour la determination de distances, et systeme de nanodosage associe

Publications (1)

Publication Number Publication Date
EP1212582A1 true EP1212582A1 (fr) 2002-06-12

Family

ID=7877905

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99941606A Withdrawn EP1212582A1 (fr) 1998-08-18 1999-08-13 Dispositif et procede pour la determination de distances, et systeme de nanodosage associe

Country Status (4)

Country Link
EP (1) EP1212582A1 (fr)
AU (1) AU5515799A (fr)
DE (1) DE19837437C2 (fr)
WO (1) WO2000011432A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2617178C1 (ru) * 2014-12-18 2017-04-21 Шлюмберже Текнолоджи Б.В. Устройство для моделирования щелевого протока жидкости

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10335533A1 (de) * 2003-07-31 2005-02-17 "Stiftung Caesar" (Center Of Advanced European Studies And Research) Berührungsloser Dehnungssensor
GB0514349D0 (en) * 2005-07-13 2005-08-17 Smiths Group Plc Apparatus and components
EP1857808A1 (fr) * 2006-05-15 2007-11-21 Sika Technology AG Dispositif de mesure

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02503713A (ja) * 1987-06-04 1990-11-01 ルコツ　バルター 光学的な変調及び測定方法
US5239183A (en) * 1991-04-30 1993-08-24 Dainippon Screen Mfg. Co., Ltd. Optical gap measuring device using frustrated internal reflection
JPH0827178B2 (ja) * 1992-11-06 1996-03-21 日本アイ・ビー・エム株式会社 ヘッド浮上量測定装置
US5557399A (en) * 1995-03-22 1996-09-17 Zygo Corporation Optical gap measuring apparatus and method
US5715060A (en) * 1996-03-11 1998-02-03 Carnegie Mellon University Apparatus and method for measuring linear nanometric distances using evanescent radiation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0011432A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2617178C1 (ru) * 2014-12-18 2017-04-21 Шлюмберже Текнолоджи Б.В. Устройство для моделирования щелевого протока жидкости

Also Published As

Publication number Publication date
DE19837437C2 (de) 2003-04-10
AU5515799A (en) 2000-03-14
WO2000011432A1 (fr) 2000-03-02
DE19837437A1 (de) 2000-03-09

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