EP0408722A1 - Procede permettant de detecter les changements de phase optique pendant le fonctionnement d'un biocapteur, appareil de biocaptage et biocapteur con u pour etre utilise dans un tel procede - Google Patents

Procede permettant de detecter les changements de phase optique pendant le fonctionnement d'un biocapteur, appareil de biocaptage et biocapteur con u pour etre utilise dans un tel procede

Info

Publication number
EP0408722A1
EP0408722A1 EP90902654A EP90902654A EP0408722A1 EP 0408722 A1 EP0408722 A1 EP 0408722A1 EP 90902654 A EP90902654 A EP 90902654A EP 90902654 A EP90902654 A EP 90902654A EP 0408722 A1 EP0408722 A1 EP 0408722A1
Authority
EP
European Patent Office
Prior art keywords
sensitized
light
stripes
coating layer
assay species
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.)
Ceased
Application number
EP90902654A
Other languages
German (de)
English (en)
Inventor
William James Stewart
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.)
Plessey Overseas Ltd
Original Assignee
Plessey Overseas Ltd
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 Plessey Overseas Ltd filed Critical Plessey Overseas Ltd
Publication of EP0408722A1 publication Critical patent/EP0408722A1/fr
Ceased 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
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/4788—Diffraction
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N2021/752—Devices comprising reaction zones

Definitions

  • the present invention concerns improvements in or relating to the construction and utilisation of optical biosensors, in particular resonant optical biosensors.
  • Such biosensors include a sensitized coating layer which is located in the evanescent region of a resonant field. Interaction between the sensitized coating layer and the assay species to which it is sensitized results in a change in the thickness of the coating layer. This change is made manifest as a change in the optical phase of a resonant signal.
  • a metallic layer or metallised grating is interposed between the sensitized coating layer and a light coupling body.
  • the sensitized coating lies in the evanescent region of an optical frequency electron resonance field.
  • the sensitized coating layer is provided as an integral part of a monitored resonant cavity.
  • Light is coupled into and out of the resonant cavity by means of prism coupling and either a thin low refractive index layer or a multi-layer dielectric mirror formed as an integral part of the mirror resonant cavity.
  • prism coupling is replaced by a grating.
  • a resonant optical biosensor 1 similar to that described in the second of the references, UK Patent Application No. 2174802, is depicted in Figure 1 of the drawings.
  • This biosensor 1 includes a mirrored resonant cavity 3 which is abutted to an open ended fluid sample container 5.
  • Light from a light source S is coupled into the resonant cavity 3 by means of a prism 10 of relatively high refractive index n 0 .
  • This prism 10 also serves to couple light from the resonant cavity 3 to a light detector D.
  • One mirror of the resonant cavity 3 is provided by a relatively low refractive index ni layer 11, of thickness ti.
  • the body 12 of the cavity is of relatively high refractive index n 2 and of thickness t 2 - Light coupling is by frustrated total internal reflection (the mirror layer 11 is thin).
  • the other mirror of the resonant cavity 3 is provided by a relatively low refractive index n 3 layer 13, of thickness t3.
  • This layer 13 is uniformly thick and is sensitized in its entirety to a given assay species. As shown, this sensitized coating layer 13 is exposed to a fluid sample 14, of refractive index n 4 and thickness t-j..
  • the effect of assay species present in the fluid sample is to provide a incremental change ⁇ t 3 in the thickness t3 of the sensitized coating layer 13 as the species is absorbed on this layer 13. This has the result of changing signal phase and shifting the resonance.
  • the biosensor response is shown in Figure 2.
  • the relative phase of the detected signal is depicted as a function of the elevation angle ⁇ of source S and detector D.
  • Curves (a) to (c) show the different responses obtained when the changes ⁇ t 3 of layer thickness t3 are zero, +5nm, and +10nm respectively.
  • the change ⁇ t 3 in layer thickness t 3 is discernible as a change in phase ⁇ .
  • the present invention is intended as a solution to the problem aforesaid. It is an objective to provide phase related measurements that are appreciably insensitive to changes of ambient temperature and the like.
  • a method for detecting optical phase changes during biosensor operation comprising the following steps: providing a resonant optical biosensor in which a coating layer thereof is in part sensitized to at least one given assay species and is patterned for causing light diffraction; exposing the patterned sensitized coating layer to a fluid sample; directing light from an extended light source towards, and resonantly coupling the same to, the patterned sensitized coating layer; collecting and focussing light diffracted from the patterned sensitized coating layer onto a light detector, defining thus a diffraction field in the plane of the light detector; and, scanning the light detector relative to the diffraction field to measure the same and thereby detect or quantify said at least one given assay species when such is present in the fluid sample.
  • That part of the coating layer that is sensitized is not optically distinguished from the remainder part of the coating layer. In these circumstances, no diffraction field is discernible.
  • this species is attracted to the layer and results in an increase in thickness in that part of the coating layer that is sensitized. Localised shift in phase, light interference and diffraction are the result. The presence of a measurable diffraction field is thus an indicator of the detection of a given assay species.
  • the quantity of the given assay species present in the fluid sample may be determined from an analysis of the diffraction field measurements.
  • first order diffraction spot position and size or position and intensity.
  • the latter is preferred as being less sensitive to surface imperfection.
  • the method aforesaid may be extended to allow the detection and quantification of one or both of two different assay species present in the fluid sample.
  • Useful information can be extracted from measurement and comparison of the position and " intensity of first and higher order diffraction spots, as will be discussed hereinafter.
  • the diffraction field is not significantly altered by changes in biosensor geometry. It is primarily determined by the configuration and thickness profile of the coating layer.
  • biosensing apparatus suitable for performing the method aforesaid, this apparatus comprising: a resonant optical biosensor in which a coating layer thereof is in part sensitized to at least one given assay species and is patterned for causing light diffraction; an extended light source; collimating means arranged to direct light from the extended light source onto the resonant coupled optical biosensor; a light detector; light focussing means arranged to direct light diffracted from the patterned sensitized coating onto the light detector thereby to define a diffraction field in the plane of the detector; and, scanning means arranged to scan the light detector relaljve to this diffraction field.
  • the diffraction field may, be scanned mechanically.
  • the light detector may consist * of a linear array of detecting elements aligned in elevation, and the light source and light detector may be moved each in a transverse direction ' to effect a scan in azimuth.
  • a light source consisting in a linear array of light emitting diodes also aligned in elevation.
  • the field may be scanned electronically.
  • the light detector and the light source may each consist in a two- dimensional array of elements, which elements are switched column to effect a scan in azimuth.
  • a resonant optical biosensor including a coating layer, wherein this coating layer is in part sensitized to at least one assay species and is patterned for causing light diffraction.
  • the coating layer aforesaid may be in part sensitized to a single given assay species.
  • the coating layer may be sensitized and patterned with a set of longitudinally extending stripes, alternate stripes thereof being sensitized to the single given assay species.
  • the coating layer aforesaid may be in part sensitized to two or more different assay species.
  • the coating layer thus may have a first part sensitized to a first assay species, a second part sensitized to a second assay species, and a remainder third part.
  • the coating layer may be sensitized with adjacent sets of first, second and third longitudinally extending stripes in which the first and second stripes are sensitized to the first and second assay species respectively and in which the first and second stripes are of different width.
  • Figure 1 is a cross-section drawing of biosensing apparatus including a biosensor of known construction
  • Figure 2 is a graph in which the phase of a detected signal in the apparatus of Figure 1 preceding is shown as a function of the elevation angle subtended by both source and detector for different values of layer thickness;
  • FIG. 3 is a perspective view of biosensing apparatus in which the sensitized coating layer of the biosensor has been modified in accord with the present invention
  • Figure 4 is a plan view of a modified sensitized coating layer, a variant of that shown in the preceding figure.
  • Figures 5 and 6 are diffraction spot patterns obtained using the apparatus of Figure 3 in which the coating layer is as provided and as modified as shown in Figure 4, respectively. DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • the reson&nt optical biosensor 1 has been modified by substituting an alternative coating layer 13' for the uniformly sensitized coating layer 13 described above.
  • the area of the substituted layer 13' is sensitized in part only. It serves as a means of imposing diffraction in the detected light field.
  • a convenient form of sensitized pattern is, illustrated in which the area of the substituted layer 13' is divided into a series of longitudinally extending stripes, stripes 15 corresponding to a part of the layer material that is sensitized to the given assay species, and stripes 17 (alternate with the stripes 15) corresponding to the remainder part of the layer material which is not so sensitized and serves to act as a localised phase reference.
  • the patterned layer 13' may be formed from a sensitized material in which that part corresponding to the reference stripes 17 is desensitized selectively.
  • the biosensor is illuminated by a divergent beam produced using a collimating lens 19 and an extended light source S'.
  • the light source S' extends a significant distance in elevation to produce an appreciable beam divergence ⁇ .
  • Light emerging from the biosensor is collected by a telescopic sight 20 and is focussed onto a light detector D' located at the focal plane.
  • the stripes 15 of sensitized material increase in thickness and become optically distinguishable from the reference stripes 17.
  • Optical interference results and a diffraction pattern becomes discernible at the focal plane of the telescopic sight 20. This is shown in Figure 5 where for clarity the zero order and first order diffraction spots only are shown.
  • the detailed structure of the diffraction pattern is dictated by the stripe geometry and is dependant upon the relative thickness of the sensitized and reference stripes 15 and 17.
  • the diffraction pattern is measured by scanning the detector D' in azimuth ⁇ across the diffraction field. Intensity and azimuth data is collected and used for quantitative analysis. More complex detection and analysis may be performed by simple modification of the biosensor described.
  • the coating layer is provided with a first part that is sensitized to a first assay species, a second part that is sensitized to a second array species, and a third remainder part.
  • the area of the coating layer 13" is, in this instance, partitioned by repeating sets of three longitudinally extending stripes 21, 22, 23.
  • the first of these stripes, stripe 21, is sensitized to the first assay species.
  • the second of these stripes, stripe 22, is sensitized to the second assay species.
  • the remainder stripe 23 has no such sensitization and provides a , reference.
  • the sensitized stripes 21 and 22 are of different widths. In the illustration, stripes 22 are the wider.
  • n is the order of the outlier (1, 2 etc); w is the width of the corresponding stripe, and W is the spatial repeat period. It is noted that spots of the same order to the left and to the right of the diffraction pattern are of equal intensity.
  • both stripes 21 and 22 will be active. However the diffraction pattern resulting is distinguishable from the foregoing in that spots of the same order to the left and to the right of the diffraction pattern will no longer be of equal intensity. An exception to this rule arises in the event that both stripes 21 and 22 result in equal phase shift.
  • the diffraction pattern is distinguishable from the diffractions patterns for either the first or second assay species, because of the different geometry of the effective layer pattern.
  • Data collected for intensity and angular position can be used in numeric analysis (deconvolution) to provide quantitative information.

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  • Chemical & Material Sciences (AREA)
  • Physics & Mathematics (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Plasma & Fusion (AREA)
  • Investigating Or Analysing Materials By Optical Means (AREA)

Abstract

La présente invention se rapporte à un appareil de biocaptage comprenant: un biocapteur optique résonant, dont une couche de revêtement est partiellement sensibilisée à au moins une espèce d'examen donnée et est configurée de façon à produire une diffraction de la lumière; une source lumineuse étendue; un organe de collimation destiné à diriger la lumière depuis la source lumineuse étendue sur le biocapteur optique couplé resonant; un détecteur de lumière; un organe de focalisation de la lumière destiné à diriger la lumière diffractée depuis la couche sensibilisée configurée sur le détecteur de lumière, afin de définir un champ de diffraction dans le plan de détecteur; et un organe de balayage destiné à balayer le détecteur de lumière par rapport à ce champ de diffraction. La présente invention se rapporte également à un procédé permettant de détecter les changements de phase optique pendant le fonctionnement du biocapteur.
EP90902654A 1989-02-08 1990-01-29 Procede permettant de detecter les changements de phase optique pendant le fonctionnement d'un biocapteur, appareil de biocaptage et biocapteur con u pour etre utilise dans un tel procede Ceased EP0408722A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB898902803A GB8902803D0 (en) 1989-02-08 1989-02-08 A method for detecting optical phase changes during biosensor operation,biosensing apparatus and a biosensor adapted for use in the same
GB8902803 1989-02-08

Publications (1)

Publication Number Publication Date
EP0408722A1 true EP0408722A1 (fr) 1991-01-23

Family

ID=10651323

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90902654A Ceased EP0408722A1 (fr) 1989-02-08 1990-01-29 Procede permettant de detecter les changements de phase optique pendant le fonctionnement d'un biocapteur, appareil de biocaptage et biocapteur con u pour etre utilise dans un tel procede

Country Status (4)

Country Link
EP (1) EP0408722A1 (fr)
JP (1) JPH03503806A (fr)
GB (1) GB8902803D0 (fr)
WO (1) WO1990009576A1 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5413939A (en) * 1993-06-29 1995-05-09 First Medical, Inc. Solid-phase binding assay system for interferometrically measuring analytes bound to an active receptor
GB9406142D0 (en) 1994-03-28 1994-05-18 British Tech Group A sensor
AU4503201A (en) * 1999-10-14 2001-06-12 University Of Utah Research Foundation Resonant optical cavities for high-sensitivity, high-throughput biological sensors and methods
US7384797B1 (en) 2000-10-12 2008-06-10 University Of Utah Research Foundation Resonant optical cavities for high-sensitivity high-throughput biological sensors and methods
WO2003023400A2 (fr) * 2001-09-13 2003-03-20 Axela Biosensors Inc. Methode et appareil d'analyse reposant sur la diffraction de lumiere
US7443507B2 (en) 2002-12-25 2008-10-28 Bio-Rad Laboratories Inc. Surface plasmon resonance sensor
US9518288B2 (en) 2008-04-11 2016-12-13 University Of Utah Research Foundation Methods and compositions related to quantitative, array based methylation analysis

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0627742B2 (ja) * 1982-12-21 1994-04-13 コムテツク リサ−チ ユニツト リミテツド 検定方法及びそのための装置
US4487839A (en) * 1983-01-05 1984-12-11 Ortho Diagnostic Systems Inc. Immunoassay methods employing patterns for the detection of soluble and cell surface antigens
US4537861A (en) * 1983-02-03 1985-08-27 Elings Virgil B Apparatus and method for homogeneous immunoassay
US4647544A (en) * 1984-06-25 1987-03-03 Nicoli David F Immunoassay using optical interference detection
EP0194132A3 (fr) * 1985-03-06 1988-08-03 Murex Corporation Imageur de détection des immunoessais et procédé
GB2197068B (en) * 1986-11-03 1990-08-08 Stc Plc Optical sensor device
CA1305921C (fr) * 1987-01-30 1992-08-04 Eric K. Gustafson Dosage immunologique par diffraction et reactifs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9009576A1 *

Also Published As

Publication number Publication date
GB8902803D0 (en) 1989-03-30
JPH03503806A (ja) 1991-08-22
WO1990009576A1 (fr) 1990-08-23

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