WO1991015751A1 - Method of improving assay sensitivity - Google Patents

Method of improving assay sensitivity Download PDF

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Publication number
WO1991015751A1
WO1991015751A1 PCT/GB1991/000567 GB9100567W WO9115751A1 WO 1991015751 A1 WO1991015751 A1 WO 1991015751A1 GB 9100567 W GB9100567 W GB 9100567W WO 9115751 A1 WO9115751 A1 WO 9115751A1
Authority
WO
WIPO (PCT)
Prior art keywords
optical
index matching
fcfd
waveguide
edge
Prior art date
Application number
PCT/GB1991/000567
Other languages
French (fr)
Inventor
John Worthington Attridge
Original Assignee
Applied Research Systems Ars Holding N.V.
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 Applied Research Systems Ars Holding N.V. filed Critical Applied Research Systems Ars Holding N.V.
Priority to JP50699791A priority Critical patent/JP3286314B2/en
Priority to US07/930,690 priority patent/US5369717A/en
Priority to DE69118178T priority patent/DE69118178T2/en
Priority to EP91907433A priority patent/EP0524224B1/en
Priority to CA002078568A priority patent/CA2078568C/en
Publication of WO1991015751A1 publication Critical patent/WO1991015751A1/en
Priority to GR960400870T priority patent/GR3019483T3/en

Links

Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64Fluorescence; Phosphorescence
    • G01N21/6428Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03Cuvette constructions
    • G01N2021/0346Capillary cells; Microcells
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64Fluorescence; Phosphorescence
    • G01N21/645Specially adapted constructive features of fluorimeters
    • G01N2021/6463Optics
    • G01N2021/6465Angular discrimination
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N2021/7769Measurement method of reaction-produced change in sensor
    • G01N2021/7786Fluorescence
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64Fluorescence; Phosphorescence
    • G01N21/645Specially adapted constructive features of fluorimeters
    • G01N21/648Specially adapted constructive features of fluorimeters using evanescent coupling or surface plasmon coupling for the excitation of fluorescence
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00Chemistry: analytical and immunological testing
    • Y10S436/804Radioisotope, e.g. radioimmunoassay

Definitions

  • the present invention relates to a method of improving the sensitivity of optical assays wherein the light signal to be analyzed emerges from the edge of an optical waveguide.
  • the invention is particularly applicable to assays carried out using fluorescence capillary fill devices (FCFD's) in which an optical waveguide forms one plate of the device.
  • FCFD's fluorescence capillary fill devices
  • FCFD's and methods for their manufacture are described in detail in EP-A-171148, whilst photometric methods including assays carried out using FCFD's are described in EP-A-170376.
  • Assays involving FCFD's rely on angular separation, in light emerging from the optical waveguide, between fluorescence originating from molecules in sample liquid within the FCFD cavity and fluorescence orginating from molecules bound, directly or indirectly, to the waveguide.
  • This angular separation occurs because fluorescent material in solution can only fluoresce into the waveguide at relatively large angles relative to the plane of the waveguide since the angle of any incident beam relative to this plane will be increased by refraction at the solution/waveguide interface.
  • Such light consequently emerges from the waveguide at large angles (e.g. > 47° relative to the axis of the waveguide) .
  • Fluorescent material bound to the surface of the waveguide emits light into the waveguide at all angles, which light thereafter emerges from the waveguide over a wide range of angles relative to the axis of the waveguide.
  • Fluorescent material bound to the surface of the waveguide emits light into the waveguide at all angles, which light thereafter emerges from the waveguide over a wide range of angles relative to the axis of the waveguide.
  • FCFD's As described in EP-A-171148, a convenient method of manufacturing FCFD's involves preparation of coated glass 1 sandwiches' from which individual FCFD's are separated by scribing and breaking. This manufacturing process permits the inexpensive bulk production of FCFD's, this being particularly desirable in view of the disposable nature of these devices.
  • the optical edge it is difficult within the context of such a bulk production process, however, to design scribing and breaking procedures which consistently produce FCFD's in which the end of the waveguide from which emerging light is detected (hereinafter referred to as "the optical edge") is optically smooth. It will be appreciated that surface irregularities at the optical edge will give rise to some degree of light scattering and consequent mixing of the narrow angle light emission attributable only to surface-bound fluorescent material and the broader angle emission attributable to both surface-bound fluorescent material and fluorescent material in solution. This inevitably degrades the signal quality and overall performance of optical assay techniques using FCFD's.
  • the present invention is based on the discovery that light scattering at the optical edge can be substantially reduced in a particularly simple and efficient manner if the optical edge is contacted with an index matching substance so as to avoid having an optical edge/air interface.
  • index matching substance is meant a substance having a refractive index similar to that of the material of the optical waveguide, e.g. having a refractive index which is ⁇ 10% that of the waveguide. Since high index glass as normally used in the production of waveguides typically has a refractive index of about 1.5, index matching substances having a refractive index in the range 1.35-1.65 are particularly appropriate for such applications.
  • Intimate contact between the optical edge and the index matching substance may be achieved by, for example, selecting an index matching substance which is a liquid or gel, or by employing precursors for a substantially transparent solid which pliably moulds to the surface of the optical edge before subsequently setting or otherwise solidifying.
  • Suitable liquid index matching substances include those traditionally employed as immersion fluids in microscopy, such as cedar oil and Canada balsam.
  • Other liquids with appropriate refractive indices include silicones, ethyl alcohol, amyl alcohol, aniline, benzene, glycerol, paraffin oil and turpentine.
  • Appropriate gels include, for example, silicone gels.
  • Suitable precursors for solids include adhesives which may, for example, be selected from appropriate epoxy and acrylate systems, and optical cements as well as plastics materials (including thermoplastics) with appropriate refractive index, for example silane elastomers.
  • readily meltable solids of appropriate refractive index e.g. naphthalene, may be applied in molten form and then allowed to cool and solidify.
  • the method of the invention may, for example, be effected by index matching the optical edge to a defined optically smooth component, such as an optical flat, which forms the first stage of an optical detector train.
  • Index matching may, for example, be made to an optical structure as described in published application WO 90/15985, the contents of which are herein incorporated by reference.
  • one or more FCFD's are positioned in a disposable holder (advantageously of the radially extending type described in published patent application WO 90/11830.
  • Such holders may if desired incorporate an optical component such as a lens to which the optical edge is matched. Holders so constructed and incorporating an index matching substance constitute a further feature of the invention.
  • Fig. 1 is a schematic representation of a portion of a disposable holder incorporating an FCFD
  • Fig.2 is a vertical section through part of an alternative form of holder incorporating an FCFD.
  • Fig.3 is an enlarged partial view of the cross section of Fig.2.
  • upper glass plate 1 and optical wave guide 2 make up an FCFD mounted by means not shown in a disposable holder (e.g. produced by injection moulding), a part of which is shown as 3.
  • the design of the holder is such that a plurality of FCFD cells radiate horizontally from a central vertical axis.
  • That part of the edge of the holder closest to optical wave guide 2 is configured as a lens 4 associating with optical detector 5.
  • Index matching substance 6, which is advantageously a solid such as an optical cement or appropriate plastic which during application pliably moulds to the optical edge 7 of waveguide 2, ensures that scattering of light between optical edge 7 and lens 4 is minimised.
  • Example 1 In the configuration shown in Fig. 2 the upper glass plate 1 and optical waveguide 2 which constitute an FCFD are mounted in a holder comprising a base unit 8 and lid 9. A glass window 10 is mounted between said base unit 8 and lid 9 and is matched to the optical edge of wave guide 2 by means of index matching substance 6.
  • Example 1 For a better understanding of the invention the following non-limitative Example is provided by way of illustration: Example 1
  • the configuration illustrated in Fig.2 is employed.
  • the glass window 10 is a flame polished microscope slide (e.g. as manufactured by Chance Propper Ltd., Smethwick, Warley, U.K.) which is cut to appropriate dimensions.
  • the height of the glass window is chosen so that those light rays 11, 12 which would normally (i.e. in the absence of index matching material) emerge from the waveguide at angles ⁇ 47° to the axis thereof are refracted by the glass window without being reflected off its edge surface 13.
  • a suitable window is 4 mm by 10 mm with a thickness of 1.0 mm.
  • the FCFD and glass window are placed in approximately moulded features in the (usually plastic) base unit 8 so that there is a small gap of approximately 0.1 mm between the optical edge 7 of the FCFD and the glass window.
  • a drop of index matching material such as a UV-curable optical adhesive (e.g. Norland Optical Adhesive 81, Norland Products Inc. , New Brunswick, U.S.A.) is then applied so that the small gap fills by capillary action and the adhesive is retained between the two components by surface tension.
  • the adhesive is then cured by exposure to ultraviolet light at a wavelength of between 320 mm and 400 mm.
  • the holder lid 9 is then attached to the base 8 and the whole may be stored for future use.

Abstract

The invention relates to a method of reducing scattering of light emerging from an optical edge of an optical waveguide. According to the invention, the optical edge is maintained in intimate contact with an index matching substance which itself also forms or intimately contacts a further optical component. The invention also relates to a disposable holder suitable for use in the method.

Description

Method of Improving Assay Sensitivity
The present invention relates to a method of improving the sensitivity of optical assays wherein the light signal to be analyzed emerges from the edge of an optical waveguide. The invention is particularly applicable to assays carried out using fluorescence capillary fill devices (FCFD's) in which an optical waveguide forms one plate of the device.
FCFD's and methods for their manufacture are described in detail in EP-A-171148, whilst photometric methods including assays carried out using FCFD's are described in EP-A-170376.
Assays involving FCFD's rely on angular separation, in light emerging from the optical waveguide, between fluorescence originating from molecules in sample liquid within the FCFD cavity and fluorescence orginating from molecules bound, directly or indirectly, to the waveguide. This angular separation occurs because fluorescent material in solution can only fluoresce into the waveguide at relatively large angles relative to the plane of the waveguide since the angle of any incident beam relative to this plane will be increased by refraction at the solution/waveguide interface. Such light consequently emerges from the waveguide at large angles (e.g. > 47° relative to the axis of the waveguide) . Fluorescent material bound to the surface of the waveguide, on the other hand, emits light into the waveguide at all angles, which light thereafter emerges from the waveguide over a wide range of angles relative to the axis of the waveguide. Thus, by measuring the intensity of fluorescent light emerging from the waveguide at relatively small angles to the axis of the guide (e.g. < 45° to the axis) , it is possible to assess the quantity of fluorescent material bound to the surface of the waveguide since the fluorescent light output in this angular zone is substantially free from fluorescence
SUBSTITUTESHEET arising from fluorescent material in solution.
As described in EP-A-171148, a convenient method of manufacturing FCFD's involves preparation of coated glass 1sandwiches' from which individual FCFD's are separated by scribing and breaking. This manufacturing process permits the inexpensive bulk production of FCFD's, this being particularly desirable in view of the disposable nature of these devices.
It is difficult within the context of such a bulk production process, however, to design scribing and breaking procedures which consistently produce FCFD's in which the end of the waveguide from which emerging light is detected (hereinafter referred to as "the optical edge") is optically smooth. It will be appreciated that surface irregularities at the optical edge will give rise to some degree of light scattering and consequent mixing of the narrow angle light emission attributable only to surface-bound fluorescent material and the broader angle emission attributable to both surface-bound fluorescent material and fluorescent material in solution. This inevitably degrades the signal quality and overall performance of optical assay techniques using FCFD's.
The present invention is based on the discovery that light scattering at the optical edge can be substantially reduced in a particularly simple and efficient manner if the optical edge is contacted with an index matching substance so as to avoid having an optical edge/air interface.
Thus according to one aspect of the invention there is provided a method of reducing scattering of light emerging from an optical edge of an optical waveguide wherein said optical edge is maintained in intimate contact with an index matching substance which itself also forms or intimately contacts a further optical component. By "index matching substance" is meant a substance having a refractive index similar to that of the material of the optical waveguide, e.g. having a refractive index which is ± 10% that of the waveguide. Since high index glass as normally used in the production of waveguides typically has a refractive index of about 1.5, index matching substances having a refractive index in the range 1.35-1.65 are particularly appropriate for such applications.
Intimate contact between the optical edge and the index matching substance may be achieved by, for example, selecting an index matching substance which is a liquid or gel, or by employing precursors for a substantially transparent solid which pliably moulds to the surface of the optical edge before subsequently setting or otherwise solidifying.
Suitable liquid index matching substances include those traditionally employed as immersion fluids in microscopy, such as cedar oil and Canada balsam. Other liquids with appropriate refractive indices include silicones, ethyl alcohol, amyl alcohol, aniline, benzene, glycerol, paraffin oil and turpentine. Appropriate gels include, for example, silicone gels. Suitable precursors for solids include adhesives which may, for example, be selected from appropriate epoxy and acrylate systems, and optical cements as well as plastics materials (including thermoplastics) with appropriate refractive index, for example silane elastomers. Alternatively, readily meltable solids of appropriate refractive index, e.g. naphthalene, may be applied in molten form and then allowed to cool and solidify.
The method of the invention may, for example, be effected by index matching the optical edge to a defined optically smooth component, such as an optical flat, which forms the first stage of an optical detector train. Index matching may, for example, be made to an optical structure as described in published application WO 90/15985, the contents of which are herein incorporated by reference. In a preferred embodiment of the invention, one or more FCFD's are positioned in a disposable holder (advantageously of the radially extending type described in published patent application WO 90/11830. Such holders may if desired incorporate an optical component such as a lens to which the optical edge is matched. Holders so constructed and incorporating an index matching substance constitute a further feature of the invention.
In the accompanying non-limitative drawings, which serve to illustrate the invention without in any way limiting the same:-
Fig. 1 is a schematic representation of a portion of a disposable holder incorporating an FCFD, and
Fig.2 is a vertical section through part of an alternative form of holder incorporating an FCFD.
Fig.3 is an enlarged partial view of the cross section of Fig.2. Referring to Fig.l in greater detail, upper glass plate 1 and optical wave guide 2 make up an FCFD mounted by means not shown in a disposable holder (e.g. produced by injection moulding), a part of which is shown as 3. It is preferred that the design of the holder is such that a plurality of FCFD cells radiate horizontally from a central vertical axis. That part of the edge of the holder closest to optical wave guide 2 is configured as a lens 4 associating with optical detector 5. Index matching substance 6, which is advantageously a solid such as an optical cement or appropriate plastic which during application pliably moulds to the optical edge 7 of waveguide 2, ensures that scattering of light between optical edge 7 and lens 4 is minimised.
In the configuration shown in Fig. 2 the upper glass plate 1 and optical waveguide 2 which constitute an FCFD are mounted in a holder comprising a base unit 8 and lid 9. A glass window 10 is mounted between said base unit 8 and lid 9 and is matched to the optical edge of wave guide 2 by means of index matching substance 6. For a better understanding of the invention the following non-limitative Example is provided by way of illustration: Example 1
The configuration illustrated in Fig.2 is employed. The glass window 10 is a flame polished microscope slide (e.g. as manufactured by Chance Propper Ltd., Smethwick, Warley, U.K.) which is cut to appropriate dimensions. As shown in Fig.3, the height of the glass window is chosen so that those light rays 11, 12 which would normally (i.e. in the absence of index matching material) emerge from the waveguide at angles <47° to the axis thereof are refracted by the glass window without being reflected off its edge surface 13. For an FCFD with an optical edge of dimensions 1.1 mm by 10 mm, a suitable window is 4 mm by 10 mm with a thickness of 1.0 mm.
During assembly of the apparatus, the FCFD and glass window are placed in approximately moulded features in the (usually plastic) base unit 8 so that there is a small gap of approximately 0.1 mm between the optical edge 7 of the FCFD and the glass window. A drop of index matching material such as a UV-curable optical adhesive (e.g. Norland Optical Adhesive 81, Norland Products Inc. , New Brunswick, U.S.A.) is then applied so that the small gap fills by capillary action and the adhesive is retained between the two components by surface tension. The adhesive is then cured by exposure to ultraviolet light at a wavelength of between 320 mm and 400 mm. The holder lid 9 is then attached to the base 8 and the whole may be stored for future use.

Claims

Claims
1. A method of reducing scattering of light emerging from an optical edge of an optical waveguide wherein said optical edge is maintained in intimate contact with an index matching substance which itself also forms or intimately contacts a further optical component.
2. A method as claimed in claim 1 wherein the index matching substance is a precursor for a substantially transparent solid capable of being pliably moulded to the surface of the optical edge before setting or otherwise solidifying.
3. A method as claimed in claim 1 or claim 2 wherein the index matching substance has a refractive index of between 1.35 and 1.65 in the visible region of the electromagnetic spectrum.
4. A method as claimed in any one of the preceding claims wherein the optical waveguide forms part of an FCFD or other capillary fill sensor cell positioned in a disposable holder.
5. A disposable holder adapted to receive one or more optical structures comprising an optical waveguide, said holder comprising one or more lenses and an index matching substance in intimate contact therewith.
6. A disposable holder as claimed in claim 5 further comprising one or more optical structures each comprising an optical waveguide.
7. A disposable holder as claimed in claim 6 wherein the optical structure is an FCFD or other capillary fill sensor cell.
PCT/GB1991/000567 1990-04-11 1991-04-10 Method of improving assay sensitivity WO1991015751A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP50699791A JP3286314B2 (en) 1990-04-11 1991-04-10 How to improve assay sensitivity
US07/930,690 US5369717A (en) 1990-04-11 1991-04-10 Optical waveguide assay unit and method of improving assay sensitivity using same
DE69118178T DE69118178T2 (en) 1990-04-11 1991-04-10 METHOD FOR IMPROVING THE SENSITIVITY OF ANALYZES
EP91907433A EP0524224B1 (en) 1990-04-11 1991-04-10 Method of improving assay sensitivity
CA002078568A CA2078568C (en) 1990-04-11 1991-04-10 Method of improving assay sensitivity
GR960400870T GR3019483T3 (en) 1990-04-11 1996-04-02 Method of improving assay sensitivity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909008261A GB9008261D0 (en) 1990-04-11 1990-04-11 Method of improving assay sensitivity
GB9008261.1 1990-04-11

Publications (1)

Publication Number Publication Date
WO1991015751A1 true WO1991015751A1 (en) 1991-10-17

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1991/000567 WO1991015751A1 (en) 1990-04-11 1991-04-10 Method of improving assay sensitivity

Country Status (12)

Country Link
US (1) US5369717A (en)
EP (1) EP0524224B1 (en)
JP (1) JP3286314B2 (en)
AT (1) ATE135818T1 (en)
AU (1) AU642736B2 (en)
CA (1) CA2078568C (en)
DE (1) DE69118178T2 (en)
DK (1) DK0524224T3 (en)
ES (1) ES2084813T3 (en)
GB (1) GB9008261D0 (en)
GR (1) GR3019483T3 (en)
WO (1) WO1991015751A1 (en)

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US5919712A (en) * 1993-05-18 1999-07-06 University Of Utah Research Foundation Apparatus and methods for multi-analyte homogeneous fluoro-immunoassays
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EP0524224B1 (en) 1996-03-20
AU642736B2 (en) 1993-10-28
GR3019483T3 (en) 1996-07-31
DK0524224T3 (en) 1996-04-15
DE69118178T2 (en) 1996-09-12
ES2084813T3 (en) 1996-05-16
DE69118178D1 (en) 1996-04-25
GB9008261D0 (en) 1990-06-13
ATE135818T1 (en) 1996-04-15
US5369717A (en) 1994-11-29
EP0524224A1 (en) 1993-01-27
JP3286314B2 (en) 2002-05-27
AU7668991A (en) 1991-10-30
CA2078568C (en) 2002-06-11
JPH05505874A (en) 1993-08-26
CA2078568A1 (en) 1991-10-12

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