WO2000019203A1 - Diagnostic method - Google Patents

Diagnostic method Download PDF

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Publication number
WO2000019203A1
WO2000019203A1 PCT/GB1999/003199 GB9903199W WO0019203A1 WO 2000019203 A1 WO2000019203 A1 WO 2000019203A1 GB 9903199 W GB9903199 W GB 9903199W WO 0019203 A1 WO0019203 A1 WO 0019203A1
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WO
WIPO (PCT)
Prior art keywords
binding agent
specific binding
marker
evanescent wave
disease state
Prior art date
Application number
PCT/GB1999/003199
Other languages
French (fr)
Inventor
Dean William Payne
Martin Bernard Mcdonnell
Michael Ian Fisher
Peter Gosling
Original Assignee
The Secretary Of State For Defence
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 The Secretary Of State For Defence filed Critical The Secretary Of State For Defence
Priority to JP2000572658A priority Critical patent/JP2002525631A/en
Priority to AU61051/99A priority patent/AU6105199A/en
Priority to EP99947672A priority patent/EP1116034A1/en
Publication of WO2000019203A1 publication Critical patent/WO2000019203A1/en

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings

Definitions

  • the present invention relates to a diagnostic method for detecting markers of disease and/or clinical and/or medical conditions in biological fluids, and the apparatus for use in such methods .
  • Markers such as proteins or other entitities which are indicative of disease states or conditions are frequently present in biological fluids such as blood, serum or urine.
  • icroalbuminuria or MATJ elevated levels of albumin in the urine
  • MATJ elevated levels of albumin in the urine
  • elevated levels >30 ⁇ g/ml
  • albumin albumin in urine
  • vascular permeability Increases in vascular permeability occur as a result of inflammatory and/or immune response to trauma or infection.
  • MAU is being regarded as a general indicator of trauma (see Gosling, P., British Journal of Hospital Medicine, 1995, 54, p285-289) .
  • the extent of microalbuminuria has been suggested as a predictor of the development of complications in the trauma patient. Rapid, bedside determination of microalbuminuria may allow the objective use of treatment for the recovery of seriously ill patients.
  • microalbuminuria has widespread application for monitoring any severe inflammatory condition resulting as a consequence of e.g. major surgery, major trauma, burn injury, acute pancreatitis, bacteraemia, acute myocardial infarction and post respiratory/cardiac arrest therapy.
  • Antibody-based precipitation methods for the detection of MAU are commercially available. These range from dipsticks to light-scattering assay's (e.g. Bayer DCA 2000). Available systems require skilled personnel, are relatively slow, and are not suitable for continuous monitoring.
  • some - assay's require supporting equipment, are only semi- quantitative and require samples and/or reagents to be added manually.
  • the present invention provides a method of diagnosing a disease state or condition, said method comprising contacting a sample of a biological fluid taken from a patient suspected of suffering from said disease state or condition with a specific binding agent for said agent, and assaying for the presence of a complex between said binding agent and said marker using an evanescent wave detection device.
  • This method allows for the rapid and/or continuous monitoring of marker levels in biological fluids. Depending upon the nature of the marker, its presence or its presence at unusual levels (either elevated or depressed) may be indicative of a clinical problem.
  • the assay may be carried out directly or competitively as would be understood in the art.
  • the specific binding agent is immobilised on the detection surface of an evanescent wave detection device and the sample is then contacted with that surface.
  • the evanescent field can then be monitored in order to determine the presence or amount of bound marker thereon.
  • the detection surface of an evanescent wave detection device may have immobilised thereon a further binding agent such as an antibody, which binds the specific binding agent, in the absence of marker.
  • a further binding agent such as an antibody, which binds the specific binding agent, in the absence of marker.
  • the marker blocks the binding of specific binding agent to the further binding agent.
  • specific binding agent __ is added to the sample to bind any marker present . Contact with the detection surface would mean that only residual unbound specific binding agent would become attached to the surface and affect the evanescent field. Thus the less bound agent is detected, the greater the amount of marker present in the sample .
  • This option may be preferable where the marker is of low molecular weight and the specific binding agent is of relatively high molecular weight since evanescent wave devices have a higher detection efficiency for high molecular weight moieties .
  • Suitable specific binding agents include antibodies, receptors, enzymes, oligonucleotides or any other bio reactive molecule depending upon the nature of the particular marker being detected, as well as binding fragments of any of these.
  • the specific binding agent will be an antibody, enzyme or receptor or a binding fragment.
  • the specific binding agent will comprise an antibody or binding fragments thereof such as F(ab) and F(ab') 2 fragments.
  • Markers may comprise proteins, sugars, lipids or even DNA or RNA, depending upon the nature of the disease state or condition being detected. Generally, the marker will comprise a protein.
  • the marker is preferably a high molecular weight, for example, having a molecular weight of greater than lOOODa.
  • markers are detected readily using evanescent wave detectors.
  • An example of such a marker is human serum albumin, which as discussed above, is a marker for inflammatory conditions when present at elevated levels in urine. Antibodies specific for this protein are available commercially.
  • the detection method of the invention can be used to detect microalbuminuria as an indicator of an inflammatory condition, for example caused as a result surgery, trauma, burn injury, acute pancreatitis, bacteraemia, acute myocardial infarction or post respiratory/cardiac arrest therapy.
  • the method of the invention can employ any evanescence based detector system which can directly measure for example antibody-antigen binding at a sensor through changes in local refractive index.
  • Suitable evanescent wave detection devices for use in the method of the invention include a resonant mirror system (RM) , a planar optical waveguide device or a surface plasmon resonance detector.
  • the evanescent wave detection device is a resonant mirror system (RM) .
  • the RM instruments uses an evanescent field to measure small changes of refractive index at the sensor surface.
  • the sensing element is an integrated optical chip consisting of a glass prism, a thin, low refractive index silica spacer layer and a thinner high refractive index waveguide layer (see Figure 1) .
  • a beam of monochromatic light is directed at the prism/spacer interface above a critical angle, it undergoes total internal reflection.
  • the light couples into the waveguide through the spacer layer via the evanescent field and propagates by multiple internal reflections before tunnelling back into the prism.
  • the RM device measures the resonant angle at which resonant light and incident light is out of phase by a factor of ⁇ radians.
  • the measured resonant angle is highly sensitive to changes in the refractive index within a few hundred nanometres of the sensor surface.
  • Binding of ligands or markers to specific binding agents or recognition elements e.g. antibodies which have been immobilised on the sensor surface alters the refractive index of the surface and consequently the resonant angle of the sensing element .
  • the specificity of the detection event is controlled by the specificity of the binding agent which is used.
  • assay's using the method of the invention can be made specific for human albumin by the immobilisation of anti- human serum albumin ( ⁇ -HSA) antibodies on the sensor surface.
  • ⁇ -HSA anti-human serum albumin
  • Monoclonal ( ⁇ -HSA) antibodies are available commercially.
  • monoclonal ( ⁇ -HAS) antibodies are immobilised on the sensor in an RM system.
  • HSA present in samples applied to the sensor surface binds to the immobilised ⁇ -HSA antibodies with consequent effects on the refractive index of the sensor surface and the resonant angle of the sensor element .
  • the change in resonant angle can be quantitated and used to determine the concentration of HSA in the sample.
  • Sensors of a resonant mirror system having thereon, a specific binding agent for a biological disease marker, for example albumin, form a further aspect of the invention.
  • multiple analytes or markers for example from 2 to 100 markers, could be detected simultaneously by providing more than one specific binding agents appropriately configured on the surface of the sensor of the detector.
  • the method of the invention could be used as the basis for the rapid screening system for a range of medical conditions or diseases.
  • the method further provides a means of continuously monitoring a patients progress, for example in an intensive care situation, where for example a urine stream from a catherized patient may be passed continuously across the detector in order to continually monitor the patients condition and allow a rapid response.
  • the detection device may be provided with a pump in order to allow a continuously stream of liquid to pass over the detector surface .
  • Figure 1 shows diagrammatically the principles of operation of a resonant mirror system.
  • the detector used was a continuous flow, multi-analyte resonant mirror (RM) system. This was constructed by Affinity Sensors and is based on the company's commercially available manual, double channel IAsys system outlined in Patent application WO
  • ⁇ -HSA antibody Biogenesis, 0220-0704
  • HSA concentration ⁇ g/ml
  • Results were achieved within -10 seconds and could be configured for continuous monitoring of HSA levels. Further work demonstrated that the assay was reproducible (10 consecutive assays) at high (292 +/-27 ⁇ g/ml, mean +/- SD) and low (7.8 +/- 1.4 ⁇ g/ml, mean +/- SD) concentrations. Once coated, the sensor surfaces could be re-used and stored for a - least a month at 4°C without affecting results.

Abstract

A method of diagnosing a disease state or condition, said method using an evanescent wave detection device such as a resonant mirror system, to detect a marker of said disease state or condition in a sample of a biological fluid taken from a patient suspected of suffering from said disease state. The method may be direct, in which case a specific binding agent for said marker is immobilised on the said detection surface, or competitive in nature. Monitoring the evanescent field allows the determination of the presence or amount of antibody/marker complex in the sample. The method is particularly suitable for the detection of elevated levels of albumin in urine, which is indicative of an inflammatory condition, for example as a result of a trauma.

Description

Diagnostic method
The present invention relates to a diagnostic method for detecting markers of disease and/or clinical and/or medical conditions in biological fluids, and the apparatus for use in such methods .
Markers such as proteins or other entitities which are indicative of disease states or conditions are frequently present in biological fluids such as blood, serum or urine. For example, icroalbuminuria or MATJ (elevated levels of albumin in the urine) is a marker of systemic capillary leakage and indicates injury as a result of trauma, surgery, burns or infection. It is characterised by elevated levels (>30μg/ml) of albumin in urine. It reflects localised and/or systemic increases in vascular permeability. Increases in vascular permeability occur as a result of inflammatory and/or immune response to trauma or infection.
Increasingly, MAU is being regarded as a general indicator of trauma (see Gosling, P., British Journal of Hospital Medicine, 1995, 54, p285-289) . Recently, the extent of microalbuminuria has been suggested as a predictor of the development of complications in the trauma patient. Rapid, bedside determination of microalbuminuria may allow the objective use of treatment for the recovery of seriously ill patients.
Commercially, analysis for microalbuminuria has widespread application for monitoring any severe inflammatory condition resulting as a consequence of e.g. major surgery, major trauma, burn injury, acute pancreatitis, bacteraemia, acute myocardial infarction and post respiratory/cardiac arrest therapy. Antibody-based precipitation methods for the detection of MAU are commercially available. These range from dipsticks to light-scattering assay's (e.g. Bayer DCA 2000). Available systems require skilled personnel, are relatively slow, and are not suitable for continuous monitoring. In addition, some - assay's require supporting equipment, are only semi- quantitative and require samples and/or reagents to be added manually.
The present invention provides a method of diagnosing a disease state or condition, said method comprising contacting a sample of a biological fluid taken from a patient suspected of suffering from said disease state or condition with a specific binding agent for said agent, and assaying for the presence of a complex between said binding agent and said marker using an evanescent wave detection device.
This method allows for the rapid and/or continuous monitoring of marker levels in biological fluids. Depending upon the nature of the marker, its presence or its presence at unusual levels (either elevated or depressed) may be indicative of a clinical problem.
The assay may be carried out directly or competitively as would be understood in the art. In a preferred direct assay, the specific binding agent is immobilised on the detection surface of an evanescent wave detection device and the sample is then contacted with that surface. The evanescent field can then be monitored in order to determine the presence or amount of bound marker thereon.
In a competitive assay, the detection surface of an evanescent wave detection device may have immobilised thereon a further binding agent such as an antibody, which binds the specific binding agent, in the absence of marker. In other words, the marker blocks the binding of specific binding agent to the further binding agent. In this assay, specific binding agent __ is added to the sample to bind any marker present . Contact with the detection surface would mean that only residual unbound specific binding agent would become attached to the surface and affect the evanescent field. Thus the less bound agent is detected, the greater the amount of marker present in the sample .
This option may be preferable where the marker is of low molecular weight and the specific binding agent is of relatively high molecular weight since evanescent wave devices have a higher detection efficiency for high molecular weight moieties .
Suitable specific binding agents include antibodies, receptors, enzymes, oligonucleotides or any other bio reactive molecule depending upon the nature of the particular marker being detected, as well as binding fragments of any of these.
Preferably the specific binding agent will be an antibody, enzyme or receptor or a binding fragment. Typically, the specific binding agent will comprise an antibody or binding fragments thereof such as F(ab) and F(ab')2 fragments.
Where necessary, they are immobilised on the sensor of the detector system using conventional methods. An example of suitable method is given by Davies, R.J. et al . , (1994) in Techniques in Protein Chemistry, pages 285-292 published by Academic Press, San Diego. Markers may comprise proteins, sugars, lipids or even DNA or RNA, depending upon the nature of the disease state or condition being detected. Generally, the marker will comprise a protein.
For good sensitivity in a direct assay, the marker is preferably a high molecular weight, for example, having a molecular weight of greater than lOOODa. Such markers are detected readily using evanescent wave detectors. An example of such a marker is human serum albumin, which as discussed above, is a marker for inflammatory conditions when present at elevated levels in urine. Antibodies specific for this protein are available commercially.
Thus the detection method of the invention can be used to detect microalbuminuria as an indicator of an inflammatory condition, for example caused as a result surgery, trauma, burn injury, acute pancreatitis, bacteraemia, acute myocardial infarction or post respiratory/cardiac arrest therapy.
It provides a rapid and reliable method, particularly useful in the recognition of trauma where rapid remedial action is essential .
The method of the invention can employ any evanescence based detector system which can directly measure for example antibody-antigen binding at a sensor through changes in local refractive index. Suitable evanescent wave detection devices for use in the method of the invention include a resonant mirror system (RM) , a planar optical waveguide device or a surface plasmon resonance detector. Preferably however, the evanescent wave detection device is a resonant mirror system (RM) . The RM instruments uses an evanescent field to measure small changes of refractive index at the sensor surface. The sensing element is an integrated optical chip consisting of a glass prism, a thin, low refractive index silica spacer layer and a thinner high refractive index waveguide layer (see Figure 1) . If a beam of monochromatic light is directed at the prism/spacer interface above a critical angle, it undergoes total internal reflection. At a defined (resonant) angle, the light couples into the waveguide through the spacer layer via the evanescent field and propagates by multiple internal reflections before tunnelling back into the prism. The RM device measures the resonant angle at which resonant light and incident light is out of phase by a factor of π radians. The measured resonant angle is highly sensitive to changes in the refractive index within a few hundred nanometres of the sensor surface.
Binding of ligands or markers to specific binding agents or recognition elements (e.g. antibodies) which have been immobilised on the sensor surface alters the refractive index of the surface and consequently the resonant angle of the sensing element .
The specificity of the detection event is controlled by the specificity of the binding agent which is used.
For example, assay's using the method of the invention can be made specific for human albumin by the immobilisation of anti- human serum albumin (α-HSA) antibodies on the sensor surface. Monoclonal (α-HSA) antibodies are available commercially.
Thus in a preferred embodiment of the method of the invention, monoclonal (α-HAS) antibodies are immobilised on the sensor in an RM system. HSA present in samples applied to the sensor surface binds to the immobilised α-HSA antibodies with consequent effects on the refractive index of the sensor surface and the resonant angle of the sensor element . The change in resonant angle can be quantitated and used to determine the concentration of HSA in the sample.
Sensors of a resonant mirror system having thereon, a specific binding agent for a biological disease marker, for example albumin, form a further aspect of the invention.
Using the method of the invention, multiple analytes or markers, for example from 2 to 100 markers, could be detected simultaneously by providing more than one specific binding agents appropriately configured on the surface of the sensor of the detector. In this way, the method of the invention could be used as the basis for the rapid screening system for a range of medical conditions or diseases.
Using the assay of the invention, discrete samples from patients may be tested rapidly. For example, where a group of individuals have been subjected to a source of potential trauma, for example a blast incident, urine samples from these individuals may be tested to determine who has suffered ill effects. However, the method further provides a means of continuously monitoring a patients progress, for example in an intensive care situation, where for example a urine stream from a catherized patient may be passed continuously across the detector in order to continually monitor the patients condition and allow a rapid response. In such a case, the detection device, may be provided with a pump in order to allow a continuously stream of liquid to pass over the detector surface . The invention will now be particularly described by way of example with reference to the accompanying diagrammatic drawings in which:
Figure 1 shows diagrammatically the principles of operation of a resonant mirror system.
Example 1
The detector used was a continuous flow, multi-analyte resonant mirror (RM) system. This was constructed by Affinity Sensors and is based on the company's commercially available manual, double channel IAsys system outlined in Patent application WO
92/03720.
To produce a continous flow, automated, multi-analyte instrument, modifications were made in collaboration with Labsystems Affinity Sensors.
It was decided that the system should be modified to allow the simultaneous measurement of 16 detection stripes over the sensor device. This would allow, in principle, the simultaneous monitoring of up to 15 different analytes and a reference channel to remove the effects of instrumental drift, temperature effects and non-specific binding.
To produce a continuous flow system the sample cell was fitted with a simple fluidics arrangement. This used RM cuvettes modified by the provision of stainless steel needle tubing. These were installed so as to permit continuous in-flow of sample and continuous aspiration of waste at a fixed but adjustable height above the sensor surface. α-HSA antibody (Biogenesis, 0220-0704) was immobilised on a dextran coated sensor surface at I4ng/mm2 and a standard curve of initial response rate (Arc a"2) against HSA concentration (μg/ml) determined. Response was linear over a range of 0- ~* 500μg/ml with a correlation coefficient of 0.96.
The level of HSA in urine samples was then determined and compared with the results achieved using conventional assays. Urine samples were diluted 1:10 in PBS the response assayed and the concentration determined using the standard curve (see Table 2) .
Table 2
Figure imgf000010_0001
A high correlation (0.997) was observed between the conventional and RM - based approaches.
Results were achieved within -10 seconds and could be configured for continuous monitoring of HSA levels. Further work demonstrated that the assay was reproducible (10 consecutive assays) at high (292 +/-27μg/ml, mean +/- SD) and low (7.8 +/- 1.4μg/ml, mean +/- SD) concentrations. Once coated, the sensor surfaces could be re-used and stored for a - least a month at 4°C without affecting results.

Claims

Claims
1. A method of diagnosing a disease state or condition, said method comprising contacting a sample of a biological fluid taken from a patient suspected of suffering from said disease state or condition with a specific binding agent for said agent , and assaying for the presence of a complex between said binding agent and said marker using an evanescent wave detection device.
2. A method according to claim 1 where' the specific binding agent is immobilised on the detection surface of an evanescent wave detection device and the sample is then contacted with that surface.
3. A method according to claim 1 or claim 2 wherein the marker has a molecular weight greater than lOOODa.
4. A method according to claim 1 where the detection surface of an evanescent wave detection device has immobilised thereon a further binding agent which binds the specific binding agent, in the absence of marker, and specific binding agent is added to the sample to bind any marker present .
5. A method according to any one of the preceding claims wherein the specific binding agent is an antibody, enzyme or receptor or a binding fragment of any of these.
6. A method according to claim 5 wherein the specific binding agent is an antibody or a binding fragment thereof.
7. A method according to any one of the preceding claims wherein the biological fluid is urine.
8. A method according to claim 7 wherein the marker is albumin.
9. A method according to claim 8 wherein the disease state diagnosed is an inflammatory condition.
10. A method according to claim 9 wherein the inflammatory condition is a result surgery, trauma, burn injury, acute pancreatitis, bacteraemia, acute myocardial infarction or post respiratory/cardiac arrest therapy
11. A method according to claim 10 for the diagnosis of trauma.
12. A method according to any one of the preceding claims wherein the evanescent wave detection device is a resonant mirror system (RM) , a planar optical waveguide device or a surface plasmon resonance detector.
13. A method according to claim 12 wherein the evanescent wave detection device is a resonant mirror system (RM) .
1 . A method according to any one of the preceding claims wherein more than one specific binding agent is immobilised on the detector surface.
15. A detection mirror of a resonant mirror system having thereon, a specific binding agent for a biological disease marker .
16. A mirror according to claim 15 wherein the specific binding agent is specific for albumin.
17. The use of an evanescent wave detection system in the diagnosis of a disease state.
18. An evanescent wave detection system having immobilised on a detection surface thereof, a specific binding agent for a marker for a disease state or condition, for use in the diagnosis of said disease state or condition.
19. An evanescent wave detection system according to claim 18 which comprises means to allow a continuous flow of sample across the detection surface.
20. A method substantially as hereinbefore described with reference to the Examples.
PCT/GB1999/003199 1998-09-26 1999-09-24 Diagnostic method WO2000019203A1 (en)

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JP2000572658A JP2002525631A (en) 1998-09-26 1999-09-24 Diagnosis method
AU61051/99A AU6105199A (en) 1998-09-26 1999-09-24 Diagnostic method
EP99947672A EP1116034A1 (en) 1998-09-26 1999-09-24 Diagnostic method

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GB9820919.0 1998-09-26

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Cited By (10)

* Cited by examiner, † Cited by third party
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JP2001330560A (en) * 2000-03-16 2001-11-30 Fuji Photo Film Co Ltd Measuring method using total reflection attenuation and its device
JP2003156432A (en) * 2001-11-22 2003-05-30 Toshiba Corp Optical waveguide type biochemical sensor
JP2003207445A (en) * 2002-01-16 2003-07-25 Toshiba Corp Portable inspecting apparatus and system
JP2003279479A (en) * 2002-01-16 2003-10-02 Toshiba Corp Optical waveguide type glucose sensor and optical waveguide type glucose measurement method
JP2005037403A (en) * 2002-01-16 2005-02-10 Toshiba Corp Optical waveguide type glucose sensor
US6903815B2 (en) 2001-11-22 2005-06-07 Kabushiki Kaisha Toshiba Optical waveguide sensor, device, system and method for glucose measurement
US7102754B2 (en) 2001-10-19 2006-09-05 Fuji Photo Film Co., Ltd. Measuring method and apparatus using attenuation in total internal reflection
JP2007206056A (en) * 2006-11-06 2007-08-16 Fujifilm Corp Measurement method and measuring system using attenuated total reflection
CN102520062A (en) * 2011-12-29 2012-06-27 中国科学院长春光学精密机械与物理研究所 Echo wall sensor based on sound evanescent field coupling
CN106443012A (en) * 2016-09-12 2017-02-22 三诺生物传感股份有限公司 Test strip, preparation method thereof and application of test strip to combined detection of microalbuminuria and beta2 microglobulin

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4371954B2 (en) 2004-08-31 2009-11-25 富士フイルム株式会社 Analysis method of test substance by surface plasmon resonance analysis
EP2384168B1 (en) 2008-12-04 2014-10-08 Searete LLC Actively-controllable sterilizing excitation delivery implants

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4810658A (en) * 1984-06-13 1989-03-07 Ares-Serono Research & Development Photometric instruments, their use in methods of optical analysis, and ancillary devices therefor
EP0326291A1 (en) * 1988-01-27 1989-08-02 AMERSHAM INTERNATIONAL plc Biological sensors
US4992385A (en) * 1986-07-24 1991-02-12 Ares-Serono Research And Development Limited Partnership Polymer-coated optical structures and methods of making and using the same
WO1991002975A1 (en) * 1989-08-21 1991-03-07 The Board Of Regents Of The University Of Washington Multiple-probe diagnostic sensor
WO1992003720A1 (en) * 1990-08-17 1992-03-05 Fisons Plc Analytical device

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4810658A (en) * 1984-06-13 1989-03-07 Ares-Serono Research & Development Photometric instruments, their use in methods of optical analysis, and ancillary devices therefor
US4992385A (en) * 1986-07-24 1991-02-12 Ares-Serono Research And Development Limited Partnership Polymer-coated optical structures and methods of making and using the same
EP0326291A1 (en) * 1988-01-27 1989-08-02 AMERSHAM INTERNATIONAL plc Biological sensors
WO1991002975A1 (en) * 1989-08-21 1991-03-07 The Board Of Regents Of The University Of Washington Multiple-probe diagnostic sensor
WO1992003720A1 (en) * 1990-08-17 1992-03-05 Fisons Plc Analytical device

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GOSLING, PETER: "Microalbuminuria: a marker of systemic disease", BRITISH JOURNAL OF HOSPITAL MEDICINE., vol. 54, no. 6, 1995, pages 285 - 290, XP000869854 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001330560A (en) * 2000-03-16 2001-11-30 Fuji Photo Film Co Ltd Measuring method using total reflection attenuation and its device
US7102754B2 (en) 2001-10-19 2006-09-05 Fuji Photo Film Co., Ltd. Measuring method and apparatus using attenuation in total internal reflection
US6903815B2 (en) 2001-11-22 2005-06-07 Kabushiki Kaisha Toshiba Optical waveguide sensor, device, system and method for glucose measurement
JP2003156432A (en) * 2001-11-22 2003-05-30 Toshiba Corp Optical waveguide type biochemical sensor
US7054514B2 (en) 2001-11-22 2006-05-30 Kabushiki Kaisha Toshiba Optical waveguide sensor, device, system and method for glucose measurement
JP2003279479A (en) * 2002-01-16 2003-10-02 Toshiba Corp Optical waveguide type glucose sensor and optical waveguide type glucose measurement method
JP2005037403A (en) * 2002-01-16 2005-02-10 Toshiba Corp Optical waveguide type glucose sensor
JP2003207445A (en) * 2002-01-16 2003-07-25 Toshiba Corp Portable inspecting apparatus and system
JP2007206056A (en) * 2006-11-06 2007-08-16 Fujifilm Corp Measurement method and measuring system using attenuated total reflection
CN102520062A (en) * 2011-12-29 2012-06-27 中国科学院长春光学精密机械与物理研究所 Echo wall sensor based on sound evanescent field coupling
CN102520062B (en) * 2011-12-29 2014-06-18 中国科学院长春光学精密机械与物理研究所 Echo wall sensor based on sound evanescent field coupling
CN106443012A (en) * 2016-09-12 2017-02-22 三诺生物传感股份有限公司 Test strip, preparation method thereof and application of test strip to combined detection of microalbuminuria and beta2 microglobulin
CN106443012B (en) * 2016-09-12 2018-11-06 三诺生物传感股份有限公司 A kind of test strips and preparation method thereof and the application in microdose urine protein and β2-microglobulin joint-detection

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