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WO1987003093A1 - Capteur de determination de la concentration d'une espece biochimique - Google Patents

Capteur de determination de la concentration d'une espece biochimique Download PDF

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Publication number
WO1987003093A1
WO1987003093A1 PCT/DK1986/000126 DK8600126W WO8703093A1 WO 1987003093 A1 WO1987003093 A1 WO 1987003093A1 DK 8600126 W DK8600126 W DK 8600126W WO 8703093 A1 WO8703093 A1 WO 8703093A1
Authority
WO
WIPO (PCT)
Prior art keywords
sensor
immobilised
response
concentration
accordance
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
PCT/DK1986/000126
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English (en)
Inventor
Anders Weber
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.)
Radiometer AS
Original Assignee
Radiometer AS
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 Radiometer AS filed Critical Radiometer AS
Publication of WO1987003093A1 publication Critical patent/WO1987003093A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems 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
    • G01N21/7703—Systems 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 using reagent-clad optical fibres or optical waveguides
    • 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
    • G01N33/5438—Electrodes

Definitions

  • the present invention relates to a sensor for determining the concentration of a biochemical species, which may be one of the constituents in an affinity pair, and with a response-giving active component reacting with the response capable of being converted into a sensor signal to the concentration of the respective biochemical species in an ambient medium, whereby a physical characteristic of the response-giving active component is modified as a function of the said concentration.
  • the first group comprises sensors the action of which is based on the fact that with every determination of concentration carried out reagent is added, containing an analog of the species, the concentration of which is to be determined, marked with a fluorescent dye, an enzyme or a similar substance.
  • This group of sensors which cannot be used for continuous determinations of concentration, are in the present context not discussed in detail.
  • the second group comprises sensors which, without any reagent, react direct to the concentration of a biochemical species, hereinafter also referred to as an analyte, in an ambient medium.
  • the majority of the sensors pertaining to the hitherto known sensors of the latter type are sensors in which one of the constituents of an affinity pair, also referred to as a receptor, is immobilised on a surface. If such a sensor and the said surface is brought into contact with a solution containing an analyte, which may be the second constituent of the affinity pair, hereinafter also referred to as a ligand, a certain amount of the ligand is adsorbed to the immobilised first constituent, until a state of thermodynamic equilibrium has been reached.
  • a solution containing an analyte which may be the second constituent of the affinity pair
  • the adsorbed amount of ligand can be determined according to a number of fundamentally different methods, including inter alia the following:
  • the surface sensors are all subject to the following fundamental limitations: (1) The surface sensors are in practice irreversible and are therefore unsuitable for continuous determination of concentration. It has therefore always been necessary to regenerate the surfaces for every determination.
  • a competitive immunosensor is described by Hirschfeld in the specification of PCT-application no. WO 84/00817.
  • the Hirschfeld sensor is built about an optical fibre to which one of the constituents is immobilised.
  • the sensor comprises in addition a certain amount of the other constituent marked with fluorophore and bound to the first constituent by affinity bonds.
  • a competitive sensor is also described by Schultz et al., 1982 in Diabetes Care 5.(3)245 and in the specification to the USA patent no. 4, 344, 438.
  • the basic idea of the sensor therein described is for a specific receptor site to be enclosed in a restricted chamber together with a so-called competing ligand capable of being bound reversibly to the specific receptor site.
  • the competing ligand competes with the analyte for the said receptor sites .
  • Installing a competitive principle in the sensor has the advantage that it enables a certain modulation of the sensor's response level and sensitivity, whereas with the above surface sensors or direct binding sensors such modulation is not possible. This becomes understandable if the binding mechanisms of the two types of sensor are considered in greater detail.
  • Equation (1) also shows that a given relative response for a given analyte concentration can only be achieved by making use of a receptor the affinity of which for the analyte can be described by the K value calculated when solving equation (1).
  • R + L RL R + M RM where R and L again designate the receptor and the analyte ligand respectively, and M designates the competing ligand.
  • R Total concentration of receptor sites (number of receptor sites/sensor volume); Total concentration of competing ligand; K': 1/K;
  • an affinity pair there are both constituents of an affinity pair. One of them is immobilised on a restricted area, possibly a surface (receptor sites), whereas the other (the ligand) is enclosed within the active part in dissolved form.
  • the ligand is marked with fluorochrome.
  • AJCL analyte which on the one hand can pass through the membrane and on the other hand can compete for receptor sites, will be able to affect the ratio between bound and free ligand within the chamber.
  • a fluorometer with a localised field of vision can be used to measure either bound or free ligand marked with fluorochrome.
  • a disadvantage of this embodiment consists in the fact that the response time of the sensor is relatively long.
  • the field of view of the fluorometer must have a certain extent to achieve a given sensitivity. Since the entire area within the field of view shall reach thermodynamic equilibrium before the sensor is in equilibrium the diffusion ways of analyte and competing ligand become relatively long. Since at the same time the diffusion coefficient of the competing ligand is low, owing to the relatively high molecular weight of the latter, see below, the response time of the sensor is bound to be relatively long. It is also a disadvantage that the separation between the active part and the ambient medium is brought about by a dialysis barrier.
  • the marked ligand Since the marked ligand is to be effectively retained by the membrane with a view to long time stability, the marked ligand must have a certain size to be retained in the sensor, whereas the substances capable of analysis must be considerably smaller so as to enable them to diffuse into the chamber. Accordingly, Schultz also describes only the use of the sensor for the determination of low-molecular compounds. Lastly, the use of fluorochrome compounds in a sensor as used with long time measuring processes is less practical inasmuch as these compounds dissociate under prolonged action of light. As a result of this instability the sensor response can impair the measuring process.
  • the sensor in accordance with the invention which is characterised in that the response-giving active part comprises a substrate part to which a certain amount of a substance, which may be the other constituent in the affinity pair, is immobilised and a substrate part to which a certain amount of the biochemical species or a competitor thereof is immobilised, whereby the substrate parts are linked by affinity bonds between the two immobilised constituents, with a degree of linkage which changes reversibly as a function of the concentration of the biochemical species in the medium, in that the response reflects a change in the degree of linkage between the substrate parts or a physical change resulting from such a change in the active part of the sensor, and in that the sensor comprises elements for converting the response from the response-giving active part into a sensor signal.
  • the substrate parts consist of an appropriate polymer or other macromolecular substance, cf. the examples below.
  • a sensor which acts in accordance with a competitive principle and, as a result, possesses the advantages associated therewith, i.e. special reversibility and an improved facility for adapting the sensor to the actual concentration range , but which at the same time differs from the Schultz sensor in several very advantageous ways.
  • the sensor according to the invention it is for instance possible to process responses according to other principles than optical fluorescence detection.
  • the sensor according to the invention When used in connection with low-molecular analytes it will be possible to reduce the response time by comparison with the Schultz sensor. This is due to the fact that with the sensor according to the invention the diffusion necessary to achieve equilibrium is limited to analyte diffusion.
  • the Schultz sensor as mentioned above, diffusion takes place of the high-molecular competitive ligand, the diffusion coefficient of which is far lower than that of the analyte, and this results in slower attainment of the equilibrium response.
  • the competitor of the analyte is immobilised by bonding to a substrate instead of being isolated from the ambient medium with the aid of a dialysis membrane.
  • the use of a non-immobilised competitor of the analyte means that the sensor must comprise a dialysis membrane so that the sensor can only be used in connection with relatively lowmolecular analytes.
  • the sensor according to the invention is based on binding the analyte analog to a macromolecular substrate. This enables the use of other detection principles, e.g. detection of light attenuation or detection of forces or pressures.
  • the biochemical species may be a constituent of a body fluid such as blood, plasma, serum, spinal fluid, saliva, urine etc.
  • a body fluid such as blood, plasma, serum, spinal fluid, saliva, urine etc.
  • constituents are polypeptides; proteins, including conjugated proteins, enzymes and hormons; antigenic polysaccharides of microbial origin; and antigenic low-molecular substances such as body fluids, agents for the treatment of plants, small peptides, aminoacids, low-molecular hormons and metabolites of these substances.
  • the biochemical species can also consist of a substance derived from plant or animal tissue cultures or by fermentation, e.g. a monoclonal antibody, or it can be a microorganism or a virus.
  • the other constituent of the affinity pair may be any substance whatsoever capable of taking part in a specific binding reaction with the biochemical species by recognising and linking up with a closely defined specific binding site or determinant in the biochemical species while giving rise to affinity binding.
  • a competitor of the biochemical species signifies a substance competing with the biochemical species and the same binding site on the other constituent of the affinity pair, thus constituting in the same way as the biochemical species a partner for this other constituent.
  • a competitor may e.g. be a fragment of the biochemical species comprising the same specific binding site as the biochemical species.
  • an affinity pair is “a ligand-antiligand pair”, “a ligand-receptor pair” and “a specific binding pair”. Also the expressions “binding site”, “receptor site”, “binding location”, “specific binding site”, “determinant” and “epitop site” are used synonymously in the majority of contexts.
  • affinity pairs are: antigen-antibody; hapteneantibody; immunoglobulin- protein A; carbohydrate-lectin; biotinavidin; hormon-hormon recptor protein and complementary nucleotide chains.
  • EP 46004 contains a more comprehensive survey of analytically interesting biochemical species capable of being constituents of an affinity pair.
  • the two substrate parts have two directly adjacent surfaces to which the two immobilised constituents are immobilised. Immobilisation of the two constituents can be brought about by any suitable immobilisation technique whatsoever.
  • each of the two surfaces consist of a material with a large specific surface area, e.g. a polymer network such as a polyamide network.
  • the degree of linkage between the two surfaces can be appropriately determined by mechanically measuring the adhesion force between the two surfaces.
  • one of the substrate parts consists of an optical wave conductor, e.g. an optical fibre or a capillary tube made of a suitable material, the other substrate part consisting of a number of small particles, e.g. latex spheres.
  • an optical wave conductor e.g. an optical fibre or a capillary tube made of a suitable material
  • the other substrate part consisting of a number of small particles, e.g. latex spheres.
  • the substrate parts, to which the two partners are immobilised consist of polymer chains of a type which, given an appropriate degree of cross-linkage, can form a gel, and between the polymer chains there is a sufficient number of cross-linkages to produce gel, these linkages consisting wholly or partly of affinity bonds between the two immobilised partners.
  • cross-linkages in the gel can thus consist of a combination of cross-linkages in the form of affinity bonds between the immobilised constituents as well as other cross-linkages, e.g. of covalent type.
  • the polymer chains may e.g. be such as occur in synthetic or natural hydro-gels, and immobilisation of the two constituents to the polymer chains can be brought about by means of covalent binding via e . g. glutaraldehyde or an oxirane. If a sensor of this type, where the polymer gel in the active response-giving part of the sensor comprises cross-linkages in the form of affinity bonds, is applied in a solution containing the biochemical species, the concentration of which is to be determined with the aid of the sensor, the number of affinity bonds in the polymer gel will decline owing to competitive inhibition.
  • Changes in the degree of cross-linkage will affect a large number of physical characteristics of the gel, e.g. the mechanical characteristics, the dielectric characteristics, the conductivity and the volume of the gel, and in principle there is a number of ways in which the response can be detected and thereafter converted to a sensor signal.
  • a change in volume can be transformed into a mechanical application of force, suitable for direct measurement with the aid of a pressure transducer.
  • a change in volume owing to a change in the gel's dry substance content per unit of volume will bring about a change in refraction index.
  • Such a change can be detected by interferometry, ellipsometry or plasmon resonance. It may be assumed that a gel comprising affinity bonds can be produced in several ways.
  • a first method of production involves the preparation of a first solution of polymer chains, the introduction of reactive groups originating from, for instance, glutaraldehyde or an oxirane on the polymer chains and immobilisation of one of the constituents by linkage to the reactive groups on the polymer chains.
  • another solution of polymer chains is produced, to which the other constituent is immobilised.
  • fig. 1 is a sketch of the response characteristics of a sensor with integral competitive principle
  • fig. 2 is a sketch of an embodiment of the sensor according to the invention.
  • Fig. 3 is a sketch of a measuring rig, including a different embodiment of the sensor according to the invention.
  • Fig. 1 is discussed in the preamble of the present specification.
  • Fig. 2 is a schematic drawing of the above mentioned embodiment of the invention, where the active response-giving part of the sensor contains a cross-linked gel comprising affinity bonds between the two immobilised constituents.
  • the sensor bearing the general designation 1 is immersed in a medium 3 containing the biochemical species, the concentration of which is to be determined with the aid of the sensor.
  • a gel 2 which is in contact with medium 5 through a perforated plate 1.
  • Gel 2 comprises affinity bonds, the concentration of which and, accordingly, the gel's degree of linkage, is acted upon by the analyte concentration.
  • a transducer element 4 possibly a pressure transducer, detects changes in the degree of linkage and converts them to a sensor signal, which through a lead 5 connected with a sensor cable 6 is conducted away and processed within a measuring instrument not illustrated.
  • Fig. 3 shows in schematic form a sensor 1 according to the invention in the form of an optical fibre treated with the one half of an affinity pair and with a coating of particles not illustrated, to which the other half of the affinity pair is immobilised.
  • the particles are held to the fibre surface by affinity bonds.
  • the coated fibre and the particles are produced as described in the following example.
  • the fibre is mounted centrally within a measuring chamber 2, which constitutes a borehole within a perspex block 3.
  • a supply channel 4 leads to one end of the measuring chamber, the other end of the measuring chamber being provided with an outlet 5 from which issues an outlet channel 6.
  • a light-emitting diode 7 is connected to one end of the fibre and constitutes a source of light, and a light-sensitive diode 11 is connected to the other end of the fibre and constitutes a light detector.
  • the light-emitting diode 7 is an IR light-emitting diode (SFH 450 from Siemens, West Germany), which emits light with a wavelength of 950 nm, and is supplied with current with a frequency of 1.4 kHz by a square-wave generator 8.
  • the light-sensitive diode 11 is a PIN diode with a high zero slope. The flow of light therefrom is lock-in detected in an averaging circuit with an averaging time constant of 1 second.
  • the detector circuit in its entirety designated 9, consists of an electrometer amplifier with a bandwidth of 10 kHz.
  • the signal therefrom is conducted via a transmission capacitor alternately to earth (when the light-emitting diode 7 is extinguished) and to an averaging operation integrator (when the light-emitting diode 7 is alight).
  • the alternation is brought about by an analog multiplexer controlled by the supply voltage of the light-emitting diode. From the integrator the signal is conducted to a logarithmic amplifier, and the signal therefrom is transmitted to the computation and reading system 10.
  • the fibre of the evanescent wave light conductor is produced from a 600 urn thick commercial quartz light conductor with polymer cladding (HCP-606; 600/630 Ensign-Bickford Optics Co., Cincinnati, USA).
  • the cladding is removed with a sharp knife and the remaining binding layer is removed by burning off in a gas flame. Then the two end faces are ground flat. After cleaning with 3 ml ammonia (25%) and 3 ml H 2 O 2 (30%) in 15 ml distilled water at 80° for 5 minutes the fibre is mounted in a rotating holder within a vacuum chamber, exposing 2 centimetres at each fibre end. A thin layer of gold is applied to the two fibre ends by vacuum metallisation. The end faces are protected by rubber caps subject to vapour metallisation.
  • a number of fibres are mounted in a glassholder which supports the fibre ends and leaves the 6 cm at the centre free.
  • the glassholder with the fibres is treated with 3 nil cone. HCl and 3 ml H 2 O 2 in 18 ml distilled water at 80° for 5 minutes.
  • the holder with the fibres is cleaned in distilled water and transferred to dry toluene via dry acetone.
  • the holder is suspended in a reaction vessel with mechanical agitator and reflux cooler.
  • the ambient air is displaced by means of dry nitrogen, and 8 ml 100% 2-glycidcxy-trimethoxysilane is added.
  • 8 ml 100% 2-glycidcxy-trimethoxysilane is added.
  • 160 ⁇ l triethylamine is added and the mixture boiled for 3 hours.
  • the holder is transferred to distilled water via relatively warm toluene, acetone and diethylether.
  • the silanised quartz is now activated by treatment for 30 minutes at 80° using HCl in water at pH 1.5. Then it is transferred to dry acetone and treated with 0.1 ml tresyl chloride and 0.2 ml pyridine in 20 ml dry acetone. The treatment is effected on ice for 10 - 20 minutes stirring slowly. The quartz is now washed in a 1:1 mixture of acetone and 1 mM HCl and then in 1 mM HCl alone and finally in distilled water.
  • the activated quartz fibres are now brought into contact with an antibody, e.g. a monoclonal antibody orientated towards mono-component porcine insulin.
  • the concentration is about 1 mg/ml in a 0.2 M phosphate buffer with a pH-value of 7.5.
  • the reaction proceeds throughout the night at 10°. It is followed by washing with 0.5 M
  • Chamber 2 is filled with a suspension of 100 ⁇ g particles/ml. In the course of time the absorbance increases towards a constant value A o . Once the absorbance has stabilised, the chamber is emptied for suspension and briefly rinsed with PBS.
  • the fibre 1 is now converted into a competitive sensor according to the invention.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
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  • Engineering & Computer Science (AREA)
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  • General Physics & Mathematics (AREA)
  • Hematology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Analytical Chemistry (AREA)
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  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)

Abstract

Le capteur (1) ci-décrit permettant de déterminer la concentration d'une espèce biochimique fonctionne d'après un principe conpétitif et la partie active (2) du capteur donnant la réponse comprend les deux partenaires dans une paire d'affinité immobilisée sur deux parties d'un substrat. L'un de ces partenaires est constitué de l'espèce biochimique ou d'un compétiteur de celle-ci.
PCT/DK1986/000126 1985-11-18 1986-11-17 Capteur de determination de la concentration d'une espece biochimique Ceased WO1987003093A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK531185A DK531185A (da) 1985-11-18 1985-11-18 Sensor til bestemmelse af koncentrationen af en biokemisk species
DK5311/85 1985-11-18

Publications (1)

Publication Number Publication Date
WO1987003093A1 true WO1987003093A1 (fr) 1987-05-21

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Application Number Title Priority Date Filing Date
PCT/DK1986/000126 Ceased WO1987003093A1 (fr) 1985-11-18 1986-11-17 Capteur de determination de la concentration d'une espece biochimique

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EP (1) EP0245396A1 (fr)
DK (1) DK531185A (fr)
WO (1) WO1987003093A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0309214A3 (fr) * 1987-09-22 1990-03-14 BAXTER INTERNATIONAL INC. (a Delaware corporation) Connecteur de sonde à fibre optique pour appareils de mesures physiologiques
WO1991002981A1 (fr) * 1989-08-25 1991-03-07 Amersham International Plc Procede d'analyse
WO1992001939A1 (fr) * 1990-07-17 1992-02-06 Amersham International Plc Detection d'ions metalliques
US6163714A (en) * 1998-07-03 2000-12-19 Torsana Diabetes Diagnostics A/S Optical sensor for in situ measurement of analytes
US6625479B1 (en) 1998-07-03 2003-09-23 Torsana Diabetes Diagnostics A/S Optical sensor for in situ measurement of analytes
EP1335200A4 (fr) * 2000-05-11 2004-03-24 Matsushita Ecology Sys Co Dispositif de capteur chimique
USRE38525E1 (en) 1998-07-03 2004-06-08 Torsana Diabetes Diagnostics A/S Optical sensor for in situ measurement of analytes

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2008747A (en) * 1977-11-25 1979-06-06 Int Diagnostic Tech Immunoassay method
WO1984000817A1 (fr) * 1982-08-09 1984-03-01 Myron J Block Dispositif et procedes d'analyse immunologique
US4481298A (en) * 1981-04-13 1984-11-06 Amf Incorporated Pre-precipitated double antibody immunoassay method
GB2141544A (en) * 1983-05-25 1984-12-19 Nat Res Dev Diagnostic device incorporating a biochemical ligand

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2008747A (en) * 1977-11-25 1979-06-06 Int Diagnostic Tech Immunoassay method
US4481298A (en) * 1981-04-13 1984-11-06 Amf Incorporated Pre-precipitated double antibody immunoassay method
WO1984000817A1 (fr) * 1982-08-09 1984-03-01 Myron J Block Dispositif et procedes d'analyse immunologique
GB2141544A (en) * 1983-05-25 1984-12-19 Nat Res Dev Diagnostic device incorporating a biochemical ligand

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0309214A3 (fr) * 1987-09-22 1990-03-14 BAXTER INTERNATIONAL INC. (a Delaware corporation) Connecteur de sonde à fibre optique pour appareils de mesures physiologiques
WO1991002981A1 (fr) * 1989-08-25 1991-03-07 Amersham International Plc Procede d'analyse
WO1992001939A1 (fr) * 1990-07-17 1992-02-06 Amersham International Plc Detection d'ions metalliques
US6163714A (en) * 1998-07-03 2000-12-19 Torsana Diabetes Diagnostics A/S Optical sensor for in situ measurement of analytes
US6625479B1 (en) 1998-07-03 2003-09-23 Torsana Diabetes Diagnostics A/S Optical sensor for in situ measurement of analytes
USRE38525E1 (en) 1998-07-03 2004-06-08 Torsana Diabetes Diagnostics A/S Optical sensor for in situ measurement of analytes
EP1335200A4 (fr) * 2000-05-11 2004-03-24 Matsushita Ecology Sys Co Dispositif de capteur chimique
US7662612B2 (en) 2000-05-11 2010-02-16 Panasonic Corporation Chemical sensor device

Also Published As

Publication number Publication date
DK531185A (da) 1987-05-19
DK531185D0 (da) 1985-11-18
EP0245396A1 (fr) 1987-11-19

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