GB2141544A - Diagnostic device incorporating a biochemical ligand - Google Patents
Diagnostic device incorporating a biochemical ligand Download PDFInfo
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- GB2141544A GB2141544A GB08413167A GB8413167A GB2141544A GB 2141544 A GB2141544 A GB 2141544A GB 08413167 A GB08413167 A GB 08413167A GB 8413167 A GB8413167 A GB 8413167A GB 2141544 A GB2141544 A GB 2141544A
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- ligand
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- 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
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/001—Enzyme electrodes
- C12Q1/002—Electrode membranes
- C12Q1/003—Functionalisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/11—Compounds covalently bound to a solid support
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/403—Cells and electrode assemblies
- G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
- G01N27/4145—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS specially adapted for biomolecules, e.g. gate electrode with immobilised receptors
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- Y—GENERAL 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
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/806—Electrical property or magnetic property
Description
1 GB 2 141 544A 1
SPECIFICATION
Diagnostic device incorporating a biochemical ligand This invention relates to a device useful in diagnostics in which a biochemical species is attached to the surface of a sensor. An important embodiment relates to a field effect transistor (FET) having a biochemical species attached to the gate thereof (a BIOCHEMFET).
A field effect transistor is a serniconductive device having two spaced apart regions of the same doping polarity, usually n-type, between which a potential difference is applied. These regions are connected by a "gate" of insulative material, usually of silica or silicon nitride.
Current flows from one of the regions ("the source") to the other region ("the drain") via an induced conducting channel under the gate and is modulated according to the electric potential applied to the gate. Contact of the gate with a material containing charged species alters the electric potential and therefore the value of the source to drain current, which can be measured.
Alternatively the source to drain current can be maintained constant by applying an additional potential to the gate and the additional potential necessary for this purpose can be measured.
The FET has been used mainly as an ion-sensitive device, known as an ISFET. The gate region is overlaid with a membrane capable of interacting selectively with ions present in a solution. That is, the membrane absorbs ions from the solution which alter the electric potential of the membrane and therefore of the gate.
US Patent 4,020,830 (C.C. Johnson, S.D. Moss and J.A. Janata, assignors to the University of Utah) describes ISFETs for use in measuring the concentration of an enzyme or substrate. A second thin film layer or membrane, having an enzyme or substrate immobilized therein is positioned over the ion-selective membrane. When the membrane containing the enzyme, for example, is contacted with a solution containing the substrate, the substrate diffuses into the membrane and reacts with the enzyme. The reaction is accompanied by a net yield or loss of ions. The ion concentration of the underlying ion-selective membrane then changes, thereby affecting its electric potential and giving rise to a measurable change in an electrical signal.
A short review of ISFETs and their application in clinical chemistry and biology is provided by J. Janata, Analytical Proceedings February 1982, pages 65-68.
In another kind of FET mentioned in US Patent 4,020,830, the gate is covered by a membrane or a hydrophobic polymer, e.g. of polyvinyl chloride or polystyrene, to which an antibody or antigen is covalently bound to the surface of the membrane. The covalent bonding of proteins to membranes is described in UK Patent Specification 1,527, 772 (The University of
Utah), in relation to "immunoelectrodes" in which a sensing electrode is surrounded by a sheath of the membrane. In one example, an electrode was coated with polyvinyl chloride, the polyvinyl chloride swelled with a solvent, dried and reacted first with epichlorohydrin and then with the protein Concanavalin A. The reaction of yeast mannan, a polysaccharide precipitated by Concanavalin A was then monitored. In another example rabbit anti-human 7S gamma-globulin antibody was substituted for Concanavalin A and the binding thereof to human 7S gamma- 40 globulin antigen at pH 5 was monitored.
US Patent 4,238,757 (Schenk, assignor to General Electric Company, New York) describes a FET in which a monomolecular layer of a protein, for example an antibody or antigen, is absorbed onto the top of the insulating layer of the gate. This is a physically attached Langmuir Blodgett layer. The reaction of the absorbed antibody with an antigen to be detected affects the 45 charge concentration in the gate and therefore the drain current.
European Patent Specification 75353 (Battelle Memorial Institute) describes a method for the determination of a species (analyte) in solution wherein the analyte is made to react with a specific reactant on a waveguide, thus modifying the optical properties of the waveguide, which are measured and compared with standard reference data obtained from calibrating samples of 50 the analyte. The reactant is a protein such as IgG. To attach it the glass is preferably etched in a grating-like pattern with HF. When the IgG (antibody) is introduced, it bonds to the etched areas. An analyte antigen will then be attracted to the IgG. The discontinuity brought about by the pattern will produce a more ordered pattern of scattered light, thus improving the efficiency with which the scattered light is collected in a photomultiplier tube.
US Patent 4334480 (Malmros) describes a semiconductor sensor for assay of an analyte in which a specific binding partner for the analyte is absorbed onto a polyacetylene semiconductor.
The polyacetylene repeating units ( = CH-CH-)n, where n is a large number, have extensive alternating conjugated pi orbitals which provide the serniconductive effect. In order to eliminate "background" variables, two such polyacetylene devices are preferably electrically balanced in 60 the same Wheatstone bridge circuit.
Japanese Patent Application Publication No. 80.10546 (Asahi Glass K.K.) describes a FET immuno-sensor in which an antibody or antigen is bounded covalently to the insulated gate.
Various methods of bonding are proposed. One method is to react the hydroxyl groups of the silica of the gate with gamma-amino propyltriethoxysilane, whereby the ethoxy groups react with 65 2 GB 2 141 544A 2 the silica and the amino group is left pendant. The amino group is then reacted with the carboxyl group of an antigen or antibody. Another method proposed is to treat the silica surface with thionyl chloride to convert the hydroxyl groups thereof to chlorine atoms and then to react the antigen or antibody, through a carboxyl or amino group thereof, with the chlorinated silica. A more direct method of bonding mentioned involves the reaction of the hydroxyl groups on the 5 silica with carboxyl or hydroxyl groups of an antigen or antibody, thereby forming ester or ether linkages.
To the applicant's knowledge, the prior art has not proposed any solution to the problem of how to attach two or more biochemical species, such as antigens or antibodies, to pre-defined areas on the surface of a "chip". Such a chip could be fabricated as a multi-gated FET, each 10 gate thereby serving as a sensor, and different biochemical species would be attached to the gates. This multi-gated FET could then be used to detect several different species. It would also be possible to attach some standard or reference biochemical species to each chip so as to provide a "control" for each diagnostic test. Although, the prior art mentions the desirability of making such multicomponent devices, see e.g. US Patent 4,020,830, column 11 line 62 to column 12 line 2 and A.U. Ramsing et al., Analytica Chimica Acta 118, 45-52 (1980) at page 51, it is not suggested therein how this can be achieved.
Chemical Abstract 93, 88076 h (1980), referring to Japanese Patent Application Publication 80.24603 (Olympus Optical Co. Ltd.), mentions ISFETs having multiple elements on a single substrate.
US Patent 4242096 (Oliviera, assignor to 3Ms Company) describes an assay for antigen using a piezoelectric oscillator pre-coated with an antigen. The oscillator is a small quartz wafer having two metal electrodes deposited thereon. When placed in an oscillator circuit the portion of quartz wafer lying between the electrodes vibrates with a precise natural frequency. The oscillator is coated first with antigen and then with a mixture of an appropriate antibody and an analyte antigen. The antigen coating is provided by absorption by self-crosslinking it on the surface of the oscillator using glutaraldehyde, or by priming the surface with poly(2-hydroxy-3dimethylamino-1,4-butane). The same wafer can be provided with a plurality of pairs of electrodes, the portion of crystal between each pair having a different characteristic frequency.
The oscillator is then coated with a mixture of antigens each serving as a specific binding partner for a different antibody, whereby the same oscillator can be contacted with several different antibodies and multiple assays carried out using the same quartz crystal. No further details are given and it is not clear how one would selectively coat the electrodes with different antibodies.
It has now been found that it is possible to position individual biochemical species in selected, 35 i.e. pre-defined, areas of the surface of sensor such as a chip. According to the present invention, the surface of a sensor is modified by attaching to it, by covalent bonding, a group containing a photoactivatable function, exposing the thus modified surface to photoactivating radiation in selected areas only of the surface, to activate the function, and reacting the function thus activated to bond covalently with a biochemical species. The biochemical species will hereinafter be referred to as ligand, a term which denotes merely that it is capable of participating in some form of binding reaction with a suitable partner. The binding may be of the affinity type, e.g. antigen or hapten-antibody or reversible enzyme- substrate, or it may be a chemical binding.
What is novel and inventive herein comprises the idea and the subsequent practical realisation 45 despite the incredibly small scale involved (even a large test chip typically measures only 3 mm X 3 mm). that it is possible to use a photoactivation technique to select minutely small areas, most suitably with the aid of a mask, and thereby successfully attach the biochemical ligand covalently in those areas only.
The invention also includes the device so made, which is definable independently of the 50 process of manufacture, as a device which comprises a sensor having a surface to which a group comprising a residue of a biochemical ligand is attached covalently, whereby a physical characteristic of the sensor varies according to whether a binding partner is bound to the ligand, characterised in that the biochemical ligand residue of the group is attached covalently to the surface of the sensor in selected areas only thereof and through a photoactivated covalent 55 linkage.
Also included within the scope of the invention is the use of such a device for assay of a binding partner of the ligand, and a kit useful in diagnostics comprising the device together with at least one binding partner for the biochemical ligand, for testing and/or standardisation of the device.
The invention is particularly applicable to attachment of the group comprising the biochemical ligand residue to a silica surface. A particularly preferred method of attachment is illustrated below, with reference to a silica surface:- 1 3 GB 2 141 544A 3 1,/0\ 1 -si- si -Si-OR + SOC1 -si-ci 1 2 1 or 1 1 4(-Si-OH) + TiCl + TiO + 2H 0 1 4 2 2 9 N -si-ci + NH CH 2 CH 2 CH 2 NH-e 3 2 >--i 0 2 N 1 (1) + Hcl + SO 2 (2) -Si-NH-CH H CH 2C 2 2NH- "3 >--i 0 2 N Photoexpose at'350 (3) 20 1 -Si-NHCH CH CH N^ 1 2 2 2 Reactive aryl nitrene (4) 0 2 N Nucleophilic 25 Addition attack 1 3 NH R (5) 6/ 2≥( 4 R R R / \ (6) 30 R I R 2. I / R 5 I Si-NHCH 2 CH 2 CH 2 N4- NH-N 6 -'li-NHCH 2 CH 2 CH 2 NH-P- N R 3 - I ()4N 35 0 2 N 4 (9) (8) Insertion R 7 H-C -:RS (7) 1.1 R 9 1 , R 7 -Si-NHCH 2 CH 2 CH 2 NH.... f \\_NH-C R 8 (10) 1 -Y=/ - 11 R 9 0 2 N (R', R5 and R 7 represent organic groups; R 2, R 3, R 4, R6, W' and R9 represent organic groups or hydrogen atoms necessary to complete the biochemical ligand molecules (5), (6) and (7).
Referring to the illustrated method, the silica produced by thermal deposition in the manufacture of a chip is mainly in an unreactive form, having such linkages as 1 --' 0 \ 1 -5i-Si- which must first be hydrolysed to a silanol, -Si-OH, form. This can be done by dipping the surface of the chip for about a minute in 1 OM sodium hydroxide, washing with water and then 60 with a hydrophilic organic solvent such as acetone and drying. Alternatively, several hours refluxing in dilute hydrochloric acid produces a hydrophHic surface, although the effect is not as pronounced in the alkali treatment.
The reactive silica surface is then reacted to replace a hydroxyl group by a more reactive function. In the illustrated method this is a chlorine atom, which can be introduced by reaction 65 4 GB 2 141 544A 4 with any chlorinating agent capable of nucleophilic displacement at a silicon atom of the hydroxyl group, e.g. thionyl chloride or a titanium chloride.
The chlorinated silica surface is then reacted directly with a compound containing a photoactivatable function at one end or in a branch of the molecule and a function at the other end capable of undergoing a nucleophilic displacement of the chlorine atom on the silicon atom. The latter will ordinarly be an amino group as in the illustrated scheme. The photoactivatable function is preferably provided by an aryl azide, e.g. 3nitro-4-aminophenyl azide, residue. Other examples of residues providing photoactivatable functions are those derived from ethyl 2diazomalonyl chloride, nitrophenyl ethers of formula 02N-,CH 3 OR where R is an alkyl group, aromatic ketones as described in Journal of Biological Chemistry 249, 3510-3518 (1974), and phosphenyl azides as described by Breslow et al., Journal of the American Chemical Society, 96, 5937-9 (1974). Other photoactivatable functions can be provided by the so-called photoaffinity labels, see e.g. Chapter 6, pages 167-179 of the book "Laboratory techniques in biochemistry and molecular biology", Volume 4 Part 1: "Chemical 20 Modification of Proteins", by A.N. Glazer, R.J. Delange and D.S. Sigman, general ed. T.S.
Work and E. Work, North-Holland Publishing Co. and American Elsevier Publishing Co. Inc.
1975.
A preferred device of the invention has a surface of silica and the biochemical ligand residue is attached to the surface through a group of formula -NH 2(C'2)n" \1 0 the left-hand end of which is attached to a silicon atom of the surface and the right-hand end of which is attached to the residue of the biochemical ligand, and n is a number from 3 to 12.
Instead of chlorination of the silica and reaction of the chlorinated silica with the group containing the photoactivatable function, it might be desirable to react the silica with a silane, for example allyidimethylchforosilane, according to the scheme:
CH3 1 1 - bt-Uti + U-Si-CH2CH = CH2 40 1 1 LP13 CH3 1 1 101 45 51.2 SI-U-1 _(;M2-CH=CH 1 1 9 CH3 0 CH, 50 1 1 -bi-u-bi-CH2-COOH 1 1 CH3 The ailyl-terminatecl siloxane is oxidised, e.g. with potassium permanganate dissolved in 55 benzene and a crown e-ther, to introduce a carboxyl torrj-!ir-us, vibich is thon reacted with a photoactivator having an amino terminus, forming an amide linkage. Other silanes such as ga m ma-g lycidoxypropyl m ono m ethoxyd i methylsi lane and cyanopropyidimethylchlorosilane could also be exploited to yield bonded phases capable of subsequent chernical modification for 60 attachment of biochemical ligands.
The following reaction scheme illustrates some methods of modifying a silica surface using a gamma-glycidoxypropyl monomethoxysilane, and attaching thereto a group comprising a bioche mical ligand (LR-ligand residue):
GB 2 141 544A 5 1 -0-Si-OH H", OR OR 0 1 A -O-Si(CH 2)3 OCR 2 CH - CH 2 -O-Si(CH 2)3 CH 2 CH-CR 2 1 1 1 tresyl chloride OR NalO 4 10 1 1 1 ' 1 1 1 OSO 2 CH 2 U 3 Biochemical ligand Biochemical Biochemical ligand ligand 15 1 ' p 0 H -0-Si-(CH) OCR CH-N-(LR) 4. 1 1 1 2 3 2 -0-Si-(CH 2)3 OCR 2 CHCH 2 -NH-(LR) 1 - 1 NaBH4 20 The spacing or bridging arm of the surface-modifying molecule should not be too long, in order to ensure that the sensing function of the device is easily activated by the binding interaction of the biochemical ligand and in order to avoid complications in linking it to the silicon atom. A long carbon-chain spacing arm would create a hydrophobic layer on the silica which might be detrimental, for example, when an enzyme is attached. The enzymic interaction will often be dependent on loss or gain of protons, which will not readily penetrate a hydrophobic layer to reach the sensor surface.
Photoactivation through a mask or screen can be carried out in any manner appropriate for the photoactivating group, i.e. one must choose a radiation, normally in the UV or visible region of the spectrum, to which it is sensitive, The areas selected by means of the mask for photoactivation can take any appropriate form, 35 depending on how many biochemical ligands are required to be attached. A preferred device is a multi-gated FET having one biochemical ligand attached to each gate and therefore giving an independent signal from other ligands attached to other gates.
For assay purposes a ligand attached to one gate can be left free, i.e. unbound and ready to interact with its partner in the sample to be assayed, while a ligand attached to another gate is 40 blocked from reaction with the binding partner and serves as a control or "reference" gate. In a constant current mode and with a differential amplifier on the same chip, the difference in response of the antigen-sensitive gate and the separate "reference" gate would serve as an internal compensation for any fluctuations in sample composition temperature, pH etc. It is then possible to compare the signals given by the (unbound) ligands, and thereby estimate the 45 amount of binding partner present in the sample.
It is envisaged that the invention can provide a "printed circuit" of a given biochemical ligand, which may have applications outside the diagnostic field, for example, in the develop ment of bio-computers.
The biochemical ligand will normally be a protein and therefore have an amino function. Thus 50 it may be an enzyme, antigen, antibody, receptor protein, other binding protein, or lectin for example. However, it could also be a hapten, co-enzyme, electron mediator or other biologically reactive ligand, particularly one of low molecular weight. Thus, the biochemical ligand could be a sugar or steroid. It may have some other functional group than amino for example a hydroxyl group or carboxyl group in steroid haptens. If the biochemical ligand does not have a group readily reactive with the residue left when the photoactivatable group has been photoactivated, the ligand can normally be further reacted to introduce a more appropriate group.
The silica surface could be replaced by silicon nitride (preferred) or oxynitride or by an oxide of another metal, especially aluminium, titanium (IV) or iron (111) oxides, for example, or any other film, membrane, insulator or semiconductor overlying the device.
The device of the invention need not be based on a FET. Other sensors which can be used include bipolar transistors, semiconductor or other electrodes, piezoelectric crystals, thermoelectric crystals, chargecoupled devices, opto-electronic devices such as integrated optics and waveguide sensors, fibre optic devices, other transducers and magnetic sensors in which a magnetic field strength is measured. Serniconductive devices can contain inorganic semiconduc-
6 GB 2 141 544A 6 tors such as doped silica or organic semiconductors such as polypyrrole. While the physical characteristic sensed is preferably electrical or magnetic, in view of the availability of sensors which amplify changes in electric and magnetic fields, it can in principle be any other physical characteristic, e.g. optical, thermal or the emission or absorption of other radiations.
The following Examples illustrate the invention.
EXAMPLE 1 (1) Synthesis of 4-fluoro-3-nitrophenyl azide grams of 4-fluoro-3-nitroaniline were dissolved in a mixture of 30 mi concentrated HCI and 5 mi water with warming. The solution was filtered and cooled to 2WC with stirrring. (The 10 temperature was maintained between 15 and 20C during subsequent production and reaction of the diazonium salt.) An ice-cold solution of 2. 4 grams of sodium nitrite in 5 mi water was added dropwise with stirring. The mixture was stirred for a further 30 minutes after completion of the addition, then quickly filtered and the resultant diazonium salt solution was returned to the flask. Stirring was continued during dropwise addition of a solution of 2.2 grams 15 of sodium azide in 8 mi ice-cold water. After completion of this addition, the mixture was allowed to warm and the product was collected by filtration and washed with water. After drying, the product was recrystallised from petroleum ether.
(2) Synthesis of N-(4-azide-2-nitrophenyl)- 1, 3-diaminopropane 2.5 ml (30 mM) 1,3-diaminopropane was dissolved in 25 ml ethanol. To this solution, was added a solution of 1.82 g (10 mM) 4-fluoro-3-nitrophenyl azide in 25 ml ethanol. The addition was performed dropwise with stirring. The mixture was stirred at room temperature for 16 hours. After this time, 15 ml of water were added and the pH adjusted to between 1 and 2 with concentrated HCI. This solution was filtered to remove the disubstituted amine, cooled on ice and the product was precipitated by the slow addition of concentrated aqueous ammonia with stirring. The product was collected by filtration of the cold mixture, washed with ice-cold water and dried in vacuo.
(3) Pre-treatment of the silica surface Silicon semiconductor slices having a surface layer of silica were grown thermally and divided into 3 mm square chips. The silica surfaces were hydrolysed by dipping the slices in 1 OM sodium hydroxide for 1 minute. The slice and solution were not agitated. This treatment was followed by extensive washing in water and slow drying in a stream of nitogen or argon. This yielded a very hydrophilic surface.
(4) Coupling of N-(4-azido-2-nitrophenyl)- 1, 3-diaminopropane to the silica surface Absorbed water on the silica surface was first removed by heating the slices to 1OWC under high vacuum. The slices were then immersed in freshly distilled thionyl chloride. The vessel was sealed and allowed to stand at room temperature for 24 hours. From this stage until completion 40 of coupling of the enzyme, water was rigorously excluded. After 24 hours, excess of thionyl chloride was poured off the slices, the vessel was evacuated and heated to 1 5WC under high vacuum to remove absorbed thionyl chloride, hydrogen chloride and sulphur dioxide from the surface. After cooling, a saturated solution of N-(4-azido-2-nitrophenyi)1,3-diaminopropane in dry tetrahydrofuran was added and allowed to react in the dark'at 4WC for 24 hours.
(5) Light-dependent coupling of beta-galactosidase to the surface All operations were performed under red safety light. The slices were removed from the above-mentioned reaction solution and washed in tetrahydrofuran and water and covered with about 1 micro-litre of a solution of E. coli beta-galactosidase, Sigma grade V1 I I, activity about 50 1,000 units/mi in 0. 1 M sodium phosphate buffer of pH 7.5 containing 0. 5M NaCi. The enzyme solution was kept on ice before use. The slice was exposed to light from a high pressure mercury vapour lamp (125 watts) through a mask. The incident light was first caused to be reflected from a plastic mirror which absorbs the far ultra-violet light. The mask was of aluminium having a pattern consisting of 5 circular holes arranged in a cruciform layout. The 55 exposure time was 1 minute, after which the slice was washed extensively in ice-cold buffer (0.1 M sodium phosphate, pH 7.5 containing 0.5M sodium chloride. The slice was stored in this buffer and could then be exposed to normal lighting.
(6) Assay for beta-galactosidase activity A saturated solution of 4-methylumbelliferyl beta-D-galactopyranoside was prepared in the above buffer and spread on the surface of the exposed slice. The slice was placed in a dark box under a short-wave ultra-violet lamp. Care was taken not to agitate the slice. After several minutes, blue florescence was observed, the intensity of which reproduced the pattern of 5 holes of the mask. The fluorescence is due to the release of 4- methylumbeiliferone from the 65 1 1 0:
1 7 GB 2 141 544A 7 hydrolysis of 4-methylumbelliferyi-beta-D-galactopyranoside by beta- galactosidase.
EXAMPLE 2
Example 1 was repeated, using an alternative procedure for the chlorination of the silica surface. After pre-treatment of the slices and drying as described previously, the slices were placed in 10 ml dry toluene, to which was added 0.5 ml titanium (IV) chloride. The reaction was allowed to proceed overnight. The slices were then removed, washed with dry toluene and placed in a tetrahydrofuran solution of N-(4-azido-2-nitrophenyl)-1,3- diaminopropane as described previously. Again, great care was taken to exclude moisture.
EXAMPLE 3 (1) Pre-treatment of the silica surface The precedure of Example 1, stage (3) was repeated, using a chip coated with silicon nitride instead of silica.
(2) Reaction of allyldimethylchlorosilane with the surface of the chip The slices were heated to 1 50C under high vacuum to remove absorbed water on their surfaces. They were then immerspd in 10 ml of sodium-dried toluene containing 1 ml of ally1dimethylchlorosilane and 0.1 ml dry pyridine. The reaction vessel was filtered with a condenser and drying tube to exclude moisture and the toluene is refluxed for approximately 3 20 hours. The slices were then washed exhaustively in benzene, followed by toluene and finally acetone. The hydrophobicity of the resultant surfaces indicated that the reaction has been successful.
(3) Oxidation of the allyl group mg of the macrocyclic polyether known as---1 8-crown-6- was dissolved in 100 mi benzene. The solution was shaken vigorously with a concentrated aqueous solution of potassium permanganate until the purple colour of the benzene reacted a maximum intensity. The benzene layer was separated and filtered through a 2 micrometre---Millipore-(Registered Trade Mark) filter and applied to the surface of the slices. After 2 hours at room temperature the slices were 30 washed exhaustively in benzene, followed by toluene and finally acetone. The surface reverted to a hydrophilic character, indicating the presence of the desired carboxylic acid group in place of the terminal vinyl part of the allyl group.
3 5 (4) Coupling of the N-(4-azido-2-nitrophenyl)- 1, 3-diaminopropane to the surface The slices were washed in dry tetrahydrofuran and subsequently incubated with 1-ethyl-3-(3dimethyl aminopropyl) carbodiimide (0.5 mg/mi in dry tetrahydrofuran) for 1 hour at 2WC. The slices were washed exhaustively with dry tetrahydrofuran and incubated with a saturated solution of N-(4- azido-2-nitrophenyi)-1,3-diaminopropane in dry tetrahydrofuran in the dark at 4WC for 24 hours.
(5) Light-dependent coupling of beta-galactosidase to the surface (6) Assay for beta-galactosidase activity These steps were carried out as in Example 1.
EXAMPLE 4
Modified and unmodified silicon chips (4 mm X 4 mm) prepared as described above were placed in PTFE housing and held firmly by rubber 0-rings. Electrical contact to the rear face of the chip was achieved by grinding a small amount of gallium/indium eutectic in with a diamond 50 pen in order to remove the S'02 layer grown during storage and contacting with a brass/silver rod to which electrical contact was made in the normal way.
An Ag/AgC1 microreference electrode for use with silicon chips was fabricated by pulling out 3 mm soda glass tubing to a fine capillary 0.2 mm diameter. The capillary was sealed at the fine end with a plug of 2% (w/v) agarose saturated with KCl to act as a salt bridge and sealed 55 at the other with an Ag/A9C1 wire in saturated AgC1/KCL The potential of the microreference electrode was tested versus SCE at various pH values using a high input impedance (104 ohms) Keithley Model 642 electrometer. It was found that the drift in the A9/AgC1 microreference electrode was less than 1 mV per decade in pH and was therefore considered acceptable to act as a reference electrode for the modified chips.
Sodium acetate/sodium tetraborate buffers of equi-ionic strength but different pH values were used at 20.5C in order to assess the pH responseOf S'02 and Si,N4 coated chips both before and after surface silanization and derivatization as described above. The pH response of the electrode at constant ionic strength was substantially linear, giving a slope of approximately 35 6 5 mV per pH unit over the pH range 3.5 to 7 for S'31\14-coated chips and approximately 16 mV per 6 5 16 0 8 GB 2 141 544A 8 pH unit over the pH range 2 to 9 for S'02-coated chips. The linearity was unaltered on subsequent silanization. This observation opens the way to covalently bonding such enzymes as penicillinase to silanized oxide, oxynitride or nitride with retention of the pH response and thus of fabricating an enzyme-coated FET.
EXAMPLE 5
Example 3, steps (1) to (6) were repeated except that alkaline phosphatase was used in place of beta-galactosidase and 4-methyl umbcilliferyl phosphate was used as the substrate generating fluorescence (by hydrolysis of the phosphate by alkaline phosphatase).
Claims (17)
1. A device useful in diagnostics, which device comprises a sensor having a surface to which a group comprising a residue of a biochemical ligand is attached covalently, whereby a physical characteristic of the sensor varies according to whether a binding partner is bound to the ligand, characterised in that the biochemical ligand residue of the group is attached covalently to the surface of the sensor in selected areas only thereof and through a photoacti vated covalent linkage.
2. A device according to Claim 1, wherein the biochemical ligand is an antigen or hapten and a physical characteristic of the sensor varies according to whether or not an antibody is bound to the antigen or hapten.
3. A device according to Claim 1, wherein the biochemical ligand is an antibody and a physical characteristic of the sensor varies according to whether or not an antigen or hapten is bound to the antibody.
4. A device according to Claim 1, wherein the biochemical ligand is an enzyme and a physical characteristic of the sensor varies according to whether or not a substrate is bound to 25 the enzyme.
5. A device according to Claim 1, wherein the biochemical ligand is a coenzyme, steroid, sugar, electron mediator or other low molecular weight biochemical.
6. A device according to any preceding claim, wherein the surface of the sensor is of an inorganic oxide, oxynitride or nitride.
7. A device according to Claim 6, wherein the surface is of silica or silicon nitride.
8. A device according to Claim 6, wherein the surface is of iron (111) oxide and the sensor is a device for measuring magnetic field strength.
9. A device according to Claim 6, wherein the surface is of silica or silicon nitride and the sensor is a field effect transistor.
10. A device according to any preceding claim, wherein the photoactivated linkage is provided by the photolysis of an aryl azide group.
11. A device according to Claim 10, wherein the surface is of silica and the biochemical ligand residue is attached to the surface through a group of formula -NH 2 (CH 2) U NR-i 02 W the left-hand end of which is attached to a silicon atom of the surface and the right-hand end of which is attached to the residue of the biochemical ligand, and n is a number from 3 to 12.
12. A process of preparing a device claimed in Claim 1, which process comprises modifying the surface of the sensor by attaching to it by covalent bonding a group containing a photactivatable function, exposing the thus modified surface to photoactivating radiation in selection areas only of the surface to activate the function and reacting the function thus activated to bond covalently with a compound providing a residue of the biochemical ligand.
13. A process according to Claim 12, wherein the modified surface is exposed through a mask. 55
14. A process according to Claim 12 or 13, wherein residues of different biochemical ligands are attached to different areas of the same surface.
15. A process according to Claim 12, 13 or 14, wherein the sensor is a field effect transistor, the surface is of silicon nitride and the photoactivatable function is an aryl azide group. 60
16. Use of a device according to any one of Claims 1 to 11 for assay of a binding partner of 60 the ligand.
17. A kit useful in diagnostics comprising a device claimed in any one of Claims 1 to 11 and at least one binding partner for the biochemical ligand for testing or standardisation of the device.
t- i 1 9 GB2141544A 9 Printed in the United Kingdom for Her Majesty's Stationery Office, Dd 8818935, 1984, 4235. Published at The Patent Office, 25 Southampton Buildings, London, WC2A l AY, from which copies may be obtained.
Applications Claiming Priority (1)
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GB838314523A GB8314523D0 (en) | 1983-05-25 | 1983-05-25 | Diagnostic device |
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GB8413167D0 GB8413167D0 (en) | 1984-06-27 |
GB2141544A true GB2141544A (en) | 1984-12-19 |
GB2141544B GB2141544B (en) | 1986-10-15 |
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GB838314523A Pending GB8314523D0 (en) | 1983-05-25 | 1983-05-25 | Diagnostic device |
GB08413167A Expired GB2141544B (en) | 1983-05-25 | 1984-05-23 | Diagnostic device incorporating a biochemical ligand |
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GB838314523A Pending GB8314523D0 (en) | 1983-05-25 | 1983-05-25 | Diagnostic device |
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US (1) | US4562157A (en) |
EP (1) | EP0127438B1 (en) |
JP (1) | JPH0650316B2 (en) |
CA (1) | CA1229883A (en) |
DE (1) | DE3468146D1 (en) |
DK (1) | DK256784A (en) |
GB (2) | GB8314523D0 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2180348A (en) * | 1985-08-30 | 1987-03-25 | Atomic Energy Authority Uk | Semiconducting oxide sensor |
WO1987003093A1 (en) * | 1985-11-18 | 1987-05-21 | Radiometer A/S | Sensor for determining the concentration of a biochemical species |
GB2217447A (en) * | 1988-04-21 | 1989-10-25 | Atomic Energy Authority Uk | Bonding to metal surfaces |
WO1995016204A1 (en) * | 1993-12-07 | 1995-06-15 | University Court Of The University Of Glasgow | Surface-patterned device |
Families Citing this family (234)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4994373A (en) | 1983-01-27 | 1991-02-19 | Enzo Biochem, Inc. | Method and structures employing chemically-labelled polynucleotide probes |
GB8406955D0 (en) * | 1984-03-16 | 1984-04-18 | Serono Diagnostics Ltd | Assay |
NZ211453A (en) * | 1984-03-22 | 1989-01-06 | Biotechnology Research Enterpr | Aryl azides, their preparation and use in the detection, localisation and isolation of polynucleotides |
US4704353A (en) * | 1984-04-27 | 1987-11-03 | Molecular Devices Corporation | Photoresponsive redox detection and discrimination |
US4713347A (en) * | 1985-01-14 | 1987-12-15 | Sensor Diagnostics, Inc. | Measurement of ligand/anti-ligand interactions using bulk conductance |
DE3513168A1 (en) * | 1985-04-12 | 1986-10-16 | Thomas 8000 München Dandekar | BIOSENSOR CONSISTING OF A SEMICONDUCTOR BASED ON SILICON OR CARBON-BASED (ELECTRONIC PART) AND NUCLEIN BASE (OR. OTHER BIOL. MONOMERS) |
DE3688489T2 (en) * | 1985-08-29 | 1993-09-16 | Matsushita Electric Ind Co Ltd | SENSORS USING A FIELD EFFECT TRANSISTOR AND THEIR PRODUCTION METHOD. |
AU6404286A (en) * | 1985-09-26 | 1987-04-24 | University Of Southern Mississippi, The | Piezoelectric device for detection of polynucleotide hybridization |
US5595908A (en) * | 1985-09-26 | 1997-01-21 | University Of Southern Mississipi | Piezoelectric device for detection of polynucleotide hybridization |
WO1987003095A1 (en) * | 1985-11-19 | 1987-05-21 | The Johns Hopkins University/Applied Physics Labor | Capacitive sensor for chemical analysis and measurement |
US4822566A (en) * | 1985-11-19 | 1989-04-18 | The Johns Hopkins University | Optimized capacitive sensor for chemical analysis and measurement |
US4637861A (en) * | 1985-12-16 | 1987-01-20 | Allied Corporation | Stabilized, lipid membrane-based device and method of analysis |
FR2599844B1 (en) * | 1986-06-09 | 1990-05-11 | Centre Nat Rech Scient | SOLID CONDUCTIVE PHASE FOR IMMUNOENZYMATIC ASSAY, PREPARATION METHOD THEREOF AND USE IN IMMUNOENZYMATIC ASSAY PROCESSES |
US4859538A (en) * | 1986-11-20 | 1989-08-22 | Ribi Hans O | Novel lipid-protein compositions and articles and methods for their preparation |
US5079600A (en) * | 1987-03-06 | 1992-01-07 | Schnur Joel M | High resolution patterning on solid substrates |
US4769121A (en) * | 1987-05-01 | 1988-09-06 | Biotronic Systems Corporation | Sintered pellet with biochemically active layer |
US5114674A (en) * | 1987-05-01 | 1992-05-19 | Biotronic Systems Corporation | Added array of molecular chains for interfering with electrical fields |
US5074977A (en) * | 1987-05-05 | 1991-12-24 | The Washington Technology Center | Digital biosensors and method of using same |
US4963815A (en) * | 1987-07-10 | 1990-10-16 | Molecular Devices Corporation | Photoresponsive electrode for determination of redox potential |
JP2638877B2 (en) * | 1988-02-10 | 1997-08-06 | 日本電気株式会社 | Immunochemical assay |
US5391463A (en) * | 1988-04-14 | 1995-02-21 | The United States Of America As Represented By The Secretary Of The Navy | Surface modification to create regions resistant to adsorption of biomolecules |
US5225374A (en) * | 1988-05-13 | 1993-07-06 | The United States Of America As Represented By The Secretary Of The Navy | Method of fabricating a receptor-based sensor |
US5111221A (en) * | 1988-05-13 | 1992-05-05 | United States Of America As Represented By The Secretary Of The Navy | Receptor-based sensor |
US5089387A (en) * | 1988-07-07 | 1992-02-18 | Adeza Biomedical Corporation | Dna probe diffraction assay and reagents |
EP0354543B1 (en) * | 1988-08-08 | 1992-11-11 | Biomira, Inc. | Photochemical attachment of chelating groups to biomolecules |
US5102798A (en) * | 1988-09-08 | 1992-04-07 | Allage Associates | Surface functionalized Langmuir-Blodgett films for immobilization of active moieties |
US5106751A (en) * | 1988-09-15 | 1992-04-21 | Biotronic Systems Corporation | Apparatus for supporting a biochemical sensor responsive to bubbles |
US5212050A (en) * | 1988-11-14 | 1993-05-18 | Mier Randall M | Method of forming a permselective layer |
US5200051A (en) * | 1988-11-14 | 1993-04-06 | I-Stat Corporation | Wholly microfabricated biosensors and process for the manufacture and use thereof |
US6306594B1 (en) * | 1988-11-14 | 2001-10-23 | I-Stat Corporation | Methods for microdispensing patterened layers |
US5063081A (en) * | 1988-11-14 | 1991-11-05 | I-Stat Corporation | Method of manufacturing a plurality of uniform microfabricated sensing devices having an immobilized ligand receptor |
US4927502A (en) * | 1989-01-31 | 1990-05-22 | Board Of Regents, The University Of Texas | Methods and apparatus using galvanic immunoelectrodes |
IT1229691B (en) * | 1989-04-21 | 1991-09-06 | Eniricerche Spa | SENSOR WITH ANTIGEN CHEMICALLY LINKED TO A SEMICONDUCTIVE DEVICE. |
US6955915B2 (en) | 1989-06-07 | 2005-10-18 | Affymetrix, Inc. | Apparatus comprising polymers |
US6406844B1 (en) | 1989-06-07 | 2002-06-18 | Affymetrix, Inc. | Very large scale immobilized polymer synthesis |
US6040138A (en) | 1995-09-15 | 2000-03-21 | Affymetrix, Inc. | Expression monitoring by hybridization to high density oligonucleotide arrays |
US6919211B1 (en) | 1989-06-07 | 2005-07-19 | Affymetrix, Inc. | Polypeptide arrays |
US5424186A (en) * | 1989-06-07 | 1995-06-13 | Affymax Technologies N.V. | Very large scale immobilized polymer synthesis |
US5143854A (en) * | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
US6346413B1 (en) | 1989-06-07 | 2002-02-12 | Affymetrix, Inc. | Polymer arrays |
US5527681A (en) * | 1989-06-07 | 1996-06-18 | Affymax Technologies N.V. | Immobilized molecular synthesis of systematically substituted compounds |
US5744101A (en) * | 1989-06-07 | 1998-04-28 | Affymax Technologies N.V. | Photolabile nucleoside protecting groups |
US5800992A (en) | 1989-06-07 | 1998-09-01 | Fodor; Stephen P.A. | Method of detecting nucleic acids |
US5547839A (en) | 1989-06-07 | 1996-08-20 | Affymax Technologies N.V. | Sequencing of surface immobilized polymers utilizing microflourescence detection |
US6416952B1 (en) | 1989-06-07 | 2002-07-09 | Affymetrix, Inc. | Photolithographic and other means for manufacturing arrays |
US6551784B2 (en) | 1989-06-07 | 2003-04-22 | Affymetrix Inc | Method of comparing nucleic acid sequences |
US6309822B1 (en) | 1989-06-07 | 2001-10-30 | Affymetrix, Inc. | Method for comparing copy number of nucleic acid sequences |
DE3923342A1 (en) * | 1989-07-14 | 1991-01-24 | Boehringer Mannheim Gmbh | METHOD FOR PRODUCING A SOLID-PHASE MATRIX COATED WITH AN IMMUNOLOGICALLY ACTIVE SUBSTANCE |
US5545522A (en) | 1989-09-22 | 1996-08-13 | Van Gelder; Russell N. | Process for amplifying a target polynucleotide sequence using a single primer-promoter complex |
US7049102B1 (en) | 1989-09-22 | 2006-05-23 | Board Of Trustees Of Leland Stanford University | Multi-gene expression profile |
US5252743A (en) * | 1989-11-13 | 1993-10-12 | Affymax Technologies N.V. | Spatially-addressable immobilization of anti-ligands on surfaces |
JPH05501611A (en) * | 1989-11-13 | 1993-03-25 | アフィマックス テクノロジーズ ナームロゼ ベノートスハップ | Spatially addressable immobilization of antiligands on surfaces |
US6506558B1 (en) | 1990-03-07 | 2003-01-14 | Affymetrix Inc. | Very large scale immobilized polymer synthesis |
WO1992008788A1 (en) * | 1990-11-19 | 1992-05-29 | The Board Of Trustees Of The University Of Illinois | Mutant orientable proteins and coated substrates |
DE69132843T2 (en) | 1990-12-06 | 2002-09-12 | Affymetrix Inc N D Ges D Staat | Identification of nucleic acids in samples |
EP0562025B1 (en) * | 1990-12-06 | 2001-02-07 | Affymetrix, Inc. (a Delaware Corporation) | Compounds and their use in a binary synthesis strategy |
JPH06504917A (en) * | 1991-03-09 | 1994-06-09 | ファイスンズ ピーエルシー | Analytical methods and equipment |
US6849462B1 (en) | 1991-11-22 | 2005-02-01 | Affymetrix, Inc. | Combinatorial strategies for polymer synthesis |
US6943034B1 (en) | 1991-11-22 | 2005-09-13 | Affymetrix, Inc. | Combinatorial strategies for polymer synthesis |
DE69233331T3 (en) * | 1991-11-22 | 2007-08-30 | Affymetrix, Inc., Santa Clara | Combinatorial Polymersynthesis Strategies |
US5412087A (en) * | 1992-04-24 | 1995-05-02 | Affymax Technologies N.V. | Spatially-addressable immobilization of oligonucleotides and other biological polymers on surfaces |
US5324633A (en) * | 1991-11-22 | 1994-06-28 | Affymax Technologies N.V. | Method and apparatus for measuring binding affinity |
US6468740B1 (en) | 1992-11-05 | 2002-10-22 | Affymetrix, Inc. | Cyclic and substituted immobilized molecular synthesis |
US5399497A (en) * | 1992-02-26 | 1995-03-21 | Miles, Inc. | Capsule chemistry sample liquid analysis system and method |
US5919712A (en) * | 1993-05-18 | 1999-07-06 | University Of Utah Research Foundation | Apparatus and methods for multi-analyte homogeneous fluoro-immunoassays |
US5677196A (en) * | 1993-05-18 | 1997-10-14 | University Of Utah Research Foundation | Apparatus and methods for multi-analyte homogeneous fluoro-immunoassays |
US5427663A (en) * | 1993-06-08 | 1995-06-27 | British Technology Group Usa Inc. | Microlithographic array for macromolecule and cell fractionation |
FR2716263B1 (en) * | 1994-02-11 | 1997-01-17 | Pasteur Institut | Method for aligning macromolecules by passing a meniscus and applications in a method for highlighting, separating and / or assaying a macromolecule in a sample. |
FR2716206B1 (en) * | 1994-02-11 | 1996-05-10 | Pasteur Institut | Highly specific surfaces for biological reactions, process for their preparation and method for assaying a molecule using these surfaces. |
JP3027770B2 (en) * | 1994-03-05 | 2000-04-04 | ロシュ ダイアグノスティックス ゲーエムベーハー | Interference removers for use in immunoassays |
US6015880A (en) * | 1994-03-16 | 2000-01-18 | California Institute Of Technology | Method and substrate for performing multiple sequential reactions on a matrix |
US7323298B1 (en) | 1994-06-17 | 2008-01-29 | The Board Of Trustees Of The Leland Stanford Junior University | Microarray for determining the relative abundances of polynuceotide sequences |
US7378236B1 (en) | 1994-06-17 | 2008-05-27 | The Board Of Trustees Of The Leland Stanford Junior University | Method for analyzing gene expression patterns |
US6558633B1 (en) | 1994-09-21 | 2003-05-06 | Isis Pharmaceuticals, Inc. | Chemical reaction apparatus and methods |
DE4436001C2 (en) * | 1994-10-08 | 1996-07-25 | Forschungszentrum Juelich Gmbh | Biosensor with enzyme fixed on a Si¶3¶N¶4¶ surface |
US5556752A (en) * | 1994-10-24 | 1996-09-17 | Affymetrix, Inc. | Surface-bound, unimolecular, double-stranded DNA |
US8236493B2 (en) | 1994-10-21 | 2012-08-07 | Affymetrix, Inc. | Methods of enzymatic discrimination enhancement and surface-bound double-stranded DNA |
US6974666B1 (en) * | 1994-10-21 | 2005-12-13 | Appymetric, Inc. | Methods of enzymatic discrimination enhancement and surface-bound double-stranded DNA |
US5688642A (en) * | 1994-12-01 | 1997-11-18 | The United States Of America As Represented By The Secretary Of The Navy | Selective attachment of nucleic acid molecules to patterned self-assembled surfaces |
DE19512117A1 (en) * | 1995-04-04 | 1996-10-10 | Itt Ind Gmbh Deutsche | Measuring device |
US6416714B1 (en) | 1995-04-25 | 2002-07-09 | Discovery Partners International, Inc. | Remotely programmable matrices with memories |
US5736257A (en) * | 1995-04-25 | 1998-04-07 | Us Navy | Photoactivatable polymers for producing patterned biomolecular assemblies |
US6329139B1 (en) | 1995-04-25 | 2001-12-11 | Discovery Partners International | Automated sorting system for matrices with memory |
US5751629A (en) * | 1995-04-25 | 1998-05-12 | Irori | Remotely programmable matrices with memories |
US5874214A (en) * | 1995-04-25 | 1999-02-23 | Irori | Remotely programmable matrices with memories |
US6331273B1 (en) | 1995-04-25 | 2001-12-18 | Discovery Partners International | Remotely programmable matrices with memories |
US6017496A (en) * | 1995-06-07 | 2000-01-25 | Irori | Matrices with memories and uses thereof |
FR2737012B1 (en) * | 1995-07-19 | 1997-09-12 | Suisse Electronique Microtech | DEVICE INCLUDING A BIOLOGICALLY ACTIVE SUBSTANCE IMMOBILIZED ON A COVALENT NITRIDE SUBSTRATE BY A BIFUNCTIONAL LIAISON AGENT |
EP0843739B1 (en) * | 1995-08-09 | 2007-11-07 | Adam J. Simon | Molecular combing of macromolecules through the action of a meniscus on hihgly specific surfaces |
US5830539A (en) * | 1995-11-17 | 1998-11-03 | The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of The University Of Oregon | Methods for functionalizing and coating substrates and devices made according to the methods |
US5626571A (en) | 1995-11-30 | 1997-05-06 | The Procter & Gamble Company | Absorbent articles having soft, strong nonwoven component |
EP0880598A4 (en) | 1996-01-23 | 2005-02-23 | Affymetrix Inc | Nucleic acid analysis techniques |
US6247995B1 (en) | 1996-02-06 | 2001-06-19 | Bruce Bryan | Bioluminescent novelty items |
US5876995A (en) * | 1996-02-06 | 1999-03-02 | Bryan; Bruce | Bioluminescent novelty items |
JP3764779B2 (en) | 1996-03-30 | 2006-04-12 | 株式会社東北テクノアーチ | Analysis method using convex regions |
US5958342A (en) * | 1996-05-17 | 1999-09-28 | Incyte Pharmaceuticals, Inc. | Jet droplet device |
SE9602545L (en) * | 1996-06-25 | 1997-12-26 | Michael Mecklenburg | Method of discriminating complex biological samples |
US6416960B1 (en) | 1996-08-08 | 2002-07-09 | Prolume, Ltd. | Detection and visualization of neoplastic tissues and other tissues |
US6020047A (en) * | 1996-09-04 | 2000-02-01 | Kimberly-Clark Worldwide, Inc. | Polymer films having a printed self-assembling monolayer |
WO1998026277A2 (en) | 1996-12-12 | 1998-06-18 | Prolume, Ltd. | Apparatus and method for detecting and identifying infectious agents |
US5922550A (en) * | 1996-12-18 | 1999-07-13 | Kimberly-Clark Worldwide, Inc. | Biosensing devices which produce diffraction images |
US5773308A (en) * | 1997-02-10 | 1998-06-30 | The United States Of America As Represented By The Secretary Of The Navy | Photoactivatable o-nitrobenzyl polyethylene glycol-silane for the production of patterned biomolecular arrays |
US6180288B1 (en) | 1997-03-21 | 2001-01-30 | Kimberly-Clark Worldwide, Inc. | Gel sensors and method of use thereof |
EP0874242B2 (en) * | 1997-04-21 | 2009-06-03 | Randox Laboratories Ltd. | Device and apparatus for the simultaneous detection of multiple analytes |
CZ297165B6 (en) * | 1997-04-21 | 2006-09-13 | Randox Laboratories Ltd. A British Company Of Ardmore | Solid state device for performing multi-analyte assays |
US6060327A (en) | 1997-05-14 | 2000-05-09 | Keensense, Inc. | Molecular wire injection sensors |
US6699667B2 (en) | 1997-05-14 | 2004-03-02 | Keensense, Inc. | Molecular wire injection sensors |
US7220550B2 (en) * | 1997-05-14 | 2007-05-22 | Keensense, Inc. | Molecular wire injection sensors |
US20070166741A1 (en) * | 1998-12-14 | 2007-07-19 | Somalogic, Incorporated | Multiplexed analyses of test samples |
US6242246B1 (en) * | 1997-12-15 | 2001-06-05 | Somalogic, Inc. | Nucleic acid ligand diagnostic Biochip |
WO2003070984A1 (en) * | 2002-02-15 | 2003-08-28 | Somalogic, Inc. | Methods and reagents for detecting target binding by nucleic acid ligands |
JP2002508386A (en) | 1997-12-16 | 2002-03-19 | ザ・ユニバーシティー・オブ・サスカチワン・テクノロジーズ・インコーポレーテッド | Conductive metal-containing nucleic acids |
US6060256A (en) | 1997-12-16 | 2000-05-09 | Kimberly-Clark Worldwide, Inc. | Optical diffraction biosensor |
US20030096232A1 (en) | 1997-12-19 | 2003-05-22 | Kris Richard M. | High throughput assay system |
JP2002502977A (en) | 1998-02-04 | 2002-01-29 | インビトロジェン コーポレイション | Microarrays and their uses |
EP1064360B1 (en) | 1998-03-27 | 2008-03-05 | Prolume, Ltd. | Luciferases, gfp fluorescent proteins, their nucleic acids and the use thereof in diagnostics |
EP1925320A3 (en) | 1998-03-27 | 2008-09-03 | Prolume, Ltd. | Luciferases, fluorescent proteins, nucleic acids encoding the luciferases and fluorescent proteins and the use thereof in diagnostics |
US6723564B2 (en) | 1998-05-07 | 2004-04-20 | Sequenom, Inc. | IR MALDI mass spectrometry of nucleic acids using liquid matrices |
US6897073B2 (en) * | 1998-07-14 | 2005-05-24 | Zyomyx, Inc. | Non-specific binding resistant protein arrays and methods for making the same |
US20020119579A1 (en) * | 1998-07-14 | 2002-08-29 | Peter Wagner | Arrays devices and methods of use thereof |
US6576478B1 (en) * | 1998-07-14 | 2003-06-10 | Zyomyx, Inc. | Microdevices for high-throughput screening of biomolecules |
US6682942B1 (en) | 1998-07-14 | 2004-01-27 | Zyomyx, Inc. | Microdevices for screening biomolecules |
US6406921B1 (en) | 1998-07-14 | 2002-06-18 | Zyomyx, Incorporated | Protein arrays for high-throughput screening |
US6545264B1 (en) | 1998-10-30 | 2003-04-08 | Affymetrix, Inc. | Systems and methods for high performance scanning |
US6221579B1 (en) | 1998-12-11 | 2001-04-24 | Kimberly-Clark Worldwide, Inc. | Patterned binding of functionalized microspheres for optical diffraction-based biosensors |
US7160869B2 (en) * | 1998-12-16 | 2007-01-09 | University Of Saskatchewan | Biologically active metal-containing nucleic acids |
US6579673B2 (en) | 1998-12-17 | 2003-06-17 | Kimberly-Clark Worldwide, Inc. | Patterned deposition of antibody binding protein for optical diffraction-based biosensors |
US6129896A (en) * | 1998-12-17 | 2000-10-10 | Drawn Optical Components, Inc. | Biosensor chip and manufacturing method |
ATE307881T1 (en) * | 1999-03-30 | 2005-11-15 | Netech Inc | METHOD FOR SELECTIVE SEPARATION OF BLOOD CELLS USING LECTIN |
US6248537B1 (en) | 1999-05-28 | 2001-06-19 | Institut Pasteur | Use of the combing process for the identification of DNA origins of replication |
US7192729B2 (en) | 1999-07-06 | 2007-03-20 | General Atomics | Methods for assaying homocysteine |
US6743585B2 (en) | 1999-09-16 | 2004-06-01 | Agilent Technologies, Inc. | Methods for preparing conjugates |
US7167615B1 (en) | 1999-11-05 | 2007-01-23 | Board Of Regents, The University Of Texas System | Resonant waveguide-grating filters and sensors and methods for making and using same |
US6399295B1 (en) | 1999-12-17 | 2002-06-04 | Kimberly-Clark Worldwide, Inc. | Use of wicking agent to eliminate wash steps for optical diffraction-based biosensors |
WO2001062968A2 (en) * | 2000-02-25 | 2001-08-30 | General Atomics | Mutant nucleic binding enzymes and use thereof in diagnostic, detection and purification methods |
US7109315B2 (en) | 2000-03-15 | 2006-09-19 | Bruce J. Bryan | Renilla reniformis fluorescent proteins, nucleic acids encoding the fluorescent proteins and the use thereof in diagnostics, high throughput screening and novelty items |
US6610504B1 (en) | 2000-04-10 | 2003-08-26 | General Atomics | Methods of determining SAM-dependent methyltransferase activity using a mutant SAH hydrolase |
AU5951201A (en) | 2000-05-04 | 2001-11-12 | Univ Yale | High density protein arrays for screening of protein activity |
US20020110843A1 (en) * | 2000-05-12 | 2002-08-15 | Dumas David P. | Compositions and methods for epitope mapping |
CA2423924A1 (en) * | 2000-09-27 | 2002-04-04 | Surmodics, Inc. | High density arrays |
US20030082604A1 (en) * | 2000-09-27 | 2003-05-01 | Swanson Melvin J. | High density arrays |
FR2818662B1 (en) * | 2000-12-22 | 2003-09-19 | Commissariat Energie Atomique | METHOD FOR IMMOBILIZATION OF PROBES, ESPECIALLY FOR MAKING BIOLOGICAL CHIPS |
US20060029955A1 (en) | 2001-03-24 | 2006-02-09 | Antonio Guia | High-density ion transport measurement biochip devices and methods |
US20050009004A1 (en) * | 2002-05-04 | 2005-01-13 | Jia Xu | Apparatus including ion transport detecting structures and methods of use |
JP2004532527A (en) * | 2001-05-24 | 2004-10-21 | ユニバーシティ・オブ・サスカチェワン・テクノロジーズ・インコーポレイテッド | Nucleic acid circuit device and method |
EP1432786B1 (en) | 2001-09-06 | 2009-07-22 | Genomic Profiling Systems, Inc. | Rapid detection of replicating cells |
US7098041B2 (en) | 2001-12-11 | 2006-08-29 | Kimberly-Clark Worldwide, Inc. | Methods to view and analyze the results from diffraction-based diagnostics |
US7102752B2 (en) | 2001-12-11 | 2006-09-05 | Kimberly-Clark Worldwide, Inc. | Systems to view and analyze the results from diffraction-based diagnostics |
US20030119203A1 (en) | 2001-12-24 | 2003-06-26 | Kimberly-Clark Worldwide, Inc. | Lateral flow assay devices and methods for conducting assays |
US8367013B2 (en) | 2001-12-24 | 2013-02-05 | Kimberly-Clark Worldwide, Inc. | Reading device, method, and system for conducting lateral flow assays |
US6837171B1 (en) | 2002-04-29 | 2005-01-04 | Palmer/Snyder Furniture Company | Lightweight table with unitized table top |
US20040048311A1 (en) * | 2002-01-24 | 2004-03-11 | Dana Ault-Riche | Use of collections of binding sites for sample profiling and other applications |
US7223534B2 (en) | 2002-05-03 | 2007-05-29 | Kimberly-Clark Worldwide, Inc. | Diffraction-based diagnostic devices |
US7214530B2 (en) | 2002-05-03 | 2007-05-08 | Kimberly-Clark Worldwide, Inc. | Biomolecule diagnostic devices and method for producing biomolecule diagnostic devices |
US7771922B2 (en) | 2002-05-03 | 2010-08-10 | Kimberly-Clark Worldwide, Inc. | Biomolecule diagnostic device |
US7118855B2 (en) | 2002-05-03 | 2006-10-10 | Kimberly-Clark Worldwide, Inc. | Diffraction-based diagnostic devices |
US7485453B2 (en) | 2002-05-03 | 2009-02-03 | Kimberly-Clark Worldwide, Inc. | Diffraction-based diagnostic devices |
US7223368B2 (en) | 2002-05-03 | 2007-05-29 | Kimberly-Clark Worldwide, Inc. | Diffraction-based diagnostic devices |
US7091049B2 (en) | 2002-06-26 | 2006-08-15 | Kimberly-Clark Worldwide, Inc. | Enhanced diffraction-based biosensor devices |
US7441703B2 (en) | 2002-08-20 | 2008-10-28 | Illumina, Inc. | Optical reader for diffraction grating-based encoded optical identification elements |
US7872804B2 (en) | 2002-08-20 | 2011-01-18 | Illumina, Inc. | Encoded particle having a grating with variations in the refractive index |
US7508608B2 (en) | 2004-11-17 | 2009-03-24 | Illumina, Inc. | Lithographically fabricated holographic optical identification element |
US7901630B2 (en) | 2002-08-20 | 2011-03-08 | Illumina, Inc. | Diffraction grating-based encoded microparticle assay stick |
AU2003265583C1 (en) | 2002-08-20 | 2009-05-21 | Cyvera Corporation | Diffraction grating-based optical identification element |
US7923260B2 (en) | 2002-08-20 | 2011-04-12 | Illumina, Inc. | Method of reading encoded particles |
US7399643B2 (en) | 2002-09-12 | 2008-07-15 | Cyvera Corporation | Method and apparatus for aligning microbeads in order to interrogate the same |
US7164533B2 (en) | 2003-01-22 | 2007-01-16 | Cyvera Corporation | Hybrid random bead/chip based microarray |
US7900836B2 (en) | 2002-08-20 | 2011-03-08 | Illumina, Inc. | Optical reader system for substrates having an optically readable code |
US7285424B2 (en) | 2002-08-27 | 2007-10-23 | Kimberly-Clark Worldwide, Inc. | Membrane-based assay devices |
US7432105B2 (en) | 2002-08-27 | 2008-10-07 | Kimberly-Clark Worldwide, Inc. | Self-calibration system for a magnetic binding assay |
US7314763B2 (en) | 2002-08-27 | 2008-01-01 | Kimberly-Clark Worldwide, Inc. | Fluidics-based assay devices |
US20100255603A9 (en) | 2002-09-12 | 2010-10-07 | Putnam Martin A | Method and apparatus for aligning microbeads in order to interrogate the same |
EP1540592A1 (en) | 2002-09-12 | 2005-06-15 | Cyvera Corporation | Method and apparatus for labeling using diffraction grating-based encoded optical identification elements |
US7092160B2 (en) | 2002-09-12 | 2006-08-15 | Illumina, Inc. | Method of manufacturing of diffraction grating-based optical identification element |
AU2003270726A1 (en) | 2002-09-12 | 2004-04-30 | Cidra Corporation | Diffraction grating-based encoded micro-particles for multiplexed experiments |
CA2498916A1 (en) | 2002-09-12 | 2004-03-25 | Cyvera Corporation | Chemical synthesis using diffraction grating-based encoded optical elements |
US7169550B2 (en) * | 2002-09-26 | 2007-01-30 | Kimberly-Clark Worldwide, Inc. | Diffraction-based diagnostic devices |
IL152746A0 (en) * | 2002-11-11 | 2003-06-24 | Yissum Res Dev Co | Biosensor for molecules |
US7781172B2 (en) | 2003-11-21 | 2010-08-24 | Kimberly-Clark Worldwide, Inc. | Method for extending the dynamic detection range of assay devices |
US7247500B2 (en) | 2002-12-19 | 2007-07-24 | Kimberly-Clark Worldwide, Inc. | Reduction of the hook effect in membrane-based assay devices |
US20040180368A1 (en) * | 2002-12-23 | 2004-09-16 | Affymetrix, Inc. | Method for producing a high density nucleic acid array using activators |
US20040197819A1 (en) | 2003-04-03 | 2004-10-07 | Kimberly-Clark Worldwide, Inc. | Assay devices that utilize hollow particles |
US7851209B2 (en) | 2003-04-03 | 2010-12-14 | Kimberly-Clark Worldwide, Inc. | Reduction of the hook effect in assay devices |
US20040248323A1 (en) | 2003-06-09 | 2004-12-09 | Protometrix, Inc. | Methods for conducting assays for enzyme activity on protein microarrays |
US20070026406A1 (en) * | 2003-08-13 | 2007-02-01 | Iconix Pharmaceuticals, Inc. | Apparatus and method for classifying multi-dimensional biological data |
US20050053949A1 (en) * | 2003-09-08 | 2005-03-10 | Silin Vitalii Ivanovich | Biochip for proteomics applications |
US7943395B2 (en) | 2003-11-21 | 2011-05-17 | Kimberly-Clark Worldwide, Inc. | Extension of the dynamic detection range of assay devices |
US20050112703A1 (en) | 2003-11-21 | 2005-05-26 | Kimberly-Clark Worldwide, Inc. | Membrane-based lateral flow assay devices that utilize phosphorescent detection |
US7713748B2 (en) | 2003-11-21 | 2010-05-11 | Kimberly-Clark Worldwide, Inc. | Method of reducing the sensitivity of assay devices |
US7943089B2 (en) | 2003-12-19 | 2011-05-17 | Kimberly-Clark Worldwide, Inc. | Laminated assay devices |
US7433123B2 (en) | 2004-02-19 | 2008-10-07 | Illumina, Inc. | Optical identification element having non-waveguide photosensitive substrate with diffraction grating therein |
WO2006001896A2 (en) * | 2004-04-26 | 2006-01-05 | Iconix Pharmaceuticals, Inc. | A universal gene chip for high throughput chemogenomic analysis |
US7384760B2 (en) * | 2004-04-30 | 2008-06-10 | General Atomics | Methods for assaying inhibitors of S-adenosylhomocysteine (SAH) hydrolase and S-adenosylmethionine (SAM)-dependent methyltransferase |
WO2005124650A2 (en) * | 2004-06-10 | 2005-12-29 | Iconix Pharmaceuticals, Inc. | Sufficient and necessary reagent sets for chemogenomic analysis |
US7521226B2 (en) | 2004-06-30 | 2009-04-21 | Kimberly-Clark Worldwide, Inc. | One-step enzymatic and amine detection technique |
US7588892B2 (en) * | 2004-07-19 | 2009-09-15 | Entelos, Inc. | Reagent sets and gene signatures for renal tubule injury |
WO2006020363A2 (en) | 2004-07-21 | 2006-02-23 | Illumina, Inc. | Method and apparatus for drug product tracking using encoded optical identification elements |
DE602005019791D1 (en) | 2004-11-16 | 2010-04-15 | Illumina Inc | METHOD AND DEVICE FOR READING CODED MICROBALLS |
US7604173B2 (en) | 2004-11-16 | 2009-10-20 | Illumina, Inc. | Holographically encoded elements for microarray and other tagging labeling applications, and method and apparatus for making and reading the same |
WO2006055735A2 (en) | 2004-11-16 | 2006-05-26 | Illumina, Inc | Scanner having spatial light modulator |
EP1846759A1 (en) * | 2005-02-10 | 2007-10-24 | Commisariat à l'énergie Atomique | Method for the photochemical attachment of biomolecules to a substrate |
US20060199207A1 (en) * | 2005-02-24 | 2006-09-07 | Matysiak Stefan M | Self-assembly of molecules using combinatorial hybridization |
US8921102B2 (en) | 2005-07-29 | 2014-12-30 | Gpb Scientific, Llc | Devices and methods for enrichment and alteration of circulating tumor cells and other particles |
US9057046B2 (en) | 2005-09-26 | 2015-06-16 | Rapid Micro Biosystems, Inc. | Cassette containing growth medium |
US7623624B2 (en) | 2005-11-22 | 2009-11-24 | Illumina, Inc. | Method and apparatus for labeling using optical identification elements characterized by X-ray diffraction |
US20070198653A1 (en) * | 2005-12-30 | 2007-08-23 | Kurt Jarnagin | Systems and methods for remote computer-based analysis of user-provided chemogenomic data |
DK1994171T3 (en) * | 2006-01-17 | 2015-06-15 | Somalogic Inc | Multiplex Analyses of test samples |
US8679308B2 (en) * | 2006-03-15 | 2014-03-25 | Honeywell International Inc. | Biosensor membrane and methods related thereto |
US7830575B2 (en) | 2006-04-10 | 2010-11-09 | Illumina, Inc. | Optical scanner with improved scan time |
US11001881B2 (en) | 2006-08-24 | 2021-05-11 | California Institute Of Technology | Methods for detecting analytes |
WO2007143669A2 (en) * | 2006-06-05 | 2007-12-13 | California Institute Of Technology | Real time micro arrays |
US11525156B2 (en) | 2006-07-28 | 2022-12-13 | California Institute Of Technology | Multiplex Q-PCR arrays |
US8048626B2 (en) * | 2006-07-28 | 2011-11-01 | California Institute Of Technology | Multiplex Q-PCR arrays |
US11560588B2 (en) | 2006-08-24 | 2023-01-24 | California Institute Of Technology | Multiplex Q-PCR arrays |
US20100021885A1 (en) * | 2006-09-18 | 2010-01-28 | Mark Fielden | Reagent sets and gene signatures for non-genotoxic hepatocarcinogenicity |
US8975026B2 (en) | 2007-01-16 | 2015-03-10 | Somalogic, Inc. | Method for generating aptamers with improved off-rates |
US7964356B2 (en) * | 2007-01-16 | 2011-06-21 | Somalogic, Inc. | Method for generating aptamers with improved off-rates |
US7855054B2 (en) * | 2007-01-16 | 2010-12-21 | Somalogic, Inc. | Multiplexed analyses of test samples |
US7947447B2 (en) | 2007-01-16 | 2011-05-24 | Somalogic, Inc. | Method for generating aptamers with improved off-rates |
US8906700B2 (en) | 2007-11-06 | 2014-12-09 | Ambergen, Inc. | Methods and compositions for phototransfer |
US20110003708A1 (en) * | 2007-12-27 | 2011-01-06 | Compugen Ltd. | Biomarkers for the prediction of renal injury |
US8940142B2 (en) | 2008-05-05 | 2015-01-27 | The Regents Of The University Of California | Functionalized nanopipette biosensor |
US8703416B2 (en) | 2008-07-17 | 2014-04-22 | Somalogic, Inc. | Method for purification and identification of sperm cells |
CA2738317C (en) | 2008-09-24 | 2020-01-14 | Straus Holdings Inc. | Imaging analyzer for testing analytes |
PL3327110T3 (en) | 2011-11-07 | 2020-07-27 | Rapid Micro Biosystems, Inc. | Cassette for sterility testing |
CN107841461A (en) | 2012-04-16 | 2018-03-27 | 快速微型生物系统公司 | Cell culture apparatus |
CN105190310B (en) | 2013-03-11 | 2018-04-10 | 托莱多大学 | For internal in-situ and/or the biological inductor device and its manufacture and use method of real-time target setting analysis thing |
US10378044B1 (en) * | 2013-10-01 | 2019-08-13 | FemtoDx | Methods for increasing the molecular specificity of a nanosensor |
CA2967022A1 (en) * | 2014-11-07 | 2016-05-12 | Proteosense | Devices, systems, and methods for the detection of analytes |
US9708647B2 (en) | 2015-03-23 | 2017-07-18 | Insilixa, Inc. | Multiplexed analysis of nucleic acid hybridization thermodynamics using integrated arrays |
US9499861B1 (en) | 2015-09-10 | 2016-11-22 | Insilixa, Inc. | Methods and systems for multiplex quantitative nucleic acid amplification |
WO2017155858A1 (en) | 2016-03-07 | 2017-09-14 | Insilixa, Inc. | Nucleic acid sequence identification using solid-phase cyclic single base extension |
CN107228939B (en) * | 2016-03-26 | 2019-02-12 | 北京勤邦生物技术有限公司 | Detect enzyme linked immunological kit and its application of morphine and codeine |
EP3937780A4 (en) | 2019-03-14 | 2022-12-07 | InSilixa, Inc. | Methods and systems for time-gated fluorescent-based detection |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1252336A (en) * | 1968-07-19 | 1971-11-03 | ||
US4020830A (en) * | 1975-03-12 | 1977-05-03 | The University Of Utah | Selective chemical sensitive FET transducers |
GB1550151A (en) * | 1975-11-26 | 1979-08-08 | Kansai Paint Co Ltd | Immobilizing enzymes and microbial cells |
GB1550465A (en) * | 1975-11-26 | 1979-08-15 | Kansai Paint Co Ltd | Immobilizing enzymes and microbial cells |
US4238757A (en) * | 1976-03-19 | 1980-12-09 | General Electric Company | Field effect transistor for detection of biological reactions |
GB2071669A (en) * | 1980-02-28 | 1981-09-23 | Italfarmaco Spa | Es as supports of enzymatic activity and copolymers thus oprocess for the preparation of copolymers of polysaccharidbtained |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE407115B (en) * | 1975-10-06 | 1979-03-12 | Kabi Ab | PROCEDURES AND METAL ELECTRODES FOR THE STUDY OF ENZYMATIC AND OTHER BIOCHEMICAL REACTIONS |
SE431257B (en) * | 1977-11-03 | 1984-01-23 | Du Pont | SET AND DEVICE FOR IMMUNAL ANALYSIS WITH MAGNETIC METAL OR METAL OXIDE AS A BRAND |
US4242096A (en) * | 1977-11-14 | 1980-12-30 | Minnesota Mining And Manufacturing Company | Immunoassay for antigens |
DE2758507C3 (en) * | 1977-12-28 | 1981-05-27 | Byk-Mallinckrodt Chemische Produkte Gmbh, 6057 Dietzenbach | Stabilized biochemical preparations, processes for their production and their use |
JPS608745B2 (en) * | 1978-02-14 | 1985-03-05 | 三洋化成工業株式会社 | Immunologically active substance-frosted glass composite, method for producing the same, and measurement reagent containing the composite |
US4314821A (en) * | 1979-04-09 | 1982-02-09 | Minnesota Mining And Manufacturing Company | Sandwich immunoassay using piezoelectric oscillator |
US4444892A (en) * | 1980-10-20 | 1984-04-24 | Malmros Mark K | Analytical device having semiconductive organic polymeric element associated with analyte-binding substance |
US4334880A (en) * | 1980-10-20 | 1982-06-15 | Malmros Mark K | Analytical device having semiconductive polyacetylene element associated with analyte-binding substance |
AU557816B2 (en) * | 1981-09-18 | 1987-01-08 | Prutec Ltd. | Method for the determination of species in solution with an optical wave-guide |
US4444878A (en) * | 1981-12-21 | 1984-04-24 | Boston Biomedical Research Institute, Inc. | Bispecific antibody determinants |
-
1983
- 1983-05-25 GB GB838314523A patent/GB8314523D0/en active Pending
-
1984
- 1984-05-23 EP EP84303497A patent/EP0127438B1/en not_active Expired
- 1984-05-23 DE DE8484303497T patent/DE3468146D1/en not_active Expired
- 1984-05-23 GB GB08413167A patent/GB2141544B/en not_active Expired
- 1984-05-24 DK DK256784A patent/DK256784A/en not_active Application Discontinuation
- 1984-05-24 JP JP59105642A patent/JPH0650316B2/en not_active Expired - Lifetime
- 1984-05-24 CA CA000455006A patent/CA1229883A/en not_active Expired
- 1984-05-25 US US06/614,121 patent/US4562157A/en not_active Expired - Lifetime
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1252336A (en) * | 1968-07-19 | 1971-11-03 | ||
US4020830A (en) * | 1975-03-12 | 1977-05-03 | The University Of Utah | Selective chemical sensitive FET transducers |
US4020830B1 (en) * | 1975-03-12 | 1984-09-04 | ||
GB1550151A (en) * | 1975-11-26 | 1979-08-08 | Kansai Paint Co Ltd | Immobilizing enzymes and microbial cells |
GB1550465A (en) * | 1975-11-26 | 1979-08-15 | Kansai Paint Co Ltd | Immobilizing enzymes and microbial cells |
US4238757A (en) * | 1976-03-19 | 1980-12-09 | General Electric Company | Field effect transistor for detection of biological reactions |
GB2071669A (en) * | 1980-02-28 | 1981-09-23 | Italfarmaco Spa | Es as supports of enzymatic activity and copolymers thus oprocess for the preparation of copolymers of polysaccharidbtained |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2180348A (en) * | 1985-08-30 | 1987-03-25 | Atomic Energy Authority Uk | Semiconducting oxide sensor |
WO1987003093A1 (en) * | 1985-11-18 | 1987-05-21 | Radiometer A/S | Sensor for determining the concentration of a biochemical species |
GB2217447A (en) * | 1988-04-21 | 1989-10-25 | Atomic Energy Authority Uk | Bonding to metal surfaces |
WO1995016204A1 (en) * | 1993-12-07 | 1995-06-15 | University Court Of The University Of Glasgow | Surface-patterned device |
Also Published As
Publication number | Publication date |
---|---|
JPS59225343A (en) | 1984-12-18 |
CA1229883A (en) | 1987-12-01 |
US4562157A (en) | 1985-12-31 |
GB8314523D0 (en) | 1983-06-29 |
JPH0650316B2 (en) | 1994-06-29 |
DK256784D0 (en) | 1984-05-24 |
EP0127438B1 (en) | 1987-12-16 |
GB8413167D0 (en) | 1984-06-27 |
GB2141544B (en) | 1986-10-15 |
DE3468146D1 (en) | 1988-01-28 |
DK256784A (en) | 1984-11-26 |
EP0127438A1 (en) | 1984-12-05 |
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732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20000523 |