Enzyme Or Microbe Electrode Patents (Class 435/817)
  • Patent number: 6300123
    Abstract: A sensor uses an immobilized affinity component capable of interacting with analyte species and being associated with a conducting polymer such that the interaction of the affinity component and the analyte induces change in the electrical properties of the polymer. An AC signal is applied to the polymer, and the induced change in impedance resulting from the interaction is measured. The impedance is measured at a frequency or frequencies corresponding to a peak or peaks in the relationship between frequency and impedance change for the polymer and the analyte. The measurement may be made by reference to the imaginary or real component of impedance. The polymer may be in the form of a layer bridging two electrodes between which the impedance is measured. The two electrodes may together define an interdigitated electrode assembly.
    Type: Grant
    Filed: July 19, 1999
    Date of Patent: October 9, 2001
    Assignee: The Victoria University of Manchester
    Inventors: Pankaj M. Vadgama, Keith S. R. Warriner
  • Patent number: 6284478
    Abstract: A small diameter flexible electrode designed for subcutaneous in vivo amperometric monitoring of glucose is described. The electrode is designed to allow “one-point” in vivo calibration, i.e., to have zero output current at zero glucose concentration, even in the presence of other electroreactive species of serum or blood. The electrode is preferably three or four-layered, with the layers serially deposited within a recess upon the tip of a polyamide insulated gold wire. A first glucose concentration-to-current transducing layer is overcoated with an electrically insulating and glucose flux limiting layer (second layer) on which, optionally, an immobilized interference-eliminating horseradish peroxidase based film is deposited (third layer). An outer (fourth) layer is biocompatible.
    Type: Grant
    Filed: December 4, 1996
    Date of Patent: September 4, 2001
    Assignee: E. Heller & Company
    Inventors: Adam Heller, Michael V. Pishko
  • Patent number: 6281006
    Abstract: An electrochemical affinity assay system for detection of ligand—ligand receptor binding.
    Type: Grant
    Filed: August 24, 1998
    Date of Patent: August 28, 2001
    Assignee: Therasense, Inc.
    Inventors: Adam Heller, Charles N. Campbell
  • Patent number: 6277627
    Abstract: The present invention relates to a glucose biosensor comprising a genetically engineered Glucose Binding Protein (GBP). In a specific embodiment, the invention relates to a GBP engineered to include mutations that allow site specific introduction of environmentally sensitive reporter groups. The signal of these prosthetic groups changes linearly with the degree of glucose binding. Thus, the glucose sensor of the invention can be used, for example, for detection of glucose in blood or industrial fermentation processes.
    Type: Grant
    Filed: December 31, 1998
    Date of Patent: August 21, 2001
    Assignee: Duke University
    Inventor: Homme W. Hellinga
  • Patent number: 6261440
    Abstract: Provided are microparticle forms of carbon, carbon catalysts and carbon-containing electrically conductive materials which are covalently linked to peroxidase. The carbon:peroxidase conjugates are suitable for use as substrates in conventional electrodes. Surprisingly, the conjugates display very little sensitivity to known interfering substances and thus are suitable for use as interference free electrodes.
    Type: Grant
    Filed: September 12, 1997
    Date of Patent: July 17, 2001
    Assignee: Abbott Laboratories
    Inventors: Timothy P. Henning, Thomas G. Spring
  • Patent number: 6225108
    Abstract: The invention relates to a microsensor for the measurement of the presence and the concentration of a primary medium, for example nitrate, in an environment where the microsensor is placed. The microsensor has a casing which surrounds a transducer and a reservoir containing nutrients. The transducer has a tip placed at a distance from the opening of the casing. Between the transducer tip and the opening is a reaction chamber with bacteria. The bacteria metabolises the primary medium (nitrate) into a secondary medium (nitrous oxide) which is detected by the transducer. The casing has a passage that stretches to the reservoir behind the transducer tip. Through the passage nutrients are fed to the bacteria whereby their activity can be maintained.
    Type: Grant
    Filed: May 7, 1999
    Date of Patent: May 1, 2001
    Inventors: Lars Hauer Larsen, Niels Peter Revsbech, Thomas Kjær
  • Patent number: 6214612
    Abstract: A cholesterol sensor for quantitative determination of cholesterol is provided containing an electrode system and a reaction reagent system. The electrode system contains a measuring electrode such as a carbon electrode and a counter electrode, and the reaction reagent system contains cholesterol dehydrogenase, nicotinamide adenine dinucleotide and an oxidized electron mediator. Electron mediators include ferricyanide, 1,2-naphthoquinone-4-sulfonate, 2,6-dichlorophenol indophenol, dimethylbenzoquinone, 1-methoxy-5-methylphenazinium sulfate, methylene blue, gallocyanine, thionine, phenazine methosulfate and Meldola's blue. Diaphorase, cholesterol esterase and a surfactant may also be present. The electrode system is on an insulating base plate, and the base plate has a covering member containing a groove that is a sample supplying channel which extends from an end of the base plate to the electrode system.
    Type: Grant
    Filed: March 3, 1997
    Date of Patent: April 10, 2001
    Assignee: Matsushita Electric Industrial Co., Ltd.
    Inventors: Tomohiro Yamamoto, Shin Ikeda, Toshihiko Yoshioka, Shiro Nankai, Junko Iwata
  • Patent number: 6212416
    Abstract: The invention provides an electrochemical sensor system for measuring analyte concentrations in a fluid sample. The invention is particularly useful for measuring analytes such as glucose in a patient. An implantable glucose sensor includes a disc-shaped sensor body containing multiple anodes on opposing sides of the sensor body. Electrodes including an anode and a cathode are connected to a transmitter which transmits radio signals to an external receiver and computer where data is processed to yield glucose concentration figures. An enzyme layer coating the anodes specifically reacts with glucose to increase signals generated by the anodes in response to the presence of glucose. In an alternate embodiment, some of the anodes are coated with the enzyme to generate a first signal, and other anodes that are not coated generate a second signal for comparison with the first signal to eliminate effects of interfering substances on the accuracy of the glucose measurement.
    Type: Grant
    Filed: May 22, 1998
    Date of Patent: April 3, 2001
    Assignee: Good Samaritan Hospital and Medical Center
    Inventors: W. Kenneth Ward, Eric S. Wilgus
  • Patent number: 6180346
    Abstract: An electrode and method of preparing an electrode by electropolymerizing a film on the conductive working surface of an electrode. The electrode is modified by reductive electropolymerization of a thin film of poly[Ru(vbpy)32+] or poly[Ru(vbpy)32+/vba] (vbpy=4-vinyl-4′methyl-2,2′-bipyridine and vba=p-vinylbenzoic acid) and the electrode is used for the electrochemical detection of aqueous GMP, poly[G], and surface immobilized single-stranded DNA probes. The film is formed from a co-polymer of a mediator such as Ru(vbpy)32+ and a functionalized moiety having a carboxylate group such as p-vinylbenzoic acid. A DNA probe is attached covalently to the carboxylate group via a carbodiimide reaction followed by amidation of an amino-linked single-stranded DNA.
    Type: Grant
    Filed: March 12, 1999
    Date of Patent: January 30, 2001
    Assignee: The Universtiy of North Carolina at Chapel Hill
    Inventors: H. Holden Thorp, Allyn C. Ontko
  • Patent number: 6180335
    Abstract: The present invention is a disposable element for assaying food samples and a method for using the element. The disposable element includes a container having first, second, and third ports, a prefilter disposed in the container, an immuno-sorbent layer having antibodies to a target microbe affixed thereto, the immuno-sorbent layer also being disposed in the container, and an electrode in contact with the immuno-sorbent layer. The prefilter and immuno-sorbent layers are positioned in the container such that a sample introduced into the first port passes through the prefilter and the immuno-sorbent layer when a pressure differential is created between the first and third ports. In addition, liquid entering the second port passes through the immuno-sorbent layer, but not the prefilter, when a pressure differential is created between the second and third ports. The prefilter preferably has a pore size between 10 and 30 microns.
    Type: Grant
    Filed: September 30, 1999
    Date of Patent: January 30, 2001
    Assignee: University of New Mexico
    Inventors: Ebtisam S. Wilkins, Plamen B Atanassov, Dmitri M. Ivnitski, Ihab A. Abdel-Hamid
  • Patent number: 6180416
    Abstract: The invention relates generally to methods, systems, and devices for measuring the concentration of target analytes present in a biological system using a series of measurements obtained from a monitoring system and a Mixtures of Experts (MOE) algorithm. In one embodiment, the present invention describes a method for measuring blood glucose in a subject.
    Type: Grant
    Filed: September 30, 1998
    Date of Patent: January 30, 2001
    Assignee: Cygnus, Inc.
    Inventors: Ronald T. Kurnik, Jonathan James Oliver, Russell O. Potts, Steven Richard Waterhouse, Timothy C. Dunn, Yalia Jayalakshmi, Matthew J. Lesho, Janet A. Tamada, Charles W. Wei
  • Patent number: 6156173
    Abstract: A biosensor comprises a space part for sucking and housing a sample formed of two upper and lower plates, the two plates being stuck together by an adhesive layer, the space part for sucking and housing the sample being constituted so as to be partially opened in the peripheral part and partially closed by the adhesive layer, and has a working electrode having at least glucose oxidase immobilized thereon and a counter electrode on the same plane of the plate.
    Type: Grant
    Filed: January 18, 2000
    Date of Patent: December 5, 2000
    Assignee: NOK Corporation
    Inventors: Masao Gotoh, Hiroki Mure, Hiroshi Shirakawa
  • Patent number: 6153069
    Abstract: The present invention relates to a novel method and apparatus for the amperometric determination of an analyte, and in particular, to an apparatus for amperometric analysis utilizing a novel disposable electroanalytical cell for the quantitative determination of biologically important compounds from body fluids.
    Type: Grant
    Filed: February 9, 1995
    Date of Patent: November 28, 2000
    Assignee: Tall Oak Ventures
    Inventors: Paul A. Pottgen, Neil J. Szuminsky, Jonathan L. Talbott, Joseph Jordan, deceased, Colina L. Jordan, legal representative
  • Patent number: 6133046
    Abstract: An apparatus for detecting an analyte in a sample, including a cell with at least one fixed electrode, at least one mobile electrode opposite the fixed electrode, the mobile electrode being configured to move with respect to the fixed electrode, and a sample receiving cavity defined by a space between the fixed electrode and the mobile electrode, wherein a surface of at least one of the fixed electrode and mobile electrode facing the sample receiving cavity is configured to bound a ligand of the analyte to be detected. The apparatus also includes a displacement mechanism configured to move the mobile electrode; and an external circuit connected to the fixed electrode and to the mobile electrode, and configured to measure a parameter having a value depending on the presence between the fixed electrode and the mobile electrode of the analyte to be detected.
    Type: Grant
    Filed: June 30, 1999
    Date of Patent: October 17, 2000
    Assignee: Commissariat a l'Energie Atomique
    Inventor: Jean-Frederic Clerc
  • Patent number: 6132955
    Abstract: An electrode can be derivitized by contacting it with a derivitizing solution to make it more sensitive to a desired analyte signal as opposed to interfering signals in an assay. Particularly, in an electrochemiluminescence (ECL) immunoassay the working electrode can be derivitized to be more sensitive to desired analyte signals, as opposed to interfering non-bound conjugate or serum matrix signals.
    Type: Grant
    Filed: September 3, 1997
    Date of Patent: October 17, 2000
    Assignee: IGEN International, Inc.
    Inventors: David Talley, Jonathan K. Leland, Gary F. Blackburn
  • Patent number: 6121009
    Abstract: A small diameter flexible electrode designed for subcutaneous in vivo amperometric monitoring of glucose is described. The electrode is designed to allow "one-point" in vivo calibration, i.e., to have zero output current at zero glucose concentration, even in the presence of other electroreactive species of serum or blood. The electrode is preferably three or four-layered, with the layers serially deposited within a recess upon the tip of a polyamide insulated gold wire. A first glucose concentration-to-current transducing layer is overcoated with an electrically insulating and glucose flux limiting layer (second layer) on which, optionally, an immobilized interference-eliminating horseradish peroxidase based film is deposited (third layer). An outer (fourth) layer is biocompatible.
    Type: Grant
    Filed: July 16, 1999
    Date of Patent: September 19, 2000
    Assignee: E. Heller & Company
    Inventors: Adam Heller, Michael V. Pishko
  • Patent number: 6117684
    Abstract: A flow cell for use in an analytical system of the type that may be used to test water samples for specific analytes. The flow cell reduces or eliminates the effects of backpressure on a liquid stream passing through the flow cell. This allows a sensor to be incorporated with the flow cell and enables the sensor to provide consistent output with respect to the analyte being tested without introducing signal error due to backpressure fluctuations.
    Type: Grant
    Filed: February 9, 1999
    Date of Patent: September 12, 2000
    Assignee: Zellweger Analytics, Inc.
    Inventors: Scott W. Stieg, James A. Dittmar, Karin L. Bogren
  • Patent number: 6114172
    Abstract: In order to determine the biological oxygen demand of sewage, a sample of sewage is taken into a reaction vessel in which there is a biological bath which is kept moving turbulently by an agitator. An oxygen probe measure the oxygen consumption per unit time. After each measuring cycle the reaction vessel is rinsed with diluting water and is then ready for another measuring cycle. The reaction vessel penetrates into the sewage to be tested. The sewage sample enters the reaction vessel via an aperture.
    Type: Grant
    Filed: July 9, 1998
    Date of Patent: September 5, 2000
    Assignee: Isco Inc.
    Inventor: Friedrich W. Siepmann
  • Patent number: 6110696
    Abstract: A diagnostic kit, method, and apparatus for electrochemically determining the presence or concentration of an analyte in a sample. A mixture is formed which includes the sample, an enzyme acceptor polypeptide, an enzyme donor polypeptide, and a labeled substrate. The enzyme donor polypeptide is capable of combining with the enzyme acceptor polypeptide to form an active enzyme complex. The formation of such the active enzyme complex is responsive to the presence or concentration of the analyte in the fluid sample. The active enzyme hydrolyzes the labeled substrate, resulting in the generation of an electroactive label, which can then be oxidized at the surface of an electrode. A current resulting from the oxidation of the electroactive compound can be measured and correlated to the concentration of the analyte in the sample.
    Type: Grant
    Filed: June 26, 1995
    Date of Patent: August 29, 2000
    Assignees: Roche Diagnostics Corporation, Boehringer Mannheim GmbH
    Inventors: Mary E. Brown, Hans-Joachim Guder, John G. R. Hurrell, Lance S. Kuhn, Robert J. McEnroe, Rebecca W. Muddiman, Mary Luann Ochs
  • Patent number: 6107080
    Abstract: A biosensor apparatus for detecting a binding event between a ligand and receptor. The apparatus includes an electrode substrate coated with a high-dielectric hydrocarbon-chain monolayer, and having ligands attached to the exposed monolayer surface. Binding of a receptor to the monolayer-bound ligand, and the resultant perturbation of the monolayer structure, causes ion-mediated electron flow across the monolayer. In one embodiment, the monolayers have a coil-coil heterodimer embedded therein, one subunit of which is attached to the substrate, and the second of which carries the ligand at the monolayer surface.
    Type: Grant
    Filed: April 24, 1997
    Date of Patent: August 22, 2000
    Assignee: McGill University
    Inventor: R. Bruce Lennox
  • Patent number: 6100045
    Abstract: The present invention relates to diagnostic assays whereby the detection means is based on electrochemical reactions. This means that the label to be detected provides an electric signal. Preferred labels are enzymes giving such a signal. Provided is a flow cell whereby a solid phase is provided in a flow stream of the sample, in close proximity to a working electrode to detect any electrical signal. In a typical embodiment, a sample is mixed with molecule having specific binding affinity for an analyte of which the presence in the sample is to be detected, whereby said specific binding molecule is provided with a label. The conjugate of labelled specific binding molecule and analyte is then immobilized on the solid phase in the vicinity of the working electrode, the flow cell is rinsed with a solution and afterwards a substrate solution for the label (an enzyme) is provided upon which an electrical signal is generated and can be detected by the working electrode.
    Type: Grant
    Filed: February 9, 1998
    Date of Patent: August 8, 2000
    Assignee: DSM N.V.
    Inventor: Remco Maria Van Es
  • Patent number: 6096497
    Abstract: The device described herein is an enzyme-based biosensor for detecting and/or quantifying molecules of interest. The biosensor relies on the following properties shared by all enzymes: (1) that enzymes are highly specific molecules designed to bind with only one analyte type or one class of analyte molecules; (2) that enzymes contain charges; (3) that enzymes undergo significant spacial fluctuation during periods of interaction with substrates; and (4) that these spacial fluctuations cause the charged moieties on the enzyme to move and thus generate a measurable electrostatic potential (voltage) in both the enzyme and support layers. The instant device determines analyte presence/concentration through measurement of changes in voltage or current in a conducting or semiconducting support material as a result of changes in the position of immobilized charged enzyme molecules during their interaction with analyte.
    Type: Grant
    Filed: July 7, 1998
    Date of Patent: August 1, 2000
    Assignee: Biosensor Systems Design, Inc.
    Inventor: Alan Joseph Bauer
  • Patent number: 6083710
    Abstract: A small diameter flexible electrode designed for subcutaneous in vivo amperometric monitoring of glucose is described. The electrode is designed to allow "one-point" in vivo calibration, i.e., to have zero output current at zero glucose concentration, even in the presence of other electroreactive species of serum or blood. The electrode is preferably three or four-layered, with the layers serially deposited within a recess upon the tip of a polyamide insulated gold wire. A first glucose concentration-to-current transducing layer is overcoated with an electrically insulating and glucose flux limiting layer (second layer) on which, optionally, an immobilized interference-eliminating horseradish peroxidase based film is deposited (third layer). An outer (fourth) layer is biocompatible.
    Type: Grant
    Filed: June 16, 1999
    Date of Patent: July 4, 2000
    Assignee: E. Heller & Company
    Inventors: Adam Heller, Michael V. Pishko
  • Patent number: 6071392
    Abstract: A cholesterol sensor is disclosed which comprises an electrode system having a measuring electrode and a counter electrode formed on an electrically insulating base plate, an electrode coating layer for covering the electrode system and a reaction reagent layer formed on or in the vicinity of the electrode coating layer, wherein the reaction reagent layer comprises at least an enzyme for catalyzing cholesterol oxidation, an enzyme having a cholesterol ester hydrolyzing activity and a surfactant, the electrode coating layer comprises at least one selected from the group consisting of water-soluble cellulose derivatives and saccharides and is contained at such a concentration that imparts sufficient viscosity to a sample solution for enabling it to hinder invasion of said surfactant into said electrode system when said electrode coating layer is dissolved in said sample solution supplied to said sensor.
    Type: Grant
    Filed: June 3, 1998
    Date of Patent: June 6, 2000
    Assignee: Matsushita Electric Industrial Co., Ltd.
    Inventors: Tomohiro Yamamoto, Toshihiko Yoshioka, Shiro Nankai
  • Patent number: 6071391
    Abstract: A biosensor comprises a space part for sucking and housing a sample formed of two upper and lower plates, the two plates being stuck together by an adhesive layer, the space part for sucking and housing the sample being constituted so as to be partially opened in the peripheral part and partially closed by the adhesive layer, and has a working electrode having at least glucose oxidase immobilized thereon and a counter electrode on the same plane of the plate.
    Type: Grant
    Filed: December 15, 1997
    Date of Patent: June 6, 2000
    Assignee: Nok Corporation
    Inventors: Masao Gotoh, Hiroki Mure, Hiroshi Shirakawa
  • Patent number: 6059946
    Abstract: The present invention provides a stable and cost-effective biosensor. The biosensor includes an electrically insulating base plate, an electrode system that includes at least a working electrode and counter electrode formed on the base plate, a reaction layer containing at least an enzyme, an electron acceptor that is formed on, or in the vicinity of, the electrode system, and a divalent water-soluble metallic salt provided in, or in the vicinity of, the reaction layer.
    Type: Grant
    Filed: April 13, 1998
    Date of Patent: May 9, 2000
    Assignee: Matsushita Electric Industrial Co., Ltd.
    Inventors: Keiko Yukawa, Toshihiko Yoshioka, Shiro Nankai
  • Patent number: 6051392
    Abstract: The present invention provides a measurement device facilitating accurate quantitation of a substrate from a trace amount of sample and a highly reliable quantitating method of a substrate. The method uses an analysis element comprising a pair of electrodes for electrochemically quantitating reaction between a substrate in a sample and an oxidoreductase. One of the electrodes of the analysis element is a membrane formed on an inner wall of a cylindrical hollow space having an opening and the other is a needle. The needle electrode is projected temporarily external to the hollow space to puncture a subject and the resultant sample is collected from the subject.
    Type: Grant
    Filed: June 9, 1999
    Date of Patent: April 18, 2000
    Assignee: Matsushita Electric Industrial Co., Ltd.
    Inventors: Shin Ikeda, Motokazu Watanabe, Toshihiko Yoshioka, Shiro Nankai
  • Patent number: 6033866
    Abstract: A highly sensitive sensor for the amperometric assay of glucose in aqueous media having a face-to-face sandwich configuration is provided which comprises a sensing electrode strip containing a first redox mediator in an electrically conductive coating and a reference electrode strip in simultaneous contact with a reagent strip containing a second redox mediator which is sandwiched between the active electrode surfaces. An opening is provided in the reference electrode for the introduction of samples. In one embodiment, a whole blood separation membrane is interposed between the reference electrode and the reagent strip to filter red blood cells and other particles from whole blood to enable direct assay of glucose without sample preparation. The sensing electrode comprises a non-conductive support member having an electrically conductive layer containing the first redox mediator.
    Type: Grant
    Filed: December 8, 1997
    Date of Patent: March 7, 2000
    Assignee: Biomedix, Inc.
    Inventors: Dingli Guo, Paul Shieh, Esfir Goldberg
  • Patent number: 6030827
    Abstract: A chemical sensor includes an enzyme layer, a diffusion layer and an analyte barrier layer positioned over the diffusion layer. Apertures are formed by microfabrication in the analyte barrier layer to allow controlled analyte flux to the diffusion layer.
    Type: Grant
    Filed: January 23, 1998
    Date of Patent: February 29, 2000
    Assignee: i-Stat Corporation
    Inventors: Graham Davis, Chao Lin, Imants R. Lauks, Raymond J. Pierce
  • Patent number: 6030828
    Abstract: The invention relates to a microsensor for determining the concentration of a primary substrate by measuring the concentration of a secondary substrate. The microsensor comprises a transducer (1) for measuring the secondary substrate. The transducer (1) is surrounded by a first casing (8), which has an opening (9) with a barrier (10). The first casing (8) surrounds a second casing (11), also with an opening (12) with a barrier (13). In the first casing (8) between the barrier (10) and barrier (13), a reaction space (15) is formed. In the reaction space (15) an environment with catalytic components is contained. By measuring the concentration of the secondary substrate, the presence of the primary substrate can be determined.
    Type: Grant
    Filed: May 1, 1998
    Date of Patent: February 29, 2000
    Assignee: Unisense APS.
    Inventors: Lars Riis Damgaard, Niels Peter Revsbech
  • Patent number: 6020052
    Abstract: An improved laminated enzyme containing membrane for polarographic sensors and methods of making these membranes are disclosed. The laminated membrane comprises an outer, support layer having pores therein of greater than about 300 angstrom units in diameter and this outer membrane has a pore density of less than 6.times.10.sup.8 pores/cm.sup.2. The porosity of the outer membrane may be on the order of 0.001-0.2%. An enzyme layer is interposed between the support layer and an inner, barrier layer; the latter positioned near the working electrode of the polarographic cell. The enzyme layer comprises a buffer solution dispersed therein wherein the molarity of the buffer solution is between about 1.times.10.sup.-6 to 0.1 M. The enzyme layer is highly dense as measured by a molar response ratio of ferrocyanide:H.sub.2 O.sub.2 of less than about 0.05.
    Type: Grant
    Filed: January 28, 1998
    Date of Patent: February 1, 2000
    Assignee: YSI Incorporated
    Inventor: Jay M. Johnson
  • Patent number: 6017440
    Abstract: A sensor array for detecting a microorganism comprising first and second sensors electrically connected to an electrical measuring apparatus, wherein the sensors comprise a region of nonconducting organic material and a region of conducting material compositionally that is different than the nonconducting organic material and an electrical path through the regions of nonconducting organic material and the conducting material. A system for identifying microorganisms using the sensor array, a computer and a pattern recognition algorithm, such as a neural net are also disclosed.
    Type: Grant
    Filed: December 11, 1998
    Date of Patent: January 25, 2000
    Assignee: California Institute of Technology
    Inventors: Nathan S. Lewis, Michael S. Freund
  • Patent number: 6011001
    Abstract: A protein such as an enzyme or antibody is immobilized by crosslinking crystals of the protein with a multifunctional crosslinking agent. The crosslinked protein crystals may be lyophilized for storage. A preferred protein is an enzyme such as thermolysin, elastase, asparaginase, lysozyme, lipase or urease. Crosslinked enzyme crystals preferably retain at least 91% activity after incubation for three hours in the presence of a concentration of Pronase.TM. that causes the soluble uncrosslinked form of the enzyme to lose at least 94% of its initial activity under the same conditions. A preferred enzyme:Pronase.TM. ratio is 40:1. Enzyme crystals that are crosslinked may be microcrystals having a cross-section of 10.sup.-1 mm or less.
    Type: Grant
    Filed: June 7, 1995
    Date of Patent: January 4, 2000
    Assignee: Vertex Pharmaceuticals, Inc.
    Inventors: Manuel A. Navia, Nancy L. St. Clair
  • Patent number: 6004768
    Abstract: Proteins such as enzymes and antibodies are immobilized by crosslinking crystals of the proteins such as microcrystals having a cross-section of 10.sup.-1 mm or less with a multifunctional crosslinking agent. The crosslinked protein crystals may be lyophilized for storage. Crystals of an enzyme such as thermolysin, elastase, asparaginase, lysozyme, lipase or urease may be crosslinked to provide crosslinked enzyme crystals that retain at least 91% activity after incubation for three hours in the presence of a concentration of Pronase.TM. that causes the soluble uncrosslinked form of the enzyme to lose at least 94% of its initial activity under the same conditions. A preferred Pronase.TM.:enzyme ratio is 1:40.
    Type: Grant
    Filed: June 7, 1995
    Date of Patent: December 21, 1999
    Assignee: Vertex Pharmaceuticals, Inc.
    Inventors: Manuel A. Navia, Nancy L. St. Clair
  • Patent number: 6001617
    Abstract: A method and apparatus for cell culture wherein cultured cells adhere and divide, in a monolayer, on an optically transparent planar electrode in the culture vessel. An electric current is applied between the planar electrode and a counter electrode so as to create an electric field between the electrodes which influences the characteristics of the cells growing thereon. In a preferred embodiment the planar electrode may be an optically transparent conducting layer coated onto the culture vessel bottom or the culture vessel may be made of an optically transparent electrically conducting material. The apparatus is particularly useful for the introduction of different biologically important molecules into cells or for cell fusion.
    Type: Grant
    Filed: June 1, 1990
    Date of Patent: December 14, 1999
    Assignee: Queen's University at Kingston
    Inventor: Leda Raptis
  • Patent number: 5997817
    Abstract: An electrochemical biosensor test strip with four new features. The test strip includes an indentation for tactile feel as to the location of the strips sample application port. The sample application port leads to a capillary test chamber, which includes a test reagent. The wet reagent includes from about 0.2% by weight to about 2% by weight polyethylene oxide from about 100 kilodaltons to about 900 kilodaltons mean molecular weight, which makes the dried reagent more hydrophilic and sturdier to strip processing steps, such as mechanical punching, and to mechanical manipulation by the test strip user. The roof of the capillary test chamber includes a transparent or translucent window which operates as a "fill to here" line, thereby identifying when enough test sample (a liquid sample, such as blood) has been added to the test chamber to accurately perform a test. The test strip may further include a notch located at the sample application port. The notch reduces a phenomenon called "dose hesitation".
    Type: Grant
    Filed: December 5, 1997
    Date of Patent: December 7, 1999
    Assignee: Roche Diagnostics Corporation
    Inventors: William F. Crismore, Nigel A. Surridge, Daniel R. McMinn, Richard J. Bodensteiner, Eric R. Diebold, R. Dale Delk, David W. Burke, Jiaxiong Jason Ho, Robert Kitchel Earl, Brian A. Heald
  • Patent number: 5976529
    Abstract: A protein such as an enzyme or antibody is immobilized by crosslinking crystals of the protein with a multifunctional crosslinking agent. The crosslinked protein crystals may be lyophilized for storage. A preferred protein is an enzyme such as thermolysin, elastase, asparaginase, lysozyme, lipase or urease. Crosslinked enzyme crystals preferably retain at least 91% activity after incubation for three hours in the presence of a concentration of Pronase.TM. that causes the soluble uncrosslinked form of the enzyme to lose at least 94% of its initial activity under the same conditions. A preferred enzyme:Pronase.TM. ratio is 1:40. Enzyme crystals that are crosslinked may be microcrystals having a cross-section of 10.sup.-1 mm or less.
    Type: Grant
    Filed: June 7, 1995
    Date of Patent: November 2, 1999
    Assignee: Vertex Pharmaceuticals, Inc.
    Inventors: Manuel A. Navia, Nancy L. St. Clair
  • Patent number: 5972199
    Abstract: A sensor for the detection and measurement of an analyte in a biofluid. The sensor includes two enzymes. One type of sensor measures the concentration of hydrogen peroxide using a thermostable peroxidase enzyme that is immobilized in a redox hydrogel to form a sensing layer on a working electrode. This sensor also includes a hydrogen peroxide-generating second enzyme which is insulated from the redox hydrogel and electrode. This second enzyme generates hydrogen peroxide in response to the presence of an analyte or analyte-generated compound. The second enzyme may be insulated from the electrode by placement of an electrically insulating layer between the sensing layer and the second enzyme layer.
    Type: Grant
    Filed: February 11, 1997
    Date of Patent: October 26, 1999
    Assignee: E. Heller & Company
    Inventors: Adam Heller, Mark S. Vreeke
  • Patent number: 5964993
    Abstract: A sensor that is capable of accurately measuring glucose and other analytes in low oxygen environments is provided. The sensor employs an enzyme-containing membrane comprising a semi-interpenetrating polymer network which is infiltrated by an enzyme. The enzyme-containing membrane increases oxygen transport to the enzyme such that oxygen is not a limiting factor in the oxidation taking place at the enzyme.
    Type: Grant
    Filed: December 19, 1996
    Date of Patent: October 12, 1999
    Assignee: Implanted Biosystems Inc.
    Inventors: Elmo A. Blubaugh, Jr., Alan R. Brunsman
  • Patent number: 5965380
    Abstract: A small diameter flexible electrode designed for subcutaneous in vivo amperometric monitoring of glucose is described. The electrode is designed to allow "one-point" in vivo calibration, i.e., to have zero output current at zero glucose concentration, even in the presence of other electroreactive species of serum or blood. The electrode is preferably three or four-layered, with the layers serially deposited within a recess upon the tip of a polyamide insulated gold wire. A first glucose concentration-to-current transducing layer is overcoated with an electrically insulating and glucose flux limiting layer (second layer) on which, optionally, an immobilized interference-eliminating horseradish peroxidase based film is deposited (third layer). An outer (fourth) layer is biocompatible.
    Type: Grant
    Filed: January 12, 1999
    Date of Patent: October 12, 1999
    Assignee: E. Heller & Company
    Inventors: Adam Heller, Michael V. Pishko
  • Patent number: 5958199
    Abstract: Disclosed is a high performance biosensor free from the effect of any components existing in a sample solution other than a substrate. The biosensor comprises an electrically insulating base plate, an electrode system including a working electrode and a counter electrode provided on the base plate, and a reaction layer containing a hydrophilic polymer, an enzyme and an electron acceptor located over the electrode system. The reaction layer contains an excess amount of hydrophilic polymer in a range of 150 to 1,000% by weight of the enzyme.
    Type: Grant
    Filed: March 12, 1997
    Date of Patent: September 28, 1999
    Assignee: Matsushita Electric Industrial Co., Ltd.
    Inventors: Yoshiko Miyamoto, Toshihiko Yoshioka, Shiro Nankai
  • Patent number: 5952188
    Abstract: A reusable immobilized microbial composition is formulated. The formulated microbial composition comprises a synergistic mixture of the bacterial strains of Enterobacter cloaca, Citrobacter amalonaticus, Pseudomonas aeruginosa,Yersinia enterocolitica, Klebsiella oxytoca, Enterobacter sakazaki and Serratia liquefaciens. The formulated microbial composition is immobilized on an appropriate immobilizing agent to form beads. The said beads are tested as microbial seeding material for BOD analysis using Glucose Glutamic Acid (GGA) as a reference standard. The obtained BOD values by the formulated beads are compared with BOD values obtained by sewage as seeding material using synthetic samples as well as industrial effluents. The formulated microbial beads are ready-to-use as well as reusable seeding material in BOD analysis. The said beads can be reused up to five times with same efficacy.
    Type: Grant
    Filed: July 10, 1998
    Date of Patent: September 14, 1999
    Assignee: Council of Scientific & Industrial Research
    Inventors: Rita Kumar, Anil Kumar, Alka Sharma, Sharad Vishwanath Gangal, Santosh Daya Ram Makhijani
  • Patent number: 5928918
    Abstract: Biological components such as enzymes are immobilized in a three-dimensional cross-linked hydrophobic polymer. An enzyme is mixed with an aqueous solvent and a non-crosslinked prepolymer having an essentially nonpolar main chain with attached polar hydrophilic groups and cross-linking groups. The resultant mixture is exposed to cross-linking temperatures to react the prepolymer via the cross-linking groups without additional catalyst or cross-linking agents, and the aqueous solvent is evaporated to form a three-dimensional cross-linked hydrophobic polymer matrix containing the enzyme. The prepolymer can be an oil alkyl resin containing the main chain with attached polar hydrophilic groups and cross-linking groups. The oil alkyl resin is cross-linked by autoxidation, and aqueous solvent is evaporated to form the polymer matrix.
    Type: Grant
    Filed: April 14, 1997
    Date of Patent: July 27, 1999
    Assignee: AVL Medical Instruments AG
    Inventors: Helmut Offenbacher, Bernhard Schaffar, Massoud Ghahramani
  • Patent number: 5922183
    Abstract: A thin film matrix for biomolecules, suitable for forming electrochemical and biosensors comprising a general class of materials known as hydrous metal oxides which are also conductive or semiconductive of electrons and which have been shown to have excellent stability against dissolution or irreversible reaction in aqueous and nonaqueous solutions. The composites are bifunctional, providing both amperometric and potentiometric (pH) transduction. The thin film composites of the oxides and biological molecules such as enzymes, antibodies, antigens and DNA strands can be used for both amperometric and potentiometric sensing. Hydrous Ir oxide is the preferred matrix embodiment, but conducting or semiconducting oxides, of Ru, Pd, Pt, Zr, Ti and Rh and mixtures thereof have similar features. The hydrous oxides are very stable against oxidation damage.
    Type: Grant
    Filed: June 23, 1997
    Date of Patent: July 13, 1999
    Assignee: EIC Laboratories, Inc.
    Inventor: R. David Rauh
  • Patent number: 5922188
    Abstract: A biosensor includes: an insulating substrate; an electrode system formed on the insulating substrate which has a working electrode and a counter electrode; and a reaction layer formed on the insulating substrate which contains an oxidoreductase and an electron acceptor. The electron acceptor is ferricinium ion derived from ferrocene electrolyte.
    Type: Grant
    Filed: March 7, 1997
    Date of Patent: July 13, 1999
    Assignee: Matsushita Electric Industrial Co., Ltd.
    Inventors: Shin Ikeda, Tomohiro Yamamoto, Toshihiko Yoshioka, Shiro Nankai, Shigeki Joko, Junko Iwata
  • Patent number: 5914026
    Abstract: An implantable sensor comprising a biocompatible electroconductive case which houses a measuring electrode, a reference electrode, an auxiliary electrode, and an electronic circuit for measuring the response of the measuring electrode where the measuring electrode, reference electrode and auxiliary electrode are not in direct electrical contact with one another is provided. The implantable sensor of the present invention is particularly useful as a glucose sensor, especially when an enzyme-containing membrane is included in the measuring electrode.
    Type: Grant
    Filed: January 6, 1997
    Date of Patent: June 22, 1999
    Assignee: Implanted Biosystems Inc.
    Inventors: Elmo A. Blubaugh, Jr., Alan R. Brunsman, Kevin L. Houser
  • Patent number: 5906921
    Abstract: A biosensor is disclosed for application to a method for quantitative measurement of a substrate comprising a first step of causing a substrate contained in a sample to react with an oxidoreductase specific to the substrate in the presence of an electron mediator in oxidized state, a second step of applying a potential to a working electrode for reducing the electron mediator in oxidized state that remains not reduced in the first step, and a third step of measuring a reduction current flowing across the working electrode and a counter electrode. The biosensor comprises an electrically insulating base plate, an electrode system having a working electrode and a counter electrode formed on the base plate, and a reaction layer which is formed on or in the vicinity of the electrode system and contains at least an oxidoreductase and an electron mediator, the counter electrode including at least a reductant of a redox compound or an electrolytically oxidizable metal.
    Type: Grant
    Filed: September 24, 1998
    Date of Patent: May 25, 1999
    Assignee: Matsushita Electric Industrial Co., Ltd.
    Inventors: Shin Ikeda, Toshihiko Yoshioka, Shiro Nankai
  • Patent number: 5888805
    Abstract: A detecting apparatus is disclosed, that comprises plural measurement devices with respective sensors and a support for holding the measurement devices in such a manner that the individual sensors contact a culture broth, the turbidity, dissolved oxygen, dissolved carbon dioxide the temperature, pH, and so forth of the culture broth being obtained by the measurement devices.
    Type: Grant
    Filed: May 28, 1997
    Date of Patent: March 30, 1999
    Assignees: Rikagaku Kenkyusho, Komatsugawa Chemical Engineering Co., Ltd.
    Inventors: Isao Endo, Teruyuki Nagamune, Kozo Inoue, Kinichi Kawamura
  • Patent number: RE36268
    Abstract: The present invention relates to a novel method and apparatus for the amperometric determination of an analyte, and in particular, to an apparatus for amperometric analysis utilizing a novel disposable electroanalytical cell for the quantitative determination of biologically important compounds from body fluids.
    Type: Grant
    Filed: July 12, 1996
    Date of Patent: August 17, 1999
    Assignee: Boehringer Mannheim Corporation
    Inventors: Neil J. Szuminsky, Joseph Jordan, deceased, Paul A. Pottgen, Jonathan L. Talbott
  • Patent number: RE36991
    Abstract: A biosensor for rapid quantification of a specific component contained in various biological samples with high accuracy has an electrically insulating base, an electrode system including a working electrode and a counter electrode formed on one face of the insulating base, and a reaction layer formed on the insulating base in close contact with the electrode system. The reaction layer contains at least a hydrophilic polymer, a buffer and an enzyme which is separated from the buffer.
    Type: Grant
    Filed: August 13, 1999
    Date of Patent: December 19, 2000
    Assignee: Matsushita Electric Industrial Co., Ltd.
    Inventors: Tomohiro Yamamoto, Mariko Miyashita, Toshihiko Yoshioka, Satoko Tsuji (nee Fujisawa), Shiro Nankai