WO2001013102A1 - Capteurs et procedes analytiques d'utilisation - Google Patents

Capteurs et procedes analytiques d'utilisation Download PDF

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Publication number
WO2001013102A1
WO2001013102A1 PCT/GB2000/003054 GB0003054W WO0113102A1 WO 2001013102 A1 WO2001013102 A1 WO 2001013102A1 GB 0003054 W GB0003054 W GB 0003054W WO 0113102 A1 WO0113102 A1 WO 0113102A1
Authority
WO
WIPO (PCT)
Prior art keywords
enzyme
sensor device
cavities
cavity
core
Prior art date
Application number
PCT/GB2000/003054
Other languages
English (en)
Inventor
Pankaj Madganal Vadgama
Original Assignee
Iit Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Iit Limited filed Critical Iit Limited
Priority to AU63075/00A priority Critical patent/AU6307500A/en
Priority to CA002381714A priority patent/CA2381714A1/fr
Priority to JP2001517153A priority patent/JP2003507709A/ja
Priority to EP00949814A priority patent/EP1203228A1/fr
Publication of WO2001013102A1 publication Critical patent/WO2001013102A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
    • A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
    • 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

Definitions

  • This invention relates to improved sensor devices and methods for their analytical use, and more particularly to improved forms of enzyme electrodes .
  • procedures and devices which can enable the presence and amount of particular components (analytes) in biological media to be measured without having to rely on taking samples periodically and taking them away to be analysed in a laboratory.
  • Such old "sampling" procedures - though usually accurate - are too slow and involve a significant delay in obtaining the result of the measurement, and in many circumstances this delay can be inconvenient and even dangerous to a subject.
  • glucose is vital for life and its level is greatly affected by some conditions, for example diabetes ellitus.
  • Other analytes e.g. drugs and metabolic products, are also of comparable interest.
  • a sensor device for a continuous monitoring system, it is very desirable to implant a sensor device in the biological environment or medium, and especially an in vivo environment, so that parameters of a living environment or process can be made.
  • the only routinely usable monitoring system for an ambulatory diabetic would be either a portable or an in vivo device.
  • implant devices have been proposed, but their success and applicability vary considerably.
  • the devices or approaches suggested hitherto could, in principle, eventually allow for reliable monitoring but they suffer from various deficiencies and are not entirely satisfactory. For example, many can lack sensitivity or specificity and, as results are often plotted as graphs, show difficulty in making true measurements independently of base-line or response slope variability in such graphs. Further, in some cases it can be impossible to arrive at meaningful in vivo data without in vivo calibration, particularly in a tissue matrix, and the implant may even provoke tissue rejection.
  • a sensor device substantially in the form of a needle incorporating a sensor electrode.
  • Such an electrode may be used in conjunction with a reference electrode - which may be combined with the sensing electrode in the sensor device or may be used separately from it, for example on the skin of the subject.
  • Such sensors commonly use an active sensor electrode in conjunction with an enzyme, so that the sensor device can be made to respond to selected analyte species which would in themselves be inactive at the electrode and so would not be detected by it, e.g. glucose oxidase for measuring glucose content.
  • analyte species which would in themselves be inactive at the electrode and so would not be detected by it, e.g. glucose oxidase for measuring glucose content.
  • various forms of coating materials or membranes are commonly proposed for regulating the access of analyte to the active electrode or reducing interference from other compounds which could interfere with the effectiveness of the measurements of the desired analyte if they reach the electrode surface.
  • Present devices can be too large for easy use (e.g. they may cause undue discomfort to the subject) so greater miniaturisation is desirable to reduce the effect the implanted sensor may have on the subject's behaviour and tolerance of the implant. Also it is desirable to achieve a size of device which allows for an adequate balance between rigidity and flexibility, so that the device is more durable and more easily implanted.
  • miniaturised devices which can overcome such disadvantages can be achieved by modifying the shape of the sensor device (especially one incorporating a wire electrode) by forming cavities in the otherwise smooth material of the sensor device and using these cavities to retain the enzyme.
  • the enzyme can be retained within the profile of the sensor device and, as it no longer needs to protrude beyond the surface of the sensor device, it is thereby rendered less susceptible to being removed by friction or abrasion during insertion into tissue.
  • new sensor devices comprising an enzyme electrode sensor in which active electrode material carries an enzyme, characterised in that the enzyme is retained within one or more cavities formed in the said electrode sensor. By placing the cavity (or cavities) along the length of the electrode core, the enzyme therein can face laterally instead of being on a mechanically vulnerable wire tip.
  • the core of active electrode material may be made of any of the conventional conducting materials known for use in the art of sensor electrodes.
  • it is a noble metal, for example gold or platinum, or an alloy of these with each other or one or more other elements .
  • the material is platinum itself, but as platinum itself is relatively soft it can be hardened by alloying with a proportion of iridium.
  • the shape of the sensor device is most conveniently of a substantially circular cross-section, as is customarily the case when the active electrode material is a wire core, e.g. conventional drawn metal wire as available commercially, but may be be of any other cross-section if desired.
  • the size of the core material is preferably in the range 50 to 150 yum. though larger or smaller sizes may be used if desired. Our aim is to use as thin a core as can be found to be practical, consistent with the requirement that its strength and integrity are not impaired by the size of the cavities .
  • the senor As the purpose of the construction is for the sensor to present an enzyme-covered surface to its environment, it will normally be found that if any bare active electrode material is also exposed to the environment it will interfere with the measurements made at the surface beneath the enzyme. A bare surface of active electrode material can be tolerated if such interference does not occur, but the preferred form is that in which a core of the active electrode material is covered with a coating of insulating material to prevent bare active electrode material coming into contact with the environment media and the analyte to be detected and measured.
  • insulating material should be suitably durable, stable and resistant to the environment media, effectively sealed over the core of active electrode material, and - when intended for use in vivo - be suitably bio-compatible and harmless in use. Such materials are well known in the art .
  • the cavities required for our invention may be made in several ways.
  • One way is for the insulation to be stripped off to expose a bare core of active electrode material and form the cavity into which the enzyme can then be placed.
  • both the insulation and some of the core of active electrode material can be removed by using an appropriate micro-machining technique, so that the insulation is removed and a cavity is also formed in the core of active electrode material itself. This latter procedure has the advantage that the fabrication is simplified and also that the cavities in the active electrode material allow for a greater surface area of the active electrode material to be exposed to enzyme and used to generate stronger signal outputs .
  • the cavities may be formed by conventional procedures, for example drilling, punching, grinding, boring, cutting, or any combination of these techniques, and the size and shape of the cavities may take any form which is considered most convenient and capable of retaining the desired enzyme in sufficient quantity.
  • the number of cavities may be as large or small as desired, and will be determined to some degree by the size, shape and position of the cavities used in any particular instance.
  • Our preference is for the cavities to be of a size up to about half of the overall thickness of the sensor material, so that the strength of the sensor is not unduly reduced. The optimum in any particular case may be readily determined by simple trial .
  • the method used for forming the cavities may be a mechanical one, though that can be difficult on the micro-scale required; therefore we prefer to use an ion beam or laser method (commonly referred to a "micro-machining") as this is more easily used on the scale of size involved here.
  • a laser or ion beam can be used to etch, cut or bore into the material of the sensor to form the required cavities .
  • suitable shapes for the cavities include circular, oval, square, polygonal, cruciform, star-shaped and combinations of these.
  • the cavities may regular or irregular in their, size, shape, number and distribution, though it is generally preferred (as being more convenient) to make all the cavities of substantially the same shape and size.
  • the form of the cavities should be chosen so that they can readily retain the enzyme; thus dish-shaped cavities may be less efficient if the enzyme is not strongly held, and cavities which are more like "pits" are usually to be preferred as they achieve a stronger hold on their enzyme contents.
  • Another useful cavity shape is a slot cut into the sensor in a substantially lengthways direction (i.e. in the direction of the axis of a wire electrode) , as this can minimise the number of cavities to be made.
  • the size of the slot (length and breadth) may be varied to suit particular needs and usually are not critical.
  • An especially useful form of cavity is one which passes completely through the core of electrode material, in effect forming a tunnel, open at both ends, running transversely to the general direction of the inner core. This allows the enzyme to be packed into this tunnel and the enzyme contents to be exposed to analyte and (in the case of an oxidase) also oxygen, as needed for reaction - thus giving very effective enzymatic action and consequent measurement efficiency.
  • the cavity may contain more than one enzyme, e.g. as laminate layers, so that a succession of reactions can be catalysed one enzyme acting on an analyte substrate to form a product which, in turn, is acted upon by the second enzyme to generate a further product which can then be satisfactorily detected and measured at the active electrode surface .
  • the enzyme may be used in conventional formulations and compositions, and placed in the cavities and retained therein by conventional coating methods and fixing methods.
  • the enzyme may be applied as a composition which coats and fills the cavities (e.g. by dipping) followed by wiping or passing through a collar to remove the surplus and especially any on the main surface where it is not required.
  • the enzyme can then be fixed in place by cross-linking, e.g. by treatment with glutaraldehyde .
  • the enzyme may be any of the conventional enzymes used in sensor enzyme electrodes for electrochemical analysis, but we find oxidase or dehydrogenase enzymes are most useful.
  • An especially useful example is glucose oxidase, which allows the device to be used for detection and measurement of glucose concentrations in tissues. Though we describe our invention with particular reference to glucose and glucose oxidase, however, it is not limited to this specific system and it is applicable to other substrate/enzyme systems, of which several are well known in the art for analytical purposes .
  • the sensor devices of our invention preferably also comprise coatings over the enzymes held within the cavities .
  • additional layers of material may be deposited over the enzyme after that has been put into the cavities .
  • Such over- coating layers may be composed of materials of appropriate permeability (simple or selective) to regulate the passage of components from a sample under examination to the enzyme and active electrode surface, or excluding or limiting access by materials which could interfere with the measurements. These materials are well known in the art and are usually in a thin form which serves as a permselective membrane, and may be applied by conventional means also well known in the art.
  • Such materials include various polymers and polymer compositions, e.g. polyaryl ether sulphones and modified polyurethanes .
  • the electrodes of this invention may be used by any of the conventional procedures well known in the art, but of all the electrochemical procedures available we prefer to use an amperometric procedure with the active electrode material as the anode .
  • the sensor devices of our invention can be used in vivo or in vitro, and the mode of insertion into the sites for making measurements are conventional. For in vivo sites, they may be inserted directly (transcutaneously into tissue) or through a cannula or even fine tubing, e.g. of nylon.
  • the advantages of the invention are especially in the way it provides new sensors which are small, light in weight, and potentially much more robust, flexible and suitable for implantation without attendant discomfort and other problems .
  • Other advantages stem from the way in which the new sensors provide a different orientation and profile for the sensing surfaces - side-oriented micro-machined sensing surfaces - to the samples under examination,
  • Figures 1 to 4 represent, in perspective view, various forms of sensor electrode devices of according to this invention and the type and disposition of cavities, and Figures 5 to 10 illustrate cross-sectional views through such sensor devices at the position at which the cavity is made.
  • Figures 1 to 4 show a thin platinum wire covered with insulation (1) , with the said insulation covering the end (2) as well as the main body (1) .
  • (3) is adapted for continuation on and connection to the electrical measuring system (not shown) .
  • Figure 1 which shows the simplest form of the invention, the insulated wire (1) is pierced by a hole (4) to form a cavity (5) which is filled with an immobilised enzyme composition.
  • FIG 2 there is shown a form in which the insulated wire (l) is pierced by a series of holes (6) , each forming cavities filled with immobilised enzyme as in Figure 1.
  • Figure 3 there is shown a form in which the insulated wire (l) is pierced by a series of holes (7) , each forming cavities filled with immobilised enzyme as in Figure 1 but of a shape different from those in Figure 2, i.e. cruciform instead of round.
  • the slot (8) has been made by cutting out the cover layer of insulation but without cutting into the core of platinum wire itself, but a further alternative (not shown) is that of cutting the slot into the core of platinum metal in addition to cutting away the outer layer of insulation.
  • the insulated wire comprises a core of thin platinum wire (1) covered by an outer layer of insulation
  • a cavity (3) has been bored through the inner platinum wire core, passing through it completely from one side to the other, and is filled with an immobilised enzyme composition.
  • the enzyme-filled cavity (3) is coated at each end with a layer of a membrane coating (4) which acts to protect the enzyme and provide a chosen degree of selectivity or regulation of access of components of the surrounding medium to the enzyme .
  • the cavity (3) has been bored through the inner platinum wire core, passing through it completely from one side to the other, and is filled with an immobilised enzyme composition as in Figure 6, except that two different enzyme compositions (3A) and (3B) are used to fill the cavity (3) .
  • the enzyme contents are coated at each end with a layer of a membrane coating (4) as in Figure 6.
  • the arrangement is essentially the same as for Figure 5 except that the cavity (3) is bored through the outer insulation layer (2) and also into the inner platinum wire core to form an inner pit in the platinum.
  • This form has the advantage of having a larger surface area of the platinum exposed to enzyme and this produces greater response signals for measurement.
  • Figure 10 the construction is that of Figure 6 but shows - with added arrows (9) - indication of flows of fluid past the membrane-covered apertures in the insulation. These flows may be fast or slow, large or small, and may be the same or different .
  • One variant which is practicable is for the two flows (9A) and (9B) to be different -- with one (9B) being the sample medium, from which analyte components can diffuse in to the enzyme through the membrane, while the other flow (9B) can provide similar access by diffusion for necessary substrates for the enzyme system.
  • (9A) may provide the main source of glucose to a glucose oxidase system while (9B) may provide more of the oxygen necessary for the enzyme to function.
  • the insulated platinum wire may be etched to remove the insulation layer and expose the platinum within, and subsequent polymerisation or other conventional techniques may be used to deposit the enzyme on the platinum surface. Covering the enzyme in the cavity can be achieved by conventional techniques, for example application from solution by dipping. The thickness of the coating may vary, but should be thin enough to allow adequate diffusion of a desired analyte without unduly impeding the ability of the material contacting the enzyme to change frequently enough to give a satisfactory overall view of the rate of changes there may be in the medium surrounding the sensor device .
  • the etching and boring operations indicated above were carried out using a copper laser.
  • the thin platinum wire used is a commercially available one, as commonly used for making wire electrodes, since it is not necessary to use a special wire. If the coating of insulation on commercially available wire is not suitable for use in any particular intended environment, the coating as supplied can if necessary be removed and replaced by re- coating with a more suitable insulation or a coating of the preferred insulation material may be deposited over the one already on the commercial wire.
  • insulated monopolar platinum wire electrodes having an outer diameter of 50 to 150 yum and a series of laser-drilled transaxial cavities (which we refer to as fenestrations) each approximately 30 urn in diameter for wire-shaft enzyme loading to be made without undue difficulty.
  • These provide embodiments provide protection for the active enzyme and have unique device geometry; configurations as illustrated provide side-oriented enzyme surfaces in micro-machined sensing surfaces designed to retain and protect them. Construction as in Figure 6 in particular internalises the enzyme in the working electrode, giving a unique twin- surface enzyme with radial product diffusion into the surrounding platinum surface. The greater area of active platinum surface (i.e. surface exposed to the enzyme) can improve the efficiency with which the enzyme functions and so improve the measurements, for example in the linearity of response.
  • the device can be inserted into tissue and, though the tip naturally must enter first, this entry does not damage the enzyme-containing areas of the surface.
  • the wire is pure platinum it may be too soft for direct insertion insertion to be easy, so subcutaneous implantation of such "soft" wires will be through narrow bore nylon tubes.
  • direct insertion can be made easier by using a platinum/iridium alloy wire, which is more rigid.

Abstract

L'invention concerne des capteurs comportant une enzyme située à l'intérieur d'une ou plusieurs cavités formées dans un coeur-électrode actif. Les cavités ont la longueur de ce coeur, pour que les enzymes soient tournées latéralement au lieu de faire face à l'extrémité mécaniquement vulnérable ou d'être au niveau de cette extrémité. On améliore ainsi l'efficacité et la facilité d'utilisation. On choisira spécialement des électrodes de type fil-électrode, de préférence à base de platine, et les cavités peuvent prendre la forme de trous découpés dans le revêtement isolant sur un fil ou découpés plus profondément dans le matériau du coeur-électrode proprement dit (par exemple, perçage au laser). Les modes de réalisation préférés pour la cavité sont la fente latérale, d'une part, et le trou de type tunnel découpé dans le coeur pour dénuder l'enzyme aux deux extrémités, d'autre part, sachant que l'on peut ensuite couvrir l'enzyme au moyen d'une membrane poreuse ou permsélective. Les capteurs considérés sont utiles pour les mesures ampérométriques d'analysats en milieu biologique, et particulièrement pour la mesure du glucose de sang/sérum en prenant l'oxydase comme enzyme.
PCT/GB2000/003054 1999-08-11 2000-08-08 Capteurs et procedes analytiques d'utilisation WO2001013102A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU63075/00A AU6307500A (en) 1999-08-11 2000-08-08 Sensor devices and analytical methods for their use
CA002381714A CA2381714A1 (fr) 1999-08-11 2000-08-08 Capteurs et procedes analytiques d'utilisation
JP2001517153A JP2003507709A (ja) 1999-08-11 2000-08-08 センサ装置及び該センサを用いた分析方法
EP00949814A EP1203228A1 (fr) 1999-08-11 2000-08-08 Capteurs et procedes analytiques d'utilisation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9918839.3 1999-08-11
GB9918839A GB9918839D0 (en) 1999-08-11 1999-08-11 Sensor devices and analytical methods for their use

Publications (1)

Publication Number Publication Date
WO2001013102A1 true WO2001013102A1 (fr) 2001-02-22

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Application Number Title Priority Date Filing Date
PCT/GB2000/003054 WO2001013102A1 (fr) 1999-08-11 2000-08-08 Capteurs et procedes analytiques d'utilisation

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EP (1) EP1203228A1 (fr)
JP (1) JP2003507709A (fr)
AU (1) AU6307500A (fr)
CA (1) CA2381714A1 (fr)
GB (1) GB9918839D0 (fr)
WO (1) WO2001013102A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005072861A1 (fr) * 2004-01-21 2005-08-11 Applera Corporation Dispositif laser et procede permettant de former un fosse dans un substrat d'hybridation
WO2009019470A1 (fr) * 2007-08-09 2009-02-12 Glysure Ltd Appareil de détection
US7972487B2 (en) 2001-12-21 2011-07-05 Roche Diagnostics Operations, Inc. Micro-band electrode
US10791928B2 (en) 2007-05-18 2020-10-06 Dexcom, Inc. Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise
EP3769903A1 (fr) * 2019-07-26 2021-01-27 Heraeus Deutschland GmbH & Co KG Procédé de préparation d'un filament traité par l'interaction d'un filament avec au moins un faisceau de traitement dans des étapes de traitement n

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015155841A (ja) * 2014-02-20 2015-08-27 株式会社村田製作所 バイオセンサ

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0264210A2 (fr) * 1986-10-15 1988-04-20 Canpolar Inc. Sonde chimique et senseur enzymatique pour cette sonde
WO1996006947A1 (fr) * 1994-09-01 1996-03-07 Adam Heller Electrode sous-cutanee de surveillance du glucose
WO1996014026A1 (fr) * 1994-11-04 1996-05-17 Elan Medical Technologies Limited Dispositif d'administration de liquide avec regulation par analyte, et appareil de controle d'un analyte
US5660163A (en) * 1993-11-19 1997-08-26 Alfred E. Mann Foundation For Scientific Research Glucose sensor assembly
WO1998058250A2 (fr) * 1997-06-16 1998-12-23 Elan Corporation, Plc Procedes d'etalonnage et de test d'un capteur servant a mesurer un analyte in vivo et dispositifs utilises dans ces procedes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0264210A2 (fr) * 1986-10-15 1988-04-20 Canpolar Inc. Sonde chimique et senseur enzymatique pour cette sonde
US5660163A (en) * 1993-11-19 1997-08-26 Alfred E. Mann Foundation For Scientific Research Glucose sensor assembly
WO1996006947A1 (fr) * 1994-09-01 1996-03-07 Adam Heller Electrode sous-cutanee de surveillance du glucose
WO1996014026A1 (fr) * 1994-11-04 1996-05-17 Elan Medical Technologies Limited Dispositif d'administration de liquide avec regulation par analyte, et appareil de controle d'un analyte
WO1998058250A2 (fr) * 1997-06-16 1998-12-23 Elan Corporation, Plc Procedes d'etalonnage et de test d'un capteur servant a mesurer un analyte in vivo et dispositifs utilises dans ces procedes

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7972487B2 (en) 2001-12-21 2011-07-05 Roche Diagnostics Operations, Inc. Micro-band electrode
WO2005072861A1 (fr) * 2004-01-21 2005-08-11 Applera Corporation Dispositif laser et procede permettant de former un fosse dans un substrat d'hybridation
US10791928B2 (en) 2007-05-18 2020-10-06 Dexcom, Inc. Analyte sensors having a signal-to-noise ratio substantially unaffected by non-constant noise
WO2009019470A1 (fr) * 2007-08-09 2009-02-12 Glysure Ltd Appareil de détection
EP3769903A1 (fr) * 2019-07-26 2021-01-27 Heraeus Deutschland GmbH & Co KG Procédé de préparation d'un filament traité par l'interaction d'un filament avec au moins un faisceau de traitement dans des étapes de traitement n

Also Published As

Publication number Publication date
AU6307500A (en) 2001-03-13
JP2003507709A (ja) 2003-02-25
GB9918839D0 (en) 1999-10-13
CA2381714A1 (fr) 2001-02-22
EP1203228A1 (fr) 2002-05-08

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