EP1800122A1 - Element d'essai analytique a transmission de donnees sans fil - Google Patents

Element d'essai analytique a transmission de donnees sans fil

Info

Publication number
EP1800122A1
EP1800122A1 EP05792596A EP05792596A EP1800122A1 EP 1800122 A1 EP1800122 A1 EP 1800122A1 EP 05792596 A EP05792596 A EP 05792596A EP 05792596 A EP05792596 A EP 05792596A EP 1800122 A1 EP1800122 A1 EP 1800122A1
Authority
EP
European Patent Office
Prior art keywords
data
test element
analytical test
instrument
module
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05792596A
Other languages
German (de)
English (en)
Inventor
Bernd Roesicke
Manfred Seidenstricker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Original Assignee
F Hoffmann La Roche AG
Roche Diagnostics GmbH
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 F Hoffmann La Roche AG, Roche Diagnostics GmbH filed Critical F Hoffmann La Roche AG
Publication of EP1800122A1 publication Critical patent/EP1800122A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/6848Needles
    • A61B5/6849Needles in combination with a needle set
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/0002Remote monitoring of patients using telemetry, e.g. transmission of vital signals via a communication network
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483Physical analysis of biological material
    • G01N33/487Physical analysis of biological material of liquid biological material
    • G01N33/48785Electrical and electronic details of measuring devices for physical analysis of liquid biological material not specific to a particular test method, e.g. user interface or power supply
    • G01N33/48792Data management, e.g. communication with processing unit
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2560/00Constructional details of operational features of apparatus; Accessories for medical measuring apparatus
    • A61B2560/02Operational features
    • A61B2560/0204Operational features of power management
    • A61B2560/0214Operational features of power management of power generation or supply
    • A61B2560/0219Operational features of power management of power generation or supply of externally powered implanted units
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2560/00Constructional details of operational features of apparatus; Accessories for medical measuring apparatus
    • A61B2560/02Operational features
    • A61B2560/0223Operational features of calibration, e.g. protocols for calibrating sensors
    • A61B2560/0228Operational features of calibration, e.g. protocols for calibrating sensors using calibration standards
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02Details of sensors specially adapted for in-vivo measurements
    • A61B2562/0295Strip shaped analyte sensors for apparatus classified in A61B5/145 or A61B5/157
    • YGENERAL 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
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00Chemistry: analytical and immunological testing
    • Y10T436/11Automated chemical analysis
    • Y10T436/110833Utilizing a moving indicator strip or tape

Definitions

  • the present invention relates to a system for determining the concentration of an analyte from a body fluid. Furthermore, the invention relates to a method for producing such a system.
  • carrier-bound rapid tests have become established in specialized laboratories, but especially for use outside of fixed laboratories. Based on a specially developed dry chemistry, such carrier-bound rapid tests, in spite of the often complex reactions involving sensitive reagents, are simple and uncomplicated, even by laymen.
  • carrier-bound rapid tests are test strips for the determination of the blood glucose content in diabetics.
  • analyte eg, blood glucose
  • a body fluid e.g, blood
  • the function of piercing to create a skin opening and the detection function are usually divided into several components, e.g. B. a lancing device for stinging and generating a blood drop, and an analytical test element, for.
  • a test strip for receiving the blood drop, the forwarding of the blood from the receiving site to the detection area, and the detection of an analyte, eg. B. the blood glucose.
  • lancets and matching devices are offered, which allow a low-pain and reliable blood collection.
  • lancets and lancing devices are the commercially available devices (lancing devices) and lancets Glucolet from Bayer AG and Softclix * from Roche Diagnostics GmbH. Such lancets and devices are z.
  • B. Accu-Chek Sensor from Roche Diagnostics
  • test strip a test element
  • the test strip is brought into contact, for example, with a drop of blood previously obtained by means of a finger-stick lancing device.
  • the blood is transported on the test strip to the area where the detection chemistry is located.
  • the analyte sought reacts with the detection chemistry and thereby generates a measurable signal, eg. B. an electric current pulse or a color change.
  • the measuring signal is evaluated by the measuring device and the user is shown the current blood glucose value on the display of the blood sugar device.
  • Glucose metering regularly, for example, several times a day to perform. For each measurement, a new test strip is needed, which is provided in storage boxes of, for example, 50 pieces. It should be noted that the test strips may have a different quality and different properties depending on the batch, which affect the measurement result. It is therefore necessary to calibrate the glucose meter before inserting the strip. The reason for these fluctuations lies in unavoidable tolerances during the production of the test strips as well as in the sensitive detection chemistry. In order to compensate for this, extensive samples of each production batch are measured and batch-specific calibration data are determined from this. These data are delivered to the customer along with the test strips, but are not visible to the customer. The data record consists of a batch number and values describing a correction function.
  • the reservoir contains a printed number coding, which must be entered via a corresponding input unit on the glucose meter to adjust the glucose meter to the test strip located in this storage box.
  • a film foil is included with each test strip package.
  • the transparent film sheet contains a bar code containing binary-coded coefficients of an n-th order polynomial.
  • an electronic storage medium, a ROM key is stored on the test strip, on which a complete set of the coefficients of a polynomial is stored (see US Pat. No. 5,053,199 ).
  • test strip for the Reflochek ® from Roche Diagnostics GmbH, for example, has printed a bar code, and the Reflotron @ strips (Roche Diagnostics GmbH), a magnetic strip is glued.
  • the calibration unit in this blood glucose measurement system consists of a receiving unit that interacts with a transmitter unit on the test carrier to wirelessly transmit a signal that reflects the quality and / or properties of the test strip. This wireless and non-contact transmission of the calibration data ensures that the user does not have to perform additional calibration steps on the currently used test strip. It is only necessary that the test carrier is held in the vicinity of the meter, which z. B. when inserted into the meter is the case. The receiving unit and the transmitting unit in this case form a so-called transponder system.
  • Puers describes a transponder system used in orthopedic implants (Linking sensor Systems with telemetry: impact on the system design; Sensors and Actuators (1996) 169-174).
  • J. Black et al. an implementable amperometric glucose sensor with integrated telemetry unit (Integrated Sensor-telemetry System for in vivo glucose monitoring, Sensors and Actuators (1996) 147-153).
  • WO 031 00942 describes a pacemaker which receives its energy via a transponder from an extracorporeal battery unit. In return, the pacemaker sends its state of charge to the outside.
  • US 6,217,744 relates to a disposable for blood glucose measurement, which transmits its measurement data via a transponder to the information device, wherein the blood sample itself serves as an electrolyte for the battery in the disposable.
  • a transponder system comprises a reading system, which here corresponds to the receiving unit in the instrument, and the actual transponder, in this case the transmitting unit on the test strip. From the reading system, the energy required for the measurement is introduced into the test strip, ie the test strip does not have its own power supply. The transmitting unit on the test strip in turn sends the stored calibration data and the measuring signals of the current measurement to the measuring device.
  • the transponders are usually realized with microprocessors in silicon technology. Although silicon chip production costs have dropped significantly in recent years due to miniaturization, integration and optimization of manufacturing processes, they are still so high that they would disproportionately increase the cost of a measurement if each individual test strip discarded after a single measurement were equipped with such a silicon chip.
  • the invention describes a system which ensures that the correct calibration data are used in each case for the purpose of permutation.
  • the quality of the measured values is improved by increasing the measurement accuracy through an improved measurement setup.
  • the non-interchangeable calibration data is ensured by storing the batch identification and the calibration data on each test strip.
  • the transponder technology mentioned at the beginning is used.
  • the electrical components are formed on the analytical test element at least partially on the basis of polymer electronics.
  • the quality of the measured values is increased according to the invention by galvanically isolating the electrochemical measuring system to the outside.
  • the transponder technology mentioned above is used for this galvanic isolation.
  • the electrical components on the analytical test element are at least partially formed on the basis of polymeielection.
  • transponder technology is particularly advantageous for systems for determining an analyte from a body fluid using polymer electronics.
  • the polymer electronics are based on the fact that certain polymers (eg pentacene, polythiophene) have semiconducting properties and thus electronic circuits can be realized.
  • Test Strip (From Organic Transistor to Plastic Chip, Physics Journal 2 (2003) No. 2, pp. 31-36).
  • the punctiform fields are formed, for example, by the application of voltage to column and row lines by means of a decoder circuit, preferably of semiconducting polymers (Polymer Memory, Technology Review September 2002, p. 31).
  • a decoder circuit preferably of semiconducting polymers (Polymer Memory, Technology Review September 2002, p. 31).
  • Integrated Plastic Circuits IPC
  • Organic Electronics Polytronic, Electronic Plastic, Organic Semiconductors, or Conductive Polymers
  • These polymers can be applied, for example, by simple printing techniques such as offset, pad printing, screen printing or even technologies similar to laser or ink jet printing, for. B. using polymers in solution (so-called electronic ink).
  • electronic ink polymers in solution
  • This technique is particularly advantageous when applied to flat carrier films, as is commonly the case with analytical test elements.
  • printing and laminating techniques are already routinely used for the production of analytical test elements, the polymer electronics can be easily integrated into the existing production process.
  • DE 102 53 154 describes how the
  • test strips are produced in so-called endless processes (roll-to-roll processes).
  • the rolls are then separated into test strips and filled into packaging units (cans, magazines).
  • samples of each production batch are taken and validated.
  • the determined deviations from the nominal values are converted into a data record via an algorithm and stored on a data medium.
  • the packaged test strips are combined with the data carriers and delivered ready-made.
  • transponder technology in combination with the polymer electronics makes it possible to apply a transponder to the analytical test element in a simple and easily integrated manner into a roll-to-roll production Process step.
  • a transponder made of polymer electronics is extremely inexpensive to produce, which is particularly important for individual measuring strips that are discarded after a single use, of great importance.
  • the invention makes it possible to provide the analytical test elements with a batch identification during the roll-to-roll process, and to apply the calibration data to the scattered and packaged test elements without contact. Ie. saving the calibration data to a separate data carrier and ensuring the correct packaging of the test strips with the corresponding data carrier is eliminated.
  • the transponder system can be used both to load data onto the analytical test element and to query data stored on the test element or generated during the measurement.
  • the batch numbers of the test elements filled in a packaging unit can first be queried by a special reading unit.
  • the reading unit contains the calibration data for the corresponding batch numbers.
  • the reading unit selects the appropriate calibration data and transmits it to the test elements.
  • the stored data can finally be queried.
  • the number of response signals can be used to check whether the correct number of test strips has been packaged and whether all test strips have stored the correct data record.
  • the analytical test elements in addition to the batch also with a unique
  • Identification number to be so specific to describe each individual test strip and query. In this way, the method according to the invention ensures that the correct calibration data are used for each measurement and swapping is precluded, both during assembly in the production and in the customer's application.
  • the batch-specific calibration data can be, for example, a complete calibration curve, or certain interpolation points are defined, to which a defined curve pattern stored, for example, in the instrument, is adapted.
  • the calibration curve may be represented as a polynomial function, where, for example, either the entire function or, preferably, the variables of the polynomial serve as lot-specific calibration data while the polynomial function is stored in the instrument.
  • the curve or the polynomial function can also be stored instead of directly in the instrument on a ROM key, which is enclosed with the instrument and inserted into the instrument by the customer. If at a later time the curve must be adapted, for example, when introducing a new generation of test strips with slightly different measurement behavior, the instrument can be adapted by simply replacing the ROM key.
  • the batch-specific calibration data are stored on the analytical test element or on its packaging, and the curve of the calibration curve is stored in the instrument, for example in the form of a polynomial function.
  • the curve of the calibration curve is stored in the instrument, for example in the form of a polynomial function.
  • An alternative possibility is that several calibration curves, for example under different identification numbers, are stored on a ROM key and the identification number of the calibration curve matching this charge is stored on the test strip.
  • electrochemical measurements are DC or low-frequency processes, ie they are essentially galvanic, ie current-conducting, mechanisms which lead to fault currents which, on the one hand, can falsify the measured values and, on the other hand, the chemical reaction itself. In order to circumvent this problem, one uses today often complex isolation amplifier.
  • the electrochemical measurement systems are separated so far that only the connection over the inevitable liquid, electrochemical path beslehl itself.
  • This "single connection" does not provide a superimposed circuit through which parasitic electrical current can flow.
  • transformer isolation amplifiers are usually expensive, since small variables (current, voltage) must be converted consuming into alternating sizes.
  • an additional current source galvanically isolated from the rest of the system would have to be provided.
  • batteries or transformers separate power supplies, which have a relatively large size.
  • optical separation systems there are also optical separation systems.
  • the measured values obtained as electrical constants are transmitted with light barriers. In optical Separation systems, however, the supply energy can be transmitted only within limits and with relatively poor efficiency.
  • transponders are also suitable for electrically isolating electrical systems instead of isolating amplifiers.
  • the combination of transponder technology and polymer electronics according to the invention makes it possible to provide an analytical test element that can be produced cost-effectively in large quantities, in which parasitic leakage currents are avoided by galvanic decoupling.
  • the required transmission of small measured values at high potential differences is possible with transponders without potential carryover.
  • the energy in the form of an alternating voltage is transmitted in a transforming manner according to the induction principle of the read module located in the instrument wirelessly and without contact to the transmitter module located on the analytical test element.
  • the flat, applied to films structure structures of the polymer electronics allow a good, linear magnetic transmission of the signals across the transformer coils.
  • the energy starts the measurement on the analytical test element.
  • the electrical measurement signal is first obtained as a constant value (current or voltage), then converted into a variable and then inductively transmitted to the instrument, for example, by magnetic field coupling in the near field by the signal is modulated onto a carrier frequency.
  • the system according to the invention therefore enables contactless, bidirectional data transmission.
  • Transmission coils applied with polymer electronics can lie extremely close to one another or one above the other, for example at a distance of 0.1 mm. This allows the use of small coil dimensions, which is particularly advantageous in the course of miniaturization of the analytical test elements.
  • polymer electronics not only planar structures, but by the use of multiple layers three-dimensional structures such as a field effect transistor can be applied (organic field-effect transistor - the breakthrough at last, Chemphyschem 2001, 2, 163-165).
  • the invention relates to a system for determining the concentration of an analyte in a body fluid, which contains an analytical test element and an instrument separately therefrom, wherein at least a part of the electrical components of the analytical test element is formed on the basis of polymer electronics.
  • On the analytical test element is an area with detection chemistry for detection of the analyte and the instrument has an evaluation unit for the evaluation of data.
  • a preferred embodiment of the invention relates to a system described above, wherein there is a transmission module for the wireless transmission of data on the analytical test element and the instrument has a read module for the wireless transmission of data. Transmitter module and read module work according to the transponder technology described above.
  • the system of the invention comprises the components necessary to determine the concentration of an analyte in a body fluid.
  • the system includes an analytical test element with detection chemistry and an instrument with evaluation unit.
  • the system may also include, for example, a lancing device and a display unit, these two components can be integrated into both test element or instrument as well as stand-alone units.
  • analyte is meant a component of the body fluid which reacts with the detection chemistry in the detection region, so that, starting with a certain amount of the analyte, the reaction can be measured in a measurement arrangement.
  • a preferred embodiment is to use blood as a sample liquid and to detect blood glucose as an analyte in the detection area and to determine therefrom the concentration of the blood glucose.
  • Body fluids possible. It is also possible, not just an analyte, to. R. glutglucose, but also several analytes, eg. B. HbAlC, and detect this from both a body fluid, eg. As blood, as well as from a mixture of several body fluids, eg. As blood plus interstitial fluid perform.
  • a body fluid eg. As blood
  • a mixture of several body fluids eg. As blood plus interstitial fluid perform.
  • An analytical test element is any form of carrier-bound rapid tests for diagnosis, in particular rapid tests in strip form, so-called test strips, in particular for the determination of the blood glucose content in diabetics.
  • the instrument designates the part of the system that contains the measurement signals that are used in the analytic
  • Test element are generated, receives and evaluates in the evaluation.
  • the instrument may also include a holder in which an analytical test element or packaging for one or more test elements, e.g. As a container or magazine, is positioned.
  • a display unit for. As an LCD display, in the Be integrated instrument.
  • the instrument is a battery-powered handset.
  • the electrical leads and contacts on the analytical test element are made in gold or similar inert metals, e.g. B. removed by laser ablation structured.
  • the printed conductors and contacts can also be embodied in polymer electronics instead of metal.
  • a test strip available today with gold contacts and a data carrier (eg a magnetic strip or barcode) for strip identification can be replaced by an analytical test element, in which the electrical leads and contacts are formed by polymer electronic conductor tracks and contacts are.
  • the strip identification is preferably stored in a polymer electronic memory.
  • a polymer electronic transponder for writing and reading out the memory is also located on the analytical test element.
  • the polymer electronics can be used both on the test element and in the instrument.
  • some or all of the electrical components are formed on the analytical test element on the basis of polymer electronics and in the instrument, the electronics is realized in conventional technology.
  • the transmitter module on the analytical test element serves as a transponder on which data is stored during production, such as identification data (batch number, strip type, if applicable serial number), expiry date and batch-specific calibration data. It is also possible to store additional data after production, such as current customer information, logistics data, retail information, such. B. the pharmacy, or other. For example, as soon as the test strip is inserted into the instrument, the identification data are transmitted to the instrument for checking, for example, whether the appropriate test strip for the instrument has been inserted and whether the expiration date has expired.
  • the measurement signals which are generated during the measurement of the concentration of the analyte sought can be transmitted from the test strip to the instrument.
  • the read module converts the signals received by the transmission module and forwards them to the evaluation unit in which they are evaluated.
  • the result for example the concentration of the blood glucose, is displayed in the display unit, e.g. As an LCD display, the user displayed.
  • the display unit is integrated in the instrument, but it is also possible that the display is realized in a separate unit.
  • test element may be formed as an implant or partial implant
  • instrument with the reading module is respectively worn over the test element directly on the skin or over the clothing
  • the display unit may be a type of wristwatch attached to the wrist.
  • the transmission of the data from the evaluation unit to the display unit is also realized with a transponder system.
  • further modules in particular an insulin pump or an electronic diabetic diary, can be controlled in this way.
  • the inventive transponder system for wireless transmission from an implanted test element to an extra-corporeal reading module uses frequencies in the range of 125 kHz with a range in the body of about 10 to 20 cm, as z. B. be used in implants for animal identification.
  • frequencies in the range of 13.56 MHz are used to bridge in air approximately to the distance can be.
  • data should be transmitted over longer distances, z. B. to secondary external devices, such as a PC for data management, so can be bridged with frequencies in the range of 800 to 2,000 MHz (UHF range) distances up to about 4 m.
  • the measured values which are generated during the measurement of the concentration of the analytes sought are transmitted wirelessly and without contact from the measuring module to the transmitting module. Under wireless and non-contact only the signal transmission and optionally the energy transfer should be understood as such.
  • the transponder system according to the invention.
  • at least the sensitive measurement data is transmitted wirelessly, for example, if the energy for operating the measurement on the test element is still provided via electrical contacts or if the test element has its own energy source.
  • both the sensitive measurement data is transmitted wirelessly, for example, if the energy for operating the measurement on the test element is still provided via electrical contacts or if the test element has its own energy source.
  • the contacts are formed in polymer electronics. Polymers are also insensitive to aggressive sweat. By generating a voltage peak at the contact surfaces, it is also possible to selectively weld the contacts between the test element and the measuring device and thereby reproducibly generate a very low contact resistance.
  • a further preferred embodiment of the invention relates to a system for determining the concentration of an analyte from a body fluid containing an analytical test element having a region with detection chemistry for detection of the analyte from a body fluid and a memory for storing electronic data.
  • the system includes an instrument having an evaluation unit for evaluating the data and a display unit.
  • the system is characterized in that the electrical components of the system are at least partially formed on the basis of polymer electronics.
  • the electronic data stored on the analytical test element may include a test strip identification, lot-specific calibration data, and the measurements generated in the concentration measurement.
  • the identification, z. B. Lot number, strip type and possibly also the expiration date, are preferred stored during the production of the test strip on the test element and then not changed. Therefore, this could also be realized by a fixed wiring. Otherwise, one or more writable software memory, z. As EPROM or EEPROM used. According to the invention, a rewritable polymer electronic memory is particularly preferred for this purpose.
  • a memory writable via a transponder system is necessary.
  • the transmission module receives transmitted energy from the read module, e.g. B. as soon as the analytical test element is inserted into the instrument, in particular if the analytical test element does not have its own power supply.
  • the transponder In a passive transponder system, the transponder has no own power supply and is therefore only active as long as it is in communication with the reading unit.
  • the transponders operate via magnetic field coupling in the near field, i. The transponder must be brought close enough to the reading unit.
  • the data in electrically writable memory, z. As an EPROM or an EEPROM, stored and are permanently stored after removal of energy.
  • the analytical test element does not have its own energy source.
  • the electrical energy necessary for the measurement and possibly also for storage is transmitted wirelessly via the transponder system from the instrument to the test element.
  • This embodiment is particularly advantageous in implants, since then the residence time of the implant is not affected by the life of the power source, eg. B. a battery is limited.
  • the power source eg. B. a battery is limited.
  • analytical test elements that are used as disposable for the in-vitro disposable measurement so-called disposable test strips
  • a temporary energy store in the test element for example a capacitor or an accumulator.
  • the Contact time to be handled flexibly, so z. B. continue to measure a continuous measuring system with such an energy buffer for a long time, regardless of whether the instrument is permanently in the vicinity of the test element.
  • the analytical test element has its own energy supply.
  • a so-called active transponder can be particularly useful if the test element can perform several measurements. For example, such a, z. B. (partially) - implanted, test element for 24 hours the required or set measurements perform and the user needs only once a day to transfer the measurement data from the test element to the instrument. If the test element has a rechargeable energy supply (accumulator, capacity), the energy store can be charged during data transmission if necessary.
  • the analytical test element of the system comprises a plurality of electrodes, in particular more than two electrodes, which are in contact with the detection chemistry.
  • the electrodes are connected to one or more electronic circuits, wherein the electronic circuits are galvanically isolated. Ie. the circuits have no common source of energy or common ground and are galvanically isolated to the outside so that only the connection exists over the unavoidable liquid path of the detection chemistry itself. Since the electrical contact exists only at one point, no parasitic creepage current path can build up, which could falsify the measured value. To realize the electrical isolation, for example, each circuit would have its own power supply, which would be very expensive.
  • the galvanic decoupling is solved by the Transpondersystcm. All circuits on the analytical test element have a transponder and are galvanically isolated from each other. A common reading module or a separate memory module for each transponder transfers the energy to the circuits.
  • the reading module can be located in the instrument or else on the analytical test element. In the latter case, the transmission of energy from the reading module, which is located on the test strip, to the instrument can take place either via electrical contacts or via another transponder system consisting of a common transponder or again of a plurality of transponders.
  • Simple electrochemical systems usually consist of two to three electrodes. Frequently, so-called potentiostats with 3 electrodes (working, counter and reference electrodes) are used.
  • a parasitic resistance of the counter electrode to the output of the potentiostat is critical, since this flows directly into the signal amplification. It is therefore advantageous if the entire potentiostat, except for the electrodes, is hermetically sealed with an insulating layer.
  • the transponder processes and stores, for example, no digital information, but processes the analog signal stream and transmits it to the read module.
  • the functions required for the measuring process are integrated in the transponder, such as:
  • the permanent supply of the working electrode with a potential typically some 100 mV, preferably -350 mV).
  • the transponder system is designed so that the required energy is provided by the instrument at suitable refresh intervals and stored between.
  • a potentiostat which is designed as an implant or partial implant, z.
  • z As for the continuous measurement of an analyte, it is of particular importance that can be hermetically encapsulated by the inventive use of transponder technology, the electrical system and yet information and energy can be transmitted.
  • a preferred embodiment of the invention relates to implanted analytical test elements.
  • the use of transponder technology makes it possible to implant a test element in the body and to operate without transcutaneous connections through the skin from the outside. Performs through the skin reduce the wearing comfort, z.
  • an analytical test element can be used for the continuous measurement of blood glucose in the subcutaneous fat tissue in the abdominal region and outside the skin, the instrument is held, either only temporarily to perform a measurement, or permanently, z. B. from a belt or a patch, especially in continuous measurements of the analyte in the minute range. In both cases, at least for a short time the instrument can be removed, for. For showering.
  • a preferred method for transmitting data with the transponder system according to the invention is to convert the signals, typically DC or DC signals, into a frequency and to modulate them to a carrier frequency which, for example, serves for energy transmission.
  • a variant of the invention describes the use of different carrier frequencies. This can be used to distinguish the transponder systems. In particular, if several transponders are addressed simultaneously, for example in the case of several parallel transponders on an analytical test element or when writing several test strips which are located in a packaging, it may be advantageous to address each transponder individually. By using narrow-band filters, for example, each carrier frequency can be treated individually and crosstalk can be avoided.
  • the signals transmitted by the transponder system are not limited to digital data, e.g. B. the calibration data, but also analog signals, in particular the measured values obtained in the measurement of the analyte concentration can contain.
  • the transponder systems customary today are mostly used only for the transmission of digital data.
  • DE 103 22 167 describes the use of transponders for the lavish traceability of reusable
  • the calibration and identification data of the analytical test element are in the form of digital data and those of the concentration measurement of an analytical molecule in the form of analog data.
  • the digital data is transmitted, for example, according to the above-mentioned amplitude modulation.
  • the analog data is either digitized before transmission or as analog signals, e.g. B. also with amplitude modulation transmitted.
  • the calibration and identification data stored on the analytical test element is stored either in electronic memory, e.g. B. from polymer electronics, filed or they are encoded in a magnetic strip or bar code, which is located on the test strip.
  • the measurement signals are either stored on an electronic data storage before being sent to the instrument, e.g. B. transponder system, passed, or they are passed directly without caching to the instrument.
  • the electronic memory on the analytical test element is preferably a non-volatile memory, in particular the memory or memory area in which the calibration and identification data are stored.
  • the analytical test element includes a memory for storing electronic data, which memory is also writable when the analytical test element is in a package.
  • the test strips are packaged in a container (single-test magazine or tape magazine), and then the calibration data are sent from an outside reading module through the packaging to the transponder located on the test element and stored there.
  • the packaging is in this case designed so that a wireless transmission of the data is possible, in particular, the packaging material is preferably made of plastic or cardboard, which is almost completely permeable to the transmission radiation used.
  • the analytical test element has no electrical contacts to the instrument via which data or electrical energy is transmitted between the test element and the instrument, for example because all data and, if appropriate, the energy are transmitted via a transponder system.
  • the electrical circuit on the analytical test element for example, the transponder antenna or the tracks and contacts, at least partially made of polymer electronics, but the transponder itself is designed as a silicon chip.
  • the higher manufacturing costs of the silicon chip may be acceptable for complex analytical test elements that may perform, for example, multiple measurements.
  • this embodiment may be favorable if the transponder is not located directly on the analytical test element but on a packaging for one or more test elements.
  • the system additionally includes such a packaging, in particular a container or a magazine for a plurality of test elements, for. B. a drum can be.
  • test counter which stores in the memory on the container the number of tests carried out with this container or can still be carried out. In this way, you can always ask the instrument how many unused test elements are still in the packaging are located. If this information is created only in the instrument, it could lead to malfunction, for example, when an opened container is removed from the instrument and replaced by another broken or new.
  • an indicator can be stored on the test element itself, indicating whether the test element has already been used or not.
  • a further preferred embodiment of the invention relates to a system comprising an analytical test element having an area with detection chemistry for detection of the analyte, wherein the electrical components are formed on the test element at least partially based on polymer electronics, and a packaging in which or more analytical test elements are packaged, the packaging having a memory for storing electronic data and a transmission module for the wireless transmission of data.
  • the system includes an instrument having an evaluation unit for evaluating the data and a read module for wireless transmission of data.
  • test strips are packed in a container (drum, magazine).
  • the calibration and identification data are stored on the container and not on the test elements.
  • the container for.
  • a drum with analytical test elements similar to as is used in the Accu-Chek Compact ® is inserted into the instrument and the transponder on the container sends the data to the reader module in the instrument.
  • the advantage of this variant is that, for example, only one transmission module is necessary for a plurality of test strips, in particular if the processing of the measurement signals works without a transponder (eg in the case of photo-optical test elements).
  • Einmal test strip the analytical test element does not have its own power supply. On the test element z. Batch number, strip type, expiration date and calibration data are stored.
  • the test element is removed from the packaging by the user or automatically by the instrument and, for example, brought into a holder in the instrument. The positioning of the test element in the holder ensures a correct position of the transmitting and reading module. In particular, the holder ensures the introduction of the analytical test element into the transmission and reception range of the read module.
  • the transmission and reception area describes the area within which electronic data can be exchanged wirelessly between the reading module and the transmission module. The extent of this area is particularly determined by the dimensions of the transponder coils, the energy and Frequency of the transmitted electromagnetic waves and any shielding, z. B. by metal parts defined.
  • the holder may be designed so that the transponder modules come together very close, typically to a distance of 0.1 to 3 mm. Due to the small distance that must be bridged, the transponder coils can be very small and only little power is required for wireless transmission, for example in the range of 0.1 to 10 mj. A low energy requirement is particularly advantageous for battery-operated instruments.
  • the transmission and reception area can be spatially limited to ensure that only the introduced test element is addressed and not additionally located in the vicinity of other test elements.
  • the transmitting and receiving area can also be designed so that the analytical test element for wireless data transmission, with or without a holder, for example, can be positioned close to or on the instrument.
  • the holder for introducing the analytical test element in the transmitting and receiving area can be in a package for a plurality of test elements and the package is positioned according to the instrument, for example by a
  • the transmitter module is not on the test element, but on a package that includes one or more test elements, and a holder positions the package in the instrument so that the transmitter and reader come very close together, so that the Transmitter module of the packaging is located in the transmission and reception area of the read module.
  • a further preferred embodiment of the invention relates to an analytical test element having a region with detection chemistry for detection of an analyte, wherein a transmission module and a reading module are located on the analytical test element and data is wirelessly transmitted between the two modules within the test strip.
  • a transmission module and a reading module are located on the analytical test element and data is wirelessly transmitted between the two modules within the test strip.
  • the electrical components on such an analytical test element are preferably at least partially formed on the basis of polymer electronics.
  • such an analytical test element can also wirelessly transmit data or data and energy to the instrument, e.g. Example by means of a second transponder system with a transmitter module on a test strip and a read module in the instrument.
  • the data transmitted to a transponder system within the test strip may be both digital and digital also act on analog data.
  • test strip-internal transponder system can be used to galvanically decouple the electrical circuits on a elektro ⁇ chemical test strip, the energy is transmitted from the instrument to the detection area, and the measurement signals, z. As analog voltage or current values are sent in return from the detection area to the instrument.
  • both an electrochemical and a foto ⁇ optical measuring method can be used for analytical determination, especially if, for example, in a photo-optical test strip, the measuring unit is on the test strip and thus as in an electrochemical test strip, the electrical To generate measurement signals on the test strip and to transfer to the instrument.
  • a light beam from the instrument can be directed to the detection area and a photo element located on the test strip, eg. B. a solar cell made of polymer electronics, receives the optical measurement signal and converts it into an electrical signal. This signal can then be transmitted without contact to the instrument with the transponder system.
  • a photo element located on the test strip eg. B. a solar cell made of polymer electronics
  • Photo-optical or electrochemical methods are preferred.
  • Photo-optical measuring methods are, for example, reflection photometry, absorption measurement or fluorescence measurement
  • electrochemical methods are, for example, potentiometry, amperometry, voltammetry, coulometry.
  • Another object of the invention is a method for producing an analytical test element comprising an area with detection chemistry for detection of an analyte in a body fluid, a memory for storing electronic data and a transmission module for wireless transmission of data, the manufacture comprising the steps of storing a Batch identification on the analytical test element; Packaging the analytical test element; and storing calibration data on the packaged analytical test element.
  • Another object of the invention is a method for producing an analytical test element having a region with detection chemistry for detection of an analyte in a body fluid, wherein the production of the steps Batch identification on a package having a memory for storing electronic data and a transmission module for wireless transmission of data; Packaging the analytical test element in the package; and storing calibration data on the package.
  • Another object of the invention is a method for determining the concentration of an analyte in a body fluid, comprising the steps of inserting an analytical test element comprising a region with detection chemistry for detection of an analyte in a body fluid, a memory for storing electronic data and a wireless transmission module Transmitting the data, in an instrument having an evaluation unit for the evaluation of the data and a read module for wireless transmission of the data; Applying the body fluid to the analytical test element; wireless transmission of the data from the analytical test element to the instrument; and evaluating the data in the evaluation unit of the instrument.
  • Another object of the invention is a method for determining the concentration of an analyte in a body fluid, comprising the steps of inserting a package in which one or more analytical test elements are packed with detection chemistry for detection of an analyte in a body fluid, and the packaging of a memory for Storing electronic data and a transmission module for wireless transmission of the data; Providing an analytical test element from the package; Applying the body fluid to the analytical test element; wireless transmission of the data from the packaging to an instrument comprising an evaluation unit for evaluating data and a read module for wireless transmission of the data; and evaluating the data in the evaluation unit of the instrument.
  • the batch-specific calibration data are stored on the test strip.
  • the test strip is inserted by the user into the corresponding holder in the instrument, for example by hand or the test strip storage container has a removal device that transports the test strip from the Vorats constituer in the instrument.
  • the instrument turns on automatically as soon as the test strip is inserted and is ready to measure after a short self-test.
  • the user gives the sample to be measured with body fluid.
  • the sample reacts with the detection chemistry on the test strip and generates a measurement signal.
  • this can be a color change, for example, in the case of electro-chemical systems, for example, a current signal is generated.
  • the color change is converted by the measuring optics into an electrical signal.
  • the optic is usually integrated into the instrument, but it may also be on the test strip, especially if the optic is at least partially realized in polymer electronics.
  • the calibration data are transmitted wirelessly from the test strip to the instrument or, if the optic is on the test strip, additionally the energy for operating the optics is first transmitted from the instrument to the test tire and after the measurement the measurement signals from the test strip to the instrument.
  • the measurement signals in the evaluation unit in the instrument are evaluated.
  • the instrument has a display unit, e.g. As an LCD display, which displays the measured value to the user.
  • test strips are contained in a package, e.g. B. a container.
  • the batch-specific calibration data are stored on the packaging and the transponder is also in the packaging.
  • the package is inserted by the user into the instrument, for use the instrument is turned on, preferably, automatically transporting a test strip to a position where the user can apply the sample. Subsequently, sample application and photo-optical or electro-chemical measurement is carried out as described above. Preferred dimensions are photo-optical test strips and the measuring optics are located in the instrument.
  • the calibration data are transmitted wirelessly from the transponder on the packaging to the instrument, while the optical measurement signals are received by the optics in the instrument and evaluated in the evaluation unit without inclusion of the calibration signals and preferably displayed in a display unit.
  • the calibration data are likewise transmitted wirelessly from the transponder on the packaging to the instrument and, for example, the electrical measuring signals are transmitted via electrical contacts from the test strip to the instrument, via which the energy required for generating the measuring signal is also fed.
  • FIGS. 1 to 23 schematically show schematic diagrams of specific embodiments of the invention.
  • FIG. 1 shows an analytical test element with a transponder system.
  • Figure 2 shows an inventive analytical test element inserted into an instrument.
  • FIG. 3 shows the use of a conductive polymer substrate as a data memory.
  • FIG. 4 shows the transmission of data to a plurality of analytical test elements with the transponder system according to the invention.
  • FIG. 5 shows a sketch of a system with several galvanically separated circuits.
  • FIG. 6 shows a schematic block diagram of a system with a plurality of galvanically separated circuits.
  • FIG. 7 shows a multi-electrode system with transponder.
  • FIG. 8 shows a partially implanted analytical test element.
  • FIG. 9 shows an implanted analytical test element.
  • FIG. 10 shows a basic circuit of a potentiostat transponder.
  • FIG. 11 shows an electrochemical test strip with transponder made of polymer electronics.
  • Figure 12 shows a sectional view of the test strip of Figure 11 inserted into an instrument.
  • FIG. 13 shows a photo-optical test strip with transponder made of polymer electronics.
  • FIG. 14 shows a Thomasdarstell ⁇ ng the test strip of Figure 13 inserted into an instrument.
  • FIG. 15 shows a test element with several potentiostat sensor systems.
  • FIG. 16 shows the test element from FIG. 15 inserted in an instrument.
  • Figures 17 and 18 show a partially implantable analytical test element.
  • Figures 19-21 show examples of data transfer to packaged test strips.
  • Figures 22 and 23 show a read-write memory of polymer electronics.
  • FIG. 1 shows an analytical test element 1 consisting of a substrate 2 on which there is a detection area 3 for detecting an analyte from a body fluid and a
  • Transmitter module which includes the transponder substrate 4, in or on which the
  • Transponderantcnne 5 and the transponder electronics 6 are made as Polymcrclcktronik.
  • Figure 2 shows a schematic diagram of an analytical test element 1, which is inserted into an instrument 7.
  • the identification and calibration data of the test strip are stored in the transponder electronics 6 and are transmitted via the transponder antenna 5 to the reading module 8, which is also located in the instrument 7.
  • the measurement signals determined in the detection area 3 are relayed via the electrical contacts 15 to the instrument 7.
  • the test strip shown here may be suitable for an electrochemical and for a photo-optical measurement.
  • a photo-optical test element accounts either the contacts 15 and the evaluation optics is in the instrument 7, or the evaluation is at least partially on the Integrated test strip, so that the optical measurement signals on the test element converted into electrical quantities and the electrical signals are passed through the contacts 15 to the instrument.
  • the use of a conductive polymer substrate 14 as a binary memory for electronic data is shown schematically in FIG.
  • the electronic control unit 10 controls the electrode matrix 11 in such a way that at first high-resistance zones 12 become selective low-resistance zones 13.
  • FIG. 4 shows the wireless transmission of data 9 between a read module 8 and a plurality of analytical test elements 1.
  • the transmit modules on the test element are represented here by the transponder substrate 4 and the transponder electronics 6.
  • This application can be used for example in production.
  • the test strips 1 in a package, for. B. a container that does not interfere with the electromagnetic field, packaged and a special reading module 8 in production first queries the test strip identification of the test elements to query the batch numbers, then transmits the batch-specific calibration data and finally checked by re-query whether the Data transfer was correct.
  • the test elements 1 are located in a container in the instrument or close to the instrument and the reading module 8, which is located in the instrument, reads the data from the test element.
  • test elements are returned to the container after the measurement.
  • the usage is stored on the test element, e.g. B. together with the measured values, and reported to the reading module, or sent directly to the reading module and stored there, for example, together with the measured values, or a test element to which a measured value is stored on the test element or in the instrument, automatically considered used.
  • Figure 5 shows a schematic diagram of a system with galvanically isolated circuits.
  • transponder substrate 4 On the transponder substrate 4 are a plurality of mutually insulated electrical circuits consisting of transponder antenna 5, transponder electronics 6, as well as in the deklr ⁇ -chemical detection area 3 projecting measuring electrodes 16.
  • the measurement signals are received by as many parallel antennas 17 in the reading module 8.
  • Figure 6 shows a simplified block diagram of the example shown in Figure 5, wherein also of other modules 30, z.
  • signals can be sent and / or received.
  • FIG. 7 shows a complex multi-electrode system as a potentiostat transponder for the electrochemical measurement of, for example, blood glucose and blood coagulation with electrical leads 18 which extend from the transponder electronics and antenna 6 or 5 to the measuring electrodes 16 in the detection area 3.
  • a cover layer 19 ensures a hermetic separation of the transponder system.
  • FIG. 8 shows a partially implantable lancet-like test element 1 with potentiostat transponder, which is preferably used for continuous glucose measurement.
  • the glucose concentration is regularly determined, the data stored in the transponder, and whenever the reader module 8 is in the vicinity, the signals are transmitted to the instrument. So the user can easily the instrument short time, z. B. for changing or showering, decrease.
  • the test element 1 consists of a tip 2 at one end and relatively stiff substrate 2, at the top of which the measuring electrodes 16 are located. Electrical conductor tracks 18 lead from the electrodes 16 to the other, located outside the body, transmission module consisting of transponder electronics and antenna, 6 and 5.
  • the entire test element 1 is encapsulated waterproof with a cover layer 19, only the measuring electrodes 16, forced, after outside open contacts.
  • a patch 22 can be located above the test element 1, or the reading module 8 can be comfortably worn over a clothing 22.
  • FIG. 9 shows a potentiostat test element 1 similar to the example shown in FIG. 8 as a (fully) implanted version.
  • the entire electronics, except for the measuring electrodes 16, are hermetically encapsulated in a glass or polymer capsule 23.
  • small antenna coils they are equipped with rod ferrite cores 24.
  • FIG. 10 describes a basic circuit of a potentiostat transponder.
  • the transponder electronics include u. a. a load modulator 25, an energy storage 26, z. B. in the form of a capacitance, and a voltage / frequency converter 27.
  • the rest potential 28 is permanently applied to the working electrode 29 at. 30 and 31 denote reference and counter electrodes, respectively.
  • the reading module has, inter alia, bandpass filter 32, energy transmitter and writing unit 33, reading unit 34, memory 35 and control unit 36.
  • FIG. 11 shows an analytical test element 1 with a polymer electronics transponder which operates according to an electrochemical measurement method.
  • a spacer film 51 which forms a blood capillary 50 between the substrate 2 and the cover film 52, into which the measuring electrodes 16 protrude for the electrochemical measurement.
  • the transponder antenna 5 the transponder electronics 6 and Transponder memory 54 realized in polymer electronics.
  • the transponder serves for the transmission of test strip identification and calibration data.
  • the measurement signals are transmitted via the sensor contacts 15.
  • the transmission module 37 and in particular transponder antenna 5 are positioned close to the reading module 55 and in particular to the reading module antenna 17 (see FIG. 12).
  • the reader module 55 is located here on the electronic circuit board 56 of the instrument 7, as well as the instrument contacts 70 which contact the sensor contacts 15 on the test strip 1.
  • the detection area 3 which is filled via the blood capillary 50, is located below the transponder module made of polymer electronics, consisting of transponder substrate 4, antenna 5, electronics 6 and memory 54.
  • the blood capillary 50 is replaced by the blood capillary 50 Spacer film 51 formed between the substrate 2 and cover film 52.
  • the transponder antenna 5 and the read module antenna 17 lie very close to one another and thus allow easy data transmission over a short distance (see FIG. 14).
  • the transponder module 37 is located on top of the test strip, the photometric detection area 3 is illuminated from below by the illumination 58 and read out to the optical reader 59.
  • An upper and a lower printed circuit board 56 are equipped with the reading module 55 and the optical modules 58 and 59, respectively.
  • the piece 1 in Figure 15 has a wick 3 in the form of a liquid channel, through which the sample from the inlet 60 to the outlet 61, z. B. for continuous blood glucose measurement flows.
  • Three measuring electrodes 16 of a potentiostat project into the fluid channel.
  • On the transponder substrate 4 are a polymer electronics transponder antenna 5 and the transponder electronics 6, which is constructed of polymer electronics or (at least partially) with silicon chips.
  • Parallel to the first potentiostat sensor system there is still a parallel system of identical design, whereby both systems are galvanically separated from each other.
  • the parallel transponder antennas 5 on the test element 1 correspond to the corresponding read module antennas 17, which pass the data to the reader module electronics 55, for a wireless data transmission 9 (see FIG. 16).
  • FIGS. 17 and 18 Another example of a continuously measuring analytical test element 1 is shown in FIGS. 17 and 18.
  • the substrate 2 has a needle-shaped end, which is pierced through the skin 20 into the tissue 21, so that the measuring electrodes 16 can measure directly in the tissue 21.
  • the potentiostat electronics and the transponder module 37 are the flat extracorporeal part of the substrate 2 as polymer electronics or silicon chip.
  • a cover layer 19 encapsulates the electronics except for the measuring electrodes.
  • a patch 62 fixes the test element 1 on the skin.
  • FIGS. 19 to 21 show examples of data programming in production and logistics.
  • a read module 8 writes the lot-specific during production
  • a plurality of test strip cans 63 are combined in a carton 65 into a container and are then described by a reading module 8 in production or in the logistics chain.
  • hard-wire data eg, batch or serial numbers of the test strips
  • the data does not have to be extra, but it can not be changed afterwards.
  • Figures 22 and 23 show a read-write memory of polymer electronics, as used for example for a transponder memory 54.

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Abstract

L'invention concerne un système de détermination de la concentration d'un analyte dans un liquide corporel, comprenant un élément d'essai analytique et un instrument, séparé de ce dernier, au moins une partie des composants électriques du système étant réalisée sur une base d'électronique polymère. L'élément d'essai analytique comporte une zone présentant un produit chimique d'analyse pour la détection de l'analyte, et un transpondeur pour la transmission sans fil de données spécifiques d'un lot et/ou des valeurs mesurées. L'instrument présente un module de lecture pour la transmission sans fil des données et de l'énergie à l'élément d'essai, ainsi qu'une unité d'évaluation servant à évaluer les données ou les valeurs mesurées reçues par le transpondeur.
EP05792596A 2004-10-07 2005-10-07 Element d'essai analytique a transmission de donnees sans fil Withdrawn EP1800122A1 (fr)

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DE102004048864A DE102004048864A1 (de) 2004-10-07 2004-10-07 Analytisches Testelement mit drahtloser Datenübertragung
PCT/EP2005/010806 WO2006040083A1 (fr) 2004-10-07 2005-10-07 Element d'essai analytique a transmission de donnees sans fil

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DE (1) DE102004048864A1 (fr)
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HK1111762A1 (en) 2008-08-15
WO2006040083A1 (fr) 2006-04-20
JP4808723B2 (ja) 2011-11-02
US20070237678A1 (en) 2007-10-11
CN101036053B (zh) 2012-12-05
CA2582775C (fr) 2013-03-19
DE102004048864A1 (de) 2006-04-13
CA2582775A1 (fr) 2006-04-20
CN101036053A (zh) 2007-09-12
US7988917B2 (en) 2011-08-02
JP2011085608A (ja) 2011-04-28
JP2008516209A (ja) 2008-05-15

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