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WO2004023125A2 - Systemes et procedes bases sur une spectroscopie d'impedance - Google Patents

Systemes et procedes bases sur une spectroscopie d'impedance Download PDF

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Publication number
WO2004023125A2
WO2004023125A2 PCT/IB2003/004438 IB0304438W WO2004023125A2 WO 2004023125 A2 WO2004023125 A2 WO 2004023125A2 IB 0304438 W IB0304438 W IB 0304438W WO 2004023125 A2 WO2004023125 A2 WO 2004023125A2
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WO
WIPO (PCT)
Prior art keywords
electrode
specimen
ofthe
concentration
measuring
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2003/004438
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English (en)
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WO2004023125A3 (fr
Inventor
Andreas Caduff
Etienne Hirt
Thomas W. Schrepfer
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PENDRAGON MEDICAL Ltd
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PENDRAGON MEDICAL Ltd
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Priority to AU2003264797A priority Critical patent/AU2003264797A1/en
Publication of WO2004023125A2 publication Critical patent/WO2004023125A2/fr
Publication of WO2004023125A3 publication Critical patent/WO2004023125A3/fr
Anticipated expiration legal-status Critical
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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N17/00—Investigating resistance of materials to the weather, to corrosion, or to light
    • G01N17/02—Electrochemical measuring systems for weathering, corrosion or corrosion-protection measurement
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/02—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance
    • G01N27/026—Dielectric impedance spectroscopy
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/02—Food
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/02—Food
    • G01N33/14—Beverages
    • G01N33/146—Beverages containing alcohol
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/18—Water

Definitions

  • the invention relates to systems, methods and devices for non-invasively determining the concentration of a substance in a target.
  • targets include an in- vitro or an in-vivo target containing body liquid, a non-body liquid target such as wastewater or beer, and a non-liquid target such as baby food or biological tissue.
  • a non-body liquid target such as wastewater or beer
  • a non-liquid target such as baby food or biological tissue.
  • One application of conventional impedance spectroscopy is to attempt to determine the concentration of glucose and other substances in body fluids.
  • this technology is of substantial interest for the determination of glucose concentration in blood and/or inter- or intracellular liquid.
  • Impedance spectroscopy practitioners have attempted to determine glucose concentration non-invasively. Stated another way, impedance spectroscopy practitioners have attempted to determine glucose concentration in a body liquid by analyzing the interac- tion of electromagnetic waves with the target material. The goal of such a technique is to provide a non-invasive in-vivo analysis.
  • the invention relates to systems, methods and devices for accurately and effectively determining the concentration of a substance in a target.
  • targets include: an in-vitro or an in-vivo target containing body liquid; non-body liquids such as wastewater or beer; and non-liquids such as baby food or biological tissue.
  • the invention provides a device that determines the concentration of a substance in a target.
  • the device includes a first electrode, a signal source, a measuring circuit, and a data processor.
  • the first electrode can be electrically insulated from the target, e.g., a cover layer of insulating material covers the first electrode.
  • the measured parameter(s) e.g., the magnitude ofthe impedance
  • the device capacitively couples a signal to the target and the meas- ured parameter depends therefore primarily on the conditions within the target.
  • the parameter measured in this way can then be converted to the desired concentration, e.g., by using calibration data.
  • the first electrode is part of a sensor, e.g., a microstrip nearfield antenna or at lower frequencies a fringing capacitor.
  • the microstrip nearfield antenna includes a microstrip electrode, i.e., the first electrode, surrounded by a ground electrode.
  • a modulated voltage is applied between the microstrip electrode and the ground electrode.
  • the measured parameter preferably depends on the electrical impedance of the sensor. It has been found that the concentration of various substances in the target, for example substances that can change electrical properties ofthe target (such as colloids suspensions, electrolytes, bio molecular solutions, dyes etc., affects the impedance because it changes the loss (i.e., loss of power) properties and/or the dielectric properties ofthe target.
  • substances that can change electrical properties ofthe target such as colloids suspensions, electrolytes, bio molecular solutions, dyes etc.
  • the senor forms part of a resonant circuit, which is operated at or close to its resonance frequency. Under such conditions, a change ofthe dielectric properties or loss properties ofthe target leads to shifts in the parameters ofthe resonant circuit and can therefore be measured.
  • the target can be a liquid including body liquids such as blood, extracellular fluid, intracellular fluid, interstitial fluid, and transcellular fluid, measured in vivo or in vitro.
  • the device also can be used to measure tissue flux in a body.
  • tissue flux i.e., microvascular blood flow, reducing supply of necessary molecules leading to alterations in the skin and tissue structure and thus having an impact on the impedance pattern produced by the tissue in question.
  • Embodiments ofthe invention also can be used with targets containing non- body liquids such as water in rivers, lakes, puddles, streets, waste-treatment systems, liquids present in foodstuffs, liquids present in growing crops, and liquids used during manufacturing processes.
  • targets containing non- body liquids such as water in rivers, lakes, puddles, streets, waste-treatment systems, liquids present in foodstuffs, liquids present in growing crops, and liquids used during manufacturing processes.
  • Embodiments ofthe invention provides systems for measuring the concentration of a substance in a target, such as the glucose level in blood or tissue.
  • the systems include a sensor having a strip electrode and a ring electrode arranged at the target.
  • the ring electrode is adapted for direct electrical contact with the target while the strip electrode is electrically insulated therefrom (in an alternative embodiment, the strip electrode can be in electrical contact with the target and the ring electrode be electrically isolated from the target).
  • the strip electrode is adapted to provide a large interaction length with the target.
  • the ring and strip electrodes form a capacitor in a resonant circuit.
  • a modulated voltage in the MHz range close to or at the resonance frequency is applied to the electrodes and the system measures the response ofthe target. This arrangement permits a high accuracy measurement.
  • the invention provides a method for determining the con- centration of a substance in a target.
  • the method includes arranging a sensor, e.g., a micro- strip nearfield antenna (having a microstrip electrode) at the target wherein at least part ofthe sensor can be electrically insulated from the target.
  • the method includes applying a modulated electrical voltage to the sensor for generating a modulated field in the target.
  • the method further includes measuring at least one parameter (for example the amplitude or the impedance, the phase shift, and/or the frequency), the parameter depending on a response of the target to the field.
  • the method also includes determining the concentration ofthe substance in the target based at least in part on the measured parameter
  • the method can include providing a sensor (e.g., a microstrip nearfield antenna with both a microstrip electrode and a second, ground electrode and placing the second, ground electrode in electrical contact with the target), so that, in the antenna example, the modulated electrical voltage is applied between the microstrip and the ground electrodes.
  • the method includes measuring the temperature ofthe target and using the measured temperature in the determination ofthe concentration.
  • the response ofthe target is measured by arranging a near field microstrip antenna in proximity to the target.
  • embodiments of the invention for in-vivo measurements ofthe human body.
  • embodiments of a device according to the invention include an elongate electrode having a width much smaller than its length.
  • Embodiments ofthe invention also include a holder to mount the elongate electrode to an arm or a leg with the longitudinal axis ofthe electrode extending parallel to the longitudinal axis ofthe arm or leg.
  • the methods and devices of this aspect ofthe invention have been found to be especially suited for measuring the glucose concentration in body fluid.
  • Such applications include: monitoring the concentrations of substances such as glucose or sodium chloride during biochemical processes; detection of changes in tissues ofthe body, such as those resulting from inflammatory processes in skin and underlying tissues, skin or breast cancer, and edemas; measuring tissue flux; and tracking concentrations of substances in infusions, fermenters, and cell suspensions.
  • substances such as glucose or sodium chloride during biochemical processes
  • detection of changes in tissues ofthe body such as those resulting from inflammatory processes in skin and underlying tissues, skin or breast cancer, and edemas
  • measuring tissue flux and tracking concentrations of substances in infusions, fermenters, and cell suspensions.
  • Industrial applications include: waste water analysis; measuring salt in bodies of water including street water; corrosion testing, and environmental monitoring.
  • Still other applications of embodiments of a device according to the inven- tion include monitoring the growth and harvesting of agricultural products and food and beverage processing applications.
  • Still another embodiment ofthe invention provides a system for measuring the concentration of a substance, e.g., a polluting or toxic substance, in a target, such as in product flow or in wastewater.
  • the system includes a sensor (e.g., a microstrip nearfield antenna, having a microstrip electrode surrounded by a ground electrode) arranged at the target.
  • the ground electrode is adapted for direct elec- trical contact with the target while the microstrip electrode can be electrically insulated therefrom.
  • the ground and microstrip electrodes form a capacitor in a resonant circuit.
  • the system is adapted to apply a modulated voltage in the appropriate range for the target, e.g., in the MHz range, and close to or at the resonance frequency ofthe circuit.
  • the system is adapted to apply the appropriate range to the electrodes and the system measures the response ofthe target.
  • the system can include or can be adapted to interface with a process control device such that the process being observed is managed at least under certain circumstances (e.g., when a specified concentration of a pollutant is exceeded during the process) based on impedance spectroscopy data.
  • Fig. 1 is a block circuit diagram of a one embodiment for carrying out the invention
  • Fig. 2 is a view onto a possible embodiment ofthe device
  • Fig. 3 is a section along line III-III of Fig. 2
  • Fig. 4 is the device of Fig. 3 with a wristband
  • Fig. 5 shows the behavior ofthe relative amplitude A as a function of frequency
  • Fig. 6 is a second embodiment ofthe circuit
  • Fig. 7 is an alternative electrode geometry
  • Fig. 8 a third embodiment ofthe circuit
  • Fig. 9 is a schematic of a system using the circuit of Fig. 1, in accordance with an embodiment ofthe invention.
  • FIG. 10A-F illustrate alternative embodiments of systems or portions of systems for monitoring processes such as the process illustrated in FIG. 9, and
  • FIG. 11 is a block circuit diagram of an alternative embodiment to the embodiment of FIG. 1 for carrying out the invention.
  • Fig. 1 shows a block circuit diagram of one embodiment of a device according to the invention.
  • the device includes a voltage controlled oscillator (NCO) 1 as a signal source for generating a waveform, e.g., a sine wave signal, the frequency of which depends on an input control voltage.
  • NCO voltage controlled oscillator
  • This signal is fed to two amplifiers 2, 3 (In the alternative em- bodiment of FIG. 11, the signal is fed to a single amplifier 2).
  • the output of first amplifier 2 is connected via a resistor Rl to a first signal path 4.
  • a resonant circuit 5 comprising an inductance L and a capacitor C in series is connected between first signal path 4 and ground.
  • the output of second amplifier 3 is connected via a resistor R2 to a second signal path 6.
  • Second signal path 6 is substantially identical to first signal path 4 but comprises a resistor R3 as a reference load instead of resonant circuit 5.
  • Both signal paths 4, 6 are fed to a measuring circuit 7, which determines the relative amplitude A of both signals as well as, optionally, their mutual phase shift, phi.
  • Rela- tive amplitude A can be, e.g. the amplitude of first signal path 4 in units ofthe amplitude of second signal path 6 (wherein the amplitudes are the peak values ofthe sine waves).
  • circuit 7 is a conventional circuit for measuring the relative amplitude of both signals.
  • the output signal of measuring circuit 7 is fed to a microprocessor 8, which also controls the operation of NCO 1.
  • the device in the present embodiment further includes a temperature sensor 10, a display 11 and an input device 12 with user operable controls, all of which are coupled to microprocessor 8.
  • Inductance L ofthe device of Fig. 1 can be generated by a coil and/or by the leads and electrodes of capacitor C.
  • the inductance values can range depending on various factors including the substance and target of interest. In the case of determining the concentration of glucose in a body liquid, the inductance value ranges between about 220nH and about 470nH. One embodiment uses a value of about 330 nH.
  • a sensor e.g., a near field microstrip antenna, making up part ofthe capaci- tor C ofthe device of Fig. 1 probes a target.
  • the device of Fig. 1 includes a capacitor C having electrodes adapted for placement near the target.
  • the near field microstrip antenna is located close to the target but remote from the rest ofthe device of Fig. 1. This arrangement can be useful in situations where the target itself may present an environment that could be damaging to all or part ofthe device (e.g., applications where the target comprises running water, such as waste water monitoring and/or environmental monitoring).
  • the device of Fig. 1 includes an extra antenna electrode 33 that is in electrical communication with the device but is located remote from the device.
  • the geometry ofthe electrodes is such that the electric field generated by them extends into the target. Representative examples of suitable geometries are disc ⁇ ssed below.
  • at least one ofthe electrodes ofthe capacitor is electrically insulated from the target such that capacitor C is primarily a capacitive load, the capacitance and loss of which depends on the electrical properties (i.e. the response) ofthe target at the frequency of VCO 1.
  • the depth ofthe electromagnetic fields produced is strongly dependent on the electrode/antenna geometry (defined by the distance ofthe microstrip and the ground electrodes as well as by the shape ofthe microstrip antenna/electrode itself). Decreasing the distance between the microstrip electrode and the ground electrode increases the density of the electromagnetic field lines produced by the electrodes.
  • microprocessor 8 can initiate a measurement cycle consisting of a frequency sweep of VCO 1.
  • the sweep can start at a frequency fmin below the expected resonance frequency ft) ofthe resonant circuit 5 and extend to a frequency fmax above resonance frequency fO.
  • the sweep from fmin to fmax can occur as a single sweep or as a sequence of discrete sweeps. Each sweep provides a set of data points useful in calculating the concentration ofthe substance in the liquid.
  • the VCO is a symmetrical VCO to provide low harmonics and is a FET implementation providing a relatively wide frequency range.
  • a symmetrical VCO cancels out most ofthe first harmonic because a differential signal is used.
  • a FET implementation provides a higher frequency range as less parasitic capaci- tance exists in the resonating circuit because the FET Gate can be controlled directly avoiding a capacitive coupled feedback.
  • the range ofthe frequency sweep may be influenced by the application and/or the equipment used. For example, sweeps performed on a living body may use a lower fmax than sweeps performed on a target other than a living body.
  • the electrical properties of signal path 4 will change substantially, while those of signal path 6 will vary only slightly.
  • the amplitude determined by measuring circuit A will therefore fall to a minimum A0 at fO, as shown in Fig. 5.
  • Measurement e.g., In Vivo Measurement, of a Substance, e.g., Glucose, in a Body Liquid, e.g., Blood
  • the specific conductivity p(f) and the dielectric constant ⁇ (f) for a given fluid vary depending on the type of fluid.
  • the spe- cific impedance of at least some body fluids i.e. the specific conductivity p(f) and the dielectric constant ⁇ (f)
  • the spe- cific impedance of at least some body fluids in a frequency range between 10 MHz and 2000 MHz, more particularly between 20 MHz and 70 MHz and most particularly between 38 MHz and 58 MHz, is a function ofthe properties and concentration ofthe salty (ionic) components ofthe human body, related to variations in blood glucose.
  • These salty components primarily include solvated so- dium, potassium, calcium and other minor ions and their counter ions, the primary counter ion being chloride.
  • amplitude A0 is measured as a parameter for the determination ofthe concentration ofthe substance.
  • Suitable calibration data stored in microprocessor 8 is used to convert amplitude A0 into the desired concentration level.
  • the calibration data stored in microprocessor 8 is calibration data that is appropriate for the measurement of glucose in blood.
  • the calibration data includes an offset ⁇ O, a factor ⁇ l for the relative amplitude and a factor ⁇ 2 for the temperature correction.
  • the resulting concentration equals ⁇ O + ⁇ l * (measured impedance) + ⁇ 2*temperature.
  • Measurements of other types of targets, as described herein, may have their own respective types of calibration data.
  • Temperature has an effect on permittivity and conductivity. Temperature appears to have a nonlinear effect on the measurement of impedance conducted in vivo with the current glucose monitoring device, that originates from nonlinear physiologic responses ofthe human body to temperatures conditions and changes. Changes in temperature have a more or less linear effect on ac conductivity per se. However, the human body reacts physiologically in a nonlinear way to changes in temperature. Thus, other embodiments ofthe invention take into account an appropriate temperature correction in applications where the target shows temperature dependence, e.g., nonlinear temperature dependence.
  • temperature sensor 10 In order to obtain high accuracy over a wide temperature range, one brings temperature sensor 10 into thermal contact with the target.
  • the tem- perature sensor 10 does not need to be in physical contact with the target (i.e., blood or other liquid) being measured. Rather, the temperature sensor 10 can contact the skin to obtain temperature.
  • the signals from temperature sensor 10 are used to correct the obtained result, again using calibration data obtained from calibration measurements.
  • a proper design ofthe electrodes of capacitor C permits optimization ofthe accuracy and sensitivity ofthe present device in a given application.
  • Example geometry of a device suitable for taking in-vivo measurements in a living body is shown in Figs. 2 and 3.
  • the device comprises a housing 13 closed on one side by an electrode plate 14.
  • the display 11 is arranged opposite electrode plate 14.
  • the electronic circuits 16 are arranged between electrode plate 14 and display 11.
  • Electrode plate 14 can include an electrically insulating substrate 17 with a sensor, e.g., a microstrip nearfield antenna having a microstrip electrode 18 and a top or ring/ground electrode 19 arranged on an outer side 20 thereof.
  • a bottom electrode 22 covers an inner side 21 of insulating substrate 17.
  • a plurality of through-contacts 23 is provided to connect ring/ground electrode 19 to bottom electrode 22.
  • a further through-contact 24 con- nects one end of microstrip electrode 18 to a small bond pad 25 arranged in an opening 26 of bottom electrode 22 on inner side 21.
  • Temperature sensor 10 is mounted to bottom electrode 22. The large number of through-contacts 23 ensure that bottom electrode 22 follows the temperature of ring/ground electrode 18 and therefore the temperature ofthe target closely.
  • a typical size of electrode plate 14 is 32 mm x 21 mm.
  • Bottom electrode 22 covers all of inner side 21 except for the small opening 26 and is therefore much larger than strip electrode 18.
  • Leads 28 are provided to connect bottom electrode 22, contact pad 26 and temperature sensor 10 to the electronic circuits 16.
  • the capacitor C is formed between strip electrode 18 as a first electrode and ring electrode 19 and bottom electrode 22 as a second electrode.
  • the second electrode consists of two electrode layers: a top electrode layer formed by ring electrode 19 and a bottom electrode layer formed by bottom electrode 22.
  • An electrically insulating cover layer 29 covers all of strip electrode 18 but not ring electrode 19.
  • strip electrode 18 is arranged between substrate 17 and cover layer 29.
  • Cover layer 29 is preferably made of a hard, moisture- and salt-impervious material such as glass, ceramics, a polycarbonate or diamond-like carbon (DLC) of a thickness preferably between 50 and 100 ⁇ m.
  • Figs. 2 and 3 illustrate a device that may be especially useful in applications where the device is to be disposed against a substantially flat surface, such as an area of skin on a living body.
  • the geometry and orientation shown in Figs. 2 and 3 are not limiting, however. Many different orientations, shapes, and sizes are usable in accordance with the invention.
  • the display 11 may be disposed along a side ofthe housing 13, or may be entirely separate from the housing 13 (e.g., in operable communication with the electronic circuits 16 but disposed at a location remote from the housing.)
  • the display 11 and electronic circuits 16 are disposed within a first housing while the electrode plate 14 (or other configuration of electrodes) is disposed within a second housing, the electrodes being in operable communication with the electronic circuits 16.
  • This configuration may be advantageous in embodiments ofthe invention that are used for applications and/or in environments that could cause damage and/or stress to the electronic circuits 16 and/or the display 11.
  • a holder or wristband 31 is attached to housing 13 for fixing the device to an arm or a leg of a human body with cover layer 29 facing the body and a longitudinal axis of strip electrode 18 parallel to the arm or leg.
  • ring electrode 19 comes into contact with the user's skin and the ring electrode and the area ofthe user's body in contact with the ring electrode come to a common reference potential.
  • measuring circuit 7 is preferably provided with suitable filters for selectively sampling one or more frequency components. At least one 5 measured frequency component is preferably close to the resonance frequency of resonant circuit 5 for exploiting the circuit's high sensitivity to the target's properties at that frequency.
  • the electrode geometry can be varied for adapting it to a given application. While the design of Fig. 2 is optimized for a measurement on an arm or leg, a circular design l o can be used for measurement on a flatter body part or an in-vitro sample. Further, in embodiments ofthe invention that are used in the manufacturing, environmental, and/or agricultural industries, the electrode may have a geometry adapted for the given application, such as a partially-curved shape, a ring-like shape, a triangular shape, and a cylindrical shape. These other applications are described further herein.
  • Ring electrode 19 does not necessarily have to form a closed ring as long as it provides sufficient grounding ofthe site (e.g., in this example, the body part) to be measured.
  • the ring electrode 19 can, e.g., also have a U-shape or consist of two stripes parallel to and laterally enclosing strip electrode 18. Ring electrode 19 can also be omitted completely or be covered by cover layer 29, especially for measurements (such as in-vitro measurements)
  • FIG. 6 Part of one embodiment of an alternative embodiment of a circuit according to the invention is shown in Fig. 6.
  • Fig. 6 there is no direct wired connection between resonant circuit 5 and measuring circuit 7. Rather, an antenna electrode 33 is located in proximity to the electrodes of capacitor C, and measuring circuit 7 measures the signal returned
  • antenna electrode 33 is strip shaped and arranged in parallel to strip electrode 18. Both, antenna electrode 33 and strip electrode 18 are covered by cover layer 29 and therefore electrically insulated from the target.
  • FIG. 30 The device of Figs. 6 and 7 is again sweeping VCO 1 between a frequency fmin below the resonance frequency fO of resonant circuit 5 and a frequency fmax above it.
  • measuring circuit 7 now detects a maximum amplitude A0 at fO, wherein the value of A0 depends on the response, i.e. the electrical properties ofthe target at the resonance frequency ft).
  • Changing the resonant circuit to a tank circuit also changes the reso-
  • the parameter A0 can now again be processed using calibration data as described above.
  • FIG. 8 A second embodiment of a circuit is shown in Fig. 8.
  • the capacitor C formed by the electrodes is part ofthe resonant tank circuit of an active, self-oscillating oscil- lator 40.
  • the amplitude A and frequency fO ofthe output signal of oscillator 40 depend on the capacitance and losses in capacitor C.
  • the corresponding signal is fed to measuring circuit 7, which evaluates the parameters A and fO. Measuring the corresponding parameters A and fO again allows a sensitive measurement ofthe desired concentration using calibration data.
  • the invention was used in a device for qualitatively or quantitatively displaying the concentration a substance (such as glucose) in body liquid.
  • the invention can, however, also be used in devices that automatically administer medication to a body, such as an insulin pump, where the amount and/or time for administering the medication depends on the measured concentration ofthe substance in question.
  • the invention can also be used in any other type of device that requires the measurement ofthe concentration of a substance in a target.
  • Another aspect ofthe invention is directed to using the above-described device in other medical and/or biochemical applications, such as monitoring the concentrations of substances that can change electrical properties ofthe target such as sodium during biochemical processes.
  • Biochemical processing is essential to many food, chemical, and phar- maceutical industries.
  • At least one embodiment ofthe invention is directed to an application ofthe above-described device that is suitable for serving as a measuring device for defined levels of a substance in a liquid during a biochemical process in a bioreactor.
  • One example of a biochemical process for which the invention may be used is in connection with a fermenter. Fermentation is one typical biochemical process that may be used in the production of products such as organic acids or dairy products.
  • the fermenter is an important part of an ethanol production process. Ethanol may be produced in a fermenter during the biodegradation of glucose by yeast. After sterilizing, the glucose solution is fed to a fermenter. Nutrients to support cell growth may also be provided.
  • the production of a chemical such as ethanol may be monitored to improve the efficiency ofthe process.
  • a chemical such as ethanol
  • One way this can be accomplished using the present invention is by providing a fermenter with an online sensor or a plurality of online sensors constructed and arranged to track a concentration of product(s) during the fermenting process. Impedance spectroscopy techniques according to embodiments ofthe invention can use data provided by these sensors to provide a non-invasive and online way to monitor alcohol produc- tion.
  • an initial process 50 can produce product that is then transported 52 to a new location.
  • the product is then pumped into fermenter 54.
  • a valve 56 controls flow ofthe product.
  • a sensor 58 monitors the concentration of a substance of interest in the product.
  • Elements 60 and 62 perform a second process on the product.
  • Sensor 64 monitors the concentration of a substance of interest during the second process and sensor 66 monitors the concentration of a substance of interest in the waste flow from the second process.
  • one or more ofthe sensors can provide data to a control on the valve to allow the control to manage the valve based at least in part on the sensor data. For example, if the concentration of a substance of interest goes too high, the valve control may shut the valve.
  • the devices and methods as applied to the monitoring offer- mentation may also be applicable to monitoring the manufacture and processing of brewed and/or fermented beverages, such as beer, in a substantially similar manner to that described above.
  • Figs. 10 A-F show various configurations of systems for monitoring processes as described above.
  • a pipe 70 is transporting product, e.g., wastewater, and a sensor 72 is mounted to the pipe 70.
  • the sen- sor 72 is shown in greater detail mounted onto/into a pipe.
  • the configuration ofthe sensor 72 is a shown in Figures 2 and 3.
  • Fig. 10 C an interior section ofthe pipe shows the microstrip 18 and the ring electrode 19, the ground is actually in touch with the target, i.e., the product. Yet the microstrip can be electrically insulated from the target.
  • Figs. 10 A a pipe 70 is transporting product, e.g., wastewater, and a sensor 72 is mounted to the pipe 70.
  • the sen- sor 72 is shown in greater detail mounted onto/into a pipe.
  • the configuration ofthe sensor 72 is a shown in Figures 2 and 3.
  • Fig. 10 C an interior section ofthe pipe shows the microstrip 18 and the
  • valve control 76 associated with a valve 74 in the pipe 70.
  • the sensor 72 provides data, e.g., concentration measurements of a substance of interest, to a control element 76 , e.g., a valve controller other process controller.
  • the valve control manages, e.g., closes, the valve based at least in part on the sensor data.
  • a fermentor 78 having an input pipe 80 can have a sensor 72 mounted on it.
  • the sensor can monitor the progress of a reaction.
  • the fermenter can brew a product where electrolyte concentration is changing, or the fermenter can brew beer where the concentration of a substance of interest is monitored.
  • the devices and methods ofthe invention may be applied to diagnose changes in tissue, such as those resulting from inflammatory processes in the body, cancer, and edemas.
  • Edemas are accumulations of water in tissues (although water in cells and serous cavities also may be considered to be edemas as well). These accumulations of water show a significantly different impedance pattern compared to that of healthy tissue.
  • at least superficial edemas could be discriminated from normal tissue, in a non-invasive, quick, inexpensive, and relatively pain-free manner.
  • tumor cells differ from those of the normal tissues that surround them. Tumor cells demonstrate greater permittivity (ability to resist the formation of an electrical field) and conductivity of electrical current. These find- ings are thought to occur because (a) cancer cells tend to have higher sodium and water content than normal cells, and (b) their cell membranes have different electrochemical properties.
  • the devices and methods ofthe invention could be applied to detect other types of changes in the tissue of a body, especially changes detectable near the surface ofthe skin, such as skin cancer, breast cancer, and some types of tumors.
  • the cell membrane itself contributes capacitive effects to the impedance, especially as the frequency to which the cell is subjected is increased.
  • By characterizing "high quality cells” at a given fre- quency range it is possible to use the systems and methods ofthe invention to monitor cells to determine their condition relative to the "high quality cells". For example, changes in impedance may reflect deviations from normal in the cell membrane. This may also be done with cells in suspension.
  • At least one aspect ofthe invention is directed to an application ofthe above-described device that is suitable for tracking concentrations of substances in infusions.
  • the devices and methods ofthe invention can be applied for monitoring solutions in medical use, such as sodium, potassium, or other salt solutions, to ensure constant flux and concentration.
  • a standard Sodium Chloride infusion given to a patient basically involves three risks: a) is it really NaCl and not KC1 b) is it the correct concentration c) is it still running (drift of the rate of infusion)
  • drift of the rate of infusion The above issues are particularly interesting for prenatal care units.
  • embodiments ofthe present invention can be utilized to verify concentrations and operation at the point of delivery.
  • At least one aspect ofthe invention is directed to an application ofthe above-described device that is suitable for testing foods and beverages, both during growth and during processing.
  • the invention is used to monitor the concentration of a substance (e.g., water and sodium chloride) in a food and/or beverage product being produced, such as baby food, dairy products, beer, or wine.
  • a substance e.g., water and sodium chloride
  • the pair of electrodes ofthe device could be disposed on the surface of the food product, to detect the concentration of a given substance (e.g., sodium) in the food product.
  • the devices and methods ofthe invention are applied to monitor wine processing.
  • the quality of wine is said to depend on a few parameters, one of which is the electrolyte balance and alcohol content.
  • the invention is used to monitor the transformation of glucose into alcohol, so that the process can be stopped when glucose concentration reaches a predetermined level.
  • At least one aspect ofthe invention is directed to an ap- plication ofthe above-described device that is suitable for monitoring water concentration in food and/or beverage products.
  • Monitoring water concentration may be especially useful in improving the timing and efficiency of dairy processes such as the making of butter or cheese, where the water content may have significant impact on the quality ofthe resulting product.
  • At least one aspect ofthe invention is directed to an ap- plication ofthe above-described device that is suitable for measuring the concentration of water and/or electrolytes in an agricultural product.
  • the devices and methods ofthe invention can be used to detect changes in water composition
  • the devices and methods ofthe invention have use in applications such as analysis of wastewater. For example, an accident or error occurring during production at a chemical plant could result in harmful compounds contaminating drainage water exiting the chemical plant.
  • the devices and methods ofthe inven- tion provide an inexpensive, sensitive method to monitor the exiting wastewater for this kind of occurrence.
  • the device according to the invention may be coupled to trigger an alarm when certain predetermined changes in water composition occur.
  • the devices and methods ofthe invention may be used throughout the chemical process (e.g., monitoring the status and progress of chemical processes, as de- scribed previously for the "biochemical processes" application). Examples of use of embodiments ofthe invention in such processes are shown in Figs. 10-1 IF.
  • the methods and devices ofthe invention which use RF impedance spectroscopy, are usable to characterize and measure corrosion.
  • One example of a technique for characterizing corrosion is described in U.S. Patent No. 4,238,298, incorporated herein by reference in its entirety. Passing an alternating current (A.C.) at a high frequency between two electrodes disposed in a corrosion medium will give the ohmic resistance ofthe corrosion medium. Passing an AC current at a low frequency between the electrodes gives an impedance that is equal to the sum ofthe ohmic resistance and the corrosion reaction resistance. The corrosion reaction resistance is inversely proportional to the corrosion rate ofthe metal in the medium.
  • A.C. alternating current
  • the devices and methods ofthe invention can be adapted to measure the ohmic impedance and the corrosion reaction impedances, as described above, at both low and high frequencies. It is then possible to compute the reciprocal ofthe difference between the ohmic impedance and the corrosion reaction impedance, to give the corrosion rate.
  • one application ofthe invention is for determining whether a surface (such as a street) coated with water has been treated with a substance such as road salt.
  • the invention can be used in an automobile, to detect whether a road or street has been salted (such as when it snows).
  • the invention is used in connection with a sensor head located to measure the salt content ofthe water splashing up from the wheels.
  • the devices and methods ofthe invention provide a simple, inexpensive way to monitor the quality ofthe water by monitoring the concentration of water and/or concentration of one or more substances in the water.

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Abstract

Un aspect de la présente invention concerne un dispositif qui détermine de manière non invasive la concentration d'une substance dans une cible. Ce dispositif comprend une première électrode, un circuit de mesure et un système de traitement des données. Dans un mode de réalisation de ce dispositif, la première électrode peut être électriquement isolée de la cible, par exemple au moyen d'une couche de revêtement en matériau isolant qui recouvre la première électrode.
PCT/IB2003/004438 2002-09-05 2003-09-05 Systemes et procedes bases sur une spectroscopie d'impedance Ceased WO2004023125A2 (fr)

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AU2003264797A AU2003264797A1 (en) 2002-09-05 2003-09-05 Impedance spectroscopy based systems and methods

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US7603151B2 (en) 2006-08-22 2009-10-13 Bayer Healthcare Llc Non-invasive methods of using spectral information in determining analyte concentrations
US7705980B2 (en) 2006-08-22 2010-04-27 Bayer Healthcare Llc Method for correcting a spectral image for optical aberrations using software
US8180422B2 (en) 2005-04-15 2012-05-15 Bayer Healthcare Llc Non-invasive system and method for measuring an analyte in the body
US8200307B2 (en) 2004-06-07 2012-06-12 Biovotion Ag Method and device for determining a parameter of living tissue
US8452365B2 (en) 2005-05-25 2013-05-28 Bayer Healthcare Llc Methods of using Raman spectral information in determining analyte concentrations
CN104116512A (zh) * 2010-04-27 2014-10-29 艾迪完整应用有限公司 用于无创测量血糖的设备
FR3015521A1 (fr) * 2013-12-24 2015-06-26 Univ Limoges Procede de determination du grade d'agressivite cellulaire de cellules cancereuses ou de cellules souches cancereuses
US9179856B2 (en) 2009-04-17 2015-11-10 Biovotion Ag Sensing device for body tissue properties
US9247905B2 (en) 2009-04-17 2016-02-02 Biovotion Ag Wide band field response measurement for glucose determination
EP3086118A1 (fr) * 2015-04-20 2016-10-26 Vayyar Imaging Ltd. Caractérisation de diélectrique de substances à compensation de température
US9713447B2 (en) 2005-11-10 2017-07-25 Biovotion Ag Device for determining the glucose level in body tissue
EP3521776A1 (fr) 2018-02-06 2019-08-07 Victor Augusta P. Claes Circuit de capteur et son utilisation
WO2023192983A1 (fr) * 2022-03-31 2023-10-05 Corning Incorporated Capteur sans contact pour la mesure de contenus d'un réacteur
WO2024243529A1 (fr) * 2023-05-25 2024-11-28 Amazon Technologies, Inc. Procédés non invasifs de mesure du degré de métabolisme énergétique cellulaire

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GB8622747D0 (en) * 1986-09-22 1986-10-29 Ici Plc Determination of biomass
CA2318735A1 (fr) * 1998-02-04 1999-08-12 Dermal Therapy (Barbados) Inc. Technique non effractive de determination du taux de glucose dans des liquides organiques et appareil correspondant
JP2000121589A (ja) * 1998-10-20 2000-04-28 Mitsubishi Electric Corp 流体の誘電率検知装置及びその検知方法
GB9901304D0 (en) * 1999-01-22 1999-03-10 Univ Liverpool Apparatus and method for determining dielectric properties of an electrically conductive fluid
WO2002069791A1 (fr) * 2001-03-06 2002-09-12 Pendragon Medical Ltd. Procede et dispositif destines a determiner la concentration d'une substance dans un liquide corporel

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US8200307B2 (en) 2004-06-07 2012-06-12 Biovotion Ag Method and device for determining a parameter of living tissue
US8180422B2 (en) 2005-04-15 2012-05-15 Bayer Healthcare Llc Non-invasive system and method for measuring an analyte in the body
US8452365B2 (en) 2005-05-25 2013-05-28 Bayer Healthcare Llc Methods of using Raman spectral information in determining analyte concentrations
US9713447B2 (en) 2005-11-10 2017-07-25 Biovotion Ag Device for determining the glucose level in body tissue
US8452357B2 (en) 2006-08-22 2013-05-28 Bayer Healthcare Llc Non-invasive methods of using spectral information in determining analyte concentrations
US7944556B2 (en) 2006-08-22 2011-05-17 Bayer Healthcare Llc Method for correcting a spectral image for optical aberrations using software
US7603151B2 (en) 2006-08-22 2009-10-13 Bayer Healthcare Llc Non-invasive methods of using spectral information in determining analyte concentrations
US7705980B2 (en) 2006-08-22 2010-04-27 Bayer Healthcare Llc Method for correcting a spectral image for optical aberrations using software
US9179856B2 (en) 2009-04-17 2015-11-10 Biovotion Ag Sensing device for body tissue properties
US9247905B2 (en) 2009-04-17 2016-02-02 Biovotion Ag Wide band field response measurement for glucose determination
EP3485812A1 (fr) * 2010-04-27 2019-05-22 A.D. Integrity Applications Ltd. Dispositif pour la mesure non invasive de glucose
CN104116512A (zh) * 2010-04-27 2014-10-29 艾迪完整应用有限公司 用于无创测量血糖的设备
EP2767234A3 (fr) * 2010-04-27 2014-11-05 A.D. Integrity Applications Ltd. Dispositif de mesure non invasive du glucose
CN104116512B (zh) * 2010-04-27 2017-05-17 盈通格利应用有限公司 用于无创测量血糖的设备
FR3015521A1 (fr) * 2013-12-24 2015-06-26 Univ Limoges Procede de determination du grade d'agressivite cellulaire de cellules cancereuses ou de cellules souches cancereuses
WO2015097419A1 (fr) * 2013-12-24 2015-07-02 Universite De Limoges Procédé de détermination du grade d'agressivite cellulaire de cellules cancereuses ou de cellules souches cancereuses
EP3086118A1 (fr) * 2015-04-20 2016-10-26 Vayyar Imaging Ltd. Caractérisation de diélectrique de substances à compensation de température
EP3521776A1 (fr) 2018-02-06 2019-08-07 Victor Augusta P. Claes Circuit de capteur et son utilisation
WO2019154874A1 (fr) 2018-02-06 2019-08-15 Claes Victor Augusta P Circuit de capteur et son utilisation
US11397103B2 (en) 2018-02-06 2022-07-26 Victor Augusta P. Claes Sensor circuit and use thereof
WO2023192983A1 (fr) * 2022-03-31 2023-10-05 Corning Incorporated Capteur sans contact pour la mesure de contenus d'un réacteur
WO2024243529A1 (fr) * 2023-05-25 2024-11-28 Amazon Technologies, Inc. Procédés non invasifs de mesure du degré de métabolisme énergétique cellulaire

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