CA1152155A - Glucose sensor - Google Patents
Glucose sensorInfo
- Publication number
- CA1152155A CA1152155A CA000378793A CA378793A CA1152155A CA 1152155 A CA1152155 A CA 1152155A CA 000378793 A CA000378793 A CA 000378793A CA 378793 A CA378793 A CA 378793A CA 1152155 A CA1152155 A CA 1152155A
- Authority
- CA
- Canada
- Prior art keywords
- voltage
- sweep
- limit
- glucose
- electrode
- 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.)
- Expired
Links
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 title claims abstract description 71
- 239000008103 glucose Substances 0.000 title claims abstract description 71
- 239000012530 fluid Substances 0.000 claims abstract description 15
- 239000013060 biological fluid Substances 0.000 claims abstract description 11
- 230000010354 integration Effects 0.000 claims description 10
- 230000035945 sensitivity Effects 0.000 claims description 8
- 230000002452 interceptive effect Effects 0.000 claims description 7
- 238000003487 electrochemical reaction Methods 0.000 claims description 6
- 239000000470 constituent Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims 2
- 239000000306 component Substances 0.000 abstract 1
- 238000005259 measurement Methods 0.000 description 16
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 16
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 13
- 150000001413 amino acids Chemical class 0.000 description 13
- 239000004202 carbamide Substances 0.000 description 13
- 229910052697 platinum Inorganic materials 0.000 description 8
- 239000012528 membrane Substances 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 101100001675 Emericella variicolor andJ gene Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 239000012891 Ringer solution Substances 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000002715 bioenergetic effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229940075397 calomel Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000003869 coulometry Methods 0.000 description 1
- ZOMNIUBKTOKEHS-UHFFFAOYSA-L dimercury dichloride Chemical compound Cl[Hg][Hg]Cl ZOMNIUBKTOKEHS-UHFFFAOYSA-L 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000003014 ion exchange membrane Substances 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- QHGVXILFMXYDRS-UHFFFAOYSA-N pyraclofos Chemical compound C1=C(OP(=O)(OCC)SCCC)C=NN1C1=CC=C(Cl)C=C1 QHGVXILFMXYDRS-UHFFFAOYSA-N 0.000 description 1
- 230000003716 rejuvenation Effects 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- -1 urine Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
- A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
- G01N27/3271—Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood
- G01N27/3274—Corrective measures, e.g. error detection, compensation for temperature or hematocrit, calibration
Abstract
ABSTRACT OF THE DISCLOSURE
Glucose sensing apparatus for use in biological fluids comprising an electrode and a voltage source connected to the electrode to cause a current to flow therethrough, in which the voltage applied to the electrode is varied in a sweep ranging from a first limit to a second limit and back toward the first limit, and the current at the electrode is integrated with respect to time during at least a portion of the voltage variation selected to produce a total charge sensitive to glucose concentration and relatively insensitive to other compon-ents in the fluid; alternatively the current is measured at a point in a specific region of the voltage variation.
Glucose sensing apparatus for use in biological fluids comprising an electrode and a voltage source connected to the electrode to cause a current to flow therethrough, in which the voltage applied to the electrode is varied in a sweep ranging from a first limit to a second limit and back toward the first limit, and the current at the electrode is integrated with respect to time during at least a portion of the voltage variation selected to produce a total charge sensitive to glucose concentration and relatively insensitive to other compon-ents in the fluid; alternatively the current is measured at a point in a specific region of the voltage variation.
Description
152~SS
This invention relates to sensing the cGncentration of glucose in biological fluids.
It is desirable to monitor accurately glucose concentration in biological fluids, particularly using a device that is implantable in living organisms; for example, such a device would be useful for diabetics in timing the administration of insulin and food.
Glucose concentration in simple solutions--e.g., Krebs-Ringer buffer--can be monitored electrochemically by measuring the current density at a platinum electrode while varying the electrode potential relative to a standard.
At various electrode potentials, current generated by electrochemical reactions is responsive to the glucose concentration. Accordingly, current measured while varying the electrode potential over a range, first from negative to positive ~anodic~ and then back again (cathodic), will be a function of glucose concentra-tion. See Marincic et al., "Electrochemical Glucose Oxidation on a Platinized Platinum Electrode in Krebs-Ringer Solution) I. Potentiodynamic Studies", 126 J. Electrochem. Soc. 43, Jan. 1979 and "III. Effect of Urea", 126 J. Electrochem.
Soc. Oct. 1979.
Interference with glucose measurement due to the presence of other biological substances--particularly amino acids and urea--is a serious problem.
Such substances undergo electrochemical reactions during th0 voltage sweep, generating currents independent of glucose concentration and reducing sensitivity to glucose.
Marincic et al., supra~ indicates that there is considerable sensi-tivity of current density to glucose concentration in the presence of urea with cathodic potential sweeps at potentials below about - 100 mV; that article con-cludes, however, for anodic potential sweeps, that inhibition by urea precludes glucose concentration measuremen~.
;
' ' . - , , ' - ~5~15S
Gebhart et al., "Development of an Implantable Electrocatalytic 51ucose Sensor", 5 Bioelectrochemistry and Bioenergetics 607 (1978) indicates (Figure 9) a correlation between glucose concentration in the presence of amino acids and charge produced at the electrode at a specific voltage; between periods of integration, voltage is shifted to a rejuvenation potential.
According to one aspect of the invention, by applying a voltage to thé electrode, varying the voltage in a sweep from a limit first limit to a second limit and back toward the first limit, and integrating the current at the electrode over at least a portion of the voltage sweep selected to produce a total charge sensitive to glucose concentration and to be relatively insensitive to other components in the biological fluid, an accurate measure of glucose con-centration is obtained in biological fluids.
In preferred embodiments, the portion of integration is selected so that the charge responsive to glucose concentration has predominantly the same algebraic sign throughout the portion, and so that the charge responsive to interfering components of the fluid (or to any specific interfering component) has a positive sign in one segment of the portion and a negative sign in another segment, so that the glucose-responsive charge, and thus sensltivity to glucose, is reinforced throughout the portion of integration, and the charge responsive ~20 to interfering substances at least partially cancels, thus reducing interference from those components or changes in concentration of those components. Total charge is normalized in the form of the ratio of total algebraic charge to total absolute value of charge; the lower limit of ~he voltage sweep is between -1.0 and -0.6 volts and the upper limit is between 0.7 and 1.1 volts; the voltage sweep includes dwell periods at the limits, and the rates of voltage change dur-ing the anodic and cathodic sweeps are constant; integration takes place con-tinuously during one complete voltage sweep (or, alternatively, substantially
This invention relates to sensing the cGncentration of glucose in biological fluids.
It is desirable to monitor accurately glucose concentration in biological fluids, particularly using a device that is implantable in living organisms; for example, such a device would be useful for diabetics in timing the administration of insulin and food.
Glucose concentration in simple solutions--e.g., Krebs-Ringer buffer--can be monitored electrochemically by measuring the current density at a platinum electrode while varying the electrode potential relative to a standard.
At various electrode potentials, current generated by electrochemical reactions is responsive to the glucose concentration. Accordingly, current measured while varying the electrode potential over a range, first from negative to positive ~anodic~ and then back again (cathodic), will be a function of glucose concentra-tion. See Marincic et al., "Electrochemical Glucose Oxidation on a Platinized Platinum Electrode in Krebs-Ringer Solution) I. Potentiodynamic Studies", 126 J. Electrochem. Soc. 43, Jan. 1979 and "III. Effect of Urea", 126 J. Electrochem.
Soc. Oct. 1979.
Interference with glucose measurement due to the presence of other biological substances--particularly amino acids and urea--is a serious problem.
Such substances undergo electrochemical reactions during th0 voltage sweep, generating currents independent of glucose concentration and reducing sensitivity to glucose.
Marincic et al., supra~ indicates that there is considerable sensi-tivity of current density to glucose concentration in the presence of urea with cathodic potential sweeps at potentials below about - 100 mV; that article con-cludes, however, for anodic potential sweeps, that inhibition by urea precludes glucose concentration measuremen~.
;
' ' . - , , ' - ~5~15S
Gebhart et al., "Development of an Implantable Electrocatalytic 51ucose Sensor", 5 Bioelectrochemistry and Bioenergetics 607 (1978) indicates (Figure 9) a correlation between glucose concentration in the presence of amino acids and charge produced at the electrode at a specific voltage; between periods of integration, voltage is shifted to a rejuvenation potential.
According to one aspect of the invention, by applying a voltage to thé electrode, varying the voltage in a sweep from a limit first limit to a second limit and back toward the first limit, and integrating the current at the electrode over at least a portion of the voltage sweep selected to produce a total charge sensitive to glucose concentration and to be relatively insensitive to other components in the biological fluid, an accurate measure of glucose con-centration is obtained in biological fluids.
In preferred embodiments, the portion of integration is selected so that the charge responsive to glucose concentration has predominantly the same algebraic sign throughout the portion, and so that the charge responsive to interfering components of the fluid (or to any specific interfering component) has a positive sign in one segment of the portion and a negative sign in another segment, so that the glucose-responsive charge, and thus sensltivity to glucose, is reinforced throughout the portion of integration, and the charge responsive ~20 to interfering substances at least partially cancels, thus reducing interference from those components or changes in concentration of those components. Total charge is normalized in the form of the ratio of total algebraic charge to total absolute value of charge; the lower limit of ~he voltage sweep is between -1.0 and -0.6 volts and the upper limit is between 0.7 and 1.1 volts; the voltage sweep includes dwell periods at the limits, and the rates of voltage change dur-ing the anodic and cathodic sweeps are constant; integration takes place con-tinuously during one complete voltage sweep (or, alternatively, substantially
-2-. :, :, - ' ', " ~-' ' ' '` , " '~ . ~ ' ' ~ ,' ~; " ' - ' ' ' . :
.
. ~52~5 including the anodic sweep between -0.45 volts and the upper limit, the dwell atthe upper limit, and the entire cathodic sweep); the rate of voltage change dur-ing cathodic voltage sweep may be more rapid than during the anodic voltage sweep; and the voltage sweep may include holding periods between the limits at potentials at which glucose undergoes an electrochemical reaction.
According to another aspect of the invention, glucose concentration in biological fluids can be determined by measuring the current at the electrode ata point in a specific region between 0.2 volts and 0.6 volts during the anodic voltage variation selected to be sensitive to changes in levels of glucose con-centration but relatively insensitive to levels of other constituents of the fluid.
The invention will now be described in greater detail with reference to the accompanying drawings, in which:
Figure 1 is a block diagram of the circuitry for an implantable glucose sensor embodying one aspect of the invention;
Figure 2 is a block diagram of the circuitry for an implantable glucose sensor embodying another aspect of the invention;
Figure 3a shows diagramatically, the elements of an electrode cell used with the embodiments of Figures 1 or 2;
Figure 3b shows, diagramatically, interconnections between the elec-trode cell and other components of the circuitry of Figure l;
Figures 4a, b, c, d, e and f are graphs related to the embodiment of Figure l; and Figures 5a, b, and c are graphs related to the embodiment of Figure 2.
Integration of Current Figure 1 shows in block form, one embodiment of implantable circuitry including glucose sensing cell 40. Figure 3b shows potentiostat 30 connected to .
, : . .
; . ~ .
, ~ ~5~5~i control the potential drop between glucose oxidation electrode 50 and reference electrode 52. Specifically, potentiostat 30 compares and equates that voltage (V meas.) to the voltage (V appl.) generated by function generator 20 by allowing current to flow in a measurement circuit formed by leads 51, glucose electrode 50, the biological medium, counter electrode 54, lead 53 and potentiostat 30.
Reference electrode 52 is connected to the function generator by lead 55.
In Figure 1, signal processor 60 is connected to the measurement cir-cuit and integrates current in the circuit in response to timed signals from function generator 20. Modulator/transmitter 70 is connected to signal processor 60 and transmits an FM signal corresponding to the output of processor 60 in response to a transmit signal from function generator 20. Sensor cell 40 (Figure 3a) has a glucose oxidation electrode 50 separated by barrier 56 (which is an ion exchange membrane treated to allow passage of cations only) from counter electrode 54. A glucose-permeable membrane 5~ separates electrode 50 from high molecular weight compounds in the biological medium, and a bio-compatible hydrophobic membrane 59 at the counter electrode allows reaction pro-ducts (gasses) to diffuse to surrounding tissue, while electrically insulating the electrode from that tissue. Reference electrode 52 is a silver/silver chloride electrode. Counter electrode 54 is a carbon electrode.
Glucose electrode 50 is a *Teflon-bonded platinized platinum electrode prepared as follows: An electrode sheet is formed from a suspension of *Teflon-30 (Dupont) and platinum blac~ (Engelhard), respectively. This suspension is then filtered through a membrane to give a uniform layer of the *Teflon and platinum on the membrane. This layered structure is then placed atop a platinum mesh screen with the *Teflon-platinum layer mixture contacting the platinum screen. The resultant layered structure is subjected to pressure and then sintered to obtain the final electrode structure. The electrode is cut from the sheet.
... .
*Trademark -4-, : .
~2~L55 In operation, function generator 20 generates a waveform which varies back and forth between two limits. Line 2 in Figure 4a shows a typical trapezoidal wave form in which voltage is maintained at -0.8V for 60 sec., then increased at a rate of 2 volts/min. to -~0.8V. This region of increasing voltage is called the anodic voltage sweep. After a 30 second dwell at 0.8V, voltage is decreased, again at 2 volts/mln. to the lower limit of -0.8V. The region of decreasing voltage is the cathodic voltage sweep. By selecting a voltage sweep which effectively permits glucose oxidation and rejuvenates the catalytic sur-face of the electrode, continuous sweeps and glucose concentration measurement are possible.
As the voltage is applied to the electrode, electrochemical reaction of glucose is catalyzed at electrode 50. Glucose from the surrounding tissue permeates the membrane, and reaction products are transported away from the electrode. Barrier 56 insulates the two electrodes, but allows transfer of cations to the counter electrode to complete the current measurement circuit.
The biological medium produces currents at specific portions of the voltage sweep. In particular glucose oxidation occurs at specific portions of the sweep; in those portions, the current generated ~which will include current generated as a result of reaction of background constituents as well as glucose-responsive current) can be used to indicate glucose concentration. However,electrochemical reactions due to other fluid constituents--specifically urea and amino acids--may affect ~he current measurement and hinder determination of glucose concentration.
In certain portions of the sweep, the current related to a particular interfering substance is positive in one segment of the portion and negative in another segment, while the effect of glucose-related currents is essentially positive throughout the portion. By integrating cell current over time to ob-,~,~
.. . . .
:'' ~52~
tain total charge at the electrode in that sweep portion, these glucose-rein-forcing, interference-cancelling phenomena act to improve greatly the sensi-tivity to glucose concentration while at the same time reducing the interference experienced. Specifically, signal processor 60 integrates current and provides a measurement of total algebraic charge Qt over the region of integration;
alternatively the signal processor can provide a signal representing ratio of the total algebraic charge to the absolute value of total charge Qt/¦Qt¦
The graphs of Figure 4 represent examples of operations conducted under sin~ulated physiologic conditions. They are performed at 37C under an atmosphere of 95% nitrogen, 5% CO2. The background fluid is a modified Kreb-Ringer buffer solution (0.109 M NaCl, 0.024 M NaHC03, 0.006 M MgSO4, 0.001 M
NaH2P04, pH = 7.4). Amino acids are provided in a stock solution of 23 different amino acids at concentrations proportional to physiological concentra-tions. Urea is present in the physiological concentrations indicated. The potentiostat used ~Princeton Applied Research Corp., Model PAR-173) has auto-matic IR compensation. The programmable function generator is Model 73211 from Data Trak, Research, Inc. The glucose electrode has a geometric area of 0.19 cm2, a Pt coat of 25 mg per cm2 and a real area ~from coulometric hydrogen ; stripping measurement) of 485 cm2. The reference electrode is a standard satur-ated calomel ~Hg, Hg2C12~ KCl) electrode, and the glucose permeable membrane is Nucleopore, 500 Angstrom.
When ~he above-described voltage waveform ~line 2 in Figure 4a) is applied to the Krebs-Ringer buffer alone, the current at the electrode is first negative, ~en positive and finally negatlve, as indicated by line 1 in Figure 4(a). The shaded area under llne 1 represents charge, and the positive and negative areas essentially cancel.
Figure 4b shows current measured in the system before ~line 1) and ~J
. ' .
, ss after (line 2) the addition of glucose. The difference attributable to glucose (line 3) results in a charge (shaded) which is essentially positive over the entire waveform.
With the addition of urea (Figure 4c) or amino acids (Figure 4d) to the system, the resulting current changes (line 2 in Figures 4c and d) are posi-tive in some regions of the sweep and negative in other regions, while the cur-rent responsive to glucose (line 1) remains essentially positive throughout the sweep.
The following table shows that integrating current over the entire sweep provides an algebraic value of charge (Qt) (or a normalized value of charge in the form of the ratio of algebraic to total absolute charge (Qt/¦Qt¦)) which is sensitive to glucose concentration even in the presence of changing concentrations of amino acids and urea. Figures 4e and f specifically illus-trate the above relationship in the presence of changing concentrations of amino acids.
~7~
~- ~
~L~52~55 Glucose Electrode Response to Changes in Glucose and Amino Acid Concentration Conc., mg/dl Amino Qt' Glucose Acids Urea mCoul IQtl 20.0 .087 63 35 40 22.6 .099 24.5 .107 88 35 40 26.0 .114 100 35 40 27.6 .122 113 35 40 28.0 .123 125 35 40 30.0 .132 150 35 40 31.9 .141 175 35 40 33.7 .148 200 35 40 36.3 .160 250 35 40 41.0 .180 23.8 .109 63 50 40 24.3 .111 24.9 .114 88 50 40 27.3 .126 100 50 40 28.8 .133 113 50 40 28.5 .132 125 50 40 28.9 .134 150 50 40 31.2 .144 175 50 40 34.4 .159 200 50 40 35.2 .162 250 50 40 38.5 .178 23.6 .117 63 65 40 23.7 .119 24.4 .123 88 65 40 25.2 .123 100 65 40 26.6 .136 112 65 40 26.7 .137 125 65 4~ 27.3 .140 150 65 40 29.1 .140 175 65 40 31.3 .160 200 65 40 31.9 .165 250 65 40 34.1 .177 Thus, when integrating over the entire voltage sweep, the background charge (from the background solution and from the amino acids and urea) essenti-ally cancels, while the~glucose-responsive charge is essentially positivP andJ
sensitivity to glucose lS increased by in~egration. Moreover, changes in .,..~
, ' ~
- :
, -. .
.
. , .
.5;~i5 charges associated with changes in urea and amino acid concentrations, respect-ively, essentially cancel, thus enhancing sensitivity to glucose.
Referring specifically to Figures 4c and d, it is apparent that integration need not occur over the entire voltage sweep. Examination of a specific por-tion of the sweep--substantially including the portion of the anodic sweep from -0.~5 volts to 0.8 volts, the dwell at the upper limit, and the entire cathodic sweep--also shows the requisite characteristics for selectivity and sensitivity.
Current Measurement Figure 2 shows a diagram of apparatus similar to Figure 1, except that function generator 20 signals current measurement by current measurement means 80, and transmission of a signal representing that measurement by transmitter 70.
Figures 5a, b and c represent the results of current measurement, under condi-tions described for the current integration examples above. The region between 0.2 and 0.6 volts of the anodic portion of the sweep shows a clear response to changes in glucose concentration, and a lack of response to changes in concentra-tions of amino acids and urea. Measurement at a point within that region (e.g., 0.3 volts) thus provides a measurement of glucose concentrations notwithstanding the presence of urea and amino acids. For example values of current at 0.3~ in the anodic scan for a Krebs-Ringer buffer containing 40 mg/dl of Urea and 35 mg/
dl of amino acids, taken from a plot such as Figure 5c, will show a linear rela-tionship between current and glucose concentration.
The embodiments of both Figure 1 and of Figure 2 would include a receiver (not shown) outside of the organism in which the sensor is implanted, to receive the signal transmitted by the sensor and translate that signal into data representing glucose concentration. Alternatively the receiver could trigger an alarm when glucose concentration varies outside predetermined limits.
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.
S~L55 Other Embodiments Other embodiments are within the scope of the following claims. By way of example only, the voltage waveform may be varied in several ways: the dwell times can be changed but should preferably be at least 2 seconds; the lower limit can be increased to, e.g.~ -1.0 volts, but excessive generation of hydrogen results from a limit significantly below that level. The upper limit can vary, e.g., from 0.7 to 1.1 volts; a voltage significantly above l.lV causes corrosion of the electrode. Holding periods may be introduced during the anodic and/or the cathodic portion of the sweep, preferably at potentials at which glucose reactions occur so as to increase the amount of time spent at such potentials and enhance sensitivity and selectivity to glucose; the rate of volt-age change in the anodic and cathodic sweeps may be different-e.g., the anodic sweep may be relative slower to increase the amount of time spent at voltages which produce currents sensitive and selective for glucose. With respect to the current measurement embodiment of Figure 2, the voltage variation could include discontinuities such as jumps from a limit to the measuring voltage.
It is envlsaged that the present invention be applicable to glucose sensors that are not implanted--e.g., clincial laboratory sensors and the claims are intended to include such non-implanted sensors. The biological fluids can include any fluids taken from living organisms or fluids simulating conditions in a living organism including, without limitation, blood, urine, buffer solu-tions, and saline solutions.
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. ~52~5 including the anodic sweep between -0.45 volts and the upper limit, the dwell atthe upper limit, and the entire cathodic sweep); the rate of voltage change dur-ing cathodic voltage sweep may be more rapid than during the anodic voltage sweep; and the voltage sweep may include holding periods between the limits at potentials at which glucose undergoes an electrochemical reaction.
According to another aspect of the invention, glucose concentration in biological fluids can be determined by measuring the current at the electrode ata point in a specific region between 0.2 volts and 0.6 volts during the anodic voltage variation selected to be sensitive to changes in levels of glucose con-centration but relatively insensitive to levels of other constituents of the fluid.
The invention will now be described in greater detail with reference to the accompanying drawings, in which:
Figure 1 is a block diagram of the circuitry for an implantable glucose sensor embodying one aspect of the invention;
Figure 2 is a block diagram of the circuitry for an implantable glucose sensor embodying another aspect of the invention;
Figure 3a shows diagramatically, the elements of an electrode cell used with the embodiments of Figures 1 or 2;
Figure 3b shows, diagramatically, interconnections between the elec-trode cell and other components of the circuitry of Figure l;
Figures 4a, b, c, d, e and f are graphs related to the embodiment of Figure l; and Figures 5a, b, and c are graphs related to the embodiment of Figure 2.
Integration of Current Figure 1 shows in block form, one embodiment of implantable circuitry including glucose sensing cell 40. Figure 3b shows potentiostat 30 connected to .
, : . .
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, ~ ~5~5~i control the potential drop between glucose oxidation electrode 50 and reference electrode 52. Specifically, potentiostat 30 compares and equates that voltage (V meas.) to the voltage (V appl.) generated by function generator 20 by allowing current to flow in a measurement circuit formed by leads 51, glucose electrode 50, the biological medium, counter electrode 54, lead 53 and potentiostat 30.
Reference electrode 52 is connected to the function generator by lead 55.
In Figure 1, signal processor 60 is connected to the measurement cir-cuit and integrates current in the circuit in response to timed signals from function generator 20. Modulator/transmitter 70 is connected to signal processor 60 and transmits an FM signal corresponding to the output of processor 60 in response to a transmit signal from function generator 20. Sensor cell 40 (Figure 3a) has a glucose oxidation electrode 50 separated by barrier 56 (which is an ion exchange membrane treated to allow passage of cations only) from counter electrode 54. A glucose-permeable membrane 5~ separates electrode 50 from high molecular weight compounds in the biological medium, and a bio-compatible hydrophobic membrane 59 at the counter electrode allows reaction pro-ducts (gasses) to diffuse to surrounding tissue, while electrically insulating the electrode from that tissue. Reference electrode 52 is a silver/silver chloride electrode. Counter electrode 54 is a carbon electrode.
Glucose electrode 50 is a *Teflon-bonded platinized platinum electrode prepared as follows: An electrode sheet is formed from a suspension of *Teflon-30 (Dupont) and platinum blac~ (Engelhard), respectively. This suspension is then filtered through a membrane to give a uniform layer of the *Teflon and platinum on the membrane. This layered structure is then placed atop a platinum mesh screen with the *Teflon-platinum layer mixture contacting the platinum screen. The resultant layered structure is subjected to pressure and then sintered to obtain the final electrode structure. The electrode is cut from the sheet.
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*Trademark -4-, : .
~2~L55 In operation, function generator 20 generates a waveform which varies back and forth between two limits. Line 2 in Figure 4a shows a typical trapezoidal wave form in which voltage is maintained at -0.8V for 60 sec., then increased at a rate of 2 volts/min. to -~0.8V. This region of increasing voltage is called the anodic voltage sweep. After a 30 second dwell at 0.8V, voltage is decreased, again at 2 volts/mln. to the lower limit of -0.8V. The region of decreasing voltage is the cathodic voltage sweep. By selecting a voltage sweep which effectively permits glucose oxidation and rejuvenates the catalytic sur-face of the electrode, continuous sweeps and glucose concentration measurement are possible.
As the voltage is applied to the electrode, electrochemical reaction of glucose is catalyzed at electrode 50. Glucose from the surrounding tissue permeates the membrane, and reaction products are transported away from the electrode. Barrier 56 insulates the two electrodes, but allows transfer of cations to the counter electrode to complete the current measurement circuit.
The biological medium produces currents at specific portions of the voltage sweep. In particular glucose oxidation occurs at specific portions of the sweep; in those portions, the current generated ~which will include current generated as a result of reaction of background constituents as well as glucose-responsive current) can be used to indicate glucose concentration. However,electrochemical reactions due to other fluid constituents--specifically urea and amino acids--may affect ~he current measurement and hinder determination of glucose concentration.
In certain portions of the sweep, the current related to a particular interfering substance is positive in one segment of the portion and negative in another segment, while the effect of glucose-related currents is essentially positive throughout the portion. By integrating cell current over time to ob-,~,~
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tain total charge at the electrode in that sweep portion, these glucose-rein-forcing, interference-cancelling phenomena act to improve greatly the sensi-tivity to glucose concentration while at the same time reducing the interference experienced. Specifically, signal processor 60 integrates current and provides a measurement of total algebraic charge Qt over the region of integration;
alternatively the signal processor can provide a signal representing ratio of the total algebraic charge to the absolute value of total charge Qt/¦Qt¦
The graphs of Figure 4 represent examples of operations conducted under sin~ulated physiologic conditions. They are performed at 37C under an atmosphere of 95% nitrogen, 5% CO2. The background fluid is a modified Kreb-Ringer buffer solution (0.109 M NaCl, 0.024 M NaHC03, 0.006 M MgSO4, 0.001 M
NaH2P04, pH = 7.4). Amino acids are provided in a stock solution of 23 different amino acids at concentrations proportional to physiological concentra-tions. Urea is present in the physiological concentrations indicated. The potentiostat used ~Princeton Applied Research Corp., Model PAR-173) has auto-matic IR compensation. The programmable function generator is Model 73211 from Data Trak, Research, Inc. The glucose electrode has a geometric area of 0.19 cm2, a Pt coat of 25 mg per cm2 and a real area ~from coulometric hydrogen ; stripping measurement) of 485 cm2. The reference electrode is a standard satur-ated calomel ~Hg, Hg2C12~ KCl) electrode, and the glucose permeable membrane is Nucleopore, 500 Angstrom.
When ~he above-described voltage waveform ~line 2 in Figure 4a) is applied to the Krebs-Ringer buffer alone, the current at the electrode is first negative, ~en positive and finally negatlve, as indicated by line 1 in Figure 4(a). The shaded area under llne 1 represents charge, and the positive and negative areas essentially cancel.
Figure 4b shows current measured in the system before ~line 1) and ~J
. ' .
, ss after (line 2) the addition of glucose. The difference attributable to glucose (line 3) results in a charge (shaded) which is essentially positive over the entire waveform.
With the addition of urea (Figure 4c) or amino acids (Figure 4d) to the system, the resulting current changes (line 2 in Figures 4c and d) are posi-tive in some regions of the sweep and negative in other regions, while the cur-rent responsive to glucose (line 1) remains essentially positive throughout the sweep.
The following table shows that integrating current over the entire sweep provides an algebraic value of charge (Qt) (or a normalized value of charge in the form of the ratio of algebraic to total absolute charge (Qt/¦Qt¦)) which is sensitive to glucose concentration even in the presence of changing concentrations of amino acids and urea. Figures 4e and f specifically illus-trate the above relationship in the presence of changing concentrations of amino acids.
~7~
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~L~52~55 Glucose Electrode Response to Changes in Glucose and Amino Acid Concentration Conc., mg/dl Amino Qt' Glucose Acids Urea mCoul IQtl 20.0 .087 63 35 40 22.6 .099 24.5 .107 88 35 40 26.0 .114 100 35 40 27.6 .122 113 35 40 28.0 .123 125 35 40 30.0 .132 150 35 40 31.9 .141 175 35 40 33.7 .148 200 35 40 36.3 .160 250 35 40 41.0 .180 23.8 .109 63 50 40 24.3 .111 24.9 .114 88 50 40 27.3 .126 100 50 40 28.8 .133 113 50 40 28.5 .132 125 50 40 28.9 .134 150 50 40 31.2 .144 175 50 40 34.4 .159 200 50 40 35.2 .162 250 50 40 38.5 .178 23.6 .117 63 65 40 23.7 .119 24.4 .123 88 65 40 25.2 .123 100 65 40 26.6 .136 112 65 40 26.7 .137 125 65 4~ 27.3 .140 150 65 40 29.1 .140 175 65 40 31.3 .160 200 65 40 31.9 .165 250 65 40 34.1 .177 Thus, when integrating over the entire voltage sweep, the background charge (from the background solution and from the amino acids and urea) essenti-ally cancels, while the~glucose-responsive charge is essentially positivP andJ
sensitivity to glucose lS increased by in~egration. Moreover, changes in .,..~
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.
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.5;~i5 charges associated with changes in urea and amino acid concentrations, respect-ively, essentially cancel, thus enhancing sensitivity to glucose.
Referring specifically to Figures 4c and d, it is apparent that integration need not occur over the entire voltage sweep. Examination of a specific por-tion of the sweep--substantially including the portion of the anodic sweep from -0.~5 volts to 0.8 volts, the dwell at the upper limit, and the entire cathodic sweep--also shows the requisite characteristics for selectivity and sensitivity.
Current Measurement Figure 2 shows a diagram of apparatus similar to Figure 1, except that function generator 20 signals current measurement by current measurement means 80, and transmission of a signal representing that measurement by transmitter 70.
Figures 5a, b and c represent the results of current measurement, under condi-tions described for the current integration examples above. The region between 0.2 and 0.6 volts of the anodic portion of the sweep shows a clear response to changes in glucose concentration, and a lack of response to changes in concentra-tions of amino acids and urea. Measurement at a point within that region (e.g., 0.3 volts) thus provides a measurement of glucose concentrations notwithstanding the presence of urea and amino acids. For example values of current at 0.3~ in the anodic scan for a Krebs-Ringer buffer containing 40 mg/dl of Urea and 35 mg/
dl of amino acids, taken from a plot such as Figure 5c, will show a linear rela-tionship between current and glucose concentration.
The embodiments of both Figure 1 and of Figure 2 would include a receiver (not shown) outside of the organism in which the sensor is implanted, to receive the signal transmitted by the sensor and translate that signal into data representing glucose concentration. Alternatively the receiver could trigger an alarm when glucose concentration varies outside predetermined limits.
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.
S~L55 Other Embodiments Other embodiments are within the scope of the following claims. By way of example only, the voltage waveform may be varied in several ways: the dwell times can be changed but should preferably be at least 2 seconds; the lower limit can be increased to, e.g.~ -1.0 volts, but excessive generation of hydrogen results from a limit significantly below that level. The upper limit can vary, e.g., from 0.7 to 1.1 volts; a voltage significantly above l.lV causes corrosion of the electrode. Holding periods may be introduced during the anodic and/or the cathodic portion of the sweep, preferably at potentials at which glucose reactions occur so as to increase the amount of time spent at such potentials and enhance sensitivity and selectivity to glucose; the rate of volt-age change in the anodic and cathodic sweeps may be different-e.g., the anodic sweep may be relative slower to increase the amount of time spent at voltages which produce currents sensitive and selective for glucose. With respect to the current measurement embodiment of Figure 2, the voltage variation could include discontinuities such as jumps from a limit to the measuring voltage.
It is envlsaged that the present invention be applicable to glucose sensors that are not implanted--e.g., clincial laboratory sensors and the claims are intended to include such non-implanted sensors. The biological fluids can include any fluids taken from living organisms or fluids simulating conditions in a living organism including, without limitation, blood, urine, buffer solu-tions, and saline solutions.
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' .
'
Claims (18)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Apparatus for sensing the concentration of glucose in biological fluids comprising an electrode, a voltage source, means for applying the voltage source to the electrode to cause a current flow therethrough, means for varying said applied voltage in a sweep ranging from a first limit to a second limit and back toward said first limit, and means for integrating current at the electrode with respect to time during at least a portion of said voltage variation selected to produce a total charge sensitive to glucose concentration and relatively insensitive to other components in the fluid.
2. The apparatus of claim 1 in which said portion is selected so that the charge responsive to glucose concentration has predominantly the same algebraic sign throughout said portion, and so that the charge responsive to interfering components of said fluid has a positive sign in one segment of said portion and a negative sign in another segment of said portion, whereby the glucose-respon-sive charge, and thus sensitivity to glucose, is reinforced, and the charge responsive to interfering substances at least partially cancels, thus reducing such interference.
3. The apparatus of claim 1 or 2 in which the lower limit of such voltage sweep is between -1.0 and -0.6 volts and the upper limit is between 0.7 and 1.1 volts, said sweep including an anodic sweep from said lower to said upper limit and a cathodic sweep from said upper to said lower limit.
4. The apparatus of claim 1 or 2 in which said voltage sweep includes dwell periods at said upper and lower limits, and the rate of voltage change during said anodic and cathodic sweeps is constant.
5. The apparatus of claim 1 or 2 in which said integration takes place continuously during one complete voltage sweep.
6. The apparatus of claim 1 or 2 in which said integration occurs sub-stantially including the anodic sweep between -0.45 volts and said upper limit, the dwell at said upper limit, and the entire cathodic voltage sweep.
7. The apparatus of claim 1 or 2 in which the rate of voltage change dur-ing said cathodic voltage sweep is more rapid than during said anodic voltage sweep.
8. The apparatus of claim 1 or 2 in which said varying of said applied voltage ceases during holding periods between said limits, said holding periods being at potentials at which glucose undergoes an electrochemical reaction.
9. The apparatus of claim 1 or 2 in which said portion is selected so that the charge attributable to any specific interfering component of the fluid cancels, whereby changes in concentration of that specific component do not affect the charge measured.
10. The apparatus of claim 1 or 2 in which said apparatus includes means to normalize said total charge in the form of the ratio of the total algebraic charge to the total absolute value of said charge.
11. A method for sensing the concentration of glucose in biological fluids comprising the steps of applying a voltage to an electrode to cause a current flow therethrough, varying said applied voltage in a sweep ranging from a first limit to a second limit and back toward said first limit, and integrating cur-rent with respect to time over at least one portion of said voltage variation selected to give a total charge sensitive to glucose concentration and rela-tively insensitive to other components in the fluid.
12. Apparatus for sensing the concentration of glucose in biological fluids comprising an electrode, a voltage source, means for applying the voltage source to the electrode to cause a current to flow therethrough, means for vary-ing said applied voltage from a first limit to a second limit and back toward said first limit, and means for measuring current at the electrode at a point, between 0.2 volts and 0.6 volts during the anodic variation of the voltage sweep, selected to be sensitive to changes in levels of glucose concentration in said fluid, but relatively insensitive to levels of other constituents of said fluid.
13. Apparatus of claim 12 in which said lower limit of said voltage varia-tion is between -1.0 and -0.6 volts and the said upper limit is between 0.7 and 1.1 volts.
14. Apparatus of claim 12 in which the rate of change of said voltage variation is constant between said limits, and includes dwell periods at each limit.
15. Apparatus according to claim 14 in which said dwell periods are greater than 2 seconds.
16. Apparatus according to claim 10 wherein said voltage variation includes an anodic sweep and a cathodic sweep, said rate of voltage variation being between 0.5 volts/min and 4 volts/min.
17. Apparatus according to claim 16 in which the rate of voltage change during said cathodic sweep is more rapid than during said anodic sweep.
18. A method for sensing the concentration of glucose in biological fluids comprising applying a voltage to an electrode to cause a current to flow there-through, varying said applied voltage in a sweep ranging from a first limit to a second limit and back toward said first limit, and measuring said current at a point in a specific region, between 0.2 volts and 0.6 volts during the anodic variation of said voltage, selected to be sensitive to changes in levels of glucose concentration in said fluid, but relatively insensitive to levels of other constituents of said fluid.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US06/155,198 US4340458A (en) | 1980-06-02 | 1980-06-02 | Glucose sensor |
US155,198 | 1980-06-02 |
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CA1152155A true CA1152155A (en) | 1983-08-16 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA000378793A Expired CA1152155A (en) | 1980-06-02 | 1981-06-01 | Glucose sensor |
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US (2) | US4340458A (en) |
EP (1) | EP0052148A4 (en) |
JP (1) | JPS57500899A (en) |
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BR (1) | BR8108636A (en) |
CA (1) | CA1152155A (en) |
CH (1) | CH660922A5 (en) |
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- 1981-06-01 CA CA000378793A patent/CA1152155A/en not_active Expired
- 1981-06-01 EP EP19810901848 patent/EP0052148A4/en not_active Withdrawn
- 1981-06-01 JP JP56502289A patent/JPS57500899A/ja active Pending
- 1981-06-01 NL NL8120252A patent/NL8120252A/nl unknown
- 1981-06-01 GB GB8202427A patent/GB2089048B/en not_active Expired
- 1981-06-01 CH CH726/82A patent/CH660922A5/en not_active IP Right Cessation
- 1981-06-01 AU AU74126/81A patent/AU546417B2/en not_active Ceased
- 1981-06-01 BR BR8108636A patent/BR8108636A/en unknown
- 1981-06-01 DE DE813152065T patent/DE3152065A1/en not_active Withdrawn
- 1981-06-01 WO PCT/US1981/000725 patent/WO1981003546A1/en not_active Application Discontinuation
- 1981-06-02 MX MX187601A patent/MX151191A/en unknown
-
1982
- 1982-01-29 NO NO82820274A patent/NO159421C/en unknown
- 1982-01-29 SE SE8200511A patent/SE434887B/en not_active IP Right Cessation
- 1982-02-01 DK DK42982A patent/DK42982A/en not_active Application Discontinuation
- 1982-02-02 FI FI820328A patent/FI68323C/en not_active IP Right Cessation
- 1982-04-22 US US06/370,735 patent/US4396464A/en not_active Expired - Lifetime
-
1983
- 1983-07-25 SE SE8304129A patent/SE434888B/en not_active IP Right Cessation
Cited By (1)
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US4890620A (en) * | 1985-09-20 | 1990-01-02 | The Regents Of The University Of California | Two-dimensional diffusion glucose substrate sensing electrode |
Also Published As
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MX151191A (en) | 1984-10-09 |
DE3152065A1 (en) | 1982-08-12 |
EP0052148A1 (en) | 1982-05-26 |
GB2089048B (en) | 1985-01-30 |
CH660922A5 (en) | 1987-05-29 |
NO820274L (en) | 1982-01-29 |
SE8304129L (en) | 1983-07-25 |
GB2140567A (en) | 1984-11-28 |
EP0052148A4 (en) | 1983-06-15 |
GB8404395D0 (en) | 1984-03-28 |
AU7412681A (en) | 1981-12-21 |
SE434887B (en) | 1984-08-20 |
FI68323C (en) | 1985-08-12 |
NO159421B (en) | 1988-09-12 |
NO159421C (en) | 1988-12-21 |
GB2089048A (en) | 1982-06-16 |
GB2140567B (en) | 1985-06-05 |
JPS57500899A (en) | 1982-05-20 |
US4396464A (en) | 1983-08-02 |
BR8108636A (en) | 1982-04-13 |
FI68323B (en) | 1985-04-30 |
SE434888B (en) | 1984-08-20 |
WO1981003546A1 (en) | 1981-12-10 |
US4340458A (en) | 1982-07-20 |
NL8120252A (en) | 1982-05-03 |
DK42982A (en) | 1982-02-01 |
FI820328L (en) | 1982-02-02 |
AU546417B2 (en) | 1985-08-29 |
SE8304129D0 (en) | 1983-07-25 |
SE8200511L (en) | 1982-01-29 |
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