CA1206856A - Method and associated materials for measuring glucose level in body fluids - Google Patents
Method and associated materials for measuring glucose level in body fluidsInfo
- Publication number
- CA1206856A CA1206856A CA000397815A CA397815A CA1206856A CA 1206856 A CA1206856 A CA 1206856A CA 000397815 A CA000397815 A CA 000397815A CA 397815 A CA397815 A CA 397815A CA 1206856 A CA1206856 A CA 1206856A
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- Prior art keywords
- glucose
- monitor
- charge
- indicator
- binding
- 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.)
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Classifications
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- 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
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/827—Lectins
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
- Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
- Y10T436/143333—Saccharide [e.g., DNA, etc.]
- Y10T436/144444—Glucose
Abstract
ABSTRACT
A method for measuring the level of glucose in animal body fluids such as blood and urine, comprises contacting the body fluid with a glucose indicator comprising a reversible complex of a carbohydrate component, a binding macromolecular component, and an indicator element bound to one of the com-ponents, and maintaining the body fluid in contact with the indicator for a period of time sufficient to permit any glu-cose present in the body fluid to displace the carbohydrate component in the complex, and to thereby release the indicator element to signify the presence of glucose. Preferably, the macromolecular component comprises one or more lectins; and the carbohydrate component may be one or more of the sugars for which testing is desired.
In one embodiment of the present invention, the indicator may comprise a dye or color-forming radical, associated with either the lectin or the carbohydrate, incorporated in a test strip or kit, for rapid, in vitro glucose level measurement.
Alternately, the indicator may be a glucose monitor comprising an electrode adapted for in vivo measurement of glucose con-centration, by implantation in registry with the body fluid system of the animal for which measurement is desired.
A method for measuring the level of glucose in animal body fluids such as blood and urine, comprises contacting the body fluid with a glucose indicator comprising a reversible complex of a carbohydrate component, a binding macromolecular component, and an indicator element bound to one of the com-ponents, and maintaining the body fluid in contact with the indicator for a period of time sufficient to permit any glu-cose present in the body fluid to displace the carbohydrate component in the complex, and to thereby release the indicator element to signify the presence of glucose. Preferably, the macromolecular component comprises one or more lectins; and the carbohydrate component may be one or more of the sugars for which testing is desired.
In one embodiment of the present invention, the indicator may comprise a dye or color-forming radical, associated with either the lectin or the carbohydrate, incorporated in a test strip or kit, for rapid, in vitro glucose level measurement.
Alternately, the indicator may be a glucose monitor comprising an electrode adapted for in vivo measurement of glucose con-centration, by implantation in registry with the body fluid system of the animal for which measurement is desired.
Description
1~68S6 METHOD AND ASSOCIATED MATERIALS FOR
MEASURING GLUCOSE LEVEL IN BODY FLUIDS
The present application relates to a method and associated system for measuring glucose in animal body fluids, and particularly to both the in vitro and in Vito measurements of glucose levels.
The detection and measurement of glucose in body fluids, such as blood, urine and cerebro-spinal fluid, provides in-formation that is crucial to a proper assessment of the functions of the body. Thus, hype- and hyperglycemic condo-lions, which result from abnormal variations in blood glucose level, require prompt and accurate measurement, in instances such as the administration of emergency medical attention to patients exhibiting these conditions, to avert their detriment tat and potentially fatal effects. Likewise, ongoing measure-mint of blood glucose levels is frequently necessary for patients with continuing diabetic conditions, to retain better control over them.
Several methods have been used in the instance of periodic measurement of glucose levels. Two methods that are currently in wide use comprise the chemical, and enzymatic method. The chemical method utilizes a sample of body Lydia that is is fated and reacted with compounds capable ox oxidizing glucose and producing a color change. This technique is semi~quanti-native, but has the primary drawback that it is not specific for glucose and will give false readings with other sugars and body components with which the oxidants will react.
The enzymatic method for periodic glucose measurement employs the enzyme glucose oxidize which oxidizes available glucose to form gluconic acid and hydrogen peroxide. Generally, a Luke dye is utilized, so that the hydrogen peroxide byproduct I ' ~2~i8~
may be reacted with the dye to form a particular color identi-lying the presence of glucose. This method is deficient in that it is a kinetic analysis that varies with temperature and time, and requires a specific apparatus with a quantitative measurement of the color bearing composition.
The ongoing in viva measurement of glucose levels, has been attempted by a variety of apparatus, including indwelling probes, however these devices have proved wanting for specificity and frequently suffer from interference from other biological come pounds. For example, Cotton et at., Transplantation and Olin-teal Immunology, volume X, Pages 165-173, Amsterdam (1978), disclose a system including an electronic glucose sensor elect tribally connected to an insulin reservoir and pump. In this system, the sensor responds Jo rising glucose levels, and in-struts the reservoir and pump to automatically dispense inappropriate quantity of insulin into the bloodstream. The sensor employs a platinum electrode catalyst for the purpose of oxidizing glucose. The use of the catalyst, however, no-dupes the specificity of the electrodes as interference with other metabolizes and resulting unreliability occurs.
Soeldner et a., NIX Publication zoo 76-~854 (1976), at Pages 267-277, propose a glucose-sensitiYe implant electrode, that utilizes an immobilized quantity of the enzyme glucose oxidize, that by its action on available glucose in the blood stimulates an Jon exchange that causes a corresponding differential in-current that may be sensed and reported by the electrode. The mechanism of glucose oxidize activity with body fluid, is also used in a corresponding in vitro test, where the formation of hydrogen peroxide by the reaction of the enzyme, in the presence of a Luke dye, results in a visible color reaction. The in viva system of Soeldner et at. is deficient in that the enzyme glucose oxidize is unstable in this environment, and therefore is an unreliable determinant of glucose concentrations.
I ~2~6~56 From the above, it is apparent that a method and associated materials and apparatus for glucose level measurement, is needed on both the periodic, in vitro level, as well as the continuous, in viva level.
In accordance with the present invention, a method for measure in the level of glucose in animal body fluids is disclosed which comprises contacting a portion of a given body fluid with a glucose indicator comprising a reversible complex of a car-bohydrate component, a binding macro molecular component and an indicator element bound to one of the components. The sample of body fluid is maintained in contact with the glucose India actor for a period of time sufficient to permit the glucose present to displace the carbohydrate component in the fevers-isle complex, whereby the indicator element is released to signify the presence of glucose.
In one embodiment of the invention, the glucose indicator of the invention comprises the reversible complex of the carbon hydrate component the binding macro molecular component and the indicator element. The carbohydrate component may comprise carbohydrate oligomers of dlffering-size, and the macromolecu-far component may be carbohydrate-binding proteins such as pectins, with specific blinding affinities or particular carbon hydrates. on this embodiment, the indicator element is prey-drably a dye or a color-formln~ radical, that may be associated or bound Jo either the carbohydrate oligomer en the pectin.
In operation, the reversible complex between the carbohydrate oligomer and the pectin dissociates in contact with glucose present in the fluid sample, to the extent that such glucose is present and this dissociation permits the indicator element to give a color reaction.
In an alternate embodiment of the invention the glucose in-dilator may comprise an indwelling monitor or the continuous -4- ~685~
measurement of glucose having a variable electrical charge and disposed in registry with the system of body fluid to be monk-toned. The monitor is adapted to measure changes in glucose concentration as a function of changes in electrical charge, and includes a charge-transfer medium wherein the binding macro molecular component is a reversible complex, and the carbohydrate component bears an electrical charge, and thereby comprises a portion ox the indicator element as well. Thus, body fluids capable of passing through the monitor and having increased glucose levels, cause the charge-bearing choirboy-drape to be released to the electrical field of the monitor, with the corresponding increase on the flow of electrical charge, serving to indicate the variation on glucose level of the fluid.
The glucose monitor may comprise an electrode, with an anode and cathode spaced apart from each other, and the electrical charge-transfer medium located i h between. The macro molecular and carbohydrate components, may respectively be selected from those materials specified with reference to the glucose India actor, described above. The charge-bearing carbohydrate come pennants may comprise carbohydrates havlnQ charged substituents bound whereto, and in one embodiment 9 the subunits of carbon hydrate ollgomers may each bear a given unit charge, so that oligomers of differing chain length will offer a charge eon-responding linearly in magnitude Jo the number of recurring carbohydrate units. Also, any incremental changes in electrical charge w~thtn the monitor, resulting from low-level inductive effects, may be easily measured my existing electrical drag-Gnostic equipment, available for measurement of charge differ-entoils of this order. In such way, the electrode may compensate for signal variations that are extraneous to the parameter being measured.
I
The present glucose indicators, may thus comprise a color-forming strip, or an electrode, each encased within a semi-permeable membrane, so that the primary components of the indicator, would remain encased while the glucose-bearing body fluid would be capable of passing there through.
. .
- Specific pectins may be utilized in association with specific carbohydrates, to test for particular sugars present in the body fluid. The glucose indicator may comprise a variety or continuum of such lectin-carbohydrate oligomer complexes, each evidencing a variant indicator reaction responsive to the presence of differences in the identity or concentration of sugars present.
The glucose indicator may be prepared with one of the coupon-ens irreversibly bound to a suitable and insoluble support, and enclosed within a selectively permeable membrane and the final article may assume the form of a strip. A kit is like-wise contemplated comprising the glucose indicator in strip form and a color chart identifying the specific concentrations and identities of the sugars tested for.
I The glucose monitor including the electrode described earlier, may be either implanted alone or in conjunction with appear-private insulin dispensing means or the like. An appropriate current-responsive meter may be selected from equipment avail-able in the art, and specifically calibrated to reflect pro-else changes in glucose concentration.
The present invention offers a simple ye accurate and reliable method for determining glucose concentrations in body fluids, that provides medically significant quantitative identification of glucose. The operation of the present indicator is less subject to variations due Jo time and temperature parameters and is therefore more reliable.
Accordingly, it is a principal object of the present invention to provide a method for measuring glucose levels in animal body fluids.
It is a further object of the present invention to provide a method as aforesaid, which may be utilized either us a con-tenuous monitoring technique, or for periodic measurements.
It is a further object of the present invention to provide a method as aforesaid which yields reliable results.
It is a still further object of the present invention to pro-vise a glucose indicator for periodic glucose level measure-mint, that operates in direct response to the changes in glut cove concentration.
It is a still further object of the present invention to pro vise an indicator as aforesaid, comprising an indwelling glut cove monitor adapted to measure clangs in glucose concentration as a function of changes in electrical charge.
Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing descrip~
Sheehan as well as the ~ollowlng drawings.
FIGURE 1 is a schematic plan view illustrating the spatial relation of the components of the glucose indicator of the present lnventionO
FIGURE 2 is a schematic plan view illustrating the possible construction of a glucose monitor in accordance with the present invention.
The measurement of glucose concentrations in body fluids in accordance with the present invention may be performed on either a periodic basis, or on a continuing bass as described hereinafter. Periodic measurement makes use of a glucose indicator which, when contacted with a sample of the body -Fluid, quantitatively identifies the glucose by means of the reaction of an indicator element such as a dye. In such in-stance, the glucose indicator comprises a reversible complex of a carbohydrate component, a binding macro molecular component and an indicator element associated with one of said components Continuous measurement of glucose concentrations by means of the present invention, makes use of an indwelling glucose monitor that resides in fluid registry with the system of the body fluid under measurement, and measures concentration of glucose as a function of changes in electrical charge. The glucose monitor utilizes a charge-transfer medium comprising a reversible complex of a binding macro-molecular component, and a charge-bearing carbohydrate component that reversibly dissociates from the macro molecular component, to cause a variation in electrical acti~lty within the monitor that may be linearly related to the concentration of glucose in the body fluid.
An ilnportant element of both embodiments of the present invent lion, is the binding macro molecular component. The term "macro molecular component" as utilized herein, refers primarily to molecules that evidence reversible binding capability with other micro- or macromolecules. Examples of molecules meeting the foregoing definition include natural binding proteins, enzymes, regulatory proteins and synthetically modified bind-in molecules, such as chemically modified proteins. Of these the natural proteins known as pectins are preferred herein I
Pectins are carbohydrate-bindin~ proteins of plants and ant-mats that exhibit a variety of specificities for carbohydrates (Lit et at., Ann. Review of Biochemistry, 42, 541 (1973), IT
Goldstein and CUE. Hayes, Ad. in Carbohydrate Chemistry and Biochemistry, Vol. 35, US Tip son and D. Horton, ens.
(Academic Press, New York 1978, pp. 128-341). Pectins, and in particular the pectin known as Concanavalin A, a Jack Bean pectin, exhibit a natural affinity for various sugars which, more particularly, is a function of the number of saccharine subunits of the given sugar. For example, Concanavalin A, which is specific for glucose and muons, will not bind with galactose; particularly, specificity is shown for I-D-mannopyranose and ~-D-glucopyranose.
Other pectins, such as soybean pectins show similar specific-lo lies; thus, soybean lectlns are specific for DUN acetylgalac-Tasmania ant ~-D-galactose units, and wheat germ pectin is specific For DUN acetylglucosamine. The preferred pectin, Concana~alin A, is also observed to have an increased affinity for multiples of glucose up to 6.
The carbohydrate component preferably comprises a sugar, and includes the simple sugars or monosaccharides as well as their low molecular weight condensation polymers, known as the ol~gosaccharides~ that conventionally contain from two to nine monosaccharide units. Many of the sugars are naturally occur-lung, and may be found in animal body fluid. Partlcularly9a carbohydrate component may comprise glucose in the monomeric no oligomeric form; glucose oligomers may include other saccharides such as muons and galactose9 and may be either recovered from nature or synthetically prepared. The naturally occurring oligosaccharides are often associated with protein or lipid fractions, and may be utilized herein in such form.
, " .
- 9 - so The specific carbohydrate component useful in the present in-mention is chosen on the basis of its equivalence in affinity for the formation of the reversible complex with the macro-molecular component, with the material or agent to be detected and measured by the indicators disclosed herein. Thus, for example as the pectin Concanavalin A has an increasing affinity for glucose oligomers with greater numbers of moo-saccharine units; correspondingly, this affinity Gould extend to concentrations of glucose in a fluid sample that would correspond in range. In particular, the corresponding range of glucose concentrations in body fluids lies within the physic logical range of 10 - 400 mg/dl.
Accordingly, a glucose indicator could be prepared as thus-treated in FIGURE 1, with a plurality of pectin molecules, each I disposed on a substrate, and reversibly associated with carbon hydrate components of differing Sue representing a continuum ox saccharine units corresponding to the physiological range of glucose, Relatively low levels of glucose concentration would be unable to displace the higher oligomers, but would readily displace the oligomers of corresponding affinity which in turn would permit the associated indicator element to signify the presence of glucose in that concentration.
The exact operation of the reversible complex is discussed below.
The reversible complex that constitutes the indicator of the embodiment of FIGURE 1, and the electrical charge-transfer medium of the embodiment illustrated in FIGURE 2, comprises a reaction between the macro molecular component and the choirboy-drape component, as generally noted above. This reaction must be reversible and non-covalent. The bonding that occurs between the respective components is caused by non-coYalent forces such as hydrophobic, ionic hydrogen bonding forces and the like. Such interactions are known in the art, and - 1 o- ~%~368S~
their effects on molecular affinity and recognition have been described for example, in Korolkovas_et at., "Essentials of Medicinal Chemistry", pup 44-8l, John Wiley & Sons, l976, and the particular reactions of proteins and carbohydrates has been reviewed in Goldstein, IT Ed., Carbohydrate-Protein Interaction, AS Symposium Series No. 88 ~l979). An example of a reversible interaction is the interaction between an enzyme and its substrate or a competitive inhibitor thereof.
As describe earlier on brief the present reversible complex between the carbohydrate component and the macro molecular come potent operates in a state of dynamic equilibrium, as the ma-tonal in the body fluid being tested for, and the carbohydrate component compete for association with the macro molecular come potent. In the instance where the macro molecular component is a pectin, and the material under test is glucose at certain levels of concentration, the glucose indicator illustrated in FIGURE l, and the charge-transfer medium of the glucose monk-ion illustrated on FIGURE 2, both participate in an equilibrium that arises between the glucose at the particular concentration and the reversible complex bearing a corresponding carbohydrate component, to complex with the pectin.
In the instance of the embodiment of FIGURE lo the displace-mint of the carbohydrate component of a particular reversible complex permits the indicator associated with that complex, to signify the presence of the particular concentration of glucose, preferably by a color-forming reaction. In the instance where the glucose indicator comprises an indwelling monitor, the displacement of the electrical charge-bearing carbohydrate component of a particular reversible complex permits the car-bohydrate to effect the level of electrical charge in the monitor to thereby signify the presence of the particular concentration of glucose.
I
Z~1~856 In the instance where a glucose indicator is prepared for the periodic measurement of glucose levels in body fluid, the indicator element may be associated with either the carbohydrate component or the macro molecular component, for the sole function of signifying the dissociation of these components, and the corresponding presence of glucose. In this embodiment, therefore, the indictor component may be a color-forming material such as a dye or a color-forming radical that is freed or otherwise chemically altered by the dissociation of the carbohydrate and the macro molecular come pennants, to produce a color-forming reaction. The indicator element may also include a compound or portion thereof that forms a precipitate upon such dissociation and the invention therefore us not limited to color-formin~ materials exclusively.
For example a dye such as an arylhydrazine may be reacted Thea the reducing end of a carbohydrate oligomer to form a stable addition product such as an arylosazone, which will give a color reaction when the carbohydrate component and the macro molecular component are dissociated. By utilizing dip-fervent hydrazines in combination with different oligomers no-spDnsive to individual concentrations of glucose it is possible to develop a mixture of ligands exhibiting variations in color formation and affinity for particular luckiness, whereby dip-errant concentrations of glucose will cause the formation of differing color reactions. Rerun to FIGURE 1, the disco-scion of different dyes with different chain length oligomers illustrates the manner in which the discrete levels of glucose concentration on fluid samples can be identified.
The indicator element of the first embodiment of the invention, may be associated with the monomolecular component, rather than the carbohydrate component, however, with the same manner of operation. Thus, the specific dyes such as Radiomen, isothiocyanate, 4 Dimethylaminoazobenzene-4'-sulfinyl chloride and the like, that are capable of reacting with proteins, may -12- ~2~68~6 be incorporated onto the macro molecular components In this embodiment, the carbohydrate component, rather than the macro molecular component would be fixedly attached to a substrate and the dissociation ox the carbohydrate and the macro molecular component would set the latter free permitting the attached dye to form its color reaction The disposition of the respective components on the substrate will be disk cussed later on with reference to the preparation of the indicator of the present invention.
In a further embodiment, the indicator element may comprise a particular functional group that may be associated with the carbohydrate or the macro molecular component, and which would be capable of forming the colored complex with an immobilized dye included with the glucose indicator, when the respective component bearing the functional group is displaced For example, a sulfhydryl group may be incorporated into the carbohydrate component, and would, upon its release, react with a number of reagents, such as 5,5l-dithiobis (nutria-benzoic acid), to develop a color.
In general, the method of the present invention comprises contacting the indicators described herein with a quantity of an animal body fluid, and maintaining the indicators in contact with the fluid for a period of time sufficient for the indicators to signify the presence and quint, if any, I ox the maternal- being tested for, in this case glucose. Thus, analysis of body fluid for the presence of glucose may be con-dueled by placing the fluid in contact with the glucose in-dilators, and maintaining such contact for a period of time sufficient to enable the reversible complex between a par-titular macro molecular component and its corresponding carbon hydrate component, to dissociate in favor of a complex involve - in the macro molecular component and the glucose, whether in vitro or in viva, which latter event will be signified by the -13~ 68S6 indicator. In the instance, for example, where the in vitro indicator comprises a pectin such as Concanavalin A reversibly bound to a glucose oligomer bearing a particular dye, the indicator wound be placed in contact with a drop of body fluid which would he maintained in contact with the indicator for a period of time, such as, for example, up to five minutes, whereupon equilibrium between the glucose present and the reversible complex will have been reached, and the indicator element comprising the dye will have given its color reaction.
In the instance where the glucose indicator comprises an in-dwelling monitor or electrode, the monitor may be either temporarily or permanently implanted in the body in registry with the system of body fluid to be measured. The monitor is then electrically connected to appropriate current genera cling and current measuring means. The glucose in the body fluid passing through the monitor competes for the immobilized lect~n, and results in the release of the charge-bearing car-bohydrate to permit the latter to change the electrical charge of the monitor. The reversible nature of the complex permits the charge-bearing carbohydrate to reassociate with the fee-tin, in the instance where the glucose level in the body fluid drops.
The glucose indicator of the embodiment illustrated in FIGURE 1 and the charge-transfer medium of the glucose monitor, thus-treated in FIGURE 2, may both be prepared as follows The particular pectin or pectins chosen for use may be fixed to a suitable insoluble support, such as cellulose, agrees, pies-tic, glass and the like, by either covalent bonding or non-covalent adsorption, The technique of solid state immobilize-lion of enzymes and other proteins on resins, films, test tubes glass beads and the like are well known (see e.g., Zaborsky, C. "Immobilized Enzymes", CRC Press, Cleveland, 1973; Lowe, CUR. and Dean, PUG "The Chemistry of Affinity Chromatog-rough", Affinity Chromatography, John Wiley and Sons, NAY., ~2~1~85~
197~; Axon, et at., US. Patent No. 3,645,852j and Kramer, et at., US. Patent No. 4,039,413). For example, the pectin may be attached to a cellulose support by activation of the support with cyanogen halide, reaction with cyan uric acid, peridot oxidation, epoxide formation, and reaction with various bifunctional reagents, such as bis-ox;nane, dip methyl adipimate, phenol-2, 4-disulfonyl chloride, and divinely cellophane Preferably, a cellulose strip is reacted with cyanogen bromide, and the thus activated cellulose strip is then incubated with Concanavalin A, and the reaction later stopped by -the addition thereto of Gleason.
With respect to the indicator illustrated in FIGURE 1, it is to be understood that this embodiment includes the instance where the carbohydrate component is anchored to a substrate by techniques equally well known in the art, so that the various moo- and oli~osaccharides may be permanently bound to the substrate and reversibly associated with the respective pectins.
As noted earlier, the specific carbohydrate components may be either recovered from nature or synthetically prepared. Par-titular carbohydrates may be prepared by, for example limited acid hydrolysis of manning to form oligomers of varying length which are then separable by chromatography, to recover the specific oligosaccharides.
In the instance where the in vitro indicator of FIGURE 1 is being prepared, the carbohydrate components recovered above may either be fixedly bound to the substrate, or reacted with various dyes to form the conjugates illustrated schematically in FIGURE 1. Thus oligomers of varying chain length may bear different dyes as illustrated, and as described in detail earlier.
Sue In the instance where the charge transfer medium of the em-bodiment of FIGURE 2 is under preparation the recovered carbohydrate components may be treated to dispose one or more charges thereon. In particular, ionic charges may be disk posed on the carbohydrates by reacting appropriate substitu-ens or moieties with either the hydroxyl groups of the car-bohydrates, or the alluded group disposed at the reducing end of the carbohydrate A variety of substituents having negative charges could be so introduced, as follows:
3 2 ,, SHEA CH2-N-CH2-CH3, or arylhydraz;nes of variant negative or positive charge. Naturally, the fore-going substituents are merely illustrative of those materials that might be reacted with the carbohydrate components to achieve the ionic or charged state, as the invention encom-passes all equivalent substituents that are non-toxic to the body fluid within its scope Once both of the components are prepared, the carbohydrate and macro molecular components are brought into contact with each other, and establish the reversible complexes described earlier with respect to each of the embodiments of the present invention. Thus, for example, the glucose indicator of FIG-USE 1 may be prepared in strip form, and, after the reversible complexes are formed, may be cowered with a semi-permeable membrane designed to permit glucose and the dye-car'Dohydrate complex to diffuse readily here through In such instance, a variety of semi-permeable membranes are well known and may be used for in vitro testing equipment of this type, and in-elude several natural and synthetic resinous materials evidence in pore size, etc., conducive to this application.
Referring again to FIGURE 1, the schematically illustrated strip would be placed in contact with the fluid sample, with the pores of the membrane sufficiently large to permit the ~16-?685~
passage of glucose there through to compete for the formation of a reversible complex with the support-bound pectin. Upon the displacement of the carbohydrate component by the glucose, the dye, such as "Dye 1", would be free to form a color react lion to signify it displacement, to indicate the concentration of the glucose in the investigated body fluid.
The indicator described with reference to FI-GU~F 1, could be prepared as part of a kit, including the indicator in strip form, together with a suitable color chart providing a spectrum of colors, and their quantitative or qualitati Ye so gnificance, to facilitate the rapid analysis of test results. Thus, a series of colors would be outlined that would denote portico-far glucose concentration levels to enable the user of the kit to rapidly determine glucose levels from the color reaction of the indicator strip The simplicity of this kit would facile-late its use by both trained medical staff, as jell as the patients themselves.
The preparation and use of the glucose monitor comprising the alternate embodiment of the present invention, may be under-stood with reference to FIGURE 2. Thus, a monitor is schematic gaily illustrated comprising eleckrode`10, having a housing 12 with an anode 14 and a cathode 16 mounted inside, and in spaced apart relation to each other. As the present illustration is schematic, it can be visualized that conventional means for external electrical connection can be provided to interface with anode 14 and cathode 16, to provide means for current air-culation and measurement in conjunction with an appropriate source of electric current, and current metering means, not shown, which may be cnnnecteJ to electrode I in electrical series therewith.
In accordance with conventional electrode construction, a source of electrical current transfer is disposed within -17- ~ZGG~6 housing 12, to permit the passage of charge between anode 14 and cathode 16. In the present electrode, this charge source may comprise in whole or in part, electrical charge-transfer medium 18, which, as schematically illustrated, comprises a segment of immobilized macro molecular material such as a lectln, that is either bound to a solid substrate, or is itself polymerized and solidified. The lect;n 20 may have attached thereto one or more charge-bearing carbohydrates such as thus-treated at I Carbohydrate 22 is shown with recurring succor-ire units that bear negatively charged substituents 24. Sub-stituents 24 may comprise negatively charged moieties that may be chemically attached to the respective carbohydrate by reaction either with one or more of the hydroxyl groups of the carbohydrate, or by attachment of the moiety to the aide-I Hyde at the reducing end thereof. Also, the charge of a given carbohydrate subunit may vary from that of other subunits, to give further differentiation an specificity to particular glut cove fractions in the body fluid. In this way, further refine-mint of the electrical charge-transfer medium is possible, to define both quantitatively and qualitatively, the presence of particular sugars in body fluids. The preparation of the charge-bearing carbohydrate components in this fashion, is described earlier herein.
In similar fashion to the preparation of the indicator of FIGURE 1, the charge-transfer medium 18 may be prepared with a continuum of charge-bear~ng carbohydrates 22, each carbon hydrate having a differing subunit number and a correspondingly different magnitude of charge. Likewise, carbohydrates of differing composition, i.e. variant saccharides, may be bound to the same lectln 20, to provide a wide spectrum of glucose detection.
Referring again to FIGURE 2, housing 12 provides a means for the passage there through of the body fluid, to permit the ingress and egress of glucose, schematically illustrated and labeled 26. To this end, a membrane 28 may be provided, sun-rounding all or a portion of housing 12, to provide selective permeability fac;l;tat;ng the free movement there through of glucose.
A variety of polymeric materials may be utilized to prepare membrane 28, and such materials may exhibit selectivity based upon differentials in porosity, as well as surface charge. In such instance, the polymeric materials may form into the mom-brine, bearing the desired surface charge, or the formed mom-brine may subsequently be treated Jo provide such charge thereon.
Suitable polymeric materials may be selected from positively charged and negatively charged materials, as well as materials possessing both positive and negative charge. For example, positively charged materials may comprise polyvinyl pardon;
negatively charged materials may be selected from polyacrylic acid and polyethylene terephthalate; and a polymeric material possessing a combined positive and negative charge may comprise a polystyrene sulfonate-vinylbenzyl trim ethyl ammonium color-ire copolymer. Naturally, the foregoing materials are merely illustrative of suitable polymers that may be utilized in preparation of membrane 28, and the invention is accordingly I not limited to these specific materials, but rather encompasses those materials possessing the requisite porosity and charge capability set forth above.
As noted earlier, charge-transfer medium 18, including pectin 20 and charge-bearing carbohydrates 22 may be prepared generally in the same manner outlined with respect to the embodiment of -19- Sue FIGURE 1. Thus after the individual pectins 20 are fixed to a suitable insoluble support, and the particular charge-bearing carbohydrates 22 are prepared, these respective come pennants may be brought in contact with each other to establish the desired reversible complexes of medium 18. After the formation of these reversible complexes, medium 18 may be mounted within housing 12, between anode 14 and cathode 16 as illustrated. Housing 12 may then be covered with membrane 28 to complete the assembly of monitor 10.
The operation of monitor 10 in the corresponding method for continuously measuring glucose levels of an in viva basis comprises the implantation of the monitor within the body of the animal, and in registry with the system of body fluids to be observed As mentioned earlier the monitor may remain implanted either temporarily or indefinitely, and may be elect tribally connected to current generating and measuring means, to provide a calibrated continuous indication of glucose levels.
As noted earlier, the current measuring means or gauge may be appropriately calibrated, so that specific incremental vane-lions in glucose level may be noted and appropriate remedial action taken. In such connection, the present invention may be utilized in combination with an appropriate dispensing means, for the automatic administration of an anteed such as ins-fin, in the instance where the present invention is applied to US a d~abetlc condition by fluid registry with the bloodstream As the present monitor will be required to operate in fluid media containing a variety of ions other than those that exist or may be fornled by the action of the present charge-transfer medium, one or more reference electrodes may be appropriately linked to the monitor for the purpose of detecting ions that are unrelated to the function of the monitor. For example, such electrodes may sense the presence of inorganic ions having Jo ` ~L2~S6 it no relation to the level of glucose, and could provide eon-recta on to the present monitor Jo avoid false indication of increased glucose levels. Linkage ox these reverence electrodes is well known, and may be accomplished by connection in a Whetstone Bridge arrangement or equivalent disposition, -to permit the reference electrodes to provide the needed cornea-lion. The particular form of such connection does not form a part of the present invention. ; `
The invention may be embodied in other forms or carried out in other ways without departing from the spirit or essential char-acterlstics thereof. The present invention lo therefore to be considered as in all respects illustrative and no restrict live, the scope of the invention being indicated by the appended claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein, .
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MEASURING GLUCOSE LEVEL IN BODY FLUIDS
The present application relates to a method and associated system for measuring glucose in animal body fluids, and particularly to both the in vitro and in Vito measurements of glucose levels.
The detection and measurement of glucose in body fluids, such as blood, urine and cerebro-spinal fluid, provides in-formation that is crucial to a proper assessment of the functions of the body. Thus, hype- and hyperglycemic condo-lions, which result from abnormal variations in blood glucose level, require prompt and accurate measurement, in instances such as the administration of emergency medical attention to patients exhibiting these conditions, to avert their detriment tat and potentially fatal effects. Likewise, ongoing measure-mint of blood glucose levels is frequently necessary for patients with continuing diabetic conditions, to retain better control over them.
Several methods have been used in the instance of periodic measurement of glucose levels. Two methods that are currently in wide use comprise the chemical, and enzymatic method. The chemical method utilizes a sample of body Lydia that is is fated and reacted with compounds capable ox oxidizing glucose and producing a color change. This technique is semi~quanti-native, but has the primary drawback that it is not specific for glucose and will give false readings with other sugars and body components with which the oxidants will react.
The enzymatic method for periodic glucose measurement employs the enzyme glucose oxidize which oxidizes available glucose to form gluconic acid and hydrogen peroxide. Generally, a Luke dye is utilized, so that the hydrogen peroxide byproduct I ' ~2~i8~
may be reacted with the dye to form a particular color identi-lying the presence of glucose. This method is deficient in that it is a kinetic analysis that varies with temperature and time, and requires a specific apparatus with a quantitative measurement of the color bearing composition.
The ongoing in viva measurement of glucose levels, has been attempted by a variety of apparatus, including indwelling probes, however these devices have proved wanting for specificity and frequently suffer from interference from other biological come pounds. For example, Cotton et at., Transplantation and Olin-teal Immunology, volume X, Pages 165-173, Amsterdam (1978), disclose a system including an electronic glucose sensor elect tribally connected to an insulin reservoir and pump. In this system, the sensor responds Jo rising glucose levels, and in-struts the reservoir and pump to automatically dispense inappropriate quantity of insulin into the bloodstream. The sensor employs a platinum electrode catalyst for the purpose of oxidizing glucose. The use of the catalyst, however, no-dupes the specificity of the electrodes as interference with other metabolizes and resulting unreliability occurs.
Soeldner et a., NIX Publication zoo 76-~854 (1976), at Pages 267-277, propose a glucose-sensitiYe implant electrode, that utilizes an immobilized quantity of the enzyme glucose oxidize, that by its action on available glucose in the blood stimulates an Jon exchange that causes a corresponding differential in-current that may be sensed and reported by the electrode. The mechanism of glucose oxidize activity with body fluid, is also used in a corresponding in vitro test, where the formation of hydrogen peroxide by the reaction of the enzyme, in the presence of a Luke dye, results in a visible color reaction. The in viva system of Soeldner et at. is deficient in that the enzyme glucose oxidize is unstable in this environment, and therefore is an unreliable determinant of glucose concentrations.
I ~2~6~56 From the above, it is apparent that a method and associated materials and apparatus for glucose level measurement, is needed on both the periodic, in vitro level, as well as the continuous, in viva level.
In accordance with the present invention, a method for measure in the level of glucose in animal body fluids is disclosed which comprises contacting a portion of a given body fluid with a glucose indicator comprising a reversible complex of a car-bohydrate component, a binding macro molecular component and an indicator element bound to one of the components. The sample of body fluid is maintained in contact with the glucose India actor for a period of time sufficient to permit the glucose present to displace the carbohydrate component in the fevers-isle complex, whereby the indicator element is released to signify the presence of glucose.
In one embodiment of the invention, the glucose indicator of the invention comprises the reversible complex of the carbon hydrate component the binding macro molecular component and the indicator element. The carbohydrate component may comprise carbohydrate oligomers of dlffering-size, and the macromolecu-far component may be carbohydrate-binding proteins such as pectins, with specific blinding affinities or particular carbon hydrates. on this embodiment, the indicator element is prey-drably a dye or a color-formln~ radical, that may be associated or bound Jo either the carbohydrate oligomer en the pectin.
In operation, the reversible complex between the carbohydrate oligomer and the pectin dissociates in contact with glucose present in the fluid sample, to the extent that such glucose is present and this dissociation permits the indicator element to give a color reaction.
In an alternate embodiment of the invention the glucose in-dilator may comprise an indwelling monitor or the continuous -4- ~685~
measurement of glucose having a variable electrical charge and disposed in registry with the system of body fluid to be monk-toned. The monitor is adapted to measure changes in glucose concentration as a function of changes in electrical charge, and includes a charge-transfer medium wherein the binding macro molecular component is a reversible complex, and the carbohydrate component bears an electrical charge, and thereby comprises a portion ox the indicator element as well. Thus, body fluids capable of passing through the monitor and having increased glucose levels, cause the charge-bearing choirboy-drape to be released to the electrical field of the monitor, with the corresponding increase on the flow of electrical charge, serving to indicate the variation on glucose level of the fluid.
The glucose monitor may comprise an electrode, with an anode and cathode spaced apart from each other, and the electrical charge-transfer medium located i h between. The macro molecular and carbohydrate components, may respectively be selected from those materials specified with reference to the glucose India actor, described above. The charge-bearing carbohydrate come pennants may comprise carbohydrates havlnQ charged substituents bound whereto, and in one embodiment 9 the subunits of carbon hydrate ollgomers may each bear a given unit charge, so that oligomers of differing chain length will offer a charge eon-responding linearly in magnitude Jo the number of recurring carbohydrate units. Also, any incremental changes in electrical charge w~thtn the monitor, resulting from low-level inductive effects, may be easily measured my existing electrical drag-Gnostic equipment, available for measurement of charge differ-entoils of this order. In such way, the electrode may compensate for signal variations that are extraneous to the parameter being measured.
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The present glucose indicators, may thus comprise a color-forming strip, or an electrode, each encased within a semi-permeable membrane, so that the primary components of the indicator, would remain encased while the glucose-bearing body fluid would be capable of passing there through.
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- Specific pectins may be utilized in association with specific carbohydrates, to test for particular sugars present in the body fluid. The glucose indicator may comprise a variety or continuum of such lectin-carbohydrate oligomer complexes, each evidencing a variant indicator reaction responsive to the presence of differences in the identity or concentration of sugars present.
The glucose indicator may be prepared with one of the coupon-ens irreversibly bound to a suitable and insoluble support, and enclosed within a selectively permeable membrane and the final article may assume the form of a strip. A kit is like-wise contemplated comprising the glucose indicator in strip form and a color chart identifying the specific concentrations and identities of the sugars tested for.
I The glucose monitor including the electrode described earlier, may be either implanted alone or in conjunction with appear-private insulin dispensing means or the like. An appropriate current-responsive meter may be selected from equipment avail-able in the art, and specifically calibrated to reflect pro-else changes in glucose concentration.
The present invention offers a simple ye accurate and reliable method for determining glucose concentrations in body fluids, that provides medically significant quantitative identification of glucose. The operation of the present indicator is less subject to variations due Jo time and temperature parameters and is therefore more reliable.
Accordingly, it is a principal object of the present invention to provide a method for measuring glucose levels in animal body fluids.
It is a further object of the present invention to provide a method as aforesaid, which may be utilized either us a con-tenuous monitoring technique, or for periodic measurements.
It is a further object of the present invention to provide a method as aforesaid which yields reliable results.
It is a still further object of the present invention to pro-vise a glucose indicator for periodic glucose level measure-mint, that operates in direct response to the changes in glut cove concentration.
It is a still further object of the present invention to pro vise an indicator as aforesaid, comprising an indwelling glut cove monitor adapted to measure clangs in glucose concentration as a function of changes in electrical charge.
Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing descrip~
Sheehan as well as the ~ollowlng drawings.
FIGURE 1 is a schematic plan view illustrating the spatial relation of the components of the glucose indicator of the present lnventionO
FIGURE 2 is a schematic plan view illustrating the possible construction of a glucose monitor in accordance with the present invention.
The measurement of glucose concentrations in body fluids in accordance with the present invention may be performed on either a periodic basis, or on a continuing bass as described hereinafter. Periodic measurement makes use of a glucose indicator which, when contacted with a sample of the body -Fluid, quantitatively identifies the glucose by means of the reaction of an indicator element such as a dye. In such in-stance, the glucose indicator comprises a reversible complex of a carbohydrate component, a binding macro molecular component and an indicator element associated with one of said components Continuous measurement of glucose concentrations by means of the present invention, makes use of an indwelling glucose monitor that resides in fluid registry with the system of the body fluid under measurement, and measures concentration of glucose as a function of changes in electrical charge. The glucose monitor utilizes a charge-transfer medium comprising a reversible complex of a binding macro-molecular component, and a charge-bearing carbohydrate component that reversibly dissociates from the macro molecular component, to cause a variation in electrical acti~lty within the monitor that may be linearly related to the concentration of glucose in the body fluid.
An ilnportant element of both embodiments of the present invent lion, is the binding macro molecular component. The term "macro molecular component" as utilized herein, refers primarily to molecules that evidence reversible binding capability with other micro- or macromolecules. Examples of molecules meeting the foregoing definition include natural binding proteins, enzymes, regulatory proteins and synthetically modified bind-in molecules, such as chemically modified proteins. Of these the natural proteins known as pectins are preferred herein I
Pectins are carbohydrate-bindin~ proteins of plants and ant-mats that exhibit a variety of specificities for carbohydrates (Lit et at., Ann. Review of Biochemistry, 42, 541 (1973), IT
Goldstein and CUE. Hayes, Ad. in Carbohydrate Chemistry and Biochemistry, Vol. 35, US Tip son and D. Horton, ens.
(Academic Press, New York 1978, pp. 128-341). Pectins, and in particular the pectin known as Concanavalin A, a Jack Bean pectin, exhibit a natural affinity for various sugars which, more particularly, is a function of the number of saccharine subunits of the given sugar. For example, Concanavalin A, which is specific for glucose and muons, will not bind with galactose; particularly, specificity is shown for I-D-mannopyranose and ~-D-glucopyranose.
Other pectins, such as soybean pectins show similar specific-lo lies; thus, soybean lectlns are specific for DUN acetylgalac-Tasmania ant ~-D-galactose units, and wheat germ pectin is specific For DUN acetylglucosamine. The preferred pectin, Concana~alin A, is also observed to have an increased affinity for multiples of glucose up to 6.
The carbohydrate component preferably comprises a sugar, and includes the simple sugars or monosaccharides as well as their low molecular weight condensation polymers, known as the ol~gosaccharides~ that conventionally contain from two to nine monosaccharide units. Many of the sugars are naturally occur-lung, and may be found in animal body fluid. Partlcularly9a carbohydrate component may comprise glucose in the monomeric no oligomeric form; glucose oligomers may include other saccharides such as muons and galactose9 and may be either recovered from nature or synthetically prepared. The naturally occurring oligosaccharides are often associated with protein or lipid fractions, and may be utilized herein in such form.
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- 9 - so The specific carbohydrate component useful in the present in-mention is chosen on the basis of its equivalence in affinity for the formation of the reversible complex with the macro-molecular component, with the material or agent to be detected and measured by the indicators disclosed herein. Thus, for example as the pectin Concanavalin A has an increasing affinity for glucose oligomers with greater numbers of moo-saccharine units; correspondingly, this affinity Gould extend to concentrations of glucose in a fluid sample that would correspond in range. In particular, the corresponding range of glucose concentrations in body fluids lies within the physic logical range of 10 - 400 mg/dl.
Accordingly, a glucose indicator could be prepared as thus-treated in FIGURE 1, with a plurality of pectin molecules, each I disposed on a substrate, and reversibly associated with carbon hydrate components of differing Sue representing a continuum ox saccharine units corresponding to the physiological range of glucose, Relatively low levels of glucose concentration would be unable to displace the higher oligomers, but would readily displace the oligomers of corresponding affinity which in turn would permit the associated indicator element to signify the presence of glucose in that concentration.
The exact operation of the reversible complex is discussed below.
The reversible complex that constitutes the indicator of the embodiment of FIGURE 1, and the electrical charge-transfer medium of the embodiment illustrated in FIGURE 2, comprises a reaction between the macro molecular component and the choirboy-drape component, as generally noted above. This reaction must be reversible and non-covalent. The bonding that occurs between the respective components is caused by non-coYalent forces such as hydrophobic, ionic hydrogen bonding forces and the like. Such interactions are known in the art, and - 1 o- ~%~368S~
their effects on molecular affinity and recognition have been described for example, in Korolkovas_et at., "Essentials of Medicinal Chemistry", pup 44-8l, John Wiley & Sons, l976, and the particular reactions of proteins and carbohydrates has been reviewed in Goldstein, IT Ed., Carbohydrate-Protein Interaction, AS Symposium Series No. 88 ~l979). An example of a reversible interaction is the interaction between an enzyme and its substrate or a competitive inhibitor thereof.
As describe earlier on brief the present reversible complex between the carbohydrate component and the macro molecular come potent operates in a state of dynamic equilibrium, as the ma-tonal in the body fluid being tested for, and the carbohydrate component compete for association with the macro molecular come potent. In the instance where the macro molecular component is a pectin, and the material under test is glucose at certain levels of concentration, the glucose indicator illustrated in FIGURE l, and the charge-transfer medium of the glucose monk-ion illustrated on FIGURE 2, both participate in an equilibrium that arises between the glucose at the particular concentration and the reversible complex bearing a corresponding carbohydrate component, to complex with the pectin.
In the instance of the embodiment of FIGURE lo the displace-mint of the carbohydrate component of a particular reversible complex permits the indicator associated with that complex, to signify the presence of the particular concentration of glucose, preferably by a color-forming reaction. In the instance where the glucose indicator comprises an indwelling monitor, the displacement of the electrical charge-bearing carbohydrate component of a particular reversible complex permits the car-bohydrate to effect the level of electrical charge in the monitor to thereby signify the presence of the particular concentration of glucose.
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Z~1~856 In the instance where a glucose indicator is prepared for the periodic measurement of glucose levels in body fluid, the indicator element may be associated with either the carbohydrate component or the macro molecular component, for the sole function of signifying the dissociation of these components, and the corresponding presence of glucose. In this embodiment, therefore, the indictor component may be a color-forming material such as a dye or a color-forming radical that is freed or otherwise chemically altered by the dissociation of the carbohydrate and the macro molecular come pennants, to produce a color-forming reaction. The indicator element may also include a compound or portion thereof that forms a precipitate upon such dissociation and the invention therefore us not limited to color-formin~ materials exclusively.
For example a dye such as an arylhydrazine may be reacted Thea the reducing end of a carbohydrate oligomer to form a stable addition product such as an arylosazone, which will give a color reaction when the carbohydrate component and the macro molecular component are dissociated. By utilizing dip-fervent hydrazines in combination with different oligomers no-spDnsive to individual concentrations of glucose it is possible to develop a mixture of ligands exhibiting variations in color formation and affinity for particular luckiness, whereby dip-errant concentrations of glucose will cause the formation of differing color reactions. Rerun to FIGURE 1, the disco-scion of different dyes with different chain length oligomers illustrates the manner in which the discrete levels of glucose concentration on fluid samples can be identified.
The indicator element of the first embodiment of the invention, may be associated with the monomolecular component, rather than the carbohydrate component, however, with the same manner of operation. Thus, the specific dyes such as Radiomen, isothiocyanate, 4 Dimethylaminoazobenzene-4'-sulfinyl chloride and the like, that are capable of reacting with proteins, may -12- ~2~68~6 be incorporated onto the macro molecular components In this embodiment, the carbohydrate component, rather than the macro molecular component would be fixedly attached to a substrate and the dissociation ox the carbohydrate and the macro molecular component would set the latter free permitting the attached dye to form its color reaction The disposition of the respective components on the substrate will be disk cussed later on with reference to the preparation of the indicator of the present invention.
In a further embodiment, the indicator element may comprise a particular functional group that may be associated with the carbohydrate or the macro molecular component, and which would be capable of forming the colored complex with an immobilized dye included with the glucose indicator, when the respective component bearing the functional group is displaced For example, a sulfhydryl group may be incorporated into the carbohydrate component, and would, upon its release, react with a number of reagents, such as 5,5l-dithiobis (nutria-benzoic acid), to develop a color.
In general, the method of the present invention comprises contacting the indicators described herein with a quantity of an animal body fluid, and maintaining the indicators in contact with the fluid for a period of time sufficient for the indicators to signify the presence and quint, if any, I ox the maternal- being tested for, in this case glucose. Thus, analysis of body fluid for the presence of glucose may be con-dueled by placing the fluid in contact with the glucose in-dilators, and maintaining such contact for a period of time sufficient to enable the reversible complex between a par-titular macro molecular component and its corresponding carbon hydrate component, to dissociate in favor of a complex involve - in the macro molecular component and the glucose, whether in vitro or in viva, which latter event will be signified by the -13~ 68S6 indicator. In the instance, for example, where the in vitro indicator comprises a pectin such as Concanavalin A reversibly bound to a glucose oligomer bearing a particular dye, the indicator wound be placed in contact with a drop of body fluid which would he maintained in contact with the indicator for a period of time, such as, for example, up to five minutes, whereupon equilibrium between the glucose present and the reversible complex will have been reached, and the indicator element comprising the dye will have given its color reaction.
In the instance where the glucose indicator comprises an in-dwelling monitor or electrode, the monitor may be either temporarily or permanently implanted in the body in registry with the system of body fluid to be measured. The monitor is then electrically connected to appropriate current genera cling and current measuring means. The glucose in the body fluid passing through the monitor competes for the immobilized lect~n, and results in the release of the charge-bearing car-bohydrate to permit the latter to change the electrical charge of the monitor. The reversible nature of the complex permits the charge-bearing carbohydrate to reassociate with the fee-tin, in the instance where the glucose level in the body fluid drops.
The glucose indicator of the embodiment illustrated in FIGURE 1 and the charge-transfer medium of the glucose monitor, thus-treated in FIGURE 2, may both be prepared as follows The particular pectin or pectins chosen for use may be fixed to a suitable insoluble support, such as cellulose, agrees, pies-tic, glass and the like, by either covalent bonding or non-covalent adsorption, The technique of solid state immobilize-lion of enzymes and other proteins on resins, films, test tubes glass beads and the like are well known (see e.g., Zaborsky, C. "Immobilized Enzymes", CRC Press, Cleveland, 1973; Lowe, CUR. and Dean, PUG "The Chemistry of Affinity Chromatog-rough", Affinity Chromatography, John Wiley and Sons, NAY., ~2~1~85~
197~; Axon, et at., US. Patent No. 3,645,852j and Kramer, et at., US. Patent No. 4,039,413). For example, the pectin may be attached to a cellulose support by activation of the support with cyanogen halide, reaction with cyan uric acid, peridot oxidation, epoxide formation, and reaction with various bifunctional reagents, such as bis-ox;nane, dip methyl adipimate, phenol-2, 4-disulfonyl chloride, and divinely cellophane Preferably, a cellulose strip is reacted with cyanogen bromide, and the thus activated cellulose strip is then incubated with Concanavalin A, and the reaction later stopped by -the addition thereto of Gleason.
With respect to the indicator illustrated in FIGURE 1, it is to be understood that this embodiment includes the instance where the carbohydrate component is anchored to a substrate by techniques equally well known in the art, so that the various moo- and oli~osaccharides may be permanently bound to the substrate and reversibly associated with the respective pectins.
As noted earlier, the specific carbohydrate components may be either recovered from nature or synthetically prepared. Par-titular carbohydrates may be prepared by, for example limited acid hydrolysis of manning to form oligomers of varying length which are then separable by chromatography, to recover the specific oligosaccharides.
In the instance where the in vitro indicator of FIGURE 1 is being prepared, the carbohydrate components recovered above may either be fixedly bound to the substrate, or reacted with various dyes to form the conjugates illustrated schematically in FIGURE 1. Thus oligomers of varying chain length may bear different dyes as illustrated, and as described in detail earlier.
Sue In the instance where the charge transfer medium of the em-bodiment of FIGURE 2 is under preparation the recovered carbohydrate components may be treated to dispose one or more charges thereon. In particular, ionic charges may be disk posed on the carbohydrates by reacting appropriate substitu-ens or moieties with either the hydroxyl groups of the car-bohydrates, or the alluded group disposed at the reducing end of the carbohydrate A variety of substituents having negative charges could be so introduced, as follows:
3 2 ,, SHEA CH2-N-CH2-CH3, or arylhydraz;nes of variant negative or positive charge. Naturally, the fore-going substituents are merely illustrative of those materials that might be reacted with the carbohydrate components to achieve the ionic or charged state, as the invention encom-passes all equivalent substituents that are non-toxic to the body fluid within its scope Once both of the components are prepared, the carbohydrate and macro molecular components are brought into contact with each other, and establish the reversible complexes described earlier with respect to each of the embodiments of the present invention. Thus, for example, the glucose indicator of FIG-USE 1 may be prepared in strip form, and, after the reversible complexes are formed, may be cowered with a semi-permeable membrane designed to permit glucose and the dye-car'Dohydrate complex to diffuse readily here through In such instance, a variety of semi-permeable membranes are well known and may be used for in vitro testing equipment of this type, and in-elude several natural and synthetic resinous materials evidence in pore size, etc., conducive to this application.
Referring again to FIGURE 1, the schematically illustrated strip would be placed in contact with the fluid sample, with the pores of the membrane sufficiently large to permit the ~16-?685~
passage of glucose there through to compete for the formation of a reversible complex with the support-bound pectin. Upon the displacement of the carbohydrate component by the glucose, the dye, such as "Dye 1", would be free to form a color react lion to signify it displacement, to indicate the concentration of the glucose in the investigated body fluid.
The indicator described with reference to FI-GU~F 1, could be prepared as part of a kit, including the indicator in strip form, together with a suitable color chart providing a spectrum of colors, and their quantitative or qualitati Ye so gnificance, to facilitate the rapid analysis of test results. Thus, a series of colors would be outlined that would denote portico-far glucose concentration levels to enable the user of the kit to rapidly determine glucose levels from the color reaction of the indicator strip The simplicity of this kit would facile-late its use by both trained medical staff, as jell as the patients themselves.
The preparation and use of the glucose monitor comprising the alternate embodiment of the present invention, may be under-stood with reference to FIGURE 2. Thus, a monitor is schematic gaily illustrated comprising eleckrode`10, having a housing 12 with an anode 14 and a cathode 16 mounted inside, and in spaced apart relation to each other. As the present illustration is schematic, it can be visualized that conventional means for external electrical connection can be provided to interface with anode 14 and cathode 16, to provide means for current air-culation and measurement in conjunction with an appropriate source of electric current, and current metering means, not shown, which may be cnnnecteJ to electrode I in electrical series therewith.
In accordance with conventional electrode construction, a source of electrical current transfer is disposed within -17- ~ZGG~6 housing 12, to permit the passage of charge between anode 14 and cathode 16. In the present electrode, this charge source may comprise in whole or in part, electrical charge-transfer medium 18, which, as schematically illustrated, comprises a segment of immobilized macro molecular material such as a lectln, that is either bound to a solid substrate, or is itself polymerized and solidified. The lect;n 20 may have attached thereto one or more charge-bearing carbohydrates such as thus-treated at I Carbohydrate 22 is shown with recurring succor-ire units that bear negatively charged substituents 24. Sub-stituents 24 may comprise negatively charged moieties that may be chemically attached to the respective carbohydrate by reaction either with one or more of the hydroxyl groups of the carbohydrate, or by attachment of the moiety to the aide-I Hyde at the reducing end thereof. Also, the charge of a given carbohydrate subunit may vary from that of other subunits, to give further differentiation an specificity to particular glut cove fractions in the body fluid. In this way, further refine-mint of the electrical charge-transfer medium is possible, to define both quantitatively and qualitatively, the presence of particular sugars in body fluids. The preparation of the charge-bearing carbohydrate components in this fashion, is described earlier herein.
In similar fashion to the preparation of the indicator of FIGURE 1, the charge-transfer medium 18 may be prepared with a continuum of charge-bear~ng carbohydrates 22, each carbon hydrate having a differing subunit number and a correspondingly different magnitude of charge. Likewise, carbohydrates of differing composition, i.e. variant saccharides, may be bound to the same lectln 20, to provide a wide spectrum of glucose detection.
Referring again to FIGURE 2, housing 12 provides a means for the passage there through of the body fluid, to permit the ingress and egress of glucose, schematically illustrated and labeled 26. To this end, a membrane 28 may be provided, sun-rounding all or a portion of housing 12, to provide selective permeability fac;l;tat;ng the free movement there through of glucose.
A variety of polymeric materials may be utilized to prepare membrane 28, and such materials may exhibit selectivity based upon differentials in porosity, as well as surface charge. In such instance, the polymeric materials may form into the mom-brine, bearing the desired surface charge, or the formed mom-brine may subsequently be treated Jo provide such charge thereon.
Suitable polymeric materials may be selected from positively charged and negatively charged materials, as well as materials possessing both positive and negative charge. For example, positively charged materials may comprise polyvinyl pardon;
negatively charged materials may be selected from polyacrylic acid and polyethylene terephthalate; and a polymeric material possessing a combined positive and negative charge may comprise a polystyrene sulfonate-vinylbenzyl trim ethyl ammonium color-ire copolymer. Naturally, the foregoing materials are merely illustrative of suitable polymers that may be utilized in preparation of membrane 28, and the invention is accordingly I not limited to these specific materials, but rather encompasses those materials possessing the requisite porosity and charge capability set forth above.
As noted earlier, charge-transfer medium 18, including pectin 20 and charge-bearing carbohydrates 22 may be prepared generally in the same manner outlined with respect to the embodiment of -19- Sue FIGURE 1. Thus after the individual pectins 20 are fixed to a suitable insoluble support, and the particular charge-bearing carbohydrates 22 are prepared, these respective come pennants may be brought in contact with each other to establish the desired reversible complexes of medium 18. After the formation of these reversible complexes, medium 18 may be mounted within housing 12, between anode 14 and cathode 16 as illustrated. Housing 12 may then be covered with membrane 28 to complete the assembly of monitor 10.
The operation of monitor 10 in the corresponding method for continuously measuring glucose levels of an in viva basis comprises the implantation of the monitor within the body of the animal, and in registry with the system of body fluids to be observed As mentioned earlier the monitor may remain implanted either temporarily or indefinitely, and may be elect tribally connected to current generating and measuring means, to provide a calibrated continuous indication of glucose levels.
As noted earlier, the current measuring means or gauge may be appropriately calibrated, so that specific incremental vane-lions in glucose level may be noted and appropriate remedial action taken. In such connection, the present invention may be utilized in combination with an appropriate dispensing means, for the automatic administration of an anteed such as ins-fin, in the instance where the present invention is applied to US a d~abetlc condition by fluid registry with the bloodstream As the present monitor will be required to operate in fluid media containing a variety of ions other than those that exist or may be fornled by the action of the present charge-transfer medium, one or more reference electrodes may be appropriately linked to the monitor for the purpose of detecting ions that are unrelated to the function of the monitor. For example, such electrodes may sense the presence of inorganic ions having Jo ` ~L2~S6 it no relation to the level of glucose, and could provide eon-recta on to the present monitor Jo avoid false indication of increased glucose levels. Linkage ox these reverence electrodes is well known, and may be accomplished by connection in a Whetstone Bridge arrangement or equivalent disposition, -to permit the reference electrodes to provide the needed cornea-lion. The particular form of such connection does not form a part of the present invention. ; `
The invention may be embodied in other forms or carried out in other ways without departing from the spirit or essential char-acterlstics thereof. The present invention lo therefore to be considered as in all respects illustrative and no restrict live, the scope of the invention being indicated by the appended claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein, .
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Claims (38)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method for measuring the level of glucose in animal body fluids comprising placing a sample of said body fluid in contact with a glucose indicator, said indicator com-prising a reversible complex of a carbohydrate component, a binding macromolecular component and an indicator element associated with one of said components, maintain-ing said body fluid in contact with said glucose indicator for a period of time sufficient for any glucose present in said body fluid to displace said carbohydrate component in a complex with said binding macromolecular component, and for said indicator element to be released thereby to signify the presence and level of said glucose.
2. The method of Claim 1 wherein said glucose indicator is provided in strip form.
3. The method of Claim 1 wherein said glucose indicator comprises an indwelling glucose monitor adapted for con-tinuous, in vivo measurement of said glucose level.
4. The method of Claim 2 including removing excess body fluid from said indicator after said indicator element is released.
5. The method of Claim 1 wherein said binding macro-molecular component comprises a binding protein, said carbohydrate component comprises a sugar selected from the group consisting of monosaccharides, oligosaccharides and mixtures thereof, and said indicator element is selected from the group consisting of color-forming materials capable of forming precipitates, and mixtures thereof.
6. The method of Claim 2 wherein said binding macro-molecular component comprises a binding protein, said carbohydrate component comprises a sugar selected from the group consisting of monosaccharides, oligosaccharides and mixtures thereof, and said indicator element is selected from the group consisting of color-forming materials capable of forming precipitates, and mixtures thereof.
7. The method of Claim 3 wherein said binding macro-molecular component comprises a binding protein, said carbohydrate component comprises a sugar selected from the group consisting of monosaccharides, oligosaccharides and mixtures thereof, and said indicator element is selected from the group consisting of color-forming materials capable of forming precipitates, and mixtures thereof.
8. The method of Claim 5, Claim 6 or Claim 7 wherein said binding macromolecular component is fixedly attached to an inert, insoluble substance, said carbo-hydrate component is bound thereto in said reversible complex, and said indicator element is bonded to said carbohydrate component.
9. The method of Claim 2 including the further step of comparing the activity of said indicator element after release with the results of comparative tests of said indicator element associated with given levels of said glucose.
10. The method of Claim 9 wherein said indicator element is a plurality of different color-forming materials, and said comparative tests are disposed on said color-forming materials with specific concentra-tions of said glucose.
11. The method of Claim 3 wherein said glucose monitor includes a charge-transfer medium comprising a rever-sible complex of a binding macromolecular component, and a charge-bearing carbohydrate component, said reversible complex adapted to react with said glucose to change the level of electrical charge sensed by said glucose monitor;
said glucose monitor is placed in fluid registry with the system of body fluid of said animal, for which glucose level measurement is to be made;
said monitor is maintained in fluid registry with said system for a period of time sufficient for said body fluid to permeate said monitor, and for any glucose present in said body fluid to react with said reversible complex; and said glucose level is measured by measuring the level of electrical charge sensed by said monitor, said level of electrical charge varying as a function of the con-centration of said glucose.
said glucose monitor is placed in fluid registry with the system of body fluid of said animal, for which glucose level measurement is to be made;
said monitor is maintained in fluid registry with said system for a period of time sufficient for said body fluid to permeate said monitor, and for any glucose present in said body fluid to react with said reversible complex; and said glucose level is measured by measuring the level of electrical charge sensed by said monitor, said level of electrical charge varying as a function of the con-centration of said glucose.
12. A method for the continuous in vivo measurement of glucose in animal body fluids comprising:
A. preparing an indwelling glucose monitor adapted to electrically sense variations in the concentration of said glucose in said body fluid, said glucose monitor including a charge-transfer medium comprising a rever-sible complex of a binding macromolecular component, and a charge-bearing carbohydrate component, said reversible complex adapted to react with said glucose to change the level of electrical charge sensed by said glucose monitor;
B. placing said glucose monitor in fluid registry with the system of body fluid to be monitored;
C. maintaining said glucose monitor in fluid registry with said system for a period of time sufficient for said body fluid to permeate said glucose monitor, and for any glucose present in said body fluid to react with said reversible complex, and D. measuring the level of electrical charge sensed by said glucose monitor;
wherein said level of electrical charge varies as a function of the concentration of said glucose, and said monitor is adapted to continually measure variations therein.
A. preparing an indwelling glucose monitor adapted to electrically sense variations in the concentration of said glucose in said body fluid, said glucose monitor including a charge-transfer medium comprising a rever-sible complex of a binding macromolecular component, and a charge-bearing carbohydrate component, said reversible complex adapted to react with said glucose to change the level of electrical charge sensed by said glucose monitor;
B. placing said glucose monitor in fluid registry with the system of body fluid to be monitored;
C. maintaining said glucose monitor in fluid registry with said system for a period of time sufficient for said body fluid to permeate said glucose monitor, and for any glucose present in said body fluid to react with said reversible complex, and D. measuring the level of electrical charge sensed by said glucose monitor;
wherein said level of electrical charge varies as a function of the concentration of said glucose, and said monitor is adapted to continually measure variations therein.
13. The method of Claim 12 wherein said charge-bearing carbohydrates are retained within said glucose monitor, to enable said glucose monitor to sense reductions in said glucose concentration, and to perform said con-tinual measurement.
14. The method of Claim l? wherein, in accordance with Step B, said glucose monitor is implanted within the body of said animal.
15. The method of Claim 14 wherein said glucose monitor is permanently maintained in fluid registry with said system, and said monitor continually measures variations in the concentration of said glucose.
16. The method of Claims 12, 13 or 14 wherein said glucose concentration is measured with reference to a current-responsive meter calibrated for such purpose.
17. The method of Claim 12 wherein said glucose monitor comprises an electrode having an anode, a cathode spaced apart therefrom, and said electrical charge-transfer medium disposed therebetween.
18. The method of Claims 12 or 17 wherein said charge-bearing carbohydrate component is retained within said monitor by a selectively permeable membrane.
19. The method of Claim 12 wherein said binding macro-molecular component comprises a binding protein, said charge-bearing carbohydrate component comprises a sugar having an ionic charge disposed thereon, said sugar selected from monosaccharides, oligosaccharides, and mixtures thereof.
20. The method of Claim 17 wherein said binding macro-molecular component comprises a binding protein, said charge-bearing carbohydrate component comprises a sugar having an ionic charge disposed thereon, said sugar selected from monosaccharides, oligosaccharides, and mixtures thereof.
21. The method of Claim 12 or Claim 20 wherein said binding macromolecular component is fixedly attached to an inert, insoluble substance, and said charge-bearing carbohydrate component is bound to said macromolecular component in a reversible complex.
22. The method of Claim 12 wherein said charge-bearing carbohydrate component has bound thereto, at least one ionic substituent.
23. The method of Claim 17 wherein said charge-bearing carbohydrate component has bound thereto, at least one ionic substituent.
24. A glucose monitor for the continuous, in vivo meas-urement of glucose in animal body fluids comprising:
A. an electrode adapted to electrically sense varia-tions in the concentration of said glucose in said body fluid;
B. said electrode including a charge-transfer medium comprising a reversible complex of a binding macromolecular component, and a charge-bearing carbohydrate component;
C. said reversible complex adapated to react with said glucose to change the level of electrical charge sensed by said electrode, to thereby indicate corresponding varia-tions in said glucose concentration.
A. an electrode adapted to electrically sense varia-tions in the concentration of said glucose in said body fluid;
B. said electrode including a charge-transfer medium comprising a reversible complex of a binding macromolecular component, and a charge-bearing carbohydrate component;
C. said reversible complex adapated to react with said glucose to change the level of electrical charge sensed by said electrode, to thereby indicate corresponding varia-tions in said glucose concentration.
25. The monitor of Claim 24 wherein said electrode comprises:
A. an electrode housing;
B. an anode and a cathode mounted in said housing and spaced apart from each other; and C. said charge-transfer material disposed between said anode and said cathode.
A. an electrode housing;
B. an anode and a cathode mounted in said housing and spaced apart from each other; and C. said charge-transfer material disposed between said anode and said cathode.
26. The monitor of Claim 25 wherein said electrode is enclosed within a membrane selectively permeable to said body fluid and adapted to permit the passage therethrough of said glucose, but to prevent the passage therethrough of said charge-bearing carbohydrate.
27. The monitor of Claim 26 wherein said selectively permeable membrane is porous, and defines a pore size limit-ing passage therethrough to said body fluid, and said glucose.
28. The monitor of Claim 27 wherein said selectively permeable membrane defines a surface charge thereon, to pre-vent the egress from said electrode, of said charge-bearing carbohydrate.
29. The monitor of Claims 24, 25 or 26 wherein said binding macromolecular component is selected from the group consisting of natural binding proteins, synthetic binding proteins and mixtures thereof.
30. The monitor of Claim 24 wherein said charge-bearing carbohydrate component comprises a sugar having one or more reactive sites thereof bound to an ionic substituent, said sugar selected from the group consisting of monosaccharides, oligosaccharides, and mixtures thereof.
31. The monitor of Claim 24 wherein said ionic sub-stituent is selected from the group consisting of -SO3-: CH2-CH3; arylhydrazincs having electrically charged substit-uents; and mixtures thereof.
32. The monitor of Claim 24 wherein said charge-bearing carbohydrate component comprises a sugar having one or more reactive sites thereof bound to an ionic substituent, said sugar selected from the group consisting of monosaccharides, oligosaccharides, and mixtures thereof.
33. The monitor of Claim 24 wherein said binding macromolecular component comprises one or more lectins, and said charge-bearing carbohydrate component comprises monosac-charides and oligosaccharides containing a material selected from the group consisting of glucose, mannose and mixtures thereof.
34. The monitor of Claim 33 wherein said binding mac-romolecular component comprises Concanavalin A, and said oligosaccharides contain up to about 6 monosaccharide units.
35. The monitor of Claims 24, 25 or 26 wherein said re-versible complex is affixed to an inert, insoluble substrate.
36. The monitor of Claim 25 wherein said reversible complex is affixed to an inert, insoluble substrate.
37. The monitor of Claim 26 wherein said reversible complex is affixed to an inert, insoluble substrate.
38. The monitor of Claim 36 or Claim 37.
wherein said substrate is prepared from a material selected from the group consisting of natural and synthetic resins, ceramic materials, and mixtures thereof.
wherein said substrate is prepared from a material selected from the group consisting of natural and synthetic resins, ceramic materials, and mixtures thereof.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/241,991 US4330299A (en) | 1981-03-09 | 1981-03-09 | Article and method for measuring glucose level in body fluids |
| US241,991 | 1981-03-09 | ||
| US343,128 | 1982-01-27 | ||
| US06/343,128 US4436094A (en) | 1981-03-09 | 1982-01-27 | Monitor for continuous in vivo measurement of glucose concentration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1206856A true CA1206856A (en) | 1986-07-02 |
Family
ID=26934751
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000397815A Expired CA1206856A (en) | 1981-03-09 | 1982-03-08 | Method and associated materials for measuring glucose level in body fluids |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US4436094A (en) |
| EP (1) | EP0060133B1 (en) |
| AU (1) | AU545134B2 (en) |
| CA (1) | CA1206856A (en) |
| DE (1) | DE3276969D1 (en) |
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| US3615228A (en) * | 1969-11-20 | 1971-10-26 | Dow Chemical Co | Glucose determination method employing orthotoluidine |
| US4348387A (en) * | 1979-07-31 | 1982-09-07 | The Rockefeller University | Method and system for the controlled release of biologically active substances to a body fluid |
| US4436094A (en) * | 1981-03-09 | 1984-03-13 | Evreka, Inc. | Monitor for continuous in vivo measurement of glucose concentration |
-
1982
- 1982-01-27 US US06/343,128 patent/US4436094A/en not_active Expired - Fee Related
- 1982-03-08 CA CA000397815A patent/CA1206856A/en not_active Expired
- 1982-03-09 AU AU81204/82A patent/AU545134B2/en not_active Ceased
- 1982-03-09 DE DE8282301188T patent/DE3276969D1/en not_active Expired
- 1982-03-09 EP EP82301188A patent/EP0060133B1/en not_active Expired
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| US4436094A (en) | 1984-03-13 |
| EP0060133B1 (en) | 1987-08-12 |
| AU8120482A (en) | 1982-09-23 |
| AU545134B2 (en) | 1985-07-04 |
| DE3276969D1 (en) | 1987-09-17 |
| EP0060133A1 (en) | 1982-09-15 |
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