(12) United States Patent
`Bonnecaze et al.
`
`I 1111111111111111 11111 lllll lllll 111111111111111 1111111111 1111111111 11111111
`US006579690B 1
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,579,690 Bl
`Jun.17,2003
`
`(54) BLOOD ANALYTE MONITORING
`THROUGH SUBCUTANEOUS
`MEASUREMENT
`
`(75)
`
`Inventors: Roger T. Bonnecaze, Austin, TX (US);
`Angela C. Freeland, Austin, TX (US)
`
`(73) Assignee: TheraSense, Inc., Alameda, CA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.:
`
`09/530,938
`
`(22) PCT Filed:
`
`Oct. 4, 1998
`
`(86) PCT No.:
`
`PCT/US98/25685
`
`§ 371 (c)(l),
`(2), ( 4) Date:
`
`Jul. 24, 2000
`
`(87) PCT Pub. No.: WO99/29230
`
`PCT Pub. Date: Jun. 17, 1999
`
`Related U.S. Application Data
`(60) Provisional application No. 60/067,603, filed on Dec. 5,
`1997, and provisional application No. 60/067,601, filed on
`Dec. 5, 1997.
`Int. Cl.7 .................................................. C12Q 1/54
`(51)
`(52) U.S. Cl. .............................. 435/14; 435/4; 435/817
`(58) Field of Search ................................ 435/14, 4, 28,
`435/817
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,953,552 A * 9/1990 DeMarzo
`
`OTHER PUBLICATIONS
`
`Schmidtke et al. (1998). Measurement and modeling of the
`transient difference between blood and subcutaneous glu(cid:173)
`cose concentrations in the rat after injection of insulin.
`PNAS 95: 294-299.*
`Baker et al. (1996). Dynamic delay and maximal dynamic
`error in continuous biosensors. Anal Chem 68 (8): 1292-7. *
`Fraser, D., "An Introduction To In Vivo Biosensing:
`Progress and Problems", Biosensors In The Body: Continu(cid:173)
`ous In Vivo Monitoring, pp. 1-56 (1997).
`Jansson, P. et al., "Characterization By Microdialysis Of
`Intercellular Glucose Level In Subcutaneous Tissue In
`Humans",Am. J. Physiol., vol. 255, No. 2, pp. E218-E220
`(1988).
`Meyerhoff, C. et al., "On Line Continuous Monitoring Of
`Subcutaneous Tissue Glucose In Men By Combining Por(cid:173)
`table Glucosensor With Microdialysis", Diabetologia, vol.
`35, No. 11, pp. 1087-1092 (1992).
`Pfeiffer, E., et al., "On Line Continuous Monitoring Of
`Subcutaneous Tissue Glucose Is Feasible By Combining
`Portable Glucosesensor With Microdialyis", Hormone and
`Metabolic Research, vol. 25, pp. 121-124 (1993).
`
`Pickup, J. et al., "In Vivo Molecular Sensing In Diabetes
`Mellitus: An Implantable Glucose Sensor With Direct Elec(cid:173)
`tron Transfer", Diabetologia, vol. 32, pp. 213-217 (1989).
`Quinn, C. et al., "Kinetics Of Glucose Delivery To Subcu(cid:173)
`taneous Tissue In Rats Measured with 0.3-mm Amperomet(cid:173)
`ric Microsensors", Am. J. Physiol., vol. 269, No. 1, pp.
`E155-E161 (1995).
`Schmidt, F. et al., "Glucose Concentration In Subcutaneous
`Extracellular Space", Diabetes Care, vol. 16, pp. 695-700
`(1993).
`Schwilden, H. et al., "A Pharmacokinetic Model Identifica(cid:173)
`tion And Parameter Estimation As An Ill-Posed Problem",
`Eur. J. Clin. Pharmacol., vol. 45, No. 6, pp. 545-550 (1993).
`Sparacino, G. et al., "Stochastic Deconvolution Method To
`Reconstruct Insulin Secretion Rate After A Glucose Stimu(cid:173)
`lus", IEEE Trans. on Biomed. Eng., vol. 43, No. 5, pp.
`512-529 (1996).
`Sternberg, F. et al., "Letters To The Editor: Comments On
`Subcutaneous Glucose Monitoring", Diabetologia, vol. 37,
`No. 5, pp. 540---541 (1994).
`Thome-Duret, V. et al., "Use Of A Subcutaneous Glucose
`Sensor To Detect Decreases In Glucose Concentration Prior
`To Observation in Blood", Anal. Chem., vol. 68, pp.
`3822-3826 (1996).
`Velho, G. et al., "Determination Of Peritoneal Glucose
`Kinetics In Rats: Implications For The Peritoneal Implan(cid:173)
`tation Of Closed-Loop Insulin Delivery Systems", Diabe(cid:173)
`tologia, vol. 32, pp. 331-336 (1989).
`
`* cited by examiner
`
`Primary Examiner-Ralph Gitomer
`(74) Attorney, Agent, or Firm-Merchant & Gould P.C.
`
`(57)
`
`ABSTRACT
`
`One embodiment of the invention is a method for obtaining
`an estimate of an analyte concentration in a first fluid. First,
`measurements of an analyte concentration in a second fluid
`are obtained using a sensing device. An analyte concentra(cid:173)
`tion estimate in the first fluid is determined from these
`measurements by minimizing the relation: fl:b ]=x2[b ]+A 1P
`[b ], where b is a vector representing analyte concentration in
`the first body fluid, X2[b] is a function representing a fit
`between the estimates and the measurements, A is a weight(cid:173)
`ing function, and W[b] is a function indicating smoothness
`of the analyte concentration estimates in the first fluid.
`Another embodiment includes a sensing device for obtaining
`the measurements of an analyte concentration in the first
`fluid and a processor configured and arranged to determine
`the analyte concentration in the first body fluid according to
`this method. This method and device can be used, for
`example, to determine blood glucose concentration from
`measurements of the glucose concentration in subcutaneous
`tissue. These measurements may be made using in vitro or
`in vivo samples. In some instances, a subcutaneously
`implanted sensing device, such as electrochemical sensor, is
`used to make the measurements.
`
`15 Claims, 39 Drawing Sheets
`
`Page 1 of 79
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`

`

`US 6,579,690 Bl
`
`1
`BLOOD ANALYTE MONITORING
`THROUGH SUBCUTANEOUS
`MEASUREMENT
`
`2
`body fluid using analyte concentration measurements from a
`second body fluid. In particular, the present invention
`includes methods and devices for the determination of blood
`glucose concentration using glucose concentration measure(cid:173)
`s ments from subcutaneous fluids.
`One embodiment of the invention is a method for obtain-
`ing an estimate of an analyte concentration in a first fluid.
`First, measurements of an analyte concentration in a second
`fluid are obtained using a sensing device. An analyte con(cid:173)
`centration estimate in the first body fluid is determined from
`these measurements by minimizing the relation:
`
`10
`
`This application is a 371 of PCT/US98/25685 filed Oct.
`4, 1998 which claims benefit of provisional applications
`60/067,603 and 60/067,601, both filed Dec. 5, 1997.
`The present invention is, in general, directed to devices
`and methods for the monitoring of the concentration of an
`analyte, such as glucose, using a subcutaneous sensor. More
`particularly, the present invention relates to devices and
`methods for the monitoring of an analyte using a subcuta(cid:173)
`neous electrochemical sensor to provide information to a
`patient about the level of the analyte in blood.
`BACKGROUND OF THE INVENTION
`The monitoring of the level of analytes, such as glucose,
`lactate or oxygen, in certain individuals is vitally important
`to their health. High or low levels of these analytes may have
`detrimental effects. For example, the monitoring of glucose
`is particularly important to individuals with diabetes, as they
`must determine when insulin is needed to reduce glucose
`levels in their bodies or when additional glucose is needed
`to raise the level of glucose.
`A variety of methods have been used to measure analyte
`concentrations. For example, colorimetric, electrochemical,
`and optical methods have been developed for the determi(cid:173)
`nation of blood glucose concentration. Implanted electro(cid:173)
`chemical sensors may be used to periodically or continu(cid:173)
`ously monitor glucose ( or other analyte) concentration.
`Although sensors accurately measure the glucose concen(cid:173)
`tration when inserted directly into the bloodstream, infection 30
`may occur at this implantation site.
`A variety of sensors have been developed for implantation
`in subcutaneous tissue to measure the subcutaneous glucose
`concentration, which is thought to be well correlated with
`the blood glucose concentration at steady-state. Subcutane(cid:173)
`ously implanted glucose sensors, such as miniaturized elec(cid:173)
`trodes "wired" to glucose oxidase, are one technology that
`hold promise for continuous monitoring of blood glucose
`levels by diabetic patients. These sensors measure subcuta(cid:173)
`neous glucose concentrations as glucose diffuses from the
`blood into the subcutaneous tissue and then to the enzyme
`electrode surface. At this surface, the glucose is oxidized and
`the reaction causes electrons to be transferred to the elec(cid:173)
`trode surface. The resulting current is proportional to the
`concentration of glucose in the region of implantation.
`In many cases, it is important to be able to convert a value
`from a subcutaneous concentration to a blood concentration.
`For example, a subcutaneous sensor may be calibrated using
`blood measurements or a diagnosis or method of treatment
`may depend on the knowledge of the blood analyte concen(cid:173)
`tration that is obtained using a subcutaneous sensor.
`However, a lag typically results between the blood and
`subcutaneous glucose concentrations as the blood glucose
`level increases or decreases. In addition, the subcutaneous
`analyte concentrations obtained from sensor measurements
`may be different from the blood analyte concentration
`because of the existence of a mass transfer barrier. Thus,
`there is a need to develop devices and methods that can
`convert subcutaneous analyte measurements to blood ana(cid:173)
`lyte concentrations to ensure accuracy, compatibility, and 60
`comparability between measurements made by subcutane(cid:173)
`ous electrochemical sensors and those made using other
`conventional blood analysis techniques.
`
`where b is a vector representing analyte concentration in the
`15 first fluid, x2[b] is a function representing a fit between the
`estimates and the measurements, A is a weighting function,
`and 1P[b] is a function indicating smoothness of the analyte
`concentration estimates in the first body fluid. Another
`embodiment includes a sensing device for obtaining the
`20 measurements of analyte concentration in the first fluid and
`a processor configured and arranged to determine the analyte
`concentration according to this method.
`This method and device can be used, for example, to
`determine blood glucose concentration from measurements
`25 of the glucose concentration in subcutaneous tissue. These
`measurements may be made using in vitro or in vivo
`samples. In some instances, a subcutaneously implanted
`sensing device, such as an electrochemical sensor, is used to
`make the measurements.
`Another embodiment is a method of determining blood
`analyte concentration including obtaining a subcutaneous
`analyte concentration from a subcutaneous region using a
`sensing device and determining a blood analyte concentra(cid:173)
`tion from the subcutaneous analyte concentration based on
`35 a) mass transfer of the analyte from blood to the subcuta(cid:173)
`neous region and b) uptake of the analyte by subcutaneous
`cells in the subcutaneous region. Examples of analytes
`include glucose, lactate, and oxygen. Yet another embodi(cid:173)
`ment is an analyte measurement device including a proces-
`40 sor configured and arranged to determine the analyte con(cid:173)
`centration according to this method and an optical sensing
`device, such as an electrochemical sensor, for obtaining the
`measurements of analyte concentration in the first fluid. In
`some instances, the electrochemical sensor may be subcu-
`45 taneously implanted and the analyte measurement device
`may periodically or continuously monitor glucose.
`The above summary of the present invention is not
`intended to describe each disclosed embodiment or every
`implementation of the present invention. The Figures and
`50 the detailed description which follow more particularly
`exemplify these embodiments.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The invention may be more completely understood in
`55 consideration of the following detailed description of vari(cid:173)
`ous embodiments of the invention in connection with the
`accompany drawings, in which:
`FIG. 1 is a block diagram of one embodiment of a
`subcutaneous analyte monitor using a subcutaneously
`implantable analyte sensor, according to the invention;
`FIG. 2 is a top view of one embodiment of an analyte
`sensor, according to the invention;
`FIG. 3Ais a cross-sectional view of the analyte sensor of
`65 FIG. 2;
`FIG. 3B is a cross-sectional view of another embodiment
`of an analyte sensor, according to the invention;
`
`SUMMARY OF THE INVENTION
`Generally, the present invention relates to methods and
`devices for determination of analyte concentration in one
`
`Page 2 of 79
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`US 6,579,690 Bl
`
`3
`FIG. 4A is a cross-sectional view of a third embodiment
`of an analyte sensor, according to the invention;
`FIG. 4B is a cross-sectional view of a fourth embodiment
`of an analyte sensor, according to the invention;
`FIG. 5 is an expanded top view of a tip portion of the
`analyte sensor of FIG. 2;
`FIG. 6 is a cross-sectional view of a fifth embodiment of
`an analyte sensor, according to the invention;
`FIG. 7 is an expanded top view of a tip-portion of the 10
`analyte sensor of FIG. 6;
`FIG. 8 is an expanded bottom view of a tip-portion of the
`analyte sensor of FIG. 6;
`FIG. 9 is a side view of the analyte sensor of FIG. 2;
`FIG. 10 is a top view of the analyte sensor of FIG. 6;
`FIG. 11 is a bottom view of the analyte sensor of FIG. 6;
`FIG. 12 is an expanded side view of one embodiment of
`a sensor and an insertion device, according to the invention;
`FIGS. 13A, 13B, 13C are cross-sectional views of three 20
`embodiments of the insertion device of FIG. 12;
`FIG. 14 is a cross-sectional view of one embodiment of a
`on-skin sensor control unit, according to the invention;
`FIG. 15 is a top view of a base of the on-skin sensor
`control unit of FIG. 14;
`FIG. 16 is a bottom view of a cover of the on-skin sensor
`control unit of FIG. 14;
`FIG. 17 is a perspective view of the on-skin sensor control
`unit of FIG. 14 on the skin of a patient;
`FIG. 18A is a block diagram of one embodiment of an
`on-skin sensor control unit, according to the invention;
`FIG. 18B is a block diagram of another embodiment of an
`on-skin sensor control unit, according to the invention;
`FIGS. 19A, 19B, 19C, and 19D are cross-sectional views 35
`of four embodiments of conductive contacts disposed on an
`interior surface of a housing of an on-skin sensor control
`unit, according to the invention;
`FIGS. 19E and 19F are cross-sectional views of two
`embodiments of conductive contacts disposed on an exterior
`surface of a housing of an on-skin sensor control unit,
`according to the invention;
`FIGS. 20A and 20B are schematic diagrams of two
`embodiments of a current-to-voltage converter for use in an
`analyte monitoring device, according to the invention;
`FIG. 21 is a block diagram of one embodiment of an open
`loop modulation system for use in an analyte monitoring
`device, according to the invention;
`FIG. 22 is a block diagram of one embodiment of a 50
`receiver/display unit, according to the invention;
`FIG. 23 is a front view of one embodiment of a receiver/
`display unit;
`FIG. 24 is a front view of a second embodiment of a
`receiver/display unit;
`FIG. 25 is a block diagram of one embodiment of a drug
`delivery system, according to the invention;
`FIG. 26 is a perspective view of the internal structure of
`an insertion gun, according to the invention;
`FIG. 27A is a top view of one embodiment of an on-skin
`sensor control unit, according to the invention;
`FIG. 27B is a top view of one embodiment of a mounting
`unit of the on-skin sensor control unit of FIG. 27A;
`FIG. 28A is a top view of another embodiment of an 65
`on-skin sensor control unit after insertion of an insertion
`device and a sensor, according to the invention;
`
`4
`FIG. 28B is a top view of one embodiment of a mounting
`unit of the on-skin sensor control unit of FIG. 28A;
`FIG. 28C is a top view of one embodiment of a housing
`for at least a portion of the electronics of the on-skin sensor
`5 control unit of FIG. 28A;
`FIG. 28D is a bottom view of the housing of FIG. 28C;
`FIG. 28E is a top view of the on-skin sensor control unit
`of FIG. 28A with a cover of the housing removed;
`FIG. 29 is another embodiment of an analyte sensor;
`FIG. 30 is a graph of experimental data (smooth line)
`from a rat during an intravenous insulin injection and a
`prediction using an inverse model with no regularization
`( oscillating line);
`FIG. 31 is a graph of simulated blood glucose response
`(solid line) and three models used to simulate subcutaneous
`glucose response including a) kr=O, b) kr=l, K,,,=B)3, and
`c) kr=l, K,,,=B 0 ;
`FIG. 32 is a graph of simulated subcutaneous glucose
`response with white noise ( dotted line) and time-correlated
`noise (solid line) at a noise level of 1 %;
`FIG. 33 is a graph of first- and second-order regularization
`for a solution of blood glucose concentration based on
`25 simulated subcutaneous glucose concentration;
`FIG. 34 is a graph of error magnification factor versus
`weighting factor for zeroeth-, first-, and second-order regu(cid:173)
`larization;
`FIG. 35 is a graph of error magnification factor versus
`30 weighting factor for zeroeth-, first, and second-order
`regularization, varying values of window size and data
`sampling time;
`FIG. 36 is a graph of magnification factor versus weight(cid:173)
`ing factor for kr=O and Nllt=l.481;
`FIG. 37 is a graph of magnification factor versus weight(cid:173)
`ing factor including white noise or time-correlated noise in
`the simulated subcutaneous glucose concentration;
`FIG. 38 is a graph of squared model error versus weight
`40 factor;
`FIG. 39 is a graph of magnification factor versus weight(cid:173)
`ing factor for a) kr=O and b) kr=l, K,,,=B 0 ;
`FIG. 40 is a graph of glucose concentration illustrating a
`decline in concentration of glucose after intravenous injec-
`45 tion of insulin;
`FIG. 41 is a graph of estimated glucose concentration of
`a subcutaneously implanted sensor (dotted line), an intra(cid:173)
`vascularly implanted sensor (solid line), and venous blood
`glucose concentration ( circles) after an i.v. bolus of insulin.
`FIG. 42 is a graph of average difference (n=7) of subcu(cid:173)
`taneous glucose estimates relative to actual blood glucose
`measurements, % difference=l00 X (subcutaneous
`estimate-blood measurement)/(blood measurement);
`FIG. 43 is a graph of subcutaneous glucose concentration
`predicted using a forward model (dotted lines) based on data
`from a jugular sensor and measured subcutaneous glucose
`concentration (solid line); and
`FIG. 44 includes graphs for seven rats comparing blood
`60 glucose concentration as determined by a sensor (solid line)
`and predicted by an inverse model with regularization
`( dashed line).
`While the invention is amenable to various modifications
`and alternative forms, specifics thereof have been shown by
`way of example in the drawings and will be described in
`detail. It should be understood, however, that the intention is
`not to limit the invention to the particular embodiments
`
`15
`
`55
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`US 6,579,690 Bl
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`5
`described. On the contrary, the intention is to cover all
`modifications, equivalents, and alternatives falling within
`the spirit and scope of the invention as defined by the
`appended claims.
`
`DETAILED DESCRIPTION OF IBE
`INVENTION
`
`The present invention is applicable to a method and
`analyte measurement systems for determining analyte con(cid:173)
`centration in one body fluid (e.g., blood) from measured
`analyte concentrations in another body fluid (e.g., subcuta(cid:173)
`neous fluid). Suitable analyte measurement systems typi(cid:173)
`cally include a sensing device and a processor. The analyte
`measurement system may be configured and arranged to
`provide readings as required by a user when, for example,
`the user provides a sample to the device. In other
`embodiments, the analyte measurement system may be
`configured and arranged to be permanently or temporarily
`attached to an animal (such as a human) to provide periodic
`or continuous monitoring.
`For example, the analyte measurement system can be an
`analyte monitoring system using a subcutaneously implant(cid:173)
`able electrochemical sensor for the in vivo determination of
`a blood concentration of an analyte, such as, for example,
`glucose, lactate, or oxygen. The sensor can be, for example,
`subcutaneously implanted in a patient for the continuous or
`periodic monitoring of the analyte. The analyte monitoring
`system typically includes a subcutaneously implantable sen(cid:173)
`sor and a processor coupled to the sensor to determine the
`blood analyte concentration from the sensor measurements.
`A variety of suitable sensing devices are available. A
`suitable sensing device is configured and arranged to pro(cid:173)
`vide some signal, for example, an optical ( e.g., color change,
`absorption, transmission, or fluorescence) or electrical sig(cid:173)
`nal ( e.g., a change in current, potential, capacitance, or
`conductivity) that is related to a level of the analyte in the
`sample. Suitable sensing devices include electrochemical
`sensing devices, optical sensing devices, and colorimetric
`sensing devices. A sample of a body fluid may be provided,
`conveyed, or transported to the sensing device for in vitro
`determination of the analyte concentration in the body fluid.
`In other embodiments, the sensing device (e.g., an electro(cid:173)
`chemical sensor) may be implanted to provide in vivo
`determination of analyte concentration. In yet other
`embodiments, the sensing device (e.g., an optical device)
`may be directed toward the animal or a sample from the
`animal and the analyte concentration determined by, for
`example, interaction of light with the tissue and/or body
`fluid of the animal.
`The determination of blood glucose concentration from
`subcutaneous glucose measurements is used herein as an
`illustration. It will be understood that other analytes may
`also be measured. It will also be understood that the devices
`and methods described herein can be applied to the deter(cid:173)
`mination of analyte concentration in body fluids, other than
`blood, based on measurement of analyte concentration in a
`second body fluid.
`The following definitions are provided for terms used
`herein:
`A "counter electrode" refers to an electrode paired with
`the working electrode, through which passes a current equal
`in magnitude and opposite in sign to the current passing
`through the working electrode. In the context of the
`invention, the term "counter electrode" is meant to include
`counter electrodes which also function as reference elec(cid:173)
`trodes (i.e., a counter/reference electrode).
`
`10
`
`15
`
`6
`An "electrochemical sensor" is a device configured to
`detect the presence and/or measure the level of an analyte in
`a sample via electrochemical oxidation and reduction reac(cid:173)
`tions on the sensor. These reactions are transduced to an
`5 electrical signal that can be correlated to an amount,
`concentration, or level of an analyte in the sample.
`"Electrolysis" is the electrooxidation or electroreduction
`of a compound either directly at an electrode or via one or
`more electron transfer agents.
`A compound is "immobilized" on a surface when it is
`entrapped on or chemically bound to the surface.
`A "non-leachable" or "non-releasable" compound or a
`compound that is "non-leachably disposed" is meant to
`define a compound that is affixed on the sensor such that it
`does not substantially diffuse away from the working surface
`of the working electrode for the period in which the sensor
`is used (e.g., the period in which the sensor is implanted in
`a patient or measuring a sample).
`Components are "immobilized" within a sensor, for
`example, when the components are covalently, ionically, or
`20 coordinatively bound to constituents of the sensor and/or are
`entrapped in a polymeric or sol-gel matrix or membrane
`which precludes mobility.
`An "electron transfer agent" is a compound that carries
`electrons between the analyte and the working electrode,
`either directly, or in cooperation with other electron transfer
`agents. One example of an electron transfer agent is a redox
`mediator.
`A "working electrode" is an electrode at which the analyte
`30 ( or a second compound whose level depends on the level of
`the analyte) is electrooxidized or electro reduced with or
`without the agency of an electron transfer agent.
`A "working surface" is that portion of the working
`electrode which is coated with or is accessible to the electron
`35 transfer agent and configured for exposure to an analyte(cid:173)
`containing fluid.
`A "sensing layer" is a component of the sensor which
`includes constituents that facilitate the electrolysis of the
`analyte. The sensing layer may include constituents such as
`40 an electron transfer agent, a catalyst which catalyzes a
`reaction of the analyte to produce a response at the electrode,
`or both. In some embodiments of the sensor, the sensing
`layer is non-leachably disposed in proximity to or on the
`working electrode.
`A "non-corroding" conductive material includes non(cid:173)
`metallic materials, such as carbon and conductive polymers.
`Sensing Devices
`The methods and devices of the invention are illustrated
`using electrochemical sensors. However, it will be under-
`so stood that a variety of sensing devices, including
`electrochemical, optical, and colorimetric sensing devices
`may be used. Moreover, the methods and devices are illus(cid:173)
`trated using implantable sensing devices, however, it will be
`understood that other non-implantable sensing devices can
`ss be used.
`A variety of subcutaneously implantable sensors are avail(cid:173)
`able for use. Examples of such sensors and analyte mea(cid:173)
`surement systems incorporating the sensors are described in
`U.S. Pat. No. 5,593,852 and U.S. patent applications Ser.
`60 Nos. 09/034,372, 09/034,422, and 09/070,677, all of which
`are incorporated herein by reference. An example of one
`sensor is illustrated in FIG. 29 and described in detail in U.S.
`Pat. No. 5,593,852. This sensor includes a metal or carbon
`working electrode 2 with an electrically insulating material
`65 4 wrapped around the electrode. A recess 6 is provided by,
`for example, removing a portion of the working electrode 2.
`This leaves an exposed surface 18 of the working electrode.
`
`25
`
`45
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`US 6,579,690 Bl
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`7
`8
`A sensing layer 8 is formed over the exposed surface 18.
`may also include at least one counter electrode 60 (or
`The sensing layer 8 may include a redox mediator and/or a
`counter/reference electrode) and/or at least one reference
`redox enzyme. In at least some embodiments, the redox
`electrode 62 (see FIG. 8). The counter electrode 60 and/or
`mediator and/or redox enzyme are non-leachably disposed
`reference electrode 62 may be formed on the substrate 50 or
`in the sensor, as described in U.S. Pat. No. 5,593,852.
`5 may be separate units. For example, the counter electrode
`Exemplary redox mediators and redox enzymes are
`and/or reference electrode may be formed on a second
`described in U.S. Pat. No. 5,593,852 and U.S. patent appli(cid:173)
`substrate which is also implanted in the patient or, for some
`cations Ser. Nos. 09/034,372, 09/034,422, and 09/070,677.
`embodiments of the implantable sensors, the counter elec(cid:173)
`An optional glucose diffusion limiting layer 10, an
`trode and/or reference electrode may be placed on the skin
`optional interferent eliminating layer 12, and an optional
`10 of the patient with the working electrode or electrodes being
`biocompatible layer 14 can be formed in the recess 6. These
`implanted into the patient. The use of an on-the-skin counter
`layers are described in more detail in U.S. Pat. No. 5,593,
`and/or reference electrode with an implantable working
`852.
`electrode is described in U.S. Pat. No. 5,593,852, incorpo-
`Another Sensor and an Analyte Monitoring System
`rated herein by reference.
`The analyte monitoring systems of the present invention
`The working electrode or electrodes 58 are formed using
`can be utilized under a variety of conditions. The particular 15
`conductive traces 52 disposed on the substrate 50. The
`configuration of a sensor and other units used in the analyte
`counter electrode 60 and/or reference electrode 62, as well
`monitoring system may depend on the use for which the
`as other optional portions of the sensor 42, such as a
`analyte monitoring system is intended and the conditions
`temperature probe 66 (see FIG. 8), may also be formed using
`under which the analyte monitoring system will operate.
`One embodiment of the analyte monitoring system includes 20 conductive traces 52 disposed on the substrate 50. These
`conductive traces 52 may be formed over a smooth surface
`a sensor configured for implantation into a patient or user.
`of the substrate 50 or within channels 54 formed by, for
`For example, implantation of the sensor may be made in the
`arterial or venous systems for direct testing of analyte levels
`example, embossing, indenting or otherwise creating a
`depression in the substrate 50.
`in blood. Alternatively, a sensor may be implanted in the
`A sensing layer 64 (see FIGS. 3A and 3B) is often formed
`interstitial tissue for determining the analyte level in inter- 25
`proximate to or on at least one of the working electrodes 58
`stitial fluid. This level may be correlated and/or converted to
`to facilitate the electrochemical detection of the analyte and
`analyte levels in blood or other fluids. The site and depth of
`the determination of its level in the sample fluid, particularly
`implantation may affect the particular shape, components,
`if the analyte can not be electrolyzed at a desired rate and/or
`and configuration of the sensor. Subcutaneous implantation
`30 with a desired specificity on a bare electrode. The sensing
`may be preferred, in some cases, to limit the depth of
`layer 64 may include an electron transfer agent to transfer
`implantation of the sensor. Sensors may also be implanted in
`other regions of the body to determine analyte levels in other
`electrons directly or indirectly between the analyte and the
`working electrode 58. The sensing layer 64 may also contain
`fluids. Examples of suitable sensor for use in the analyte
`monitoring systems of the invention are described in U.S.
`a catalyst to catalyze a reaction of the analyte. The compo-
`35 nents of the sensing layer may be in a fluid or gel that is
`patent application Ser. No. 09/034,372, incorporated herein
`proximate to or in contact with the working electrode 58.
`by reference.
`One embodiment of the analyte monitoring system 40 for
`Alternatively, the components of the sensing layer 64 may
`use with an implantable sensor 42, and particularly for use
`be disposed in a polymeric or sol-gel matrix that is proxi(cid:173)
`mate to or on the working electrode 58. Preferably, the
`with a subcutaneously implantable sensor, is illustrated in
`block diagram form in FIG. 1. The analyte monitoring
`40 components of the sensing layer 64 are non-leachably dis(cid:173)
`system 40 includes, at minimum, a sensor 42, a portion of
`posed within the sensor 42. More preferably, the compo(cid:173)
`nents of the sensor 42 are immobilized within the sensor 42.
`which is configured for implantation (e.g., subcutaneous,
`In addition to the electrodes 58, 60, 62 and the sensing
`venous, or arterial implantation) into a patient, and a sensor
`control unit 44. The sensor 42 is coupled to the sensor
`layer 64, the sensor 42 may also include a temperature probe
`control unit 44 which is typically attached to the skin of a
`45 (see FIGS. 6 and 8), a mass transport limiting layer 74 (see
`FIG. 9), a biocompatible layer 75 (see FIG. 9), and/or other
`patient. The sensor control unit 44 operates the sensor 42,
`optional components, as described below. Each of these
`including, for example, providing a voltage across the
`electrodes of the sensor 42 and collecting signals from the
`items enhances the functioning of and/or results from the
`sensor 42. The sensor control unit 44 may evaluate the
`sensor 42, as discussed below.
`signals from the sensor 42 and/or transmit the signals to one
`50 The Substrate
`or more optional receiver/display units 46, 48 for evaluation.
`The substrate 50 may be formed using a variety of
`The sensor control unit 44 and/or the receiver/display units
`non-conducting materials, including, for example, poly(cid:173)
`46, 48 may display or otherwise communicate the current
`meric or plastic materials and ceramic materials. Suitable
`level of the analyte. Furthermore, the sensor con