(12) United States Patent
`Heller et al.
`
`USOO6560471B1
`(10) Patent No.:
`US 6,560,471 B1
`(45) Date of Patent:
`May 6, 2003
`
`6,275,717 B1 * 8/2001 Gross et al. ................ 600/309
`6,360,888 B1 * 3/2002 McIvor et al. .............. 206/305
`6,366,794 B1 * 4/2002 Moussy et al. ............. 600/345
`* cited b
`cited by examiner
`Primary Examiner Max F. Hindenburg
`SSStirli EXOiinifier
`aVin Natnithithadha
`ASSi
`Examiner Navin Natnithithadh
`74Y A
`A
`Firm-Merchant & Gould PC
`ttorney, Agent, or Firm-Merchant
`OUIC ..
`ABSTRACT
`(57)
`An analyte monitor includes a Sensor, a Sensor control unit,
`and a display unit. The Sensor has, for example, a Substrate,
`a recessed channel formed in the Substrate, and conductive
`material disposed in the recessed channel to form a working
`electrode. The Sensor control unit typically has a housing
`adapted for placement on Skin and is adapted to receive a
`portion of an electrochemical Sensor. The Sensor control unit
`also includ
`ducti
`disposed
`also includes tWO Or more COnductVe COntactS dSDOSed On
`the housing and configured for coupling
`the hOuSing and COn
`red Or COupling to tWO Or more
`contact pads on the Sensor. A transmitter is disposed in the
`housing and coupled to the plurality of conductive contacts
`for transmitting data obtained using the Sensor. The display
`unit has a receiver for receiving data transmitted by the
`transmitter of the Sensor control unit and a displav coupled
`play coup
`to the receiver for displaying an indication of a level of an
`analyte. The analyte monitor may also be part of a drug
`delivery system to alter the level of the analyte based on the
`data obtained using the Sensor.
`
`64 Claims, 31 Drawing Sheets
`
`48
`
`
`
`
`
`
`
`
`
`
`
`LARGE
`RECEIVER
`AND DISPLAY
`UNIT
`
`(54) ANALYTE MONITORING DEVICE AND
`METHODS OF USE
`
`(75) Inventors: Adam Heller, Austin, TX (US); Steven
`H. Drucker, Oakland, CA (US);
`Robert Y. Jin, Castro Valley, CA (US);
`Jeffery V. Funderburk Fa ss
`(US)
`s
`s
`
`(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 97 days.
`
`(21) Appl. No.: 09/753,746
`(22) Filed:
`Jan. 2, 2001
`(51) Int. Cl." .............................. A61B5/05, A61 B 500
`7
`(52) U.S. Cl. ....................... 600347,600/345 600,365,
`s
`s 6007309
`(58) Field of Search 600,347,354,357.
`5. i.
`s
`s
`s
`s
`References Cited
`
`(56)
`
`s
`
`U.S. PATENT DOCUMENTS
`4,703,756 A * 11/1987 Gough et al. ............... 128/903
`5,660,163 A * 8/1997 Schulman et al. ..... 204/403.11
`5,711,861. A * 1/1998 Ward et al. ............ 204/403.09
`6,175,752 B1 * 1/2001 Say et al. ................... 128/903
`
`
`
`0 N.
`
`SMALL RECEIVER
`AND
`DISPLAY UNIT
`
`
`
`42
`
`
`
`SENSOR
`
`SENSOR
`CONTROL
`UNIT
`
`Page 1 of 66
`
`

`

`U.S. Patent
`
`May6, 2003
`
`Sheet 1 of 31
`
`US 6,560,471 B1
`
`Sv
`
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`
`Page 2 of 66
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`Page 2 of 66
`
`
`
`
`

`

`U.S. Patent
`U.S. Patent
`
`May 6, 2003
`May 6, 2003
`
`Sheet 2 of 31
`Sheet 2 of 31
`
`US 6,560,471 B1
`US 6,560,471 B1
`
`FIG. 2
`FIG. 2
`
`
`
`-
`
`42
`42
`Lo
`/
`
`65
`
`52
`
`58
`
`51
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`
`53
`
`50
`
`49
`
`57
`
`Page 3 of 66
`
`Page 3 of 66
`
`

`

`U.S. Patent
`
`May 6, 2003
`
`Sheet 3 of 31
`
`US 6,560,471 B1
`
`FIG. J.A
`
`FIG. 3B
`
`
`
`
`
`FIG. 9
`
`
`
`FIG. 4A
`
`
`
`Page 4 of 66
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`

`

`U.S. Patent
`
`May 6, 2003
`
`Sheet 4 of 31
`
`US 6,560,471 B1
`
`FIG. 4B
`
`64
`
`63
`
`60
`
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`62
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`61
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`50
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`58
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`50
`
`FIG. 5
`
`58
`
`60
`
`64
`
`64
`
`Page 5 of 66
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`

`

`U.S. Patent
`
`May 6, 2003
`
`Sheet 5 of 31
`
`US 6,560,471 B1
`
`FIG. 6
`
`FIG. 7
`
`66
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`
`Page 6 of 66
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`

`

`U.S. Patent
`
`May 6, 2003
`
`Sheet 6 of 31
`
`US 6,560,471 B1
`
`FIG. 1 O
`
`
`
`49 49a,
`
`49 49
`
`49
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`49a
`
`Page 7 of 66
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`

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`U.S. Patent
`U.S. Patent
`
`May 6, 2003
`May 6, 2003
`
`Sheet 7 of 31
`Sheet 7 of 31
`
`US 6,560,471 B1
`US 6,560,471 B1
`
`FIG. 11
`FIG. 11
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`52
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`66
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`Page 8 of 66
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`Page 8 of 66
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`

`

`U.S. Patent
`
`May 6, 2003
`
`Sheet 8 of 31
`
`US 6,560,471 B1
`
`FIG. 12
`
`42
`
`127
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`126
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`Page 9 of 66
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`

`

`U.S. Patent
`
`May 6, 2003
`
`Sheet 9 of 31
`
`US 6,560,471 B1
`
`F.G. 15
`
`FIG. 16
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`82
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`76
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`Page 10 of 66
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`

`

`U.S. Patent
`U.S. Patent
`
`May 6, 2003
`May 6, 2003
`
`Sheet 10 of 31
`Sheet 10 of 31
`
`US 6,560,471 B1
`US 6,560,471 B1
`
`FIG. 17
`FIG. 17
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`Page 11 of 66
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`Page 11 of 66
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`

`

`U.S. Patent
`
`May 6, 2003
`
`Sheet 11 of 31
`
`US 6,560,471 B1
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`Page 12 of 66
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`

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`U.S. Patent
`
`May6, 2003
`
`Sheet 12 of 31
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`

`U.S. Patent
`
`May 6, 2003
`
`Sheet 13 of 31
`
`US 6,560,471 B1
`
`FIG. 19A
`
`FIG. 19B
`
`FIG. 19C
`
`FIG. 19D
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`Page 14 of 66
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`

`

`U.S. Patent
`
`May 6, 2003
`
`Sheet 14 of 31
`
`US 6,560,471 B1
`
`FIG. 20A
`
`131
`
`138 1
`
`136
`
`130
`
`INPUT FROM
`SENSOR 42
`
`REFERENCE
`VOLTAGE
`
`FIG. 20B
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`CLK CLK
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`INPUT FROM SENSOR
`42
`REFERENCE VOLTAGE
`
`
`
`146
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`142
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`140
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`Page 15 of 66
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`

`

`U.S. Patent
`
`May 6, 2003
`
`Sheet 15 0f 31
`
`US 6,560,471 B1
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`Page 16 of 66
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`

`

`U.S. Patent
`
`May 6, 2003
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`Sheet 16 of 31
`
`US 6,560,471 B1
`
`FIG. 22
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`162
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`DEVICE
`
`Page 17 of 66
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`

`

`U.S. Patent
`
`May 6, 2003
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`Sheet 17 of 31
`
`US 6,560,471 B1
`
`154
`
`162
`
`FIG. 25
`
`164
`
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`
`
`Page 18 of 66
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`U.S. Patent
`
`May 6, 2003
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`Sheet 18 of 31
`
`US 6,560,471 B1
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`Page 19 of 66
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`

`

`May 6, 2003
`May6, 2003
`
`Sheet 19 of 31
`Sheet 19 of 31
`
`US 6,560,471 B1
`US 6,560,471 B1
`
`U.S. Patent
`U.S. Patent
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`Page 20 of 66
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`Page 20 of 66
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`

`

`U.S. Patent
`U.S. Patent
`
`May 6, 2003
`May 6, 2003
`
`
`
`Sheet 20 of 31
`Sheet 20 Of 31
`
`US 6,560,471 B1
`
`US 6,560,471 B1
`
`Page 21 of 66
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`Page 21 of 66
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`

`

`US 6,560,471 B1
`
`U.S. Patent
`
`
`
`FIG.27B
`
`May 6, 2003
`
`Sheet 21 of 31
`
`Page 22 of 66
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`Page 22 of 66
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`

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`U.S. Patent
`U.S. Patent
`
`May 6, 2003
`May 6, 2003
`
`Sheet 22 of 31
`Sheet 22 of 31
`
`US 6,560,471 B1
`US 6,560,471 B1
`
`3
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`FIG.28A
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`Page 23 of 66
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`Page 23 of 66
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`

`

`U.S. Patent
`U.S. Patent
`
`May 6, 2003
`May 6, 2003
`
`Sheet 23 of 31
`Sheet 23 of 31
`
`US 6,560,471 B1
`US 6,560,471 B1
`
`
`
`Page 24 of 66
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`Page 24 of 66
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`

`

`U.S. Patent
`U.S. Patent
`
`May 6, 2003
`May 6, 2003
`
`Sheet 24 of 31
`Sheet 24 of 31
`
`US 6,560,471 B1
`US 6,560,471 B1
`
`
`
`76
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`74
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`Page 25 of 66
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`Page 25 of 66
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`U.S. Patent
`U.S. Patent
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`May 6, 2003
`May 6, 2003
`
`Sheet 25 of 31
`Sheet 25 of 31
`
`US 6,560,471 B1
`US 6,560,471 B1
`
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`Page 26 of 66
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`Page 26 of 66
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`

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`U.S. Patent
`U.S. Patent
`
`May 6, 2003
`May 6, 2003
`
`Sheet 26 of 31
`Sheet 26 of 31
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`US 6,560,471 B1
`US 6,560,471 B1
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`
`
`Page 27 of 66
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`Page 27 of 66
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`

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`U.S. Patent
`
`May 6, 2003
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`Sheet 27 of 31
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`US 6,560,471 B1
`
`Arnolyte
`Level
`
`
`
`C1--D1+E1
`
`Sernsor
`Current
`
`FIG, 29
`
`Page 28 of 66
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`U.S. Patent
`
`May 6, 2003
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`Sheet 28 of 31
`
`US 6,560,471 B1
`
`Tronsmission
`Medium
`Tronsmitters
`Receiver
`—
`234
`
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`FIG, 30
`
`Page 29 of 66
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`U.S. Patent
`U.S. Patent
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`May 6, 2003
`May 6, 2003
`
`Sheet 29 of 31
`Sheet 29 of 31
`
`US 6,560,471 B1
`US 6,560,471 B1
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`
`
`
`
`254
`254
`
`FIG, 31.
`FIG. 31
`
`Page 30 of 66
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`Page 30 of 66
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`U.S. Patent
`U.S. Patent
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`May 6, 2003
`May 6, 2003
`
`Sheet 30 of 31
`Sheet 30 of 31
`
`US 6,560,471 B1
`US 6,560,471 B1
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`
`
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`66
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`263
`
`FIG, 32
`FIG, 32
`
`Page 31 of 66
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`Page 31 of 66
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`U.S. Patent
`U.S. Patent
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`May 6, 2003
`May 6, 2003
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`Sheet 31 of 31
`Sheet 31 of 31
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`
`
`FIG.33
`
`FIG.33
`
`US 6,560,471 B1
`US 6,560,471 B1
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`274
`
`278
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`Page 32 of 66
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`

`1
`ANALYTE MONITORING DEVICE AND
`METHODS OF USE
`
`US 6,560,471 B1
`
`FIELD OF THE INVENTION
`The present invention is, in general, directed to devices
`and methods for the in Vivo monitoring of an analyte, Such
`as glucose or lactate. More particularly, the present inven
`tion relates to devices and methods for the in vivo monitor
`ing of an analyte using an electrochemical Sensor to provide
`information to a patient about the level of the analyte.
`BACKGROUND OF THE INVENTION
`The monitoring of the level of glucose or other analytes,
`Such as lactate or oxygen, in certain individuals is vitally
`important to their health. High or low levels of glucose or
`other analytes may have detrimental effects. 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 in their bodies.
`A conventional technique used by many diabetics for
`personally monitoring their blood glucose level includes the
`periodic drawing of blood, the application of that blood to a
`test Strip, and the determination of the blood glucose level
`using colorimetric, electrochemical, or photometric detec
`tion. This technique does not permit continuous or automatic
`monitoring of glucose levels in the body, but typically must
`be performed manually on a periodic basis. Unfortunately,
`the consistency with which the level of glucose is checked
`varies widely among individuals. Many diabetics find the
`periodic testing inconvenient and they Sometimes forget to
`test their glucose level or do not have time for a proper test.
`In addition, Some individuals wish to avoid the pain asso
`ciated with the test. These situations may result in hyperg
`lycemic or hypoglycemic episodes. An in Vivo glucose
`Sensor that continuously or automatically monitors the indi
`vidual’s glucose level would enable individuals to more
`easily monitor their glucose, or other analyte, levels.
`A variety of devices have been developed for continuous
`or automatic monitoring of analytes, Such as glucose, in the
`blood stream or interstitial fluid. A number of these devices
`use electrochemical Sensors which are directly implanted
`into a blood vessel or in the Subcutaneous tissue of a patient.
`However, these devices are often difficult to reproducibly
`and inexpensively manufacture in large numbers. In
`addition, these devices are typically large, bulky, and/or
`inflexible, and many can not be used effectively outside of
`a controlled medical facility, Such as a hospital or a doctor's
`office, unless the patient is restricted in his activities.
`Some devices include a Sensor guide which rests on or
`near the skin of the patient and may be attached to the patient
`to hold the Sensor in place. These Sensor guides are typically
`bulky and do not allow for freedom of movement. In
`addition, the Sensor guides or the Sensors include cables or
`wires for connecting the Sensor to other equipment to direct
`the Signals from the Sensors to an analyzer. The size of the
`Sensor guides and presence of cables and wires hinders the
`convenient use of these devices for everyday applications.
`There is a need for a Small, compact device that can operate
`the Sensor and provide Signals to an analyzer without
`Substantially restricting the movements and activities of a
`patient.
`The patient's comfort and the range of activities that can
`be performed while the Sensor is implanted are important
`considerations in designing extended-use Sensors for con
`
`2
`tinuous or automatic in Vivo monitoring of the level of an
`analyte, Such as glucose. There is a need for a Small,
`comfortable device which can continuously monitor the
`level of an analyte, Such as glucose, while Still permitting the
`patient to engage in normal activities. Continuous and/or
`automatic monitoring of the analyte can provide a warning
`to the patient when the level of the analyte is at or near a
`threshold level. For example, if glucose is the analyte, then
`the monitoring device might be configured to warn the
`patient of current or impending hyperglycemia or hypogly
`cemia. The patient can then take appropriate actions.
`
`15
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`SUMMARY OF THE INVENTION
`Generally, the present invention relates to methods and
`devices for the continuous and/or automatic in Vivo moni
`toring of the level of an analyte using a Subcutaneously
`implantable Sensor. Many of these devices are Small and
`comfortable when used, thereby allowing a wide range of
`activities. One embodiment is a Sensor control unit having a
`housing adapted for placement on Skin. The housing is also
`adapted to receive a portion of an electrochemical Sensor.
`The Sensor control unit includes two or more conductive
`contacts disposed on the housing and configured for cou
`pling to two or more contact pads on the Sensor. A trans
`mitter is disposed in the housing and coupled to the plurality
`of conductive contacts for transmitting data obtained using
`the Sensor. The Sensor control unit may also include a variety
`of optional components, Such as, for example, adhesive for
`adhering to the Skin, a mounting unit, a receiver, a proceSS
`ing circuit, a power Supply (e.g., a battery), an alarm System,
`a data Storage unit, a watchdog circuit, and a measurement
`circuit. Other optional components are described below.
`Another embodiment of the invention is a Sensor assem
`bly that includes the sensor control unit described above.
`The Sensor assembly also includes a Sensor having at least
`one working electrode and at least one contact pad coupled
`to the working electrode or electrodes. The Sensor may also
`include optional components, Such as, for example, a
`counter electrode, a counter/reference electrode, a reference
`electrode, and a temperature probe. Other components and
`options for the Sensor are described below.
`A further embodiment of the invention is an analyte
`monitoring System that includes the Sensor control unit
`described above. The analyte monitoring System also
`includes a Sensor that has at least one working electrode and
`at least one contact pad coupled to the working electrode or
`electrodes. The analyte monitoring System also includes a
`display unit that has a receiver for receiving data from the
`Sensor control unit and a display coupled to the receiver for
`displaying an indication of the level of an analyte. The
`display unit may optionally include a variety of components,
`Such as, for example, a transmitter, an analyzer, a data
`Storage unit, a watchdog circuit, an input device, a power
`Supply, a clock, a lamp, a pager, a telephone interface, a
`computer interface, an alarm or alarm System, a radio, and
`a calibration unit. Further components and options for the
`display unit are described below. In addition, the analyte
`monitoring System or a component of the analyte monitoring
`System may optionally include a processor capable of deter
`mining a drug or treatment protocol and/or a drug delivery
`System.
`Yet another embodiment of the invention is an insertion
`kit for inserting an electrochemical Sensor into a patient. The
`insertion kit includes an inserter. A portion of the inserter has
`a sharp, rigid, planer Structure adapted to Support the Sensor
`during insertion of the electrochemical Sensor. The insertion
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`kit also includes an insertion gun having a port configured to
`accept the electrochemical Sensor and the inserter. The
`insertion gun has a driving mechanism for driving the
`inserter and electrochemical Sensor into the patient, and a
`retraction mechanism for removing the inserter while leav
`ing the Sensor within the patient.
`Another embodiment is a method of using an electro
`chemical Sensor. A mounting unit is adhered to skin of a
`patient. An insertion gun is aligned with a port on the
`mounting unit. The electrochemical Sensor is disposed
`within the insertion gun and then the electrochemical Sensor
`is inserted into the Skin of the patient using the insertion gun.
`The insertion gun is removed and a housing of the Sensor
`control unit is mounted on the mounting base. A plurality of
`conductive contacts disposed on the housing is coupled to a
`plurality of contact pads disposed on the electrochemical
`Sensor to prepare the Sensor for use.
`One embodiment of the invention is a method for detect
`ing failures in an implanted analyte-responsive Sensor. An
`analyte-responsive Sensor is implanted into a patient. The
`analyte-responsive Sensor includes N working electrodes,
`where N is an integer and is two or greater, and a common
`counter electrode. Signals generated at one of the N working
`electrodes and at the common counter electrode are then
`obtained and the sensor is determined to have failed if the
`Signal from the common counter electrode is not N times the
`Signal from one of the working electrodes, within a prede
`termined threshold limit.
`Yet another embodiment is a method of calibrating an
`electrochemical Sensor having one or more working elec
`trodes implanted in a patient. A Signal is generated from each
`of the working electrodes. Several conditions are tested to
`determine if calibration is appropriate. First, the Signals from
`each of the one or more working electrodes should differ by
`less than a first threshold amount. Second, the Signals from
`each of the one or more working electrodes should be within
`a predetermined range. And, third, a rate of change of the
`Signals from each of the one or more working electrodes
`should be less than a Second threshold amount. A calibration
`value is found assaying a calibration Sample of a patient's
`body fluid. The calibration value is then related to at least
`one of the Signals from the one or more working electrodes
`if the conditions described above are met.
`A further embodiment is a method for monitoring a level
`of an analyte. A Sensor is inserted into a skin of a patient and
`a Sensor control unit is attached to the skin of the patient.
`Two or more conductive contacts on the Sensor control unit
`are coupled to contact pads on the Sensor. Then, using the
`Sensor control unit, data is collected regarding a level of an
`analyte from Signals generated by the Sensor. The collected
`data is transmitted to a display unit and an indication of the
`level of the analyte is displayed on the display unit.
`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
`the detailed description which follow more particularly
`exemplify these embodiments.
`BRIEF DESCRIPTION OF THE DRAWINGS
`The invention may be more completely understood in
`consideration of the following detailed description of Vari
`ous embodiments of the invention in connection with the
`accompanying 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;
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`FIG. 2 is a top view of one embodiment of an analyte
`Sensor, according to the invention;
`FIG. 3A is a cross-sectional view of the analyte sensor of
`FIG. 2;
`FIG. 3B is a cross-sectional view of another embodiment
`of an analyte Sensor, according to the invention;
`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
`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
`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
`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
`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;
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`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
`on-skin Sensor control unit after insertion of an insertion
`device and a Sensor, according to the invention;
`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
`control unit of FIG. 28A:
`FIG. 28D is a bottom view of the housing of FIG. 28C;
`and
`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 depicts two sensor current-analyte level profiles
`at differing temperatures.
`FIG. 30 depicts three code division multiple access
`(CDMA) transmitters simultaneously transmitting across a
`transmission medium to a CDMA receiver.
`FIG. 31 depicts a data message that may be transmitted
`under an interleaved transmission Scheme.
`FIG. 32 depicts one possible embodiment of a transmitter
`disposed upon a Substrate.
`FIG. 33 depicts an insertion device, Sensor, insertion gun
`and mounting unit, which can be assembled and Sold
`together in an insertion kit.
`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
`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 THE
`INVENTION
`The present invention is applicable to an analyte moni
`toring System using an implantable Sensor for the in vivo
`determination of a concentration of an analyte, Such as
`glucose or lactate, in a fluid. The Sensor can be, for example,
`Subcutaneously implanted in a patient for the continuous or
`periodic monitoring an analyte in a patient's interstitial fluid.
`This can then be used to infer the glucose level in the
`patient's bloodstream. Other in Vivo analyte Sensors can be
`made, according to the invention, for insertion into a vein,
`artery, or other portion of the body containing fluid. The
`analyte monitoring System is typically configured for moni
`toring the level of the analyte over a time period which may
`range from days to weeks or longer.
`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
`trodes (i.e., a counter/reference electrode).
`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
`tions on the Sensor. These reactions are transduced to an
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`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
`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
`(or a Second compound whose level depends on the level of
`the analyte) is electrooxidized or electroreduced 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
`transfer agent and configured for exposure to an analyte
`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
`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
`metallic materials, Such as carbon and conductive polymers.
`Analyte Sensor Systems
`The analyte monitoring Systems of the present invention
`can be utilized under a variety of conditions. The particular
`configuration of a Sensor and other units used in the analyte
`monitoring System may depend on the use for which the
`analyte monitoring System is intended and the conditions
`under which the analyte monitoring System will operate.
`One embodiment of the analyte monitoring System includes
`a Sensor configured for implantation into a patient or user.
`For example, implantation of the Sensor may be made in the
`arterial or venous Systems for direct testing of analyte levels
`in blood. Alternatively, a Sensor may be implanted in the
`interstitial tissue for determining the analyte level in inter
`stitial fluid. This level may be correlated and/or converted to
`analyte levels in blood or other fluids. The site and depth of
`implantation may affect the particular shape, components,
`and configuration of the Sensor. Subcutaneous implantation
`may be preferred, in Some cases, to limit the depth of
`implantation of the Sensor. Sensors may also be implanted in
`other regions of the body to determine analyte levels in other
`fluids. Examples of Suitable Sensor for use in the analyte
`monitoring Systems of the invention are described in U.S.
`patent application, Ser. No. 09/034,372, incorporated herein
`by reference.
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`One embodiment of the analyte monitoring system 40 for
`use with an implantable Sensor 42, and particularly for use
`with a Subcutaneously implantable Sensor, is illustrated in
`block diagram form in FIG. 1. The analyte monitoring
`System 40 includes, at minimum, a Sensor 42, a portion of
`which is configured for implantation (e.g., Subcutaneous,
`venous, or arterial implantation) into a patient, and a Sensor
`control unit 44. The sensor 42 is coupled to the sensor
`control unit 44 which is typically attached to the skin of a
`patient. The Sensor control unit 44 operates the Sensor 42,
`including, for example, providing a Voltage acroSS the
`electrodes of the Sensor 42 and collecting Signals from the
`sensor 42. The sensor control unit 44 may evaluate the
`Signals from the Sensor 42 and/or transmit the Signals to one
`or more optional receiver/display units 46, 48 for evaluation.
`The sensor control unit 44 and/or the receiver/display units
`46, 48 may display or otherwise communicate the current
`level of the analyte. Furthermore, the sensor control unit 44
`and/or the receiver/display units 46, 48 may indicate to the
`patient, Via, for example, an audible, Visual, or other
`Sensory-Stimulating alarm, when the level of the analyte is
`at or near a threshold level. In Some embodiments, a
`electrical shock can be delivered to the patient as a warning
`through one of the electrodes or the optional temperature
`probe of the Sensor. For example, if glucose is monitored
`then an alarm may be used to alert the patient to a hypogly
`cemic or hyperglycemic glucose level and/or to impending
`hypoglycemia or hyperglycemia.
`The Sensor
`A sensor 42 includes at least one working electrode 58
`formed on a Substrate 50, as shown in FIG. 2. The sensor 42
`may also include at least one counter electrode 60 (or
`counter/reference electrode) and/or at least one reference
`electrode 62 (see FIG. 8). The counter electrode 60 and/or
`reference electrode 62 may be formed on the substrate 50 or
`may be separate units. For example, the counter electrode
`and/or reference electrode may be formed on a Second
`Substrate which is also implanted in the patient or, for Some
`embodiments of the implantable Sensors, the counter elec
`trode and/or reference electrode may be placed on the skin
`of the patient with the working electrode or electrodes being
`implanted into the patient. The use of an on-the-skin counter
`and/or reference electrode with an implantable work