(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2004/0193025A1
`(43) Pub. Date:
`Sep. 30, 2004
`Steil et al.
`
`US 20040193025A1
`
`(54)
`
`(75)
`
`(73)
`(21)
`(22)
`
`(62)
`
`CLOSED-LOOP METHOD FOR
`CONTROLLING INSULIN INFUSION
`
`Inventors: Garry M. Steil, Pasadena, CA (US);
`Kerstin Rebrin, South Pasadena, CA
`(US)
`Correspondence Address:
`Paul H. Kovelman, Esq.
`MEDTRONIC MINIMED, INC.
`18000 Devonshire Street
`Northridge, CA 91325-1219 (US)
`Assignee: MEDTRONIC MINIMED, INC.
`Appl. No.:
`10/816,021
`
`Filed:
`
`Mar. 31, 2004
`Related U.S. Application Data
`Division of application No. 08/871,831, filed on Jun.
`9, 1997, now Pat. No. 5,954,643.
`
`Publication Classification
`
`(51) Int. Cl." ....................................................... A61B 5/00
`(52) U.S. Cl. .............................................. 600/316; 604/65
`(57)
`ABSTRACT
`
`A closed loop infusion System controls the rate that fluid is
`infused into the body of a user. The closed loop infusion
`System includes a Sensor System, a controller, and a delivery
`System. The Sensor System includes a Sensor for monitoring
`a condition of the user. The Sensor produces a Sensor Signal,
`which is representative of the condition of the user. The
`Sensor Signal is used to generate a controller input. The
`controller uses the controller input to generate commands to
`operate the delivery System. The delivery System infuses a
`liquid into the user at a rate dictated by the commands from
`the controller. Preferably, the sensor system monitors the
`glucose concentration in the body of the user, and the liquid
`infused by the delivery system into the body of the user
`includes insulin.
`
`
`
`
`
`
`
`
`
`12
`
`22
`
`CONTROLLER
`
`COMMANDS
`
`16
`
`SENSOR SIGNAL
`
`
`
`
`
`
`
`
`
`
`
`14
`
`NSULIN
`DELIVERY
`SYSTEM
`
`GLUCOSE
`SENSOR
`SYSTEM
`
`
`
`
`
`
`
`2O
`
`24
`t
`NSULIN
`
`18
`
`BLOODGUCOSELEVEL
`
`Page 1 of 67
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`

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`Patent Application Publication Sep. 30,2004 Sheet 1 of 40
`
`US 2004/0193025 A1
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`
`Page 2 of 67
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`Page 2 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 3 of 40
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`US 2004/0193025 A1
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`Page 4 of 67
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`

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`Patent Application Publication Sep. 30, 2004 Sheet 4 of 40
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`US 2004/0193025A1
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`Page 5 of 67
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`
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`Page 6 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 6 of 40
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`Page 7 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 7 of 40
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`US 2004/0193025 A1
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`53
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`36
`IIT? H-21
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`Page 8 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 8 of 40
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`Page 9 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 9 of 40
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`US 2004/0193025 A1
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`INFUSION PUMP
`
`PRE-FILTER
`Eator
`CONTROLLER
`
`
`
`
`
`28
`
`
`
`
`
`
`
`PRE-FILTER
`FILTER
`CALIBRATOR
`
`
`
`
`
`
`
`
`
`FILTER
`CALIBRATOR
`CONTROLLER
`
`(a)
`
`(b)
`28
`
`
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`
`
`
`
`FILTER
`CALIBRATOR
`
`
`
`
`
`FIG. 8
`
`Page 10 of 67
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`

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`Patent Application Publication Sep. 30,
`2004 Sheet 10 of 40
`
`US 2004/0193025 A1
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`X
`
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`
`Page 11 of 67
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`

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`Patent Application Publication Sep. 30, 2004 Sheet 11 of 40
`
`US 2004/0193025 A1
`
`26
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`:
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`SENSOR
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`is
`
`70
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`68
`A/D
`CONVERTERDs. TRANSMTER )
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`a sle was
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`
`Page 12 of 67
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`

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`Patent Application Publication Sep. 30, 2004 Sheet 12 of 40
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`US 2004/0193025 A1
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`Page 13 of 67
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`

`

`Patent Application Publication Sep. 30, 2004 Sheet 13 of 40
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`US 2004/0193025 A1
`
`
`
`Sig
`
`FIG. 12
`
`Page 14 of 67
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`

`

`Patent Application Publication Sep. 30, 2004 Sheet 14 of 40
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`US 2004/0193025 A1
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`
`
`lsig
`
`FIG. 13
`
`Page 15 of 67
`
`

`

`Patent Application Publication Sep. 30, 2004 Sheet 15 of 40
`
`US 2004/0193025 A1
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`y Cl
`212
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`D
`222
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`218
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`
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`
`Page 16 of 67
`
`

`

`Patent Application Publication Sep. 30, 2004 Sheet 16 of 40
`
`US 2004/0193025 A1
`
`/
`
`
`
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`
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`302
`
`306
`Wsig VOLTAGE Ds
`CONVERTER
`MEASUREMENT
`TRIGGER
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`
`310
`
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`
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`FIG. 15
`
`Page 17 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 17 of 40
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`US 2004/0193025 A1
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`
`
`Page 18 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 18 of 40
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`US 2004/0193025 A1
`
`
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`907 ------------------|----------------------------------------------
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`
`Page 19 of 67
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`

`

`Patent Application Publication Sep. 30, 2004 Sheet 19 of 40
`
`US 2004/0193025A1
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`O
`cy
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`Page 20 of 67
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`

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`Patent Application Publication Sep. 30, 2004 Sheet 20 of 40
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`US 2004/0193025 A1
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`
`
`Page 21 of 67
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`

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`Patent Application Publication Sep. 30, 2004 Sheet 21 of 40
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`US 2004/0193025 A1
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`
`
`Page 22 of 67
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`

`

`Patent Application Publication Sep. 30, 2004 Sheet 22 of 40
`
`US 2004/0193025 A1
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`O
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`Page 23 of 67
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`

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`Patent Application Publication Sep. 30, 2004 Sheet 23 of 40
`
`US 2004/0193025 A1
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`O
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`CN
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`Page 24 of 67
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`

`

`Patent Application Publication Sep. 30, 2004 Sheet 24 of 40
`
`US 2004/0193025 A1
`
`
`
`006
`
`009
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`
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`(l/10ujd) NITOSN||
`
`Page 25 of 67
`
`

`

`Patent Application Publication Sep. 30, 2004 Sheet 25 of 40
`
`US 2004/0193025 A1
`
`(a)
`
`G
`
`G
`
`(b)
`
`(d)
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`
`Page 26 of 67
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`

`

`Patent Application Publication Sep. 30, 2004 Sheet 26 of 40
`
`US 2004/0193025 A1
`
`PLASMA INSULINLEVEL
`
`(a)
`
`30 GLUCOSEUPTAKERATE
`
`20 450
`(mg/min per kg FFM)
`10
`
`
`
`448
`
`(b)
`
`O
`
`FIG. 25
`
`Page 27 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 27 of 40
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`US 2004/0193025 A1
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`
`
`
`
`
`
`
`
`
`
`
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`
`
`
`
`Page 28 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 28 of 40
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`US 2004/0193025A1
`
`BODY
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
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`
`
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`
`
`
`INSULIN PUMP
`
`INSULIN IS INTRODUCED INTO THE
`INTERSTITIAL FLUID (ISF) OF THE
`SUBCUTANEOUSTISSUE OF THE
`BODY
`
`NSULINDIFFUSES FROM THEISF
`SURROUNDING THE CANNULAINTO
`BLOOD PLASMAIN THE MAIN
`CIRCULATORY SYSTEM.
`
`INSULINDIFFUSES FROM THE
`BLOOD PLASMA INTO THEISF
`THROUGHOUT THE BODY
`
`INSULIN BINDS WITH AND
`ACTIVATES MEMBRANE RECEPTOR
`PROTEINS ON TISSUE CELLS.
`
`
`
`GLUCOSE IS REMOVED FROM THE
`SF BY PERMEATING THE
`ACTIVATED CELL MEMBRANES.
`(ISF GLUCOSEDECREASES)
`
`GLUCOSE DIFFUSES FROM THE BLOOD
`PLASMAINTO THEISFTOMAINTAINA
`BALANCED THE GLUCOSE
`CONCETRATION BETWEEN THE TWO,
`(BLOODGLUCOSEDECREASES)
`
`THE GLUCOSE IN THE ISF
`DECREASES AS IT IS TAKENUPBY
`CELS.
`
`GLUCOSE IN THE SENSOR
`MEMBRANEDECREASES.
`
`FIG. 27
`
`Page 29 of 67
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`

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`Patent Application Publication Sep. 30, 2004 Sheet 29 of 40
`
`US 2004/0193025 A1
`
`150
`
`100
`INSULIN (uJ/ml)
`
`50
`
`150
`
`
`
`100
`INSULIN (UU/ml)
`50
`
`O
`
`120
`60
`TIME (min)
`
`18O
`
`FIG. 28
`
`Page 30 of 67
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`

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`Patent Application Publication Sep. 30, 2004 Sheet 30 of 40
`
`US 2004/0193025A1
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`400
`300
`200
`
`100
`
`O
`
`120
`100
`
`O
`
`60
`
`120
`
`180
`
`
`
`Page 31 of 67
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`

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`Patent Application Publication Sep. 30, 2004 Sheet 31 of 40
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`US 2004/0193025 A1
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`
`
`GLUCOSE
`
`(a)
`
`SENSOR
`SENSITIVITY
`
`510
`?
`
`(b)
`
`O
`
`TIME
`
`R
`
`SENSOR
`RESISTANCE
`
`(C)
`
`O
`
`TIME
`
`FIG. 31
`
`Page 32 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 32 of 40
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`US 2004/0193025 A1
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MEASURE
`lsig AND WCtr
`
`
`
`CALCULATE
`RESISTANCE
`
`CALCULATE
`dR/dt
`
`
`
`IS
`dR/dt >
`REPLACEMENT
`THRESHOLD2
`
`
`
`S
`dR/dt >
`RECALIBRAE
`THRESHOLD2
`
`
`
`YES
`
`RECALIBRATE
`SENSOR
`
`FIG. 32
`
`
`
`
`
`REPLACE
`SENSOR
`
`Page 33 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 33 of 40
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`US 2004/0193025 A1
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`350
`300
`250
`O
`si 20
`815
`O
`100--------------
`
`l
`TIME (DAYS)
`
`15
`
`2
`
`0.15
`
`0.1
`RS
`0.05
`
`(b)
`
`
`
`0.5
`
`1
`TIME (DAYS)
`
`15
`
`2
`
`is
`
`l
`TIME (DAYS)
`FIG. 33
`
`Page 34 of 67
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`

`

`Patent Application Publication Sep. 30, 2004 Sheet 34 of 40
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`US 2004/0193025 A1
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`
`
`.
`
`Page 35 of 67
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`

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`Patent Application Publication Sep. 30, 2004 Sheet 35 of 40
`
`US 2004/0193025 A1
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`(b)
`
`TIME
`
`TIME
`
`FIG. 35
`
`o TIME
`
`(b) r
`
`TIME
`FIG. 36
`
`Page 36 of 67
`
`

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`Patent Application Publication Sep. 30, 2004 Sheet 36 of 40
`
`US 2004/0193025 A1
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0
`
`Page 37 of 67
`
`

`

`Patent Application Publication Sep. 30, 2004 Sheet 37 of 40
`
`US 2004/0193025 A1
`
`(a)
`400
`50
`200
`Z2
`s
`O
`O>
`A.
`08/13 00:00 08/13 12:00 08/14 00:00 08/14 12:00 08/15 00:00 08/15 12:00 08/16 00:00
`1.5
`S 1
`0.5
`08/1300:00 08/13 12:00 08/1400.00 08/14 12.00 08/15 00:00 08/1512.00 08/16 00:00
`25 26
`a 15
`(C)
`É's
`O
`08/13 00:00 08/13 12:00 08/14 00:00 08/14 12:00 08/15 00:00 08/15 12:00 08/16 00:00
`
`(b)
`
`
`
`o? O
`08/13 00:00 08/13 12:00 08/14 00:00 08/14 12:00 08/15 00:00 08/15 12:00 08/16 00:00
`
`
`
`(d)
`
`
`
`" There horror
`were
`
`08:20:00 08/13 12:00 08/14 00:00 08/1412:00 08/15 00:00 08/15 12:00 08/16 00:00
`
`
`
`(f)
`
`
`
`:
`5 0.5
`2 0
`A.
`08/13 00:00 08/13 12:00 08/14 00:00 08/14 12:00 08/15 00:00 08/15 12.00 08/16 00:00
`TIME (DAYS)
`FIG. 38
`
`(h)
`
`Page 38 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 38 of 40
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`US 2004/0193025 A1
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`
`
`
`
`
`
`
`
`Processed
`Glucose
`Values
`
`
`
`
`
`
`
`
`
`
`
`Processed
`Glucose
`Values
`
`
`
`
`
`PD Controller
`(artificial Beta-cell)
`
`commands
`
`Subcutaneous
`insulin
`compensation
`
`
`
`compensated
`commands
`
`Subcutaneous
`insulin delivery
`system
`
`Sensor
`Compensation,
`calibration and
`filters
`
`Raw Glucose
`Sensor Values
`
`Glucose sensor
`
`Sensor
`Readings
`
`Body
`
`FIG. 39a
`
`PD Controller
`(artificial Beta-cell)
`
`Commands
`
`IV insulin delivery
`system
`
`insulin
`
`Body
`
`
`
`Insulin
`
`Blood
`
`Extrapolation and
`FIR filter
`
`Raw Glucose
`Sensor Values
`
`Auto blood withdrawal
`and glucose determination
`
`FIG. 39b
`
`Page 39 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 39 of 40
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`US 2004/0193025 A1
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`
`
`410
`
`peristaltic roller
`(reversible) 420
`
`catheter
`
`400
`
`sensor unit
`(GOD based sensor)
`
`flush volume
`
`reservoir
`
`fixed catheter plus flush volume
`
`FG. 40
`
`Page 40 of 67
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`Patent Application Publication Sep. 30, 2004 Sheet 40 of 40
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`US 2004/0193025 A1
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`3DO
`
`2 O O
`
`1OO
`
`
`
`- P--D :
`--- adaptive PD :
`
`(a)
`
`(b)
`
`O
`
`6
`
`120
`Title
`
`1 BO
`
`24D
`
`FIG. 41
`
`Page 41 of 67
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`

`

`US 2004/0193025 A1
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`Sep. 30, 2004
`
`CLOSED-LOOP METHOD FOR CONTROLLING
`INSULIN INFUSION
`
`RELATED APPLICATIONS
`0001. This application is continuation-in-part of U.S.
`application Ser. No. 09/586,175 filed Jun. 1, 2000, entitled
`“Closed Loop System For Controlling Insulin Infusion,”
`which claims priority on U.S. Provisional Application serial
`No. 60/137,601 filed Jun. 3, 1999, entitled “Closed Loop
`Algorithms For Continuous Monitoring And Insulin Infu
`Sion,” and U.S. Provisional Application serial No. 60/162,
`255 filed Oct. 29, 1999 and entitled “Closed Loop Algo
`rithms For Continuous Monitoring And Insulin Infusion,” all
`of which are specifically incorporated by reference herein.
`
`FIELD OF THE INVENTION
`0002 This invention relates to closed loop drug delivery
`Systems and more Specifically to Systems for controlling the
`infusion rate of insulin based on continuously monitored
`body glucose levels.
`
`BACKGROUND OF THE INVENTION
`0003. The pancreas of a normal healthy person produces
`and releases insulin into the blood Stream in response to
`elevated blood plasma glucose levels. Beta cells (B-cells),
`which reside in the pancreas, produce and Secrete the insulin
`into the blood stream, as it is needed. If B-cells become
`incapacitated or die, a condition known as Type I diabetes
`mellitus (or in Some cases if f-cells produce insufficient
`quantities of insulin, Type II diabetes), then insulin must be
`provided to the body from another source.
`0004 Traditionally, since insulin cannot be taken orally,
`insulin has been injected with a Syringe. More recently, use
`of infusion pump therapy has been increasing, especially for
`delivering insulin for diabetics. For example, external infu
`Sion pumps are worn on a belt, in a pocket, or the like, and
`deliver insulin into the body via an infusion tube with a
`percutaneous needle or a cannula placed in the Subcutaneous
`tissue. As of 1995, less than 5% of Type I diabetics in the
`United States were using infusion pump therapy. Presently
`over 7% of the more than 900,000 Type I diabetics in the
`U.S. are using infusion pump therapy. And the percentage of
`Type I diabetics that use an infusion pump is growing at an
`absolute rate of over 2% each year. Moreover, the number of
`Type I diabetics is growing at 3% or more per year. In
`addition, growing numbers of insulin using Type II diabetics
`are also using infusion pumps. Physicians have recognized
`that continuous infusion provides greater control of a dia
`betic's condition, and are also increasingly prescribing it for
`patients. Although offering control, pump therapy can Suffer
`from Several complications that make use of traditional
`external infusion pumps less desirable for the user.
`
`SUMMARY OF THE DISCLOSURE
`0005 According to an embodiment of the invention, a
`closed loop infusion System and method for controlling
`blood glucose concentration in the body of a user is
`described. Embodiments of the present invention include
`obtaining a blood glucose level from the body of the user,
`generating commands by a proportional plus, integral plus,
`derivative (PID) controller from the obtained glucose level,
`and infusing a liquid into the body of the user in response to
`
`the commands. In particular embodiments, the PID control
`ler is a bilinear PID controller.
`0006 According to another embodiment of the invention,
`a closed loop infusion System is for infusing a fluid into a
`user. The closed loop infusion System includes a Sensor
`System, a controller, and a delivery System. The Sensor
`System includes a Sensor for monitoring a condition of the
`user. The Sensor produces a Sensor Signal, which is repre
`Sentative of the condition of the user, and is used to generate
`a controller input. The controller uses the controller input to
`generate commands that affect the operation of the delivery
`System. Accordingly, the delivery System infuses a liquid
`into the user. In particular embodiments, glucose concen
`tration is monitored by the Sensor System, and the liquid
`delivered to the user includes insulin. In preferred embodi
`ments, the Sensor System sends a message, generated using
`the Sensor Signal, to the delivery System. The message is
`used to generate the controller input. In particular embodi
`ments, the Sensor is a Subcutaneous Sensor in contact with
`interstitial fluid. In further particular embodiments, two or
`more Sensors are included in the Sensor System. Still in
`further embodiments, the blood glucose concentration is
`obtained through an IV catheter or a vascular Sensor. In
`addition, in particular embodiments the liquid is delivered to
`through an IV catheter connected to the body of the user.
`0007. In preferred embodiments, the sensor system is
`predominately external to the user's body. And the delivery
`System is predominately external to the user's body. In
`alternative embodiments, the Sensor System is predomi
`nately internal to the user's body. In other alternative
`embodiments, the delivery System is predominately internal
`to the user's body.
`0008. In preferred embodiments, the controller uses a
`first Set of one or more controller gains when the glucose
`concentration is higher than a desired basal glucose concen
`tration and the controller uses a Second Set of one or more
`controller gains when the glucose concentration is lower
`than a desired basal glucose concentration. In alternative
`embodiments, the controller uses a first Set of one or more
`controller gains when the glucose concentration is increas
`ing and a Second Set of one or more controller gains when
`the glucose concentration is decreasing. In further alterna
`tive embodiments, the controller uses a first Set of one or
`more controller gains when the glucose concentration is
`higher than a desired basal glucose concentration and the
`glucose concentration is increasing, and the controller uses
`a Second Set of one or more controller gains when the
`glucose concentration is higher than a desired basal glucose
`concentration and the glucose concentration is decreasing;
`and the controller uses a third Set of one or more controller
`gains when the glucose concentration is lower than a desired
`basal glucose concentration and the glucose concentration is
`increasing, and the controller uses a fourth Set of one or
`more controller gains when the glucose concentration is
`lower than a desired basal glucose concentration and the
`glucose concentration is decreasing.
`0009. In preferred embodiments, one or more controller
`gains are Selected Such that the commands generated by the
`controller cause the delivery System to infuse insulin into the
`body of the user in response to a glucose concentration at a
`rate Similar to the rate that beta cells would release insulin
`in an individual with a healthy normally functioning pan
`
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`creas. Alternatively, one or more controller gains are
`Selected So that the commands generated by the controller
`cause the delivery system to infuse insulin into the body of
`the user in response to a glucose concentration at a rate Such
`that the insulin concentration profile in the user's blood
`Stream is similar to the insulin concentration profile that
`would be generated by the release of insulin beta cells in an
`individual with a healthy normally functioning pancreas. In
`other alternative embodiments, a post-controller lead/lag
`compensator is used to modify the commands generated by
`the controller to cause the delivery System to infuse insulin
`into the body of the user in response to a glucose concen
`tration at a rate Such that the insulin concentration profile in
`the user's blood Stream is similar to the insulin concentration
`profile that would be generated by the release of insulin beta
`cells in an individual with a healthy normally functioning
`pancreas.
`0010. In preferred embodiments, one or more controller
`gains are Selected by a method that includes the Step of
`measuring an insulin response of at least one individual with
`a healthy normally functioning pancreas and calculating the
`controller gains that cause the commands to generally match
`the insulin response of at least one individual. In particular
`embodiments, the derivative gain K is calculated using the
`first phase insulin response (p1) measured from a normal
`glucose tolerant (NGT) individual. In further particular
`embodiments, one or more controller gains are calculated
`from a ratio of one or more controller gains.
`0011. In preferred embodiments, one or more controller
`gains includes at least one tuning parameter. In particular
`embodiments, the tuning parameter is a post-controller
`lead/lag compensator is used to modify the commands
`generated by the controller to compensate for an insulin
`delivery delay due to infusing insulin into a user tissue
`rather than directly into the user's blood stream. In addi
`tional embodiments, the tuning parameter is an integrator
`clip. Still further embodiments, the tuning parameter is a
`feedback of predicted plasma insulin. Yet further embodi
`ments, the tuning parameter is an integrator leak.
`0012. In alternative embodiments, the controller is influ
`enced by inputs of more than one measured body charac
`teristic. For example, measured body characteristics that
`might be used to influence the controller include one or more
`amino acid concentrations, one or more gastrointestinal
`hormone concentrations, one or more other hormone con
`centrations, blood pH, interstitial fluid (ISF) pH, one or more
`blood glucose concentrations, and one or more interstitial
`fluid (ISF) glucose concentrations. In particular embodi
`ments, the Sensor is a multi-Sensor that measures both
`glucose concentration and pH.
`0013 In preferred embodiments, the sensor system pro
`duces a diagnostic Signal in addition to the Sensor Signal, and
`the diagnostic Signal is used to indicate when the Sensor
`Signal accuracy has diminished.
`0.014. Other features and advantages of the invention will
`become apparent from the following detailed description,
`taken in conjunction with the accompanying drawings which
`illustrate, by way of example, various features of embodi
`ments of the invention.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`0015. A detailed description of embodiments of the
`invention will be made with reference to the accompanying
`drawings, wherein like numerals designate corresponding
`parts in the Several figures.
`0016 FIG. 1 is a block diagram of a closed loop glucose
`control System in accordance with an embodiment of the
`present invention.
`0017 FIG. 2 is a front view of closed loop hardware
`located on a body in accordance with an embodiment of the
`present invention.
`0018 FIG.3(a) is a perspective view of a glucose sensor
`System for use in an embodiment of the present invention.
`0.019 FIG. 3(b) is a side cross-sectional view of the
`glucose sensor system of FIG.3(a).
`0020 FIG. 3(c) is a perspective view of a sensor set of
`the glucose sensor system of FIG. 3(a) for use in an
`embodiment of the present invention.
`0021 FIG. 3(d) is a side cross-sectional view of the
`sensor set of FIG. 3(c).
`0022 FIG. 4 is a cross sectional view of a sensing end of
`the sensor of FIG. 3(d).
`0023 FIG. 5 is a top view of an infusion device with a
`reservoir door in the open position, for use in an embodi
`ment of the present invention.
`0024 FIG. 6 is a side view of an infusion set with the
`insertion needle pulled out, for use in an embodiment of the
`present invention.
`0025 FIG. 7 is a circuit diagram of a sensor and its
`power Supply in accordance with an embodiment of the
`present invention.
`0026 FIG. 8(a) is a diagram of a single device and its
`components in accordance with an embodiment of the
`present invention.
`0027 FIG. 8(b) is a diagram of two devices and their
`components in accordance with an embodiment of the
`present invention.
`0028 FIG. 8(c) is another diagram of two devices and
`their components in accordance with an embodiment of the
`present invention.
`0029 FIG. 8(d) is a diagram of three devices and their
`components in accordance with an embodiment of the
`present invention.
`0030 FIGS. 9 is a table listing the devices of FIGS. 8
`(a-d) and their components.
`0031
`FIG. 10 is a block diagram of the glucose sensor
`system of FIG. 3(a).
`0032 FIG. 11(a) is a detailed block diagram of an A/D
`converter for the glucose sensor system of FIG. 10 in
`accordance with an embodiment of the present invention.
`0033 FIG. 11(b) is a detailed block diagram of the A/D
`converter for the glucose sensor system of FIG. 10 with a
`pulse duration output Selection option in accordance with an
`embodiment of the present invention.
`
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`
`0034 FIG. 12 is a circuit diagram of an I-F A/D con
`verter of FIG. 10 accompanied by charts of node signals in
`accordance with an embodiment of the present invention.
`0035 FIG. 13 is another circuit diagram of an I-F A/D
`converter of FIG. 10 accompanied by charts of node signals
`in accordance with an embodiment of the present invention.
`0.036
`FIG. 14 is still another circuit diagram of an I-F
`A/D converter of FIG. 10 accompanied by charts of node
`Signals in accordance with an embodiment of the present
`invention.
`0037 FIG. 15 is a circuit diagram of an I-V A/D con
`verter of FIG. 10 in accordance with an embodiment of the
`present invention.
`0.038
`FIG. 16 is a block diagram of the glucose sensor
`system of FIG. 10 with a pre-filter and a filter in accordance
`with an embodiment of the present invention.
`0039 FIG. 17 is a chart of an example of a pre-filter of
`FIG. 16 and its effects on digital sensor values Dsig in
`accordance with an embodiment of the present invention.
`0040 FIG. 18 is frequency response chart for a filter of
`FIG. 16 in accordance with an embodiment of the present
`invention.
`0041 FIG. 19(a) is a plot of a filtered and an unfiltered
`Sensor Signal Over time in accordance with an embodiment
`of the present invention.
`0042 FIG. 19(b) is close up of a section of the plot of
`FIG. 19(a) in accordance with an embodiment of the present
`invention.
`0.043
`FIG. 20 is a cross-sectional view of a sensor set
`and an infusion Set attached to the body in accordance with
`an embodiment of the present invention.
`0044 FIG. 21 is a frequency response chart of a time
`delay correcting Weiner filter in accordance with an embodi
`ment of the present invention.
`004.5
`FIG. 22 is a plot of a digital sensor values Dsig
`before and after time delay correction compared to actual
`glucose measurements over time in accordance with an
`embodiment of the present invention.
`0046 FIG. 23(a) is a diagram of a glucose clamp (glu
`cose level with respect to time).
`0047 FIG. 23(b) is a plot of insulin concentration in a
`normal glucose tolerant (NGT) individual in response to
`various magnitudes of glucose clamps of FIG. 23(a).
`FIG. 24(a) is a diagram of a glucose clamp.
`0048)
`0049 FIG. 24(b) is a diagram of a proportional insulin
`response to the glucose clamp of FIG. 24(a) in accordance
`with an embodiment of the present invention.
`0050 FIG. 24(b) is a diagram of a proportional insulin
`response to the glucose clamp of FIG. 24(a) in accordance
`with an embodiment of the present invention.
`0051 FIG. 24(c) is a diagram of an integral insulin
`response to the glucose clamp of FIG. 24(a) in accordance
`with an embodiment of the present invention.
`
`0.052 FIG. 24(d) is a diagram of a derivative insulin
`response to the glucose clamp of FIG. 24(a) in accordance
`with an embodiment of the present invention.
`0053 FIG. 24(e) is a diagram of a combined propor
`tional, integral, and derivative insulin response to the glu
`cose clamp of FIG. 24(a) in accordance with an embodi
`ment of the present invention.
`0054 FIG. 25(a) is a plot of insulin responses to a
`glucose clamp for exercise trained and normal individuals.
`0.055 FIG.25(b) is a bar chart of glucose uptake rates for
`exercise trained and normal individuals.
`0056 FIG. 26 is a block diagram of a closed loop system
`to control blood glucose levels through insulin infusion
`based on glucose level feedback in accordance with an
`embodiment of the present invention.
`0057 FIG. 27 is a detailed block diagram of the portion
`of the control loop of FIG. 26 that is in the body in
`accordance with an embodiment of the present invention.
`0.058 FIGS. 28(a and b) are plots of measured insulin
`responses of two different normal glucose tolerant (NGT)
`individuals to a glucose clamp for use with an embodiment
`of the present invention.
`0059 FIG.29(a) is a plot of two different glucose sensor
`outputs compared to glucose meter readings during a glu
`cose clamp in accordance with an embodiment of the present
`invention.
`0060 FIG.29(b) is a plot of actual insulin concentration
`in blood compared to a controller commanded insulin con
`centration in response to the glucose clamp of FIG.29(a) in
`accordance with an embodiment of the present invention.
`0061 FIG. 30 is a top view of an end of a multi-sensor
`for measuring both glucose concentration and pH in accor
`dance with an embodiment of the present invention.
`0062 FIG. 31(a) is a representative drawing of blood
`glucose compared to Sensor measured blood glucose over
`time in accordance with an embodiment of the present
`invention.
`0063 FIG. 31(b) is a representative drawing of sensor
`sensitivity over the same period of time as FIG. 31(a) in
`accordance with an embodiment of the present invention.
`0064 FIG. 31(c) is a representative drawing of sensor
`resistance over the same period of time as FIG. 31(a) in
`accordance with an embodiment of the present invention.
`0065 FIG. 32 is a block diagram using the derivative of
`Sensor resistance to determine when to recalibrate or replace
`the Sensor in accordance with an embodiment of the present
`invention.
`0066 FIG.33(a) is a plot of an analog sensor signal Isig
`over time in accordance with an embodiment of the present
`invention.
`0067 FIG. 33(b) is a plot of sensor resistance over the
`same period of time as FIG. 32(a) in accordance with an
`embodiment of the present invention.
`0068 FIG.33(c) is a plot of the derivative of the sensor
`resistance of FIG. 32(b) in accordance with an embodiment
`of the present invention.
`
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`
`0069 FIG. 34(a) is a bottom view of a telemetered
`characteristic monitor in accordance with an embodiment of
`the present invention.
`0070 FIG. 34(b) is a bottom view of a different teleme
`tered characteristic monitor in accordance with an embodi
`ment of the present invention.
`0071 FIG. 35(a) is a drawing of a blood plasma insulin
`response to a glucose clamp in a normal glucose tolerant
`(NGT) individual in accordance with an embodiment of the
`present invention.
`0072 FIG.35(b) is a drawing of the blood plasma insulin
`response of FIG. 35(a) when delayed due to insulin being
`delivered to the Subcutaneous tissue instead of directly into
`the blood stream in accordance with an embodiment of the
`present invention.
`0073 FIG. 36(a) is a drawing of blood plasma insulin
`concentration over time after an insulin bolus is delivered
`directly into the blood Stream in accordance with an embodi
`ment of the present invention.
`0074 FIG. 36(b) is a drawing of a blood plasma insulin
`concentration over time after an insulin bolus is delivered
`into the Subcutaneous tissue in accordance with an embodi
`ment of the present invention.
`0075 FIG. 37 is a block diagram of the closed loop
`system of FIG. 26 with the addition of a post-controller
`compensator and a derivative filter in accordance with an
`embodiment of the present invention.
`0.076 FIG.38(a) is a plot of sensor signal measurements
`and Via measurements with respect to time in accordance
`with an embodiment of the present invention.
`0077 FIG. 38(b) is a plot of a measured counter elec
`trode Voltage Vcnt with respect to time in accordance with
`an embodiment of the present invention.
`0078 FIG.38(c) is a plot of calculated sensor sensitivity
`with respect to time in accordance with an embodiment of
`the present invention.
`0079 FIG. 38(d) is a plot of a calculation of sensor
`resistance RS with respect to time in accordance with an
`embodiment of the present invention.
`0080 FIG.38(e) is a plot of another calculation of sensor
`resistance RS with respect to time in accordance with an
`embodiment of the present invention.
`0081 FIG. 38(f) is a plot of the derivative of sensor
`resistance Rs, of FIG.38(d) with respect to time in accor
`dance with an embodiment of the present invention.
`0082 FIG. 38(g) is a plot of the derivative of the sensor
`resistance Rs of FIG. 38(e) with respect to time in accor
`dance with an embodiment of the present invention.
`0083 FIG.38(h) is a plot of when sensors were replaced
`with respect to time in accordance with an embodiment of
`the present invention.
`0084 FIGS. 39(a) and (b) are a block diagrams of a
`closed loop glucose control System in accordance with
`embodiments of the present invention.
`0085 FIG. 40 is a block diagram of auto blood with
`drawal and return in accordance