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`US 20060224109Al
`
`c19) United States
`c12) Patent Application Publication
`Steil et al.
`
`c10) Pub. No.: US 2006/0224109 Al
`Oct. 5, 2006
`(43) Pub. Date:
`
`(54) CLOSED LOOP SYSTEM FOR
`CONTROLLING INSULIN INFUSION
`
`(75)
`
`Inventors: Garry M. Steil, Pasadena, CA (US);
`Kerstin Rebrin, South Pasadena, CA
`(US)
`
`Correspondence Address:
`MEDTRONIC MINIMED INC.
`18000 DEVONSHIRE STREET
`NORTHRIDGE, CA 91325-1219 (US)
`
`(73)
`
`Assignee: MEDTRONIC MINIMED, INC.
`
`(21)
`
`Appl. No.:
`
`11/417,426
`
`(22)
`
`Filed:
`
`May 3, 2006
`
`Related U.S. Application Data
`
`(60)
`
`Division of application No. 10/335,275, filed on Dec.
`31, 2002, which is a continuation-in-part of applica(cid:173)
`tion No. 09/586,175, filed on Jun. 1, 2000, now Pat.
`No. 6,558,351.
`
`(60) Provisional application No. 60/162,255, filed on Oct.
`29, 1999. Provisional application No. 60/137,601,
`filed on Jun. 3, 1999.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`A61M 31/00
`(2006.01)
`A61B 5105
`(2006.01)
`(52) U.S. Cl. ............................. 604/66; 604/503; 600/347
`
`(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.
`
`30
`
`I
`
`Page 1 of 67
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`Page 2 of 67
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`

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`Patent Application Publication Oct. 5, 2006 Sheet 2 of 40
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`Patent Application Publication Oct. 5, 2006 Sheet 4 of 40
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`

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`Patent Application Publication Oct. 5, 2006 Sheet 5 of 40
`
`US 2006/0224109 Al
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`REF
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`Page 6 of 67
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`

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`Patent Application Publication Oct. 5, 2006 Sheet 6 of 40
`
`US 2006/0224109 Al
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`54
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`Page 7 of 67
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`Patent Application Publication Oct. 5, 2006 Sheet 7 of 40
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`US 2006/0224109 Al
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`Page 8 of 67
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`Patent Application Publication Oct. 5, 2006 Sheet 8 of 40
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`Page 9 of 67
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`Patent Application Publication Oct. 5, 2006 Sheet 9 of 40
`
`US 2006/0224109 Al
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`INFUSION PUMP
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`Page 10 of 67
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`Page 11 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 11 of 40
`
`US 2006/0224109 Al
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`Page 13 of 67
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`Patent Application Publication Oct. 5, 2006 Sheet 13 of 40
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`Page 14 of 67
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`Patent Application Publication Oct. 5, 2006 Sheet 14 of 40
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`Page 17 of 67
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`Patent Application Publication Oct. 5, 2006 Sheet 17 of 40
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`Patent Application Publication Oct. 5, 2006 Sheet 18 of 40
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`Patent Application Publication Oct. 5, 2006 Sheet 20 of 40
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`10
`4
`TIME (hr)
`
`lsig (nA)
`
`50
`
`25
`
`0 - 4 - - - . . - - - - - - . - - - . . . - - - - - - - - . - - - - - - - 1
`5.0
`6.5
`6.0
`5.5
`7.0
`7.5
`TIME (hr)
`FIG. 19
`
`Page 21 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 21 of 40
`
`US 2006/0224109 Al
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`422
`
`528
`
`420
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`32
`
`0
`
`0
`
`0
`
`0 44
`
`0
`
`0
`
`0
`
`0
`
`36
`
`56
`
`FIG. 20
`
`Page 22 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 22 of 40
`
`US 2006/0224109 Al
`
`C)
`-=:::t"
`
`C)
`C'-.J
`
`C)
`.---I
`
`c..o
`C'-.J
`
`~ \
`
`LC)
`(Y)
`
`C>
`(Y)
`
`I...(")
`C'-.J
`
`C)
`C'-.J
`
`L.!")
`.---I
`
`C>
`.---I
`
`C)
`
`C)
`
`LLJ
`0
`:::::J
`!::=
`z
`(.!J
`c:x::
`~
`
`..........
`
`....c ---c..,
`
`.._....
`CJ
`LLJ
`0::
`LL
`
`.---I
`
`0-J .
`CJ
`LL
`
`Page 23 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 23 of 40
`
`US 2006/0224109 Al
`
`C)
`-=:::::t""
`C'J
`
`C)
`ex::>
`......--4
`
`C)
`C'J
`.....--I
`
`C )
`(.C)
`
`•
`
`C)
`C)
`.....--1
`
`C)
`LI'.)
`
`C',.J
`C',.J
`
`-
`
`..----..
`C
`E
`.
`(.9
`LL.J
`~ LL
`r--
`
`00
`C'J
`tj"
`
`C ) C'J
`(V) CV)
`tj" tj"
`
`•
`
`C>
`L(")
`C'J
`
`C)
`LO
`.....--1
`
`tu)
`
`(/)
`
`--"'O
`E ---L1...J
`0 u
`::::>
`__J
`(.!J
`
`Page 24 of 67
`
`

`

`> ....
`....
`O'I --- 0
`
`1,0
`0
`
`.i;...
`N
`N
`
`0
`0
`N
`rJ'1
`c
`
`0 ....
`
`0
`.i;...
`
`.i;...
`N
`.....
`rJ'1 =- ('D
`
`('D
`
`O'I
`0
`0
`N
`Ul
`:-+-
`0
`
`(')
`
`.... 0 =
`.... 0 = ""O = O" -....
`"e -....
`>
`('D = .....
`~ .....
`""O
`
`~ .....
`
`(')
`
`"e
`
`~ .....
`
`(')
`
`FIG. 23
`TIME (mn)
`
`120
`
`90
`
`60
`
`30
`
`0
`
`-30
`
`0 ,.____.__.____.___.__.___......____._____.___.____.___.___....____..__.__.,____.__ ___ ____,
`
`(b)
`
`3.00 mM
`
`5.44 mM
`
`7.94 mM
`
`12.83 mM
`LlG
`
`I
`
`'
`
`'
`
`TT
`
`,,,-'
`,-
`
`,-'
`
`.
`
`(D. ELAHI DIABETES CARE 19:278-286 1996)
`
`HYPERGLYCEMIC CLAMPS
`
`300
`
`600
`
`INSULIN (pmol/L)
`
`900 ,--------------------,
`
`(a)
`
`1 ___________________ _! ~G
`
`GLC (mM) :,,=G,+~G
`
`Page 25 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 25 of 40
`
`US 2006/0224109 Al
`
`J,----Gc
`
`G 8
`
`(a)
`
`(b)
`
`(c)
`
`(d) ~
`
`(e)
`
`442
`
`FIG. 24
`
`Page 26 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 26 of 40
`
`US 2006/0224109 Al
`
`PLASMA INSULIN LEVEL
`i
`
`Tl T l l
`444
`J
`446-:i>--•
`
`----------
`
`200
`
`(uU/ml) 150
`100
`
`5 0
`0 ----------------
`Tl ME (min)
`
`GLUCOSE UPTAKE RATE
`
`30
`
`20 450
`
`448
`
`(mg/min per kg FFM)
`
`10
`
`FIG. 25
`
`( )
`a
`
`(b)
`
`Page 27 of 67
`
`

`

`.... 0 =
`""O = O" -....
`.... 0 =
`t "e -....
`
`~ .....
`
`(')
`
`('D = .....
`~ .....
`""O
`
`> ....
`....
`O'I --- 0
`
`1,0
`0
`
`.i;...
`N
`N
`
`0
`0
`N
`rJJ
`c
`
`0 ....
`
`0
`.i;...
`
`-....J
`N
`.....
`rJJ =(cid:173)
`
`('D
`('D
`
`O'I
`0
`0
`N
`~Ul
`:-+-
`0
`
`(')
`
`~ .....
`
`(')
`
`I
`
`:
`
`I
`
`1NsuuNi I cur~¼BEous I 1NsuuN
`\ :~--124
`
`BODY
`
`:
`
`24°"'
`
`PUMP
`
`COMM AN D .--I 1-N S_,__U _LI N--,1
`DELIVERY
`INSULIN
`
`I
`
`34
`
`I
`
`,22
`
`,20
`
`12
`
`,
`
`.dx
`d
`
`dx
`j I ~
`
`•
`
`ESTIMATE
`GLUCOSE
`BLOOD
`ADJUSTED
`PRESENT
`I
`ERROR
`LEVEL
`GLUCOSE
`GE
`
`LEVEL GB -
`GLUCOSE
`BLOOD
`BASAL
`D.ESIRED
`
`TISSUE
`
`CUTANE-OUS
`
`SU .. B
`
`1s~I GLUCOSE:
`
`I
`
`BLOOD
`
`LEVEL
`
`STREAM
`BLOOD
`
`TISSUE
`
`I
`
`I
`
`I
`
`I
`
`I
`
`I
`I
`I
`I
`
`----------------------------
`
`FIG. 26
`
`CALIBRATION
`
`LEVEL
`GLUCOSE
`ISF
`
`SENSOR
`:
`:
`:
`
`/
`26
`
`-SIGNAL
`SENSOR
`
`&
`FILTER
`
`/
`
`16
`
`G
`ESTIMATE
`GLUCOSE
`BLOOD
`PRESENT ./ 452
`
`ALGORITHMS
`CORRECTION
`
`454
`
`Page 28 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 28 of 40
`
`US 2006/0224109 Al
`
`I
`
`I
`BO DY
`
`~
`
`I
`INSULIN PUMP
`I
`I
`INSULIN IS INTRODUCED INTO THE
`INTERSTITIAL FLUID (ISF) OF THE
`SUBCUTANEOUS TISSUE OF THE
`BODY
`I
`INSULIN DIFFUSES FROM THE ISF
`SURROUNDING THE CANNULA INTO
`BLOOD PLASMA IN THE MAIN
`CIRCULATORY SYSTEM.
`I
`INSULIN DIFFUSES FROM THE
`BLOOD PLASMA INTO THE ISF
`THROUGHOUT THE BODY
`I
`INSULIN BINDS WITH AND
`ACTIVATES MEMBRANE RECEPTOR
`PROTEINS ON TISSUE CELLS.
`I
`GLUCOSE IS REMOVED FROM THE
`ISF BY PERMEATING THE
`ACTIVATED CELL MEMBRANES.
`(ISF GLUCOSE DECREASES)
`I
`GLUCOSE DIFFUSES FROM THE BLOOD
`PLASMA INTO THE ISF TO MAINTAIN A
`BALANCED THE GLUCOSE
`CONCETRATION BETWEEN THE TWO.
`(BLOOD GLUCOSE DECREASES)
`I
`THE GLUCOSE IN THE ISF
`DECREASES AS IT IS TAKEN UP BY
`CELLS.
`I
`GLUCOSE IN THE SENSOR
`MEMBRANE DECREASES.
`I
`I
`
`FIG. 27
`
`Page 29 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 29 of 40
`
`US 2006/0224109 Al
`
`150
`
`100
`INSULIN (uU/ml)
`
`50
`
`0
`
`•
`
`0
`
`•
`
`(a)
`
`• •
`
`•
`
`120
`60
`TIME (mn)
`
`180
`
`150.-------------.
`
`100
`INSULIN (uU/ml)
`
`50
`
`•
`•
`
`•
`
`(b)
`
`0 ~~~~~~~~~~
`0
`60
`120
`180
`TIME (mn)
`
`FIG. 28
`
`Page 30 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 30 of 40
`
`US 2006/0224109 Al
`
`...--...
`400
`-0
`t:i!> 300
`---
`E
`200
`LJ..J
`C/)
`0 u
`100
`=> _,J
`
`(.!)
`
`0
`
`- 120
`
`E
`...__
`=>
`::l
`.__...
`z::
`::::i
`=>
`(/)
`z::
`
`100
`80
`60
`40
`20
`0
`
`• 460
`-462
`- · - · 464
`
`-
`
`(a)
`
`•
`
`(b)
`
`120
`
`180
`
`.
`.
`. '\
`
`•
`
`0
`
`• 456
`458
`
`-
`
`•
`
`60
`TIME (min)
`
`FIG. 29
`
`✓ 508
`
`502
`
`FIG. 30
`
`Page 31 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 31 of 40
`
`US 2006/0224109 Al
`
`0
`
`0
`
`0
`
`SENSOR
`SENSITIVITY
`
`SENSOR
`RESISTANCE
`
`TIME
`
`TIME
`
`TIME
`
`FIG. 31
`
`(b)
`
`(c)
`
`Page 32 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 32 of 40
`
`US 2006/0224109 Al
`
`MEASURE
`lsig AND Vctr
`
`CALCULATE
`RESISTANCE
`
`CALCULATE
`dR/dt
`
`IS
`dRsfdt >
`REPLACEMENT
`THRESHOLD?
`
`IS
`dRsfdt >
`RECALIBRATE
`THRESHOLD?
`
`YES
`
`RECALIBRATE
`SENSOR
`
`FIG. 32
`
`NO
`
`YES
`
`REPLACE
`SENSOR
`
`Page 33 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 33 of 40
`
`US 2006/0224109 Al
`
`50 ······-···--
`(a) 0o
`
`o.3
`
`-
`
`'
`'
`'
`
`0.5
`
`- -- --
`
`'
`
`~ .... -.. - - - - -.... - -. -:- .. -
`.
`.
`1
`TIME (DAYS)
`
`-----:---------------------:----------
`.
`.
`.
`.
`'
`'
`2
`1.5
`
`0 . 1 5~ - - - - - - - - - - - - - - - - - - - - - ,
`
`0.1 ---· · --- · · · --· · · · ·· i · · · --· · · · · · -· · · · · --~- · · -· · · · -
`Rs
`0.05 --···-······
`
`- - . - : - -
`
`- --
`
`. - - - - - . - - - - ~- - - - - . - - . - - - - -
`'
`'
`
`.... ------------------······-----
`
`- - - - -:- - - .. - - - - - - - - - - .. - - -~ - - - - -. -. -
`.
`.
`'
`
`'
`
`(b) 0o t _ _ - -~ - - -~ - - -~ - -~ 2 - - - - '
`0.5
`1
`1.5
`TIME (DAYS)
`
`524
`l 0 r - -~ c - - - - - - - - - - - - - - - - - - - - - ,
`5 ................ ·< · .... ..
`
`-------:---------------------,--------··
`'
`'
`'
`'
`'
`'
`'
`'
`'
`'
`'
`'
`
`0 ~ I \W , , I
`.
`dRs/dt
`-5 ................. ·: · .................. ·:· .. -...... .
`
`-10.__ _ _ ...__~----~----.w.~----~----'
`0.3
`0.5
`1
`1.5
`2
`(C) 0
`TIME (DAYS)
`FIG. 33
`
`Page 34 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 34 of 40
`
`US 2006/0224109 Al
`
`c:,
`C'-J
`LO
`
`00
`.----.
`LO
`
`0
`
`-..c::2 -
`
`-cu -
`
`tj(cid:173)
`
`(Y') .
`CJ
`l...1-
`
`Page 35 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 35 of 40
`
`US 2006/0224109 Al
`
`(a)
`
`(b)
`
`(a)
`
`(b)
`
`TIME
`
`TIME
`
`FIG. 35
`
`TIME
`
`TIME
`FIG. 36
`
`Page 36 of 67
`
`

`

`> ....
`....
`O'I --- 0
`
`1,0
`0
`
`.i;...
`N
`N
`
`0
`0
`N
`rJJ
`c
`
`O'I
`~
`.....
`rJJ =(cid:173)
`
`('D
`('D
`
`0 ....
`
`0
`.i;...
`
`O'I
`0
`0
`N
`~Ul
`:-+-
`0
`
`(')
`
`~ .....
`
`(')
`
`.... 0 =
`""O = O" -....
`.... 0 =
`t "e -....
`
`~ .....
`
`(')
`
`('D = .....
`~ .....
`""O
`
`TISSUE
`
`CUTANE-OUS
`
`su'B
`
`LEVEL
`
`18 __. GLUCOSE
`
`BLOOD
`
`STREAM
`I BLOOD
`
`: GLUCOSE
`i
`:
`/
`
`ISF
`
`I
`
`/
`)
`i
`
`I ----------------------------
`
`I
`
`SENSOR -LEVEL
`
`/
`26
`
`FIG. 37
`
`16
`
`~ SIGNAL
`SENSOR
`I
`
`CALIBRATION
`
`&
`FILTER
`
`COMPENSATED
`
`COMMAND
`DELIVERY
`INSULIN
`
`COMMAND
`DELIVERY
`INSULIN
`\
`
`PUMP
`
`\
`\
`
`COMPENSATOR
`
`LEAD/LAG
`
`;
`/24
`
`BODY
`
`,20
`
`TISSUE
`
`CUTANEOUS I INSULIN
`
`SUB-~
`
`: ~-(cid:173)
`:
`
`I
`
`,
`
`I
`
`I
`
`UP10 CONTROLLER LicoMP INSULIN INSULIN:
`
`.----'-~
`\
`34
`
`24
`
`POST-
`
`522
`
`,12
`
`BLOOD
`PRESENT✓ 452
`
`G
`ESTIMATE
`'---~-__, GLUCOSE
`
`454--1 ALGORITHMS
`CORRECTION
`
`~~-~
`
`.I ~dx
`
`dx
`d
`
`\ 1 .!
`
`ERROR
`LEVEL
`GLUCOSE
`GE
`
`ESTIMATE
`GLUCOSE
`BLOOD
`ADJUSTED+
`PRESENT
`LEVEL G8
`GLUCOSE
`BLOOD
`BASAL
`DESIRED
`
`_
`
`Page 37 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 37 of 40
`
`US 2006/0224109 Al
`
`(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
`
`~500~ ~ -~:~~
`Jo~
`l
`~J
`: ! ,___,.,-....__r-1,V I ~ lb)
`
`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
`
`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
`
`.
`.
`.
`.
`.
`-0 01
`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
`6 2.----,-----,--------~----,-----,----,
`
`00 08/16 00~::
`
`~~~f ~ lo
`~::ro Di
`i ~I~
`
`I !
`
`! I
`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
`
`}hi
`
`Page 38 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 38 of 40
`
`US 2006/0224109 Al
`
`PID Controller
`(artificial Beta-cell)
`
`commands
`
`Subcutaneous
`insulin
`compensation
`
`compensated
`commands
`
`Subcutaneous
`insulin delivery
`syslem
`
`Processed
`Glucose
`Values
`
`Sensor
`compensation,
`calibration and
`filters
`
`Insulin
`
`Raw Glucose
`Sensor Values
`
`Glucose sensor
`
`Sensor
`Readings
`
`Body
`
`FIG. 39a
`
`PIO Controller
`(artificial Beta-cell)
`
`Commands
`
`IV insulin delivery
`system
`
`'"'"';" _;'--------------,00, I ~l
`
`Processed
`Glucose
`Values
`
`Extrapolation and
`FIR filler
`
`Raw Glucose
`Sensor Values~-
`
`Auto blood withdrawal
`and glucose determination
`
`Blood
`
`14----------j
`
`FIG. 39b
`
`Page 39 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 39 of 40
`
`US 2006/0224109 Al
`
`peristaltic roller
`(reversible) 420
`
`410
`
`catheter
`
`400
`
`sensor unit
`(GOD based sensor)
`
`flush volume
`
`reservoir
`
`:fixed catheter plus flush volume
`
`FIG. 40
`
`Page 40 of 67
`
`

`

`Patent Application Publication Oct. 5, 2006 Sheet 40 of 40
`
`US 2006/0224109 Al
`
`'5
`..._
`0)
`.§_ 200
`w
`en
`0
`0
`:> 100
`...I
`C)
`
`- - - •
`
`•
`
`• • . , •
`
`• • • • • • • • •
`
`•
`
`• • • • • • • • • • • • • • • • • •
`
`• • • • • • • L., • • •
`
`--- -- --- -...... - - -- ------ -- - -- -- -- -- -- --- -- --- --- - --- --- -.... --- -- -- -
`.
`.
`.
`.
`.
`.
`.
`.
`'
`o..i.........--~·----~---~--------r-· ____ ,.........
`'
`
`1 5 0 - - - - - - - - - - - - - - - - -~ - - - -~
`
`e
`:3 100
`:::!.
`z
`:J
`:)
`en 50
`z
`
`0
`
`60
`
`120
`Time
`
`1 BO
`
`240
`
`FIG. 41
`
`(a)
`
`(b)
`
`Page 41 of 67
`
`

`

`US 2006/0224109 Al
`
`Oct. 5, 2006
`
`1
`
`CLOSED LOOP SYSTEM FOR CONTROLLING
`INSULIN INFUSION
`
`the commands. In particular embodiments, the PID control(cid:173)
`ler is a bilinear PID controller.
`
`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 Ser.
`No. 60/137,601 filed Jun. 3, 1999, entitled "Closed Loop
`Algorithms For Continuous Monitoring And Insulin Infu(cid:173)
`sion," and U.S. Provisional Application Ser. No. 60/162,255
`filed Oct. 29, 1999 and entitled "Closed Loop Algorithms
`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 (~-cells),
`which reside in the pancreas, produce and secrete the insulin
`into the blood stream, as it is needed. If ~-cells become
`incapacitated or die, a condition known as Type I diabetes
`mellitus (or in some cases if ~-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(cid:173)
`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(cid:173)
`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
`
`[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(cid:173)
`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(cid:173)
`tration is monitored by the sensor system, and the liquid
`delivered to the user includes insulin. In preferred embodi(cid:173)
`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(cid:173)
`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(cid:173)
`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(cid:173)
`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(cid:173)
`ing and a second set of one or more controller gains when
`the glucose concentration is decreasing. In further alterna(cid:173)
`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-
`
`Page 42 of 67
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`

`

`US 2006/0224109 Al
`
`Oct. 5, 2006
`
`2
`
`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(cid:173)
`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 Kn is calculated using the
`first phase insulin response (cpl) 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(cid:173)
`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(cid:173)
`ments, the tuning parameter is an integrator leak.
`
`[0012]
`In alternative embodiments, the controller is influ(cid:173)
`enced by inputs of more than one measured body charac(cid:173)
`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(cid:173)
`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(cid:173)
`ments, the sensor is a multi-sensor that measures both
`glucose concentration and pH.
`
`[0013]
`In preferred embodiments, the sensor system pro(cid:173)
`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.
`
`[0014] 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(cid:173)
`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.
`
`[0019] 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(cid:173)
`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 i