Upload
truonglien
View
222
Download
0
Embed Size (px)
Citation preview
Pathways to Achieving a Bionic Pathways to Achieving a Bionic Pancreas Pancreas
Jay S. Jay S. SkylerSkyler, MD, MACP, MD, MACPProfessor, Division of Endocrinology, Diabetes, and MetabolismProfessor, Division of Endocrinology, Diabetes, and Metabolism
and Associate Director, Diabetes Research Instituteand Associate Director, Diabetes Research InstituteUniversity of Miami Miller School of MedicineUniversity of Miami Miller School of Medicine
Adjunct Professor, Barbara Davis Center for Childhood DiabetesAdjunct Professor, Barbara Davis Center for Childhood DiabetesUniversity of Colorado University of Colorado
•• Was on Board of Directors of Was on Board of Directors of MinimedMinimed, Inc. , Inc. (prior to acquisition by Medtronic) at time of (prior to acquisition by Medtronic) at time of development of the first subcutaneous development of the first subcutaneous continuous glucose monitoring systemcontinuous glucose monitoring system
•• Currently on Board of Directors of Currently on Board of Directors of DexComDexCom, , Inc Inc ––
““the Glucose Sensor Companythe Glucose Sensor Company””
Disclosure of Relevant Financial Disclosure of Relevant Financial RelationshipsRelationships
““The BeginningsThe Beginnings”” 1960s1960s
KadishKadish
AH: Trans Am Soc AH: Trans Am Soc ArtifArtif
Intern Organs 1963;9:363Intern Organs 1963;9:363––367.367.
Glucose Enzyme ElectrodeGlucose Enzyme Electrode
•• NatureNature; volume 214; 986; volume 214; 986--988, June 3, 1967988, June 3, 1967
•• SJ Updike and GP HicksSJ Updike and GP Hicks
Glucose Oxidase
silver
platinum
+
-
600 mv
Concept of MiniaturizationConcept of Miniaturization
Essential ComponentsEssential Components
•• Glucose MeasurementGlucose Measurement•• Algorithm for RegulationAlgorithm for Regulation•• Insulin DeliveryInsulin Delivery
Bedside Bedside ““Artificial PancreasArtificial Pancreas”” 1970s1970s
GCIISGCIISSuccess in developing GCIIS was achieved Success in developing GCIIS was achieved
nearly simultaneously in the 1970s by nearly simultaneously in the 1970s by groups in: groups in:
•• Toronto, CanadaToronto, Canada•• Ulm, GermanyUlm, Germany•• Montpellier, FranceMontpellier, France•• Sydney, Australia Sydney, Australia •• Osaka, JapanOsaka, Japan
Pfeiffer EF, Pfeiffer EF, et alet al. 1974.. 1974.
BiostatorBiostatorGlucose Controlled Insulin Infusion SystemGlucose Controlled Insulin Infusion System
Nikkiso STGNikkiso STG--2222
Continuous Subcutaneous Continuous Subcutaneous Insulin Delivery (CSII)Insulin Delivery (CSII)
1980s1980s
Latest Pump TechnologyLatest Pump Technology
Implantable Implantable ““Artificial PancreasArtificial Pancreas”” 1990s1990s
Physiologic Insulin Delivery Physiologic Insulin Delivery
PancreasSystemic
Circulation
Portal Vein
Liver
InsulinAmylin
Peritoneal Insulin AbsorptionPeritoneal Insulin AbsorptionAbsorption following 1 u/kg IP injectionAbsorption following 1 u/kg IP injection
Double tracer method in dogsDouble tracer method in dogs
PortalPortal
PeripheralPeripheralPeak AbsorptionPeak Absorption
20 min20 min
28 min28 min
Proportion Absorbed 51%Proportion Absorbed 51%
49%49%
Radziuk et al Am J Physiol 1994; 266:E750Radziuk et al Am J Physiol 1994; 266:E750--E759E759
Implantable Insulin PumpImplantable Insulin Pump
Implantable Insulin Pump & External ControllerImplantable Insulin Pump & External Controller
Implantable Glucose SensorImplantable Glucose Sensor
Implantable Glucose SensorImplantable Glucose Sensor
DS Bindra, Y Zhang, GS Wilson, R Sternberg, DR Thévenot, D Moatti, G Reach,, Anal. Chem.,1991:63: 1692-1696
Implantable Glucose SensorImplantable Glucose Sensor
Implantable Sensor & PumpImplantable Sensor & Pump
Implantable Sensor & PumpImplantable Sensor & PumpSensor Tip
Abdominal Lead Assembly (ALA)
Catheter Tip for Insulin Delivery
Catheter Header with Inlet Port
Sensor Connection to the Pump
Inlet to Pump
2007B
Implanted Closed LoopImplanted Closed Loop
““MoonMoon”” ––
The First Implantable Closed The First Implantable Closed
Loop SystemLoop System
5050100100
150150200200
250250300300
350350
400400
16 Wed16 Wed 17 Thu17 Thu 18 Fri18 Fri 19 Sat19 Sat 20 Sun20 Sun 21 Mon21 Mon 22 Tue22 Tue 23 Wed23 WedAugust 2000August 2000
Gluc
ose (
mg/
dL)
Gluc
ose (
mg/
dL) CLOSED LOOP CONTROLCLOSED LOOP CONTROL
ManualManualControlControl
ManualManualControlControl
Automatic ControlAutomatic ControlBeginsBegins
ControlControlTerminatedTerminated
Closed Loop Glucose Regulation withClosed Loop Glucose Regulation withImplanted Pump & Implanted Glucose SensorImplanted Pump & Implanted Glucose Sensor
Pancreatectomized CaninePancreatectomized Canine
First Human Closed Loop ResultsFirst Human Closed Loop Results
6989D-vivo-4/6(+10%)
70g 70g 40g 15g15g
70g
70g 40g 5g
0
50
100
150
200
250
300
350
10
20
30
40
50
0.0
0.1
0.2
12PMApr 2001
11 Wed 12PM 12 Thu 12PM
Sensor & Reference Glucose, Insulin Assay, Carbs, Pump StrokesSensor # 6989
Glu
cose
(m
g/dL
) Insulin Assay
Insu
lin (
Uni
ts)
Closed Loop Closed Loop -- Patient #3Patient #3
0306090
120150180210240270
0
2
4
12PM
Aug 2001
29 Wed 12PM 30 Thu 12PM
Glucose and Insulin Graph for 7037.....................15076From 8/27/01 To 8/30/01 10:44:00 AM
Glu
cose
(m
g / d
L)
Insu
lin
(U)
Date & Time [Insulin Bin Size = 30 min]
SubcutaneousSubcutaneous Continuous Glucose Monitoring Continuous Glucose Monitoring
(CGM)(CGM) 2000s2000s
Continuous Glucose Monitoring System (CGMS)Continuous Glucose Monitoring System (CGMS)
Guardian Telemetered Glucose Monitoring Guardian Telemetered Glucose Monitoring SystemSystem
50
GlucoWatchGlucoWatch®®
Biographer Biographer
Perspiration Detectors
Battery Compartment
DexCom Seven PlusDexCom Seven Plus Continuous Glucose MonitorContinuous Glucose Monitor
Sensor Delivery Unit
NavigatorNavigator Continuous Glucose MonitorContinuous Glucose Monitor
ReceiverTransmitter
Current Glucose SensorsCurrent Glucose Sensors
External External ““Artificial PancreasArtificial Pancreas”” 2000s2000s
External Closed Loop DeliveryExternal Closed Loop Delivery
External ClosedExternal Closed--Loop Setup for Loop Setup for Canine StudiesCanine Studies
Q W E R T Y U I O P { } |
A S D F G H J K L : " Enter; 'Z X C V B N M < > ?
/ Shift.,
ESC F1 F2 F3 F4 F5 F6 F7 F8 F 9 F10 F11 F12 Insert Delete Scroll Print
1 2 3 4 5 6 7 8 9 0 _ +
\][
1 2 Alt
Shift
- =
Alt
~`
Tab
PUMP
(U/h
)PU
MP (U
/h)
manualmanual closedclosed--looploop
6am6am noonnoon 6pm6pm midnightmidnight 6am6am00
22
44
66
88
recalibrationrecalibration
mealmeal mealmeal
Plasma GlucosePlasma GlucoseSensor GlucoseSensor Glucose
GLUC
OSE
(mg/
dl)
GLUC
OSE
(mg/
dl)
00
100100
200200
300300
400400
500500
Closed Loop Glucose Regulation withClosed Loop Glucose Regulation withCSII & Subcutaneous Glucose SensorCSII & Subcutaneous Glucose Sensor
Pancreatectomized CaninePancreatectomized Canine
59
Glucose Control During ClosedGlucose Control During Closed--LoopLoop
6A Noon 6P MidN 6A Noon 6P0
100
200
300 Reference BGSensor Glucosesetpoint
Glu
cose
(mg/
dl)
MeanMean DaytimeDaytime Peak PPPeak PP
All SubjectsAll Subjects 142 142
5353 148 148
5454 207 207
5454
Weinzimer et al. Diabetes Care 31:934 May 2008
6A Noon 6P MidN 6A Noon 6P0
100
200
300Closed Loop (N=8)
mealssetpoint
Hybrid CL (N=9)
Glu
cose
(mg/
dl)
Reference Glucose Levels in Reference Glucose Levels in Closed Loop vs. Hybrid ControlClosed Loop vs. Hybrid Control
MeanMean DaytimeDaytime Peak PPPeak PP
Full CLFull CL 147 147
5858 154 154
6060 219 219
5454HybridHybrid 138 138
4949 143 143
5050 196 196
5252Weinzimer et al. Diabetes Care 31:934 May 2008
•• Testing of the robustness and sensitivity of control algorithmsTesting of the robustness and sensitivity of control algorithms•• Experiments with extreme scenarios that cannot be tested in Experiments with extreme scenarios that cannot be tested in
vivovivo•• Accelerated development of closedAccelerated development of closed--loop controlloop control
In Silico Experiments allow for:In Silico Experiments allow for:
Reaction of three “subjects” to the same meal containing 75g CHO
Insulin pump failure locking the pump at maximum insulin infusion rate
Time (hours) Acknowledgment: B. Kovatchev and C. Cobelli 61
Realistic Virtual Clinical TrialsRealistic Virtual Clinical Trials•• A complete artificial A complete artificial --cell system testing platform, allowing:cell system testing platform, allowing:
–– Systematic analysisSystematic analysis–– Component Verification and ValidationComponent Verification and Validation–– Complete system V&VComplete system V&V–– PnP for PnP for in silicoin silico patientspatients–– PnP for control algorithmsPnP for control algorithms
Dassau Dassau et alet al., 2009, "., 2009, "In Silico In Silico Evaluation Platform for Artificial Pancreatic Evaluation Platform for Artificial Pancreatic ‐‐Cell Development Cell Development ––
a Dynamic Simulator for Closeda Dynamic Simulator for Closed‐‐Loop Control with HardwareLoop Control with Hardware‐‐
inin‐‐thethe‐‐Loop." Loop." Diabetes Technol Ther 11(3): 187Diabetes Technol Ther 11(3): 187‐‐194194
• Overnight Control• Full 24 hour Control
Q W E R T Y U I O P { } |
A S D F G H J K L : " Enter; 'Z X C V B N M < > ?
/ Shift.,
ESC F 1 F2 F 3 F 4 F 5 F 6 F 7 F8 F 9 F10 F11 F12 Insert Delete Scroll Print
1 2 3 4 5 6 7 8 9 0 _ +
\][
1 2 Alt
Shift
- =
Alt
~`
Tab Q W E R T Y U I O P { } |
A S D F G H J K L : " Enter; 'Z X C V B N M < > ?
/ Shift.,
ESC F 1 F2 F 3 F 4 F 5 F 6 F 7 F8 F 9 F10 F11 F12 Insert Delete Scroll Print
1 2 3 4 5 6 7 8 9 0 _ +
\][
1 2 Alt
Shift
- =
Alt
~`
Tab
ElEl--Khatib F H et al. Sci Transl Med 2010;2:27ra27Khatib F H et al. Sci Transl Med 2010;2:27ra27--27ra2727ra27
Boston Boston closedclosed--loop BG control loop BG control
Next Step: Automatic Shut Off for Projected Next Step: Automatic Shut Off for Projected HypoglycemiaHypoglycemia
•• All automatic pump suspensions All automatic pump suspensions ≥≥
60 min during prior CL study60 min during prior CL study
•• Plasma and sensor glucose at the Plasma and sensor glucose at the time of suspension time of suspension
•• Nadir plasma and sensor glucose Nadir plasma and sensor glucose for each suspension eventfor each suspension event
Pathway to a ClosedPathway to a Closed--Loop Artificial PancreasLoop Artificial Pancreas
Very Low Glucose Very Low Glucose Insulin Off PumpInsulin Off Pump
Shuts off due to userShuts off due to usernot responding tonot responding tolowlow--glucose alarmglucose alarm
HypoglycemiaHypoglycemiaMinimizerMinimizer
Predictive hypoPredictive hypoalarms alarms →→reductionreduction
or cessation ofor cessation ofinsulin delivery belowinsulin delivery below
LOW THRESHOLDLOW THRESHOLD
11 22Hypo/HyperHypo/Hyper
HyperglcemiaHyperglcemiaMinimizerMinimizer
Same as (2), butSame as (2), butallows insulin dosingallows insulin dosing
above above HIGH THRESHOLDHIGH THRESHOLD(ie above 200mg/dl)(ie above 200mg/dl)
33
Automated Automated Basal / HybridBasal / HybridClosed LoopClosed Loop
Fully closed loopFully closed loopwith mealwith meal--time manual time manual
assist bolusingassist bolusing
44
Fully AutomatedFully AutomatedInsulin Insulin
Closed LoopClosed Loop
55
Fully AutomatedFully AutomatedInsulin +Insulin +
AntiAnti--insulininsulinClosed LoopClosed Loop
66
Issues to Be ResolvedIssues to Be Resolved
causes hyper/hypo peaks
•• Current insulins work too slowly and last too Current insulins work too slowly and last too longlong
•• Amylin Amylin –– the second the second
cell hormone cell hormone ––
is is
missing in people with type 1 diabetesmissing in people with type 1 diabetes•• Glucagon may be needed to obviate Glucagon may be needed to obviate
hypoglycemiahypoglycemia