Ironic Zurich12
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Transcript of Ironic Zurich12
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Zurich, April 27th, 2012
Implantable/Wearable System for
on-line Monitoringof Human Metabolic Conditions
(Implantable-IRONIC)
G. De Micheli,
Q. Huang, L. Thoeny-Meyer, Y. Leblebici,C. Dehollain, F. Grassi, S. Carrara
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Outline
Introduction:
Objectives, motivation and roadmap
New nano-biosensor technology
Nanostructured sensors
Experimental results and comparisons
New micro-electronic circuits
Data acquisition and energy harvesting
System bio-compatibility and tests
Conclusions and outlook2
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Project objective
Design implantable/wearable systems for
continuous monitoring of human metabolism
Remotely-powered cylinderDimension: 2.5x15mm
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Engineering roadmap
November 2010I1: Prototype of glucose sensor (10x32mm)
November 2011I2: Prototype of sensor for various metabolites andexperiments with animals (10x32mm)
I3: Integrated components for sensor (2.2x15mm)
Spring 2013I3: Assembly and test of multi-metabolite sensor (2.2x15mm)
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Prototype I2
Implanted nano-bio-sensortargeting various metabolites
On-mouse telemetry system
Patch-model
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7.8mm13.1mm
4.8 mm
24.7mm
Collaboration with antenna group
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Prototype I3
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Molecular Sensors
pH Sensor
Temperature Sensor
Integrated Circuit
2.2mm
inductive coil
Prototype I3IC CMOS circuit for RF and detection
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Components for new prototype I3
Passive multi-sensor silicon interposer (2.2x12mm)
Data acquisition chip (1.5x1.5mm)
Micro-antenna(2x15 mm)
Enclosure (not shown)
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Features Remote powering of implantable biosensors
through inductive link
Short-range bidirectional communicationwith the implanted sensors
Long-range communication with remote devices
Improved wearability
Possibility to place it directly over the implant area
Completely stand-alone, no wires are needed
Battery powered
Advantages
External data/power patch
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Scientific highlights
Realization and test of nano-structuredsensors for various metabolitesIncreased sensitivity and lower LOD
New genetically-engineered probes for higher robustness
Integrated low-power programmable dataacquisition electronics
Power and data transmission meansMulti-layer inductive coil for power/data transmission
Experimentation with various means of transmission
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Outline
Introduction:
Objectives, motivation and roadmap
New nano-biosensor technology
Nanostructured sensors
Experimental results and comparisons
New micro-electronic circuits
Data acquisition and energy harvesting
System bio-compatibility and tests
Conclusions and outlook12
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Probe Enzymes Endogenousmetabolites
Glucose Oxidase Glucose
Lactate Oxidase Lactate
Glutamate Oxidase Glutamate
Glucose Oxidase& Hexokinase
ATP
Sensing various metabolites
TARGETS
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Nano-Bio-Sensors Macro-AssemblyBARE ELECTRODE
CARBON NANOTUBES
CNTs + PROBE ENZYMES
Boero, Carrara et al. / IEEE PRIME 2009Boero, Carrara et al. / IEEE ICME 2010De Venuto, al. et Carrara / IEEE Senors 2010Boero, Carrara et al. / Sensors & Actuators B 2011Carrara et al. / Biosensors and Bioelectronics 2011Boero, Carrara et al. / IEEE T on NanoBioScience 2011
3.6 nm
5.2 nm
4.9 nm
10.3 1.14 nm
19.9 3.38 nm
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Selective electro-deposition of probes
CHITOSAN Chitosan PolysaccharideLiquid-to-solid state according to pH
Electric field to:
Put probe in position and alter pH
Entrap enzymes and CNT
Biocompatible and reversible
Electrodeposition600 +1.5 V Chitosan 0.7% CNT 1 mg/ml pH 5
Array 40 Array 10
Electrocleaning600 -2V PBS 1x pH 7.4
Array 10 bright field Array 10 dark field
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In-vitro measurement setup
L. Bolomey 16
PC
Base Station
Implant
capsuleElectrode
Cable
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Glucose Monitoring
Continuous monitoring of glucose with the single metaboliteremote system and a glucose Bio-Nano-Sensor
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Lactate Monitoring
Continuous monitoring of lactate with the single metaboliteremote system and a lactate nano-biosensor
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Increased sensitivity
Sensor sensitivity is enhanced by
nano-structuring the electrodes
~ 7.5 times more
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System Sensitivities
Sensitivity and range of the bio-nano-sensors
System Sensitivities
Metabolite Sensitivity Range Limit of Detection (S/N = 3)
Glucose 27.7 A/mM cm2 0.54 mM 73 M
Lactate 40.1 A/mM cm2 0.5
2.5 mM 28 M
Glutamate 25.5 A/mM cm2 0.52 mM 195 M
ATP 3.42 A/mM cm2 0.51.4 mM 208 M
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Engineered enzymes for biosensors
Motivation: fabrication of effective and more stablebiosensors for accurate diagnosis
Solution: integration into biosensing platforms oftailor-designed biorecognition moleculeswith
higher affinity with analytes higher stability
higher electron transfer rates
residues able to provide an oriented or more stable immobilization
Wild typeenzyme
Modified enzyme aN-terminal residue
f h d
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The best sensing
parameters
Active up 50daysafterdeposition
0
10
20
30
40
50
0 20 40 60
Sensitivity
(AmM-1c
m-2)
Time (day)
0
50
100
150
200
0 20 40 60
Detection
Limit
(mM)
Time (day)
Lactateoxidase
Sensitivity[A mM-1 cm-2]
DetectionLimit [M]
LinearRange [mM]
HistidineTag 35.6 6.2 30 6 0.2-1
Wild type 18.8 6.8 110 21 0.2-0.8
Commercial 26.6 5.8 58 21 0.2-1
24
Comparison of three Lactate Oxidases
fromAerococcus viridans for biosensing
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Outline
Introduction:
Objectives, motivation and roadmap
New nano-biosensor technology
Nanostructured sensors
Experimental results and comparisons
New micro-electronic circuits
Data acquisition and energy harvesting
System bio-compatibility and tests
Conclusions and outlook25
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VHDL-AMS cell model
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Data acquisition electronics
Multi target sensing
Enable CV actuation and readout
Enable CA initiation and readout
Low power due to remotely powering
of the implantable device
Low noise due to weak sensor signal
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Circuit Design
A very slow ramp generatorcircuit for CV initialization
Readout circuitfor CV and CAreadout
Potentiostat andmultiplexer
Time (s)
V(
v)
V(
v)I
()uA Output
Voltage
Biosensor current
CA voltage (V)
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Frontend Electronics:first prototype
Three different readout circuit blocks
for CV and CA readout
The fabricated chip is compared with
laboratory instruments.
Measurement results for lactatedetection using the fabricated chip
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Frontend Electronics:second prototype
New features: 5 different probes
Enable CV actuation and readout for up to 3 targets with sub A current
Enable CA initiation and readout for up to 2 targets with sub A current
Embedded pH and temperature sensing that are highly needed for data calibration
Low power due to remotely powering of the implantable device
Low noise due to weak sensor signal
Ready for system integration due to multiplexing scheme and pitch size
Ramp generator
and CV readoutPH sensing
Temperaturesensing
Potentiostat
CA readout
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IronIC Patch
PerformanceUp to 15 mW transmitted within 6 mm in air
Downlink communication up to 100 kbps
Bluetooth communication (Class-2)
Uplink communication with real-time threshold
check up to 66.6 kbps
Autonomy
Stand-by mode: 10 hours
Power mode: 1.5 hours
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Multilayer InductorsAdvantages
Inductors are realized on different PCBs,
stacked, and electrically connected
Link efficiency can be preserved despite area
reduction
Measures on the Designed Inductors
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Measures on the Designed Inductors
Communication is achieved at 100 kbps
1.17 mW (17mm Bovine Tissue)
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Bio-compatibility study
Development of a new biocompatible polymericpackage for hermetic encapsulation of individual
chips at IMEC Leuven2011-2012
Test of the biocompatible package with cell
cultures to test toxicity at IMEC
Leuven - 2012
Tests on induced inflammation on animal models
(mice) at IRB
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Tests with Animals
The Air Pouch Model in mice has been used to test the
inflammatory behavior of the monitoring implants
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System Biocompatibility
Tests of inflammation induced in mouse
by the implanted sensor system
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Outline
Introduction:
Objectives, motivation and roadmap
New nano-biosensor technology
Nanostructured sensors
Experimental results and comparisons
New micro-electronic circuits
Data acquisition and energy harvesting
System bio-compatibility and tests
Conclusions and outlook37
I l t bl IRONIC
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Implantable-IRONICCurrent status
Implantable/wearable system for health monitoring
Top-down design:
Implant design based on four major components
Sensor, interposer, chip, antenna
External patch and communication link
Bottom-up research
Multi-target sensing Integrated low-power electronics
Power and data transmission
New target molecules
Animal models 38
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Implantable-IRONICConclusions
Contributions to bio-engineering
Design of a versatile bio-sensing platform
Fusion of various disciplines
Successful test of implant I2 in mice
Contributions to fundamental research
Nano-biosensors with superior properties
Design of novel electronic circuits for low-power, low-noise data acquisition and tranmission
New energy harvesting methods with 3D coils
Technology transfer with partner Menarini39