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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)

    4

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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

    11

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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

    21

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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

    27

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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