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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

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Outline

Introduction:










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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

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Comparison of three Lactate Oxidases

fromAerococcus viridans for biosensing


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Outline

Introduction:










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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:









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

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