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G. De Micheli,
Q. Huang, L. Thoeny-Meyer, Y. Leblebici,
   C. Dehollain, F. Grassi, S. Carrara

Implantable/Wearable System for
       on-line Monitoring
 of Human Metabolic Conditions




       (Implantable-IRONIC)
Implanted devices for monitoring




 In/Out tubing
 Almost only for diabetes       A. Menarini Diagnostics, Florence

 Almost only for glucose

GlucoDay® and GlucoMenDay® consist of a micro-pump
   and a biosensor coupled to a micro-dialysis system
                                                                     4
Target objective

Cylinder: about 2 mm in diameter
   and below 20 mm in length




            Fully implanted system with
         sensors, electronics and transmission   5
Challenges in implant design

 Miniaturization:
    Small size, low-power consumption, low-impact
 Biocompatibility:
    Membrane design
 A set of target measurements
    Molecules, pH, temperature, pressure
 Reliable, highly-sensitive readout electronics
    Data processing and/or transmission
 Commercial feasibility is related to volume production


              Platform-based design
                                                           6
The platform and its components

 Specific components
    Probes and electrodes
    Chambers and fluidic circuits
 Electronic components
    Transconductance amplifier and data conversion
    Transmission and powering
                       Probes
                      Electrodes
            Readout           Potentiostat
                 Signal processing
                   Transmission
                      Powering
                                                      7
The electrochemical sensing principles
                                                              Oxidation peak
                                        Oxidation Potential




               V
                                     Reduction Potential
                     I
                                  Reduction peak


Peak position returns the molecule signature the sample

Peak current returns the concentration of the target



                                                                               8
Electrode functionalization

 A probe is a molecule reacting with a selected target
    Many possibilities
    Our goal is modularity and targeting proteins
 Oxidases (e.g., glucose oxidase)
    React with target and release H2O2
    H2O2 oxidizes at a specific potential (close to 650mv) generating
     current
    Chronoamperometry – measure current in a time window
 Cytochrome P450 (family of enzymes)
    React with target(s) and generate current at specific potentials
    Cyclic voltammetry– measure current while sweeping voltage



                                                                    9
Cytochromes for biosensors




                             11
Electrode nanostructure




                          12
Enhanced Nano-Bio-Sensing
           BARE ELECTRODE



              CARBON NANOTUBES




                CNTs + PROBE ENZYMES




                                       13
Enhanced Nano-Bio-Sensing

           RANDOMLY ORIENTED



              VERTICAL




                   BENT




                               14
Increased sensitivity




~ 7.5 times more




  Sensor sensitivity is enhanced by
    nano-structuring the electrodes   15
Single/multiple target sensing

 Extending or arraying the probes
    Proximity and interference of molecules
    Separate chambers and fluidics
 Using probe with different redox potentials
    Cyclic voltammetry
    Analyze different redox peaks




                                Etoposide electrochemical detection

                                                               16
Platform design challenges

 Design modular platform that can be adapted to
    Single/multiple targets
 Parametrize components and potentiostat
    Potentials must vary slowly
    Watch out for drifts and noise
 Transconductance amplifier
    High-sensitivity, linearity, low noise
 Overall low-power consumption for data acquisition,
  processing and transmission
    Power can be transmitted as magnetic field




                                                    17
Block diagram of the Biosensing Platform




                                           18
First Block     Third Block




                                        1.525 mm
Second                         I/F
 Block                      converter




                      Ramp generator




                 1.525 mm
Energy & data transmission



                            Z(load)




Power consumption vs. complexity
                                      20
Energy & data transmission




                             21
Prototype for in vivo remote monitoring




                      LéandreBolomey, PhD. Thesis, EPFL


                                                          22
Glucose Monitoring (CNT+GOD)




                               24
Lactate Remote Monitoring (CNT+LOD)




                                 25
ATP Monitoring (CNT+GOD+Hexokinase)

                         -700
                                    Sensitivity = 34.2 pA / M mm2
                         -600
                                       Detection limit 346 μM
current variation (nA)




                         -500
                                         average standard deviation: 29.89

                         -400            sensitivity: 34.2 pA/ M mm2
                                                    Interstitial ATP
                         -300

                         -200

                         -100

                           0
                                    80
                                0        200        400         600          800   1000   1200   1400
                                                                [ATP] uM                          26
Performance of biosensors




                            27
Conclusions

 Medical implants are an important testbed for
  advanced electronic and sensor design
 Specific issues relate to co-design of sensors and
  electronics:
    New materials, nanostructuring, new circuits
    Low-energy sensing and computation
 Platform-based design is key to low-cost production
  and to commercialization
    Challenges to integration are both technical and commercial




                                                               28
Thank you

 PhD Students
1.    Jacopo Olivo
2.    Sara Ghoreishizadeh
3.    Irene Taurino
4.    EnverGürhan Kilinç
5.    Giulia Siciliano
6.    Roger Ulrich          Scientists and Collaborators:
7.    Tom Kleier            1.   Thomas Burger
8.    Beat Muheim           2.   Michele Proietti
9.    Michael Fairhead      3.   Renate Reiss
10.   Michael Richter       4.   Thomas Ramsauer
                            5.   Frank Gürkaynak


                                                       29

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I-ironic

  • 1. G. De Micheli, Q. Huang, L. Thoeny-Meyer, Y. Leblebici, C. Dehollain, F. Grassi, S. Carrara Implantable/Wearable System for on-line Monitoring of Human Metabolic Conditions (Implantable-IRONIC)
  • 2. Implanted devices for monitoring  In/Out tubing  Almost only for diabetes A. Menarini Diagnostics, Florence  Almost only for glucose GlucoDay® and GlucoMenDay® consist of a micro-pump and a biosensor coupled to a micro-dialysis system 4
  • 3. Target objective Cylinder: about 2 mm in diameter and below 20 mm in length Fully implanted system with sensors, electronics and transmission 5
  • 4. Challenges in implant design  Miniaturization:  Small size, low-power consumption, low-impact  Biocompatibility:  Membrane design  A set of target measurements  Molecules, pH, temperature, pressure  Reliable, highly-sensitive readout electronics  Data processing and/or transmission  Commercial feasibility is related to volume production Platform-based design 6
  • 5. The platform and its components  Specific components  Probes and electrodes  Chambers and fluidic circuits  Electronic components  Transconductance amplifier and data conversion  Transmission and powering Probes Electrodes Readout Potentiostat Signal processing Transmission Powering 7
  • 6. The electrochemical sensing principles Oxidation peak Oxidation Potential V Reduction Potential I Reduction peak Peak position returns the molecule signature the sample Peak current returns the concentration of the target 8
  • 7. Electrode functionalization  A probe is a molecule reacting with a selected target  Many possibilities  Our goal is modularity and targeting proteins  Oxidases (e.g., glucose oxidase)  React with target and release H2O2  H2O2 oxidizes at a specific potential (close to 650mv) generating current  Chronoamperometry – measure current in a time window  Cytochrome P450 (family of enzymes)  React with target(s) and generate current at specific potentials  Cyclic voltammetry– measure current while sweeping voltage 9
  • 10. Enhanced Nano-Bio-Sensing BARE ELECTRODE CARBON NANOTUBES CNTs + PROBE ENZYMES 13
  • 11. Enhanced Nano-Bio-Sensing RANDOMLY ORIENTED VERTICAL BENT 14
  • 12. Increased sensitivity ~ 7.5 times more Sensor sensitivity is enhanced by nano-structuring the electrodes 15
  • 13. Single/multiple target sensing  Extending or arraying the probes  Proximity and interference of molecules  Separate chambers and fluidics  Using probe with different redox potentials  Cyclic voltammetry  Analyze different redox peaks Etoposide electrochemical detection 16
  • 14. Platform design challenges  Design modular platform that can be adapted to  Single/multiple targets  Parametrize components and potentiostat  Potentials must vary slowly  Watch out for drifts and noise  Transconductance amplifier  High-sensitivity, linearity, low noise  Overall low-power consumption for data acquisition, processing and transmission  Power can be transmitted as magnetic field 17
  • 15. Block diagram of the Biosensing Platform 18
  • 16. First Block Third Block 1.525 mm Second I/F Block converter Ramp generator 1.525 mm
  • 17. Energy & data transmission Z(load) Power consumption vs. complexity 20
  • 18. Energy & data transmission 21
  • 19. Prototype for in vivo remote monitoring LéandreBolomey, PhD. Thesis, EPFL 22
  • 22. ATP Monitoring (CNT+GOD+Hexokinase) -700 Sensitivity = 34.2 pA / M mm2 -600 Detection limit 346 μM current variation (nA) -500 average standard deviation: 29.89 -400 sensitivity: 34.2 pA/ M mm2 Interstitial ATP -300 -200 -100 0 80 0 200 400 600 800 1000 1200 1400 [ATP] uM 26
  • 24. Conclusions  Medical implants are an important testbed for advanced electronic and sensor design  Specific issues relate to co-design of sensors and electronics:  New materials, nanostructuring, new circuits  Low-energy sensing and computation  Platform-based design is key to low-cost production and to commercialization  Challenges to integration are both technical and commercial 28
  • 25. Thank you PhD Students 1. Jacopo Olivo 2. Sara Ghoreishizadeh 3. Irene Taurino 4. EnverGürhan Kilinç 5. Giulia Siciliano 6. Roger Ulrich Scientists and Collaborators: 7. Tom Kleier 1. Thomas Burger 8. Beat Muheim 2. Michele Proietti 9. Michael Fairhead 3. Renate Reiss 10. Michael Richter 4. Thomas Ramsauer 5. Frank Gürkaynak 29

Editor's Notes

  1. It has been shown that administration of ATP at micro-molar concentrations can block tumor growth18-20. A possible application of our sensor, which is sensitive to micro-molar concentrations, is the monitoring of ATP in tumors: ensuring constant control of ATP concentration may represent a tool to personalize the anticancer therapy, helping to minimize the side effects coming from over-dosage of the compound, and to establish the optimal amount for the maximum therapeutic effect.