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  • Electrochemical, Multi-analyte Biosensor Array for

    Neurotransmitter Detection

    Anita Karegar

    MS Thesis Presentation

    8th March 2007

  • Committee Members • Advisor

    – Dr. Tom Chen • Department of Electrical and Computer Engineering

    • Committee members – Dr. Charles Henry

    • Department of Chemistry – Dr. Stuart Tobet

    • Department of Biomedical Sciences – Dr. George Collins

    • Department of Electrical and Computer Engineering

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter

    Detection 2

  • Presentation Outline • Why do we need to detect neurotransmitter gradient? • Motivation of thesis • Review of existing sensors to detect neurotransmitters and their

    limitations • Proposed approach • Basic electrochemistry fundamentals • Electrochemical sensor array

    • Sensor array design • Electrochemical experimental Results • Observations and conclusions

    • VLSI interface to sensor array • Preamplifier design • Simulation results • Summary of specifications

    • Interface of sensor array to designed preamplifier • Future work

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter

    Detection 3

  • Significance Of Neurotransmitters • Nitric Oxide (NO)

    – Endothelial-derived relaxation factor – Crucial role in neural communication in central and peripheral nervous

    system – Physiological functions and behaviors regulated through hypothalamic

    circuits • Dopamine (DA)

    – Precursor of Norepinephrine (another major neurotransmitter) – Parkinson’s disease, Psychosis, Schizophrenia

    • Serotonin (5-HT) – Biochemistry of depression, migraine, bipolar disorder and anxiety – Hormone and growth factor

    • GABA – Inhibitory neurotransmitter – Spinal cord and cortical cell migration – Alteration of the cells movements in early brain development

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter

    Detection 4

  • Motivation of Thesis

    • Objective – To detect diffusion profile of Nitric Oxide (NO)

    that regulates physiological functions and behaviors

    • To design a sensor array to provide high spatial resolution (~ sub µm) for capturing cell-to-cell interactions.

    • To integrate sensor array with signal processing and storage circuits to allow continuous measurement in real-time.

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter

    Detection 5

  • Existing Work for Nitric Oxide (NO) Detection

    • Electrochemical Methods – High sensitivity – Fast response time – Fabrication of electrodes with dimensions in micrometers – Analytical information in electrical domain – Continuous measurement

    • Electrochemical method generally used – Amperometry – Cyclic voltammetry

    • Limitations – Electrode fouling

    • Cleaning of an electrode from time to time using cyclic voltammetry – Poor selectivity

    • Electrode surface modification with conducting/non-conducting polymers

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter

    Detection 6

  • Existing Work for NO Detection • Electrode material ([Kim,98], [Pontie,99])

    – Carbon fiber, Glassy carbon, Platinum, Gold, Pt/Ir alloy • Individual electrode dimensions ([Bedioui,03])

    – Diameter: 0.8 µm – 500 µm – Length: 6 µm - 1 mm

    • Electrode arrangement ([Naware,03], [Zhang,03]) – Single electrode based – Multi-electrode array

    • Multi-electrode array fabrication ([George,01], [Zhang,03]) – Photolithography of graphite carbon on Si wafer – Screen printing of carbon electrodes on Si wafer

    • Sensitivity ([Bedioui,03]) – 2.05 nA/µM to 10.5 nA/µM

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter

    Detection 7

  • Existing Work for NO Detection • Linear range (Current Vs Concentration) ([Bedioui,03])

    – 100nM to 20 µM • Detection limit (S/N = 3) ([Bedioui,03])

    – 10 nM to 570 nM • Response time ([Bedioui,03])

    – 10 ms to 4 s • Electrochemical Method ([Bedioui,03], [Kwang,03], [Mao,03])

    – Two or three electrode systems – Cyclic Voltammetry, Differential pulse voltammtery, Amperometry – Oxidation potential of NO: +0.7 - +0.9 V Vs Ag/AgCl reference electrode

    • NO calibration method ([Bedioui,03], [Zhang,03]) – Dilution of saturated NO solution to prepare standards – S-nitroso-acetyl-DL-penicillamine (SNAP) to generate known

    concentration of NO Electrochemical, Multi-Analyte

    Biosensor Array for Neurotransmitter Detection

    8

  • Existing Work for NO Detection • Electrode surface modification ([Pontie,99], [Park, 98], [Bedioui, 03])

    – Reasons • Selectivity against interferences e.g. Ascorbic acid, Nitrite, Dopamine • Sensitivity (catalytic electrochemical oxidation of NO)

    – Coating materials • Conducting polymers (catalytic electrochemical oxidation)

    – E.g. metal-porphyrin, metal-phthalocynine and M(salen) with central metal ion as Mn, Ni, Fe and Co

    • Non-conducting polymers (Permselectivity, charge repulsion) – Resorcinol, o-phenylenediamine, m-phenylenediamine, nafion

    • Combination of conducting and non-conducting polymers – E.g. Ni-porphyrin + nafion + o-phenylenediamine, M(salen) + nafion

    – Methods • Electropolymerization • Dip coating • Spin coating

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter

    Detection 9

  • Limitations of Existing NO Sensors • Existing microelectrode diameter ranges from few microns to few

    hundred microns. – Unable to provide enough spatial resolution for capturing cell-to-

    cell interaction • Designed for single analyte detection • Experimental setup involves discrete components such as

    potentiostat, data acquisition system, sensor array. – bulky – Costly – prone to noise

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter

    Detection 10

  • Proposed Approach • To create electrochemical microelectrode based sensor array integrated

    with on-chip signal processing and storage circuits to allow multi-analyte analysis with high spatial and temporal resolution in real time

    Existing Approach Proposed Approach

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter Detection 11

  • Basic Electrochemistry • Electrochemical cell

    – A set of two electrodes separated by one or more electrolyte phases

    – Electrode-electrolyte Interfacial potential difference

    – Working electrode – Reference electrode – Oxidation – Reduction

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter Detection 12

  • Two Electrode System • Working (WE) and

    reference (RE) electrode • Redox potential is applied

    across WE and RE and current is measured through WE

    • Limitations – High IRs drop if current I or

    solution resistance Rs is high

    – Deviation of RE interfacial potential from equilibrium

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter Detection 13

  • Three Electrode System • Working, reference and

    auxiliary/counter electrode

    • Redox potential is applied across WE and RE and current is measured between WE and AE

    • Advantages – Negligible current through

    RE – Minimization of solution

    potential drop by placing RE near WE

    14Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter Detection

  • Four Electrode System • Two working electrodes

    along with reference and auxiliary electrodes

    • Oxidation potential at WEG (generator) and reduction potential at WEC (collector)

    • Improved sensitivity – Redox cycling – WEs laid down in inter-

    digitated manner

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter Detection 15

  • Electrochemical Experimental Setup

    • The potentiostat senses potential between WE and RE and maintains it by controlling the potential between WE and AE

    • The potential maintained at WE Vs RE can be constant potential as in amperometry or potential varying with time as in cyclic voltammetry

    • Exists a unique relationship between current and potential

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter Detection 16

  • Cyclic Voltammetry • Potential across WE and

    RE is swept linearly with time and i-E graph (voltammogram) is plotted.

    • Involves reduction along with oxidation

    • Cyclic voltammogram provides unique signature of a given compound

    • Limitations – Background signal

    correction – Poor detection limit

    Electrochemical, Multi-Analyte Biosensor Array for Neurotransmitter Detection 17

  • Amperometry • Potential step is applied

    at WE Vs RE and i-t graph is plotted

    • Redox potential applied is specific to analyte

    • Improved detection limit • Fast response time • Limitations

    – Selectivity – Electrode fouling

    Electrochemical, Multi-Analyte Biosensor A