Design, Fabrication, and Characterization of Microelectrodes for Brain-Machine Interfaces

Permanent Link: http://ufdc.ufl.edu/UFE0041223/00001

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Title: Design, Fabrication, and Characterization of Microelectrodes for Brain-Machine Interfaces
Physical Description: 1 online resource (174 p.)
Language: english
Creator: Patrick, Erin
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010


Subjects / Keywords: bmi, corrosion, microelectrode, neural, recording, tungsten
Electrical and Computer Engineering -- Dissertations, Academic -- UF
Genre: Electrical and Computer Engineering thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation


Abstract: The long-term goal in the design of brain-machine interfaces (BMIs) is to restore communication and control of prosthetic devices to individuals with loss of motor function due to spinal cord injuries, amyotrophic lateral sclerosis, or muscular dystrophy, for example. One of the great challenges in this effort is to develop implantable systems that are capable of processing the activity of large ensembles of cortical neurons. This work presents the design, fabrication, characterization, and in vivo testing of a neural recording platform for a pre-clinical application. The recording platform is a flexible, polyimide-based microelectrode array that can be hybrid-packaged with custom electronics in a fully-implantable form factor. Results from the microelectrode array integrated with an amplifier integrated circuit include data from in vivo neural recordings showing consistent single-unit discrimination over 42 days. Moreover, results from the electrochemical assessment of the corrosion properties of the tungsten microwire electrodes used on the microelectrode array admonish the use of tungsten in long-term implants.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Erin Patrick.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: Nishida, Toshikazu.
Local: Co-adviser: Orazem, Mark E.

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Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041223:00001

Permanent Link: http://ufdc.ufl.edu/UFE0041223/00001

Material Information

Title: Design, Fabrication, and Characterization of Microelectrodes for Brain-Machine Interfaces
Physical Description: 1 online resource (174 p.)
Language: english
Creator: Patrick, Erin
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010


Subjects / Keywords: bmi, corrosion, microelectrode, neural, recording, tungsten
Electrical and Computer Engineering -- Dissertations, Academic -- UF
Genre: Electrical and Computer Engineering thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation


Abstract: The long-term goal in the design of brain-machine interfaces (BMIs) is to restore communication and control of prosthetic devices to individuals with loss of motor function due to spinal cord injuries, amyotrophic lateral sclerosis, or muscular dystrophy, for example. One of the great challenges in this effort is to develop implantable systems that are capable of processing the activity of large ensembles of cortical neurons. This work presents the design, fabrication, characterization, and in vivo testing of a neural recording platform for a pre-clinical application. The recording platform is a flexible, polyimide-based microelectrode array that can be hybrid-packaged with custom electronics in a fully-implantable form factor. Results from the microelectrode array integrated with an amplifier integrated circuit include data from in vivo neural recordings showing consistent single-unit discrimination over 42 days. Moreover, results from the electrochemical assessment of the corrosion properties of the tungsten microwire electrodes used on the microelectrode array admonish the use of tungsten in long-term implants.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Erin Patrick.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: Nishida, Toshikazu.
Local: Co-adviser: Orazem, Mark E.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041223:00001

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@ 2010 Erin Patrick


This work was funded by a grant form the National Institute of Health, NS053561.

I would like to thank my chair advisor, Dr. Toshi Nishida, for his guidance and

supportive advice throughout my undergraduate and graduate degrees at the University

of Florida. I would also like to acknowledge my co-chair advisor, Dr. Mark Orazem, for

the use of his lab equipment and thank him for his guidance and continued support

throughout this project. My other committee members, Dr. Justin Sanchez, Dr. John

Harris, and Dr. Jose Principe deserve thanks for their advice and technical assistance

on this project.

I would like to acknowledge the Neuroprosthetics Research Group, headed

by Dr. Justin Sanchez, at the University of Florida for the animal care and in vivo

experimentation. Babak Mahmoudi and Jack DiGiovanna deserve thanks and credit for

performing the implantation surgeries. I am also thankful for the discussions and sample

microelectrodes from Dr. Vincent Vivier. Other technical assistance was provided at the

University of Florida by Dr. Andrew Rinzler for the use of parylene-C vapor deposition

tools and Al Ogden with packaging and numerous fabrication processing suggestions. I

would also like to acknowledge the staff at the Major Analytical Instrumentation Center

(MAIC) at the University of Florida for the scanning-electron micrograph (SEM) images

and energy dispersive x-ray (EDS) analysis of the electrode samples. The Electrical and

Computer Engineering staff also deserves thanks for their help and guidance.

My colleagues, Viswanath Sankar and William Rowe, deserve thanks for their

assistance throughout this project. I would also like to thank all the students of the

Interdisciplinary Microsystems Group and Professor Orazem's group for their technical

advice during numerous discussions. Jie Xu and Sheng-fen Yen from the Computational

Neuroengineering Group at the University of Florida deserve acknowledgement for the

design of the cmos amplifier used in this work.

I thank my family for their love and encouragement. My mom, Jan Patrick, and

sisters, Keri and Anna Patrick, have given me great support. Above all, I thank my loving

husband for his continued support and encouragement and my newest inspiration, baby



ACKNOWLEDGMENTS .......................

LIST O F TABLES ...........................

LIST O F FIG URES ..........................

ABSTRACT .............................


1 INTRO DUCTION ........................

1.1 Overview and Motivation .................
1.1.1 Brain-Machine Interfaces ............
1.1.2 Neural Recording Mechanisms for BMIs ....
1.1.3 Microelectrode Array Goals, Requirements, and
1.2 Contributions to the Field .. ..............
1.3 Dissertation Organization ................

. 3



2.1 T he N euron . . .
2.2 Extracellular Neural Recording .. ....................
2.3 Microelectrode Arrays for Neural Recording ................
2.3.1 Single Microwire Electrodes .....................
2.3.2 M icrow ire Arrays .. .. .. .. .. .. .. .
2.3.3 Silicon Micromachined Microelectrode Arrays ........... The Michigan array .. ................. The Utah array ............. .. ...... Other Si microelectrode arrays ..............
2.3.4 Polymer Micromachined Microelectrode Arrays ..........
2.3.5 Comprehensive Microelectrode Array Summary ..........
2.4 Tissue Response to Intracortical Microelectrodes .............
2.5 Im plications . . .


3.1 Electrode-Electrolyte Interface .. ....................
3.1.1 The Nonfaradaic Interface .. ...................
3.1.2 The Faradaic Interface .. .....................

3.1.3 Interface Summary .. ................
3.2 Need for Electrochemical Analysis of Electrode Materials
3.3 Im plications . .

: : : : : : : : :


4.1 Generation 1 .................... .............. 62
4.1.1 Fabrication ................... ........... 63
4.1.2 Bench-Top Electrical Testing .... 65
4.1.3 Implantation ... ...... .. .. ...... .. 66
4.1.4 Surgical Recording ..... .... ....... .. ... .. 67
4.1.5 Sum m ary . .. 67
4.2 Generation 2 .......... ....... ............... 69
4.2.1 Fabrication . .. 71
4.2.2 Bench-Top Electrical Testing .... 72
4.2.3 Im plantation . .. 74
4.2.4 Surgical Recording ........................... 74
4.2.5 Sum m ary . .. 76
4.3 UF Microelectrode Summary ... 78


5.1 D esign . . 80
5.2 Fabrication . .. 82
5.3 Power System for Amplifier-Microelectrode System .... 86
5.4 Experimental Setup with TDT Recording System ... 88
5.5 Bench-Top Characterization ..... .. ..... 90
5.5.1 Effect of Grounding Reference Input to Amplifier ... 90
5.5.2 Effect of EMI on Noise Floor ...................... 93
5.5.3 Impedance Concerns with On-Chip Amplifier ... 94
5.5.4 Lessons Learned for Integration with the Integrate-and-Fire Chip 100
5.5.5 Frequency Response and Impulse Response of System 101
5.6 In-Vivo Testing . . 102
5.6.1 In-Vivo Recording Results ....................... 104
5.6.2 Post-Implant Electrode Assessment ... 108
5.7 S um m ary . . 110


6.1 Electrochemical Impedance Spectroscopy ... 112
6.1.1 Graphical Data Analysis Techniques ... 114
6.1.2 ErrorAnalysis ........................... 117
6.2 Microelectrodes used for Electrochemical Characterization ... 119
6.3 Quality Control of Microelectrode Fabrication .. 120
6.3.1 Quality Control Methods . 121 Graphical analysis . ... 122
6.3.2 Quality Control Results and Discussion . 124 Ideal behavior .......................124 Non-ideal behavior. . .. 125
6.3.3 Quality Control Summary ... 127


7.1 Materials and Instrumentation .................
7.2 Experimental Results ......................
7.2.1 EIS of Tungsten and Platinum in Phosphate Buffered S
7.2.2 EIS of Tungsten and Platinum in Phosphate Buffered S
Hydrogen Peroxide ....................
7.2.3 Images of Tungsten Corrosion .
7.3 Analysis and Discussion .....................
7.3.1 Calculation of Open Circuit Potential Referred to SHE
7.3.2 Possible Electrochemical Reactions on Tungsten .
7.3.3 Rate of Tungsten Corrosion . Calculation of Corrosion Rate . Comparison of Corrosion Rates .
7.3.4 Possible Electrochemical Reactions on Platinum .
7.4 Conclusions.. .........................

8 SUMMARY AND CONCLUSION ...................

8.1 Summary of the UF-Microelectrode Array .
8.2 Summary of the Electrochemical Analysis .
8.3 Suggestions for Future Work ..................

REFERENCES.............. ..................

BIOGRAPHICAL SKETCH .. .....................

aline .
aline and




. 154

. 154
. 156
. 157

. 160

Table page

1-1 Comparison of electrode lifetimes ..... .. ... ... 20

4-1 Neuronal Yield for Generation 1 Microelectrode Array ... 68

4-2 Performance of Generation 2 Microelectrode Array .. 76

5-1 Voltage Specifications for UF Amplifier . 88

5-2 Noise floor . .. .. .. 94

5-3 Neuronal Yield for Generation 2b Microelectrode Array 105

6-1 Values of a and Qeff for ideal electrodes from Figure 6-6 and Figure 6-7 125

6-2 Values of a and Qef for non-ideal electrodes extracted from Figure 6-10 and
Figure 6-11 .. .. .. . .. 126

7-1 Composition of Phosphate Buffered Saline ..... 132

7-2 Species considered in calculation of the Pourbaix diagram presented as Figure
7 -1 2 . . 14 1

7-3 Corrosion rates for tungsten ........................... 148

7-4 Species considered in calculation of the Pourbaix diagram presented as Figure
7-17. .......... ... . 150

8-1 Critical Loading Force for Metal Microwires ... 158



Physical representation of recording electrodes . .

Schematic of micro-wire electrode array interface with neurons in the cortex.

Schematic of a neuron and action potential. ... ...

Extracellular recording of an action potential with respect to a distant electrode.

Simulated extracellular voltage from a typical layer 5 cortical pyramidal cell. .

































Microwire electrode arrays. ............................. 31

Examples of the 2-D Michigan microelectrode array. ... 33

3-D Michigan microelectrode array. ..... ....... 34

Utah microelectrode array ................... ........... 35

Polyimide-based microelectrode array (Arizona State, Gen 1). ... 38

Parylene-based microelectrode array (U. of Michigan). ... 38

Polyimide-based microelectrode array (Arizona State, Gen 2). ... 39

Polyimide-based microelectrode array (Fraunhofer Institute). ... 40

Polyimide-based microelectrode array (U. of Tokyo). 40

Parylene-based microelectrode array (U. Of Tokyo). ... 41

Polyimide-based microelectrode array (U. of British Columbia). ... 42

Typical tethering scheme of a rigid microelectrode array. ..... 46

Equilibrium electrode/electrolyte interface. .... 53

Equivalent circuit for the nonfaradaic interface [1]. ... 56

Equivalent circuit for faradaic interface [1]. . 57

I-V relationship of two reactions occurring at the interface. .. 58

Flexible substrate microelectrode array. .... ........ 63

Fabrication process flow for generation 1 microelectrode. .. 64

Equivalent circuit for electrode/electrolyte interface. . 65

Surgical implantation of generation 1 microelectrode. .... 66

4-5 Data from neural recording in the rat motor cortex ... 69

4-6 Corrosion of electrode ................... ............. 70

4-7 Polymer microelectrode array with Omnetics connector ... 71

4-8 Fabrication process of generation 2 microelectrode array. ... 72

4-9 Equivalent circuit for electrode/electrolyte interface. ... 73

4-10 In vivo testing of generation 2 .............. .. .......... 75

4-11 Data from neural recording.. ........................... 77

4-12 Spike sorting results ................. ............ .. 77

5-1 In vivo placement of microelectrode array on rodent skull. ... 83

5-2 Flexible polyimide microelectrode array with integrated amplifier. ... 83

5-3 UF amplifier-microelectrode system showing the flexibility of the electrode
substrate . . .. 84

5-4 Fabrication process flow for UF amplifier-microelectrode system. ... 85

5-5 Amplifier die with gold stud bumps on bondpads. .. 85

5-6 Contents of power box. ................... ........... 87

5-7 Input/output connections for power box. .... 87

5-8 Experimental setup with TDT recording system. ... 88

5-9 Time series noise floor affected by RA8GA preamplifier input setting ....... .89

5-10 Time series noise floor seen on the TDT recording program. ... 91

5-11 Amplifier connections showing floating vs. grounded reference configuration. 92

5-12 Square root of the power spectral density of the amplifier-microelectrode system
showing effect of the reference connection on the noise floor. ... 93

5-13 Square root of the power spectral density of noise floor showing effect of EMI. 94

5-14 Comparison of impedances ............................ 95

5-15 Differential amplification of neural signal .... 96

5-16 Attenuation factor of Vd as a function of Ze and Zref corresponding to voltage
division at input of the amplifier ................ .......... .. 97

5-17 Percent attenuation of V ................. ... .......... 97

5-18 Attenuation factor of Vc as a function of Ze and Zref corresponding to voltage
division at input of the amplifier . ... 98

5-19 Percent of the common-mode signal that will be amplified. ... 99

5-20 Normalized effective common-mode rejection ratio as a function of the difference
of the impedance between recording electrode and reference electrode. 100

5-21 Effective common-mode rejection ratio as a function of frequency for impedance
values in the UF microelectrode array. . .. 101

5-22 Frequency response of amplifier-microelectrode system. The pass-band gain
is 39 dB. . . 102

5-23 Impulse response of amplifier-microelectrode system. .. 103

5-24 Flexible substrate electrode array implanted in rodent model. ... 104

5-25 Large amplitude action potentials recorded on day of implantation. ...... .105

5-26 Action potential of a single neuron spike sorted over the implanted period. 106

5-27 Noise floor for the electrode array over the implanted duration. ... 107

5-28 Signal-to-noise ratio for the electrode array over the implant duration. 108

5-29 SEM images of tungsten micro-wires before and after 87 days implanted. 110

5-30 EDS results of two sites on one electrode after 87 days in vivo. ... 111

6-1 EIS experim ental set-up .. .. .. .. .. .. .. ... 113

6-2 Equivalent circuits for blocking and reactive system. ... 114

6-3 Bode plots of a blocking and reactive system. . ... 115

6-4 Impedance of blocking and reactive systems. . ... 116

6-5 Impedance for blocking and reactive systems with CPE. ... 116

6-6 Impedance of four Pt electrodes insulated in epoxy and polished with A102
paper. ...................................... .... 124

6-7 CPE coefficient Q of ideal electrodes as a function of frequency. ... 125

6-8 Imaginary impedance of the ideal electrodes in dimensionless units with respect
to dimensionless frequency K .................. ........ 126

6-9 Derivative of the logarithm of dimensionless imaginary impedance of the ideal
electrodes with respect to the logK. ... 127

6-10 Impedance of four Pt electrodes insulated in epoxy and polished with A102
paper. ...................................... .... 128

6-11 CPE coefficient Q of the non-ideal electrodes as a function of frequency. 128

6-12 Plot of imaginary impedance of the non-ideal electrodes in dimensionless units
with respect to dimensionless frequency K. ... 129

6-13 Derivative of the logarithm of imaginary impedance of the non-ideal electrodes
with respect to logK................... .............. 129

7-1 Schematic of working electrode for EIS measurements. ... 131

7-2 Impedance of tungsten and platinum electrodes in PBS. ... 133

7-3 Equivalent circuits for blocking and reactive systems. 133

7-4 Impedance of a platinum electrode in phosphate buffered saline over time. .134

7-5 Impedance of a gold-plated tungsten electrode in phosphate buffered saline
over 15 days . .. 135

7-6 Impedance of tungsten electrode showing 02 concentration dependance. 135

7-7 Impedance of a platinum and gold-plated tungsten electrode in PBS plus H202 136

7-8 Photographs of a tungsten electrode before and after immersion in PBS for
the specified period of tim e .............................. 137

7-9 Photographs of gold-plated tungsten electrodes before (top) and after (bottom)
immersion in PBS for the specified period of time. . 138

7-10 Photographs of a gold-plated tungsten electrodes before and after immersion
in an electrolyte containing PBS and H202 for the specified period of time. 138

7-11 Schematic representation of electrochemical cell. . 139

7-12 Pourbaix diagram of tungsten in phosphate buffered saline. ... 140

7-13 Pourbaix diagram of tungsten in phosphate buffered saline and 30 mM H202. 143

7-14 Effect of increased cathode surface area on galvanic interaction of tungsten
and gold. ........................................ 144

7-15 OCP over time for gold-plated tungsten and tungsten electrodes in PBS. 145

7-16 Nyquist plots used for calculation of the polarization resistance, R,. .. 147

7-17 Pourbaix diagram of platinum in phosphate buffered saline and 30 mM hydrogen
peroxide. ........................................ 149

7-18 Cyclic voltammogram of a platinum electrode in an electrolyte containing PBS
and 30 m M H202 .................................... 150

Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy



Erin Patrick

August 2010

Chair: Toshikazu Nishida
Cochair: Mark Orazem
Major: Electrical and Computer Engineering

The long-term goal in the design of brain-machine interfaces (BMIs) is to restore

communication and control of prosthetic devices to individuals with loss of motor

function due to spinal cord injuries, amyotrophic lateral sclerosis, or muscular dystrophy,

for example. One of the great challenges in this effort is to develop implantable systems

that are capable of processing the activity of large ensembles of cortical neurons.

This work presents the design, fabrication, characterization, and in vivo testing of a

neural recording platform for a pre-clinical application. The recording platform is a

flexible, polyimide-based microelectrode array that can be hybrid-packaged with custom

electronics in a fully-implantable form factor. Results from the microelectrode array

integrated with an amplifier integrated circuit include data from in vivo neural recordings

showing consistent single-unit discrimination over 42 days. Moreover, results from

the electrochemical assessment of the corrosion properties of the tungsten microwire

electrodes used on the microelectrode array admonish the use of tungsten in long-term



1.1 Overview and Motivation

Neurological disorders result in irreversible damage to the peripheral or central

nervous system and greatly reduce the quality of life of the afflicted individual. While

great strides have been made in understanding neurological disorders and mitigating

deleterious effects, cures for these disorders via effective regeneration of a severely

impaired central nervous system is not a near-term solution. Amytrophic Lateral

Sclerosis (ALS) and spinal cord injuries, which make-up a large portion of all paralysis

cases, contribute together 15,000 new cases each year [2]. Epilepsy is estimated

to cost $15.5 billion annually and approximately 200,000 new cases are diagnosed

each year [3]. These examples are just a few of many neurological disorders affecting

people today. Fortunately, engineering can provide hope to some by providing alternate

methods for regaining lost function due to neurological disorders.

Neural prosthetic technologies, or neuroprostheses, are designed to replace,

repair, or augment function for individuals with vision, hearing, or motor impairments.

Neuroprostheses interface with the nervous system and either transmit or receive neural

information in order to perform a task. Examples of sensory prosthetics are retinal and

cochlear implants for the blind and deaf. These prosthetics code images or sound taken

from wearable cameras and microphones into electrical impulses which are used to

stimulate retinal or auditory nerves, respectively. The cochlear implant is best known

and is commercially available [4, 5]. Another neuroprosthesis uses functional electrical

stimulation (FES) to therapeutically modulate neural activity in the brain of people with

Parkinson's disease, epilepsy, and depression [6-8]. Electrical signals are sent via the

prosthetic into a targeted portion of the patient's brain mitigating the debilitating effects

of their condition.

Motor neuroprostheses aim to provide control of external devices such as prosthetic

limbs, computer programs, and motorized wheel chairs with signals from the central

or peripheral nervous systems. An example of a peripheral nervous system motor

prosthetic is a prosthetic robotic arm that electrically interfaces with a peripheral

nerve in an amputee's shoulder [9]. Signals from peripheral nerves in the shoulder

of the amputated arm provide the commands for the robotic arm. Alternatively, motor

neuroprostheses that interface with the central nervous system are commonly called

brain-machine interfaces, (BMIs) or brain-computer interfaces (BCls). They ideally

provide the means for thought control of external devices by recording central nervous

system (CNS) neural activity and decoding motor intention [10]. These systems may

potentially be used as therapy for individuals with paralysis of the extremities caused

by injury or neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS),

muscular dystrophy, or other diseases that cause a "locked-in" condition.

1.1.1 Brain-Machine Interfaces

BMI systems comprise of four processes: recording neural activity, interpreting the

activity as an intended action, controlling a device that performs the intended action,

and providing feedback to the subject [4]. An example of possible BMI function for a

quadriplegic is directional control of a motorized wheel chair via brain signals. The

type of neural activity used to provide such commands varies with application and

researcher. However, preclinical studies primarily use neural activity in the motor cortex

[11, 12]. Therefore, in the proposed scenario, directional control of a mechanical wheel

chair could be administered by the neural activity that occurs when thinking about

moving an arm.

Progress on BMI systems has been made in preclinical and clinical studies. Chapin

et al. showed real-time control of a robotic arm via cortical signals elicited by a fore-limb

lever pressing action done by a rat [11]. Others have shown effective 1D and 3D control

of robotic arms [12] and cursors on screens [13, 14] in BMIs in primates. Carmena et

al. presented first time results of real-time control of two movements (reaching and

grasping) in a visual feedback closed loop BMI system in a primate [15]. Velliste et al's

experiments show the potential of BMIs for multidimensional control of a robotic arm in

an interactive closed loop system, where monkeys were able to feed themselves [16].

Recent clinical trials using BMIs allowed a tetrapalegic patient to control a cursor on a

computer screen, play a video game, adjust the volume and channel of a television, and

control a simple robotic hand [17]. Electrodes were implanted into the arm area of the

patient's motor cortex. By imagining hand movements, the patient was able to provide

signals to control the BMI devices.

1.1.2 Neural Recording Mechanisms for BMIs

Neural activity for BMIs can be measured with electroencephalographic (EEG)

electrodes, electrocorticographic (ECoG) electrodes, or intracortical microelectrode

arrays. Figure 1-1 shows a representation of each recording electrode. Each electrode

measures neuronal electrical activity with different spatial and temporal resolution. EEG

electrodes reside on the scalp, measure neural activity across a spatial diameter of 3

cm, and provide signals with frequency content up to 70 Hz only [10]. ECoG electrodes

reside on the surface of the brain, average neural activity over 0.5 cm and can record

signals with much higher frequency content [10]. Typically, the bandwidth of ECoG

recordings is 10 Hz to 200 Hz [10]. However, this bandwidth is normally limited by

the amplification hardware. New research shows that ECoG electrodes can provide

signals with meaningful frequency content up to 6 kHz [18]. Intracortical microelectrodes

penetrate into the cortex and have recording sites with areas similar to a neural cell

body (50 pm 200 pm) Microelectrodes provide the least spatial averaging and can

accurately record the action potential waveform from single neurons, often called single

unit recording. The frequency content of signals recorded from microelectrodes is also

limited by the amplification hardware; normally, frequencies up to 6 kHz are measured.

EEG Electrode


Intracortical .- Electrodes
Microelectrodes .

:. *... ., i

., ,. 1

Neural Tissue I

Figure 1-1. Physical representation of recording electrodes.

All papers mentioned in Section 1.1.1, which show BMI control of external devices,

use intracortical microelectrode arrays for measurement of the neural signals [11-

15, 17]. Their research suggests that single unit recording is useful for the analysis

of complex motor function. Therefore, this work focuses on the design of a recording

system that incorporates intracortical microelectrode arrays.

1.1.3 Microelectrode Array Goals, Requirements, and Challenges

The ultimate role of the intracortical microelectrode array is to provide accurate

measurement of neuronal activity when chronically implanted. Long-term efficacy

requires recording characteristics such as high signal-to-noise ratio, the ability to

measure consistent signals from the same neurons over time, and high yield within an

array. For eventual clinical use, the microelectrode array must retain a nonrestrictive

interface with the patient. This requirement points toward a wireless system that

measures and transmits necessary information in a minimal package. Thus, integration

with electronic circuitry and power systems is necessary for intracortical-recording

microelectrode arrays used in chronic applications.

The recording characteristics are controlled by many factors; only some of which

can be controlled by design. The designer can assure that the microelectrode will

not catastrophically fail by mechanical or electrical means and has low noise. Thus,

microelectrode arrays should be made out of robust materials that will not break nor

corrode and all electronic wiring or circuitry must be hermetically sealed. Also, the

microelectrodes and interface electronics must be designed to have low intrinsic noise

and measures should be provided to minimize electromagnetic interference such that

the signal-to-noise ratio can be as high as possible. One factor that is not controlled

by the microelectrode array design is surgical placement in the cortex. The strength

of the recorded signal, and hence the signal-to-noise ratio, depends on how close the

electrode resides to the neuronal cell body. Also, high yield within an array requires

that all electrodes in the array be placed close enough to a neuron or multiple neurons

to measure their signal. Even though the designer has no control of precise electrode

placement for each electrode in a static array, there is high probability that the electrode

will be positioned near enough to a neuron to measure its action potential because

of high neuronal density [19]. Biocompatibility is another factor determining stable

recording characteristics. The relationship between material choice and biocompatibility

is not straightforward and will be discussed in more detail in Chapter 2.

A current issue with commercial and noncommercial microelectrodes for neural

recording is loss of signal over time. Table 1-1 shows the three most common electrode

technologies used for BMIs and their efficacy over time. They include micromachined

arrays from the University of Michigan and the University of Utah and non-micromachined

microwire arrays. The general trend is a decrease in the number of electrodes able to

record single units (i.e. active electrodes), over time. This loss of recording function over

time is the result of many biological factors described in more detail in Chapter 2 that

plague all microelectrode designs listed in Table 1-1 [20]. Methods to mitigate this effect

are a topic of current research in the field, though are not a part of this work.

Table 1-1. Comparison of electrode lifetimes
Technology Electrode Percentage Reference
Material of active
over time
Micromachined Pt 92%/12 weeks Vetter,
silicon shank 92%/18 weeks Kipke, et
electrode with al., 2004
flexible cable [21]
Micromachined Pt 45%/12 weeks Rousche,
Silicon bed of nails 18%/52 weeks Normann,
electrode 1998 [22]
Micro-wire electrode W 80%/12 weeks Williams,
45%/25 weeks Kipke,
1999 [23]
Micro-wire electrode Ir 62%/1 week Liu,
25%/151 weeks McCreery,
2006 [24]

1.2 Contributions to the Field

The work presented in this document is the first step in building a fully-implantable,

wireless microelectrode array for cortical recording. The project, Florida Wireless

Integrated Recording Electrode (FWIRE), capitalizes on a data processing scheme

that provides advantages over existing recording microelectrode system designs [25].

This work establishes a flexible platform for an implantable neural recording system

integrated with microwire electrodes and an application specific integrated circuit

(ASIC) amplifier. This design results in a compact device capable of being positioned

subcutaneously while only the microelectrodes penetrate the cortex. A process flow

using non-silicon MEMS techniques and flip-chip bonding is achieved. Two generations

testing the efficacy of a micromachined, flexible, ployimide substrate with nickel [26]

and tungsten [27] microwire electrodes have been realized. The latest generation with

tungsten microwire electrodes and an integrated amplifier shows adequate in vivo

recording results over a 42 day period [28, 29]. An average noise floor of 4.5 Vprms

and average signal to noise ratios of 3.5 (11 dB) are consistently seen over the implant


Furthermore, this work exemplifies a method for thorough electrochemical

characterization of electrode recording-site materials and provides undocumented

results for tungsten microelectrodes [30]. Corrosion rates for tungsten microelectrodes

with and without a gold-tungsten galvanic couple are quantified in electrolytes modeling

in vivo chemistry. Corrosion rates on the order of 100 pm/yr are seen for tungsten

electrodes immersed in 0.9% phosphate buffered saline, while corrosion rates on

the order of 10,000 pm/yr are seen for tungsten electrodes immersed in a solution

containing 0.9 % phosphate buffered saline and 30 mM of hydrogen peroxide. The

hydrogen peroxide is added to model the extracellular chemistry during a foreign-body

inflammatory response. These results provide insight into the long-term longevity of

tungsten microwire electrode arrays used in in vivo recording applications.

Moreover, a method to assess the quality of the seal between the insulation and

the microelectrode surface is introduced [31]. This method uses graphical analysis of

the impedance data and thus is relatively simple. This method may be used for quality

control of microelectrodes used in the fields of electrophysiology or electroanalytical


1.3 Dissertation Organization

The remaining text is organized as follows. Chapter 2 discusses the electrophysiology

of a neuron, describes the physics of signal transduction at the electrode surface via

electrochemical theory, and presents existing microelectrode technologies and their

issues. Chapter 3 presents the physics behind the electrode-electrolyte interface

and the need for electrochemical assessment of electrode recording-site materials.

Chapter 4 presents sequential progress of the polymer-based UF microelectrode

array. Details of the fabrication steps of microelectrode arrays as well as bench-top
characterization and acute in vivo results for two generations of microelectrode

arrays are given. Chapter 5 explains in detail the design and characterization of a
UF microelectrode array hybrid-packaged with an amplifier integrated circuit. Details
of the system noise, the grounding scheme, and the requirements for interfacing with

commercial data-processing and recording hardware are given. In vivo results show the

performance of the microelectrode system for chronic applications. Chapter 7 presents
the theory, experimental methods, and results of electrochemical assessment of

platinum and tungsten for recording electrode materials. The corrosion of the electrode
or production of unwanted chemical species is assessed. Chapter 8 summarizes the

results of this work and advises a plan for future microelectrode designs.


This chapter conveys the necessary background for the design of the UF

microelectrode array. Understanding of the measurement target is presented through

an overview of the neuron, followed by a discussion of the neuronal signal known as

the action potential. Then, the transduction mechanism at the metal recording site and

tissue interface is discussed and mathematically portrayed via electrochemical theory.

The next section provides details of the structures and fabrication methods of existing

microelectrodes and microelectrode arrays for neural recording applications including

microwire, silicon-micromachined, and polyimide-micromachined microelectrode

arrays. The strengths and weaknesses of the reviewed designs are discussed at the

close of this section. Next, histological reports that portray the biocompatibility of

implanted microelectrodes are reviewed. The biological immune response is identified

for intracortical microelectrodes. Finally, from the background information are presented.

2.1 The Neuron

Neurons provide the means for cognitive function and as such are targeted by

BMI systems. Pyramidal cells in the motor cortex, which are most commonly targeted

by BMIs, provide the necessary information for motor muscle control. Their action

potentials, which are electrical signals generated by the neurons, are recorded and

their firing pattern is decoded in BMI systems. Figure 2-1 shows a schematic of an

intracortical microwire microelectrode interfacing with neurons in the brain. If placed in

close proximity to a cell, the microelectrode can record the neuron's ionic signals as it

communicates with other neurons.

To understand how an action potential is generated, the physiology of a neuron

is explained. The soma is the cell body; dendrites and the axon make-up the neural

extensions, or neurites, as shown in Figure 2-1 [32]. The dendrites receive signals from

other neurons, while the axon transmits signals to other neurons. The axon may be


A p ic a l ...................... ....................... ......................
Dendrite Soma Recording

Dendrites /


Figure 2-1. Schematic of micro-wire electrode array interface with neurons in the cortex.

insulated along its length and periodically have uninsulated nodes (Nodes of Ranvier)

that act to reestablish an action potential as it propagates. Neurons are connected in

a weblike fashion with the axon of one neuron attaching to the dendrites of others via

a synapse. One neuron may have on the order of 10,000 dendritic connections [32].

The neuron is insulated by a thin membrane on which ion channels reside. The ion

channels are gated by proteins that only allow the passage of specific ions. Ion channels

may be neurotransmitter-gated or voltage-gated meaning that either neurotransmitters

or voltage may modulate the proteins allowing ions to pass. Ionic current occurring at

dendritic synapses has the ability to trigger an action potential in the receiving neuron

by depolarizing the resting potential of the soma to a certain value. The resting potential

inside a neural cell body is close to -65 mV with respect to the surrounding fluid [32].

When the afferent, or incoming, current from dendritic synapses increases the cell

potential above a certain threshold voltage, an action potential proceeds as follows.

Voltage-gated ion channels residing on the cell membrane open and allow the entry of

sodium ions, Na+. This influx of sodium marks the start of an action potential. About one
millisecond after the sodium channel opens, voltage-gated potassium channels open
allowing the exit of potassium ions, K+. The efflux of K+ brings the cell potential down
past its resting potential, then both channels turn off. After some time, the cell potential
achieves its resting potential due to the continuous activity of ion pumps that transport
ions across the cellular membrane against their concentration gradient. A representation
of the intracellular waveform is given in Figure 2-2.



Intracellular Action
0:- AI

0 _




_ 0





Figure 2-2. Schematic of a neuron and action potential.

Microelectrodes placed in the vicinity of a neuron measure the extracellular potential

associated with an action potential. The next section will explain the underlying physics

of this recording.

2.2 Extracellular Neural Recording

In viewing the recording microelectrode array as a sensor, it is important to identify

the signal and how it is measured. As stated previously, intracortical microelectrodes

for BMIs need to measure action potentials generated by neurons, which are physically

represented by the influx and efflux of ions through a neuron's cellular membrane.

Figure 2-2, presented earlier, showed the action potential waveform measured via the

potential difference from the inside of the cell to the outside of the cell. An intracortical

microelectrode measures the extracellular potential of a nearby neuron with respect to

a distant electrode. This potential difference is then fed into a differential amplifier as

shown in Figure 2-3. The waveforms shown in Figure 2-3 are characteristic of recorded

and amplified signals. Henze et al. showed that the measured waveform will be close to

the the first derivative of the intracellular waveform [19].
Measured action -.--.-.-. -.-.- -.


C0 Vref

&* 0 -------- -

0 A Amplified action
0 potential

Figure 2-3. Extracellular recording of an action potential with respect to a distant

Moreover, the shape and amplitude of the recorded extracellular voltage depends

on the placement of the electrode with respect to the neuron. Figure 2-4 shows

simulated results for the extracellular potential of a layer V cortical pyramidal cell during

an action potential [33]. The circle in the center of the figure represents the soma, while

Figure 2-4.

Simulated extracellular voltage from a typical layer 5 cortical pyramidal cell
[reprinted from Journal of Computational Neuroscience, vol. 6, no. 2, G. R.
Holt and C. Koch, Electrical interactions via the extracellular potential near
cell bodies, p. 174, Figure 4, 1999, with permission from Springer
Science+Business Media].

the axon hillock, shown in white, is protruding from the bottom. The apical dentritic tree

protrudes from the top of the soma. Other branches are dendrites. Their results suggest

that the largest potentials are near the axon hillock and that all potentials are reduced as

distance away from the cell increases. Experimental results from Henze et al. showed

that extracellular voltages from CA1 hipocampal rat pyramidal neurons are measurable

from microelectrodes as far as 140 pm from the cell body, but that amplitudes greater

than 60 pV must be measured within 50 pm [19]. Drake et al. reported that the farthest

distance they could experimentally record from a neuron cell body in the rat cortex

is 180 pm [34]. Thus it is clear that the relative placement of the microelectrode with

respect to the neuron determines the magnitude and shape of the measured action


Physics of extracellular Recording: Quantitative physical insight can be obtained

from the phenomenological discussion above through the use of electrochemical theory,

named electrodiffusion in the literature [35]. The transient voltage measured with

respect to a distant reference electrode is determined by the changing concentration

of ionic species near the recording electrode. The mathematical relationship between

electrostatic potential and ionic concentration are discussed next.

The governing equation for the ionic flux in dilute solutions for one species, N,, is

given as

N, = -zpFcV D,V c,+ c,v, (2-1)

where N, is expressed in mol-cm-2.s-1, z, is the number of proton charges carried by

the ion, u, is the mobility of the species, F is Faraday's constant, c, is concentration, 0 is

electrostatic potential, D, is the diffusion coefficient of the species,and v is the velocity of

the bulk fluid [36]. The three terms on the right side of the equation correspond to mass

transport due to electric-field-induced drift, diffusion, and convection, respectively. In this

case, the convection term is zero.

Next, mass balance for a volume element requires that the accumulation, or time

rate of positive change of the concentration, must equal the negative of the divergence

of the flux.
8 cl
= V N,. (2-2)
Combining (2-1) and (2-2) gives a time dependent differential equation relating potential

and concentration.
0 Cl,
a zlp,Fc, V + D,V c, (2-3)

Using Poisson's equation allows one to solve for the potential for given initial and

boundary conditions. Poisson's equation is given as

7 2- = z, c, F (2-4)

where p is charge density and E is the permittivity of the medium. The voltage measured

by the differential amplifier is

AV = e Oref, (2-5)

where 0e is the electrostatic potential at the intracortical microelectrode and Oref is the

electrostatic potential at a distant reference electrode. In many recording systems, the

reference electrode is a large area metal screw that is driven through the skull and rests

in the cerebrospinal fluid above the cortex. Therefore, only single unit action potentials

from neurons near the implanted microelectrode are recorded. This derivation provides

the mathematical framework for numerical modeling of the potential measured by

microelectrodes. Future modeling studies could investigate the effects of electrode size

and scar tissue encapsulation on the measured potential waveform.

The next section reviews the design, structure, and fabrication of existing intracortical

microelectrodes and microelectrode arrays.

2.3 Microelectrode Arrays for Neural Recording

The UF microelectrode array incorporates strengths from many of the existing

microelectrode array designs. This section highlights the designs and fabrication steps

of microelectrodes and microelectrode arrays used for neuronal recoding from the

1970's to the present.

2.3.1 Single Microwire Electrodes

Salcman pioneered the way for single unit recordings with glass or polyimide

insulated Pt/lr microwires that were individually implanted into the cortex [37, 38]. The

purpose of his design was to allow for the implanted electrodes to be connected to a

very thin and flexible wire that would provide strain relief for brain motion with respect to

the skull. However, their design was not practical for recording from a large number of

neurons. Hence, following designs incorporated arrays of recording sites.

2.3.2 Microwire Arrays

Microwire arrays have a simple form. They use commercially available wires

with diameters ranging from 20 to 50 pm and materials that are strong enough to

be manipulated without bending and inserted into the neural tissue without buckling

(typically tungsten, iridium, or a platinum/iridium alloy). The wires are typically

coated with a few micrometers of an insulating polymer and held in an array by some

connecting structure. A detailed description of microelectrode arrays made from discrete

wires was given by Williams [23]. A jig was used to separate and secure 35 pm diameter

tungsten microwires insulated in polyimide while they were assembled into a row of

11 parallel wires and attached to a connector. The final array consisted of two rows

of eleven microwires, cut to the same length by tungsten-carbide surgical scissors,

and electrically connected to a back-end connector. Lui et al. constructed microwire

arrays from Pt/lr wires insulated in parylene-C that were 35 or 50 pm in diameter and

electrochemically polished to a conical tip. Sixteen wires were perpendicularly attached

to a backplate in a 4 by 4 grid [24]. Two companies have commercial microwire arrays

that resemble these published designs: Tucker Davis Technologies and Microprobe,

Inc. Tucker Davis Technologies uses polyimide coated tungsten microwires and printed

circuit board technologies to make arrays of 16 electrode sites (2 rows of 8 wires) [39].

The microwires are bonded to a printed circuit board that attaches to a connector. Many

other configurations without the printed circuit board are also made by the company.

Microprobe Inc. makes arrays out of Pt/lr or tungsten microwires that are sharpened to a

point and have parylene-C as the insulating material. They also have a design in which

the microwires are attached perpendicular to a back-plate with a flexible cable of wires

extending to a connector (not shown in Figure 2-5) [40].

a. b. c.
Figure 2-5. Microwire electrode arrays. a) Williams array [reprinted from Brain Research
Protocols, vol. 4, no. 3, J. C. Williams et al., Long-term neural recording
characteristics of wire microelectrode arrays implanted in cerebral cortex," p.
305, Figure 2, 1999, with permission from Elsevier. b) MicroProbe Inc. array.
[http://www.microprobes.com/] c) Tucker Davis Technologies array.

2.3.3 Silicon Micromachined Microelectrode Arrays

Though microwire arrays have been proven to be effective, micromachined

electrodes introduce many advantages that are attractive to researchers in the field.

Advantages include precise control of electrode geometry and spacing, the elimination

or reduction of time consuming hand-assembly steps, and most importantly, the ability

for integration with interface electronics necessary for wireless implantable systems.

The sequential progress of two leading designs of silicon microelectrode arrays will be

discussed next, followed by other less common designs. The Michigan array

The University of Michigan has a current Si microelectrode array based on 38

years of research. Kensall Wise in 1970 (then at Stanford) published a micromachining

process to build a planar array of one to three 10 mm x 100 pm x 100 pm Si beams

that tapered to a point. Gold lines were deposited on the beams and all but a 1000 pm2

recording area at the tip was insulated with SiO2 [41]. Microelectromechanical System

(MEMS) technology was just beginning at that time and process techniques such

as photolithography, wet chemical etching of bulk Si, and vapor deposition and

electroplating of metals were used. In 1985, Wise and Najafi published a refined

version of the aforementioned microelectrode [42]. Design changes included a single

Si shank, or beam, with multiple electrode sites along the top surface. Changes in

the fabrication process included diffusion of boron that effectively defined the probe

geometry when used as etch stop in the wet chemical etch. Tantalum or polysilicon

lines were deposited between either silicon oxide or silicon nitride dielectric layers as

the electrode leads. Then gold was deposited and patterned to form the recording sites.

The resulting probe dimensions were 3 mm length, 50 pm width at the base and 25 pm

at the tapered end, and 15 pm thickness. Their process flow was compatible with the

integration of complimentary metal-oxide-transistor (CMOS) electronics. In 1986 and

1992, the Michigan group published results incorporating amplification, multiplexing, and

buffering electronics on their previous design [43, 44].

The next addition to the Michigan microelectrode design was a Si ribbon cable

made to provide a flexible interface between the Si microelectrode and back-end

connections [45]. Discrete insulated wires used for interconnections in previous designs

would often fail over time rendering the implanted probe useless and proved to be a

manufacturing burden [45]. The Si cable was fabricated using a process flow similar

to the microelectrodes discussed before. Cables 2.5 cm long, 100 pm wide, and 5 pm

thick were made. They were then ultrasonically wire-bonded to a microelectrode and

the connection point was reinforced with a bead of silicone rubber. Figure 2-6 shows

a diagram of a Michigan microelectrode array and a picture of a completed one with

multiple shanks making a 2-D depth array. Neural Nexus is a spin-off company from the

University of Michigan that sells numerous variations of the 2-D Michigan microelectrode


The next advancement of the technology was to make a 3-D array. Hoogerwerf et

al. reported a design that bonds 2-D Si microelectrode arrays perpendicularly to a Si

platform with an integrated Si cable [46]. The 2-D arrays were fit through slots in the



'NTE C ,V.wEC ,r

Sf IMUL-1 rN3
PC OROASv s OTe -3



Figure 2-6.

Examples of the 2-D Michigan microelectrode array. a)[Reprinted from
Proceedings of the IEEE, vol. 96, K. Wise et al., "Microelectrodes,
microelectronics, and implantable neural microsystems," p. 1185, Figure 1,
2008, with permission from IEEE.] b)[Reprinted from Annual International
Conference of the IEEE Engineering in Medicine and Biology Society, R.J.
Vetter et al., "Development of a Microscale Implantable Neural Interface
(MINI) Probe System," p. 7342, Figure 2, 2005 with permission from IEEE.]

platform, held in place by spacer bars, and then were electrically connected by selective

electroplating nickel to bridge the gap between platform and array. The interconnect

structure was then hermetically sealed by reflowed glass and epoxy. A figure of the

3-D array is shown in Figure 2-7. A summary of more modifications to the Michigan

design are described here. Later designs changed the recording-site metal from gold

to platinum or iridium [21, 47], incorporated parylene rather than Si cables [48] and

added wireless capability [47, 49]. The general approach suggested by Michigan for

future microelectrode arrays is to have all amplification, signal processing, telemetry,

and power electronics resting subcutaneously on the skull. Flexible parylene cables

were used to connect two or three dimensional Si microelectrode array implanted in the

cortex, distancing the electronics and reducing the susceptibility of tissue heating [49].

Figure 2-7. 3-D Michigan microelectrode array [reprinted from Proceedings of the IEEE,
vol. 96, K. Wise et al., "Microelectrodes, microelectronics, and implantable
neural microsystems," p. 1188, Figure 5, 2008, with permission from IEEE]. The Utah array

The Utah array is the other popular micromachined microelectrode array. Richard

Normann, the founder of the Utah array, first designed the Utah array for a visual

stimulating prosthesis, where local stimulation was applied in the visual cortex [50].

It has since been widely used as a CNS recording prosthesis as well. Cyberkinetics

licensed the technology and has marketed the Utah microelectrode array with their

"Brain Gate" system for recording in the central nervous system. A clinical trial was

performed with the Brain Gate system as a BMI for the severely motor impaired [17].

The Utah array was first fabricated as follows. Starting from a 1.7 mm thick silicon

wafer, thermomigration was performed to make trails of p Si from one side of the wafer

to the other in a 10 by 10 array. A dicing saw was used to cut in the spaces between

the doped Si trials leaving a three dimensional structure of 1.5 mm columns that are

electrically isolated at the base by pn junctions. The columns were 150 pm square and

1.5 mm tall, with center to center spacing of 400 pm. The structure was then put through

two isotropic wet etches to first decrease the column area and then to taper the tips. The

resulting geometry of one probe is a cone shape while the group resembles a "bed of

nails". Gold and platinum thin film layers were deposited consecutively on the first 50

pm to 100 pm of each tip and thin gold wires were bonded to the backside of the wafer

making the interconnect.

The next generation of Utah arrays shown in Figure 2-8 included the following

changes. A different layering of tip electrode metals (Pt/Ti/W/Pt) was used and an

insulation layer of polyimide was placed on the remaining part of the the probe shanks

[22, 51]. Also, the electrical isolation of electrodes was improved by using a glass

dielectric as the insulation between the probe sites on the back of the wafer [51]. Later

changes in the fabrication process allowed the length of the probes to vary in one

direction, effectively giving a three dimensional array of the recording sites in space

[52]. In a more recent publication, batch fabrication is shown for the Utah array in

Figure 2-8. Utah microelectrode array [reprinted from Proceedings of SPIE The
International Society for Optical Engineering, R. Bhandari et al., "System
integration of the Utah electrode array using a biocompatible flip chip under
bump metallization scheme, p. 1567, Figure 1, 2007 with permission from

which they tout a maskless process. Here parylene-c is used instead of polyimide as

an insulation for the Si probe shanks, and the etching scheme has been changed to

increase geometrical uniformity by incorporating a customized wafer holder which spins

the wafer in the etching solution [53].

Most recent publications show the design of a fully implantable, wireless system.

Utah's approach is to flip-chip bond all electronics and power and telemetry hardware

onto the the back of the Si platform on which the electrodes are fabricated [53]. The

electrodes are implanted into the cortex while the electronics rest on the top of the

cortex. The design is constrained by tissue heating because of the close proximity to

neural tissue [54]. Other Si microelectrode arrays

Two other Si micromachined microelectrode arrays to note are discussed here. One

design is by a group in Sweden affiliated with the company Acreo and the other is by a

group at Arizona State University. Both have, novel design concepts; however, neither

have received as much reference in literature as the Utah or Michigan arrays.

The group from Sweden fabricated arrays (named VSAMUEL) similar in shape

to the Michigan array in that electrode sites were placed along the shank of Si

micromachined probes [55]. The difference in their process flow was the use of a silicon

on insulator (SOl) wafer and the use of deep reactive ion etch (DRIE) for the removal

of the bulk silicon. In a later publication, they discussed the ability to use a direct write

system that will customize electrode site layout in a practical manner [56]. Instead of

using masks to etch the silicon nitride insulation layer on top of the recording sites, they

use a direct write laser beam to open the Pt or Ir recording sites. This reduces cost in

producing custom designs that need, for example, a variation of electrode spacing [56].

A collaboration between Arizona State University and Sandia National Laboratories

resulted in a Si-based actuated microelectrode array [57]. To circumvent loss of signal

over time, this group designed and fabricated a system that allowed repositioning of the

implanted microelectrode array. They used the SUMMiT-V microfabrication technology to

build thermal actuators into a probe structure. Two recording electrodes could be moved

up or down in steps via a MEMS structure that used a ratchet scheme. Preliminary in

vivo results were given, but no publications on its efficacy have been found.

2.3.4 Polymer Micromachined Microelectrode Arrays

In order to better mechanically match the softer and more flexible neural tissue,

polymer-based-intracortical-microelectrode arrays were introduced to the field [58, 59].

In 2001, two groups published independent papers on polyimide-based microelectrodes.

Only a handful of other designs have emerged since then. Most will be discussed in this

section. The Arizona State design is described first.

A research effort starting at Arizona State University by Daryl Kipke's group used

micromachining techniques to process a microelectrode structure that consisted

of a layer of thin-film metal sandwiched between 10 pm thick layers of polyimide

[58]. Using a Si wafer to handle the processing steps, a sacrificial layer of SiO2 was

deposited, then polyimide was spin deposited and cured, followed by gold deposition

and patterning. Then a top layer of polyimide was spun as the top insulation layer.

Reactive ion etching removed polyimide from the 30 pm by 30 pm recording sites and

larger bond pads. Platinum was deposited and patterned as the final electrode material.

Then the polyimide structure was removed via chemical etch from the handle wafer.

Their devices had two recording sites on one polyimide shank and a variety of designs

with three or more shanks. One example is depicted in Figure 2-9. The devices were

highly flexible and would buckle under the force needed for insertion through the cortex,

so incisions had to be done in order for the microelectrode array to be implanted [58].

Acute studies showed promising results in their first publication.

Later publications by Kipke, who had since moved to the University of Michigan,

introduced a parylene-based microelectrode array with microfluidics for drug delivery

[60] and an open architecture microelectrode with subcellular dimensions seen in

Figure 2-10 [61]. The second parylene design was not yet a functional microelectrode in

Figure 2-9. Polyimide-based microelectrode array (Arizona State, Gen 1) [reprinted from
IEEE Trans. Biomed. Eng., P. Rousche et al., Flexible polyimide-based
intracortical electrode arrays with bioactive capability, vol. 48, no. 3, p. 363,
Figure 1(g), 2001, with permission from IEEE].

that no recording sites were made on the structure. Their goal was rather to assess the

tissue reaction to the polymer implant for subsequent versions.

Figure 2-10. Parylene-based microelectrode array (U. of Michigan) [reprinted from
Biomaterials, J. Seymour and D. Kipke, Neural probe design for reduced
tissue encapsulation in cns, vol. 28, pp. 3596, Figure 1(a), 2007, with
permission from Elsevier].

A new group at Arizona State published a next generation of the Kipke microelectrode

in reference [58]. They designed for increased stiffness that allowed implantation into

the cortex without buckling [62]. Using an SOI wafer, a similar polyimide-metal structure

was fabricated. The structure was then removed from the bulk Si resulting in a 20

pm thick polyimide structure with 5 pm of Si beneath. Si was then selectively etched

away from sections requiring flexibility such as the back-end cable. A photograph is the

devices is shown in Figure 2-11.


from Journal of Micromechanics and Microengineering, K. Lee et al.,
"Polyimide-based intracortical neural implant with improved structural
stiffness. vol 14, issue 1, p.35, Figure 4(a), 2004, with permission from

Stieglitz and Gross, of Germany, published a similar polyimide microelectrode

design as the Kipke group in 2002, except their fabrication process allowed for front

and back side electrode arrangements as depicted in Figure 2-12 [63]. They also plated

platinum black on the electrode sites to decrease their impedance. This group has

numerous papers on sieve, cuff, and planar polymer electrode arrays that are mainly

geared for PNS stimulating and or recording prostheses [64]. The publication mentioned

first [63] was the only polymer-based microelectrode targeting intracortical recording and

no in vivo results were given.

Another research group that has experience in fabricating polymer microelectrode

arrays is at the University of Tokyo [65]. They have published a series of designs using

polyimide and parylene-C. Their first device was a planar polyimide array fabricated

much like the ones already mentioned; however, they incorporated a magnetic layer

(nickel) on the shanks that allowed the electrode shanks to be tilted out of plane in a

magnetic field as shown in Figure 2-13 [65]. The microelectrodes, perpendicular to the

Figure 2-12. Polyimide-based microelectrode array (Fraunhofer Institute) [reprinted from
Sensors and Actuators B: Chemical, T. Stieglitz, "Flexible BIOMEMS with
electrode arrangements on front and back side as key component in neural
prostheses and biohybrid systems." vol. 83, p. 12, figure 5, 2002, with
permission from Elsevier].

cable and back-end connection, were then inserted without buckling into the brain for

acute results.

Figure 2-13. Polyimide-based microelectrode array (U. of Tokyo) [reprinted from Journal
of Micromechanics and Microengineering, S. Takeuchi et al., 3d Flexible
multichannel neural probe array,, vol. 14, p. 106, Figure 4(c), 2004. with
permission from IOP].

This group's next series of publications changed gears and started with a design

that used parylene-C and microfluidic channels. Again, metal for the electrode sites and

lead wiring was sandwiched between layers of parylene-C [66]. Microfluidic channels

were structured in the parylene layers by patterning photoresist between the layers and

subsequently removing it, leaving a void [66]. Photographs of this device are shown in

Figure 2-14. In this paper, insertion into the cortex was achieved by inserting heated

polyethylene glycol (PEG), a biodegradable polymer, into the microfluidic channel. After

cooling, the PEG made the structure stiff enough to be inserted in to the tissue without

buckling. Over time, the biodegradable polymer would dissolve leaving the flexible

parylene structure in the brain. Subsequent papers, used this same design and added

biodegradable microspheres with bioactive agents to the PEG [67, 68]. Neural growth

factor (NRG) was encapsulated in microspheres which were seeded in PEG and set in

the microchannel. Acute results were given showing potential for future use [68].

A Tyk"-AP A

Figure 2-14. Parylene-based microelectrode array (U. Of Tokyo) [reprinted from 26th
Annual Internationals Conference of the IEEE EMBS, T. Suzuki et al.,
Flexible neural probes with micro-fluidic channels for stable interface with
the nervous system, p. 4058, figure 3, 2004, with permission from IEEE].

The final design discussed in this section refers to a publication from Karen Cheung

at the University of British Columbia. A flexible microelectrode array is made using

polyimide (shown in Figure 2-15), which geometrically resembles a single shank

Michigan microelectrode array [69]. The metal for the electrode sites as well as lead

wiring is platinum. There were 16 electrode sites, 25 pm in diameter, patterned in a

row on a 15 p m thick, 2 mm long, and 195 pm wide shank, which tapered to 35 p

m. A longer, monolithicly-fabricated cable attached to a back-end connector. They

claimed their flexible device was implanted without bulking and caused minimal immune

response after 8 weeks in vivo.

Figure 2-15. Polyimide-based microelectrode array (U. of British Columbia) [reprinted
from Biosensors and Bioelectronics, K. C. Cheung et al., Flexible polyimide
microelectrode array for in vivo recordings and current source density
analysis, vol. 22, no. 8, p. 1786, Figures 2(a), 3(a), 2007, with permission
from Elsevier].

2.3.5 Comprehensive Microelectrode Array Summary

Micro-wire arrays have been the workhorse microelectrode design for research

labs using BMIs for neural prostheses [11, 12]. They possess the necessary small

size needed for implantation and are well established in the field [70]. However, it is

difficult to scale-up microwire arrays due to assembly and size constraints. The increase

in the number of total recording sites, consistency of recording-site geometry and

surface structure, and integrated electronics, are some advantages of micromachined

microelectrodes over discretely assembled micro-wire arrays. Si-micromachined

electrodes such as the Michigan and Utah probe have been gaining popularity. Clinical

trials with the Utah electrode have occurred [17].

The reviewed micromachined microelectrode designs also have distinct disadvantages.

The Michigan and VSAMUEL array have recording sites that are positioned along the

shank of the probe. Thus, the majority of the recording sites will be recording from

neural tissue that has been damaged during the implantation process. It may be argued

that the quality of the recorded signals from those sites will be decreased compared to

a recording site placed at the tip of a probe. Furthermore, one documented issue with

the Michigan electrodes is that they are prone to breaking during implantation because

of their fragile nature [71]. The Utah array design also has some issues. First, the length

of the implanted probes are limited to the thickness of the bulk silicon wafer (1.5 mm)

[72]. Severe tissue encapsulation due to the dense array has been documented for the

Utah array that directly led to inhibited recording performance and eventual migration out

of the cortex [22]. Also, in designs that incorporate electronics onto the backside of the

Utah electrode, power constraints due to tissue heating are a concern [54].

Polymer-based micromachined microelectrode arrays have the same advantages

as Si-micromachined electrodes plus the possible benefit of a better mechanical match

to the soft neural tissue and increased strain relief from external forces. However, all

of the polymer-based designs have electrode sites placed on the side of the probe

shank rather than the tip and the majority of the designs must require an incision into

the neural tissue before implantation. Moreover, whether polymer-based microelectrode

arrays really do increase the longevity of neural recording is yet to be unequivocally

determined. What has been documented is both the acute and chronic response of

brain tissue to intracortical microelectrodes. This immune response is discussed next.

2.4 Tissue Response to Intracortical Microelectrodes

The reason for the decrease in active electrodes over time as shown in Table 1-1 is

investigated in this section. Based on histological studies of brain tissue after prolonged

implantation, researchers have a detailed understanding of the immune response to

microelectrodes [20, 73, 74]. Their results suggest the foreign body (i.e. microelectrode

array), elicits a chronic immune response that has detrimental effects to surrounding

healthy neurons.

Before the histological results are discussed, a review of the cellular make-up of

the brain is given. The cells that constitute brain tissue are neurons and glial cells,

which consist of oligodendrocytes, astrocytes, and microglia [20]. Neurons, account

for less than 25% of the total number of cells. The glial cells make up the remaining.

Oligodendrocytes create myelin found on neurons. Astrocytes and microglia respond

to injury in the brain. When an injury occurs, the astrocytes and microglia become

activated and move to the injury site [75]. Microglia secret reactive oxygen intermediates

(ROls) in what is called the "respiratory burst" [75] as well as cytotoxic enzymes. Their

goal is to break down cellular debris and consume damaged cells. The production rate

of the ROls in microglia increases greatly when activated. ROls include O,, H202, and


Researchers have given histological reports on the immune response of the brain

to silicon [74, 76] and polymer [61] based microelectrodes. All reported two immune

responses: one due to the injury imposed by the implantation of the electrodes and

another due to the persistent presence of the microelectrodes. The injury of the neural

tissue caused by insertion signaled activated astrocytes and microglia to migrate to the

area of implant. A cluster of these cells, called a glial scar, could be seen as far as a

few hundred micrometers around the implant [76]. This response was dependent on

probe size as a larger probe would do more damage to the surrounding tissue during

insertion. Over time the initial wound response would diminish and all papers reported

a more compact sheath of cells containing reactive astrocytes and activated microglia

around the implanted microelectrode. This sheath of cells would remain constant after

four weeks of implantation [73] and did not correlate to the size of the implanted probe

(except for subcellular sizes [61]). Thus, the authors surmised that this response was

due to the chronic presence of the probe.

Three theories exist on the effect of immune response on the recording properties

of the microelectrode. The glial scar that forms around the microelectrode either 1)

electrically isolates the electrode from endogenous electrical signals, 2) physically

moves nearby neurons away from the electrode or, 3) releases cytotoxic chemicals

that result in neuronal death. An in vitro study showed that layers of cells mimicking

an inflammatory, or immune reaction, placed on a microelectrode only increased the

impedance seen by the electrode by 2-3 times, which is not enough to be the cause

of signal loss [77]. Biran et al. surmised that if neurons were being displaced from the

electrode they would see a higher density of neurons outside of the glial scar [74]. Their

results were not consistent with that theory and instead showed that chronic immune

response, as well as creating a thick sheath of cells around the implant, actually results

in the death of nearby neurons. Biran et al. showed that within a 100 pm radius of the

implant there was a 40% loss of neurons. They suggested that neuronal death due

to the presence of active microglia is the major contributor to diminishing recording

performance over time. Corroborating this statement, researchers linked the damage of

neurons in neurodegenerative diseases such as Alzheimer's Disease, amytrophic lateral

sclerosis (ALS), and Parkinson's disease to ROls produced by reactive microglia [78].

In summary, it was surmised that the chronically implanted microelectrode array will

elicit a continual immune response, which allows microglia to be continually activated

and release cytotoxic chemicals [73]. It was shown that due to the release of such

chemicals, the neurons near the implant die, and it was proposed that this mechanism

rather than electrical isolation or the distancing of neurons due to a glial scarring was

the most significant contributor to decreased recording capability over time[79]. Thus,

the next logical progression of research was to assess why the microelectrodes were

producing a chronic immune response.

Strain Induced Immune Response: Recent studies showed a difference in

microglial activity in implants that are rigidly tethered to the skull to ones that are floating

in the brain [79, 80]. The histological studies reviewed in Section 2.4 conventionally

tethered the implanted array to the skull of the subject. The tethering consisted of

securing the implanted shank at the craniotomy site to the surrounding skull with a rigid

medical adhesive [73, 74, 76]. Figure 2-16 shows how a typical rigid microelectrode

Bone Screw Methacylate



which the arachnoid layer is attached [81]. The pia is a membrane attached to the

surface of the cortex. In between the pia and the arachnoid layer exists a space filled

with cerebral spinal fluid that cushions the brain [81]. The absence of mechanical

attachment in the subarachnoid space also allows the brain to move with respect to the

skull when the head undergoes large rotational accelerations [37].

If a force is applied to the back-end of the rigid microelectrode in Figure 2-16 (the

part protruding from the skull), strain may be transferred along the probe. This may

act to loosen the skull connection over time as well as displace the electrode tip within

the brain tissue. Moreover, if the brain moves with respect to the skull under head

rotation, the tip of the implanted electrode will move with respect to the brain if it is rigidly

connected to the skull.

Front-end strain relief is not a new concept. Salcman et al. discussed in their

1973 paper the need for strain relief of a single microwire electrode for chronic

neurophysiologic recordings [37]. They recognized that an implanted electrode can

be displaced relative to its secured connection point at the skull due to rotation of the

head and subsequent movement of the brain with respect to the skull. Their electrode

design, which implemented a thin, flexible, gold wire between the electrode in the cortex

and the external connection, limited motion of the electrode tip to 10 pm for a 1 mm

displacement of the brain with respect to the skull.

However, as microelectrode arrays rather than single electrodes became necessary

for BMI systems, front-end strain relief was omitted in many Si-based designs in order to

incorporate many electrode channels. Two exceptions, the Utah and Microprobe "bed of

nails" designs claim to have front end strain relief by having thin and flexible gold wires

connecting the implanted electrodes to the back-end connector. No modeling has been

done to quantify how well their wire bundle provides strain relief, however. A "back of

the envelope calculation" suggests that if they use 25 pm diameter wire-bonding wire as

the single connection to the electrode channels, then the resulting effective thickness

of the 100 wire cable is 100x25 pm or 250 pm, which would have significantly reduced

flexibility. Moreover, the hybrid nature of the back-end wire connection is prone to failure.

Mechanical modeling of tethering induced strain has been performed for Si and

polymer microelectrodes resembling the Michigan electrode geometry [82]. This

paper first showed that Si shank microelectrodes, rigidly tethered to the skull, transfer

significant strain to the surrounding brain tissue from a radial or tangential force applied

at the top of the cortex and result in tip displacement. They also showed that tissue

adhesion will act to decrease the resulting tip displacement for a given force.

Sabbaroyan et al. performed similar modeling of a Si Michigan microelectrode array

in comparison with a polyimide array of the same dimensions [83]. Their results showed

a 65%-94% decrease in strain at the electrode tip due to force in the tangential direction

with a polyimide electrode. No change was seen in the resulting stress between a Si

and polyimide microelectrode for a tethering force in the radial direction-along the long

axis of the probe.

Therefore, using conventional tethering techniques, the resulting strain seen

by the neural tissue is dependent on the flexibility of the implanted shank. Most

histological studies described in Section 2.4 use Si shank microelectrode arrays and

found persistent microglial activation. Biran et al. used Si shank microelectrode arrays

as well and noted a pronounced difference between ones that were conventionally

secured to the skull or broken off and left free floating in the brain tissue; the floating one

produced significantly less microglial response [79]. Kim et al. showed similar results

with flexible, polymer hollow fibers that were either fixated to the skull or left to float

in the brain tissue [80]. Their results showed an even greater decrease in microglial

response in the free-floating cases than [79]. Thus, a flexible substrate design that

minimizes tethering forces on the implanted microelectrode array is supported.

2.5 Implications

Designing an intracortical microelectrode array capable of long-term in vivo

recording requires an interdisciplinary view. The necessary biology and electrophysiology

must be known in order to determine the relative size and shape of the electrode

array as well as the best measurement procedure. In order to have sufficient spatial

resolution, the electrode sites must be comparable to the size of the neural cell body.

Hughes et al. and Lempka et al. suggest that recording site areas should be around 400

pm2 for optimal signal-to-noise ratio [84, 85]. Measuring and amplifying the extracellular
voltage with respect to a reference electrode located within the cerebral spinal fluid,

but not in the cortex, insures that action potentials from neurons within 200 pm of the

implanted microelectrode will be measured.

By reviewing the numerous microelectrode array designs, advantages and

disadvantages are apparent for the different design schemes. Out of the pros and

cons listed in Section 2.3.5, some of the most important points used in the design of the

UF microelectrode array are as follows. Microwire arrays that do not use microfabrication

techniques and are discretely assembled are not easily compatible with the integration

of electronics for a fully-implantable system. Platforms for electronics that reside on

the cortex, as in the Utah array, have power constraints because of tissue heating.

Moreover, catastrophic failure may be induced by the fracture of brittle materials used

in the the implanted microelectrode. This work presents a microelectrode design

that incorporates robust materials that will not break and can be integrated with

application-specific-integrated circuits (ASICs) in a way that minimizes the amount

of space needed for integration and places the electronics away from the cortex on top

of the skull.

Knowledge of the immune response and how it is affected by material composition,

size, mechanical properties, and implant construct is most important for long-term

efficacy of the device. Based on the papers reviewed in Section 2.4, the size and

shape of the microelectrode array has most impact on the initial wound response

rather than the chronic foreign body response. Thus, the size of the microelectrode

array should be minimized to reduce the magnitude of the initial wound. However,

the factors controlling the severity of the chronic immune response and the resulting

decrease in recording performance are not yet fully known and thus, are difficult to

design around. A microelectrode with minimal tethering to the skull made out of softer,

more flexible materials is suggested to lessen the chronic would healing response

by the research in the field so far. However, the goal of this work is to exemplify the

functionality of the Florida Wireless Integrated Recording Electrode (FWIRE) design,

which uses well-established, tungsten microwire electrodes that are integrated with a

micromachined polymer-based substrate. The UF microelectrode array capitalizes on a

design that maximizes the functionality with integrated electronics while allowing future

changes to the implanted microelectrodes to be made.

Furthermore, this work fully characterizes the electrochemical interaction at the

interface of the tungsten electrode and extracellular fluid. Corrosion of the tungsten

electrodes has been overlooked by researchers in the field thus far. This work provides

information on the corrosion of tungsten in biological solutions that has not been

reported and suggests that tungsten should not be used for long-term recording

applications. The next chapter presents the background necessary to understand

the electrochemical nature of the electrode interface.


The use of metal as an implant material is most widely known for dental and

orthopedic applications. In these cases, metal is primarily used for structural purposes.

Corrosion of the metal implants for orthopedic applications is an ongoing issue [86].

Cardiac pace makers are one example of a medical device that use metal electrodes for

electrical signal conduction into the cardiac muscle. A large body of literature is available

on the corrosion analysis of metals and metal oxides for stimulation purposes [87-90].

Neural interface prosthetics also use metal for the electrical conduction of signals at

the tissue interface. Less information on the corrosion properties of metals is available

for neural recording applications. To understand how corrosion may occur, the physics

explaining the nature of charge transfer at a metal-tissue, or electrode-electrolyte,

interface are presented in this chapter. Also, the current understanding of the corrosion

properties of tungsten (the metal of numerous intracortical microelectrodes) is

discussed, showing gaps in the knowledge base for biological applications.

3.1 Electrode-Electrolyte Interface

Consider the electrochemical nature of the electrode-electrolyte interface. The

interface has a distinct physical structure that governs ionic current flow. Two cases

are explored that have the absence or presence of electrochemical reactions at the

electrode interface, namely, nonfaradaic and faradaic.

3.1.1 The Nonfaradaic Interface

No electrochemical reactions occur at the nonfaradaic interface. An electrode

exhibiting this feature is often called a blocking electrode when no current flows at

DC conditions [36]. It is shown next that passage of current is effectively capacitively

coupled at the interface. This phenomenon is described by the double layer theory.

When an unbiased metal electrode is immersed in an electrolytic solution, a space

charge region will form at the interface [91]. Physically, this is a redistribution of charge

at the interface that arises from anisotropic forces acting on ions in solution due to

a change in boundary conditions [91]. Thermodynamically, the space charge region

can be explained by the difference in electrochemical potential, p, of the metal and

electrolyte. The equation for the electrochemical potential for one species is

p = o + zF~ (3-1)

where p/ is the chemical work and zF is the electrical work required to bring one mole

with charge z form infinity to the material phase, where F is Faraday's constant and 0 is

potentail [91].

The space charge region in metal and solution interfaces was first described by

Helmholtz and is known generically as the double layer [91]. He postulated that a

fixed layer of ionic charge would be attracted to the interface due to the difference

in electrochemical potential at equilibrium. His theory however, could not explain all

experimental results [91]. Thus, subsequent interface models have arisen giving a more

complete picture.

The following presents the Stern model of the double layer, which is a combination

of the Helmholtz-Perrin and Gouy-Chapman models. As Figure 3-1 shows, the interface

has an inner and outer Helmholtz plane (IHP and OHP, respectively). The inner plane

consists of adsorbed ions or molecules such as polarized water molecules; the outer

plane consists of solvated ions (normally cations) that are the opposite sign of the

excess charge on the metal [91]. There is a finite distance d between the centers of the

ions or molecules at the IHP and the solvated ions in the OHP. This layer constitutes

a fixed layer of charge, and therefore a fixed capacitance that does not change with

applied potential, as Helmholtz first postulated.

The next layer in the Stern double layer model is the diffuse layer. Based on a

double layer theory proposed independently by Guoy and Champman, Stern concluded

that adjacent to the layer of fixed charge at the OHP, there is a space in which charge


Bulk Electrolyte

chargedd Melal


+ D

-^ (s

~ +^ ^r


- *i

Hydrated Ions



Figure 3-1. Equilibrium electrode/electrolyte interface.

is distributed. The net charge in this area exponentially decays to zero as a function

of distance [91]. The charge on the electrode surface will equal the charge in the

Helmholtz double layer plus the charge in the diffuse layer, q, = qiHP + qdiff(X) If using

the relation,
80 q
q (3-2)
ax e

where c is permittivity [91], it can be seen that the two layers constitute two potential


Om Oref = Om OOHP + OHP Oref,


where the drop in the Helmholtz double layer is linear and exponentially decaying in the

diffuse layer [91]. The definition for capacitance is


Double Layer


C =

where q is the charge on the electrode [91]. Therefore,

1 1 1
+ (3-5)
Cdl CHdl Cdiff

where the double layer capacitance Cdl is equal to the series combination of the

Helmholtz double layer capacitance CHdl and the diffuse layer capacitance Cdiff. The

capacitance values are given by
CHdl = (3-6)

Cdiff = A cosh (3-7)
where A is the electrode area, A is the Debye length, z is the charge number of species

i, F is Faraday's constant, R is the universal gas constant, and T is temperature [91],

[36]. The diffuse layer capacitance given above is only valid for an electrolyte having one

cationic species and one anionic species with the same charge number.

In practice, the total double layer capacitance is dominated by the Helmholtz double

layer capacitance. In sufficiently concentrated solutions, Cdiff becomes much larger

than CHdl, and therefore has negligible influence on Cdl [91]. The double layer capacity

is typically 10 20 F/cm2 [92]. Since it has been shown that current is capacitively

coupled in the double layer, the current to voltage relationship in the bulk electrolyte is

considered next.

As stated in Section 2.2, the neural signal is recorded via two electrodes in the

tissue. One is in close proximity to the neuron, and the other is sufficiently far away

so as not to measure the same signal. The potential difference measured across the

two electrodes then equals the voltage dropped across the electrolyte plus the voltage

dropped across the double layer of the electrodes as

Vm = IRe + Vdl, (3-8)

where Re is the electrolyte resistance. Re, then, is the other circuit element that

physically describes the equivalent impedance of the electrode-electrolyte interface.

The following discussion will outline the derivation for an analytical equation

describing the electrolyte resistance of a disk electrode. Flux of ionic species is given by

Ni = -zuFc,V1 DVc, + vc,, (3-9)

where ui is the mobility, ci is the concentration, Di is the diffusion coefficient, and v is

velocity of species / [36]. The terms relate the flow of ions to migration, diffusion, and

convection, consecutively. The corresponding current density can be given as

i = F z,N,. (3-10)

Following the law of electroneutrality in the bulk electrolyte, the convection term is zero,

and assuming there is no concentration gradient, (3-10) yields

i = -KV0, (3-11)

where the conductivity of the electrolyte is

K = F2 iz2uiCi. (3-12)

The potential 0 in the electroneutral-bulk electrolyte satisfies Laplace's equation [36]

V20 = 0. (3-13)

The equivalent resistive term in the bulk electrolyte is then found by solving the Laplace

equation, with boundary conditions as given by (3-10) [36]. For a disk electrode with a

reference electrode a semi-infinite distance away, the resistance of the bulk electrolyte is

given as
Re (3-14)
where ro is the radius of the disk electrode.

Double Layer Bulk Electrolyte

Cdl Re

Figure 3-2. Equivalent circuit for the nonfaradaic interface [1].

Thus, the impedance of the electrode-electrolyte interface may be modeled as given

in Figure 3-2 in absence of electrochemical reactions (i.e. nonfaradaic interface) [1].

3.1.2 The Faradaic Interface

Unlike the previous case, electrochemical reactions take place at the electrode

surface in the faradaic interface. Current flow in the double layer region may occur via

double layer charging or electrochemical charge transfer [91]. The physics established

thus far, describing the double layer and bulk regions for the nonfaradaic case, also hold

true for the faradaic interface. The only new development addressed in this section is the

faradaic charge transfer mechanism at the interface.

In the faradaic interface, chemical reactions are thermodynamically favorable under

equilibrium and nonequilibrium conditions [36]. This statement means that when the

electrode is immersed in the electrolyte, reduction and oxidation reactions automatically

occur at the electrode surface. The current density produced by one reversible redox

reaction, O + ze- t= R, is given by the Butler-Volmer equation

(s OF \cF
i= i0exp q exp (-q, (3-15)

where /o is the exchange current density, Tr is the applied voltage, or overpotential, and

aa,c are the transfer coefficients for the anodic and cathodic reactions, respectively [36].
This equation shows that the total net current will be the difference of the anodic and

cathodic currents. At electrical equilibrium, or zero overpotential, the rate of oxidation

equals the rate of reduction and no net current is produced. However, anodic and

cathodic currents exist and equal the exchange current density, /i = ia = ic.

Electrochemical reactions allow charge to be transferred from the electrolyte to

the metal and visa versa. The equation for current determines the rate at which this

happens relative to an overpotential. Thus, the resistance to charge transfer given in

Qcm2 is defined by [93]

Rct = (3-16)

The Bulter-Volmer current is a nonlinear function; however, at small overpotentials, it

may be considered linear. If ac = (1 aa), (3-15) can be written as [93]

i= io(F/RT). (3-17)

Therefore, Ret is given by
Rct = (3-18)

This resistive term is placed in parallel with the double layer capacitance in the

equivalent circuit model as shown in Figure 3-3 [1].

Double Layer Bulk Electrolyte



Figure 3-3. Equivalent circuit for faradaic interface [1].

The electrochemical theory discussed so far is valid for one reversible reaction at

the electrode-electrolyte interface. The effect of multiple or mixed reactions is given next.

The graph in Figure 3-4 shows the voltage versus log current density relationship for

two arbitrary redox reactions [51]. In this scenario, the quasi-equilibrium potential and

current density for these reactions are where the lines cross for the two reactions. Thus,

oxidation of species N is occurring on the anode and reduction of species M is occurring
on the cathode. This non-reversible reaction could represent a corroding system, if
the metal is being oxidized into its ionic form [51]. The potential and current density at
which the anodic reaction rate equals the cathodic reaction rate are called the corrosion
potential, Ecorr, and corrosion current density, ico,. Notice the difference between the
exchange current density for a single reaction io.


I corr
log i (A/cm2)

Figure 3-4. I-V relationship of two reactions occurring at the interface.

Similar to (3-15), the current density at an interface with mixed reactions is

/ = exp 2.303) exp( 2.303), (3-19)
i 0p a 01 '

where /ac = T is the Tafel slope [51]. For small overpotentials, (3-19) is linearized
and the polarization resistance becomes

Rp = icorr2.33 (3-20)
2.303(o, + o,)'

where icorr = i, = [51].
3.1.3 Interface Summary

Section 3.1 considered two simple and ideal cases; the blocking and faradaic
electrode-electrolyte interface. In the blocking case, the electrode is capacitively
coupled by the double layer capacitance and allows alternating current to flow with no

change to the electrode or surrounding tissue. In the faradaic case, both direct and

time-varying current may flow via double layer charging and electrochemical reactions.

If the reactions are not reversible, then the electrode could be corroding and chemical

species could be entering into the tissue. There are other phenomena that could also

take place, including mass transfer limitation by diffusion[93]. However, the phenomena

described previously are sufficient for characterization of the electrode-electrolyte

interfaces seen in this work.

3.2 Need for Electrochemical Analysis of Electrode Materials

Tungsten is commonly used for recording sites on intracortical microelectrode

arrays. Commercial microelectrode arrays as well as many noncommercial arrays from

various research groups, including the authors', are made with tungsten microwires

[11, 15, 23, 27, 39]. Tungsten electrodes formed from 50 pm diameter microwires

are desirable for intracortical applications because of their strength and rigidity. The

microwires can be inserted into neural tissue without buckling. However, tungsten is

not impervious to corrosion. A failure mechanism for microelectronic integrated circuits

has been shown to be the corrosion of tungsten via-plugs [94]. Tungsten coils, due to

their thrombogenicity, had been used clinically to occlude unwanted vasculature and

have since been taken off the market due to degradation of the coils [95]. Sanchez et

al. showed structural modification of tungsten microwires after four weeks of in vivo

implantation [96]. Their observation suggested corrosion had occurred at the end of the

tungsten microwires.

Although the corrosion and anodic dissolution of tungsten are well documented for

acids [97-100] and bases [99-101] at various potentials, the rate and electrochemical

mechanism of tungsten corrosion in biological solutions are not well documented. In

a comprehensive study, Anik et al. showed that the dissolution of tungsten depends

on specific system conditions such as potential and pH [99]. One study used similar

conditions seen by tungsten microwires in neural recording applications. Peuster et

al. performed an in vitro assessment of the corrosion of tungsten coils in Ringer's

solution, a type of physiological saline solution, via weight loss measurements and

concluded that one coil would dissolve in 6 years [95]. Their analysis however, did not

specify a corrosion rate in units of mass per area per time and thus is not useful to

estimate corrosion in other systems. Therefore, a study that quantifies the corrosion

rate for tungsten microelectrodes used in intracortical recording applications is

needed. Moreover, the electrochemical behavior of tungsten microelectrodes should

be compared to the behavior of platinum microelectrodes, which are also widely used for

neural recording applications and considered inert for such applications [102-104].

It would be prudent to know if the inflammatory response also affects charge

transfer at the microelectrodes, since Biran et al. concluded that the presence of

microelectrodes in neural tissue elicits a chronic inflammatory response that may

lead to the injury of nearby neurons [74]. Reactive oxygen species such as H202

are produced by the reactive microglia during the inflammatory response [75]. Two

studies investigated the influence of H202 on titanium used for structural implants in

the body (i.e. hip implants), [105, 106]. They showed that millimolar concentrations of

H202 modified the natural oxide layer on the titanium resulting in decreased corrosion

resistance. To our knowledge, there are no studies that analyze the electrochemical

response of tungsten in biofluids containing H202. Since hydrogen peroxide is an

oxidizing agent, it would be beneficial to assess the reactivity of tungsten in electrolytes

containing physiological saline and H202. The reactivity of platinum in electrolytes

containing H202 has been explored [107-110]; however, the potential at which the

experiments were done is unrealistic for neural recording applications. Thus, an analysis

of the reactivity of platinum in saline electrolytes containing H202 under the conditions

seen in recording applications is also warranted.

The electrochemical analysis of tungsten and platinum electrodes is discussed in

Chapter 7. The next two chapters present the design and characterization of the UF

microelectrode array.

3.3 Implications

Electrochemical analysis of the metal-electrolyte interface provides insight into the

possibility of unfavorable electrochemical reactions occurring on electrodes used in in

vivo applications. The mechanism of charge transfer may be purely capacitive or include

a faradaic pathway. If a faradic pathway contributes to charge transfer for a recording

electrode, it would be useful to understand the electrochemical reaction or reactions

taking place. Foremost, it would be useful to assess if the electrode will corrode over

time, as corrosion would ultimately lead to failure of the device. Secondly, it would be

useful to know if the faradaic reaction is adding any unwanted species to the neural

tissue if used as an intracortical microelectrode.

The work presented in Chapter 7 aims to increase the knowledge of corrosion of

tungsten in electrolytes that model physiological media by specifying a corrosion rate

as well as the electrochemical reactions responsible for the corrosion. This work also

takes a closer look into the reactivity of platinum in solutions modeling biological media

and defines possible reaction mechanisms. In the next chapter, the UF intracortical

microelectrode array is presented.


The UF microelectrode array design leverages the recording properties of

conventional microwire electrode arrays with additional features including a flexible

micromachined ribbon cable seamlessly integrated to the rigid probes. The goal is to

produce electrode arrays that are highly customizable in terms of geometry/layout,

have similar recording properties as commercial microelectrode arrays, and are easy

to mass fabricate. Characteristics of the UF FWIRE design include the following.

The microelectrode array is capable of being inserted in to the neural tissue without

buckling, has an array of 8 channels, a standard interface with an 18 pin Omnetics

connector, provides strain relief to the back-end connections, and has a substrate

that is compatible with the integration of electronics. The chosen approach is to use

a flexible polymer substrate and incorporate microwires to the front-end of the device

to act as the recording electrode sites. Two generations of microelectrode design

are discussed in this chapter. Both generations use micromachining techniques to

realize the device. Generation 1 electroplates the microwires, while Generation 2 hybrid

packages pre-made microwires to the flexible substrate. Fabrication details, bench-top

and acute in vivo results of the microelectrode arrays are discussed in sequential order.

4.1 Generation 1

Using conventional micromachining techniques, small-profile metal traces are

enclosed between flexible polyimide insulation, making a cable, as seen in Figure 4-1.

The electrode probes extend from the cable end 2 mm and include 20 pm x 50 pm

electrode sites on the tips. The electrode area is chosen for sufficient compromise

between signal selectivity and noise performance as given by [84]. The corresponding

probe dimensions assure adequate structural integrity according to calculation using

Euler-Bernoulli beam theory. The metal traces and corresponding bond sites can be

made to any size specification and spacing distance via photolithography.

Polyimide, chosen as the cable material for its flexibility and good dielectric

properties, is widely used in the medical field as a neural implant material with negligible

tissue response [111, 112]. Parylene-C, chosen for the probe insulation material,

has also been successfully used as an insulating material on chronically implanted

microelectrodes [113-115]. Nickel is chosen as the rigid probe material due to its ability

to be electroplated easily. However, Geddes et.al. caution that nickel implants can

instigate allergic response in some individuals [116]. Therefore gold is electroplated on

the exposed Ni electrode sites to increase its biocompatibility.


Figure 4-1. Flexible substrate microelectrode array with Omnetics connector. a) Finished
device. b) Microelectrode array. c) Probe tip showing insulation along shank
and gold plating on tip.

4.1.1 Fabrication

All processing is performed on the surface of a 4 inch silicon wafer covered with

Kapton tape (which provides adequate adhesion between the subsequent polyimide

layers). The polyimide bottom insulation layer (PI 2611, HD Microsystems) is spin

deposited and cured to a final thickness of 20 pm. Sputtered nickel, 100 A, is patterned

to define the probe, wiring, and bond pad dimensions. Then Ni is electrodeposited on

the Ni seed to an average thickness of 20 pm via a 10 mA direct current for 4 hours

in a nickel sulfamate bath (Nickel S, Technic Inc.). Adhesion promoter (VM9611, HD

Microsystems) is next applied followed by three spin coatings of the PI 2611 to achieve

the final 20 pm top layer of insulation. Al (1000 A) is patterned as a hard mask for the

subsequent oxygen plasma etch. The etching process includes an 02 reactive ion

etch (RIE) that removes the polyimide from the top of the bond pads and the probe

tips. The remaining polyimide under the probe tips is isotropically etched in a plasma

barrel asher. Then the probe-cable assembly is removed from the substrate wafer and

primed for parylene-C deposition with a silane adhesion promoter (Acros Organcis). The

parylene-C vapor deposition step insulates the shank of the metal probes to a thickness

of 2-4 pm. Then the probe ends are manually cut with a blade to expose bare metal

for the electrode sites. Finally, the probes are immersed in an electroless gold plating

solution (TechnilMGold AT, 600, Technic Inc.) that covers the electrode sites as well as

the bond pad sites with 0.1 pm of gold. An Omnetics connector is then fixed to the bond

pads with silver epoxy.

u u u u u .. polyimide Bond pad sites Flexible
--- r-hlbP /

a) A Ni seed is sputtered and patterned on
cured polyimide and electroplated to
final height

b) Ni wiring is encapsulated in a top layer of

c) Polyimide is etched (RIE) from bond pad

aKapton tape
- Si wafer

Neural probe
d) Wafer is diced and device
structure removed from substrate


Parylene C insulation
e) Parylene-c insulation is vapor
deposited on the device; probe tips and
bond pad sites are exposed and gold

ana prooe structures.

Figure 4-2. Fabrication process flow for generation 1 microelectrode.


4.1.2 Bench-Top Electrical Testing

Benchtop and in vivo results are discussed in this section. EIS is used to ascertain

the impedance magnitude at the frequency range of interest, as a metric for comparison.

The minimum detectable signal is also given via an analytical model of thermal noise.

Electrochemical impedance spectroscopy was performed on one microelectrode

array in 0.9% NaCI at room temperature using a Solatron Impedance Analyzer and

Galvanostat. A silver/silver chloride reference electrode and platinum counter electrode

were used. Measurements were taken over a frequency range of 5 Hz to 10 kHz at

open circuit potential with a sinusoidal perturbation voltage of 10 mV. All data shown is

consistent with the Kramers-Kronig relation as prescribed by [117]. An impedance of 0.9

MQ 0.02 MQ is given for a single probe at 1 kHz.

Regression of the impedance data was performed to obtain an equivalent

circuit describing the physical nature of the electrode/electrolyte interface. The most

appropriate circuit that physically explains the interface consists of Re (electrolyte

resistance) in series with a parallel combination of Rt (charge transfer resistance), and

ZCPE (double layer constant phase element), where ZCPE = ((jj)Qdi)-1. The regressed
parameters are given in Figure 4-3.

Re= 22 kQ
Re RRt =6.4 M
\/ Qdl = 0.11 ns'"/
Rt a = 0.8

Figure 4-3. Equivalent circuit for electrode/electrolyte interface.

Thermal noise from the real part of the electrode/electrolyte interface impedance

is assumed to be the dominant noise source [118]. The resulting noise voltage can be

given as follows

V (rms) = 4kTJ (Re + R )d( (4-1)
V low 1 + (W,Qd Rct)

where Whigh and wuow are the high and low pass-band frequencies of the amplifier [118].

The theoretical rms noise voltage of the designed neural probe is 2 pV based on the

regressed equivalent components and frequency range of 100 Hz to 6 kHz.

4.1.3 Implantation

Adult male 250 g Sprague-Dauley rats were used to test the recording performance

of the flexible electrode arrays. All procedures have been approved by the University

of Florida IACUC Board and were performed in the University of Florida McKnight

Brain Institute. Prior to surgery, the rats were anesthetized and the surgical site was

thoroughly sterilized. The top of the skull was then exposed by a midsaggital incision

from between the eyes and the landmarks bregma and lambda are located on the

skull [119]. The microwire array was implanted to a depth of 1.66 mm as shown in

Figure 4-4 into the forelimb region of the primary motor cortex. The electrodes are

stereotaxically moved to the appropriate site and lowered to the appropriate depth

using a micropositioner (1 mm per hour) to minimize distress to the brain tissue (FHC,

Bowdowinham, ME). The array was then grounded using a 1/16" diameter stainless

steel screw. A low profile Omnetics connector was used to attach the recording wire.

Figure 4-4. Surgical implantation of generation 1 microelectrode.

4.1.4 Surgical Recording

Extra-cellular potentials recorded at 12,207 Hz during surgery were analyzed and

spike sorted using Spike2 (CED, U.K.) software package. Recordings were analyzed

over a period of 130 s at a cortical depth of 1.66 mm. To detect and sort neural activity

within each channel, an automated waveform matching system within Spike2 was used

to construct templates using threshold detection.

Once a set of waveform templates was generated for a data stream, all those

templates (noise) that did not match characteristic neural depolarization behavior were

removed. The remaining waveform templates were sorted according to amplitude and

shape, and any waveform templates that were significantly similar to each other were

combined into a single template. Clustering of waveform variance within templates was

verified through principal component analysis (PCA). Each waveform template was

statistically unique and representative of a distinct neuron within the channel. Using

these two values, the signal to noise ratio for each neuron template was calculated. To

ensure proper reporting, all spike waveform templates that possessed peak to peak

amplitude of a magnitude below three times the value of the noise floor were considered

too close to the noise to be reliably and consistently distinguished and were removed

from the study. Values of neural yield, noise floor, amplitude, and SNR are reported for

each channel within Table 4-1.

Action potential amplitudes as large as 115 pV and as small as 13 pV are

discriminated by the electrode and recording system. The average noise floor is 4

pVrms for a frequency range of 500 Hz to 6 kHz. Figure 4-5 shows recorded data from
electrode number 6.

4.1.5 Summary

A flexible substrate microelectrode array has been designed using microfabrication

techniques and tested in vivo. Acute electrophysiological recordings show excellent yield

of recordable neurons and signal to noise ratios from 10 bB to 27 dB. The neural probe

Table 4-1. Neuronal Yield for Generation 1 Microelectrode Array
Electrode 1 2 3 4 5 6 7 8
Yield (neurons) 2 2 2 3 6 5 3 4
Noise Floor (pV, 4.1 5.0 5.3 4.4 5.2 3.8 3.7 4.3
20.1 23.3 32.6 26.1 114.7 90.4 31.4 45.1
Neuron Amplitude 13.2 15.5 24.7 18.3 56.8 52.3 13.4 29.7
(pV PtP) 14.2 34.6 35.7 11.7 21.0
21.3 21.0 16.0
18.8 13.8
13.8 13.4 15.8 15.5 26.9 27.6 18.6 20.4
10.2 9.9 13.4 12.4 20.8 22.8 11.2 16.8
SNR (dB) 10.2 16.5 19.5 10.0 13.8
12.2 14.8 11.4
11.2 11.2

array consists of eight probes with gold-plated electrode sites (1000 pm2) on the tip that

protrude from a flexible cable.

Due to failure in the back-end Omnetics connection, in vivo recordings were unable

to be performed after the surgery. However, the electrode array was left implanted in

the rat's brain for a remaining 2 weeks. It then was removed and images were taken.

Remarkably, the electroplated metal of the electrode was recessed within the parylene-c

insulation as seen in Figure 4-6 by approximately 20 pm showing corrosion which

could lead to ultimate failure. Thus, nickel as well as the nickel/gold combination were

removed from future designs.

The Achilles's heel of Generation 1 is the need for electroplating of a metal to a

thickness of 20 pm or more. It is difficult to find noble metals that can be electroplated

and even harder to plate them to such a thickness. Therefore, the process flow has been




0 5 10 15 20 -40
time (s) 0.02 0.03 0 04
time (s)

Figure 4-5. Data from neural recording in the rat motor cortex at a depth of 1.66 pm
during implantation surgery. Inset shows two distinct neurons recorded by
single probe.

changed in Generation 2 to allow the incorporation of a greater number of electrode


4.2 Generation 2

This section will highlight a second generation microelectrode design that

incorporates the hybrid packaging of tungsten microwires. Generation 2 is a design

closely resembling Generation 1 in form and function. The end goal with this generation

of microelectrode arrays is to provide a viable micromachined platform on which a fully

implantable wireless system may be incorporated.

Based on the inadequacy of Generation 1, namely corrosion of the electroplated

nickel microwire, Generation 2 incorporates pre-fabricated tungsten microwires in the

design. Tungsten is chosen since it is used in commercially available microelectrode

arrays, which have large use in the neuroscience community. However, as Chapter 7


Au Ni | A A AV
^:h -^ ^ ----- ^ -- ^ A

Figure 4-6.

Energy tkeV)

Corrosion of Electrode a. SEM and EDS measurement results of typical
gold-plated nickel electrode. b. SEM and EDS meaurement results of typical
electrode after in vivo implantation for two weeks. Notice that metal had
been eroded from the surface but parylene-C insulation remains unchanged.

cautions, tungsten also corrodes in biological environments. Fortunately, the established

design is applicable to any type of metal wire.

The generation 2 microelectrode array shown in Figure 4-7 consists of three major

components: a polymer substrate with encapsulated wiring, tungsten microwires, and

nuts used for anchoring and grounding. Rigid 50 pm diameter tungsten micro-wires

are attached to the end of a micromachined flexible cable in a 1-D array, allowing for

insertion into the neural tissue without buckling. The micro-wires are spaced 250 pm

apart as prescribed for decoupled neural recording [34]. Nuts are provided for screws

that anchor the device to the skull and supply the reference potential. Incorporating

the fasteners yields a secured flat platform for future population of flip-chip bonded

electronics. Device dimensions are given in Figure 4-7.


19 mm


2.7mm' "
,-- a. b.
Figure 4-7. Polymer microelectrode array with Omnetics connector. a. Top view. b.
Flexibility of microelectrode is shown with assumed in vivo position.

4.2.1 Fabrication

The process flow for this electrode was developed based on the process used

for the previous generation electrode [26]. Changes were incorporated to improve the

quality and reliability of the end product. Aluminum was first sputter deposited on a

4-inch-diameter silicon wafer to a 1 pm thickness as the sacrificial layer. The bottom

insulation layer of polyimide (PI 2611, HD Microsystems) was then spin-deposited

along with an adhesion promoter (VM 9611, HD Microsystems) and cured at 300'C.

After four spins, the resulting thickness was 24 pm. A layer of gold was then sputter

deposited to a thickness of 0.1 pm, which was patterned via lift-off to define the wiring

and bond pads. Polyimide was next spun five times and cured to achieve a thickness

of 30 pm, thereby making the top insulation layer. Chromium was sputter deposited to

a thickness of 1000 A and patterned as a hard mask via lift-off. Then an 02 reactive

ion etch (RIE) was performed to define the device footprint, uncover bondpads and

etch grooves for guided placement of the micro-wires. Fifty pm diameter tungsten wires

insulated with polyimide (California Fine Wire) were then placed manually in the etched

grooves that formed a jig and electrically connected to the gold wiring of the substrate

using a conductive silver epoxy (Epotech). A dicing saw was used to cut the secured

micro-wires at a specified length and established a consistent, planar surface for all

recording sites. The microelectrode array was then released from the wafer by removing

the sacrificial aluminum layer using anodic metal dissolution (constant current in 10%

NaCI) as described by reference [10]. The attachment sites for the tungsten wires and

stainless steel nuts were coated with insulating epoxy (Dualbond 707, Cyberbond) and

PDMS (Silicone type A, Dow Corning). Lastly, an Omnetics connector was attached to

the array with conductive silver epoxy.

(Side View)

_ polyimide

S Al

.-- Si wafer
a) A layer of gold seed is sputtered and patterned
on cured polyimide establishing the wiring.

b) Gold wiring is encapsulated in a top layer of

Silicone elastomer
Insulating epoxy

e) Solder connections are hermetically
sealed with layersof epoxy and silicone
elastomer (PDMS).

c) RIE of polyimide form bond pad sites and
substrate geometry.

d) Insulated tungsten wires are placed into
grooves made in previous step anclectrically
connected to gold leads. Nuts for ground
screws are also soldered to gold leads.

Flexible s

Tungsten wires

wires (Top View)
g off Bo
ub 1 r fo,
_' con

Gold willing

Nut for ground screw

nd pads

f) The wafer is diced and device is released from
the Si wafer. Omnetics connectors are electrically
attached to bond pads.

Figure 4-8. Fabrication process of generation 2 microelectrode array.

4.2.2 Bench-Top Electrical Testing

A Gamry potentiostat (Series G 300) was used for electrochemical impedance

spectroscopy. Individual tungsten recording sites were measured with respect to a

large surface area platinum counter electrode and Ag/AgCI reference electrode in

0.9% phosphate buffered NaCI (Sigma) at room temperature. The perturbation voltage

was 50 mV. All experimental data were consistent with the Kramers-Kronig relation as

prescribed by reference [117]. The average impedance at 1 kHz for all recording sites

was 50 10 kQ. This value was characteristic of small surface area electrodes and was

on the same order of magnitude as electrodes in the Utah array [50].

Using the equivalent circuit model shown in Figure 4-9 to describe the electrode/electrolyte

interface, the impedance data was regressed giving the reported circuit parameters.

These parameters were determined using data in the range of 100 Hz to 10 kHz.

Re = 5.0 kQ
Re, Rt = 3.0 MO
Qdl = 11 nsa/
Rt a = 0.87

Figure 4-9. Equivalent circuit for electrode/electrolyte interface. Re is the electrolyte
resistance, Rt is the charge transfer resistance and ZCPE is the double layer
constant phase element given by ZCPE = ((j)aQdl) -1

Experimental noise data was measured for the tungsten recording sites immersed

in phosphate buffered saline at room temperature with reference to an Ag/AgCI

electrode at equilibrium. The thermal noise signal from the electrochemical interface

was amplified by a low noise voltage amplifier (Stanford Research System (SRS) 560)

with gain of 1000 and then recorded with a SRS 785 spectrum analyzer from 1 Hz to 10

kHz. The thermal noise may be calculated from the real part of the electrode/electrolyte

interface impedance as follows

V,(rms) kT (Re + Rt )d (4-2)
w J~1 (L a QdiRct)2

where Uhigh and uwow are the high and low pass-band corner frequencies of the recording

amplifier, k is Boltzmann's constant, and T is temperature [118]. The theoretical rms

noise voltage of the neural probe is 1.27 pV based on the regressed equivalent

components in the frequency range of 100 Hz to 6 kHz. The experimental rms noise

voltage determined from the noise data is 1.59 0.12 pV in the same frequency range.

4.2.3 Implantation

The flexible electrode arrays were implanted into an adult male Sprague-Dawley

rat to test the electrode-substrate configuration and recording performance. All animal

procedures have been approved by the University of Florida IACUC. The rats were first

anesthetized and the surgical site was thoroughly sterilized. The top of the skull was

exposed by a mid sagital incision between the eyes, and the landmarks bregma, and

lambda were located on the skull. A craniotomy was drilled (+1 mm anterior to bregma,

2.5 mm lateral) at the site corresponding to the forelimb region of the motor cortex [119].

At the site of the electrode implantation, the dura was removed to expose the cortex.

The entire assembly was implanted vertically as shown in Fig. 3a and lowered to a

depth of 1.66 mm using a micropositioner to minimize distress and damage to the brain

tissue. While driving the electrode, electrophysiologic recordings were used to locate

pyramidal cell activity in layer V of the cortex. During this procedure, the assembly was

observed to be rigid and no buckling was present. Once the electrode was positioned,

it was supported with cranioplastic cement (Plastics-1) attached to a screw placed

adjacent to the craniotomy. After the array was secured, the entire assembly was folded

down to lay flat against the table of the skull as shown in Fig. 3b. The flexible substrate

was then permanently grounded using a second screw.

4.2.4 Surgical Recording

Neuronal recordings were obtained using a TDT System 3 Real-time Signal

Processing System (Tucker-Davis Technologies, Alachua, FL). The headstage

was interfaced to the substrate through an Omnetics 18 pin low-profile connector.

Extracellular signals were recorded at a sampling rate of 12,207 Hz (16 bits resolution)

and bandpass filtered from 500 Hz to 6000 Hz. Data were recorded, digitized and stored

on a personal computer for use in offline analysis.

to screw #1

screw #2

screw #1
I a. b.

Figure 4-10. In vivo testing. a. Vertical implantation without buckling. b. Final placement
of microelectrode secured to skull with screw.

Action potentials were discriminated off-line with Spike2 (CED, UK). For each of

the eight electrodes, simultaneous recordings lasting 170 seconds were used in the

analysis. To detect candidate action potentials, a threshold was applied to the data

and a set of templates was formed. Signals with at least a biphasic component within

a 1.6 ms window that occurred more than 25 times with similar shape (80%) was

categorized as a new neural template. All waveforms that did not match characteristic

neural depolarization behavior were considered as noise and removed. The remaining

waveforms were sorted according to the amplitude and shape of generated templates,

and any waveform templates that were significantly similar to each other were combined

into a single template. Principal component analysis (PCA) was used to cluster

waveform variance within templates. ISI distribution curves for each neuron in the

channels displayed individual Poisson distributions as expected, and showed distinct

neurons for each unit waveform.

After the action potential waveforms were properly isolated and sorted, the

peak-to-peak amplitude (PPA) was evaluated by computing the average waveform

of all spikes belonging to the same neuron. The potential difference was then measured

from the apex of the depolarization peak to the apex of the hyperpolarization peak. In

addition to the PPA, the noise floor of each channel was evaluated by computing the

root mean square value of all signals excluding recognized neuron waveforms within the

channel. The signal-to-noise ratio (SNR) for each neuron was calculated using a ratio

of these two values. A representative section of recorded data is shown in Figure 4-11.

Here we can qualitatively see three distinct neuron waveforms with a low noise floor.

The overall performance of the electrode is quantified in terms of neuronal yield,

noise floor, peak to peak amplitude, and SNR and is reported in Table 4-2. A total of 5

waveforms could be extracted from this 8-channel array. The electrodes and recording

system performed to discriminate action potential amplitude as high as 30 pV and

as low as 12.8 pV. The average RMS noise floor is 3.3 pV. The "pile plots" of action

potentials shown in Figure 4-12 indicate the repeatability of the waveforms.

Table 4-2. Performance of Generation 2 Microelectrode Array
Electrode 1 7
Yield (neurons) 3 2
Noise Floor (pV, rms) 4.1 2.9
Neuron Amplitude 303.0 20.7
(pV, PtP) 22.3 14.2
17.3 17.1
SNR (dB) 14.7 13.8

4.2.5 Summary

A prototype of a flexible substrate tungsten microelectrode array has been

developed and tested for the Florida Wireless Implantable Recording Electrode (FWIRE)

project. This generation 2 design uses discrete tungsten micro-wires as the electrodes

in contact with the brain and a flexible polymer substrate designed to lay flat on the skull

which provides a base for future designs incorporating flip-chip bonded electronics.

Bench-top experiments give an average impedance of 50 kQ at 1 kHz and an rms noise

flJj4 3La4 32- a- f l

Figure 4-11. Data from neural recording channel number 1 in the rat motor cortex at a
depth of 1.66 pm during implantation surgery.

Neuon A Neurn B Neuron C
Figure 4-12. Three distinct neurons extracted during spike sorting in channel number 1
of the recorded data.

floor less than 2 pV. Acute recordings show signal to noise ratios as high as 17 dB

with a corresponding noise floor of 3.3 pV for two channels showing discernable action

potentials. Thus, the minimum detectable signal is limited by the recording electronics.

The presented design may be adapted to use more noble micro-wire materials such

as platinum or iridium to decrease the risk of surface modification via electrochemical

processes with tungsten wires. The hybrid manufacturing approach taken with this

design allows the microelectrode array to be implanted accurately and without buckling

as the micro-wires provide sufficient structural integrity during insertion.

4.3 UF Microelectrode Summary

Much experience in polyimide micromachining, bench-top electrical characterization,

and in vivo implantation has been gained through the realization of two generations of

microelectrodes described in this chapter. Generation 1 incorporated a process flow

using only micromachining steps. However, this required electroplating a metal as thick

as 20 pm. Severe corrosion of nickel was seen after two weeks of implantation. Thus,

the electroplating step was removed from the next generation as metals suitable for

in vivo use could not be electroplated that thick. Generation 2 used hybrid-packaging

of tungsten micro-wires to a similar polyimide substrate. This generation loses the

advantage of bulk processing, as the micro-wires have to be serially hand-assembled.

Also, there exists a greater risk of failure due to hybrid-packaged connections. However,

successful acute in vivo recording results suggest that the microelectrode may be used


Furthermore, the electrodes, or recording sites, constitute an integral design

component. Their biocompatibility and structural reliability establish the crux of a

chronically viable device. To date, there are many biocompatibility issues with rigid

probes made from microwires or Si substrates as reviewed in Section 2.4. Thus,

future BMI recording system designs must be compatible with changes in electrode

requirements as more of the biocompatibility problems are solved. The generation

2 UF microelectrode array, being hybrid-packaged, allows incorporation of other

microelectrode constructs. This capability provides advantages over the "Utah" and

"Michigan" electrode, whose Si-based electrode shanks are integral to their design.


For Brain Machine Interfaces to work as therapeutic devices for debilitated

individuals, they must provide the necessary function and reliable results for the patient's

lifetime. Therefore, strategies to optimize function and reliability determine future

recording microelectrode system designs. For a clinically viable solution, the recording

system in the BMI must be fully implantable such as cochlear implants and functional

electrical stimulation (FES) implants for Parkinson's disease. A fully-implantable

structure for BMI applications requires that electronics for amplification, data compression,

wireless telemetry, and power systems be incorporated onto the implantable microelectrode


The challenge of realizing wireless implantable neural recording systems for

Brain-Machine Interfaces has been undertaken by a handful of institutions [49,

120-122]. All designs employ hybrid integration with the electronics. The Utah

system integrates interface electronics via flip-chip bonding techniques to the top of

a Si micromachined 100x 100 electrode array implanted into the cortex [120]. The

Michigan system uses a silicon flexible cable to rout the signals from the implanted

Si micromachined electrodes to a platform containing hybrid-packaged interface

electronics located some distance away on the top of the skull [49, 123]. In the time

since the Florida Wireless Integrated Recording Electrode (FWIRE) was proposed

[122], researchers from Brown University have adopted a design very similar to the

UF design, where a flexible polymer cable connects an implantable microelectrode

array to the hybrid-packaged interface electronics, which are positioned on the skull

[121]. The Brown system employs the silicon-micromachined Utah microelectrode array,

while the FWIRE system uses tungsten microwires as the recording electrodes. The

FWIRE design further differentiates itself from the other designs by employing a novel

pulsed-based data representation scheme, which minimizes transmission bandwidth

and allows spike sorting after transmission [122, 124]. The microelectrode platform

discussed in this section is a first step in achieving a recording system with wireless

transmitting capability for the FWIRE project. It is similar to generation 2 described

previously except it includes a hybrid-packaged amplifier integrated circuit and has a

slightly different form factor and anchoring scheme. The design, fabrication, in vitro

and in vivo characterization of the amplifier-microelectrode system is described in this


5.1 Design

The design considerations for the UF implantable microelectrode array include:

1. a platform with electronics residing on the skull reducing heat transfer to brain

2. a seamless, flexible connection between implanted electrodes and platform for

3. a grounding scheme that doubles as an anchoring mechanism, and

4. hybrid-packaging techniques that allow attachment of multiple integrated circuits.

The placement of interface electronics on a platform residing on the skull rather

than on top of the cortex allows for less restrictive power constraints on the interface

electronics as tissue heating is less of a concern. This design has strategic advantages

over the fully-implantable "Utah" microelectrode array design, which places the

electronics on top of the cortex [120]. In this design, the flexible connection between

the implanted electrode array and the electronics allows out-of-plane bending such

that the electrode array may be implanted perpendicularly to the electronics platform

and planar micromachining techniques may be used for the fabrication of the device.

The flexible connection also prevents the transfer of strain to the implanted electrodes

from movement of the electronics platform. The connection is made seamless by using

the same substrate for the entire device. This design ensures a minimum number of

connection points that would require hermetic sealing and a relatively simple fabrication

process as compared to the "Michigan" design that uses a flexible cable to connect

its electrodes and interface electronics [45, 123]. A grounding scheme that doubles

as an anchoring mechanism, to our knowledge, is not used in any of the existing

designs. Since all recorded signals are typically referenced to a bone screw, this

design minimizes the space needed for the implant by making the reference, or ground,

screw the same as an anchoring screw. Lastly, a flip-chip bonding technique is used to

hybrid-package ASICs to the substrate. Flip-chip bonding rather than wire-bonding die

or soldering packaged ICs minimizes the total space needed for the chips as well as

keeps the total height of the implanted platform to a minimum. This strategy provides

advantages over the Brown university design, which uses wire-bonding techniques to

attach the ASICs. The guiding principle of the UF design is the use of a relatively simple

process flow utilizing tungsten microwires that have been used in vivo previously with

high neuronal yield in a robust and customizable manufacturing process.

System Layout: To test the neural recording system prototype with the constraints

listed above, it is implemented in a rodent-animal model. The system consists of a)

electrodes that can either be inline or offset from the substrate, b) patterned wire traces

in cable form connecting the electrode to the integrated electronics, c) an integrated

amplifier, and d) an integrated ground bolt as shown in Figure 5-1. Until the wireless

component of this design is completed, we offer access to the amplifier via a standard

Omnetics 18 pin connector. This will eventually be replaced in the final design.

The animal model is a Sprague-Dawley rat as depicted in Figure 5-1. The

electrodes must be implanted into a craniotomy (+1 mm anterior to bregma, 2.5 mm

lateral) at the site corresponding to the forelimb region of the motor cortex [119]. As

seen from the figure, the region of space available for the flexible platform to rest on

the skull is essentially the space between the Bregma and the Lambda. Also, it should

be noted that the area behind the Lambda point comprises sensitive sinus tissue, and

hence it is not advisable to secure the substrate beyond the Lambda point. Moreover,

the average width of the space between Bregma and Lambda is close to 15 mm.

The layout of the design was changed from generation 1 such that the device can be

implanted inline with the central axis of the rat skull as shown in Figure 5-1. In order

to accommodate the entire device inside the available design space (i.e. between

Bregma and Lambda), care was taken while deciding the dimensions of the substrate.

The length of the platform is 19 mm excluding the tungsten wire length, and the width

is 10 mm. Nearly one-third of the substrate will be bent over the Bregma point, thus

reducing the overall length of the flat surface well within the limits. Figure 5-2 shows the

photograph of the microelectrode array and the flexible platform carrying the amplifier

chip. The enlarged inset shows the array of 8 tungsten microwires. Figure 5-3 shows the

photograph depicting the flexibility offered by the electrode substrate. This positioning

scheme would be followed after in-vivo placement.

The electrode sites were shifted left of the midline of the device for implantation in

the appropriate area of the motor cortex. A slot for a second screw is also added in this

design, allowing less critical placement by the surgeon. Also a perpendicularly mounted

Omnetics connector is used in this design scheme.

The implantation of the electrode is performed with the help of a stereotaxic

placement system. The electrode substrate is held vertically at its rear tip and driven

slowly into the already drilled craniotomy. Keeping this procedure in mind, the entire

package is designed with a relatively rigid back end that enables an easy implantation

using the stereotaxic placement system.

5.2 Fabrication

Fabrication of the flexible electrode substrate was carried out using a process

scheme analogous to our previous electrode generation. The critical steps of the

fabrication process are shown in Figure 5-4. A 100 mm diameter Si wafer was used

as a supporting platform for all the subsequent processing steps. First, a 1 pm thick

aluminum sacrificial layer was sputter deposited. Polyimide was spin-deposited

S* electrodes
Brgm B Polyimide cable
.ik :_ C -Amplifier IC
S : E D Ground bolt
~B Omnetics connector
B. D -- -

eraural Line

f f' '. M-1 _. ,...,,

Figure 5-1. In vivo placement of microelectrode array on rodent skull. Inset shows full

Ground screw

Connector for
external wiring


Tungsten micro-wire

Figure 5-2. Flexible polyimide microelectrode array with integrated amplifier. Inset shows
the enlarged image of the tungsten microwires.

1i* Fr

Figure 5-3. UF amplifier-microelectrode system showing the flexibility of the electrode
substrate and the final implant position.

and cured as in Section 4-8 and a titanuim/gold layer was sputter deposited to a

thickness of 0.01 pm and 0.2 pm, respectively. The deposited metal was patterned

as shown in Figure 5-4 for the electrical interconnects and a top layer of polyimide

was spin-deposited and cured. Each layer of polyimide has a thickness around 20 pm.

The top polyimide layer was selectively etched anisotropically using a Reactive Ion

Etcher to uncover amplifier and Omnetics bond pads and to establish the device outline.

Insulated tungsten wires of 50 pm diameter were manually placed onto the gold traces

and electrically connected with a conductive silver epoxy (AbleBond epoxy). The devices

were separated from one another by cutting the wafer with a dicing saw. Each individual

device was released from the Si wafer by anodic dissolution of the Al sacrificial layer.

The amplifier die was then bonded to the flexible substrate via a flip-chip bonding

process. To enable an effective electrical contact to the pads of the amplifier die, gold

stud bumps of 50-70 pm diameter were placed on the die bond pads through a wire

bonding process. A photograph of the chip with stud bumps is shown in Figure 5-5

The amplifier bond pad vias on the flexible substrate were then manually filled with

a conductive silver epoxy (Ablebond). They had dimensions of 150 pm by 150 pm

to accommodate the IC pads of area 130 pm by 130 pm. The distance between

(Side View) Au
S Al

Si wafer
a) A layer of gold seed is sputtered and patterned
on cured polyimide establishing the wiring.

b) Gold wiring is encapsulated in a top layer of
polyimide and the polyimide is etched to define
bond pads and substrate geometry.

Tungsten wires

c ) Tungsten wires are placed in trenches and
electrically connected with silver epoxy.

Silver epoxy

d) The device structure is released from the Si
substrate via anodic etch of aluminum. The
connection points are hermetically sealed and
the vias for the chip are filled with silver

Silicone elastomer
Insulating epoxy

e) The amplifier chip is flip prepared with
gold stud bumps and flip-chip bonded to
the substrate and hertetically sealed..

(Top View)

Tungsten wires
flexiblesub:. a

Gold wi

SNut for anchoring screw

C Bond pads
r for Omnetics
-- connector


Amplifier IC

Nut for ground screw

f) Omnetics connectors are electrically attached to
bond pads.

Figure 5-4. Fabrication process flow for UF amplifier-microelectrode system.

Figure 5-5. Amplifier die with gold stud bumps on bondpads.

two adjacent contact pads was 120 pm. A flip-chip placement system (Model 850,

Semiconductor Equipment Corp.) was used to place the die on the substrate. A furnace

was used to cure the silver epoxy after placement and then, the amplifier die was coated

with a low-moisture-absorbing-underfill epoxy (Epo-tek 302-3M) to hermetically seal


i l i

the bond pads. Also, a vertical mountable Omnetics connector was attached to the

substrate with a conductive epoxy and supported by underfill epoxy.

5.3 Power System for Amplifier-Microelectrode System

External hardware is needed to provide power for the amplifier IC hybrid-packaged

to the UF flexible-substrate microelectrode array and for transmitting the measured

neural signals. This section describes the hardware and interface connections to

the Tucker Davis recording system. Figure 5-6 shows the circuit boards housed in a

shielded box. The circuit board on the right labeled "power board" regulates voltages

from a 6 V battery power supply that are sent to the amplifier and provides wired

pass-through connections for the measured neural signals. The buffer board on the

left consists of 8 amplifiers that buffer the 8 channel neural signals and provide low

impedance inputs to the RA8GA amplifier. The voltages regulated for the amplifier are

given in Table 5-1. The voltages Vdd and Acgnd are controlled by fixed voltage regulator

ICs, while Vbas and Vbuffer are controlled by potentiometers and are tunable. The

input/output connections on the box are illustrated in Figure 5-7. The input connections

are defined as the connections going to the implanted array and the output connections

are going to a Tucker Davis Technologies (TDT) amplifier. A commutator with DB25

connector attaches to the power box, then a head stage with an 18 pin Omnetics

connection on one end attaches to the commutator. The male Omnetics connector on

the head stage connects to a female Omnetics connector on the microelectrode array.

These connections deliver power to the UF amplifier and transfer the measured eight

channels of neural signals to the TDT signal processor. Also, a BNC connector provides

an external port to the system ground, which is used for bench-top calibration. The

output connection on the other side of the power box is a DB25 connector that attaches

via a cable to the TDT RA8GA amplifier.

Battery pack

Buffer board Power board

Figure 5-6. Contents of power box.

Pass through head stage
(18 pin Omnetics connector)
-connects to electrode array

Output DB25 connector
-neural signal output for

External BNC port to
system ground (OV)

Commutator to DB25

Pin/socket connector for 8
channel neural signal

Figure 5-7. Input/output connections for power box.

Table 5-1. Voltage Specifications for UF Amplifier
Voltages to power UF amp (V)
Vdd 5
Vss 0
ACgnd 2.5
Vbias 2.6
Vbuffer 1.5

Buffer Array TDT RA8GA
analog analog
UF signal signalopticalsignal TDT
Amp-electrode RZ2
System -0 Processor


Figure 5-8. Experimental setup with TDT recording system.

5.4 Experimental Setup with TDT Recording System

This section explains how the UF amplifier-electrode system interfaces with the

Tucker Davis Technologies (TDT) recording system and discusses specifications

regarding noise. A schematic of the system integration is given in Figure 5-8. The

UF amplifier-electrode system interfaces first with a buffer amplifier array then a TDT

variable gain amplifier (RA8GA) and then the TDT RZ2 signal processor. The TDT

RA8GA must be used after the UF amplifier-microelectrode system in order to interface

with the RZ2 signal processor that requires optical signals. The RA8GA amplifier has

three input settings: 0.1V, 1V and 10V. They amplify the incoming signal by 10, 1, and

0.1, respectively and can accommodate signals no greater than 0.1 mV, 1 V and 10 V,

respectively. The manufacturer specified scaling factors that the output voltage must be

multiplied by to get the correct output voltage are 10, 170, and 1700, respectively. The

input impedance of the RA8GA is on the order of 10 kQ [39], which poses attenuation

issues with the UF system, whose output impedance is relatively high. A buffer amplifier

Effect of TDT RA8GA Gain Setting on Noise Floor
205 10V
15- 1V



0 0.2 0.4 0.6 0.8 1
time (s)

Figure 5-9. Time series noise floor affected by RA8GA preamplifier input setting.

is used after the UF amplifier-electrode system to ensure a low impedance input to the


Choosing the correct input setting on the RA8GA to use is integral to system

performance. The output signal of the UF amplifier-microelectrode system has a dc

component at 2.5 V and and an ac component anywhere from tens of mV to hundreds

of mV. Since the RA8GA cannot AC couple the input signal, the differential signal given

as the input is the output from the UF referenced to 2.5 V rather than the system ground

of 0 V. Because the dc output of the UF system is not exactly 2.5 V, the resulting signal

going into the RA8GA is usually greater than 100 mV so the 0.1V input setting can not

be used. If used, the input signal saturates the amplifier and a voltage of 0 is seen on

the TDT viewing program. The 1V or 10V input settings can be used; however, the 10 V

input setting adds more noise to the system as shown in Figure 5-9. Thus the 1V input

setting is always used for the neural recording episodes.

To show that the UF amplifier-electrode system measures the neural signals as

effectively as the Tucker Davis electrodes, the noise floor was measured for each system

and is compared in this section. The recording setup shown in Figure 5-8 was used

to measure time series noise voltages of the UF electrode and a PZ2 preamplifier and


RZ2 recording system were used to measure time series noise for the TDT electrode.

The top plot in Figure 5-10 compares the input referred noise floors of two different UF

amplifier-electrode systems (UF1 and UF2) with the noise floor of the TDT electrode.

They are very similar. (The scaling factor for the UF system is 170/90 with the 1V input

setting.) Therefore, it has been shown that the UF amplifier-electrode system can

measure neural signals of the same magnitude as the TDT electrode system. The

bottom plot in Figure 5-10 shows the output referred noise voltages measured and

recorded by the UF electrode and the TDT RZ2 processor. There is no built-in scaling

factor in the recording software, thus the output voltage must be multiplied by 170 (scale

factor of the RA8GA 1V input setting) and divided by the gain the of the UF amplifier (90)

to get the correct input referred noise voltage.

5.5 Bench-Top Characterization

The effect of poor grounding and electromagnetic interference on the noise floor

of the system are examined in this section. The analysis of signal degradation due to

voltage division at the amplifier and reduced common mode rejection from impedance

mismatching between recording electrode and reference is provided. Lessons learned

for future integration with electronics are also given.

5.5.1 Effect of Grounding Reference Input to Amplifier

This section explores the effect of grounding the reference input of the differential

amplifier on the noise floor of the system. Figure 5-11 shows a schematic of a

hypothetical one channel amplifier and the connections if the reference input is floating

or connected to system ground. In vivo, the differential signal given to the amplifier

is always the voltage seen between a tungsten wire implanted into the cortex and a

stainless steel screw, which is lodged in the skull of the rat with the bottom in contact

with the cerebral spinal fluid that resides on top of the brain. The difference is that in the

floating case, the reference is not connected to system ground, which is 0 V referenced

to the battery ground; and in the grounded case it is.

Input Refered Noise

,, I 1, .. 1 ,, I 1 1J, J1





." I 1 Y 'I'1'

0 0.2 0.4 0.6 0.8 1
time (s)
Noise seen on TDT software

* Ij I II II 'I

.1 I I

0 0.2 0.4 0.6 0.8 1
time (s)

Figure 5-10. Time series noise floor seen on the TDT viewing program. The top plot is
the input referred noise scaled by the gain of the amplifier and the scaling
factor of the RA8GA (1V input setting). The bottom plot shows the unsealed
output referred noise voltage seen by the TDT recording program.

To understand why grounding makes a difference, a closer look is taken at how

the microelectrode is implanted and how the reference is connected to the brain fluid.

During implantation, the microelectrode array is secured to a stereotaxic apparatus

and driven into the brain tissue. The reference connection, which is the nut on the

microelectrode substrate, is attached to a temporary screw already secured to the skull

with a 1 ft long alligator clip. After the array is implanted to the final depth, it is bent over

to rest on the skull and a screw is fit into the reference nut, eliminating the alligator clip,


10 ., ,



I I, I I i I 1 I I i I I, I II



, i ll i |I r- r 1 "1 r,- ,','1q

-10 I'- '

Reference Reference
floating grounded

Vdd Vdd
Differential Chl Differential Ch
signal form signal form
tungsten tungsten (
wire and Vo wire and
reference out reference Vout
screw ref screw ref

Vss -OV Vs s 0V

Figure 5-11. Amplifier connections showing floating vs. grounded reference

and thus making the distance from the nut on the substrate to the brain fluid very short

(a few centimeters) compared to the previous case.

Results from noise measurements show that the amount of noise pick-up in the

system is greatly affected by the length of the connection from the reference input

of the amplifier (i.e. nut on the substrate), to the brain of the rat in a ungrounded

setup. Figure 5-12 shows the square root of the noise power spectral density of the

amplifier-electrode system when the reference is grounded and floating with different

lengths of reference-brain connections. In the grounded case, the amount of noise is

the same regardless of the length of the reference-brain connection. In the ungrounded

case, the noise measured with the short connection (length of the screw) is very similar

to the grounded cases; however, the noise measured with the long reference-brain

connection (1 ft alligator clip) is much greater and unacceptable for neural recording.

Thus to avoid coupling noise to the system, the reference input should always be

grounded to the ground of the amplifier. In these experiments, a beaker of saline was

used to model the brain fluid, the noise voltages are input referred, and a SRS 785

spectrum analyzer was used to measure the power spectral density of the noise.

10-2 floating-short
"N grounded-long
> /El
j) 10 ,

100 102 104
f (Hz)

Figure 5-12. Square root of the power spectral density of the amplifier-microelectrode
system showing effect of the reference connection on the noise floor.

5.5.2 Effect of EMI on Noise Floor

The last section showed the necessity of grounding the reference input; this

section shows the extent of electromagnetic interference (EMI) to a properly grounded

system. The noise floor was measured for the amplifier-microelectrode array inside

and outside of a Faraday cage. The experimental setup was similar to the last case in

that a beaker of 0.9% saline was used to model the brain fluid and both the reference

(screw attached to the nut) and channel inputs (tungsten wires) were immersed in it.

Figure 5-13 shows the power spectral density of the noise for three channels on the

array inside the Faraday cage and outside the Faraday cage. The noise measured inside

the Faraday cage is a combination of the thermal noise of the electrode-saline interface

and thermal and electronic noise of the amplifier, only. Very little EMI is measured. The

noise measured outside the Faraday cage is greatly affected by EMI as the 60 Hz power

frequency and its harmonics are seen. Since a Faraday cage cannot be implemented

in the in vivo setting with the rat, EMI will always be present in the recordings. Table 5-2

shows the extent that the EMI has on the recorded noise floor. Using the frequency

range of 500 Hz to 6 kHz, which is what is used when recording with the TDT system,

the noise floor is not increased significantly. However, wider bandwidth recordings result

in a larger noise floor. This effect needs to be kept in mind for future generations of UF

microelectrode systems.

Noise Floor without EMI Noise Floor with EMI
10-4 10-4
-chi -ch1
-ch3 -ch3
Sio5 --ch4 .c 5 ch4
Q 10-5 ch4 Q 10-6 ch
S10-6 10-

U) 10-7 U) 10-7

10-8 10-8
10 10 1 02 103 104 100 101 102 103 104
f(Hz) f(Hz)

Figure 5-13. Square root of the power spectral density of three channels on the
amplifier-microelectrode system showing how electromagnetic interference
(EMI) of the 60 Hz power line can affect noise floor (input referred). For the
case with no EMI, the microelectrode array was placed inside a double
Faraday cage.

Table 5-2. Noise floor
Electrode Channel Noise Floor without EMI (pV,,s) Noise Floor with EMI (/V,,s)
10 Hz-12.8 kHz 500 Hz-12.8k Hz 10 Hz-12.8 kHz 500 Hz-12.8kHz

1 4.73 3.46 13.8 3.52
3 4.90 3.50 19.2 3.72
4 4.87 3.56 18.5 3.69

5.5.3 Impedance Concerns with On-Chip Amplifier

Differential signal attenuation and common mode signal propagation are dependent

on the relative magnitudes of impedances corresponding to the recording electrode,

reference electrode, and input to the amplifier. Since the input impedance of the

recording amplifier is finite, an attenuation of the differential signal due to voltage

division at the input is possible. Moreover, Legatt and Stecker caution that common-mode

rejection may be compromised by mismatch of the recording and reference electrode

impedances [118, 125]. Legatt claims that amplification of common-mode signals

Recording electrode
Reference electrode
108 Amplifier input




102 103
f (Hz)

Figure 5-14. Comparison of recording electrode, reference electrode and amplifier input
impedances. Error bars on recording electrode correspond to the sample
standard deviation of 8 channels on the array.

contributes to much of the output noise seen with EEG systems. The impedance values

for the recording electrode, reference electrode, and the input to the amplifier are

given in Figure 5-14. Impedance for the amplifier was measured by the Agilent 4294A

impedance analyzer. Impedance values for the recording and reference electrodes were

measured by a Gamry 300 potentiostat and frequency response analyzer.

The following derivation, taken from Legatt et al. [125], gives analytical equations

for the voltage at the output of a differential amplifier. Scenarios relating the magnitude

of the impedance of the recording electrode to the reference electrode and input of the

amplifier are derived. Figure 5-15 shows a block diagram of common mode, Vc, and

differential, Vd, input signals interfacing with impedances of the recording and reference

electrode and the differential amplifier, where Ze is the impedance of the recording

electrode, Zref is the impedance of the reference electrode, Zamp is the input impedance

of the amplifier, V and Vb are nodal voltages, and Vo is the output signal. Vd is the

signal of interest and is the neural voltage waveform in this case. The output voltage can

Vc+Vd V-

Zref Zamp
Vc--Vd *--- ----1
Vc-Vd --- Vb

Figure 5-15. Schematic diagram of differential amplifier attached to recording electrode
and reference electrode.

be given as

Vo = G(V, Vb)+ M (V + Vb), (5-1)
where G is the gain of the amplifier and CMRR is the common-mode rejection ratio.

Using voltage division, Equation 5-1 may be stated as

Z amp Zref amp Zamp Zref Zamp
z, + ZaP Z11 + Vca.P Z' + Za,,, Z"f + Za,, (np

Two terms are shown in Equation 5-2, one relating to the differential signal and the

other to the common signal, that will be amplified and given as output. Ideally, Zamp

is much larger than Ze or Zref so that Vd is not attenuated and Vc is reduced to zero.

Figure 5-16 shows the attenuation factor of Vd for a range of Ze and Zref impedance

values when the input impedance of the amplifier is 107Q. (This impedance is very

close to the value experimentally measured at 1 kHz for the amplifier on the UF

microelectrode.) Note that the normalized value of 1 represents no attenuation of

the differential signal. The circle indicates the assumed range of impedance values

for typical recording and reference electrodes. As the figure shows, there is possibly

5% attenuation for a combination of recording and reference electrode impedances in

that range for an amplifier input impedance of 107Q. However, if the recording electrode

impedance is the same as the input impedance to the amplifier, then the attenuation


10 2 3 4 5 6
10 10 10 10 10

Figure 5-16. Attenuation factor of Vd as a function of Ze and
voltage division at input of the amplifier.





Zref corresponding to


>5 0.4

0.1 3
102 10

Figure 5-17. Percent attenuation of the differential signal Vd as a function of frequency
due to voltage division at the input of the amplifier.

is 50%. For the impedance values in the UF amplifier-microelectrode system, the

attenuation of Vd is minimal (~0.3%) as shown in Figure 5-17.

The amplification of the common mode signal is assessed next. Figure 5-18

shows the dependence of attenuation of Vc on the recording and reference electrode

105 0.3

104 0.2

103 0.1

102 103 10 105 106

Figure 5-18. Attenuation factor of Vc as a function of Ze and Zref corresponding to
voltage division at input of the amplifier.

impedances for Zamp = 107 Q. In the impedance range applicable to this work, the plot

shows that at most 5% of the common-mode signal will be amplified by the amplifier

gain and result as an unwanted disturbance in the output signal. Using the impedance

values as a function of frequency for the UF amplifier-microelectrode system, no more

than 0.8% of the common-mode signal will be amplified by the amplifier as shown in

Figure 5-19.

An effective common-mode rejection ratio dependent on the relative impedance

values of the recording and reference electrode is given next following the derivation

by Legatt et al. [125]. Assuming Ze < Zamp and Zref < Zamp, Equation 5-2 may be

simplified to

V, Vb = 2 Vd + Ve Z-p (5-3)

Va Vb = Vd amp Z amp +ZV zamp + amp (5-4)
Ze Zampp Zf amp e Zamp Zref + amp


o 0.7

E 0.6


o 0.4

o 0.2

0.1 0 1 2 3 4
10 10 10 10 10
f (Hz)

Figure 5-19. Percent of the common-mode signal Vc as a function of frequency that will
be amplified due to voltage division.


V,+ Vb= 2V+ Vd(Ze (5-5)
Z zamp
Plugging Equation 5-3 and Equation 5-5 into Equation 5-1 yields

v Gd 2 CMRRZamp +(Zre Ze)) GV CMRR(Zr ZZ) 2Zamp (56)

The effective common-mode rejection ratio is taken to be the gain associated with Vd

divided by the gain associated with Vc. Thus,

2 CMRRZi _
CMRRff = 2 CMRRZap (5-7)
2Zamp + CMRR(Zref Ze)'

using these simplifications Zamp > (Zre Ze) and CMRR > 1. Figure 5-20

shows the effective common-mode rejection ratio due to a mismatch in recording

and reference electrode impedances. According to Legatt's derivation, the effective

CMRR will be significantly decreased for a large mismatch in impedance. In this study,

or 10-1
1 10

C) 10

100 102 104 106
Ze Zref

Figure 5-20. Normalized effective common-mode rejection ratio as a function of the
difference of the impedance between recording electrode and reference

the reference electrode and recording electrode have impedances that differ by two

orders of magnitude. Figure 5-21 shows a hypothetical effective common-mode rejection

ratio using the impedance values given in Figure 5-14. The nominal CMRR for the

UF amplifier is 10,000. Thus according to Legatt's derivation, the effective CMRR will

decrease by a factor of 20. However, a measurement performed to test this hypothesis

did not show congruent results for the UF microelectrode. When the impedance of the

reference and recording electrode were matched by replacing the large area reference

screw with a 50 pm diameter tungsten microwire (similar to the recording electrode), the

amount of common-mode noise (60 Hz EMI) actually increased rather than decreased.

Therefore, other factors besides impedance mismatch contribute to the presence of 60

Hz EMI common-mode noise seen in Figure 5-13. Understanding the origin of such

factors are a topic of future research.

5.5.4 Lessons Learned for Integration with the Integrate-and-Fire Chip

The important lessons learned from the previous benchtop studies that pertain to

successful integration with a UF integrate-and-fire (IF) chip are discussed next. First,







102 103
f (Hz)

Figure 5-21. Effective common-mode rejection ratio as a function of frequency for
impedance values in the UF microelectrode array.

the reference connection to the amplifier should be connected to the system ground

(Vss) of the amplifier to reduce noise pick-up during implantation. If this can be done

on a chip level, instead of on the flexible substrate, that is advised. The signal coming

from the amplifier must be filtered to eliminate the 60 Hz power line EMI, before it is sent

to the integrate-and-fire electronics. A band-pass filter from 500 Hz to 6 kHz was used

successfully in this study.

5.5.5 Frequency Response and Impulse Response of System

The frequency response and the impulse response of the amplifier-microelectrode

system were experimentally obtained to confirm that the system will be able to correctly

record and amplify a neuronal action potential. The frequency response was measured

using an SRS785 spectrum analyzer. The input signal, 100 pV white noise, was applied

to a beaker of saline within which the microelectrode was immersed. The frequency

response of the system given in Figure 5-22 shows a pass-band gain of 39 dB. The

response of the system to pulses of width 1 ms and 100 ps are given in Figure 5-23.

Minimal distortion is seen on the 1 ms pulse; more pronounced distortion is seen in



E 20

100 1 2 3 4 5
10 10 10 10 10 10
frequency (Hz)

Figure 5-22. Frequency response of amplifier-microelectrode system. The pass-band
gain is 39 dB.

the 100 ps pulse response. Since an action potential has pulse lengths on the order

of milliseconds, this amplifier-microelectrode system measures the signal without

appreciable distortion.

5.6 In-Vivo Testing

The recording performance of the amplifier-microelectrode system was validated by

conducting an in-vivo investigation on an anesthetized rodent. The flexible microelectrode-amplifier

system was implanted into an adult male Sprague-Dawley rat. All animal procedures

have been approved by the University of Florida IACUC. The rat was anesthetized at

the beginning and the surgical site was sterilized completely. A mid sagital incision was

made between the eyes to uncover the top of the skull, and the landmarks bregma, and

lambda were then identified on the skull. A craniotomy was drilled (+1 mm anterior

to bregma, 2.5mm lateral) at the site corresponding to the forelimb region of the

motor cortex [119]. At the site of the electrode implantation, the dura was removed

to expose the cortex. The entire assembly was implanted vertically and lowered using

a micropositioner. While driving the electrode, electrophysiologic recordings were used


1 output
> 0.6
0 0.2


-0.5 0 0.5 1 1.5
time (ms)

1 -- input
a, -output
> 0.6


-0.1 0 0.1 0.2 0.3
time (ms)

Figure 5-23. Impulse response of amplifier-microelectrode system. Figure 5-23A shows
the response to a 1 ms pulse, characteristic of a neural action potential.
Figure 5-23B shows the response to a 100 ps pulse.


Figure 5-24. Flexible substrate electrode array implanted in rodent model.

to locate a depth where unit cell activity was greatest. The electrodes were driven to

a depth of 3.6 mm. During this procedure, the assembly was observed to be rigid and

no buckling was present. Once the electrode was positioned, it was supported with

cranioplastic cement (Plastics-1) attached to a screw placed adjacent to the craniotomy

(top screw in Figure 5-24). After the array was secured, the entire assembly was folded

down to lay flat against the table of the skull as shown in Figure 5-24. The flexible

substrate was then permanently grounded using a second anchoring screw.

The electrode array was implanted in the animal for 42 days and neural signals

were measured at regular intervals over the implanted duration. The results observed

from the chronic implantation of the microelectrode array are described next.

5.6.1 In-Vivo Recording Results

Recordings were made with the implanted amplifier-microelectrode system and

Tucker Davis Technologies recording software and storage hardware on the day of

surgery and intermittently over the following 42 days. On the day of surgery, many

large amplitude action potentials were measured at the final implant depth of 3.6

mm. Figure 5-25 shows characteristic spikes recorded from one channel. However,

consistent spikes of similar large amplitudes were not seen again over the implant

duration. The subsequent recordings exhibited consistent, but low amplitude neural

activity. Table 5-3 shows the yield, or the number of neurons seen consistently over the

implant duration, for each electrode on the array. Spike2 was used to sort the recorded

20 1


0 0
> -20
0 0.5 1 1.5 2 2.5 0.78 0.79 0.8 0.81 0.82 0.83
time (s) time (s)

Figure 5-25. Large amplitude action potentials recorded on day of implantation.

data for various days over the implant duration using the same methods described in

Section 4.1.4 and Section 4.2.4. Figure 5-26 depicts a characteristic action potential of

a single neuron seen consistently over the implant duration. The graphs show average

waveforms of sorted action potentials over a one minute time segment. The red lines

give the error bounds. Statistical analysis of the waveform templates prove that the

same neuron was consistently measured over the course of the implant time.

Table 5-3. Neuronal Yield for Generation 2b Microelectrode Array
Electrode Neuronal

1 2
2 1
3 3
4 2
5 1
6 1
7 0
8 1


MP11117M 11 1011111 11111911141 Ill" O

6 6 6, 6 6 6

4- 4- 4 4- 4 4-

2 2 2- 2 2- 2

0 0 0 0 0 0

-2 -2 -2 --2 -2 -2

S -4- --4 --4 -4 -4 -4-
o -6 -6 -6 -6 -6 -6-

-8 -8 --8 -8- -8 --8

10 --10- --10 --10 --10 --10-

-12 --12 -12 1 --12 --12 --12-

-14 --14 --14 --14 -14 --14-
0 1 2 0 1 2 0 1 2 0 1 2 0 1 2 0 1 2
time (ms) time (ms) time (ms) time (ms) time (ms) time (ms)

Figure 5-26. Action potential of a single neuron spike sorted over the implanted period.

Noise floor and signal to noise ratio are the other recording performance metrics

considered for the amplifier-microelectrode system. The noise floor for the electrode

array over the implant duration is shown in Figure 5-27. Day 0 corresponds to bench-top

measurements made in 0.9% saline. The bench-top noise measurement for a Tucker

Davis electrode attached to a Tucker Davis amplifier (PZ2) is given in red in the figure.

The Tucker Davis electrode noise floor is statistically similar to the noise floor for the UF

microelectrode array. Results for days 1 through 42 are taken from in vivo recordings

with the UF microelectrode array. The data points give the root mean square values

of a one second or greater segment of data, free of sorted action potentials. The error

bars correspond to the sample standard deviation of seven channels in the electrode

array. After an initial increase in the average noise floor, it remained constant around

4.5 pVrms. Figure 5-28 shows the average signal to noise ratio (SNR) across seven

channels in the array over the implant duration. SNR was calculated as the peak to

peak voltage of an action potential divided by the rms noise floor value. Results for this

electrode show SNRs as high as 5.4 on the day of surgery and consistent vales near 3.8


Day 1

Day 3 Day 13 Day 23

Day 31 Day 42

5.5 TDT


4.5 -
o 4

Z 3-

0 10 20 30 40
Implant day

Figure 5-27. Noise floor for the electrode array over the implanted duration. FWIRE
corresponds to the UF amplifier-microelectrode system and TDT
corresponds to a Tucker Davis micro-wire electrode array and PZ2

after 23 days implanted. The spike sorting results showed at least one neuron on seven

of the electrode channels. All action potentials corresponding to single neurons used for

the SNR calculation were consistently recorded from day 1 to day 42.

Performance metrics including noise floor, signal to noise ratio, and neuronal

yield showed that the amplifier-microelectrode array performed adequately. The noise

floor was statistically similar to the noise floor of a Tucker Davis electrode in in vitro

experimentation over a frequency range of 500 Hz to 6 kHz. The average noise floor

measured in vivo on the first day of implantation was less than one microvolt higher

than that measured in saline. The increase in the noise floor was assumed to be from

addition of background neuronal noise. The average noise floor then increased to a

value about one microvolt higher than it was on day one. The cause of this increase in

noise after day one is more ambiguous; however, the same trend has been reported

by the Michigan group [21]. They also measured impedance values over time and

concluded that an increase in electrode impedance by 30% to 100%, which coincided



1)^ 4


0 10 20 30 40 50
Implant day

Figure 5-28. Signal-to-noise ratio for the electrode array over the implant duration.
FWIRE corresponds to the UF amplifier-microelectrode system and TDT
corresponds to a Tucker Davis micro-wire electrode array and PZ2

with the increase in noise, was at least partially the cause of the increase in noise

floor. Tresco's group reported that increases in electrode impedance of the same

magnitude are attributed to cellular adhesion [77]. Signal to noise ratios reported

for the UF microelectrode array after day one were low compared to most published

data, but because they are dependent on the proximity of an active neuron, they are

not a relevant indication of performance quality especially when the noise floor is

adequately low. The percentage of active electrodes on the UF microelectrode array

over the implant duration stayed constant at 88% and 1 to 3 independent neurons

were measured on each active channel. Thus, the UF microelectrode array with

hybrid-packaged amplifier IC shows acceptable performance for recording applications

lasting two months.

5.6.2 Post-Implant Electrode Assessment

Motivation for the electrochemical analysis of electrode materials in this work is

given by examining the electrode sites of the UF intracortical microelectrode array after


implantation in brain tissue. Figure 5-29 shows scanning-electron-microscope (SEM)

images of the tungsten microwires used in the UF intracortical microelectrode array

before and after implantation in a rodent motor cortex. The microelectrode array was

implanted for 87 days. Images labeled a and b show electrode surfaces (cross section

of the insulated wires) after they have been cut with a dicing saw prior to implantation.

The microwires have a sub-micron layer of gold on the outside surface of the tungsten

wires, beneath the polyimide insulation. Though not easily seen in the SEM images,

a thin ring of gold between the polyimide and tungsten is exposed to the biological

environment. Images c and d show the changed state of the tungsten wire after 87

days in vivo. The inset in c highlights the area of gold exposed to the tissue. Notable

differences between the before and after images include a larger area of gold exposed

in the after state as well as a swelling of the polyimide insulation and the presence of

a film on the surface of the electrode. The larger electrode area will correspond to a

lower impedance and thus a lower thermal noise voltage at the interface; however,

the electronic noise of the amplifier will still dominate the system. Also, the resulting

measured voltage signal will be averaged over the larger surface area. A magnified

view of image d in Figure 5-30 and energy-dispersive X-ray spectroscopy (EDS) results

for two exposed regions on the electrode surface is shown in Figure 5-29. The top EDS

graph gives results characteristic of a bare tungsten surface. The bottom EDS graph

gives results characteristic of a bio-film that is rich in carbon, oxygen and nitrogen. Thus,

it is assumed that part of the bio-film became dislodged on the top right portion of the

electrode and is exposing the tungsten surface. This image shows that the tungsten is

recessed within the gold plating and the structure of the tungsten surface has changed

from being smooth to rough. In three of the electrodes in the array, the average distance

that the tungsten surface was recessed within the gold plating was measured to be

248 pV after an implantation duration of 87 days. The distance was measured via an

optical microscope where the change in focal length was measured. The corrosion of


Figure 5-29. SEM images of tungsten micro-wires before and after 87 days implanted.
a,b) Characteristic electrodes before implantation. c,d) Characteristic
electrodes after implantation. The inset in c highlights the area of gold
exposed to the tissue.

tungsten microwires is systematically studied in an in vitro experiment and the effect of

the tungsten corrosion on long-term recording performance is discussed in Chapter 7.

5.7 Summary

A prototype of a chronically implantable active microelectrode array has been

designed for a Sprague-Dawley rat and tested in a long-term in vivo experiment. This

design successfully incorporated an 8-channel amplifier IC via flip-chip bonding to a

polyimide-based substrate. Chronic recording results confirm that the amplifier-electrode

system reliably measures and amplifies single unit neural signals over 42 days. Past

42 days, signal recording was intermittent and much noisier. Analysis after explanation

showed that the polyimide layer delaminated near the Omnetics connector allowing

the ground and power signal input pads to be shorted together through the bio-fluid.

Next generations should incorporate a silicone insulation layer on the extent of the





W Ca
U- W

0 1
0 5 10 15

Figure 5-30. EDS results of two sites on one electrode after 87 days in vivo. The top
graph shows results characteristic of a bare tungsten and gold surface. The
bottom graph shows results characteristic of a bio-film.

polyimide surface. Furthermore, SEM images of the tungsten recording sites after

explanation showed considerable change in the electrode surface suggesting corrosion

of the tungsten. Though the results for 42 days do not suggest that the corrosion of

the tungsten microwire had any adverse effect on the recording performance thus far,

there is a possibility that adverse effects may occur in prolonged studies. The results

of a detailed analysis of corrosion properties of tungsten microwires are presented in

Chapter 7. The experimental methods are explained in the next chapter.

Energy (keV)


As exemplified in Chapter 5, the implanted tungsten microwires undergo corrosion.

This chapter presents the experimental methods for the electrochemical characterization

that will quantify the rate of corrosion experienced by tungsten microwires in physiological

saline solutions. The key measurement technique, electrochemical impedance

spectroscopy (EIS), is described. Uncommon graphical representations of the

impedance data that provide useful information on the interface physics are explained.

The procedure for error analysis of the measured impedance data is also described.

Moreover, the metal samples used in the EIS measurements must be different from the

microwire electrodes used in neural recording microelectrodes. Reasons for this change

are given and a method for ascertaining the quality of the sample electrodes is also


6.1 Electrochemical Impedance Spectroscopy

Electrochemical impedance spectroscopy (EIS) is a measurement technique used

to characterize charge transport at an electrochemical interface under steady-state

conditions [93]. A typical experimental set-up is shown in Figure 6-1. The working

electrode is the surface under scrutiny. The counter electrode is a large area electrode

whose interfacial phenomena may be neglected [93]. The reference electrode is an

electrode that possesses a reversible reaction with an ion in the cell solution that

has a constant and well-defined electrochemical potential [93]. By applying a small

sinusoidal voltage or current perturbation across the working and counter electrode

and subsequently measuring the resulting current or voltage signal across the working

and reference electrode, the impedance at a given frequency may be measured. Care

must be taken to ensure that the perturbation voltage is small enough to ensure that

the current to voltage relationship remains linear [126]. The perturbation signal is

swept over a range of frequencies and the resulting frequency-dependent impedance


Faraday cage
I \

Figure 6-1. EIS experimental set-up.

is characteristic of the interface between the working electrode and the electrolyte


EIS has been used in studies characterizing stimulating and recording electrodes

for pacemaker and intracortical applications as well as various studies on micro-scale

electrodes. Interfacial capacitance was assessed by EIS in physiological saline on Pt,

Ti, and TiN pacemaker electrodes used for stimulation [87, 88]. Impedance and charge

transfer characteristics of electrodeposited Ir02 in saline solution were compared to

bare metal surfaces using EIS [127]. The final application of the Ir02 plated electrodes

was for neural stimulation and recording. Platinized-platinum microelectrodes used for

neural stimulation were characterized using EIS [102]. Yang et al., Cui et al., and Ates et

al. investigated conducting polymer films grown or deposited on metal microelectrodes

via EIS [128-130]. Price et al. used EIS to assess optimal insulation thickness for their

microelectrode arrays [131]. Zhang et al. modified microelectrodes with immobilized

antibodies for selective capture of human antigens and used the change in impedance

measured by EIS as the sensing mechanism [132]. This work uses EIS to ascertain the

reactivity of a metal in biological saline solutions under quasi-equilibrium conditions, and

in the case of a reactive system undergoing corrosion; this work quantifies the corrosion

rate through extrapolation of the polarization resistance from the impedance data.


Blocking System Reactive System
Cdl Re Re

Figure 6-2. Equivalent circuits for blocking and reactive system (nonfaradaic and
faradaic interface) [1].

6.1.1 Graphical Data Analysis Techniques

This section introduces graphical techniques used to analyze electrochemical

impedance data. Bode plots of impedance magnitude and phase are frequently used

in electrical engineering to view impedance data and are also used in electrochemistry;

however, they do not show interface characteristics as well as other graphical methods.

The complex impedance plane or Nyquist plot and plots of logarithmic imaginary

impedance as a function of frequency, introduced by Orazem et al. [133], are used to

acquire meaningful information about the electrochemical system.

To compare the graphical techniques for analysis of impedance data, plots of

theoretical curves for blocking and reactive systems modeled by the equivalent circuit

diagrams in Figure 6-2 are discussed here. Figure 6-3 shows Bode plots, where

impedance magnitude and phase as a function of frequency are shown. Both blocking

and reactive systems show resistive behavior at high frequencies, denoted by the

zero degree phase angle. The blocking system is dominated by the capacitor at low

frequencies and thus shows increasing magnitude of impedance and a phase angle of

-900. The reactive system has a resistive current pathway at low frequencies, therefore;

the impedance magnitude levels off to a finite value and has phase angle of zero degree

at low frequencies.

The Nyquist plot is useful for graphical estimation of the electrolyte resistance,Re,

and the charge transfer resistance, Rot. Figure 6-4 shows a Nyquist plot, which is the

negative of the imaginary impedance as a function of the real impedance, for the two

106 0
O O Blocking 10
O x Reactive x
O -20 x
O x
0 x
0 -30
-90 X
S10 15 0 1024 1 0 -40 x 1
N -50 x
-70 O
104 -80
10 10 1 102 103 104 05 100 101 102 103 104 105
f(Hz) f(Hz)

Figure 6-3. Bode plots of a blocking and reactive system.

interface cases. The high frequency asymptote gives the value of Re for both systems.

As the frequency decreases, the imaginary impedance value will either grow toward

infinity for the blocking system or achieve a maximum and then decrease back to zero in

the reactive system. The low frequency asymptote for the reactive system gives Re Rct.

The logarithm of imaginary impedance as a function of frequency in Figure 6-4

gives a straight line of slope equal to -1 for all frequencies in the ideal blocking system

and for high frequencies in the reactive system [133]. This method of viewing impedance

data is most useful for experimental data showing non ideal behavior.

The Constant Phase Element: Experimental results of EIS measurements on

metal-electrolyte interfaces do not normally show behavior that can be completely

modeled by the reactive and blocking equivalent circuits in Figure 6-2. Deviations from

ideal cases are modeled by the constant-phase element (CPE). The constant-phase

element has a multitude of origins and is highly dependent on the system. It is

commonly suggested that CPE behavior arises from an inhomogeneous surface [134].

Regardless of the physical meaning, it can be considered an element with a distribution

of time constants, which can be modeled by Equation 6-1.

Zcpe = (6-1)


x 104




10 15
x 104

Figure 6-4. Nyquist plot (left) and logarithm of imaginary impedance as a function of
frequency (right) of blocking and reactive systems.

x 104

Zr ()

101 102 103 104 105




x 104

101 102 103 104
f (Hz)

Figure 6-5.

Nyquist plot (left) and logarithm of imaginary impedance as a function of
frequency (right) for blocking and reactive systems with a constant phase



Z (n)

where a is a number from 0 to 1, and Q is the quantity of the CPE with units sa/Qcm2

[134]. The CPE takes the place of the double layer capacitor in the interface equivalent


The Nyquist plot and logarithm of the imaginary impedance as a function of

frequency show a unique dependence with the constant-phase element. In the Nyquist

plot, the CPE makes the vertical line tilt to the right at an angle less than 900 in a

blocking system; and in a reactive system, the semicircle is depressed as shown in

Figure 6-5. In the graph of logarithm of imaginary impedance as a function of frequency,

the slope of the impedance for both systems is decreased from 1 and equals the value

of -a from Equation 6-1.

Thus, by using Nyquist plots and the logarithm of imaginary impedance as a

function of frequency instead of Bode plots, more of the interface characteristics are

apparent. The difference between a blocking and reactive system is simply given by the

shape of the Nyquist plot (eg. a straight line versus a semicircle). Furthermore, values of

circuit parameters (Re, Rot and a) are able to be estimated.

6.1.2 Error Analysis

This section explains the method used to assess stationarity, linearity, causality, and

measurement error of the measured impedance data. This method proposed by Orazem

[135] is an iterative approach that uses a measurement model, which inherently satisfies

the Kramers-Kronig relation and thereby exhibits linearity, stationarity, and causality. The

measurement model for complex impedance is given by [135]

Z = RRk (6-2)
k= 1

A resistor, Ro modeling the electrolyte resistance, is in series with k Voigt elements,

where a Voigt element is a capacitor in parallel with a resistor that has a characteristic

time constant Tk = 27rRC. Complex nonlinear least squares regression is used to fit the

experimental data to the measurement model with the largest number of Voigt elements


that is statistically significant. Then the variance for the real data for three or more

measurement scans, N, is found by

S(w) = N 1 (Cres Krk() res,Kr( ))2, (6-3)

where Cres,Kr,k(W) is the residual error of the model to the data at frequency w for scan k

and res,Kr(W) is the mean value of the residual errors at frequency w. The variance for

the imaginary part is found similarly.

Next, the variance is transformed into an error structure so that it may be applied

to a general impedance spectra. It has been shown that the variance of the real and

imaginary parts of the impedance spectra are equal [136]. Thus the error structure of

electrochemical impedance can be found when regressed to this formula

azr = aZ, = a Z, + l3Zr + 7 + 6, (6-4)

where a, 3, 7, and 6 are coefficients to be found in the regression, and Rm is the value of

the resistor used in the measurement equipment [135].

The residual error acres found above includes bias error, stochastic error and error

to the fit. However, reference [135] suggests that it can be a good estimate for the

stochastic error if the same number of Voigt elements are used to fit each scan. Then,

the model parameters account for drift in each subsequent scan, and error due to

non-stationarity is the same from one scan to another. In a more sensitive analysis

for stationarity, the error structure from Equation 6-4 is used to weight the regression

of the imaginary impedance data for one scan, and then the real part is predicted via

the Kramers-Kronig relation. If the predicted values are within the 95% confidence

interval of the regression, then the data are consistent with the Kramers-Kronig relation.

If data at the extents of the measured frequency range do not fit in the confidence

interval then, they are discarded and the procedure is performed again. Inconsistency


with Kramers-Kronig relations means that bias errors, which could be from instrument

artifacts or non-stationary behavior, are confounding the measurement.

Through this approach, an error structure representing the stochastic error is found,

and the measured data are checked for linearity, stability, and casualty. The error

structure can then be used as weighting for regression of physical models representing

the electrochemical system.

6.2 Microelectrodes used for Electrochemical Characterization

To realistically assess the electrochemical behavior of tungsten microwires used

in neural recording applications, the same microwires are used in the formation

of the working electrode for EIS. The tungsten microwires used for intracortical

microelectrodes consist of 50 pm diameter tungsten wires that are plated with a

thin layer of gold and are insulated with approximately 3 pm of polyimide. The gold

allows the microelectrode to be soldered easily. The ends of the wires are cut (via a

dicing saw) in the microelectrode fabrication process to expose the cross-section as

the recording site. During the cutting process, the insulation is pulled away from the

tungsten microwire to some extent, creating an imperfect seal. For electrochemical

characterization of the metal-to-electrolyte interface, an electrode surface with a

well defined surface area and perfect seal with the insulation is needed. Otherwise,

artifacts would arise from the imperfect insulation seal and confound interpretation of

electrochemical phenomena at the interface. Gaps at the metal-to-insulator boundary

can be modeled as porous electrodes. Many have presented unique impedance

responses due to porous electrodes [137-139]. Thus, the tungsten microwires with

polyimide insulation cannot be used. Also, the exposed sidewalls would affect the

accuracy of the estimation of the surface area needed for calculation of the corrosion

rate. Therefore, the working electrodes for the EIS study are made similarly to

conventional microelectrodes used for electrochemical applications.


The use of microelectrodes (defined as electrodes with dimensions in the

micrometer range) in electrochemical applications is briefly discussed to give a

counterpoint to microelectrodes used in brain-machine interfaces. In electroanalytical

chemistry, microelectrodes provide advantages over macroelectrodes including: fast

mass transport, reduced capacitance, and low current [140, 141]. These properties

remove the need for forced convection in the cell, reduce the RC time constant,

which allows investigation of high speed kinetics, and render the Ohmic drop over

the electrolyte resistance negligible such that use in high resistivity media is possible.

Moreover, their small size provides an obvious benefit to biological applications where

minimal tissue damage is necessary and spatial resolution is important. Wightman's

group have been using microelectrodes since the 1980's to determine the presence

of neurochemicals in the brain [142, 143], among many other applications. A more

recent application of microelectrodes is in electrochemical impedance spectroscopy

studies that employ scanning electrochemical microscopy (SECM) to assess local

characteristics of bulk materials [144, 145].

Microelectrodes and microelectrode arrays (MEAs) for electroanalytical applications

are fabricated in a number of ways [146]. Methods include insulating metal wires or

carbon fibers with glass, epoxy, or a polymer and then polishing or electrochemically

etching one end. Microfabrication techniques are used to lithographically pattern vapor

deposited thin film metals and insulating dielectrics. Microelectrode arrays are typically

fabricated using micromachining techniques. Whether made by either method, the

microelectrodes are at risk for defects such as imperfect seals between the electrode

and insulation [146]. Contaminants on the surface from perhaps a polishing step also

pose threats to the quality of the measurement [146].

6.3 Quality Control of Microelectrode Fabrication

Few papers describe a method for quality control of microelectrodes. Thormann

et al. find that square wave and AC voltammetry and short-time chronocoulometry


measurements are highly affected by imperfect seals between the metal and insulator

[147]. Results show deviation to theory though an asymmetric voltammetric response,

where the nonideal response is exacerbated as the pulse width is decreased or

frequency is increased. Koster et al. provide a method for quality control of microelectrode

arrays (MEAs) made by micromachining and used for amperometric transducers [148].

They use a combination of cyclic voltammetry, electrochemical impedance spectroscopy,

and scanning electrochemical microscopy to assess the quality of their arrays. This work

introduces a simple method that uses only electrochemical impedance spectroscopy

(EIS) to assess the quality of microelectrode fabrication.

This method uses a graphical interpretation of impedance data following Orazem et

al. [133] and Huang et al. [149-151]. In references [149-151], a method for comparing

impedance data of electrodes of differing size and electrolyte conductivity is given

as well as a criterion for distinguishing artifacts in impedance data. They proved that

geometry induced current and potential distributions at high frequencies produced

artifacts in the impedance spectra of disc electrodes. Therefore, we will use the

same method to uncover artifacts in the impedance spectra of microelectrodes due

to fabrication defects. This paper applies the method prescribed for blocking electrodes

showing constant phase element (CPE) behavior [150].

6.3.1 Quality Control Methods

It has been shown that short-time scale electrochemical measurements are

sensitive to imperfections in the metal to insulator seal in microelectrodes and that

epoxy sealed microelectrodes are highly susceptive to such defects [147]. This quality

control study uses two sets of Pt microelectrodes; one set is insulated with epoxy and

the other with glass, which is known to have high probability of achieving a crack-free

seal since glass has a similar coefficient of thermal expansion with Pt [146]. This work

shows that by graphically analyzing the high frequency impedance data of the two sets,

the quality of microelectrode fabrication may be determined for each. For this study, it

is assumed that the glass-insulated microelectrodes exhibit seals with no defects, while

the epoxy-insulated microelectrodes exhibit seals with defects, which is consistent with

what has been presented in the literature about glass-insulated versus epoxy-insulated

microelectrodes [146].

Two sets of microelectrodes were made using 50 pm diameter Pt wire (California

Fine wire). One set of Pt wires were secured in glass tubing with an insulating epoxy

and one end was polished with AO02 sandpapers. The final grit sandpaper corresponded

to 0.3 pm roughness. In the other set of electrodes, a glass tube was heated and

sealed around the Pt wire. SiC sandpaper was used to polish one end of those samples

to a final roughness of 1 pm. The unpolished side of all electrodes were electrically

connected to a gold pin connector with silver epoxy.

A Gamry Series G 300 potentiostat was used for performing electrochemical

impedance spectroscopy. Impedance responses of the Pt microelectrodes were

measured with respect to a Pt counter electrode and Ag/AgCI reference electrode in

0.9% phosphate buffered NaCI (Sigma) at room temperature. The perturbation voltage

was 10 mV, the frequency range was 10 kHz to 0.8 Hz, and all experiments were taken

at open circuit potential. All experimental data were consistent with the Kramers-Kronig

relation as prescribed by Orazem [152]. Graphical analysis

This study assumes the model for a blocking system with constant phase element

(CPE) behavior, which is commonly represented as a resistor in series with a constant

phase element [153] for Pt microelectrodes in saline solution. The equivalent circuit

impedance is given as
Z Re (6-5)

where Re is the electrolyte resistance, w is angular frequency, a is a constant less

than one, and Q is the CPE coefficient [150, 151]. Following Orazem et al. a may

be graphically found by plotting the imaginary part of the impedance as a function


of frequency [133]. In a logarithmic plot, the slope of the impedance data gives the

negative value of a. The value of Q is given by [150]

Q sin( Z) (6-6)

In References, [149-151], the authors develop a graphical method that elucidates

geometry induced artifacts in the impedance spectra for a disc electrode. They introduce

a dimensionless frequency K,
Qefr ro
K = efar (6-7)

where K is the conductivity of the electrolyte, ro is the radius of the disc electrode, and

Qeff is a value representing Q(w). Plotting the dimensionless imaginary impedance
against the dimensionless frequency K in logarithmic scale produces a straight line with

slope equal to -1 for a blocking system modeled by Equation (6-5). Their work shows

that for frequencies greater than K = 1, the impedance is influenced by the current

distribution and deviates from the ideal behavior of the impedance. The results give

slopes that deviate from -1 at frequencies greater than

f (6-8)
27 Qeff ro

where fc is the frequency at which K = 1. This frequency is inversely proportional to the

radius of the electrode and for the case in this study fc is on the order of 100 kHz, which

is beyond the frequency range of interest. Thus, artifacts due to current distribution can

be neglected.

The next section will use the graphical method of plotting imaginary impedance

versus K to assess the quality of the electrode fabrication. Specifically, this method will

be used to rule out any electrodes that have defects which allow the impedance spectra

to diverge from ideal behavior, that is a slope of imaginary impedance versus K on a

logarithmic plot not equal to -1. Based on results from [147], the physical reason for the

defect is an imperfect seal between the metal and insulator.


6.3.2 Quality Control Results and Discussion

Impedance was measured for two sets of electrodes described in Section 6.3.1.

Microelectrodes labeled 1a-4a were insulated with glass and polished with SiC

sandpaper and exhibit ideal behavior for a blocking electrode. Microelectrodes labeled

1 b-3b were insulated with epoxy and polished with A102 sandpaper. These electrodes

do not exhibit ideal behavior and have fabrication defects that can be explained with the

theory of porous electrodes [137, 139]. Ideal behavior

Imaginary impedance versus frequency and Nyquist plots for electrodes 1a-4a are

given in Figure 6-6. Results show spectra for four Pt microelectrodes that have little

o la 100 o la
10 E 2a- 2a
v 3a v 3a 0
A 4a 80 A 4a A
107 0
C 60
N 0 106
40- 0
10-1 101 103 105 0 20 40
f (Hz) Zr (MQ)

Figure 6-6. (left) Imaginary impedance as a function of frequency of four different Pt
microelectrodes insulated in glass and polished with SiC paper. The value of
-a corresponding to each electrode is found by calculating the slope of the
lines. (right) Nyquist plot of the four Pt microelectrodes.

deviation from each other. The values of a are found by fitting the plots of imaginary

impedance versus frequency to straight lines and extracting the slope via the curve

fitting tool in Matlab. The CPE coefficient is calculated by Equation (6-6) and plotted in

Figure 6-7. Values of a and Qeff used for the calculation of K are given in Table 6-1.

o la
E 2a
103 v 3a
a 4a

2 102


105 104 103 102 101 10

Figure 6-7. CPE coefficient Q as a function of frequency. The dotted lines show the
effective values used for calculation of K in equation (6-7).

Table 6-1. Values of a and Qeff for ideal electrodes from Figure 6-6 and Figure 6-7
Glass a Qeff / Q-cm-2s"
la -0.881 1.15 x 10-4
2a -0.885 1.27 x 10-4
3a -0.882 1.18 x 10-4
4a -0.885 1.59 x 10-4

The dimensionless imaginary impedance as a function of dimensionless frequency

K is shown in Figure 6-8 (using a conductivity of 0.19 mS/cm). All impedance data

superimpose on the same line as expected for ideally constructed microelectrodes.

Figure 6-9 shows the derivative of imaginary impedance with respect to K. Over the

measured frequency span, the derivative does not deviate from -1 by more than 5%.

This result suggests that any microelectrode showing derivatives that are different from

-1 by more than 5% have fabrication defects. Non-ideal behavior

The same method is followed for impedance data of electrodes 1 b-3b. From

examining the impedance data in Figure 6-10, it is evident that electrode 2b does not


o la
0.18 v 3a
A 4a


E 0.14

0.12 :]E nE]

100 102 104

Figure 6-8. Imaginary impedance of the ideal electrodes in dimensionless units with
respect to dimensionless frequency K.

show ideal behavior and would be suspect for defects; however, 1 b and 3b appear


The values for a are found by fitting the impedance spectra in Figure 6-10 to straight

lines. Only frequencies higher than 100 Hz were used to calculate a for microelectrode

2b. Values for Q are plotted in Figure 6-11 and values used to calculate K are given in

Table 6-2.

Table 6-2. Values of a and Qeff for non-ideal electrodes extracted from Figure 6-10 and
Figure 6-11
Glass a Qef / -1cm-2s"
lb -0.848 8.22 x 10-5
2b -0.662 1.53 x 10-4
3b -0.766 1.25 x 10-4

Examining the imaginary impedance as a function of K in Figure 6-12, it is evident

that microelectrode 2b does not show ideal behavior. In Figure 6-13, when the derivative

of dimensionless imaginary impedance with respect to K is plotted, the variation seen

for electrodes 1 b-3b is greater than seen for microelectrodes 1a-4a. Thus, it is likely


o la
-0.75 2a
-0.8 v 3a
S^A 4a
C; -0.85
-u -0.9
o -0.95-



10-5 10-4 10-3 10-2 10-1 100

Figure 6-9. Derivative of the logarithm of dimensionless imaginary impedance of the
ideal electrodes with respect to logK. Almost all data points lie within 5% of

that all three of the epoxy sealed microelectrodes have some fabrication defect and are

unsuitable for measurements.

6.3.3 Quality Control Summary

Since transient electrochemical measurements are shown to be sensitive to

fabrication defects [147], a graphical analysis of electrochemical impedance data is

proposed as a simple method of quality control of microelectrode fabrication. This

work analyzed impedance data of a blocking system below the frequency fc at which

geometry induced artifacts arise for microelectrodes. The results suggested that ideally

constructed microelectrodes will exhibit a slope of the imaginary impedance as a

function of dimensionless frequency K in a logarithmic plot that does not vary from

1 by more than 5%. The proposed method will also work for a reactive system. If a

reactive system is used, impedance data corresponding to frequencies greater than the

characteristic frequency given by the RC time constant of the double layer capacitance

and charge transfer resistance and lower than fc should be used in the analysis.






10-1 101 103
f (Hz)

180 ,
o lb
160 a 2b
140 v 3b ov

0 20 40 60
Zr (MQ)

Figure 6-10. (left) Imaginary impedance as a function of frequency of four different Pt
microelectrodes insulated in epoxy and polished with A102 paper. The
value of -a corresponding to each electrode is found by calculating the
slope of the lines. (right) Nyquist plot of the four Pt microelectrodes.



o 0.15

- Et ]



Figure 6-11. CPE coefficient Q of the non-ideal electrodes as a function of frequency.
The dotted lines show the effective values used for calculation of K in
equation (6-7).



N 102


10-5 10-4 10-3 10-2 10-1

Figure 6-12. Plot of imaginary impedance of the non-ideal electrodes in dimensionless
units with respect to dimensionless frequency K.

'C -0.85
-a -0.9
L -0.95

o -1.05
- -1.1


O Oo Co
0 0

00 v 0


10-5 10-4 10-3 10-2 10-1

Figure 6-13. Derivative of the logarithm of dimensionless imaginary impedance of the
non-ideal electrodes with respect to logK. Many data points differ from -1
by more than 5%.



A well controlled in vitro study on the corrosion properties of tungsten and

platinum microwires in physiological saline solutions is performed to assess the

longevity of the wires for use in neural recording microelectrode arrays. Specific

materials, instrumentation, and measurement parameters used for the impedance

measurements are described first. The results of the electrochemical impedance

spectroscopy (EIS) measurements are then presented. Analysis of the measured

impedance using the Stern-Geary equation quantifies the rate of tungsten corrosion in

biological saline solutions. The analysis of Pourbaix diagrams provides information on

the electrochemical reactions occurring on the electrode surfaces. Based on the results,

tungsten is not suitable for long-term implant use, while platinum is suitable.

7.1 Materials and Instrumentation

The working electrodes in the EIS measurements were made with tungsten or

platinum wires encased in glass or epoxy. The glass insulation process was performed

by placing the wires in borosilicate glass tubes and heating the structure in a furnace

at a temperature (T=8000C) that softens the glass. Electrodes insulated in epoxy were

made by placing the microwire in a glass tube and filling the tube with epoxy resin

(Epo-tek 302-3M). With glass or epoxy sealed tightly around the wire, one end-face was

polished with SiC sandpapers resulting in a final roughness of 1 pm and the other end

is secured to a gold connector with silver epoxy (AbleBond). The quality control method

discussed in Section 6.3 was used to identify an ideally fabricated electrode with an

adequate seal between the insulation and the electrode. Three working electrodes each

were made using 50 pm diameter gold-plated-tungsten, bare-tungsten, and platinum

microwires. The gold-plated-tungsten and platinum working electrodes were insulated

with glass, and the bare-tungsten electrode was insulated in epoxy because a furnace

was not available at that time.


Gold connector

Shrink tubing
reinforcing conductive
silver epoxy bond

Glass insulation

Metal wire
(501pm diameter)

Polished tip
1200 grit SiC sandpaper
(~Iim roughness)

Figure 7-1. Schematic of working electrode for EIS measurements.

The electrolytes used in the EIS measurements were chosen to model the in

vivo chemistry. They are 0.9% phosphate buffered saline (PBS) for healthy neural

tissue and phosphate buffered saline that contains H202 to simulate tissue undergoing

an inflammatory response. Since H202 is secreted from microglia that surround the

implanted microwire electrode, local concentrations are difficult to estimate. Pan et al.

and Fonesca et al. used hydrogen peroxide and PBS to assess corrosion of titanium

for structural implant materials [105], [106]. They used concentrations that ranged from

10 mM to 100 mM. A concentration of 30 mM H202 was chosen for this study. A salt

mixture (Sigma P-5368) was used to make the PBS with composition given in Table 7-1

and pH of 7.4.

Electrochemical impedance spectroscopy measurements were performed under

potentiostatic control using a Gamry 300 G series potentiostat/glavanostat. Cyclic

voltammetry was also performed with the Gamry system with voltage sweep rates of

50 and 100 mV/s. A silver/silver chloride reference electrode (BioAnalytical Systems

RE-5B) was used in this study. Pt or Ti large area counter electrodes were used for

Table 7-1. Composition of Phosphate Buffered Saline
Chemical Compounds Concentration (M)
NaCI 0.138
HCI 0.0027
Na2HPO4 0.01
KH2PO4 0.00176
*H202 0.03
*Concentration of H202 for electrolyte including PBS and H202

measurements in PBS electrolyte and an electrolyte containing PBS and 30 mM H202,

respectively. A Ti counter electrode was used in solutions containing H202 because

Pt was shown to be reactive. The EIS perturbation voltage was 10 mV. The frequency

range for all experiments was 0.1 Hz to 20 kHz, and all measurements were taken at

the equilibrium, or open circuit potential (OCP). The microelectrodes were polished and

thoroughly rinsed in deionized water immediately prior to immersion in the electrolyte.

Aa elapsed period of 5 minutes allowed the OCP to stabilize before the impedance

measurements were taken.

7.2 Experimental Results

The EIS results for tungsten and platinum microelectrodes immersed in a PBS

electrolyte are compared first, followed by the results of tungsten and platinum

electrodes in an electrolyte containing PBS and hydrogen peroxide. Images of corroding

tungsten microelectrodes in in vitro and in vivo settings are also given.

7.2.1 EIS of Tungsten and Platinum in Phosphate Buffered Saline

The comparison of the impedance data of platinum and tungsten microelectrodes

immersed in a PBS electrolyte are shown in Figure 7-2. The tungsten microelectrodes

exhibit reactive behavior since the impedance data for the tungsten microelectrodes

show the presence of a resistive pathway at low frequencies (e.g. the impedance data

shows a semicircle in the complex-impedance-plane plot). The platinum electrode

exhibits blocking or nonreactive behavior since its impedance data trends toward


S w 104 W
8 W 10 Au-plated W
o Au-plated W pl
S Pt
E 6
00 102

2 100

0 2 4 6 8 10-2 100 102 104 106
Zr (kQ cm2) f (Hz)

Figure 7-2. Nyquist plot (left) and imaginary impedance as a function of frequency (right)
of tungsten and platinum electrodes in PBS.

Blocking System Reactive System



Figure 7-3. Equivalent circuits for blocking and reactive systems [1].

infinity as the frequency decreases. All electrodes show constant phase element

(CPE) behavior as evidenced by the slope of the imaginary impedance as a function

of frequency differing from negative one (i.e. a = 0.9) [133]. The blocking and reactive

systems can be modeled with a resistor in series with a constant phase element or the

parallel combination of a resistor and constant phase element, respectively, as shown in

Figure 7-3 [154]. Re is the resistance of the electrolyte, Rp is the polarization resistance,

and ZCPE is the constant phase element impedance given by Equation 7-1,

cpe (= (7-1)

where w is the frequency, a is a number from 0 to 1, and Q is the CPE coefficient with

units sa/Qcm2 [134].


A day1
L day1 day 20
8 day 20 104 d

E 6 v E
0 A o
V 102

0 2 4 6 8 100 102 104
Zr (kn cm2) f (Hz)

Figure 7-4. Nyquist plot (left) of imaginary impedance as a function of frequency (right)
of a platinum electrode in phosphate buffered saline over time.

Impedance measurements taken after long periods of immersion in the electrolyte

illustrate the observation of the nonreactive nature of platinum and give insight into the

reactive nature of the tungsten electrode. Figure 7-4 shows the impedance spectra

of platinum microelectrodes after 20 days in the PBS solution still exhibiting blocking,

or unreactive, behavior. Figure 7-5 shows EIS results for a gold-plated tungsten

microelectrode in PBS over 15 days. The progression of the semi-circular curves show a

reactive system that changes over time. The change in the magnitude of the impedance

over time is an indication that the electrode surface is being modified.

The dominant cathodic reaction on the tungsten electrode is found by testing the

system reactivity to the oxygen concentration. EIS results showing the dependence

of the faradaic reaction to the concentration of oxygen is presented in Figure 7-6. The

concentration of oxygen was decreased by bubbling N2 into the solution. After one

hour of 02 displacement via bubbling, the EIS measurement results show that the

polarization resistance increases with decreased 02 content. These results suggest that

the reduction of oxygen is the rate-limiting cathodic reaction at the electrode surface.


time (days)

C- 600
O 400


0 200 400 600 800 1000 1200
Zr (Q cm2)

Figure 7-5.

0 0



10 102
f (Hz)

Nyquist plot (left) and imaginary impedance as a function of frequency (right)
of a gold-plated tungsten electrode in phosphate buffered saline over 15

aerated PBS
PBS with reduced 02

aerated PBS
PBS with reduced 0

c 1000

rUi 500

500 1000
Zr (Q cm2)

1500 2000

CE 102


100 102

Figure 7-6. Nyquist plot (left) and imaginary impedance as a function of frequency (right)
of tungsten electrodes in PBS showing dependence on 02 concentration.

7.2.2 EIS of Tungsten and Platinum in Phosphate Buffered Saline and Hydrogen

The oxidizing effect of H202 allows another cathodic pathway for charge transfer

via the reduction of H202. EIS results are again used to experimentally ascertain

the presence of a faradaic reaction in both systems. Figure 7-7 shows that faradaic

reactions are occurring on both the gold-plated tungsten and platinum electrodes when

H202 is present. The presence of a resistive pathway at the dc limit is evident by the

semicircular shapes in Figure 7-7.



tiI ei, a/,S)

o Au-plated W

30 o Au-plated W E
SPt o

E 20 2
C 00 10
10: OO 10
0 0 4

0 10 20 30 40 50 10-2 100 102 104 106
Zr (Q cm2) f (Hz)

Figure 7-7. Nyquist plot (left) and imaginary impedance as a function of frequency (right)
of a platinum and gold-plated tungsten electrode in PBS plus H202 showing
reactive behavior.

7.2.3 Images of Tungsten Corrosion

The presence of tungsten corrosion is verified and unique trends are established

by examining optical photographs taken over time. Figure 7-8 shows a polished surface

of a tungsten-only electrode compared to the surface after 23 days of immersion in

PBS. The surface after 23 days is porous and roughened. Over a shorter time interval,

Figure 7-9 shows the state of six different gold-plated tungsten electrodes before and

after immersion in PBS from one to six days. The top pictures correspond to the before

state and the bottom pictures correspond to the after state. After one day in saline,

the surface looked roughened as compared to the previous state. After two days in

saline, there was a circular section in the center of the electrode that was depressed

approximately 0.5 pm, which is out of focus in the photograph. A similar trend is seen for

the other electrodes left in saline for longer periods. Each displays a circular depression

in the center of the electrode that grows deeper with time. For the electrode left in

saline for five days, the center was depressed approximately 4 pm and was porous.

The picture of the electrode left in saline for six days shows that the entire tungsten



Days in PBS

Figure 7-8. Photographs of a tungsten electrode before and after immersion in PBS for
the specified period of time.

surface is recessed from the polished surface with the center even more depressed.

These photographs suggest that the gold-plated-tungsten electrodes experienced

uniform corrosion that was dependent on the microstructure of the drawn tungsten wires.

Over an even shorter time period, Figure 7-10 shows the change of the surface of one

gold-plated tungsten electrode in PBS and H202 over 24 hours. After one hour in the

electrolyte, recesses were seen around the edges of the gold-tungsten interface as

well as a roughened tungsten surface. The recesses on the perimeter of the electrode

are what is expected for a primary current distribution on the disc electrode surface,

where the current density is the highest at the perimeter [36]. As time progressed, the

recesses expanded inward to the center of the electrode and after 24 hours, the bulk

of the tungsten was recessed on the order of 10 pm below the original surface. These

photographs suggest a much higher corrosion rate for gold-plated tungsten in saline

solutions containing H202 than what was seen for the other two cases without H202.

7.3 Analysis and Discussion

This section analyzes faradaic reactions occurring on the electrodes and discusses

their implications on in vivo applications. Analysis using Pourbaix diagrams provides

information on possible electrochemical reactions. The Pourbaix diagram shows the

potential at which chemical and electrochemical reactions may occur on an electrode

surface in a specific electrolyte as a function of pH [155]. The thermodynamic stability


1 2 3 4 5 6

Days in PBS

Figure 7-9. Photographs of gold-plated tungsten electrodes before (top) and after
(bottom) immersion in PBS for the specified period of time.

0 1 2 3 24

Hours in PBS + 30 mM H202

Figure 7-10. Photographs of a gold-plated tungsten electrodes before and after
immersion in an electrolyte containing PBS and H202 for the specified
period of time.

of chemical species at various potential and pH ranges may be ascertained from the

diagram. Also, the voltages for hydrogen and oxygen evolution reactions are commonly

shown on the diagrams. In the Pourbaix diagrams created for this study, all potentials

are referenced to the standard hydrogen electrode (SHE). Thus, a calculation must be

performed to convert the potentials measured in this study to be with respect to the

SHE. The Pourbaix diagrams shown in this study are generated by a computer program

(CorrosionAnalyzer 1.3 Revision 1.3.33 by OLI Systems Inc).


a 13 Y 6 a'

Working / /
Metal electrode NaCI NaCI Metal
electrode ) / Ag/AgCI .
clip (W, Pt) 0.1 M 3 M clip

Figure 7-11. Schematic representation of electrochemical cell.

7.3.1 Calculation of Open Circuit Potential Referred to SHE

The open circuit potential (OPC) is the potential measured by the potentiostat of

the electrochemical cell established by the working and the reference electrodes under

zero bias or electrical equilibrium conditions. The Pourbaix diagrams show voltages with

respect to the standard hydrogen electrode (SHE), but a silver/silver chloride reference

electrode is used in the OCP measurements. Thus, the OCP data must be converted to

reference the SHE. A schematic of the electrochemical cell is depicted in Figure 7-11.

A liquid-junction potential exists between the electrolyte in the reference electrode

and the electrolyte of the working electrode. The liquid-junction potential 06 07 must

be accounted for in the conversion. As an approximate solution, the Henderson formula

(Equation 7-2) may be used even though the correct concentration profile is not defined.

T 07 = -RA (7-2)
F B6 B'


A = ,ziui,(c c,7), B6 = zf2uici, B7 = zi uic, (7-3)

and zi, ui, and c, are the charge number, mobility, and molar concentration of ionic

species i, respectively [36]. The potential of a silver/silver chloride electrode with

reference to the SHE assuming the concentration can be considered the same as the

activity is given as
U' = Ue TIn cc, (7-4)






2.0 4,0 6.0 8,0 10.0 12,0 14.(

Figure 7-12. Pourbaix diagram of tungsten in phosphate buffered saline. The box shows
range of open circuit potential over 15 days. The diagrams are generated
by CorrosionAnalyzer 1.3 Revision 1.3.33 by OLI Systems Inc.

where Ue = 0.222 V is the standard electrode potential at 25C. The electrode potential

corrected for the liquid-junction potential can be expressed as

U" = U U' ( 07), (7-5)

where U is the measured open circuit potential. For the concentrations used in this

study U' = 0.194 V and 0V 07 = -0.016 V.

7.3.2 Possible Electrochemical Reactions on Tungsten

Pourbaix diagrams are used to predict possible reactions on tungsten at the open

circuit potential. The Pourbaix diagram given in Figure 7-12 shows the thermodynamic

stability of tungsten in PBS. The diagonal lines labeled a and b correspond to the

limits of the stability of water. Above line a, oxidation of water (i.e. oxygen evolution),

is possible and below line b, reduction of water (i.e. hydrogen evolution), is possible.

Between those lines, water is stable. The vertical dashed line designates the natural pH


Table 7-2. Species considered in calculation of the Pourbaix diagram
Figure 7-12.
Aqueous Phase Solid Phase

Chloride ion(-1)
Dihydrogen orthophosphate(V) ion(-1)
Dihydrogen pyrophosphate(V) ion(-2)
Hydrogen chloride
Hydrogen ion(+1)
Hydrogen orthophosphate(V) ion (-2)
Hydrogen pyrophosphate(V) ion(-3)
Hydrogen tungstate(VI) ion(-1)
Hydroxide ion(-1)
Orthophosphoric acid
Phosphate ion(-3)
Potassium chloride
Potassium ion(+1)
Pyrophosphate ion(-4)
Pyrophosphoric(V) acid
Sodium ion(+1)
Trihydrogen pyrophosphate(V) ion(-1)
Tungsten(VI) tetraoxide ion(-2)
Tungstic(VI) acid

Pentasodium triphosphorous decaoxide
Pentasodium triphosphorous decaoxide hexahydrate
Phosphorus pentoxide dimerr)
Potassium chloride
Potassium dihydrogen orthophosphate(V)
Potassium hydrogen orthophosphate(V) hexahydrate
Potassium hydrogen orthophosphate(V) trihydrate
Potassium hydrogen phosphate(V)
Potassium hydroxide
Potassium hydroxide dihydrate
Potassium hydroxide monohydrate
Potassium orthophosphate(V)
Potassium orthophosphate(V) heptahydrate
Potassium orthophosphate(V) trihydrate
Potassium tungstate(VI)
Sodium chloride
Sodium dihydrogen orthophosphate dihydrate
Sodium dihydrogen orthophosphate monohydrate
Sodium dihydrogen orthoporthohosphate
Sodium hydrogen orthophosphate
Sodium hydrogen orthophosphate dihydrate
Sodium hydrogen orthophosphate dodecahydrate
Sodium hydrogen orthophosphate heptahydrate
Sodium hydroxide
Sodium hydroxide monohydrate
Sodium orthohosphate
Sodium orthophosphate hexahydrate
Sodium orthophosphate hydroxide dodecahydrate
Sodium orthophosphate monohydrate
Sodium orthophosphate octahydrate
Sodium pyrophosphate decahydrate
Sodium tungstate(VI)
Sodium tungstate(VI) dihydrate
Tungsten(VI) oxide

presented as

Vapor Phase
Hydrogen chloride

of the electrolyte at 7.4. The box shows the range of the measured values of the open

circuit potential for a gold-plated tungsten electrode over 15 days in solution. A list of all

chemical species considered in the formation of the Pourbaix diagram for tungsten in

PBS are given in Table 7-2. The diagram shows that the tungstic ion W02- is stable at

the OCP and that corrosion reactions are possible in this system since the box is in the

white (W02-) area. The overall anodic electrochemical reaction producing the tungstic

ion is given by Equation 7-6 [101, 155]. Possible cathodic reactions are reduction of

water and oxygen given by Equation 7-8 and Equation 7-7.

W + 4H20 WO

8H-- 6e-



02 2H20 4e- 40H-

2H20 +2e -- H2 +20H

However, the rate-limiting effect of oxygen seen in Figure 7-6 suggests that the reduction

of oxygen is the dominant cathodic reaction given by Equation 7-7.

Another possible chemical reaction is the dissolution of a tungsten oxide. Lillard et

al. showed that tungsten exposed to air has a native oxide W03 via surface-enhanced-Raman

spectroscopy [97]. The Pourbaix diagram suggests that WO3 dissolves at the cell

equilibrium potential (0.4 V vs. SHE) and 7.4 pH as given by Equation 7-9.

WO3 + H20 WO- + 2H+ (7-9)

Therefore, even if an oxide layer exists on the tungsten surface that could inhibit the

dissolution of the tungsten, eventually the oxide will be dissolved and expose the

tungsten surface.

The addition of hydrogen peroxide to the PBS allows another cathodic reaction,

the reduction of H202, to occur on the tungsten electrode surfaces. A Pourbaix diagram

showing the OCP range for a gold-plated tungsten electrode in an electrolyte containing

PBS and 30 mM of H202 is given in Figure 7-13. The chemical species considered for

the Pourbaix diagram are the same as listed in Table 7-2 with the addition of H202. The

regions of stability of H202 given by Pourbaix [155] are overlayed on the diagram. Below

the line labeled 1, reduction of H202 is possible and above line 2, oxidation of H202 is

possible. Thus, for an electrochemical system containing a tungsten electrode in PBS

and H202, the possible anodic reaction is given by Equation 7-6 and possible cathodic

reactions are given by Equation 7-7 and Equation 7-10.

H202+ 2H+ + 2e- 2H20 (7-10)

Gold-tungsten galvanic couple: The gold-plated tungsten electrode constitutes

a galvanic couple. Hence the gold has a significant role in the reactivity of the system.

Gold is stable at the equilibrium potential and pH of the system [155] and thus will



two4(aW HWoJ

potential over two days. The diagrams are generated by CorrosionAnalyzer

S20 4,0 6.0 8,0 100 12,0 141(

Figure 7-13. Pourbaix diagram of tungsten in an electrolyte containing phosphate
buffered saline and 30 mM H202. The box shows range of open circuit
potential over two days. The diagrams are generated by CorrosionAnalyzer
1.3 Revision 1.3.33 by OLI Systems Inc.

not corrode; however, it provides an exclusive surface for the cathodic reaction and

increases the corrosion rate of the tungsten[51]. As the tungsten corrodes, gold that

was plated on the outer surface of the tungsten becomes further exposed. The surface

area of the gold increases, thereby increasing the exchange current for the cathodic

reaction, and consequently the anodic reaction rate must increase to compensate,

since the net current at equilibrium must be zero. This process may be modeled

using mixed potential theory. A diagram showing a proposed mixed potential theory

is given in Figure 7-14. For simplicity, only the dominant reactions (Equation 7-6 and

Equation 7-7) are included. It is assumed that the oxidation reaction occurs only on

the tungsten (anode), and the reduction reaction occurs only on the gold (cathode).

Figure 7-14 shows a hypothetical Evan's diagram consisting of the logarithm of current

as a function of potential. As the exchange current increases for the increasing cathode

surface area for the reduction of oxygen, a new corrosion current is established as


IncreasingAu surface area
+ 10,4

4- ..................................--..........-........-
S ecorr,1

corr,1 corr,4
log current

Figure 7-14. Effect of increased cathode surface area on galvanic interaction of tungsten
and gold.

shown by the shift from lcorr,1 to Icorr,4. Assuming the tungsten area stays constant, the

resulting corrosion rate for the tungsten is thereby increased. Also, the potential of the

system increases to more noble values.

Measurements of OCP over time verify the proposed effect of the galvanic couple.

Figure 7-15 displays the measured OCP over time for the gold-plated-tungsten

electrodes and tungsten electrodes in PBS. The gold-plated-tungsten system shows

a nonlinear trend toward more positive potentials compared to the tungsten system,

which shows a more stable OCP.

In summary, two factors control the corrosion rate of tungsten in biological saline

solutions. It was shown via the dependence on the concentration of oxygen that the

corrosion of tungsten is rate-limited by the cathodic reaction. Moreover, the corrosion

rate of the tungsten is increased by the gold-tungsten galvanic couple existing in

microelectrodes used for intracortical applications. The rates of tungsten corrosion in

three different systems are quantified next.


-0.36 -


LU -0.4 W only
I W/Au couple
0) -0.42

a -0.44


0 5 10 15 20 25

Figure 7-15. OCP over time for gold-plated tungsten and tungsten electrodes in PBS.

7.3.3 Rate of Tungsten Corrosion

Various methods exist to estimate the corrosion rate of a metal. Typical methods

include exposure testing where weight loss is measured, Tafel extrapolation, and

estimation of the polarization resistance via polarization methods or electrochemical

impedance spectroscopy.[51] The small size of our sample electrode does not lend

itself to weight loss measurements and Tafel extrapolation is easily confounded by the

presence of multiple reactions [51]. Extrapolation of the polarization resistance from EIS

data rather than data from polarization measurements is preferred in the system under

study since relatively shorter times are required for the impedance measurements. Calculation of Corrosion Rate

When using EIS, the polarization resistance may be estimated by subtracting

the low frequency asymptotic value from the high frequency asymptotic value on a

Nyquist plot. The corrosion rate is calculated from the polarization resistance via the

Stern-Geary equation, Equation 7-11 [51]. The polarization resistance is inversely


related to the corrosion current density via

R = A (7-11)
2.3icorr,(a + ) ( )

where 3a and 3c are the anodic and cathodic Tafel constants, respectively, and icorr is the

corrosion current density [51]. The corrosion current density is related to the corrosion

rate as follows.

rcorr = icor (7-12)
where a is the atomic weight, n is the oxidation number, and F is Faraday's constant.

Equation 7-12 gives a corrosion rate in terms of mass loss per unit area per time. To

obtain a rate in terms of units of penetration per time, Equation 7-12 is divided by the

density of the metal to achieve millimeters per year (mm/yr), for example.

If the Tafel constants are not known, the corrosion rate may still be approximated.

The Tafel constants range between 0.06 V and 0.12 V for /3 and between 0.12 and

infinity for 3c [51]. If the most extreme values are used, the corrosion rate varies by only

a factor of two. Comparison of Corrosion Rates

The corrosion rates of the three tungsten systems (tungsten in PBS, gold-plated

tungsten in PBS, and gold-plated tungsten in PBS and 30 mM H202) were quantified by

extrapolating the polarization resistance from EIS data. Complex nonlinear least squares

regression was used to fit the experimental data to the measurement model given in

Equation 7-13.[135]

Z = Ro Rk (7-13)
k= 1
The measurement model consists of a resistor, Ro, modeling the electrolyte resistance,

in series with k Voigt elements, where a Voigt element is a capacitor in parallel with

a resistor that has a characteristic time constant -rk = 27RC. Figure 7-16 shows the

Nyquist plots of the impedance response of the three systems. All electrodes were


polished immediately prior to submersion in the electrolyte and allowed to achieve a

steady state via a settling period of five minutes. Assuming there is no oxide on the the

surface of the electrodes due to adequate polishing, the corresponding corrosion rate

for each system is calculated and given in Table 7-3. A range of values for the corrosion

rates is given because of the uncertainty of the Tafel constants. The impedance results



o 1000

' 500

W only in PBS
W/Au in PBS
W/Au in PBS + H202

/ 0 \ 1000 2000
\\ (Q cm)

E 2(


0 10 20 30
Zr (Q cm2)

Figure 7-16. Nyquist plots used for calculation of the polarization resistance, Rp, for
three tungsten systems. The solid lines show the regression results using
Equation 7-13.

predict that the corrosion of tungsten in aerated PBS will corrode at a rate of 200-500

pm/yr. The galvanic couple of the gold-plated tungsten microwire acts to increase the

corrosion rate of the system in PBS alone to 300-700 pm/yr. However, the corrosion


Table 7-3. Corrosion rates for tungsten
System Rp (MQ cm2) rcorr (mm/yr)
W in PBS 1700 0.2 < rcorr > 0.5
W/Au in PBS 1200 0.3 < rcorr > 0.7
W/Au in PBS + H202 40 10 < rorr > 20

rates predicted for the gold-plated tungsten systems are for the initial electrode area; the

rates could increase as more of the gold surface becomes exposed as described

previously. The addition of 30 mM of hydrogen peroxide to the PBS significantly

increases the corrosion rate of a gold-plated tungsten electrode to 10,000-20,000

pm/yr. Previous EIS results showed that the corrosion mechanisms are rate limited by

the cathodic reaction. Thus, the corrosion rates for each system are dependent on the

concentrations of oxygen or hydrogen peroxide, respectively, and may also be controlled

by diffusion of the species.

7.3.4 Possible Electrochemical Reactions on Platinum

As shown in Figure 7-7, a faradaic reaction occurs on platinum electrodes in saline

solutions containing hydrogen peroxide. It is important to know what electrochemical

reactions could be occurring on the platinum electrode when implanted. A Pourbaix

diagram considering the chemical species in Table 7-4 was generated for platinum in an

electrolyte of PBS and 30 mM H202 and is shown in Figure 7-17. Curves representing

the stability of H202 are superimposed on the Pourbaix diagram. At potentials below

curve 1, the reduction of H202 is possible and above curve 2, the oxidation of H202 is

possible [155]. In the region where the two reactions overlap, hydrogen peroxide may

dissociate into water on a platinum surface. The box shows the range of measured

OCP for three platinum electrodes. Thus, the Pourbaix diagram shows that reduction

of H202 is possible as a cathodic reaction in this system. The Pourbaix diagram does

not, however, suggest possible corresponding anodic reactions. Brummer et al. propose

hydrogen adsorption as possible charge transfer pathways [156]. The assumed anodic



0.0 2.0 4 .0.0 80 0,0 12.0 14.0

Figure 7-17. Pourbaix diagram of platinum in phosphate buffered saline and 30 mM
hydrogen peroxide. The red box shows range of open circuit potential. The
diagrams are generated by CorrosionAnalyzer 1.3 Revision 1.3.33 by OLI
Systems Inc.

and cathodic reactions are given respectively by Equation 7-14 and Equation 7-10

Pt H Pt + H + e-. (7-14)

Cyclic voltammetry was used to further analyze the electrochemical reactions at

the platinum surface. Cyclic voltammograms of the platinum electrodes are shown for

scan rates of 50 and 100 mV/s. By comparing these results with literature [157, 158],

the two peaks labeled H, and Hs are inferred to be the weak and strong hydrogen

adsorption peaks. Thus, hydrogen adsorption is further substantiated by Figure 7-18,

as the hydrogen adsorption peaks occur near the open circuit potential ( 0.045 V versus

SHE) of the cell.

Hydrogen adsorption and hydrogen peroxide reduction, Equation 7-14 and

Equation 7-10, have no adverse effect on the platinum surface, hence it is expected to


Table 7-4. Species considered in calculation of the Pourbaix diagram presented as

Figure 7-17.
Aqueous Phase
Chloride ion(-1)
Dihydrogen orthophosphate(V) ion(-1)
Dihydrogen pyrophosphate(V) ion(-2)
Hydrogen chloride
Hydrogen ion(+1)
Hydrogen orthophosphate(V) ion (-2)
Hydrogen peroxide
Hydrogen peroxide ion(-1)
Hydrogen pyrophosphate(V) ion(-3)
Hydroxide ion(-1)
Orthophosphoric acid
Phosphate ion(-3)
Platinum ion(+2)
Platinum ion(+4)
Platinum(ll) chloride
Platinum(ll) hydroxide
Platinum(ll) monochloride ion(+1)
Platinum(ll) monohydroxide ion(+1)
Platinum(ll) tetrachloride ion(-2)
Platinum(ll) trichloride ion(-1)
Platinum(IV) chloride
Platinum(IV) dichloride ion(+2)
Platinum(IV) hexachloride ion(-2)
Platinum(IV) monochloride ion(+3)
Platinum(IV) pentachloride ion(-1)
Platinum(IV) trichloride ion(+1)
Potassium chloride
Potassium ion(+1)
Pyrophosphate ion(-4)
Pyrophosphoric(V) acid
Sodium ion(+1)
Trihydroqen pyrophosphate(V) ion(-1)

Solid Phase
Pentasodium triphosphorous decaoxide
Pentasodium triphosphorous decaoxide hexahydrate
Phosphorus pentoxide dimerr)
Platinum(ll) chloride
Platinum(ll) hydroxide
Platinum(IV) chloride
Potassium chloride
Potassium dihydrogen orthophosphate(V)
Potassium hydrogen orthophosphate(V) hexahydrate
Potassium hydrogen orthophosphate(V) trihydrate
Potassium hydrogen phosphate(V)
Potassium hydroxide
Potassium hydroxide dihydrate
Potassium hydroxide monohydrate
Potassium orthophosphate(V)
Potassium orthophosphate(V) heptahydrate
Potassium orthophosphate(V) trihydrate
Sodium chloride
Sodium dihydrogen orthophosphate dihydrate
Sodium dihydrogen orthophosphate monohydrate
Sodium dihydrogen orthoporthohosphate
Sodium hexachloroplatinate(IV) hexahydrate
Sodium hydrogen orthophosphate
Sodium hydrogen orthophosphate dihydrate
Sodium hydrogen orthophosphate dodecahydrate
Sodium hydrogen orthophosphate heptahydrate
Sodium hydroxide
Sodium hydroxide monohydrate
Sodium orthohosphate
Sodium orthophosphate hexahydrate
Sodium orthophosphate hydroxide dodecahydrate
Sodium orthophosphate monohydrate
Sodium orthophosphate octahydrate
Sodium pyrophosphate decahydrate

100 mV/s
50 mV/s

H Hs

-1 -0.5 0 0.5 1 1.5
voltage (v SHE)

Figure 7-18. Cyclic voltammogram c
PBS and 30 mM H202

)f a platinum electrode in an electrolyte containing


Vapor Phase
Hydrogen chloride
Hydrogen peroxide




_ I

be stable. Effects on the brain tissue are most likely benign. The reduction of hydrogen

peroxide to water may even lessen degradation to nearby cells or other parts of the

implanted microelectrode (e.g. the polymer insulation). Therefore, these results confirm

that platinum as a recording site is a good choice in biological solutions.

7.4 Conclusions

A strategy for ascertaining the nature of charge transfer including which faradaic

reactions are occurring on tungsten and platinum microelectrodes in physiologic

environments has been established. Graphical analysis of EIS data was used to

ascertain the presence of faradaic reactions and extrapolation of the polarization

resistance from the impedance data was used to estimate the corrosion rate of tungsten

microwires. Analysis of Pourbaix diagrams for each system at experimentally measured

open-circuit potentials corroborated the presence of tungsten corrosion and platinum

stability and provided possible electrochemical reactions for each system.

Tungsten was shown to corrode in physiological saline environments. The

dominant electrochemical reactions on tungsten in PBS are oxidation of tungsten

to the tungstic ion and reduction of oxygen, and the dominant reactions in PBS with

H202 are oxidation of tungsten to the tungstic ion and reduction of H202 to water.

The estimated corrosion rates for a bare-tungsten microelectrode and a gold-plated

tungsten microelectrode in physiological PBS are 300-700 pm/yr. The corrosion rate

of a gold-plated tungsten microelectrode in an electrolyte containing PBS and 30

mM H202 is 10,000-20,000 pm/yr. Thus, depending on the concentration of H202

encountered by the microelectrode in vivo, the corrosion rate could vary by two orders

of magnitude. These results most likely convey the worst-case scenario. Since it

was found that the corrosion rate was limited by the rate of the dominant cathodic

reaction, the concentration of the reactive species, 02 or H202, play a major role.

The concentration of dissolved oxygen in the PBS used in the in vitro experiments is

determined by the partial pressure of oxygen in the air (150 mmHg). In comparison,

the partial pressure of oxygen in the extracellular fluid of the cortex is between 20 and

35 mmHg [159, 160]. Also, as evidenced in the SEM images of the implanted tungsten

microwire, the biological film that forms on the electrode surface may act to impede

diffusion of chemical species and effectively control the corrosion rate. The corrosion

rate for in vivo situations may be estimated by the measurement of the recess depth

of the tungsten microwires on the UF microelectrode array used in the in vivo study.

As stated in Section 5.6.2, the average depth that the tungsten surface was recessed

from the original surface after an 87 day implant period was 24 pm. The corrosion rate

in an in vivo setting is then estimated to be approximately 100 pm/yr, which is of the

same order of magnitude as the in vitro estimation of tungsten corrosion rate of 300-700

pm/yr. The corrosion rate in the in vivo setting is less than in the in vitro setting because

of decreased diffusion due to the presence of a biological film and lower concentration of

available oxygen in the brain as compared to the air. Nonetheless, these results suggest

that tungsten should not be used in long-term implants.

Besides the possibility of local toxicity due to diffusion of tungstic ions into the

cortex, the corrosion of the tungsten electrodes may impede successful long-term

recording. It has been shown that a microelectrode must be placed less than 200 pm

from the cell body to record the action potential of a neuron [19]. Over time, corrosion

could distance the recording surface from the neuron such that the action potential could

not be measured. Also, as the tungsten microwire corrodes, a hollow tube made of the

insulation and possibly gold plating is formed. This tube could provide a reservoir for

cellular build-up that would hinder the diffusion of ionic species and effectively increase

the impedance at the electrode/electrolyte interface, which would ultimately decrease

the magnitude of the measured action potential. Thus, based on the results, after only

one year, the magnitude of the action potential on a tungsten electrode should be greatly



Platinum was shown to be a much better choice for intracortical microelectrodes.

Platinum is effectively unreactive in phosphate buffered saline solutions and although a

faradic response was seen in solution containing hydrogen peroxide, the electrochemical

reactions, reduction of H202 and hydrogen-atom plating, should have less adverse

effects on long-term recording. However, the effect of local changes in the pH due to

irreversible electrochemical reactions has not been considered in this study.



Engineering efforts have the potential to make rehabilitation for people suffering

from severe motor impairment possible. Neuroprostheses that incorporate brain-machine

interfaces are technologies being developed for such problems. One integral component

in a brain-machine interface is a reliable and effective recording system. The research

presented in this document is part of a larger project (Florida Wireless Integrated

Recording Electrode (FWIRE)) that addresses the engineering challenge of an

implantable recording system. This work provides an electrode and packaging

foundation for future generations of the FWIRE device for cortical recording applications.

The specific contributions of this work include the design and fabrication of an

implantable polyimide-based microelectrode platform integrated with an amplifier IC and

full characterization of the device including analysis of in vivo recording performance

and in vitro corrosion assessment of the tungsten microelectrodes. This chapter

summarizes the knowledge gained from the studies and provides suggestions for future


8.1 Summary of the UF-Microelectrode Array

The work presented in Chapters 4 and 5 was the first step in building a fully-implantable

wireless microelectrode array. Based on the review of existing intracortical microelectrode

array designs, a design including a micromachined polymer platform and hybrid-packaging

of microwire electrodes and ICs was chosen. The flexible polyimide platform connects

the electrode array to the electronics and external connector and allows out-of-plane

bending such that the electrode array may be implanted into the cortex while the

electronics reside on the top of the skull. The placement of interface electronics

on the skull, away from the implanted electrodes, makes power constraints on the

interface electronics less restrictive because tissue heating is less of a concern. The

flexible connection also reduces the transfer of strain to the implanted electrodes from

movement of the electronics platform. Hybrid-packaging of the microwire electrodes

allows for a relatively simple process flow and adaptability of other microwire materials

or microelectrode array constructs. The flexibility of the UF microelectrode array design,

both in form and function, provides advantages over existing microelectrode array


Bench-top results of the UF microelectrode array showed performance suitable

for in vivo recording. An average impedance of 50 kQ at 1 kHz was measured for

the tungsten microwire electrodes. The noise floor of the microelectrode array, only,

was less than 1 pVrms, and the noise floor of the microelectrode-amplifier system

was approximately 3.5 pVrms for a frequency range of 500 Hz to 6 kHz. The noise

floor of the microelectrode-amplifier system was statistically similar to the noise

floor of a commercial microwire array system (Tucker Davis Technologies). The

electrode-amplifier system was able to record and amplify accurately and as expected;

its transfer function and impulse response showed a linear system able to accurately

measure small signal waveforms representative of action potentials.

The in vivo testing of the UF microelectrode array also showed adequate recording

performance. The acute recording results of the microelectrode array without the

hybrid-packaged amplifier gave high signal to noise ratios (~7 or 17 dB). The acute

results of the microelectrode-amplifier system also showed high signal to noise ratios

(~12 or 21 dB) and relatively low noise (~4.5 pVrms). The recording results of the

microelectrode-amplifier system over a 42 day implant period did not have high signal

to noise ratios (on average the SNR was 4 or 12 dB); however, the percentage of active

electrodes over the implant duration stayed constant at 88% and 1 to 3 independent

neurons were measured on each active channel. Moreover, the same neurons were

able to be consistently measured over the implant duration. Termination of the implanted

system was due to inconsistent recordings after the 42 day period and inspection after

explanation showed that delamination of the polyimide had occurred on one side of the


device. Provisions that will encapsulate the device in a biocompatible silicone elastomer

will prevent delamination in future generations.

8.2 Summary of the Electrochemical Analysis

Charge transfer via electrochemical reactions must not be overlooked in chronic

recording devices. Most of the literature that considers electrochemical interactions

on electrodes used in vivo is for stimulation applications. Little emphasis is given

on the presence of electrochemical reactions in electrodes used for non-stimulating

applications (i.e. recording). Since no current is being injected into the system, it

is true that no electrochemical reactions are forced, however; even under electrical

equilibrium conditions faradaic charge transfer may exist. If electrochemical reactions

are thermodynamically stable at the steady-state potential and pH, then they will persist

and corrosion could occur.

A method to ascertain not only the presence of electrochemical reactions at

equilibrium, but which reactions are occurring on the electrodes was presented. The

method entailed analysis of Pourbaix diagrams, which requires measurement of

the open circuit potential, and EIS on ideal samples of the recording-site material.

The corrosion of tungsten-microwire electrodes used for intracortical recording

applications was analyzed and compared to results for platinum electrodes. Two

electrolytes modeling the chemistry of extracellular fluid in the brain in the absence and

presence of an inflammatory reaction were investigated for the in vitro electrochemical

analysis: 0.9% phosphate buffered saline (PBS) and 0.9% PBS containing 30 mM

hydrogen peroxide. The oxidation and reduction reactions responsible for corrosion

were found by measurement of the open-circuit potential and analysis of Pourbaix

diagrams. The corrosion rate was estimated from the polarization resistance, which

was extrapolated from the electrochemical impedance spectroscopy data. The results

showed that tungsten microwires with or without gold plating in an electrolyte of PBS

have a corrosion rates of 300-700 pm/yr. The corrosion rate for gold-plated tungsten


microwires in an electrolyte containing PBS and 30 mM H202 was accelerated to

10,000-20,000 pm/yr. In comparison, the extent of corrosion of the gold-plated tungsten

microwires used in the in vivo characterization of the UF microelectrode array was 24

pm, on average, after 87 days implanted. This result corresponds to a corrosion rate

of 100 pm/yr, which is in agreement with the results of the in vitro study since they

over-predict the corrosion rate because neither inhibited diffusion due to the biological

film nor the decreased value of oxygen concentration in the brain are accounted for.

Moreover, the magnitude of the measured extracellular potential is highly dependent

on the position of the electrode [33]. The corrosion rate of tungsten is of concern for a

long-term implant, since the active tungsten electrode surface will most likely recede out

of range of recording from a neuron after a few years due to corrosion. Platinum was

unreactive in solutions of PBS and reactive in solutions of PBS and hydrogen peroxide.

The reactivity in solutions containing hydrogen peroxide consisted of hydrogen-atom

plating and reduction of H202, which did not adversely affect the platinum surface nor

introduce unwanted species into the electrolyte.

Also, it was found that impedance spectra of the microelectrodes are dependent

on the quality of the seal of the insulator to the electrode. Artifacts due to an imperfect

insulator seal obscured the impedance response and made characterization of the

interface difficult. This work presented a quality control method via graphical analysis of

electrochemical impedance spectroscopy data. By comparing the impedance to ideal

electrode behavior, the quality of the microelectrode-to-insulation was assessed.

8.3 Suggestions for Future Work

Due to the cumbersome method of hybrid-packaging the ICs to the existing

substrate and subsequent poor yield, an altered fabrication process is needed that will

allow sequential testing of the packaging steps. It is suggested that the microelectrodes

be integrated to a polyimide-based cable as before, but the platform for the electronics

be made separately on top of a silicon or pyrex wafer for mechanical support. Similar


fabrication steps using ployimide micromachining and thin film deposition may still be

used for the platform for the electronics. Then, the cable integrated with the electrodes

can be bonded to the electronics platform. This method allows easier testing of the

electronics before the electrodes are secured. Also, the quality of the flip-chip bonds

have the potential to be assessed if the platform for the electronics is separated from the


Tungsten should not be used in future designs because of its susceptibility to

corrosion. The advantages of using tungsten wire for intracortical microelectrodes are

because it is rigid enough to be implanted without buckling and it can be manually

positioned easily without bending, making fabrication of the arrays possible. However,

other metals could have similar characteristics. To insure probe insertion into the brain

tissue without buckling or bending, the insertion force must be less than the critical

loading force for a given electrode. The critical loading force may be derived using

Euler-Bernoulli beam theory. The critical loading force is expressed in Equation 8-1 for a

cylindrical column that is clamped on one side and pinned at the other.

For = 20 (8-1)

where E is Young's modulus and I is the area moment of inertia, and L is the length

of the column [161]. Table 8-1 shows the Young's modulus and critical loading force

for 50 pm diameter tungsten, platinum, iridium, and platinum-iridium (80% Pt, 20% Ir)

microwires that are 3 mm long. Literature prescribes an insertion force on the order of

Table 8-1. Critical Loading Force for Metal Microwires
Microwire Material E (GPa) Fcr (mN)
Tungsten 411 283
Platinum 168 116
Iridium 528 363
Platinum-Iridium (80%/20%) 198 136

1 mN into the sub-dural cortex for electrodes comparable to the size of the electrodes in


this study [162, 163]. The results in Table 8-1 suggest that all metals listed would have

sufficient material strength for insertion into the cortex as their critical loading force is

two orders of magnitude higher than what is needed for insertion. Thus, a metal other

than tungsten should be used for the next generation of devices.

Platinum-iridium is more rigid than platinum and may be a better choice for

the UF microelectrode array in terms of mechanical assembly. Its electrochemical

characteristics were not formally explored in this study; however, preliminary experiments

suggest that it will behave much like platinum. The Pourbaix diagrams for Ir and Pt show

no reactions at open circuit potentials measured for the Pt-lr electrode [155].

The electrochemical assessment of microelectrodes is not easily performed in vivo,

thus electrolytes that mimic what is seen in vivo are needed. Future electrochemical

assessment of other recording-site materials should include hydrogen peroxide since it

was shown to make appreciable differences in the cases of tungsten and platinum. The

corrosion rate of the tungsten increased by two orders of magnitude in the presence of

H202 and elicited faradaic reactions on the platinum electrode. In the platinum case, the

faradaic reaction did not corrode the electrode nor introduce unwanted electrochemical

by-products in the solution. Instead, reduction of hydrogen peroxide to water resulted.

The choice of metals that are electrochemically active but not corrosive could be chosen

to lessen cellular damage by reactive oxygen species. It is also advised to perform

an in vivo study of the electrochemistry at metal microelectrodes to confirm that small

amounts of hydrogen peroxide added to PBS is a good model for the extracellular

chemistry during an immune response.



[1] M. E. Orazem and B. Tribollet, Electrochemical Impedance Spectroscopy.
Hoboken, NJ: John Wiley and Sons, Inc., 2008.

[2] "Paralysis resource center," World Wide Web, http://www.paralysis.org/site/c.
erJMJUOxFmH/b.1169107/k.BE3A/Home.htm, 2008.

[3] "Epilepsy foundation," World Wide Web, http://www.epilepsyfoundation.org/about/
statistics.cfm, 2009.

[4] E. C. Leuthardt, S. Gerwin, D. Moran, and J. Ojemann, "The emerging world of
motor neuroprosthetics: A neurosurgical perspective," Neurosurgery, vol. 59,
no. 1,2006.

[5] F Mussa-lvaldi and L. Miller, "Brain-macine interfaces: commputational demands
and clinical needs meet basic neuroscience," Trends in Neuroscience, vol. 26,
no. 6, pp. 329-334, 2003.

[6] M. Hodaie, R. Wennberg, J. Dostrovsky, and A. Lozano, "Chronic anterior
thalamus stimulation for intractable epilepsy," Epilepsia, vol. 43, no. 6, pp.
603-608, 2002.

[7] E. Hauerman, "The deadly five," Popular Science, vol. October, pp. 47-49, 2007.

[8] G. Mone, "Happiness is a warm electrode," Popular Science, vol. October, pp.

[9] D. Tweney, "Dean kamen's robot arm grabs more publicity," World Wide Web,
http://blog.wired.com/gadgets/2008/05/dean-kamens-rob.html, 2008.

[10] A. Schwartz, X. T Cui, D. Weber, and D. Moran, "Brain-controlled interfaces:
Movement restoration with neural prosthetics," Neuron, vol. 52, pp. 205-220,

[11] J. K. Chapin, K. A. Moxon, R. S. Markowitz, and M. A. L. Nicolelis, "Real-time
control of a robot arm using simultaneously recorded neurons in the motor cortex,"
vol. 2, no. 7, pp. 664-670, 1999.

[12] J. Wessberg, C. Stambaugh, J. Krallk, P. Beck, M. Laubach, J. Chapin, J. Kim,
S. Biggs, M. Srinlvasan, and M. Nicolelis, "Real-time prediction of hand trajectory
by ensenbles of cortical neurons in primates," Nature, vol. 408, no. 16, pp.
361-365, 2000.

[13] D. M. Taylor, S. I. H. Tillery, and A. B. Schwartz, "Direct cortical control of 3d
neuroprosthetic devices," Science, vol. 296, no. 5574, pp. 1829-1832, June 7,
2002 2002.


[14] S. Musallam, B. D. Corneil, B. Greger, H. Scherberger, and R. A. Andersen,
"Cognitive control signals for neural prosthetics," Science, vol. 305, pp. 258-262,
July 9, 2004 2004.

[15] J. M. Carmena, M. A. Lebedev, R. E. Crist, J. E. O'Doherty, D. M. Santucci, D. F.
Dimitrov, P. G. Patil, C. S. Henriquez, and M. A. L. Nicolelis, "Learning to control a
brain-machine interface for reaching and grasping by primates," PLoS Biol, vol. 1,
no. 2, p. e42, 2003.

[16] M. Velliste, S. Perel, M. C. Spalding, A. S. Whitford, and A. B. Schwartz, "Cortical
control of a prosthetic arm for self-feeding," Nature, vol. 453, no. 7198, pp.

[17] L. R. Hochberg, M. D. Serruya, G. M. Friehs, J. A. Mukand, M. Saleh, A. H.
Caplan, A. Branner, D. Chen, R. D. Penn, and J. P. Donoghue, "Neuronal
ensemble control of prosthetic devices by a human with tetraplegia," Nature,
vol. 442, no. 7099, pp. 164-171, 2006.

[18] A. Gunduz, M. C. Ozturk, J. C. Sanchez, and J. C. Principe, "Echo state networks
for motor control of human ecog neuroprosthetics," ser. Proceedings of the 3rd
International IEEE EMBS Conference on Neural Engineering, Kohala Coast, HI,
United States, 1999, pp. 514-517.

[19] D. Henze, Z. Borhegyi, J. Sciscvari, A. Mamiya, K. Harris, and G. Buzaki,
"Intracellular features predicted by extracellular recordings in the hippocampus in
vivo," The Journal of Neurophysiology, vol. 84, pp. 390-400, 2000.

[20] V. Polikov, P. Tresco, and W. Reichert, "Response of brain tissue to chronically
implanted neural electrodes," Journal of Neuroscience Methods, vol. 148, pp.
1-18, 2005.

[21] R. Vetter, J. Williams, J. Hetke, E. Nunamaker, and D. R. Kipke, "Chronic neural
recording using silicon-substrate microelectrode arrays implanted in cerebral
cortex," IEEE Trans. Biomed. Eng., vol. 51, no. 6, pp. 896-904, 2004.

[22] P. J. Rousche and R. A. Normann, "Chronic recording capability of the utah
intracortical electrode array in cat sensory cortex," Journal of Neuroscience
Methods, vol. 82, no. 1, pp. 1-15, 1998.

[23] J. C. Williams, R. L. Rennaker, and D. R. Kipke, "Long-term neural recording
characteristics of wire microelectrode arrays implanted in cerebral cortex," Brain
Research Protocols, vol. 4, no. 3, pp. 303-313, 1999, tY JOUR.

[24] X. D. Liu, D. B. McCreery, L. A. Bullara, and W. F. Agnew, "Evaluation of the
stability of intracortical microelectrode arrays," leee Transactions on Neural
Systems and Rehabilitation Engineering, vol. 14, no. 1, pp. 91-100, 2006.

[25] R. Bashirullah, J. Harris, J. Sanchez, T. Nishida, and P. Jose, "Florida wireless
implantable recording electrodes (fwire) for brain machine interfaces," 2007.

[26] E. Patrick, M. Ordonez, N. Alba, J. C. Sanchez, and T. Nishida, "Design and
fabrication of a flexible substrate microelectrode array for brain machine
interfaces," in Engineering in Medicine and Biology Society, 2006. EMBS '06.
28th Annual International Conference of the IEEE, 2006, pp. 2966-2969.

[27] E. Patrick, V. Sankar, W. Rowe, S.-F. Yen, J. C. Sanchez, and T. Nishida, "Flexible
polymer substrate and tungsten microelectrode array for an implantable neural
recording system," in Engineering in Medicine and Biology Society, 2008. EMBS
'08. 30th Annual International Conference of the IEEE, 2008, pp. 3158-3161.

[28] E. Patrick, V. Sankar, W. Rowe, J. C. Sanchez, and T. Nishida, "Design of an
implantable intracortical microelectrode system for brain-machine interfaces," in
Neural Engineering, 2009. Conference Proceedings. 4th International IEEE EMBS
Conference on, 2009.

[29] E. Patrick, V. Sankar, W. Rowe, J. C. Sanchez, and T. Nishida, "An implantable
integrated low-power amplifier-microelectrode array for brain-machine interfaces,"
in Engineering in Medicine and Biology Society, 2010. EMBS '10. 32nd Annual
International Conference of the IEEE, 2010.

[30] E. Patrick, M. Orazem, J. C. Sanchez, and T. Nishida, "Corrosion of tungsten
microelectrodes used in neural recording applications," J of Neuroscience
Methods, to be submitted.

[31] E. Patrick, M. Orazem, T. Nishida, and V. Vivier, "Use of impedance spectroscopy
to assess the quality of microelectrode fabrication," Journal of the Electrochemical
Society, to be submitted.

[32] T. Trappenberg, Fundamentals of Computational Neuroscience. New York, NY:
Oxford University Press, 2002.

[33] G. R. Holt and C. Koch, "Electrical interactions via the extracellular potential near
cell bodies," Journal of Computational Neuroscience, vol. 6, no. 2, pp. 169-184,

[34] K. Drake, K. D. Wise, J. Farraye, D. J. Anderson, and S. Bement, "Performance
of planar multisite microprobes in recording extracellular single-unit intracortical
activity," IEEE Trans. Biomed. Eng., vol. 35, no. 9, pp. 719-732, 1988.

[35] C. L. Lopreore, T. M. Bartol, J. S. Coggan, D. X. Keller, G. E. Sosinsky, M. H.
Ellisman, and T. J. Sejnowski, "Computational modeling of three-dimensional
electrodiffusion in biological systems: Application to the node of ranvier," vol. 95,
no. 6, pp. 2624-2635, 2008, 0006-3495.


[36] J. Newman, Electrochemical Systems. Hoboken, NJ: John Wiley and Sons, Inc.,

[37] M. Salcman and M. Bak, "Design, fabrication and in-vivo behavior of chronic
recording intracortical microelectrodes," IEEE Trans. Biomed. Eng., vol. 20, pp.
253-260, 1973.

[38] M. Salcman and M. Bak, "A new chronic recording intracortical microelectrode,"
Med. Biol. Eng., vol. January, pp. 42-50, 1976.

[39] "Tucker davis technologies," World Wide Web, http://www.tdt.com/products/MW1 6.
htm, 2008.

[40] "Microprobe, inc." World Wide Web, http://www.microprobes.com/, 2008.

[41] K. Wise and J. Starr, "An integrated-circuit approach to extracellular
micro-electrodes," IEEE Trans. Biomed. Eng., vol. 17, pp. 238-247, 1970.

[42] K. Najafi, K. Wise, and T. Mochizuki, "A high-yield ic-compatible multichannel
recording array," IEEE Trans. Electron Devices, vol. ED-22, pp. 230-241, 1985.

[43] K. Najafi and K. D. Wise, "An implantable multielectrode array with on-chip signal
processing," IEEE Journal of Solid State Circuits, vol. sc-21, pp. 1035-1044, 1986.
[44] J. Ji and K. D. Wise, "An implantable cmos circuit interface for multiplexed
microelectrode recording arrays," IEEE Journal of Solid State Circuits, vol. 27,
no. 3, pp. 433-443,1992.

[45] J. Heteke, J. Lund, K. Najafi, K. Wise, and D. Anderson, "Silicon ribbon cables for
chronically implantable microelectrode arrays," IEEE Trans. Biomed. Eng., vol. 41,
pp. 314-321, 1994.

[46] A. Hoogerwerf and K. Wise, "A three-dimensional microelectrode array for chronic
neural recording," IEEE Trans. Biomed. Eng., vol. 41, pp. 1136-1146, 1994.

[47] K. D. Wise, D. J. Anderson, J. F. Hetke, D. R. Kipke, and K. Nijafi, "Wireless
implantable microsystems: High density electronic interfaces to the nervous
system," Proceedings of the IEEE, vol. 92, no. 76-97, 2004.

[48] Y. Yao, M. Gulari, B. Casey, J. A. Wiler, and K. D. Wise, "Silicon microelectrodes
with flexible integrated cables for neural implant applications," May 2-5 2007.

[49] K. Wise, A. Sodagar, Y. Yao, M. Gulari, and K. Najafi, "Microelectrodes,
microelectronics, and implantable neural microsystems," Proceedings of the
IEEE, vol. 96, pp. 1184-1202, 2008.


[50] P. K. Campbell, K. E. Jones, R. J. Huber, K. W. Horch, and R. A. Norman, "A
silicon-based three- dimensional neural interface: Manufacturing processes for
a intracortical electrode array," IEEE Trans. Biomed. Eng., vol. 38, pp. 758-768,

[51] D. A. Jones, Principles and Prevention of Corrosion. New York, NY: Maxmilliam
Publishing Co., 1992.

[52] A. Branner, R. B. Stein, and R. A. Normann, "Selective stimulation and recording
using a slanted multielectrode array," Annual International Conference of the IEEE
Engineering in Medicine and Biology Proceedings, vol. 1, p. 377, 1999.

[53] R. Bhandari, S. Negi, L. Rieth, M. Toepper, S. Kim, M. Klein, H. Oppermann, R. A.
Normann, and F. Solzbacher, "System integration of the utah electrode array using
a biocompatible flip chip under bump metallization scheme," ser. Proceedings of
SPIE The International Society for Optical Engineering, vol. 6525. San Diego,
CA, United States: SPIE, Bellingham WA, WA 98227-0010, United States, 2007,
p. 65251.

[54] S. Kim, P. Tathireddy, R. A. Normann, and F. Solzbacher, "Thermal impact of an
active 3-d microelectrode array implanted in the brain," IEEE Transactions on
Neural Systems and Rehabilitation Engineering, vol. 15, no. 4, pp. 493-501, 2007.

[55] P. Norlin, M. Kindlundh, A. Mouroux, K. Yoshida, and U. G. Hofmann, "A 32-site
neural recording probe fabricated by drie of soi substrates," Journal of Microme-
chanics and Microengineering, vol. 12, no. 4, pp. 414-419, 2002.

[56] M. Kindlundh, P. Norlin, and U. G. Hofmann, "A neural probe process enabling
variable electrode configurations," Sensors and Actuators B: Chemical, vol. 102,
no. 1, pp. 51-58, 2004.

[57] J. Muthuswamy, M. Okandan, and N. Jackson, "Single neuronal recordings using
surface micromachined polysilicon microelectrodes," Journal of Neuroscience
Methods, vol. 142, no. 1, pp. 45-54, 2005.

[58] P. Rousche, D. Pellinen, D. Pivin, J. Williams, R. Vetter, and D. Kipke, "Flexible
polyimide-based intracortical electrode arrays with bioactive capability," IEEE
Trans. Biomed. Eng., vol. 48, no. 3, pp. 361-371, 2001.

[59] D. O'Brien, T Nichols, and M. Allen, "Flexible microelectrode arrays with integrated
insertion devices," IEEE MEMS, pp. 216-219, 2001.

[60] D. S. Pellinen, T Moon, R. J. Vetter, R. Miriani, and D. R. Kipke, "Multifunctional
flexible parylene-based intracortical microelectrodes," ser. Annual International
Conference of the IEEE Engineering in Medicine and Biology Proceedings, vol. 7
S, Shanghai, China, 2005, pp. 5272-5275.

[61] J. Seymour and D. Kipke, "Neural probe design for reduced tissue encapsulation
in cns," Biomaterials, vol. 28, pp. 3594-3607, 2007.

[62] K. Lee, J. He, R. Clement, S. Massia, and B. Kim, "Biocompatible
benzocyclobutene (bcb)-based neural implants with micro-fluidic channel,"
Biosensors and Bioelectronics, vol. 20, no. 2, pp. 404-407, 2004.

[63] T. Stieglitz and M. Gross, "Flexible biomems with electrode arrangements on front
and back side as key component in neural prostheses and biohybrid systems,"
Sensors and Actuators B-Chemical, vol. 83, no. 1-3, pp. 8-14, 2002.

[64] T. Stieglitz, M. Schuettler, and K. P. Koch, "Implantable biomedical microsystems
for neural prostheses," IEEE Engineering in Medicine and Biology Magazine,
vol. 24, no. 5, pp. 58-65, 2005.

[65] S. Takeuchi, T. Suzuki, K. Mabuchi, and H. Fujita, "3d flexible multichannel neural
probe array," Journal of Micromechanics and Microengineering, vol. 14, pp.
104-107, 2004.

[66] T. Suzuki, D. Ziegler, K. Mabuchi, and S. Takeuchi, "Flexible neural probes with
micro-fluidic channels for stable interface with the nervous system," ser. 26th
Annual Internationals Conference of the IEEE EMBS, San Franscico, CA, USA,
September 1-5 2004, pp. 4057-4058.

[67] Y Kato, M. Nishino, I. Saito, T. Suzuki, and K. Mabuchi, "Flexible intracortical
neural probe with biodegradable polymer for delivering bioactive components," ser.
Proceedings of 2006 International Conference on Microtechnologies in Medicine
and Biology, Okinawa, Japan, 2006, pp. 143-146.

[68] Y Kato, I. Saito, T. Hoshino, T. Suzuki, and K. Mabuchi, "Preliminary study of
multichannel flexible neural probes coated with hybrid biodegradable polymer," ser.
Annual International Conference of the IEEE Engineering in Medicine and Biology
Proceedings, New York, NY, United States, 2006, pp. 660-663.

[69] K. C. Cheung, P. Renaud, H. Tanila, and K. Djupsund, "Flexible polyimide
microelectrode array for in vivo recordings and current source density analysis,"
Biosensors and Bioelectronics, vol. 22, no. 8, pp. 1783-1790, 2007.

[70] G. A. G. D. J. M. J. C. P. W. V. S. D. M. T. P. A. T. Theodore W. Berger (Chair),
John K. Chapin, "Wtec panel report on international assessment of research and
development in brain-computer interfaces," WORLD TECHNOLOGY EVALUATION

[71] R. Carter and J. Houk, "Multiple single-unit recordings for the cns using thin-film
electrode arrays," IEEE Trans Rehab Eng, vol. 1, no. 3, pp. 175-184, 1993.


[72] R. A. Normann, P. K. Campbell, and K. E. Jones, "Silicon based electrode array
for intracortical stimulation: Structural and electrical properties," ser. Proceedings
of the Annual Conference on Engineering in Medicine and Biology, vol. 11 pt
3. Seattle, WA, USA: Publ by Alliance for Engineering in Medicine and Biology,
Washington, DC, USA, 1989, pp. 939-940.

[73] D. Szarowski, M. Andersen, S. Retterer, A. Spence, M. Isaacson, H. Craighead,
J. Turner, and W. Smith, "Brain responses to micro-machined silicon devices,"
Brain Research, vol. 983, pp. 23-35, 2003.

[74] R. Biran, D. C. Martin, and P. Tresco, "Neuronal cell loss accompanies the brain
tissue response to chronically implanted silicon microelectrode arrays," Experi-
mental Neurology, vol. 195, pp. 115-126, 2005.

[75] B. Burke and C. Lewis, The Macrophage. Oxford: Oxford Medical Publications,

[76] J. Turner, W. Shain, D. Szarowski, M. Andersen, S. Martins, M. Isaacson, and
H. Craighead, "Cerebral astrocyte response to micromachined silicon implants,"
Experimental Neurology, vol. 156, pp. 33-49, 1999.

[77] D. Merrill and P. Tresco, "Impedance characterization of microarray recording
electrodes in vitro," IEEE Tran. Biomed Eng., vol. 52, pp. 1960-1965, 2005.

[78] A. Reynolds, C. Laurie, R. Mosley, and H. Gendelman, "Oxidative stress and
the pathogenesis of neurodegenerative disorders," International Review of
Neurobiology, vol. 82, pp. 297-321, 2007.

[79] R. Biran, D. C. Martin, and P. Tresco, "The brain tissue response to implanted
silicon microelectrode arrays is increased when the device is tethered to the skull,"
Journal of Biomedical Materials Research Part A, vol. 82, no. 1, pp. 169-178,

[80] Y. Kim, R. Hitchcock, M. Bridge, and P. Tresco, "Chronic response of adult
rat brain tissue to implants anchored to the skull," Biomaterials, vol. 25, pp.
2229-2237, 2004.

[81] S. Ranson, The Anatomy of the Nervous System. Philadelphia, PA: W. B.
Saunder Company, 1945.

[82] H. Lee, R. Bellamkonda, W. Sun, and M. Levenston, "Biomechanical analysis of
silicon microelectrode-induced strain in the brain," J Neural Eng, vol. 2, pp. 81-89,

[83] J. Subbaroyan, D. Martin, and D. Kipke, "A finite-element model of the mechanical
effects of implantable microelectrodes in the cerbral cortex," J Neural Eng, vol. 2,
pp. 103-113, 2005.


[84] M. P. Hughes, K. Bustamante, D. Banks, and D. J. Ewins, "Effects of electrode
size on the preformance of neural recording microelectrodes," in 1st Annual
International IEEE-EMBE, Lyon, France, 2000.

[85] S. F Lempka, M. D. Johnson, D. W. Barnett, M. A. Moffitt, K. J. Otto, D. R. Kipke,
and C. C. Mclntyre, "Optimization of microelectrode design for cortical recording
based on thermal noise considerations," in Engineering in Medicine and Biology
Society, 2006. EMBS '06. 28th Annual International Conference of the IEEE,
2006, pp. 3361 -3364.

[86] J. J. Jacobs, J. L. Gilbert, and R. M. Urban, "Current concepts review corrosion
of metal orthopaedic implants," pp. 268-82, February 1, 1998 1998.

[87] A. Norlin, J. Pan, and C. Leygral, "Investigation of electrochemical behavior for
stimulating/sensing materials for pacemaker electrode applications," J of the
ELectrochemical Society, vol. 152, no. 2, pp. J7-J15, 2005.

[88] A. Norlin, J. Pan, and C. Leygral, "Investigation of interfacial capacitance of Pt,
Ti, and TiN coated electrodes by electrochemical impedance spectroscopy,"
Biomolecular Engineering, vol. 19, pp. 67-71, 2002.

[89] S. B. Brummer and M. J. Turner, "Electrochemical considerations for safe electrical
stimulation of the nervous system with platinum electrodes," IEEE Transactions on
Biomedical Engineering, vol. BME-24, no. 1, pp. 59-63, 1977.

[90] D. R. Merrill, M. Bikson, and J. G. R. Jefferys, "Electrical stimulation of
excitable tissue: Design of efficacious and safe protocols," Journal of Neuro-
science Methods, vol. 141, no. 2, pp. 171-198, 2005, 0165-0270 doi: DOI:

[91] J. Bockris and A. Reddy, Modern Electrochemistry. New York, NY: Plenum Press,

[92] A. Hassibi, R. Navid, R. Dutton, and T. Lee, "Comprehensive study of noise
processes in electrode electrolyte interfaces," Jornal of Applied Physics, vol. 15,
pp. 1074-1082, 2004.

[93] C. Gabrielli, "Identification of electrochemical processes by frequency response,"
Schlumberger Technologies, Tech. Rep. Technical report Number 004/83, 1984.

[94] S. Bothra, H. Sur, and V. Liang, "A new failure mechanism by corrosion of
tungsten in a tungsten plug process," Microelectronics and Reliability, vol. 39,
no. 1, pp. 59-68, 1999.

[95] M. Peuster, C. Fink, and C. von Schnakenburg, "Biocompatibility of corroding
tungsten coils: in vitro assessment of degradation kinetics and cytotoxicity on
human cells," Biomaterials, vol. 24, pp. 4057-4061, 2003.


[96] J. Sanchez, N. Alba, T. Nishida, C. Batich, and P Carney, "Structural modifications
in chronic microwire electrodes for cortical neuroprosthetics: A case study," IEEE
Trans. on Neural Syst. Rehab. Eng., pp. 217-221, 2006.

[97] R. S. Lillard, G. S. Kanner, and D. P. Butt, "The nature of oxide films on tungsten
in acidic and alkaline solutions," Journal of The Electrochemical Society, vol. 145,
no. 8, pp. 2718-2725, 1998.

[98] M. Anik, "ph-dependent anodic reaction behavior of tungsten in acidic phosphate
solutions," Electrochimica Acta, vol. 54, no. 15, pp. 3943-3951, 2009.

[99] M. Anik and K. Osseo-Asare, "Effect of ph on the anodic behavior of tungsten,"
Journal of The Electrochemical Society, vol. 149, no. 6, pp. B224-B233, 2002.

[100] J. W. Johnson and C. L. Wu, "The anodic dissolution of tungsten," Journal of The
Electrochemical Society, vol. 118, no. 12, pp. 1909-1912, 1971.

[101] G. S. Kelsey, "The anodic oxidation of tungsten in aqueous base," Journal of The
Electrochemical Society, vol. 124, no. 6, pp. 814-819, 1977.

[102] C. de Haro, R. Mas, G. Abadal, J. Munoz, F. Perez-Murano, and C. Dominguez,
"Electrochemical platinum coatings for improving performance of implantable
microelectrode arrays," Biomaterials, vol. 23, no. 23, pp. 4515-4521, 2002.

[103] D. R. Kipke, "Silicon-substrate intracortical microelectrode arrays for long-term
recording of neuronal spike activity in cerebral cortex," IEEE Trans. Rehab. Eng.,
vol. 11, pp. 151-155, 2003.

[104] E. Maynard, C. Nordhausen, and R. A. Normann, "The Utah intracortical electrode
array: A recording structure for potential brain-computer interfaces," Electroen-
cephalography and Clinical Neurophysiology, vol. 102, pp. 228-239, 1997.

[105] J. Pan, D. Theirry, and C. Leygraf, "Electrochemical impedance spectroscopy
study of the passive oxide film on titanium for implant application," Electrochemica
Acta, vol. 41, pp. 1143-1153, 1996.

[106] C. Fonesca and M. Barbosa, "Corrosion behavior of titanium in biofluids
containing h2o2 studied by electrochemical impedance spectroscopy," Corro-
sion Science, vol. 43, pp. 547-559, 2001.

[107] S. B. Hall, E. A. Khudaish, and A. L. Hart, "Electrochemical oxidation of hydrogen
peroxide at platinum electrodes. part iii: Effect of temperature," Electrochimica
Acta, vol. 44, no. 14, pp. 2455-2462, 1999.

[108] S. B. Hall, E. A. Khudaish, and A. L. Hart, "Electrochemical oxidation of hydrogen
peroxide at platinum electrodes. part i: An adsorption-controlled mechanism,"
Electrochimica Acta, vol. 43, no. 5-6, pp. 579-588, 1998.


[109] S. B. Hall, E. A. Khudaish, and A. L. Hart, "Electrochemical oxidation of hydrogen
peroxide at platinum electrodes. part ii: effect of potential," Electrochimica Acta,
vol. 43, no. 14-15, pp. 2015-2024, 1998.

[110] S. B. Hall, E. A. Khudaish, and A. L. Hart, "Electrochemical oxidation of hydrogen
peroxide at platinum electrodes. part iv: phosphate buffer dependence," Elec-
trochimica Acta, vol. 44, pp. 4573-4582, 1999.

[111] S. Boppart, B. Wheeler, and C. Wallace, "A flexible perforated microelectrode
array for extended neural recordings," IEEE Trans. Biomed. Eng., vol. 39, no. 1,
pp. 37-42, 1992.

[112] A. Owens and et al, "Multi-electrode aray for measuring evoked potentials for
surface of ferret primary auditory cortex," J. Neurosci. Meth., vol. 58, pp. 209-220,

[113] G. E. Loeb, M. J. Bak, and E. M. Schmidt, "Parylene as a chronically stable,
reproducible microelectrode insulator," IEEE Trans. on Biomed. Eng., vol. 24,
no. 2, pp. 121-128, 1977.

[114] E. M. Schmidt, M. J. Bak, and J. S. Mclntosh, "Long-term chronic recording from
cortical neurons," Experimental Neurology, vol. 52, no. 3, pp. 496-506, 1976.

[115] E. M. Schmidt and J. S. Mclntosh, "Long-term implants of parylene-c coated
microelectrodes," Med. Biol. Eng. Comput., vol. 26, pp. 96-101, 1988.

[116] L. Geddes and R. Roeder, "Criteria for the selection of materials for implanted
electrodes," Annals of Biomedical Engineering, vol. 31, pp. 879-890, 2003.

[117] M. Orazem, "A systematic approach toward error structure identification for
impedance spectroscopy," J. Electroanalytical Chemistry, vol. 572, pp. 317-327,

[118] M. Stecker and T. Patterson, "Electrode impedance in neurophysiologic
recordings: 1. theroy and intrinsic contributions to noise," Am. J. END Technol.,
vol. 38, pp. 174-198, 1998.

[119] G. Paxinos, The rat brain in stereotaxic coordinates. Sydney: Academic Press,

[120] S. Kim, R. Bhandari, M. Klein, S. Negi, L. Rieth, P. Tathireddy, M. Toepper,
H. Oppermann, and F. Solzbacher, "Integrated wireless neural interface based on
the Utah electrode array," Biomedical Microdevices, vol. 11, no. 2, pp. 453-466,


[121] Y K. Song, D. A. Borton, S. Park, W. R. Patterson, C. W. Bull, F. Laiwalla,
J. Mislow, J. D. Simeral, J. P. Donoghue, and A. V. Nurmikko, "Active
microelectronic neurosensor arrays for implantable brain communication
interfaces," IEEE Transactions on Neural Systems and Rehabilitation Engineering,
vol. 17, no. 4, pp. 339-345, 2009.

[122] R. Bashirullah, J. Harris, J. Sanchez, T. Nishida, and P. Jose, "Florida wireless
implantable recording electrodes (fwire) for brain machine interfaces," in IEEE
International Symposium on Circuits and Systems, 2007.

[123] A. Sodagar, G. Perlin, Y. Yao, K. Wise, and K. Najafi, "An implantable microsystem
for wireless multi-channel cortical recording," in Transducers 2007, 2007, pp.

[124] J. Harris, J. Principe, J. Sanchez, D. Chen, and C. She, "Pulse-based signal
compression for implanted neural recording systems," in IEEE ISCAS, 2008, pp.

[125] A. Legatt, "Imparment of common mode rejection by mismatched electrode
impedances: quantitative analysis," Am. J. EEG Tech., vol. 35, pp. 296-302, 1995.

[126] B. Hirschorn, B. Tribollet, and M. E. Orazem, "On the selection of the perturbation
amplitude required to avoid nonlinear effects in impedance measurements," Israel
Journal of Chemistry, vol. 48, pp. 133-142, 2008.

[127] R. Meyer, S. Cogan, T.Nguyen, and R. Rauh, "Electrodeposited iridium oxide for
neural stimulation and recording electrodes," IEEE Trans. Neural Syst. Rehab.
Eng., vol. 9, no. 1, pp. 2-10, 2001.

[128] J. Yang and D. C. Martin, "Microporous conduction polymers on neural
microelectrode arrays ii. physical characterization," Sensors and Actuators A,
vol. 113, pp. 204-211, 2004.

[129] X. Cui and D. C. Martin, "Electrochemical deposition and characterization of
ploy(3,4-ethylenedioxythiophene) on neural microelectrode arrays," Sensors and
Actuators B, vol. 89, pp. 92-102, 2003.

[130] M. Ates and A. S. Sarac, "Electrochemical impedance spectroscopy of
poly[carbazole-co-n-p-tolylsulfonyl pyrrole] on carbon fiber microelectrodes,
equivalent circuits for modelling," Progress in Organic Coatings, vol. 65, pp.
281-287, 2009.

[131] D. T. Price, A. R. A. Rahman, and S. Bhansali, "Design rule for optimization
of microelectrodes used in electric cell-substrate impedance sensing (ecis),"
Biosensors and Bioelectronics, vol. 24, pp. 2071-2076, 2009.


[132] Y. Zhang, H. Wang, J. Nie, Y. Zhang, G. Shen, and R. Yu, "Individually
addressable microelectrode arrays fabricated with gold-coated pencil graphite
for multiplexed and high sensitive impedance immunoassays," Biosensors and
Bioelectronics, vol. 25, pp. 34-40, 2009.

[133] M. E. Orazem, N. Pebere, and B. Tribollet, "Enhanced graphical representation of
electrochemical impedance data," J. Electrochem. Soc., vol. 153, pp. B129-B136,

[134] G. Brug, A. V. den Eeden, M. Sluyters-Rehbach, and J. Sluyters, "The analysis of
electrode impedances complicated by the presence of a constant phase element,"
Electroanal. Chem., vol. 176, pp. 275-295, 1984.

[135] M. Orazem, "A systematic approach toward error structure identification for
impedance spectroscopy,," J. Electroanalytical Chemistry, vol. 572, pp. 318-327,

[136] S. Carson, M. Orazem, O. Crisalle, and L. Garcia-Rubio, "On the error structure of
impedance measurements," Jornal of Electrochemistry Society, vol. 150, no. 10,
pp. 477-490, 2003.

[137] R. Jurczakowski, C. Hitz, and A. Lasia, "Impedance of porous au based
electrodes," Journal of Electroanalytical Chemistry, vol. 572, no. 2, pp. 355-366,

[138] R. Jurczakowski, C. Hitz, and A. Lasia, "Impedance of porous gold electrodes in
the presence of electroactive species," Journal of Electroanalytical Chemistry, vol.
582, no. 1-2, pp. 85-96, 2005.

[139] H.-K. Song, Y.-H. Jung, K.-H. Lee, and L. H. Dao, "Electrochemical impedance
spectroscopy of porous electrodes: the effect of pore size distribution," Elec-
trochimica Acta, vol. 44, no. 20, pp. 3513-3519, 1999.

[140] R. J. Forster, "Microelectrodes: New dimensions in electrochemistry," Chemical
Society Reviews, vol. 23, pp. 289-297, 1994.

[141] M. Fleischmann and S. Pons, "The behavior of microelectrodes," Analytical
Chemistry, vol. 59, no. 24, pp. 1391A-1399A, 1987, doi: 10.1021/ac00151a001
0003-2700 doi: 10.1021/ac00151a001.

[142] A. G. Ewing, M. A. Dayton, and R. M. Wightman, "Pulse voltammetry with
microvoltammetric electrodes," Analytical Chemistry, vol. 53, no. 12, pp.
1842-1847, 1981, compilation and indexing terms, Copyright 2009 Elsevier
Inc. 1982020006804 00032700 MICROVOLTAMMETRIC ELECTRODES.

[143] K. P. Troyer, M. L. A. V. Heien, B. J. Venton, and R. M. Wightman, "Neurochemistry
and electroanalytical probes," Current Opinion in Chemical Biology, vol. 6, no. 5,
pp. 696-703, 2002, 1367-5931 doi: DOI: 10.1016/S1367-5931(02)00374-5.

[144] W. Pernkopf, M. Sagl, G. Fafilek, J. O. Besenhard, H. Kronberger, and G. E.
Nauer, "Applications of microelectrodes in impedance spectroscopy," Solid State
lonics, vol. 176, no. 25-28, pp. 2031-2036, 2005.

[145] C. Gabrielli, S. Joiret, M. Keddam, N. Portail, P. Rousseau, and V. Vivier, "Single
pit on iron generated by SECM: An electrochemical impedance spectroscopy
investigation," Electrochimica Acta, vol. 53, no. 25, pp. 7539-7548, 2008,
0013-4686 doi: DOI: 10.1016/j.electacta.2008.01.013.

[146] D. Rolison, "Fabrication of ultramicroelectrodes," in Ultramicroelectrodes,
M. Fleischmann, S. Pons, D. Rolison, and P. Schmidt, Eds. Datatech Systems,
Inc. (Edt.), Scientific Publishing Division, 1987, ch. 3, pp. 65-106.

[147] W. Thormann and A. M. Bond, "Application of transient electrochemical
techniques to inlaid ultra-microelectrodes: Assessment of fabrication quality,"
Journal of Electroanalytical Chemistry, vol. 218, no. 1-2, pp. 187 196, 1987.

[148] O. Koster, W. Schuhmann, H. Vogt, and W. Mokwa, "Quality control of
ultra-microelectrode arrays using cyclic voltammetry, electrochemical impedance
spectroscopy and scanning electrochemical microscopy," Sensors and Actuators,
B: Chemical, vol. 76, pp. 573-581, 2001.

[149] V. M.-W. Huang, V. Vivier, M. E. Orazem, P. Nadine, and B. Tribollet, "The
apparent CPE behavior of an ideally polarized disk electrode: A global and
local impedance analysis," J. Electrochem. Soc., vol. 154, pp. C81-C88, 2007.

[150] V. M.-W. Huang, V. Vivier, I. Frateur, M. E. Orazem, and B. Tribollet, "The global
and local impedance response of a blocking disk electrode with local CPE
behavior," J. Electrochem. Soc., vol. 154, pp. C89-C98, 2007.

[151] V. M.-W. Huang, V. Vivier, M. E. Orazem, P. Nadine, and B. Tribollet, "The
apparent CPE behavior of a disk electrode with faradaic reactions," J Elec-
trochem. Soc., vol. 154, pp. C99-C107, 2007.

[152] M. E. Orazem, "A systematic approach toward error structure identification for
impedance spectroscopy," J. Electroanal. Chem., vol. 572, pp. 317-327, 2004.

[153] G. J. Brug, A. L. G. van den Eeden, M. Sluyters-Rehbach, and J. H. Sluyters,
"The analysis of electrode impedances complicated by the presence of a constant
phase element," J. Electroanal. Chem., vol. 176, pp. 275-295, 1984.

[154] M. E. Orazem and B. Tribollet, Electrochemical Impedance Spectroscopy.
Hoboken, NJ: John Wiley & Sons, 2008.

[155] M. Pourbaix, Atlas of electrochemical equilibria. Oxford: Pergamon Press Ltd.,


[156] S. B. Brummer and M. J. Turner, "Electrochemical considerations for safe electrical
stimulation of the nervous system with platinum electrodes," IEEE Transactions on
Biomedical Engineering, vol. BME-24, no. 1, pp. 59-63, 1977.

[157] B. Ren, X. Xu, X. Q. Li, W. B. Cai, and Z. Q. Tian, "Extending surface raman
spectroscopic studies to transition metals for practical applications: li. hydrogen
adsorption at platinum electrodes," Surface Science, vol. 427-428, pp. 157-161,

[158] H. D. Yoo, J. H. Jang, B. H. Ka, C. K. Rhee, and S. M. Oh, "Impedance analysis
for hydrogen adsorption pseudocapacitance and electrochemically active surface
area of pt electrode," Langmuir, vol. 25, no. 19, pp. 11 947-11 954, 2009.

[159] A. Maas, W. Fleckenstein, D. de Jong, and H. van Santbrink, "Monitoring cerebral
oxygenation: experimental studies and preliminary clinical results of continuous
monitoring of cerebrospinal fluid and brain tissue oxygen tension," Acta Neurochir
Supply (Wien), vol. 59, p. 5057, 1993.

[160] A. Sarrafzadeh, K. Kiening, T. Bardt, G. Schneider, A. Unterberg, and W. Lanksch,
"Cerebral oxygenation in contusioned vs nonlesioned brain tissue: monitoring of
ptio2 with licox and paratrend," Acta Neurochir Suppl (Wien), vol. 71, pp. 186-189,

[161] F. Beer and E. Johnston, Mechanics of Materials. New York: McGraw Hill, 1981.

[162] C. Tian and J. He, "Monitoring insertion force and electrode impedance during
implantation of microwire electrodes," in IEEE Engineering in Medicine and
Biology 27th Annual Conference, Shanghai, China, 2005.

[163] W. Jensen, U. Hofmann, and K. Yoshida, "Assessment of subdural insertion force
of single-tine microelectrodes in rat cerebral cortex," in 25th Annual International
Conference of the IEEE Engineering in Medicine and Biology Society, Cancun,
Mexico, 2003.



Erin Elizabeth Patrick was born in Elkins, West Virginia. She graduated from

Vero Beach High School in Vero Beach, Florida in the spring of 1997 and started her

bachelor's degree at the University of Florida that next fall. In December of 2002 she

earned a Bachelor of Science in Electrical Engineering with high honors. During Erin's

undergraduate studies she did an internship at Dominion Semiconductor, a DRAM

and Flash memory manufacturing facility in Manassas, Virginia, and started working

as an undergraduate research assistant for her current advisor in the Interdisciplinary

Microsystems Group (IMG) at UF She then joined IMG as a doctoral candidate in

August of 2003. Erin earned a Doctor of Philosophy in Electrical Engineering at UF in

August of 2010. Her technical expertise is in microelectromechanical system (MEMS)

processing techniques and electrochemical impedance spectroscopy. Her research

interests include biological and chemical MEMS sensors.




ThisworkwasfundedbyagrantformtheNationalInstituteofHealth,NS053561.Iwouldliketothankmychairadvisor,Dr.ToshiNishida,forhisguidanceandsupportiveadvicethroughoutmyundergraduateandgraduatedegreesattheUniversityofFlorida.Iwouldalsoliketoacknowledgemyco-chairadvisor,Dr.MarkOrazem,fortheuseofhislabequipmentandthankhimforhisguidanceandcontinuedsupportthroughoutthisproject.Myothercommitteemembers,Dr.JustinSanchez,Dr.JohnHarris,andDr.JosePrincipedeservethanksfortheiradviceandtechnicalassistanceonthisproject.IwouldliketoacknowledgetheNeuroprostheticsResearchGroup,headedbyDr.JustinSanchez,attheUniversityofFloridafortheanimalcareandinvivoexperimentation.BabakMahmoudiandJackDiGiovannadeservethanksandcreditforperformingtheimplantationsurgeries.IamalsothankfulforthediscussionsandsamplemicroelectrodesfromDr.VincentVivier.OthertechnicalassistancewasprovidedattheUniversityofFloridabyDr.AndrewRinzlerfortheuseofparylene-CvapordepositiontoolsandAlOgdenwithpackagingandnumerousfabricationprocessingsuggestions.IwouldalsoliketoacknowledgethestaffattheMajorAnalyticalInstrumentationCenter(MAIC)attheUniversityofFloridaforthescanning-electronmicrograph(SEM)imagesandenergydispersivex-ray(EDS)analysisoftheelectrodesamples.TheElectricalandComputerEngineeringstaffalsodeservesthanksfortheirhelpandguidance.Mycolleagues,ViswanathSankarandWilliamRowe,deservethanksfortheirassistancethroughoutthisproject.IwouldalsoliketothankallthestudentsoftheInterdisciplinaryMicrosystemsGroupandProfessorOrazem'sgroupfortheirtechnicaladviceduringnumerousdiscussions.JieXuandSheng-fenYenfromtheComputationalNeuroengineeringGroupattheUniversityofFloridadeserveacknowledgementforthedesignofthecmosamplierusedinthiswork. 3




page ACKNOWLEDGMENTS .................................. 3 LISTOFTABLES ...................................... 8 LISTOFFIGURES ..................................... 9 ABSTRACT ......................................... 14 CHAPTER 1INTRODUCTION ................................... 15 1.1OverviewandMotivation ............................ 15 1.1.1Brain-MachineInterfaces ....................... 16 1.1.2NeuralRecordingMechanismsforBMIs ............... 17 1.1.3MicroelectrodeArrayGoals,Requirements,andChallenges .... 18 1.2ContributionstotheField ........................... 20 1.3DissertationOrganization ........................... 21 2BACKGROUNDONMICROELECTRODESFORNEURALRECORDING ... 23 2.1TheNeuron ................................... 23 2.2ExtracellularNeuralRecording ........................ 26 2.3MicroelectrodeArraysforNeuralRecording ................. 29 2.3.1SingleMicrowireElectrodes ...................... 29 2.3.2MicrowireArrays ............................ 30 2.3.3SiliconMicromachinedMicroelectrodeArrays ............ 31 ..................... 31 ........................ 34 ............... 36 2.3.4PolymerMicromachinedMicroelectrodeArrays ........... 37 2.3.5ComprehensiveMicroelectrodeArraySummary ........... 42 2.4TissueResponsetoIntracorticalMicroelectrodes .............. 43 2.5Implications ................................... 48 3ELECTRODE-ELECTROLYTEINTERFACEPHYSICSANDCONCERNS ... 51 3.1Electrode-ElectrolyteInterface ........................ 51 3.1.1TheNonfaradaicInterface ....................... 51 3.1.2TheFaradaicInterface ......................... 56 3.1.3InterfaceSummary ........................... 58 3.2NeedforElectrochemicalAnalysisofElectrodeMaterials ......... 59 3.3Implications ................................... 61 5


.................. 62 4.1Generation1 .................................. 62 4.1.1Fabrication ............................... 63 4.1.2Bench-TopElectricalTesting ...................... 65 4.1.3Implantation ............................... 66 4.1.4SurgicalRecording ........................... 67 4.1.5Summary ................................ 67 4.2Generation2 .................................. 69 4.2.1Fabrication ............................... 71 4.2.2Bench-TopElectricalTesting ...................... 72 4.2.3Implantation ............................... 74 4.2.4SurgicalRecording ........................... 74 4.2.5Summary ................................ 76 4.3UFMicroelectrodeSummary ......................... 78 5UFMICROELECTRODEARRAYHYBRID-PACKAGEDWITHAMPLIFIERIC 79 5.1Design ...................................... 80 5.2Fabrication ................................... 82 5.3PowerSystemforAmplier-MicroelectrodeSystem ............. 86 5.4ExperimentalSetupwithTDTRecordingSystem .............. 88 5.5Bench-TopCharacterization .......................... 90 5.5.1EffectofGroundingReferenceInputtoAmplier .......... 90 5.5.2EffectofEMIonNoiseFloor ...................... 93 5.5.3ImpedanceConcernswithOn-ChipAmplier ............ 94 5.5.4LessonsLearnedforIntegrationwiththeIntegrate-and-FireChip 100 5.5.5FrequencyResponseandImpulseResponseofSystem ...... 101 5.6In-VivoTesting ................................. 102 5.6.1In-VivoRecordingResults ....................... 104 5.6.2Post-ImplantElectrodeAssessment ................. 108 5.7Summary .................................... 110 6ELECTROCHEMICALCHARACTERIZATIONOFELECTRODES:METHODS 112 6.1ElectrochemicalImpedanceSpectroscopy .................. 112 6.1.1GraphicalDataAnalysisTechniques ................. 114 6.1.2ErrorAnalysis .............................. 117 6.2MicroelectrodesusedforElectrochemicalCharacterization ........ 119 6.3QualityControlofMicroelectrodeFabrication ................ 120 6.3.1QualityControlMethods ........................ 121 ...................... 122 6.3.2QualityControlResultsandDiscussion ................ 124 ........................ 124 ...................... 125 6.3.3QualityControlSummary ....................... 127 6


... 130 7.1MaterialsandInstrumentation ......................... 130 7.2ExperimentalResults ............................. 132 7.2.1EISofTungstenandPlatinuminPhosphateBufferedSaline .... 132 7.2.2EISofTungstenandPlatinuminPhosphateBufferedSalineandHydrogenPeroxide ........................... 135 7.2.3ImagesofTungstenCorrosion ..................... 136 7.3AnalysisandDiscussion ............................ 137 7.3.1CalculationofOpenCircuitPotentialReferredtoSHE ....... 139 7.3.2PossibleElectrochemicalReactionsonTungsten .......... 140 7.3.3RateofTungstenCorrosion ...................... 145 ................ 145 .............. 146 7.3.4PossibleElectrochemicalReactionsonPlatinum .......... 148 7.4Conclusions ................................... 151 8SUMMARYANDCONCLUSION .......................... 154 8.1SummaryoftheUF-MicroelectrodeArray .................. 154 8.2SummaryoftheElectrochemicalAnalysis .................. 156 8.3SuggestionsforFutureWork ......................... 157 REFERENCES ....................................... 160 BIOGRAPHICALSKETCH ................................ 174 7


Table page 1-1Comparisonofelectrodelifetimes ......................... 20 4-1NeuronalYieldforGeneration1MicroelectrodeArray .............. 68 4-2PerformanceofGeneration2MicroelectrodeArray ................ 76 5-1VoltageSpecicationsforUFAmplier ....................... 88 5-2Noiseoor ...................................... 94 5-3NeuronalYieldforGeneration2bMicroelectrodeArray .............. 105 6-1ValuesofandQeforidealelectrodesfromFigure 6-6 andFigure 6-7 .... 125 6-2ValuesofandQefornon-idealelectrodesextractedfromFigure 6-10 andFigure 6-11 ...................................... 126 7-1CompositionofPhosphateBufferedSaline .................... 132 7-2SpeciesconsideredincalculationofthePourbaixdiagrampresentedasFigure 7-12 .......................................... 141 7-3Corrosionratesfortungsten ............................. 148 7-4SpeciesconsideredincalculationofthePourbaixdiagrampresentedasFigure 7-17 .......................................... 150 8-1CriticalLoadingForceforMetalMicrowires .................... 158 8


Figure page 1-1Physicalrepresentationofrecordingelectrodes. ................. 18 2-1Schematicofmicro-wireelectrodearrayinterfacewithneuronsinthecortex. 24 2-2Schematicofaneuronandactionpotential. .................... 25 2-3Extracellularrecordingofanactionpotentialwithrespecttoadistantelectrode. 26 2-4Simulatedextracellularvoltagefromatypicallayer5corticalpyramidalcell. .. 27 2-5Microwireelectrodearrays. ............................. 31 2-6Examplesofthe2-DMichiganmicroelectrodearray. ............... 33 2-73-DMichiganmicroelectrodearray. ......................... 34 2-8Utahmicroelectrodearray. .............................. 35 2-9Polyimide-basedmicroelectrodearray(ArizonaState,Gen1). .......... 38 2-10Parylene-basedmicroelectrodearray(U.ofMichigan). .............. 38 2-11Polyimide-basedmicroelectrodearray(ArizonaState,Gen2). .......... 39 2-12Polyimide-basedmicroelectrodearray(FraunhoferInstitute). .......... 40 2-13Polyimide-basedmicroelectrodearray(U.ofTokyo). ............... 40 2-14Parylene-basedmicroelectrodearray(U.OfTokyo). ............... 41 2-15Polyimide-basedmicroelectrodearray(U.ofBritishColumbia). ......... 42 2-16Typicaltetheringschemeofarigidmicroelectrodearray. ............. 46 3-1Equilibriumelectrode/electrolyteinterface. ..................... 53 3-2Equivalentcircuitforthenonfaradaicinterface[ 1 ]. ................ 56 3-3Equivalentcircuitforfaradaicinterface[ 1 ]. ..................... 57 3-4I-Vrelationshipoftworeactionsoccurringattheinterface. ............ 58 4-1Flexiblesubstratemicroelectrodearray. ...................... 63 4-2Fabricationprocessowforgeneration1microelectrode. ............ 64 4-3Equivalentcircuitforelectrode/electrolyteinterface. ................ 65 4-4Surgicalimplantationofgeneration1microelectrode. ............... 66 9


................ 69 4-6Corrosionofelectrode ................................ 70 4-7PolymermicroelectrodearraywithOmneticsconnector ............. 71 4-8Fabricationprocessofgeneration2microelectrodearray. ............ 72 4-9Equivalentcircuitforelectrode/electrolyteinterface. ................ 73 4-10Invivotestingofgeneration2 ............................ 75 4-11Datafromneuralrecording. ............................. 77 4-12Spikesortingresults ................................. 77 5-1Invivoplacementofmicroelectrodearrayonrodentskull. ............ 83 5-2Flexiblepolyimidemicroelectrodearraywithintegratedamplier. ........ 83 5-3UFamplier-microelectrodesystemshowingtheexibilityoftheelectrodesubstrate ....................................... 84 5-4FabricationprocessowforUFamplier-microelectrodesystem. ........ 85 5-5Amplierdiewithgoldstudbumpsonbondpads. ................. 85 5-6Contentsofpowerbox. ............................... 87 5-7Input/outputconnectionsforpowerbox. ...................... 87 5-8ExperimentalsetupwithTDTrecordingsystem. .................. 88 5-9TimeseriesnoiseooraffectedbyRA8GApreamplierinputsetting. ...... 89 5-10TimeseriesnoiseoorseenontheTDTrecordingprogram. .......... 91 5-11Amplierconnectionsshowingoatingvs.groundedreferenceconguration. 92 5-12Squarerootofthepowerspectraldensityoftheamplier-microelectrodesystemshowingeffectofthereferenceconnectiononthenoiseoor. .......... 93 5-13SquarerootofthepowerspectraldensityofnoiseoorshowingeffectofEMI. 94 5-14Comparisonofimpedances. ............................. 95 5-15Differentialamplicationofneuralsignal ...................... 96 5-16AttenuationfactorofVdasafunctionofZeandZrefcorrespondingtovoltagedivisionatinputoftheamplier. ........................... 97 5-17PercentattenuationofVd. .............................. 97 10


........................... 98 5-19Percentofthecommon-modesignalthatwillbeamplied. ............ 99 5-20Normalizedeffectivecommon-moderejectionratioasafunctionofthedifferenceoftheimpedancebetweenrecordingelectrodeandreferenceelectrode. .... 100 5-21Effectivecommon-moderejectionratioasafunctionoffrequencyforimpedancevaluesintheUFmicroelectrodearray. ....................... 101 5-22Frequencyresponseofamplier-microelectrodesystem.Thepass-bandgainis39dB. ....................................... 102 5-23Impulseresponseofamplier-microelectrodesystem. .............. 103 5-24Flexiblesubstrateelectrodearrayimplantedinrodentmodel. .......... 104 5-25Largeamplitudeactionpotentialsrecordedondayofimplantation. ....... 105 5-26Actionpotentialofasingleneuronspikesortedovertheimplantedperiod. ... 106 5-27Noiseoorfortheelectrodearrayovertheimplantedduration. ......... 107 5-28Signal-to-noiseratiofortheelectrodearrayovertheimplantduration. ..... 108 5-29SEMimagesoftungstenmicro-wiresbeforeandafter87daysimplanted. ... 110 5-30EDSresultsoftwositesononeelectrodeafter87daysinvivo. ......... 111 6-1EISexperimentalset-up. ............................... 113 6-2Equivalentcircuitsforblockingandreactivesystem. ............... 114 6-3Bodeplotsofablockingandreactivesystem. ................... 115 6-4Impedanceofblockingandreactivesystems. ................... 116 6-5ImpedanceforblockingandreactivesystemswithCPE. ............. 116 6-6ImpedanceoffourPtelectrodesinsulatedinepoxyandpolishedwithAlO2paper. ......................................... 124 6-7CPEcoefcientQofidealelectrodesasafunctionoffrequency. ........ 125 6-8ImaginaryimpedanceoftheidealelectrodesindimensionlessunitswithrespecttodimensionlessfrequencyK. ........................... 126 6-9DerivativeofthelogarithmofdimensionlessimaginaryimpedanceoftheidealelectrodeswithrespecttothelogK. ........................ 127 11


......................................... 128 6-11CPEcoefcientQofthenon-idealelectrodesasafunctionoffrequency. ... 128 6-12Plotofimaginaryimpedanceofthenon-idealelectrodesindimensionlessunitswithrespecttodimensionlessfrequencyK. .................... 129 6-13Derivativeofthelogarithmofimaginaryimpedanceofthenon-idealelectrodeswithrespecttologK. ................................. 129 7-1SchematicofworkingelectrodeforEISmeasurements. ............. 131 7-2ImpedanceoftungstenandplatinumelectrodesinPBS. ............. 133 7-3Equivalentcircuitsforblockingandreactivesystems. ............... 133 7-4Impedanceofaplatinumelectrodeinphosphatebufferedsalineovertime. .. 134 7-5Impedanceofagold-platedtungstenelectrodeinphosphatebufferedsalineover15days. ..................................... 135 7-6ImpedanceoftungstenelectrodeshowingO2concentrationdependance. ... 135 7-7Impedanceofaplatinumandgold-platedtungstenelectrodeinPBSplusH2O2 7-8PhotographsofatungstenelectrodebeforeandafterimmersioninPBSforthespeciedperiodoftime. ............................. 137 7-9Photographsofgold-platedtungstenelectrodesbefore(top)andafter(bottom)immersioninPBSforthespeciedperiodoftime. ................ 138 7-10Photographsofagold-platedtungstenelectrodesbeforeandafterimmersioninanelectrolytecontainingPBSandH2O2forthespeciedperiodoftime. ... 138 7-11Schematicrepresentationofelectrochemicalcell. ................ 139 7-12Pourbaixdiagramoftungsteninphosphatebufferedsaline. ........... 140 7-13Pourbaixdiagramoftungsteninphosphatebufferedsalineand30mMH2O2. 143 7-14Effectofincreasedcathodesurfaceareaongalvanicinteractionoftungstenandgold. ....................................... 144 7-15OCPovertimeforgold-platedtungstenandtungstenelectrodesinPBS. .... 145 7-16Nyquistplotsusedforcalculationofthepolarizationresistance,Rp. ....... 147 7-17Pourbaixdiagramofplatinuminphosphatebufferedsalineand30mMhydrogenperoxide. ....................................... 149 12


150 13


Thelong-termgoalinthedesignofbrain-machineinterfaces(BMIs)istorestorecommunicationandcontrolofprostheticdevicestoindividualswithlossofmotorfunctionduetospinalcordinjuries,amyotrophiclateralsclerosis,ormusculardystrophy,forexample.Oneofthegreatchallengesinthiseffortistodevelopimplantablesystemsthatarecapableofprocessingtheactivityoflargeensemblesofcorticalneurons.Thisworkpresentsthedesign,fabrication,characterization,andinvivotestingofaneuralrecordingplatformforapre-clinicalapplication.Therecordingplatformisaexible,polyimide-basedmicroelectrodearraythatcanbehybrid-packagedwithcustomelectronicsinafully-implantableformfactor.Resultsfromthemicroelectrodearrayintegratedwithanamplierintegratedcircuitincludedatafrominvivoneuralrecordingsshowingconsistentsingle-unitdiscriminationover42days.Moreover,resultsfromtheelectrochemicalassessmentofthecorrosionpropertiesofthetungstenmicrowireelectrodesusedonthemicroelectrodearrayadmonishtheuseoftungsteninlong-termimplants. 14


2 ].Epilepsyisestimatedtocost$15.5billionannuallyandapproximately200,000newcasesarediagnosedeachyear[ 3 ].Theseexamplesarejustafewofmanyneurologicaldisordersaffectingpeopletoday.Fortunately,engineeringcanprovidehopetosomebyprovidingalternatemethodsforregaininglostfunctionduetoneurologicaldisorders. Neuralprosthetictechnologies,orneuroprostheses,aredesignedtoreplace,repair,oraugmentfunctionforindividualswithvision,hearing,ormotorimpairments.Neuroprosthesesinterfacewiththenervoussystemandeithertransmitorreceiveneuralinformationinordertoperformatask.Examplesofsensoryprostheticsareretinalandcochlearimplantsfortheblindanddeaf.Theseprostheticscodeimagesorsoundtakenfromwearablecamerasandmicrophonesintoelectricalimpulseswhichareusedtostimulateretinalorauditorynerves,respectively.Thecochlearimplantisbestknownandiscommerciallyavailable[ 4 5 ].Anotherneuroprosthesisusesfunctionalelectricalstimulation(FES)totherapeuticallymodulateneuralactivityinthebrainofpeoplewithParkinson'sdisease,epilepsy,anddepression[ 6 8 ].Electricalsignalsaresentviatheprostheticintoatargetedportionofthepatient'sbrainmitigatingthedebilitatingeffectsoftheircondition. 15


9 ].Signalsfromperipheralnervesintheshoulderoftheamputatedarmprovidethecommandsfortheroboticarm.Alternatively,motorneuroprosthesesthatinterfacewiththecentralnervoussystemarecommonlycalledbrain-machineinterfaces,(BMIs)orbrain-computerinterfaces(BCIs).Theyideallyprovidethemeansforthoughtcontrolofexternaldevicesbyrecordingcentralnervoussystem(CNS)neuralactivityanddecodingmotorintention[ 10 ].Thesesystemsmaypotentiallybeusedastherapyforindividualswithparalysisoftheextremitiescausedbyinjuryorneurodegenerativediseasessuchasamyotrophiclateralsclerosis(ALS),musculardystrophy,orotherdiseasesthatcausealocked-incondition. 4 ].AnexampleofpossibleBMIfunctionforaquadriplegicisdirectionalcontrolofamotorizedwheelchairviabrainsignals.Thetypeofneuralactivityusedtoprovidesuchcommandsvarieswithapplicationandresearcher.However,preclinicalstudiesprimarilyuseneuralactivityinthemotorcortex[ 11 12 ].Therefore,intheproposedscenario,directionalcontrolofamechanicalwheelchaircouldbeadministeredbytheneuralactivitythatoccurswhenthinkingaboutmovinganarm. ProgressonBMIsystemshasbeenmadeinpreclinicalandclinicalstudies.Chapinetal.showedreal-timecontrolofaroboticarmviacorticalsignalselicitedbyafore-limbleverpressingactiondonebyarat[ 11 ].Othershaveshowneffective1Dand3Dcontrolofroboticarms[ 12 ]andcursorsonscreens[ 13 14 ]inBMIsinprimates.Carmenaet 16


15 ].Vellisteetal'sexperimentsshowthepotentialofBMIsformultidimensionalcontrolofaroboticarminaninteractiveclosedloopsystem,wheremonkeyswereabletofeedthemselves[ 16 ].RecentclinicaltrialsusingBMIsallowedatetrapalegicpatienttocontrolacursoronacomputerscreen,playavideogame,adjustthevolumeandchannelofatelevision,andcontrolasimplerobotichand[ 17 ].Electrodeswereimplantedintothearmareaofthepatient'smotorcortex.Byimagininghandmovements,thepatientwasabletoprovidesignalstocontroltheBMIdevices. 1-1 showsarepresentationofeachrecordingelectrode.Eachelectrodemeasuresneuronalelectricalactivitywithdifferentspatialandtemporalresolution.EEGelectrodesresideonthescalp,measureneuralactivityacrossaspatialdiameterof3cm,andprovidesignalswithfrequencycontentupto70Hzonly[ 10 ].ECoGelectrodesresideonthesurfaceofthebrain,averageneuralactivityover0.5cmandcanrecordsignalswithmuchhigherfrequencycontent[ 10 ].Typically,thebandwidthofECoGrecordingsis10Hzto200Hz[ 10 ].However,thisbandwidthisnormallylimitedbytheamplicationhardware.NewresearchshowsthatECoGelectrodescanprovidesignalswithmeaningfulfrequencycontentupto6kHz[ 18 ].Intracorticalmicroelectrodespenetrateintothecortexandhaverecordingsiteswithareassimilartoaneuralcellbody(50m-200m).Microelectrodesprovidetheleastspatialaveragingandcanaccuratelyrecordtheactionpotentialwaveformfromsingleneurons,oftencalledsingleunitrecording.Thefrequencycontentofsignalsrecordedfrommicroelectrodesisalsolimitedbytheamplicationhardware;normally,frequenciesupto6kHzaremeasured. 17


Physicalrepresentationofrecordingelectrodes. AllpapersmentionedinSection 1.1.1 ,whichshowBMIcontrolofexternaldevices,useintracorticalmicroelectrodearraysformeasurementoftheneuralsignals[ 11 15 17 ].Theirresearchsuggeststhatsingleunitrecordingisusefulfortheanalysisofcomplexmotorfunction.Therefore,thisworkfocusesonthedesignofarecordingsystemthatincorporatesintracorticalmicroelectrodearrays. 18


Therecordingcharacteristicsarecontrolledbymanyfactors;onlysomeofwhichcanbecontrolledbydesign.Thedesignercanassurethatthemicroelectrodewillnotcatastrophicallyfailbymechanicalorelectricalmeansandhaslownoise.Thus,microelectrodearraysshouldbemadeoutofrobustmaterialsthatwillnotbreaknorcorrodeandallelectronicwiringorcircuitrymustbehermeticallysealed.Also,themicroelectrodesandinterfaceelectronicsmustbedesignedtohavelowintrinsicnoiseandmeasuresshouldbeprovidedtominimizeelectromagneticinterferencesuchthatthesignal-to-noiseratiocanbeashighaspossible.Onefactorthatisnotcontrolledbythemicroelectrodearraydesignissurgicalplacementinthecortex.Thestrengthoftherecordedsignal,andhencethesignal-to-noiseratio,dependsonhowclosetheelectroderesidestotheneuronalcellbody.Also,highyieldwithinanarrayrequiresthatallelectrodesinthearraybeplacedcloseenoughtoaneuronormultipleneuronstomeasuretheirsignal.Eventhoughthedesignerhasnocontrolofpreciseelectrodeplacementforeachelectrodeinastaticarray,thereishighprobabilitythattheelectrodewillbepositionednearenoughtoaneurontomeasureitsactionpotentialbecauseofhighneuronaldensity[ 19 ].Biocompatibilityisanotherfactordeterminingstablerecordingcharacteristics.TherelationshipbetweenmaterialchoiceandbiocompatibilityisnotstraightforwardandwillbediscussedinmoredetailinChapter 2 Acurrentissuewithcommercialandnoncommercialmicroelectrodesforneuralrecordingislossofsignalovertime.Table 1-1 showsthethreemostcommonelectrodetechnologiesusedforBMIsandtheirefcacyovertime.TheyincludemicromachinedarraysfromtheUniversityofMichiganandtheUniversityofUtahandnon-micromachinedmicrowirearrays.Thegeneraltrendisadecreaseinthenumberofelectrodesabletorecordsingleunits(i.e.activeelectrodes),overtime.ThislossofrecordingfunctionovertimeistheresultofmanybiologicalfactorsdescribedinmoredetailinChapter 2 that 19


1-1 [ 20 ].Methodstomitigatethiseffectareatopicofcurrentresearchintheeld,thougharenotapartofthiswork. Table1-1. Comparisonofelectrodelifetimes TechnologyElectrodeMaterialPercentageofactiveelectrodesovertimeReference MicromachinedsiliconshankelectrodewithexiblecablePt92%/12weeks92%/18weeksVetter,Kipke,etal.,2004[ 21 ] MicromachinedSiliconbedofnailselectrodePt45%/12weeks18%/52weeksRousche,Normann,1998[ 22 ] Micro-wireelectrodeW80%/12weeks45%/25weeksWilliams,Kipke,1999[ 23 ] Micro-wireelectrodeIr62%/1week25%/151weeksLiu,McCreery,2006[ 24 ] 25 ].Thisworkestablishesaexibleplatformforanimplantableneuralrecordingsystemintegratedwithmicrowireelectrodesandanapplicationspecicintegratedcircuit(ASIC)amplier.Thisdesignresultsinacompactdevicecapableofbeingpositionedsubcutaneouslywhileonlythemicroelectrodespenetratethecortex.Aprocessowusingnon-siliconMEMStechniquesandip-chipbondingisachieved.Twogenerationstestingtheefcacyofamicromachined,exible,ployimidesubstratewithnickel[ 26 ]andtungsten[ 27 ]microwireelectrodeshavebeenrealized.Thelatestgenerationwith 20


28 29 ].Anaveragenoiseoorof4.5Vrmsandaveragesignaltonoiseratiosof3.5(11dB)areconsistentlyseenovertheimplantduration. Furthermore,thisworkexempliesamethodforthoroughelectrochemicalcharacterizationofelectroderecording-sitematerialsandprovidesundocumentedresultsfortungstenmicroelectrodes[ 30 ].Corrosionratesfortungstenmicroelectrodeswithandwithoutagold-tungstengalvaniccouplearequantiedinelectrolytesmodelinginvivochemistry.Corrosionratesontheorderof100m/yrareseenfortungstenelectrodesimmersedin0.9%phosphatebufferedsaline,whilecorrosionratesontheorderof10,000m/yrareseenfortungstenelectrodesimmersedinasolutioncontaining0.9%phosphatebufferedsalineand30mMofhydrogenperoxide.Thehydrogenperoxideisaddedtomodeltheextracellularchemistryduringaforeign-bodyinammatoryresponse.Theseresultsprovideinsightintothelong-termlongevityoftungstenmicrowireelectrodearraysusedininvivorecordingapplications. Moreover,amethodtoassessthequalityofthesealbetweentheinsulationandthemicroelectrodesurfaceisintroduced[ 31 ].Thismethodusesgraphicalanalysisoftheimpedancedataandthusisrelativelysimple.Thismethodmaybeusedforqualitycontrolofmicroelectrodesusedintheeldsofelectrophysiologyorelectroanalyticalchemistry. 2 discussestheelectrophysiologyofaneuron,describesthephysicsofsignaltransductionattheelectrodesurfaceviaelectrochemicaltheory,andpresentsexistingmicroelectrodetechnologiesandtheirissues.Chapter 3 presentsthephysicsbehindtheelectrode-electrolyteinterfaceandtheneedforelectrochemicalassessmentofelectroderecording-sitematerials.Chapter 4 presentssequentialprogressofthepolymer-basedUFmicroelectrode 21


5 explainsindetailthedesignandcharacterizationofaUFmicroelectrodearrayhybrid-packagedwithanamplierintegratedcircuit.Detailsofthesystemnoise,thegroundingscheme,andtherequirementsforinterfacingwithcommercialdata-processingandrecordinghardwarearegiven.Invivoresultsshowtheperformanceofthemicroelectrodesystemforchronicapplications.Chapter 7 presentsthetheory,experimentalmethods,andresultsofelectrochemicalassessmentofplatinumandtungstenforrecordingelectrodematerials.Thecorrosionoftheelectrodeorproductionofunwantedchemicalspeciesisassessed.Chapter 8 summarizestheresultsofthisworkandadvisesaplanforfuturemicroelectrodedesigns. 22


ThischapterconveysthenecessarybackgroundforthedesignoftheUFmicroelectrodearray.Understandingofthemeasurementtargetispresentedthroughanoverviewoftheneuron,followedbyadiscussionoftheneuronalsignalknownastheactionpotential.Then,thetransductionmechanismatthemetalrecordingsiteandtissueinterfaceisdiscussedandmathematicallyportrayedviaelectrochemicaltheory.Thenextsectionprovidesdetailsofthestructuresandfabricationmethodsofexistingmicroelectrodesandmicroelectrodearraysforneuralrecordingapplicationsincludingmicrowire,silicon-micromachined,andpolyimide-micromachinedmicroelectrodearrays.Thestrengthsandweaknessesoftherevieweddesignsarediscussedatthecloseofthissection.Next,histologicalreportsthatportraythebiocompatibilityofimplantedmicroelectrodesarereviewed.Thebiologicalimmuneresponseisidentiedforintracorticalmicroelectrodes.Finally,fromthebackgroundinformationarepresented. 2-1 showsaschematicofanintracorticalmicrowiremicroelectrodeinterfacingwithneuronsinthebrain.Ifplacedincloseproximitytoacell,themicroelectrodecanrecordtheneuron'sionicsignalsasitcommunicateswithotherneurons. Tounderstandhowanactionpotentialisgenerated,thephysiologyofaneuronisexplained.Thesomaisthecellbody;dendritesandtheaxonmake-uptheneuralextensions,orneurites,asshowninFigure 2-1 [ 32 ].Thedendritesreceivesignalsfromotherneurons,whiletheaxontransmitssignalstootherneurons.Theaxonmaybe 23


Schematicofmicro-wireelectrodearrayinterfacewithneuronsinthecortex. insulatedalongitslengthandperiodicallyhaveuninsulatednodes(NodesofRanvier)thatacttoreestablishanactionpotentialasitpropagates.Neuronsareconnectedinaweblikefashionwiththeaxonofoneneuronattachingtothedendritesofothersviaasynapse.Oneneuronmayhaveontheorderof10,000dendriticconnections[ 32 ].Theneuronisinsulatedbyathinmembraneonwhichionchannelsreside.Theionchannelsaregatedbyproteinsthatonlyallowthepassageofspecicions.Ionchannelsmaybeneurotransmitter-gatedorvoltage-gatedmeaningthateitherneurotransmittersorvoltagemaymodulatetheproteinsallowingionstopass.Ioniccurrentoccurringatdendriticsynapseshastheabilitytotriggeranactionpotentialinthereceivingneuronbydepolarizingtherestingpotentialofthesomatoacertainvalue.Therestingpotentialinsideaneuralcellbodyiscloseto-65mVwithrespecttothesurroundinguid[ 32 ].Whentheafferent,orincoming,currentfromdendriticsynapsesincreasesthecellpotentialaboveacertainthresholdvoltage,anactionpotentialproceedsasfollows.Voltage-gatedionchannelsresidingonthecellmembraneopenandallowtheentryof 24


2-2 Figure2-2. Schematicofaneuronandactionpotential. 25


2-2 ,presentedearlier,showedtheactionpotentialwaveformmeasuredviathepotentialdifferencefromtheinsideofthecelltotheoutsideofthecell.Anintracorticalmicroelectrodemeasurestheextracellularpotentialofanearbyneuronwithrespecttoadistantelectrode.ThispotentialdifferenceisthenfedintoadifferentialamplierasshowninFigure 2-3 .ThewaveformsshowninFigure 2-3 arecharacteristicofrecordedandampliedsignals.Henzeetal.showedthatthemeasuredwaveformwillbeclosetothetherstderivativeoftheintracellularwaveform[ 19 ]. Figure2-3. Extracellularrecordingofanactionpotentialwithrespecttoadistantelectrode. Moreover,theshapeandamplitudeoftherecordedextracellularvoltagedependsontheplacementoftheelectrodewithrespecttotheneuron.Figure 2-4 shows 26


33 ].Thecircleinthecenterofthegurerepresentsthesoma,while Figure2-4. Simulatedextracellularvoltagefromatypicallayer5corticalpyramidalcell[reprintedfromJournalofComputationalNeuroscience,vol.6,no.2,G.R.HoltandC.Koch,Electricalinteractionsviatheextracellularpotentialnearcellbodies,p.174,Figure4,1999,withpermissionfromSpringerScience+BusinessMedia]. theaxonhillock,showninwhite,isprotrudingfromthebottom.Theapicaldentritictreeprotrudesfromthetopofthesoma.Otherbranchesaredendrites.Theirresultssuggestthatthelargestpotentialsareneartheaxonhillockandthatallpotentialsarereducedasdistanceawayfromthecellincreases.ExperimentalresultsfromHenzeetal.showedthatextracellularvoltagesfromCA1hipocampalratpyramidalneuronsaremeasurablefrommicroelectrodesasfaras140mfromthecellbody,butthatamplitudesgreaterthan60Vmustbemeasuredwithin50m[ 19 ].Drakeetal.reportedthatthefarthestdistancetheycouldexperimentallyrecordfromaneuroncellbodyintheratcortexis180m[ 34 ].Thusitisclearthattherelativeplacementofthemicroelectrodewith 27


35 ].Thetransientvoltagemeasuredwithrespecttoadistantreferenceelectrodeisdeterminedbythechangingconcentrationofionicspeciesneartherecordingelectrode.Themathematicalrelationshipbetweenelectrostaticpotentialandionicconcentrationarediscussednext. Thegoverningequationfortheionicuxindilutesolutionsforonespecies,Ni,isgivenas whereNiisexpressedinmolcm2s1,ziisthenumberofprotonchargescarriedbytheion,uiisthemobilityofthespecies,FisFaraday'sconstant,ciisconcentration,iselectrostaticpotential,Diisthediffusioncoefcientofthespecies,andvisthevelocityofthebulkuid[ 36 ].Thethreetermsontherightsideoftheequationcorrespondtomasstransportduetoelectric-eld-induceddrift,diffusion,andconvection,respectively.Inthiscase,theconvectiontermiszero. Next,massbalanceforavolumeelementrequiresthattheaccumulation,ortimerateofpositivechangeoftheconcentration,mustequalthenegativeofthedivergenceoftheux. Combining( 2 )and( 2 )givesatimedependentdifferentialequationrelatingpotentialandconcentration. 28


"=PziciF whereischargedensityand"isthepermittivityofthemedium.Thevoltagemeasuredbythedifferentialamplieris whereeistheelectrostaticpotentialattheintracorticalmicroelectrodeandrefistheelectrostaticpotentialatadistantreferenceelectrode.Inmanyrecordingsystems,thereferenceelectrodeisalargeareametalscrewthatisdriventhroughtheskullandrestsinthecerebrospinaluidabovethecortex.Therefore,onlysingleunitactionpotentialsfromneuronsneartheimplantedmicroelectrodearerecorded.Thisderivationprovidesthemathematicalframeworkfornumericalmodelingofthepotentialmeasuredbymicroelectrodes.Futuremodelingstudiescouldinvestigatetheeffectsofelectrodesizeandscartissueencapsulationonthemeasuredpotentialwaveform. Thenextsectionreviewsthedesign,structure,andfabricationofexistingintracorticalmicroelectrodesandmicroelectrodearrays. 37 38 ].Thepurposeofhisdesignwastoallowfortheimplantedelectrodestobeconnectedtoaverythinandexiblewirethatwouldprovidestrainreliefforbrainmotionwithrespectto 29


23 ].Ajigwasusedtoseparateandsecure35mdiametertungstenmicrowiresinsulatedinpolyimidewhiletheywereassembledintoarowof11parallelwiresandattachedtoaconnector.Thenalarrayconsistedoftworowsofelevenmicrowires,cuttothesamelengthbytungsten-carbidesurgicalscissors,andelectricallyconnectedtoaback-endconnector.Luietal.constructedmicrowirearraysfromPt/Irwiresinsulatedinparylene-Cthatwere35or50mindiameterandelectrochemicallypolishedtoaconicaltip.Sixteenwireswereperpendicularlyattachedtoabackplateina4by4grid[ 24 ].Twocompanieshavecommercialmicrowirearraysthatresemblethesepublisheddesigns:TuckerDavisTechnologiesandMicroprobe,Inc.TuckerDavisTechnologiesusespolyimidecoatedtungstenmicrowiresandprintedcircuitboardtechnologiestomakearraysof16electrodesites(2rowsof8wires)[ 39 ].Themicrowiresarebondedtoaprintedcircuitboardthatattachestoaconnector.Manyothercongurationswithouttheprintedcircuitboardarealsomadebythecompany.MicroprobeInc.makesarraysoutofPt/Irortungstenmicrowiresthataresharpenedtoapointandhaveparylene-Castheinsulatingmaterial.Theyalsohaveadesigninwhichthemicrowiresareattachedperpendiculartoaback-platewithaexiblecableofwiresextendingtoaconnector(notshowninFigure 2-5 )[ 40 ]. 30


Microwireelectrodearrays.a)Williamsarray[reprintedfromBrainResearchProtocols,vol.4,no.3,J.C.Williamsetal.,Long-termneuralrecordingcharacteristicsofwiremicroelectrodearraysimplantedincerebralcortex,p.305,Figure2,1999,withpermissionfromElsevier.b)MicroProbeInc.array.[http://www.microprobes.com/]c)TuckerDavisTechnologiesarray.[http://www.tdt.com/] 41 ].MicroelectromechanicalSystem(MEMS)technologywasjustbeginningatthattimeandprocesstechniquessuchasphotolithography,wetchemicaletchingofbulkSi,andvapordepositionand 31


42 ].DesignchangesincludedasingleSishank,orbeam,withmultipleelectrodesitesalongthetopsurface.Changesinthefabricationprocessincludeddiffusionofboronthateffectivelydenedtheprobegeometrywhenusedasetchstopinthewetchemicaletch.Tantalumorpolysiliconlinesweredepositedbetweeneithersiliconoxideorsiliconnitridedielectriclayersastheelectrodeleads.Thengoldwasdepositedandpatternedtoformtherecordingsites.Theresultingprobedimensionswere3mmlength,50mwidthatthebaseand25matthetaperedend,and15mthickness.Theirprocessowwascompatiblewiththeintegrationofcomplimentarymetal-oxide-transistor(CMOS)electronics.In1986and1992,theMichigangrouppublishedresultsincorporatingamplication,multiplexing,andbufferingelectronicsontheirpreviousdesign[ 43 44 ]. ThenextadditiontotheMichiganmicroelectrodedesignwasaSiribboncablemadetoprovideaexibleinterfacebetweentheSimicroelectrodeandback-endconnections[ 45 ].Discreteinsulatedwiresusedforinterconnectionsinpreviousdesignswouldoftenfailovertimerenderingtheimplantedprobeuselessandprovedtobeamanufacturingburden[ 45 ].TheSicablewasfabricatedusingaprocessowsimilartothemicroelectrodesdiscussedbefore.Cables2.5cmlong,100mwide,and5mthickweremade.Theywerethenultrasonicallywire-bondedtoamicroelectrodeandtheconnectionpointwasreinforcedwithabeadofsiliconerubber.Figure 2-6 showsadiagramofaMichiganmicroelectrodearrayandapictureofacompletedonewithmultipleshanksmakinga2-Ddeptharray.NeuralNexusisaspin-offcompanyfromtheUniversityofMichiganthatsellsnumerousvariationsofthe2-DMichiganmicroelectrodearrays. Thenextadvancementofthetechnologywastomakea3-Darray.Hoogerwerfetal.reportedadesignthatbonds2-DSimicroelectrodearraysperpendicularlytoaSiplatformwithanintegratedSicable[ 46 ].The2-Darraysweretthroughslotsinthe 32


Examplesofthe2-DMichiganmicroelectrodearray.a)[ReprintedfromProceedingsoftheIEEE,vol.96,K.Wiseetal.,Microelectrodes,microelectronics,andimplantableneuralmicrosystems,p.1185,Figure1,2008,withpermissionfromIEEE.]b)[ReprintedfromAnnualInternationalConferenceoftheIEEEEngineeringinMedicineandBiologySociety,R.J.Vetteretal.,DevelopmentofaMicroscaleImplantableNeuralInterface(MINI)ProbeSystem,p.7342,Figure2,2005withpermissionfromIEEE.] platform,heldinplacebyspacerbars,andthenwereelectricallyconnectedbyselectiveelectroplatingnickeltobridgethegapbetweenplatformandarray.Theinterconnectstructurewasthenhermeticallysealedbyreowedglassandepoxy.Agureofthe3-DarrayisshowninFigure 2-7 .AsummaryofmoremodicationstotheMichigandesignaredescribedhere.Laterdesignschangedtherecording-sitemetalfromgoldtoplatinumoriridium[ 21 47 ],incorporatedparyleneratherthanSicables[ 48 ]andaddedwirelesscapability[ 47 49 ].ThegeneralapproachsuggestedbyMichiganforfuturemicroelectrodearraysistohaveallamplication,signalprocessing,telemetry,andpowerelectronicsrestingsubcutaneouslyontheskull.FlexibleparylenecableswereusedtoconnecttwoorthreedimensionalSimicroelectrodearrayimplantedinthecortex,distancingtheelectronicsandreducingthesusceptibilityoftissueheating[ 49 ]. 33


3-DMichiganmicroelectrodearray[reprintedfromProceedingsoftheIEEE,vol.96,K.Wiseetal.,Microelectrodes,microelectronics,andimplantableneuralmicrosystems,p.1188,Figure5,2008,withpermissionfromIEEE]. 50 ].IthassincebeenwidelyusedasaCNSrecordingprosthesisaswell.CyberkineticslicensedthetechnologyandhasmarketedtheUtahmicroelectrodearraywiththeirBrainGatesystemforrecordinginthecentralnervoussystem.AclinicaltrialwasperformedwiththeBrainGatesystemasaBMIfortheseverelymotorimpaired[ 17 ]. TheUtaharraywasrstfabricatedasfollows.Startingfroma1.7mmthicksiliconwafer,thermomigrationwasperformedtomaketrailsofp+Sifromonesideofthewafertotheotherina10by10array.AdicingsawwasusedtocutinthespacesbetweenthedopedSitrialsleavingathreedimensionalstructureof1.5mmcolumnsthatareelectricallyisolatedatthebasebypnjunctions.Thecolumnswere150msquareand1.5mmtall,withcentertocenterspacingof400m.Thestructurewasthenputthrough 34


ThenextgenerationofUtaharraysshowninFigure 2-8 includedthefollowingchanges.Adifferentlayeringoftipelectrodemetals(Pt/Ti/W/Pt)wasusedandaninsulationlayerofpolyimidewasplacedontheremainingpartofthetheprobeshanks[ 22 51 ].Also,theelectricalisolationofelectrodeswasimprovedbyusingaglassdielectricastheinsulationbetweentheprobesitesonthebackofthewafer[ 51 ].Laterchangesinthefabricationprocessallowedthelengthoftheprobestovaryinonedirection,effectivelygivingathreedimensionalarrayoftherecordingsitesinspace[ 52 ].Inamorerecentpublication,batchfabricationisshownfortheUtaharrayin Figure2-8. Utahmicroelectrodearray[reprintedfromProceedingsofSPIE-TheInternationalSocietyforOpticalEngineering,R.Bhandarietal.,SystemintegrationoftheUtahelectrodearrayusingabiocompatibleipchipunderbumpmetallizationscheme,p.1567,Figure1,2007withpermissionfromIEEE]. whichtheytoutamasklessprocess.Hereparylene-cisusedinsteadofpolyimideasaninsulationfortheSiprobeshanks,andtheetchingschemehasbeenchangedto 35


53 ]. Mostrecentpublicationsshowthedesignofafullyimplantable,wirelesssystem.Utah'sapproachistoip-chipbondallelectronicsandpowerandtelemetryhardwareontothethebackoftheSiplatformonwhichtheelectrodesarefabricated[ 53 ].Theelectrodesareimplantedintothecortexwhiletheelectronicsrestonthetopofthecortex.Thedesignisconstrainedbytissueheatingbecauseofthecloseproximitytoneuraltissue[ 54 ]. ThegroupfromSwedenfabricatedarrays(namedVSAMUEL)similarinshapetotheMichiganarrayinthatelectrodesiteswereplacedalongtheshankofSimicromachinedprobes[ 55 ].Thedifferenceintheirprocessowwastheuseofasilicononinsulator(SOI)waferandtheuseofdeepreactiveionetch(DRIE)fortheremovalofthebulksilicon.Inalaterpublication,theydiscussedtheabilitytouseadirectwritesystemthatwillcustomizeelectrodesitelayoutinapracticalmanner[ 56 ].Insteadofusingmaskstoetchthesiliconnitrideinsulationlayerontopoftherecordingsites,theyuseadirectwritelaserbeamtoopenthePtorIrrecordingsites.Thisreducescostinproducingcustomdesignsthatneed,forexample,avariationofelectrodespacing[ 56 ]. AcollaborationbetweenArizonaStateUniversityandSandiaNationalLaboratoriesresultedinaSi-basedactuatedmicroelectrodearray[ 57 ].Tocircumventlossofsignalovertime,thisgroupdesignedandfabricatedasystemthatallowedrepositioningoftheimplantedmicroelectrodearray.TheyusedtheSUMMiT-Vmicrofabricationtechnologytobuildthermalactuatorsintoaprobestructure.Tworecordingelectrodescouldbemoved 36


58 59 ].In2001,twogroupspublishedindependentpapersonpolyimide-basedmicroelectrodes.Onlyahandfulofotherdesignshaveemergedsincethen.Mostwillbediscussedinthissection.TheArizonaStatedesignisdescribedrst. AresearcheffortstartingatArizonaStateUniversitybyDarylKipke'sgroupusedmicromachiningtechniquestoprocessamicroelectrodestructurethatconsistedofalayerofthin-lmmetalsandwichedbetween10mthicklayersofpolyimide[ 58 ].UsingaSiwafertohandletheprocessingsteps,asacriciallayerofSiO2wasdeposited,thenpolyimidewasspindepositedandcured,followedbygolddepositionandpatterning.Thenatoplayerofpolyimidewasspunasthetopinsulationlayer.Reactiveionetchingremovedpolyimidefromthe30mby30mrecordingsitesandlargerbondpads.Platinumwasdepositedandpatternedasthenalelectrodematerial.Thenthepolyimidestructurewasremovedviachemicaletchfromthehandlewafer.Theirdeviceshadtworecordingsitesononepolyimideshankandavarietyofdesignswiththreeormoreshanks.OneexampleisdepictedinFigure 2-9 .Thedeviceswerehighlyexibleandwouldbuckleundertheforceneededforinsertionthroughthecortex,soincisionshadtobedoneinorderforthemicroelectrodearraytobeimplanted[ 58 ].Acutestudiesshowedpromisingresultsintheirrstpublication. LaterpublicationsbyKipke,whohadsincemovedtotheUniversityofMichigan,introducedaparylene-basedmicroelectrodearraywithmicrouidicsfordrugdelivery[ 60 ]andanopenarchitecturemicroelectrodewithsubcellulardimensionsseeninFigure 2-10 [ 61 ].Thesecondparylenedesignwasnotyetafunctionalmicroelectrodein 37


Polyimide-basedmicroelectrodearray(ArizonaState,Gen1)[reprintedfromIEEETrans.Biomed.Eng.,P.Rouscheetal.,Flexiblepolyimide-basedintracorticalelectrodearrayswithbioactivecapability,vol.48,no.3,p.363,Figure1(g),2001,withpermissionfromIEEE]. thatnorecordingsitesweremadeonthestructure.Theirgoalwasrathertoassessthetissuereactiontothepolymerimplantforsubsequentversions. Figure2-10. Parylene-basedmicroelectrodearray(U.ofMichigan)[reprintedfromBiomaterials,J.SeymourandD.Kipke,Neuralprobedesignforreducedtissueencapsulationincns,vol.28,pp.3596,Figure1(a),2007,withpermissionfromElsevier]. AnewgroupatArizonaStatepublishedanextgenerationoftheKipkemicroelectrodeinreference[ 58 ].Theydesignedforincreasedstiffnessthatallowedimplantationintothecortexwithoutbuckling[ 62 ].UsinganSOIwafer,asimilarpolyimide-metalstructurewasfabricated.ThestructurewasthenremovedfromthebulkSiresultingina20mthickpolyimidestructurewith5mofSibeneath.Siwasthenselectivelyetched 38


2-11 Figure2-11. Polyimide-basedmicroelectrodearray(ArizonaState,Gen2)[reprintedfromJournalofMicromechanicsandMicroengineering,K.Leeetal.,Polyimide-basedintracorticalneuralimplantwithimprovedstructuralstiffness.vol14,issue1,p.35,Figure4(a),2004,withpermissionfromIOP]. StieglitzandGross,ofGermany,publishedasimilarpolyimidemicroelectrodedesignastheKipkegroupin2002,excepttheirfabricationprocessallowedforfrontandbacksideelectrodearrangementsasdepictedinFigure 2-12 [ 63 ].Theyalsoplatedplatinumblackontheelectrodesitestodecreasetheirimpedance.Thisgrouphasnumerouspapersonsieve,cuff,andplanarpolymerelectrodearraysthataremainlygearedforPNSstimulatingandorrecordingprostheses[ 64 ].Thepublicationmentionedrst[ 63 ]wastheonlypolymer-basedmicroelectrodetargetingintracorticalrecordingandnoinvivoresultsweregiven. AnotherresearchgroupthathasexperienceinfabricatingpolymermicroelectrodearraysisattheUniversityofTokyo[ 65 ].Theyhavepublishedaseriesofdesignsusingpolyimideandparylene-C.Theirrstdevicewasaplanarpolyimidearrayfabricatedmuchliketheonesalreadymentioned;however,theyincorporatedamagneticlayer(nickel)ontheshanksthatallowedtheelectrodeshankstobetiltedoutofplaneinamagneticeldasshowninFigure 2-13 [ 65 ].Themicroelectrodes,perpendiculartothe 39


Polyimide-basedmicroelectrodearray(FraunhoferInstitute)[reprintedfromSensorsandActuatorsB:Chemical,T.Stieglitz,FlexibleBIOMEMSwithelectrodearrangementsonfrontandbacksideaskeycomponentinneuralprosthesesandbiohybridsystems.vol.83,p.12,gure5,2002,withpermissionfromElsevier]. cableandback-endconnection,weretheninsertedwithoutbucklingintothebrainforacuteresults. Figure2-13. Polyimide-basedmicroelectrodearray(U.ofTokyo)[reprintedfromJournalofMicromechanicsandMicroengineering,S.Takeuchietal.,3dFlexiblemultichannelneuralprobearray,,vol.14,p.106,Figure4(c),2004.withpermissionfromIOP]. Thisgroup'snextseriesofpublicationschangedgearsandstartedwithadesignthatusedparylene-Candmicrouidicchannels.Again,metalfortheelectrodesitesandleadwiringwassandwichedbetweenlayersofparylene-C[ 66 ].Microuidicchannelswerestructuredintheparylenelayersbypatterningphotoresistbetweenthelayersandsubsequentlyremovingit,leavingavoid[ 66 ].PhotographsofthisdeviceareshowninFigure 2-14 .Inthispaper,insertionintothecortexwasachievedbyinsertingheatedpolyethyleneglycol(PEG),abiodegradablepolymer,intothemicrouidicchannel.After 40


67 68 ].Neuralgrowthfactor(NRG)wasencapsulatedinmicrosphereswhichwereseededinPEGandsetinthemicrochannel.Acuteresultsweregivenshowingpotentialforfutureuse[ 68 ]. Figure2-14. Parylene-basedmicroelectrodearray(U.OfTokyo)[reprintedfrom26thAnnualInternationalsConferenceoftheIEEEEMBS,T.Suzukietal.,Flexibleneuralprobeswithmicro-uidicchannelsforstableinterfacewiththenervoussystem,p.4058,gure3,2004,withpermissionfromIEEE]. ThenaldesigndiscussedinthissectionreferstoapublicationfromKarenCheungattheUniversityofBritishColumbia.,Aexiblemicroelectrodearrayismadeusingpolyimide(showninFigure 2-15 ),whichgeometricallyresemblesasingleshankMichiganmicroelectrodearray[ 69 ].Themetalfortheelectrodesitesaswellasleadwiringisplatinum.Therewere16electrodesites,25mindiameter,patternedinarowona15mthick,2mmlong,and195mwideshank,whichtaperedto35m.Alonger,monolithicly-fabricatedcableattachedtoaback-endconnector.Theyclaimedtheirexibledevicewasimplantedwithoutbulkingandcausedminimalimmuneresponseafter8weeksinvivo. 41


Polyimide-basedmicroelectrodearray(U.ofBritishColumbia)[reprintedfromBiosensorsandBioelectronics,K.C.Cheungetal.,Flexiblepolyimidemicroelectrodearrayforinvivorecordingsandcurrentsourcedensityanalysis,vol.22,no.8,p.1786,Figures2(a),3(a),2007,withpermissionfromElsevier]. 11 12 ].Theypossessthenecessarysmallsizeneededforimplantationandarewellestablishedintheeld[ 70 ].However,itisdifculttoscale-upmicrowirearraysduetoassemblyandsizeconstraints.Theincreaseinthenumberoftotalrecordingsites,consistencyofrecording-sitegeometryandsurfacestructure,andintegratedelectronics,aresomeadvantagesofmicromachinedmicroelectrodesoverdiscretelyassembledmicro-wirearrays.Si-micromachinedelectrodessuchastheMichiganandUtahprobehavebeengainingpopularity.ClinicaltrialswiththeUtahelectrodehaveoccurred[ 17 ]. Thereviewedmicromachinedmicroelectrodedesignsalsohavedistinctdisadvantages.TheMichiganandVSAMUELarrayhaverecordingsitesthatarepositionedalongtheshankoftheprobe.Thus,themajorityoftherecordingsiteswillberecordingfromneuraltissuethathasbeendamagedduringtheimplantationprocess.Itmaybeargued 42


71 ].TheUtaharraydesignalsohassomeissues.First,thelengthoftheimplantedprobesarelimitedtothethicknessofthebulksiliconwafer(1.5mm)[ 72 ].SeveretissueencapsulationduetothedensearrayhasbeendocumentedfortheUtaharraythatdirectlyledtoinhibitedrecordingperformanceandeventualmigrationoutofthecortex[ 22 ].Also,indesignsthatincorporateelectronicsontothebacksideoftheUtahelectrode,powerconstraintsduetotissueheatingareaconcern[ 54 ]. Polymer-basedmicromachinedmicroelectrodearrayshavethesameadvantagesasSi-micromachinedelectrodesplusthepossiblebenetofabettermechanicalmatchtothesoftneuraltissueandincreasedstrainrelieffromexternalforces.However,allofthepolymer-baseddesignshaveelectrodesitesplacedonthesideoftheprobeshankratherthanthetipandthemajorityofthedesignsmustrequireanincisionintotheneuraltissuebeforeimplantation.Moreover,whetherpolymer-basedmicroelectrodearraysreallydoincreasethelongevityofneuralrecordingisyettobeunequivocallydetermined.Whathasbeendocumentedisboththeacuteandchronicresponseofbraintissuetointracorticalmicroelectrodes.Thisimmuneresponseisdiscussednext. 1-1 isinvestigatedinthissection.Basedonhistologicalstudiesofbraintissueafterprolongedimplantation,researchershaveadetailedunderstandingoftheimmuneresponsetomicroelectrodes[ 20 73 74 ].Theirresultssuggesttheforeignbody(i.e.microelectrodearray),elicitsachronicimmuneresponsethathasdetrimentaleffectstosurroundinghealthyneurons. Beforethehistologicalresultsarediscussed,areviewofthecellularmake-upofthebrainisgiven.Thecellsthatconstitutebraintissueareneuronsandglialcells, 43


20 ].Neurons,accountforlessthan25%ofthetotalnumberofcells.Theglialcellsmakeuptheremaining.Oligodendrocytescreatemyelinfoundonneurons.Astrocytesandmicrogliarespondtoinjuryinthebrain.Whenaninjuryoccurs,theastrocytesandmicrogliabecomeactivatedandmovetotheinjurysite[ 75 ].Microgliasecretreactiveoxygenintermediates(ROIs)inwhatiscalledtherespiratoryburst[ 75 ]aswellascytotoxicenzymes.Theirgoalistobreakdowncellulardebrisandconsumedamagedcells.TheproductionrateoftheROIsinmicrogliaincreasesgreatlywhenactivated.ROIsincludeO2,H2O2,andOH. Researchershavegivenhistologicalreportsontheimmuneresponseofthebraintosilicon[ 74 76 ]andpolymer[ 61 ]basedmicroelectrodes.Allreportedtwoimmuneresponses:oneduetotheinjuryimposedbytheimplantationoftheelectrodesandanotherduetothepersistentpresenceofthemicroelectrodes.Theinjuryoftheneuraltissuecausedbyinsertionsignaledactivatedastrocytesandmicrogliatomigratetotheareaofimplant.Aclusterofthesecells,calledaglialscar,couldbeseenasfarasafewhundredmicrometersaroundtheimplant[ 76 ].Thisresponsewasdependentonprobesizeasalargerprobewoulddomoredamagetothesurroundingtissueduringinsertion.Overtimetheinitialwoundresponsewoulddiminishandallpapersreportedamorecompactsheathofcellscontainingreactiveastrocytesandactivatedmicrogliaaroundtheimplantedmicroelectrode.Thissheathofcellswouldremainconstantafterfourweeksofimplantation[ 73 ]anddidnotcorrelatetothesizeoftheimplantedprobe(exceptforsubcellularsizes[ 61 ]).Thus,theauthorssurmisedthatthisresponsewasduetothechronicpresenceoftheprobe. Threetheoriesexistontheeffectofimmuneresponseontherecordingpropertiesofthemicroelectrode.Theglialscarthatformsaroundthemicroelectrodeeither1)electricallyisolatestheelectrodefromendogenouselectricalsignals,2)physicallymovesnearbyneuronsawayfromtheelectrodeor,3)releasescytotoxicchemicals 44


77 ].Biranetal.surmisedthatifneuronswerebeingdisplacedfromtheelectrodetheywouldseeahigherdensityofneuronsoutsideoftheglialscar[ 74 ].Theirresultswerenotconsistentwiththattheoryandinsteadshowedthatchronicimmuneresponse,aswellascreatingathicksheathofcellsaroundtheimplant,actuallyresultsinthedeathofnearbyneurons.Biranetal.showedthatwithina100mradiusoftheimplanttherewasa40%lossofneurons.Theysuggestedthatneuronaldeathduetothepresenceofactivemicrogliaisthemajorcontributortodiminishingrecordingperformanceovertime.Corroboratingthisstatement,researcherslinkedthedamageofneuronsinneurodegenerativediseasessuchasAlzheimer'sDisease,amytrophiclateralsclerosis(ALS),andParkinson'sdiseasetoROIsproducedbyreactivemicroglia[ 78 ]. Insummary,itwassurmisedthatthechronicallyimplantedmicroelectrodearraywillelicitacontinualimmuneresponse,whichallowsmicrogliatobecontinuallyactivatedandreleasecytotoxicchemicals[ 73 ].Itwasshownthatduetothereleaseofsuchchemicals,theneuronsneartheimplantdie,anditwasproposedthatthismechanismratherthanelectricalisolationorthedistancingofneuronsduetoaglialscarringwasthemostsignicantcontributortodecreasedrecordingcapabilityovertime[ 79 ].Thus,thenextlogicalprogressionofresearchwastoassesswhythemicroelectrodeswereproducingachronicimmuneresponse. 79 80 ].ThehistologicalstudiesreviewedinSection 2.4 conventionallytetheredtheimplantedarraytotheskullofthesubject.Thetetheringconsistedofsecuringtheimplantedshankatthecraniotomysitetothesurroundingskullwitharigidmedicaladhesive[ 73 74 76 ].Figure 2-16 showshowatypicalrigidmicroelectrode 45


Typicaltetheringschemeofarigidmicroelectrodearray.Insetshowsthemeningiallayers. arrayisimplantedinthebrainandsecuredtotheskullviaabonescrewandmethylmethacrylateabondingcement.Theinsetshowsthemeningiallayersbetweentheskullandthesurfaceofthecortex.Theduraistherstmembranebelowtheskulltowhichthearachnoidlayerisattached[ 81 ].Thepiaisamembraneattachedtothesurfaceofthecortex.Inbetweenthepiaandthearachnoidlayerexistsaspacelledwithcerebralspinaluidthatcushionsthebrain[ 81 ].Theabsenceofmechanicalattachmentinthesubarachnoidspacealsoallowsthebraintomovewithrespecttotheskullwhentheheadundergoeslargerotationalaccelerations[ 37 ]. Ifaforceisappliedtotheback-endoftherigidmicroelectrodeinFigure 2-16 (thepartprotrudingfromtheskull),strainmaybetransferredalongtheprobe.Thismayacttoloosentheskullconnectionovertimeaswellasdisplacetheelectrodetipwithinthebraintissue.Moreover,ifthebrainmoveswithrespecttotheskullunderheadrotation,thetipoftheimplantedelectrodewillmovewithrespecttothebrainifitisrigidlyconnectedtotheskull. 46


37 ].Theyrecognizedthatanimplantedelectrodecanbedisplacedrelativetoitssecuredconnectionpointattheskullduetorotationoftheheadandsubsequentmovementofthebrainwithrespecttotheskull.Theirelectrodedesign,whichimplementedathin,exible,goldwirebetweentheelectrodeinthecortexandtheexternalconnection,limitedmotionoftheelectrodetipto10mfora1mmdisplacementofthebrainwithrespecttotheskull. However,asmicroelectrodearraysratherthansingleelectrodesbecamenecessaryforBMIsystems,front-endstrainreliefwasomittedinmanySi-baseddesignsinordertoincorporatemanyelectrodechannels.Twoexceptions,theUtahandMicroprobebedofnailsdesignsclaimtohavefrontendstrainreliefbyhavingthinandexiblegoldwiresconnectingtheimplantedelectrodestotheback-endconnector.Nomodelinghasbeendonetoquantifyhowwelltheirwirebundleprovidesstrainrelief,however.Abackoftheenvelopecalculationsuggeststhatiftheyuse25mdiameterwire-bondingwireasthesingleconnectiontotheelectrodechannels,thentheresultingeffectivethicknessofthe100wirecableis10025mor250m,whichwouldhavesignicantlyreducedexibility.Moreover,thehybridnatureoftheback-endwireconnectionispronetofailure. MechanicalmodelingoftetheringinducedstrainhasbeenperformedforSiandpolymermicroelectrodesresemblingtheMichiganelectrodegeometry[ 82 ].ThispaperrstshowedthatSishankmicroelectrodes,rigidlytetheredtotheskull,transfersignicantstraintothesurroundingbraintissuefromaradialortangentialforceappliedatthetopofthecortexandresultintipdisplacement.Theyalsoshowedthattissueadhesionwillacttodecreasetheresultingtipdisplacementforagivenforce. Sabbaroyanetal.performedsimilarmodelingofaSiMichiganmicroelectrodearrayincomparisonwithapolyimidearrayofthesamedimensions[ 83 ].Theirresultsshoweda65%-94%decreaseinstrainattheelectrodetipduetoforceinthetangentialdirection 47


Therefore,usingconventionaltetheringtechniques,theresultingstrainseenbytheneuraltissueisdependentontheexibilityoftheimplantedshank.MosthistologicalstudiesdescribedinSection 2.4 useSishankmicroelectrodearraysandfoundpersistentmicroglialactivation.Biranetal.usedSishankmicroelectrodearraysaswellandnotedapronounceddifferencebetweenonesthatwereconventionallysecuredtotheskullorbrokenoffandleftfreeoatinginthebraintissue;theoatingoneproducedsignicantlylessmicroglialresponse[ 79 ].Kimetal.showedsimilarresultswithexible,polymerhollowbersthatwereeitherxatedtotheskullorlefttooatinthebraintissue[ 80 ].Theirresultsshowedanevengreaterdecreaseinmicroglialresponseinthefree-oatingcasesthan[ 79 ].Thus,aexiblesubstratedesignthatminimizestetheringforcesontheimplantedmicroelectrodearrayissupported. 84 85 ].Measuringandamplifyingtheextracellularvoltagewithrespecttoareferenceelectrodelocatedwithinthecerebralspinaluid,butnotinthecortex,insuresthatactionpotentialsfromneuronswithin200moftheimplantedmicroelectrodewillbemeasured. Byreviewingthenumerousmicroelectrodearraydesigns,advantagesanddisadvantagesareapparentforthedifferentdesignschemes.Outoftheprosand 48


2.3.5 ,someofthemostimportantpointsusedinthedesignoftheUFmicroelectrodearrayareasfollows.Microwirearraysthatdonotusemicrofabricationtechniquesandarediscretelyassembledarenoteasilycompatiblewiththeintegrationofelectronicsforafully-implantablesystem.Platformsforelectronicsthatresideonthecortex,asintheUtaharray,havepowerconstraintsbecauseoftissueheating.Moreover,catastrophicfailuremaybeinducedbythefractureofbrittlematerialsusedinthetheimplantedmicroelectrode.Thisworkpresentsamicroelectrodedesignthatincorporatesrobustmaterialsthatwillnotbreakandcanbeintegratedwithapplication-specic-integratedcircuits(ASICs)inawaythatminimizestheamountofspaceneededforintegrationandplacestheelectronicsawayfromthecortexontopoftheskull. Knowledgeoftheimmuneresponseandhowitisaffectedbymaterialcomposition,size,mechanicalproperties,andimplantconstructismostimportantforlong-termefcacyofthedevice.BasedonthepapersreviewedinSection 2.4 ,thesizeandshapeofthemicroelectrodearrayhasmostimpactontheinitialwoundresponseratherthanthechronicforeignbodyresponse.Thus,thesizeofthemicroelectrodearrayshouldbeminimizedtoreducethemagnitudeoftheinitialwound.However,thefactorscontrollingtheseverityofthechronicimmuneresponseandtheresultingdecreaseinrecordingperformancearenotyetfullyknownandthus,aredifculttodesignaround.Amicroelectrodewithminimaltetheringtotheskullmadeoutofsofter,moreexiblematerialsissuggestedtolessenthechronicwouldhealingresponsebytheresearchintheeldsofar.However,thegoalofthisworkistoexemplifythefunctionalityoftheFloridaWirelessIntegratedRecordingElectrode(FWIRE)design,whichuseswell-established,tungstenmicrowireelectrodesthatareintegratedwithamicromachinedpolymer-basedsubstrate.TheUFmicroelectrodearraycapitalizesonadesignthatmaximizesthefunctionalitywithintegratedelectronicswhileallowingfuturechangestotheimplantedmicroelectrodestobemade. 49




Theuseofmetalasanimplantmaterialismostwidelyknownfordentalandorthopedicapplications.Inthesecases,metalisprimarilyusedforstructuralpurposes.Corrosionofthemetalimplantsfororthopedicapplicationsisanongoingissue[ 86 ].Cardiacpacemakersareoneexampleofamedicaldevicethatusemetalelectrodesforelectricalsignalconductionintothecardiacmuscle.Alargebodyofliteratureisavailableonthecorrosionanalysisofmetalsandmetaloxidesforstimulationpurposes[ 87 90 ].Neuralinterfaceprostheticsalsousemetalfortheelectricalconductionofsignalsatthetissueinterface.Lessinformationonthecorrosionpropertiesofmetalsisavailableforneuralrecordingapplications.Tounderstandhowcorrosionmayoccur,thephysicsexplainingthenatureofchargetransferatametal-tissue,orelectrode-electrolyte,interfacearepresentedinthischapter.Also,thecurrentunderstandingofthecorrosionpropertiesoftungsten(themetalofnumerousintracorticalmicroelectrodes)isdiscussed,showinggapsintheknowledgebaseforbiologicalapplications. 36 ].Itisshownnextthatpassageofcurrentiseffectivelycapacitivelycoupledattheinterface.Thisphenomenonisdescribedbythedoublelayertheory. Whenanunbiasedmetalelectrodeisimmersedinanelectrolyticsolution,aspacechargeregionwillformattheinterface[ 91 ].Physically,thisisaredistributionofcharge 51


91 ].Thermodynamically,thespacechargeregioncanbeexplainedbythedifferenceinelectrochemicalpotential,,ofthemetalandelectrolyte.Theequationfortheelectrochemicalpotentialforonespeciesis where0isthechemicalworkandzFistheelectricalworkrequiredtobringonemolewithchargezforminnitytothematerialphase,whereFisFaraday'sconstantandispotentail[ 91 ]. ThespacechargeregioninmetalandsolutioninterfaceswasrstdescribedbyHelmholtzandisknowngenericallyasthedoublelayer[ 91 ].Hepostulatedthataxedlayerofionicchargewouldbeattractedtotheinterfaceduetothedifferenceinelectrochemicalpotentialatequilibrium.Histheoryhowever,couldnotexplainallexperimentalresults[ 91 ].Thus,subsequentinterfacemodelshavearisengivingamorecompletepicture. ThefollowingpresentstheSternmodelofthedoublelayer,whichisacombinationoftheHelmholtz-PerrinandGouy-Chapmanmodels.AsFigure 3-1 shows,theinterfacehasaninnerandouterHelmholtzplane(IHPandOHP,respectively).Theinnerplaneconsistsofadsorbedionsormoleculessuchaspolarizedwatermolecules;theouterplaneconsistsofsolvatedions(normallycations)thataretheoppositesignoftheexcesschargeonthemetal[ 91 ].ThereisanitedistancedbetweenthecentersoftheionsormoleculesattheIHPandthesolvatedionsintheOHP.Thislayerconstitutesaxedlayerofcharge,andthereforeaxedcapacitancethatdoesnotchangewithappliedpotential,asHelmholtzrstpostulated. ThenextlayerintheSterndoublelayermodelisthediffuselayer.BasedonadoublelayertheoryproposedindependentlybyGuoyandChampman,SternconcludedthatadjacenttothelayerofxedchargeattheOHP,thereisaspaceinwhichcharge 52


Equilibriumelectrode/electrolyteinterface. isdistributed.Thenetchargeinthisareaexponentiallydecaystozeroasafunctionofdistance[ 91 ].ThechargeontheelectrodesurfacewillequalthechargeintheHelmholtzdoublelayerplusthechargeinthediffuselayer,qm=qIHP+qdi(x).Ifusingtherelation, whereispermittivity[ 91 ],itcanbeseenthatthetwolayersconstitutetwopotentialdrops wherethedropintheHelmholtzdoublelayerislinearandexponentiallydecayinginthediffuselayer[ 91 ].Thedenitionforcapacitanceis 53


91 ].Therefore, wherethedoublelayercapacitanceCdlisequaltotheseriescombinationoftheHelmholtzdoublelayercapacitanceCHdlandthediffuselayercapacitanceCdi.Thecapacitancevaluesaregivenby and coshzFOHP whereAistheelectrodearea,istheDebyelength,zisthechargenumberofspeciesi,FisFaraday'sconstant,Ristheuniversalgasconstant,andTistemperature[ 91 ],[ 36 ].Thediffuselayercapacitancegivenaboveisonlyvalidforanelectrolytehavingonecationicspeciesandoneanionicspecieswiththesamechargenumber. Inpractice,thetotaldoublelayercapacitanceisdominatedbytheHelmholtzdoublelayercapacitance.Insufcientlyconcentratedsolutions,CdibecomesmuchlargerthanCHdl,andthereforehasnegligibleinuenceonCdl[ 91 ].Thedoublelayercapacityistypically1020F=cm2[ 92 ].Sinceithasbeenshownthatcurrentiscapacitivelycoupledinthedoublelayer,thecurrenttovoltagerelationshipinthebulkelectrolyteisconsiderednext. AsstatedinSection 2.2 ,theneuralsignalisrecordedviatwoelectrodesinthetissue.Oneisincloseproximitytotheneuron,andtheotherissufcientlyfarawaysoasnottomeasurethesamesignal.Thepotentialdifferencemeasuredacrossthetwoelectrodesthenequalsthevoltagedroppedacrosstheelectrolyteplusthevoltagedroppedacrossthedoublelayeroftheelectrodesas 54


Thefollowingdiscussionwilloutlinethederivationforananalyticalequationdescribingtheelectrolyteresistanceofadiskelectrode.Fluxofionicspeciesisgivenby whereuiisthemobility,ciistheconcentration,Diisthediffusioncoefcient,andvisvelocityofspeciesi[ 36 ].Thetermsrelatetheowofionstomigration,diffusion,andconvection,consecutively.Thecorrespondingcurrentdensitycanbegivenas Followingthelawofelectroneutralityinthebulkelectrolyte,theconvectiontermiszero,andassumingthereisnoconcentrationgradient,( 3 )yields wheretheconductivityoftheelectrolyteis Thepotentialintheelectroneutral-bulkelectrolytesatisesLaplace'sequation[ 36 ] TheequivalentresistiveterminthebulkelectrolyteisthenfoundbysolvingtheLaplaceequation,withboundaryconditionsasgivenby( 3 )[ 36 ].Foradiskelectrodewithareferenceelectrodeasemi-innitedistanceaway,theresistanceofthebulkelectrolyteisgivenas 4r0,(3) wherer0istheradiusofthediskelectrode. 55


Equivalentcircuitforthenonfaradaicinterface[ 1 ]. Thus,theimpedanceoftheelectrode-electrolyteinterfacemaybemodeledasgiveninFigure 3-2 inabsenceofelectrochemicalreactions(i.e.nonfaradaicinterface)[ 1 ]. 91 ].Thephysicsestablishedthusfar,describingthedoublelayerandbulkregionsforthenonfaradaiccase,alsoholdtrueforthefaradaicinterface.Theonlynewdevelopmentaddressedinthissectionisthefaradaicchargetransfermechanismattheinterface. Inthefaradaicinterface,chemicalreactionsarethermodynamicallyfavorableunderequilibriumandnonequilibriumconditions[ 36 ].Thisstatementmeansthatwhentheelectrodeisimmersedintheelectrolyte,reductionandoxidationreactionsautomaticallyoccurattheelectrodesurface.Thecurrentdensityproducedbyonereversibleredoxreaction,O+ze=R,isgivenbytheButler-Volmerequation RTexpcF RT,(3) wherei0istheexchangecurrentdensity,istheappliedvoltage,oroverpotential,anda,carethetransfercoefcientsfortheanodicandcathodicreactions,respectively[ 36 ].Thisequationshowsthatthetotalnetcurrentwillbethedifferenceoftheanodicandcathodiccurrents.Atelectricalequilibrium,orzerooverpotential,therateofoxidation 56


Electrochemicalreactionsallowchargetobetransferredfromtheelectrolytetothemetalandvisaversa.Theequationforcurrentdeterminestherateatwhichthishappensrelativetoanoverpotential.Thus,theresistancetochargetransfergivenincm2isdenedby[ 93 ] @i.(3) TheBulter-Volmercurrentisanonlinearfunction;however,atsmalloverpotentials,itmaybeconsideredlinear.Ifc=(1a),( 3 )canbewrittenas[ 93 ] Therefore,Rctisgivenby i0F.(3) ThisresistivetermisplacedinparallelwiththedoublelayercapacitanceintheequivalentcircuitmodelasshowninFigure 3-3 [ 1 ]. Figure3-3. Equivalentcircuitforfaradaicinterface[ 1 ]. Theelectrochemicaltheorydiscussedsofarisvalidforonereversiblereactionattheelectrode-electrolyteinterface.Theeffectofmultipleormixedreactionsisgivennext.ThegraphinFigure 3-4 showsthevoltageversuslogcurrentdensityrelationshipfortwoarbitraryredoxreactions[ 51 ].Inthisscenario,thequasi-equilibriumpotentialandcurrentdensityforthesereactionsarewherethelinescrossforthetworeactions.Thus, 57


51 ].Thepotentialandcurrentdensityatwhichtheanodicreactionrateequalsthecathodicreactionratearecalledthecorrosionpotential,Ecorr,andcorrosioncurrentdensity,icorr.Noticethedifferencebetweentheexchangecurrentdensityforasinglereactioni0. Figure3-4. I-Vrelationshipoftworeactionsoccurringattheinterface. Similarto( 3 ),thecurrentdensityataninterfacewithmixedreactionsis aicexp2.303 c,(3) wherea,c=RT 51 ].Forsmalloverpotentials,( 3 )islinearizedandthepolarizationresistancebecomes 2.303(a+c),(3) whereicorr=ia=ic[ 51 ]. 3.1 consideredtwosimpleandidealcases;theblockingandfaradaicelectrode-electrolyteinterface.Intheblockingcase,theelectrodeiscapacitivelycoupledbythedoublelayercapacitanceandallowsalternatingcurrenttoowwithno 58


93 ].However,thephenomenadescribedpreviouslyaresufcientforcharacterizationoftheelectrode-electrolyteinterfacesseeninthiswork. 11 15 23 27 39 ].Tungstenelectrodesformedfrom50mdiametermicrowiresaredesirableforintracorticalapplicationsbecauseoftheirstrengthandrigidity.Themicrowirescanbeinsertedintoneuraltissuewithoutbuckling.However,tungstenisnotimpervioustocorrosion.Afailuremechanismformicroelectronicintegratedcircuitshasbeenshowntobethecorrosionoftungstenvia-plugs[ 94 ].Tungstencoils,duetotheirthrombogenicity,hadbeenusedclinicallytooccludeunwantedvasculatureandhavesincebeentakenoffthemarketduetodegradationofthecoils[ 95 ].Sanchezetal.showedstructuralmodicationoftungstenmicrowiresafterfourweeksofinvivoimplantation[ 96 ].Theirobservationsuggestedcorrosionhadoccurredattheendofthetungstenmicrowires. Althoughthecorrosionandanodicdissolutionoftungstenarewelldocumentedforacids[ 97 100 ]andbases[ 99 101 ]atvariouspotentials,therateandelectrochemicalmechanismoftungstencorrosioninbiologicalsolutionsarenotwelldocumented.Inacomprehensivestudy,Aniketal.showedthatthedissolutionoftungstendependsonspecicsystemconditionssuchaspotentialandpH[ 99 ].Onestudyusedsimilarconditionsseenbytungstenmicrowiresinneuralrecordingapplications.Peusteret 59


95 ].Theiranalysishowever,didnotspecifyacorrosionrateinunitsofmassperareapertimeandthusisnotusefultoestimatecorrosioninothersystems.Therefore,astudythatquantiesthecorrosionratefortungstenmicroelectrodesusedinintracorticalrecordingapplicationsisneeded.Moreover,theelectrochemicalbehavioroftungstenmicroelectrodesshouldbecomparedtothebehaviorofplatinummicroelectrodes,whicharealsowidelyusedforneuralrecordingapplicationsandconsideredinertforsuchapplications[ 102 104 ]. Itwouldbeprudenttoknowiftheinammatoryresponsealsoaffectschargetransferatthemicroelectrodes,sinceBiranetal.concludedthatthepresenceofmicroelectrodesinneuraltissueelicitsachronicinammatoryresponsethatmayleadtotheinjuryofnearbyneurons[ 74 ].ReactiveoxygenspeciessuchasH2O2areproducedbythereactivemicrogliaduringtheinammatoryresponse[ 75 ].TwostudiesinvestigatedtheinuenceofH2O2ontitaniumusedforstructuralimplantsinthebody(i.e.hipimplants),[ 105 106 ].TheyshowedthatmillimolarconcentrationsofH2O2modiedthenaturaloxidelayeronthetitaniumresultingindecreasedcorrosionresistance.Toourknowledge,therearenostudiesthatanalyzetheelectrochemicalresponseoftungsteninbiouidscontainingH2O2.Sincehydrogenperoxideisanoxidizingagent,itwouldbebenecialtoassessthereactivityoftungsteninelectrolytescontainingphysiologicalsalineandH2O2.ThereactivityofplatinuminelectrolytescontainingH2O2hasbeenexplored[ 107 110 ];however,thepotentialatwhichtheexperimentsweredoneisunrealisticforneuralrecordingapplications.Thus,ananalysisofthereactivityofplatinuminsalineelectrolytescontainingH2O2undertheconditionsseeninrecordingapplicationsisalsowarranted. 60


TheworkpresentedinChapter 7 aimstoincreasetheknowledgeofcorrosionoftungsteninelectrolytesthatmodelphysiologicalmediabyspecifyingacorrosionrateaswellastheelectrochemicalreactionsresponsibleforthecorrosion.Thisworkalsotakesacloserlookintothereactivityofplatinuminsolutionsmodelingbiologicalmediaanddenespossiblereactionmechanisms.Inthenextchapter,theUFintracorticalmicroelectrodearrayispresented. 61


TheUFmicroelectrodearraydesignleveragestherecordingpropertiesofconventionalmicrowireelectrodearrayswithadditionalfeaturesincludingaexiblemicromachinedribboncableseamlesslyintegratedtotherigidprobes.Thegoalistoproduceelectrodearraysthatarehighlycustomizableintermsofgeometry/layout,havesimilarrecordingpropertiesascommercialmicroelectrodearrays,andareeasytomassfabricate.CharacteristicsoftheUFFWIREdesignincludethefollowing.Themicroelectrodearrayiscapableofbeinginsertedintotheneuraltissuewithoutbuckling,hasanarrayof8channels,astandardinterfacewithan18pinOmneticsconnector,providesstrainrelieftotheback-endconnections,andhasasubstratethatiscompatiblewiththeintegrationofelectronics.Thechosenapproachistouseaexiblepolymersubstrateandincorporatemicrowirestothefront-endofthedevicetoactastherecordingelectrodesites.Twogenerationsofmicroelectrodedesignarediscussedinthischapter.Bothgenerationsusemicromachiningtechniquestorealizethedevice.Generation1electroplatesthemicrowires,whileGeneration2hybridpackagespre-mademicrowirestotheexiblesubstrate.Fabricationdetails,bench-topandacuteinvivoresultsofthemicroelectrodearraysarediscussedinsequentialorder. 4-1 .Theelectrodeprobesextendfromthecableend2mmandinclude20m50melectrodesitesonthetips.Theelectrodeareaischosenforsufcientcompromisebetweensignalselectivityandnoiseperformanceasgivenby[ 84 ].ThecorrespondingprobedimensionsassureadequatestructuralintegrityaccordingtocalculationusingEuler-Bernoullibeamtheory.Themetaltracesandcorrespondingbondsitescanbemadetoanysizespecicationandspacingdistanceviaphotolithography. 62


111 112 ].Parylene-C,chosenfortheprobeinsulationmaterial,hasalsobeensuccessfullyusedasaninsulatingmaterialonchronicallyimplantedmicroelectrodes[ 113 115 ].Nickelischosenastherigidprobematerialduetoitsabilitytobeelectroplatedeasily.However,Geddeset.al.cautionthatnickelimplantscaninstigateallergicresponseinsomeindividuals[ 116 ].ThereforegoldiselectroplatedontheexposedNielectrodesitestoincreaseitsbiocompatibility. Figure4-1. FlexiblesubstratemicroelectrodearraywithOmneticsconnector.a)Finisheddevice.b)Microelectrodearray.c)Probetipshowinginsulationalongshankandgoldplatingontip. 63


Figure4-2. Fabricationprocessowforgeneration1microelectrode. 64


Electrochemicalimpedancespectroscopywasperformedononemicroelectrodearrayin0.9%NaClatroomtemperatureusingaSolatronImpedanceAnalyzerandGalvanostat.Asilver/silverchloridereferenceelectrodeandplatinumcounterelectrodewereused.Measurementsweretakenoverafrequencyrangeof5Hzto10kHzatopencircuitpotentialwithasinusoidalperturbationvoltageof10mV.AlldatashownisconsistentwiththeKramers-Kronigrelationasprescribedby[ 117 ].Animpedanceof0.9M0.02Misgivenforasingleprobeat1kHz. Regressionoftheimpedancedatawasperformedtoobtainanequivalentcircuitdescribingthephysicalnatureoftheelectrode/electrolyteinterface.ThemostappropriatecircuitthatphysicallyexplainstheinterfaceconsistsofRe(electrolyteresistance)inserieswithaparallelcombinationofRct(chargetransferresistance),andZCPE(doublelayerconstantphaseelement),whereZCPE=((j!)Qdl)1.TheregressedparametersaregiveninFigure 4-3 Figure4-3. Equivalentcircuitforelectrode/electrolyteinterface. Thermalnoisefromtherealpartoftheelectrode/electrolyteinterfaceimpedanceisassumedtobethedominantnoisesource[ 118 ].Theresultingnoisevoltagecanbegivenasfollows 65


118 ].Thetheoreticalrmsnoisevoltageofthedesignedneuralprobeis2Vbasedontheregressedequivalentcomponentsandfrequencyrangeof100Hzto6kHz. 119 ].Themicrowirearraywasimplantedtoadepthof1.66mmasshowninFigure 4-4 intotheforelimbregionoftheprimarymotorcortex.Theelectrodesarestereotaxicallymovedtotheappropriatesiteandloweredtotheappropriatedepthusingamicropositioner(1mmperhour)tominimizedistresstothebraintissue(FHC,Bowdowinham,ME).Thearraywasthengroundedusinga1/16diameterstainlesssteelscrew.AlowproleOmneticsconnectorwasusedtoattachtherecordingwire. Figure4-4. Surgicalimplantationofgeneration1microelectrode. 66


Onceasetofwaveformtemplateswasgeneratedforadatastream,allthosetemplates(noise)thatdidnotmatchcharacteristicneuraldepolarizationbehaviorwereremoved.Theremainingwaveformtemplatesweresortedaccordingtoamplitudeandshape,andanywaveformtemplatesthatweresignicantlysimilartoeachotherwerecombinedintoasingletemplate.Clusteringofwaveformvariancewithintemplateswasveriedthroughprincipalcomponentanalysis(PCA).Eachwaveformtemplatewasstatisticallyuniqueandrepresentativeofadistinctneuronwithinthechannel.Usingthesetwovalues,thesignaltonoiseratioforeachneurontemplatewascalculated.Toensureproperreporting,allspikewaveformtemplatesthatpossessedpeaktopeakamplitudeofamagnitudebelowthreetimesthevalueofthenoiseoorwereconsideredtooclosetothenoisetobereliablyandconsistentlydistinguishedandwereremovedfromthestudy.Valuesofneuralyield,noiseoor,amplitude,andSNRarereportedforeachchannelwithinTable 4-1 Actionpotentialamplitudesaslargeas115Vandassmallas13Varediscriminatedbytheelectrodeandrecordingsystem.Theaveragenoiseooris4Vrmsforafrequencyrangeof500Hzto6kHz.Figure 4-5 showsrecordeddatafromelectrodenumber6. 67


NeuronalYieldforGeneration1MicroelectrodeArray Electrode12345678 Yield(neurons)22236534 NoiseFloor(V,rms) 20.123.332.626.1114.790.431.445.1 NeuronAmplitude13.215.524.718.356.852.313.429.7 (V,PtP)14.234.635.711.721.0 21.321.016.0 18.813.8 17.4 13.813.415.815.526.927.618.620.4 10.29.913.412.420.822.811.216.8 SNR(dB)10.216.519.510.013.8 12.214.811.4 11.211.2 10.5 arrayconsistsofeightprobeswithgold-platedelectrodesites(1000m2)onthetipthatprotrudefromaexiblecable. Duetofailureintheback-endOmneticsconnection,invivorecordingswereunabletobeperformedafterthesurgery.However,theelectrodearraywasleftimplantedintherat'sbrainforaremaining2weeks.Itthenwasremovedandimagesweretaken.Remarkably,theelectroplatedmetaloftheelectrodewasrecessedwithintheparylene-cinsulationasseeninFigure 4-6 byapproximately20mshowingcorrosionwhichcouldleadtoultimatefailure.Thus,nickelaswellasthenickel/goldcombinationwereremovedfromfuturedesigns. TheAchilles'sheelofGeneration1istheneedforelectroplatingofametaltoathicknessof20mormore.Itisdifculttondnoblemetalsthatcanbeelectroplatedandevenhardertoplatethemtosuchathickness.Therefore,theprocessowhasbeen 68


Datafromneuralrecordingintheratmotorcortexatadepthof1.66mduringimplantationsurgery.Insetshowstwodistinctneuronsrecordedbysingleprobe. changedinGeneration2toallowtheincorporationofagreaternumberofelectrodematerials. BasedontheinadequacyofGeneration1,namelycorrosionoftheelectroplatednickelmicrowire,Generation2incorporatespre-fabricatedtungstenmicrowiresinthedesign.Tungstenischosensinceitisusedincommerciallyavailablemicroelectrodearrays,whichhavelargeuseintheneurosciencecommunity.However,asChapter 7 69


CorrosionofElectrodea.SEMandEDSmeasurementresultsoftypicalgold-platednickelelectrode.b.SEMandEDSmeaurementresultsoftypicalelectrodeafterinvivoimplantationfortwoweeks.Noticethatmetalhadbeenerodedfromthesurfacebutparylene-Cinsulationremainsunchanged. cautions,tungstenalsocorrodesinbiologicalenvironments.Fortunately,theestablisheddesignisapplicabletoanytypeofmetalwire. Thegeneration2microelectrodearrayshowninFigure 4-7 consistsofthreemajorcomponents:apolymersubstratewithencapsulatedwiring,tungstenmicrowires,andnutsusedforanchoringandgrounding.Rigid50mdiametertungstenmicro-wiresareattachedtotheendofamicromachinedexiblecableina1-Darray,allowingforinsertionintotheneuraltissuewithoutbuckling.Themicro-wiresarespaced250mapartasprescribedfordecoupledneuralrecording[ 34 ].Nutsareprovidedforscrewsthatanchorthedevicetotheskullandsupplythereferencepotential.Incorporatingthefastenersyieldsasecuredatplatformforfuturepopulationofip-chipbondedelectronics.DevicedimensionsaregiveninFigure 4-7 70


PolymermicroelectrodearraywithOmneticsconnector.a.Topview.b.Flexibilityofmicroelectrodeisshownwithassumedinvivoposition. 26 ].Changeswereincorporatedtoimprovethequalityandreliabilityoftheendproduct.Aluminumwasrstsputterdepositedona4-inch-diametersiliconwafertoa1mthicknessasthesacriciallayer.Thebottominsulationlayerofpolyimide(PI2611,HDMicrosystems)wasthenspin-depositedalongwithanadhesionpromoter(VM9611,HDMicrosystems)andcuredat300C.Afterfourspins,theresultingthicknesswas24m.Alayerofgoldwasthensputterdepositedtoathicknessof0.1m,whichwaspatternedvialift-offtodenethewiringandbondpads.Polyimidewasnextspunvetimesandcuredtoachieveathicknessof30m,therebymakingthetopinsulationlayer.Chromiumwassputterdepositedtoathicknessof1000Aandpatternedasahardmaskvialift-off.ThenanO2reactiveionetch(RIE)wasperformedtodenethedevicefootprint,uncoverbondpadsandetchgroovesforguidedplacementofthemicro-wires.Fiftymdiametertungstenwiresinsulatedwithpolyimide(CaliforniaFineWire)werethenplacedmanuallyintheetched 71


Figure4-8. Fabricationprocessofgeneration2microelectrodearray. 72


117 ].Theaverageimpedanceat1kHzforallrecordingsiteswas5010k.ThisvaluewascharacteristicofsmallsurfaceareaelectrodesandwasonthesameorderofmagnitudeaselectrodesintheUtaharray[ 50 ]. UsingtheequivalentcircuitmodelshowninFigure 4-9 todescribetheelectrode/electrolyteinterface,theimpedancedatawasregressedgivingthereportedcircuitparameters.Theseparametersweredeterminedusingdataintherangeof100Hzto10kHz. Figure4-9. Equivalentcircuitforelectrode/electrolyteinterface.Reistheelectrolyteresistance,RtisthechargetransferresistanceandZCPEisthedoublelayerconstantphaseelementgivenbyZCPE=((j!)Qdl)1. ExperimentalnoisedatawasmeasuredforthetungstenrecordingsitesimmersedinphosphatebufferedsalineatroomtemperaturewithreferencetoanAg/AgClelectrodeatequilibrium.Thethermalnoisesignalfromtheelectrochemicalinterfacewasampliedbyalownoisevoltageamplier(StanfordResearchSystem(SRS)560)withgainof1000andthenrecordedwithaSRS785spectrumanalyzerfrom1Hzto10kHz.Thethermalnoisemaybecalculatedfromtherealpartoftheelectrode/electrolyteinterfaceimpedanceasfollows where!highand!lowarethehighandlowpass-bandcornerfrequenciesoftherecordingamplier,kisBoltzmann'sconstant,andTistemperature[ 118 ].Thetheoreticalrmsnoisevoltageoftheneuralprobeis1.27Vbasedontheregressedequivalent 73


119 ].Atthesiteoftheelectrodeimplantation,thedurawasremovedtoexposethecortex.TheentireassemblywasimplantedverticallyasshowninFig.3aandloweredtoadepthof1.66mmusingamicropositionertominimizedistressanddamagetothebraintissue.Whiledrivingtheelectrode,electrophysiologicrecordingswereusedtolocatepyramidalcellactivityinlayerVofthecortex.Duringthisprocedure,theassemblywasobservedtoberigidandnobucklingwaspresent.Oncetheelectrodewaspositioned,itwassupportedwithcranioplasticcement(Plastics-1)attachedtoascrewplacedadjacenttothecraniotomy.Afterthearraywassecured,theentireassemblywasfoldeddowntolayatagainstthetableoftheskullasshowninFig.3b.Theexiblesubstratewasthenpermanentlygroundedusingasecondscrew. 74


Actionpotentialswerediscriminatedoff-linewithSpike2(CED,UK).Foreachoftheeightelectrodes,simultaneousrecordingslasting170secondswereusedintheanalysis.Todetectcandidateactionpotentials,athresholdwasappliedtothedataandasetoftemplateswasformed.Signalswithatleastabiphasiccomponentwithina1.6mswindowthatoccurredmorethan25timeswithsimilarshape(80%)wascategorizedasanewneuraltemplate.Allwaveformsthatdidnotmatchcharacteristicneuraldepolarizationbehaviorwereconsideredasnoiseandremoved.Theremainingwaveformsweresortedaccordingtotheamplitudeandshapeofgeneratedtemplates,andanywaveformtemplatesthatweresignicantlysimilartoeachotherwerecombinedintoasingletemplate.Principalcomponentanalysis(PCA)wasusedtoclusterwaveformvariancewithintemplates.ISIdistributioncurvesforeachneuroninthechannelsdisplayedindividualPoissondistributionsasexpected,andshoweddistinctneuronsforeachunitwaveform. Aftertheactionpotentialwaveformswereproperlyisolatedandsorted,thepeak-to-peakamplitude(PPA)wasevaluatedbycomputingtheaveragewaveformofallspikesbelongingtothesameneuron.Thepotentialdifferencewasthenmeasuredfromtheapexofthedepolarizationpeaktotheapexofthehyperpolarizationpeak.In 75


4-11 .Herewecanqualitativelyseethreedistinctneuronwaveformswithalownoiseoor. Theoverallperformanceoftheelectrodeisquantiedintermsofneuronalyield,noiseoor,peaktopeakamplitude,andSNRandisreportedinTable 4-2 .Atotalof5waveformscouldbeextractedfromthis8-channelarray.Theelectrodesandrecordingsystemperformedtodiscriminateactionpotentialamplitudeashighas30Vandaslowas12.8V.TheaverageRMSnoiseooris3.3V.ThepileplotsofactionpotentialsshowninFigure 4-12 indicatetherepeatabilityofthewaveforms. Table4-2. PerformanceofGeneration2MicroelectrodeArray Electrode17 Yield(neurons)32 NoiseFloor(V,rms)4.12.9 NeuronAmplitude303.020.7 (V,PtP)22.314.2 12. 17.317.1 SNR(dB)14.713.8 9.9 76


Datafromneuralrecordingchannelnumber1intheratmotorcortexatadepthof1.66mduringimplantationsurgery. Figure4-12. Threedistinctneuronsextractedduringspikesortinginchannelnumber1oftherecordeddata. oorlessthan2V.Acuterecordingsshowsignaltonoiseratiosashighas17dBwithacorrespondingnoiseoorof3.3Vfortwochannelsshowingdiscernableactionpotentials.Thus,theminimumdetectablesignalislimitedbytherecordingelectronics.Thepresenteddesignmaybeadaptedtousemorenoblemicro-wirematerialssuchasplatinumoriridiumtodecreasetheriskofsurfacemodicationviaelectrochemicalprocesseswithtungstenwires.Thehybridmanufacturingapproachtakenwiththisdesignallowsthemicroelectrodearraytobeimplantedaccuratelyandwithoutbucklingasthemicro-wiresprovidesufcientstructuralintegrityduringinsertion. 77


Furthermore,theelectrodes,orrecordingsites,constituteanintegraldesigncomponent.Theirbiocompatibilityandstructuralreliabilityestablishthecruxofachronicallyviabledevice.Todate,therearemanybiocompatibilityissueswithrigidprobesmadefrommicrowiresorSisubstratesasreviewedinSection 2.4 .Thus,futureBMIrecordingsystemdesignsmustbecompatiblewithchangesinelectroderequirementsasmoreofthebiocompatibilityproblemsaresolved.Thegeneration2UFmicroelectrodearray,beinghybrid-packaged,allowsincorporationofothermicroelectrodeconstructs.ThiscapabilityprovidesadvantagesovertheUtahandMichiganelectrode,whoseSi-basedelectrodeshanksareintegraltotheirdesign. 78


ForBrainMachineInterfacestoworkastherapeuticdevicesfordebilitatedindividuals,theymustprovidethenecessaryfunctionandreliableresultsforthepatient'slifetime.Therefore,strategiestooptimizefunctionandreliabilitydeterminefuturerecordingmicroelectrodesystemdesigns.Foraclinicallyviablesolution,therecordingsystemintheBMImustbefullyimplantablesuchascochlearimplantsandfunctionalelectricalstimulation(FES)implantsforParkinson'sdisease.Afully-implantablestructureforBMIapplicationsrequiresthatelectronicsforamplication,datacompression,wirelesstelemetry,andpowersystemsbeincorporatedontotheimplantablemicroelectrodesubstrate. ThechallengeofrealizingwirelessimplantableneuralrecordingsystemsforBrain-MachineInterfaceshasbeenundertakenbyahandfulofinstitutions[ 49 120 122 ].Alldesignsemployhybridintegrationwiththeelectronics.TheUtahsystemintegratesinterfaceelectronicsviaip-chipbondingtechniquestothetopofaSimicromachined100100electrodearrayimplantedintothecortex[ 120 ].TheMichigansystemusesasiliconexiblecabletoroutthesignalsfromtheimplantedSimicromachinedelectrodestoaplatformcontaininghybrid-packagedinterfaceelectronicslocatedsomedistanceawayonthetopoftheskull[ 49 123 ].InthetimesincetheFloridaWirelessIntegratedRecordingElectrode(FWIRE)wasproposed[ 122 ],researchersfromBrownUniversityhaveadoptedadesignverysimilartotheUFdesign,whereaexiblepolymercableconnectsanimplantablemicroelectrodearraytothehybrid-packagedinterfaceelectronics,whicharepositionedontheskull[ 121 ].TheBrownsystememploysthesilicon-micromachinedUtahmicroelectrodearray,whiletheFWIREsystemusestungstenmicrowiresastherecordingelectrodes.TheFWIREdesignfurtherdifferentiatesitselffromtheotherdesignsbyemployinganovelpulsed-baseddatarepresentationscheme,whichminimizestransmissionbandwidth 79


122 124 ].ThemicroelectrodeplatformdiscussedinthissectionisarststepinachievingarecordingsystemwithwirelesstransmittingcapabilityfortheFWIREproject.Itissimilartogeneration2describedpreviouslyexceptitincludesahybrid-packagedamplierintegratedcircuitandhasaslightlydifferentformfactorandanchoringscheme.Thedesign,fabrication,invitroandinvivocharacterizationoftheamplier-microelectrodesystemisdescribedinthischapter. 1. aplatformwithelectronicsresidingontheskullreducingheattransfertobraintissue, 2. aseamless,exibleconnectionbetweenimplantedelectrodesandplatformforelectronics, 3. agroundingschemethatdoublesasananchoringmechanism,and 4. hybrid-packagingtechniquesthatallowattachmentofmultipleintegratedcircuits. Theplacementofinterfaceelectronicsonaplatformresidingontheskullratherthanontopofthecortexallowsforlessrestrictivepowerconstraintsontheinterfaceelectronicsastissueheatingislessofaconcern.Thisdesignhasstrategicadvantagesoverthefully-implantableUtahmicroelectrodearraydesign,whichplacestheelectronicsontopofthecortex[ 120 ].Inthisdesign,theexibleconnectionbetweentheimplantedelectrodearrayandtheelectronicsallowsout-of-planebendingsuchthattheelectrodearraymaybeimplantedperpendicularlytotheelectronicsplatformandplanarmicromachiningtechniquesmaybeusedforthefabricationofthedevice.Theexibleconnectionalsopreventsthetransferofstraintotheimplantedelectrodesfrommovementoftheelectronicsplatform.Theconnectionismadeseamlessbyusingthesamesubstratefortheentiredevice.Thisdesignensuresaminimumnumberofconnectionpointsthatwouldrequirehermeticsealingandarelativelysimplefabrication 80


45 123 ].Agroundingschemethatdoublesasananchoringmechanism,toourknowledge,isnotusedinanyoftheexistingdesigns.Sinceallrecordedsignalsaretypicallyreferencedtoabonescrew,thisdesignminimizesthespaceneededfortheimplantbymakingthereference,orground,screwthesameasananchoringscrew.Lastly,aip-chipbondingtechniqueisusedtohybrid-packageASICstothesubstrate.Flip-chipbondingratherthanwire-bondingdieorsolderingpackagedICsminimizesthetotalspaceneededforthechipsaswellaskeepsthetotalheightoftheimplantedplatformtoaminimum.ThisstrategyprovidesadvantagesovertheBrownuniversitydesign,whichuseswire-bondingtechniquestoattachtheASICs.TheguidingprincipleoftheUFdesignistheuseofarelativelysimpleprocessowutilizingtungstenmicrowiresthathavebeenusedinvivopreviouslywithhighneuronalyieldinarobustandcustomizablemanufacturingprocess. 5-1 .Untilthewirelesscomponentofthisdesigniscompleted,weofferaccesstotheamplierviaastandardOmnetics18pinconnector.Thiswilleventuallybereplacedinthenaldesign. TheanimalmodelisaSprague-DawleyratasdepictedinFigure 5-1 .Theelectrodesmustbeimplantedintoacraniotomy(+1mmanteriortobregma,2.5mmlateral)atthesitecorrespondingtotheforelimbregionofthemotorcortex[ 119 ].Asseenfromthegure,theregionofspaceavailablefortheexibleplatformtorestontheskullisessentiallythespacebetweentheBregmaandtheLambda.Also,itshouldbenotedthattheareabehindtheLambdapointcomprisessensitivesinustissue,andhenceitisnotadvisabletosecurethesubstratebeyondtheLambdapoint.Moreover, 81


5-1 .Inordertoaccommodatetheentiredeviceinsidetheavailabledesignspace(i.e.betweenBregmaandLambda),carewastakenwhiledecidingthedimensionsofthesubstrate.Thelengthoftheplatformis19mmexcludingthetungstenwirelength,andthewidthis10mm.Nearlyone-thirdofthesubstratewillbebentovertheBregmapoint,thusreducingtheoveralllengthoftheatsurfacewellwithinthelimits.Figure 5-2 showsthephotographofthemicroelectrodearrayandtheexibleplatformcarryingtheamplierchip.Theenlargedinsetshowsthearrayof8tungstenmicrowires.Figure 5-3 showsthephotographdepictingtheexibilityofferedbytheelectrodesubstrate.Thispositioningschemewouldbefollowedafterin-vivoplacement. Theelectrodesiteswereshiftedleftofthemidlineofthedeviceforimplantationintheappropriateareaofthemotorcortex.Aslotforasecondscrewisalsoaddedinthisdesign,allowinglesscriticalplacementbythesurgeon.AlsoaperpendicularlymountedOmneticsconnectorisusedinthisdesignscheme. Theimplantationoftheelectrodeisperformedwiththehelpofastereotaxicplacementsystem.Theelectrodesubstrateisheldverticallyatitsreartipanddrivenslowlyintothealreadydrilledcraniotomy.Keepingthisprocedureinmind,theentirepackageisdesignedwitharelativelyrigidbackendthatenablesaneasyimplantationusingthestereotaxicplacementsystem. 5-4 .A100mmdiameterSiwaferwasusedasasupportingplatformforallthesubsequentprocessingsteps.First,a1mthickaluminumsacriciallayerwassputterdeposited.Polyimidewasspin-deposited 82


Figure5-2. Flexiblepolyimidemicroelectrodearraywithintegratedamplier.Insetshowstheenlargedimageofthetungstenmicrowires. 83


UFamplier-microelectrodesystemshowingtheexibilityoftheelectrodesubstrateandthenalimplantposition. andcuredasinSection 4-8 andatitanuim/goldlayerwassputterdepositedtoathicknessof0.01mand0.2m,respectively.ThedepositedmetalwaspatternedasshowninFigure 5-4 fortheelectricalinterconnectsandatoplayerofpolyimidewasspin-depositedandcured.Eachlayerofpolyimidehasathicknessaround20m.ThetoppolyimidelayerwasselectivelyetchedanisotropicallyusingaReactiveIonEtchertouncoveramplierandOmneticsbondpadsandtoestablishthedeviceoutline.Insulatedtungstenwiresof50mdiameterweremanuallyplacedontothegoldtracesandelectricallyconnectedwithaconductivesilverepoxy(AbleBondepoxy).Thedeviceswereseparatedfromoneanotherbycuttingthewaferwithadicingsaw.EachindividualdevicewasreleasedfromtheSiwaferbyanodicdissolutionoftheAlsacriciallayer. Theamplierdiewasthenbondedtotheexiblesubstrateviaaip-chipbondingprocess.Toenableaneffectiveelectricalcontacttothepadsoftheamplierdie,goldstudbumpsof50-70mdiameterwereplacedonthediebondpadsthroughawirebondingprocess.AphotographofthechipwithstudbumpsisshowninFigure 5-5 Theamplierbondpadviasontheexiblesubstratewerethenmanuallylledwithaconductivesilverepoxy(Ablebond).Theyhaddimensionsof150mby150mtoaccommodatetheICpadsofarea130mby130m.Thedistancebetween 84


FabricationprocessowforUFamplier-microelectrodesystem. Figure5-5. Amplierdiewithgoldstudbumpsonbondpads. twoadjacentcontactpadswas120m.Aip-chipplacementsystem(Model850,SemiconductorEquipmentCorp.)wasusedtoplacethedieonthesubstrate.Afurnacewasusedtocurethesilverepoxyafterplacementandthen,theamplierdiewascoatedwithalow-moisture-absorbing-underllepoxy(Epo-tek302-3M)tohermeticallyseal 85


5-6 showsthecircuitboardshousedinashieldedbox.Thecircuitboardontherightlabeledpowerboardregulatesvoltagesfroma6Vbatterypowersupplythataresenttotheamplierandprovideswiredpass-throughconnectionsforthemeasuredneuralsignals.Thebufferboardontheleftconsistsof8ampliersthatbufferthe8channelneuralsignalsandprovidelowimpedanceinputstotheRA8GAamplier.ThevoltagesregulatedfortheamplieraregiveninTable 5-1 .ThevoltagesVddandAcgndarecontrolledbyxedvoltageregulatorICs,whileVbiasandVbuerarecontrolledbypotentiometersandaretunable.Theinput/outputconnectionsontheboxareillustratedinFigure 5-7 .TheinputconnectionsaredenedastheconnectionsgoingtotheimplantedarrayandtheoutputconnectionsaregoingtoaTuckerDavisTechnologies(TDT)amplier.AcommutatorwithDB25connectorattachestothepowerbox,thenaheadstagewithan18pinOmneticsconnectionononeendattachestothecommutator.ThemaleOmneticsconnectorontheheadstageconnectstoafemaleOmneticsconnectoronthemicroelectrodearray.TheseconnectionsdeliverpowertotheUFamplierandtransferthemeasuredeightchannelsofneuralsignalstotheTDTsignalprocessor.Also,aBNCconnectorprovidesanexternalporttothesystemground,whichisusedforbench-topcalibration.TheoutputconnectionontheothersideofthepowerboxisaDB25connectorthatattachesviaacabletotheTDTRA8GAamplier. 86


Contentsofpowerbox. Figure5-7. Input/outputconnectionsforpowerbox. 87


VoltageSpecicationsforUFAmplier VoltagestopowerUFamp(V) Vdd5Vss0Acgnd2.5Vbias2.6Vbuer1.5 Figure5-8. ExperimentalsetupwithTDTrecordingsystem. 5-8 .TheUFamplier-electrodesysteminterfacesrstwithabufferamplierarraythenaTDTvariablegainamplier(RA8GA)andthentheTDTRZ2signalprocessor.TheTDTRA8GAmustbeusedaftertheUFamplier-microelectrodesysteminordertointerfacewiththeRZ2signalprocessorthatrequiresopticalsignals.TheRA8GAamplierhasthreeinputsettings:0.1V,1Vand10V.Theyamplifytheincomingsignalby10,1,and0.1,respectivelyandcanaccommodatesignalsnogreaterthan0.1mV,1Vand10V,respectively.Themanufacturerspeciedscalingfactorsthattheoutputvoltagemustbemultipliedbytogetthecorrectoutputvoltageare10,170,and1700,respectively.TheinputimpedanceoftheRA8GAisontheorderof10k[ 39 ],whichposesattenuationissueswiththeUFsystem,whoseoutputimpedanceisrelativelyhigh.Abufferamplier 88


TimeseriesnoiseooraffectedbyRA8GApreamplierinputsetting. isusedaftertheUFamplier-electrodesystemtoensurealowimpedanceinputtotheRA8GA. ChoosingthecorrectinputsettingontheRA8GAtouseisintegraltosystemperformance.TheoutputsignaloftheUFamplier-microelectrodesystemhasadccomponentat2.5VandandanaccomponentanywherefromtensofmVtohundredsofmV.SincetheRA8GAcannotACcoupletheinputsignal,thedifferentialsignalgivenastheinputistheoutputfromtheUFreferencedto2.5Vratherthanthesystemgroundof0V.BecausethedcoutputoftheUFsystemisnotexactly2.5V,theresultingsignalgoingintotheRA8GAisusuallygreaterthan100mVsothe0.1Vinputsettingcannotbeused.Ifused,theinputsignalsaturatestheamplierandavoltageof0isseenontheTDTviewingprogram.The1Vor10Vinputsettingscanbeused;however,the10VinputsettingaddsmorenoisetothesystemasshowninFigure 5-9 .Thusthe1Vinputsettingisalwaysusedfortheneuralrecordingepisodes. ToshowthattheUFamplier-electrodesystemmeasurestheneuralsignalsaseffectivelyastheTuckerDaviselectrodes,thenoiseoorwasmeasuredforeachsystemandiscomparedinthissection.TherecordingsetupshowninFigure 5-8 wasusedtomeasuretimeseriesnoisevoltagesoftheUFelectrodeandaPZ2preamplierand 89


5-10 comparestheinputreferrednoiseoorsoftwodifferentUFamplier-electrodesystems(UF1andUF2)withthenoiseooroftheTDTelectrode.Theyareverysimilar.(ThescalingfactorfortheUFsystemis170/90withthe1Vinputsetting.)Therefore,ithasbeenshownthattheUFamplier-electrodesystemcanmeasureneuralsignalsofthesamemagnitudeastheTDTelectrodesystem.ThebottomplotinFigure 5-10 showstheoutputreferrednoisevoltagesmeasuredandrecordedbytheUFelectrodeandtheTDTRZ2processor.Thereisnobuilt-inscalingfactorintherecordingsoftware,thustheoutputvoltagemustbemultipliedby170(scalefactoroftheRA8GA1Vinputsetting)anddividedbythegaintheoftheUFamplier(90)togetthecorrectinputreferrednoisevoltage. 5-11 showsaschematicofahypotheticalonechannelamplierandtheconnectionsifthereferenceinputisoatingorconnectedtosystemground.Invivo,thedifferentialsignalgiventotheamplierisalwaysthevoltageseenbetweenatungstenwireimplantedintothecortexandastainlesssteelscrew,whichislodgedintheskulloftheratwiththebottomincontactwiththecerebralspinaluidthatresidesontopofthebrain.Thedifferenceisthatintheoatingcase,thereferenceisnotconnectedtosystemground,whichis0Vreferencedtothebatteryground;andinthegroundedcaseitis. 90


TimeseriesnoiseoorseenontheTDTviewingprogram.ThetopplotistheinputreferrednoisescaledbythegainoftheamplierandthescalingfactoroftheRA8GA(1Vinputsetting).ThebottomplotshowstheunscaledoutputreferrednoisevoltageseenbytheTDTrecordingprogram. Tounderstandwhygroundingmakesadifference,acloserlookistakenathowthemicroelectrodeisimplantedandhowthereferenceisconnectedtothebrainuid.Duringimplantation,themicroelectrodearrayissecuredtoastereotaxicapparatusanddrivenintothebraintissue.Thereferenceconnection,whichisthenutonthemicroelectrodesubstrate,isattachedtoatemporaryscrewalreadysecuredtotheskullwitha1ftlongalligatorclip.Afterthearrayisimplantedtothenaldepth,itisbentovertorestontheskullandascrewistintothereferencenut,eliminatingthealligatorclip, 91


Amplierconnectionsshowingoatingvs.groundedreferenceconguration. andthusmakingthedistancefromthenutonthesubstratetothebrainuidveryshort(afewcentimeters)comparedtothepreviouscase. Resultsfromnoisemeasurementsshowthattheamountofnoisepick-upinthesystemisgreatlyaffectedbythelengthoftheconnectionfromthereferenceinputoftheamplier(i.e.nutonthesubstrate),tothebrainoftheratinaungroundedsetup.Figure 5-12 showsthesquarerootofthenoisepowerspectraldensityoftheamplier-electrodesystemwhenthereferenceisgroundedandoatingwithdifferentlengthsofreference-brainconnections.Inthegroundedcase,theamountofnoiseisthesameregardlessofthelengthofthereference-brainconnection.Intheungroundedcase,thenoisemeasuredwiththeshortconnection(lengthofthescrew)isverysimilartothegroundedcases;however,thenoisemeasuredwiththelongreference-brainconnection(1ftalligatorclip)ismuchgreaterandunacceptableforneuralrecording.Thustoavoidcouplingnoisetothesystem,thereferenceinputshouldalwaysbegroundedtothegroundoftheamplier.Intheseexperiments,abeakerofsalinewasusedtomodelthebrainuid,thenoisevoltagesareinputreferred,andaSRS785spectrumanalyzerwasusedtomeasurethepowerspectraldensityofthenoise. 92


Squarerootofthepowerspectraldensityoftheamplier-microelectrodesystemshowingeffectofthereferenceconnectiononthenoiseoor. 5-13 showsthepowerspectraldensityofthenoiseforthreechannelsonthearrayinsidetheFaradaycageandoutsidetheFaradaycage.ThenoisemeasuredinsidetheFaradaycageisacombinationofthethermalnoiseoftheelectrode-salineinterfaceandthermalandelectronicnoiseoftheamplier,only.VerylittleEMIismeasured.ThenoisemeasuredoutsidetheFaradaycageisgreatlyaffectedbyEMIasthe60Hzpowerfrequencyanditsharmonicsareseen.SinceaFaradaycagecannotbeimplementedintheinvivosettingwiththerat,EMIwillalwaysbepresentintherecordings.Table 5-2 showstheextentthattheEMIhasontherecordednoiseoor.Usingthefrequencyrangeof500Hzto6kHz,whichiswhatisusedwhenrecordingwiththeTDTsystem,thenoiseoorisnotincreasedsignicantly.However,widerbandwidthrecordingsresult 93


Figure5-13. Squarerootofthepowerspectraldensityofthreechannelsontheamplier-microelectrodesystemshowinghowelectromagneticinterference(EMI)ofthe60Hzpowerlinecanaffectnoiseoor(inputreferred).ForthecasewithnoEMI,themicroelectrodearraywasplacedinsideadoubleFaradaycage. Table5-2. Noiseoor ElectrodeChannel NoiseFloorwithoutEMI(Vrms) NoiseFloorwithEMI(Vrms) 10Hz-12.8kHz 500Hz-12.8kHz 10Hz-12.8kHz 500Hz-12.8kHz 14.733.4613.83.5234.903.5019.23.7244.873.5618.53.69 118 125 ].Legattclaimsthatamplicationofcommon-modesignals 94


Comparisonofrecordingelectrode,referenceelectrodeandamplierinputimpedances.Errorbarsonrecordingelectrodecorrespondtothesamplestandarddeviationof8channelsonthearray. contributestomuchoftheoutputnoiseseenwithEEGsystems.Theimpedancevaluesfortherecordingelectrode,referenceelectrode,andtheinputtotheamplieraregiveninFigure 5-14 .ImpedancefortheamplierwasmeasuredbytheAgilent4294Aimpedanceanalyzer.ImpedancevaluesfortherecordingandreferenceelectrodesweremeasuredbyaGamry300potentiostatandfrequencyresponseanalyzer. Thefollowingderivation,takenfromLegattetal.[ 125 ],givesanalyticalequationsforthevoltageattheoutputofadifferentialamplier.Scenariosrelatingthemagnitudeoftheimpedanceoftherecordingelectrodetothereferenceelectrodeandinputoftheamplierarederived.Figure 5-15 showsablockdiagramofcommonmode,Vc,anddifferential,Vd,inputsignalsinterfacingwithimpedancesoftherecordingandreferenceelectrodeandthedifferentialamplier,whereZeistheimpedanceoftherecordingelectrode,Zrefistheimpedanceofthereferenceelectrode,Zampistheinputimpedanceoftheamplier,VaandVbarenodalvoltages,andV0istheoutputsignal.Vdisthesignalofinterestandistheneuralvoltagewaveforminthiscase.Theoutputvoltagecan 95


Schematicdiagramofdifferentialamplierattachedtorecordingelectrodeandreferenceelectrode. begivenas CMRR(Va+Vb),(5) whereGisthegainoftheamplierandCMRRisthecommon-moderejectionratio.Usingvoltagedivision,Equation 5 maybestatedas TwotermsareshowninEquation 5 ,onerelatingtothedifferentialsignalandtheothertothecommonsignal,thatwillbeampliedandgivenasoutput.Ideally,ZampismuchlargerthanZeorZrefsothatVdisnotattenuatedandVcisreducedtozero.Figure 5-16 showstheattenuationfactorofVdforarangeofZeandZrefimpedancevalueswhentheinputimpedanceoftheamplieris107.(Thisimpedanceisveryclosetothevalueexperimentallymeasuredat1kHzfortheamplierontheUFmicroelectrode.)Notethatthenormalizedvalueof1representsnoattenuationofthedifferentialsignal.Thecircleindicatestheassumedrangeofimpedancevaluesfortypicalrecordingandreferenceelectrodes.Asthegureshows,thereispossibly5%attenuationforacombinationofrecordingandreferenceelectrodeimpedancesinthatrangeforanamplierinputimpedanceof107.However,iftherecordingelectrodeimpedanceisthesameastheinputimpedancetotheamplier,thentheattenuation 96


AttenuationfactorofVdasafunctionofZeandZrefcorrespondingtovoltagedivisionatinputoftheamplier. Figure5-17. PercentattenuationofthedifferentialsignalVdasafunctionoffrequencyduetovoltagedivisionattheinputoftheamplier. is50%.FortheimpedancevaluesintheUFamplier-microelectrodesystem,theattenuationofVdisminimal(s0.3%)asshowninFigure 5-17 Theamplicationofthecommonmodesignalisassessednext.Figure 5-18 showsthedependenceofattenuationofVcontherecordingandreferenceelectrode 97


AttenuationfactorofVcasafunctionofZeandZrefcorrespondingtovoltagedivisionatinputoftheamplier. impedancesforZamp=107.Intheimpedancerangeapplicabletothiswork,theplotshowsthatatmost5%ofthecommon-modesignalwillbeampliedbytheampliergainandresultasanunwanteddisturbanceintheoutputsignal.UsingtheimpedancevaluesasafunctionoffrequencyfortheUFamplier-microelectrodesystem,nomorethan0.8%ofthecommon-modesignalwillbeampliedbytheamplierasshowninFigure 5-19 Aneffectivecommon-moderejectionratiodependentontherelativeimpedancevaluesoftherecordingandreferenceelectrodeisgivennextfollowingthederivationbyLegattetal.[ 125 ].AssumingZeZampandZrefZamp,Equation 5 maybesimpliedto Similarly, 98


Percentofthecommon-modesignalVcasafunctionoffrequencythatwillbeampliedduetovoltagedivision. and PluggingEquation 5 andEquation 5 intoEquation 5 yields Theeffectivecommon-moderejectionratioistakentobethegainassociatedwithVddividedbythegainassociatedwithVc.Thus, usingthesesimplicationsZamp(ZrefZe)andCMRR1.Figure 5-20 showstheeffectivecommon-moderejectionratioduetoamismatchinrecordingandreferenceelectrodeimpedances.AccordingtoLegatt'sderivation,theeffectiveCMRRwillbesignicantlydecreasedforalargemismatchinimpedance.Inthisstudy, 99

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Normalizedeffectivecommon-moderejectionratioasafunctionofthedifferenceoftheimpedancebetweenrecordingelectrodeandreferenceelectrode. thereferenceelectrodeandrecordingelectrodehaveimpedancesthatdifferbytwoordersofmagnitude.Figure 5-21 showsahypotheticaleffectivecommon-moderejectionratiousingtheimpedancevaluesgiveninFigure 5-14 .ThenominalCMRRfortheUFamplieris10,000.ThusaccordingtoLegatt'sderivation,theeffectiveCMRRwilldecreasebyafactorof20.However,ameasurementperformedtotestthishypothesisdidnotshowcongruentresultsfortheUFmicroelectrode.Whentheimpedanceofthereferenceandrecordingelectrodewerematchedbyreplacingthelargeareareferencescrewwitha50mdiametertungstenmicrowire(similartotherecordingelectrode),theamountofcommon-modenoise(60HzEMI)actuallyincreasedratherthandecreased.Therefore,otherfactorsbesidesimpedancemismatchcontributetothepresenceof60HzEMIcommon-modenoiseseeninFigure 5-13 .Understandingtheoriginofsuchfactorsareatopicoffutureresearch. 100

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Effectivecommon-moderejectionratioasafunctionoffrequencyforimpedancevaluesintheUFmicroelectrodearray. thereferenceconnectiontotheampliershouldbeconnectedtothesystemground(Vss)oftheampliertoreducenoisepick-upduringimplantation.Ifthiscanbedoneonachiplevel,insteadofontheexiblesubstrate,thatisadvised.Thesignalcomingfromtheampliermustbelteredtoeliminatethe60HzpowerlineEMI,beforeitissenttotheintegrate-and-reelectronics.Aband-passlterfrom500Hzto6kHzwasusedsuccessfullyinthisstudy. 5-22 showsapass-bandgainof39dB.Theresponseofthesystemtopulsesofwidth1msand100saregiveninFigure 5-23 .Minimaldistortionisseenonthe1mspulse;morepronounceddistortionisseenin 101

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Frequencyresponseofamplier-microelectrodesystem.Thepass-bandgainis39dB. the100spulseresponse.Sinceanactionpotentialhaspulselengthsontheorderofmilliseconds,thisamplier-microelectrodesystemmeasuresthesignalwithoutappreciabledistortion. 119 ].Atthesiteoftheelectrodeimplantation,thedurawasremovedtoexposethecortex.Theentireassemblywasimplantedverticallyandloweredusingamicropositioner.Whiledrivingtheelectrode,electrophysiologicrecordingswereused 102

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Impulseresponseofamplier-microelectrodesystem.Figure 5-23A showstheresponsetoa1mspulse,characteristicofaneuralactionpotential.Figure 5-23B showstheresponsetoa100spulse. 103

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Flexiblesubstrateelectrodearrayimplantedinrodentmodel. tolocateadepthwhereunitcellactivitywasgreatest.Theelectrodesweredriventoadepthof3.6mm.Duringthisprocedure,theassemblywasobservedtoberigidandnobucklingwaspresent.Oncetheelectrodewaspositioned,itwassupportedwithcranioplasticcement(Plastics-1)attachedtoascrewplacedadjacenttothecraniotomy(topscrewinFigure 5-24 ).Afterthearraywassecured,theentireassemblywasfoldeddowntolayatagainstthetableoftheskullasshowninFigure 5-24 .Theexiblesubstratewasthenpermanentlygroundedusingasecondanchoringscrew. Theelectrodearraywasimplantedintheanimalfor42daysandneuralsignalsweremeasuredatregularintervalsovertheimplantedduration.Theresultsobservedfromthechronicimplantationofthemicroelectrodearrayaredescribednext. 5-25 showscharacteristicspikesrecordedfromonechannel.However,consistentspikesofsimilarlargeamplitudeswerenotseenagainovertheimplant 104

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5-3 showstheyield,orthenumberofneuronsseenconsistentlyovertheimplantduration,foreachelectrodeonthearray.Spike2wasusedtosorttherecorded Figure5-25. Largeamplitudeactionpotentialsrecordedondayofimplantation. dataforvariousdaysovertheimplantdurationusingthesamemethodsdescribedinSection 4.1.4 andSection 4.2.4 .Figure 5-26 depictsacharacteristicactionpotentialofasingleneuronseenconsistentlyovertheimplantduration.Thegraphsshowaveragewaveformsofsortedactionpotentialsoveraoneminutetimesegment.Theredlinesgivetheerrorbounds.Statisticalanalysisofthewaveformtemplatesprovethatthesameneuronwasconsistentlymeasuredoverthecourseoftheimplanttime. Table5-3. NeuronalYieldforGeneration2bMicroelectrodeArray ElectrodeNeuronalYield 12 21 33 42 51 61 70 81 105

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Actionpotentialofasingleneuronspikesortedovertheimplantedperiod. Noiseoorandsignaltonoiseratioaretheotherrecordingperformancemetricsconsideredfortheamplier-microelectrodesystem.ThenoiseoorfortheelectrodearrayovertheimplantdurationisshowninFigure 5-27 .Day0correspondstobench-topmeasurementsmadein0.9%saline.Thebench-topnoisemeasurementforaTuckerDaviselectrodeattachedtoaTuckerDavisamplier(PZ2)isgiveninredinthegure.TheTuckerDaviselectrodenoiseoorisstatisticallysimilartothenoiseoorfortheUFmicroelectrodearray.Resultsfordays1through42aretakenfrominvivorecordingswiththeUFmicroelectrodearray.Thedatapointsgivetherootmeansquarevaluesofaonesecondorgreatersegmentofdata,freeofsortedactionpotentials.Theerrorbarscorrespondtothesamplestandarddeviationofsevenchannelsintheelectrodearray.Afteraninitialincreaseintheaveragenoiseoor,itremainedconstantaround4.5Vrms.Figure 5-28 showstheaveragesignaltonoiseratio(SNR)acrosssevenchannelsinthearrayovertheimplantduration.SNRwascalculatedasthepeaktopeakvoltageofanactionpotentialdividedbythermsnoiseoorvalue.ResultsforthiselectrodeshowSNRsashighas5.4onthedayofsurgeryandconsistentvalesnear3.8 106

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Noiseoorfortheelectrodearrayovertheimplantedduration.FWIREcorrespondstotheUFamplier-microelectrodesystemandTDTcorrespondstoaTuckerDavismicro-wireelectrodearrayandPZ2amplier. after23daysimplanted.Thespikesortingresultsshowedatleastoneneurononsevenoftheelectrodechannels.AllactionpotentialscorrespondingtosingleneuronsusedfortheSNRcalculationwereconsistentlyrecordedfromday1today42. Performancemetricsincludingnoiseoor,signaltonoiseratio,andneuronalyieldshowedthattheamplier-microelectrodearrayperformedadequately.ThenoiseoorwasstatisticallysimilartothenoiseoorofaTuckerDaviselectrodeininvitroexperimentationoverafrequencyrangeof500Hzto6kHz.Theaveragenoiseoormeasuredinvivoontherstdayofimplantationwaslessthanonemicrovolthigherthanthatmeasuredinsaline.Theincreaseinthenoiseoorwasassumedtobefromadditionofbackgroundneuronalnoise.Theaveragenoiseoorthenincreasedtoavalueaboutonemicrovolthigherthanitwasondayone.Thecauseofthisincreaseinnoiseafterdayoneismoreambiguous;however,thesametrendhasbeenreportedbytheMichigangroup[ 21 ].Theyalsomeasuredimpedancevaluesovertimeandconcludedthatanincreaseinelectrodeimpedanceby30%to100%,whichcoincided 107

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Signal-to-noiseratiofortheelectrodearrayovertheimplantduration.FWIREcorrespondstotheUFamplier-microelectrodesystemandTDTcorrespondstoaTuckerDavismicro-wireelectrodearrayandPZ2amplier. withtheincreaseinnoise,wasatleastpartiallythecauseoftheincreaseinnoiseoor.Tresco'sgroupreportedthatincreasesinelectrodeimpedanceofthesamemagnitudeareattributedtocellularadhesion[ 77 ].SignaltonoiseratiosreportedfortheUFmicroelectrodearrayafterdayonewerelowcomparedtomostpublisheddata,butbecausetheyaredependentontheproximityofanactiveneuron,theyarenotarelevantindicationofperformancequalityespeciallywhenthenoiseoorisadequatelylow.ThepercentageofactiveelectrodesontheUFmicroelectrodearrayovertheimplantdurationstayedconstantat88%and1to3independentneuronsweremeasuredoneachactivechannel.Thus,theUFmicroelectrodearraywithhybrid-packagedamplierICshowsacceptableperformanceforrecordingapplicationslastingtwomonths. 108

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5-29 showsscanning-electron-microscope(SEM)imagesofthetungstenmicrowiresusedintheUFintracorticalmicroelectrodearraybeforeandafterimplantationinarodentmotorcortex.Themicroelectrodearraywasimplantedfor87days.Imageslabeledaandbshowelectrodesurfaces(crosssectionoftheinsulatedwires)aftertheyhavebeencutwithadicingsawpriortoimplantation.Themicrowireshaveasub-micronlayerofgoldontheoutsidesurfaceofthetungstenwires,beneaththepolyimideinsulation.ThoughnoteasilyseenintheSEMimages,athinringofgoldbetweenthepolyimideandtungstenisexposedtothebiologicalenvironment.Imagescanddshowthechangedstateofthetungstenwireafter87daysinvivo.Theinsetinchighlightstheareaofgoldexposedtothetissue.Notabledifferencesbetweenthebeforeandafterimagesincludealargerareaofgoldexposedintheafterstateaswellasaswellingofthepolyimideinsulationandthepresenceofalmonthesurfaceoftheelectrode.Thelargerelectrodeareawillcorrespondtoalowerimpedanceandthusalowerthermalnoisevoltageattheinterface;however,theelectronicnoiseoftheamplierwillstilldominatethesystem.Also,theresultingmeasuredvoltagesignalwillbeaveragedoverthelargersurfacearea.AmagniedviewofimagedinFigure 5-30 andenergy-dispersiveX-rayspectroscopy(EDS)resultsfortwoexposedregionsontheelectrodesurfaceisshowninFigure 5-29 .ThetopEDSgraphgivesresultscharacteristicofabaretungstensurface.ThebottomEDSgraphgivesresultscharacteristicofabio-lmthatisrichincarbon,oxygenandnitrogen.Thus,itisassumedthatpartofthebio-lmbecamedislodgedonthetoprightportionoftheelectrodeandisexposingthetungstensurface.Thisimageshowsthatthetungstenisrecessedwithinthegoldplatingandthestructureofthetungstensurfacehaschangedfrombeingsmoothtorough.Inthreeoftheelectrodesinthearray,theaveragedistancethatthetungstensurfacewasrecessedwithinthegoldplatingwasmeasuredtobe248Vafteranimplantationdurationof87days.Thedistancewasmeasuredviaanopticalmicroscopewherethechangeinfocallengthwasmeasured.Thecorrosionof 109

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SEMimagesoftungstenmicro-wiresbeforeandafter87daysimplanted.a,b)Characteristicelectrodesbeforeimplantation.c,d)Characteristicelectrodesafterimplantation.Theinsetinchighlightstheareaofgoldexposedtothetissue. tungstenmicrowiresissystematicallystudiedinaninvitroexperimentandtheeffectofthetungstencorrosiononlong-termrecordingperformanceisdiscussedinChapter 7 110

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EDSresultsoftwositesononeelectrodeafter87daysinvivo.Thetopgraphshowsresultscharacteristicofabaretungstenandgoldsurface.Thebottomgraphshowsresultscharacteristicofabio-lm. polyimidesurface.Furthermore,SEMimagesofthetungstenrecordingsitesafterexplantationshowedconsiderablechangeintheelectrodesurfacesuggestingcorrosionofthetungsten.Thoughtheresultsfor42daysdonotsuggestthatthecorrosionofthetungstenmicrowirehadanyadverseeffectontherecordingperformancethusfar,thereisapossibilitythatadverseeffectsmayoccurinprolongedstudies.TheresultsofadetailedanalysisofcorrosionpropertiesoftungstenmicrowiresarepresentedinChapter7.Theexperimentalmethodsareexplainedinthenextchapter. 111

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AsexempliedinChapter 5 ,theimplantedtungstenmicrowiresundergocorrosion.Thischapterpresentstheexperimentalmethodsfortheelectrochemicalcharacterizationthatwillquantifytherateofcorrosionexperiencedbytungstenmicrowiresinphysiologicalsalinesolutions.Thekeymeasurementtechnique,electrochemicalimpedancespectroscopy(EIS),isdescribed.Uncommongraphicalrepresentationsoftheimpedancedatathatprovideusefulinformationontheinterfacephysicsareexplained.Theprocedureforerroranalysisofthemeasuredimpedancedataisalsodescribed.Moreover,themetalsamplesusedintheEISmeasurementsmustbedifferentfromthemicrowireelectrodesusedinneuralrecordingmicroelectrodes.Reasonsforthischangearegivenandamethodforascertainingthequalityofthesampleelectrodesisalsopresented. 93 ].Atypicalexperimentalset-upisshowninFigure 6-1 .Theworkingelectrodeisthesurfaceunderscrutiny.Thecounterelectrodeisalargeareaelectrodewhoseinterfacialphenomenamaybeneglected[ 93 ].Thereferenceelectrodeisanelectrodethatpossessesareversiblereactionwithanioninthecellsolutionthathasaconstantandwell-denedelectrochemicalpotential[ 93 ].Byapplyingasmallsinusoidalvoltageorcurrentperturbationacrosstheworkingandcounterelectrodeandsubsequentlymeasuringtheresultingcurrentorvoltagesignalacrosstheworkingandreferenceelectrode,theimpedanceatagivenfrequencymaybemeasured.Caremustbetakentoensurethattheperturbationvoltageissmallenoughtoensurethatthecurrenttovoltagerelationshipremainslinear[ 126 ].Theperturbationsignalissweptoverarangeoffrequenciesandtheresultingfrequency-dependentimpedance 112

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EISexperimentalset-up. ischaracteristicoftheinterfacebetweentheworkingelectrodeandtheelectrolytemedium. EIShasbeenusedinstudiescharacterizingstimulatingandrecordingelectrodesforpacemakerandintracorticalapplicationsaswellasvariousstudiesonmicro-scaleelectrodes.InterfacialcapacitancewasassessedbyEISinphysiologicalsalineonPt,Ti,andTiNpacemakerelectrodesusedforstimulation[ 87 88 ].ImpedanceandchargetransfercharacteristicsofelectrodepositedIrO2insalinesolutionwerecomparedtobaremetalsurfacesusingEIS[ 127 ].ThenalapplicationoftheIrO2platedelectrodeswasforneuralstimulationandrecording.Platinized-platinummicroelectrodesusedforneuralstimulationwerecharacterizedusingEIS[ 102 ].Yangetal.,Cuietal.,andAtesetal.investigatedconductingpolymerlmsgrownordepositedonmetalmicroelectrodesviaEIS[ 128 130 ].Priceetal.usedEIStoassessoptimalinsulationthicknessfortheirmicroelectrodearrays[ 131 ].Zhangetal.modiedmicroelectrodeswithimmobilizedantibodiesforselectivecaptureofhumanantigensandusedthechangeinimpedancemeasuredbyEISasthesensingmechanism[ 132 ].ThisworkusesEIStoascertainthereactivityofametalinbiologicalsalinesolutionsunderquasi-equilibriumconditions,andinthecaseofareactivesystemundergoingcorrosion;thisworkquantiesthecorrosionratethroughextrapolationofthepolarizationresistancefromtheimpedancedata. 113

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Equivalentcircuitsforblockingandreactivesystem(nonfaradaicandfaradaicinterface)[ 1 ]. 133 ],areusedtoacquiremeaningfulinformationabouttheelectrochemicalsystem. Tocomparethegraphicaltechniquesforanalysisofimpedancedata,plotsoftheoreticalcurvesforblockingandreactivesystemsmodeledbytheequivalentcircuitdiagramsinFigure 6-2 arediscussedhere.Figure 6-3 showsBodeplots,whereimpedancemagnitudeandphaseasafunctionoffrequencyareshown.Bothblockingandreactivesystemsshowresistivebehaviorathighfrequencies,denotedbythezerodegreephaseangle.Theblockingsystemisdominatedbythecapacitoratlowfrequenciesandthusshowsincreasingmagnitudeofimpedanceandaphaseangleof-90.Thereactivesystemhasaresistivecurrentpathwayatlowfrequencies,therefore;theimpedancemagnitudelevelsofftoanitevalueandhasphaseangleofzerodegreeatlowfrequencies. TheNyquistplotisusefulforgraphicalestimationoftheelectrolyteresistance,Re,andthechargetransferresistance,Rct.Figure 6-4 showsaNyquistplot,whichisthenegativeoftheimaginaryimpedanceasafunctionoftherealimpedance,forthetwo 114

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Bodeplotsofablockingandreactivesystem. interfacecases.ThehighfrequencyasymptotegivesthevalueofReforbothsystems.Asthefrequencydecreases,theimaginaryimpedancevaluewilleithergrowtowardinnityfortheblockingsystemorachieveamaximumandthendecreasebacktozerointhereactivesystem.ThelowfrequencyasymptoteforthereactivesystemgivesRe+Rct. ThelogarithmofimaginaryimpedanceasafunctionoffrequencyinFigure 6-4 givesastraightlineofslopeequalto-1forallfrequenciesintheidealblockingsystemandforhighfrequenciesinthereactivesystem[ 133 ].Thismethodofviewingimpedancedataismostusefulforexperimentaldatashowingnonidealbehavior. 6-2 .Deviationsfromidealcasesaremodeledbytheconstant-phaseelement(CPE).Theconstant-phaseelementhasamultitudeoforiginsandishighlydependentonthesystem.ItiscommonlysuggestedthatCPEbehaviorarisesfromaninhomogeneoussurface[ 134 ].Regardlessofthephysicalmeaning,itcanbeconsideredanelementwithadistributionoftimeconstants,whichcanbemodeledbyEquation 6 (j!)Q,(6) 115

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Nyquistplot(left)andlogarithmofimaginaryimpedanceasafunctionoffrequency(right)ofblockingandreactivesystems. Figure6-5. Nyquistplot(left)andlogarithmofimaginaryimpedanceasafunctionoffrequency(right)forblockingandreactivesystemswithaconstantphaseelement. 116

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134 ].TheCPEtakestheplaceofthedoublelayercapacitorintheinterfaceequivalentcircuits. TheNyquistplotandlogarithmoftheimaginaryimpedanceasafunctionoffrequencyshowauniquedependencewiththeconstant-phaseelement.IntheNyquistplot,theCPEmakestheverticallinetilttotherightatananglelessthan90inablockingsystem;andinareactivesystem,thesemicircleisdepressedasshowninFigure 6-5 .Inthegraphoflogarithmofimaginaryimpedanceasafunctionoffrequency,theslopeoftheimpedanceforbothsystemsisdecreasedfrom1andequalsthevalueoffromEquation 6 Thus,byusingNyquistplotsandthelogarithmofimaginaryimpedanceasafunctionoffrequencyinsteadofBodeplots,moreoftheinterfacecharacteristicsareapparent.ThedifferencebetweenablockingandreactivesystemissimplygivenbytheshapeoftheNyquistplot(eg.astraightlineversusasemicircle).Furthermore,valuesofcircuitparameters(Re,Rctand)areabletobeestimated. 135 ]isaniterativeapproachthatusesameasurementmodel,whichinherentlysatisestheKramers-Kronigrelationandtherebyexhibitslinearity,stationarity,andcausality.Themeasurementmodelforcompleximpedanceisgivenby[ 135 ] Aresistor,R0modelingtheelectrolyteresistance,isinserieswithkVoigtelements,whereaVoigtelementisacapacitorinparallelwitharesistorthathasacharacteristictimeconstantk=2RC.ComplexnonlinearleastsquaresregressionisusedtottheexperimentaldatatothemeasurementmodelwiththelargestnumberofVoigtelements 117

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whereres,Kr,k(!)istheresidualerrorofthemodeltothedataatfrequency!forscankand Next,thevarianceistransformedintoanerrorstructuresothatitmaybeappliedtoageneralimpedancespectra.Ithasbeenshownthatthevarianceoftherealandimaginarypartsoftheimpedancespectraareequal[ 136 ].Thustheerrorstructureofelectrochemicalimpedancecanbefoundwhenregressedtothisformula where,,,andarecoefcientstobefoundintheregression,andRmisthevalueoftheresistorusedinthemeasurementequipment[ 135 ]. Theresidualerrorresfoundaboveincludesbiaserror,stochasticerroranderrortothet.However,reference[ 135 ]suggeststhatitcanbeagoodestimateforthestochasticerrorifthesamenumberofVoigtelementsareusedtoteachscan.Then,themodelparametersaccountfordriftineachsubsequentscan,anderrorduetonon-stationarityisthesamefromonescantoanother.Inamoresensitiveanalysisforstationarity,theerrorstructurefromEquation 6 isusedtoweighttheregressionoftheimaginaryimpedancedataforonescan,andthentherealpartispredictedviatheKramers-Kronigrelation.Ifthepredictedvaluesarewithinthe95%condenceintervaloftheregression,thenthedataareconsistentwiththeKramers-Kronigrelation.Ifdataattheextentsofthemeasuredfrequencyrangedonottinthecondenceintervalthen,theyarediscardedandtheprocedureisperformedagain.Inconsistency 118

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Throughthisapproach,anerrorstructurerepresentingthestochasticerrorisfound,andthemeasureddataarecheckedforlinearity,stability,andcasuality.Theerrorstructurecanthenbeusedasweightingforregressionofphysicalmodelsrepresentingtheelectrochemicalsystem. 137 139 ].Thus,thetungstenmicrowireswithpolyimideinsulationcannotbeused.Also,theexposedsidewallswouldaffecttheaccuracyoftheestimationofthesurfaceareaneededforcalculationofthecorrosionrate.Therefore,theworkingelectrodesfortheEISstudyaremadesimilarlytoconventionalmicroelectrodesusedforelectrochemicalapplications. 119

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140 141 ].Thesepropertiesremovetheneedforforcedconvectioninthecell,reducetheRCtimeconstant,whichallowsinvestigationofhighspeedkinetics,andrendertheOhmicdropovertheelectrolyteresistancenegligiblesuchthatuseinhighresistivitymediaispossible.Moreover,theirsmallsizeprovidesanobviousbenettobiologicalapplicationswhereminimaltissuedamageisnecessaryandspatialresolutionisimportant.Wightman'sgrouphavebeenusingmicroelectrodessincethe1980'stodeterminethepresenceofneurochemicalsinthebrain[ 142 143 ],amongmanyotherapplications.Amorerecentapplicationofmicroelectrodesisinelectrochemicalimpedancespectroscopystudiesthatemployscanningelectrochemicalmicroscopy(SECM)toassesslocalcharacteristicsofbulkmaterials[ 144 145 ]. Microelectrodesandmicroelectrodearrays(MEAs)forelectroanalyticalapplicationsarefabricatedinanumberofways[ 146 ].Methodsincludeinsulatingmetalwiresorcarbonberswithglass,epoxy,orapolymerandthenpolishingorelectrochemicallyetchingoneend.Microfabricationtechniquesareusedtolithographicallypatternvapordepositedthinlmmetalsandinsulatingdielectrics.Microelectrodearraysaretypicallyfabricatedusingmicromachiningtechniques.Whethermadebyeithermethod,themicroelectrodesareatriskfordefectssuchasimperfectsealsbetweentheelectrodeandinsulation[ 146 ].Contaminantsonthesurfacefromperhapsapolishingstepalsoposethreatstothequalityofthemeasurement[ 146 ]. 120

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147 ].Resultsshowdeviationtotheorythoughanasymmetricvoltammetricresponse,wherethenonidealresponseisexacerbatedasthepulsewidthisdecreasedorfrequencyisincreased.Kosteretal.provideamethodforqualitycontrolofmicroelectrodearrays(MEAs)madebymicromachiningandusedforamperometrictransducers[ 148 ].Theyuseacombinationofcyclicvoltammetry,electrochemicalimpedancespectroscopy,andscanningelectrochemicalmicroscopytoassessthequalityoftheirarrays.Thisworkintroducesasimplemethodthatusesonlyelectrochemicalimpedancespectroscopy(EIS)toassessthequalityofmicroelectrodefabrication. ThismethodusesagraphicalinterpretationofimpedancedatafollowingOrazemetal.[ 133 ]andHuangetal.[ 149 151 ].Inreferences[ 149 151 ],amethodforcomparingimpedancedataofelectrodesofdifferingsizeandelectrolyteconductivityisgivenaswellasacriterionfordistinguishingartifactsinimpedancedata.Theyprovedthatgeometryinducedcurrentandpotentialdistributionsathighfrequenciesproducedartifactsintheimpedancespectraofdiscelectrodes.Therefore,wewillusethesamemethodtouncoverartifactsintheimpedancespectraofmicroelectrodesduetofabricationdefects.Thispaperappliesthemethodprescribedforblockingelectrodesshowingconstantphaseelement(CPE)behavior[ 150 ]. 147 ].ThisqualitycontrolstudyusestwosetsofPtmicroelectrodes;onesetisinsulatedwithepoxyandtheotherwithglass,whichisknowntohavehighprobabilityofachievingacrack-freesealsinceglasshasasimilarcoefcientofthermalexpansionwithPt[ 146 ].Thisworkshowsthatbygraphicallyanalyzingthehighfrequencyimpedancedataofthetwosets,thequalityofmicroelectrodefabricationmaybedeterminedforeach.Forthisstudy,it 121

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146 ]. Twosetsofmicroelectrodesweremadeusing50mdiameterPtwire(CaliforniaFinewire).OnesetofPtwiresweresecuredinglasstubingwithaninsulatingepoxyandoneendwaspolishedwithAlO2sandpapers.Thenalgritsandpapercorrespondedto0.3mroughness.Intheothersetofelectrodes,aglasstubewasheatedandsealedaroundthePtwire.SiCsandpaperwasusedtopolishoneendofthosesamplestoanalroughnessof1m.Theunpolishedsideofallelectrodeswereelectricallyconnectedtoagoldpinconnectorwithsilverepoxy. AGamrySeriesG300potentiostatwasusedforperformingelectrochemicalimpedancespectroscopy.ImpedanceresponsesofthePtmicroelectrodesweremeasuredwithrespecttoaPtcounterelectrodeandAg/AgClreferenceelectrodein0.9%phosphatebufferedNaCl(Sigma)atroomtemperature.Theperturbationvoltagewas10mV,thefrequencyrangewas10kHzto0.8Hz,andallexperimentsweretakenatopencircuitpotential.AllexperimentaldatawereconsistentwiththeKramers-KronigrelationasprescribedbyOrazem[ 152 ]. 153 ]forPtmicroelectrodesinsalinesolution.Theequivalentcircuitimpedanceisgivenas (j!)Q,(6) whereReistheelectrolyteresistance,!isangularfrequency,isaconstantlessthanone,andQistheCPEcoefcient[ 150 151 ].FollowingOrazemetal.maybegraphicallyfoundbyplottingtheimaginarypartoftheimpedanceasafunction 122

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133 ].Inalogarithmicplot,theslopeoftheimpedancedatagivesthenegativevalueof.ThevalueofQisgivenby[ 150 ] InReferences,[ 149 151 ],theauthorsdevelopagraphicalmethodthatelucidatesgeometryinducedartifactsintheimpedancespectraforadiscelectrode.TheyintroduceadimensionlessfrequencyK, whereistheconductivityoftheelectrolyte,r0istheradiusofthediscelectrode,andQeisavaluerepresentingQ(!).PlottingthedimensionlessimaginaryimpedanceagainstthedimensionlessfrequencyKinlogarithmicscaleproducesastraightlinewithslopeequalto1forablockingsystemmodeledbyEquation( 6 ).TheirworkshowsthatforfrequenciesgreaterthanK=1,theimpedanceisinuencedbythecurrentdistributionanddeviatesfromtheidealbehavioroftheimpedance.Theresultsgiveslopesthatdeviatefrom1atfrequenciesgreaterthan 2 wherefcisthefrequencyatwhichK=1.Thisfrequencyisinverselyproportionaltotheradiusoftheelectrodeandforthecaseinthisstudyfcisontheorderof100kHz,whichisbeyondthefrequencyrangeofinterest.Thus,artifactsduetocurrentdistributioncanbeneglected. ThenextsectionwillusethegraphicalmethodofplottingimaginaryimpedanceversusKtoassessthequalityoftheelectrodefabrication.Specically,thismethodwillbeusedtoruleoutanyelectrodesthathavedefectswhichallowtheimpedancespectratodivergefromidealbehavior,thatisaslopeofimaginaryimpedanceversusKonalogarithmicplotnotequalto1.Basedonresultsfrom[ 147 ],thephysicalreasonforthedefectisanimperfectsealbetweenthemetalandinsulator. 123

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6.3.1 .Microelectrodeslabeled1a-4awereinsulatedwithglassandpolishedwithSiCsandpaperandexhibitidealbehaviorforablockingelectrode.Microelectrodeslabeled1b-3bwereinsulatedwithepoxyandpolishedwithAlO2sandpaper.Theseelectrodesdonotexhibitidealbehaviorandhavefabricationdefectsthatcanbeexplainedwiththetheoryofporouselectrodes[ 137 139 ]. 6-6 .ResultsshowspectraforfourPtmicroelectrodesthathavelittle Figure6-6. (left)ImaginaryimpedanceasafunctionoffrequencyoffourdifferentPtmicroelectrodesinsulatedinglassandpolishedwithSiCpaper.Thevalueofcorrespondingtoeachelectrodeisfoundbycalculatingtheslopeofthelines.(right)NyquistplotofthefourPtmicroelectrodes. deviationfromeachother.ThevaluesofarefoundbyttingtheplotsofimaginaryimpedanceversusfrequencytostraightlinesandextractingtheslopeviathecurvettingtoolinMatlab.TheCPEcoefcientiscalculatedbyEquation( 6 )andplottedinFigure 6-7 .ValuesofandQeusedforthecalculationofKaregiveninTable 6-1 124

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CPEcoefcientQasafunctionoffrequency.ThedottedlinesshowtheeffectivevaluesusedforcalculationofKinequation( 6 ). Table6-1. ValuesofandQeforidealelectrodesfromFigure 6-6 andFigure 6-7 GlassQe/1cm2s 6-8 (usingaconductivityof0.19mS/cm).Allimpedancedatasuperimposeonthesamelineasexpectedforideallyconstructedmicroelectrodes.Figure 6-9 showsthederivativeofimaginaryimpedancewithrespecttoK.Overthemeasuredfrequencyspan,thederivativedoesnotdeviatefrom1bymorethan5%.Thisresultsuggeststhatanymicroelectrodeshowingderivativesthataredifferentfrom1bymorethan5%havefabricationdefects. 6-10 ,itisevidentthatelectrode2bdoesnot 125

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ImaginaryimpedanceoftheidealelectrodesindimensionlessunitswithrespecttodimensionlessfrequencyK. showidealbehaviorandwouldbesuspectfordefects;however,1band3bappearacceptable. ThevaluesforarefoundbyttingtheimpedancespectrainFigure 6-10 tostraightlines.Onlyfrequencieshigherthan100Hzwereusedtocalculateformicroelectrode2b.ValuesforQareplottedinFigure 6-11 andvaluesusedtocalculateKaregiveninTable 6-2 Table6-2. ValuesofandQefornon-idealelectrodesextractedfromFigure 6-10 andFigure 6-11 GlassQe/1cm2s 6-12 ,itisevidentthatmicroelectrode2bdoesnotshowidealbehavior.InFigure 6-13 ,whenthederivativeofdimensionlessimaginaryimpedancewithrespecttoKisplotted,thevariationseenforelectrodes1b-3bisgreaterthanseenformicroelectrodes1a-4a.Thus,itislikely 126

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DerivativeofthelogarithmofdimensionlessimaginaryimpedanceoftheidealelectrodeswithrespecttologK.Almostalldatapointsliewithin5%of1. thatallthreeoftheepoxysealedmicroelectrodeshavesomefabricationdefectandareunsuitableformeasurements. 147 ],agraphicalanalysisofelectrochemicalimpedancedataisproposedasasimplemethodofqualitycontrolofmicroelectrodefabrication.Thisworkanalyzedimpedancedataofablockingsystembelowthefrequencyfcatwhichgeometryinducedartifactsariseformicroelectrodes.TheresultssuggestedthatideallyconstructedmicroelectrodeswillexhibitaslopeoftheimaginaryimpedanceasafunctionofdimensionlessfrequencyKinalogarithmicplotthatdoesnotvaryfrom1bymorethan5%.Theproposedmethodwillalsoworkforareactivesystem.Ifareactivesystemisused,impedancedatacorrespondingtofrequenciesgreaterthanthecharacteristicfrequencygivenbytheRCtimeconstantofthedoublelayercapacitanceandchargetransferresistanceandlowerthanfcshouldbeusedintheanalysis. 127

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(left)ImaginaryimpedanceasafunctionoffrequencyoffourdifferentPtmicroelectrodesinsulatedinepoxyandpolishedwithAlO2paper.Thevalueofcorrespondingtoeachelectrodeisfoundbycalculatingtheslopeofthelines.(right)NyquistplotofthefourPtmicroelectrodes. Figure6-11. CPEcoefcientQofthenon-idealelectrodesasafunctionoffrequency.ThedottedlinesshowtheeffectivevaluesusedforcalculationofKinequation( 6 ). 128

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Plotofimaginaryimpedanceofthenon-idealelectrodesindimensionlessunitswithrespecttodimensionlessfrequencyK. Figure6-13. Derivativeofthelogarithmofdimensionlessimaginaryimpedanceofthenon-idealelectrodeswithrespecttologK.Manydatapointsdifferfrom1bymorethan5%. 129

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Awellcontrolledinvitrostudyonthecorrosionpropertiesoftungstenandplatinummicrowiresinphysiologicalsalinesolutionsisperformedtoassessthelongevityofthewiresforuseinneuralrecordingmicroelectrodearrays.Specicmaterials,instrumentation,andmeasurementparametersusedfortheimpedancemeasurementsaredescribedrst.Theresultsoftheelectrochemicalimpedancespectroscopy(EIS)measurementsarethenpresented.AnalysisofthemeasuredimpedanceusingtheStern-Gearyequationquantiestherateoftungstencorrosioninbiologicalsalinesolutions.TheanalysisofPourbaixdiagramsprovidesinformationontheelectrochemicalreactionsoccurringontheelectrodesurfaces.Basedontheresults,tungstenisnotsuitableforlong-termimplantuse,whileplatinumissuitable. 6.3 wasusedtoidentifyanideallyfabricatedelectrodewithanadequatesealbetweentheinsulationandtheelectrode.Threeworkingelectrodeseachweremadeusing50mdiametergold-plated-tungsten,bare-tungsten,andplatinummicrowires.Thegold-plated-tungstenandplatinumworkingelectrodeswereinsulatedwithglass,andthebare-tungstenelectrodewasinsulatedinepoxybecauseafurnacewasnotavailableatthattime. 130

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SchematicofworkingelectrodeforEISmeasurements. TheelectrolytesusedintheEISmeasurementswerechosentomodeltheinvivochemistry.Theyare0.9%phosphatebufferedsaline(PBS)forhealthyneuraltissueandphosphatebufferedsalinethatcontainsH2O2tosimulatetissueundergoinganinammatoryresponse.SinceH2O2issecretedfrommicrogliathatsurroundtheimplantedmicrowireelectrode,localconcentrationsaredifculttoestimate.Panetal.andFonescaetal.usedhydrogenperoxideandPBStoassesscorrosionoftitaniumforstructuralimplantmaterials[ 105 ],[ 106 ].Theyusedconcentrationsthatrangedfrom10mMto100mM.Aconcentrationof30mMH2O2waschosenforthisstudy.Asaltmixture(SigmaP-5368)wasusedtomakethePBSwithcompositiongiveninTable 7-1 andpHof7.4. ElectrochemicalimpedancespectroscopymeasurementswereperformedunderpotentiostaticcontrolusingaGamry300Gseriespotentiostat/glavanostat.CyclicvoltammetrywasalsoperformedwiththeGamrysystemwithvoltagesweepratesof50and100mV/s.Asilver/silverchloridereferenceelectrode(BioAnalyticalSystemsRE-5B)wasusedinthisstudy.PtorTilargeareacounterelectrodeswereusedfor 131

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CompositionofPhosphateBufferedSaline ChemicalCompoundsConcentration(M) NaCl0.138HCl0.0027Na2HPO40.01KH2PO40.00176 *H2O20.03 7-2 .Thetungstenmicroelectrodesexhibitreactivebehaviorsincetheimpedancedataforthetungstenmicroelectrodesshowthepresenceofaresistivepathwayatlowfrequencies(e.g.theimpedancedatashowsasemicircleinthecomplex-impedance-planeplot).Theplatinumelectrodeexhibitsblockingornonreactivebehaviorsinceitsimpedancedatatrendstoward 132

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Nyquistplot(left)andimaginaryimpedanceasafunctionoffrequency(right)oftungstenandplatinumelectrodesinPBS. Figure7-3. Equivalentcircuitsforblockingandreactivesystems[ 1 ]. innityasthefrequencydecreases.Allelectrodesshowconstantphaseelement(CPE)behaviorasevidencedbytheslopeoftheimaginaryimpedanceasafunctionoffrequencydifferingfromnegativeone(i.e.=0.9)[ 133 ].Theblockingandreactivesystemscanbemodeledwitharesistorinserieswithaconstantphaseelementortheparallelcombinationofaresistorandconstantphaseelement,respectively,asshowninFigure 7-3 [ 154 ].Reistheresistanceoftheelectrolyte,Rpisthepolarizationresistance,andZCPEistheconstantphaseelementimpedancegivenbyEquation 7 (j!)Q,(7) where!isthefrequency,isanumberfrom0to1,andQistheCPEcoefcientwithunitss/cm2[ 134 ]. 133

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Nyquistplot(left)ofimaginaryimpedanceasafunctionoffrequency(right)ofaplatinumelectrodeinphosphatebufferedsalineovertime. Impedancemeasurementstakenafterlongperiodsofimmersionintheelectrolyteillustratetheobservationofthenonreactivenatureofplatinumandgiveinsightintothereactivenatureofthetungstenelectrode.Figure 7-4 showstheimpedancespectraofplatinummicroelectrodesafter20daysinthePBSsolutionstillexhibitingblocking,orunreactive,behavior.Figure 7-5 showsEISresultsforagold-platedtungstenmicroelectrodeinPBSover15days.Theprogressionofthesemi-circularcurvesshowareactivesystemthatchangesovertime.Thechangeinthemagnitudeoftheimpedanceovertimeisanindicationthattheelectrodesurfaceisbeingmodied. Thedominantcathodicreactiononthetungstenelectrodeisfoundbytestingthesystemreactivitytotheoxygenconcentration.EISresultsshowingthedependenceofthefaradaicreactiontotheconcentrationofoxygenispresentedinFigure 7-6 .TheconcentrationofoxygenwasdecreasedbybubblingN2intothesolution.AfteronehourofO2displacementviabubbling,theEISmeasurementresultsshowthatthepolarizationresistanceincreaseswithdecreasedO2content.Theseresultssuggestthatthereductionofoxygenistherate-limitingcathodicreactionattheelectrodesurface. 134

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Nyquistplot(left)andimaginaryimpedanceasafunctionoffrequency(right)ofagold-platedtungstenelectrodeinphosphatebufferedsalineover15days. Figure7-6. Nyquistplot(left)andimaginaryimpedanceasafunctionoffrequency(right)oftungstenelectrodesinPBSshowingdependenceonO2concentration. 7-7 showsthatfaradaicreactionsareoccurringonboththegold-platedtungstenandplatinumelectrodeswhenH2O2ispresent.ThepresenceofaresistivepathwayatthedclimitisevidentbythesemicircularshapesinFigure 7-7 135

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Nyquistplot(left)andimaginaryimpedanceasafunctionoffrequency(right)ofaplatinumandgold-platedtungstenelectrodeinPBSplusH2O2showingreactivebehavior. 7-8 showsapolishedsurfaceofatungsten-onlyelectrodecomparedtothesurfaceafter23daysofimmersioninPBS.Thesurfaceafter23daysisporousandroughened.Overashortertimeinterval,Figure 7-9 showsthestateofsixdifferentgold-platedtungstenelectrodesbeforeandafterimmersioninPBSfromonetosixdays.Thetoppicturescorrespondtothebeforestateandthebottompicturescorrespondtotheafterstate.Afteronedayinsaline,thesurfacelookedroughenedascomparedtothepreviousstate.Aftertwodaysinsaline,therewasacircularsectioninthecenteroftheelectrodethatwasdepressedapproximately0.5m,whichisoutoffocusinthephotograph.Asimilartrendisseenfortheotherelectrodesleftinsalineforlongerperiods.Eachdisplaysacirculardepressioninthecenteroftheelectrodethatgrowsdeeperwithtime.Fortheelectrodeleftinsalineforvedays,thecenterwasdepressedapproximately4mandwasporous.Thepictureoftheelectrodeleftinsalineforsixdaysshowsthattheentiretungsten 136

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PhotographsofatungstenelectrodebeforeandafterimmersioninPBSforthespeciedperiodoftime. surfaceisrecessedfromthepolishedsurfacewiththecenterevenmoredepressed.Thesephotographssuggestthatthegold-plated-tungstenelectrodesexperienceduniformcorrosionthatwasdependentonthemicrostructureofthedrawntungstenwires.Overanevenshortertimeperiod,Figure 7-10 showsthechangeofthesurfaceofonegold-platedtungstenelectrodeinPBSandH2O2over24hours.Afteronehourintheelectrolyte,recesseswereseenaroundtheedgesofthegold-tungsteninterfaceaswellasaroughenedtungstensurface.Therecessesontheperimeteroftheelectrodearewhatisexpectedforaprimarycurrentdistributiononthediscelectrodesurface,wherethecurrentdensityisthehighestattheperimeter[ 36 ].Astimeprogressed,therecessesexpandedinwardtothecenteroftheelectrodeandafter24hours,thebulkofthetungstenwasrecessedontheorderof10mbelowtheoriginalsurface.Thesephotographssuggestamuchhighercorrosionrateforgold-platedtungsteninsalinesolutionscontainingH2O2thanwhatwasseenfortheothertwocaseswithoutH2O2. 155 ].Thethermodynamicstability 137

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Photographsofgold-platedtungstenelectrodesbefore(top)andafter(bottom)immersioninPBSforthespeciedperiodoftime. Figure7-10. Photographsofagold-platedtungstenelectrodesbeforeandafterimmersioninanelectrolytecontainingPBSandH2O2forthespeciedperiodoftime. ofchemicalspeciesatvariouspotentialandpHrangesmaybeascertainedfromthediagram.Also,thevoltagesforhydrogenandoxygenevolutionreactionsarecommonlyshownonthediagrams.InthePourbaixdiagramscreatedforthisstudy,allpotentialsarereferencedtothestandardhydrogenelectrode(SHE).Thus,acalculationmustbeperformedtoconvertthepotentialsmeasuredinthisstudytobewithrespecttotheSHE.ThePourbaixdiagramsshowninthisstudyaregeneratedbyacomputerprogram(CorrosionAnalyzer1.3Revision1.3.33byOLISystemsInc). 138

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Schematicrepresentationofelectrochemicalcell. 7-11 Aliquid-junctionpotentialexistsbetweentheelectrolyteinthereferenceelectrodeandtheelectrolyteoftheworkingelectrode.Theliquid-junctionpotentialmustbeaccountedforintheconversion.Asanapproximatesolution,theHendersonformula(Equation 7 )maybeusedeventhoughthecorrectconcentrationproleisnotdened. FAln(B=B) where andzi,ui,andciarethechargenumber,mobility,andmolarconcentrationofionicspeciesi,respectively[ 36 ].Thepotentialofasilver/silverchlorideelectrodewithreferencetotheSHEassumingtheconcentrationcanbeconsideredthesameastheactivityisgivenas FlncCl,(7) 139

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Pourbaixdiagramoftungsteninphosphatebufferedsaline.Theboxshowsrangeofopencircuitpotentialover15days.ThediagramsaregeneratedbyCorrosionAnalyzer1.3Revision1.3.33byOLISystemsInc. whereU=0.222Visthestandardelectrodepotentialat25C.Theelectrodepotentialcorrectedfortheliquid-junctionpotentialcanbeexpressedas whereUisthemeasuredopencircuitpotential.FortheconcentrationsusedinthisstudyU0=0.194Vand=0.016V. 7-12 showsthethermodynamicstabilityoftungsteninPBS.Thediagonallineslabeledaandbcorrespondtothelimitsofthestabilityofwater.Abovelinea,oxidationofwater(i.e.oxygenevolution),ispossibleandbelowlineb,reductionofwater(i.e.hydrogenevolution),ispossible.Betweenthoselines,waterisstable.TheverticaldashedlinedesignatesthenaturalpH 140

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SpeciesconsideredincalculationofthePourbaixdiagrampresentedasFigure 7-12 SolidPhase VaporPhase Pentasodiumtriphosphorousdecaoxide WaterChlorideion(-1) Pentasodiumtriphosphorousdecaoxidehexahydrate HydrogenDihydrogenorthophosphate(V)ion(-1) Phosphoruspentoxide(dimer) HydrogenchlorideDihydrogenpyrophosphate(V)ion(-2) Potassiumchloride OxygenHydrogen Potassiumdihydrogenorthophosphate(V) Hydrogenchloride Potassiumhydrogenorthophosphate(V)hexahydrate Hydrogenion(+1) Potassiumhydrogenorthophosphate(V)trihydrate Hydrogenorthophosphate(V)ion(-2) Potassiumhydrogenphosphate(V) Hydrogenpyrophosphate(V)ion(-3) Potassiumhydroxide Hydrogentungstate(VI)ion(-1) Potassiumhydroxidedihydrate Hydroxideion(-1) Potassiumhydroxidemonohydrate Orthophosphoricacid Potassiumorthophosphate(V) Oxygen Potassiumorthophosphate(V)heptahydrate Phosphateion(-3) Potassiumorthophosphate(V)trihydrate Potassiumchloride Potassiumtungstate(VI) Potassiumion(+1) Sodiumchloride Pyrophosphateion(-4) Sodiumdihydrogenorthophosphatedihydrate Pyrophosphoric(V)acid Sodiumdihydrogenorthophosphatemonohydrate Sodiumion(+1) Sodiumdihydrogenorthoporthohosphate Trihydrogenpyrophosphate(V)ion(-1) Sodiumhydrogenorthophosphate Tungsten(VI)tetraoxideion(-2) Sodiumhydrogenorthophosphatedihydrate Tungstic(VI)acid Sodiumhydrogenorthophosphatedodecahydrate Sodiumhydrogenorthophosphateheptahydrate Sodiumhydroxide Sodiumhydroxidemonohydrate Sodiumorthohosphate Sodiumorthophosphatehexahydrate Sodiumorthophosphatehydroxidedodecahydrate Sodiumorthophosphatemonohydrate Sodiumorthophosphateoctahydrate Sodiumpyrophosphatedecahydrate Sodiumtungstate(VI) Sodiumtungstate(VI)dihydrate Tungsten Tungsten(VI)oxide 7-2 .ThediagramshowsthatthetungsticionWO24isstableattheOCPandthatcorrosionreactionsarepossibleinthissystemsincetheboxisinthewhite(WO24)area.TheoverallanodicelectrochemicalreactionproducingthetungsticionisgivenbyEquation 7 [ 101 155 ].PossiblecathodicreactionsarereductionofwaterandoxygengivenbyEquation 7 andEquation 7 W+4H2O!WO24+8H++6e(7) O2+2H2O+4e!4OH(7) 141

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However,therate-limitingeffectofoxygenseeninFigure 7-6 suggeststhatthereductionofoxygenisthedominantcathodicreactiongivenbyEquation 7 Anotherpossiblechemicalreactionisthedissolutionofatungstenoxide.Lillardetal.showedthattungstenexposedtoairhasanativeoxideWO3viasurface-enhanced-Ramanspectroscopy[ 97 ].ThePourbaixdiagramsuggeststhatWO3dissolvesatthecellequilibriumpotential(0.4Vvs.SHE)and7.4pHasgivenbyEquation 7 WO3+H2O!WO24+2H+(7) Therefore,evenifanoxidelayerexistsonthetungstensurfacethatcouldinhibitthedissolutionofthetungsten,eventuallytheoxidewillbedissolvedandexposethetungstensurface. TheadditionofhydrogenperoxidetothePBSallowsanothercathodicreaction,thereductionofH2O2,tooccuronthetungstenelectrodesurfaces.APourbaixdiagramshowingtheOCPrangeforagold-platedtungstenelectrodeinanelectrolytecontainingPBSand30mMofH2O2isgiveninFigure 7-13 .ThechemicalspeciesconsideredforthePourbaixdiagramarethesameaslistedinTable 7-2 withtheadditionofH2O2.TheregionsofstabilityofH2O2givenbyPourbaix[ 155 ]areoverlayedonthediagram.Belowthelinelabeled1,reductionofH2O2ispossibleandaboveline2,oxidationofH2O2ispossible.Thus,foranelectrochemicalsystemcontainingatungstenelectrodeinPBSandH2O2,thepossibleanodicreactionisgivenbyEquation 7 andpossiblecathodicreactionsaregivenbyEquation 7 andEquation 7 H2O2+2H++2e!2H2O(7) 155 ]andthuswill 142

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Pourbaixdiagramoftungsteninanelectrolytecontainingphosphatebufferedsalineand30mMH2O2.Theboxshowsrangeofopencircuitpotentialovertwodays.ThediagramsaregeneratedbyCorrosionAnalyzer1.3Revision1.3.33byOLISystemsInc. notcorrode;however,itprovidesanexclusivesurfaceforthecathodicreactionandincreasesthecorrosionrateofthetungsten[ 51 ].Asthetungstencorrodes,goldthatwasplatedontheoutersurfaceofthetungstenbecomesfurtherexposed.Thesurfaceareaofthegoldincreases,therebyincreasingtheexchangecurrentforthecathodicreaction,andconsequentlytheanodicreactionratemustincreasetocompensate,sincethenetcurrentatequilibriummustbezero.Thisprocessmaybemodeledusingmixedpotentialtheory.AdiagramshowingaproposedmixedpotentialtheoryisgiveninFigure 7-14 .Forsimplicity,onlythedominantreactions(Equation 7 andEquation 7 )areincluded.Itisassumedthattheoxidationreactionoccursonlyonthetungsten(anode),andthereductionreactionoccursonlyonthegold(cathode).Figure 7-14 showsahypotheticalEvan'sdiagramconsistingofthelogarithmofcurrentasafunctionofpotential.Astheexchangecurrentincreasesfortheincreasingcathodesurfaceareaforthereductionofoxygen,anewcorrosioncurrentisestablishedas 143

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Effectofincreasedcathodesurfaceareaongalvanicinteractionoftungstenandgold. shownbytheshiftfromIcorr,1toIcorr,4.Assumingthetungstenareastaysconstant,theresultingcorrosionrateforthetungstenistherebyincreased.Also,thepotentialofthesystemincreasestomorenoblevalues. MeasurementsofOCPovertimeverifytheproposedeffectofthegalvaniccouple.Figure 7-15 displaysthemeasuredOCPovertimeforthegold-plated-tungstenelectrodesandtungstenelectrodesinPBS.Thegold-plated-tungstensystemshowsanonlineartrendtowardmorepositivepotentialscomparedtothetungstensystem,whichshowsamorestableOCP. Insummary,twofactorscontrolthecorrosionrateoftungsteninbiologicalsalinesolutions.Itwasshownviathedependenceontheconcentrationofoxygenthatthecorrosionoftungstenisrate-limitedbythecathodicreaction.Moreover,thecorrosionrateofthetungstenisincreasedbythegold-tungstengalvaniccoupleexistinginmicroelectrodesusedforintracorticalapplications.Theratesoftungstencorrosioninthreedifferentsystemsarequantiednext. 144

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OCPovertimeforgold-platedtungstenandtungstenelectrodesinPBS. 51 ]ThesmallsizeofoursampleelectrodedoesnotlenditselftoweightlossmeasurementsandTafelextrapolationiseasilyconfoundedbythepresenceofmultiplereactions[ 51 ].ExtrapolationofthepolarizationresistancefromEISdataratherthandatafrompolarizationmeasurementsispreferredinthesystemunderstudysincerelativelyshortertimesarerequiredfortheimpedancemeasurements. 7 [ 51 ].Thepolarizationresistanceisinversely 145

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whereaandcaretheanodicandcathodicTafelconstants,respectively,andicorristhecorrosioncurrentdensity[ 51 ].Thecorrosioncurrentdensityisrelatedtothecorrosionrateasfollows. nF,(7) whereaistheatomicweight,nistheoxidationnumber,andFisFaraday'sconstant.Equation 7 givesacorrosionrateintermsofmasslossperunitareapertime.Toobtainarateintermsofunitsofpenetrationpertime,Equation 7 isdividedbythedensityofthemetaltoachievemillimetersperyear(mm/yr),forexample. IftheTafelconstantsarenotknown,thecorrosionratemaystillbeapproximated.TheTafelconstantsrangebetween0.06Vand0.12Vforaandbetween0.12andinnityforc[ 51 ].Ifthemostextremevaluesareused,thecorrosionratevariesbyonlyafactoroftwo. 7 .[ 135 ] Themeasurementmodelconsistsofaresistor,R0,modelingtheelectrolyteresistance,inserieswithkVoigtelements,whereaVoigtelementisacapacitorinparallelwitharesistorthathasacharacteristictimeconstantk=2RC.Figure 7-16 showstheNyquistplotsoftheimpedanceresponseofthethreesystems.Allelectrodeswere 146

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7-3 .ArangeofvaluesforthecorrosionratesisgivenbecauseoftheuncertaintyoftheTafelconstants.Theimpedanceresults Figure7-16. Nyquistplotsusedforcalculationofthepolarizationresistance,Rp,forthreetungstensystems.ThesolidlinesshowtheregressionresultsusingEquation 7 predictthatthecorrosionoftungsteninaeratedPBSwillcorrodeatarateof200-500m/yr.Thegalvaniccoupleofthegold-platedtungstenmicrowireactstoincreasethecorrosionrateofthesysteminPBSaloneto300-700m/yr.However,thecorrosion 147

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Corrosionratesfortungsten SystemRp(Mcm2)rcorr(mm/yr) WinPBS17000.2rcorr0.5 W/AuinPBS12000.3rcorr0.7 W/AuinPBS+H2O24010rcorr20 ratespredictedforthegold-platedtungstensystemsarefortheinitialelectrodearea;theratescouldincreaseasmoreofthegoldsurfacebecomesexposedasdescribedpreviously.Theadditionof30mMofhydrogenperoxidetothePBSsignicantlyincreasesthecorrosionrateofagold-platedtungstenelectrodeto10,000-20,000m/yr.PreviousEISresultsshowedthatthecorrosionmechanismsareratelimitedbythecathodicreaction.Thus,thecorrosionratesforeachsystemaredependentontheconcentrationsofoxygenorhydrogenperoxide,respectively,andmayalsobecontrolledbydiffusionofthespecies. 7-7 ,afaradaicreactionoccursonplatinumelectrodesinsalinesolutionscontaininghydrogenperoxide.Itisimportanttoknowwhatelectrochemicalreactionscouldbeoccurringontheplatinumelectrodewhenimplanted.APourbaixdiagramconsideringthechemicalspeciesinTable 7-4 wasgeneratedforplatinuminanelectrolyteofPBSand30mMH2O2andisshowninFigure 7-17 .CurvesrepresentingthestabilityofH2O2aresuperimposedonthePourbaixdiagram.Atpotentialsbelowcurve1,thereductionofH2O2ispossibleandabovecurve2,theoxidationofH2O2ispossible[ 155 ].Intheregionwherethetworeactionsoverlap,hydrogenperoxidemaydissociateintowateronaplatinumsurface.TheboxshowstherangeofmeasuredOCPforthreeplatinumelectrodes.Thus,thePourbaixdiagramshowsthatreductionofH2O2ispossibleasacathodicreactioninthissystem.ThePourbaixdiagramdoesnot,however,suggestpossiblecorrespondinganodicreactions.Brummeretal.proposehydrogenadsorptionaspossiblechargetransferpathways[ 156 ].Theassumedanodic 148

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Pourbaixdiagramofplatinuminphosphatebufferedsalineand30mMhydrogenperoxide.Theredboxshowsrangeofopencircuitpotential.ThediagramsaregeneratedbyCorrosionAnalyzer1.3Revision1.3.33byOLISystemsInc. andcathodicreactionsaregivenrespectivelybyEquation 7 andEquation 7 Pt-H!Pt+H++e.(7) Cyclicvoltammetrywasusedtofurtheranalyzetheelectrochemicalreactionsattheplatinumsurface.Cyclicvoltammogramsoftheplatinumelectrodesareshownforscanratesof50and100mV/s.Bycomparingtheseresultswithliterature[ 157 158 ],thetwopeakslabeledHwandHsareinferredtobetheweakandstronghydrogenadsorptionpeaks.Thus,hydrogenadsorptionisfurthersubstantiatedbyFigure 7-18 ,asthehydrogenadsorptionpeaksoccurneartheopencircuitpotential(0.045VversusSHE)ofthecell. Hydrogenadsorptionandhydrogenperoxidereduction,Equation 7 andEquation 7 ,havenoadverseeffectontheplatinumsurface,henceitisexpectedto 149

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SpeciesconsideredincalculationofthePourbaixdiagrampresentedasFigure 7-17 SolidPhase VaporPhase Pentasodiumtriphosphorousdecaoxide WaterChlorideion(-1) Pentasodiumtriphosphorousdecaoxidehexahydrate HydrogenDihydrogenorthophosphate(V)ion(-1) Phosphoruspentoxide(dimer) HydrogenchlorideDihydrogenpyrophosphate(V)ion(-2) Platinum HydrogenperoxideHydrogen Platinum(II)chloride OxygenHydrogenchloride Platinum(II)hydroxide Hydrogenion(+1) Platinum(IV)chloride Hydrogenorthophosphate(V)ion(-2) Potassiumchloride Hydrogenperoxide Potassiumdihydrogenorthophosphate(V) Hydrogenperoxideion(-1) Potassiumhydrogenorthophosphate(V)hexahydrate Hydrogenpyrophosphate(V)ion(-3) Potassiumhydrogenorthophosphate(V)trihydrate Hydroxideion(-1) Potassiumhydrogenphosphate(V) Orthophosphoricacid Potassiumhydroxide Oxygen Potassiumhydroxidedihydrate Phosphateion(-3) Potassiumhydroxidemonohydrate Platinumion(+2) Potassiumorthophosphate(V) Platinumion(+4) Potassiumorthophosphate(V)heptahydrate Platinum(II)chloride Potassiumorthophosphate(V)trihydrate Platinum(II)hydroxide Sodiumchloride Platinum(II)monochlorideion(+1) Sodiumdihydrogenorthophosphatedihydrate Platinum(II)monohydroxideion(+1) Sodiumdihydrogenorthophosphatemonohydrate Platinum(II)tetrachlorideion(-2) Sodiumdihydrogenorthoporthohosphate Platinum(II)trichlorideion(-1) Sodiumhexachloroplatinate(IV)hexahydrate Platinum(IV)chloride Sodiumhydrogenorthophosphate Platinum(IV)dichlorideion(+2) Sodiumhydrogenorthophosphatedihydrate Platinum(IV)hexachlorideion(-2) Sodiumhydrogenorthophosphatedodecahydrate Platinum(IV)monochlorideion(+3) Sodiumhydrogenorthophosphateheptahydrate Platinum(IV)pentachlorideion(-1) Sodiumhydroxide Platinum(IV)trichlorideion(+1) Sodiumhydroxidemonohydrate Potassiumchloride Sodiumorthohosphate Potassiumion(+1) Sodiumorthophosphatehexahydrate Pyrophosphateion(-4) Sodiumorthophosphatehydroxidedodecahydrate Pyrophosphoric(V)acid Sodiumorthophosphatemonohydrate Sodiumion(+1) Sodiumorthophosphateoctahydrate Trihydrogenpyrophosphate(V)ion(-1) Sodiumpyrophosphatedecahydrate CyclicvoltammogramofaplatinumelectrodeinanelectrolytecontainingPBSand30mMH2O2

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Tungstenwasshowntocorrodeinphysiologicalsalineenvironments.ThedominantelectrochemicalreactionsontungsteninPBSareoxidationoftungstentothetungsticionandreductionofoxygen,andthedominantreactionsinPBSwithH2O2areoxidationoftungstentothetungsticionandreductionofH2O2towater.Theestimatedcorrosionratesforabare-tungstenmicroelectrodeandagold-platedtungstenmicroelectrodeinphysiologicalPBSare300-700m/yr.Thecorrosionrateofagold-platedtungstenmicroelectrodeinanelectrolytecontainingPBSand30mMH2O2is10,000-20,000m/yr.Thus,dependingontheconcentrationofH2O2encounteredbythemicroelectrodeinvivo,thecorrosionratecouldvarybytwoordersofmagnitude.Theseresultsmostlikelyconveytheworst-casescenario.Sinceitwasfoundthatthecorrosionratewaslimitedbytherateofthedominantcathodicreaction,theconcentrationofthereactivespecies,O2orH2O2,playamajorrole.TheconcentrationofdissolvedoxygeninthePBSusedintheinvitroexperimentsisdeterminedbythepartialpressureofoxygenintheair(150mmHg).Incomparison, 151

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159 160 ].Also,asevidencedintheSEMimagesoftheimplantedtungstenmicrowire,thebiologicallmthatformsontheelectrodesurfacemayacttoimpedediffusionofchemicalspeciesandeffectivelycontrolthecorrosionrate.ThecorrosionrateforinvivosituationsmaybeestimatedbythemeasurementoftherecessdepthofthetungstenmicrowiresontheUFmicroelectrodearrayusedintheinvivostudy.AsstatedinSection 5.6.2 ,theaveragedepththatthetungstensurfacewasrecessedfromtheoriginalsurfaceafteran87dayimplantperiodwas24m.Thecorrosionrateinaninvivosettingisthenestimatedtobeapproximately100m/yr,whichisofthesameorderofmagnitudeastheinvitroestimationoftungstencorrosionrateof300-700m/yr.Thecorrosionrateintheinvivosettingislessthanintheinvitrosettingbecauseofdecreaseddiffusionduetothepresenceofabiologicallmandlowerconcentrationofavailableoxygeninthebrainascomparedtotheair.Nonetheless,theseresultssuggestthattungstenshouldnotbeusedinlong-termimplants. Besidesthepossibilityoflocaltoxicityduetodiffusionoftungsticionsintothecortex,thecorrosionofthetungstenelectrodesmayimpedesuccessfullong-termrecording.Ithasbeenshownthatamicroelectrodemustbeplacedlessthan200mfromthecellbodytorecordtheactionpotentialofaneuron[ 19 ].Overtime,corrosioncoulddistancetherecordingsurfacefromtheneuronsuchthattheactionpotentialcouldnotbemeasured.Also,asthetungstenmicrowirecorrodes,ahollowtubemadeoftheinsulationandpossiblygoldplatingisformed.Thistubecouldprovideareservoirforcellularbuild-upthatwouldhinderthediffusionofionicspeciesandeffectivelyincreasetheimpedanceattheelectrode/electrolyteinterface,whichwouldultimatelydecreasethemagnitudeofthemeasuredactionpotential.Thus,basedontheresults,afteronlyoneyear,themagnitudeoftheactionpotentialonatungstenelectrodeshouldbegreatlyattenuated. 152

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Engineeringeffortshavethepotentialtomakerehabilitationforpeoplesufferingfromseveremotorimpairmentpossible.Neuroprosthesesthatincorporatebrain-machineinterfacesaretechnologiesbeingdevelopedforsuchproblems.Oneintegralcomponentinabrain-machineinterfaceisareliableandeffectiverecordingsystem.Theresearchpresentedinthisdocumentispartofalargerproject(FloridaWirelessIntegratedRecordingElectrode(FWIRE))thataddressestheengineeringchallengeofanimplantablerecordingsystem.ThisworkprovidesanelectrodeandpackagingfoundationforfuturegenerationsoftheFWIREdeviceforcorticalrecordingapplications.Thespeciccontributionsofthisworkincludethedesignandfabricationofanimplantablepolyimide-basedmicroelectrodeplatformintegratedwithanamplierICandfullcharacterizationofthedeviceincludinganalysisofinvivorecordingperformanceandinvitrocorrosionassessmentofthetungstenmicroelectrodes.Thischaptersummarizestheknowledgegainedfromthestudiesandprovidessuggestionsforfutureresearch. 154

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Bench-topresultsoftheUFmicroelectrodearrayshowedperformancesuitableforinvivorecording.Anaverageimpedanceof50kat1kHzwasmeasuredforthetungstenmicrowireelectrodes.Thenoiseoorofthemicroelectrodearray,only,waslessthan1Vrms,andthenoiseoorofthemicroelectrode-ampliersystemwasapproximately3.5Vrmsforafrequencyrangeof500Hzto6kHz.Thenoiseoorofthemicroelectrode-ampliersystemwasstatisticallysimilartothenoiseoorofacommercialmicrowirearraysystem(TuckerDavisTechnologies).Theelectrode-ampliersystemwasabletorecordandamplifyaccuratelyandasexpected;itstransferfunctionandimpulseresponseshowedalinearsystemabletoaccuratelymeasuresmallsignalwaveformsrepresentativeofactionpotentials. TheinvivotestingoftheUFmicroelectrodearrayalsoshowedadequaterecordingperformance.Theacuterecordingresultsofthemicroelectrodearraywithoutthehybrid-packagedampliergavehighsignaltonoiseratios(7or17dB).Theacuteresultsofthemicroelectrode-ampliersystemalsoshowedhighsignaltonoiseratios(12or21dB)andrelativelylownoise(4.5Vrms).Therecordingresultsofthemicroelectrode-ampliersystemovera42dayimplantperioddidnothavehighsignaltonoiseratios(onaveragetheSNRwas4or12dB);however,thepercentageofactiveelectrodesovertheimplantdurationstayedconstantat88%and1to3independentneuronsweremeasuredoneachactivechannel.Moreover,thesameneuronswereabletobeconsistentlymeasuredovertheimplantduration.Terminationoftheimplantedsystemwasduetoinconsistentrecordingsafterthe42dayperiodandinspectionafterexplantationshowedthatdelaminationofthepolyimidehadoccurredononesideofthe 155

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Amethodtoascertainnotonlythepresenceofelectrochemicalreactionsatequilibrium,butwhichreactionsareoccurringontheelectrodeswaspresented.ThemethodentailedanalysisofPourbaixdiagrams,whichrequiresmeasurementoftheopencircuitpotential,andEISonidealsamplesoftherecording-sitematerial.Thecorrosionoftungsten-microwireelectrodesusedforintracorticalrecordingapplicationswasanalyzedandcomparedtoresultsforplatinumelectrodes.Twoelectrolytesmodelingthechemistryofextracellularuidinthebrainintheabsenceandpresenceofaninammatoryreactionwereinvestigatedfortheinvitroelectrochemicalanalysis:0.9%phosphatebufferedsaline(PBS)and0.9%PBScontaining30mMhydrogenperoxide.Theoxidationandreductionreactionsresponsibleforcorrosionwerefoundbymeasurementoftheopen-circuitpotentialandanalysisofPourbaixdiagrams.Thecorrosionratewasestimatedfromthepolarizationresistance,whichwasextrapolatedfromtheelectrochemicalimpedancespectroscopydata.TheresultsshowedthattungstenmicrowireswithorwithoutgoldplatinginanelectrolyteofPBShaveacorrosionratesof300-700m/yr.Thecorrosionrateforgold-platedtungsten 156

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33 ].Thecorrosionrateoftungstenisofconcernforalong-termimplant,sincetheactivetungstenelectrodesurfacewillmostlikelyrecedeoutofrangeofrecordingfromaneuronafterafewyearsduetocorrosion.PlatinumwasunreactiveinsolutionsofPBSandreactiveinsolutionsofPBSandhydrogenperoxide.Thereactivityinsolutionscontaininghydrogenperoxideconsistedofhydrogen-atomplatingandreductionofH2O2,whichdidnotadverselyaffecttheplatinumsurfacenorintroduceunwantedspeciesintotheelectrolyte. Also,itwasfoundthatimpedancespectraofthemicroelectrodesaredependentonthequalityofthesealoftheinsulatortotheelectrode.Artifactsduetoanimperfectinsulatorsealobscuredtheimpedanceresponseandmadecharacterizationoftheinterfacedifcult.Thisworkpresentedaqualitycontrolmethodviagraphicalanalysisofelectrochemicalimpedancespectroscopydata.Bycomparingtheimpedancetoidealelectrodebehavior,thequalityofthemicroelectrode-to-insulationwasassessed. 157

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Tungstenshouldnotbeusedinfuturedesignsbecauseofitssusceptibilitytocorrosion.Theadvantagesofusingtungstenwireforintracorticalmicroelectrodesarebecauseitisrigidenoughtobeimplantedwithoutbucklinganditcanbemanuallypositionedeasilywithoutbending,makingfabricationofthearrayspossible.However,othermetalscouldhavesimilarcharacteristics.Toinsureprobeinsertionintothebraintissuewithoutbucklingorbending,theinsertionforcemustbelessthanthecriticalloadingforceforagivenelectrode.ThecriticalloadingforcemaybederivedusingEuler-Bernoullibeamtheory.ThecriticalloadingforceisexpressedinEquation 8 foracylindricalcolumnthatisclampedononesideandpinnedattheother. L2,(8) whereEisYoung'smodulusandIistheareamomentofinertia,andListhelengthofthecolumn[ 161 ].Table 8-1 showstheYoung'smodulusandcriticalloadingforcefor50mdiametertungsten,platinum,iridium,andplatinum-iridium(80%Pt,20%Ir)microwiresthatare3mmlong.Literatureprescribesaninsertionforceontheorderof Table8-1. CriticalLoadingForceforMetalMicrowires MicrowireMaterialE(GPa)Fcr(mN) Tungsten411283Platinum168116Iridium528363Platinum-Iridium(80%/20%)198136 1mNintothesub-duralcortexforelectrodescomparabletothesizeoftheelectrodesin 158

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162 163 ].TheresultsinTable 8-1 suggestthatallmetalslistedwouldhavesufcientmaterialstrengthforinsertionintothecortexastheircriticalloadingforceistwoordersofmagnitudehigherthanwhatisneededforinsertion.Thus,ametalotherthantungstenshouldbeusedforthenextgenerationofdevices. Platinum-iridiumismorerigidthanplatinumandmaybeabetterchoicefortheUFmicroelectrodearrayintermsofmechanicalassembly.Itselectrochemicalcharacteristicswerenotformallyexploredinthisstudy;however,preliminaryexperimentssuggestthatitwillbehavemuchlikeplatinum.ThePourbaixdiagramsforIrandPtshownoreactionsatopencircuitpotentialsmeasuredforthePt-Irelectrode[ 155 ]. Theelectrochemicalassessmentofmicroelectrodesisnoteasilyperformedinvivo,thuselectrolytesthatmimicwhatisseeninvivoareneeded.Futureelectrochemicalassessmentofotherrecording-sitematerialsshouldincludehydrogenperoxidesinceitwasshowntomakeappreciabledifferencesinthecasesoftungstenandplatinum.ThecorrosionrateofthetungstenincreasedbytwoordersofmagnitudeinthepresenceofH2O2andelicitedfaradaicreactionsontheplatinumelectrode.Intheplatinumcase,thefaradaicreactiondidnotcorrodetheelectrodenorintroduceunwantedelectrochemicalby-productsinthesolution.Instead,reductionofhydrogenperoxidetowaterresulted.Thechoiceofmetalsthatareelectrochemicallyactivebutnotcorrosivecouldbechosentolessencellulardamagebyreactiveoxygenspecies.ItisalsoadvisedtoperformaninvivostudyoftheelectrochemistryatmetalmicroelectrodestoconrmthatsmallamountsofhydrogenperoxideaddedtoPBSisagoodmodelfortheextracellularchemistryduringanimmuneresponse. 159

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[1] M.E.OrazemandB.Tribollet,ElectrochemicalImpedanceSpectroscopy.Hoboken,NJ:JohnWileyandSons,Inc.,2008. [2] Paralysisresourcecenter,WorldWideWeb, http://www.paralysis.org/site/c.erJMJUOxFmH/b.1169107/k.BE3A/Home.htm ,2008. [3] Epilepsyfoundation,WorldWideWeb, http://www.epilepsyfoundation.org/about/statistics.cfm ,2009. [4] E.C.Leuthardt,S.Gerwin,D.Moran,andJ.Ojemann,Theemergingworldofmotorneuroprosthetics:Aneurosurgicalperspective,Neurosurgery,vol.59,no.1,2006. [5] F.Mussa-IvaldiandL.Miller,Brain-macineinterfaces:commputationaldemandsandclinicalneedsmeetbasicneuroscience,TrendsinNeuroscience,vol.26,no.6,pp.329,2003. [6] M.Hodaie,R.Wennberg,J.Dostrovsky,andA.Lozano,Chronicanteriorthalamusstimulationforintractableepilepsy,Epilepsia,vol.43,no.6,pp.603,2002. [7] E.Hauerman,Thedeadlyve,PopularScience,vol.October,pp.47,2007. [8] G.Mone,Happinessisawarmelectrode,PopularScience,vol.October,pp.57,2007. [9] D.Tweney,Deankamen'srobotarmgrabsmorepublicity,WorldWideWeb, http://blog.wired.com/gadgets/2008/05/dean-kamens-rob.html ,2008. [10] A.Schwartz,X.T.Cui,D.Weber,andD.Moran,Brain-controlledinterfaces:Movementrestorationwithneuralprosthetics,Neuron,vol.52,pp.205,2006. [11] J.K.Chapin,K.A.Moxon,R.S.Markowitz,andM.A.L.Nicolelis,Real-timecontrolofarobotarmusingsimultaneouslyrecordedneuronsinthemotorcortex,vol.2,no.7,pp.664,1999. [12] J.Wessberg,C.Stambaugh,J.Krallk,P.Beck,M.Laubach,J.Chapin,J.Kim,S.Biggs,M.Srinlvasan,andM.Nicolelis,Real-timepredictionofhandtrajectorybyensenblesofcorticalneuronsinprimates,Nature,vol.408,no.16,pp.361,2000. [13] D.M.Taylor,S.I.H.Tillery,andA.B.Schwartz,Directcorticalcontrolof3dneuroprostheticdevices,Science,vol.296,no.5574,pp.1829,June7,20022002. 160

PAGE 161

S.Musallam,B.D.Corneil,B.Greger,H.Scherberger,andR.A.Andersen,Cognitivecontrolsignalsforneuralprosthetics,Science,vol.305,pp.258,July9,20042004. [15] J.M.Carmena,M.A.Lebedev,R.E.Crist,J.E.O'Doherty,D.M.Santucci,D.F.Dimitrov,P.G.Patil,C.S.Henriquez,andM.A.L.Nicolelis,Learningtocontrolabrain-machineinterfaceforreachingandgraspingbyprimates,PLoSBiol,vol.1,no.2,p.e42,2003. [16] M.Velliste,S.Perel,M.C.Spalding,A.S.Whitford,andA.B.Schwartz,Corticalcontrolofaprostheticarmforself-feeding,Nature,vol.453,no.7198,pp.1098,2008. [17] L.R.Hochberg,M.D.Serruya,G.M.Friehs,J.A.Mukand,M.Saleh,A.H.Caplan,A.Branner,D.Chen,R.D.Penn,andJ.P.Donoghue,Neuronalensemblecontrolofprostheticdevicesbyahumanwithtetraplegia,Nature,vol.442,no.7099,pp.164,2006. [18] A.Gunduz,M.C.Ozturk,J.C.Sanchez,andJ.C.Principe,Echostatenetworksformotorcontrolofhumanecogneuroprosthetics,ser.Proceedingsofthe3rdInternationalIEEEEMBSConferenceonNeuralEngineering,KohalaCoast,HI,UnitedStates,1999,pp.514. [19] D.Henze,Z.Borhegyi,J.Sciscvari,A.Mamiya,K.Harris,andG.Buzaki,Intracellularfeaturespredictedbyextracellularrecordingsinthehippocampusinvivo,TheJournalofNeurophysiology,vol.84,pp.390,2000. [20] V.Polikov,P.Tresco,andW.Reichert,Responseofbraintissuetochronicallyimplantedneuralelectrodes,JournalofNeuroscienceMethods,vol.148,pp.1,2005. [21] R.Vetter,J.Williams,J.Hetke,E.Nunamaker,andD.R.Kipke,Chronicneuralrecordingusingsilicon-substratemicroelectrodearraysimplantedincerebralcortex,IEEETrans.Biomed.Eng.,vol.51,no.6,pp.896,2004. [22] P.J.RouscheandR.A.Normann,Chronicrecordingcapabilityoftheutahintracorticalelectrodearrayincatsensorycortex,JournalofNeuroscienceMethods,vol.82,no.1,pp.1,1998. [23] J.C.Williams,R.L.Rennaker,andD.R.Kipke,Long-termneuralrecordingcharacteristicsofwiremicroelectrodearraysimplantedincerebralcortex,BrainResearchProtocols,vol.4,no.3,pp.303,1999,tY-JOUR. [24] X.D.Liu,D.B.McCreery,L.A.Bullara,andW.F.Agnew,Evaluationofthestabilityofintracorticalmicroelectrodearrays,IeeeTransactionsonNeuralSystemsandRehabilitationEngineering,vol.14,no.1,pp.91,2006. 161

PAGE 162

R.Bashirullah,J.Harris,J.Sanchez,T.Nishida,andP.Jose,Floridawirelessimplantablerecordingelectrodes(fwire)forbrainmachineinterfaces,2007. [26] E.Patrick,M.Ordonez,N.Alba,J.C.Sanchez,andT.Nishida,Designandfabricationofaexiblesubstratemicroelectrodearrayforbrainmachineinterfaces,inEngineeringinMedicineandBiologySociety,2006.EMBS'06.28thAnnualInternationalConferenceoftheIEEE,2006,pp.2966. [27] E.Patrick,V.Sankar,W.Rowe,S.-F.Yen,J.C.Sanchez,andT.Nishida,Flexiblepolymersubstrateandtungstenmicroelectrodearrayforanimplantableneuralrecordingsystem,inEngineeringinMedicineandBiologySociety,2008.EMBS'08.30thAnnualInternationalConferenceoftheIEEE,2008,pp.3158. [28] E.Patrick,V.Sankar,W.Rowe,J.C.Sanchez,andT.Nishida,Designofanimplantableintracorticalmicroelectrodesystemforbrain-machineinterfaces,inNeuralEngineering,2009.ConferenceProceedings.4thInternationalIEEEEMBSConferenceon,2009. [29] E.Patrick,V.Sankar,W.Rowe,J.C.Sanchez,andT.Nishida,Animplantableintegratedlow-poweramplier-microelectrodearrayforbrain-machineinterfaces,inEngineeringinMedicineandBiologySociety,2010.EMBS'10.32ndAnnualInternationalConferenceoftheIEEE,2010. [30] E.Patrick,M.Orazem,J.C.Sanchez,andT.Nishida,Corrosionoftungstenmicroelectrodesusedinneuralrecordingapplications,J.ofNeuroscienceMethods,tobesubmitted. [31] E.Patrick,M.Orazem,T.Nishida,andV.Vivier,Useofimpedancespectroscopytoassessthequalityofmicroelectrodefabrication,JournaloftheElectrochemicalSociety,tobesubmitted. [32] T.Trappenberg,FundamentalsofComputationalNeuroscience.NewYork,NY:OxfordUniversityPress,2002. [33] G.R.HoltandC.Koch,Electricalinteractionsviatheextracellularpotentialnearcellbodies,JournalofComputationalNeuroscience,vol.6,no.2,pp.169,1999. [34] K.Drake,K.D.Wise,J.Farraye,D.J.Anderson,andS.Bement,Performanceofplanarmultisitemicroprobesinrecordingextracellularsingle-unitintracorticalactivity,IEEETrans.Biomed.Eng.,vol.35,no.9,pp.719,1988. [35] C.L.Lopreore,T.M.Bartol,J.S.Coggan,D.X.Keller,G.E.Sosinsky,M.H.Ellisman,andT.J.Sejnowski,Computationalmodelingofthree-dimensionalelectrodiffusioninbiologicalsystems:Applicationtothenodeofranvier,vol.95,no.6,pp.2624,2008,0006-3495. 162

PAGE 163

J.Newman,ElectrochemicalSystems.Hoboken,NJ:JohnWileyandSons,Inc.,2004. [37] M.SalcmanandM.Bak,Design,fabricationandin-vivobehaviorofchronicrecordingintracorticalmicroelectrodes,IEEETrans.Biomed.Eng.,vol.20,pp.253,1973. [38] M.SalcmanandM.Bak,Anewchronicrecordingintracorticalmicroelectrode,Med.Biol.Eng.,vol.January,pp.42,1976. [39] Tuckerdavistechnologies,WorldWideWeb, http://www.tdt.com/products/MW16.htm ,2008. [40] Microprobe,inc.WorldWideWeb, http://www.microprobes.com/ ,2008. [41] K.WiseandJ.Starr,Anintegrated-circuitapproachtoextracellularmicro-electrodes,IEEETrans.Biomed.Eng.,vol.17,pp.238,1970. [42] K.Naja,K.Wise,andT.Mochizuki,Ahigh-yieldic-compatiblemultichannelrecordingarray,IEEETrans.ElectronDevices,vol.ED-22,pp.230,1985. [43] K.NajaandK.D.Wise,Animplantablemultielectrodearraywithon-chipsignalprocessing,IEEEJournalofSolidStateCircuits,vol.sc-21,pp.1035,1986. [44] J.JiandK.D.Wise,Animplantablecmoscircuitinterfaceformultiplexedmicroelectroderecordingarrays,IEEEJournalofSolidStateCircuits,vol.27,no.3,pp.433,1992. [45] J.Heteke,J.Lund,K.Naja,K.Wise,andD.Anderson,Siliconribboncablesforchronicallyimplantablemicroelectrodearrays,IEEETrans.Biomed.Eng.,vol.41,pp.314,1994. [46] A.HoogerwerfandK.Wise,Athree-dimensionalmicroelectrodearrayforchronicneuralrecording,IEEETrans.Biomed.Eng.,vol.41,pp.1136,1994. [47] K.D.Wise,D.J.Anderson,J.F.Hetke,D.R.Kipke,andK.Nija,Wirelessimplantablemicrosystems:Highdensityelectronicinterfacestothenervoussystem,ProceedingsoftheIEEE,vol.92,no.76-97,2004. [48] Y.Yao,M.Gulari,B.Casey,J.A.Wiler,andK.D.Wise,Siliconmicroelectrodeswithexibleintegratedcablesforneuralimplantapplications,May2-52007. [49] K.Wise,A.Sodagar,Y.Yao,M.Gulari,andK.Naja,Microelectrodes,microelectronics,andimplantableneuralmicrosystems,ProceedingsoftheIEEE,vol.96,pp.1184,2008. 163

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P.K.Campbell,K.E.Jones,R.J.Huber,K.W.Horch,andR.A.Norman,Asilicon-basedthree-dimensionalneuralinterface:Manufacturingprocessesforaintracorticalelectrodearray,IEEETrans.Biomed.Eng.,vol.38,pp.758,1991. [51] D.A.Jones,PrinciplesandPreventionofCorrosion.NewYork,NY:MaxmilliamPublishingCo.,1992. [52] A.Branner,R.B.Stein,andR.A.Normann,Selectivestimulationandrecordingusingaslantedmultielectrodearray,AnnualInternationalConferenceoftheIEEEEngineeringinMedicineandBiology-Proceedings,vol.1,p.377,1999. [53] R.Bhandari,S.Negi,L.Rieth,M.Toepper,S.Kim,M.Klein,H.Oppermann,R.A.Normann,andF.Solzbacher,Systemintegrationoftheutahelectrodearrayusingabiocompatibleipchipunderbumpmetallizationscheme,ser.ProceedingsofSPIE-TheInternationalSocietyforOpticalEngineering,vol.6525.SanDiego,CA,UnitedStates:SPIE,BellinghamWA,WA98227-0010,UnitedStates,2007,p.65251. [54] S.Kim,P.Tathireddy,R.A.Normann,andF.Solzbacher,Thermalimpactofanactive3-dmicroelectrodearrayimplantedinthebrain,IEEETransactionsonNeuralSystemsandRehabilitationEngineering,vol.15,no.4,pp.493,2007. [55] P.Norlin,M.Kindlundh,A.Mouroux,K.Yoshida,andU.G.Hofmann,A32-siteneuralrecordingprobefabricatedbydrieofsoisubstrates,JournalofMicrome-chanicsandMicroengineering,vol.12,no.4,pp.414,2002. [56] M.Kindlundh,P.Norlin,andU.G.Hofmann,Aneuralprobeprocessenablingvariableelectrodecongurations,SensorsandActuatorsB:Chemical,vol.102,no.1,pp.51,2004. [57] J.Muthuswamy,M.Okandan,andN.Jackson,Singleneuronalrecordingsusingsurfacemicromachinedpolysiliconmicroelectrodes,JournalofNeuroscienceMethods,vol.142,no.1,pp.45,2005. [58] P.Rousche,D.Pellinen,D.Pivin,J.Williams,R.Vetter,andD.Kipke,Flexiblepolyimide-basedintracorticalelectrodearrayswithbioactivecapability,IEEETrans.Biomed.Eng.,vol.48,no.3,pp.361,2001. [59] D.O'Brien,T.Nichols,andM.Allen,Flexiblemicroelectrodearrayswithintegratedinsertiondevices,IEEEMEMS,pp.216,2001. [60] D.S.Pellinen,T.Moon,R.J.Vetter,R.Miriani,andD.R.Kipke,Multifunctionalexibleparylene-basedintracorticalmicroelectrodes,ser.AnnualInternationalConferenceoftheIEEEEngineeringinMedicineandBiology-Proceedings,vol.7S,Shanghai,China,2005,pp.5272. 164

PAGE 165

J.SeymourandD.Kipke,Neuralprobedesignforreducedtissueencapsulationincns,Biomaterials,vol.28,pp.3594,2007. [62] K.Lee,J.He,R.Clement,S.Massia,andB.Kim,Biocompatiblebenzocyclobutene(bcb)-basedneuralimplantswithmicro-uidicchannel,BiosensorsandBioelectronics,vol.20,no.2,pp.404,2004. [63] T.StieglitzandM.Gross,Flexiblebiomemswithelectrodearrangementsonfrontandbacksideaskeycomponentinneuralprosthesesandbiohybridsystems,SensorsandActuatorsB-Chemical,vol.83,no.1-3,pp.8,2002. [64] T.Stieglitz,M.Schuettler,andK.P.Koch,Implantablebiomedicalmicrosystemsforneuralprostheses,IEEEEngineeringinMedicineandBiologyMagazine,vol.24,no.5,pp.58,2005. [65] S.Takeuchi,T.Suzuki,K.Mabuchi,andH.Fujita,dexiblemultichannelneuralprobearray,JournalofMicromechanicsandMicroengineering,vol.14,pp.104,2004. [66] T.Suzuki,D.Ziegler,K.Mabuchi,andS.Takeuchi,Flexibleneuralprobeswithmicro-uidicchannelsforstableinterfacewiththenervoussystem,ser.26thAnnualInternationalsConferenceoftheIEEEEMBS,SanFranscico,CA,USA,September1-52004,pp.4057. [67] Y.Kato,M.Nishino,I.Saito,T.Suzuki,andK.Mabuchi,Flexibleintracorticalneuralprobewithbiodegradablepolymerfordeliveringbioactivecomponents,ser.Proceedingsof2006InternationalConferenceonMicrotechnologiesinMedicineandBiology,Okinawa,Japan,2006,pp.143. [68] Y.Kato,I.Saito,T.Hoshino,T.Suzuki,andK.Mabuchi,Preliminarystudyofmultichannelexibleneuralprobescoatedwithhybridbiodegradablepolymer,ser.AnnualInternationalConferenceoftheIEEEEngineeringinMedicineandBiology-Proceedings,NewYork,NY,UnitedStates,2006,pp.660. [69] K.C.Cheung,P.Renaud,H.Tanila,andK.Djupsund,Flexiblepolyimidemicroelectrodearrayforinvivorecordingsandcurrentsourcedensityanalysis,BiosensorsandBioelectronics,vol.22,no.8,pp.1783,2007. [70] G.A.G.D.J.M.J.C.P.W.V.S.D.M.T.P.A.T.TheodoreW.Berger(Chair),JohnK.Chapin,Wtecpanelreportoninternationalassessmentofresearchanddevelopmentinbrain-computerinterfaces,WORLDTECHNOLOGYEVALUATIONCENTERINC,BALTIMOREMD,Tech.Rep.,2007. [71] R.CarterandJ.Houk,Multiplesingle-unitrecordingsforthecnsusingthin-lmelectrodearrays,IEEETransRehabEng,vol.1,no.3,pp.175,1993. 165

PAGE 166

R.A.Normann,P.K.Campbell,andK.E.Jones,Siliconbasedelectrodearrayforintracorticalstimulation:Structuralandelectricalproperties,ser.ProceedingsoftheAnnualConferenceonEngineeringinMedicineandBiology,vol.11pt3.Seattle,WA,USA:PublbyAllianceforEngineeringinMedicineandBiology,Washington,DC,USA,1989,pp.939. [73] D.Szarowski,M.Andersen,S.Retterer,A.Spence,M.Isaacson,H.Craighead,J.Turner,andW.Smith,Brainresponsestomicro-machinedsilicondevices,BrainResearch,vol.983,pp.23,2003. [74] R.Biran,D.C.Martin,andP.Tresco,Neuronalcelllossaccompaniesthebraintissueresponsetochronicallyimplantedsiliconmicroelectrodearrays,Experi-mentalNeurology,vol.195,pp.115,2005. [75] B.BurkeandC.Lewis,TheMacrophage.Oxford:OxfordMedicalPublications,2002. [76] J.Turner,W.Shain,D.Szarowski,M.Andersen,S.Martins,M.Isaacson,andH.Craighead,Cerebralastrocyteresponsetomicromachinedsiliconimplants,ExperimentalNeurology,vol.156,pp.33,1999. [77] D.MerrillandP.Tresco,Impedancecharacterizationofmicroarrayrecordingelectrodesinvitro,IEEETran.BiomedEng.,vol.52,pp.1960,2005. [78] A.Reynolds,C.Laurie,R.Mosley,andH.Gendelman,Oxidativestressandthepathogenesisofneurodegenerativedisorders,InternationalReviewofNeurobiology,vol.82,pp.297,2007. [79] R.Biran,D.C.Martin,andP.Tresco,Thebraintissueresponsetoimplantedsiliconmicroelectrodearraysisincreasedwhenthedeviceistetheredtotheskull,JournalofBiomedicalMaterialsResearchPartA,vol.82,no.1,pp.169,2007. [80] Y.Kim,R.Hitchcock,M.Bridge,andP.Tresco,Chronicresponseofadultratbraintissuetoimplantsanchoredtotheskull,Biomaterials,vol.25,pp.2229,2004. [81] S.Ranson,TheAnatomyoftheNervousSystem.Philadelphia,PA:W.B.SaunderCompany,1945. [82] H.Lee,R.Bellamkonda,W.Sun,andM.Levenston,Biomechanicalanalysisofsiliconmicroelectrode-inducedstraininthebrain,J.NeuralEng,vol.2,pp.81,2005. [83] J.Subbaroyan,D.Martin,andD.Kipke,Anite-elementmodelofthemechanicaleffectsofimplantablemicroelectrodesinthecerbralcortex,J.NeuralEng,vol.2,pp.103,2005. 166

PAGE 167

M.P.Hughes,K.Bustamante,D.Banks,andD.J.Ewins,Effectsofelectrodesizeonthepreformanceofneuralrecordingmicroelectrodes,in1stAnnualInternationalIEEE-EMBE,Lyon,France,2000. [85] S.F.Lempka,M.D.Johnson,D.W.Barnett,M.A.Moftt,K.J.Otto,D.R.Kipke,andC.C.McIntyre,Optimizationofmicroelectrodedesignforcorticalrecordingbasedonthermalnoiseconsiderations,inEngineeringinMedicineandBiologySociety,2006.EMBS'06.28thAnnualInternationalConferenceoftheIEEE,2006,pp.33613364. [86] J.J.Jacobs,J.L.Gilbert,andR.M.Urban,Currentconceptsreview-corrosionofmetalorthopaedicimplants,pp.268,February1,19981998. [87] A.Norlin,J.Pan,andC.Leygral,Investigationofelectrochemicalbehaviorforstimulating/sensingmaterialsforpacemakerelectrodeapplications,JoftheELectrochemicalSociety,vol.152,no.2,pp.J7J15,2005. [88] A.Norlin,J.Pan,andC.Leygral,InvestigationofinterfacialcapacitanceofPt,Ti,andTiNcoatedelectrodesbyelectrochemicalimpedancespectroscopy,BiomolecularEngineering,vol.19,pp.67,2002. [89] S.B.BrummerandM.J.Turner,Electrochemicalconsiderationsforsafeelectricalstimulationofthenervoussystemwithplatinumelectrodes,IEEETransactionsonBiomedicalEngineering,vol.BME-24,no.1,pp.59,1977. [90] D.R.Merrill,M.Bikson,andJ.G.R.Jefferys,Electricalstimulationofexcitabletissue:Designofefcaciousandsafeprotocols,JournalofNeuro-scienceMethods,vol.141,no.2,pp.171,2005,0165-0270doi:DOI:10.1016/j.jneumeth.2004.10.020. [91] J.BockrisandA.Reddy,ModernElectrochemistry.NewYork,NY:PlenumPress,1970. [92] A.Hassibi,R.Navid,R.Dutton,andT.Lee,Comprehensivestudyofnoiseprocessesinelectrodeelectrolyteinterfaces,JornalofAppliedPhysics,vol.15,pp.1074,2004. [93] C.Gabrielli,Identicationofelectrochemicalprocessesbyfrequencyresponse,SchlumbergerTechnologies,Tech.Rep.TechnicalreportNumber004/83,1984. [94] S.Bothra,H.Sur,andV.Liang,Anewfailuremechanismbycorrosionoftungsteninatungstenplugprocess,MicroelectronicsandReliability,vol.39,no.1,pp.59,1999. [95] M.Peuster,C.Fink,andC.vonSchnakenburg,Biocompatibilityofcorrodingtungstencoils:invitroassessmentofdegradationkineticsandcytotoxicityonhumancells,Biomaterials,vol.24,pp.4057,2003. 167

PAGE 168

J.Sanchez,N.Alba,T.Nishida,C.Batich,andP.Carney,Structuralmodicationsinchronicmicrowireelectrodesforcorticalneuroprosthetics:Acasestudy,IEEETrans.onNeuralSyst.Rehab.Eng.,pp.217,2006. [97] R.S.Lillard,G.S.Kanner,andD.P.Butt,Thenatureofoxidelmsontungsteninacidicandalkalinesolutions,JournalofTheElectrochemicalSociety,vol.145,no.8,pp.2718,1998. [98] M.Anik,ph-dependentanodicreactionbehavioroftungsteninacidicphosphatesolutions,ElectrochimicaActa,vol.54,no.15,pp.3943,2009. [99] M.AnikandK.Osseo-Asare,Effectofphontheanodicbehavioroftungsten,JournalofTheElectrochemicalSociety,vol.149,no.6,pp.B224B233,2002. [100] J.W.JohnsonandC.L.Wu,Theanodicdissolutionoftungsten,JournalofTheElectrochemicalSociety,vol.118,no.12,pp.1909,1971. [101] G.S.Kelsey,Theanodicoxidationoftungsteninaqueousbase,JournalofTheElectrochemicalSociety,vol.124,no.6,pp.814,1977. [102] C.deHaro,R.Mas,G.Abadal,J.Munoz,F.Perez-Murano,andC.Dominguez,Electrochemicalplatinumcoatingsforimprovingperformanceofimplantablemicroelectrodearrays,Biomaterials,vol.23,no.23,pp.4515,2002. [103] D.R.Kipke,Silicon-substrateintracorticalmicroelectrodearraysforlong-termrecordingofneuronalspikeactivityincerebralcortex,IEEETrans.Rehab.Eng.,vol.11,pp.151,2003. [104] E.Maynard,C.Nordhausen,andR.A.Normann,TheUtahintracorticalelectrodearray:Arecordingstructureforpotentialbrain-computerinterfaces,Electroen-cephalographyandClinicalNeurophysiology,vol.102,pp.228,1997. [105] J.Pan,D.Theirry,andC.Leygraf,Electrochemicalimpedancespectroscopystudyofthepassiveoxidelmontitaniumforimplantapplication,ElectrochemicaActa,vol.41,pp.1143,1996. [106] C.FonescaandM.Barbosa,Corrosionbehavioroftitaniuminbiouidscontainingh2o2studiedbyelectrochemicalimpedancespectroscopy,Corro-sionScience,vol.43,pp.547,2001. [107] S.B.Hall,E.A.Khudaish,andA.L.Hart,Electrochemicaloxidationofhydrogenperoxideatplatinumelectrodes.partiii:Effectoftemperature,ElectrochimicaActa,vol.44,no.14,pp.2455,1999. [108] S.B.Hall,E.A.Khudaish,andA.L.Hart,Electrochemicaloxidationofhydrogenperoxideatplatinumelectrodes.parti:Anadsorption-controlledmechanism,ElectrochimicaActa,vol.43,no.5-6,pp.579,1998. 168

PAGE 169

S.B.Hall,E.A.Khudaish,andA.L.Hart,Electrochemicaloxidationofhydrogenperoxideatplatinumelectrodes.partii:effectofpotential,ElectrochimicaActa,vol.43,no.14-15,pp.2015,1998. [110] S.B.Hall,E.A.Khudaish,andA.L.Hart,Electrochemicaloxidationofhydrogenperoxideatplatinumelectrodes.partiv:phosphatebufferdependence,Elec-trochimicaActa,vol.44,pp.4573,1999. [111] S.Boppart,B.Wheeler,andC.Wallace,Aexibleperforatedmicroelectrodearrayforextendedneuralrecordings,IEEETrans.Biomed.Eng.,vol.39,no.1,pp.37,1992. [112] A.Owensandetal,Multi-electrodearayformeasuringevokedpotentialsforsurfaceofferretprimaryauditorycortex,J.Neurosci.Meth.,vol.58,pp.209,1995. [113] G.E.Loeb,M.J.Bak,andE.M.Schmidt,Paryleneasachronicallystable,reproduciblemicroelectrodeinsulator,IEEETrans.onBiomed.Eng.,vol.24,no.2,pp.121,1977. [114] E.M.Schmidt,M.J.Bak,andJ.S.McIntosh,Long-termchronicrecordingfromcorticalneurons,ExperimentalNeurology,vol.52,no.3,pp.496,1976. [115] E.M.SchmidtandJ.S.McIntosh,Long-termimplantsofparylene-ccoatedmicroelectrodes,Med.Biol.Eng.Comput.,vol.26,pp.96,1988. [116] L.GeddesandR.Roeder,Criteriafortheselectionofmaterialsforimplantedelectrodes,AnnalsofBiomedicalEngineering,vol.31,pp.879,2003. [117] M.Orazem,Asystematicapproachtowarderrorstructureidenticationforimpedancespectroscopy,J.ElectroanalyticalChemistry,vol.572,pp.317,2004. [118] M.SteckerandT.Patterson,Electrodeimpedanceinneurophysiologicrecordings:1.theroyandintrinsiccontributionstonoise,Am.J.ENDTechnol.,vol.38,pp.174,1998. [119] G.Paxinos,Theratbraininstereotaxiccoordinates.Sydney:AcademicPress,1997. [120] S.Kim,R.Bhandari,M.Klein,S.Negi,L.Rieth,P.Tathireddy,M.Toepper,H.Oppermann,andF.Solzbacher,IntegratedwirelessneuralinterfacebasedontheUtahelectrodearray,BiomedicalMicrodevices,vol.11,no.2,pp.453,2009. 169

PAGE 170

Y.K.Song,D.A.Borton,S.Park,W.R.Patterson,C.W.Bull,F.Laiwalla,J.Mislow,J.D.Simeral,J.P.Donoghue,andA.V.Nurmikko,Activemicroelectronicneurosensorarraysforimplantablebraincommunicationinterfaces,IEEETransactionsonNeuralSystemsandRehabilitationEngineering,vol.17,no.4,pp.339,2009. [122] R.Bashirullah,J.Harris,J.Sanchez,T.Nishida,andP.Jose,Floridawirelessimplantablerecordingelectrodes(fwire)forbrainmachineinterfaces,inIEEEInternationalSymposiumonCircuitsandSystems,2007. [123] A.Sodagar,G.Perlin,Y.Yao,K.Wise,andK.Naja,Animplantablemicrosystemforwirelessmulti-channelcorticalrecording,inTransducers2007,2007,pp.69. [124] J.Harris,J.Principe,J.Sanchez,D.Chen,andC.She,Pulse-basedsignalcompressionforimplantedneuralrecordingsystems,inIEEEISCAS,2008,pp.344. [125] A.Legatt,Imparmentofcommonmoderejectionbymismatchedelectrodeimpedances:quantitativeanalysis,Am.J.EEGTech.,vol.35,pp.296,1995. [126] B.Hirschorn,B.Tribollet,andM.E.Orazem,Ontheselectionoftheperturbationamplituderequiredtoavoidnonlineareffectsinimpedancemeasurements,IsraelJournalofChemistry,vol.48,pp.133,2008. [127] R.Meyer,S.Cogan,T.Nguyen,andR.Rauh,Electrodepositediridiumoxideforneuralstimulationandrecordingelectrodes,IEEETrans.NeuralSyst.Rehab.Eng.,vol.9,no.1,pp.2,2001. [128] J.YangandD.C.Martin,Microporousconductionpolymersonneuralmicroelectrodearraysii.physicalcharacterization,SensorsandActuatorsA,vol.113,pp.204,2004. [129] X.CuiandD.C.Martin,Electrochemicaldepositionandcharacterizationofploy(3,4-ethylenedioxythiophene)onneuralmicroelectrodearrays,SensorsandActuatorsB,vol.89,pp.92,2003. [130] M.AtesandA.S.Sarac,Electrochemicalimpedancespectroscopyofpoly[carbazole-co-n-p-tolylsulfonylpyrrole]oncarbonbermicroelectrodes,equivalentcircuitsformodelling,ProgressinOrganicCoatings,vol.65,pp.281,2009. [131] D.T.Price,A.R.A.Rahman,andS.Bhansali,Designruleforoptimizationofmicroelectrodesusedinelectriccell-substrateimpedancesensing(ecis),BiosensorsandBioelectronics,vol.24,pp.2071,2009. 170

PAGE 171

Y.Zhang,H.Wang,J.Nie,Y.Zhang,G.Shen,andR.Yu,Individuallyaddressablemicroelectrodearraysfabricatedwithgold-coatedpencilgraphiteformultiplexedandhighsensitiveimpedanceimmunoassays,BiosensorsandBioelectronics,vol.25,pp.34,2009. [133] M.E.Orazem,N.Pebere,andB.Tribollet,Enhancedgraphicalrepresentationofelectrochemicalimpedancedata,J.Electrochem.Soc.,vol.153,pp.B129B136,2006. [134] G.Brug,A.V.denEeden,M.Sluyters-Rehbach,andJ.Sluyters,Theanalysisofelectrodeimpedancescomplicatedbythepresenceofaconstantphaseelement,Electroanal.Chem.,vol.176,pp.275,1984. [135] M.Orazem,Asystematicapproachtowarderrorstructureidenticationforimpedancespectroscopy,,J.ElectroanalyticalChemistry,vol.572,pp.318,2004. [136] S.Carson,M.Orazem,O.Crisalle,andL.Garcia-Rubio,Ontheerrorstructureofimpedancemeasurements,JornalofElectrochemistrySociety,vol.150,no.10,pp.477,2003. [137] R.Jurczakowski,C.Hitz,andA.Lasia,Impedanceofporousaubasedelectrodes,JournalofElectroanalyticalChemistry,vol.572,no.2,pp.355,2004. [138] R.Jurczakowski,C.Hitz,andA.Lasia,Impedanceofporousgoldelectrodesinthepresenceofelectroactivespecies,JournalofElectroanalyticalChemistry,vol.582,no.1-2,pp.85,2005. [139] H.-K.Song,Y.-H.Jung,K.-H.Lee,andL.H.Dao,Electrochemicalimpedancespectroscopyofporouselectrodes:theeffectofporesizedistribution,Elec-trochimicaActa,vol.44,no.20,pp.3513,1999. [140] R.J.Forster,Microelectrodes:Newdimensionsinelectrochemistry,ChemicalSocietyReviews,vol.23,pp.289,1994. [141] M.FleischmannandS.Pons,Thebehaviorofmicroelectrodes,AnalyticalChemistry,vol.59,no.24,pp.1391AA,1987,doi:10.1021/ac00151a0010003-2700doi:10.1021/ac00151a001. [142] A.G.Ewing,M.A.Dayton,andR.M.Wightman,Pulsevoltammetrywithmicrovoltammetricelectrodes,AnalyticalChemistry,vol.53,no.12,pp.1842,1981,compilationandindexingterms,Copyright2009ElsevierInc.198202000680400032700MICROVOLTAMMETRICELECTRODES. [143] K.P.Troyer,M.L.A.V.Heien,B.J.Venton,andR.M.Wightman,Neurochemistryandelectroanalyticalprobes,CurrentOpinioninChemicalBiology,vol.6,no.5,pp.696,2002,1367-5931doi:DOI:10.1016/S1367-5931(02)00374-5. 171

PAGE 172

W.Pernkopf,M.Sagl,G.Falek,J.O.Besenhard,H.Kronberger,andG.E.Nauer,Applicationsofmicroelectrodesinimpedancespectroscopy,SolidStateIonics,vol.176,no.25-28,pp.2031,2005. [145] C.Gabrielli,S.Joiret,M.Keddam,N.Portail,P.Rousseau,andV.Vivier,SinglepitonirongeneratedbySECM:Anelectrochemicalimpedancespectroscopyinvestigation,ElectrochimicaActa,vol.53,no.25,pp.7539,2008,0013-4686doi:DOI:10.1016/j.electacta.2008.01.013. [146] D.Rolison,Fabricationofultramicroelectrodes,inUltramicroelectrodes,M.Fleischmann,S.Pons,D.Rolison,andP.Schmidt,Eds.DatatechSystems,Inc.(Edt.),ScienticPublishingDivision,1987,ch.3,pp.65. [147] W.ThormannandA.M.Bond,Applicationoftransientelectrochemicaltechniquestoinlaidultra-microelectrodes:Assessmentoffabricationquality,JournalofElectroanalyticalChemistry,vol.218,no.1-2,pp.187196,1987. [148] O.Koster,W.Schuhmann,H.Vogt,andW.Mokwa,Qualitycontrolofultra-microelectrodearraysusingcyclicvoltammetry,electrochemicalimpedancespectroscopyandscanningelectrochemicalmicroscopy,SensorsandActuators,B:Chemical,vol.76,pp.573,2001. [149] V.M.-W.Huang,V.Vivier,M.E.Orazem,P.Nadine,andB.Tribollet,TheapparentCPEbehaviorofanideallypolarizeddiskelectrode:Aglobalandlocalimpedanceanalysis,J.Electrochem.Soc.,vol.154,pp.C81C88,2007. [150] V.M.-W.Huang,V.Vivier,I.Frateur,M.E.Orazem,andB.Tribollet,TheglobalandlocalimpedanceresponseofablockingdiskelectrodewithlocalCPEbehavior,J.Electrochem.Soc.,vol.154,pp.C89C98,2007. [151] V.M.-W.Huang,V.Vivier,M.E.Orazem,P.Nadine,andB.Tribollet,TheapparentCPEbehaviorofadiskelectrodewithfaradaicreactions,J.Elec-trochem.Soc.,vol.154,pp.C99C107,2007. [152] M.E.Orazem,Asystematicapproachtowarderrorstructureidenticationforimpedancespectroscopy,J.Electroanal.Chem.,vol.572,pp.317,2004. [153] G.J.Brug,A.L.G.vandenEeden,M.Sluyters-Rehbach,andJ.H.Sluyters,Theanalysisofelectrodeimpedancescomplicatedbythepresenceofaconstantphaseelement,J.Electroanal.Chem.,vol.176,pp.275,1984. [154] M.E.OrazemandB.Tribollet,ElectrochemicalImpedanceSpectroscopy.Hoboken,NJ:JohnWiley&Sons,2008. [155] M.Pourbaix,Atlasofelectrochemicalequilibria.Oxford:PergamonPressLtd.,1966. 172

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S.B.BrummerandM.J.Turner,Electrochemicalconsiderationsforsafeelectricalstimulationofthenervoussystemwithplatinumelectrodes,IEEETransactionsonBiomedicalEngineering,vol.BME-24,no.1,pp.59,1977. [157] B.Ren,X.Xu,X.Q.Li,W.B.Cai,andZ.Q.Tian,Extendingsurfaceramanspectroscopicstudiestotransitionmetalsforpracticalapplications:Ii.hydrogenadsorptionatplatinumelectrodes,SurfaceScience,vol.427-428,pp.157,1999. [158] H.D.Yoo,J.H.Jang,B.H.Ka,C.K.Rhee,andS.M.Oh,Impedanceanalysisforhydrogenadsorptionpseudocapacitanceandelectrochemicallyactivesurfaceareaofptelectrode,Langmuir,vol.25,no.19,pp.11947954,2009. [159] A.Maas,W.Fleckenstein,D.deJong,andH.vanSantbrink,Monitoringcerebraloxygenation:experimentalstudiesandpreliminaryclinicalresultsofcontinuousmonitoringofcerebrospinaluidandbraintissueoxygentension,ActaNeurochirSuppl(Wien),vol.59,p.5057,1993. [160] A.Sarrafzadeh,K.Kiening,T.Bardt,G.Schneider,A.Unterberg,andW.Lanksch,Cerebraloxygenationincontusionedvsnonlesionedbraintissue:monitoringofptio2withlicoxandparatrend,ActaNeurochirSuppl(Wien),vol.71,pp.186,1998. [161] F.BeerandE.Johnston,MechanicsofMaterials.NewYork:McGrawHill,1981. [162] C.TianandJ.He,Monitoringinsertionforceandelectrodeimpedanceduringimplantationofmicrowireelectrodes,inIEEEEngineeringinMedicineandBiology27thAnnualConference,Shanghai,China,2005. [163] W.Jensen,U.Hofmann,andK.Yoshida,Assessmentofsubduralinsertionforceofsingle-tinemicroelectrodesinratcerebralcortex,in25thAnnualInternationalConferenceoftheIEEEEngineeringinMedicineandBiologySociety,Cancun,Mexico,2003. 173

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ErinElizabethPatrickwasborninElkins,WestVirginia.ShegraduatedfromVeroBeachHighSchoolinVeroBeach,Floridainthespringof1997andstartedherbachelor'sdegreeattheUniversityofFloridathatnextfall.InDecemberof2002sheearnedaBachelorofScienceinElectricalEngineeringwithhighhonors.DuringErin'sundergraduatestudiesshedidaninternshipatDominionSemiconductor,aDRAMandFlashmemorymanufacturingfacilityinManassas,Virginia,andstartedworkingasanundergraduateresearchassistantforhercurrentadvisorintheInterdisciplinaryMicrosystemsGroup(IMG)atUF.ShethenjoinedIMGasadoctoralcandidateinAugustof2003.ErinearnedaDoctorofPhilosophyinElectricalEngineeringatUFinAugustof2010.Hertechnicalexpertiseisinmicroelectromechanicalsystem(MEMS)processingtechniquesandelectrochemicalimpedancespectroscopy.HerresearchinterestsincludebiologicalandchemicalMEMSsensors. 174