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DESIGN, FABRICATION, AND CHARACTERIZATION OF MICROELECTRODES FOR
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
@ 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
TABLE OF CONTENTS
LIST O F TABLES ...........................
LIST O F FIG URES ..........................
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 ................
2 BACKGROUND ON MICROELECTRODES FOR NEURAL RECORDING ..
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 ...........
126.96.36.199 The Michigan array .. .................
188.8.131.52 The Utah array ............. .. ......
184.108.40.206 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 ELECTRODE-ELECTROLYTE INTERFACE PHYSICS AND CONCERNS .
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 UF RECORDING MICROELECTRODE ARRAY
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 UF MICROELECTRODE ARRAY HYBRID-PACKAGED WITH AMPLIFIER IC 79
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 ELECTROCHEMICAL CHARACTERIZATION OF ELECTRODES: METHODS 112
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
220.127.116.11 Graphical analysis . ... 122
6.3.2 Quality Control Results and Discussion . 124
18.104.22.168 Ideal behavior .......................124
22.214.171.124 Non-ideal behavior. . .. 125
6.3.3 Quality Control Summary ... 127
7 ELECTROCHEMICAL CHARACTERIZATION ELECTRODES: RESULTS .
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 .
126.96.36.199 Calculation of Corrosion Rate .
188.8.131.52 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 ..................
BIOGRAPHICAL SKETCH .. .....................
LIST OF TABLES
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
LIST OF FIGURES
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 . ... 56
Equivalent circuit for faradaic interface . . 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
DESIGN, FABRICATION, AND CHARACTERIZATION OF MICROELECTRODES FOR
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 . Epilepsy is estimated
to cost $15.5 billion annually and approximately 200,000 new cases are diagnosed
each year . 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 . 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 . 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 . 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 . Others have shown effective 1D and 3D control
of robotic arms  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 . 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 .
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 . 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 . 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 . Typically, the bandwidth of ECoG
recordings is 10 Hz to 200 Hz . 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 . 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.
Intracortical .- Electrodes
:. *... ., 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 . 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 . 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
Micromachined Pt 92%/12 weeks Vetter,
silicon shank 92%/18 weeks Kipke, et
electrode with al., 2004
flexible cable 
Micromachined Pt 45%/12 weeks Rousche,
Silicon bed of nails 18%/52 weeks Normann,
electrode 1998 
Micro-wire electrode W 80%/12 weeks Williams,
45%/25 weeks Kipke,
Micro-wire electrode Ir 62%/1 week Liu,
25%/151 weeks McCreery,
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 .
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 
and tungsten  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 . 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 . 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.
BACKGROUND ON MICROELECTRODES FOR NEURAL RECORDING
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 . 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
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 .
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 .
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.
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 .
Measured action -.--.-.-. -.-.- -.
&* 0 -------- -
0 A Amplified action
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 . The circle in the center of the figure represents the soma, while
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
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 . Drake et al. reported that the farthest
distance they could experimentally record from a neuron cell body in the rat cortex
is 180 pm . 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 . 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
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 . 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.
= V N,. (2-2)
Combining (2-1) and (2-2) gives a time dependent differential equation relating potential
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 . 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 . 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) .
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) .
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.
184.108.40.206 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 . 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 . 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 . 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 . 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 . The 2-D arrays were fit through slots in the
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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  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 .
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].
220.127.116.11 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 .
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 .
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 . 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
. 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 .
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 . 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 .
18.104.22.168 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 . 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 . 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 .
A collaboration between Arizona State University and Sandia National Laboratories
resulted in a Si-based actuated microelectrode array . 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
. 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 .
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
 and an open architecture microelectrode with subcellular dimensions seen in
Figure 2-10 . 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 . They designed for increased stiffness that allowed implantation into
the cortex without buckling . 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 . 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 . The publication mentioned
first  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 . 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 . 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
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 . Microfluidic channels
were structured in the parylene layers by patterning photoresist between the layers and
subsequently removing it, leaving a void . 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 .
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 . 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
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 . 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 .
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 . 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)
. 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 . Also, in designs that incorporate electronics onto the backside of the
Utah electrode, power constraints due to tissue heating are a concern .
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
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 . 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 . Microglia secret reactive oxygen intermediates
(ROls) in what is called the "respiratory burst"  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  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 . 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  and did not correlate to the size of the implanted probe
(except for subcellular sizes ). 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 . 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 . 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 .
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 . 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. 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 . 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 . 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 .
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 . 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 . 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 . 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 . 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 . Their results showed an even greater decrease in microglial
response in the free-floating cases than . Thus, a flexible substrate design that
minimizes tethering forces on the implanted microelectrode array is supported.
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.
ELECTRODE-ELECTROLYTE INTERFACE PHYSICS AND CONCERNS
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 .
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 . 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 . 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 . 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
The space charge region in metal and solution interfaces was first described by
Helmholtz and is known generically as the double layer . 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 . Thus, subsequent interface models have arisen giving a more
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 . 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
~ +^ ^r
Figure 3-1. Equilibrium electrode/electrolyte interface.
is distributed. The net charge in this area exponentially decays to zero as a function
of distance . 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
where c is permittivity , 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 . The definition for capacitance is
where q is the charge on the electrode . Therefore,
1 1 1
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 ,
. 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 . The double layer capacity
is typically 10 20 F/cm2 . Since it has been shown that current is capacitively
coupled in the double layer, the current to voltage relationship in the bulk electrolyte is
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 / . 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 
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) . For a disk electrode with a
reference electrode a semi-infinite distance away, the resistance of the bulk electrolyte is
where ro is the radius of the disk electrode.
Double Layer Bulk Electrolyte
Figure 3-2. Equivalent circuit for the nonfaradaic interface .
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) .
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 . 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 . 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 .
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 
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 
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 .
Double Layer Bulk Electrolyte
Figure 3-3. Equivalent circuit for faradaic interface .
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 . 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 . 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.
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 . For small overpotentials, (3-19) is linearized
and the polarization resistance becomes
Rp = icorr2.33 (3-20)
2.303(o, + o,)'
where icorr = i, = .
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. 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 . 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 . Sanchez et
al. showed structural modification of tungsten microwires after four weeks of in vivo
implantation . Their observation suggested corrosion had occurred at the end of the
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 . 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 . 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 . Reactive oxygen species such as H202
are produced by the reactive microglia during the inflammatory response . 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
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.
UF RECORDING MICROELECTRODE ARRAY
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 . 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 . 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.
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
b) Ni wiring is encapsulated in a top layer of
c) Polyimide is etched (RIE) from bond pad
- Si wafer
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 . 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 . 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 .
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.
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 . 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.
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
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
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
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
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
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 . 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.
,-- 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.
The process flow for this electrode was developed based on the process used
for the previous generation electrode . 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 . 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.
.-- 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
e) Solder connections are hermetically
sealed with layersof epoxy and silicone
c) RIE of polyimide form bond pad sites and
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.
wires (Top View)
g off Bo
ub 1 r fo,
Nut for ground screw
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 . 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 .
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 . 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.
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 .
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
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
SNR (dB) 14.7 13.8
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.
UF MICROELECTRODE ARRAY HYBRID-PACKAGED WITH AMPLIFIER IC
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 . 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
, 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
. 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
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 . 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 . 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.
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
Brgm B Polyimide cable
.ik :_ C -Amplifier IC
S : E D Ground bolt
~B Omnetics connector
B. D -- -
f f' '. M-1 _. ,...,,
Figure 5-1. In vivo placement of microelectrode array on rodent skull. Inset shows full
Figure 5-2. Flexible polyimide microelectrode array with integrated amplifier. Inset shows
the enlarged image of the tungsten microwires.
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
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.
c ) Tungsten wires are placed in trenches and
electrically connected with 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
e) The amplifier chip is flip prepared with
gold stud bumps and flip-chip bonded to
the substrate and hertetically sealed..
SNut for anchoring screw
C Bond pads
r for Omnetics
Nut for ground screw
f) Omnetics connectors are electrically attached to
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.
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)
Buffer Array TDT RA8GA
UF signal signalopticalsignal TDT
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 , 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
0 0.2 0.4 0.6 0.8 1
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
Noise seen on TDT software
* Ij I II II 'I
.1 I I
0 0.2 0.4 0.6 0.8 1
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'- '
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.
j) 10 ,
100 102 104
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
Noise Floor without EMI Noise Floor with EMI
Sio5 --ch4 .c 5 ch4
Q 10-5 ch4 Q 10-6 ch
U) 10-7 U) 10-7
10 10 1 02 103 104 100 101 102 103 104
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
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
108 Amplifier input
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. , 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 *--- ----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
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
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
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. . Assuming Ze < Zamp and Zref < Zamp, Equation 5-2 may be
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
0.1 0 1 2 3 4
10 10 10 10 10
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)
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)
Zamp CMRR Zamp CMRR
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,
100 102 104 106
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,
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
100 1 2 3 4 5
10 10 10 10 10 10
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
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 . 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
-0.5 0 0.5 1 1.5
1 -- input
-0.1 0 0.1 0.2 0.3
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
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
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 3 Day 13 Day 23
Day 31 Day 42
T [ FIRE
0 10 20 30 40
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 . They also measured impedance values over time and
concluded that an increase in electrode impedance by 30% to 100%, which coincided
0 10 20 30 40 50
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 . 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.
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
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.
ELECTROCHEMICAL CHARACTERIZATION OF ELECTRODES: METHODS
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 . 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 . 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 . 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 . The perturbation signal is
swept over a range of frequencies and the resulting frequency-dependent impedance
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 . 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 . 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 . 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 . 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) .
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. , 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
O O Blocking 10
O x Reactive x
O -20 x
S10 15 0 1024 1 0 -40 x 1
N -50 x
10 10 1 102 103 104 05 100 101 102 103 104 105
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 . 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 .
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)
Figure 6-4. Nyquist plot (left) and logarithm of imaginary impedance as a function of
frequency (right) of blocking and reactive systems.
101 102 103 104 105
101 102 103 104
Nyquist plot (left) and logarithm of imaginary impedance as a function of
frequency (right) for blocking and reactive systems with a constant phase
where a is a number from 0 to 1, and Q is the quantity of the CPE with units sa/Qcm2
. 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
 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 
Z = RRk (6-2)
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 . 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 .
The residual error acres found above includes bias error, stochastic error and error
to the fit. However, reference  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 . 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 . Contaminants on the surface from perhaps a polishing step also
pose threats to the quality of the measurement .
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
. 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 .
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.  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 .
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 . 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 . 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
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 .
22.214.171.124 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  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 . In a logarithmic plot, the slope of the impedance data gives the
negative value of a. The value of Q is given by 
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,
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
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
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 , 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].
126.96.36.199 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
N 0 106
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.
103 v 3a
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.
188.8.131.52 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
0.18 v 3a
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. Values of a and Qeff for non-ideal electrodes extracted from Figure 6-10 and
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
-0.8 v 3a
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 , 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
160 a 2b
140 v 3b ov
0 20 40 60
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.
- 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
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.
O Oo Co
00 v 0
S OVO 17V
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%.
ELECTROCHEMICAL CHARACTERIZATION ELECTRODES: RESULTS
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.
silver epoxy bond
1200 grit SiC sandpaper
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 , . 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)
*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
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
Re ZCPE Re
Figure 7-3. Equivalent circuits for blocking and reactive systems .
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) . 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 . 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 .
L day1 day 20
8 day 20 104 d
E 6 v E
0 A o
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.
0 200 400 600 800 1000 1200
Zr (Q cm2)
Nyquist plot (left) and imaginary impedance as a function of frequency (right)
of a gold-plated tungsten electrode in phosphate buffered saline over 15
PBS with reduced 02
PBS with reduced 0
Zr (Q cm2)
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
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
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 . 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 . 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 . 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
Aqueous Phase Solid Phase
Dihydrogen orthophosphate(V) ion(-1)
Dihydrogen pyrophosphate(V) ion(-2)
Hydrogen orthophosphate(V) ion (-2)
Hydrogen pyrophosphate(V) ion(-3)
Hydrogen tungstate(VI) ion(-1)
Trihydrogen pyrophosphate(V) ion(-1)
Tungsten(VI) tetraoxide ion(-2)
Pentasodium triphosphorous decaoxide
Pentasodium triphosphorous decaoxide hexahydrate
Phosphorus pentoxide dimerr)
Potassium dihydrogen orthophosphate(V)
Potassium hydrogen orthophosphate(V) hexahydrate
Potassium hydrogen orthophosphate(V) trihydrate
Potassium hydrogen phosphate(V)
Potassium hydroxide dihydrate
Potassium hydroxide monohydrate
Potassium orthophosphate(V) heptahydrate
Potassium orthophosphate(V) trihydrate
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 monohydrate
Sodium orthophosphate hexahydrate
Sodium orthophosphate hydroxide dodecahydrate
Sodium orthophosphate monohydrate
Sodium orthophosphate octahydrate
Sodium pyrophosphate decahydrate
Sodium tungstate(VI) dihydrate
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
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 . 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
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  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  and thus will
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. 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
Figure 7-14. Effect of increased cathode surface area on galvanic interaction of tungsten
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.
LU -0.4 W only
I W/Au couple
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. 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 . 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.
184.108.40.206 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 . 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 . 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 . If the most extreme values are used, the corrosion rate varies by only
a factor of two.
220.127.116.11 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
Z = Ro Rk (7-13)
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
W only in PBS
W/Au in PBS
W/Au in PBS + H202
/ 0 \ 1000 2000
\\ (Q cm)
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
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 . 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 . 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
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
Dihydrogen orthophosphate(V) ion(-1)
Dihydrogen pyrophosphate(V) ion(-2)
Hydrogen orthophosphate(V) ion (-2)
Hydrogen peroxide ion(-1)
Hydrogen pyrophosphate(V) ion(-3)
Platinum(ll) monochloride ion(+1)
Platinum(ll) monohydroxide ion(+1)
Platinum(ll) tetrachloride ion(-2)
Platinum(ll) trichloride ion(-1)
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)
Trihydroqen pyrophosphate(V) ion(-1)
Pentasodium triphosphorous decaoxide
Pentasodium triphosphorous decaoxide hexahydrate
Phosphorus pentoxide dimerr)
Potassium dihydrogen orthophosphate(V)
Potassium hydrogen orthophosphate(V) hexahydrate
Potassium hydrogen orthophosphate(V) trihydrate
Potassium hydrogen phosphate(V)
Potassium hydroxide dihydrate
Potassium hydroxide monohydrate
Potassium orthophosphate(V) heptahydrate
Potassium orthophosphate(V) trihydrate
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 monohydrate
Sodium orthophosphate hexahydrate
Sodium orthophosphate hydroxide dodecahydrate
Sodium orthophosphate monohydrate
Sodium orthophosphate octahydrate
Sodium pyrophosphate decahydrate
-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
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.
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 . 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.
SUMMARY AND CONCLUSION
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 . 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 . 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 .
The electrochemical assessment of microelectrodes is not easily performed in vivo,
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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.
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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.
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 18.104.22.168TheMichiganarray ..................... 31 22.214.171.124TheUtaharray ........................ 34 126.96.36.199OtherSimicroelectrodearrays ............... 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 ........................ 121 188.8.131.52Graphicalanalysis ...................... 122 6.3.2QualityControlResultsandDiscussion ................ 124 184.108.40.206Idealbehavior ........................ 124 220.127.116.11Non-idealbehavior ...................... 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 18.104.22.168CalculationofCorrosionRate ................ 145 22.214.171.124ComparisonofCorrosionRates .............. 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
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
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
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)4.15.05.34.126.96.36.199.3 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
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
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
Frequencyresponseofamplier-microelectrodesystem.Thepass-bandgainis39dB. the100spulseresponse.Sinceanactionpotentialhaspulselengthsontheorderofmilliseconds,thisamplier-microelectrodesystemmeasuresthesignalwithoutappreciabledistortion. 119 ].Atthesiteoftheelectrodeimplantation,thedurawasremovedtoexposethecortex.Theentireassemblywasimplantedverticallyandloweredusingamicropositioner.Whiledrivingtheelectrode,electrophysiologicrecordingswereused 102
Impulseresponseofamplier-microelectrodesystem.Figure 5-23A showstheresponsetoa1mspulse,characteristicofaneuralactionpotential.Figure 5-23B showstheresponsetoa100spulse. 103
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
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
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
Noiseoorfortheelectrodearrayovertheimplantedduration.FWIREcorrespondstotheUFamplier-microelectrodesystemandTDTcorrespondstoaTuckerDavismicro-wireelectrodearrayandPZ2amplier. after23daysimplanted.Thespikesortingresultsshowedatleastoneneurononsevenoftheelectrodechannels.AllactionpotentialscorrespondingtosingleneuronsusedfortheSNRcalculationwereconsistentlyrecordedfromday1today42. Performancemetricsincludingnoiseoor,signaltonoiseratio,andneuronalyieldshowedthattheamplier-microelectrodearrayperformedadequately.ThenoiseoorwasstatisticallysimilartothenoiseoorofaTuckerDaviselectrodeininvitroexperimentationoverafrequencyrangeof500Hzto6kHz.Theaveragenoiseoormeasuredinvivoontherstdayofimplantationwaslessthanonemicrovolthigherthanthatmeasuredinsaline.Theincreaseinthenoiseoorwasassumedtobefromadditionofbackgroundneuronalnoise.Theaveragenoiseoorthenincreasedtoavalueaboutonemicrovolthigherthanitwasondayone.Thecauseofthisincreaseinnoiseafterdayoneismoreambiguous;however,thesametrendhasbeenreportedbytheMichigangroup[ 21 ].Theyalsomeasuredimpedancevaluesovertimeandconcludedthatanincreaseinelectrodeimpedanceby30%to100%,whichcoincided 107
Signal-to-noiseratiofortheelectrodearrayovertheimplantduration.FWIREcorrespondstotheUFamplier-microelectrodesystemandTDTcorrespondstoaTuckerDavismicro-wireelectrodearrayandPZ2amplier. withtheincreaseinnoise,wasatleastpartiallythecauseoftheincreaseinnoiseoor.Tresco'sgroupreportedthatincreasesinelectrodeimpedanceofthesamemagnitudeareattributedtocellularadhesion[ 77 ].SignaltonoiseratiosreportedfortheUFmicroelectrodearrayafterdayonewerelowcomparedtomostpublisheddata,butbecausetheyaredependentontheproximityofanactiveneuron,theyarenotarelevantindicationofperformancequalityespeciallywhenthenoiseoorisadequatelylow.ThepercentageofactiveelectrodesontheUFmicroelectrodearrayovertheimplantdurationstayedconstantat88%and1to3independentneuronsweremeasuredoneachactivechannel.Thus,theUFmicroelectrodearraywithhybrid-packagedamplierICshowsacceptableperformanceforrecordingapplicationslastingtwomonths. 108
SEMimagesoftungstenmicro-wiresbeforeandafter87daysimplanted.a,b)Characteristicelectrodesbeforeimplantation.c,d)Characteristicelectrodesafterimplantation.Theinsetinchighlightstheareaofgoldexposedtothetissue. tungstenmicrowiresissystematicallystudiedinaninvitroexperimentandtheeffectofthetungstencorrosiononlong-termrecordingperformanceisdiscussedinChapter 7 110
EDSresultsoftwositesononeelectrodeafter87daysinvivo.Thetopgraphshowsresultscharacteristicofabaretungstenandgoldsurface.Thebottomgraphshowsresultscharacteristicofabio-lm. polyimidesurface.Furthermore,SEMimagesofthetungstenrecordingsitesafterexplantationshowedconsiderablechangeintheelectrodesurfacesuggestingcorrosionofthetungsten.Thoughtheresultsfor42daysdonotsuggestthatthecorrosionofthetungstenmicrowirehadanyadverseeffectontherecordingperformancethusfar,thereisapossibilitythatadverseeffectsmayoccurinprolongedstudies.TheresultsofadetailedanalysisofcorrosionpropertiesoftungstenmicrowiresarepresentedinChapter7.Theexperimentalmethodsareexplainedinthenextchapter. 111
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
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
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
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
Nyquistplot(left)andlogarithmofimaginaryimpedanceasafunctionoffrequency(right)ofblockingandreactivesystems. Figure6-5. Nyquistplot(left)andlogarithmofimaginaryimpedanceasafunctionoffrequency(right)forblockingandreactivesystemswithaconstantphaseelement. 116
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
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
Throughthisapproach,anerrorstructurerepresentingthestochasticerrorisfound,andthemeasureddataarecheckedforlinearity,stability,andcasuality.Theerrorstructurecanthenbeusedasweightingforregressionofphysicalmodelsrepresentingtheelectrochemicalsystem. 137 139 ].Thus,thetungstenmicrowireswithpolyimideinsulationcannotbeused.Also,theexposedsidewallswouldaffecttheaccuracyoftheestimationofthesurfaceareaneededforcalculationofthecorrosionrate.Therefore,theworkingelectrodesfortheEISstudyaremadesimilarlytoconventionalmicroelectrodesusedforelectrochemicalapplications. 119
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
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
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
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
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
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
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
DerivativeofthelogarithmofdimensionlessimaginaryimpedanceoftheidealelectrodeswithrespecttologK.Almostalldatapointsliewithin5%of1. thatallthreeoftheepoxysealedmicroelectrodeshavesomefabricationdefectandareunsuitableformeasurements. 147 ],agraphicalanalysisofelectrochemicalimpedancedataisproposedasasimplemethodofqualitycontrolofmicroelectrodefabrication.Thisworkanalyzedimpedancedataofablockingsystembelowthefrequencyfcatwhichgeometryinducedartifactsariseformicroelectrodes.TheresultssuggestedthatideallyconstructedmicroelectrodeswillexhibitaslopeoftheimaginaryimpedanceasafunctionofdimensionlessfrequencyKinalogarithmicplotthatdoesnotvaryfrom1bymorethan5%.Theproposedmethodwillalsoworkforareactivesystem.Ifareactivesystemisused,impedancedatacorrespondingtofrequenciesgreaterthanthecharacteristicfrequencygivenbytheRCtimeconstantofthedoublelayercapacitanceandchargetransferresistanceandlowerthanfcshouldbeusedintheanalysis. 127
(left)ImaginaryimpedanceasafunctionoffrequencyoffourdifferentPtmicroelectrodesinsulatedinepoxyandpolishedwithAlO2paper.Thevalueofcorrespondingtoeachelectrodeisfoundbycalculatingtheslopeofthelines.(right)NyquistplotofthefourPtmicroelectrodes. Figure6-11. CPEcoefcientQofthenon-idealelectrodesasafunctionoffrequency.ThedottedlinesshowtheeffectivevaluesusedforcalculationofKinequation( 6 ). 128
Plotofimaginaryimpedanceofthenon-idealelectrodesindimensionlessunitswithrespecttodimensionlessfrequencyK. Figure6-13. Derivativeofthelogarithmofdimensionlessimaginaryimpedanceofthenon-idealelectrodeswithrespecttologK.Manydatapointsdifferfrom1bymorethan5%. 129
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
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
CompositionofPhosphateBufferedSaline ChemicalCompoundsConcentration(M) NaCl0.138HCl0.0027Na2HPO40.01KH2PO40.00176 *H2O20.03 7-2 .Thetungstenmicroelectrodesexhibitreactivebehaviorsincetheimpedancedataforthetungstenmicroelectrodesshowthepresenceofaresistivepathwayatlowfrequencies(e.g.theimpedancedatashowsasemicircleinthecomplex-impedance-planeplot).Theplatinumelectrodeexhibitsblockingornonreactivebehaviorsinceitsimpedancedatatrendstoward 132
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
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
Nyquistplot(left)andimaginaryimpedanceasafunctionoffrequency(right)ofagold-platedtungstenelectrodeinphosphatebufferedsalineover15days. Figure7-6. Nyquistplot(left)andimaginaryimpedanceasafunctionoffrequency(right)oftungstenelectrodesinPBSshowingdependenceonO2concentration. 7-7 showsthatfaradaicreactionsareoccurringonboththegold-platedtungstenandplatinumelectrodeswhenH2O2ispresent.ThepresenceofaresistivepathwayatthedclimitisevidentbythesemicircularshapesinFigure 7-7 135
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
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
Photographsofgold-platedtungstenelectrodesbefore(top)andafter(bottom)immersioninPBSforthespeciedperiodoftime. Figure7-10. Photographsofagold-platedtungstenelectrodesbeforeandafterimmersioninanelectrolytecontainingPBSandH2O2forthespeciedperiodoftime. ofchemicalspeciesatvariouspotentialandpHrangesmaybeascertainedfromthediagram.Also,thevoltagesforhydrogenandoxygenevolutionreactionsarecommonlyshownonthediagrams.InthePourbaixdiagramscreatedforthisstudy,allpotentialsarereferencedtothestandardhydrogenelectrode(SHE).Thus,acalculationmustbeperformedtoconvertthepotentialsmeasuredinthisstudytobewithrespecttotheSHE.ThePourbaixdiagramsshowninthisstudyaregeneratedbyacomputerprogram(CorrosionAnalyzer1.3Revision1.3.33byOLISystemsInc). 138
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
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
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
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
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
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
OCPovertimeforgold-platedtungstenandtungstenelectrodesinPBS. 51 ]ThesmallsizeofoursampleelectrodedoesnotlenditselftoweightlossmeasurementsandTafelextrapolationiseasilyconfoundedbythepresenceofmultiplereactions[ 51 ].ExtrapolationofthepolarizationresistancefromEISdataratherthandatafrompolarizationmeasurementsispreferredinthesystemunderstudysincerelativelyshortertimesarerequiredfortheimpedancemeasurements. 7 [ 51 ].Thepolarizationresistanceisinversely 145
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
7-3 .ArangeofvaluesforthecorrosionratesisgivenbecauseoftheuncertaintyoftheTafelconstants.Theimpedanceresults Figure7-16. Nyquistplotsusedforcalculationofthepolarizationresistance,Rp,forthreetungstensystems.ThesolidlinesshowtheregressionresultsusingEquation 7 predictthatthecorrosionoftungsteninaeratedPBSwillcorrodeatarateof200-500m/yr.Thegalvaniccoupleofthegold-platedtungstenmicrowireactstoincreasethecorrosionrateofthesysteminPBSaloneto300-700m/yr.However,thecorrosion 147
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
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
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
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
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
33 ].Thecorrosionrateoftungstenisofconcernforalong-termimplant,sincetheactivetungstenelectrodesurfacewillmostlikelyrecedeoutofrangeofrecordingfromaneuronafterafewyearsduetocorrosion.PlatinumwasunreactiveinsolutionsofPBSandreactiveinsolutionsofPBSandhydrogenperoxide.Thereactivityinsolutionscontaininghydrogenperoxideconsistedofhydrogen-atomplatingandreductionofH2O2,whichdidnotadverselyaffecttheplatinumsurfacenorintroduceunwantedspeciesintotheelectrolyte. Also,itwasfoundthatimpedancespectraofthemicroelectrodesaredependentonthequalityofthesealoftheinsulatortotheelectrode.Artifactsduetoanimperfectinsulatorsealobscuredtheimpedanceresponseandmadecharacterizationoftheinterfacedifcult.Thisworkpresentedaqualitycontrolmethodviagraphicalanalysisofelectrochemicalimpedancespectroscopydata.Bycomparingtheimpedancetoidealelectrodebehavior,thequalityofthemicroelectrode-to-insulationwasassessed. 157
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
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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