Bioelectric Interface - eng.snu.ac.kr

Neural Prosthetic Engineering

Bioelectric Interface

1


The Metal-Electrolyte interface

2

Neuron

Electrode

Electrolyte (Body)

Neural Prosthetic Engineering 3

Neuron

Ion Channel

Electrolyte


ENa EK EL

GNa GK GL

Cm

+

-

Vm

Im

?


S. Musallam, et al., “A floating metal microelectrode array for chronicimplantation,” Journal of Neuroscience Methods 160, 2007, pp. 122–127.S. J. Oh, et al., “Neural Interface with a Silicon Neural Probe in theAdvancement of Microtechnology,” BioTechnology and Bioprocessengineering, Volume 8, 2003, pp. 252-256

Sister M. E. Merriam, et al., “A Three-Dimensional 64-site FoldedElectrode Array Using Planar Fabrication,” Journals ofMicroelectromechanical Systems, Vol. 20, pp. 594-600, 2011.Richard A. Normann, et al., “A neural interface for a cortical visionprosthesis,” Vision Research, 39, pp. 2577–2587, 1999.S. E. Lee, et al., “A Flexible Depth Probe Using Liquid Crystal Polymer”,IEEE Transactions on Biomedical Engineering, Volume 59, 2012, pp.2085-2094.11


ENa EK EL

GNa GK GL

Cm

+

-

Vm

Imsite

Side

Metal

Insulation Site

Top

Electrolyte


Capacitive Interface

7


Resistive Interface(Faradaic)

e- C

A

C’

A’

electrodeelectrodesurface

Bulk

Mass transfer

e-

C

A

C’’

A’’

electrode Bulkelectrodesurface

double layer

Electron transfer

8


Partially Both. So a simple model may be

• Most metal electrodes have partial Faradaic, partial capacitive charge injections under the practical bias voltages.

9


A more complete model of Electrode Impedance Ze is,

• Equivalent Circuit

Zw

Rs

Cd

Rct

Rs solution resistance

Cd double layer capacitance

Rct charge transfer resistance

Zw impedance to Mass transfer

10


Equivalent Circuit Modeling for Neural Recording

11

ENa EK EL

GNa GK GL

Cm

Rspread

Rseal

CS

Ze

Zin

+

+

--Vout

Vm

Rm

Im

Im1 Im2

site

Top Side

– Optimum Conditions

are achieved by the

following, but some are

difficult to achieve or

have conflicting

conditions with others.

• Smaller Ze

• Smaller area of

electrode

• Smaller R spread

• Larger R seal

• Larger Z input of

amplifier


Neural Probe

• What is neural probe?

– Microstructure that connects neural tissue of brain and electronics

• It is used to

– Record and/or Stimulate specific sites of the brain

• Substrate Material

– Metal

– Silicon

– Polymer

• Structure

– 2-dimensional

• Single shank, multi channels

• Multi shanks, single channel per a shank

– 3-dimensional

• Multi shanks, multi channels per a shank

12

S. Musallam, et al., “A floating metal microelectrode array for chronicimplantation,” Journal of Neuroscience Methods 160, 2007, pp. 122–127.S. J. Oh, et al., “Neural Interface with a Silicon Neural Probe in theAdvancement of Microtechnology,” BioTechnology and Bioprocessengineering, Volume 8, 2003, pp. 252-256

Sister M. E. Merriam, et al., “A Three-Dimensional 64-site FoldedElectrode Array Using Planar Fabrication,” Journals ofMicroelectromechanical Systems, Vol. 20, pp. 594-600, 2011.Richard A. Normann, et al., “A neural interface for a cortical visionprosthesis,” Vision Research, 39, pp. 2577–2587, 1999.S. E. Lee, et al., “A Flexible Depth Probe Using Liquid Crystal Polymer”,IEEE Transactions on Biomedical Engineering, Volume 59, 2012, pp.2085-2094.11


Neural Probe

Richard A. Normann, et al., “A neural interface for a cortical visionprosthesis,” Vision Research, 39, pp. 2577–2587, 1999.S. E. Lee, et al., “A Flexible Depth Probe Using Liquid Crystal Polymer”,IEEE Transactions on Biomedical Engineering, Volume 59, 2012, pp.2085-2094.Chowdhury, Tk. “Fabrication of extremely fine glass micropipetteelectrodes,” J. Phys. E-Sci. Instrum., 2, 1969, 1087-1090.David H. Hubel, “Tungsten Microelectrode for Recording from SingleUnits,” Science, Vol. 125, No. 3247, 1957, pp. 549-550.Shoji Takeuchi, et al., “3D flexible multichannel neural probe array,” J.Micromech. Microeng., 14, pp.104-107, 2004.

Glass Micropipettes Electrodes

Metal Wire Electrodes

Microfabricated Electrodes- Silicon Based Electrodes

- Polymer Based electrodes


Glass Micropipette Electrodes

Electrolyte

Solution

Glass Pipette

Metal Wire

Electrode

• Glass micropipette electrodes can record current flowing through a single

or multiple ion channels of cells. : Patch Clamp

• A glass micropipette containing electrolyte solution is tightly sealed onto

the cell membrane and isolates a patch of cell membrane electrically.

•Currents through the ion channels in this patch flow into the micropipette

and are recorded by an metal wire electrode.

http://www.leica-microsystems.com/science-lab/the-patch-clamp-technique/https://en.wikipedia.org/wiki/Patch_clamp

A patch clamp recording of current reveals

transitions between two conductance

states of a single ion channel

: closed (at top) and open (at bottom).

http://www.leica-microsystems.com/science-lab/the-patch-clamp-technique/

https://en.wikipedia.org/wiki/Patch_clamp


Metal Wire Based Neural Probes

• Metal wire – less than 100μm in diameter

– insulated except for a small exposed

area at the tip which forms the

recording or stimulation site.

• Metal wire : platinum, iridium, platinum-

iridium, gold, stainless steel, and tungsten.

• Insulation material : quartz glass, teflon,

polyimide, and parylene.

•1 Metal wire = 1 Electrode site

• To make a multi channel electrode array,

number of metal wires are linearly

increased.

S. Musallam, et al., “A floating metal microelectrode array for chronicimplantation,” Journal of Neuroscience Methods 160, 2007, pp. 122–127.Hirokazu Takahashi, et al., “Easy-to-Prepare Assembly Array of TungstenMicroelectrodes,” IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING,VOL. 52, 2005, pp. 952–956.


Silicon Based Neural Probes

• Using silicon batch micromachining, microprobes with

– well defined shanks

– and precise placement of recording sites

have been made with high accuracy and repeatability at low cost.

• Also, active probes have been made.

– on-probe signal processing circuitry

– integrated micro actuators driving the electrode shank

• The fabrication of silicon based neural probes includes – Deposition of a metal layer on an insulated substrate

– Patterning the metal layer • recording sites, read-out pads for connecting to external circuitry, and interconnecting traces between them.

– Additional insulating layer deposition over the whole structure

– Opening of the recording sites and bonding pads


Michigan Probe

• Michigan Probe

– A variety of neural electrodes including single-shaft, multi-shaft, and 3-D-stacked layouts

– Integrated with microelectronic circuitry for signal processing

– Typically involved anisotropic etching with ethylene diamine pyrocatechol (EDP) and using a boron-etch-stop.

• The process is based on the fact that the etch rate for p-type silicon is much slower than for un-doped silicon.

• Boron diffusion is first performed on silicon to define the shaft shape

• EDP wet etching to release the probe shafts

• Gold, platinum, or iridium metal is used for recording sites

• The insulation on top of silicon substrate is made with triple layers of silicon dioxide, silicon nitride, and silicon dioxide.

• Interconnection is made with a 4–5 μm thick polysilicon cables

– weak cables and easy to break leading to lower yield for long lengths because of the high aspect ratio and lack of robustness.

– Mechanical weakness of the probes causes the probes to crack and shatter and may cause severe damage and disturbance to the brain tissue during insertion.

Sister M. E. Merriam, et al., “A Three-Dimensional 64-site FoldedElectrode Array Using Planar Fabrication,” Journals ofMicroelectromechanical Systems, Vol. 20, pp. 594-600, 2011.K. D. WISE , et al., “Wireless Implantable Microsystems: High-DensityElectronic Interfaces to the Nervous System,” PROCEEDINGS OF THEIEEE, VOL. 92, NO. 1, pp. 76-97, 2004.


Fabrication of Michigan Probe

• high temperature boron diffusion and selective wet etch [1]

– hard to control thickness

18

• Anisotropic wet etching for probe shaping[2]

– reproducible and uniform probe dimensions

[1] Anderson, David J., et al. "Batch fabricated thin-film electrodes for stimulation of the central auditory system." Biomedical Engineering, IEEE Transactions on36.7 (1989): 693-704.[2] Takahashi, Kouro, and Tadayuki Matsuo. "Integration of multi-microelectrode and interface circuits by silicon planar and three-dimensional fabrication technology." Sensors and Actuators 5.1 (1984): 89-99.


Utah Probe

• Utah Probe (Utah electrode array)

– Typically made from 1.83mm thick boron doped silicon substrates (resistivity of 0.01 Ω-

cm) using diamond dicing saw.

• A diamond dicing saw is used to create the electrode columns.

• Acid etching smoothes the pillars and creates sharpened probe tips.

• Probe tips are coated with metal for recording and stimulation. (Gold, platinum, and iridium)

• Polyimide is used to coat the probes as the insulation layer with only the recording sites

exposed.

• Read-out pads : ultrasonically bonded on the back of the array to a set of aluminum.

– The stiffness of the metal wires makes the probe unsuitable for chronic implantation.

• Interconnections : polyimide insulated gold wires

– Probe length limited by the silicon wafer thickness

• The longest reported probe length : 1.5 mm.

– Only one recording site can be made on each probe shank

Richard A. Normann, et al., “A neural interface for a cortical visionprosthesis,” Vision Research, 39, pp. 2577–2587, 1999.


Fabrication of Utah Probe

20

Campbell, Patrick K., et al. "A silicon-based, three-dimensional neural

interface: manufacturing processes for an intracortical electrode

array."Biomedical Engineering, IEEE Transactions on 38.8 (1991): 758-

768.

1. thermomigration 2. sawing 3. Dynamic etching (tip sharpening)

Multi-channel Utah probe


Electrodes for Neural Stimulation

• Applications

– Visual prostheses, Auditory cortical prostheses, Intraspinalelectrodes, etc.

• Common challenges– Chronic, safe, high degree of functional specificity.

• Constraints (small tip area vs. charge density)

– small tip area - approaching the size of the surrounding neurons so that selective stimulation of the neurons can be obtained.

– As the surface area of the exposed tip is reduced, the charge density (typlically reported in mC/cm2) increases for constant stimulus charge (charge density limits). irreversible damage to the metal stimulation

microelectrode inserted into the cortex. Near the tip of the electrode, neural stimulation takes place via current that passes from the electrode tip to the surrounding neurons. (Courtesy of Cyberkinetics, Inc.)

21He, Bin. Neural engineering. Vol. 3. Springer Science & Business Media, 2007.


Neural Recording vs. Stimulation

• For Neural Recording, the Electrode Impedance is the most relevant parameter to show effectiveness of the electrode.

• For Neural Stimulation, however, the ability to deliver Charge, effectively and safely, to the Neuron, with small electrode surface area, is more relevant.

• Delivered Charge causes membrane potential change to excite neuron.

• In general, the larger the Effective surface area of the electrode is, the smaller the electrode impedance and the larger the charge delivery capacity.

• Effective surface area vs. Geometric surface area: The effective surface area considers actual 3- dimensional surface structure, while the geometric one is the 2-dimensional capture of such.

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Resulting transmembrane potential (Vm’)

++

+

+

+

+-- ---

The distribution of charges and potentials

Direction and strengths of the field vectors

Voltage change induced by the external field (DVm)

Vm’

Vm

Axon hillock

Active

Electrode

x

x

x

Ψ

Ψ

Ψ

Transmembrane potential (Vm) at resting condition

Vm’ = Vm +

DVm

DVm

-

Reference

Electrode


Charge Storage Capacity

• The capability of charge delivery of the electrode is expressed in CSC

• Charge storage capacity (CSC)

– Definition - The total amount of charge per unit geometric surface area(GSA) available from an electrode.

• Cathodal charge storage capacity(CSCc)

– Cathodic (negative) charges only

– Essential measure of the total amount of charge available for a stimulation pulse

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How to measure Charge storage capacity

• All electrodes are characterized in vitro immersed in phosphate buffered saline(PBS)

• Through Cyclic Voltammetric (CV) techniques at a proper scan rate (e.g. 50mV/s).

• A three electrode Potentiostat setup is used.

• Working electrode is the DUT.

• Reference electrode is where Triangular Voltage Waveform is applied.

• Current is measured from the Auxiliary (Counter) electrode- Working electrode Current Path.

• Plot potential versus current,and calculate the area of close loop line

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A

V

Potentiostat

Referenceelectrode

Workingelectrode

Auxiliaryelectrode

E(-)

t

E0

Ei

Eλ

λ0

ab

cd

ef

gh


Charge storage capacity

• Ion concentration and CV plot

O-R ion concentration vs. voltage

Cyclic voltammogram

26

Seungmo Oh, Electrochemistry, 2nd edition, 2014, Freedom Academy

E(-)

t

E0

Ei

Eλ

λ0

ab

cd

ef

gh


CSC

• Cathodal charge storage capacity (CSCC)

– The time integral of the cathodic current during a potential sweep from 0.8 V and -0.6 V

– The area is directly proportional to CSCC

because of the constant sweep rate.

• Example: CV plot of Pt and AIROF(Activated IrOx)

– charge capacity of AIROF electrode is much higher than that of Pt electrode

• Water Window defines Safe region

– the potential range over which no electrolysis of water

27He, Bin. Neural engineering. Vol. 3. Springer Science & Business Media, 2007.

Cyclic Voltammogram


“Safe” neural stimulation

• The safe electrochemical window ( “water window”)- A voltage range that doesn’t induce Hydrolysis.

- -0.6V ~ 0.8V.

• Electrode of large CSC should be used. - Large CSC can be achieved by(1) increasing the effective surface of the electrode(2) using appropriate electrode material with large

CSC (e.g. Pt, IrO, TiN)

• Use balanced waveform to prevent charge accumulation (Biphasic Pulse)

Biphasic Stimulationcurrent Pulse

D.R. Merrill et al. / Journal of Neuroscience Methods ,141 (2005) 171-198

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Current Pulse & Charge Injection Capacity

• Biphasic, charge-balanced current pulse

– To avoid damage to the electrode or surrounding tissue, net charge is zero by using two current phases.

– Charge-balanced: Qcathode = Ic × tc = Ia × ta = Qanode

• The Maximum charge injection capacity

– the charge that can be injected without polarizing the electrode beyond the potentials for reduction or oxidation of water.

– It depends to varying degrees on

• the current density, the pulse frequency, and the relative magnitudes of Ic and Ia.

• The geometry, and porosity of the electrode also impact the uniformity and magnitude of the polarization

Charge Injection Limits of Pt and Electrode Coating Materials Used or Contemplated for Applications in the CNS

Material Mechanism Charge limit (mC/cm2) Applications

Pt and Pt-Ir alloys Faradaic 0.05-0.15 Pacing, nerve cuff electrodes, DBS

Activated iridium oxide Faradaic 1-3.5 Intracortical stimulation

Thermal iridium oxide Faradaic ~1 Cardiac pacing

Sputtered iridium oxide Faradaic >0.5 Limited to IDEs

Tantalum/Ta2O5 Capacitive -0.5 Limited to animal studies

Titanium nitride Capacitive ~1 Cardiac pacing

IC Cathodic current10 µA

~ 10 mAta Anodic half-phase period

50 µs ~ 10 ms

tC Cathodic half-phase period50 µs

~ 10 msIa Anodic current

10 µA ~ 10 mA

td Interphase dwell 0-1 ms Pulse per second10

~250 Hz

Biphasic, charge-balanced current pulse

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He, Bin. Neural engineering. Vol. 3. Springer Science & Business Media, 2007.


Polymer Based Neural Probes

• Recently, various polymeric materials have been studied to make neural probes because of

their flexibility and compatibility with semiconductor processes.– Polyimide

– Parylene

– Liquid Crystal Polymer (LCP)

• However, polyimide and parylene are too flexible to be inserted into brain tissues.– Additional reinforcement structures or specific insertion methods are needed.

• Hybrid with rigid material

Patrick J. Rousche, et al., “Flexible Polyimide-Based IntracorticalElectrode Arrays with Bioactive Capability,” IEEE TRANSACTIONS ONBIOMEDICAL ENGINEERING, VOL. 48, NO. 3, pp.361–371, 2001.

Shoji Takeuchi, et al., “3D flexible multichannel neural probe array,” J.Micromech. Microeng., 14, pp.104-107, 2004.Eric G.R. Kima, et al., “A hybrid silicon–parylene neural probe with locallyflexible regions,” Sensors and Actuators B, 195, pp.416–422, 2014.


Fabrication of Polyimide based Probe

31Cheung, Karen C., et al. "Flexible polyimide microelectrode array for invivo recordings and current source density analysis." Biosensors andBioelectronics 22.8 (2007): 1783-1790.

FabricationPolyimide based probe


LCP- Based Neural Probes

• Liquid crystal polymer (LCP)-based neural depth probes are flexible, not easily broken, and do

not require a guide tool for insertion.

– Liquid crystal polymer

• Thermoplastic polymer consisting of both a rigid and flexible monomer

• Good biocompatibility

• Low moisture absorption rates (∼0.02%) and a low moisture permeability

• Good long-term chemical resistance against most acids, bases, and solvents over a broad temperature range

– Stiffness of the probe could be controlled by the thickness of the LCP film

[5] S. E. Lee, et al., “A Flexible Depth Probe Using Liquid CrystalPolymer”, IEEE Transactions on Biomedical Engineering, Volume 59,2012, pp. 2085-2094.


Fabrication of LCP based probe

• Liquid crystal polymer (LCP) based probe[1]

– Good biocompatibility

– Low moisture absorption rates (∼0.02%) and a low moisture permeability

– Good long-term chemical resistance against most acids, bases, and solvents

over a broad temperature range

– Stiffness of the probe could be controlled by the thickness of the LCP film

• Fabrication of LCP based probe [2,3]

[1] S. Lee et al., TBME, 59 (7), 2085-2094,2012[2] J. Jeong et al., In: BMES annual meeting 2014.[3] K.S. Min et al., Otology and Neurotology, 35(7): 1179-1186, 2014.


Reference

• He, Bin. Neural engineering. Vol. 3. Springer Science & Business Media, 2007.

• Bretschneider, Franklin, and Jan R. De Weille. Introduction to electrophysiological methods and instrumentation. Academic Press, 2006.

• Cogan, The Annual Review of Biomedical Engineering, 2008. 10:275–309.

• Mohamad HajjHassan, Sensors 2008. 8:6704-6726.

• Patrick K. Campbell, lEEE Transactions on Biomedical Engineering, 1991, 38:758-768.

• K. D. Wise, Proceedings of the IEEE, 2004, 92:76-97.

• S. Musallam, et al., “A floating metal microelectrode array for chronic implantation,” Journal of Neuroscience Methods 160, 2007, pp. 122–127.

• S. J. Oh, et al., “Neural Interface with a Silicon Neural Probe in the Advancement of Microtechnology,” BioTechnologyand Bioprocess engineering, Volume 8, 2003, pp. 252-256

• Sister M. E. Merriam, et al., “A Three-Dimensional 64-site Folded Electrode Array Using Planar Fabrication,” Journals of Microelectromechanical Systems, Vol. 20, pp. 594-600, 2011.

• Richard A. Normann, et al., “A neural interface for a cortical vision prosthesis,” Vision Research, 39, pp. 2577–2587, 1999.

• S. E. Lee, et al., “A Flexible Depth Probe Using Liquid Crystal Polymer”, IEEE Transactions on Biomedical Engineering, Volume 59, 2012, pp. 2085-2094.

• A. L. HODGKIN AND A. F. HUXLEY, "Action potentials recorded from inside a nerve fibre," Nature, vol. 144, 1939, pp. 710-711.,

• Richard A. Normann, et al., “A neural interface for a cortical vision prosthesis,” Vision Research, 39, pp. 2577–2587, 1999.

• S. E. Lee, et al., “A Flexible Depth Probe Using Liquid Crystal Polymer”, IEEE Transactions on Biomedical Engineering, Volume 59, 2012, pp. 2085-2094.

• Chowdhury, Tk. “Fabrication of extremely fine glass micropipette electrodes,” J. Phys. E-Sci. Instrum., 2, 1969, 1087-1090.

34


Reference

• David H. Hubel, “Tungsten Microelectrode for Recording from Single Units,” Science, Vol. 125, No. 3247, 1957, pp. 549-550.

• Shoji Takeuchi, et al., “3D flexible multichannel neural probe array,” J. Micromech. Microeng., 14, pp.104-107, 2004.• S. Musallam, et al., “A floating metal microelectrode array for chronic implantation,” Journal of Neuroscience Methods

160, 2007, pp. 122–127.• Hirokazu Takahashi, et al., “Easy-to-Prepare Assembly Array of Tungsten Microelectrodes,” IEEE TRANSACTIONS ON

BIOMEDICAL ENGINEERING, VOL. 52, 2005, pp. 952–956.• Richard A. Normann, et al., “A neural interface for a cortical vision prosthesis,” Vision Research, 39, pp. 2577–2587, 1999.• Sister M. E. Merriam, et al., “A Three-Dimensional 64-site Folded Electrode Array Using Planar Fabrication,” Journals of

Microelectromechanical Systems, Vol. 20, pp. 594-600, 2011.• K. D. WISE , et al., “Wireless Implantable Microsystems: High-Density Electronic Interfaces to the Nervous System,”

PROCEEDINGS OF THE IEEE, VOL. 92, NO. 1, pp. 76-97, 2004.• Maria Kindlundh, et al., “A neural probe process enabling variable electrode configurations,” Sensors and Actuators B,

102, pp.51–58, 2004.• Peter Norlin , et al., “A 32-site neural recording probe fabricated by DRIE of SOI substrates,” J. Micromech. Microeng.,

12, pp.414–419, 2002.• Patrick J. Rousche, et al., “Flexible Polyimide-Based Intracortical Electrode Arrays with Bioactive Capability,” IEEE

TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 48, NO. 3, pp.361–371, 2001.• Shoji Takeuchi, et al., “3D flexible multichannel neural probe array,” J. Micromech. Microeng., 14, pp.104-107, 2004.• Eric G.R. Kima, et al., “A hybrid silicon–parylene neural probe with locally flexible regions,” Sensors and Actuators B, 195,

pp.416–422, 2014.• S. E. Lee, et al., “A Flexible Depth Probe Using Liquid Crystal Polymer”, IEEE Transactions on Biomedical Engineering,

Volume 59, 2012, pp. 2085-2094.

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Bioelectric Interface - eng.snu.ac.kr