Interfacing with the brain using organic electronics

Institut Mines‐Télécom

George MalliarasDepartment of Bioelectronics, Microelectronics Center of ProvenceEmail: malliaras@emse.fr ; Twitter: @GeorgeMalliaras

Our location

Department of Bioelectronics – www.bel.emse.fr2

Microelectronics Center of ProvenceInaugurated 2008

La Timone Hospital

AMU Medical School

Outline

Introduction to neural interfacing

Why organics?

Conducting polymers yield new capabilities for neuroscience

• Recording single neurons without penetrating the brain

• Recording brain activity with high signal‐to‐noise ratio

• Stopping seizures (in vitro) with localized drug delivery

Ion transport in conducting polymers

Materials challenges ahead

Bioelectronics: Coupling biology and electronics

Mostly soft

Complex signaling

Dynamic

Electrons/holes

Static

SensingDiagnosis

ActuationTherapy

Importance of neural interfacing

100 billion neurons in the human brain, organized in networks

Their communication holds the key for understanding how the brain works

These networks can be rewired by diseases such as epilepsy, cancer, …

Stimulation of these networks is increasingly being used as therapy

EEG ECoG sEEG

Epilepsy

Affects 1‐2% of world population

Temporal lobe epilepsy (TLE) is most frequent form in adults

TLE is often drug resistant

Key challenges:

Improve electrode performance

Make less invasive recordings

Deep brain stimulation for Parkinson’s

Brain/machine interfaces

L.R. Hochberg, D. Bacher, B. Jarosiewicz, N.Y. Masse, J.D. Simeral, J. Vogel, S. Haddadin, J. Liu, P. van der Smagt, and J.P. Donoghue, Nature 485, 372 (2012).

From discovery to therapy

Luigi Galvani(1737 – 1798)

Pacemaker circa 1957

Arne Larsson, first to receive implantable pacemaker in 1958. He received a total

of 26 pacemakers and died at 86.

NanostimLeadless pacemaker

Implantable electronic medical devices

Artificial limbs controlled by the brain(Penn Center for Brain Injury and Repair)

Cochlear implant(Cochlear)

Implantable defibrillator(Medtronic)

Approved devices:• Heart pacemakers – 600,000 per year• Cochlear implants (hearing) – 300,000 patients• Spinal cord stimulators (pain relief) – 15,000 per year• Deep brain stimulators (Parkinson’s)• Phrenic nerve stimulators (assisted breathing)• Sacral nerve stimulators (bladder control)• Vagus nerve stimulators (epilepsy)• Retinal implants (vision)

In development:• Functional electrical stimulation (standing and gait)• Brain Computer Interfaces (control of robotic limbs)• DBS (severe psychiatric conditions) • Vestibular prostheses (balance) • Vision prostheses (vision) • Cortical prostheses (epilepsy detection & suppression)

Medical technologies raise ethical questions

Young Frankenstein, 20th Century FOX (1974)

1771: Galvani’s experiments 1958: First implantable pacemaker Today: Implantable defibrillator

Hype versus reality

Dr. Octopus in Spiderman 2

Boy hearing for the first time

Organic electronics

Thin film transistors Photovoltaics

DuPont

Someya Lab

Light emitting diodes

Samsung

Astron FIAMM

Heliatek

Typical organic semiconductors

CH3 CH3

Pentacene

PPPPPV

PEDOTP3HT

Carbon as a semiconductor

R. Hoffman, C. Janiak, C. Kollmar, Macromolecules 24, 13, 3725‐3746, (1991).

EG ħ2p22maN

CH2=CH2

Hybridization: sp2 and pZ

Particle in a box:

PEDOT doped with PSS

SO3H SO3H SO3H SO3H SO3- SO3H SO3H SO3H

p‐type doped material

Holes on PEDOTSulfonate ions on PSS

Holes in the form of polaronsPolyanion immobilizes dopants

σ = 1000 S/cm

Electrically neutral

Conducting polymers match properties of tissue

Slide courtesy of Dave Martin (U. Delaware)

Conducting polymers show mixed conductivity

J. Rivnay, R.M. Owens, and G.G. Malliaras, Chem. Mater. 26, 679 (2014).

Mixed conductivity leads to novel/state‐of‐the‐art devices

Conducting polymer microelectrodesrecord single neurons from brain surface

Levels of neural interfacing

schalklab.org

Ultimate resolution

EEG: Network level (~ 1 cm)

ECoG: Intermediate

sEEG: Single neuron (~ 10 µm)

It was not considered possible to obtain single neuron recordingswithout penetrating the brain

State‐of‐the‐art ECoG circa 2010

Rogers group (UIUC)

Conducting polymers improve neural interfaces

Work of Martin, Wallace, Inganäs, …

Electrochemical growth on pre‐patterned metal

electrodes

Conducting polymers lower interfacial impedance

Different “nature” of capacitance across the electrode/electrolyte interface

MetalAu

PEDOT:PSS+

Polymer

Similar roughness

Ultra‐conformable PEDOT:PSS microelectrodes

D. Khodagholy, T. Doublet, M. Gurfinkel, P. Quilichini, E. Ismailova, P. Leleux, T. Herve, S. Sanaur, C. Bernard, and G.G. Malliaras, Adv. Mater. 36, H268 (2011).

Parylene C – 4 μm thickPEDOT:PSS

Ultra‐conformable ECoG arrays

w/ Christophe Bernard (INSERM)

50 μm

d=2.2mm

PEDOT:PSS electrodes outperform Au electrodes

w/ Christophe Bernard (INSERM)D. Khodagholy, T. Doublet, M. Gurfinkel, P. Quilichini, E. Ismailova, P. Leleux, T. Herve, S. Sanaur, C. Bernard, and G.G. Malliaras, Adv. Mater. 36, H268 (2011).

Auelectrodes

PEDOT:PSSelectrodes

Detection of single neurons from brain surface

w/ Dion Khodagholy, György Buzsáki (NYU)D. Khodagholy, J.N. Gelinas, T. Thesen, W. Doyle, O. Devinsky, G.G. Malliaras and G. Buzsáki, Natrure Neurosci. 18, 310 (2015)

10 ms by 50 mV

Electrocorticography in rats

256 electrodes, 10 x 10 μm2 with 30 μm inter‐electrode spacing

Translation to the clinic

w/ Dion Khodagholy, György Buzsáki (NYU)D. Khodagholy, J.N. Gelinas, T. Thesen, W. Doyle, O. Devinsky, G.G. Malliaras and G. Buzsáki, Natrure Neurosci. 18, 310 (2015)

500 ms by 500 mV

20 ms by 40 mV

Acute recordings in human patients

Organic electrochemical transistors record brain activity with record‐high SNR

Field‐effect transistors for neural recordings

Field‐effect transistor (FET)C’max = 5 μF/cm2

M. Voelker and P. Fromherz, Small 1, 206 (2005).

+++++ Vg

IdSi++++

- - - - - - - - -

Fromherz group, MPI

The organic electrochemical transistor (OECT)

No insulator between channel and electrolyte

First OECT: H.S. White, G.P. Kittlesen, and M.S. Wrighton, J. Am. Chem. Soc. 106, 5375 (1984).

Volumetric response of capacitance in PEDOT:PSS

For d=130 nm:C’ = 500 μF/cm2

100× larger than double layer capacitance

C* = 39 F/cm3

J. Rivnay, P. Leleux, M. Ferro, M. Sessolo, A. Williamson, D.A. Koutsouras, D. Khodagholy, M. Ramuz, X. Strakosas, R.M. Owens, C. Benar, J.‐M. Badier, C. Bernard, and G.G. Malliaras, SCIENCE Advances 1, e1400251 (2015).

Device model

cd W dx

......

D.A. Bernards and G.G. Malliaras, Adv. Funct. Mater. 17, 3538 (2008)

Ionic circuit(electrochemistry)

Electronic circuit(solid state physics)

-- -- -

+Gate Electrode

Characteristics of OECTs

J. Rivnay, P. Leleux, M. Sessolo, D. Khodagholy, T. Hervé, M. Fiocchi, G. G. Malliaras, Adv. Mater. 25, 7010 (2013).

High transconductance OECTs

D. Khodagholy, J. Rivnay, M. Sessolo, M. Gurfinkel, P. Leleux, L.H. Jimison, E. Stavrinidou, T. Herve, S. Sanaur, R.M. Owens, and G.G. Malliaras, Nature Comm. 4, 2133 (2013).

In vivo recordings using transistors

w/ Christophe Bernard (INSERM)

Transistor

SNR = 52.7 dB

SNR = 30.2 dB

Electrode

D. Khodagholy, T. Doublet, P. Quilichini, M. Gurfinkel, P. Leleux, A. Ghestem, E. Ismailova, T. Herve, S. Sanaur, C. Bernard, and G.G. Malliaras , Nature Comm. 4, 1575 (2013).

Transistors enable less invasive recordings

w/ Christophe Bernard (INSERM) D. Khodagholy, T. Doublet, P. Quilichini, M. Gurfinkel, P. Leleux, A. Ghestem, E. Ismailova, T. Herve, S. Sanaur, C. Bernard, and G.G. Malliaras , Nature Comm. 4, 1575 (2013).

Transistor

Surfaceelectrode

Depthelectrode

Model for OECT operation

SO3- SO3

ID=W∙d∙e∙μ∙p(x)∙[dV(x)/dx]

IDp(x)=SO3

‐ – M+(x)

M+(x)=(C*/e)∙[VG – V(x)]

Integrating Id over the length of the channel:

ID=(W∙d/L)∙μ∙C*∙[VT – VG + VD/2]∙VD IDSAT=[W /(2∙L)] ∙d ∙μ∙C*∙[VT – VG]2

VT= e∙SO3‐/C*

Scaling with geometry

10-5 10-4 10-310-5

RS C (s)

∙ ∙ ∙ ∗ ∙J. Rivnay, P. Leleux, M. Ferro, M. Sessolo, A. Williamson, D.A. Koutsouras, D. Khodagholy, M. Ramuz, X. Strakosas, R.M. Owens, C. Benar, J.‐M. Badier, C. Bernard, and G.G. Malliaras, SCIENCE Advances1, e1400251 (2015).

High transconductance means high SNR

w/ Christian Benar, Jean‐Michel Badier Bernard (INSERM)

J. Rivnay, P. Leleux, M. Ferro, M. Sessolo, A. Williamson, D.A. Koutsouras, D. Khodagholy, M. Ramuz, X. Strakosas, R.M. Owens, C. Benar, J.‐M. Badier, C. Bernard, and G.G. Malliaras, SCIENCE Advances 1, e1400251 (2015).

Organic electronic ion pumpscontrol epileptiform activity

The organic electronic ion pump

Work at Linkoping University and Karolinska InstituteD. T. Simon, S. Kurup, K. C. Larsson, R. Hori, K. Tybrandt,

M. Goiny, E. H. Jager, M. Berggren, B. Canlon, and A. Richter‐Dahlfors, Nature Materials 8, 742 (2009).

Ion pump operation

-- ---+

+ ++++

- - - - - -- -

PEDOT:PSS PEDOT:PSSPSS

Ion pump for local delivery in neural networks

w/ Christophe Bernard (INSERM), Magnus Berggren (Linköping)

Local delivery of GABA suppress seizure activity

Scaling with geometry

10-5 10-4 10-310-5

RS C (s)

∙ ∙ ∙ ∗ ∙J. Rivnay, P. Leleux, M. Ferro, M. Sessolo, A. Williamson, D.A. Koutsouras, D. Khodagholy, M. Ramuz, X. Strakosas, R.M. Owens, C. Benar, J.‐M. Badier, C. Bernard, and G.G. Malliaras, SCIENCE Advances1, e1400251 (2015).

Institut Mines‐Télécom Department of Bioelectronics – www.bel.emse.fr48

1 10 100 10000.01

2 /Vs)

C* (F/cm3)

+EG,GOPSPEDOT:PSS

+EG,GOPSP3HT‐SO3‐

Recent New High‐performer(Iain McCulloch, Imperial)

50% EG

5‐10% EG

μC* as the materials figure of merit

-(C4H9)4N+

P3HT‐SO3‐

(+EG +GOPS)

μC* = 7.2 F/cmVsμ = 0.05 cm2/VsC* = 144 F/cm3

w/ M. Thelakkat, U. Bayreuth

S. Inal, J. Rivnay, P. Leleux, M. Ferro, M. Ramuz, J.C. Brendel, M. Schmidt, M. Thelakkat, and G.G. Malliaras, Adv. Mater. 26, 7450 (2014).

PEDOT:PSS(+EG, +GOPS)

μC* = 128 F/cmVsμ = 3.3 cm2/VsC* = 39 F/cm3

Such maps provide a way to compare materials as potential

candidates in OECTs

Institut Mines‐Télécom Department of Bioelectronics – www.bel.emse.fr49

PEDOT:PSS as a champion material

Phase separated morphology

Hole transport in PEDOT‐rich domains, ion transport in PSS matrix

“Moving front” measurements

K. Aoki, T. Aramoto and Y. Hoshino, Journal of Electroanalytical Chemistry 340, 127 (1992).T. Johansson, N. K. Persson and O. Inganas, Journal of the Electrochemical Society 151, E119 (2004).

X. Wang and E. Smela, The Journal of Physical Chemistry C 113, 369 (2008).

holesions 2D geometry makes

analysis difficult

A simple way to measure ion transport

Electrolyte PEDOT:PSS Au

Dedoped Doped

Barrier

++ SO3

E. Stavrinidou, P. Leleux, H. Rajaona, D. Khodagholy, J. Rivnay, M. Lindau, S. Sanaur, and G.G. Malliaras, Adv. Mater. 25, 4488 (2013).

ℓ ∙ ∙

∙ 2 ∙ ∙2

Ions are highly mobile in PEDOT:PSS

E. Stavrinidou, P. Leleux, H. Rajaona, D. Khodagholy, J. Rivnay, M. Lindau, S. Sanaur, and G.G. Malliaras, Adv. Mater. 25, 4488 (2013).

K+ mobility in film

K+ density in film

(cm‐3)

PEDOT:PSS 1.4 ∙ 10 5.9 ∙ 10

PEDOT:PSS :GOPS 1.9 ∙ 10 3.2 ∙ 10

Linking ion transport and electrode impedance

E. Stavrinidou, M. Sessolo, B. Winther‐Jensen, S. Sanaur, and G.G. Malliaras, AIP Advances 4, 017127 (2014).

Open questions

We should leverage our understandingof electronic processes in organics

How do we envision ion injection• Field‐dependence?• Hydrophilicity, hydration?• Connection to mechanical properties?• Dependence on ion size?

What is the optimal material• Balance between crystalline and amorphous domains?• Separate paths of ionic/electronic transport – copolymers?

Characterization in aqueous media

metal polymer

electrolyte

Conclusions

Organic bioelectronics represents an emerging research direction.

Conducting polymers are leading to new capabilities for neuroscience:• Non‐invasive, high SNR recordings of brain activity in animal models

and in the clinic• Localized drug delivery that can stop seizure in in vitromodel

Mixed conductivity of organics a key advantage.

We need to leverage advances in understanding electronic structure & transport to describe mixed conductivity and design better materials.

Acknowledgements Neuroengineering team at BEL

Jonathan Rivnay, Sahika Inal, Mary Donahue, Marc Ferro, Dimitris Koutsouras, Thomas Lonjaret, Ilke Uguz, Eloise Bihar, Marcel Brändlein, Shahab Rezaei Mazinani, JolienPas, Esma IsmailovaColleagues @ BEL: Xenofon Strakosas, Roisin Owens

Institute of Systems NeuroscienceAnimal research: Adam Williamson, Attila Kaszas, Christophe Bernard Clinical: Jean‐Michel Badier, Christian Benar

University of Linköping (Sweden)Amanda Jonsson, Loig Kergoat, Daniel Simon, Magnus Berggren

Microvitae TechnologiesPierre Leleux, Thierry Hervé

Other Collaborators Dion Khodagholy, György Buzsáki (NYU), Michele Sessolo (Valencia), Seiichi Takamatsu (AIST), Marc Ramuz (EMSE).

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