Interfacing with the brain using organic electronics

Institut Mines‐Télécom

Interfacing with the brain using organic electronics

George MalliarasDepartment of Bioelectronics, Microelectronics Center of ProvenceEmail: [email protected] ; 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

Hard

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


NN

CH3 CH3

O

NAl

3

TPD

Alq3

Pentacene

n n

S

O O

n

S n

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

S

O O

S

O O

S

O O

S

O O

S

O O

S

O O

S

O O

S

O O

+ *

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


S

O O

S

O O

S

O O

S

O O

S

O O

S

O O

S

O O

S

O O

+ *

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).

SiO2

+++++ 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


dx

V(x)

Vg

cd W dx

Rs

......

Q(x)

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

Ionic circuit(electrochemistry)

Electronic circuit(solid state physics)

-- -- -

++

-

+

- -

-

+

+Gate Electrode

+

-

++

++

+ + +

+

+


S

O O

S

O O

S

O O

S

O O

S

O O

S

O O

S

O O

S

O O

+ *


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

1 μA

10 mV

1 s

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-

SO3- SO3

-

SO3-

++

++

++SO3

-

M+

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


b

10-5 10-4 10-310-5

10-4

10-3

(s)

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




Local delivery of GABA suppress seizure activity




Scaling with geometry


b

10-5 10-4 10-310-5

10-4

10-3

(s)

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

0.1

1

10

e (cm

2 /Vs)

C* (F/cm3)

+EG,GOPSPEDOT:PSS

+EG,GOPSP3HT‐SO3‐

Recent New High‐performer(Iain McCulloch, Imperial)

0% EG

50% EG

5‐10% EG

μC* as the materials figure of merit

S

SOO

O

* n

-(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


Glass

Electrolyte PEDOT:PSS Au

Vappl

Dedoped Doped

Barrier

+‐+

‐

++

++ SO3

-

SO3-

SO3-

SO3-

SO3-

SO3-

SO3-

SO3-

SO3-

SO3-

++

++

++

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

RI RC

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).


For more information:

Department of Bioelectronics (BEL)

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Interfacing with the brain using organic electronics