Toward Brain-Microsystem Interfaces for the Treatment of Neurodegenerative Diseases

Transcript of Toward Brain-Microsystem Interfaces for the Treatment of Neurodegenerative Diseases

8/17/2019 Toward Brain-Microsystem Interfaces for the Treatment of Neurodegenerative Diseases

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Toward Brain-MicrosystemInterfaces for the Treatment ofNeurodegenerative Diseases

Mohamad Sawan, Professor, Canada Research ChairPolystim Neurotech Laboratory

Polytechnique Montréal, Québec, Canada

Annual Plenary Meeting, SwissTech Convention Center,EPFL, April 25th-26th, 2016

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Toward Brain-Microsystem Interfaces for the Treatment of Neurodegenerative DiseasesPage 2

Emerging Bioelectronics (Brain-Machine Interfaces)

!"#$"!!%$"# $" '$%() *+,((

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Current State-of-the-Art of the Single and Dual Chamber Pacemaker. Medtronic,

Emerging Bioelectronics (Brain-Machine Interfaces)

Braingate

Mind-Driven Decision

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Brain and Central Nervous Systems Disorders

The Toll of Main Brain/Nervous SystemDisorders is higher than $500B/Y.

! Neuroscience

" Investigation tools

! Neural prosthetics

"

Mind-Driven Rehab.

•

Cochlear (CNS)• Hearing Loss (CNS)

• Visual (CNS)

• Parkinson (DBS)

• Epilepsy (VNS, CNS)

• Alzheimer (CNS)

•

Dystonia (DBS)• Lesch-Nyhan (DBS)

• Bradykinesia (DBS)

• Depression (VNS)

• Tumors (CNS)

• Spinal-cord injuries

•

Paralysis

• Cardiovascular (Stroke)

• Tourette syndrome (DBS)

• etc..

http://www.sfn.org/skins/main/pdf/brainfacts/brainfacts.pdf

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Niels et al, "Glyconanotechnology" ,Chemical Soc. Rev., 2013

Physiologic Systems: Basic Knowledge

Neurotransmitters

are about the size

of a Single amino

acid molecule, but

some of them

may be the size ofproteins.

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Research activities

Micro-electronics

Micro-fluidics

&

Optics

Micro-fabrication

Biology &Medical

WirelessLinks

HarvestingEnergy

In vivo

& In vitroTests

Assembly &Packaging

Micro-systems

Applications Applications

RESEARCH FIELDS: !ELECTRONICS, !SYSTEMS, BIOMEDICAL

Multidisciplinarity

MedicalDevices

Sensors

&Actuators

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# Motivation $ Brain’s neural tissues and diseases

#

Neural-based Investigations $ Recording, Stimulation and Closed-loop Methods

# Cell Analysis Protocols$ Manipulation, Recording and Stimulation

# Cell Biosensing Techniques and Tools $ ISFET-based detection

$ DEP-based manipulation

$ Capacitive measurement

$

Magnetic-based methods$ Smart Petri-dish introdution

#

Summary$ Future directions

# Resources

Outline

Brain-Machine Interfaces

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32 EEG-256 fNIRS Wearable, & icEEG for Onset Detection

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Multi-chip multi-channelneural interface

0.4 mm

Neurorecording Biopotentials/Spikes & Power Management

Filter

Output

buffersFilter

Test blocks

Outputbuffers

The detector

CMOS 0.18 !m272x257 !m2, 780 nW

Teager Energy Operator

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Visual implant

Wirelesstransceiver

Stimulation & monitoring chips

Control module Antenna

Matrix of electrodes

Flip-chip device

Intracortical Neurostimulation : Recover Vision

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# Resources

Outline

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# Cell based protocols include:

o Manipulation : Separation, Localization, and Sorting.

o Recording and Stimulation: Neural cells, viability testing.

o Detection and Analyses: Proliferation rate monitoring, Physiological

properties such as pH, and O2.

Cell Manipulation, Recording, Stimulation, Detection, "

# Techniques used for cell manipulation can be divided as follows:o Electrophoresis (EP): Involves applying a uniform EF across a

charged particle, causing it to polarize, inducing a net particle

migration.

o Dielectrophoresis (DEP): Force arises from induced dipoles in cells

exposed to a non-uniform EF. Cell properties (C, G) affect results.o Magnetophoresis (MP): Based on array of microcoils used to avoid

any direct cell handling. Cells must be magnetically labeled.

o Optical Trap: Target cells are trapped by laser forces at the focalpoint, excess cells are excluded by controlling the EF using DEP.

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# Traditional cell-based assays are usually time-consuming, laborintensive, and require bulky equipment.

# On contrary, integrated cell-based sensors can provide variousadvantages: size, speed and accuracy.

!"#$ "&' ()"*+,-) ()#./)0-"** #"-.*) 1/*2-)# 3 45 267

8/ *"9)*:&; .(/

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# An array of 16384 blocks in CMOSfor recording and stimulation ofindividual cells.

# Recording of cardiac cells activity.

# Cells were paced by single-electrode

stimulation.

Ex.1: CMOS Chip for Single-cell Recording/Stimulation

3D reconstructionof cells

Ceramic substrate, culture chamber & die

Chip architecture and PCB components

Huys et al., Single-cell recording and stimulation with a 16k micro-nail electrode array integrated on a 0.18 µm CMOS chip, Lab on a Chip, 2012

Micro-nail passivated

electrodes,

SEM image,

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Ballini et al., A 1024-Channel CMOS MEA With 26,400 Electrodes for Recording/Stimulation of Electrogenic Cells In Vitro, JSSC 2014

# Simultaneous recording from neurons at high spatiotemporal. Stimulation capability is used for investigating plasticity and learning processes;

# The system incorporates 1024 channels composed of 26,400 pt electrodes over alarge sensing area (3.85mm x 2.10mm);

# Readout channels record signals from a user-specified selection.

Ex.2: MEAs for In Vitro Recording/Stimulation of Cells

SEM image of the chip plated with rat neurons

.

Chip micrograph and packaged device

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# Resources

Outline

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# Extracellular acidification rate is an indicator of cellular metabolism.

# ISFET allows to measure: cell metabolism, pH, O2, etc.

# ISFET in CMOS provides: Fast response, small size, & high sensitivity.

ISFET for Cell Studies

Simplified diagram

V Chem

= E ref = 2.303! .V

T . pH + "

# ISFET can be modeledby a MOSFET, passive

elements (CGouy-Chapman & Chelmholtz)

and pH-dependentvoltage source.

0 0.5 1 1.5 2 2.5 3 3.5 40

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1x 10

-

VGS

pH=2

pH=4

pH=6

pH=8

pH=10

pH=12

pH=12

VDS= 0.1

VDS= 0.5

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DC-

+

-

+

ID

ID

RDS

S

D

ref electrode

ISFET

Output

+

-

# This interfacecontains S-D

Follower, 50mV/pH,and pH dynamic

range of 1-14, used

in applications.

ISFET for Cell Studies, Modeling

Application Membrane Electrodes

DNA sequencing Tantalum 1.5-13M

Bacteria detect. K+- sensitive 6

Cellular imaging Si3N4 16x16

Water safety NA single

ISFET Biosensor applications

# Single & large array of ISFET were introduced for measuring pH of culturedtumor cell.

# Ion Torrent Inc. commercializes arrays (1.5M) for DNA sequencing.

# Despite advances in ISFETs, flexible platforms still needed to provide:

$ Real-time monitoring, Resolution, Portability, Reproducibility, Cost, etc.

# Some applications need to show whether pH has exceeded a threshold

# In cell culture, acidity of the media due to lactate production is of interest.

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# Approach for pHmeasurement

using ISFETdigitalinverters.

# Three ISFET-based inverterconfigurations

Proposed Digital ISFET Platform and readout circuit

   B

   i  o  s   i  g  n  a   l  s

   Q  u  a  n   t   i   t  a   t   i  v  e

   D  a   t  a

Flexibility

# Vth sensitivity to pH for each configuration.

# Configuration 1 has the highest sensitivity.

–

Fast, no ADC, robust to noise and non-idealities

~~~

~~~

~~~

~~~

ISF-P

ISF-N MOS-N

ISF-P MOS-P

ISF-N

1 2 3

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Fabrication results: Packaging and pH Variation

•

Encapsulated chips were exposed to three pHbuffers; pH values of 4, 7, and 10.

•

Reference electrode in Ag/AgCl

• Voltage change of each pixel prior and after addition

of 500 !l of pH buffers. Biocompatible epoxy. Centrifuge

tube for analyte solutions.

0

10

20

30

40

50

60

  -   0 .   1

   0 .   4

   0 .   9

   1 .   4

   1 .   9

   2 .   4

   2 .   9

   3 .   4 4

   S  w   i   t  c   h  e   d  p   i  x  e   l  s

Input voltage (V)

pH=4 ph=7 pH=10

• As Vin increases, pixels switch tozero.

• Some pixels don’t switch due to

trapped charge on ISFET threshold

voltage.

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# Resources

Outline

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# Lab-on-Chip architectures for DEP-based cell manipulation & detection.

# All DEP features such as frequency, phase, and amplitude of signals onelectrodes are controlled through a CMOS chip.

# Intended for neurotransmitters detection and separation.

DEP-Based LOC for Particles Manipulation and Detection

Simplified Block-diagram of

the LoC

DEP-based LoC microsystem architecture

using planar electrodes.

Miled and Sawan,”DEP-based integrated lab-on-chip for nano/micro-particles manipulation and capacitive detection" TBioCAS, 2012.

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Biosensors for Neurotransmitters’ Detection

F sphere = p •!( ) E

F sphere = 2! a3Re

" 0K

1

*K

2#K

1( )2K

1

+K 2

%

& &

(

)  )  * E   2

Dielectrophoresis Electrodes: (a)Mixing; (b)

Sensinginterdigitiated; (c)

L-Shaped motionand separation.

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Biosensor: Lab-on-chip based Devices

Microelectrodes forneurotransmitters apps Microfluidic for watermonitoring apps

Layer 1

Layer 2

Layer 3

Layer 4

Layer 5

Layer 5b

Layer 6

Layer 5c

Layer 7

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# Resources

Outline

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Capacitive Sensor for Lab-on-Chip Applications

I S  ! I

R = f

.

V  DD.

"C

Vout   =!C

C int

. K .V  DD

CMOS chip

Encapsulation

#$ Capacitive Interface Circuit

FPGA Platform

Chemical (Biological) sample

SE RE

Electrical Package

1-bit DAC

MDAC MCM MC1

IDAC

SDAC SCM qn Dm D1

SC1

Calibration circuit

M8

M6 M4

M10

M12

Vb2

Vb1 IR M2

M14 CR

Ck1

Ck2

CBCM

M7 Vb1M1

M13

M5 M3

ID1

CS

IS

M9 Vb2

M11 Ck3

Vout

Cint

M10

Is-IR

Vdd

Gnd

Gnd

IR

0 40 80

      "                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         C

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          (                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              p                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   F                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           )

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1 2 3 4 5 8.6

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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          (                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              p                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   F                                                                                                                                                                                                      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                                                                                                                                                                                                                                                                                                             9.4

Dielectric constant Chip samples

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#$ CBCM

Serial Decoder

CS

CR

IS

IR

%3%1 %2

Vout+

Vout-

%4

Out

Clock Generator

Decoded Output

FPGA

CMOS Chip

Capacitive Sensor for Lab-on-Chip Applications

Ix+ (CS,CR ,t)

Cint-

Vref-

Vref+

c o m p a r a t o r

Ix- (CR ,CS,t)

SW1

I!(CR ,t)

I"(CR ,t)

Cint+SW2

Vout+

Vout-

Out

Out

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CapacitiveElectrodes

2.5 mm C M O S 0 . 3 5 ! m

Vout+ -Vout-

Vout (V)

3

4

5

6

W = Water A = Acetone

E = EthanolM = Methanol

D = Dichlorimethane

10 30 50 70 95

Ethanol% in Water

Lab-on-Chip based Biosensors: results

CMOS Tech. 0.35!mSensitivity(mV/fF)

350

Dynamicrange

10fF

Supply voltage ±3.3V

Output voltage Diff.

Powerconsumption

0.3!W@1kHz

(a)

(a)

(b)

(b)

(c)

(c)

Positive & Negative DEP manipulationof 15 !m algae cell

0

1

2

3

4

5

6

E M D W AOrganic Solutions

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#


# Cell Analysis Protocols$

Manipulation, Recording and Stimulation




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# Resources

Outline

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Bonding wire

CMOS circuits

Microfluidic structure

Microcoil substrate

PCB board

Discrete components Via or pad

Magnetic Detection of Toxins & Pathogens

Magnetic Immunoassay towards Protein Toxins Detection

0

( )m x x x x x y z

B B B F V B B B

x y z µ

! " " "= + +

" " "

( )mag m F V H B= ! "#

Magnetophoresis

Detecting

toxins &

pathogens

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0

00 0

1(1 )

22 ( )

L f f

L L L C !

"= # $

+"

1( )( )

on

n OX In T

RW C VCC V V

L!

=

" "

VCC

Output

M1 M2

M3 M4

M5 M6

M7 M8

M9

M10

M11

"#$%&'# )*%+, -. /0%1 2#345/0%1#,%*6307#8

•

Measurementof Mouse IgG

based on thisplate, & Goat

Fc-specificanti-mouse

IgG were

performed.

0( )4

eV s L

Vout  sL R

!

=+

Magnetic Detection of Toxins & Pathogens (Cont’d)

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# Resources

Outline

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# Cell analyses include: viability testing, proliferation rate monitoring (thenumber of actively dividing cells in a sample) and physiologicalproperties measurement such as pH, O2 and CO2

# Traditional cell proliferation assay include :

$ Fluorescence labeling of the live/dead cells

$ Measuring metabolic activity of a population of cells

# These are time consuming methods, labor intensive and require bulkyequipment.

We propose:

# A CMOS capacitive biosensor for tracking the growth of adherent cells

& analyzing the effect of anti-cancer agents on the cells behavior.# The platform is composed of an array of 8x8 capacitive sensors

integrated with 8-channel readout system.

# An 8-channel differential #" modulator used on the same CMOS chip.

Living Cell Detection and Analyses: Smart Petri-Dish

Nabovati , Ghafarzadeh, Sawan, “Smart Petri-Dish: fully integrated cell imaging platform for real-time assessment of living cells”, 2015

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Smart Petri-Dish: Integrated Platform for Cells Assessment

-0,2

0,8

1,8

2,8

3,8

1 6 11 16 21

O u t p u t V o l t a g e c h a n g e ( V )

Culture Time (h)

Chip with cells

Chip with media

Adhesion

Cell growth

Detachments

Cultured HEK293 cells

Capacitive monitoring of H1299 Cells (50k/ml)

0 min 12 hrs

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Neurotransmitters detection

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Embedded medical devices : Power sources

•

Energy scavenging, power harvesting :• MEMS, Vibration, Thermoelectric, Piezoelectric, etc

• Fuel Cells (electrochemical, reaction of Hydrogen/Oxygen)

• Bioreceptors (Glucose, Enzyme, Neural cells, etc).

• Booster using Inductive Ring Oscillator

• Radio signals.

• Inductive powering• Transcutaneous RF: no internal power source

• Primary: Wearable systems including battery

• Secondary: Implants w/ rechargeable battery if needed.

1V, 1uA,from 50 mV

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Outline

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Summary

Design Challenges are Multidimensional%

Arrays combining various techniques

(Capacitive and ISFET)

% Larger Petri-Dish platforms

%

Bioprotocoles%

Energy and transmission interfaces.

BMBI for Neurosensing and Treatment& Multi-channel Intracortical Recording and Neurostimulation

&

LoC-Based Neurotransmitter Detection

& Various Integrated biosensor platforms

& Monitoring pH levels using array of ISFET pairs (chemical switch).

&

Electro- and Magneto-phoresis cell manipulation and measurements

&

Petri-Dish platform.

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# National Sciences and Engineering Research Council of Canada (NSERC)# Canadian Institutes of Health Research (CIHR)# Canada Research Chair on Smart Medical Devices (CRC)#

Quebec Research Funds : Nature and technologies (FRQNT)

# ReSMiQ, and CMC Microsystems, and Co

#

Collaborators from Engineering and Medical Schools in Montreal.# Interns, Master and PhD Students. Postdoc Fellows, Research Associates..

R Q N T

sawan ieee org

Acknowledgments

ww polys#m ca

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Invitation to ISCAS 2016 in Montreal

Toward Brain-Microsystem Interfaces for the Treatment of Neurodegenerative Diseases

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Transcript of Toward Brain-Microsystem Interfaces for the Treatment of Neurodegenerative Diseases