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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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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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# 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
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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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# 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
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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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# 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
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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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# 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
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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 )
0.1
0.3
0.5
1 2 3 4 5 8.6
9.0 C 0
( p F ) 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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# 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
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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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# 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
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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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# 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
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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