Integrated Circuit Design for Impedance Spectroscopy ...
Transcript of Integrated Circuit Design for Impedance Spectroscopy ...
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Integrated Circuit Design for Impedance
Spectroscopy Applications
27.08.2015
Dr.-Ing. Paola Vega-Castillo
IEEE CAS Summer School, 18.08.2015
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Agenda
• Cell impedance
• Impedance spectroscopy
• Impedance spectroscopy IC architectures
• Lock-in amplifier IC
• Conclusion
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Impedance in biomedical/biological applications
• Bioimpedance analysis (dialysis)
• Cardiography (strokes)
• Renal ischemia monitoring
• Atherosclerotic lesion differentiation
• Prostate biopsies
• Sciatic nerve injury monitoring
• Detection of proteins, DNA hybridization, common allergens
• Cell characterization
• Electrical impedance tomography
• Impedance flow cytometry
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Cell Impedance Spectrum
ionicdiffusionout of themembrane membrane,
organelle andmacromolecule
polarization
molecularpolarization and
relaxation ofwater
-Dispersion region
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Cell Impedance Spectrum (2)
Gregory, W. et al. “The Cole relaxation frequency as a parameter to identify cancer in breast tissue”. Medical Physics, Vol. 39, No. 7, July 2012
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Frequency Response
• The frequency behavior of tissue, bood and fat reportedso far for animals and humans presents the followinggeneral cualitative log-log tendency
f
Perm
itti
vity
(F/m
)
f
Co
nd
uct
ivit
y(S
/m)
Gabriel et al. „The dielectric properties of biological tissues: I. Literature Survey“. Phys. Med. Biol. 41 (1996) 2231–2249
10-100 S/m in -dispersion0.01-1 S/m in -dispersion
10-100 in -dispersion106-108 in -dispersion
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Impedance Measurement Systems/ICs
Company System Maximum Frequency
Analog Devices IC AD5933, AD5934 100kHz
Texas Instruments IC AFE4300 1MHz
Bionas Bionas Discovery 2500Bionas Discovery adconreader
Cellasys IMOLA 10kHz
Ibidi/Applied Biophysics ECIS 100kHz
Molecular Devices CellKey 100MHz
nanoAnalytics CellZscope 100kHz
Roche Diagnostics xCELLigence 50kHz
Commercial systems monitor the impedance change in time at a fixed frequency
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Cell impedance spectroscopy applications
• Basic research of celular properties, viability and cellconcentration
• Biomass characterization(Nacke, 2001) (Hautmann, 2001)
• Tissue characterization (Jäger, 2006)
• Stem cell studies
• Drug testing (Asphahani, 2007) (Meissner, 2011)
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Cell impedance spectroscopy applications
• Cancer detection (Kim, 2009) (Qiao, 2012) (Aberg, 2004) (O’Rourke, 2007)
– Electrical signatureaccording to diseasestadium by changes in themembrane (Han, 2007)
• Cancer cells present lowerimpedance– Higher water and salts
content (Sha, 2002)
– Different density (Zou, 2003)
– Different membranepermeability (Zou, 2003)
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• Impedance changes are indicators of cellular damage– Changes in morphology (low
frequency)
– Cellular death (high frequency)
Example: Toxicology
(Meissner, 2013)
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Impedance Change by Cell Damage
• At low frequency, the membrane presents a high impedance
• Morphological changes open intercellular gaps, decreasing the impedance
• At high frequency, the membrane impedance is low, intra and extracellular current flow– Less influence of intercellular gaps
• Formation of membrane pores, cellular death, exchange of intra and extracellular liquid
(Meissner, 2013)
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Traditional Impedance Spectroscopy
• Most impedance spectroscopy approaches do not rely on integrated measurement systems
• Integrated impedance measurement system– May enable high frequency characterization
– May include improved features in compact format
coaxial
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Z measurement at high frequency
27.08.2015
Reported measurements up to 40GHz
Dubuc et al. Broadband microwave biosensing based on interdigitated capacitor for Lab-on-Chip applications
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System Requirements
-Non invasive, non destructive procedure, nocell modification required
-Simultaneousmeasurements desirable to enable fast analysis undersame environmental and age conditions
- Real time measurements- Larger frequencyspectrum for new experiments (1kHz-10GHz)
Grenier (2013)
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Why high f impedance spectroscopy?
• Reduce influence of membrane and double layer capacitance
• No water and ionic-conduction related impedance screening effect
• Information about organelles and proteines could be obtained electrically
• Biomolecule signature mapping possible
• May enable phenotype discrimination
• Non-ionizing radiation (in vivo measurements)
• Capacitive and conductive contrast
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Time to digital converter system
Current to voltageconverter
sample
stimulusTIA TIA Z
sample
VV Z
Z
,
stimulus
sample TIA
peak TIA
VZ Z
V
Microcontrollerunit
Conversion to square waves
Comparators
Obtains time difference between risingedges, duty cycle proportional to
impedance angle
SR-latch
2sampleZ
t
T
Time to digital converter
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Time to digital converter system
• 10mV stimulus voltage• Input current ranging from 10nA-100μA • Variable TIA gain from 1.6kΩ-63MΩ• 100Ω-1MΩ over a frequency range of 100Hz-10MHz• Phase detector distinguishes a minimum of 200ps time difference • 0.18μm CMOS, 1.8V
a) 40kHz stimulus (×50), b) TIA output, c) Phase detector output, d) Peak detector output
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Phase and amplitude detector
• Four-point measurement• 0.35-μm CMOS technology, 100 Hz to 100 kHz
Instrumentationamplifier
Amplifies V at sensing resistor to V at sample
Converts to square signals
Multiplicador
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Lock-in Capacitive Sensing
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Digital Lock-in Amplifier
• Coherent detector but input signal is digital
• For antibody detection
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Lock in amplifier
• IHP SiGe 130nm bipolar technology• fT = 240GHz, fosc = 290GHz
( )sin
cos( )
Linearized phase detector: output proportional to phase difference of two input signalsSinusoidal phase detector: output proportional to sine or cosine of the phase difference between two input signals
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Lock-in amplifier (2)
,
,
sin( t )
sin( )
sin( 90 )
Real Part
sin( t ) sin( )
0.5 cos(2 t ) cos( )
Imaginary Part
sin( t ) sin(
measurement m Z
osc p
osc q p
out measurement osc m Z p
out m p Z Z
out measurement osc q m Z p
V V
V V t
V V t
V V V V V t
V V V
V V V V V
90 )
0.5 cos(2 t 90 ) cos( 90 )
0.5 sin(2 t ) sin( )
out m p Z Z
out m p Z Z
t
V V V
V V V
Quadrature oscillator
Mixers
After low pass filtering, DC components proportional to the sine and cosineof the angle of the impedance are left
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Quadrature Voltage Controlled Oscillators
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Varactors
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Parasitic effects in integrated inductors
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Eddy Currents
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Equivalent circuit of integrated inductor
Acople por substrato
Pérdidas por
substrato
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Inductor Layout
• Upper metal layers to decrease R
• Carefully select external diameter, number of turns and interconnect width to ensure enough flux is enclosed by internal diameter
• Larger external diameter increases fsr but decreases Q– Typical diameter < 200μm
• Metal width 10- 20 μm– Decreases Rs and increases Q
– Larger witdhs more affected by skin effect, RS increases
• Turn spacing S– Minimal S, but consider capacitive effects
– S and L increases, mutual inductance M decreases
• Number of turns– Area and shape must be convenient for floorplan
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Inductor Layout (2)
• Decrease eddy currents– Use high resistivity substrates
– No metal planes over or underthe inductor
– No doped regions underinductor
• Enough distance fromunconnected metals– At least 5 times metal width
• Minimal internal diameterlarger than 5 times metal width, or 1/3 externaldiameter
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Example of inductor integration
42µm
350pH
Port 1
Port 2
Port 3
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Wide range CMOS Quadrature VCO
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Amplifier
• Broadband amplifiers need to provide a relatively constant gain and a linear phase response
• Cherry-Hooper topology is a compact alternative
• Peaking techniques usually present low phase linearity, which is not desirable for these purposes.
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Amplifier (2)
• Gain, n and Q controlled by Rf, R2/R1, IEE1 and IEE2.
• Pole frequency and Q could be increased by: – increasing IEE2: increases
number of emitters for each transistor, needswider interconnects duethe increased current
– decreasing Rf : gain would be significantly affected
– decreasing R2/R1: increaseR1 without affecting the output swing.
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Output Buffer
Bias and coupling Emiter followerEmiter follower
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Gilbert Mixers - Bipolar
The output differential current is:
out tanh tanh2 2
Y XEE
t t
V VI I
V V
Con |Vx| y |Vy| << Vt
EEout 2
I( ); K
(2 )X Y
T
I K V VV
Con |Vx| y |Vy| >> Vt opera como un detector de fase lineal
Gilbert mixer cell is a cross-coupled differential amplifier
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Gilbert Mixers - MOS
out ( )2
X Y
KI V V
Advantages of Gilbert MixersProvides both LO and RF Rejection at the IF outputAll ports inherently isolated from each otherIncreased linearity compared to single balancedImproved suppression of spurious products (all even order products of the LO and/or the RF are suppressed)High intercept points.Less sensitive to supply voltage noise due to differential topology.
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Basic Demonstrator
Basic impedance
measurement demonstrator
610 x 540 µm2
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Quadrature VCO
340µm2
278µm258µm, 125pH
Resistencias
Capacitores
Transistores del oscilador
Seguidores de emisor
Varactores MOS
Filtrado de DC y acople de impedancia
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Institute of Nano- and Medical Electronics TUHH
Bioingeneering ResearchProgram ITCR
10GHz IC DesignMultiplexer upto 10GHz
ZellCharmProject
- High frequency impedancemeasurements
- Electric field exposure of human cells
- Electrical characterization of human cells
- Microfluidics- System architecture
Academic Cooperation
Electronics Engineering School