Integrated Circuit Design for Impedance

Spectroscopy Applications

27.08.2015

Dr.-Ing. Paola Vega-Castillo

IEEE CAS Summer School, 18.08.2015

Agenda

• Cell impedance

• Impedance spectroscopy

• Impedance spectroscopy IC architectures

• Lock-in amplifier IC

• Conclusion

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

Cell Impedance Spectrum

ionicdiffusionout of themembrane membrane,

organelle andmacromolecule

polarization

molecularpolarization and

relaxation ofwater

-Dispersion region

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

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

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

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)

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)

• Impedance changes are indicators of cellular damage– Changes in morphology (low

frequency)

– Cellular death (high frequency)

Example: Toxicology

(Meissner, 2013)

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)

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

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

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)

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

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

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

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

Lock-in Capacitive Sensing

Digital Lock-in Amplifier

• Coherent detector but input signal is digital

• For antibody detection

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

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

Quadrature Voltage Controlled Oscillators

Varactors

Parasitic effects in integrated inductors

Eddy Currents

Equivalent circuit of integrated inductor

Acople por substrato

Pérdidas por

substrato

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

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

Example of inductor integration

42µm

350pH

Port 1

Port 2

Port 3

Wide range CMOS Quadrature VCO

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.

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.

Output Buffer

Bias and coupling Emiter followerEmiter follower

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

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.

Basic Demonstrator

Basic impedance

measurement demonstrator

610 x 540 µm2

Quadrature VCO

340µm2

278µm258µm, 125pH

Resistencias

Capacitores

Transistores del oscilador

Seguidores de emisor

Varactores MOS

Filtrado de DC y acople de impedancia

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