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Title: UltraWideband Electronics, Design Methods, Algorithms, and Systems for Dielectric Spectroscopy of Is


1
Ultra-Wideband Electronics, Design Methods,
Algorithms, and Systems for Dielectric
Spectroscopy of Isolated B16 Tumor Cells in
Liquid Medium Erick N. MaxwellDefense of
Doctoral DissertationChairperson Venkat
Bhethanabotla, Ph.D. Major ProfessorThomas
Weller, Ph.D. Committee Kenneth A. Buckle,
Ph.D., P.E. Dennis K. Killinger, Ph.D.Geoffrey
Okogbaa, Ph.D.Arthur David Snider, Ph.D., P.E.
2
OUTLINE
  • Introduction
  • Literature Review
  • Research Question
  • Approach and Methodology
  • Contributions (4 of 5)
  • Future Work and Direction of Research
  • Conclusion
  • Acknowledgements

3
INTRODUCTIONBackground and Motivation
0200 / 0200
  • Isolated tumor cells (ITCs) are individual tumor
    cells
  • spread to the lymph nodes or general circulation,
    which includes
  • Blood and
  • bone marrow
  • ITCs are believed to be a mechanism involved in
    formation of tumors in distant sites
  • Significance of circulating ITCs in the blood has
    not been established due to conflicting results
  • Reported on a connection between circulating
    tumors in blood and the formation of hematogenous
    metastasis
  • Keiichiro Uchikura and others,
  • Reported that in 15 of sentinel lymph nodes in
    which ITCs are detected, no metastasis is found
  • Hermanek, Hutter, Sobin
  • Consequently, the independent prognostic
    significance of circulating ITCs has not been
    proven
  • The tumor-lymph node-metastasis (TNM)
    classification system
  • The Most widely used means for classifying spread
    of malignant tumors
  • Does not assign clinical significance to the
    occurrence of ITCs

4
INTRODUCTIONBackground and Motivation (Continued)
0100 / 0300
  • The Pathology Associates of Lexington,
    Pennsylvania stated the following
  • Regardless of the lack of any current consensus
    as to the significance of isolated tumor
    cells...excellence in surgical pathology practice
    requires that a staging lymph node exam actually
    be truly negative when diagnosed as negative.
  • Although a physician may consider the results
    insignificant, it does not effect the reporting
    that comes from the Pathologist
  • Detecting, quantifying, and characterizing ITCs
    is an integral part of the metastatic work-up for
    cancer patients
  • Surgical pathologist and cytologist have an
    interest in characterizing ITCs
  • For its potential to provide data for cancer
    staging, classification and treatment

5
INTRODUCTIONResearch Question
0210 / 0510
  • The Problem
  • An optimal method for detecting single tumor
    cells not established (Weaver, Krag, et. al.)
  • Two categories for available methods
  • Morphologic methods i.e. HE-Staining and
    IHC-Staining
  • Nonmorpologic methods i.e. Flow cytometry
  • HE-staining is non-ideal because
  • A single section evaluates less than 1 of the
    lymph node
  • Not used exclusively for diagnosing disease
  • Flow cytometry
  • Has emerged as a useful application in clinical
    pathology
  • Range in price from 50,000.00 to 500,000.00
  • Paraskevas, et al used dielectric spectroscopy
    (DS) for evaluating oil-based emulsions
  • high-sensitivity,
  • low-cost tool
  • This research applies frequency-and time-domain
    dielectric spectroscopy to characterize and
    quantify ITCs in medium
  • To what extent are different volumes of cancer
    cells electrically distinctive?
  • What formalism should be applied for
    distinguishing ITCs?
  • Does the literature support a hypothesis that
    they are distinctive?

6
LITERATURE REVIEWDielectric Spectroscopy
0320 / 0830
  • What is dielectric spectroscopy (DS)?
  • measures material properties over frequency by
    capturing polarization effects
  • Dielectric Material
  • A material is a dielectric if it
    stores/dissipates energy with application/removal
    of E-field
  • The term Permittivity describes this
    interaction
  • Kramers-Kronig Relations
  • Provides a set of mathematical properties that
    connect the real and imaginary parts for any
    complex analytic function
  • If an oscillatory force is applied to a physical
    system
  • Force is applied in one direction during ½ cycle
    and reversed
  • The system does not respond instantaneously to
    the change in direction (or response function)
  • As frequency increases system has less time to
    react before force changes direction
  • the response function diminishes with an increase
    in frequency
  • Provides a fundamental description for dielectric
    response of a material (real-dissipation)
  • Peter Debye
  • Provided a formula to capture the Kramers-Kronig
    system response for dielectric material
  • Called the system response dielectric relaxation
    (or dielectric dispersion)
  • Called the delay between the application of an
    external electric field and orientation of an
    electric dipole moment a Phase delay
  • permittivity decreases from a static value at low
    frequencies to a smaller value at high
    frequencies
  • attributed occurrence of material relaxation to
    dipole polarization

Dielectric mechanisms versus dispersion type.
7
LITERATURE REVIEWB16-F10 Cell Characterization
0300 / 1130
  • Irimajiri, Hanai and Inouye demonstrated that
    every shelled particle interface in a suspension
    gives rise to a single Debye-type dispersion
  • Consider the structure of B16-F10 mice tumor
    cells
  • are generally round in shape with a single cell
    membrane and cytoplasm
  • Based on the microscopic structure it is
    reasonable to anticipate molecular, atomic, and
    sub-atomic dielectric mechanisms
  • Asami
  • Characteristic polarization for heterogeneous
    systems is interfacial polarization, which
    demonstrates ß dispersion,
  • Asserted that the microscopic mechanisms may be
    ignored because they are not dominant in a cell
    suspension
  • Pauly and Schwan showed that for biological cells
    the dispersions degenerate to a single dispersion
    process
  • What this means is that a Cole-Cole dispersion
    model is sufficient
  • Now Lets Consider What support is there for
    relating permittivity to cell quantity?
  • Maxwell-Wagner
  • formula for describing the dielectric behavior of
    mixtures
  • provides a means to extract properties of
    individual cells from measurement of the cell
    suspension
  • cell suspension is a function of the permittivity
    of the medium and cell as well as volume fraction
    that cells occupy
  • Maxwell-Wagner formalism supports the possibility
    for using the permittivity of a mixture to
    estimate the volume fraction of cells in the
    suspension!

8
LITERATURE REVIEWB16-F10 Cell Characterization
(Continued)
0130 / 1300
  • What measurement technique?
  • There are many challenges with T/R methods
  • T/R Fixtures
  • Not suitable for holding liquid samples
  • High fixture complexity and cost
  • Frequency domain dielectric spectroscopy (FDDS)
  • No ideal method for extracting permittivity
    exists
  • Time domain dielectric spectroscopy (TDDS)
  • Provides best resolution of structural properties
    of cell
  • Simple, low-cost circuits for generating
    sub-nanosecond tunable pulses unavailable

NIST-National Institute of Standards and
Technology
9
RESEARCH QUESTION AND CONTRIBUTIONS
0100 / 1400
  • Provide an answer to the question
  • To what extent are different volumes of cancer
    cells electrically distinctive? (by relating
    dielectric properties to cell quantity)
  • Contribute
  • Novel circuits for tunable pulse generation
    (ultra-wideband generators) by proposing a new
    approach to generator design,
  • A technique and circuits for shaping
    sub-nanosecond UWB pulses,
  • A low-cost method for transmission-reflection
    (T/R) measurements that is based on the
    construction of a fixture from semi-rigid coaxial
    transmission line with a Teflon-PolyTetraFlouroEth
    ylene (PTFE) core, for measuring liquid
    specimens,
  • A genetic algorithm (GA) approach for
    permittivity extraction which circumvents the
    problem of half-wavelength resonance in the
    Nicholson-Ross-Weir (NRW) technique and extends
    Oswalds approach, and
  • An investigation of the capacity for dielectric
    spectroscopy to quantify isolated B16-F10 tumor
    cells in McCoys liquid medium.

10
APPROACH AND METHODOLOGYOverview
0100 / 1500
  • UWB measurement of cancer cells in media
  • circuits
  • techniques
  • models

11
UWB SIGNAL GENERATIONOverview
0230 / 1730
  • What is UWB?
  • An intentional radiator that, at any point in
    time, has a
  • Fractional bandwidth equal to or greater than
    0.20 or
  • 10dB bandwidth equal to or greater than 500
    MHz...
  • What has been done in low cost Generator Designs?
  • Step Recovery Diodes (SRDs) usedAgilent, Lesha
    et.al,
  • J. Han and C. Nguyen Microstrip Generators /
    Tunable
  • What are the primary challenges?
  • Theoretical framework not well defined
  • Solid-state tunable generators have complex
    topology
  • Loss in symmetry
  • How we addressed these challenges?
  • Conventionally
  • SRDs in series configuration
  • Generate impulse/Gaussian then tune pulse
  • Change the philosophy for producing pulse
  • New philosophy circumvents challenges
  • Produce a step/square waveform using an SRD
  • Provide a mechanism for tuning rise-time of the
    step

UWB Signals
Complex Topology
Loss in symmetry
12
UWB SIGNAL GENERATION Background
0200 / 1930
  • A SRD is a p-n junction diode
  • stores electric charge during forward conduction
  • rapidly removes these charges during reverse
    conduction
  • Time associated with transition can be less than
    60 psec
  • called snap-off, charge-storage, and memory
    varactor diode
  • Boff, Moll and Shen noted that this fast
    transitioning edge occurs in a p-n junction diode
    that is doped with linearly or exponentially
    graded impurity
  • New philosophy requires square wave or step
  • Model a SRD clipping circuit
  • Peak of positive and negative going sinusoid is
    clipped
  • Transforms a sinusoid to a fast edge square wave

13
UWB SIGNAL GENERATION Results and Discussion
0130 / 2100
(C)
(E)
(A)
(D)
(B)
(F)
14
UWB SIGNAL GENERATION Summary
0130 / 2230
  • Contributions
  • A new design approach
  • Low complexity tunable UWB pulse generator
  • Advantages
  • Simple design,
  • Positive- and negative-going pulses possible
  • Disadvantages
  • Lower voltages due to shunt diode
  • Capacitive tuning complicates transmission line
    approaches for differentiation
  • Capacitor is an integral part of RF/Microwave
    differentiator
  • Must decouple the VERC and differentiator circuit

To circumvent disadvantages provide an
alternative method for derivation
15
UWB PULSE SHAPINGIntroduction
0030 / 2300
16
UWB PULSE SHAPINGOverview
0200 / 2500
  • What is UWB pulse shaping?
  • Pulse formation (or pulse shaping)
  • critical to the performance of a UWB system
  • used to optimize spectrum for meeting FCC
    emission spec
  • In communication, radar, and DS measurement
    systems
  • What has been done in pulse shaping designs?
  • GaAs MESFETs, non-linear transmission lines,
    short-circuit stubs and resistive-reactive
    circuits
  • waveform response to circuit reactance is
    fundamental
  • reactive elements form a simple RC or RL network
  • What are the primary challenges?
  • RC time constant requires lt 20 pF cap for shaping
    (50O)
  • Stray or parasitic capacitance can easily modify
    waveform
  • How we addressed those challenges?
  • Coupled-line coupler and Schottky detector
    differentiators
  • Provides a means to isolate VERC and
    differentiator
  • Mutual and junction capacitances are small enough




17
WAVEFORM DIFERENTIATOR Background
0130 / 2630
(A)
(A)

(B)
(B)
(C)
18
WAVEFORM DIFERENTIATOR Background (Continued)
0130 / 2800
(A)
(B)
(A)

(C)
(B)
19
WAVEFORM DIFERENTIATORResults and Discussion
(Continued)
0100 / 2900
MCS3P Fabrication and Measurement
Multi-Port Circuit for Simultaneous Shaping of
Sub-nanosecond Pulses
20
WAVEFORM DIFERENTIATORSummary
0050 / 2950
  • Contributions
  • Novel techniques and circuits for sub-nanosecond
    pulse differentiation, including
  • Novel coupled-line coupler differentiator
  • Novel Schottky detector differentiator
  • Multi-port Circuit for Simultaneous Shaping of
    Sub-nanosecond Pulses
  • Advantages
  • Provides alternatives to sub-nanosecond pulse
    shaping
  • Disadvantages
  • Minor variations in fabricated design has a
    notable effect on signal

21
TEST FIXTRUE DESIGNIntroduction
0010 / 3000
22
T/R TEST FIXTRUE DESIGNOverview
0250 / 3250
  • Why T/R test fixture design?
  • TEM mode of propagation
  • Complex relative permittivity and permeability
  • What has been done in T/R fixture designs?
  • Applied in variety of dielectric measurement
    systems including produce, biomaterials, and UWB
  • Constructed with an air core
  • What are the primary challenges?
  • Most suitable for measuring solids (NIST)
  • Sample holder separate from fixture (must be
    small)
  • Intricate and high cost!
  • How we addressed those challenges?
  • Construct a fixture without an air core
  • Semi-rigid coaxial transmission line w/
    Teflon-PTFE

23
T/R TEST FIXTRUE DESIGNBackground
0200 / 3450
  • Nicholson Ross Weir Technique
  • provides a solution for extracting complex
    relative permittivity and permeability
  • from measured S-parameters
  • fixture step-discontinuity at PTFE-specimen
  • characteristic impedance (Zw) for semi-rigid line
    based on continuous interface
  • Somlo showed that a step capacitance (Cd) may
    describes coaxial step in outer conductor

24
T/R TEST FIXTRUE DESIGNResults and Discussion
0220 / 3710
Adjusting NRW Algorithm for step-discontinuity
Simulated
  • A simple approach to correcting for the effects
    of the coaxial step was developed.
  • This approach entailed
  • Computing permittivity with and without a step
    discontinuity over several simulated sample
    values
  • Calculating an error for difference between
    computed permittivity values,
  • Fitting an equation to the calculated error, and
  • Correcting NRW permittivity

Measured
25
T/R TEST FIXTRUE DESIGNSummary
0110 / 3820
  • Contributions
  • Low-cost, Low-complexity, T/R Fixture capable of
    measuring liquids
  • Advantages
  • (See Contribution)
  • Disadvantages
  • Sample preparation is difficult
  • Fixture dimensions is critical in permittivity
    measurement
  • Fixture is leaky
  • NRW approach problematic

We need a new approach to permittivity
determination
Genetic Algorithm approach was developed to
circumvent problems
26
PROPERTIES OF CANCER CELLS Introduction
0010 / 3830
27
PROPERTIES OF CANCER CELLS Background
0150 / 4020
  • Describe Tumor Cells
  • B16-F10 tumor line was derived by
  • Injecting B16 tumor cells into syngeneic C57BL/6
    mice
  • Harvesting the secondary growth after two to
    three weeks
  • Placing the tissue in a culture and
  • Injecting into new syngeneic mice
  • Note The above process was repeated ten times ?
    designation F10
  • B16 line is desirable because
  • Shows stable metastatic properties, even after
    many tissue subcultures
  • American Type Culture Collection supplied the
    primary B16-F10 tissue culture for this research
  • Harvesting tissue from mice was unnecessary
  • Growing cells in culture mandatory to achieve
    large counts for testing
  • Describe McCoys Medium
  • Culturing environment for growing and testing
    cells
  • Required 5-8 days in culture to achieve desired
    cell volume (3 M cells/mL)
  • Cell growth/death continued even during testing

28
PROPERTIES OF CANCER CELLS Results and Discussion
0230 / 4250
  • Characterized B16 cell suspensions of 0, 1, 2 and
    3 M cells/mL
  • Frequency domain system (32 samples, 8 per test
    volume)
  • Time domain system (32 samples, 8 per test
    volume)
  • Paired t-test was conducted to determine the
    significance differences between these volumes
  • The Goal to disprove null hypothesis there is no
    difference in the static permittivity
  • 90 confidence level
  • If area under one-tail t-distribution was less
    than 10 significance level ? Reject Null
    Hypothesis

29
PROPERTIES OF CANCER CELLS Results and
Discussion (Continued)
0200 / 4450

30
PROPERTIES OF CANCER CELLS Summary
0040 / 4530
  • Contributions
  • A preliminary investigation of the capacity for
    dielectric spectroscopy to quantify isolated
    B16-F10 tumor cells in McCoys liquid medium
  • Advantages
  • Despite cell contamination in frequency domain
    data and
  • Secondary reflections in time-domain system
  • ITCs can be characterized using dielectric
    spectroscopy
  • dielectric spectroscopy relates to cell quantity
  • Disadvantages
  • Cell preparation difficult
  • Dielectric spectroscopy requires an evenly
    distributed population of cells
  • Advantage of UWB measurement system not evident

31
Future Work and Direction
0310 / 4840
  • Conduct FDDS testing again
  • Verify cell contamination at 1 M cells/mL
  • Goal of reducing standard uncertainty
  • Solve problem with secondary reflection in TDDS
  • Reflection due to reversed reflection from sample
    interface
  • Delayed this reflection in subsequent experiment
  • Increasing length of transmission line between
    the Sinusoidal source and UWB Generator
  • Conduct TDDS testing again
  • Standard uncertainty mainly due to uneven cell
    distribution in population
  • Develop a method for ensuring consistent sampling
    of population
  • Reduce standard uncertainty in the measurement
    results
  • Test smaller volumes
  • Different volumes of cancer cells were
    electrically distinctive so long as the cell
    volumes are large enough to overcome the sources
    of uncertainty
  • Revisit hemocytometer for verifying cell volumes

32
Conclusion
0120 / 5000
  • Designed/Fabricated Novel UWB Pulse Shapers and
    Generators
  • Establishing an approach for UWB generator design
  • Modeling / Characterizing of SRD for simulation
  • 3 Novel Circuits (2 Provisional patents)
  • Schottky detector and
  • coupled-line coupler differentiators
  • MCS3P circuit
  • VERC technique/Circuit
  • Developed a T/R Fixture ( Provisional Patent)
  • Introduced an enhanced Genetic Algorithm approach
    to parametric extraction
  • C using Microsoft Visual C 2005 express
    edition
  • Genetic Algorithm Library from MIT
  • Preliminary testing of ITCs in medium
  • Using low cost time and frequency domain
    dielectric measurement system
  • Showed correlation between tumor cell quantity
    and electric permittivity
  • Concluding Statement
  • Tools of research are necessary for experiments
    to assess the prognostic significance ITCs
  • DS has the potential to provide data unavailable
    using conventional methods
  • It offers another modality from which information
    can be assembled for increased prognostic value
    for Cytologists and Pathologists

33
Acknowledgements
0000 / 0000
  • Special Thanks to
  • Dr. Tom Weller (Advisor)
  • Bernard Batson
  • Dr. Tom Fare (Rosetta Inpharmatics)
  • Dr. Mark Jaroszeski (Dept. of Chemical
    Engineering)
  • Jose Rey (Dept. of Biomedical Engineering)
  • Dr. Jeffrey Harrow (VA Medical Center)
  • Committee Members
  • Dr. Kenneth A. Buckle
  • Dr. Dennis K. Killinger
  • Dr. Geoffrey Okogbaa
  • Dr. Arthur David Snider
  • Chairperson
  • Dr. Venkat Bhethanabotla
  • This work was supported financially in part by
  • Center for Wireless and Microwave Information
    Systems
  • Harris Corporation
  • Florida Education Fund (McKnight Fellow)
  • National Science Foundation (USF-IGERT)

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