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EARLY DETECTION OF EARLY DETECTION OF MALIGNANT TUMORS USING MALIGNANT TUMORS USING
MAGNETICLY INDUCED MAGNETICLY INDUCED PRESSURE WAVESPRESSURE WAVES
Idan Steinberg - 25.11.2010Idan Steinberg - 25.11.2010
Introduction
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Early detection of malignant tumorsCancer is responsible for almost 25% of all deaths in the US! [1]Most common types of cancer in developed countries are: Lung, breast, prostate and colon [2].
Estimated numbers of new cancer cases (incidence) and deaths (mortality) in
2002 [1]
Early detection of cancer greatly improves patient survival and quality of life. e.g: Kakinuma R. has shown that regular screening tests for lung cancer improved the 5-year survival rates from 49% to 84%! [3]
Model Experiments Summary
5-year relative survival rates among patients diagnosed with selected cancers 2005 [4]
Theoretical Results
Introduction
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Existing methods for screeningMethodAdvantagesDrawbacks
MammographyRelatively accurate
Ionizing radiation, Uncomfortable
PSA + Physical exam
Very simple, Low cost and low risk
Very high false positives
ColonoscopyActual view of the colon, Samples
Uncomfortable, Risk of complications
Occult bloodVery simple, Low cost and low risk
Low accuracy
CT-ScanAccurate High doses of Ionizing radiation, Expensive
MRIAccurate, Non ionizing radiation
Extremely expensive, Needs special housing
Model Experiments SummaryTheoretical Results
Introduction
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Magneto-Acoustic detection Phase I:
Nano-particles injection
Antibody conjugated MNP solution
Tumor
Tumor with conjugated MNPacting as acoustic dipole
Acoustic probe
Phase II:Magneto-Acoustic detection
External Magnetic field
Model Experiments SummaryTheoretical Results
Introduction
5
Research Goals
The goal of this research is to provide a theoretical & experimental Proof of Concept of such a method
To date, no method exists for early detection of cancer that is general, accurate, low cost and has high throughput.
To overcome the drawbacks of existing methods, we propose a new method for early cancer detection which is based upon magneto-acoustic detection of tumor specific super-paramagnetic nano-particles.
Model Experiments SummaryTheoretical Results
Introduction
Analytic model allows the understanding and optimization of the system
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Magneto-Acoustic analytic model To asses the feasibility, an analytic models was developed & validated by comparison to both FEM model and experiments
Model assumptions: 1. Axial symmetry2. Spherical rigid tumor
Model Experiments SummaryTheoretical Results
Analytic model allows the understanding and optimization of the system
Introduction
7 Model structure Solenoid Geometrical
Parameters
Inductance ModelMagnetic Flux Model
Electrical Circuit Model
,zB z t
, , ,i W R ZR D N N
,S SR L
SI t
Solenoid Current
Solenoid Electrical Parameters
Magnetic Force Model
Mechanical Forces Model
Acoustic ModelAcoustic Sensor
Model
Magnetic Flux Density
Tumor Acceleration
,MF z tMagnetic Force
A t
Acoustic Pressure
, ,P r z t
SN t I tElectromagnetic
Noise
Acoustic Signal
S t
1b
3
1a
2
4
5 6
Model Experiments SummaryTheoretical Results
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Magnetic flux generated by a solenoid
Introduction Model Experiments Summary
Axial magnetic flux of a single current loop:
For multiple windings - integrate with respect to z and R:
For the flux gradient - differentiate with respect to z :
Theoretical Results
Results
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Magnetic forces acting on the tumor
The magnetic body force on the entire tumor results from minimal energy considerations:
Langevin dynamics predicts the magnetization of the tumor volume:
Introduction Model Experiments SummaryTheoretical Results
Results
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Mechanical forces & The equation of motion Mechanical forces are surface forces:
• Elastic retention force of the displaced tissue• Drag force due to tumor speed
Under the assumptions of rigid and spherical tumor the two forces can be expressed as:
Introduction Model Experiments Summary
Combining all three force together with Newton's second law yields a non linear, second order differential equation:
Theoretical Results
Results
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Acoustic pressure fieldThe acoustic pressure field is calculated by the scalar wave equation. Tumor induced motion creates an acoustic dipole source term.
Solution by separation of variables:
Introduction Model Experiments SummaryTheoretical Results
Results
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Acoustic sensor model
Introduction Model Experiments SummaryTheoretical Results
1. Acoustic signal proportional to the acceleration of the skin:
The measured signal from the acoustic sensor is due to:
2. Additive EM noise from the solenoids: NEM(t)=Is(t)*Hm
3. Additive measurement white noise: Nw(t)
The sum is convolved with the sensor transfer function: Hs
Results
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Simulated magnetic flux density
Introduction Model Theoretical Results Experiments Summary
The model and FEM both predicts the rapid decay of the magnetic field
FEM confirms that the effect of deviations from the symmetry axis is small
Model
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Simulated magnetic force
Introduction Model Theoretical Results Experiments Summary
For the magnetic flux operating point, the magnetization is well within the linear range
Maximal force is achieved 0.5 mm after the solenoid. The magnetic force decays exponentially with distance.
Model
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Simulated time-varying forces
Introduction Model Theoretical Results Experiments Summary
Force amplitude varies from 20 N/m3 up to 200 N/m3 and higher. The magnetic force is the dominant force. The elastic force determines the equilibrium displacement.
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Simulated motion of the tumor
Introduction Model Theoretical Results Experiments Summary
The displacement is practically constant & in the nm scale. The velocity is one order of magnitude higher (still very small). The acceleration is much higher and measurable.
Model
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Simulated pressure field
Introduction Model Experiments SummaryTheoretical Results
Tumor location
Traveling
wave
Standing wave
Model
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Simulated acoustic signal
Introduction Model Experiments SummaryTheoretical Results
The acoustic signal presents a series of alternating peaks. for deeper the tumors, the peaks are smaller and more spread. Also, the delay is greater.
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Experimental setup I
Introduction Model Experiments DiscussionTheoretical Results
Aim: measurement of the electrical properties of the solenoids Method : Inductance was measured at 36 kHz using a Wheatstone bridge circuit.
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Experiment I - results
Introduction Model Experiments DiscussionTheoretical Results
Solenoids 1,2 do not fit the model predictions due to problems in production. Solenoids 3,4 accurately fit the model (less 5% error)
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Experimental setup II
Introduction Model Experiments DiscussionTheoretical Results
Aim: measurement of the magnetic field of the solenoids
Method : Measurements were taken using a fluxmeter at various points in space with different axial and radial distances.
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Experiment II - results
Introduction Model Experiments SummaryTheoretical Results
Solenoids 3,4 generate almost equal magnetic fields which are in accordance with the model. Deviations from the 95% confidence intervals only occur close to the solenoids due to fringe effects.
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Experiment II - results - cont.
Introduction Model Experiments SummaryTheoretical Results
The radial dependence of the magnetic field is negligible (less then 5% at 5 mm radial distance). This effect allows the calculation of the field only on the symmetry axis.
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Experimental setup III
Introduction Model Experiments SummaryTheoretical Results
Aim: measurement of the magnetic force acting on MNPs immersed in a diamagnetic solution (Feridex®).Method : MNP solution was weighted with an accurate laboratory weight.
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Experiment III - results
Introduction Model Experiments SummaryTheoretical Results
Again, measurements correlate very well with the theoretical model. Small deviations only occur at close distances. The magnetic force decays rapidly (faster then a mono-exponent) affecting the depth of detection
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Experimental setup IV
Introduction Model Experiments SummaryTheoretical Results
Aim: measurement of the acoustic signal received from a phantom of the tissue and MNP conjugated tumor.Method : Measurements were performed on an agar tissue phantom inside an acoustic bath. Signal was measured without magnetic field, without tumor phantom and with both.
DC PSU
Modulator
Amplifier
Oscilloscope A\D
ch1 ch2
Signal
Acoustic sensor
Solenoid 1
Solenoid 2
Trigger
Power
Acoustic bath + tumor phantom
27 Experiment IV - results
Introduction Model Experiments SummaryTheoretical Results
Estimation of the EM noise using a 10-th order moving average is good at low frequencies. The estimated acoustic signal is a bit noisy but still clearly presents the typical peak structure predicted by the model.
28 Experiment IV - results - cont.
Introduction Model Experiments SummaryTheoretical Results
The Root Mean Square of Differences between the estimated acoustic signal and the model is 8%. Comparing the model with the estimated acoustic signal in the absence of the tumor phantom results in an RMSD measure of 35%!
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Summary1. Magneto-Acoustic detection was proved to be feasible
both theoretically and experimentally 2. Extensive analytic and numeric models were developed3. Based on the analytic model an experimental setup
was optimized and built4. The model predict accurately the results of all
laboratory experiments5. Magneto-Acoustic detection shows great promise for
quick detection of deep tumors (up to a few cm beneath the skin)
Introduction Model Experiments SummaryTheoretical Results
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Future WorkThree main goals to be achieved:
1. Estimation of tumor parameters: size depth location (e.g. by triangulation)
2. increase test efficiency (higher fields, multiple sensors, robust signal processing algorithm)
3. In-vitro & In-vivo experiments up to clinical trials
Introduction Model Experiments SummaryTheoretical Results
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Reference1. Parkin, D. M. et al. CA Cancer J Clin 2005;55:74-108.2. J. L. Mulshine, M.D. and D. C. Sullivan, M.D. N Engl J Med 2005;352:2714-20.3. Kakinuma R. et al. Proceedings of the Lung Cancer Workshop, Tokyo,
November 7, 2003:18.4. Kalambur V S, Han B, Hammer B E, Shield T W and Bischof J C 2005 In vitro
characterization of movement, heating and visualization of magnetic nanoparticles for biomedical applications Nanotechnology 16 1221–33
5. Akira I. et al. Magnetite nanoparticle - loaded anti-HER2 immunoliposomes, for combination of antibody therapy with hyperthermia, Cancer Letters 212 (2004) 167–175
6. Shinkai M. et al. Targeting Hyperthermia for Renal Cell Carcinoma Using Human MN Antigen specific Magnetoliposomes. Jpn. J. Cancer Res. 92, 1138–1146, 2001
7. Biao L.E. et al , Preparation of tumor-specific magnetoliposomes and their application for hyperthermia, Chem. Eng. Jpn, 2001
Introduction Model Experiments SummaryTheoretical Results
Introduction
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Super-Paramagnetic Nano-Particles (MNPs)
Ferromagnetic: High magnetization, Many domains, HysteresisSuper-paramagnetic: High magnetization, 1 domain, No hysteresis
Model Experiments SummaryTheoretical Results
Introduction
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Tumor Targeting MNPs are made of iron oxide core (~10 nm diameter) with
different biocompatible coatings [4]. Nano–particles are small enough to diffuse from the blood vessel
into the tissue. Conjugated antibodies allows for targeting different cancer
types:• HER2 - Breast Cancer[5].• MN - renal cell carcinoma [6]• U251- SP (G22 antibody) - Glioma [7]
Antibody
Coating
SPM Core
Model Experiments SummaryTheoretical Results
Introduction
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Comparison with other MNP based methods
Model Experiments SummaryTheoretical Results
MethodScanTime
s
Accuracy
DepthCostPlacement
MRI scans with MNPs as contrast agents [53]
1/2 Hr1 mmTens of
cmVery High
Special Housing
Thermography withMNP specific heating [15]
1 HrA few mm1 cmLowPoint of Care
Ultrasound scans with PFC [55]
A few minutes
1 cmA few cmLowMedical Center
Ultrasound excitation of asymmetric MNPs with Magnetic measurements [57]
1/2 HrA few mmA few cmHighSpecial Housing
Doppler measurements of magnetically excited MNPs [14]
A few minutes
1 cmA few cmMediumMedical Center
This work - Measurements of pressure waves induced by magnetically excited MNPs
<1 MinUnknownUnknownLowPoint of Care
Introduction
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Solenoid design Solenoid design posses some challenges to the designer:
1.Large number of windings: magnetic field/Ampere ↑, current ↓.2.No good model for inductance.3.Hysteresis loss & eddy currents at the magnetic core, Skin effect, Capacitance between windings
Model Experiments SummaryTheoretical Results
Results
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Solenoid optimization
Introduction Model Theoretical Results Experiments Summary
The model predicts an optimal number of windings. Optimization criterion was maximal force applied on 3cm deep tumor.
Model
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Limitations1. High Electro-Magnetic noise limits
measurement accuracy. A possible solution is the use of an acoustic waveguide to distance the sensor.
2. The method only applies to solid tumors, with known specific antigens.
3. Organs filled with air or other fluids will block the acoustic signal
Introduction Model Experiments SummaryTheoretical Results
Breast tissue is flattened out between the two solenoid Breast tissue is flattened out between the two solenoids in a similar
fashion to mammography. Then an alternating magnetic field is applied. A single or multiple acoustic sensors can then pick the
signal on the breast surface. s in a similar fashion to mammography. Then an alternating magnetic field is applied. A
single or multiple acoustic sensors can then pick the signal on the breast surface.
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Example application
Introduction Model Experiments SummaryTheoretical Results
Breast tissue is flattened out between the two solenoids in a similar fashion to mammography. Then an alternating magnetic field is applied. A single or multiple acoustic sensors can then pick the signal on the breast surface.