tumor detection using antibodies conjugated magnetic nanoparticles arie levy, israel gannot...
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Tumor detection using antibodies conjugated magnetic nanoparticles
Arie Levy, Israel GannotBiomedical Engineering Department Tel Aviv University Israel
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Thermography
First Introduced at 1956 [1] Increased angiogenesis and
metabolism around tumors [2] Temperature rise at the skin surface
above the tumor. Detection by IR cameras. Computer aided
detection
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Thermography - cont
Advantages: [2]Radiation freeContact freeNon InvasiveLow Cost
DisadvantagesLow sensitivity for small & deep tumors [3]Not tumor specificSubjective
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Detect & Treat Approach
Antibody conjugated MNP solution
Tumor
Low power external AMF
IR Camera, used as a detector
Tumor + accumulated MNP
1. MNP Injection 2. Tumor Detection
High power external AMF
IR camera used as a sensor for feedback
3. Treatment
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TBT vs. Thermography
The heat can be turned on and off – good reference can be achieved
The heat emanating from the tumor is considerably larger.
The heat source is tumor specific. Objective- no need for special skills. Treatment can be combined at the
same session.
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Magnetic Nanoparticles[4]
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Magnetic Nanoparticles
Coil
Magnetic Nanoparticl
es
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Magnetic Nanoparticles
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Targeting Small enough to diffuse from blood
vessel Antibodies targeting Binding sites
HER2 – Breast Cancer[5]. MN – renal cell carcinoma [6] U251-SP (G22 antibody) – Glioma [7]
Antibody
Coating
Magnetic Nanoparticle
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Experiment Setup
DAQ unit
70x40mm glass cup filled with US Gel
0.5mm polymeric cover
DC power supply
Micrometer stage
1KΩ SMT resistor
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Experiment Setup – cont.
Tumor Phantom
Tissue Phantom
IR Camera
RF Generator
Coil
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Problem Definition & Assumptions
Small tumor (<5mm) – point heat source. The tissue was numerically modeled using
COMSOL according the Pennes bioheat equation [8]:
Thermal properties – conductivity , perfusion . metabolism – are assumed.
Unknown Location (X,Y, Depth).
Tumor
Tissue Surface
Tissue
D2mm
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Tumor Detection Challenge
The temperature difference at the tissue surface is very low regarding measurement noise level
Without Noise
With Noise
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Detection Protocol
1. Reference data is recorded.2. Magnetic field/heat source is turned
on.3. Sequence of IR images is recorded.4. The data is processed using MATLAB in
order to detect the tumor and its location.
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Detection Algorithm
Time Averaging
Pre calculated estimation
Input
data set
Reference
data set
Hot Spot Detection
Noise Filtering
Hot Spot Classification
Tumor size & location
Pre Processing
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Pre Processing
Original IR Data Original Data Minus Reference Data
Region of Interest SelectionFiltered Data
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Hot Spot Selection
ROI border
“True” Hot Spot
“False” Hot Spot
Y
X
Tem
pera
ture
cha
nge
[Deg
C]
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Hot Spot Classification
Tem
pera
ture
cha
nge
[Deg
C]
YX
2mm Hot Spot
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Hot Spot Classification T
empe
ratu
re c
hang
e [D
eg C
]
YX
12mm Hot Spot
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Hot spot classification
Normalization of each prediction to the hot spot data.
Calculating matching value for each prediction:
Thresholding. Interpolation. Depth estimation according to maximum
matching.
2),,(
2),,,,(1
k i j kjidkw
kjipk i j kjidkwMv
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Hot Spot Classification
Recorded Temperature change
Normalized predicted temperature change for tumor depths 1-10[mm]
Best match: 4mm prediction
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Hot Spot Classification
Max at 4mmDetection Threshold
Prediction Depth [mm]
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Experiments
Setup 1 (US gel):3 different emitted powers. Up to 14mm depth.Idle (“no tumor”) measurement.
Setup 2 (Procine).Validation using 3mm depth tumor.
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Training
140 measurements for idle (“no tumor”) and worst case (13mm 400mW) states.
0 0.001 0.002 0.003 0.004 0.005 0.006 0.007 0.008 0.009 0.010
0.05
0.1
0.15
0.2
0.25
Peak value [K]
Pro
babi
lity
Idle and worst case stats distribution of peak value
Tumor set
Tumor gaussian fitIdle set
Idle gaussian fit
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Sensitivity & Specificity
Specificity:98.68%
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Depth Estimation
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Other Results Low power detection.
Procine model validation.
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Magnetic Acoustic Detection -MAD
Magnetic coil
Pulsed magnetic field
Tissue
Magnetically marked tumor
Acoustic shock wave
Acoustic sensor
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MAD - Simulation
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MAD – Experimental Setup
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MAD - Results
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Summary
TBT Up to 14mm detection was demonstrated. Sub-millimeter tumors can be detected. Highly specific detection. Limited to near to surface tumors.MAD Potentially could detect deeper tumors. Simple setup.
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Future work TBT:
Algorithm refinement.In vivo validation.
MADProof of concept.Setup improvement.
Treatment.Rotating Magnetic field.Double conjugation.
Treatment. Additional imaging modalities. Endoscopic Imaging. Subsurface imaging. In Vivo Experiments.
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Thank You…
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Reference1. R. N. Lawson. Implications of surface temperature in thediagnosis of breast cancer. Canada Med Assoc J, 75:309–310, 19562. WC Amalu. Infrared imaging of the breast – an overview.
Medical device and systems, cahpter 25, 2006 3. Statement on use thermography to detect breast cancer,
NBCC, 1999, www.nbcc.org.au.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
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Reference5. Akira Ito et al. Magnetite nanoparticle-loaded anti-HER2
immunoliposomes, for combination of antibody therapy with hyperthermia, Cancer Letters 212 (2004) 167–175
6. M Shinkai et al. Targeting Hyperthermia for Renal Cell Carcinoma Using Human MN Antigenspecific Magnetoliposomes. Jpn. J. Cancer Res. 92, 1138–1146, 2001
7. Biao LE et al , Preparation of tumor-specific magnetoliposomes and their application for hyperthermia, Chem. Eng. Jpn, 2001
8. HH Pennes. Analysis of Tissue and Arterial Blood Temperatures in the Resting Human Forearm. Journal of Applied Physiology, 1948