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Biophotonics and medical imaging Johannes F. de Boer* Director Institute LaserLaB Professor Physics Department, VU University, Amsterdam and Rotterdam Ophthalmic Institute *Commercial interest: Intellectual property
The impact of physics on imaging in healthcare Anna Berthe Röntgen: Hand mit Ringen Wilhelm Röntgen's first "medical" x-ray, of his wife's hand, taken on 22 December 1895
X-Ray, CT, MRI, PET, Ultrasound These techniques are a mainstay of medical imaging
Currently used medical imaging methods Radiology 1 mm
1 cm Radio nucleotide DOT PET
MRI CT US
Pathology 10 µm 1 µm
100 µm
LIGHT, e.g., Microscopy OCT
HFUS MRI X-Ray, CT
Diagnostic capability Low resolution
Organ Level
Organ Level Tumor Staging
Architectural, Cellular, Optical Biopsy
Histopathology is the golden standard especially for cancer diagnosis DOT: Diffuse Optical Tomography; PET: Positron Emission Tomography; MRI Magnetic Resonance Imaging; CT: Computed Tomography; US: Ultra Sound; HFUS: High Frequency Ultra Sound; OCT: Optical Coherence Tomography.
OCT is analogous to ultrasound imaging Uses infrared light in stead of sound Speed of sound ~ 1480 m/sec (in water) Speed of light – 3x108 m/sec
Human skin 5 mm wide x 1.6 mm deep Resolution: 10-30 µm Interferometry is used to measure small time delays of scattered photons
Principle of OCT
B-Scan
A-line
Low-Coherence Interferometry Reference Sample
Source
Detector Low-Coherence Source! Detector!
Detector!
Coherent Source! λ!
Mirror Displacement!
Coherence! Length!
Mirror Displacement!
Low Coherence Fringe 2λ ln 2 0.44 λ0 FWHM = Lc = 0 = π Δλ Δλ 2
λ3
λ2
λ1
0
ΔL
2
The human eye
OCT in ophthalmology: Fercher and Fujimoto groups (early 1990’s) High resolution OCT: Fujimoto, Drexler (late 1990’s)
Measurements
Example: • 1 OCT B-scan in 6 s • 1536 A-lines per B-scan • 1024 pixels / A-line • dynamic range ~35 dB
• resolution in depth 6 !m • resolution in width ~ 20-30 !m • 32 video frames / 6 s • B-scans post processed to remove motion artifacts
Time Domain and Spectral Domain OCT configurations Fujimoto (1991)
Huang, D., Swanson, E.A., Lin, C.P., Schuman, J.S., Stinson, W.G., Chang, W., Hee, M.R., Flotte, T., Gregory, K., Puliafito, C.A., and Fujimoto, J.G., Optical coherence tomography. Science, 1991. 254(5035): p. 1178-81.
Fercher (1995) Source
Fiber
50/50 Reference arm Splitter Sample arm
Grating Detector array
Lens
mirror
Spectrum to PC for processing
Lens Grating
A. F. Fercher, C. K. Hitzenberger, G. Kamp, and S. Y. El-Zaiat, “Measurements of intraocular distances by backscattering spectral interferometry,” Opt. Comm. 117, 43-48 (1995).
Detector Array (CCD)
SD-OCT I (k ) = I r (k ) + 2 I s (k ) I r (k ) ∑ α n cos( k z n ) + I s (k ) n
FFT
[
]
⎧ 2 2 2 2 ⎫ FT [ I (k )] = Γ ( z ) ⊗ ⎨δ (0) + ∑ α n δ ( z − z n ) +∑α n δ ( z + z n ) + O I s I r ⎬ n n ⎩ ⎭ −1
2
2
FFT
SNRSD =
ηPsampleτ i Eν
Experimental verification of sensitivity Experimental SNR TD = 44.3 dB SD = 50 dB
50
TD-OCT 4msec/depth profile SD-OCT 100µsec/depth profile
Theoretical prediction TD = 46.7 dB (QE=0.85, BW = 100kHz SD = 51.9 dB (QE = 0.28, τi = 100 µs)
Signal [dB]
40
Sample arm power = 1.27 nW
30
20
10
SNR difference = 5.7 dB
0
SNR benefit = 5.7 + 16 = 21.7 dB
0
200
400
600
Depth [µm]
Demonstrated SNR improvement of 21.7 dB (factor of 150) N. Nassif et al. Optics Letters 29 (5), 480 (2004)
First video rate images of the human retina (2003-2004)
Width 6.4 mm, depth 1.7 mm, 1000 depth profiles
2x Magni fied
N. A. Nassif et al., Opt. Express 12, 367-376 (2004)
UHR-SD-OCT Fovea
6 x 6 mm
6 x 1.1 mm
B. Cense et al. Opt. Express 12, 2435-2447 (2004)
Age related Macular Degeneration (AMD) AMD is the leading cause of blindness in people over age 65 years in Western countries 8 million people affected in the US alone 10% of AMD patients will develop neovascularization under the retinal pigmented epithelium or in the subretinal space Current treatment: anti VEGF therapy Current diagnosis: include Fluorescein Angiography (FA), indocyanine green angiography (ICG), and OCT
70-year-old male, presenting with blurred vision (OD)
70-year-old male (OD) Location 1
A: Drusen, B: Blood clot, C: Subretinal fluid, D: RPE detachment. Image size 7.55 mm x 1.95 mm.
70-year-old male (OD) Location 2
A: Cystic changes, B: Blood clot, C: Weak scattering in photoreceptors, D: Subretinal Fluid, E: Strong scattering in photoreceptors, F: RPE detachment, G: confirmed CNV from FA. The OCT image suggests this is type 1 CNV.
70-year-old male (OD) Location 3
A: Strong scattering from photoreceptors in the periphery of the subretinal fluid. Image size 7.55 mm x 1.95
Optical Doppler Tomography Velocity component parallel to beam = v x cos(θ) Doppler frequency shift: Δf = 2vcos(θ)/λc Velocity: v = Δf λc /2cos(θ)
First ODT demonstration: T. Milner First flow measurement in the eye: Izatt Group
High Resolution Doppler OCT (ODT) Sequential A-lines A-line 1 ΔT
A-line 2
ω=Δφ/ΔT Δφ
Y. Zhao et al. Optics Letters 24: 114-116, 2000.
Phase-resolved OCT angiography
B. Braaf, K.A. Vermeer, K.V. Vienola, J.F. de Boer, Optics Express, 20, 20516-20534 (2012)
Acknowledgement JFdB group members Boy Braaf Jianan Li Mattijs de Groot Joshua Mo Koen Vermeer Frank Helderman Miriam Moester
Clinical collaborators Glaucoma: Hans Lemij AMD: Jan van Meurs Lung: Joop de Langen, Hans Daniels Fluorescence: Guus van Dongen
Past group members Ki Hean Kim Hyle Park Many more
Funding: NWO Groot, FOM NIG project grant, NIH R21, VICI (ZonMW), CORR research funds (ROI), MS foundation (VU/ROI)
