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)