1. Near Infrared Devices in Biomedical Applications Elisabeth S. Papazoglou, Ph.D. School of Biomedical Engineering Drexel University October 2004

2. Outline - BIOMEDICAL PHOTONICS - OPTICAL PROPERTIES OF TISSUE - RADIATIVE TRANSPORT MODEL - Diffusion approximation - NIR WINDOW - PHOTON MIGRATION SPECTROSCOPY - Frequency Domain - ADVANTAGES / DISADVANTAGES - APPLICATIONS - ETHICAL CHALLENGES

3. Biomedical Photonics Biomedical Photonics vs. Biomedical Optics Electromagnetic spectrum – Gamma rays - 10 19 –X-rays - 1nm to 1 Angstrom / 10 18 Hz – Ultra violet - 10 16 - 10 17 Hz – Visible - 10 15 Hz –Infrared (near and far) 1 mm - 1 micron / 10 - 10 12 Hz –Microwave - 1 cm / 10 8 - 10 12 Hz – Radio frequency - 1 m / 10 8 Hz

4. ELECTROMAGNETIC SPECTRUM

6. http://www.phy.ntnu.edu.tw/java/emWave/emWave.html Wave Animation

8. WHAT IS LIGHT ? Classical Viewpoint – Light is a oscillating EM field / E is continuous –Electromagnetic wave Electric / Magnetic Field - Polarization Quantum Viewpoint –Photons - E = h Both representations are used to describe light propagation in tissues

9. WHAT IS LIGHT ? Classical Viewpoint – Light is a oscillating EM field / E is continuous –Electromagnetic wave Electric / Magnetic Field - Phase and Polarization Quantum Viewpoint –Photons - E = h Both representations are used to describe light propagation in tissues

10. Fundamental Optical Properties Index of refraction, n ( ) Scattering Cross Section,  s Differential Scattering Cross Section Absorption cross section,  a

11. Index of Refraction Complex Index of Refraction Index of Refraction = Real Part Phase velocity and wavelength of light in medium Wave Frequency - independent of n

12. 1 2   nn nn

13. Reflection and Refraction Light path redirection due to boundary –Reflection and Refraction –Snell’s Law Normal Incidence REFLECTION

14. TYPES OF REFLECTION Interface Reflection = Fresnel Reflection Diffuse Reflectance –Subsurface origin

15. Scattering Incident Wave Scattered Wave n1n1 n2n2

16. Biomedical Applications - Scattering Diagnostic Applications –Size, Morphology, Structure – Lipid membranes, nuclei, collagen fibers Therapeutic Applications –Optimal Light Dosimetry (Light treatment) - Delivery

17. Scattering Cross Section S is propagation direction of wave relative to scatterer Scattering Coefficient Mean Free Path

18. Absorption Cross Section Absorption Coefficient Absorption Mean Free Path= Absorption length

19. Beer Lambert Law Extinction Coefficient (cm 2 /mol) Molar concentration mol/cm 3 TRANSMISSION ATTENUATION ABSORBANCE

20. Absorption and Emission Absorption Spectrum - Dependence Absorbed Light is dissipated Photon emission Non radiatively / Kinetic energy transfer Luminence Fluorescence, Phosphorescence

21. Coherent and Incoherent Light Coherence –Ability to maintain non random phase relationship in space and time and exhibit stable interference effects Speckle pattern from laser (light amplification by stimulated emission of radiation) Incoherent light –Random spatial and temporal phase patterns – No Interference

22. Rayleigh Limit Tissue structure size << Photon Wavelength –Rayleigh Limit- Scatterer sees uniform electric field - Dipole moment can be mathematically expressed – Elastic scattering / Energy incident photon = Energy Scattering Photon INELASTIC SCATTERING - RAMAN –LOSE ENERGY - STOKES – GAIN ENERGY = ANTI-STOKES 1,000,000 Rayleigh photons for 1 Raman photon

23. Mie Theory Light scattering by spherical objects - – Any size to wavelength ratio Mie regime - where wavelength and scatterer are of the same order of magnitude -Biomedical Applications = 500 to 1000 nm wavelength -Many cellular structures are of similar size

24. Absorption Energy is “extracted” from the light by molecules Diagnostic Applications - Energy Transitions at certain wavelengths - fingerprints Therapeutic Applications - Absorption of energy from a laser is the primary mechanism - Electronic, Vibrational, Rotational Levels

25. Some concepts - Interference Contribution Total Electric Field - Two light scatterers Total Energy = Square of Amplitude  = medium permittivity E 1. E 2 > 0 constructive interference E 1. E 2 < 0 destructivee interference Average Interference E 1. E 2 = 0

26. Multiple Scattering L L

27. Mutliple Scattering - “Decoherence” Radiation Transport Model Power Scattered Out of Incident Wave Remaining power after passing through layer Meaning of What is it if it is zero???

28.  Layers in length L of thickness deltaz As  increases --- exponential convergence No absorption - Power Expansion

29. Limiting Cases When can we say Waves Scattered only Once Multiple versus Single Scattering

30. Radiation Transport (Boltzmann Equation) DYNAMICS

31. dA r dd  Light power - Specific intensity I

32. Incident and Diffuse Light Coherent Light Coherent and Incoherent Light

33. Incident and Diffuse Light - Single scattering 0 at steady state 0 = ignore multiple scattering

34. Absorption Dominant Limit Straight line path of length s parallel to s^ is ---- Remember????

35. Scattering Phase Function SPF = Fraction of light scattered in s from incidence at s’ G= average cosine of scatter = measure of scatter retained in the forward direction

36. Limits of g g=0 for Rayleigh scattering –Forward and backward scattering are equally probable g > 0 g< 0 G is an “anisotropy measure”

37. Scattering Dominant Limit: The Diffusion Approximation Reduced Scattering Coefficient Diffusion Coefficient Attenuation of medium

38. Diffusion Equation Total Intensity Angular Dependence of specific intensity Net Intensity Vector Fick’s Law

39. Discussion Points Human Tissue -Effective Refractive Index Water - Index? Compare to other constituents? Melanin - ? Whole tissue ? Brain / Kidney? Tooth ?? Index mismatch between lipids and cytoplasm

40. Scattering Properties Size of organelles in cells = 100 nm -6 micron Mitochondria are primary scatterers - 0.5-2 microns Cell Nucleus = 4-6 micron in range Melanosomes are 100 nm to 2 microns Erythrocytes = 2 micron thick / 7-9 micron in diameter

41. Absorption Properties Therapeutic Window - 600-1300 nm Orange to NIR 600 region - hemoglobin / oxy and deoxy < 600 DNA, Tryptophan and Tyrosine 900 -1000 Water Absorption is very strong

42. Importance of Diffuse Light Diffuse reflectance Volume of tissue sampled Information about the bulk of the medium Limits of –Absorption Dominant Region – Scattering Dominant Region - Diffusion Approximation

45. Melanosomes for light skinned caucasians, fv = 1-3% for well-tanned caucasions and Mediterraneans, fv = 11-16% for darkly pigmented Africans, fv = 18-43%. [Jacques 1996]:

47. Photon Migration Spectroscopy Combine experiments with model based data analysis Absorption and scattering of highly scattering media 600-1000 nm Photons propagate randomly Incoherent photons Probes tissue vasculature BROAD MEDICAL APPLICATIONS

48. FREQUENCY DOMAIN INSTRUMENTS PHASE SHIFT  MODULATION DECREASE = RATIO OF DC/AC FREQUENCY OF OSCILLATION REMAINS THE SAME AB = Absorbance L=Photon Path length (cm) [C]= Absorber Concentration  is the molar extinction coefficient moles/liter cm -1 or cm 2 /mole What is L???

49. IMPORTANT POINTS Absorption and scattering coefficicents Rayleigh Limit / Mie Theory / Mie regime Define g - g = 0, g positive, g negative Extinction Coefficient Diffusion and Absorption Approximation Diffuse Reflectance Spectroscopy Therapeutic Window Melanin as a confounding factor Applications of NIR - Limitations