Series in Optics and Optoelectronics

An Introduction to Biomedical Optics

R Splinter Analytica Sciences, Inc. Concord, North Carolina, USA

B A Hooper Arete Associates Arlington, Virginia, USA

>£,) Taylor & Francis Taylor & Francis Group

New York London

Taylor & Francis is an imprint of the Taylor & Francis Group, an informa business

Contents

Section I General Biomedical Optics Theory

1 Introduction to the Use of Light for Diagnostic and Therapeutic Modalities 3

1.1 What Is Biomedical Optics? 3 1.2 Biomedical Optics Timeline 4

1.2.1 Elementary Optical Discoveries 4 1.2.2 Development of Optical Devices 6 1.2.3 Scientific Advancements in Optics Theory 9

1.3 Historical Events in Therapeutic and Diagnostic Use of Light 14 1.3.1 Development of Therapeutic Applications of

Light in Medicine 14 1.3.1.1 Development of Diagnostic Optical Applications 17

1.4 Light Sources 18 1.5 Current State of the Art 19 1.6 Summary 20

2 Review of Optical Principles: Fundamental Electromagnetic Theory and Description of Light Sources 23

2.1 Definitions in Optics 23 2.2 Kirchhoff's Laws of Radiation 27

2.2.1 Planck Function for BlackBody Radiation 28 2.3 Electromagnetic Wave Theory 30

2.3.1 Gauss's Law 30 2.3.2 Faraday's Law 32 2.3.3 Maxwell Equations 33 2.3.4 Energy and Momentum of Electromagnetic Waves 35 2.3.5 Coherence of Electromagnetic Waves 36

2.3.5.1 Temporal Coherence 36 2.3.5.2 Spatial Coherence 37

2.3.6 Interference of Electromagnetic Waves 37 2.3.7 Phase Velocity 38 2.3.8 Group Velocity 38 2.3.9 Cauchy Theorem 39

2.3.10 Electromagnetic Wave Spectrum 42 2.3.10.1 Television and Radio Waves 42 2.3.10.2 Microwaves Waves 42 2.3.10.3 Infrared Waves 42 2.3.10.4 Visible Light Waves 42 2.3.10.5 Ultraviolet Waves 43 2.3.10.6 X-Ray Waves 43 2.3.10.7 Gamma Radiation Waves and Cosmic Rays 43

2.4 Light Sources 44 2.4.1 Broadband Light Sources 45 2.4.2 Laser Operation 46

2.4.2.1 Einstein Population Inversion 47 2.4.2.2 Achieving a Metastable State 50 2.4.2.3 Harnessing the Photons in the Laser Medium 51 2.4.2.4 Amplification 52

2.4.3 Laser Light Sources 53 2.4.3.1 Chemical Laser 53 2.4.3.2 Diode Laser or Semiconductor Laser 54 2.4.3.3 Dye Laser 55 2.4.3.4 Gas Laser 56 2.4.3.5 Solid-State Lasers 57 2.4.3.6 Free-Electron Laser (FEL) 58

2.5 Applications of Various Lasers 61 2.6 Summary 63

3 Review of Optical Principles: Classical Optics 69

3.1 Geometrical Optics 69 3.1.1 Huygens' Principle 70 3.1.2 Laws of Geometrical Optics 70

3.1.2.1 Law of Rectilinear Propagation 71 3.1.2.2 Law of Reflection 71 3.1.2.3 Law of Refraction (Snell's Law) 72 3.1.2.4 Law of Diffraction 73 3.1.2.5 Law of Conservation of Energy 78

3.1.3 Fermat's Principle 78 3.1.4 Ray Optics 78

3.1.4.1 Critical Angle 80 3.1.4.2 Brewster Angle of Polarization 80 3.1.4.3 Lens Makers' Equation 82 3.1.4.4 Optical Instruments 84

3.2 Other Optical Principles 85 3.2.1 Dispersion 85

3.3 Quantum Physics 85 3.3.1 Schrödinger Equation 86

3.4 Gaussian Optics 87

3.4.1 Matrix Methods in Gaussian Optics 88 3.4.2 Fourier Optics 90

3.5 Summary 91

4 Review of Optical Interaction Properties 95

4.1 Absorption and Scattering 95 4.1.1 Light and Atom Interaction Overview 95 4.1.2 Absorption 97

4.1.2.1 Classical Theory of Absorption 97 4.1.2.2 Lorentz Model 98 4.1.2.3 Beer-Lambert-Bouguer Law of Absorption 99

4.1.3 Scattering 99 4.1.3.1 Rayleigh Scattering 99

4.1.4 Mie Scattering 101 4.1.4.1 Scattering Phase Function 101

4.1.5 Raman Scattering 101 4.1.5.1 Simple Atom and Molecule Models 102 4.1.5.2 Material Polarization 109 4.1.5.3 Biochemistry Applications 114

4.2 Doppler Effect 115 4.3 Summary 118

5 Light-Tissue Interaction Variables 121

5.1 Laser Variables 121 5.1.1 Laser Power 121 5.1.2 Light Delivery Protocol 121 5.1.3 Power Density Profile of the Beam 125 5.1.4 Gaussian Beam Profile 126 5.1.5 Top-Hat Beam Profile 127 5.1.6 Irradiation Spot Size 128 5.1.7 Power Density and Energy Density of a Light Source 129 5.1.8 Local Beam Angle of Incidence with the Tissue 130 5.1.9 Collimated or Diffuse Irradiation 130 5.1.10 Light Wavelength 132 5.1.11 Repetition Rate 132 5.1.12 Pulse Length 132 5.1.13 Light Delivery Pulse Modulation 132

5.2 Tissue Variables 133 5.2.1 Optical Properties of the Tissue 133

5.2.1.1 Tissue Index of Refraction 134 5.2.2 Surface Contour 135 5.2.3 Tissue Temperature 135 5.2.4 Thermodynamic Tissue Properties 135 5.2.5 Tissue Blood Flow and Blood Content 136

5.3 Light Transportation Theory 137

5.3.1 The Time-Dependent Angular and Spatial Photon Energy Rate Distribution 138

5.3.2 Steady-State Angular and Spatial Photon Energy Rate Distribution 140

5.3.3 Boundary Conditions 140 5.3.4 Radiation Definitions for Turbid Media 140

5.3.4.1 Photon Power Related to Radiance 140 5.3.4.2 Radiance Incident on a Volume (Fluence Rate) 141 5.3.4.3 Photon Power Density in Medium 141 5.3.4.4 Photon Radiative Flux 141 5.3.4.5 Photon Radiation Pressure 141 5.3.4.6 Penetration Depth 142

5.4 Light Propagation under Dominant Absorption 142 5.4.1 Description of Angular Distribution of Scatter 142

5.5 Summary 146 5.6 Nomenclature 146

6 Light-Tissue Interaction Theory 155

6.1 Approximations of the Equation of Radiative Transport 155 6.1.1 Spherical-Harmonics Substitution Method to Solve the

Equation of Radiative Transport 155 6.1.1.1 Taylor Expansion of Radiance 156

6.1.2 Diffusion Approximation of the Equation of Radiative Transfer 158 6.1.2.1 Isotropie Source Solution 166

6.1.3 Discrete-Ordinate Method for Solving the Equation of Radiative Transport 166 6.1.3.1 Two-Flux Theory 166 6.1.3.2 Three-Flux Theory 173 6.1.3.3 Special Situation for Infinite Slab 176

6.1.4 Light Distribution under Infinite Wide Beam Irradiation 177 6.1.5 Numerical Method to Solve the Equation of Radiative

Transport 177 6.2 Summary 177

7 Numerical and Deterministic Methods in Light-Tissue Interaction Theory 181

7.1 Numerical Method to Solve the Equation of Radiative Transport ....181 7.1.1 Monte Carlo Simulation 182

7.1.1.1 Simulation Process 182 7.1.1.2 Light-Tissue Interaction Model 186 7.1.1.3 Random Walk Model 187 7.1.1.4 Light Propagation Model Components 190

7.2 Measurement of Optical Parameters 195 7.2.1 Invasive Techniques 197

7.2.1.1 Integrating Sphere Measurements 197 7.2.1.2 Fiberoptic Probing to Determine the

Optical Properties 201 7.2.2 Noninvasive Techniques 203

7.2.2.1 Specular Reflectance Measurement 203 7.2.2.2 Diffuse Backscatter Measurement by CCD

Camera Imaging 203 7.2.2.3 Diffuse Backscatter by Fiberoptic Area

Measurement 206 7.2.2.4 Diffuse Backscatter Measurement by

Interferometric Probing 207 7.2.2.5 Diffuse Forward Remittance Measurement 207 7.2.2.6 Diffuse Forward Scatter Measurement by

CCD Camera Imaging 207 7.2.2.7 Time-Resolved Reflectance and Transmittance

Measurement 208 7.3 Temperature Effects of Light-Tissue Interaction 211

7.3.1 The Bioheat Equation 212 7.3.2 Computer Modeling of Absorption, Heat Dissipation,

and Photocoagulation 213 7.3.3 Damage Integral 213 7.3.4 The Damage State 214

7.4 Summary 214

8 Light-Tissue Interaction Mechanisms and Applications: Photophysical 219

8.1 Range of Photophysical Mechanisms 219 8.2 Photoablation 220

8.2.1 Ablation Threshold 221 8.2.2 Pulsed Laser-Tissue Interaction 222 8.2.3 Pulsed Vaporization 223 8.2.4 Definition of a Pulsed Laser 227 8.2.5 Ultraviolet Laser Ablation 228

8.2.5.1 Photochemical Breakdown 228 8.2.5.2 Rate of Bond-Breaking 230 8.2.5.3 Bond-Breaking Depth 231 8.2.5.4 Gas Production during Photoablation 232

8.3 Photoacoustics 233 8.3.1 History of the Photoacoustic Effect 233 8.3.2 The Photoacoustic Effect 234

8.3.2.1 Displacement 236 8.3.2.2 Sound Propagation 238

8.3.3 Detection of the Photoacoustic Signal 241 8.3.4 Theory of Photoacoustic Wave Propagation 241 8.3.5 Electromechanical Effects during Photoacoustic Interaction ....242

8.4 Birefringence Effects 243 8.4.1 Schlieren Imaging 244 8.4.2 Conventional Töepler Schlieren Configuration 248 8.4.3 Ronchi Ruling Focusing Schlieren Configuration 249

8.5 Polarization Effects 250 8.5.1 Polarization in Nature 251 8.5.2 Polarization in Medical Imaging 252

8.6 Optical Activity 253 8.6.1 Glucose Concentration Determination 256

8.7 Evanescent Wave Interaction in Biomedical Optics 257 8.7.1 Evanescent Optical Waves 257 8.7.2 Precise, ControUed Light Delivery with Evanescent

Optical Waves 261 8.7.3 Tissue Ablation with FEL-Generated Evanescent

Optical Waves 264 8.8 Phase Interference Effects 268

8.8.1 Interferometry in Medical Imaging 268 8.9 Spectroscopy 269

8.9.1 Light Scattering Spectroscopy (LSS) 269 8.9.2 Fourier Transform Infrared (FTIR) Spectroscopy 270 8.9.3 Ultrafast Spectroscopy 271 8.9.4 Time-Resolved Spectroscopy 271 8.9.5 Raman Scattering Spectroscopy 271 8.9.6 Coherent Anti-Stokes Raman Spectroscopy 279 8.9.7 Time-Resolved Raman Spectroscopy 279 8.9.8 Raman Spectroscopy Advantages and Disadvantages 280

8.10 Endoscopy 281 8.10.1 Light Delivery with Optical Fibers 282 8.10.2 Medical Applications Using Endoscopy 282

8.10.2.1 Arthroscopy 282 8.10.2.2 Bronchoscopy 283 8.10.2.3 Cardiology 283 8.10.2.4 Cystoscopy 283 8.10.2.5 Fetoscopy 283 8.10.2.6 Gastrointestinal Endoscopy 283 8.10.2.7 Laparoscopy 284 8.10.2.8 Neuroendoscopy 284 8.10.2.9 Otolaryngology 284

8.11 Summary 284

9 Light-Tissue Interaction Mechanisms and Applications: Photochemical 289

9.1 Basic Photochemical Principles 289 9.1.1 Photosynthesis 290 9.1.2 SunTanning 291 9.1.3 Light-Reactive Biological Chromophores 291

9.2 Photochemical Effects 291 9.2.1 Photodynamic Therapy 292

9.2.1.1 The Photosensitizer Excitation Process 292 9.2.1.2 The Role of Oxygen 294 9.2.1.3 Mechanisms in PDT to Induce Cell Death 295 9.2.1.4 Light Delivery 296 9.2.1.5 Photosensitizers 297 9.2.1.6 Dosimetry 300 9.2.1.7 Clinical Applications 305 9.2.1.8 Light Sources 310 9.2.1.9 Advantages of PDT 311 9.2.1.10 Disadvantages and Limitations 312

9.2.2 WoundHealing 312 9.3 Summary 314

10 Light-Tissue Interaction Mechanisms and Applications: Photobiological 317

10.1 Photobiological Biostimulation 317 10.2 Photobiological Effects 320

10.2.1 Photothermal 321 10.2.1.1 Photocoagulation 321 10.2.1.2 Reversible Photocoagulation 322 10.2.1.3 Irreversible Photocoagulation 322 10.2.1.4 Damage Integral 325

10.2.2 Medical Applications of the Photothermal Effect 327 10.2.2.1 Thermal Effects in Treatment of

Port-Wine Stains 327 10.2.2.2 Tissue Closure and Welding 333 10.2.2.3 Current Tissue Closure Methods 335

10.2.3 Photobiological Nonthermal Interaction 335 10.3 Excitation of Chromophores 335 10.4 Optic Nerve-Cell Depolarization under the Influence of

Light (Vision) 336 10.4.1 Quantum Photon Dots as Biological

Fluorescent Markers 337 10.4.2 Optical Properties of Quantum Dots 337

10.5 Summary 339

Section II Therapeutic Applications of Light

11 Therapeutic Applications of Light: Photophysical 345

11.1 Delivery Considerations 346 11.2 Pulsed Laser Use in Cardiology 349

11.2.1 Pulsed Laser-Tissue Interaction 349 11.2.1.1 Ablation Rate 351

11.2.2 Laser Plaque Molding (Angioplasty) 354

11.2.3 Laser Thrombolysis 354 11.2.4 Laser Valvulotomy and Valve Debridement 354 11.2.5 Transmyocardial Revascularization 356

11.3 Dentistry and Oral Surgery 359 11.3.1 Photo Curing 359 11.3.2 Dental Drill 359 11.3.3 Etching 361 11.3.4 Tooth Hardening 362 11.3.5 Scaling 362

11.4 Ophthalmology 362 11.5 Optical Tweezers 364

11.5.1 Rayleigh Regime Particle Force 367 11.5.2 Mie Regime Particle Force 368 11.5.3 Size Region between the Rayleigh and Mie Regime 371 11.5.4 Applications of Optical Tweezers 373

11.6 Summary 373

12 Therapeutic Applications of Light: Photochemical 377

12.1 Vascular Welding 377 12.2 Cosmetic Surgery 378

12.2.1 Inflammatory Disease Lesion Treatment 380 12.2.2 Pigmented Lesion Treatment 382

12.3 Oncology 384 12.3.1 Photodynamic Therapy 384

12.4 Summary 388

13 Therapeutic Applications of Light: Photobiological 389

13.1 Cardiology and Cardiovascular Surgery 389 13.1.1 Arrhythmogenic Laser Applications 389 13.1.2 Laser Photocoagulation 391 13.1.3 Arrhythmie Node Ablation 401 13.1.4 Atrial Ablation 401

13.2 Soft Tissue Treatment 402 13.3 Dermatology 402

13.3.1 Vascular Lesion Treatment 403 13.4 Fetal Surgery 407 13.5 Gastroenterology 409 13.6 General Surgery 410 13.7 Gynecology 411 13.8 Neurosurgery 411 13.9 Ophthalmology 412 13.10 Pulmonology and Otorhinolaryngology 413 13.11 Otolaryngology, Ear, Nose and Throat (ENT), and

Maxillofacial Surgery 414 13.12 Podiatry 416

13.13 Urology 416 13.13.1 Lasers in the Treatment of Benign

Prostatic Hyperplasia 417 13.13.1.1 Nd:YAG for Prostate Tissue Ablation 419 13.13.1.2 Contact Tip Technology for Prostate

Ablation 419 13.13.1.3 Free Beam KTP and KTP/Nd:YAG for

Prostatectomy 419 13.13.1.4 Holmium:YAG for Prostate Tissue

Ablation 419 13.13.1.5 Holmium Laser Enucleation of the

Prostate—HoLEP 420 13.14 Summary 420

Section III Diagnostic Applications of Light

14 Diagnostic Methods Using Light: Photophysical 425 14.1 Optical Microscopy 425

14.1.1 Diffraction in the Far-Field 429 14.2 Various Microscopic Techniques 439

14.2.1 Confocal Microscopy 439 14.2.2 Multiphoton Imaging 442

14.2.2.1 Two-Photon Microscopy 442 14.2.2.2 Advantages of Two-Photon Microscopy 446 14.2.2.3 Limitations of Two-Photon Microscopy 447

14.3 Near-Field Scanning Optical Microscope 448 14.3.1 The Concept of the Near-Field Scanning Optical

Microscope 449 14.3.2 General Design of the Near-Field Scanning Optical

Microscope 449 14.3.3 Near-Field Scanning Optical Microscope Tip 450

14.3.3.1 Feedback Mechanisms Employed to Maintain a Constant Tip and Sample Separation 452

14.3.3.2 Shear-Force-Mode Tip Feedback 453 14.3.3.3 Tapping-Mode Tip Feedback 454 14.3.3.4 Intensity Imaging 455 14.3.3.5 Phase Imaging 456

14.4 Spectral Range Diagnostics 457 14.4.1 Lab-on-a-CHIP 459 14.4.2 Coherent X-Ray Imaging 460

14.4.2.1 Ultrafast X-Ray Pulses Reveal Atoms in Motion 460

14.4.2.2 Free Electron Laser Protein X-Ray Holography 461

14.5 Holographie Imaging 462 14.6 Polarization Imaging 463

14.7 Transillumination Imaging 464 14.7.1 Examination of the Male Genitalia of Infants 465 14.7.2 Transillumination for Detection of Pneumothorax in

Premature Infants 465 14.7.2.1 Continuous Monitoring for Pneumothorax

Detection 466 14.7.3 Transillumination of Infant Brain 467 14.7.4 Diffuse Optical Tomography 468

14.7.4.1 Theoretical Background of Diffuse Optical Tomography 469

14.7.4.2 Optical Heterodyning 472 14.8 Optical Coherence Tomography 476

14.8.1 Conventional Optical Coherence Tomography Systems 477 14.8.2 Light Sources and Coherence Length 479 14.8.3 Theory of Optical Coherence Tomography 482 14.8.4 Operation of the Fiberoptic Michelson

Interferometer 483 14.8.5 Correlation Theory 487 14.8.6 The Effect of Scattering on the Visibility

Function 492 14.8.7 Image Acquisition Process 494 14.8.8 Applications of Optical Coherence Tomography to

Physical Problems 496 14.8.8.1 Optical Coherence Tomography in Dentistry 497 14.8.8.2 Polarization-Sensitive Optical Coherence

Tomography 498 14.8.8.3 Phase-Resolved Optical Coherence

Tomography 498 14.8.8.4 Spectroscopic Optical Coherence

Tomography 499 14.8.8.5 Time-Domain Optical Coherence

Tomography 500 14.8.8.6 Color-Doppler Time-Domain Optical

Coherence Tomography 500 14.8.8.7 Spectral-Domain Optical Coherence

Tomography or Fourier-Domain Optical Coherence Tomography 501

14.9 Ballistic Photon Imaging 503 14.10 Reflectometry 506 14.11 Evanescent Wave Imaging Applications 506

14.11.1 Evanescent Optical Wave Device Designs 507 14.12 Medical Thermography 509 14.13 Photoacoustic Imaging 512

14.13.1 AcousticWave 519 14.13.2 Medical Imaging Applications 520

14.13.2.1 Acoustooptical Imaging of Teeth 521

14.13.2.2 Photoacoustic Excitation and Wave Propagation 524

14.14 Terahertz Imaging 526 14.15 Summary 528

15 Diagnostic Methods Using Light: Photochemical 531

15.1 Fluorescence Imaging 531 15.1.1 Fluorescence Molecular Explanation 532 15.1.2 Fluorescent Molecules 535 15.1.3 Fading 536

15.2 Ratio Fluorescence Microscopy 537 15.2.1 Fluorescence Resonance Energy Transfer (FRET)

Microscopy 537 15.2.2 Mechanism of Fluorescent Resonant Energy

Transfer Imaging 538 15.2.3 Fluorescence Resonance Energy Transfer Pair 540 15.2.4 Problems with Fluorescence Resonance Energy

Transfer Microscopy Imaging 541 15.3 Raman Spectroscopy with Near-Field Scanning Optical

Microscopy (NSOM) Employed 541 15.3.1 Fluorescence Resonance

Emission Transfer 542 15.3.2 Applications in Biology 543

15.4 Optical "Tongue" 543 15.4.1 Mechanism of Operation 544 15.4.2 Taste Stimuli Transduction 544 15.4.3 Taste Transduction Mechanisms 544 15.4.4 Taste Processes 545 15.4.5 Combinatorial Libraries 545 15.4.6 Charge-Coupled Device Detection 548

15.5 Summary 549

16 Diagnostic Methods Using Light: Photobiological 551

16.1 Immunostaining ("Functional Imaging") 551 16.2 Immunofluorescence 552 16.3 Diagnostic Applications of Spectroscopy 554

16.3.1 Detection of Dental Cavities and Caries 554 16.3.2 Optical Detection of Erythema 555

16.4 Fiberoptic Sensors 557 16.4.1 Biosensors 558 16.4.2 FiberOptic Biosensor Design 559

16.4.2.1 Fiberoptic Fluorescence Sensors 559 16.4.2.2 Fiberoptic Sensors in Gastrointestinal

Applications 559 16.4.2.3 Fiberoptic Immunosensors 560

16.4.2.4 Medical Immunosensor 560 16.4.2.5 Environmental Biosensor 561 16.4.2.6 Public Health 561

16.4.3 Distributed Fiberoptic Sensors 561 16.4.3.1 Time-of-Flight Measurement Using Laser

Light 562 16.4.3.2 Time-of-Flight Measurement Using

LED Light 562 16.4.4 Plastic-Clad Fiber 562 16.4.5 Limitations of Fiberoptic Sensors 563

16.5 Optical Coherence Tomography in Dentistry 563 16.6 Optical Biopsy 563 16.7 Determination of Blood Oxygenation 567

16.7.1 Pulse Oximetry 568 16.8 Electroiuminescent Electrophysiologic Mapping 570 16.9 Quantum Dots as Biological Fluorescent Markers 572

16.9.1 Future Considerations of Quantum Dot Imaging 573 16.10 Compilation of the Optical Requirements for Wavelength

Selection Based on the Desired Effects 573 16.11 Summary 574

Index .577