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Spie Press Book

Handbook of Optical Biomedical Diagnostics, Second Edition: 2-Volume Set (Vols. PM262 and PM263)
Editor(s): Valery V. Tuchin
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Book Description

Since the publication of the first edition of the Handbook in 2002, optical methods for biomedical diagnostics have developed in many well-established directions, and new trends have also appeared. To encompass all current methods, the text has been updated and expanded into two volumes.

  • Volume 1: Light - Tissue Interaction features eleven chapters, five of which focus on the fundamental physics of light propagation in turbid media such as biological tissues. The six following chapters introduce near-infrared techniques for the optical study of tissues and provide a snapshot of current applications and developments in this dynamic and exciting field. Topics include the scattering of light in disperse systems, the optics of blood, tissue phantoms, a comparison between time-resolved and continuous-wave methods, and optoacoustics.

  • Volume 2: Methods begins by describing the basic principles and diagnostic applications of optical techniques based on detecting and processing the scattering, fluorescence, FT IR, and Raman spectroscopic signals from various tissues, with an emphasis on blood, epithelial tissues, and human skin. The second half of the volume discusses specific imaging technologies, such as Doppler, laser speckle, optical coherence tomography (OCT), and fluorescence and photoacoustic imaging.

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    Book Details

    Date Published: 25 October 2016
    Pages: 1410
    Volume: PM264

    Table of Contents
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    Table of Contents

    Editor's Introduction
    List of Contributors

    Part I: Light-Tissue Interaction: Diagnostic Aspects
    Dmitry A. Zimnyakov and Lihong V. Wang

    1 Introduction to Light Scattering by Biological Objects
    Nikolai G. Khlebtsov, Irina L. Maksimova, Igor Meglinski, Lihong V. Wang, and Valery V. Tuchin
    1.1 Introduction
    1.2 Extinction and Scattering of Light in Disperse Systems: Basic Theoretical Approaches
    1.3 Theoretical Methods for Single-Particle Light-Scattering Calculations
         1.3.1 Basic parameters for single-particle light scattering
         1.3.2 Exact analytical and numerical methods
     Separation of variables and T-matrix methods (SVM and TM)
     Integral equation method (IEM)
     Discrete dipole approximation (DDA)
         1.3.3 Approximate theories
     Rayleigh approximation
     Rayleigh-Debye-Gans (RDG) approximation
     Anomalous diffraction (AD) and related approximations
         1.3.4 Other methods and approximations
    1.4 Extinction and Scattering by Aggregated and Compounded Structures
         1.4.1 Approximate and DDA methods
         1.4.2 Superposition method
         1.4.3 T-matrix formalism for cluster scattering
         1.4.4 Fractal aggregates
    1.5 Extinction and Scattering by Plasmon-Resonant Particles
         1.5.1 Localized plasmon resonance of small metal spheres
         1.5.2 Metal nanorods
         1.5.3 Metal nanoshells
         1.5.4 Coupled plasmon resonances: bisphere and linear chain examples
    1.6 Tissue Structure and Relevant Optical Models
         1.6.1 Continuous and discrete models of tissues
         1.6.2 Shape and sizes of particles in discrete tissue models
         1.6.3 Optical constants of tissues, heterogeneity, and optical softness
         1.6.4 Anisotropy of tissues
         1.6.5 Volume fraction of the particles
         1.6.6 Effects of spatial ordering
         1.6.7 Fractal properties of tissues
    1.7 Light Scattering by Densely Packed Correlated Particles
         1.7.1 Pair distribution function g(r)
         1.7.2 Light scattering by a system of particles in the single scattering approximation
         1.7.3 Angular characteristics for polarized light scattering
         1.7.4 Spectral characteristics of scattering systems
         1.7.5 Consideration of multiple scattering effects in the system of densely packed particles
         1.7.6 Birefringence of a system of anisotropic particles
    1.8 Application of Radiative Transfer Theory to Tissue Optics
         1.8.1 Approximation methods for solution of the radiation transfer equation
     The first-order approximation
     Diffusion approximation
     Small-angular approximation
     Flux theory
     Vector radiative transfer equation
         1.8.2 Monte Carlo simulation
     Simulation algorithm
     Calculation of LSM for multiple scattering system
     Degree of linear and circular polarization of light interacting with tissues
     Simulation of two-dimensional reflection and transmission LSM
     Simulation of the spectra of transmission, reflection, and scattering
    1.9 Nephelometry and Polarization Methods for the Diagnostics of Bio-objects
         1.9.1 Relations between the LSM elements: depolarization criterion
         1.9.2 Angular dependence of the scattering intensity of nondepolarized light
         1.9.3 Measurements of the angular dependences of the scattering matrix elements
         1.9.4 The LSM for some biological objects
         1.9.5 Effects of circular light probing and optical activity
    1.10 Controlling of Optical Properties of Tissues
    1.11 Circularly Polarized Light
    1.12 Summary

    2 Optics of Blood
    Anna N. Yaroslavsky and Ilya V. Yaroslavsky
    2.1 Introduction
    2.2 Physical Properties of Blood Cells
         2.2.1 Red blood cells
         2.2.2 Leukocytes
         2.2.3 Platelets
    2.3 Optical Properties of Oxy-hemoglobin and Deoxy-hemoglobin
    2.4 Absorption and Scattering of Light by a Single Erythrocyte
         2.4.1 Absorption and scattering cross-sections, scattering phase function
         2.4.2 Experimental determination of blood extinction coefficient and scattering phase function
         2.4.3 Analytical and numerical methods to approximate single light scattering in blood
     Mie theory
     WKB approximation
     RGD approximation
     Fraunhofer and anomalous diffraction approximations
     Semi-analytical and numerical methods
     Empirical phase functions
    2.5 Optical Properties of Blood
         2.5.1 Integrating sphere technique
         2.5.2 Blood preparation and handling
         2.5.3 Algorithms used to determine optical properties of whole and diluted human blood from the integrating sphere measurements
     The Monte Carlo method
     The adding-doubling method
    2.6 Summary of the Optical Properties of Diluted and Whole Human Blood
         2.6.1 Optical properties of blood determined using direct techniques
         2.6.2 Optical properties of blood determined using indirect techniques
    2.7 Practical Relevance of Blood Optics

    3 Propagation of Pulses and Photon Density Waves in Turbid Media
    Ilya V. Yaroslavsky, Anna N. Yaroslavsky, and Juan Rodriguez
    3.1 Introduction
    3.2 Time-Dependent Transport Theory
    3.3 Techniques for Solving the Time-Dependent Transport Equation
         3.3.1 Reduction to steady-state case
         3.3.2 Spherical harmonics method
         3.3.3 Discrete ordinate method
         3.3.4 Distributed-source approach
    3.4 Monte Carlo Method
         3.4.1 Sampling of random variables
         3.4.2 Generic time-resolved Monte Carlo algorithm
         3.4.3 Photon weighting
         3.4.4 Shortcut technique in the frequency domain
         3.4.5 Local estimate technique
         3.4.6 Hybrid technique
    3.5 Diffusion approximation
         3.5.1 Time-dependent diffusion equation
         3.5.2 Solutions for simple geometries
     Infinite medium
     Semi-infinite medium
         3.5.3 Numerical techniques
    3.6 Beyond Diffusion Approximation
    3.7 Role of the Single-Scattering Delay Time
    3.8 Concluding Remarks

    4 Coherence Phenomena and Statistical Properties of Multiply Scattered Light
    Dmitry A. Zimnyakov
    4.1 Introduction
    4.2 Weak Localization of Light in Disordered and Weakly Ordered Media
    4.3 Correlation Properties of Multiple-Scattered Coherent Light: Basic Principles and Methods
         4.3.1 Theoretical background for correlation analysis of multiple-scattered dynamic speckles
         4.3.2 Diffusing-wave spectroscopies and related techniques
    4.4 Evaluation of the Pathlength Density: Basic Approaches
         4.4.1 The concept of the pathlength density for description of light propagation in disordered media
         4.4.2 Diffusion approximation
         4.4.3 Other approaches
    4.5 Manifestations of Self-similarity in Multiple Scattering of Coherent Light by Disordered Media
    4.6 Diagnostic Applications of Light Coherence Phenomena in Multiple Scattering: Recent Applications in Biomedicine and Material Science
    4.7 Conclusion

    5 Tissue Phantoms
    Alexander B. Pravdin, George Filippidis, Giannis Zacharakis, Theodore G. Papazoglou, and Valery V. Tuchin
    5.1 Introduction
    5.2 General Approaches to Phantom Development
         5.2.1 Basic concept
         5.2.2 Mie theory predictions for scattering and absorption properties of particle suspensions
    5.3 Scattering Media for Phantom Preparation
         5.3.1 Fat emulsions as scattering media in tissue phantoms
         5.3.2 Milk in phantoms
         5.3.3 Polymer latex spheres in construction of tissue-like phantoms
         5.3.4 Mineral particles as scatterers in solid phantoms
    5.4 Light-Absorbing Media for Phantom Preparation
         5.4.1 Common microscopy stains in liquid and solid phantoms
         5.4.2 Dyes as light-absorbing components of tissue-simulating phantoms
         5.4.3 Inorganic ions as absorbers in solid and liquid tissue phantoms
         5.4.4 From the dyes to pigments and absorbing particles in phantoms
         5.4.5 Phantoms containing hemoglobin
    5.5 Smart Phantoms
         5.5.1 Multifunctional phantoms
         5.5.2 Phantoms mimicking vascular systems
         5.5.3 Phantoms of organs
    5.6 Phantoms with Optically Active Media
         5.6.1 Introduction
         5.6.2 Optically active tissue phantoms
         5.6.3 Conclusion
    5.7 Summary

    Part II: Tissue Near-Infrared Spectroscopy and Imaging
    Sergio Fantini and Ilya V. Yaroslavsky

    6 Time-Resolved Imaging in Diffusive Media
    Heidrun Wabnitz, Juan Rodriguez, Ilya Yaroslavsky, Anna Yaroslavsky, Harold Battarbee, and Valery V. Tuchin
    6.1 Introduction
         6.1.1 Looking through turbid tissues with conventional imaging techniques
         6.1.2 Sharpening images in diffusive media: the early history of the time-resolved method
    6.2 General Concepts in Time-Resolved Imaging through Highly Diffusive Media
         6.2.1 Transmittance methods
     Time-gated shadowgraphs
     Diffuse transmittance imaging
         6.2.2 Time-resolved optical tomography
     The back-projection technique
     Diffuse tomography methods
         6.2.3 Depth-resolved imaging
     Coherent backscattering
     Diffuse reflectance imaging
    6.3 Experimental Tools for Time-Resolved Imaging
         6.3.1 General considerations
         6.3.2 Pulsed light sources
     Mode-locked lasers
     Pulsed semiconductor lasers
     Other laser systems
         6.3.3 Detection systems based on time-correlated single-photon counting
     TCSPC principle
     Detectors for TCSPC
         6.3.4 Other high-speed detection systems
     Streak cameras
     Gated cameras
         6.3.5 Light guides
    6.4 Technical Designs for Time-Resolved Imaging
         6.4.1 Transmittance imaging
     Time-gated 2D projections
     Diffuse transmittance imaging
         6.4.2 Time-resolved optical tomography
         6.4.3 Reflectance imaging
     Depth-resolved coherence imaging
     Diffuse reflectance imaging
    6.5 Toward Clinical Applications
         6.5.1 Time-domain optical mammography
         6.5.2 Time-domain optical brain imaging
     Optical tomography of the infant brain
     Functional optical brain imaging and cerebral oximetry in adults
     Perfusion assessment by ICG bolus tracking
    6.6 Conclusions

    7 Frequency-Domain Techniques for Tissue Spectroscopy and Imaging
    Sergio Fantini and Angelo Sassaroli
    7.1 Introduction
    7.2 Instrumentation, Modulation Methods, and Signal Detection
         7.2.1 Light sources and modulation techniques
         7.2.2 Pulsed sources
         7.2.3 Optical detectors
         7.2.4 Homodyne and heterodyne detection
         7.2.5 A frequency-domain tissue spectrometer
    7.3 Frequency-Domain Diffusion Theory for Quantitative Tissue Spectroscopy
         7.3.1 The Boltzmann transport equation (BTE)
         7.3.2 Derivation of the diffusion equation (DE) from the BTE
         7.3.3 The diffusion equation in the frequency domain
         7.3.4 Solutions to the frequency-domain diffusion equation
     Infinite geometry
     Semi-infinite geometry
     Two-layered geometry
         7.3.5 Multi-distance tissue spectroscopy
         7.3.6 Multi-frequency tissue spectroscopy
    7.4 Tissue Spectroscopy and Oximetry
         7.4.1 Optical properties of biological tissue
         7.4.2 Absorption spectroscopy of tissue
         7.4.3 Quantification of hemoglobin concentration and saturation in tissue
         7.4.4 Absolute brain measurements with semi-infinite and two-layer models
         7.4.5 Measurements of optical scattering in tissue
    7.5 Optical Imaging of Tissues
         7.5.1 General concepts
         7.5.2 The phase information in frequency domain optical imaging
         7.5.3 Optical mammography and other applications
         7.5.4 Imaging of finger joints
    7.6 Prospects for Frequency-Domain Spectroscopy and Imaging of Tissue

    8 Monitoring of Brain Activity with Near-Infrared Spectroscopy
    Hui Gong, Qingming Luo, Shaoqun Zeng, Shoko Nioka, Yasufumi Kuroda, and Britton Chance
    8.1 Introduction
         8.1.1 Brain mapping by time-resolved and frequency-domain imaging systems
         8.1.2 The concepts of NIRS signal as a measure of neuronal activities
    8.2 Continuous Wave Functional Near-Infrared Imager
         8.2.1 Photon migration
         8.2.2 Instrumentation and performance
    8.3 Monitoring of Human Brain Activity with CW Functional Optical Imager
         8.3.1 Motor cortex in finger tapping
         8.3.2 n-back test
         8.3.3 The study of developmental dyslexia children
         8.3.4 Stem recognition performance measurement
         8.3.5 Pinpoint source location for ocular nonselective attention
         8.3.6 Cognitive conflict control
         8.3.7 Motor skill learning
         8.3.8 Thinking process and learning: "insight signal" through verbal stimuli
         8.3.9 PFC responses to emotional stresses
         8.3.10 Optical neuronal signals in the visual cortex
    8.4 Future Prospects

    9 Signal Quantification and Localization in Tissue Near-Infrared Spectroscopy
    Stephen J. Matcher
    9.1 Introduction
    9.2 Oximetry
         9.2.1 Optical spectroscopy
         9.2.2 Noninvasive hemoglobin spectroscopy
         9.2.3 Near-infrared spectroscopy (NIRS)
    9.3 Tissue Near-Infrared Spectroscopy
         9.3.1 Oxygen-dependent chromophores
     Cytochrome-aa3 (cytochrome-oxidaze)
         9.3.2 Oxygen-independent chromophores
     Other cytochromes
    9.4 Spectroscopy in a Highly Scattering Medium
    9.5 Absolute Measurements
         9.5.1 Use of a "forward model" of light transport
     Spatially resolved spectroscopy (SRS)
     Time-resolved spectroscopy (TRS)
     The microscopic Beer-Lambert law
     Practical TRS systems and their applications
     Frequency-domain spectroscopy
         9.5.2 Chemometric methods
    9.6 Quantified Trend Measurements
         9.6.1 Determination of the DPF at a given wavelength
     Time-resolved methods
     Time-domain measurements
     Frequency-domain measurements
     "Tracer" methods
         9.6.2 Determination of the wavelength dependence of pathlength
         9.6.3 Instrumentation
         9.6.4 Algorithms
     The "UCL" algorithm
     The "SAPPORO" algorithm
     The "DUKE-P" algorithm
     The "KEELE" algorithm
     Algorithm comparison
    9.7 Use of Quantified Trend Measurements to Infer Absolute Blood Flow, Blood Volume, Hemoglobin Saturation, and Tissue Oxygen Consumption
         9.7.1 Venous saturation via venous occlusion plethysmography
         9.7.2 Skeletal muscle blood flow
         9.7.3 Absolute muscle oxygen consumption
         9.7.4 Cerebral blood flow (CBF)
         9.7.5 Cerebral blood volume (CBV)
    9.8 Effects of Tissue Geometry and Heterogeneity
         9.8.1 Light transport models
     Two-layer diffusion models
     The Monte Carlo model
     The finite-element method
     Hybrid diffusion-radiosity models
     Discrete absorber models
         9.8.2 Effects of tissue heterogeneity
     Quantified trend
     Absolute measurements
         9.8.3 Summary
    9.9 Chapter Summary
    9.10 Recent Developments

    10 Near-Infrared Spectroscopy in Multimodal Brain Research
    Teemu Myllyla, Vladislav Toronov, Jurgen Claassen, Vesa Kiviniemi, and Valery V. Tuchin
    10.1 Introduction
         10.1.1 Functional imaging of the brain
         10.1.2 Towards multimodality
    10.2 Realization of NIRS in Multimodal Setups
         10.2.1 NIRS head caps
    10.3 fNIRS Combined with Different Techniques: Possibilities and Challenges
         10.3.1 fNIRS and neuroimaging
         10.3.2 Blood pressure and cerebral blood flow
    10.4 Novel Approaches and Examples of Current Multimodal studies
         10.4.1 Combining TCD with fNIRS
         10.4.2 Development of hyperspectral fNIRS
         10.4.3 Brain imaging utilizing fNIRS combined with seven modalities
    10.5 Enhancement of In-Depth NIRS Imaging
         10.5.1 Transmittance of cranium tissues in the NIR
         10.5.2 Optical clearing of tissues
         10.5.3 OCA diffusion
         10.5.4 In vivo optical clearing of skull
    10.6 Chapter Summary

    11 Measurement of Optical Fluence Distribution and Optical Properties of Tissues Using Time-Resolved Profiles of Optoacoustic Pressure
    Ivan M. Pelivanov, Alexander A. Karabutov, Tatiana D. Khokhlova, and Alexander A. Oraevsky
    11.1 Methods to Study Light Distribution in Tissue
    11.2 Two Modes of Optoacoustic Detection
    11.3 Stages of the Optoacoustic Phenomena
    11.4 Specific Features of Depth Distribution of the Absorbed Optical Energy in Optically Scattering Media
         11.4.1 Monte Carlo method
         11.4.2 Analytical approach: solution of light transfer equation in the 3P and 5P approximations
    11.5 Time-Resolved Optoacoustic Measurement of Depth Distribution of the Absorbed Optical Energy and Optical Properties in Scattering Media
         11.5.1 Temporal profile of the LIP
         11.5.2 Diffraction transformation of the LIP
         11.5.3 Absorbed optical energy profiles measured in forward mode
         11.5.4 Determination of the effective optical attenuation, absorption, and reduced scattering coefficients
         11.5.5 Possibility of in vivo measurements of tissue's optical properties in backward mode
    11.6 Technical Requirements for Time-Resolved Optoacoustic Detection
    11.7 Summary and Biomedical Applications

    Part III: Scattering, Fluorescence, and Infrared Fourier Transform Spectroscopy of Tissues
    Alexander V. Priezzhev and Juergen Lademann

    1 Optical Study of RBC Aggregation in Whole Blood Samples and on the Single-Cell Level
    Alexander V. Priezzhev, Kisung Lee, Nikolai N. Firsov, and Juergen Lademann
    1.1 Introduction to the Microrheological Structure of Blood: Biophysical and Clinical Aspects
    1.2 Importance of Quantitative Measurement of Red Blood Cell Aggregation and Deformability Parameters
    1.3 Arrangement of a Couette Chamber-Based Laser Backscattering Aggregometer
         1.3.1 Measurement procedure
    1.4 Kinetics of the Aggregation and Disaggregation Process
         1.4.1 Determination of the characteristic parameters of the aggregation and disaggregation process
    1.5 Parameters Influencing the Aggregation and Disaggregation Measurements
         1.5.1 Effect of blood sample temperature
         1.5.2 Effect of blood sample oxygenation
         1.5.3 Effect of sedimentation
         1.5.4 Effect of hematocrit
    1.6 Comparison of Aggregation and Disaggregation Measurements with Sedimentation Measurements
    1.7 Laser Tweezers as a New Tool for Studying RBC Aggregation at the Single-Cell Level
         1.7.1 Laser tweezers operation principle and experimental arrangement
         1.7.2 Sample preparation and measurement procedure
    1.8 Hemorheological Characterization of Various Diseases by Aggregation and Disaggregation Measurements of Blood Samples

    2 Light Scattering Spectroscopy of Epithelial Tissues: Principles and Applications
    Lev T. Perelman and Vadim Backman
    2.1 Introduction
    2.2 Microscopic Architecture of Mucosal Tissues
         2.2.1 Morphology of the cell
         2.2.2 Histology of mucosae
         2.2.3 Introduction to histopathology of early cancer and dysplasia
    2.3 Principles of Light Scattering
         2.3.1 Rigorous solution of the direct scattering problem
         2.3.2 Approximate solutions of the scattering problem
         2.3.3 Numerical solutions of the scattering problem
    2.4 Light Scattering by Cells and Subcellular Structures
    2.5 Light Transport in Superficial Tissues
    2.6 Detection of Cancer with Light Scattering Spectroscopy
         2.6.1 Diagnosis of early cancer and precancerous lesions with diffusely scattered light
         2.6.2 Diagnosis of early cancer and precancerous lesions with single-scattered light
         2.6.3 Imaging of early cancer and precancerous lesions with endoscopic polarized scanning spectroscopy instrument
    2.7 Confocal Light Absorption and Scattering Spectroscopic Microscopy

    3 Reflectance and Fluorescence Spectroscopy of Human Skin in vivo
    Yuri P. Sinichkin, Nikiforos Kollias, George I. Zonios, Sergei R. Utz, and Valery V. Tuchin
    3.1 Introduction
    3.2 Human Skin Back-Reflectance and Autofluorescence Spectra Formation
         3.2.1 Diffuse reflectance spectrum
         3.2.2 Autofluorescence spectra
    3.3 Simple Optical Models of Human Skin
         3.3.1 Simple skin model for reflectance analysis
         3.3.2 Simple skin model for autofluorescence analysis
    3.4 Combined Reflectance and Fluorescence Spectroscopy Method for in vivo Skin Examination
         3.4.1 Correction of the internal absorption effect in fluorescence emission
         3.4.2 Determination of melanin and erythema indices
         3.4.3 Monitoring of hemoglobin oxygenation
    3.5 Color Perception of Human Skin Back-Reflectance and Fluorescence Emission
         3.5.1 Color analysis of reflectance and fluorescence spectra
         3.5.2 Color imaging
    3.6 Polarization Reflectance Spectroscopy
    3.7 Polarization Imaging
    3.8 Sunscreen Evaluation Using Reflectance and Fluorescence Spectroscopy
    3.9 Control of Skin Optical Properties
         3.9.1 Introduction
         3.9.2 Skin compression and stretching
         3.9.3 Immersion optical clearing
     In vitro spectrophotometry
     In vivo spectral reflectance measurement
     Frequency-domain measurements
         3.9.4 Skin blood flow imaging
         3.9.5 OCT imaging
         3.9.6 Confocal microscopy
         3.9.7 Fluorescence and Raman signal detection
         3.9.8 The second harmonic generation
         3.9.9 Skin heating
         3.9.10 UV radiation
         3.9.11 Applications
         3.9.12 Conclusion
    3.10 Conclusion

    4 Infrared and Raman Spectroscopy of Human Skin in vivo
    Gerald W. Lucassen, Peter J. Caspers, Gerwin J. Puppels, Maxim E. Darvin, and Juergen Lademann
    4.1 Introduction: Basic Principles of IR and Raman Spectrosopy
    4.2 Fourier-Transform Infrared Spectroscopy of Human Skin Stratum Corneum in vivo
         4.2.1 Experimental ATR-FTIR setup
         4.2.2 Human skin stratum corneum spectra and band assignments
         4.2.3 ATR-FTIR spectrum of water
     Water-bending mode and low-wavenumber region
         4.2.4 Stratum corneum hydration measurements
     OH stretch region
     Fit on water spectrum
         4.2.5 Band analysis of hydrated and normal skin
     Penetration depth of the IR beam
     Fits of the hydrated skin stratum corneum spectra
     Comparison with MF and IR absorbance ratio
    4.3 Confocal Raman Microspectroscopy of Human Skin in vivo
         4.3.1 Setup for in vivo confocal Raman microspectroscopy
         4.3.2 Water and natural moisturizing factor in human skin epidermis
         4.3.3 Raman spectra of human skin constituents in vitro
         4.3.4 Profiling the water content and NMF content in human skin in vivo
    4.4 Resonance Raman Spectroscopy of Cutaneous Carotenoids in vivo
         4.4.1 Properties and role of cutaneous carotenoids
         4.4.2 Setup for in vivo resonance Raman spectroscopy of carotenoids
         4.4.3 Selective detection of carotenoids in the human skin
         4.4.4 In vivo measurements of the influence of UV irradiation on the human skin
         4.4.5 In vivo measurements of the influence of IR irradiation on the human skin
         4.4.6 In vivo measurements of the influence of the VIS irradiation on the human skin
         4.4.7 Factors influencing the concentration of carotenoids in the human skin
         4.4.8 Distribution of carotenoids in the human skin
    4.5 Conclusions

    5 Fluorescence Technologies in Biomedical Diagnostics
    Herbert Schneckenburger, Wolfgang S. L. Strauss, Karl Stock, and Rudolf Steiner
    5.1 Introduction
         5.1.1 Fundamentals
         5.1.2 Potential diagram
         5.1.3 Jablonski diagram and kinetic rates
         5.1.4 Fluorescence anisotropy
    5.2 Intrinsic and Extrinsic Fluorescence
         5.2.1 Intrinsic fluorophores
         5.2.2 Fluorescent markers
    5.3 Spectroscopic, Microscopic, and Imaging Techniques
         5.3.1 Fluorescence spectroscopy
         5.3.2 Fluorescence microscopy
         5.3.3 Imaging techniques
    5.4 Time-Resolved Fluorescence Spectroscopy and Imaging
         5.4.1 Time-correlated single photon counting
         5.4.2 Phase fluorometry
         5.4.3 Time-gated fluorescence spectroscopy
         5.4.4 Time-resolved fluorescence imaging
    5.5 Total Internal Reflection Fluorescence Spectroscopy and Microscopy (TIRFS/TIRFM)
         5.5.1 Theory of TIRFS/TIRFM
         5.5.2 Technical setup
         5.5.3 Combination of TIRFS/TIRFM with innovative fluorescence microscopic techniques
         5.5.4 Application of TIRFS/TIRFM in cell biology
    5.6 Energy Transfer Spectroscopy
         5.6.1 Basic mechanisms
         5.6.2 FRET applications
    5.7 Wide-Field 3D Microscopy
         5.7.1 Structured illumination
         5.7.2 Light sheet fluorescence microscopy (LSFM)
    5.8 Laser Scanning and Multiphoton Microscopy
         5.8.1 Introduction
         5.8.2 Performance of confocal laser scanning microscopes
         5.8.3 Applications of CLSM
         5.8.4 Multiphoton microscopy
         5.8.5 Super-resolution and single-molecule detection
    5.9 Concluding Remarks

    Part IV: Coherent-Domain Methods for Biological Flows and Tissue Ultrastructure Monitoring
    J. David Briers and Sean J. Kirkpatrick

    6 Laser Speckles, Doppler and Imaging Techniques for Blood and Lymph Flow Monitoring
    Ivan V. Fedosov, Yoshihisa Aizu, Valery V. Tuchin, Naomichi Yokoi, Izumi Nishidate, Vladimir P. Zharov, and Ekaterina I. Galanzha
    6.2 Doppler and Speckle Techniques
         6.2.1 Laser Doppler technique
         6.2.2 Laser speckle technique
         6.2.3 Interrelation
    6.3 Two-Wavelength Near-Infrared Speckle Imaging
         6.3.1 Optical system
         6.3.2 Frame-rate analysis of blood flow
         6.3.3 Blood flow measurements in humans
         6.3.4 Blood flow measurements in rats
         6.3.5 Simultaneous monitoring of blood flow and concentration
         6.3.6 Experiments on rats
    6.4 Low-Coherence Speckle Interferometry
    6.5 Quantitiave Characterization of Blood Flow Rate
         6.5.1 The use of laser Doppler anemometry for measurements of absolute blood flow velocity
         6.5.2 Intravital particle image velocimetry of capillary blood flow
    6.6 Intravital Microscopy (IM) for Monitoring Blood and Lymph Flows
    6.7 Intravital Transmission Digital Microscopy (ITDM)
    6.8 Intravital Fluroescent Digital Microscopy (IFDM)
    6.9 Optical Clearing
    6.10 In vivo Flow Cytometry
    6.11 In vivo Lymph Flow Cytometry (LFC)
    6.12 Animal Models
    6.13 Biomedical Applications
         6.13.1 Optical lymphography
     Indocyanine Green (ICG) Lymphography
     Integrated fluorescent angio- and lymphography
     Monitoring lymph flow profiles
         6.13.2 In vivo label-free imaging of lymphatic function
     Lymph flow
     Experimental lymphedema
     Nicotine intoxication
     Nitric oxide
     High-power laser�induced thermal effects on lymph vessels
         6.13.3 In vivo flow cytometry
     Label-free image flow cytometry
     Fluorescent image flow cytometry

    7 Real-Time Imaging of Microstructure and Function Using Optical Coherence Tomography
    Christine P. Hendon and Andrew M. Rollins
    7.1 Introduction
    7.2 Optical Coherence Tomography Principles
         7.2.1 Time-domain OCT
         7.2.2 Frequency-domain OCT
     Light sources
    7.3 Functional Imaging
         7.3.1 Doppler OCT
         7.3.2 Polarization-sensitive OCT
    7.4 Applications of OCT
         7.4.1 Opthamology
         7.4.2 Cardiology
         7.4.3 Oncology
    7.5 Conclusions

    8 Speckle Technologies for Monitoring and Imaging of Tissues and Tissue-Like Phantoms
    Dmitry A. Zimnyakov, Olga V. Ushakova, David J. Briers, and Valery V. Tuchin
    8.1 Introduction
    8.2 Diffusing-Wave Spectroscopy (DWS) as a Tool for Tissue Structure and Cell Flow Monitoring
    8.3 Laser Speckle Contrast Analysis (LASCA) for Measuring Blood Flow
         8.3.1 Statistical properties of laser speckle
         8.3.2 Time-varying speckle
         8.3.3 Full-field methods
         8.3.4 Single-exposure speckle photography
         8.3.5 Laser speckle contrast analysis (LASCA)
         8.3.6 The question of speckle size
         8.3.7 Theory
         8.3.8 Practical considerations
         8.3.9 Early applications of the LASCA technique
         8.3.10 Important developments of the basic LASCA technique
         8.3.11 Conclusions
    8.4 Modification of Speckle Contrast Analysis to Improve Depth Resolution and to Characterize Scattering Properties of a Probed Medium
    8.5 Various Modifications of Laser Speckle Contrast Imaging
    8.6 Imaging Using Contrast Measurements of Partially Developed Speckles
    8.7 Monitoring of Tissue Thermal Modification with a Bundle-Based Full-Field Speckle Analyzer
    8.8 Summary

    9 Optical Assessment of Tissue Mechanics
    Sean J. Kirkpatrick, Donald D. Duncan, Brendan F. Kennedy, and David D. Sampson
    9.1 Introduction
    9.2 Introduction to Prior Edition
    9.3 Tissue Mechanics and Medicine
         9.3.1 Dermatology
         9.3.2 Oncology
         9.3.3 Ophthalmology
         9.3.4 Cardiology
         9.3.5 Other application areas
    9.4 Constitutive Relations in Biological Tissues
    9.5 Laser Speckle Patterns Arising from Biological Tissues
         9.5.1 First-order statistics
         9.5.2 Second-order statistics
    9.6 Elastography Measurements by Tracking Translating Laser Speckle: The Transform Method
         9.6.1 Potential error sources
         9.6.2 Applications of laser speckle elastography to hard and soft tissues
    9.7 Alternative Processing Algorithms for Calculating Speckle Shift
         9.7.1 Nonparametric speckle shift estimators
         9.7.2 Parametric speckle shift estimators A minimum mean square error estimator
    9.8 Expanding to Higher Dimensions
    9.9 What is Really Measured in Laser Speckle-Tracking Elastography
    9.10 In vivo Laser Speckle Tracking Optical Elastography
    9.11 Performance Comparisons
    9.12 Generalizations
    9.13 Elastography of Tissues with Optical Coherence Tomography
         9.13.1 Variants of OCE
     Compression OCE
     Surface wave/shear wave OCE
         9.2.2 OCE probes
    9.14 Acoustically Modulated Speckle Imaging
    9.15 Conclusions

    10 Optical Clearing of Tissues: Benefits for Biology, Medical Diagnostics, and Phototherapy
    E. A. Genina, A. N. Bashkatov, Yuri P. Sinichkin, I. Yu. Yanina, and V. V. Tuchin
    10.1 Fundamentals of Optical Clearing (OC) of Tissues and Cells
    10.2 Immersion OC
    10.3 Compression OC
    10.4 Photochemical, Thermal, and Photothermal OC
    10.5 Applications in Biology and Medicine
         10.5.1 Optical coherence tomography
         10.5.2 Optical projection tomography
         10.5.3 Fluorescence imaging
         10.5.4 Photoacoustic imaging
         10.5.5 Nonlinear and Raman microscopy
         10.5.6 Terahertz spectroscopy
    10.6 Determination of OCA and Drug Diffusion Coefficients in Tissues
    10.7 Conclusion


    This Handbook is the second edition of the monograph initially published in 2002. The first edition described some aspects of laser/cell and laser/tissue interactions that are basic for biomedical diagnostics and presented many optical and laser diagnostic technologies prospective for clinical applications. The main reason for publishing such a book was the achievements of the last millennium in light scattering and coherent light effects in tissues, and in the design of novel laser and photonics techniques for the examination of the human body. Since 2002, biomedical optics and biophotonics have had rapid and extensive development, leading to technical advances that increase the utility and market growth of optical technologies. Recent developments in the field of biophotonics are wide-ranging and include novel light sources, delivery and detection techniques that can extend the imaging range and spectroscopic probe quality, and the combination of optical techniques with other imaging modalities.

    The innovative character of photonics and biophotonics is underlined by two Nobel prizes in 2014 awarded to Eric Betzig, Stefan W. Hell, and William E. Moerner�"for the development of super-resolved fluorescence microscopy" and to Isamu Akasaki, Hiroshi Amano, and Shuji Nakamura�"for the invention of efficient blue light-emitting diodes which has enabled bright and energy-saving white light sources." The authors of this Handbook have a strong input in the development of new solutions in biomedical optics and biophotonics and have conducted cutting-edge research and developments over the last 10 - 15 years, the results of which were used to modify and update early written chapters. Many new, world-recognized experts in the field have joined the team of authors who introduce fresh blood in the book and provide a new perspective on many aspects of optical biomedical diagnostics.

    The optical medical diagnostic field covers many spectroscopic and laser technologies based on near-infrared (NIR) spectrophotometry, fluorescence and Raman spectroscopy, optical coherence tomography (OCT), confocal microscopy, optoacoustic (photoacoustic) tomography, photon-correlation spectroscopy and imaging, and Doppler and speckle monitoring of biological flows. These topics - as well as the main trends of the modern laser diagnostic techniques, their fundamentals and corresponding basic research on laser�tissue interactions, and the most interesting clinical applications - are discussed in the framework of this Handbook. The main unique features of the book are as follows:

    1. Several chapters of basic research that discuss the updated results on light scattering, speckle formation, and other nondestructive interactions of laser light with tissue; they also provide a basis for the optical and laser medical diagnostic techniques presented in the other chapters.
    2. A detailed discussion of blood optics, blood and lymph flow, and blood-aggregation measurement techniques, such as the well-recognized laser Doppler method, speckle technique, and OCT method.
    3. A discussion of the most-recent prospective methods of laser (coherent) tomography and spectroscopy, including OCT, optoacoustic (photoacoustic) imaging, diffusive wave spectroscopy (DWS), and diffusion frequency-domain techniques.

    The intended audience of this book consists of researchers, postgraduate and undergraduate students, biomedical engineers, and physicians who are interested in the design and applications of optical and laser methods and instruments for medical science and practice. Due to the large number of fundamental concepts and basic research on laser�tissue interactions presented here, it should prove useful for a much broader audience that includes students and physicians, as well. Investigators who are deeply involved in the field will find up-to-date results for the topics discussed. Each chapter is written by representatives of the leading research groups who have presented their classic and most recent results. Physicians and biomedical engineers may be interested in the clinical applications of designed techniques and instruments, which are described in a few chapters. Indeed, laser and photonics engineers may also be interested in the book because their acquaintance with a new field of laser and photonics applications can stimulate new ideas for lasers and photonic devices design. The two volumes of this Handbook contain 21 chapters, divided into four parts (two per volume):

    • Part I describes the fundamentals and basic research of the extinction of light in dispersive media; the structure and models of tissues, cells, and cell ensembles; blood optics; coherence phenomena and statistical properties of scattered light; and the propagation of optical pulses and photon-density waves in turbid media. Tissue phantoms as tools for tissue study and calibration of measurements are also discussed.
    • Part II presents time-resolved (pulse and frequency-domain) imaging and spectroscopy methods and techniques applied to tissues, including optoacoustic (photoacoustic) methods. The absolute quantification of the main absorbers in tissue by a NIR spectroscopy method is discussed. An example biomedical application - the possibility of monitoring brain activity with NIR spectroscopy - is analyzed.
    • Part III presents various spectroscopic techniques of tissues based on elastic and Raman light scattering, Fourier transform infrared (FTIR), and fluorescence spectroscopies. In particular, the principles and applications of backscattering diagnostics of red blood cell (RBC) aggregation in whole blood samples and epithelial tissues are discussed. Other topics include combined back reflectance and fluorescence, FTIR and Raman spectroscopies of the human skin in vivo, and fluorescence technologies for biomedical diagnostics.
    • The final section, Part IV, begins with a chapter on laser Doppler microscopy, one of the representative coherent-domain methods applied to monitoring blood in motion. Methods and techniques of real-time imaging of tissue ultrastructure and blood flows using OCT is also discussed. The section also describes various speckle techniques for monitoring and imaging tissue, in particular, for studying tissue mechanics and blood and lymph flow.

    Financial support from a FiDiPro grant of TEKES, Finland (40111/11) and Academic D.I. Mendeleev Fund Program of Tomsk National Research State University have helped me complete this book project. I greatly appreciate the cooperation and contribution of all of the authors and co-editors, who have done a great work on preparation of this book. I would like to express my gratitude to Eric Pepper and Tim Lamkins for their suggestion to prepare the second edition of the Handbook and to Scott McNeill for assistance in editing the manuscript. I am very thankful to all of my colleagues from the Chair and Research Education Institute of Optics and Biophotonics at Saratov National Research State University and the Institute of Precision Mechanics and Control of RAS for their collaboration, fruitful discussions, and valuable comments. I am very grateful to my wife and entire family for their exceptional patience and understanding.

    Valery V. Tuchin
    May 2016

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