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  • BE12CH12-Boustany ARI 14 June 2010 16:59

    Microscopic Imaging and Spectroscopy with Scattered Light Nada N. Boustany,1 Stephen A. Boppart,2

    and Vadim Backman3 1Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey 08854; email: nboustan@rci.rutgers.edu 2Departments of Electrical and Computer Engineering, Bioengineering, and Medicine, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; email: boppart@illinois.edu 3Department of Biomedical Engineering, McCormick School of Engineering and Applied Science, Northwestern University, Evanston, Illinois 60208; email: v-backman@northwestern.edu

    Annu. Rev. Biomed. Eng. 2010. 12:285–314

    First published online as a Review in Advance on May 7, 2010

    The Annual Review of Biomedical Engineering is online at bioeng.annualreviews.org

    This article’s doi: 10.1146/annurev-bioeng-061008-124811

    Copyright c© 2010 by Annual Reviews. All rights reserved

    1523-9829/10/0815-0285$20.00

    Key Words

    light scattering, optical imaging, microscopy, tissue diagnosis, cell analysis

    Abstract

    Optical contrast based on elastic scattering interactions between light and matter can be used to probe cellular structure, cellular dynamics, and im- age tissue architecture. The quantitative nature and high sensitivity of light scattering signals to subtle alterations in tissue morphology, as well as the ability to visualize unstained tissue in vivo, has recently generated significant interest in optical-scatter-based biosensing and imaging. Here we review the fundamental methodologies used to acquire and interpret optical scatter data. We report on recent findings in this field and present current advances in optical scatter techniques and computational methods. Cellular and tissue data enabled by current advances in optical scatter spectroscopy and imaging stand to impact a variety of biomedical applications including clinical tissue diagnosis, in vivo imaging, drug discovery, and basic cell biology.

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  • BE12CH12-Boustany ARI 14 June 2010 16:59

    Contents

    1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 2. ELASTIC LIGHT SCATTERING AS A SOURCE

    OF OPTICAL CONTRAST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 3. PHYSICAL INTERPRETATION OF THE OPTICAL SCATTER DATA . . . . . . 288 4. ADVANTAGES OF UTILIZING LIGHT SCATTERING FOR SENSING . . . . 291 5. BIOLOGICAL INTERPRETATION OF THE OPTICAL SCATTER DATA

    IN UNLABELED OR FLUORESCENTLY LABELED SAMPLES . . . . . . . . . . . . 292 5.1. Isolating the Scattering Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292 5.2. Multimodal Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 5.3. Biological Specificity Acquired by Training Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293

    6. LIGHT SCATTER SPECTROSCOPY TO ASSESS TISSUES IN VIVO . . . . . . . 294 7. IMAGING BASED ON OPTICAL SCATTER CONTRAST . . . . . . . . . . . . . . . . . . . 295

    7.1. In Vivo Confocal Reflectance Microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 7.2. Optical Coherence Tomography and Microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 7.3. Optical Scatter Imaging Based on Fourier Filtering . . . . . . . . . . . . . . . . . . . . . . . . . . 299 7.4. Quantitative Phase Microscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

    8. COMPUTATIONAL METHODS IN OPTICAL SCATTER IMAGING AND SPECTROSCOPY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 8.1. Finite-Difference Time-Domain Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 8.2. Interferometric Synthetic Aperture Microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

    9. FUTURE AND EMERGING DIRECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 9.1. Contrast Agents for Optical Scatter Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 9.2. Biological Dynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

    10. CONCLUSION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

    1. INTRODUCTION

    In contrast with X rays, which travel with relatively little scatter through biological tissues, elec- tromagnetic waves at optical wavelengths are significantly scattered at biological interfaces. This scattering of light by optically inhomogeneous biological tissues has posed a limitation on high- resolution, three-dimensional imaging of thick biological tissues and in general has prevented whole-body, optical tomographic imaging on the scale of X-ray computed tomography. Nonethe- less, elastic scattering of light at tissue, cellular, and subcellular interfaces provides an important source of natural biological contrast that can be harnessed to provide quantitative measurements of cellular and tissue states. Thus significant advances in optical technology have recently focused on utilizing this fundamental form of light-tissue interaction to enable optical-scatter-based imag- ing and sensing. High-resolution optical scatter sensing is usually limited to tissue surfaces, thin specimens, or weakly scattering tissues. However, important biomedical and biological applica- tions ranging from cancer diagnosis to cell and developmental biology have been achieved even in this limited scattering regime. This review presents recent advances in optical scatter imaging and spectroscopy and includes a description of novel methodologies and the biological data that can be derived from them.

    286 Boustany · Boppart · Backman

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  • BE12CH12-Boustany ARI 14 June 2010 16:59

    2. ELASTIC LIGHT SCATTERING AS A SOURCE OF OPTICAL CONTRAST

    Aside from absorption by blood and certain tissue pigments (e.g., melanin) in specific wavelength ranges (1), elastic scattering is by far the most prevalent form of light interaction with biologi- cal tissue, with elastic scattering cross sections that are several orders of magnitude larger than fluorescence or inelastic Raman scattering.

    In contrast with fluorescence, which carries information about the excited energy state of a specific biochemical, elastic scattering does not involve photon absorption, and the atoms involved do not make a transition to an excited state before the scattering process takes place. Because the process is elastic and does not involve absorption (Figure 1a), the scattered light has the same frequency as the incident light, and elastic scattering can occur for a broad range of incident wave- lengths. (A detailed quantum description of the scattering process can be found in Reference 2.) In a typical measurement, light incident on a scattering source is elastically scattered in different directions upon interaction with the scattering source. By measuring the magnitude, phase, and the angular dependency or wavelength dependency of the scattered far field, one can retrieve information about the scattering sources’ cross sections (or extinction resulting from scattering), structure, and refractive index (3). The dependency of scattering on the polarization of the inci- dent field can also be used to study the birefringent or dichroic properties of the scattering source (3, 4). Figure 1c shows an illustration of light scatter irradiance as a function of angle and size for two spheres of different diameter (Figure 1b). As noted in the figure, the angular intensity depends on the ratio of the particles’ refractive index to the surrounding medium’s refractive index, and on

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