Advances in Optical Imaging for Clinical Medicine E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Veröffentlichungsjahr: 2011

Beschreibung

This book provides students, teachers, researchers and clinicians with a strong and established source of information on advanced optical technologies that show real promise of being translated to clinical use.

Leseprobe

Table of Contents

Series Page

Title Page

Copyright

Dedication Page

Contributors

Preface

Chapter 1: Introduction to optical imaging in clinical medicine

1.1 Brief history of optical imaging

1.2 Introduction to medical imaging

1.3 Outline of the book

References

Chapter 2: Traditional Imaging Modalities in Clinical Medicine

2.1 Introduction

2.2 Diagnostic imaging technologies

2.3 Imaging for radiation therapy planning

2.4 Image-guided radiation therapy

2.5 Conclusions

References

Chapter 3: Current imaging approaches and further imaging needs in clinical medicine: A clinician's perspective

3.1 Ophthalmic imaging

3.2 Imaging of the gastrointestinal mucosa

3.3 Cardioimaging

3.4 Neuroimaging: current technologies and further needs

References

Chapter 4: Advances in Retinal Imaging

4.1 Introduction

4.2 Prevalent retinal diseases

4.3 Traditional imaging technologies

4.4 Advanced imaging technologies

4.5 Imaging beyond disease detection

4.6 Conclusions

References

Bibliography

Chapter 5: Confocal Microscopy of Skin Cancers

5.1 Introduction

5.2 Imaging of normal skin in vivo

5.3 Imaging of Cutaneous Neoplasms In Vivo: Correlation with dermoscopy and histopathology

5.4 Mosaicing of excised skin ex vivo

5.5 Intraoperative Mapping of Surgical Margins

5.6 Challenging cases

5.7 Future perspectives

References

Chapter 6: High-resolution optical coherence tomography imaging in gastroenterology

6.1 Introduction

6.2 Optical coherence tomography

6.3 Clinical gastrointestinal imaging

6.4 Future directions

6.5 Conclusions

References

Chapter 7: High-resolution confocal endomicroscopy for gastrointestinal cancer detection

7.1 Introduction and motivation

7.2 Conventional confocal endomicroscopy

7.3 Dual-axis confocal endomicroscopy

7.4 Toward larger fields of view: mosaicing

7.5 Summary and future directions

References

Chapter 8: High-resolution Optical Imaging in Interventional Cardiology

8.1 Introduction

8.2 Current invasive imaging modalities in interventional cardiology

8.3 High-resolution optical coherence tomography imaging in cardiology

8.4 Current Limitation of OCT

8.5 Future developments

8.6 Conclusions

References

Chapter 9: Fluorescence Lifetime Spectroscopy in Cardio- and Neuroimaging

9.1 Introduction

9.2 Fluorescence lifetime spectroscopy in tissue characterization

9.3 Time-resolved fluorescence spectroscopy: instrumentation

9.4 Time-resolved fluorescence spectroscopy: data analysis methods

9.5 Atherosclerotic plaque

9.6 Primary brain tumors

9.7 Concluding remarks

References

Chapter 10: Advanced Optical Methods for Functional Brain Imaging: Time-Domain Functional Near-Infrared Spectroscopy

10.1 Introduction

10.2 Optical technologies for noninvasive neural activity mapping

10.3 Optical imaging of depth-resolved functional activity in the cortex

10.4 Novel approaches to TD fNIRS

10.5 Conclusions

References

Chapter 11: Advances in Optical Mammography

11.1 Introduction

11.2 Structure and physiology of the human female breast: an optical perspective

11.3 Optical imaging breast technology

11.4 In vivo optical properties of a healthy breast

11.5 Optical imaging in breast oncology

11.6 Multimodality approaches

11.7 Summary

References

Chapter 12: Photoacoustic Tomography

12.1 Introduction

12.2 Photoacoustic theory

12.3 PAT imaging methods

12.4 Photoacoustic wave equations

12.5 Finite-element and model-based PAT reconstruction methods

12.6 Quantitative PAT

12.7 PAT imaging instrumentation

12.8 In vivo applications

References

Chapter 13: Optical Imaging and Measurement of Angiogenesis

13.1 Introduction

13.2 Angiogenesis: a brief overview

13.3 Potential clinical applications

13.4 Optical techniques to image angiogenesis

13.5 Other modalities

13.6 Conclusions

References

Chapter 14: High-resolution Phase-Contrast Optical Coherence Tomography for Functional Biomedical Imaging

14.1 Introduction

14.2 Time-domain phase-sensitive interferometry

14.3 Spectral-domain phase-sensitive interferometry

14.4 Applications of differential phase-contrast imaging

14.5 Comparison of time- and spectral-domain phase-sensitive systems

14.6 Conclusions

References

Chapter 15: Polarization imaging

15.1 Introduction

15.2 Polarization analysis

15.3 Polarization microscopy

15.4 Other polarization-sensitive techniques

15.5 Biomedical applications

15.6 Other polarization imaging applications

15.7 Conclusions

References

Chapter 16: Nanotechnology Approaches to Contrast Enhancement in Optical Imaging and Disease-Targeted Therapy

16.1 Introduction

16.2 Nanotechnology-based contrast agents for optical imaging and targeted therapy

16.3 Enhanced-contrast optical imaging using functionalized nanoprobes

16.4 Nanotechnology-based drug delivery systems for disease-targeted therapy and tissue regeneration

16.5 Conclusions

References

Chapter 17: Molecular probes for optical contrast enhancement of gastrointestinal cancers

17.1 Introduction

17.2 DNA microarrays for target identification

17.3 Phage display

17.4 Potential targets and possible pitfalls

17.5 Probe design

17.6 Conclusions

References

Index

Copyright © 2010 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.

Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data:

Advances in optical imaging for clinical medicine / [edited by] Nicusor Iftimia, William R.

Brugge, Daniel X. Hammer.

p. cm. (Wiley Series in Biomedical engineering and multidisciplinary integrated systems)

Includes bibliographical references.

ISBN 978-0-470-61909-4 (cloth)

1. Diagnostic imaging. 2. Clinical medicine. I. Iftimia, Nicusor. II. Brugge, William R.

III. Hammer, Daniel X. IV. Series: Wiley series in biomedical engineering

and multi-disciplinary integrated systems.

[DNLM: 1. Diagnostic Imaging-trends. 2. Clinical medicine-methods.

3. Diagnostic Imaging-methods. 4. Optical devices-trends. WN 180 A2445 2010]

RC78.7.D53A3887 2010

616.07′54–dc22

2010008434

To my parents, family, colleagues, and friends

Nicusor Iftimia

To my father, a physicist, and my wife, Joan Brugge, for their inspiration

William R. Brugge

To Owen

Daniel X. Hammer

Contributors

Taner Akkin, Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota

Mansoor Amiji, Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts

Fred S. Azar, Siemens Corporate Research, Inc., Princeton, New Jersey

Juliana Casagrande Tavoloni Braga, Hospital A. C. Camargo, São Paulo, Brazil

Brett E. Bouma, Harvard Medical School and Wellman Center for Photomedicine at the Massachusetts General Hospital, Boston, Massachusetts

William R. Brugge, Department of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts

Pramod Butte, Cedars–Sinai Medical Center, Los Angeles, California

Matteo Caffini, Dipartiménto di Fisica, Politècnico di Milano, Milan, Italy

Jin-Man Cho, Department of Cardiology, Massachusetts General Hospital, Boston, Massachusetts

Sevdenur Cizginer, Department of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts

Christopher H. Contag, Department of Pediatrics and of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California

Davide Contini, IIT Research Unit and Dipartiménto di Fisica, Politècnico di Milano, Milan, Italy

Rinaldo Cubeddu, IIT Research Unit and Dipartiménto di Fisica, Politècnico di Milano, Milan, Italy

Digant P. Davé, Bioengineering Department, University of Texas–Arlington, Arlington, Texas

Peter K. Dempsey, Department of Neurosurgery, Lahey Clinic, Burlington, Massachusetts; Tufts University School of Medicine, Boston, Massachusetts

Daniel Gareau, Department of Biomedical Engineering, Oregon Health and Science University, Portland, Oregon

Daniel X. Hammer, Medical Technologies Department, Physical Sciences, Inc., Andover, Massachusetts

Jonathan W. Hardy, Department of Pediatrics and of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California

Ileana Iftimia, Radiation Oncology Department, Lahey Clinic, Burlington, Massachusetts; Tufts University School of Medicine, Boston, Massachusetts

Nicusor Iftimia, Medical Technologies Department, Physical Sciences, Inc., Andover, Massachusetts

Xavier Intes, Biomedical Engineering Department, Rensselaer Polytechnic Institute, Troy, New York

Ik-Kyung Jang, Department of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Huabei Jiang, Department of Biomedical Engineering, University of Florida, Gainesville, Florida

Javier A. Jo, Texas A&M University, College Station, Texas

Cetin Karaca, Department of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts

Thomas J. Kiernan, Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Nippon Medical School, Tokyo, Japan

Itay Klaz, Dermatology Service, Memorial Sloan–Kettering Cancer Center, New York, New York

Jonathan T. C. Liu, Department of Biomedical Engineering, State University of New York at Stony Brook, Stony Brook, New York

Anson W. Lowe, Department Gastroenterology, Stanford University School of Medicine, Stanford, California

Laura Marcu, Department of Biomedical Engineering, University of California–Davis, Davis, California

Ashfaq A. Marghoob, Dermatology Service, Memorial Sloan–Kettering Cancer Center, New York, New York

Lara Milane, Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts

Kyoichi Mizuno, Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Nippon Medical School, Tokyo, Japan

Herbert Mower, Radiation Oncology Department, Lahey Clinic, Burlington, Massachusetts; Tufts University School of Medicine, Boston, Massachusetts

Mircea Mujat, Medical Technologies Department, Physical Sciences, Inc., Andover, Massachusetts

Amy Oldenburg, Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Antonio Pifferi, IIT Research Unit and Dipartiménto di Fisica, Politècnico di Milano, Milan, Italy

Milind Rajadhyaksha, Dermatology Service, Memorial Sloan–Kettering Cancer Center, New York, New York

Joel S. Schuman, UPMC Eye Center, Eye and Ear Institute, Ophthalmology and Visual Science Research Center, Department of Ophthalmology, University of Pittsburgh School of Medicine; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh; Center for the Neural Basis of Cognition, Carnegie Mellon University and University of Pittsburgh; Pittsburgh, Pennsylvania

Alon Scope, Dermatology Service, Memorial Sloan–Kettering Cancer Center, New York, New York

Brian S. Sorg, J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida

Lorenzo Spinelli, Istituto di Fotonica e Nanotecnologie–Sezióne di Milano, Milan, Italy

Melissa J. Suter, Harvard Medical School and Wellman Center for Photomedicine at the Massachusetts General Hospital, Boston, Massachusetts

Guillermo J. Tearney, Harvard Medical School and Wellman Center for Photomedicine at the Massachusetts General Hospital, Boston, Massachusetts

Alessandro Torricelli, IIT Research Unit and Dipartiménto di Fisica, Politècnico di Milano, Milan, Italy

Gadi Wollstein, UPMC Eye Center, Eye and Ear Institute, Ophthalmology and Visual Science Research Center, Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Bryan P. Yan, Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Nippon Medical School, Tokyo, Japan

Zhen Yuan, Department of Biomedical Engineering, University of Florida, Gainesville, Florida

Preface

Clinical medicine lies at the nexus of the perspectives of physicians, researchers, engineers, physicists, technicians, philanthropists, insurers, administrators, venture capitalists, entrepreneurs, and, most of all, those afflicted with a health-related condition. Anyone who has worked in a field even remotely related to clinical medicine realizes that even with the vast expenditure of effort on the part of communities that comprise the first groups listed above, the results are sometimes unsatisfactory to all, and especially to the patients and their relatives. There are many reasons for the challenge in moving a potentially promising technology from laboratory bench to bedside, despite the best intentions of all involved. One of them is that no matter how much money and labor are behind an idea in a medically related field, it will always be a difficult prospect to reach full realization of that idea in a manner that is safe, efficacious, cost-effective, and easy to use.

The impact of new advances in clinical medicine can be observed easily by analyzing the trends in life expectancy. Up until the early twentieth century, life expectancy rarely exceeded 40 years, even in the most developed countries (see Figure P.1a). Today we can reasonably assume that a large percentage of us, and the majority of our children, will become octogenerians. However, the asymptotical trend means that it will be more difficult to achieve an increase in life expectancy of 0.1 year today than it was to achieve an increase of 10 years in the twentieth century. This is in part related to stress-related diseases in a modern society, and to the ease in spreading new viruses or new forms of cancer in a globalized society. Fortunately, many accomplishments in medical research in the last 30 years, such as the development of monoclonal antibodies and other targeted therapies, the identification of cancer-associated genes, and the introduction of computer-assisted imaging, have contributed significantly to the development of new tools that have helped control some of these life-expectancy impacting factors. For example, a very clear trend has been observed in increasing cancer survival rates (see Figure P.1b), due in part to new advances in gene therapy, as well as to the development of new tools that allow for early diagnosis of cancer at the cellular level. Since the complete mapping of the human genome in 2003, the field of biological science has flourished, and the prospect of the eradication of inherited or transmitted diseases using viral vectors and other gene therapies has started to become a reality.

The future of medical technologies will be impacted, on one hand by the biotech-driven trend of elucidating natural processes of health, disease, and healing in order to exploit understanding of the natural sciences to solve medical problems, and on the other, by the technology-centric trend of developing hardware, largely surgical or at least interventional technology, that may achieve dramatically better surgical/interventional endpoints. If today it takes more than ten years for a technology or drug to become widely available clinically, in the future it is expected to take significantly less time. The new pace, while challenging for researchers striving to remain at the forefront of their respective fields, is exciting for all to behold.

Advances in Optical Imaging for Clinical Medicine was written to provide a fragment of this perspective to students, researchers, and clinicians. It is designed to educate those who are new to the field of biomedical optics, and to provide a snapshot of the current technologies for the rest of us. Biomedical optics and biomedical imaging lie at the nexus of several fields, including biology, optics, physics, mechanical engineering, electrical engineering, and computer science. It is not uncommon; in fact, the converse is now rare that a system soon to be deployed in the clinic has custom optical, electrical, and mechanical components all managed and controlled with specialized software, firmware, and user interface. This requires more extensive collaboration and coordination between researchers, clinicians, and engineers in fields that may not have previously communicated so extensively with one another. It also requires the individual researcher to become familiar with the fundamental concepts, jargon, and current research trends in fields outside their own. We hope that this text will aid in such knowledge transfer and communication.

A book on optical imaging, even one restricted to fields related to clinical medicine, is bound to be incomplete. We have sought to highlight many fields where the pace of technical advancement has been particularly rapid, with the recognition that some areas outside our own limited scope may be experiencing or will soon experience similar great progress. We regretfully leave to other authors coverage of fields that we have omitted.

We would like to thank all the contributors, especially Mircea Mujat, who provided valuable assistance in the editing process, as well as to our publishers for very good feedback throughout the editing process. We would also like to thank all of our teachers, mentors, fellow researchers, and collaborators, who are too numerous to list individually.

Nicusor Iftimia

William R. Brugge

Daniel X. Hammer

August 2010

Chapter 1

Introduction to optical imaging in clinical medicine

Nicusor Iftimia and Daniel X. Hammer

Physical Sciences, Inc., Andover, Massachusetts

William R. Brugge

Massachusetts General Hospital, Boston, Massachusetts

1.1 Brief history of optical imaging

Throughout history, as soon as a piece of optical apparatus was invented, human beings have used it to gaze both outward and inward. The refractive power of simple lenses made from quartz dates back to antiquity. The modern refractive telescope was invented in the Netherlands by Lippershey in 1608 and refined and used widely by Galileo in Italy during the Renaissance to discover the satellites of Jupiter, among other extraterrestrial objects. The modern microscope was also invented in the Netherlands several years earlier, in 1595, by the same lens and eyeglass makers (Lippershey, Sacharias Jansen, and his son, Zacharias). Soon thereafter it was used to probe the microarchitecture of the human cell. Both telescopes and microscopes have evolved considerably over the years, guided by the elegantly simple fundamental physical laws that govern optical image formation by refraction proffered mathematically by Willebrord Snellius in 1621. Indeed, the principles of optics can simultaneously seem exceedingly simple and irreducibly complex. The early work in the Renaissance on the theory of diffraction and dispersion was led by Descartes, Huygens, and Newton, and was followed by the famous double-slit experiment of Young, which was subsequently supported by theory and calculations by Fresnel. The end of the nineteenth century saw the application of interferometry (Michelson) followed by the rise of quantum optics in the twentieth century. These scientific giants and their work provide the framework upon which all the fields and applications discussed in this book are built.

1.2 Introduction to medical imaging

The dawn of the modern era of medical diagnosis can be traced to 1896, when Wilhelm Roentgen captured the first x-ray image, that of his wife's hand (1). The development of radiology grew rapidly after that. Many noninvasive radiologic methodologies have been invented and applied successfully in clinical medicine and other areas of biomedical research. For the first 50 years of radiology, the primary examination involved creating an image by focusing x-rays through the body part of interest and directing them onto a single piece of film inside a special cassette. Later, modern x-ray techniques have been developed to significantly improve both the spatial resolution and the contrast detail. This improved image quality allows the diagnosis of smaller areas of pathology than could be detected with older technology. The next development involved the use of fluorescent screens and special glasses so that the physician could see x-ray images in real time. This caused the physician to stare directly into the x-ray beam, creating unwanted exposure to radiation. A major development along the way was the application of pharmaceutical contrast agents (dyes) to help visualize, for the first time, blood vessels, the digestive and gastrointestinal systems, bile ducts, and the gallbladder. The discovery of the image intensifier in 1955 has also contributed to the further blossoming of x-ray-based technology. Digital imaging techniques were implemented in the 1970s with the first clinical use and acceptance of the computed tomography (CT) scanner, invented by Godfrey Hounsfield (2).

Nuclear medicine (also called radionuclide scanning) also came into play in the 1950s. Nuclear medicine studies require the introduction into the body of very low-level radioactive chemicals. These radionuclides are taken up by the organs in the body and then emit faint radiation signals which are detected using special instrumentation. Imaging techniques that derive contrast from nuclear atoms, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), reveal information about the spatiotemporal distribution of a target-specific radiopharmaceutical, which in turn yields information about various physiological processes, such as glucose metabolism and blood volume and flow (3, 4, 5). Magnetic resonance imaging (MRI) provides structural and functional information from concentration, mobility, and chemical bonding of hydrogen (6, 7). All this information is essential for the early detection, diagnosis, and treatment of disease.

In the 1960s the principles of sonar (developed extensively during World War II) were applied to diagnostic imaging. The process involves placing a small device called a transducer against the skin of a patient near the region of interest, such as the kidneys. The transducer produces a stream of inaudible high-frequency sound waves that penetrate the body and bounce off the organs inside. The transducer detects sound waves as they bounce off or echo back from the internal structures and contours of the organs. These waves are received by an ultrasound machine and turned into live pictures through the use of computers and reconstruction software. For example, in ultrasonography, images reveal tissue boundaries (6).

In addition to these traditional imaging modalities, optical imaging began to play a significant role in clinical medicine in early 1960. Optical imaging at both the macroscopic and microscopic levels is used intensively these days by clinicians for diagnosis and treatment. New advances in optics, data acquisition, and image processing made possible the development of novel optical imaging technologies, including diffuse tomography, confocal microscopy, fluorescence microscopy, optical coherence tomography, and multiphoton microscopy, which can be used to image tissue or biological entities with enhanced contrast and resolution (8). Optical imaging technologies are more affordable than conventional radiological technologies and provide both structural and functional information with enhanced resolution. However, the optical techniques still lack sensitivity and specificity for cancer detection. Within the past few years, there has been increased interest in improving the clinical effectiveness of optical imaging by combining two or more optical imaging approaches (or integrating optical imaging technologies into traditional imaging modalities) (9, 10, 11).

Emerging optical technologies are now combined with novel exogenous contrast agents, including several types of nanovectors (e.g., nanoparticles, ligands, quantum dots), which can be functionalized with various agents (such as antibodies or peptides) that are highly expressed by cancer receptors (12, 13, 14, 15). These techniques provide improved sensitivity and specificity and make possible in situ labeling of cellular proteins to obtain a clearer understanding of the dynamics of intracellular networks, signal transduction, and cell–cell interactions (16, 17, 18, 19, 20). Ultimately, the combination of these new molecular and nanotechnology approaches with new high-resolution microscopic and spectroscopic techniques (e.g., optical coherence tomography, optical fluorescence microscopy, scanning probe microscopy, electron microscopy, and mass spectrometry imaging) can offer molecular resolution, high sensitivity, and a better understanding of the cell's complex “machinery” in basic research. The resulting accelerated progress in diagnostic medicine could pave the way to more inventive and powerful gene- and pharmacologically based therapies.

1.3 Outline of the book

The desire for powerful optical diagnostic modalities has motivated the development of powerful imaging technologies, image reconstruction procedures, three-dimensional rendering, and data segmentation algorithms. In particular, the overwhelming problem of light scattering that occurs when optical radiation propagates through tissue and severely limits the ability to image internal structure is discussed. The broad range of methods that have been proposed during the past decade or so to improve imaging performance are presented. The relative merits and limitations of the various experimental methods are discussed. We consider whether the new advanced approaches will contribute further to the likelihood of successful transition from benchtop to bedside. A brief presentation of each chapter follows.

Chapter 2 outlines traditional clinical imaging modalities and their use in therapy planning and guidance, including ultrasound (US), x-ray imaging, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). Although these imaging technologies provide good structural and functional information, they have inherent safety issues (especially x-ray/CT and those used in nuclear medicine—PET/SPECT), and their resolution is limited. Future advances in medical imaging may be possible by combining these traditional imaging modalities with novel optical, molecular, and nano-imaging approaches. The advantages of these multimodal approaches enable higher-resolution structural and functional imaging and disease detection in its early stage when the therapy success rate is relatively high.

Chapter 3 outlines the current imaging approaches in clinical medicine and is authored by leading clinicians from several prestigious teaching hospitals in the United States. This chapter is organized in four independent sections dealing with ophthalmic imaging, imaging of the gastrointestinal mucosa, cardioimaging, and neuroimaging. Current technological approaches, their limitations, and further needs are presented in detail.

Because the eye is the only transparent organ in the body accessible to in vivo and noninvasive examination, it is often the first and best venue for the application of new optical imaging techniques. Optical coherence tomography (OCT) is a prime example. Before this technique spread rapidly to other fields of inquiry, it was perfected in ophthalmology. The optics of the eye can be limiting in terms of theoretical achievable resolution (i.e., ocular aberrations, numerical aperture, etc.) compared to conventional or confocal microscopy. These limitations have, however, provided opportunities for the development of tools to overcome them (e.g., adaptive optics). Chapter 4 is a monograph of the optical-based imaging modalities for ophthalmic use, including conventional fundus imaging, OCT, and scanning laser ophthalmoscopy, and also new technologies such as adaptive optics and polarization imaging.

Confocal microscopy, invented by Minsky in 1957, is an elegant and simple method for achieving high image contrast by reduction of light scatter from adjacent (lateral and axial) voxels. Chapter 5 focuses on reflectance confocal microscopy (RCM) for skin cancer detection. RCM enables real-time in vivo visualization of nuclear and cellular morphology. The ability to observe nuclear and cellular details clearly sets this imaging modality apart from other noninvasive imaging technologies, such as MRI, OCT, and high-frequency ultrasound. The lateral resolution of RCM, typically 0.2 to 1.0\ μm, enables tissue imaging with a resolution comparable to that of high-magnification histology. As a result, RCM is being developed as a bedside tool for the diagnosis of melanoma and nonmelanoma skin cancers. The development and testing of advanced RCM instrumentation by the Memorial Sloan–Kettering cancer microscopy group is discussed in detail in this chapter.

Chapter 6 is devoted to the clinical applications of OCT in gastroenterology, including the esophagus, stomach, colon, duodenum, and the pancreatic and biliary ducts. OCT is an attractive tool for the interrogation of gastrointestinal tissue because it rapidly acquires optical sections at resolutions comparable to those of architectural histology, is a noncontact imaging modality, does not require a transducing medium, relies on endogenous contrast, and unlike the collection of forceps biopsies, is nonexcisional. Traditional assessment of gastrointestinal tissues is typically performed by endoscopy with accompanying forceps biopsy in organs with a larger-diameter lumen (esophagus and colon) or with brush cytology in the pancreatic or biliary ducts. OCT has shown promise for targeting premalignant mucosal lesions, grading and staging cancer progression, and reducing the risks and sampling error associated with biopsy acquisition. Although biopsy has traditionally been considered the gold standard for the diagnosis of gastrointestinal pathology, in many cases this assessment suffers greatly from sampling errors, with only a small percentage of the involved tissue being imaged. This is especially evident in cases where the disease may be focally distributed. Recent use of high-speed Fourier-domain OCT in the gastrointestinal tract has made significant strides toward comprehensive imaging, which may help to reduce the sampling error associated with the current assessment.

The most recent advances in confocal endomicroscopy for gastrointestinal (GI) cancer diagnosis are presented in Chapter 7. Confocal endomicroscopy is a rapidly emerging optical imaging modality that is currently being translated to routine clinical use. Advances in miniaturization have led to the development of numerous fiber optic–based confocal microscopes which may be deployed through the instrument channel of a conventional endoscope, or permanently packaged within the tip of a custom endoscope. Confocal endomicroscopes can enable real-time, high-resolution, three-dimensional visualization of epithelial tissues for improved early detection of disease and for image-guided interventions such as physical biopsies and endoscopic mucosal resection. Current research effort has focused on overcoming the limitations of confocal microscopy. For example, its limited field of view is now overcome by real-time generation of a mosaic of stitched images. The application of confocal microscopy for the interrogation of epithelial surfaces in the GI tract presents unique design challenges. Therefore, this chapter focuses on clinical motivation, challenges, design parameters, and other fundamental aspects of GI endomicroscopy. Also discussed are the latest efforts to develop miniature confocal microscopes that are compatible with those of GI endoscopy.

Chapter 8 presents recent progress in minimally invasive approaches in interventional cardiology (IC). The diagnosis of vulnerable plaques occupies an important part of this chapter. The structure of these plaques (i.e., hard core, fluid-filled lesions accessible only with depth-resolved techniques) makes them the most difficult to diagnose, yet they seem to be responsible for most deleterious coronary events. Identification and visualization of high-risk plaques are key to designing customized therapeutic approaches. The ultimate goal is to accurately categorize high-risk patients, target therapy to appropriate areas of vulnerable plaque, and thus prevent or reduce the probability of adverse events. A number of minimally invasive imaging modalities currently in use are presented, including intravascular ultrasound (IVUS) and angioscopy. Also presented are promising new investigational methodologies, including OCT, intracoronary thermography, near-infrared spectroscopy, and intracoronary MRI. OCT in particular uniquely enables excellent resolution of coronary architecture and precise characterization of plaque morphology.

An overview of time-resolved (lifetime) laser-induced fluorescence spectroscopy (TR-LIFS) is presented in Chapter 9. TR-LIFS instrumentation, methodologies for in vivo characterization, and diagnosis of biological systems are presented in detail. Emphasis is placed on the translational research potential of TR-LIFS and on determining whether intrinsic fluorescence signals can be used to provide useful contrast for the diagnosis of high-risk atherosclerotic plaque and brain tumors intraoperatively.

Chapter 10 outlines the use of near-infrared spectroscopy (NIRS) for noninvasive monitoring of brain hemodynamics and oxidative metabolism (i.e., oxygenation status). This technology is capable of monitoring cerebral activity in response to various stimuli (motor, visual, and cognitive) and therefore is currently being used to study functional processes in the brain, to diagnose mental diseases, and more precisely, to localize brain injuries. Clinical demonstration and widespread use of this technology is expected to increase in the coming years because of its promise for functional imaging. In particular, major breakthroughs are expected in cutting-edge techniques such as time-domain functional near-infrared spectroscopy. Current research systems employ low-power pulsed diode lasers and complex, efficient detection instrumentation. Future prototype clinical instruments will achieve higher signal/noise ratios through the use of ultrafast (picoseconds), high-power (>1 W) broadband fiber laser and miniaturized, sensitive, and fast photonic crystal devices combined with high-throughput photodetection electronics.

Chapter 11 describes the application of NIRS to mammography. In optical mammography, diagnosis is based on the detection of local differential concentrations of endogenous absorbers and/or scatterers between normal and diseased breast tissue. Various implementation approaches in conjugation with MR imaging are discussed in detail. The prevalence and implication of age, hormonal status, weight, and demographic factors on complex structural changes in the breast are discussed as well. Such intra- and interpatient variations affect the effectiveness of these imaging modalities adversely and to date have restricted wide clinical use to a specific demographic or time window. As clinical optical mammography matures, its potential impact on cancer management will become more clearly defined. The main applications of this optical technology, as proposed by the Network for Translational Research in Optical Imaging, are monitoring of neoadjuvant chemotherapy response, screening for subpopulations of women in which mammography does not work well, and optical imaging as an adjunct to x-ray mammography.

A promising new optical technology called photoacoustic tomography (PAT) is introduced in Chapter 12 for breast imaging. Research interest in laser-induced PAT is growing rapidly, largely because of its unique capability of combining high-contrast optical imaging with high-resolution ultrasound in the same instrument. Recent in vivo studies have shown that the optical absorption contrast ratio between tumor and normal tissues in the breast can be as high as 3 : 1 in the near-infrared region, due to significantly increased tumor vascularity. However, optical imaging has low spatial resolution, due to strong light scattering. Ultrasound imaging can provide better resolution than optical imaging due to less scattering of acoustic waves. However, the contrast for ultrasound imaging is low, and it is often incapable of revealing diseases in early stages. In a single hybrid imaging modality, PAT combines the advantages of optical and ultrasound imaging while avoiding the limitations of each. PAT imaging can penetrate to a depth of about 1 cm with an axial resolution of less than 100\ μm at a wavelength of 580 nm. PAT has shown the potential to detect breast cancer, to probe brain functioning in small animals, and to assess vascular and skin diseases.

Chapter 13 focuses on the application of optical imaging to tissue angiogenesis monitoring. Angiogenesis is a process fundamental to several normal tissue physiological functions and responses as well as to many pathological conditions. The ability to monitor and quantify angiogenesis clinically could aid in the management of certain diseases, healing responses, and therapies. While several methods for measurement of angiogenesis are under development and are being implemented using conventional medical imaging modalities, optical techniques have also shown potential. To properly design and evaluate optical techniques to measure angiogenesis, an appreciation of the complex physiology of the process is necessary. Methodology to quantify angiogenesis and independent test optical measurements are also needed. The fundamental characteristics of angiogenesis, measurement methods, and the current state of optical techniques are reviewed briefly in this chapter.

Chapter 14 introduces a relatively new technology, called phase-contrast optical coherence tomography. This technique can detect subwavelength changes in optical pathlength (OPL) by measuring the phase of an interference signal. Although phase information is readily available in any interferometric setup, environmental noise corrupts the phase information, rendering it difficult to use. Robust phase measurement requires interferometer designs that cancel common-mode noise. This can be achieved with common path and differential phase interferometric implementations. Measurement of depth-resolved subwavelength changes in OPL is now possible for novel optical imaging applications. Phase-sensitive low-coherence interferometry in both time- and spectral-domain implementation, as well as their potential for biomedical applications (including surface profilometry, quantitative phase-contrast microscopy, and optical detection of neural action potentials), are described in this chapter.

Polarization is a fundamental property of light that can be harnessed to provide additional contrast without staining or labeling. Imaging technologies that detect and visualize the interaction of tissue with polarized light, revealing structural or chemical characteristics not visible with standard intensity imaging, are described in Chapter 15. The anisotropic real and imaginary parts of the refractive index of tissue are fundamental properties that can be quantified through the detection of transmitted or reflected polarized light. The linear and circular birefringence and dichroism also calculated with polarimetric techniques can help to differentiate normal and diseased tissue. Currently, linear birefringence is most often measured because it is related to the highly organized structure of collagen. Circular birefringence and linear and circular dichroism, which are related to other structural and chemical anisotropies, are generally not explored. Whereas traditional light-scattering techniques normally probe only size distribution and concentration of particles, polarized light scattering is sensitive to shape, orientation, and internal structure of the particles, as well as to structural characteristics of the global system. Applications of this technology to the fields of biomedicine, materials science, and industrial and military sensors are presented in this chapter.

Chapter 16 covers the use of various nanotechnologies for contrast enhancement in optical imaging. Optical imaging technologies are more affordable than traditional radiological technologies and provide both structural and functional information with enhanced resolution. However, they still lack sensitivity and specificity for cancer detection. Therefore, in the past few years there has been increasing interest in improving clinical effectiveness of optical imaging by combining emerging optical technologies with novel exogenous contrast agents, including several types of nanovectors (e.g., nanoparticles, ligands, quantum dots), which can be functionalized with various agents (such as antibodies or peptides) that are expressed highly by cancer receptors. In this way, it becomes possible to label proteins in live cells and obtain a clearer understanding of the dynamics of intracellular networks, signal transduction, and cell–cell interactions in addition to improving sensitivity and specificity. Use of the enhanced sensitivity and specificity of molecular imaging approaches in medicine has the potential to affect positively the prevention, diagnosis, and treatment of various diseases, including cancer. These new molecular and nanotechnology approaches with new developments in microscopic and spectroscopic techniques toward high spatial resolution (i.e., optical coherence tomography, optical fluorescence microscopy, etc.) are presented to some extent in this chapter. Implications of the various nanotechnologies for more efficient drug delivery and tissue regeneration are discussed as well.

Chapter 17 focuses on the use of molecular probes for optical contrast enhancement of GI cancers. The surface of the GI tract is accessible to direct examination via endoscopy. The most common GI cancers originate in the superficial mucosa, where unscattered ballistic photons can penetrate to depths that are relevant for interrogating tissue properties and detecting cellular markers. Improvements in instrumentation now permit the detection of these photons to depths that were not possible previously. In addition, molecular probes whose binding characteristics are verified by microscopy facilitate rapid wide-field detection of precancerous lesions over large areas, followed by closer inspection with endomicroscopy. Probes that detect GI cancer have been identified and the clinical application of both contrast-enhancing agents and specific molecular diagnostic reagents capable of revealing early disease markers is on the horizon. The effort ongoing toward the development of GI cancer probes and detection reagents is presented in detail in this chapter.

A broad cross section of optical imaging research and clinical technology development for early disease detection and therapy guidance is described in the book. We recognize that the broadness of the biomedical optical imaging field makes it likely that we have omitted many important investigations in our sampling. Moreover, the rapid pace of discovery, although exciting for all the authors, also provided the challenge of trying to hit a moving target. We hope that the book will provide a foundation of knowledge upon which future technological developments in optical imaging will materialize.

References

1. Stanton, A., Wilhelm Conrad Röntgen on a new kind of rays: translation of a paper read before the Würzburg Physical and Medical Society, 1895 Nature, Vol. 53, No. 1896, pp. 274–276.

2. Ambrose, J., and Hounsfield, G., Computerized transverse axial tomography, Br. J. Radiol., Vol. 46, No. 542, 1973, pp. 148–149.

3. Terpogossian, M.M., et al., Positron-emission transaxial tomograph for nuclear imaging (Pett), Radiology, Vol. 114, No. 1, 1975, pp. 89–98.

4. Nutt, R., The history of positron emission tomography, Mol. Imaging Biol., Vol. 4, No. 1, 2002, pp. 11–26.

5. Patton, J.A., and Budinger, T.F. (eds.), Single Photon Emission Computed Tomography, 4th ed., Diagnostic Nuclear Medicine, M.P. Sandler et al. (eds.), Lippincott Williams & Wilkins, Philadelphia, 2003.

6. Lauterbur, P.C., Image formation by induced local interactions: examples employing nuclear magnetic resonance, Nature, Vol. 242, No. 5394, 1973, pp. 190–191.

7. Shung, K.K., Diagnostic Ultrasound: Imaging and Blood Flow Measurements, Taylor & Francis Group, CRC Press Book, Boca Raton, FL, 2005.

8. Fujimoto, J.G., and Farkas, D., Biomedical Optical Imaging, Oxford University Press, New York, 2009.

9. Nahrendorf, M., Sosnovik, D.E., and Weissleder, R., MR-optical imaging of cardiovascular molecular targets, Basic Res. Cardiol., Vol. 103, No. 2, 2008, pp. 87–94.

10. Cherry, S.R., Multimodality in vivo imaging systems: Twice the power or double the trouble? Annu. Rev. Biomed. Eng., Vol. 8, 2006, pp. 35–62.

11. Serganova, I., and Blasberg, R.G., Multi-modality molecular imaging of tumors, Hematol. Oncol. Clin. North Am., Vol. 20, No. 6, 2006, pp. 1215.

12. Licha, K., Schirner, M., and Henry, G., Optical agents, Handb. Exp. Pharmacol., Vol. 185, Pt. 1, 2008, pp. 203–222.

13. Zhang, L.M., et al., Molecular imaging of Akt kinase activity, Nat. Med., Vol. 13, No. 9, 2007, pp. 1114–1119.

14. Medintz, I.L., et al., Quantum dot bioconjugates for imaging, labelling and sensing, Nat. Mater., Vol. 4, No. 6, 2005, pp. 435–446.

15. Weissleder, R., and Ntziachristos, V., Shedding light onto live molecular targets, Nat. Med., Vol. 9, No. 1, 2003, pp. 123–128.

16. Kumar, S., and Richards-Kortum, R., Optical molecular imaging agents for cancer diagnostics and therapeutics, Nanomedicine, Vol. 1, No. 1, 2006, pp. 23–30.

17. Morgan, N.Y., et al., Real time in vivo non-invasive optical imaging using near-infrared fluorescent quantum dots, Acad. Radiol., Vol. 12, No. 3, 2005, pp. 313–323.

18. Wang, H.Z., et al., Detection of tumor marker CA125 in ovarian carcinoma using quantum dots, Acta Biochim. Biophys. Sin., Vol. 36, No. 10, 2004, pp. 681–686.

19. Jaiswal, J.K., et al., Long-term multiple color imaging of live cells using quantum dot bioconjugates, Nat. Biotechnol., Vol. 21, No. 1, 2003, pp. 47–51.

20. Brigger, I., Dubernet, C., and Couvreur, P., Nanoparticles in cancer therapy and diagnosis, Adv. Drug Deliv. Rev., Vol. 54, No. 5, 2002, pp. 631–651.

Chapter 2

Traditional Imaging Modalities in Clinical Medicine

Ileana Iftimia and Herbert Mower

Lahey Clinic, Burlington, Massachusetts; Tufts University School of Medicine, Boston, Massachusetts

2.1 Introduction

In this chapter we present a brief overview of the most important traditional imaging modalities currently used in clinical medicine for diagnosis and treatment. The human body is an incredibly complex system. A real challenge for researchers and physicians is acquiring and processing information about the human body with the purpose of using these data for diagnosis and treatment. The use of imaging to interpret biological processes is in continuous expansion, not only in clinical medicine but also in the biomedical research field. For example, in ultrasonography, images reveal tissue boundaries. X-ray films and computed tomography (CT) images reveal the intrinsic properties of the regions of the body through which they are transmitted, such as atomic number, physical density, and electron density. Nuclear medicine images, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), reveal information about spatial or spatiotemporal distribution of a target-specific radiopharmaceutical, which in turn yields information about various physiological processes, such as glucose metabolism and blood volume and flow. Magnetic resonance imaging (MRI) gives information about the structure and function of the body, using data such as concentration, mobility, and the chemical bonding of hydrogen. All this information is essential for the early detection, diagnosis, and treatment of disease.