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Bioimaging Bioimaging Imaging by Light and Electromagnetics in Medicine and Biology Edited by Shoogo Ueno First edition published 2020 by CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 and by CRC Press 2 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN © 2020 Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, LLC Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume respon- sibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact [email protected] Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. ISBN: 978-0-367-20304-7 (hbk) ISBN: 978-0-367-49043-0 (pbk) ISBN: 978-0-429-26097-1 (ebk) Typeset in Times by Deanta Global Publishing Services, Chennai, India Contents Preface..............................................................................................................................................vii Acknowledgments .......................................................................................................................... xiii Editor ...............................................................................................................................................xv List of Contributors ........................................................................................................................xvii Chapter 1 Introduction ..................................................................................................................1 Shoogo Ueno Chapter 2 Molecular Imaging of Viable Cancer Cells................................................................ 15 Mako Kamiya and Yasuteru Urano Chapter 3 Molecular Vibrational Imaging by Coherent Raman Scattering ...............................37 Yasuyuki Ozeki, Hideaki Kano, and Naoki Fukutake Chapter 4 Magnetic Resonance Imaging: Principles and Applications ...................................... 75 Masaki Sekino and Shoogo Ueno Chapter 5 Chemical Exchange Saturation Transfer and Amide Proton Transfer Imaging ...... 101 Takashi Yoshiura Chapter 6 Diffusion Magnetic Resonance Imaging in the Central Nervous System ............... 121 Kouhei Kamiya, Yuichi Suzuki, and Osamu Abe Chapter 7 Magnetic Particle Imaging .......................................................................................155 Keiji Enpuku and Takashi Yoshida Chapter 8 Sensing of Magnetic Nanoparticles for Sentinel Lymph Nodes Biopsy .................. 185 Masaki Sekino and Moriaki Kusakabe Chapter 9 Optimizing Reporter Gene Expression for Molecular Magnetic Resonance Imaging: Lessons from the Magnetosome ...............................................................201 Qin Sun, Frank S. Prato, and Donna E. Goldhawk v vi Contents Chapter 10 Magnetic Control of Biogenic Micro-Mirror ........................................................... 215 Masakazu Iwasaka Chapter 11 Non-Invasive Techniques in Brain Activity Measurement Using Light or Static Magnetic Fields Passing Through the Brain ............................................................ 233 Osamu Hiwaki Index ..............................................................................................................................................249 Preface Biomedical imaging and sensing technologies have been rapidly developing and expanding in a variety of felds in medicine and biology. This book, titled Bioimaging: Imaging by Light and Electromagnetics in Medicine and Biology, explores new horizons in bioimaging from the molecu- lar and cellular level to the human brain. Bioimaging is applied in a variety of felds with numerous techniques in different spectrums. For this book, we limit the focus to imaging by light and electro- magnetics for application in medicine and biology. In 2015, we edited a book titled Biomagnetics: Principles and Applications of Biomagnetic Stimulation and Imaging. Also published by CRC Press Taylor & Francis Group, one-third of the book was related to bioimaging, but molecular imaging was not included. However, imaging and sensing technologies have rapidly accelerated since that time. I received an inquiry from the editor in physics at CRC Press Taylor & Francis Group in August 2018, asking me about the possibility of a new book. It was a good opportunity for me to start making a new framework. I, fortunately, have coworkers and scientists in different institutions, col- leagues at the University of Tokyo, and friends overseas, who are experts in biomedical imaging. I planned to make the book consist of more than ten chapters from the molecular level to the human brain. It is fortunate that 11 chapters arrived by the deadline of manuscript submission, although a few chapters did not arrive by the cutoff date. The rest will be hopefully available in an online read- able version in parallel to this published book. A brief outline of each chapter is as follows: CHAPTER 1. INTRODUCTION (SHOOGO UENO) A history of the discovery of electromagnetic felds is briefy described in the opening chapter. After classifcation of electromagnetic felds from lower frequencies to higher frequencies, medi- cal devices and biomedical imaging systems used in different frequency bands are discussed. The vacuum ultraviolet ray with a wavelength of around 200 nm is the boundary of ionizing radiation and non-ionizing radiation. It is emphasized that medical devices and biomedical imaging tools are used in different frequency bands either in the ionizing radiation region or in the non-ionizing radiation region. Then, the history and overview of imaging tools are described. In advances in biomedical imag- ing and stimulation, these include computed tomography (CT), magnetic resonance imaging (MRI), magnetoencephalography (MEG), transcranial magnetic stimulation (TMS), magnetic particle imaging (MPI), and near-infrared spectroscopic (NIRS) imaging. In advances in molecular and cellular imaging, green fuorescent protein (GFP), optical fuorescence and cancer therapy, optoge- netics and studies of neuronal circuit dynamics in the brain, Raman scattering and coherent Raman scattering (CRS) microscopy, molecular imaging based on MRI, and magnetic orientation of living systems and biogenic micromirrors are introduced. CHAPTER 2. MOLECULAR IMAGING OF VIABLE CANCER CELLS (MAKO KAMIYA AND YASUTERU URANO) Molecular imaging that visualizes cellular functions or molecular processes inside the body is described in Chapter 2. Probes used for molecular imaging are targeted to biomarkers for specifc visualization of targets or pathways. Optical imaging based on fuorescence emission from fuoro- phores is introduced as a promising technique. To achieve a reliable molecular imaging for the detection of viable cancer cells, two categories of unique optical fuorescence imaging probes are developed: always-on probes and activatable vii viii Preface probes. Always-on probes consist of fuorescent reporting units (fuorophores) linked to tumor-tar- geting moieties such as antibodies, affbodies, or small-molecular ligands. Activatable probes of which fuorescence is initially suppressed is turned on by a molecular switch at tumor sites, provid- ing a cancer-specifc signal with high sensitivity and a high tumor-to-background signal ratio. In this chapter, frst, optical fuorescence imaging probes available for visualizing cancer cells are reviewed. Second, activatable probes, which offer particular advantages in terms of provid- ing a cancer-specifc signal with high sensitivity and a high tumor-to-background signal ratio, are explored. Third, various switching mechanisms and design strategies for activatable bioimaging probes are discussed. Finally, some applications demonstrating the usefulness of the designed probes are presented. CHAPTER 3. MOLECULAR VIBRATIONAL IMAGING WITH COHERENT RAMAN SCATTERING (YASUYUKI OZEKI, HIDEAKI KANO, AND NAOKI FUKUTAKE) Raman scattering is a light scattering phenomenon involving molecular vibration of substances that interact with light, providing the vibrational spectrum of molecules. The Raman scattering technique has the potential to observe the behavior of molecules, however, the intensity of Raman scattering is quite weak, and it takes a long acquisition time. Coherent Raman scattering (CRS) microscopy using two-color and/or broadband laser pulses is introduced to overcome the problems in the original Raman scattering technique. CRS enables a dramatic improvement in the acquisition time and sensitivity of Raman scattering. Optical microscopy based on CRS allows for biological imaging with molecular vibrational contrast. CRS microscopy is opening up a variety of applications which include label-free molecular anal- ysis of cells and tissues, monitoring of metabolic activities, and supermultiplex imaging with more than ten colors. In this chapter, the general concepts and recent applications of CRS microscopy are described. Specifcally, the basic principles of CARS and stimulated Raman scattering (SRS) microscopy are explained, showing practical instrumentations. The applications to label-free imaging, metabolic imaging, and supermultiplex or ultramultiplex imaging are introduced. In addition, the classical and quantum-mechanical pictures for various CRS processes as well as the theory of image formation in CRS microscopy are explained in detail. CHAPTER 4. MAGNETIC RESONANCE IMAGING: PRINCIPLES AND APPLICATIONS (MASAKI SEKINO AND SHOOGO UENO) Magnetic resonance imaging (MRI) provides a wealth of anatomical and physiological information. The advantages of MRI over other modalities are high spatial resolution and no radiation exposure. This chapter gives a basic introduction to MRI consisting of physical principles and a few biomedi- cal applications such as functional imaging of the brain, mapping of electric properties of tissues, and MRI-guided focused ultrasound therapy. An MRI system is equipped with a strong magnet which induces nuclear magnetization in the target body. The MRI signals originate from the rotation of the nuclear magnetization under the magnetic felds. The application of a gradient magnetic feld causes a spatial variation of signal frequency and an image is reconstructed by means of Fourier transformation. Details of these phe- nomena are comprehensively presented with schematic illustrations, sample images, and equations. Functional MRI visualizes a local change in blood oxygenation associated with neuronal electrical activities. The magnetic susceptibility of blood depends on the oxygenation level, which affects the signal intensity of the MRI. Functional MRI is applicable to both evoked and spontaneous brain activities. The neuronal activities are relevant to electrical properties of tissues. P reface ix Applications of MRI include mapping of electrical properties such as conductivity, permittivity, and weak magnetic felds arising from neuronal currents. Pattern recognition and various artifcial intelligence techniques are attracting attention because of the ability to extract information from MRI. State-of-the-art imaging processing techniques for MRI are also introduced in this chapter. CHAPTER 5. CHEMICAL EXCHANGE SATURATION TRANSFER AND AMIDE PROTON TRANSFER IMAGING (TAKASHI YOSHIURA) Molecular imaging based on MRI is an attractive and challenging theme to be studied for both basic research and clinical diagnosis. Chemical exchange saturation transfer (CEST) is a novel molecular magnetic resonance (MR) contrast based on saturation transfer from solutes to bulk water molecules via proton exchanges. CEST helps detect low concentration molecules in vivo. A variety of diamagnetic and paramagnetic compounds have been proposed as exogenous CEST agents for specifc purposes such as reporting pH or monitoring metabolism, although only a few are clinically applicable. On the other hand, recent studies have shown the feasibility and possible clinical impact of CEST imaging of endogenous mobile molecules with amide, amine, and hydroxyl protons. Amide proton transfer (APT) imaging is a specifc type of CEST imaging which detects endogenous mobile proteins and peptides in tissue. Currently, APT imaging is considered to be the most clinically relevant CEST imaging, and it has actually started to show promising results, especially in oncologic imaging. In this chapter, frst, the theory of CEST and APT imaging are explained with illustrated fgures. Next, the proposed clinical utilities of CEST and APT imaging and their pitfalls are described. Finally, potentials for future development are discussed. CHAPTER 6. DIFFUSION MAGNETIC RESONANCE IMAGING IN THE CENTRAL NERVOUS SYSTEM (KOUHEI KAMIYA, YUICHI SUZUKI, AND OSAMU ABE) Diffusion MRI measures the diffusion of water molecules along different directions. Such informa- tion provides images sensitive to the underlying tissue structure on the order of micrometers, with orders of magnitude below the nominal image voxel size. Because of this unique advantage, diffu- sion MRI gained popularity in both clinical and scientifc communities. Its power to probe tissue microstructure non-invasively made a signifcant impact on clinical medicine, as represented by the discovery of a profound decrease of apparent diffusivity in acute stroke in 1990. Also, diffusion anisotropy observed in the nervous tissue led to the development of diffusion tensor imaging (DTI), as well as a methodology for tracing macroscopic fber tracts (tractography) that is now widely applied for presurgical planning. Since these founding works, signifcant improvements have been made in both scanner hardware and acquisition schemes, pushing the limit of the available data range for clinical study. These have led to the development of several newer analytic frameworks suitable for extended acquisition, as well as advanced tractography methods, enhancing our under- standing of diseases and brain anatomy. Moreover, a biologically inspired compartmental model has been proposed in an effort to derive metrics that are ready for naïve interpretation and translation to histology such as axon diameter, intra-cellular water fraction, and compartmental diffusivities. This chapter describes what has been achieved so far with diffusion MRI, focusing on applica- tions in clinical scanners and a discussion about the problems currently under debate. The frst part of chapter is devoted to basic concepts of conventional DTI and tractography, along with a few examples which showcase the contribution of diffusion imaging to clinical medicine. The second part introduces technical advances that followed DTI. Applications of tractography for quantifca- tion of the brain network, i.e., connectome, are also briefy described. Finally, limitations, pitfalls, and challenges in modern diffusion imaging are discussed.

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