Advances in Biophotonics (NATO Science)

ADVANCES IN BIOPHOTONICS

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Series I. Life and Behavioural Sciences – Vol. 369

ISSN: 1566-7693

Advances in Biophotonics

Edited by

Brian C. Wilson Ontario Cancer Institute and University of Toronto, Toronto, Canada

Valery V. Tuchin Institute of Optics and Biophotonics, Saratov State University, Saratov, Russia

and

Stoyan Tanev Vitesse Re-Skilling™ Canada, Kanata, Canada

Amsterdam • Berlin • Oxford • Tokyo • Washington, DC Published in cooperation with NATO Public Diplomacy Division

Proceedings of the NATO Advanced Study Institute on Biophotonics: From Fundamental Principles to Health, Environment, Security and Defence Applications Ottawa, Canada 29 September – 9 October 2004

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Advances in Biophotonics B.C. Wilson et al. (Eds.) IOS Press, 2005 © 2005 IOS Press. All rights reserved.

Preface Brian C. WILSON a, Valery V. TUCHIN b and Stoyan TANEV c a Ontario Cancer Institute/University of Toronto, Canada b Institute of Optics and Biophotonics, Saratov State University, Russia c Vitesse Re-Skilling™ Canada, Kanata, Ontario, Canada

Introduction This volume is the result of the first NATO Advanced Study Institute (ASI) on the topic “Biophotonics: From Fundamental Principles to Health, Environment, Security and Defence Applications” held in Ottawa, Canada, September 29 – October 9, 2004. This ASI was particularly timely, since the field of biophotonics is rapidly emerging in both academia and industry: for example, the number of hits for “biophotonics” if it is entered in the internet search engine Google® has quadrupled in the last year. The meeting was notable for the extent of international attendance, with 116 participants from 18 different countries, including a very high representation from former Sovietbloc countries, demonstrating the intense interest in this topic. A full list of the speakers and topics covered at the ASI is given below. What then is biophotonics? In the most general terms, it is the convergence of photonics and life sciences. Photonics – the science and technology of light generation, manipulation and measurement – has itself seen a remarkable expansion in the past 20 years, both in research and in commercialization, particularly in telecommunications. Despite, or perhaps partly because of, the downturn in this sector, there has been substantial transfer of photonic technologies in the past 5 years into biophotonics applications. Nowhere is this clearer than in the sub-surface tissue imaging technique of optical coherence tomography (discussed in the chapters by V.V. Tuchin and B.C. Wilson), in which many of the key components are taken straight from optical telecom (light sources, fiber splitters, optical circulators, etc). This technology transfer has greatly accelerated the development of biophotonic techniques and applications. Conversely, the life sciences have an increasing need for new technologies to which photonics can make significant contributions. As biology and medicine move into the post-genomics era, it is increasingly important to have highly sensitive tools for probing cells, tissues and whole organism structure and functions. The optical spectrum (UV-visible-infrared) is well suited to this, since the quantum energy of optical photons is comparable to molecular energy levels of biomolecules, so that optical spectroscopies and imaging techniques provide rich biomolecular information. Examples are given in the chapters by J. Chan and colleagues and S. Lane et al. in biochemical analysis and in single-cell analysis, respectively, using Raman spectroscopy. The sensitivity of modern optical techniques even allows measurements of single molecules, as discussed by T. Huser et al. Through photonic technologies such optical fibers, as discussed in the chapter by M. Ben-David and I. Gannot, and sensitive imaging detectors, these measurements can often be done in a non- or minimally-invasive

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way, which is tremendously valuable for clinical and remote-sensing applications. The technological elegance of photonics is illustrated both by this chapter and that by Cartwright in the domain of optical biosensors, which are becoming ubiquitous in many applications, including biomedical, environmental and bio/chemo security. This breadth of applications of specific optical techniques is well illustrated also in the chapter by V.M. Savov on chemiluminscence and bioluminescence. At the same time, optical wavelengths are comparable to cellular/subcellular structure dimensions, so that imaging at very high spatial resolution is possible. Photonic technologies have thus revolutionized the field of optical microscopy, as illustrated in the chapters by H. Schneckenburger and by T. Huser et al. In clinical medicine this ability to probe and image tissues is leading to a wide range of novel diagnostic methods. Examples of these techniques are given by Matthews and colleagues. In parallel, therapeutic applications of light have developed rapidly over the past 20 years, with many applications of surgical lasers operating by photothermal or photomechanical interactions with tissue. The application of photochemical interactions is presented in the chapter by B.C. Wilson on the specific technique of photodynamic therapy using light-activated drugs. The principles of photobiology that underlie these photothermal, photochemical and photomechanical effects are discussed in depth by P. Prasad. Complementing this, S. Tanev and colleagues provide an introduction to some exact modeling methods of tissue optics that determine how light energy is distributed in tissue, while V.V. Tuchin examines light propagation and interactions with blood, both theoretically and experimentally. Understanding these lighttissue interactions is key to optimizing the delivery of light to tissue, for both treatments and diagnostics. Finally, the new field of nanotechnology is now penetrating into biophotonics. Examples include the use of nanoparticles such as metal nanospheres or rods and quantum dots for enhanced cell and tissue imaging and local light energy absorption. The chapter by C.E. Talley et al. discusses one specific implementation, namely the use of nanoparticles for enhancing Raman biospectroscopy. As will be evident, this volume is not intended as a comprehensive text on biophotonics. Rather, it presents ‘snapshots’ of some of the most exciting developments, from a perspective of photonic technologies, and life-sciences applications. The editors hope that the reader will be equally excited and encouraged to pursue further in-depth reading, using the extensive references provide by the authors of each chapter.

1. Speakers and Topics Introduction to Biophotonics Dr. Paras Prasad, Institute for Lasers, Photonics and Biophotonics, University at Buffalo, USA Biochip and Nano-Technologies and Applications Dr. Tuan Vo-Dinh, Center for Advanced Biomedical Photonics, ORNL, USA Biophotonics – an Emerging Technology Paradigm Dr. Bill Colston, Lawrence Livermore National Laboratory, USA

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Eye Optics – Fundamentals, Instrumentation and Applications Dr. Réjean Munger, University of Ottawa Eye Institute, Canada Optics of Blood – Methods and Applications Dr. Alexander Priezzhev, Moscow State University, Russia Commercialization Aspects of Confocal Microscopy Dr. Ted Dixon, Biomedical Photometrics Inc. and University of Waterloo, Canada Photonics in the Neurosciences Dr. Yves de Koninck, Centre de Recherche Robert-Giffard, Université Laval, QC, Canada Biophotonics Light Delivery Systems Dr. Moshe Ben-David, Tel-Aviv University, Israel Integrated Biosensors Dr. Alexander Cartwright, State University of New York at Buffalo, USA Applications of Biophotonics Dr. Dennis Matthews, Center for Biophotonics Science and Technology University of California at Davis, USA Fluorescence Spectroscopy and Microscopy Dr. Herbert Schneckenburger, Fachhoschschulee Aalen Biophotonics Group Institute of Applied Research, Germany Photodynamic Therapy Dr. Brian Wilson, Ontario Cancer Institute and University of Toronto, Canada Bioluminescence and Chemiluminescence Dr. Varban Savov, Medical Physics Department, Sofia University, Bulgaria Tissue and Blood Optical Properties Control Dr. Valery Tuchin, Saratov State University, Saratov, Russia Biophotonics Simulations: Light Scattering from Bio-Cells Dr. Stoyan Tanev, Vitesse Re-Skilling™ Canada Inc. Single Molecule Microscopy and Spectroscopy Dr. Thomas Huser, Center for Biophotonics Science and Technology, University of California at Davis, USA Micro-Raman Spectroscopy and Laser Trapping Dr. James Chan, Center for Biophotonics Science and Technology, University of California at Davis, USA

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Nanoparticle Based Surfaced Enhanced Raman Spectroscopy Dr. Chad Talley, Center for Biophotonics Science and Technology, University of California at Davis, USA Mathematical Analysis of Raman Spectra Dr. Steve Lane, Center for Biophotonics Science and Technology, University of California at Davis, USA

2. Acknowledgements The editors would like to express their gratitude to all organizations that have supported and actively participated in this ASI. These include: the NATO Security through Science Program in Brussels, Belgium, for the finical grant that has initiated the organization of the ASI; Vitesse Re-Skilling™ Canada (www.vitesse.ca), for initiating the ASI and taking the responsibility of its program design, project management and implementation; the Canadian Institute for Photonic Innovations (www.cipi.ulaval.ca), as a valuable partner in the organization and for supporting the participation of Canadian students; the Canadian Institutes for Health Research for financially supporting the organization of the ASI and sharing the vision of the strategic importance of fostering biophotonics R&D in Canada; the Center for Biophotonics Science and Technology with the University of California at Davis as leading institution, for the financial support and for setting up the biophotonics demonstration session, together with scientists from the Laboratory for Applied Biophotonics, Photonics Research Ontario/University Health Network (www.uhnres.utoronto.ca/biophotonics), Toronto; the Canadian Department of Foreign Affairs, and specifically its Global Partnership Program, together with the International Science and Technology Center in Moscow, Russia, for supporting the participation of Russian scientists; the Canadian International Development Agency together with the Science and Technology Center in Kiev, Ukraine, for supporting the participation of Ukrainian scientists; and last but not least the State University of New York at Buffalo and its Institute for Lasers, Photonics and Biophotonics for supporting the participation of their students and helping the initial program design of the ASI.

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Contents Preface Brian C. Wilson, Valery V. Tuchin and Stoyan Tanev

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Fibers and Waveguides for Medical Applications Moshe Ben-David and Israel Gannot

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Integrated Optical Sensors for Biophotonics Alexander Cartwright The Finite-Difference Time-Domain Method in the Biosciences: Modelling of Light Scattering by Biological Cells in Absorptive and Controlled Extra-Cellular Media Stoyan Tanev, Wenbo Sun, Norman Loeb, Paul Paddon and Valery Tuchin Control of Tissue and Blood Optical Properties Valery V. Tuchin

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Photobiology for Biophotonics Paras N. Prasad

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Raman Spectroscopy: Chemical Analysis of Biological Samples James W. Chan, Douglas S. Taylor, Theodore Zwerdling, Stephen M. Lane, Chad E. Talley, Christopher W. Hollars and Thomas Huser

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Raman Spectral Analysis: A Case Study Stephen M. Lane, James Chan, Thomas Huser, Ko Ihara, Chad Talley, Douglas Taylor and Theodore Zwerdling

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Nanoparticle-Based Surface-Enhanced Raman Spectroscopy Chad E. Talley, Thomas Huser, Christopher W. Hollars, Leonard Jusinski, Ted Laurence and Stephen Lane

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Fluorescence Spectroscopy and Microscopy Herbert Schneckenburger

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Single Molecule Fluorescence Microscopy and Spectroscopy Thomas Huser, Christopher W. Hollars, James W. Chan, Samantha Fore, Chad E. Talley and Stephen M. Lane

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Chemiluminescence and Bioluminescence: Mechanisms, Fundamental Principles and Applications Varban М. Savov Photodynamic Therapy Brian C. Wilson

228 241

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Overview of Research Activities at the NSF Center for Biophotonics Science and Technology D. Matthews, R. Alvis, J. Boggan, F. Chuang, S. Fore, C. Lagarias, C. Lieber, A Parikh, R. Ramsamooj, R. Rao, J. Rutledge, D. Sharpiro, S. Simon, D. Taylor, K. Trautman, C. Troppmann, R. Devere White, Y. Yeh, X. Zhu, E. Zusman, T. Zwerdling, S. Lane, O. Bakijan, R. Balhorn, J. Bearinger, C. Carter, J. Chan, H. Chapman, M. Cosman, S. Demos, J. Dunn, C. Hollars, T. Huser, E. Ingerman, D. Maitland, S. Marchesini, J. Perkins, N. Shen, C. Talley, K. Venkateswaren, F. Weber, D. Agard, S. Burch, M. Gustaffson, D. Saloner, J. Sedat, C. Contag, R. Shinde, T. Wang, J. Groves, M. Howells, A. Burger, D. Sardar, O. Savas, J. Spence, B. Douk, A. Sharma, S. Spiller and B. Wilson Author Index

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Advances in Biophotonics B.C. Wilson et al. (Eds.) IOS Press, 2005 © 2005 IOS Press. All rights reserved.

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Fibers and Waveguides for Medical Applications Moshe BEN-DAVID and Israel GANNOT Department of Biomedical Engineering Faculty of Engineering Tel-Aviv University Tel-Aviv 69978, Israel

Introduction Optical fibers and waveguides are basically just a mean to transmit radiation from one point to the other. The input can be any source at the optical spectrum and the target can be any interaction subject. In the field of biomedical optics we have two main ways of using this delivery device: either deliver energy from a laser source to the human body to perform interactions (tissue removal, heating, cutting, etc.) or it can deliver signals from the human tissue (heat, fluorescence) and the target will be the appropriate detector. Laser delivery via fibers enables easy manipulation of the beam to the operating table. It becomes crucial when minimal invasive surgery is carried out. In this case the fiber is inserted through the working channel of an endoscope and an operation can take place within body cavities, through existing openings of the body or through minor cuts made through the skin. The opposite way is receiving signals from the body to a detector. This enables the use of fiber as a vehicle to transmit signals for diagnostic purposes. These signals enable us to study tissue structure, tumor detection or tissue temperature. Things could have been very simple if one fiber could serve all purposes but unfortunately this is not the case. The optical spectrum is very wide. Useful wavelengths can vary from very short at the X-ray side, to the mid and far infrared on the other side. Not all materials are transparent along this spectrum. Signals can very from nanoJoules to Joules and not every material can handle high powers. Fibers need to be bent to very small diameters (as is the case in the distal tip of a endoscope) and each material is brittle to some extent. Pulses can be very short, i.e. in the femtosecond range, or the radiation can be continuous wave (CW). Short pulses can be broaden while transmitted and this should be taken into consideration for time of flight measurements. Short pulses can have very high peak power and materials have damage thresholds. Transmission is not linear and can change with wavelength. It can also change with bending and this may change the beam shape. Biocompatibility is also an

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M. Ben-David and I. Gannot / Fibers and Waveguides for Medical Applications

important issue, since hazardous materials cannot be inserted into the human body no matter how efficient they are in delivering laser radiation. With all the above in mind, fibers and waveguides became a large field of research. There is often more than one solution to any given application and each solution is partially covering the requirements of the ultimate fiber. In the next paragraphs we will discuss the various fibers and waveguides developed for medical purposes. We will discus traditional and new materials and we will describe possible applications. Fibers will be presented going from short to the longer wavelengths. However, since visible wavelengths were the first to be transmitted by fibers and X-ray waveguides are a more recent development, we have decided to leave the X-ray transmission to the end of this chapter.

1. Fibers for the UV, Visible and NIR In 1966 Kao and Hockham [1] described a new concept for a transmission medium. They suggested the possibility of information transmission by optical fiber. In 1970 scientists at Croning Inc. [2], fabricated silica optical fiber with a loss of 20 dB/km. This relatively low attenuation (at the time) suggested that optical communication could become a reality. A concentrated effort followed, and by the mid 1980s there were reports of low-loss silica fibers that were close to the theoretical limit. Today, silica-based fiber optics is a mature technology with major impact in telecommunications, laser power transmission, laser delivery and sensing for medicine, industry, military, as well as other optical and electro optical systems. The spectral range is 200-2400 nm. The basic structure of such a fiber (Figure 1) is core clad, based on silica (SiO2) as the core and silica doped with other elements (i.e. germanium, boron, fluorine and others) to change the index of refraction. This core-clad fiber is coated with a plastic jacket to permit better bending capabilities. The fibers can be drawn in any length needed. The typical attenuation is in order of less than 1 dB/km. The fiber can be few micrometers core up to a few millimeters and can deliver multimode or single mode radiation. It has a numerical aperture, which limits the input angle to the fiber. The transmission parameters can be analyzed by tray tracing methods based on the fiber parameters. Silica-based glass fibers can be optically transparent from the near ultraviolet (NUV) to the mid-infrared (MIR) range of the electromagnetic spectrum. Optical fibers made from these glasses are widely used in the near infrared (NIR) at wavelengths close to the zero material dispersion (1310nm) and minimum loss (1550nm) wavelengths of silica. Such fibers provide the backbone of modern optical telecommunication networks. Since the late 1970s these fibers have been manufactured routinely. It is possible to manufacture very long fibers with very low attenuation (0.2dB/km). Multicomponent glasses, specifically soda-lime silicate (Na2O-CaO-SiO2) and sodium borosilicate (Na2O-B2O3-SiO2) and related compositions in which silica comprises less then 75% mol of the glass were early candidates for optical communication fibers. Core cladding index differences were typically achieved by varying the concentration or type of alkali in the respective glasses or by adding GeO2 to the core glass. Graded index profiles in the fiber could be tailored by using crucible

M. Ben-David and I. Gannot / Fibers and Waveguides for Medical Applications

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designs, which permitted more, or less, interfacial contact and interdiffusion between the core and cladding glasses during the fiber draw. Up to the mid 1970’s significant efforts were made to fabricate low-loss, multicomponents telecommunication fibers. It was recognized that Raleigh scattering in many multi-component silicate glasses could be lower than in high silica content glasses and that the achievable losses were largely determined by extrinsic impurities. Many innovative approaches were tried to minimize these impurities. The efforts yielded fibers with losses as low as 3.4 dB/km at 840nm. Further loss reduction was dependent on reducing –OH contamination to sub parts per million and transition metals to low ppm levels. The intrinsically lower strength, reliability and radiation hardness of these fibers also present significant obstacles for their practical utilization. High silica content fibers are compositionally simple. In most instances, the cladding glass is 100% SiO2 while the core glass is 90 to 95% SiO2 with a few percent of dopants to increase the refractive index in order to achieve a guiding structure. The cladding glass in the vicinity of the core may also be doped to achieve specific refractive profiles. These fibers are sensitive to moisture. Given the opportunity, moisture can diffuse from the surface to the core of the fiber with an attendant increase in attenuation at communication wavelengths due to overtone and combination absorptions of OH vibration. Exposure to ionizing radiation can produce defect centers that also contribute to optical loss. Natural radiation, which is approximately 0.1-1 rad/year, can be sufficient to produce significant degradation over system lifetime. For practical purposes the strength of a fiber should be sufficient to withstand initial handling stresses, including those generated in cabling and deployment. Furthermore, this strength should not degrade during the system lifetime.

clad core

clad

Figure 1. Schematic drawing of an optical fiber

The spectral transmission behavior of such a fiber is shown in Figures 2 and 3.

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M. Ben-David and I. Gannot / Fibers and Waveguides for Medical Applications

Figure 2. High OH silica fiber (Courtesy of Polymicro, Phoenix, Arizona)

Figure 3. Low OH silica fiber (Courtesy of Polymicro, Phoenix, Arizona)

High-OH fibers (Fig. 2) have better transmission in the UV range, while low -OH fibers (Fig. 3) transmit better at NIR wavelengths. In the deep UV