THE SCIENCE OF PHOTOTHERAPY: AN INTRODUCTION The Science of Phototherapy: An Introduction by Leonard I. Grossweiner † Illinois Institute of Technology, Chicago, IL, U.S.A. edited by Linda R. Jones College of Charleston , Charleston, SC, U.S.A. co-authors James B. Grossweiner Edward Hospital, Naperville, IL, U.S.A. and B.H. Gerald Rogers University of Chicago Pritzker School of Medicine, Chicago, IL, U.S.A. A C.I.P. Catalogue record for this book is available from the Library of Congress. ISBN 1-4020-2883-0 (HB) ISBN 1-4020-2885-7 (e-book) Published by Springer, P.O. Box 17, 3300 AA Dordrecht, The Netherlands. Sold and distributed in North, Central and South America by Springer, 101 Philip Drive, Norwell, MA 02061, U.S.A. In all other countries, sold and distributed by Springer, P.O. Box 322, 3300 AH Dordrecht, The Netherlands. Printed on acid-free paper springeronline.com All Rights Reserved © 2005 Springer No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed in the Netherlands. TABLE OF CONTENTS Foreword vii Preface ix Acknowledgements xiii In Memoriam: Leonard I. Grossweiner xv Chapter 1 An Overview of Phototherapy 1 Chapter 2 Optical Physics and Biotechnology 9 Chapter 3 Phototherapy light sources 57 Chapter 4 Quantum Description of Light Interactions with Matter 93 Chapter 5 Tissue Optics 143 Chapter 6 Photochemical Damage to Biological Systems 171 Chapter 7 Optical Methods of Imaging and Diagnosis 197 Chapter 8 Light Dosimetry Modeling for Phototherapy 211 Chapter 9 Laser Interactions with Tissues 225 v vi Chapter 10 Photodynamic Therapy: Science and Technology 243 Chapter 11 Photodynamic Therapy: Clinical Aspects 275 Chapter 12 Phototherapy of Skin Disease: Science and Technology 299 Chapter 13 Phototherapy of Neonatal Jaundice 329 Glossary 337 Index 367 FOREWORD Leonard Grossweiner was proud of his career as a scientist. He once told me that he had accomplished more than he had dreamed, as a person who finished college on the GI bill after World War II and who obtained the doctorate in physics in night school while working full-time as a chemical engineer. He found and opened “windows of opportunity” in the most unlikely places. How would a stranger assess his accomplishments? Well … when he came to Illinois Institute of Technology [IIT], the Physics department had a limited variety of basic research activities, as well as traditional undergraduate and graduate programs. He developed new courses in statistical mechanics, quantum mechanics, and solid state physics, while maintaining an active experimental research program using flash photolysis to study organic molecules. He studied the hydrated electron, which plays a central role in producing radiation damage in biological materials, and he began an intensive and thorough study of biological physics. He was a leader in founding the American Society for Photobiology over thirty years ago. His research in photobiology broadened and deepened, and he became a leading world expert in tissue optics. His analysis of this subject is characterized by its breadth. He explored and understood a broad range of the aspects of tissue optics at a fundamental level. He made theoretical calculations of heat flow, comparing them with data taken on phantom samples -- as well as potatoes, hamburger, and beefsteak. He studied and understood enzyme migration and dosimetry in the body. He participated in clinical trials, and actually counseled terminally ill patients on their treatment protocol. Others may have explored one aspect or another of photophysics in more detail, but very few understood it with such breadth. Leonard Grossweiner was my role model, for being able to concentrate upon the goals of a project, and to avoid being side-tracked by tangential issues. He understood that one must focus upon important questions, and ignore matters that would ultimately turn out to be extraneous and inconsequential. He understood that our most important resource, and perhaps the most irreplaceable resource, was time itself. By his example we learned how to focus upon important issues, and not to dwell upon things that could not be changed. He always knew instinctively what the “next step” should be, and refused to be discouraged by disappointments. He vii viii showed us that there is a great distinction between a “lack of resources” to develop a project and a “lack of ideas”. While my colleagues and I found his disciplined approach to be difficult at times, we understood that he always was supportive of the person who worked hard to discover something new. He supported his students, his colleagues, and his collaborators, and set an example that we could all hope to emulate. We miss him. Porter W Johnson IIT, Chicago IL 2004 PREFACE The beneficial effects of sunlight are a ubiquitous concept in folk medicine originating from sun worship. Indian medical literature dating to 1500 BC describes a treatment of non-pigmented areas of skin by applying black seeds of the plant Bavachee or Vasuchika followed by exposure of the skin to sunlight. This plant was identified as Psoralea corylifolia which contains photosensitizing psoralen compounds. Similar references appear in Buddhist literature from about 200 AD and in 10th century Chinese documents from the Sung period. The clearing of psoriasis by exposing the skin to sunlight has been known for at least a century. Sunlight also has deleterious biological effects. Exposure of horses, sheep, and cattle to sunlight after ingestion of certain plants leads to ulceration, and infection, and in severe cases, convulsions and death. In some regions of Arabia white horses were not used and even non-pigmented patches on colored horses were darkened with henna or tobacco juice. In the Tarentine fields of Italy only black sheep were grown because the white ones grew ill after exposure to sunlight. The connection between plants of the genus Hypericum and the sunlight sensitivity of grazing animals was made in the 19th century, if not earlier. The active photosensitizer was identified with the red pigment hypericin which is found in some insects and plants including St. John's wort. The cell killing properties of ultraviolet light are well known. The use of germidical lamps for this purpose is receiving new consideration in connection with the increasing incidence of contaminated food products. The possible link between skin cancer in humans and sunlight exposure had been suspected for many years based on statistical correlations between skin cancer incidence and the average intensity of sunlight. Recent basic research provides essentially incontrovertible evidence that frequent sunlight exposure generates DNA lesions which can initiate skin cancer. This anecdotal history provides ample evidence that light can act as a powerful drug, either alone or in combination with chemical agents. The objective in a phototherapy is to utilize the beneficial action of light for treatment of disease while minimizing the harmful effects. The era of controlled phototherapy started at the turn of the 20th century. Niels Finsen, the father of modern phototherapy, discovered that natural sunlight and ultraviolet radiation from a carbon arc are beneficial treatments for cutaneous tuberculosis. Finsen received the Nobel Prize in medicine for his pioneering work in 1903. The slow acceptance of phototherapy in the ix x U.S. may have resulted from a residual distrust of a discredited blue light therapy for arthritis and other afflictions proposed Augustus J. Pleasonton, a Civil War general. Regulatory approvals of clinical phototherapy started in the 1960s. Although the currently approved procedures are relatively few in number, each of them is directed to a major affliction that affects a large patient population. One of the first approved phototherapies was the treatment of severe plaque-type psoriasis with crude coal tar followed by ultraviolet irradiation of the diseased skin. This approach has been largely superceded by whole-body ultraviolet irradiations and by exposing the skin to "black light" after oral administration of a psoralen drug. This photochemotherapy termed "PUVA" was motivated by knowledge of the ancient writings. The treatment of jaundice in pre-term and very young infants by exposing the skin to blue light is a widely used phototherapy. Photodynamic therapy of malignant tumors (PDT) utilizes the combined action of normally benign red light and a photosensitizing drug that localizes in solid tumors after intravenous administration. PDT is approved in the U.S. for cancer of the esophagus and early-stage lung cancer and for other cancers elsewhere, including malignancies of the skin, urinary bladder, and gastrointestinal tract. The PDT approach has been extended to non-cancer diseases, including new light treatments for "wet" age-related macular degeneration and pre-cancerous skin disease, actinic keratosis. PDT motivated significant advances in related areas including fluorescence diagnosis of cancer and non-invasive optical imaging. The recent laser treatments of port wine stain and other vascular lesions follow directly from modeling of skin interactions with light based on tissue optics. Phototherapy exemplifies scientific medicine in which basic research and new technologies developed in parallel with the clinical applications. The author's principal objective was to provide a consistent and logical treatment of the entire field for readers coming from different professional backgrounds. Accordingly, some of the content may be very familiar to some readers and quite new to others. Chapter 1 provides an overview of the entire field of phototherapy which may be useful for a reader who wishes to concentrate on specific topics. Chapter 2 though Chapter 4 emphasize the underlying basic science of phototherapy and the relevant optical-electronics technology.