CRC PR E S S Boca Raton London New York Washington, D.C. Nanoscale Technology in Biological Systems Edited by Ralph S. Greco Fritz B. Prinz R. Lane Smith Copyright © 2005 by Taylor & Francis This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher. All rights reserved. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe. Visit the CRC Press Web site at www.crcpress.com © 2005 by CRC Press No claim to original U.S. Government works International Standard Book Number 0-8493-1940-4 Printed in the United States of America 1 2 3 4 5 6 7 8 9 0 Printed on acid-free paper Library of Congress Cataloging-in-Publication Data Catalog record is available from the Library of Congress Copyright © 2005 by Taylor & Francis Dedication This textbook is dedicated to all of the surgical residents at the Stanford University School of Medicine and all of the graduate students in the School of Engineering at Stanford whose work has been an inspiration to the editors, in the laboratory, the clinic and in the preparation of this manuscript. Copyright © 2005 by Taylor & Francis Preface In 1959, Richard P. Feynman, Professor of Physics at the California Institute of Technology and Nobel Laureate, delivered an address at the American Physical Society, which is given the credit for inspiring the field of nanotechnology. Published in Engineering and Science, Feynman’s address entitled “Plenty of Room at the Bottom” described a new field of science dealing with “the problem of manipulating and controlling things on a small scale.”* Feynman theorized that the development of improved electron microscopes would allow scientists to view the components of DNA, RNA, and proteins, to develop miniature computers and miniature machine systems, as well as to manip- ulate materials at the atomic level. “Perhaps this doesn’t excite you to do it and only economics will do so. Then I want to do something; but I can’t do it at the present moment, because I haven’t prepared the ground. It is my intention to offer a prize of $1000 to the first guy who can take the information on the page of a book and put it on an area 1/25,000 smaller in linear scale in such a manner that it can be read by an electron microscope.” Secondarily, Feynman said, “And I want to offer another prize — if I can figure out how to phrase it so that I don’t get into a mess of arguments about definitions — of another $1000 to the first guy who makes an operating electric motor — a rotating electric motor, which can be controlled from the outside and, not counting the lead-in wires, is only 1/64 inch cube.” In addition, he ended, “I do not expect that such prizes will have to wait very long for claimants.” He was right. His second challenge was achieved in 1960 by an engineer named William McLellan. McLellan constructed his small motor by hand using tweezers and a microscope. The nonfunctioning motor currently resides in a display at the California Institute of Technology. It took until 1985 for Thomas Newman, then a graduate student at Stanford, to achieve the first challenge by using a computer- controlled, finely focused pencil electron beam to write, in an area 5.9 micrometers square, the first page of Charles Dickens’ A Tale of Two Cities. In the 40 plus years since Feynman’s challenges, the field of nanotechnology has advanced in many directions and at an astonishing pace. Some of the earliest advances, which made the burgeoning field feasible, were in microscopy and included not just the scanning electron microscope and the transmission electron microscope, but the scanning tunneling microscope and the atomic force microscope. With these in hand, scientists were able to begin to observe and manipulate structures at a scale measured in nanometers. The field of nanotechnology has since developed rapidly. It is considered likely by most experts that nanotechnology will influence energy more than any other industry, but that its application to biology and medicine * Richard Feynman’s talk at the December 29, 1959, annual meeting of the American Physical Society at the California Institute of Technology (Caltech), first published in the February 1960 issue of Caltech's Engineering and Science. Copyright © 2005 by Taylor & Francis is inevitable. In 2000, President Bill Clinton announced the founding of the U.S. National Nanotechnology Initiative (NNI). In the last three years this national insti- tute has grown in scope and support, with a federal budget in 2003 of $710.2 million. Governments in Europe, Japan, and other Asian nations have responded with com- petitive investments in programs that are national in scope. Although the era of nanotechnology is in its infancy, as it comes into full maturity there undoubtedly will be profound implications on not only many branches of science, but in all of our lives on a daily basis. Ralph S. Greco, M.D. Copyright © 2005 by Taylor & Francis Acknowledgments We would like to express our appreciation to Stephanie Fouchy, without whose assistance the preparation of this book would not have been possible. Copyright © 2005 by Taylor & Francis Editors Ralph S. Greco is the Johnson & Johnson Distinguished Professor at the Stanford University School of Medicine. He is also Chief of the Division of General Surgery at Stanford and the Director of the General Surgery Training Program. Dr. Greco joined the faculty at Stanford in the year 2000. He graduated cum laude from Fordham University in 1964 and the Yale Medical School in 1968. His internship and residency was served at Yale New Haven Hospital, and after two years of military service, he became an Assistant Professor at the Rutgers Medical School (which later changed its name to Robert Wood Johnson Medical School) in 1975. He became Chief of the Division of General Surgery there in 1982 and Chief of Surgery at Robert Wood Johnson University Hospital in 1997. Dr. Greco is a member of the American Surgical Association, the Society of University Surgeons, the Society for Biomaterials, the Association of Program Direc- tors in Surgery, and the Surgical Infection Society, among many other surgical societies. He is board certified in General Surgery and is a Fellow of the American College of Surgeons. Dr. Greco has been the recipient of research grants from the National Heart, Lung and Blood Institute and served as a consultant to the NHLBI and the NSF. Dr. Greco is the recipient of six patents on various aspects of antibiotic bonding and has published more than 100 papers in the scientific literature. His research interest is focused on biomaterials, vascular grafts, the host response to implantable biomaterial surfaces, and surface modification of biomaterials. When he arrived at Stanford he began a collaboration with Friedrich Prinz and R. Lane Smith in a related, but new area, namely the nanofabrication of new biomaterial surfaces and their potential application to a new generation of biomaterials for clinical applications. Fritz B. Prinz is the Rodney H. Adams Professor at the Standford University School of Engineering, and Department Chair, Mechanical Engineering. His current research focuses on the design and manufacturing of micro- and nanoscale devices. Examples include fuel cells and bioreactors. He is interested in materials selection, scaling theory, electro-chemical phenomena, and quantum modeling. He initiated a project on the observation of reduction-oxidation reactions in biological cells. He received his Ph.D. in Vienna in 1975. Professor Prinz directs the Rapid Prototyping Laboratory (RPL), which is ded- icated to improving product design and scientific discovery through efficient use of rapid prototyping. The RPL focuses its efforts on two different application domains. One is energy, the other biology. The RPL is exploring processing methods to build thin film solid oxide fuel cells with relatively low operating temperatures. Such fuel cells hold the promise of high efficiency and cost-effective production. The electro- chemical measurement techniques available to Prinz’ group, together with their Copyright © 2005 by Taylor & Francis ability to build sensors with nanoscale dimensions, help in observing oxida- tion–reduction reactions not only in fuel cells but also in biological cells. The RPL studies mass transport within and between lipid bilayers to gain insights into the physics and thermodynamics of electrochemical phenomena of thin biological mem- branes. RPL has a rich infrastructure and long tradition with respect to designing and manufacturing structures that are difficult, if not impossible, to make with conventional techniques. Examples include three-dimensional biodegradable tissue crafts and devices made with focused ion beam methods in a layered fashion. R. Lane Smith is a Professor (Research) in the Department of Orthopaedic Surgery at Stanford University, Stanford, California. He has served as codirector and director of the Orthopaedic Research Laboratory at Stanford University since 1977 and currently holds a position at the Rehabilitation Research and Development Center at the VA Palo Alto Health Care System, where he is a career research scientist. He received his Ph.D. from the University of Texas at Austin in 1971. His graduate work was followed by postdoctoral study at the Friedrich Miescher Institute in Basel, Switzerland and a membrane-pathobiology fellowship at Stanford University. Dr. Smith’s research focuses on fundamental problems directed at understanding the molecular mechanisms influencing metabolism of cartilage and bone during normal homeostasis and pathogenesis. His currently funded research examines fundamental mechanisms by which mechanical stimulation may function as a productive stimulus for tissue regeneration. His research has provided insight into how mechanical loading can function to induce increased synthesis of critical cartilage macromolecules. This work has culminated in a patent that describes a process for increasing chondrocyte matrix synthesis that has been licensed to a privately held company. The company has targeted cartilage repair as a therapeutic area for commercialization and has recently received FDA approval for phase 1 trials with their product. His experimental approach to the effects of mechanical loading on extracellular matrix has been extended to adult human mesenchymal stem cells. Dr. Smith is on the Editorial Board of the Journal of Biomedical Materials Research (Applied Biomaterials) and has been a member of various national scien- tific review panels. He is a reviewer for numerous journals in the fields of biochem- istry, biomaterials, and extracellular matrix biology. He is a member of the Ortho- paedic Research Society, Society for Biomaterials, International Cartilage Repair Society, and Federation for Experimental Biology and Medicine. Dr. Smith has published more than 104 peer-reviewed papers, 18 review articles and book chapters, and 150 meeting abstracts and presentations. Copyright © 2005 by Taylor & Francis Contributors David Altman Graduate Student Department of Biochemistry Stanford University School of Medicine Stanford, California Seoung-Jai Bai Graduate Student Department of Mechanical Engineering Rapid Prototyping Laboratory Stanford University School of Medicine Stanford, California Anne-Elise Barbu Undergraduate Student Department of Biology University of California at Davis Davis, California Stephane Barbu, M.S. Director High Frequency ASIC Products Maxim Integrated Products Sunnyvale, California Stephan Busque, M.D. M.Sc., FRCSC Associate Professor of Surgery Director, Adult Kidney and Pancreas Transplantation Program Stanford University School of Medicine Palo Alto, California Brent R. Constantz, Ph.D. Consulting Associate Professor Department of Engineering Stanford University Stanford, California Christopher H. Contag, Ph.D Assistant Professor Departments of Pediatrics, Radiology, and Microbiology & Immunology Molecular Imaging Program at Stanford Stanford University School of Medicine Stanford, California Chris J. Elkins, Ph.D. San Diego School of Medicine University of California San Diego, California Plamena Entcheva, Ph.D. Graduate Student Departments of Civil and Environmental Engineering, Biological Sciences, and Geological and Environmental Sciences Stanford University Stanford, California Rainer Fasching, Ph.D. Research Associate Department of Mechanical Engineering Rapid Prototyping Laboratory Stanford University Stanford, California Michael E. Gertner, M.D. Lecturer in Surgery Co-director, Surgical Innovative Program Department of Surgery Stanford University School of Medicine Stanford, California Copyright © 2005 by Taylor & Francis Ralph S. Greco, M.D. Johnson & Johnson Distinguished Professor Chief, Division of General Surgery Stanford University School of Medicine Stanford, California Kyle Hammerick Graduate Student Department of Mechanical Engineering Rapid Prototyping Laboratory Stanford University Stanford, California Christopher R. Jacobs, Ph.D. Associate Professor Departments of Mechanical Engineering and Biomedical Engineering Stanford University Stanford, California D. Denison Jenkins, M.D. Resident in General Surgery Department of Surgery Stanford University School of Medicine Stanford, California Theo Kofidis, M.D. Graduate Student Department of Cardiothoracic Surgery Stanford University School of Medicine Stanford, California Thomas M. Krummel, M.D. Emile Holman Professor Chair, Department of Surgery Stanford University School of Medicine Stanford, California Michael D. Kuo, M.D. Center for Translational Medical Systems: Radiology San Diego School of Medicine University of California San Diego, California Martin Morf, Ph.D. Professor of ETH Consulting Professor, EE Department SSPL/Center for Integrated Systems Stanford University Stanford, California Jeffrey A. Norton, M.D. Professor of Surgery Chief of Surgical Oncology Division of General Surgery Stanford University School of Medicine Stanford, California Fritz B. Prinz, Ph.D. Rodney H. Adams Professor of Engineering Chair, Department of Mechanical Engineering Department of Materials Science and Engineering Stanford University Stanford, California Robert C. Robbins, M.D. Director, Stanford Cardiovascular Institute Associate Professor Department of Cardiothoracic Surgery Stanford University School of Medicine Stanford, California Hootan Roozrokh, M.D. Clinical Instructor Department of Surgery Stanford University School of Medicine Stanford, California WonHyoung Ryu Graduate Student Department of Mechanical Engineering Rapid Prototyping Laboratory Stanford University Stanford, California Copyright © 2005 by Taylor & Francis [...]... Likewise, side chain substitution, cross-linking, and branching all affect the physical properties of polymers Increasing the size of side groups or branches, or increasing the cross-linking of the main chains all result in a poorer degree of molecular packing This retards the polymer crystallization rate, thereby decreasing the melting temperature of a material.10,29 Similarly, changes in temperature... 2000, more than 35 countries have developed programs in nanotechnology 70 Furthermore, worldwide government funding of nanotechnology has increased approximately five-fold since 1997, exceeding 2 billion dollars in 2002 70 In the United States alone, the National Nanotechnology Initiative, established by President Bill Clinton in 2000, has grown rapidly in both scope and support, with a 2002 federal budget... Biomaterials in Tissue Engineering 1.5.2 Micro/Nanotechnology and Biomaterials 1.5.2.1 Microfabrication and Microtechnology 1.5.2.2 Nanofabrication and Nanotechnology 1.6 Conclusion References Copyright © 2005 by Taylor & Francis 1.1 INTRODUCTION Over the last two centuries, the field of medicine has increasingly utilized biomaterials in the investigation and treatment of disease Common examples include... systems is being investigated for the controlled release of a variety of agents including insulin, streptokinase, lysozyme, and salmon calcitonin.44 In addition, a recently recognized advantage of hydrogels is that they may have the ability to protect embedded drugs, peptides, or proteins from the potentially harsh biological environment This may enable the oral delivery of engineered proteins, which... medication in a controlled fashion The use of such systems for the delivery of insulin for the treatment of diabetes is currently being investigated.65 Figure 1.3 and Figure 1.4 represent examples of MEMS technology in medicine 1.5.2.2 Nanofabrication and Nanotechnology Nanotechnology has been defined as “research and technology development at the atomic, molecular, and macromolecular levels in the length... grouped into three categories based on their biologic behavior in certain environments: the relatively bioinert ceramics, the bioreactive or surface reactive ceramics, and the biodegradable or reabsorbable ceramics Relatively bioinert bioceramics are nonabsorbable carbon-containing ceramics, alumina, zirconia, and silicon nitrides 19 While in a biological host, relatively bioinert ceramics maintain their... Biomaterials, in The Biomedical Engineering Handbook, Bronzino JD, Ed., Boca Raton, FL, CRC Press LLC, 1995 4 Naughton GK From lab bench to market: critical issues in tissue engineering, Ann N Y Acad Sci., 2002, 961, 372–385 5 Griffith LG Emerging design principles in biomaterials and scaffolds for tissue engineering, Ann N Y Acad Sci., 2002, 961, 83–95 6 Langer R, Peppas NA Advances in biomaterials,... and nanofabrication techniques are being utilized to create “smart” biomaterials and implants that can detect and respond to various tissue and cellular stimuli 1.5.1 BIOMATERIALS IN TISSUE ENGINEERING In a recent review, Griffith defined tissue engineering as “the process of creating living, physiological, three-dimensional tissues and organs utilizing specific combinations of cells, cell scaffolds,... with increasing molecular weight, the chains of a polymer become longer and less mobile, resulting in a more rigid material.29 Similarly, changing the chemical composition of the backbone or side chains can change the physical properties of the polymer 10 For example, the substitution of a backbone carbon in a polyethylene with divalent oxygen increases the rotational freedom of the chain, resulting in. .. implants in soft tissue refixation: experimental evaluation, clinical experience, and future needs, Injury, 2002, 33, Suppl 2, B17–B24.) including sutures, wound dressings, fracture plates and screws, and controlledrelease delivery systems.41 In addition, biodegradable matrices and scaffolds show a great deal of promise in the field of tissue engineering due to their ability to degrade while encouraging . modeling. He initiated a project on the observation of reduction-oxidation reactions in biological cells. He received his Ph.D. in Vienna in 1975. Professor Prinz directs the Rapid Prototyping Laboratory. were specifically designed for use inside the human body and saw application in multiple disciplines of medicine including orthopedics, cardiovascular surgery, ophthalmology, and wound healing but also in biological cells. The RPL studies mass transport within and between lipid bilayers to gain insights into the physics and thermodynamics of electrochemical phenomena of thin biological