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Nanomedicine Design of Particles, Sensors, Motors, Implants, Robots, and Devices Artech House Series Engineering in Medicine & Biology Series Editors Martin L. Yarmush, Harvard Medical School Christopher J. James, University of Southampton Advanced Methods and Tools for ECG Data Analysis, Gari D. Clifford, Francisco Azuaje, and Patrick E. McSharry, editors Advances in Photodynamic Therapy: Basic, Translational, and Clinical, Michael Hamblin and Pawel Mroz, editors Biological Database Modeling, Jake Chen and Amandeep S. Sidhu, editors Biomedical Informatics in Translational Research, Hai Hu, Michael Liebman, and Richard Mural Biomedical Surfaces, Jeremy Ramsden Genome Sequencing Technology and Algorithms, Sun Kim, Haixu Tang, and Elaine R. Mardis, editors Inorganic Nanoprobes for Biological Sensing and Imaging, Hedi Mattoussi and Jinwoo Cheon, editors Intelligent Systems Modeling and Decision Support in Bioengineering, Mahdi Mahfouf Life Science Automation Fundamentals and Applications, Mingjun Zhang, Bradley Nelson, and Robin Felder, editors Microscopic Image Analysis for Life Science Applications, Jens Rittscher, Stephen T. C. Wong, and Raghu Machiraju, editors Nanomedicine Design of Particles, Sensors, Motors, Implants, Robots, and Devices, Mark J. Schulz, Vesselin N. Shanov, and Yeoheung Yun, editors Nanoreactor Engineering for Life Sciences and Medicine, Agnes Ostafin and Katharina Landfester, editors Next Generation Artificial Vision Systems: Reverse Engineering the Human Visual System, Maria Petrou and Anil Bharath, editors Systems Bioinformatics: An Engineering Case-Based Approach, Gil Alterovitz and Marco F. Ramoni, editors Systems Engineering Approach to Medical Automation, Robin Felder Translational Approaches in Tissue Engineering and Regenerative Medicine, Jeremy Mao, Gordana Vunjak-Novakovic, Antonios G. Mikos, and Anthony Atala, editors Nanomedicine Design of Particles, Sensors, Motors, Implants, Robots, and Devices Mark J. Schulz Vesselin N. Shanov Yeoheung Yun Editors artechhouse.c; om Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the U. S. Library of Congress. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library. ISBN-13: 978-1-59693-279-1 Cover design by Igor Valdman Cover images provided by Robert Freitas, Elena Heister, Thierry Lutz, Hui Zhang, Xuesong Feng, Yi Shu, Faqing Yuan, Peixuan Guo, Yin Yin Guo, Tomomi Nemoto, and Keith A. Crutcher. © 2009 Artech House. All rights reserved. Printed and bound in the United States of America. No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without permission in writing from the publisher. All terms mentioned in this book that are known to be trademarks or service marks have been appropriately capitalized. Artech House cannot attest to the accuracy of this information. Use of a term in this book should not be regarded as affecting the validity of any trademark or service mark. 10 9 8 7 6 5 4 3 2 1 The coeditors and chapter authors hope that this book will help to free future generations of humanity from disease that mankind has endured for thousands of years. Mark J. Schulz also dedicates his contribution to the memory of his parents, Jeanne and Joseph Schulz, and sister, Margaret Schulz. Contents Preface xvii Outline of the Book xix CHAPTER 1 A Nanotechnology Framework for Medical Innovation 1 1.1 Introduction 1.2 Descriptive Systems Modeling 1.2.1 Examples of Descriptive Systems Modeling 1.3 Instrumentation Needed to Develop DSM 1.4 Nanomaterials Made for Medicine 1.5 Implantable Nanomedical Devices 1.6 Nanorobots 1.6.1 Nanorobots for Revolutionizing Medicine 1.6.2 Nanorobot Factory 1.6.3 Biological Nanorobots 1.7 Biodegradable Metals for Temporary Implantable 1.7 Nanomedical Devices 1.8 Integration of Nanodevices in the Body 1.9 Safety and Ethical Implications of Nanomedicine 1.10 Efficiently Working Together Using Shared Resources 1.11 Chapter Summary and Conclusions Problems Acknowledgments References 17 18 19 20 21 22 22 22 PART I Nanoscale Materials and Particles 25 CHAPTER 2 Synthesis of Carbon Nanotube Materials for Biomedical Applications 27 2.1 Introduction to Nanoscale Materials 2.2 Synthesis of Long Carbon Nanotube Arrays 2.3 Characterization of CNT Arrays 2.3.1 Scanning Electron Microscopy and Transmission Electron 2.3.1 Microscopy 2.3.2 Raman Spectroscopy and Thermal Gravimetric Analysis 2.4 Patterned CNT Arrays 2.5 Production Scale Up of CNT Arrays at UC 2.5.1 Magnetron Sputtering for Substrate Preparation 1 2 3 4 6 8 10 12 16 17 27 29 31 31 31 32 32 32 vii viii Contents 2.6 Spinning Carbon Nanotubes into Thread 2.6.1 Mechanics of Array Spinning 2.6.2 Direct Spinning of Thread from Long CNT Arrays 2.6.3 Catalyst and Substrates for Growing of Spinable CNT Arrays 2.6.4 Spinning Thread from DWCNT Arrays 2.6.5 Pulling Ribbon from CNT Arrays 2.6.6 Post-Treatment of the CNT Thread 2.7 Mechanical and Electrical Characterization of CNT Thread 2.7.1 Tensile Testing of CNT Thread 2.7.2 Electrical Properties of CNT Thread 2.7.3 Temperature Dependence of the CNT Thread Resistance 2.7.4 Electrical Properties of CNT Ribbon 2.8 Nano-Handling of CNTs Using a Nanomanipulator Inside an ESEM 2.8.1 Instrumentation 2.8.2 Handling CNT Bundles 2.8.3 Building Nanomedical Devices Using the Nanomanipulator 2.9 Carbon Nanotube Threads in Wireless, Biomedical Sensor Applications 2.9.1 Wireless Communication and the Modern World 2.9.2 Development of CNT Thread-Based Antenna at UC 2.9.3 Future Medical Application of the CNT Thread Antenna 2.10 Applications of CNT Materials in Nanomedicine 2.10.1 Carbon Nanotube Array Immunosensor 2.10.2 Carbon Nanotube Actuators 2.10.3 Carbon Nanotube Materials as Scaffolds for Supporting 2.10.3 Directional Neurite Growth 2.11 Summary and Conclusions Problems Acknowledgments References CHAPTER 3 Functionalized Carbon Nanotubes as Multimodal Drug Delivery Systems for Targeted Cancer Therapy 3.1 Introduction to Targeted Cancer Therapy 3.1.1 Cancer Statistics 3.1.2 Present-Day Cancer Treatment and Associated Problems 3.1.3 A Brief Insight into Targeting Strategies 3.2 Carbon Nanotubes: A Versatile Material 3.2.1 Definition and Synthesis of Carbon Nanotubes 3.2.2 Characterization of Carbon Nanotubes 3.2.3 Purification of Carbon Nanotubes 3.2.4 Functionalization of Carbon Nanotubes for 3.2.4 Biomedical Applications 3.3 Carbon Nanotubes as Nanovectors for Multimodal Drug Delivery 3.3.1 Carbon Nanotube Drug Delivery Systems Based on 3.3.1 Surface Functionalization 35 36 36 38 38 40 42 43 43 43 44 46 46 46 47 47 49 49 49 50 51 51 52 53 54 54 55 55 61 61 61 62 63 65 65 67 69 70 71 71 Contents ix 3.3.2 Carbon Nanotube Drug Delivery Systems Based on Filling 3.3.2 of the Inner Cavity 3.4 Challenges and Future Prospects 3.4.1 Toxicological Aspects 3.4.2 In Vivo Biodistribution of Carbon Nanotubes 3.5 Conclusion Problems Acknowledgments References CHAPTER 4 Composite Nanoparticles for Cancer Imaging and Therapy: Engineering Surface, Composition, and Shape 4.1 Introduction 4.1.1 Nanoscience and Medicine: The Need and the Opportunity 4.1.2 Nanodevices 4.1.3 Principles of Nanodevice Design 4.2 Materials for Nanodevice Fabrication 4.2.1 Dendrimers 4.2.2 Engineering Size, Charge, and Surface Functionality of 4.2.2 PAMAM Dendrimers 4.2.3 Dendrimer Nanocomposites: Engineering Composition 4.2.4 Inorganic Nanoparticles: Engineering Shape 4.3 Application Examples of Nanodevices 4.3.1 Nanoparticles in Cancer Imaging 4.3.2 Application Examples of Dendrimer Nanodevices 4.3.3 Perspectives on Biomedical Applications of Shaped 4.3.3 Nanocrystals 4.4 Summary Problems References CHAPTER 5 Three-Dimensional Lithographically Structured Self-Assembled Biomedical Devices 5.1 5.2 5.3 5.4 Introduction Basics of Lithographic Fabrication The Need for Three-Dimensional Biomedical Devices Present Day Lithographically Structured Biomedical Devices 5.4.1 Drug Delivery Devices 5.4.2 Structural Devices 5.4.3 Implantable Organic /Electronic Devices 5.4.4 Microfluidic Devices for Diagnosis and Cell Growth 5.4.5 Soft and Wet 3-D Devices 5.4.6 Tissue Scaffolds—Growing Live Devices 5.4.7 Interactions with Body Components 77 80 80 84 85 85 86 86 95 95 95 97 98 98 98 99 105 109 113 113 116 117 118 118 120 127 127 130 132 134 135 135 137 137 138 139 139 x Contents 5.5 Combination of Lithography and Self-Assembly to 5.5 Construct 3-D Devices 5.5.1 Three-Dimensional Self-Assembled Containers 5.5.2 Multilayer Thin Film Stress for 3-D Self Assembly 5.5.3 Three-Dimensional Constructs for Cell Culture 5.5.4 Microscale Tetherless Gripper (Chemically Triggered 5.5.4 Microsurgical Tools) 5.6 Conclusions 5.7 Future Directions Problems Acknowledgments References Selected Bibliography CHAPTER 6 Nanosized Magnetite for Biomedical Applications 140 140 145 145 147 148 148 148 150 150 155 157 6.1 Introduction 6.2 Crystalline Structure 6.2.1 Bulk Magnetite 6.2.2 Structural Characteristics of Nanoparticles 6.3 Nanosized Magnetism 6.3.1 Multidomain and Monodomain Particles: 6.3.1 Superparamagnetism 6.3.2 Experimental Data 6.4 Magnetic Particles and Biomedical Applications 6.4.1 Magnetite and Bioworld 6.4.2 Biomedical Applications of Magnetic Single-Domain Particles 6.5 Conclusions Problems References 163 171 175 175 177 183 185 185 CHAPTER 7 Progress in the Use of Aligned Carbon Nanotubes to Support Neuronal Attachment and Directional Neurite Growth 189 7.1 Background 7.1.1 CNS Regeneration Occurs Under Some Conditions 7.1.2 Factors That Inhibit or Stimulate Axonal Regeneration 7.1.3 The Geometry Hypothesis 7.1.4 Artificial Substrates Can Promote Axonal Regeneration 7.1.5 Carbon Nanotubes and Axonal Regeneration 7.1.6 Aligned Carbon Nanotubes as a Potential Scaffold for 7.1.6 Axonal Regeneration 7.1.7 CNT Cytotoxicity 7.2 Recent Progress 7.2.1 Preparation of CNTs 7.2.2 Neuronal Cultures 157 158 158 160 163 189 189 190 190 192 193 194 195 195 196 196 Contents xi 7.2.3 Neuronal Attachment and Neurite Outgrowth on 7.2.3 Aligned CNTs 7.3 Future Directions and Challenges Problems Acknowledgments References 196 201 202 203 203 CHAPTER 8 RNA Ring-Geared Bacteriophage phi29 DNA Packaging Nanomotor for Nanotechnology and Gene Delivery 211 8.1 Introduction 8.2 Components Related to the phi29 DNA Packaging Motor 8.2.1 phi29 pRNA 8.2.2 phi29 Procapsid 8.2.3 Gp16 8.2.4 DNA-gp3 8.2.5 Fiber (gp8.5), and Neck and Tail (gp9, gp11-12) Proteins 8.3 Construction of the Biomimetic phi29 DNA Packaging Motor 8.4 Structure of pRNA 8.5 Mechanism of the phi29 Motor Function 8.5.1 Symmetry Argument: Pentamer or Hexamer 8.5.2 ATP Hydrolysis Provides the Driving Force of the phi29 8.5.2 DNA Packaging Motor 8.5.3 Possible Models for phi29 Motor Function 8.5.4 Single Molecule Approaches to Elucidate Motor Mechanism 8.6 Potential Applications of the phi29 Motor in Nanotechnology and 8.6 Gene Therapy 8.6.1 A Nanomotor with the Potential to Be Incorporated 8.6.1 into Nanodevices 8.6.2 Connector Arrays for Nanotechnology 8.6.3 Polyvalent Gene Delivery System Using Phi29 pRNA 8.6.4 Engineered phi 29 Connectors as Therapeutic Tools 8.6.5 phi29 DNA Packaging Motors Act as Tools for Gene Therapy 8.6.6 The DNA-Packaging Motor as a DNA-Sequencing Apparatus 8.6.6 or Molecular Sorter 8.7 Prospectives Problems References 211 212 212 213 214 215 215 215 216 217 217 219 219 221 222 222 224 225 226 226 227 227 227 228 PART II Electronic Biomedical Devices 237 CHAPTER 9 Magnetic Nanomaterials, Nanotubes, and Nanomedicine 239 9.1 Introduction 9.1.1 Nanotechnology and Nanomedicine 9.1.2 Magnetic Nanomaterials 239 239 241 xii Contents 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.1.3 Magnetic Nanomedicine 9.1.4 Status Physical Background for Magnetic Nanomedicine 9.2.2 Magnetic Manipulation 9.2.3 Fundamentals of Nanomagentism Magnetic Nanoparticles 9.3.1 Basics of Magnetic Nanoparticles 9.3.2 Synthesis Techniques 9.3.3 Functionalization Techniques 9.3.4 Biomedical Applications of Magnetic Nanoparticles Magnetic Nanowires 9.4.1 Typical Structures of Magnetic Nanowires 9.4.2 Synthesis of Magnetic Nanowires 9.4.3 Functionalization of Magnetic Nanowires 9.4.4 Biomecial Applications of Magnetic Nanowires Magnetic Nanotubes 9.5.1 Magnetism of Magnetic Nanotubes 9.5.2 Multifunctionality of Magnetic Nanotubes 9.5.3 Synthesis of Magnetic Nanotubes 9.5.4 Biomedical Applications Magnetic Biosensors 9.6.1 Typical Magnetic Biosensing Schemes 9.6.2 Magnetoresistance-Based Sensors 9.6.3 Hall-Effect Sensors 9.6.4 Sensors Detecting Magnetic Relaxations 9.6.5 Sensors Detecting Ferrofluid Susceptibility Magnetic Biochips Prospects Problems References 242 242 243 243 244 247 247 248 251 252 254 254 254 256 257 260 260 263 263 265 267 267 270 271 272 275 276 276 277 277 CHAPTER 10 Mobile Microscopic Sensors for In Vivo Diagnostics 285 10.1 Introduction 10.2 Robot Capabilities and Environment 10.2.1 Sensing 10.2.2 Communication 10.2.3 Motion: Passive and Active 10.2.4 Computation 10.2.5 Power 10.3 Using Microscopic Robots 10.4 Evaluating Robot Behaviors 10.4.1 Theoretical Studies 10.4.2 Modeling Multiple Physical Effects 10.4.3 Validation Experiments 10.5 Example Task: High-Resolution Diagnostics 10.5.1 Diagnostic Task Environment 285 287 287 289 290 291 292 292 294 294 296 300 300 301 Contents xiii 10.5.2 Control 10.5.3 Detection Performance 10.5.4 Using the Diagnostic Information 10.6 Discussion Problems References 302 303 304 305 307 308 CHAPTER 11 Microcantilever Biomedical Sensors 313 The Microcantilever Platform Value of Biosensors in Cancer Diagnostics and Prognostication Cantilever Preparation Biomolecular Detection Assays 11.4.1 Detection of PSA 11.5 Implantable Sensors 11.6 Conclusion Problems References 313 315 316 316 317 318 319 321 322 CHAPTER 12 Nanoimaging and In-Body Nanostructured Devices for Diagnostics and Therapeutics 325 11.1 11.2 11.3 11.4 12.1 Introduction 12.2 Technology for In Vivo Sensing 12.2.1 Atomic Force Microscopy for Multimodal and 12.2.1 Multidimensional Imaging 12.2.2 Nanoimaging, Nanosensing and Intermolecular Interactions 12.2.3 Parallel Arrays of Sensors to Detect Complementary 12.2.3 Interactions 12.3 In-Body Nanosensors and Nanodevices 12.3.1 Edema Sensor 12.3.2 Remote Controlled, Magnetically Navigated Robot Capsule 12.3.3 Mobile Microscopic Robots 12.4 Conclusions Problems References 325 326 333 336 338 341 343 344 344 345 CHAPTER 13 Microfabricated Devices for Detecting Circulating Tumor Cells in Cancer Patient Blood Samples 347 13.1 Clinical Challenge 13.2 Technical Challenge 13.3 Techniques for Detecting CTC in Blood 13.3.1 Cell Enrichment Methods 13.3.2 Microfabricated Devices 13.4 Clinical Value of CTC Capture and Characterization 13.5 Cancer Stem Cells and Metastasis 347 348 349 349 352 356 358 326 328 xiv Contents 13.6 Application of Nanotechnology in CTC Capture 13.7 Conclusion Problems References 358 359 359 360 PART III Tiny Machines 365 CHAPTER 14 Medical Nanorobotics: The Long-Term Goal for Nanomedicine 367 14.1 14.2 14.3 14.4 14.5 14.6 14.7 14.8 Introduction From Nanoparticles to Nanorobots Diamondoid Materials in Nanorobotics Early Steps Toward Diamondoid Molecular Manufacturing Massive Parallelism Enables Practical Molecular Manufacturing Examples of Diamondoid Medical Nanorobots An Ideal Nanorobotic Pharmaceutical Delivery Vehicle Conclusion Problems References CHAPTER 15 Potential Strategies for Advanced Nanomedical Device Ingress and Egress, Natation, Mobility, and Navigation 15.1 Introduction 15.2 Potential Nanodevice Ingress Strategies 15.2.1 Hypodermic Injection and Dermal Burrowing 15.2.2 Aerosol Inhalation and Traversing the 15.2.2 Blood/Brain Barrier (BBB) 15.2.3 Transdermal Patch, Diffusive Gel, or Eye/Ear Drops 15.3 Molecular Motors 15.3.1 Powering Molecular Motors 15.3.2 Piezoelectric Elements 15.3.3 Molecular Propellers 15.4 Constraints on Molecular Motors 15.4.1 Brownian Motion 15.4.2 Brownian Shuttles 15.4.3 Viscous Forces 15.5 Traversing the Circulatory System 15.5.1 Whole Blood Composition and Viscosity 15.6 Traversing the Lymphatic System 15.7 Phagocyte Avoidance Strategies 15.8 Nanometric Biomimetic Analogs for Potential Nanomedical 15.8 Device Motility and Ambulatory Movement 15.8.1 Cilia and Flagella 15.8.2 Myosin and Actin 15.8.3 Kinesin and Dynein 367 368 371 373 378 379 382 387 387 388 393 393 394 394 396 397 398 399 399 399 400 401 402 402 403 403 406 406 407 408 410 410 Contents xv 15.9 Nanodevice Aqueous Motility 15.9.1 Biomimetic Flagellar Propulsion Using Nanotubes 15.9.2 Nanoscale Earthworm Analog 15.9.3 External Magnetic Propulsion 15.9.4 Ultrasonic Peristaltic Propulsion 15.9.5 Nanofluidic Channels: Behavior and Potential for Propulsion 15.10 Ambulatory Nanomedical Devices 15.10.1 DNA Robot 15.10.2 Nanowalker 15.11 Hypothetical Concept for Clinically Localized GPS Navigation 15.11 Applied to Advanced Autonomous Nanomedical Devices 15.12 Nanodevice Egress Strategies 15.13 Conclusion Problems References 411 411 412 412 412 413 413 414 415 415 416 417 417 418 CHAPTER 16 Nanoscale Mechanics for Medicine 423 16.1 Introduction 16.2 Nanoinjection and Nanotube Biocompatibility 16.2.1 Nanoinjection 16.2.2 Nanotube Biocompatibility 16.3 Nanometer Propulsion 16.3.1 Rotational Nanomotors 16.3.2 Linear Nanomotors 16.3.3 Surface-Tension-Driven Nanomotors 16.4 Nanomechanical Radios and Sensors 16.4.1 Nanotube Radio Receiver 16.4.2 Nanotube Radio Transmitter 16.4.3 Nanomechanical Mass Sensing Problems Acknowledgments References 423 423 423 424 426 426 427 429 430 430 433 434 436 436 436 PART IV Biological Integration and Characterization 439 CHAPTER 17 Integration of Manmade Nanostructures with Biological Systems: Diagnosis of Cancer Using Semiconductor Quantum-Dot Biomolecule Complexes 441 17.1 17.2 17.2 17.3 17.3 Introduction Semiconductor Quantum Dots and Their Adaptation for Nanodiagnostics Semiconductor Quantum Dots as Applied to the Study of Cellular Properties 441 442 447 xvi Contents 17.4 Semiconductor-Quantum-Dots—Biomolecule Complexes Used 17.4 in the Study of Carcinogenic Cells and in Cancer Diagnosis 17.5 Conclusion Problems Acknowledgments References 450 453 453 454 454 CHAPTER 18 Two-Photon Microscopy for In Vivo Analysis of Neural and Secretory Activities 459 18.1 The Need for Noninvasive Imaging 18.2 Features of Two-Photon Excited Fluorescence Microscopy 18.2.1 Deep and Benign Observations 18.2.2 Replacement for Ultraviolet Sources 18.2.3 Avoiding Self-Shielding Effects and Compensating for 18.2.3 Photobleaching 18.2.4 Precise, Simultaneous Multicolor Fluorescence Imaging 18.3 Overview of the Optical System 18.4 In Vivo Imaging of the Cerebral Neocortex 18.5 Imaging of Secretory Functions 18.6 Future Possibilities Problems Acknowledgments References 459 460 462 463 464 464 465 467 469 470 472 472 472 CHAPTER 19 Nanoscale Engineering of Electrodes, Biosensors, and Protein Surfaces 475 19.1 Introduction 19.2 Carbon Nanotube Electrode and Biosensor Development 19.2.1 Carbon Nanotube Array Synthesis 19.2.2 Carbon Nanotube Array Electrode 19.2.3 Individual Carbon Nanotube Electrode 19.2.4 Carbon Nanotube Array Biosensor 19.2.5 Initial Development of a CNT Array Electrode for 19.2.5 Prostate Cancer Cell Detection 19.3 New Polymer Synthesis for High Throughput Experimental Design 19.3.1 Biophotoresist Synthesis 19.3.2 Photolithography for Protein Patterning 19.3.3 Protein Patterning 19.4 Summary and Conclusions Problems Acknowledgments References 475 476 476 476 479 480 481 484 484 485 486 487 487 487 488 About the Editors List of Contributors 491 493 Index 497 Preface Our body is run by biological molecules interacting with a medley of biological cells. These molecules are nanoscale in size while the cells in our body are microscale in size. To prevent and treat disease, and to extend the human lifespan, it is obvious that we must be able to "work" at the nano- and microscales. Working at such small scales requires developing new tools and medical procedures that have extraordinary finesse and precision. Controlling life by manipulating biological materials at the nanoscale defines a new area of interdisciplinary research that we call nanomedicine. Nanomedicine is a rapidly growing field that is difficult to survey, especially in one book. The outline for this book went through three sets of reviews by experts. In the end, the authors have carefully assembled an integrated set of perspectives that describe where we are now and where we think we should be headed to put nanomedicine into applications as quickly as possible. The book is written by experienced and new researchers in the fields of medicine, science, and engineering. The book will help to focus research on promising areas that can have a tremendous payoff in terms of improving human health. Nanomedicine research currently appears segmented between biologists, chemists, and medical doctors on one hand, and physicists and engineers on the other. The biomedical cadre view nanomedicine as developmental or synthetic biology dealing with soft materials, while engineers and physicists generally view nanomedicine as developing hard abiotic devices and robots that can repair biological systems. This book seeks to bridge the two perspectives and apply engineering principles to design integrated biotic and abiotic devices. The book describes nanostructured materials and devices that are considered technically feasible to produce and that have high potential to produce major advances in medicine in the near future. In this book devices will be defined to mean something constructed to perform a biomedical function. Devices may be particles that image or deliver drugs or electromechanical systems that sense and respond to external stimuli. This definition matches the general use of the word devices in the nanomedicine community. A brief description of nanomedicine materials, devices, and systems is given next to set the stage for reading the book. An outline of the book follows the background. Nanomedicine Materials. Nanomedicine materials are the basic biotic and abiotic matter from which devices are built. In this book, development of responsive materials and devices is emphasized. A responsive material responds to external stimuli and converts energy from one form to another. Sensing, actuation, and energy harvesting are the usual functions of responsive or smart materials. Nanoscale smart materials including structural and electronic materials will be used for making devices and for reinforcing, supplementing, monitoring, controlling, and providing therapy to mitigate disease. Nanoscale materials must be designed to interface with biological materials. Nanoscale materials might be called biologically xvii xviii Preface responsive materials. Nanoscale materials in general include hard and soft, wet and dry, and biotic and abiotic materials that are either nanostructured, or contain nanoscale and nanophase components. These materials are formed with nanoscale structure in order to provide unique capabilities and multifunctional properties, and will be the gateway to building devices that can treat a formidable number of disease states at their own scale. Ultimately, the goal of nanomedicine is to produce new and responsive materials and devices to probe and measure nanoscale and microscale biological materials to prevent, detect, and cure disease and improve the quality of human life. The study of nanomedicine materials and devices may become a new primary focus of interdisciplinary research in the physical, engineering, and life sciences fields. Nanomedicine relies heavily on our ability to synthesize and build nano- and microscale materials and devices. Another objective of nanomedicine is life extension. This requires that disease be prevented or else detected early and treated, and that deterioration of the body be repaired. The development of preventative medicine, early diagnostics, therapy, and regenerative medicine can be greatly helped by nanoscale responsive materials and responsive biosensors that sense and respond to the measurement. Nanomedicine Devices. Nanomedicine devices are sensors, motors, mechanisms, machines, or transducers that perform work and measure or control the state of biological or mechanical systems. The design of nanomedicine devices may be the most technologically sophisticated engineering mankind has ever attempted. Devices are the end goal and what physicians want. Medical devices, in general, can be classified according to their invasiveness. Nanotechnology will allow devices to go inside a patient's body without the harmful effects typically associated with invasive medicine. Nanoscale structural, electronic, and bionic materials will eventually be used to build electronically powered parts of the body and new devices that provide special capabilities needed to repair the body. Responsive materials and devices with nanostructures that can respond to external stimuli are especially promising. Techniques for the design of responsive materials and strategies for their application are discussed in the book. Nanoscale sensors will be used to understand cellular signaling, to monitor chemicals that affect neurodegenerative diseases, and to detect metastasis in cancer. Ion channel nanoscale membranes will be used to improve the sensitivity of biosensors. Nanoscale actuators will be used to promote growth of tissue, as biomimetic valves, and artificial muscle. Nanotube actuator materials can also be used in reverse to harvest power from blood flow in the body. Active membrane fuel cells are also possible. Carbon nanotubes will allow development of miniature antennas that can go inside the body to power tiny machines or operate nanoelectronic brain sensors. Active biosensors will overcome the problem of biofouling to allow sensors to work in the body for extended periods. Nanostructured robots will be able to perform surgery on living cells and on the beating heart. Improvements from nanotechnology will yield enhanced catheters, endoscopes, needles for electrostimulation, smart stents, gene or cell transfection systems, syringes for less traumatic sampling, local delivery of therapeutic agents, online monitoring sensors for detection of circulating molecules with low concentration, and untold other advances. By reducing the size of the components interacting Outline of the Book xix with the biological samples, micro- and nanotechnologies are expected to bring real breakthroughs by introducing novel concepts for improved instrumental biocompatibility and sustainable power supply. Noninvasive medical devices like sensors for glucose monitoring, particles, magnetic, and surface electrodes could also benefit from miniaturization and integration of several functions on a chip or on a device. Data acquisition and processing from these devices will be thought of in an integrated approach including consideration of wireless nanotechnology. Nanomedicine Systems. Nanomedicine systems are considered as assemblies of sensors, actuators, nanostructured robots, smart particles for imaging and drug delivery (i.e., devices that can monitor and control processes and perform functions at the cellular level and above). Systems can have different levels of complexity and scale. For example, manmade nanosensors might be integrated with the human neural system as part of a hybrid personal diagnostic system. The human body is the most complex system known, and therefore the systems level perspective is important in the book. In particular, how nanoscale devices interface with the human, called nano-micro and meso-macro-scale interface design, is also discussed from a systems integration and characterization perspective. The book takes a comprehensive approach covering a spectrum of areas pertinent to nanomedicine and the interface of biology with non-biology. In February 2008, the inventor Ray Kurzweil said to BBC that "(by 2029) machines and humans will eventually merge through devices implanted in the body to boost intelligence and health." He said that in regard of nanobots. How close are we to having nanobots? What are the advances in nanoengineering so far? What is coming in the future? What are the most promising projects and lines of investigation? This book provides current information to help in answering these questions. Outline of the Book Nanomedicine Design of Particles, Sensors, Motors, Implants, Robots, and Devices is uniquely focused to serve as a primary reference book and a source of new ideas for the design and application of nanomedicine materials and devices. The innate interdisciplinary nature of nanomedicine makes the book applicable to readers from a wide array of fields. Faculty members, graduate students, postdoctoral researchers, undergraduates, industry researchers, venture capitalists, consulting engineers, and others working in the field of medicine and biology can benefit from the book. A solution manual accompanies the book for use in teaching and for reference by professionals, and to stimulate exploration down new paths of research. The supplementary materials and solutions manual is available through Artech (www. artechhouse.com). The problem set/solution manual is independent by chapter and will test understanding of the chapter materials and provide suggestions on where to attack barrier problems in the field. The book will be ideal for teaching graduate level survey courses that deal with fundamental nanomedicine devices. The book is broken down into an introduction chapter that gives a nanotechnology framework for medical innovation and then chapters that discuss different applications. Chapter 1 includes a clinical perspective and lays out the xx Preface need for nanotechnology to meet the major challenges and provide what is lacking in medicine. The rest of the book is organized from a technological science point of view dealing with various devices and considerations for putting the devices into application. The complexity of nanomedicine is reduced by arranging the book into four general areas: Part I, Nanoscale Materials and Particles; Part II, Electronic Biomedical Devices; Part III, Tiny Machines; and Part IV, Biological Integration and Characterization. These sections present practical concepts, new experimental procedures, design of new bioactive devices, and chapter problems to stimulate interdisciplinary innovation and to acquaint the downstream potential user with new technologies. The book also examines integration, biocompatibility, and safety issues related to implementation of devices inside the body. Since the field of nanomedicine is expanding quickly, readers are strongly encouraged to investigate the references provided in this book and to survey the recent literature to obtain the most comprehensive view of nanomedicine devices in their area of interest. The literature survey will also allow readers to become aware of the extraordinary work that could not be included in this book due to space limitations or time limitations. The authors of this book are mechanical, electrical, biomedical, chemical, and materials engineers, chemists, physicists, and medical doctors. The idea for this book came from Mr. Wayne Yuhasz who is the Executive Acquisitions Editor at Artech House Publishers. It is his and the authors' belief that tiny machines and devices can revolutionize the field of medicine. There is unlimited potential for neuro-electronic interfaces, cell repair machines, nanorobots, flesh welders, in vivo therapy, photonic, bionic, and nanoelectromechanical delivery devices for drugs, machines, shock wave assisted therapeutic devices, selective dissection of tissues by liquid jets, minimally intrusive drug and DNA delivery, controlling the molecular circuitries in cells, and control of the interactions of biomolecules to help doctors create cures for diseases based on how the body's cells actually function. We need physicians, chemists, biologists, physicists, engineers, and materials scientists to work together to build nanodevices that can revolutionize medicine and translate scientific advances into new options for patients. A powerful example where nanomedicine can help is in cancer. In a tumor, we don't see 80% of the life (cell divisions). Clinicians would like a digital sensor that can detect a single cancer cell early in a concentration of millions of normal cells in blood, or detect overexpression of growth factors that accompany cancer at picomolar concentration. It is our hope that this book helps to drive nanomedicine forward rapidly and beneficially by providing the ideas needed to engineer life itself and transcend biology so that humans will live happily to an old age. CHAPTER 1 A Nanotechnology Framework for Medical Innovation Mark J. Schulz, Weifeng Li, Vesselin Shanov, Yeoheung Yun, Chaminda Jayasinghe, Pravahan Salunke, Ge Li, Wondong Cho, Douglas Hurd, Sergey Yarmolenko, and Svetlana Fialkova 1.1 Introduction Nanomedicine is the development of nanostructured materials and devices to improve human health and performance. Nanomedicine, or tiny medicine, has a big future because it is a way to design small devices such as sensors, particles, and microrobots that can go inside our body and do what we want them to do [1, 2; see also supplementary information]. This chapter concisely outlines a nanotechnology framework for creating these small devices and explains how these devices can fight disease and improve our health now and in the future. The discussion will cover hard nanotechnology, which deals with abiotic materials that have nanoscale structure, and soft nanotechnology, which deals with biological materials. A key aspect of nanotechnology is that it is highly interdisciplinary. The mix of disciplines is producing startling advances in fundamental and translational research and a richer understanding of biological processes. From the perspective of problems in our society, it can be argued that disease is at the top of the list because every natural death is caused by disease. This considers aging a disease that can be affected by nanotechnology. The disease that may be the most frightening, and where something radical needs to be done to stop it, is cancer. It was reported in the December 22, 2008, issue of Time Magazine that in the year 2010 cancer will overtake heart disease as the leading cause of death worldwide according to the World Health Organization. The problem is that cancer cells can survive when other cells cannot. And cancer cells adapt to resist therapy. Thus new and more sophisticated medicine is needed to alleviate cancer. Screening tests are important to detect cancer early when it is most effectively treated. Screening is done to check parameters of the body (chemical, protein, electrical) that are markers of cancer. A problem is that many parameters of the body are difficult to sense or monitor, especially in vivo. Thus an important advance for fighting cancer and other disease is to develop improved sensors and instrumentation that can measure desired chemical and biological parameters of the body. A descriptive systems modeling (DSM) approach that uses words to describe experiments is proposed here for modeling disease. Therapeutic inputs can be applied to DSM models and the outputs that describe the response of the body can be measured to determine the effect 1 2 A Nanotechnology Framework for Medical Innovation of the therapy. New sensors and computer interpretation will reduce the need for animal and human testing. An area where record-keeping and simulation modeling are needed to make advances in nanomedicine is drug development. In 2008, Nature Materials magazine estimated that 130 nanotech-based drugs and delivery systems are currently being developed worldwide. Therefore, characterizing the efficacy of the large number of nanotechnology experiments will be an important aspect of nanomedicine research. A large database will be needed just to keep track of all the nanomedicine research results. A DSM approach that uses words to describe experiments can also be useful here. Looking ahead, we also expect that nanomedicine research will expand beyond the traditional research laboratory, and that a common standard for describing and cataloging results will be needed. It was reported in several newspapers [3] that "Hobbyists can now tinker with genes." This provides the possibility to discover a cure for cancer "in the garage." At-home nanomedicine is likely not far behind the grassroots gene science. Synthesis of various types of nanoparticles using chemical and electrochemical processes and functionalization of these particles can be done with standard facilities. However, characterization of the result requires more sophisticated instrumentation. A DSM database can help researchers around the world to model and predict the outcomes of using various therapeutic nanoparticles. Also, a database is needed for safety reasons to guide and regulate nanoparticle research. An overview of the DSM approach is given next, and is followed by a discussion of the various aspects of instrumentation, materials, and research that are important to make advances in medicine within the framework of nanotechnology. 1.2 Descriptive Systems Modeling Producing advances in nanotechnology involves complex interdisciplinary biological, mechanical, and electrical systems research. The complexity of nanomedicine might be handled more easily by using DSM, which uses words rather than equations to represent biological processes. A biological system to be described or modeled can be any biological process, organ, or the entire body, and different levels of detail can be used to describe the various systems. The physiological conditions or parameters of the system are called the states of the system. Inputs or stimuli are external or internal effects that cause the system to change state. The states that are measured are called the outputs. The descriptive systems representation thus describes or predicts in words rather than through equations the response and outputs of the system due to different inputs. The relationships between the inputs and outputs describe important physiological characteristics and the functioning of the system. This chapter proposes various techniques to gather information to develop DSM for nanomedicine. Nanomedicine systems are complex because there are a huge number of combinations of possible inputs and responses. Describing the behavior of nano- and biosystems will require an artificial reasoning algorithm to predict outputs due to inputs that have not been empirically tested. Then a physician can describe an input (such as a drug dose) in words, use DSM to predict the response of the system, and 1.2 Descriptive Systems Modeling 3 receive a description in words of the predicted effect of the therapy. Knowing how a system functions can in turn help us understand how to make advances in nanomedicine and allow us to test drugs on a computer descriptively before performing animal testing or prescribing medication to a patient. The descriptive systems approach will fill in the semiquantitative research and clinical area that falls in between highly analytical methods (such as biochemistry that applies to small systems and their interactions or systems biology that uses differential equations to describe the dynamic response of systems) and subjective, anecdotal, and empirical practice. A cancer biologist or physician, for instance, may not believe that systems biology equations can describe the complexity of cancer. Therefore, DSM may be an appropriate intermediary framework from which to model nanomedicine that will improve our health and lengthen our lifespans. DSM should be easy to accept by the medical community because it builds on techniques that physicians already use, which include differential diagnosis, which is mainly a systematic method to identify unknowns [4]; computer-aided differential diagnosis, which is the use of computer algorithms to assist in making a differential diagnosis; The Electronic Medical Textbook [5], which was developed as a medical knowledge base for physicians to optimize both their specialties and activities in clinical practice considering 3,500 diseases; and computer-aided medical expert systems for clinical laboratory diagnosis, which references electronic forms of human knowledge and imitates human thinking and decision-making. The use of expert systems and DSM can improve medical decisions made by physicians and patients [6]. 1.2.1 Examples of Descriptive Systems Modeling The human body is a complex system whose parameters change on short and long time scales due to aging and other factors. Inputs affect the state or condition of the body and consist of almost any physical or chemical variable such as temperature, food, drugs, and mechanical force. The states of the body are all the variables that define the health and physiological condition of the body. It is obvious that all of these variables cannot easily be described using equations. But a description using words is possible. State variables that can be measured and described are called the outputs of the body. Any intervention by the person or a physician to affect the condition of the body based on the outputs is called feedback. There can be many inputs and outputs that are time-dependent. Certain outputs are automatically sensed by the human and purposely used in the feedback system. There are also internal feedback mechanisms in the body that operate automatically. As an example, suppose a virus is an input to a person's body. The body will internally sense a foreign material and automatically generate a feedback reaction to generate antibodies to kill the virus. The person may also see a physician who could measure the body temperature and take a saliva sample (these are external sensing functions) and then prescribe antibiotics and medicine as external inputs. This is an example of combined internal and external sensing and feedback. Since the body is represented as a system with inputs and outputs, the inputs can be adjusted to drive the output to be a desired condition. In this way, a person can be monitored and tested to study disease. The steps to guarding the health of the body are to understand and model the behavior of the body, sense the response of 4 A Nanotechnology Framework for Medical Innovation the body, and choose appropriate inputs to move the response of the body to a desirable condition. The biological processes for example might represent biological pathways involved in cancer spreading. As an example of DSM, suppose one output variable from the body is the number of circulating tumor cells (CTC) in blood. We want this state variable to be zero. But it is difficult to measure this variable to tell if it is zero. In fact, we would like to monitor this variable continuously to give early warning of cancer spreading called metastasis. Our hypothesis is: The body can be monitored using sensors to detect CTCs and to guide therapy. To test this hypothesis, new experimentation is needed to help develop multi-input, multioutput DSM to determine if the body can be successfully monitored to detect cancer early by measuring CTCs, and to direct therapy. Biology is a descriptive science while mathematics is an analytical discipline. A goal is to first develop DSM based on qualitative and descriptive medicine and continuously move toward being more quantitative and predictive. Instrumentation and new devices including sensors will be the enabling technology to develop accurate systems models. A proposed model for biomedical processes is illustrated in Figure 1.1. Using this model, the physician should be able to enter patient data into the reasoning algorithm and test different possible therapeutic inputs. The descriptive reasoning algorithm would provide a prediction of the outcome of the treatment for the individual patient. A database of input and output test results (e.g., measuring CTC concentration after different therapies with feedback) is needed to build enough information to make reasonable predictions. An area where DSM might do a good job is in risk-benefit analysis and developing individualized medicine. Software could be developed to stratify patients based on their individual genetic differences and other factors and determine the best particular technology for a niche patient population. As an example, there is often a dilemma in cardiovascular therapy choosing between stenting and bypass surgery. The possibility of a reaction to drug elution and the occurrence of in-stent restenosis for a specific individual patient must be weighed against the risk of mortality for bypass surgery. DSM would provide statistics to trade off the two therapies. 1.3 Instrumentation Needed to Develop DSM Instrumentation is an underlying enabling technology leading to advances in multiple fields. New instrumentation for nanomedicine research is briefly mentioned. Inputs Feedback Biological Process Model Biological or Physician Based Feedback Rules Figure 1.1 Outputs Internal and External Sensing Proposed input-output descriptive systems model (DSM) of a biological system. 1.3 Instrumentation Needed to Develop DSM 5 Subcellular Nanotechnology Subcellular nanotechnology is described as using tiny instrumentation to characterize cellular processes, which is in contrast to typical methods of fluorescence that are used to study chemical processes in cells. A nanomanipulator [7, 8] is an instrument that can move probes or tools with nanometer precision. Measurements that can be made using the nanomanipulators include intracellular sensing of pH, making electrochemical impedance measurements with nanoscale spatial resolution, probing, nanoinjection, patch clamping, optical manipulation using light to trap and move small biological particles, cellular nanosurgery, nanoetching, and manipulation and etching of single proteins. Biological Nanotomography Biological nanotomography or bionanotomography is an exciting new high-throughput approach for obtaining 3-D, quantifiable information. Nanotomography [9] or computed tomography (CT) uses X-rays to create cross-sections from a 3-D object that later can be used to recreate a virtual model without destroying the original model. The term nano is used to indicate that the pixel sizes of the cross-sections are in the nanometer range. Nanotomography will be useful in studying how nanodevices operate in the body, and the outcomes of implantology, especially at the interfaces between tissue and biodegradable implants. Integrated AFM and FTIR for Materials Characterization A new infrared spectroscopy technique for determining the molecular composition of the surfaces of materials at high spatial resolution is being developed by combining atomic force microscopy (AFM) with Fourier-transform infrared spectroscopy (FTIR). This new analytical technique involves the use of an AFM to detect the response of a material to the absorption of modulated infrared radiation from an FTIR spectrometer and is referred to as AFM/FTIR spectroscopy. When the technique of AFM/FTIR spectroscopy is completely developed, it may be used to probe the molecular structure of interphases in polymer materials and adhesive bonds. The instrument may also be used to study nanoparticles being developed for imaging and therapy [10]. Luminescent Imaging Luminescent imaging is used to study functionalization (chemical modification of the surface) of biosensor electrodes, the structure of biological motors, ion channel activity in immunology, cancer pathways, and other applications. A single molecule imaging system has been developed that can view biological molecules such as DNA, RNA, and other molecules that are smaller than the 200-nm diffraction limit of standard optical microscopy systems [11, 12]. Also recently developed is a custom confocal microscope that allows individual pixel examination of protein interactions by detecting the spectrum and lifetime of fluorescent labels on proteins [11]. High-resolution luminescent imaging will be useful to study nonspecific binding and antibiofouling techniques for nanodevices. 6 A Nanotechnology Framework for Medical Innovation Batch Synthesis of Nanoparticles Mass producing nanoparticles and electrical components will be needed for creating nanomedicine devices. Synthesis of carbon nanotubes (CNT) can be scaled up using the ET6000 nanofurnace [13]. Another approach to scaling up production of nanoparticles is to use a vertical reactor and large wafers. A close coupled showerhead is used to introduce reagents into the reactor through a water-cooled showerhead surface over the entire area of deposition [14]. Base Flow CVD Synthesis of CNT Improving synthesis of nanotubes is needed, which would be a breakthrough in nanotechnology because short CNT and defects in CNT have limited their applications. Our group [15] is investigating an alternate method that we call base flow CVD. The idea is to simplify the CVD process by reversing the way the gases are supplied to the CNT nucleation zone. This is one approach to improve conventional CVD in which a catalyst is deposited on an alumina buffer layer on a SiO2/Si wafer. During synthesis the catalyst may gradually change composition and this causes defects to occur in the CNT and eventual stopping of CNT growth. Base Flow CVD supplies the carbon atoms near to the nucleation site. Further Needs in Instrumentation for Nanomedicine New instrumentation needed to accelerate nanotechnology and nanomedicine research includes a method of identifying and characterizing defects in CNT that is more sensitive than Raman spectroscopy and that is faster and less expensive than high-resolution transmission electron microscopy. Different types of individual defects must be identified and matched to the synthesis conditions that caused the defects. The defects must also be related to the changes in properties of the nanotube including the chemical, electrical, thermal, and mechanical and other properties. It would be useful to measure these properties during the synthesis process. Functionalization of nanotubes must also be characterized with a technique that does not use fluorescence. 1.4 Nanomaterials Made for Medicine Nanomaterials are defined as those materials whose structural elements such as clusters and crystallites have dimensions in the 100-nm range or smaller. Nanomaterials is a general term that includes; nanoscale materials where the material itself is at the nanoscale size; nanophase materials, which are hybrid materials that have a nanoscale phase or component; and nanostructured materials, where the material structure has nanoscale size or features. A characteristic of nanomaterials is their improved properties compared to their bulk states. The new properties and large surface areas per volume of material have been used to develop functional nanomaterials for cancer diagnosis and therapeutics ranging from delivering chemotherapy molecules in nano-sized capsules to functional nanomaterials that deliver thermal and radiotherapy at specific targeted sites. A review of various 1.4 Nanomaterials Made for Medicine 7 nanotechnologies in cancer therapy and diagnostics is given by Hede and Huilgol [16]. Four subareas of functional nanomaterials that will be important to creating nanomedicine are described below. Several of these ideas come from National Science Foundation initiatives [17]. Artificial Biomaterials and Systems Artificial nanobiomaterials and enhanced systems are of interest to regenerate tissue, bone, and organs. Also of interest are implants that can grow and adapt to the body for applications like pediatric othopedics [15] Nanomaterials for Sustainability in the Body Materials and biomanufacturing research should consider sustainability in the body in terms of wear, toxicity, and energy supply. Examples include fundamental research on synthesis, properties and mechanisms of biologically friendly nanocoatings, chemicals, and materials, materials for energy harvesting, thermoelectric conversion, new energy storage methods like biological fuel cells, biogalvanic batteries, and biodegradable metals for implants, sensors, and drug delivery vectors that can dissolve in the body without toxicity when they are no longer needed. Novel magnetic nanomaterials are described in Chapter 9. Smart Nanomaterials for Biology and Medicine Smart nanostructured materials and biomedical devices have properties that can be changed by external stimuli. These stimuli include stress, temperature, moisture, pH, electric or magnetic fields, and biological stimuli for use in sensing and actuation. Applications of such adaptive materials and systems range from the ability to control artificial muscles to sense different physiological variables inside the body, possibly including temperature, pressure, acceleration, strain, chemicals, proteins, microbes, cells, axon potentials, and almost any physical variable. These smart or "responsive" materials might also have the potential to be self-healing and self-regenerating like the human body [18]. Nanoparticles for Cancer Therapy Thermal, magnetic, chemical, and radioactive nanoparticles may be used to image and kill cancer cells. Several chapters in the book discuss this. However, the most near-term nanoparticle application might be gold nanoshells, which have already entered clinical trials. Jennifer West and Naomi Halas at Rice University [19] have constructed gold nanoshells that can absorb light or scatter it. The nanoshells are designed to absorb infrared light and image cancer cells or heat up. When they heat up, they will cauterize cancer cells. The nanoshells are injected into the patient's bloodstream and they pass through the leaky vasculature and collect in the tumor. An optical fiber inserted into the tumor illuminates the nanoshells with infrared light. The light heats the nanoshells and kills the tumor. Clinical trials are now being conducted at three medical centers in Texas on patience with head and neck 8 A Nanotechnology Framework for Medical Innovation cancers. Nanospectra Biosciences will commercialize the nanoshells. An advantage of photothermal ablation is that no drug is used. Drug-free therapy lessens the potential for toxicity. But toxicity could also come from the particle itself. Another type of thermal treatment of cancer is done using iron-oxide nanoparticles. These particles are injected directly into the tumor and are heated using alternating magnetic fields that are easily tolerated by patients. Clinical trials of the magnetic anticancer nanoparticles are being conducted by MagForce Nanotechnologies in Berlin, Germany. This technique reportedly is not toxic and is promising for use against glioblastoma brain cancer and prostate cancer. Thermal treatment may not be useful in all circumstances. An alternative is the use of nanoparticles that carry drugs. Multimodal nanoparticles are also being investigated that can deliver drugs, radiation, and thermal treatment. The particle might also be used for imaging. The multimode approach may have the advantage that if one mode fails, another might succeed. 1.5 Implantable Nanomedical Devices Implantable nanomedical devices science and technology is a pioneering integrative research area that seeks to realize Nobel laureate Richard Feynman's vision to develop tiny machines that have exquisite finesse and can go inside the body and "do what we want them to do." Richard Feynman believed that development of tiny machines could not be avoided because they would revolutionize health care. Recently there has been more interest in Feynman's ideas. In February 2008, inventor Ray Kurzweil said to the BBC in regard to nanorobots, that "by 2029 machines and humans will eventually merge through devices implanted in the body to boost intelligence and health." Also in 2008, Tad Hogg of Hewlett-Packard described plausible extensions of currently demonstrated nanoscale electronics, sensors, and motors relying on directed/automatic assembly of hard nanotechnology that can enable development of nonbiological robots that are stronger, faster, and with more operational programmability than is possible with biological organisms (see Chapter 10). Developing nanomedicine includes development of implantable nanomedical devices based on smart materials, small sensors and actuators, and nanoscale and nanostructured materials. Implantable nanomedical devices will provide revolutionary medical benefits by operating within the body. Implantable nanomedical devices can sense and continuously monitor their environment, perform simple tasks such as delivering drugs, sampling fluids, cleaning arteries, and killing cancer cells. The first approach to develop implantable medical devices was based on engineering of biological systems (e.g., bacteria executing simple programs). However, biological organisms have limited material properties and computational speed. Polymer particles and viruses are also being tested in the literature to deliver drugs or knock out genes and are sometimes referred to as nanomedicine devices. But biological/polymer materials are classified as soft nanotechnology and are limited in terms of sensing and actuation capability. Developing implantable medical devices based on nanostructured electronics, sensors, and actuators, and methods of directed and automatic assembly of these tiny components is transformative research that will not only have tremendous 1.5 Implantable Nanomedical Devices 9 impact on the early detection of diseases but also enhance our understanding of disease progression. With this knowledge, many novel and advanced smart implantable devices are feasible. This groundwork also holds promise for the development of future implants such as artificial organs. We strongly believe that just as novel drug and gene therapies have unlimited potential in the treatment and cure of human disease, so does the clinical application of implantable devices. As an example of the potential for implantable devices, it is revolutionary to be able to develop nanoparticles that provide a one-stop treatment to suppress cancer. But going farther, it would also be revolutionary to have a sensor continuously monitoring for the beginning of cancer and to provide therapy at the beginning to prevent the tumor in the first place. The initial focus of implantable nanomedical devices is on hard nanotechnology, which uses nonbiological nanoscale components to develop devices that are stronger, faster, and with more functionality than is possible with biological organisms. Tiny electromechanical components built using custom synthesized nanotubes, nanowires, and other nanoscale materials with desired properties will be self-assembled or assembled with manipulators in electron microscopes with nanoscale precision. The tiny devices will enable physicians to understand and control medical processes in the body that are presently inaccessible to investigation. A distinguishing feature of nanomedicine is that it is charting a new course by developing sophisticated devices that can explore inside the body, which has never been done before, and which should produce major advances in biology and medicine. The scope of this research spans from basic nanoscience through to solving interdisciplinary technological challenges in device design. Research that needs to be performed to create nanomedicine devices is organized within three basic science and technology areas described below. Nanomaterials and biological interfaces. Nanomedicine research depends on nanomaterials such as carbon nanotubes (CNT) and metal nanowires (NW). In most of nanomedicine research, building devices requires tailored nanomaterials. When it comes to nanodevices, the nanoparticle becomes a device and thus materials science matters. Technical areas that are important for nanomaterials development are nanotube synthesis, spinning of thread/ribbon, nanowire development, and interfaces and biocompatibility. Biosensor development. Biosensors are miniature sensors that measure biological media. Electronic biosensor platforms that can measure chemicals and proteins inside the body for extended periods should be developed. Technical areas that are important for biosensor development are sensor platform configuration, wireless communication and biofouling and particularly fibrosis at the tip of the sensor, and sensor functionalization chemistry. Bioactuator development. Bioactuators are miniature actuators that manipulate biological media. Nanotubes are used to manufacture miniature electronic components called carbotronics, which include microsolenoids and super R, L, C circuit elements. Technical areas important for bioactuator development are actuation, communication/control, and biocompatibility. 10 1.6 A Nanotechnology Framework for Medical Innovation Nanorobots Nanorobots are conceptual microscopic devices that would work at the molecular and cellular level to perform tasks in medical and other fields. Nanorobots will be built using nanoscale materials like carbon nanotubes, metal nanowires, and perhaps diamondoid materials. Building devices using nanoscale materials and parts is called nanomanufacturing. Nanomanufacturing could revolutionize medicine, but the technical barriers and costs to develop nanorobots are large. On the other hand, as Richard Feynman said, "tiny machines" is an area that cannot be avoided. The field of nanorobotics will grow more rapidly now because of the new instrumentation and communication technologies becoming available. An overview of the state of the art of nanorobotics research is given next, and then research examples are described. How to build tiny machines is an open question. No one has been able to fabricate microscopic robots using nanoscale materials. One approach is to "engineer biology." The alternate approach is new fabrication using nonbiological materials. Whichever approach is taken, it must be cheap to make large numbers of robots. Designs must consider the high surface area to volume ratio, high strength, and fast dynamics (electronics) of tiny devices. Inertial forces are small, viscous friction where force is proportional to velocity dominates (see Richard Feynman's talk; "There's Plenty of Room at the Bottom"). Brownian motion causes random movements of microscopic devices. This is explained by T. Hogg and P. Kuekes [20]. Powering robots is a challenge that might be met using biogalvanic batteries, glucose, or electromagnetic waves. Communication and control are barriers to robot design and are considered in [20]. Current robots are millimeter-size. Future nanorobots will be 100 to 1,000 times smaller. Some possible features of nanorobots are briefly discussed next (see also Chapter 14). Drug delivery directly to the site of injury or infection may be the first application of nanorobots because the robot can be very simple, actually just a particle that recognizes the target and is triggered to deliver drugs or do something else. An actuator single degree of freedom robot might be developed next. A robot that uses small tools to remove blockages and plaque and break clots into small pieces would be a revolutionary tool for physicians. Precautions are needed to prevent large clot fragments breaking free as they may cause blockage in other parts of the circulatory system. Electromagnetic radiation emission or ultrasonic wave generators in nanorobots may be used to destroy cancerous cells. A ruptured cancer cell might release proteins that could cause the cancer to spread. Microwaves might break the chemical bonds in the cancerous cell, killing it without rupturing the cell wall. Focused ultrasound might be used to produce high pressure and temperature at the cell killing it. The resonant frequencies of nanoscale circuits are high because the components are small. The high frequencies can be tuned to be in the ultrasound or microwave range as needed. Powering the nanorobot to produce radiation or waves might be done through inductive coupling and a transformer. A nanorobot might also heat the cancer cell to kill it. Heating might be done using microwaves, ultrasonic waves, or a laser. Tiny lasers could burn away harmful material like arterial plaque, cancerous cells, or blood clots. The nanorobot may need to be almost in contact with the cell or material to transfer enough energy 1.6 Nanorobots 11 because of the dissipating environment in the body. Electrical therapy using two nanotube electrodes protruding from the nanorobot could kill cancer cells by generating an electric current and heating the cell until it dies. On the other hand, electrical therapy has been shown to promote healing in wounds. Nanorobots may be beneficial to use in regenerative medicine, implantology, repair of injuries, and stimulation of bone growth. Nanorobot biosensors could use electrodes to measure pH, ion concentrations, or use receptors such as aptamers or antibodies to detect protein markers of disease. Telescoping may keep the electrodes clean from biofouling and allow the nanorobot to have a smaller profile for movement. The nanorobot could also sense electrical signals in nerves and in the brain. These signals could help to diagnose neurodegenerative diseases such as epilepsy. Overall, there are probably almost as many applications for nanorobots as there are diseases. At this point, getting some initial devices working in the field is important to stimulate further research and to overcome the skepticism and fear about having nanoscale robots operating in the body. Simulations will be very important to provide confidence in putting nanorobots into application. A graphics simulation approach has been developed for nano-assembly automation for medicine; see information on the Center for Automation in Nanobiotech [21]. Nanorobot control design for molecular manipulation and the use of evolutionary agents to enable the robustness of the design are described. Simulation of bloodborne nanosensors is described in Chapter 10. Multiphysics modeling of robots in the body environment is suggested. The robots may also be built using partially biodegradable materials including polymers and metals. Biodegradable Mg for example is being modeled in the body environment using COMSOL [22]. We believe that developing biodegradable robots is very important because they will help overcome some of the fears about the potential toxicity and self-replication of the robots. Robots that gradually dissolve and disappear from the body provide confidence in their safety. The subject of biodegradable metals is very new and important and recently the NSF is paying attention to it, see information on the ERC Center for RMB [23]. Surgery using nanorobots is a more long-term goal and could especially help in cancer therapy. Nanorobots may be able to remove malignant tissue more completely and reduce the chance of cancer reoccurring. Nanorobots for laparoscopic surgery are simulated using software described by Cavalcanti et al. Laparoscopic surgery is a minimally invasive surgery in which a fiber-optic light and video camera are inserted through a small incision in the body and are used to guide surgical instruments that perform the surgery. The da Vinci surgical system is one such surgical system in which four robot arms are remotely operated by the physician. Surgical teleoperation with nanorobots in theory would allow highly precise surgery and is proposed using a cell phone RF wireless or inductive wireless communication. A diamondoid surface of the robot is proposed to minimize fibrinogen. Three major challenges to be met in developing tiny machines and eventually nanorobots are (1) engineering them to be effective, (2) making them safe so that the nanorobot doesn't hurt surrounding healthy tissue or cause an immune response or toxicity in the body, and (3) mass-producing the devices. Dedicated research teams around the world are working on creating practical medical nanorobots to treat everything from heart disease to cancer. Robots likely will work in swarms to diag- 12 A Nanotechnology Framework for Medical Innovation nose and treat disease. Simple robots will come first with one or two functions and will make a large impact in many areas. Later, semiautonomous nanorobots could stay in the patient's body for a limited time and be cleared or degrade and disappear. New robots could be used as needed. Temporary and permanent implantable sensors and devices will also be used in the body. In the future, engineering and biology will come together to make our bodies become resistant to disease, increase our strength, and improve our intelligence. 1.6.1 Nanorobots for Revolutionizing Medicine Treating heart disease, cancer, and sensing using nanorobots is proposed here. Nanorobots to Maintain the Circulatory System The most common disease of the coronary arteries is arteriosclerosis, commonly known as hardening of the arteries. Arteriosclerosis is the thickening and stiffening of the artery walls from too much pressure and usually refers to several diseases in which the arterial wall thickens and loses its elasticity. Arteriosclerosis can occur in the arteries in the brain, kidneys, heart, abdominal aorta, or legs. Atherosclerosis is the precise term for formation of plaques on the arterial walls. Atherosclerosis can lead to arteriosclerosis. Plaque is a combination of cholesterol and other fats, calcium, and other elements carried in the blood. Plaque builds up in the small blood vessels that feed the heart. This plaque buildup can eventually narrow the arteries so that blood flow to the heart is inadequate and symptoms of insufficient blood flow called angina develop. Angina is loosely used to describe chest pain caused by lack of oxygen to the heart due to poor blood supply. In addition to angina or chest pain, atherosclerosis and arteriosclerosis can produce fatigue, shortness of breath, and an abnormal heart beat or arrhythmia. Plaque also can tear the artery walls and form blood clots that can lead to a heart attack. Often, there are no symptoms of arteriosclerosis until a heart attack occurs. A famous and beloved newsman in the United States, Tim Russert, died from a heart attack in 2008 due to cholesterol plaque rupturing in an artery, causing sudden coronary thrombosis. To remove this type of plaque from arteries, the following procedures are performed: angioplasty, coronary artery bypass graft surgery, coronary stent, and rotational atherectomy. Proposed in this chapter is a nanorobot that will operate in the circulatory system as shown in Figure 1.2(a). The robot must work in moving blood crowded with cells and various chemicals and with small vessels. The robot can perform work on the circulatory system or exchange chemicals with tissue. The robot must be comparable to the size of the cells. Initial work on developing this primitive nanorobot is being performed at the University of Cincinnati. The nanorobot has one moving part that is a linear actuator called a nanosolenoid. This actuator might be used as a chisel or ultrasound generator to remove plaque or treat stenosis in arteries. The concept nanorobot is shown in Figure 1.3. The nanorobot would be 3 µm in diameter and 5 µm long, which is smaller than the red cells in our blood that are about 7 µm wide. The bloodborne medical nanorobot will travel through the bloodstream and pass through the arteries and possibly capillaries in the human body [24]. The 1.6 Nanorobots 13 (a) (b) Fascicle Axon capillary Nanoparticle receptor Figure 1.2 (Color plate 1) The human circulatory and nervous systems. (a) Nanodevices might be used to clean and maintain the circulatory system. (b) Other nanodevices might act as artificial dendrite receptors to sense the condition of the body and use the nervous system for signal transmission. (this figure contains figures modified from: http://www.unithertechnology conference.com/downloads.html, presentation "Coordinating microscopic robots for nanomedicine" by Tad Hogg) Polymer encapsulation Ni Nanobar Magnetic flux lines CNT electrical coil Figure 1.3 Nanorobot concept, cross-section view. The electromagnetic solenoid nanorobot has one moving part, which is a rectangular nickel nanobar that is the core of a solenoid. Actuation is based on a nanosolenoid consisting of carbon nanotubes wound around the nickel nanobar. One coil at a time is energized to move the core back and forth generating acoustic waves in the blood (only the right coil is energized in the figure). The acoustic waves have high pressure and can abrade material and clean surfaces. The length of the nanorobot is five microns—small enough to pass through arteries and capillaries in the body. The robot could be oriented and positioned by a static magnetic field. Black circles with holes in the figure represent the CNT electrical coil. nanorobots would be actuated by an alternating magnetic field from outside or inside the body. Analysis and design of the inductive coupling from a coil on the skin to the nanorobot is being performed and will define the performance of the device. The nanorobots would be actuated in select regions of the body where plaque occurs. A steady magnetic field possibly could be applied to hold the nanorobots longer in the area of interest. Many robots would be distributed in the blood and they would be actuated together in the region of interest and collectively they would wear away plaque and deposits on the inside of the blood vessels. The nanorobots could be injected into the body and they could be expelled from the body in different ways. Only a concept nanorobot design is available at this stage, but long carbon nanotubes and nickel nanowires (NW) needed to build the nanorobot are available. 14 A Nanotechnology Framework for Medical Innovation Procedures to assemble a prototype robot using a nanomanipulator in an environmental scanning electron microscope are being developed. Mass production of many robots that would be needed to have a significant effect in the body might be done using self-assembly during synthesis of CNT. A bundle of long carbon nanotubes must be coiled around a Ni NW to form a solenoid that has a huge inductance for its small size. The first step of drawing CNT from an array is shown in Figure 1.4(a). The Ni NWs as produced have a strong attraction to a magnet. The CNT in the bundle are double wall with an outer diameter of about 10 nm and can carry a large current and be wound into coils with a large number of turns (see Figure 1.4(b)), which means the efficiency of nanodevices may be much greater than conventional large electronics. Because of the large surface area, CNT behave as supercapacitors in an electrolyte. Because CNT can be coiled in a large number of turns, they form a superinductor with inductance: L = μ 0 N 2 A / l where the constant μ is the permeability of free space, N is the number of turns, A is the cross-sectional area of the coil, and l is the length of the coil. Due to the N2 effect, a nanotube coil can have a huge inductance. Moreover, we are also developing straight nanotube thread that has a huge inductance. Thus, CNT and thread can have tailored R, L, and C properties depending on the electrolyte around the CNT. Heating may limit the current applied so that cells are not damaged, or the nanorobot could be used to kill cells by heating. The two coils would be switched on and off alternately. The frequency of oscillation can be designed based on the resistance, inductance, and capacitance properties of the CNT coil. The nanorobot solenoid may operate using a rectifier and capacitor to apply a DC field that is switched or directly coupled to the exciter coil at the resonant frequency of the circuit. Many of these nanorobots would be operating simultaneously chipping away at the plaque on the artery walls and then the robots would eventually be removed from the body. This solenoid can operate at high frequency and an ultrasound effect is expected, which means that high pressure and temperatures could be generated. Care will be needed not to break off large pieces of plaque or puncture the artery walls. The nanorobot itself may respond to the magnetic field excitation, but at a different frequency from the solenoid. A magnetic resonance imaging (MRI) system, for example, generates high magnetic fields that can magnetically guide the nanorobot in the three dimen- (a) (b) Figure 1.4 Nanorobot being developed at the University of Cincinnati: (a) nanomanipulator arm pulling CNT from an array; and (b) closeup view of the nanotubes being pulled from the array and joining to form long fibers. The next step is to wind up the fiber around the Ni NW, flip, and wind up the second coil. See Chapter 2 for more details on producing CNT and joining them. 1.6 Nanorobots 15 sions and hence control its movement and orientation in the body. Imaging may also be done simultaneously with control of the nanorobot. But MRI is expensive (see the Center for Imaging Research [25]), and the precision of the control is not known at this time. Researchers [25] suggested that in-body micro-MRI can be developed. Nanorobots for Cancer Therapy The nanorobot solenoid actuator may also kill cancer cells and do surgery. The nanosolenoid nanorobot is a possible new approach for cancer therapy that does not use nanoparticles, radiation, drugs, or heat. A disadvantage of nanoparticles that are used for cancer therapy is that the filtering system of the body eliminates many (up to 99%) of the particles before they can be used to deliver a drug or apply hyperthermia. It is particularly difficult to get the particles inside large tumors. And particles that contain drugs may be toxic to other parts of the body. Since there are larger vessels at tumors, the nanorobot might be able to penetrate into the tumor. The nanorobot could then apply focused ultrasound to break the cancer cells apart. This nanosolenoid nanorobot may be one of the first examples of Richard Feynman's vision coming true of tiny machines that can go inside the body to repair things. One of the limitations of this research and the reason the research is taking a long time to produce devices is the cost. It is very expensive to obtain and maintain the microscopy, nanomanipulator, and electronics instrumentation needed to build nanodevices. The societal impacts of developing implantable devices lies in providing tiny medical devices based on biosensors and bioactuators to go inside the body to detect and cure disease, repair the body, slow aging, and extend the human lifespan. Most medical problems have a need for sensing or actuation. Physicians need and desire to get their hands on actual physical systems that they can begin experimenting with. A goal of nanomedicine research should be to develop device platforms that in five years could be delivered in sufficiently large quantities to enable therapeutic and diagnostic applications. The potential impact of tiny machines that operate inside our body is as wide open as our imagination. The Holy Grail is to develop implantable medical devices and robots based on nanostructured electronics, sensors, and actuators, and to develop methods of directed and automatic assembly of these tiny components. Neural Integrated Nanorobot Biosensor Nanorobots might be used to act as artificial dendrite receptors to sense the condition of the body using the nervous system for signal transmission. Figure 1.2(b) shows the human nervous system. In this concept, nanorobot biosensors would go inside the body and attach to dendrites. The biosensor would transduce a physiological measurement into axon potentials that would be passed through the nervous system to the brain similar to a sensing of touch, temperature, or pressure. This biomimetic approach may solve the signal transduction problem for in-body communication. Fouling of the nanorobot biosensor will have to be prevented in order to make certain measurements. The telescoping solenoid nanorobot could provide a 16 A Nanotechnology Framework for Medical Innovation retractable electrode that is self-cleaning. The sensors added to the nervous system would potentially measure temperature, pressure, acceleration, electrical impulses, chemicals, and proteins. These variables could be used to monitor our health. 1.6.2 Nanorobot Factory The medical utility of nanodevices has been discussed in applications ranging from sensing to repair of arteries. Nanomanufacturing, also called nanoassembly or nanoconstruction, is discussed now because low-cost, mass production of nanodevices will be required. Miniaturization and biocompatibility are related chief technical goals in all the application thrusts and their specific goals. This section is to develop the tools/materials to be used to realize the applications. Developing a nanorobot factory provides an opportunity for synergy between different applications of nanorobots. The first objective of the nanofactory is to find a set of common materials and engineering standards that all applications can use, and then build a central fabrication/assembly facility that can be shared or duplicated. A nanorobotics factory is proposed to work inside an ESEM to make nanorobots and superelectronics parts. The nanomanufacturing factory will use tiny machines to mass produce electromechanical parts and then a variety of implantable nanomaterial scaffolds, sensors, and integrated active microelectromechanical-systems (MEMS), nanoelectromechannical systems (NEMS), and devices. Most of the nano- and microsensor technology needed to develop nanorobots is still under development and the initial goal is to get it working reliably in a lab environment and in an in vitro environment (with serum contact) before moving to the additional complexities of implantation in the body. There is a potential high relative sensitivity of NEMS for detecting cells/viruses/proteins/small molecules. A semipermeable membrane will keep out macrophages, but anything that lets protein through seems likely to lead to rapid fouling of the sensor electrodes by opsonized (opsonin is an antibody in blood serum that causes bacteria or other foreign cells to become more susceptible to the action of phagocytes) serum proteins. NEMS in vivo applications for small molecule detection (and to keep out proteins) are daunting from a signal to noise point of view. An integration plan is to engineer and build a MEMS assembler that works in low vacuum for assembly of devices. Figure 1.5 shows a nanorobot factory concept with two stages of manufacturing; in-vacuum (a) (b) (+) (-) Figure 1.5 Nanorobot factory concept with two stages of manufacturing: (a) in-vacuum processing inside an environmental scanning electron microscope showing a CNT ribbon being drawn from the CNT array, electrically fused, and wound onto a roll; and (b) in-air processing under an optical microscope where the ribbon is unwound, coated, dried, and rewound onto a Teflon coated Ni NW to form the main body of the robot actuator. 1.7 Biodegradable Metals for Temporary Implantable Nanomedical Devices 17 processing inside an environmental scanning electron microscope; and in-air processing under an optical microscope. The nanorobots produced will be about 5 μm in size. Later, self-assembly approaches using chemical vapor deposition (CVD) and physical vapor deposition (PVD) will be explored. 1.6.3 Biological Nanorobots Electromechanical devices and robots may be easier to design than biological devices and robots. However, a good source of motility strategies, navigation routes, and immune system avoidance strategies may be parasites that reliably navigate from organ to organ across their lifecycle (preferably incurring minimal tissue damage in the process). Most of these are not free swimming in the fast-moving circulation. Worm motility could be much more versatile and robust than that of a tiny submarine. While electromechanical devices will have ample specific power (relative to a biological entity) the worms may still adequately navigate with lower power. Use of biological organisms may be slow now, but modifying their metabolism rate may speed them up. The main attraction of bacterial organisms is that they can be precisely targeted. Bacteria may also be superior in terms of biocompatibility as compared to abiotic robots. In Chapter 8, Guo describes a bacteriophage phi29 DNA-packaging nanomotor for gene delivery. Tad Hogg proposed the idea of a hybrid robot. A combined bacteria and synthetic nanoparticle robot is described in [26]. The bacteria can swim and hence pull a particle load toward specific locations; using bacteria that orient toward magnetic fields allows external steering of the bacteria. This hybrid approach would be useful to reduce biofouling and energy requirements. Chapters 10 and 14 are oriented more toward nonbiological robots due to their potential for faster CPU and stronger materials—though they are more difficult to build. The bacteria-nanoparticle hybrid guided from outside is a step toward more autonomous robots. 1.7 Biodegradable Metals for Temporary Implantable Nanomedical Devices Certain nanomedical devices do not need to remain permanently in the body. Therefore, this section takes a different approach than the last section that considers long-term implantable nanomedical devices or removal of devices by the filtering systems in the body. Here we discuss biodegradable devices (sensors and actuators) that corrode and eventually disappear from the body. Iron (Fe) and magnesium (Mg) are two metals that are biodegradable. Iron may corrode too slowly in the body for many applications. There are also biodegradable polymers. But biodegradable polymers do not have the strength and stiffness of metals. Ideally, a biodegradable metal should degrade in the biological system at a desired rate and not be toxic or adversely affect the already existing metal-organic molecules and enzymes in the physiological environment. Also, the metal should not harmfully interact with the external environment and should not be antigenic (cause an adverse immune response). Mg alloys are good candidates for biomedical implants and devices. However, Fe is being considered for implants in certain applications (e.g., 18 A Nanotechnology Framework for Medical Innovation biocorrodible iron stents). Of late, Mg and its alloys are the most studied metal for use as biodegradable implants because of their potential nontoxicity, similar mechanical properties to bone, biocompatibility, and biodegradability [23]. The by-products of corrosion (chemicals, gas, and possibly particles) are released into the body as the implant corrodes. Assessment of the effect of these corrosion products on cells is needed. In addition, time dependant electrochemical characterization of Mg in different solutions coupled with in vivo testing is needed to understand the applicability of Mg as an implant material. 1.8 Integration of Nanodevices in the Body This section deals with the effectiveness, biocompatibility, and toxicity of nanodevices and particles in the body. This topic was briefly discussed in previous sections. Biofouling is the buildup of proteins and cells on implantable devices. Biofouling, clotting, and inflammation are a serious problem and can limit the lifetime of biosensors and devices that operate in the body. A nanoporous alumina membrane material and diamond-like films that reduce protein absorption and are compatible with cells are reported in [26]. Nanopatterned surfaces can reduce biofouling. The morphology of a surface with posts can be designed to allow or prevent cell adhesion. Various coatings are also being developed to prevent biofouling. Also, a telescoping electrode that is self-cleaning may be developed based on the solenoid robot described herein. Biofouling becomes less of a problem when nanoparticles/nanorobots are used temporarily in the body. Nanoparticles can be cleared from the body by the liver, spleen, and lymphatic system, or they can be eaten and remain in macrophages. Certain types of nanoparticles appear to have low toxicity (see Chapter 3). Others can enter cells and have a potential for toxicity or immune response. Toxicity depends on the size, shape, material, chemical functionalization, and concentration of the nanoparticles. This means that studying toxicity of nanoparticles is a significant task. Conflicting results are reported in the literature concerning the toxicity of different nanoparticles, and some experiments use unrealistic doses. The effect of combinations of nanoparticles and the long-term effects of nanoparticles also need to be investigated. Nanomedicine research in some cases has been delayed due to potential unknown toxicities of nanoparticles or nanomaterials. Regeneration of nerves using carbon nanotube thread and ribbon scaffolds may help the paralyzed walk again. Nanoparticles may be a breakthrough in fighting cancer. Some risk is justified to allow the lame to walk and to stop cancer. Different types of cells have different reactions to nanomaterials and the effect in one animal may not be the same in another animal or in humans. Thus, studying nanoparticle toxicity will require large effort and time. But research in critical areas where otherwise hope is small should not be stopped until toxicity is fully investigated. Determining the toxicity of CNT has been one of the most pressing questions. Nanoparticles certainly present possible risks, both medically and environmentally, due to unknown interactions and the effects nanotubes have on cells and living organisms. The reactive or catalytic prop- 1.9 Safety and Ethical Implications of Nanomedicine 19 erties that nanotubes may exhibit are also a concern. In general, any foreign body will elicit reactions from the immune system wherein biofouling, clotting, infection, and thrombosis are possible. Nanostructured membranes and coatings being developed provide hope for lessening these reactions and making implantable devices biocompatible [26]. Biofouling of devices is a problem that is being investigated by many research teams. A goal is to increase the circulation half-life of devices so they can do their job and then get out. There are 60,000 miles of blood vessels in the body. During circulation, particles are deactivated and filtered out of the body by proteins absorbed onto the particle, macrophages, phagocytes, and organs. Other approaches to increase the device half-life are mentioned next. Most proteins and cells in the body are negatively charged. Positively charged particles are removed from the body quickly. Thus, designing a particle or device that has a negative potential may be one way to increase the half-life of the device. Coating particles with poly-ethylene-glycol (PEG) or heparinizing the particle (to treat with heparin to prevent coagulation) may increase the circulation half-life of the particle. Nanopatterning the surface of the particle may also help, but the proteins that will attack the particle first are on the order of nanometers in size. A flexible nanotube forest coated onto a particle may reduce protein fouling but the possible toxicity of the particle must be considered [27]. An active biosensor that mechanically cleans the surface is an approach that would require precise design of the device. Creating nanomedicine hinges in part on solving possible toxicity problems. DSM would be useful to categorize toxicity effects and develop materials that are not toxic. There are also certain preclinical and regulatory issues that must be discussed and planned in order to get these sensors and devices quickly into the hands of physicians for use in healthcare and medicine. 1.9 Safety and Ethical Implications of Nanomedicine Safety is a concern when using artificial materials and nanodevices to repair and enhance the performance of the body. A nanodevice could pose a safety risk by altering the physical or mental performance of the body. Nanopills that are high-pressure cylinders that release oxygen are predicted to enhance athletic performance by allowing a person to run at full speed for 10 minutes without exhaustion. But the enhanced oxygen supply may overtax other parts of the body and this would be a safety concern. Also, what will the standard be for athletic competition when nanopills are available? Other types of nanopills may affect thinking and this is a safety concern. Biologically adaptive electronic (bioadaptronic) devices or smart materials can modify their behavior based on the state of the body. This is a feedback control process and must be designed to ensure stability and safety in the event of system degradation. This is also known as fault-tolerant control and it should be implemented on future in-body nanomedicine systems. Nanomedicine may be used to extend the human lifespan by curing the diseases of aging. The study of life extension is called biogerentology [28]. There will be safety concerns when trying to slow the aging process and trying to repair the body. What are the dangers of putting nanorobots in the body? Robots built using hard nanotechnology would not be able 20 A Nanotechnology Framework for Medical Innovation to self-replicate. Biological types of nanorobots are of more concern for self-replicating or having an adverse effect on biological cells and organs. Ethical considerations also come up when repairing the aging body and trying to slow aging. What could happen if the average lifespan was increased considering there are currently 6 billion people on Earth? Looking ahead at safety and ethics is important to provide guidelines on how to produce beneficial nanomedicine. DSM could reduce the need for animal testing and shorten clinical testing bringing innovation to clinical applications quicker.1 A final note of caution is due now with reference to its source which is anonymous NSF reviewers. The toxicity hazard and pollution potential of nanomaterials (e.g. powdered nanotubes used for reinforcing polymers) were recognized long after they became commonplace in the laboratories. This has lead to many new programs of research studying their potential problems. We must not make a similar mistake in our quest for nanomedicine. Given the fact that world population is growing, and with it is a growing inequity in our access to healthcare and other resources, it is prudent to collaborate with a bioethicist to examine the unintended consequences of living much longer and healthier lives with the help of nanotechnology. 1.10 Efficiently Working Together Using Shared Resources This section suggests how people and organizations can most efficiently work together using shared intellectual and physical resources. At the highest level, nanomedicine international centers of excellence for research and education could be established to focus effort to solve the most pressing problems in medicine. International organizations cooperating on research can provide the greatest expertise and instrumentation to solve problems. Intellectual property becomes a barrier to collaborations in some cases but a clear policy put in place at the beginning can produce agreement. Cooperative research using shared resources can lead to more rapid advances in nanomedicine and more intellectual property than could be produced by individual institutions because resources are used more efficiently. It is important to make rapid progress in the area of nanomedicine to be competitive because this field of research progresses so quickly. This leads to the question of how to make the fastest progress in a research laboratory with a given amount of funding resources. There are many factors that go into answering this question. We have considered this question in a university setting where students are the researchers. We assume that students are all equally paid and efficient and their pay does not change over the period of the project. Also assumed is that the students can work together efficiently, the work can be done in parallel using more than one student if desired, and facilities are available and their cost does not depend on the number of students. These assumptions do not always apply of course, but they are a useful starting point. With these assumptions, two outcomes are apparent. First, the cost of performing a project is the same regardless of the number of students working on the project. This is so because if n students are working on a project at 1/n of the total effort each, the total effort is the same, given our assumptions. Second, the calendar time to complete the project decreases in inverse proportion to the number of students working on the project. The total man-hours of work is the same, but the pro- 1.11 Chapter Summary and Conclusions 21 ject is completed faster in terms of calendar time as the number of students increases. If a project takes one year of time for one student to complete, adding more students reduces the project duration. Thus two students can complete the project 50% faster than one student. Three students can complete the project 17% faster than two students and 67% faster than one student. Four students can complete the project 8% faster than three students, and so on. There is a decreasing advantage as more students are added. When organization and management of the project are considered, too many students would make the project less efficient. But it is significant that two or three students working on a project with individual but related tasks might finish the project in half the time or less at the same cost. In general, benefits of working in teams of two or more students are that the research may progress faster and be more competitive to secure funding especially from industry and small business innovative research (SBIR) type projects, results are faster to commercialization and applications, students learn more working in teams and it prepares them for working in industry, it is fun to work with others, and more joint publications and invention disclosures can result from working in teams. On the down side, working in teams means more sharing of ideas and helping others, which some people do not prefer. 1.11 Chapter Summary and Conclusions This chapter has provided a framework for nanomedicine research to enable development of devices that can be temporarily used or implanted in the body. The science to be investigated is described in the context of various important medical applications. A descriptive systems modeling approach was proposed to be used with new sensors and devices described in the book to treat diseases such as cancer in a systematic way. New instrumentation that can help in nanoscale research was discussed along with biocompatibility, toxicity, safety, and ethics of nanomedicine. International collaboration was emphasized to advance medicine. While there are significant barriers to be overcome, the vision of nanomedicine is transformative and will have significant impact on the early detection of diseases and also enhance our understanding of disease progression. Discoveries by working at the nanoscale can lead to new instrumentation and technologies that benefit human health. Knowledge gained will cut across many disciplines including physical, chemical, biological, and engineering sciences. Specific subgoals, such as implantable devices that, in a label-free manner, reversibly sense proteins in the body, and developing an efficient way to communicate these biomolecular signals to an external source outside the body could be transformational in their own right. The major contribution of this chapter is to stimulate development of new approaches for sensing, imaging, and therapy to fight cancer and other diseases. The ideas are extremely cutting edge and straddle many frontier areas of interdisciplinary research. Many of the anticipated breakthroughs of nanomedicine are mind-boggling, and give a feeling of science fiction come alive. If successful, they will provide revolutionary benefits in health care and can boost American competitiveness in the global economy across innumerable established and newly emergent areas in nanotechnology and nanomedicine. 22 A Nanotechnology Framework for Medical Innovation Problems 1.1 Nanomedicine literature survey. Perform a literature search in your area of interest related to nanomedicine research. Compile a review paper in the area and submit it to a nanotechnology journal for possible publication. Review papers are useful because they describe the state of the art in the field of research. Review papers usually attract a lot of readers and journals like to publish review papers. A review of the literature is also a good way to begin a research thesis or dissertation. 1.2 Communication with in-body sensors. Determine the characteristics of near-field (magnetic) and far-field (RF) coupling for communicating with sensors imbedded inside the body. 1.3 Biocompatibility of nanodevices. Select a few new approaches (e.g., nanopatterning, applying voltage) to prevent biofouling of nanodevices and perform in vivo experiments to evaluate the approaches. Patent an approach if successful. Publish the results to help the nanomedicine community. Acknowledgments This interdisciplinary work was sponsored by NSF grant 0727250 with technical monitor Shaochen Chen, by North Carolina A&T SU through the Office of Naval Research with technical monitor Ignacio Perez, NSF grant CMS-0510823 with te