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					Contents


List of Contributors .................................................................................. xv
Foreword ............................................................................................... xix
Preface .................................................................................................. xxi

 1. Biomolecular Sensing for Cancer Diagnostics Using Carbon Nanotubes                                      1
    Jun Li and M. Meyyappan
     1.1. Introduction.............................................................................        1
     1.2. Carbon Nanotubes.....................................................................            2
     1.3. Carbon Nanotube Electrodes ........................................................              3
          1.3.1 Characteristics of a Good Electrode........................................                3
          1.3.2 Why Use Nanoelectrode? ....................................................                4
          1.3.3 Why Use Carbon Nanotubes? ...............................................                  5
          1.3.4 Fabrication of CNT Nanoelectrodes........................................                  5
     1.4. Preliminary Results....................................................................          8
          1.4.1 Electronic Nano-Chip Development .......................................                   8
          1.4.2 Electrochemical Properties of CNT Nanoelectrode Arrays ............                       11
          1.4.3 Functionalization of Oligonucleotide Probes .............................                 12
          1.4.4 Electrochemical Detection of DNA Hybridization ......................                     14
     1.5. Summary ................................................................................        16
          Acknowledgements....................................................................            17
          References ..............................................................................       17

 2. Microspheres for Drug Delivery                                                                        19
    Kyekyoon “Kevin” Kim and Daniel W. Pack
     2.1. Introduction.............................................................................       19
     2.2. Background .............................................................................        20
          2.2.1 Factors Affecting Release Rates ............................................              20
          2.2.2 Recent Applications of Controlled Release Microspheres .............                      21
     2.3. Fabrication of Polymer Micro- and Nanoparticles ..............................                  24
          2.3.1 Techniques for Fabricating Uniform Microspheres......................                     25
          2.3.2 Techniques for Fabricating Uniform Core-Shell Microparticles ......                       29
          2.3.3 Use of Electrohydrodynamic Spraying for Fabrication of Uniform
                Micro and Nanospheres.......................................................              33
     2.4. Controlled Release from Precision Microspheres ...............................                  35
          2.4.1 In-vitro Release from Uniform Microspheres ............................                   36
viii                                                                                           CONTENTS


            2.4.2 In-vitro Release from Mixtures of Uniform Microspheres.............                   37
            2.4.3 In vitro Release with Double-Wall Microspheres........................                39
            2.4.4 Release of Macromolecules from Monodisperse Microspheres.......                       40
       2.5. Conclusions.............................................................................    41
            References ..............................................................................   42

 3. Nanoscale Polymer Fabrication for Biomedical Applications                                            51
    L. James Lee
     3.1. Introduction.............................................................................     51
     3.2. Potential Biomedical Applications of Polymer Nanostructures...............                    52
          3.2.1 Drug Delivery and Gene Therapy...........................................               52
          3.2.2 Medical Diagnostics and Nanofluidics.....................................                53
          3.2.3 Tissue Engineering and Bioreactors........................................              54
     3.3. Mold (Master) Making and Prototyping...........................................               55
          3.3.1 Non-Cleanroom based Mold Making and Prototyping .................                       55
          3.3.2 Cleanroom based Mold Making.............................................                57
     3.4. Nanoscale Polymer Replication.....................................................            62
          3.4.1 Soft Lithography ...............................................................        63
          3.4.2 Nanoimprinting ................................................................         63
          3.4.3 Injection Molding at the Nanoscale ........................................             71
          3.4.4 Other Technologies ............................................................         73
     3.5. Assembly and Bonding ...............................................................          80
     3.6. Conclusions and Future Directions.................................................            83
          References ..............................................................................     89

 4. 3D Micro- and Nanofabrication and Their Medical Application                                          97
    E. Di Fabrizio, F. Perennes, F. Romanato, S. Cabrini, D. Cojoc, M. Tormen,
    L. Businaro, L. Vaccari, R. Z. Proietti, and Rakesh Kumar
     4.1. Introduction.............................................................................     97
     4.2. 3D Micro and Nanofabrication......................................................            98
          4.2.1 3D Fabrication by X-ray and Deep X-ray Lithography for
                Biomedical Application ......................................................            98
          4.2.2 3D Microparts for Transdermal Drug Delivery System ................                     102
     4.3. Emerging Methods for 3D Micro and Nanofabrication ........................                    107
          4.3.1 Two Photon assisted Microfabrication .....................................              108
          4.3.2 Nanoimprint and Soft Lithography .........................................              112
          4.3.3 Focused Ion Beam Lithography for 3 Dimensional Structures........                       115
     4.4. Hybrid Lithography Approach ......................................................            121
          4.4.1 X-ray and Nanoimprint Lithography for 3D Patterning ................                    121
          4.4.2 Lithography at Interface-Binary Resist Process Combined with
                Multiple Tilted XRL and EBL Lithography ..............................                  123
     4.5. 3D Trapping and Micro Manipulation by Means of Optical Tweezers......                         129
          4.5.1 Optical Tweezers Enabled 3D Trapping and
                Micromanipulation ............................................................          129
          4.5.2 3D Micromanipulation of Cells by Means of Optical Tweezers ......                       133
     4.6. Mems Devices for Biomedical Applications .....................................                136
CONTENTS                                                                                              ix


          4.6.1 Self-standing Metallic Nanogap MEMS Structures for Nano
                Trapping Application.......................................................... 137
          Conclusions............................................................................. 138
          References .............................................................................. 139

5. Sacrificial Oxide Layer for Drug Delivery                                                          145
   Piyush M. Sinha and Mauro Ferrari
    5.1. Introduction.............................................................................   145
    5.2. Silicon Dioxide Fabrication..........................................................       146
         5.2.1 Thermally Grown Oxide......................................................           147
         5.2.2 Deposited Silicon Dioxide ...................................................         148
         5.2.3 Thermally Grown Oxide vs Deposited Oxide ............................                 149
         5.2.4 Silicon-On-Insulator (SOI) as Sacrificial Layer..........................              149
    5.3. Sacrificial Oxide Etching.............................................................       150
         5.3.1 Etch Mechanism ...............................................................        150
         5.3.2 Etch Selectivity.................................................................     152
         5.3.3 Stiction...........................................................................   152
         5.3.4 On-Chip Packaging............................................................         153
    5.4. Application of Sacrificial Oxide in Devices ......................................           153
         5.4.1 Sacrificial Oxide for MEMS .................................................           154
         5.4.2 Sacrificial Oxide in ICs .......................................................       162
    5.5. Summary ................................................................................    166
         References ..............................................................................   166

6. Carbon Nanotube Biosensors                                                                        171
   Pingang He and Liming Dai
    6.1. Introduction.............................................................................   171
    6.2. The Structure and Chemical Reactivity of Carbon Nanotubes ................                  172
    6.3. Functionalization of Carbon Nanotubes...........................................            173
         6.3.1 Non-covalent Functionalization.............................................           173
         6.3.2 Chemically Covalent Modification .........................................             175
    6.4. Fabrication of Carbon Nanotube Electrodes......................................             178
         6.4.1 Non-aligned Carbon Nanotube Electrodes ................................               178
         6.4.2 Aligned Carbon Nanotube Electrodes .....................................              182
    6.5. Carbon Nanotube Biosensors........................................................          185
         6.5.1 Protein and Enzyme Biosensors.............................................            185
         6.5.2 DNA Sensors ...................................................................       191
    6.6. Conclusion ..............................................................................   198
         Acknowledgements....................................................................        198
         References ..............................................................................   198

7. Characterization Methods for Quality Control of Nanopore
   and Nanochannel Membranes                                                                       203
   Carlo Cosentino, Francesco Amato, and Mauro Ferrari
    7.1. Introduction............................................................................. 203
    7.2. Microscopy Observation ............................................................. 205
x                                                                                                 CONTENTS


        7.3.   Bubble Point............................................................................    207
        7.4.   Gas Permeability.......................................................................     210
        7.5.   Permoporometry .......................................................................      211
        7.6.   Thermoporometry .....................................................................       212
        7.7.   Electrical Conductance ...............................................................      213
        7.8.   Ultrasonic Spectroscopy..............................................................       214
        7.9.   Molecular Transport ..................................................................      216
               7.9.1 Classical Transport Models ..................................................         216
               7.9.2 Diffusion Through Nanochannels...........................................             218
               References ..............................................................................   222

    8. Magnetic Nanoparticles for MR Imaging                                                               227
       Lee Josephson
        8.1. Introduction.............................................................................     227
        8.2 A Brief History Of Polymer Coated Iron Oxide Nanoparticles
             As Pharmaceuticals ....................................................................       227
        8.3 Magneto/optical Nanoparticles As Optical Probes...............................                 230
        8.4 Magnetic Nanoparticles As Biosensors ............................................              231
        8.5 Magnetic Nanoparticles For Cell Loading And Tracking By MRI............                        232
        8.6 Molecularly Targeted Nanoparticle Based MRI Contrast Agents .............                      234
        8.7 The Future ...............................................................................     235
             References ...............................................................................    235

    9. Polymer Design for Nonviral Gene Delivery                                                           239
       Kam W. Leong
        9.1 Introduction..............................................................................     239
             9.1.1 Barriers for Nonviral Gene Transfer........................................             240
        9.2 Synthetic Polymeric Gene Carriers .................................................            243
             9.2.1 Polyethyleneimine .............................................................         243
             9.2.2 Polylysine .......................................................................      243
             9.2.3 Poly(α -(4-aminobutyl)-L-glycolic acid)..................................               246
             9.2.4 Polyamidoamine Dendrimer .................................................              247
             9.2.5 Poly((2-dimethylamino)ethyl methacrylate)..............................                 248
             9.2.6 Poly(β-amino ester) ...........................................................         248
             9.2.7 Polyphosphazene...............................................................          249
             9.2.8 Cyclodextrin-containing Polycation........................................              250
             9.2.9 Polyphosphoester ..............................................................         251
        9.3 Natural Polymeric Gene Carriers....................................................            254
             9.3.1 Chitosan .........................................................................      254
        9.4 Biomaterials Approach to Gene Delivery..........................................               256
        9.5 Summary.................................................................................       258
            References ...............................................................................     259

10. Dip-Pen Technologies for Biomolecular Devices                                                   265
    Debjyoti Banerjee
    10.1 Introduction.............................................................................. 265
CONTENTS                                                                                               xi


    10.2 General Applications ..................................................................      268
    10.3 Bio-molecular Patterning using Dpn................................................           269
         10.3.1 Nano-Pattering of Oligonucleotides Using DPN ........................                 270
         10.3.2 Nano-Patterning of Protein and Petides Using DPN....................                  276
         10.3.3 Nano-Patterning of Composite Bio-Molecular Structures .............                   291
    10.4 Dpn Bio-Molecular Devices for Cell and Virus Capture........................                 292
    10.5 Using Microfluidics for Dpn Applications in Biomolecular Patterning ......                    295
         10.5.1 Analysis .........................................................................    296
         10.5.2 Computational Fluid Dynamic (CFD) Simulation ......................                   297
         10.5.3 Fabrication......................................................................     298
         10.5.4 Experimental Apparatus .....................................................          299
         10.5.5 Results and Discussion.......................................................         299
    10.6 Summary, Conclusion and Future Direction ......................................              302
         References ...............................................................................   303

11. Engineered Inorganic-Binding Polypeptides for Bionanotechnology                                   307
    Candan Tamerler and Mehmet Sarikaya
    11.1 Introduction..............................................................................   307
    11.2 Selection of Inorganic Binding Polypeptides......................................            309
    11.3 Binding Affinity of Inorganic-Binding Polypeptides ............................               312
         11.3.1 Molecular Adsorption of GEPI .............................................            312
         11.3.2 Physical Specificity and Molecular Modeling ...........................                314
    11.4 Potential Applications of Molecular Biomimetics in Bio-And
         Nanobiotechnology ....................................................................       316
         11.4.1 GEPI-Assisted Cell and Phage Sorting and Differentiation ...........                  317
         11.4.2 Target Immobilization via Engineered Polypeptides as Molecular
                Erector Films...................................................................      318
         11.4.3 Genetically Engineered Bifunctional GEPI-Alkaline Phosphatase
                Molecular Construct: Expressing both Catalytic and
                Inorganic-Binding Activity ..................................................         320
         11.4.4 Bionanofabrication: Silica Synthesis Using Inorganic
                Binding Polypeptides.........................................................         321
    11.5 Future Prospects and Potential Applications in Nanotechnology..............                  322
         Acknowledgements ....................................................................        323
         References ...............................................................................   323

12. Dynamic Nanodevices Based on Protein Molecular Motors                                             327
    Dan V. Nicolau
    12.1 Introduction..............................................................................   327
    12.2 Protein Molecular Motors—Biophysical Aspects................................                 328
         12.2.1 Rotary Motors..................................................................       328
         12.2.2 Linear Motors ..................................................................      329
         12.2.3 Actin/Microtubule Polymerisation .........................................            333
    12.3 Nanodevices Based on Protein Molecular Motors—Operational Aspects...                         333
         12.3.1 Motility Assays and Single Molecule Techniques ......................                 333
         12.3.2 Interaction of Motor Proteins with the Device Environment..........                   336
xii                                                                                            CONTENTS


      12.4 Design, Fabrication and Operation of Protein Molecular Motors-Based
           Nanodevices .............................................................................    341
           12.4.1 Lateral Confinement of Movement for Motile Elements...............                     341
           12.4.2 Control of Unidirectional Movement by External Means .............                    343
           12.4.3 Control of Unidirectional Movement by Self-Assembled Tracks ....                      346
           12.4.4 On-Off Control of the Operation of Protein Molecular Motors
                  Devices..........................................................................     347
      12.5 Prototypes of Nanodevices Based on Protein Molecular Motors..............                    349
           12.5.1 Sensing Devices ...............................................................       350
           12.5.2 Nanomechanical Devices ....................................................           350
           12.5.3 Information Storage and Processing .......................................            354
      12.6 Perspectives..............................................................................   354
      12.7 Conclusion...............................................................................    356
           Acknowledgements ....................................................................        357
           References ...............................................................................   357

13. Nanodevices in Biomedical Applications                                                              363
    Bryan Ronain Smith, Mark Ruegsegger, Philip A. Barnes, Mauro Ferrari,
    and Stephen C. Lee
    13.1 Introduction..............................................................................     363
         13.1.1 Defining Nanotechnology and Nanodevices .............................                    363
    13.2 Opportunities for Biomedical Nanotechnology: Technological and
         Biological ................................................................................    366
         13.2.1 Device Assembly..............................................................           366
         13.2.2 Targeting: Delimiting Nanotherapeutic Action in
                Three-Dimensional Space ...................................................             373
         13.2.3 Triggering: Spatially and Temporally Delimiting
                Nanotherapeutic Action ......................................................           374
         13.2.4 Sensing Approaches ..........................................................           380
         13.2.5 Imaging Using Nanotherapeutic Contrast Agents.......................                    383
    13.3 Specific Therapeutic Applications of Hybrid Nanodevices.....................                    385
         13.3.1 Hybrid Nanotherapeutic Devices in Oncology ..........................                   385
         13.3.2 Nanotherapeutics for Cardiovascular Applications .....................                  396
         13.3.3 Hybrid Nanotherapeutics and Specific Host Immune Responses ....                          388
    13.4 Conclusions..............................................................................      389
         Acknowledgements ....................................................................          390
         References ...............................................................................     390

14. Modeling Biomolecular Transport at the Nanoscale                                                    399
    A. T. Conlisk
    14.1 Introduction..............................................................................     399
    14.2 Background..............................................................................       402
    14.3 Governing Equations for Synthetic Ion Channels in the Continuum
          Regime: The Poisson-Nernst-Planck System .....................................                403
    14.4 The One-Dimensional Poisson-Nernst-Planck Equations ......................                     406
    14.5 Hindered Diffusion Concepts ........................................................           408
    14.6 Calculating the Electrical Potential .................................................         412
CONTENTS                                                                                              xiii


    14.7 Ionic and Biomolecular Transport: Comparison with Experiment ............                    416
    14.8 Brownian Dynamics ...................................................................        423
    14.9 Molecular Dynamics Simulations ...................................................           427
    14.10 Summary ...............................................................................     431
          Acknowledgements...................................................................         432
          References..............................................................................    433

15. Nanotechnology in Cancer Drug Therapy: A Biocomputational
    Approach                                                                                          435
    Hermann B. Frieboes, John P. Sinek, Orhan Nalcioglu, John P. Fruehauf,
    and Vittorio Cristini
    15.1 Introduction..............................................................................   435
         15.1.1 Challenges with Chemotherapy ............................................             435
         15.1.2 Possibilities of Nanotechnology ............................................          436
         15.1.3 Chemotherapy via Nanoparticles...........................................             436
         15.1.4 Challenges of Nanotechnology .............................................            437
         15.1.5 Biocomputation in Cancer Treatment .....................................              437
    15.2 Issues with Chemotherapy: How Nanotechnology can Help and the
         Role of Biocomputation...............................................................        438
         15.2.1 Drug Resistance ...............................................................       438
         15.2.2 Drug Toxicity ..................................................................      439
         15.2.3 Drug Targeting.................................................................       439
         15.2.4 Drug Transport.................................................................       440
         15.2.5 Drug Dosage and Scheduling ...............................................            442
         15.2.6 Drug Concentration ...........................................................        455
         15.2.7 Drug Release ...................................................................      447
    15.3 Biocomputation at the System Level ...............................................           450
         15.3.1 Modeling at the Nanoscale ..................................................          450
         15.3.2 Modeling at the Tumor Scale ...............................................           452
         15.3.3 Modeling of Cancer Therapy................................................            453
    15.4 Outlook on Modeling ..................................................................       456
         References ...............................................................................   456

16. Nanomechanics and Tissue Pathology                                                                461
    Jason Sakamoto, Paolo Decuzzi, Francesco Gentile, Stanislav I. Rokhlin,
    Lugen Wang, Bin Xie, and Senior Author: Mauro Ferrari
    16.1 Introduction..............................................................................   461
         16.1.1 Background.....................................................................       461
         16.1.2 The Diagnostic Conundrum .................................................            463
         16.1.3 Oncologic Opportunity: Breast Cancer....................................              463
         16.1.4 Screening for Malignant Melanoma .......................................              465
    16.2 The Classic Approach: Characterization-Mode Ultrasound and
         Continuum Mechanics Model........................................................            467
         16.2.1 Continuum Mechanics Description of Ultrasonic Wave
                Propagation.....................................................................      467
    16.3 An Introduction to “Doublet Mechanics”..........................................             471
         16.3.1 Connotations and Interpretation of Doublet Mechanics................                  471
xiv                                                                                              CONTENTS


             16.3.2 Microstrains and Microstresses: A Deeper Insight into Doublet
                    Mechanics ......................................................................      472
             16.3.3 Comparison with Other Theories...........................................             473
      16.4   Doublet Mechanics within the Linear Elastic Framework (Mathematical
             Formulation of Doublet Mechanics) ................................................           474
             16.4.1 Microstructure .................................................................      474
             16.4.2 Microstrains ....................................................................     474
             16.4.3 Microstresses and Transition to Macrostresses ..........................              476
             16.4.4 Linear Elastic Doublet Mechanics .........................................            478
      16.5   Plane Waves Propagation within the Linear Elastodynamics of Doublet
             Mechanics ...............................................................................    479
             16.5.1 Significance of the Analysis.................................................          479
             16.5.2 Dynamic Scaling Equations .................................................           479
             16.5.3 Plane Elastic Waves in Granular Media...................................              480
             16.5.4 Discussion ......................................................................     483
      16.6   Reflection and Transmission of Plane Waves (Numerical Applications
             of Doublet Mechanics to Malignant Tissue) ......................................             483
             16.6.1 The Reflection Equations ....................................................          484
             16.6.2 Solution of the Equations: the Forward Problem........................                486
             16.6.3 The Inverse Problem and the Doublet Mechanics Parameters
                    Identification ...................................................................     487
             16.6.4 The Doublet Mechanics Approach: Final Marks........................                   488
      16.7   Experimental Practice .................................................................      488
             16.7.1 Characterization-Mode Ultrasound ........................................             488
             16.7.2 Characterization-Mode Ultrasound System ..............................                489
             16.7.3 The Model ......................................................................      489
             16.7.4 Tissue Preparation.............................................................       490
             16.7.5 Experimental Findings: Breast Cancer detection........................                491
      16.8   Nanomechanical Method for the Molecular Analysis of Breast Cancer .....                      494
             16.8.1 Introduction ....................................................................     494
             16.8.2 The HER-2/neu Oncogene...................................................             494
             16.8.3 HER-2/neu Exploitation .....................................................          495
             16.8.4 Ultrasound Interaction with Tissues with Targeted Nanoparticles ...                   497
             16.8.5 Preliminary Results: Randomly Distributed Particles in the Bulk....                   497
             16.8.6 Preliminary Results: Randomly distributed particles upon
                    an interface .....................................................................    499
      16.9   Future of Characterization-Mode Ultrasound .....................................             499
             Acknowledgements ....................................................................        501
             References ...............................................................................   501

About the Editors.................................................................................. 505
Index .................................................................................................. 507
http://www.springer.com/978-0-387-25563-7

				
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