Preface ........................................................ xv
1 Extracellular Matrix Proteins for Stem Cell Fate ............. 1
Betül Çelebi-Saltik
1.1 Human Stem Cells, Sources, and Niches ................... 2
1.2 Role of Extrinsic and Intrinsic Factors ................. 5
1.2.1 Shape ............................................ 5
1.2.2 Topography Regulates Cell Fate ................... 6
1.2.3 Stiffness and Stress ............................. 6
1.2.4 Integrins ........................................ 7
1.2.5 Signaling via Integrins .......................... 9
1.3 Extracellular Matrix of the Mesenchyme: Human Bone
Marrow ................................................. 11
1.4 Biomimetic Peptides as Extracellular Matrix Proteins ... 13
References .................................................. 15
2 The Superficial Mechanical and Physical Properties of
Matrix Microenvironment as Stem Cell Fate Regulator ......... 23
Mohsen Shahrousvand, Gity Mir Mohamad Sadeghi and Ali Salimi
2.1 Introduction ........................................... 24
2.2 Fabrication of the Microenvironments with Different
Properties in Surfaces ................................. 25
2.3 Effects of Surface Topography on Stem Cell Behaviors ... 28
2.4 Role of Substrate Stiffness and Elasticity of
Matrix on Cell Culture ................................. 31
2.5 Stem Cell Fate Induced by Matrix Stiffness and
Its Mechanism .......................................... 31
2.6 Competition/Compliance between Matrix Stiffness and
Other Signals and Their Effect on Stem Cells Fate ...... 33
2.6 Effects of Matrix Stiffness on Stem Cells in
Two Dimensions versus Three Dimensions ................. 33
2.8 Effects of External Mechanical Cues on Stem Cell Fate
from Surface Interactions Perspective .................. 35
2.9 Conclusions ............................................ 36
Acknowledgments ............................................. 36
References .................................................. 37
3 Effects of Mechanotransduction on Stem Cell Behavior ........ 45
Bahar Bilgen and Sedat Odabas
3.1 Introduction ........................................... 45
3.2 The Concept of Mechanotransduction ..................... 47
3.3 The Mechanical Cues of Cell Differentiation and Tissue
Formation on the Basis of Mechanotransduction .......... 48
3.4 Mechanotransduction via External Forces ................ 49
3.4.1 Mechanotransduction via Bioreactors ............. 50
3.4.2 Mechanotransduction via Particle-based Systems .. 53
3.4.3 Mechanotransduction via Other External Forces ... 55
3.5 Mechanotransduction via Bioinspired Materials .......... 56
3.6 Future Remarks and Conclusion .......................... 56
Declaration of Interest ..................................... 57
References .................................................. 57
4 Modulation of Stem Cells Behavior Through Bioactive
Surfaces .................................................... 67
Eduardo D. Gomes, Rita C. Assunção-Silva, Nuno Sousa,
Nuno A. Silva and António J. Salgado
4.1 Lithography ............................................ 68
4.2 Micro and Nanopatterning ............................... 72
4.3 Microfluidics .......................................... 73
4.4 Electrospinning ........................................ 73
4.5 Bottom-up/Top-down Approaches .......................... 76
4.6 Substrates Chemical Modifications ...................... 77
4.6.1 Biomolecules Coatings ........................... 78
4.6.2 Peptide Grafting ................................ 79
4.7 Conclusion ............................................. 80
Acknowledgements ............................................ 81
References .................................................. 81
5 Influence of Controlled Micro- and Nanoengineered
Environments on Stem Cell Fate ..............................
Anna Lagunas, David Caballero and Josep Samitier
5.1 Introduction to Engineered Environments for the
Control of Stem Cell Differentiation ................... 88
5.1.1 Stem Cells Niche In Vivo: A Highly Dynamic
and Complex Environment ......................... 88
5.1.2 Mimicking the Stem Cells Niche In Vitro:
Engineered Biomaterials ......................... 90
5.2 Mechanoregulation of Stem Cell Fate .................... 91
5.2.1 From In Vivo to In Vitro: Influence of the
Mechanical Environment on Stem Cell Fate ........ 91
5.2.2 Regulation of Stem Cell Fate by Surface
Roughness ....................................... 92
5.2.3 Control of Stem Cell Differentiation by
Micro- and Nanotopographic Surfaces ............. 94
5.2.4 Physical Gradients for Regulating Stem Cell
Fate ............................................ 98
5.3 Controlled Surface Immobilization of Biochemical
Stimuli for Stem Cell Differentiation ................. 102
5.3.1 Micro- and Nanopatterned Surfaces: Effect of
Geometrical Constraint and Ligand Presentation
at the Nanoscale ............................... 102
5.3.2 Biochemical Gradients for Stem Cell
Differentiation ................................ 109
5.4 Three-dimensional Micro- and Nanoengineered
Environments for Stem Cell Differentiation ............ 114
5.4.1 Three-dimensional Mechanoregulation of Stem
Cell Fate ...................................... 115
5.4.2 Three-dimensional Biochemical Patterns for
Stem Cell Differentiation ...................... 121
5.5 Conclusions and Future Perspectives ................... 124
References ................................................. 124
6 Recent Advances in Nanostructured Polymeric Surface:
Challenges and Frontiers in Stem Cells ..................... 143
Ilaria Armentano, Samantha Mattioli, Francesco Morena,
Chiara Argentati, Sabata Martino, Luigi Torre and
Josè Maria Kenny
6.1 Introduction .......................................... 144
6.2 Nanostructured Surface ................................ 146
6.3 Stem Cell ............................................. 148
6.4 Stem Cell/Surface Interaction ......................... 149
6.5 Microscopic Techniques Used in Estimating Stem
Cell/Surface .......................................... 150
6.5.1 Fluorescence Microscopy ........................ 150
6.5.2 Electron Microscopy ............................ 151
6.5.3 Atomic Force Microscopy ........................ 155
6.5.3.1 Instrument ................................. 156
6.5.3.2 Cell Nanomechanical Motion ................. 158
6.5.3.3 Mechanical Properties ...................... 158
6.6 Conclusions and Future Perspectives ................... 160
References ................................................. 160
7 Laser Surface Modification Techniques and Stem Cells
Applications ............................................... 167
Çaǧri Kaan Akkan
7.1 Introduction .......................................... 168
7.2 Fundamental Laser Optics for Surface Structuring ...... 168
7.2.1 Definitive Facts for Laser Surface
Structuring .................................... 169
7.2.1.1 Absorptivity and Reflectivity of the
Laser Beam by the Material Surface ......... 169
7.2.1.2 Effect of the Incoming Laser Light
Polarization ............................... 170
7.2.1.3 Operation Mode of the Laser ................ 171
7.2.1.4 Beam Quality Factor ........................ 172
7.2.1.5 Laser Pulse Energy/Power ................... 173
7.2.2 Ablation by Laser Pulses ....................... 174
7.2.2.1 Focusing the Laser Beam .................... 174
7.2.2.2 Ablation Regime ............................ 175
7.3 Methods for Laser Surface Structuring ................. 176
7.3.1 Physical Surface Modifications by Lasers ....... 176
7.3.1.1 Direct Structuring ......................... 177
7.3.1.2 Beam Shaping Optics ........................ 179
7.3.1.3 Direct Laser Interference Patterning ....... 182
7.3.2 Chemical Surface Modification by Lasers ........ 183
7.3.2.1 Pulsed Laser Deposition .................... 183
7.3.2.2 Laser Surface Alloying ..................... 186
7.3.2.3 Laser Surface Oxidation and Nitriding ...... 188
7.4 Stem Cells and Laser-modified Surfaces ................ 189
7.5 Conclusions ........................................... 193
References ................................................. 194
8 Plasma Polymer Deposition: A Versatile Tool for Stem Cell
Research ................................................... 199
M.N. Macgregor-Ramiasa and K. Vasilev
8.1 Introduction .......................................... 199
8.2 The Principle and Physics of Plasma Methods for
Surface Modification .................................. 201
8.2.1 Plasma Sputtering, Etching an Implantation ..... 202
8.2.2 Plasma Polymer Deposition ...................... 203
8.3 Surface Properties Influencing Stem Cell Fate ......... 204
8.3.1 Plasma Methods for Tailored Surface Chemistry .. 205
8.3.1.1 Oxygen-rich Surfaces ....................... 206
8.3.1.2 Nitrogen-rich Surfaces ..................... 210
8.3.1.3 Systematic Studies and Copolymers .......... 212
8.3.2 Plasma for Surface Topography .................. 213
8.3.3 Plasma for Surface Stiff^ness .................. 216
8.3.4 Plasma for Gradient Substrata .................. 217
8.3.5 Plasma and 3D Scaffolds ........................ 220
8.4 New Trends and Outlook ................................ 221
8.5 Conclusions ........................................... 221
References ................................................. 222
9 Three-dimensional Printing Approaches for the Treatment
of Critical-sized Bone Defects ............................. 233
Sara Salehi, Bilal A. Naved and Warren L. Grayson
9.1 Background ............................................ 234
9.1.1 Treatment Approaches for Critical-sized Bone
Defects ........................................ 234
9.1.2 History of the Application of 3D Printing to
Medicine and Biology ........................... 235
9.2 Overview of 3D Printing Technologies .................. 236
9.2.1 Laser-based Technologies ....................... 237
9.2.1.1 Stereolithography .......................... 237
9.2.1.2 Selective Laser Sintering .................. 238
9.2.1.3 Selective Laser Melting .................... 238
9.2.1.4 Electron Beam Melting ...................... 239
9.2.1.5 Two-photon Polymerization .................. 239
9.2.2 Extrusion-based Technologies ................... 240
9.2.2.1 Fused Deposition Modeling .................. 240
9.2.2.2 Material Jetting ........................... 240
9.2.3 Ink-based Technologies ........................ 241
9.2.3.1 Inkjet 3D Printing ......................... 241
9.2.3.2 Aerosol Jet Printing ....................... 241
9.3 Surgical Guides and Models for Bone Reconstruction .... 242
9.3.1 Laser-based Surgical Guides .................... 242
9.3.2 Extrusion-based Surgical Guides ................ 242
9.3.3 Ink-based Surgical Guides ...................... 244
9.4 Three-dimensionally Printed Implants for Bone
Substitution .......................................... 244
9.4.1 Laser-based Technologies for Metallic Bone
Implants ....................................... 246
9.4.2 Extrusion-based Technologies for Bone
Implants ....................................... 247
9.4.3 Ink-based Technologies for Bone Implants ....... 248
9.5 Scaffolds for Bone Regeneration ....................... 248
9.5.1 Laser-based Printing for Regenerative
Scaffolds ...................................... 249
9.5.2 Extrusion-based Printing for Regenerative
Scaffolds ...................................... 249
9.5.3 Ink-based Printing for Regenerative Scaffolds .. 252
9.5.4 Pre- and Post-processing Techniques ............ 253
9.5.4.1 Pre-processing ............................. 253
9.5.4.2 Post-processing: Sintering ................. 259
9.5.4.3 Post-processing: Functionalization ......... 259
9.6 Bioprinting ........................................... 260
9.7 Conclusion ............................................ 264
List of Abbreviation ....................................... 265
References ................................................. 266
10 Application of Bioreactor Concept and Modeling Techniques
to Bone Regeneration and Augmentation Treatments ........... 279
Oscar A. Deccó and Jésica I. Zuchuat
10.1 Bone Tissue Regeneration ............................. 280
10.1.1 Proinflammatory Cytokines ...................... 281
10.1.2 Transforming Growth Factor Beta ................ 281
10.1.3 Angiogenesis in Regeneration ................... 282
10.2 Actual Therapeutic Strategies and Concepts to
Obtain an Optimal Bone Quality and Quantity ........... 283
10.2.1 Guided Bone Regeneration Based on Cells ........ 284
10.2.1.1 Embryonic Stem Cells ...................... 284
10.2.1.2 Adult Stem Cells .......................... 284
10.2.1.3 Mesenchymal Stem Cells .................... 285
10.2.2 Guided Bone Regeneration Based on Platelet-
Rich Plasma (PRP) and Growth Factors ........... 286
10.2.2.1 Bone Morphogenetic Proteins ............. 289
10.2.3 Guided Bone Regeneration Based on Barrier
Membranes ...................................... 290
10.2.4 Guided Bone Regeneration Based on Scaffolds .... 292
10.3 Bioreactors Employed for Tissue Engineering in Guided
Bone Regeneration ..................................... 293
10.3.1 Spinner Flask Bioreactors ...................... 294
10.3.2 Rotating Wall Bioreactors ...................... 295
10.3.3 Perfusion Bioreactors .......................... 295
10.4 Bioreactor Concept in Guided Bone Regeneration and
Tissue Engineering: In Vivo Application ............... 296
10.4.1 Sand Blasting .................................. 298
10.4.2 Chemical Treatment ............................. 299
10.4.3 Heat Treatment ................................. 300
10.5 New Multidisciplinary Approaches Intended to Improve
and Accelerate the Treatment of Injured and/or
Diseased Bone ......................................... 305
10.5.1 Application of Bioreactor in Dentistry:
Therapies for the Treatment of Maxillary Bone
Defects ........................................ 306
10.5.2 Application of Bioreactor in Cases
of Osteoporosis ................................ 309
10.6 Computational Modeling: An Effective Tool to Predict
Bone Ingrowth 312 References .......................... 313
11 Stem Cell-based Medicinal Products: Regulatory
Perspectives ............................................... 323
Deniz Ozdil and Halil Murat Aydin
11.1 Introduction .......................................... 323
11.2 Defining Stem Cell-based Medicinal Products ........... 325
11.3 Regional Regulatory Issues for Stem Cell Products ..... 328
11.4 Regulatory Systems for Stem Cell-based Technologies ... 329
11.4.1 The US Regulatory System ....................... 330
11.5 Stem Cell Technologies: The European Regulatory
System ................................................ 338
References ................................................. 342
12 Substrates and Surfaces for Control of Pluripotent Stem
Cell Fate and Function ..................................... 343
Akshaya Srinivasan, Yi-Chin Toh, Xian Jun Loh and Wei
Seong Toh
12.1 Introduction .......................................... 344
12.2 Pluripotent Stem Cells ................................ 344
12.3 Substrates for Maintenance of Self-renewal and
Pluripotency of PSCs .................................. 346
12.3.1 Cellular Substrates ............................ 346
12.3.2 Acellular Substrates ........................... 347
12.3.2.1 Biological Matrices ....................... 347
12.3.2.2 ECM Components ............................ 350
12.3.2.3 Decellularized Matrices ................... 352
12.3.2.4 Cell Adhesion Molecules ................... 353
12.3.2.5 Synthetic Substrates ...................... 354
12.4 Substrates for Promoting Differentiation of PSCs ...... 357
12.4.1 Cellular Substrates ............................ 357
12.4.2 Acellular Substrates ........................... 358
12.4.2.1 Biological Matrices ....................... 358
12.4.2.2 ECM Components ............................ 360
12.4.2.3 Decellularized Matrices ................... 364
12.4.2.4 Cell Adhesion Molecules ................... 365
12.4.2.5 Synthetic Substrates ...................... 365
12.5 Conclusions ........................................... 368
Acknowledgments ............................................ 369
References ................................................. 369
13 Silk as a Natural Biopolymer for Tissue Engineering ........ 381
Ayşe Ak Can and Gamze Bölükbaşi Ateş
13.1 Introduction .......................................... 382
13.1.1 Mechanical Properties .......................... 383
13.1.2 Biodegradation ................................. 384
13.1.3 Biocompatibility ............................... 385
13.2 SF as a Biomaterial ................................... 385
13.2.1 Fibroin Hydrogels and Sponges .................. 386
13.2.2 Fibroin Films and Membranes .................... 388
13.2.3 Nonwoven and Woven Silk Scaffolds .............. 388
13.2.4 Silk Fibroin as a Bioactive Molecule Delivery .. 388
13.3 Biomedical Applications of Silk-based Biomaterials .... 389
13.3.1 Bone Tissue Engineering ........................ 389
13.3.2 Cartilage Tissue Engineering ................... 391
13.3.3 Ligament and Tendon Tissue Engineering ......... 393
13.3.4 Cardiovascular Tissue Engineering .............. 393
13.3.5 Skin Tissue Engineering ........................ 395
13.3.6 Other Applications of Silk Fibroin ............. 395
13.4 Conclusion and Future Directions ...................... 395
References ................................................. 396
14 Applications of Biopolymer-based, Surface-modified
Devices in Transplant Medicine and Tissue Engineering ...... 401
Ashim Malhotra, Gulnaz Javan and Shivani Soni
14.1 Introduction to Cardiovascular Disease ................ 402
14.2 Need Assessment for Biopolymer-based Devices in
Cardiovascular Therapeutics ........................... 402
14.3 Emergence of Surface Modification Applications in
Cardiovascular Sciences: A Historical Perspective ..... 403
14.4 Nitric Oxide Producing Biosurface Modification ........ 405
14.5 Surface Modification by Extracellular Matrix Protein
Adherence ............................................. 406
14.6 The Role of Surface Modification in the Construction
of Cardiac Prostheses ................................. 407
14.7 Biopolymer-based Surface Modification of Materials
Used in Bone Reconstruction ........................... 408
14.8 The Use of Biopolymers in Nanotechnology .............. 411
14.8.1 Protein Nanoparticles .......................... 412
14.8.1.1 Albumin-based Nanoparticles and Surface
Modification .............................. 413
14.8.1.2 Collagen-based Nanoparticles and Surface
Modification .............................. 414
14.8.1.3 Gelatin-based Nanoparticle Systems ........ 415
14.8.2 Polysaccharide-based Nanoparticle Systems ...... 415
14.8.2.1 The Use of Alginate for Surface
Modifications ............................. 415
14.8.2.2 The Use of Chitosan-based Nanoparticles
and Chitosan-based Surface Modification ... 416
14.8.2.3 The Use of Chitin-based Nanoparticles
and Chitin-based Surface Modification ..... 418
14.8.2.4 The Use of Cellulose-based Nanoparticles
and Cellulose-based Surface Modification .. 419
15 References 420 15 Stem Cell Behavior on Microenvironment
Mimicked Surfaces .......................................... 425
M. Özgen Öztürk Öncel and Bora Garipcan
15.1 Introduction .......................................... 426
15.2 Stem Cells ............................................ 427
15.2.1 Definition and Types ........................... 427
15.2.1.1 Embryonic Stem Cells ...................... 428
15.2.1.2 Adult Stem Cells .......................... 428
15.2.1.3 Reprogramming and Induced Pluripotent
Stem Cells ................................ 429
15.2.2 Stem Cell Niche ................................ 429
15.3 Stem Cells: Microenvironment Interactions ............. 430
15.3.1 Extracellular Matrix ........................... 431
15.3.2 Signaling Factors .............................. 431
15.3.3 Physicochemical Composition .................... 432
15.3.4 Mechanical Properties .......................... 432
15.3.5 Cell-Cell Interactions ......................... 433
15.4 Biomaterials as Stem Cell Microenvironments ........... 433
15.4.1 Surface Chemistry .............................. 433
15.4.2 Surface Hydrophilicity and Hydrophobicity ...... 436
15.4.3 Substrate Stiffness ............................ 437
15.4.4 Surface Topography ............................. 437
15.5 Biomimicked and Bioinspired Approaches ................ 438
15.5.1 Bone Tissue Regeneration ....................... 441
15.5.2 Cartilage Tissue Regeneration .................. 442
15.5.3 Cardiac Tissue Regeneration .................... 443
15.6 Conclusion ............................................ 444
References ................................................. 444
Index ......................................................... 453
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