Intelligent Nanomaterials

Scrivener Publishing

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Advanced Materials Series

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Intelligent Nanomaterials

Edited by

Ashutosh Tiwari, Yogendra Kumar Mishra, Hisatoshi Kobayashi and

Anthony P. F. Turner

Second edition

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v

Contents

Preface xvii

Part 1 Nanomaterials, Fabrication and Biomedical Applications

1 Electrospinning Materials for Skin Tissue Engineering 3

Beste Kinikoglu1.1 Skin Tissue Engineering Scaffolds 4

1.1.1 Materials Used in Skin Tissue Engineering Scaffolds 51.1.1.1 Natural Scaffolds 61.1.1.2 Synthetic Scaffolds 7

1.1.2 Scaffold Production Techniques Used in Skin Tissue Engineering 91.1.2.1 Freeze-drying 91.1.2.2 Electrospinning 11

1.2 Conclusions 14References 15

2 Electrospinning: A Versatile Technique to Synthesize Drug Delivery Systems 21

Xueping Zhang, Dong Liu and Tianyan You2.1 Introduction 212.2 The Types of Delivered Drugs 22

2.2.1 Antitumor/Anticancer Drugs 222.2.2 Antibiotic 242.2.3 Growth Factors 262.2.4 Nucleic Acids 272.2.5 Proteins 28

vi Contents

2.3 Polymers Used in Electrospinning 292.3.1 Natural Polymers 30

2.3.1.1 Chitosan 302.3.1.2 Silk Fibroin 302.3.1.3 Cellulose Acetate 32

2.3.2 Synthetic Polymers 322.3.2.1 Synthetic Homopolymers 322.3.2.2 Synthetic Copolymers 33

2.3.3 Polymer Blends 342.3.3.1 Blends of Natural Polymers 342.3.3.2 Blends of Natural and Synthetic Polymers 352.3.3.3 Blends of Synthetic Polymers 362.3.3.4 Other Multicomponent Polymer Mixtures 36

2.4 The Development of Electrospinning Process for Drug Delivery 362.4.1 Coaxial Electrospinning 372.4.2 Emulsion Electrospinning 382.4.3 Multilayer Electrospinning 392.4.4 Magnetic Nanofiber 402.4.5 Post-modification of Electrospun Scaffolds 41

2.5 Conclusions 41Acknowledgment 42References 42

3 Electrospray Jet Emission: An Alternative Interpretation Invoking Dielectrophoretic Forces 51

Francesco Aliotta, Oleg Gerasymov and Pietro Calandra3.1 Introduction 523.2 Electrospray: How It Works? 543.3 Historical Background 633.4 How the Current (and Wrong) Description of the

Electrospray Process Has Been Generated? 653.5 What Is Wrong in the Current Description? 683.6 Some Results Shedding More Light 703.7 Discriminating between Electrophoretic and

Dielectrophoretic Forces 723.8 Some Theoretical Aspects of Dielectrophoresis 763.9 Conclusions 83References 86

Contents vii

4 Advanced Silver and Oxide Hybrids of Catalysts During Formaldehyde Production 91

Anita Kovač Kralj4.1 Introduction 924.2 The Catalysis 93

4.2.1 Limited Hybrid Catalyst Methodology 944.3 Case Study 95

4.3.1 Silver Process 954.3.2 Oxide Process 96

4.4 Limited Hybrid Catalyst Method for Formaldehyde Production 974.4.1 Analyzing the Pure Catalyst Process 974.4.2 Graphical Presentation of Catalyst Process 974.4.3 Advanced Hybrid Catalyst Process 984.4.4 Choosing the Best Advanced Hybrid

Catalyst Process 1014.4.5 Simulation of the Best Advanced Hybrid

Catalyst Process 1024.5 Conclusion 1044.6 Nomenclatures 105References 105

5 Physico-chemical Characterization and Basic Research Principles of Advanced Drug Delivery Nanosystems 107

Natassa Pippa, Stergios Pispas and Costas Demetzos5.1 Introduction 1085.2 Basic Research Principles and Techniques for the

Physicochemical Characterization of Advanced Drug Delivery Nanosystems 1085.2.1 Microscopy 108

5.2.1.1 Optical Microscopy 1085.2.1.2 Electron Microscopy 1095.2.1.3 Scanning Probe Microscopy 109

5.2.2 Thermal Analysis 1115.2.2.1 Classification of Thermal Analysis

Techniques 1115.2.2.2 Differential Scanning Calorimetry 113

viii Contents

5.2.3 Measurements of Size Distribution and ζ-Potential of Nanocolloidal Dispersion Systems and Their Evaluation 1175.2.3.1 Photon Correlation Spectroscopy (PCS)

and Other Light-scattering Techniques 1185.3 Conclusions 122References 122

6 Nanoporous Alumina as an Intelligent Nanomaterial for Biomedical Applications 127

Moom Sinn Aw and Dusan Losic6.1 Introduction 1276.2 Nanoporous Anodized Alumina as a

Drug Nano-carrier 1296.2.1 Intelligent Properties of NAA

for Drug Delivery 1296.3 Biocompatibility of NAA and NNAA Materials 1386.4 NAA for Diabetic and Pancreatic Applications 1436.5 NAA Applications in Orthopedics 1446.6 NAA Applications for Heart, Coronary, and

Vasculature Treatment 1486.7 NAA in Dentistry 1506.8 Conclusions and Future Prospects 152Acknowledgment 153References 154

7 Nanomaterials: Structural Peculiarities, Biological Effects, and Some Aspects of Application 161

N.F. Starodub, M.V. Taran, A.M. Katsev,

C. Bisio and M. Guidotti7.1 Introduction 1627.2 Physicochemical Properties Determining the

Bioavailability and Toxicity of Nanoparticles 1647.3 Current Nanoecotoxicological Knowledge 168

7.3.1 Main Causes of NPs Toxicity 1697.3.2 Risk Assessment for NPs in the Environment 1707.3.3 Peculitiaries of Effects of Some NPs

on the Living Objects 1717.3.3.1 Experiments with Luminescent Bacteria 1717.3.3.2 Daphnias as Indicators of Influence of

Nanostructured Material 174

Contents ix

7.3.3.3 Investigations with Model Plants 1747.3.3.4 Experiments with Plants under

Real Conditions 1767.3.3.5 Effect of NPs of Some Oxide Metals

on the Bioluminescent Bacteria 1777.3.3.6 Reaction of Daphnias on the

Effect of Some NPs 1807.3.3.7 Effect of the Nanostructured Solids

on the Physiological Characteristics of the Common Bean (Phaseolus vulgaris) 181

7.3.3.8 Effect of the Colloidal NPs on the Plants at Grow under Carbonate Chlorosis Conditions 182

7.4 Modern Direction of the Application of Nanostructured Solids in Detoxication Processes 1867.4.1 From Conventional Decontamination

to Innovative Nanostructured Systems 1867.5 Conclusions 188Acknowledgments 189References 189

8 Biomedical Applications of Intelligent Nanomaterials 199

M. D. Fahmy, H. E. Jazayeri, M. Razavi, M. Hashemi,

M. Omidi, M. Farahani, E. Salahinejad, A. Yadegari,

S. Pitcher and Lobat Tayebi8.1 Introduction 2008.2 Polymeric Nanoparticles 202

8.2.1 General Features 2028.2.2 Poly-d,l-lactide-co-glycolide 2038.2.3 Polylactic Acid 2038.2.4 Polycaprolactone (PCL) 2048.2.5 Chitosan 2048.2.6 Gelatin 2048.2.7 Potential and Challenges 205

8.3 Lipid-based Nanoparticles 2068.3.1 Different Types 2068.3.2 Applications 207

8.3.2.1 Intrinsic Stimuli 2078.3.2.2 Extrinsic Stimuli 208

8.3.3 Potential and Challenges 211

x Contents

8.4 Carbon Nanostructures 2138.4.1 General Feature 2138.4.2 Zero-dimensional Carbon Nanostructures 2138.4.3 One-dimensional Carbon Nanostructures 2158.4.4 Two-dimensional Carbon Nanostructures 2168.4.5 Three-dimensional Carbon Nanostructures 2178.4.6 Potential and Challenges 218

8.5 Nanostructured Metals 2198.5.1 Nitinol 2198.5.2 Other Metallic Nanoparticles 2208.5.3 Potential and Challenges 221

8.6 Hybrid Nanostructures 2238.6.1 Smart Nanostructured Platforms for

Drug Delivery 2248.6.1.1 Metal-based Smart Composite

and Hybrid Nanostructures 2248.6.1.2 Carbon-based Smart Composite

and Hybrid Nanostructures 2258.6.2 Smart Nanostructures for Diagnostic Imaging 226

8.6.2.1 Metal-based Smart Composite and Hybrid Nanostructures 227

8.6.2.2 Carbon-based Smart Composite and Hybrid Nanostructures 227

8.7 Concluding Remarks 228References 229

Part 2 Nanomaterials for Energy, Electronics, and Biosensing

9 Phase Change Materials as Smart Nanomaterials for Thermal Energy Storage in Buildings 249

M. Kheradmand, M. Abdollahzadeh, M. Azenha

and J.L.B. de Aguiar9.1 Introduction 2509.2 Phase Change Materials: Definition, Principle of

Operation, and Classifications 2529.3 PCM-enhanced Cement-based Materials 2549.4 Hybrid PCM for Thermal Storage 255

Contents xi

9.5 Numerical Simulations 2679.5.1 Numerical Simulation of Heat Transfers

in the Context of Building Physics 2679.5.2 Governing Equations 268

9.6 Thermal Modeling of Phase Change 2699.6.1 The Enthalpy-porosity Method 2699.6.2 The Effective Heat Capacity Method 2709.6.3 Numerical Simulation of

Small-scale Prototype 2719.6.4 Results of the Numerical Simulations

of Prototype 2729.6.5 Case Study of a Simulated Building 2739.6.6 Results of Thermal Behavior and Energy Saving 2769.6.7 Global Performance of a Building Systems with

Hybrid PCM 2779.7 Nanoparticle-enhanced Phase Change Material 280

9.7.1 Modeling nanoparticle-enhanced PCM 2829.7.2 Definition of the Case study 2839.7.3 Results of Case Study with Nanoparticle-

enhanced Phase Change Material 2849.8 Conclusions (General Remarks) 288References 289

10 Nanofluids with Enhanced Heat Transfer Properties for Thermal Energy Storage 295

Manila Chieruzzi, Adio Miliozzi, Luigi Torre and

José Maria Kenny10.1 Introduction 29610.2 Thermal Energy Storage 298

10.2.1 Sensible Heat Thermal Storage 301 10.2.2 Latent Heat Thermal Storage 303 10.2.3 Thermochemical Storage 309 10.2.4 Final Remarks 313

10.3 Nanofluids for Thermal Energy Storage 313 10.3.1 Base Fluid 316 10.3.2 Nanoparticles 318 10.3.3 Methods of Nanofluid Preparation 327

10.4 Nanofluids Based on Molten Salts: Enhancement of Thermal Properties 330

10.4.1 Specific Heat 331 10.4.2 Latent Heat of Fusion and

Melting Temperature 340

xii Contents

10.4.3 Thermal Conductivity 344 10.4.4 Thermal Storage 347

10.5 Conclusions 349References 351

11 Resistive Switching of Vertically Aligned Carbon Nanotubes for Advanced Nanoelectronic Devices 361

O.A. Ageev, Yu. F. Blinov, M.V. Il’ina, B.G. Konoplev

and V.A. Smirnov11.1 Introduction 36211.2 Theoretical Description of Resistive Switching

Mechanism of Structures Based on VACNT 363 11.2.1 The Modeling of the Deformation of the

VACNT Affected by a Local External Electric Field 364

11.2.2 The Modeling of the Processes of Polarization and Piezoelectric Charge Accumulation in a Vertically Aligned Carbon Nanotube 370

11.2.3 The Modeling of the Memristor Effect in the Structure Based on a Vertically Aligned Carbon Nanotube 374

11.3 Techniques for Measuring the Electrical Resistivity and Young’s Modulus of VACNT Based on Scanning Probe Microscopy 377

11.3.1 Techniques for Measuring Young’s Modulus of VACNT Based on Nanoindentation 378

11.3.2 Techniques for Measuring the Electrical Resistivity of VACNT Based on Scanning Tunnel Microscopy 382

11.4 Experimental Studies of Resistive Switching in Structures Based on VACNT Using Scanning Tunnel Microscopy 384

References 391

12 Multi-objective Design of Nanoscale Double Gate MOSFET Devices Using Surrogate Modeling and Global Optimization 395

Toufik Bentrcia, Fayçal Djeffal and Elasaad Chebaki12.1 Introduction 39612.2 Downscaling Parasitic Effects 400

Contents xiii

12.2.1 Short Channel Effect 401 12.2.1.1 Drain-induced Barrier Lowering 401 12.2.1.2 Channel Length Modulation 401 12.2.1.3 Carrier Mobility Reduction 402

12.2.2 Quantum Mechanical Confinement Effect 402 12.2.2.1 Inversion Charge Displacement 403 12.2.2.2 Poly-silicon Gate Depletion 403 12.2.2.3 Threshold Voltage Shift 403

12.2.3 Hot-carrier Effect 404 12.2.3.1 Impact-ionization 404 12.2.3.2 Carrier Injection 405 12.2.3.3 Interface Trap Formation 405

12.3 Modeling Framework 405 12.3.1 Design of Computer Experiments 406 12.3.2 Metamodel Development 408 12.3.3 Multi-objective Optimization 410

12.4 Simulation and Results 41212.5 Concluding Remarks 422References 422

13 Graphene-based Electrochemical Biosensors: New Trends and Applications 427

Georgia-Paraskevi Nikoleli, Stephanos Karapetis,

Spyridoula Bratakou, Dimitrios P. Nikolelis,

Nikolaos Tzamtzis and Vasillios N. Psychoyios 13.1 Introduction 428 13.2 Scope of This Review 429 13.3 Graphene and Sensors 430 13.4 Graphene Nanomaterials Used in Electrochemical

(Bio)sensors Fabrication 430 13.5 Graphene-based Enzymatic Electrodes 432

13.5.1 Graphene-based Electrochemical Enzymatic Biosensors for Glucose Detection 432

13.5.2 Graphene-based Electrochemical Enzymatic Biosensors for Hydrogen Peroxide Detection 434

13.5.3 Graphene-based Electrochemical Enzymatic Biosensors for NADH Detection 435

13.5.4 Graphene-based Electrochemical Enzymatic Biosensors for Cholesterol Detection 435

13.5.5 Graphene-based Electrochemical Enzymatic Biosensors for Urea Detection 437

13.6 Graphene-based Electrochemical DNA Sensors 437 13.7 Graphene-based Electrochemical Immunosensors 439

13.7.1 Graphene-based Electrochemical Immunosensors for Biomarker Detection 440

13.7.2 Graphene-based Electrochemical Immunosensors for Pathogen Detection 441

13.8 Commercial Activities in the Field of Graphene Sensors 442

13.9 Recent Developments in the Field of Graphene Sensors 442

13.10 Conclusions and Future Prospects 443Acknowledgments 445References 445

Part 3 Smart Nanocomposites, Fabrication, and Applications

14 Carbon Fibers-based Silica Aerogel Nanocomposites 451

Agnieszka Ślosarczyk14.1 Introduction to Nanotechnology 45114.2 Chemistry of Sol–gel Process 454

14.2.1 Characterization and Application of Silica Aerogels 454

14.2.2 Synthesis of Silica Gels via Sol–gel Process 456 14.2.3 Aging of Silica Gels 459 14.2.4 Methods of Drying of Silica Gels 460

14.3 Types of Silica Aerogel Nanocomposites 462 14.3.1 Reinforcing the Silica Aerogel and

Xerogel Structure in the Synthesis Stage 462 14.3.2 Metal- and Metal Oxide-based Silica Aerogels 464 14.3.3 Polymer-based Silica Aerogels 466 14.3.4 Fiber-based Silica Aerogels 468

14.4 Carbon Fiber-based Silica Aerogel Nanocomposites 476 14.4.1 Characterization of Carbon Fibers and

Chemical Modification of Their Surface 478 14.4.2 Synthesis of Silica Aerogel: Carbon Fiber

Nanocomposites in Relation to the Type of Precursor 481

14.4.3 Drying of Silica Gel: Carbon Fiber Nanocomposites 482

xiv Contents

14.4.4 Research Methods Applied 484 14.4.5 Physical and Chemical Characterization of

Silica Aerogel and Xerogel Nanocomposites 48514.5 Conclusions 493References 494

15 Hydrogel–Carbon Nanotubes Composites for Protection of Egg Yolk Antibodies 501

Bellingeri Romina, Alustiza Fabrisio, Picco Natalia,

Motta Carlos, Grosso Maria C, Barbero Cesar,

Acevedo Diego and Vivas Adriana15.1 Introduction 50215.2 Polymeric Hydrogels 504

15.2.1 Synthetic and Natural Hydrogels 504 15.2.2 Intelligent Hydrogels 505 15.2.3 Characterization of Hydrogels 506

15.3 Carbon Nanotubes 507 15.3.1 Dispersion of Carbon Nanotubes 508 15.3.2 Toxicity of Carbon Nanotubes 509 15.3.3 Noncovalent Functionalization Strategies 509 15.3.4 Covalent Functionalization Strategies 510

15.4 Polymer–CNT Composites 511 15.4.1 Drug Delivery 512 15.4.2 Tissue Engineering 513 15.4.3 Electrical Cell Stimulation 514 15.4.4 Antimicrobial Materials 515

15.5 Egg Yolk Antibodies Protection 51515.6 In Vitro Evaluation of Nanocomposite Performance 51715.7 In Vivo Evaluation of Nanocomposite Performance 518

15.7.1 Nanotechnology for Bovine Production Applications 519

15.7.2 Nanotechnology for Porcine Production Applications 519

15.7.3 Nanotechnology Applications in Other Animal Species 520

15.8 Concluding Remarks and Future Trends 521References 522

Contents xv

xvi Contents

16 Green Fabrication of Metal Nanoparticles 533

Anamika Mubayi, Sanjukta Chatterji and Geeta Watal16.1 Introduction 53316.2 Development of Herbal Medicines 53516.3 Green Synthesis of Nanoparticles 53616.4 Characterization of Phytofabricated Nanoparticles 53916.5 Impact of Plant-mediated Nanoparticles on

Therapeutic Efficacy of Medicinal Plants 540 16.5.1 Antidiabetic Potential 543 16.5.2 Antioxidant Potential 545 16.5.3 Antimicrobial Potential 548

16.6 Conclusions 550References 551

Index 555

Preface

Nanoscale materials exhibit extraordinary physical and chemical features which play a very important role in their applications in advanced tech-nologies. Due to their technological relevance, these materials have been a major driving force in academia as well as industries for laying down the foundation of new smart products for the benefit of society. During the last couple of decades, significant progress has been made towards developing new types of nanomaterials by various methods, i.e., physical, chemical and biological, including unconventional strategies directly inspired by nature. The functionality of these nanoscale structures increases when they are further functionalized with different atomic, molecular, and biological entities, etc., in the form of hybrids and composites. The intelligent mate-rials exhibit the capability of responding to the change generated by any signal—chemical, electrical, optical, etc.—as a consequence of any external defined stimuli. Functional nanoscale materials are best suited for the class of intelligent materials. A lot of progress has already been made over the last decades towards intelligent materials, and the emergence of specific material features engineered by exploiting their excellent nanoscale fea-tures has been witnessed.

The use of nanomaterials in very small dimensional forms is not some-thing new. Actually, they have been used continuously ever since ancient times; for example, Swarna Bhasma nanoparticles were utilized in Ayurveda, the ancient medical system of India. However, the term “nanotechnology” was first coined by Prof. Richard Feynman in 1959 in his very famous lec-ture, “There’s Plenty of Room at the Bottom.” At very small length scales, materials exhibit entirely new properties in comparison to their bulk coun-terparts. Nanomaterials belong to an important class of materials in which at least one dimension is in the nanometer region, at least in the range of 1–100 nm. As the dimension of the materials is reduced, the surface-to-volume ratio increases, and in the nanometer range it increases more dras-tically (almost every atom is at the surface). The surface of any material is considered a defect because the periodicity breaks down and each atom at the surface, the so-called “dangling atoms,” is loosely bound as compared

xvii

xviii Preface

to atoms in the interior. With reduction in size, the surface contribution, i.e., the density of dangling atoms, increases significantly, leading to very high surface free energies of these nanomaterials. This very high surface energy leads to extraordinary physical and chemical properties which are very suitable for advanced applications in the fields of physical, chemical and biomedical engineering, etc.

As far as length scales are concerned, 1–100 nm is not an absolute defini-tion for a material to be called a nanomaterial. The quantum confinement effect, i.e., discretization in electronic states below certain dimensions, should be taken as an appropriate concept for defining the dimensions of nanoscale materials, which is referred to as the de Broglie wavelength for that particular material. Based on dimensional confinement, nanomateri-als are typically classified as 0D, 1D and 2D materials, and each of them exhibit important properties suitable for different applications. However, the dimensional classification is also not limited to de Broglie wavelength value; people have defined their own terminologies as per utilization sim-plicities. Even a bulk material which is loaded with nanoscale particles from other materials, e.g., gold nanoparticles on a polymer fiber, can be called nanomaterial because it exhibits all the nanoscale features necessary for certain applications. Actually these are rather more important in terms of intelligent nanomaterials because on one hand they exhibit extraordi-nary features; but on the other hand, these features are easily accessible in any desired form due to their dimensionally compact designs in the form of devices, sensors, composites, etc.

In bulk form, the properties of the materials are only of interest for par-ticular applications, but when these materials are transformed into nano-materials, they are of interest for almost every application because of their totally different properties. Therefore, the creation of different nanomateri-als by different strategies has always been of interest and has been a high priority. The top-down and bottom-up growth strategies have been very common in the last decade and have indeed contributed to the remark-able progress towards commercialization of nanomaterials in the form of smart technologies and products. But in the last couple of years, progress in unconventional nanostructuring strategies has shown significant poten-tial. Efficient utilization of nanoscale properties has always been a chal-lenge apart from synthesis because in order to extract their response, they have to be interfaced with real-world devices. Cleanroom technologies are very much on-trend for nanointegration, but in order to overcome limita-tions like high cost, long processing time, etc., a new form of nanomate-rial has been introduced, which is known as 3D nanomaterials. These 3D nanomaterials are made from nanoscale building blocks, which exhibit the

Preface xix

desired nanoscale features, and are also large enough (~ cm3 scale) to be easily utilized for any desired applications. Mixed top-down and bottom-up strategies are followed to fabricate these materials but conventional methods like making pores by selective chemical etching also provide effi-cient 3D nanostructuring. These 3D nanomaterials are rather important for advanced applications because they can be easily functionalized with desired molecular species and are potentially very intelligent nanomaterial candidates. Therefore, a large variety of nanomaterials already exist and new forms of nanomaterials are being developed which can play a very important role in advancing society by introducing smart technological products using intelligent nanomaterials. Thus, these very small materials can have a very big impact on human life.

Keeping in mind the importance of these very small materials in our society, we have decided to let the scientific as well as general communities know what has been happening on this front in the form of a book entitled “Intelligent Nanomaterials.” The first edition of this book was published in November 2011, in which brief overviews on advanced inorganic and organic nanomaterials in terms of their fabrications, characterizations and applications were covered. In the meantime, this field has witnessed some further developments which are covered in this 2nd edition of Intelligent Nanomaterials, which focuses on compound nanomaterials for advanced biomedical applications, smart nanomaterials for energy storage, carbon nanomaterials for nanoelectronics, biosensing and advanced composite-based applications. Special emphasis has been given to fundamental infor-mation, synthesis of materials, characterizations, and applications—all presented in an elaborative manner. We have tried our best to cover each and every aspect so that readers can come to have a broader understand-ing of the fundamentals behind intelligent nanomaterials and their scope of advanced applications.

Overall, this book presents a detailed and comprehensive overview of the state-of-the-art development of different nanoscale intelligent materi-als for advanced applications. Apart from fundamental aspects of fabri-cation and characterization of nanomaterials, it also covers key advanced principles involved in utilization of functionalities of these nanomateri-als in appropriate forms. It is very important to develop and understand the cutting-edge principles of how to utilize nanoscale intelligent features in the desired fashion. These unique nanoscopic properties can either be accessed when the nanomaterials are prepared in the appropriate form, e.g., composites, or in integrated nanodevice form for direct use as elec-tronic sensing devices. In both cases, the nanostructure has to be appropri-ately prepared, carefully handled, and properly integrated into the desired

xx Preface

application in order to efficiently access its intelligent features. These aspects are overviewed in detail in three themed sections with relevant chapters. The fundamental principles behind the fabrication of different nano-materials, composites, and nanoelectronic devices are covered according to their applications in targeted drug delivery, energy harvesting, memory devices, and electrochemical biosensing. Also included are other advanced composite-based biomedical applications which will be of interest to inter-disciplinary readers from physics, materials science, nanoscience, bioma-terials, engineering and, most importantly, biomedical materials-related life science communities. The general audience of this book is readers with backgrounds across the fields of physics, chemistry, materials science and engineering, nanotechnology, biosensors and bioelectronics, biomaterials science, nanobiotechnology, and advanced biomedical engineering.

We would like to express our gratitude to all the contributors for their collective and fruitful work. It is their efforts and expertise that have made this volume comprehensive, valuable and unique. We are also grateful to Sachin Mishra and Sophie Thompson, managing editors of the Advanced Materials Series, for their help and useful suggestions in preparing this book.

EditorsAshutosh Tiwari, PhD, DSc

Yogendra Kumar Mishra, PhD, Dr. Habil.Hisatoshi Kobayashi, PhD

Anthony P. Turner, PhDAugust 2016

Part 1

NANOMATERIALS, FABRICATION

AND BIOMEDICAL

APPLICATIONS

3

Ashutosh Tiwari et al. (eds.) Intelligent Nanomaterials, Second Edition, (3–20) © 2017

Scrivener Publishing LLC

1

Electrospinning Materials for Skin Tissue Engineering

Beste Kinikoglu

Department of Medical Biology, School of Medicine, Acibadem University,

Istanbul, Turkey

AbstractIn skin tissue engineering, an appropriate physical environment at the cell–

scaffold interface profoundly affects the overall behavior of the engineered tissue.

Therefore, it is crucial to control and engineer the cell–scaffold interface by inves-

tigating the physicochemical properties that would enhance specific and desir-

able cell behaviors. Cells cultured in 3D environments behave differently from

those cultured in a 2D environment, adopting more in vivo-like morphologies.

The 3D fibrous scaffolds composed of nanoscale multifibrils prepared by electro-

spinning with the aim of mimicking the supramolecular architecture and the bio-

logical functions of the natural extracellular matrix (ECM) as much as possible

have attracted a great deal of attention in skin tissue engineering. They have shown

great potential to mimic skin ECM (which has fibers in the range of 10–50 nm) in

both morphology and composition, and many studies using fibrous, electrospun

(ES) dermal scaffolds have yielded promising results. Nanofibrous scaffolds based

on pure collagen, collagen/silk fibroin, poly lactic-co-glycolic acid (PLGA)/poly-

l-lactic acid (PLLA), carboxyethyl chitosan/poly(vinyl alcohol), gelatin, PLGA/

chitosan, polycaprolactone, and elastin-like recombinant polymers were found

to promote keratinocyte and fibroblast attachment and proliferation, indicat-

ing the potential of ES, nanofibrous materials as future wound dressings for skin

regeneration.

Keywords: Electrospinning, skin tissue engineering, scaffolds, biopolymers,

synthetic polymers, elastin-like recombinant polymers

Corresponding author: beste.kinikoglu@acibadem.edu.tr

4 Intelligent Nanomaterials

1.1 Skin Tissue Engineering Scaffolds

Skin is the largest organ in humans and serves as a protective barrier at the interface between the human body and the surrounding environment [1, 2]. It protects the underlying organs against pathogenic microbial agents, mechanical disturbances, and UV radiation; it also prevents loss of body fluid and plays a very important role in immune defense and thermoregu-lation [3]. Skin is basically composed of two layers: a stratified epidermis and an underlying dense connective tissue, that is, dermis. These two are attached to each other at the basement membrane region. Skin comprises several different cell types. Keratinocytes are the most common cell type in the epidermis and form the surface barrier layer. Melanocytes are found in the lower layer of the epidermis and provide skin color. Fibroblasts form the lower dermal layer and provide strength and resilience [2, 4].

The predominant function of tissue-engineered skin is to restore barrier function to patients in whom this has been severely compromised, as in the cases of burns, soft tissue traumas, skin necrosis, scars, congenital giant nevus, and skin tumors. Methods for tissue-engineering skin include: cells delivered on their own, cells delivered within two- (2D) or three-dimen-sional (3D) biomaterials, biomaterials for replacement of the skin’s dermal layer (both with and without cells), and biomaterials/scaffolds to support the replacement of both the epidermis and dermis [2, 5].

For the treatment of deep wounds such as full-thickness burns, where the epidermis and all of the dermis is lost, it is necessary to replace both epi-dermal and dermal layers of the skin. For such cases, the tissue-engineered skin substitute should be full thickness, comprising both layers. For the reconstruction of such full-thickness skin equivalents, a 3D dermal scaf-fold is required to support the growth of fibroblasts and synthesis of new extracellular matrix (ECM) [2]. The general approach in full-thickness skin tissue engineering is first to design a suitable biocompatible, porous 3D scaffold with good mechanical properties. This scaffold is then seeded with fibroblasts, where they synthesize several types of collagen, glycoproteins, glycosaminoglycans of human ECM, and thus induce a remodeling of the initial matrix [6]. The resulting living dermal equivalent could be used either to prepare the wound for epidermalization in the treatment of burns or as a bioactive tissue releasing growth factors in the treatment of chronic wounds [7, 8]. This dermal equivalent is epidermalized by keratinocytes to obtain a full-thickness skin equivalent. The culture of keratinocytes on top of the dermal equivalent and at an air–liquid interface gives rise to a fully differentiated stratified epidermis. The air–liquid interface mimics the in vivo environment and is achieved by placing the skin equivalents

Electrospinning Materials for Skin Tissue Engineering 5

on semipermeable membranes such that the keratinocytes are directly exposed to air and ambient oxygen concentration, while the underlying dermis is in contact with the nutrient medium absorbed by the membrane. This configuration promotes epidermal differentiation. The quality of the dermal equivalent determines the quality of the multistratified epidermis [9], and the quality of the former is very much dependent on the scaffold. The scaffold aims to mimic the natural ECM by providing volume and sites for cell attachment, proliferation, migration, and synthesis of new ECM. Like the natural ECM itself, the scaffold modulates the phenotype of dif-ferent cell types involved, their gene expression, changes at proteome of the seeded cells, and function of the seeded cells [2, 10].

Nanofibrous structures have great potential with their biomimetic architecture for promoting cell growth and maintaining cell functions, and it has been demonstrated that a 3D nanofibrous structure similar to that of naturally occurring ECM provides better physical and mechanical micro-environment for cell proliferation and differentiation [11]. Electrospinning provides a relatively simple approach to fabricate macro- to nanoscaled fibers that are within the size range of the ECM. This chapter covers old- and new-generation materials used in the fabrication of skin tissue-engineering scaffolds; methods for producing these scaffolds, with special emphasis on electrospinning; discusses their advantages and disadvan-tages; and ends with conclusions and future perspectives.

1.1.1 Materials Used in Skin Tissue Engineering Scaffolds

At the cell–scaffold interface, both an appropriate physical and a chemi-cal environment profoundly affect the overall behavior of the engineered tissue [12]. Cellular behavior and subsequent tissue development at the cell–scaffold interface involve adhesion, motility, proliferation, differentia-tion, and functional maturity [13]. Therefore, it is crucial to control and engineer the cell–scaffold interface by investigating the physicochemical properties that would enhance specific and desirable cell behaviors. The anticipated outcome of this research would be the development of a bioac-tive soft tissue scaffold for skin tissue engineering [2].

Any 3D skin equivalent should contain a scaffold which, when seeded with fibroblasts, would form the dermis equivalent. The choice for the scaffold material is a crucial one since the success of the tissue-engineered implant depends mostly on it. The ideal scaffold to be used in skin tis-sue engineering must not induce a toxic or immune response or result in excessive inflammation. It should have an acceptably low level of disease risk, be slowly biodegradable, support the reconstruction of normal tissue,

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and have similar mechanical and physical properties to the skin it replaces. In addition, it should be readily available and capable of being prepared and stored with a long shelf life [2, 4]. Porosity is also a very important property of the scaffold because a dermal scaffold should possess an opti-mum pore size and distribution to allow fibroblast infiltration and prolif-eration, and also cell communication and medium perfusion. A scaffold suitable for intrinsic vascularization must have a high porosity (>40–60%) and an interconnected pore structure [14]. Scaffolds used in skin tissue engineering can be broadly grouped as natural scaffolds and synthetic scaf-folds according to the origin of the polymeric material used.

1.1.1.1 Natural Scaffolds

Natural scaffolds are either cadaver- or animal-derived de-epithelialized acellular matrices, or they are mostly constructed using natural polymers extracted from animals. Human, bovine, and porcine acellular lyophi-lized dermises; porcine small intestine submucosa; porcine-reconstituted dermal collagen; bovine tendon collagen; porcine-fortified atelocollagen; hyaluronic acid membrane; and ECM derived from fibroblasts are com-mercially available natural matrices for skin reconstruction [15]. Natural polymers have the advantage of responding to the environment via degra-dation and remodeling through the action of the enzymes. They are also generally nontoxic, even at high concentrations [16]. Among natural poly-mers, collagen is the most commonly used in scaffold fabrication due to its high biocompatibility and biodegradability. In addition, it is adhesive, fibrous, cohesive, and can be used in combination with other materials. On the other hand, it might be antigenic through telopeptides, though it is possible to remove these small telopeptides proteolytically before use [17]. The dermis itself is also composed mainly of collagen, mainly collagen type I with some collagen type III in the deeper layers. Collagen used in the construction of dermal scaffolds gave promising results in tissue engineer-ing of skin, though it was usually used in combination with other materials to increase the strength of the resulting scaffold. Other natural materials such as chitosan [18], human plasma [19, 20], gelatin [21–23], glycosami-noglycans [23], hyaluronic acid [24, 25], and silk [26] were also used, alone or in combination with collagen, for the same purpose.

1.1.1.1.1 CollagenCollagen is the most abundant protein in all animals. One-third of total pro-tein in humans and three-quarters of the dry weight of skin is collagen. It is the predominant component of the ECM [27]. The superfamiliy of collagens can be divided into 19 groups according to their fiber-to-fiber relations and

Electrospinning Materials for Skin Tissue Engineering 7

organization. Collagen type I is the most abundant collagen type found in various tissues and belongs to the family of collagens that form fibrils along with types II, III, V, and XI. All fibril forming collagens are similar in size, and they all contain large triple helical domains with about 1000 amino acids or 330 Gly–X–Y– repeats per chain. Moreover, they are first synthesized as larger precursors which are later on processed to collagens by cleavage of N-propeptides and C-propeptides by specific proteinases. Another com-mon property of these collagens is that they all assemble into cross-striated fibrils in which each molecule is displaced about one-quarter of its length relative to its nearest neighbor along the axis of the fibril [28]. Collagen type I contains α1 and α2 chains and forms a α1[I]2α2[I] triple helix [29].

Besides the dermis of skin, it is also found in oral mucosa, bone, tendon, and ligament [27]. Network-forming collagens include type IV collagens found in basement membranes, and type XIII and X collagens. Compared to fibril forming collagens, type IV collagen has a longer collagenous domain which consists of about 1400 amino acids in –Gly–X–Y– repeats that are frequently interrupted by short noncollagenous sequences. The molecules self-assemble to form net-like structures in which monomers associate at the C-termini to form dimers and at the N-termini to form tet-ramers. Besides these end-to-end interactions, the triple-helical domains intertwine to form supercoiled structures [28].

1.1.1.2 Synthetic Scaffolds

Synthetic polymers such as poly(glycolic acid), poly(lactic acid) and their copolymers, poly(p-dioxanone), and copolymers of trimethylene carbon-ate and glycolide are popular in tissue engineering due to the researcher’s ability to tailor mechanical properties and degradation kinetics to suit vari-ous applications and the possibility to fabricate them into various shapes with desired morphologic features and chemical groups [30]. A recently emerged, new class of biomaterials is elastin-like recombinant polymers, also called as elastin-like recombinamers (ELR). Recombinant polymers are proteins designed using recombinant DNA technology and contain desired peptide sequences for advanced applications in biotechnology. The following section summarizes the properties and use of this remarkable synthetic biomaterial in tissue engineering.

1.1.1.2.1 Recombinant Polymers: Elastin-like Recombinant PolymerRecently, researchers started to use ELR polymers as another category of materials for tissue engineering. All the properties displayed by biological materials and systems are entirely determined by the physical and chemical properties of their monomers and their sequence. Materials science began

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to take advantage of the power of new techniques in molecular biology and genetic engineering such as recombinant DNA technology, which allows the introduction of a synthetic gene in the genetic content of a microor-ganism, plant, or other eukaryotic organisms and induce the production of its encoded protein-based polymer (PBP) as a recombinant protein [31]. These macromolecules are generically named as “recombinamers” [32]. This technology is superior to any other polymer synthesis technology in terms of the control, complexity, and fine-tuning possibility that it offers. Using this technology, it is possible to bioengineer PBPs of more complex and well-defined structure.

Elastin-like recombinamers (ELRs) form a class of these biocompat-ible PBPs. They are composed of the pentapeptide repeat Val–Pro–Gly–Xaa–Gly (VPGXG), which is derived from the hydrophobic domain of tropoelastin and where X represents any natural or modified amino acid, except for proline [33]. At low temperatures, ELRs are soluble in aqueous solutions, but as the solution temperature is raised, they become insoluble and aggregate at a critical temperature, termed the inverse transition tem-perature (Tt). This process is reversible, meaning that when the tempera-ture is lowered below Tt, the ELR aggregate resolubilizes. ELRs can also be designed to respond to other physical stimuli such as redox, pH, light, etc. by incorporation of suitable guest residues in the polypeptide chain at the fourth position [33]. After the finding of the extraordinary biocompatibility of the VPGVG-based ELRs, their in vitro capabilities for tissue engineering were tested [32]. When the simple cross-linked matrices of poly(VPGVG)s were tested for cell adhesion, it was found that cells did not adhere at all to this matrix and no fibrous capsule formed around it when implanted [34]. Soon after, these polypeptide molecules were enriched with short peptides having specific bioactivity, which were easily inserted into the polymer sequence. The first active peptides inserted in the polymer chain were the well-known general-purpose cell adhesion tripeptide RGD (R = l-arginine, G = glycine, and D = l-aspartic acid) and the REDV (E = l-glutamic acid and V = l-valine), which is specific to endothelial cells. The resulting bioac-tivated VPGVG derivatives, especially those based on RGD, showed a high capacity to promote cell attachment [31]. The elastin-like recombinamer H-RGD6 contains 6 monomers of RGD, a histidine-tag, 6 aspartic acids, 24 lysines, and 7 histidines, which are charged residues (Figure 1.1).

1.1.1.2.2 Electrospun Elastin-like Recombinant Polymers for Tissue Engineering

ELRs have been used as coatings [35] and films [36] for improved cell attachment, as hydrogels to promote chondrogenesis [37–39] or as polymer