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Biomedical Applications and Toxicology of Carbon Nanomaterials

Biomedical Applications and Toxicology of Carbon Nanomaterials

Chunying Chen, Haifang Wang

ISBN: 978-3-527-69286-6

Apr 2016

543 pages

Description

An overview of biomedical applications and the toxicity properties of carbon nanomaterials aimed at helping to avoid detrimental health effects while laying the groundwork for further research in this highly relevant field.
Summarizing recent research, the book starts with the synthesis and functionalization of carbon nanomaterials, as well as identification and detection in biosystems. It then moves on to the interaction between carbon nanoparticles and biocomponents, focusing on the toxicity and mechanisms to various organs and systems and potential biomedical applications as well. Each section highlights the challenges, outlines unanswered questions, and suggests directions for further research and development efforts.

List of Contributors XIX

Preface XXV

1 Synthesis, Functionalization, and Characterization 1
Jianxun Xu, Xing Lu, and Baowen Li

1.1 Introduction 1

1.2 Fullerenes and Metallofullerenes 1

1.2.1 Synthesis and Purification 2

1.2.1.1 Synthesis 2

1.2.1.2 Purification 2

1.2.2 Chemical Functionalization 3

1.2.2.1 Carbene Reaction 3

1.2.2.2 Bingel–Hirsch Reaction 4

1.2.2.3 Prato Reaction 5

1.2.2.4 Bis-Silylation 5

1.2.2.5 Diels–Alder Reaction and Benzyne Reaction 5

1.2.2.6 Singly Bonded Addition 6

1.2.2.7 Supramolecular Complexes of EMFs 6

1.2.3 Characterization 6

1.2.3.1 Synchrotron Radiation Powder Diffraction (SRPD)/Rietveld/MEM 6

1.2.3.2 Nuclear Magnetic Resonance (NMR) Spectroscopy 7

1.2.3.3 Theoretical Calculation 7

1.2.3.4 Single-Crystal X-ray Diffraction Crystallography 7

1.2.3.5 Others 8

1.2.4 Questions and Future Directions 8

1.3 Carbon Nanotubes 8

1.3.1 Synthesis 9

1.3.1.1 Arc Discharge Method 9

1.3.1.2 Laser Ablation Method 10

1.3.1.3 CVD Method 10

1.3.1.4 Synthesis of CNTs with a Defined Structure 10

1.3.2 Functionalization 11

1.3.2.1 Covalent Chemical Reactions 11

1.3.2.2 Noncovalent Modifications 11

1.3.3 Characterization 12

1.3.3.1 Microscopic Characterizations 12

1.3.3.2 Spectroscopic Characterizations 13

1.3.4 Questions and Future Directions 13

1.4 Graphene 14

1.4.1 Synthesis and Characterization 14

1.4.2 Functionalization of Graphene and Graphene Oxide 17

1.4.3 Prospects and Challenges 18

1.5 Summary and Outlook 20

References 21

2 Identification and Detection of Carbon Nanomaterials in Biological Systems 29
Haifang Wang, Zheng-Mei Song, Yi-Fan Yang, Aoneng Cao, and Yuanfang Liu

2.1 Introduction 29

2.2 Available Techniques for Qualitative and Quantitative Determination 30

2.2.1 Optical Microscopic Observation 30

2.2.2 Electron Microscopic (EM) Observation 31

2.2.3 Raman Spectroscopic Measurement 33

2.2.4 Fluorescence Analysis 36

2.2.4.1 Intrinsic Fluorescence Analysis 36

2.2.4.2 Labeled Fluorescence Analysis 39

2.2.5 Isotope Labeling Method 39

2.2.5.1 Radioisotope Labeling 40

2.2.5.2 Stable Isotope Labeling 43

2.2.5.3 Tips for Isotopic Labeling 43

2.2.6 Chromatographic Technique 45

2.2.7 Flow Cytometry Method 45

2.2.8 Other Methods 46

2.3 Summary and Outlook 47

Acknowledgments 48

References 48

3 Biodistribution and Pharmacokinetics of Carbon Nanomaterials In Vivo 55
Sheng-Tao Yang, Xiaoyang Liu, and Jingru Xie

3.1 Introduction 55

3.2 Amorphous Carbon Nanoparticles 55

3.2.1 Ultrafine Carbon Particles 56

3.2.2 Carbon Nanoparticles 58

3.2.3 Carbon Dots 59

3.3 sp2 Carbon Nanomaterials 62

3.3.1 Fullerene 62

3.3.2 Carbon Nanotubes 69

3.3.3 Carbon Nanohorns 77

3.3.4 Graphene 80

3.3.5 Graphene Quantum Dots 85

3.4 Nanodiamonds 87

3.5 Summary and Outlook 89

Acknowledgments 90

References 90

4 Interaction of Carbon Nanomaterials and Components in Biological Systems 97
Jian Tian and Cuicui Ge

4.1 Introduction 97

4.2 Factors Affecting Interaction 99

4.2.1 Characteristics of Carbon Nanomaterials 99

4.2.1.1 Size and Layer 99

4.2.1.2 Surface Modification and Functionalization 100

4.2.2 Biological Microenvironment 102

4.2.2.1 pH 103

4.2.2.2 Ionic Strength 104

4.2.2.3 Weak Interactions 104

4.2.2.4 Cell Selectivity 105

4.3 Interaction of Carbon Nanomaterials with Various Components in Biological Systems 107

4.3.1 Characterization and Methodology of Interaction of Carbon Nanomaterials with Components in the Biological System 107

4.3.2 Carbon Nanomaterial–Phospholipid Interaction 108

4.3.3 Carbon Nanomaterial–Protein Interaction 111

4.3.4 Carbon Nanomaterial–DNA Interaction 115

4.3.5 Carbon Nanomaterial–Cell Interaction 119

4.4 Conclusion and Perspectives 120

References 122

5 Biomedical Applications of Carbon Nanomaterials 131
Liangzhu Feng and Zhuang Liu

5.1 Introduction 131

5.2 Biomedical Applications of Fullerenes 132

5.2.1 Fullerenes as Antioxidants and Neuroprotective Agents 132

5.2.2 Fullerenes as Antitumor Agents 134

5.2.3 Metallofullerenes as MRI Contrast Agent 136

5.2.4 Fullerenes for Other Applications 136

5.3 Biomedical Applications of Carbon Nanotubes 137

5.3.1 Carbon Nanotubes for Drug Delivery 138

5.3.1.1 Carbon Nanotubes for the Delivery of Small Drug Molecules 139

5.3.1.2 Carbon Nanotubes for the Delivery of Biomacromolecules 141

5.3.2 Carbon Nanotubes for Photothermal and Combined Therapies of Tumors 142

5.3.2.1 Carbon Nanotubes for PhotothermalTherapy of Tumors 142

5.3.2.2 Carbon Nanotubes for CombinedTherapies of Tumors 143

5.3.3 Carbon Nanotubes for Bioimaging 144

5.3.3.1 Carbon Nanotubes for Fluorescence Imaging 144

5.3.3.2 Carbon Nanotubes for Raman Imaging 145

5.3.3.3 Carbon Nanotubes for Photoacoustic Imaging 145

5.3.3.4 Carbon Nanotubes for Other Bioimaging Modalities 145

5.3.4 Carbon Nanotubes for Other Biomedical Applications 146

5.4 Biomedical Applications of Graphene 146

5.4.1 Graphene for Drug Delivery 147

5.4.1.1 Graphene for the Delivery of Small Drug Molecules 148

5.4.1.2 Graphene for the Delivery of Biomacromolecules 148

5.4.2 Graphene for Photothermal and CombinedTherapies of Tumors 151

5.4.3 Graphene for Bioimaging 152

5.4.4 Graphene for Other Biomedical Applications 153

5.5 Conclusion and Perspectives 153

Acknowledgments 154

References 155

6 Pulmonary Effects of Carbon Nanomaterials 163
Liying Wang, Donna C. Davidson, Vincent Castranova, and Yon Rojanasakul

6.1 Introduction 163

6.2 Physicochemical Properties of Carbon Nanomaterials 164

6.2.1 Types of Carbon Nanomaterials 165

6.2.2 Effects of Size 165

6.2.3 Effects of Agglomeration State 166

6.2.4 Aspect Ratio Considerations 168

6.2.5 Surface Modifications 168

6.3 Fate of Pulmonary Exposed Carbon Nanoparticles (Deposition, Distribution, Translocation, and Clearance) 169

6.3.1 Deposition and Distribution of Carbon Nanoparticles in the Lung 169

6.3.2 Translocation of Carbon Nanoparticles 172

6.3.3 Clearance of Carbon Nanomaterials from the Lungs 175

6.4 Carbon Nanomaterial–Induced Lung Responses 176

6.4.1 Key/Specific Target Lung Cell Types of Pulmonary-Exposed Carbon Nanoparticles 176

6.4.2 Lung Inflammation 178

6.4.3 Immune Response 179

6.4.4 Fibrosis 180

6.4.5 Genotoxicity 181

6.4.6 Cancer 182

6.4.7 Cardiovascular Effects Following Pulmonary Exposure of Carbon Nanomaterials 184

6.5 Summary 184

Disclaimer 184

References 189

7 Cardiovascular and Hemostatic Effects of Carbon Nanomaterials 195
Xiaoyong Deng, Cheng Li, Jiajun Wang, and Pan Chen

7.1 Background 195

7.2 Carbon Nanotubes 195

7.2.1 Hemotoxicity of CNTs 196

7.2.1.1 What Is Hemotoxicity 196

7.2.1.2 Complement System 197

7.2.1.3 Red Blood Cells 199

7.2.1.4 Hemostatic System and Coagulation/Thrombosis/Atheroma 200

7.2.2 Effects on Cardiovascular System 201

7.3 Fullerenes 203

7.3.1 Fullerenes’ Escape from Lungs into Circulation 203

7.3.2 Toxicity of Fullerenes on the Cardiovascular System 204

7.4 Graphene-Related Nanomaterials 205

7.5 Conclusions and Outlook 208

Acknowledgments 208

References 208

8 Modulation of the Immune System by Fullerene and Graphene Derivatives 213
Ligeng Xu and Chunying Chen

8.1 Introduction 213

8.2 The Immunological Effects of Fullerene and Its Derivatives 213

8.2.1 Fullerene Derivatives Can Inhibit Inflammation via Blocking ROS Generation 213

8.2.2 Fullerene Derivatives Promote Immune Responses via Modulating Macrophages and/or Antigen Presenting Cells (APCs) 215

8.3 Immunological Effects of Graphene and Its Derivatives 222

8.3.1 Immunological Effect of Pristine Graphene 225

8.3.2 Immunological Effects of Graphene Oxide and Its Derivatives 227

8.4 Perspectives and Outlook 231

References 234

9 Neuro-, Hepato-, and Nephrotoxicity of Carbon-based Nanomaterials 239
Jia Yao and Yongbin Zhang

9.1 Carbon-based Nanomaterials: Introduction 239

9.2 Neurotoxicity of Carbon-based Nanomaterials 240

9.2.1 Blood–Brain Barrier and BBB Penetration by Carbon-based Nanomaterials 240

9.2.2 Neurotoxicity of Carbon Nanotubes 241

9.2.3 Strategies to Reduce Neurotoxicity of Carbon Nanotubes 243

9.2.4 Neurotoxicity of Other Carbon-based Nanomaterials 244

9.3 Hepato and Nephrotoxicity of Carbon-based Nanomaterials 245

9.3.1 Carbon Nanotube Biodistribution in the Liver and Kidney 245

9.3.2 Biodistribution of Other Carbon Nanomaterials 248

9.3.3 Hepatotoxicity of Carbon Nanotubes 251

9.3.4 Carbon Nanotube Nephrotoxicity/Renal Toxicity 254

9.3.5 Hepatotoxicity and Nephrotoxicity of Other Types of Carbon-based Nanomaterials 254

9.4 Points of Consideration for Toxicity Evaluation of Carbon-based Nanomaterials 257

9.5 Summary 259

Acknowledgments 259

References 259

10 Genotoxicity and Carcinogenic Potential of Carbon Nanomaterials 267
Todd A. Stueckle, Linda Sargent, Yon Rojanasakul, and Liying Wang

10.1 Introduction 267

10.1.1 Engineered Nanomaterials and Long-Term Disease Risk: An Introduction 269

10.1.2 Carcinogenesis: A Multistep Process 270

10.1.2.1 Genotoxicity and Initiation 271

10.1.2.2 Promotion 272

10.1.2.3 Progression 274

10.1.3 Current Knowledge and Challenges in Carcinogenesis Studies 274

10.2 Carbon Nanomaterials: Genotoxicity and Carcinogenic Potential 275

10.2.1 Physicochemical Properties of ECNMs 275

10.2.2 Ultrafine Carbon Black 276

10.2.2.1 In Vivo Studies 277

10.2.2.2 In Vitro Studies 278

10.2.3 Carbon Nanotubes 278

10.2.3.1 In Vivo Studies 279

10.2.3.2 In Vitro Studies 291

10.2.4 Fullerenes and Derivatives 296

10.2.4.1 In Vivo Studies 297

10.2.4.2 In Vitro Studies 299

10.2.5 Graphene and Graphene Oxide 300

10.2.5.1 In Vivo Studies 302

10.2.5.2 In Vitro Studies 304

10.2.6 Carbon Nanofibers and Other Particles 307

10.2.6.1 In Vivo Studies 307

10.2.6.2 In Vitro Studies 308

10.3 Future Challenges in Carbon Nanomaterial Carcinogenesis Risk Assessment 308

10.3.1 Exposure Characterization and Fate 308

10.3.2 Dosimetry 309

10.3.3 Model Choice 310

10.3.4 Systematic Evaluation of Genotoxicity 311

10.3.5 Role of ROS and Inflammation 311

10.4 Assessment of ECNM-Induced Genotoxicity and Carcinogenesis 312

10.4.1 Recommendations for Screening ENMs for Carcinogenic Potential 312

10.4.2 Systematic Screening Paradigm and Workflow for ENM Carcinogenicity Risk Assessment 314

10.5 Concluding Remarks 316

Acknowledgments 316

Disclaimer 316

References 317

11 Effect on Reproductive System of Carbon Nanomaterials 333
Ying Liu and Chunying Chen

11.1 Introduction 333

11.2 Effects of Carbon Nanomaterials on the Reproductive System 334

11.2.1 Carbon Nanotubes 335

11.2.2 Fullerene Derivatives 340

11.2.3 Carbon Black Nanoparticles 340

11.3 Insights into the Molecular Mechanisms 342

11.3.1 Potential Toxicity to the Female Reproductive System 342

11.3.2 Potential Toxicity to Male Reproduction of Carbon Nanomaterials 343

11.3.3 Potential Toxicity to Offspring of Carbon Nanomaterials 345

11.3.4 Impact on the Endocrine Organs and Hormone Biosynthesis/Metabolism 346

11.3.5 Others 348

11.4 Conclusion and Perspectives 348

Acknowledgments 352

References 352

12 Immunological Responses Induced by Carbon Nanotubes Exposed to Skin and Gastric and Intestinal System 357
Haiyan Xu, JieMeng, Qiang Ma, and Xiaojin Li

12.1 Introduction 357

12.2 Biological Effects of CNTs by Dermal Exposure 358

12.2.1 In Vitro Assessment in Dermal-Related Cell Lines 358

12.2.2 In Vivo Studies on the Responses Elicited by Skin Exposed with CNTs 361

12.3 Immunological Reactions Elicited by Subcutaneous Administration of MWCNTs 362

12.3.1 Preparation and Characterization of Multiwalled Carbon Nanotubes for Uses in Studies 362

12.3.2 Distribution of Subcutaneously Injected Carbon Nanotubes 363

12.3.3 Immunological Responses Induced by Subcutaneously Injected MWCNTs 369

12.3.3.1 Macrophages Responses Exerted by MWCNTs 370

12.3.3.2 MWCNTs Attract Naïve Monocyte Macrophages Through Activating Macrophages in the Subcutis 373

12.3.3.3 Subcutaneously Injected MWCNTs Induce Complement Activation 375

12.3.3.4 Subcutaneously Injected MWCNTs Elevate Pro-inflammatory Cytokines in the Blood 376

12.4 Immunological Responses Induced by Subcutaneous Administration of MWCNTs in Tumor-Bearing Mice 377

12.4.1 MWCNTs Induce Systematic Immune Responses in Tumor-Bearing Mice 378

12.4.2 MWCNTs Upregulate Multiple Pro-inflammatory Cytokines in the Blood 378

12.4.3 MWCMTs Mediate Cytotoxicity of Lymphocytes 379

12.4.4 MWCNTs Induce Complement Activation 380

12.4.5 MWCNTs Attract Monocyte-Macrophages to Affect the Microenvironment of Tumor Mass 380

12.5 CNTs as Antigen Delivery System to Enhance Immune Responses Against Tumors 383

12.6 Immunological Responses of Gastric and Intestinal Systems Exposed to Carbon Nanotubes 386

References 389

13 Modulation of Immune System by Carbon Nanotubes 397
Marit Ilves and Harri Alenius

13.1 Immune System 397

13.1.1 Innate Immunity Cells and Their Main Functions 398

13.1.2 Adaptive Immunity Cells andTheir Main Functions 399

13.2 Carbon Nanotubes (CNTs) and Innate Immunity 400

13.2.1 Complement Activation 401

13.2.2 Macrophages 402

13.2.3 Activation of Inflammasome Complex and IL-1β Secretion 405

13.2.4 Neutrophils 406

13.2.5 Innate Lymphoid Cells (ILCs) 408

13.2.6 Dendritic Cells 408

13.3 CNTs and Adaptive Immunity 409

13.3.1 The Effects of CNTs on Vaccine Delivery and Immunotherapy 409

13.3.2 Utilization of CNT Scaffolds in the Expanding and Modulation of Immune Cells 411

13.3.3 Immunosuppressive Effects of CNTs 413

13.4 The Effect of CNTs in Allergy and Asthma 414

13.4.1 Allergic Reactions and Their Immunological Mechanisms 414

13.4.2 Asthma 415

13.4.3 Allergic Pulmonary Inflammation Induced by Airway Exposure to CNTs 417

13.4.4 Modulation of Allergen-Induced Airway Inflammation by Exposure to CNTs 418

13.4.5 CNT in the Context of Mast Cells and Eosinophils 420

13.4.6 Role of IL-33 Pathway in CNT-Induced Allergic Responses 420

13.5 Conclusions and Future Prospects 422

References 424

14 Carbon Dots: Synthesis, Bioimaging, and Biosafety Assessment 429
Jie Wang and Yao He

14.1 Introduction 429

14.1.1 Synthesis and Fabrication of C-dots 429

14.1.2 Bioimaging of C-dots 431

14.1.3 Biosafety Assessment of C-dots 432

14.2 Synthetic Strategies 433

14.2.1 Microwave-Assisted Methods 433

14.2.2 Hydrothermal Carbonization 434

14.2.3 Electrochemical Synthesis 437

14.2.4 Chemical Oxidation 439

14.2.5 Ultrosonication 442

14.2.6 Plasma Treatment 444

14.2.7 Laser Ablation Methods 445

14.2.8 Supported Methods 446

14.2.9 Thermal Routes 448

14.3 C-Dots-based Fluorescent Probes for Bioimaging Applications 450

14.3.1 Fluorescent Probes for Bioimaging Applications 450

14.3.2 In Vitro Imaging 451

14.3.3 In Vivo Imaging 456

14.3.4 Conclusion 462

14.4 Toxicity Assessment 462

14.4.1 In Vitro Toxicity Assessment 463

14.4.2 In Vivo Toxicity Assessment 469

14.4.3 Conclusion 475

14.5 Perspectives 477

14.5.1 Unequivocal PL Mechanism 477

14.5.2 Expanding the Spectral Coverage 478

14.5.3 QY Improvement 478

14.5.4 Bioimaging 478

14.5.5 Toxicity Assessment 479

References 479

15 Transport in the Environment and Ecotoxicity of Carbon Nanomaterials 487
Yingying Xu and Chunying Chen

15.1 Introduction 487

15.2 Transport of Carbon Nanomaterials in the Environment 488

15.2.1 Entry of Carbon Nanomaterials into the Environment 488

15.2.2 Fate and Transformation in the Environment 488

15.2.2.1 Oxidation 488

15.2.2.2 Photochemical Transformation 490

15.2.2.3 Dissolution and Precipitation 491

15.2.2.4 Adsorption 492

15.2.2.5 Biodegradation 493

15.3 Ecotoxicity of Fullerene 494

15.3.1 Effect of Fullerene on Microorganisms 494

15.3.2 Effect of Fullerene on Animals 495

15.3.2.1 Effect of Fullerene on Invertebrates 495

15.3.2.2 Effect of Fullerene on Vertebrates 496

15.3.3 Effect of Fullerene on Plants 496

15.3.3.1 Effect of Fullerene on Algae 496

15.3.3.2 Effect of Fullerene on Higher Plants 497

15.4 Ecotoxicity of Carbon Nanotubes (CNTs) 498

15.4.1 Effect of CNTs on Microorganisms 498

15.4.2 Effect of CNTs on Animals 499

15.4.2.1 Effect of CNTs on Invertebrates 499

15.4.2.2 Effect of CNTs on Vertebrates 501

15.4.3 Effect of CNTs on Plants 502

15.4.3.1 Effect of CNTs on Algae 502

15.4.3.2 Effect of CNTs on Higher Plants 503

15.5 Ecotoxicity of Graphene 504

15.6 Conclusion and Perspectives 506

Acknowledgments 506

References 506

16 Exposure Scenarios in the Workplace and Risk Assessment of Carbon Nanomaterials 515
Rui Chen and Chunying Chen

16.1 Introduction 515

16.1.1 Background 515

16.1.2 Exposure Routes and Exposure Scenarios 515

16.1.3 Exposure Metrics 516

16.1.4 Occupation Exposure Limit for Carbon Nanomaterials 516

16.1.5 Strategy for Exposure Assessment of Carbon Nanomaterials 517

16.2 Potential Exposure in theWorkplace 519

16.2.1 Carbon Nanotubes 519

16.2.2 Fullerenes, Metallofullerenes, and Graphenes 525

16.3 Exposure Risk Assessment and Engineering Control 527

16.3.1 Risk Assessment Strategy on Carbon Nanomaterials 527

16.3.2 Inhalation Exposure Assessment Method 529

16.3.3 Exposure Controls 530

16.4 Summary and Outlook 531

Acknowledgments 531

References 531

Index 535