3D and 4D Printing in Biomedical Applications
Process Engineering and Additive Manufacturing

Preface xvii

1 3D/4D Printing in Additive Manufacturing: Process Engineering and Novel Excipients 1
Christian Muehlenfeld and Simon A. Roberts

1.1 Introduction 1

1.2 The Process of 3D and 4D Printing Technology 1

1.3 3D/4D Printing for Biomedical Applications 2

1.4 Smart or Responsive Materials for 4D Biomedical Printing 3

1.5 Classification of 3D and 4D Printing Technologies 7

1.5.1 Fused Filament Fabrication (FFF) – Extrusion-Based Systems 7

1.5.2 Powder Bed Printing (PBP) – Droplet-Based Systems 10

1.5.3 Stereolithographic (SLA) Printing – Resin-Based Systems 12

1.5.4 Selective Laser Sintering (SLS) Printing – Laser-Based Systems 15

1.6 Conclusions and Perspectives 17

References 17

2 3D and 4D Printing Technologies: Innovative Process Engineering and Smart Additive Manufacturing 25
Deck Tan, Ali Nokhodchi, and MohammedManiruzzaman

2.1 Introduction 25

2.2 Types of 3D Printing Technologies 25

2.2.1 Stereolithographic 3D Printing (SLA) 25

2.2.2 Powder-Based 3D Printing 26

2.2.3 Selective Laser Sintering (SLS) 27

2.2.4 Fused Deposition Modeling (FDM) 28

2.2.5 Semisolid Extrusion (EXT) 3D Printing 29

2.2.6 Thermal Inkjet Printing 30

2.3 FDM 3D Printing Technology 31

2.3.1 FDM 3D Printing Applications in Unit Dose Fabrications and Medical Implants 33

2.4 Hot Melt Extrusion Technique to Produce 3D Printing Polymeric Filaments 34

2.5 Smart Medical Implants Integrated with Sensors 35

2.5.1 Examples of Medical Implants with Sensors 36

2.6 4D Printing and Future Perspectives 38

2.6.1 4D Printing and Its Transition in Material Fabrication 38

2.6.2 Shape Memory or Stimuli-Responsive Mechanism of 4D Printing 39

2.6.3 Factors Affecting 4D Printing 40

2.6.3.1 Humidity-Responsive Materials 40

2.6.3.2 Temperatures 41

2.6.3.3 Electronic and Magnetic Stimuli 43

2.6.3.4 Light 45

2.6.4 Future Perspectives of 4D Printing 45

2.7 Regulatory Aspects 46

2.8 Conclusions 48

References 48

3 3D Printing: A Case of ZipDose^®Technology –World’s First 3D Printing Platform to Obtain FDA Approval for a Pharmaceutical Product 53
Thomas G.West and Thomas J. Bradbury

3.1 Introduction 53

3.2 Terminology 53

3.3 Historical Context forThis Form of 3D Printing 54

3.4 ZipDose^®Technology 56

3.5 3D PrintingMachines and Pharmaceutical Process Design 60

3.5.1 Overview 60

3.5.2 Generalized Process in the Pharmaceutical Context 62

3.5.3 Exemplary 3DP Machine Designs 65

3.6 Development of SPRITAM® 70

3.6.1 Product Concept and Need 70

3.6.2 Regulatory Approach 71

3.6.3 Introduction of the Technology to FDA 72

3.6.4 Target Product Profile 72

3.6.5 Synopsis of Formulation and Clinical Development 73

3.7 Conclusion 76

Acknowledgments 77

References 77

4 Manufacturing of Biomaterials via a 3D Printing Platform 81
Patrick Thayer, Hector Martinez, and Erik Gatenholm

4.1 AdditiveManufacturing and Bioprinting 81

4.2 Bioinks 83

4.2.1 Printability Control – Bioink Composition and Environmental Factors 83

4.2.2 Mechanisms for Filament Formation and Stability 85

4.3 3D Bioprinting Systems 87

4.3.1 Multifaceted Systems 88

4.3.2 Major Components 88

4.3.3 Pneumatic Printhead 89

4.3.4 Mechanical Displacement Printhead 89

4.3.5 Inkjet Printhead 91

4.3.6 Heated and Cooled Printheads 91

4.3.7 High-Temperature Extruder 92

4.3.8 Multimaterial Printhead 92

4.3.9 Heated and Cooled Printbed 94

4.3.10 Clean Chamber Technology 94

4.3.11 Video-Capture Printhead and Sensors 94

4.3.12 Integrated Intelligence 95

4.4 Applications 95

4.4.1 Internal Architecture 96

4.4.2 Integrated Vascular Networks and Microstructure Patterning 98

4.4.3 PersonalizedMedicine 99

4.5 Steps Necessary for Broader Application 101

References 102

5 Bioscaffolding: A New Innovative Fabrication Process 113
Rania Abdelgaber, David Kilian, and Hendrik Fiehn

5.1 Introduction: From Bioscaffolding to Bioprinting 113

5.2 Scaffolding 115

5.2.1 Properties of Scaffolds 115

5.2.2 Bioprinters vs Common 3D Printers: Approaches for Extrusion of Polymers 116

5.2.3 Comparing Cell Seeding Techniques to 3D Bioprinting or Cell-Laden Hydrogels 117

5.2.3.1 From Printing to Bioprinting 117

5.2.3.2 Approaches of Stabilizing Printed Constructs 118

5.2.4 Examples/Applications of Cell-Seeded Scaffolds 119

5.2.5 Data Processing of 3D CAD Data for Bioscaffolds 119

5.3 Bioprinted Scaffolds 120

5.3.1 Bioinks 120

5.3.2 Tools for Multimaterial Printing 123

5.3.3 Multimaterial Scaffold 124

5.3.4 Core–Shell Scaffolds 126

5.3.5 Additional Technical Equipment 128

5.3.6 Piezoelectric Pipetting Technology 128

5.3.7 Usage of Piezoelectric Inkjet Technology with Bioscaffolds 130

5.4 Applications of Bioscaffolder and Bioprinting Systems 132

5.4.1 Individualized Implants and Tissue Constructs 132

5.4.2 Green Bioprinting 133

5.4.3 Challenges for Clinical Applications of Bioprinted Scaffolds in Tissue and Organ Engineering 134

5.4.4 4D Printing 135

5.5 Conclusion 137

References 137

6 Potential of 3D Printing in Pharmaceutical Drug Delivery and Manufacturing 145
Maren K. Preis

6.1 Introduction 145

6.2 Pharmaceutical Drug Delivery 145

6.3 Conventional Manufacturing vs 3D Printing 146

6.4 Advanced Applications for Improved Drug Delivery 148

6.5 Instrumentations 148

6.6 Location of 3D Printing Manufacturing 149

6.6.1 Pharmaceutical Industry 149

6.6.2 At the Point of Care 150

6.6.3 Print-at-Home 150

6.7 Regulatory Aspects 151

6.8 Summary 151

References 151

7 Emerging 3D Printing Technologies to Develop Novel Pharmaceutical Formulations 153
Christos I. Gioumouxouzis, Georgios K. Eleftheriadis, and Dimitrios G. Fatouros

7.1 Introduction 153

7.2 FDM 3D Printing 153

7.3 Pressure-Assisted Microsyringe 173

7.4 SLA 3D Printing 175

7.5 Powder Bed 3D Printing 175

7.6 SLS 3D Printing 178

7.7 3D Inkjet Printing 179

7.8 Conclusions 180

References 180

8 Modulating Drug Release from3D Printed Pharmaceutical Products 185
Julian Quodbach

8.1 Introduction 185

8.2 Pharmaceutically Used 3D Printing Processes and Techniques 186

8.2.1 Process Flow of 3D Printing Processes 186

8.2.2 Inkjet-Based Printing Technologies 187

8.2.3 Extrusion-Based Printing Techniques 187

8.2.4 Laser-Based Techniques 188

8.3 Modifying the Drug Release Profile from 3D Printed Dosage Forms 189

8.3.1 Approaches to Modify the Drug Release 189

8.3.2 Modifying the Drug Release by Formulation Variation 189

8.3.2.1 Fused Filament Fabrication 189

8.3.2.2 Other Printing Techniques 194

8.3.3 Manipulating the Dosage Form Geometry as a Means to Modify API Release 195

8.3.3.1 Fused Filament Fabrication 196

8.3.3.2 Drop-on-Drop Printing 197

8.3.4 Dissolution Control via Directed Diffusion and Compartmentalization 199

8.3.4.1 Drop-on-Powder Printing 199

8.3.4.2 Fused Filament Fabrication 202

8.3.4.3 Printing with Pressure-Assisted Microsyringes 205

8.4 Conclusion 206

References 207

9 Novel Excipients and Materials Used in FDM 3D Printing of Pharmaceutical Dosage Forms 211
Ming Lu

9.1 Introduction 211

9.2 Biodegradable Polyester 219

9.2.1 Polylactic Acid (PLA) 219

9.2.2 Poly(ε-caprolactone) (PCL) 220

9.3 Polyvinyl Polymer 221

9.3.1 Polyvinyl Alcohol (PVA) 221

9.3.2 Ethylene Vinyl Acetate (EVA) 223

9.3.3 Polyvinylpyrrolidone (PVP) 224

9.3.4 Soluplus 225

9.4 Cellulosic Polymers 225

9.4.1 Hydroxypropyl Cellulose (HPC) 226

9.4.2 Hydroxypropyl Methylcellulose (HPMC) 227

9.4.3 Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) 228

9.5 Polymethacrylate-Based Polymers 229

9.5.1 Eudragit RL/RS 230

9.5.2 Eudragit L100-55 231

9.5.3 Eudragit E 100 232

9.6 Conclusion 233

References 234

10 Recent Advances of NovelMaterials for 3D/4D Printing in Biomedical Applications 239
Jasim Ahmed

10.1 Introduction 239

10.2 Materials for 3DP 240

10.3 Rheology 241

10.4 Ceramics for 3D Printing 241

10.5 Polymers and Biopolymers for 3D Printing 243

10.5.1 Polylactide (PLA) 245

10.5.2 Poly(ε-caprolactone) (PCL) 245

10.5.3 Hyaluronic Acid 245

10.6 4D Printing 246

10.6.1 Bioprinting 246

10.6.2 Smart or Intelligent Materials 249

10.6.2.1 Thermal Stimuli-Induced Transformation 249

10.6.2.2 Hydrogel 253

10.7 3D and 4D Printed Bone Scaffolds with Novel Materials 255

10.7.1 3DP/4DP for Drug Delivery and Bioprinting 259

10.7.2 Polyurethane-Based Scaffolds for Tissue Engineering 260

10.8 Future and Prospects 263

References 264

11 Personalized Polypills Produced by Fused Deposition Modeling 3D Printing 273
Sheng Qi, Jehad Nasereddin, and Fahad Alqahtani

11.1 Introduction 273

11.2 Polypharmacy and Polypills 275

11.2.1 Clinical Evidence and Current State of the Art 275

11.2.2 Future Personalization 276

11.3 FDM 3D Printing of Pharmaceutical Solid Dosage Forms 279

11.3.1 Basic Principle of FDM 3D Printing 279

11.3.2 Printing Parameter Control 281

11.3.3 Drug-Loading Methods 285

11.4 Key Challenges in the Development of FDM 3D Printed Personalized Polypills 287

11.4.1 Printable Pharmaceutical Materials 287

11.4.2 Printing Precision and Printer Redesign 288

11.4.3 Regulatory Barriers for Personalized Polypill Printing 290

11.5 Conclusions and Future Remarks 292

References 292

12 3D Printing of Metallic Cellular Scaffolds for Bone Implants 297
Xipeng Tan and Yu Jun Tan

12.1 Introduction 297

12.2 Metal 3D Printing Techniques for Bone Implants 299

12.2.1 Selective Laser Melting 301

12.2.2 Selective Electron Beam Melting 302

12.3 Biometals for Bone Implants 303

12.3.1 Nondegradable Biometals 304

12.3.2 Biodegradable Biometals 305

12.3.3 3D Printing of Biometals 306

12.3.3.1 Ti–6Al–4V ELI Alloy 306

12.3.3.2 CoCrMo Alloy 307

12.3.3.3 Stainless Steel 316L Alloy 307

12.3.3.4 NiTi Shape Memory Alloy 308

12.3.3.5 Tantalum 309

12.3.3.6 Mg and Its Alloy 309

12.4 Cellular Structure Design 310

12.4.1 Stochastic and Reticulated Cellular Design 311

12.4.2 Bend- and Stretch-Dominated Cellular Design 312

12.4.3 Scaffold Design Feasibility 312

12.5 Outlook 313

References 314

13 3D and 4D Scaffold-Free Bioprinting 317
Chin Siang Ong, Pooja Yesantharao, and Narutoshi Hibino

13.1 Introduction 317

13.2 3D Scaffold-Free Bioprinting 318

13.2.1 Principles 318

13.2.2 Spheroid Optimization 318

13.2.3 3D Bioprinting 322

13.2.4 Decannulation and Functional Assessment 325

13.3 4D Bioprinting 326

13.3.1 Properties of “Smart” Materials 328

13.3.2 General Approaches 328

13.3.2.1 “Smart” Scaffolds 328

13.3.2.2 In Vivo Bioprinting 331

13.3.2.3 Hybrid Techniques 332

13.3.3 4D Bioprinting Technologies 332

13.3.4 Applications 334

13.3.5 Limitations and Future Directions 336

13.4 4D Scaffold-Free Bioprinting 337

13.5 Conclusion 338

Acknowledgments 338

References 338

14 4D Printing and Its Biomedical Applications 343
Saeed Akbari, Yuan-Fang Zhang, DongWang, and Qi Ge

14.1 Introduction 343

14.2 3D Printing Technologies with Potential for 4D Printing 344

14.2.1 Fused Deposition Modeling (FDM) 344

14.2.2 Direct InkWriting (DIW) 345

14.2.3 Inkjet 347

14.2.4 Projection Stereolithography (pSLA) 348

14.3 Soft Active Materials for 4D Printing 349

14.3.1 Shape Memory Polymers 349

14.3.2 Hydrogels 354

14.3.3 Other SAMs 356

14.4 Biomedical Applications of 4D Printing 358

14.4.1 Temperature-Actuated 4D Printing 358

14.4.2 Humidity-Actuated 4D Printing 363

14.5 Conclusion and Outlook 365

References 366

15 Current Trends and Challenges in Biofabrication Using Biomaterials and Nanomaterials: Future Perspectives for 3D/4D Bioprinting 373
Luciano P. Silva

15.1 Introduction 373

15.2 Biofabrication as a Multidisciplinary to Interdisciplinary Research Field 375

15.3 Biofabrication as a Multifaceted Approach 377

15.4 Biofabrication Beyond Biomedical Pharmaceutical Applications 377

15.5 The Diversity of Techniques Used in Biofabrication 378

15.6 Natural Resources as Sources of Biomaterials Useful for Biofabrication 380

15.7 Nanomaterials as Much More Than Just New Building Blocks for Biofabrication 382

15.8 3D Bioprinting as the New Gold Standard for Biofabrication 383

15.9 When 3D Bioprinting Is Not Sufficient for Bioconstruction: 4D Bioprinting 385

15.10 An Overview about Current Bottlenecks in Biofabrication 385

15.10.1 Does 3D Model Matter in Biofabrication? 386

15.10.2 Does Size and Time Matter in Biofabrication? 386

15.10.3 Do Choice Materials and Cells Matters in Biofabrication? 387

15.10.4 Does Maturation of the Bioconstructs Matter in Biofabrication? 387

15.10.5 Do CharacterizationMethods Matters in Biofabrication? 388

15.10.6 Does Economic and Social Impact Matter Biofabrication? 388

15.10.7 Does Ethical and Legal Issues Matter in Biofabrication? 389

15.11 Conclusion 390

References 390

16 Orthopedic Implant Design and Analysis: Potential of 3D/4D Bioprinting 423
Chang JiangWang and Kevin B. Hazlehurst

16.1 Orthopedic Implant Design with 3D Printing 423

16.1.1 Bone Properties and Orthopedic Implants 423

16.1.2 3D Printing and Porous Implant Design 426

16.2 Analysis of 3D Printed Orthopedic Implants 428

16.2.1 Mechanical Properties of Porous Structures 429

16.2.2 Experimental Testing of 3D Printed Femoral Stems 433

16.2.3 Finite Element Analysis of Porous Stems with 3D Printing 435

16.3 3D Printed Orthopedic Implant Installation and Instrumentation 437

16.4 Orthopedic Implants Manufactured with 4D Printing 439

16.5 Summary 439

References 440

17 Recent Innovations in Additive Manufacturing across Industries: 3D Printed Products and FDA’s Perspectives 443
Brett Rust, Olga Tsaponina, andMohammedManiruzzaman

17.1 Introduction 443

17.2 CurrentWidely Used Processes across Industries 443

17.2.1 Fused Deposition Modeling (FDM) 443

17.2.2 Stereolithography (SLA) and Digital Light Processing (DLP) 444

17.2.3 Selective Laser Sintering (SLS) 445

17.3 Emerging 3D Printing Processes and Technologies 446

17.3.1 Continuous Liquid Interface Production (CLIP) 446

17.3.2 Multi Jet Fusion (MJF) 446

17.4 Industry Uses of AdditiveManufacturing Technologies 447

17.5 Material and Processes for Medical and Motorsport Sectors 449

17.6 Medical Industry Usage and Materials Development 452

17.7 3D Printing of Medical Devices: FDA’s Perspectives 455

17.7.1 FDA’s Role in 3D Printing of Materials 455

17.7.2 Classifications of Medical Devices from FDA’s Viewpoint 456

17.7.3 Medical Applications of 3D Printing and FDA’s Expectations 457

17.7.4 Person-Specific Devices 458

17.7.5 Process of 3D Printing of Various Medical Devices 458

17.7.6 Materials Used in 3D Printed Devices Overall 459

17.7.7 Materials Used in Specific Application (Printed Dental Devices) 460

17.8 Conclusions 461

References 461

Index 463

Mohammed Maniruzzaman, PhD, is currently a Lecturer (equivalent to tenured Assistant Professor) in Pharmaceutics and Drug Delivery at University of Sussex, UK. Prior to this, he was appointed as a Research Fellow (Industrial) at the University of Greenwich, UK.