3D and 4D Printing in Biomedical Applications

A professional guide to 3D and 4D printing technology in the biomedical and pharmaceutical fields

3D and 4D Printing in Biomedical Applications offers an authoritative guide to 3D and 4D printing technology in the biomedical and pharmaceutical arenas. With contributions from an international panel of academic scholars and industry experts, this book contains an overview of the topic and the most current research and innovations in pharmaceutical and biomedical applications. This important volume explores the process optimization, innovation process, engineering, and platform technology behind printed medicine.
In addition, information on biomedical developments include topics such as on shape memory polymers, 4D bio-fabrications and bone printing.

The book covers a wealth of relevant topics including information on the potential of 3D printing for pharmaceutical drug delivery, examines a new fabrication process, bio-scaffolding, and reviews the most current trends and challenges in biofabrication for 3D and 4D bioprinting. This vital resource:

-Offers a comprehensive guide to 3D and 4D printing technology in the biomedical and pharmaceutical fields
-Includes information on the first 3D printing platform to get FDA approval for a pharmaceutical product
-Contains a review of the current 3D printed pharmaceutical products
-Presents recent advances of novel materials for 3D/4D printing and biomedical applications

Written for pharmaceutical chemists, medicinal chemists, biotechnologists, pharma engineers, 3D and 4D Printing in Biomedical Applications explores the key aspects of the printing of medical and pharmaceutical products and the challenges and advances associated with their development.

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 (R)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 (R)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 (R) 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( -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( -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