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<p>Preface xvii</p> <p><b>1 3D/4D Printing in Additive Manufacturing: Process Engineering and Novel Excipients 1<br /></b><i>Christian Muehlenfeld and Simon A. Roberts</i></p> <p>1.1 Introduction 1</p> <p>1.2 The Process of 3D and 4D Printing Technology 1</p> <p>1.3 3D/4D Printing for Biomedical Applications 2</p> <p>1.4 Smart or Responsive Materials for 4D Biomedical Printing 3</p> <p>1.5 Classification of 3D and 4D Printing Technologies 7</p> <p>1.5.1 Fused Filament Fabrication (FFF) – Extrusion-Based Systems 7</p> <p>1.5.2 Powder Bed Printing (PBP) – Droplet-Based Systems 10</p> <p>1.5.3 Stereolithographic (SLA) Printing – Resin-Based Systems 12</p> <p>1.5.4 Selective Laser Sintering (SLS) Printing – Laser-Based Systems 15</p> <p>1.6 Conclusions and Perspectives 17</p> <p>References 17</p> <p><b>2 3D and 4D Printing Technologies: Innovative Process Engineering and Smart Additive Manufacturing 25<br /></b><i>Deck Tan, Ali Nokhodchi, and MohammedManiruzzaman</i></p> <p>2.1 Introduction 25</p> <p>2.2 Types of 3D Printing Technologies 25</p> <p>2.2.1 Stereolithographic 3D Printing (SLA) 25</p> <p>2.2.2 Powder-Based 3D Printing 26</p> <p>2.2.3 Selective Laser Sintering (SLS) 27</p> <p>2.2.4 Fused Deposition Modeling (FDM) 28</p> <p>2.2.5 Semisolid Extrusion (EXT) 3D Printing 29</p> <p>2.2.6 Thermal Inkjet Printing 30</p> <p>2.3 FDM 3D Printing Technology 31</p> <p>2.3.1 FDM 3D Printing Applications in Unit Dose Fabrications and Medical Implants 33</p> <p>2.4 Hot Melt Extrusion Technique to Produce 3D Printing Polymeric Filaments 34</p> <p>2.5 Smart Medical Implants Integrated with Sensors 35</p> <p>2.5.1 Examples of Medical Implants with Sensors 36</p> <p>2.6 4D Printing and Future Perspectives 38</p> <p>2.6.1 4D Printing and Its Transition in Material Fabrication 38</p> <p>2.6.2 Shape Memory or Stimuli-Responsive Mechanism of 4D Printing 39</p> <p>2.6.3 Factors Affecting 4D Printing 40</p> <p>2.6.3.1 Humidity-Responsive Materials 40</p> <p>2.6.3.2 Temperatures 41</p> <p>2.6.3.3 Electronic and Magnetic Stimuli 43</p> <p>2.6.3.4 Light 45</p> <p>2.6.4 Future Perspectives of 4D Printing 45</p> <p>2.7 Regulatory Aspects 46</p> <p>2.8 Conclusions 48</p> <p>References 48</p> <p><b>3 3D Printing: A Case of ZipDose^®Technology –World’s First 3D Printing Platform to Obtain FDA Approval for a Pharmaceutical Product 53<br /></b><i>Thomas G.West and Thomas J. Bradbury</i></p> <p>3.1 Introduction 53</p> <p>3.2 Terminology 53</p> <p>3.3 Historical Context forThis Form of 3D Printing 54</p> <p>3.4 ZipDose^®Technology 56</p> <p>3.5 3D PrintingMachines and Pharmaceutical Process Design 60</p> <p>3.5.1 Overview 60</p> <p>3.5.2 Generalized Process in the Pharmaceutical Context 62</p> <p>3.5.3 Exemplary 3DP Machine Designs 65</p> <p>3.6 Development of SPRITAM® 70</p> <p>3.6.1 Product Concept and Need 70</p> <p>3.6.2 Regulatory Approach 71</p> <p>3.6.3 Introduction of the Technology to FDA 72</p> <p>3.6.4 Target Product Profile 72</p> <p>3.6.5 Synopsis of Formulation and Clinical Development 73</p> <p>3.7 Conclusion 76</p> <p>Acknowledgments 77</p> <p>References 77</p> <p><b>4 Manufacturing of Biomaterials via a 3D Printing Platform 81<br /></b><i>Patrick Thayer, Hector Martinez, and Erik Gatenholm</i></p> <p>4.1 AdditiveManufacturing and Bioprinting 81</p> <p>4.2 Bioinks 83</p> <p>4.2.1 Printability Control – Bioink Composition and Environmental Factors 83</p> <p>4.2.2 Mechanisms for Filament Formation and Stability 85</p> <p>4.3 3D Bioprinting Systems 87</p> <p>4.3.1 Multifaceted Systems 88</p> <p>4.3.2 Major Components 88</p> <p>4.3.3 Pneumatic Printhead 89</p> <p>4.3.4 Mechanical Displacement Printhead 89</p> <p>4.3.5 Inkjet Printhead 91</p> <p>4.3.6 Heated and Cooled Printheads 91</p> <p>4.3.7 High-Temperature Extruder 92</p> <p>4.3.8 Multimaterial Printhead 92</p> <p>4.3.9 Heated and Cooled Printbed 94</p> <p>4.3.10 Clean Chamber Technology 94</p> <p>4.3.11 Video-Capture Printhead and Sensors 94</p> <p>4.3.12 Integrated Intelligence 95</p> <p>4.4 Applications 95</p> <p>4.4.1 Internal Architecture 96</p> <p>4.4.2 Integrated Vascular Networks and Microstructure Patterning 98</p> <p>4.4.3 PersonalizedMedicine 99</p> <p>4.5 Steps Necessary for Broader Application 101</p> <p>References 102</p> <p><b>5 Bioscaffolding: A New Innovative Fabrication Process 113<br /></b><i>Rania Abdelgaber, David Kilian, and Hendrik Fiehn</i></p> <p>5.1 Introduction: From Bioscaffolding to Bioprinting 113</p> <p>5.2 Scaffolding 115</p> <p>5.2.1 Properties of Scaffolds 115</p> <p>5.2.2 Bioprinters vs Common 3D Printers: Approaches for Extrusion of Polymers 116</p> <p>5.2.3 Comparing Cell Seeding Techniques to 3D Bioprinting or Cell-Laden Hydrogels 117</p> <p>5.2.3.1 From Printing to Bioprinting 117</p> <p>5.2.3.2 Approaches of Stabilizing Printed Constructs 118</p> <p>5.2.4 Examples/Applications of Cell-Seeded Scaffolds 119</p> <p>5.2.5 Data Processing of 3D CAD Data for Bioscaffolds 119</p> <p>5.3 Bioprinted Scaffolds 120</p> <p>5.3.1 Bioinks 120</p> <p>5.3.2 Tools for Multimaterial Printing 123</p> <p>5.3.3 Multimaterial Scaffold 124</p> <p>5.3.4 Core–Shell Scaffolds 126</p> <p>5.3.5 Additional Technical Equipment 128</p> <p>5.3.6 Piezoelectric Pipetting Technology 128</p> <p>5.3.7 Usage of Piezoelectric Inkjet Technology with Bioscaffolds 130</p> <p>5.4 Applications of Bioscaffolder and Bioprinting Systems 132</p> <p>5.4.1 Individualized Implants and Tissue Constructs 132</p> <p>5.4.2 Green Bioprinting 133</p> <p>5.4.3 Challenges for Clinical Applications of Bioprinted Scaffolds in Tissue and Organ Engineering 134</p> <p>5.4.4 4D Printing 135</p> <p>5.5 Conclusion 137</p> <p>References 137</p> <p><b>6 Potential of 3D Printing in Pharmaceutical Drug Delivery and Manufacturing 145<br /></b><i>Maren K. Preis</i></p> <p>6.1 Introduction 145</p> <p>6.2 Pharmaceutical Drug Delivery 145</p> <p>6.3 Conventional Manufacturing vs 3D Printing 146</p> <p>6.4 Advanced Applications for Improved Drug Delivery 148</p> <p>6.5 Instrumentations 148</p> <p>6.6 Location of 3D Printing Manufacturing 149</p> <p>6.6.1 Pharmaceutical Industry 149</p> <p>6.6.2 At the Point of Care 150</p> <p>6.6.3 Print-at-Home 150</p> <p>6.7 Regulatory Aspects 151</p> <p>6.8 Summary 151</p> <p>References 151</p> <p><b>7 Emerging 3D Printing Technologies to Develop Novel Pharmaceutical Formulations 153<br /></b><i>Christos I. Gioumouxouzis, Georgios K. Eleftheriadis, and Dimitrios G. Fatouros</i></p> <p>7.1 Introduction 153</p> <p>7.2 FDM 3D Printing 153</p> <p>7.3 Pressure-Assisted Microsyringe 173</p> <p>7.4 SLA 3D Printing 175</p> <p>7.5 Powder Bed 3D Printing 175</p> <p>7.6 SLS 3D Printing 178</p> <p>7.7 3D Inkjet Printing 179</p> <p>7.8 Conclusions 180</p> <p>References 180</p> <p><b>8 Modulating Drug Release from3D Printed Pharmaceutical Products 185<br /></b><i>Julian Quodbach</i></p> <p>8.1 Introduction 185</p> <p>8.2 Pharmaceutically Used 3D Printing Processes and Techniques 186</p> <p>8.2.1 Process Flow of 3D Printing Processes 186</p> <p>8.2.2 Inkjet-Based Printing Technologies 187</p> <p>8.2.3 Extrusion-Based Printing Techniques 187</p> <p>8.2.4 Laser-Based Techniques 188</p> <p>8.3 Modifying the Drug Release Profile from 3D Printed Dosage Forms 189</p> <p>8.3.1 Approaches to Modify the Drug Release 189</p> <p>8.3.2 Modifying the Drug Release by Formulation Variation 189</p> <p>8.3.2.1 Fused Filament Fabrication 189</p> <p>8.3.2.2 Other Printing Techniques 194</p> <p>8.3.3 Manipulating the Dosage Form Geometry as a Means to Modify API Release 195</p> <p>8.3.3.1 Fused Filament Fabrication 196</p> <p>8.3.3.2 Drop-on-Drop Printing 197</p> <p>8.3.4 Dissolution Control via Directed Diffusion and Compartmentalization 199</p> <p>8.3.4.1 Drop-on-Powder Printing 199</p> <p>8.3.4.2 Fused Filament Fabrication 202</p> <p>8.3.4.3 Printing with Pressure-Assisted Microsyringes 205</p> <p>8.4 Conclusion 206</p> <p>References 207</p> <p><b>9 Novel Excipients and Materials Used in FDM 3D Printing of Pharmaceutical Dosage Forms 211<br /></b><i>Ming Lu</i></p> <p>9.1 Introduction 211</p> <p>9.2 Biodegradable Polyester 219</p> <p>9.2.1 Polylactic Acid (PLA) 219</p> <p>9.2.2 Poly(ε-caprolactone) (PCL) 220</p> <p>9.3 Polyvinyl Polymer 221</p> <p>9.3.1 Polyvinyl Alcohol (PVA) 221</p> <p>9.3.2 Ethylene Vinyl Acetate (EVA) 223</p> <p>9.3.3 Polyvinylpyrrolidone (PVP) 224</p> <p>9.3.4 Soluplus 225</p> <p>9.4 Cellulosic Polymers 225</p> <p>9.4.1 Hydroxypropyl Cellulose (HPC) 226</p> <p>9.4.2 Hydroxypropyl Methylcellulose (HPMC) 227</p> <p>9.4.3 Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) 228</p> <p>9.5 Polymethacrylate-Based Polymers 229</p> <p>9.5.1 Eudragit RL/RS 230</p> <p>9.5.2 Eudragit L100-55 231</p> <p>9.5.3 Eudragit E 100 232</p> <p>9.6 Conclusion 233</p> <p>References 234</p> <p><b>10 Recent Advances of NovelMaterials for 3D/4D Printing in Biomedical Applications 239<br /></b><i>Jasim Ahmed</i></p> <p>10.1 Introduction 239</p> <p>10.2 Materials for 3DP 240</p> <p>10.3 Rheology 241</p> <p>10.4 Ceramics for 3D Printing 241</p> <p>10.5 Polymers and Biopolymers for 3D Printing 243</p> <p>10.5.1 Polylactide (PLA) 245</p> <p>10.5.2 Poly(ε-caprolactone) (PCL) 245</p> <p>10.5.3 Hyaluronic Acid 245</p> <p>10.6 4D Printing 246</p> <p>10.6.1 Bioprinting 246</p> <p>10.6.2 Smart or Intelligent Materials 249</p> <p>10.6.2.1 Thermal Stimuli-Induced Transformation 249</p> <p>10.6.2.2 Hydrogel 253</p> <p>10.7 3D and 4D Printed Bone Scaffolds with Novel Materials 255</p> <p>10.7.1 3DP/4DP for Drug Delivery and Bioprinting 259</p> <p>10.7.2 Polyurethane-Based Scaffolds for Tissue Engineering 260</p> <p>10.8 Future and Prospects 263</p> <p>References 264</p> <p><b>11 Personalized Polypills Produced by Fused Deposition Modeling 3D Printing 273<br /></b><i>Sheng Qi, Jehad Nasereddin, and Fahad Alqahtani</i></p> <p>11.1 Introduction 273</p> <p>11.2 Polypharmacy and Polypills 275</p> <p>11.2.1 Clinical Evidence and Current State of the Art 275</p> <p>11.2.2 Future Personalization 276</p> <p>11.3 FDM 3D Printing of Pharmaceutical Solid Dosage Forms 279</p> <p>11.3.1 Basic Principle of FDM 3D Printing 279</p> <p>11.3.2 Printing Parameter Control 281</p> <p>11.3.3 Drug-Loading Methods 285</p> <p>11.4 Key Challenges in the Development of FDM 3D Printed Personalized Polypills 287</p> <p>11.4.1 Printable Pharmaceutical Materials 287</p> <p>11.4.2 Printing Precision and Printer Redesign 288</p> <p>11.4.3 Regulatory Barriers for Personalized Polypill Printing 290</p> <p>11.5 Conclusions and Future Remarks 292</p> <p>References 292</p> <p><b>12 3D Printing of Metallic Cellular Scaffolds for Bone Implants 297<br /></b><i>Xipeng Tan and Yu Jun Tan</i></p> <p>12.1 Introduction 297</p> <p>12.2 Metal 3D Printing Techniques for Bone Implants 299</p> <p>12.2.1 Selective Laser Melting 301</p> <p>12.2.2 Selective Electron Beam Melting 302</p> <p>12.3 Biometals for Bone Implants 303</p> <p>12.3.1 Nondegradable Biometals 304</p> <p>12.3.2 Biodegradable Biometals 305</p> <p>12.3.3 3D Printing of Biometals 306</p> <p>12.3.3.1 Ti–6Al–4V ELI Alloy 306</p> <p>12.3.3.2 CoCrMo Alloy 307</p> <p>12.3.3.3 Stainless Steel 316L Alloy 307</p> <p>12.3.3.4 NiTi Shape Memory Alloy 308</p> <p>12.3.3.5 Tantalum 309</p> <p>12.3.3.6 Mg and Its Alloy 309</p> <p>12.4 Cellular Structure Design 310</p> <p>12.4.1 Stochastic and Reticulated Cellular Design 311</p> <p>12.4.2 Bend- and Stretch-Dominated Cellular Design 312</p> <p>12.4.3 Scaffold Design Feasibility 312</p> <p>12.5 Outlook 313</p> <p>References 314</p> <p><b>13 3D and 4D Scaffold-Free Bioprinting 317<br /></b><i>Chin Siang Ong, Pooja Yesantharao, and Narutoshi Hibino</i></p> <p>13.1 Introduction 317</p> <p>13.2 3D Scaffold-Free Bioprinting 318</p> <p>13.2.1 Principles 318</p> <p>13.2.2 Spheroid Optimization 318</p> <p>13.2.3 3D Bioprinting 322</p> <p>13.2.4 Decannulation and Functional Assessment 325</p> <p>13.3 4D Bioprinting 326</p> <p>13.3.1 Properties of “Smart” Materials 328</p> <p>13.3.2 General Approaches 328</p> <p>13.3.2.1 “Smart” Scaffolds 328</p> <p>13.3.2.2 In Vivo Bioprinting 331</p> <p>13.3.2.3 Hybrid Techniques 332</p> <p>13.3.3 4D Bioprinting Technologies 332</p> <p>13.3.4 Applications 334</p> <p>13.3.5 Limitations and Future Directions 336</p> <p>13.4 4D Scaffold-Free Bioprinting 337</p> <p>13.5 Conclusion 338</p> <p>Acknowledgments 338</p> <p>References 338</p> <p><b>14 4D Printing and Its Biomedical Applications 343<br /></b><i>Saeed Akbari, Yuan-Fang Zhang, DongWang, and Qi Ge</i></p> <p>14.1 Introduction 343</p> <p>14.2 3D Printing Technologies with Potential for 4D Printing 344</p> <p>14.2.1 Fused Deposition Modeling (FDM) 344</p> <p>14.2.2 Direct InkWriting (DIW) 345</p> <p>14.2.3 Inkjet 347</p> <p>14.2.4 Projection Stereolithography (pSLA) 348</p> <p>14.3 Soft Active Materials for 4D Printing 349</p> <p>14.3.1 Shape Memory Polymers 349</p> <p>14.3.2 Hydrogels 354</p> <p>14.3.3 Other SAMs 356</p> <p>14.4 Biomedical Applications of 4D Printing 358</p> <p>14.4.1 Temperature-Actuated 4D Printing 358</p> <p>14.4.2 Humidity-Actuated 4D Printing 363</p> <p>14.5 Conclusion and Outlook 365</p> <p>References 366</p> <p><b>15 Current Trends and Challenges in Biofabrication Using Biomaterials and Nanomaterials: Future Perspectives for 3D/4D Bioprinting 373<br /></b><i>Luciano P. Silva</i></p> <p>15.1 Introduction 373</p> <p>15.2 Biofabrication as a Multidisciplinary to Interdisciplinary Research Field 375</p> <p>15.3 Biofabrication as a Multifaceted Approach 377</p> <p>15.4 Biofabrication Beyond Biomedical Pharmaceutical Applications 377</p> <p>15.5 The Diversity of Techniques Used in Biofabrication 378</p> <p>15.6 Natural Resources as Sources of Biomaterials Useful for Biofabrication 380</p> <p>15.7 Nanomaterials as Much More Than Just New Building Blocks for Biofabrication 382</p> <p>15.8 3D Bioprinting as the New Gold Standard for Biofabrication 383</p> <p>15.9 When 3D Bioprinting Is Not Sufficient for Bioconstruction: 4D Bioprinting 385</p> <p>15.10 An Overview about Current Bottlenecks in Biofabrication 385</p> <p>15.10.1 Does 3D Model Matter in Biofabrication? 386</p> <p>15.10.2 Does Size and Time Matter in Biofabrication? 386</p> <p>15.10.3 Do Choice Materials and Cells Matters in Biofabrication? 387</p> <p>15.10.4 Does Maturation of the Bioconstructs Matter in Biofabrication? 387</p> <p>15.10.5 Do CharacterizationMethods Matters in Biofabrication? 388</p> <p>15.10.6 Does Economic and Social Impact Matter Biofabrication? 388</p> <p>15.10.7 Does Ethical and Legal Issues Matter in Biofabrication? 389</p> <p>15.11 Conclusion 390</p> <p>References 390</p> <p><b>16 Orthopedic Implant Design and Analysis: Potential of 3D/4D Bioprinting 423<br /></b><i>Chang JiangWang and Kevin B. Hazlehurst</i></p> <p>16.1 Orthopedic Implant Design with 3D Printing 423</p> <p>16.1.1 Bone Properties and Orthopedic Implants 423</p> <p>16.1.2 3D Printing and Porous Implant Design 426</p> <p>16.2 Analysis of 3D Printed Orthopedic Implants 428</p> <p>16.2.1 Mechanical Properties of Porous Structures 429</p> <p>16.2.2 Experimental Testing of 3D Printed Femoral Stems 433</p> <p>16.2.3 Finite Element Analysis of Porous Stems with 3D Printing 435</p> <p>16.3 3D Printed Orthopedic Implant Installation and Instrumentation 437</p> <p>16.4 Orthopedic Implants Manufactured with 4D Printing 439</p> <p>16.5 Summary 439</p> <p>References 440</p> <p><b>17 Recent Innovations in Additive Manufacturing across Industries: 3D Printed Products and FDA’s Perspectives 443<br /></b><i>Brett Rust, Olga Tsaponina, andMohammedManiruzzaman</i></p> <p>17.1 Introduction 443</p> <p>17.2 CurrentWidely Used Processes across Industries 443</p> <p>17.2.1 Fused Deposition Modeling (FDM) 443</p> <p>17.2.2 Stereolithography (SLA) and Digital Light Processing (DLP) 444</p> <p>17.2.3 Selective Laser Sintering (SLS) 445</p> <p>17.3 Emerging 3D Printing Processes and Technologies 446</p> <p>17.3.1 Continuous Liquid Interface Production (CLIP) 446</p> <p>17.3.2 Multi Jet Fusion (MJF) 446</p> <p>17.4 Industry Uses of AdditiveManufacturing Technologies 447</p> <p>17.5 Material and Processes for Medical and Motorsport Sectors 449</p> <p>17.6 Medical Industry Usage and Materials Development 452</p> <p>17.7 3D Printing of Medical Devices: FDA’s Perspectives 455</p> <p>17.7.1 FDA’s Role in 3D Printing of Materials 455</p> <p>17.7.2 Classifications of Medical Devices from FDA’s Viewpoint 456</p> <p>17.7.3 Medical Applications of 3D Printing and FDA’s Expectations 457</p> <p>17.7.4 Person-Specific Devices 458</p> <p>17.7.5 Process of 3D Printing of Various Medical Devices 458</p> <p>17.7.6 Materials Used in 3D Printed Devices Overall 459</p> <p>17.7.7 Materials Used in Specific Application (Printed Dental Devices) 460</p> <p>17.8 Conclusions 461</p> <p>References 461</p> <p>Index 463</p>

<p><b>Mohammed Maniruzzaman, PhD,</b> 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.</p>

<p><b>A professional guide to 3D and 4D printing technology in the biomedical and pharmaceutical fields</b> <p><i>3D and 4D Printing in Biomedical Applications</i> 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 shape memory polymers, 4D bio-fabrications and bone printing. <p>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: <ul> <li>Offers a comprehensive guide to 3D and 4D printing technology in the biomedical and pharmaceutical fields</li> <li>Includes information on the first 3D printing platform to get FDA approval for a pharmaceutical product</li> <li>Contains a review of the current 3D printed pharmaceutical products</li> <li>Presents recent advances of novel materials for 3D/4D printing and biomedical applications</li> </ul> <p>Written for pharmaceutical chemists, medicinal chemists, biotechnologists, pharma engineers, <i>3D and 4D Printing in Biomedical Applications</i> explores the key aspects of the printing of medical and pharmaceutical products and the challenges and advances associated with their development.

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