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Cover
Preface
1 3D/4D Printing in Additive Manufacturing: Process Engineering and Novel Excipients
1. 1.1 Introduction
2. 1.2 The Process of 3D and 4D Printing Technology
3. 1.3 3D/4D Printing for Biomedical Applications
4. 1.4 Smart or Responsive Materials for 4D Biomedical Printing
5. 1.5 Classification of 3D and 4D Printing Technologies
6. 1.6 Conclusions and Perspectives
7. References
2 3D and 4D Printing Technologies: Innovative Process Engineering and Smart Additive Manufacturing
1. 2.1 Introduction
2. 2.2 Types of 3D Printing Technologies
3. 2.3 FDM 3D Printing Technology
4. 2.4 Hot Melt Extrusion Technique to Produce 3D Printing Polymeric Filaments
5. 2.5 Smart Medical Implants Integrated with Sensors
6. 2.6 4D Printing and Future Perspectives
7. 2.7 Regulatory Aspects
8. 2.8 Conclusions
9. References
3 3D Printing: A Case of ZipDose® Technology – World's First 3D Printing Platform to Obtain FDA Approval for a Pharmaceutical Product
1. 3.1 Introduction
2. 3.2 Terminology
3. 3.3 Historical Context for This Form of 3D Printing
4. 3.4 ZipDose® Technology
5. 3.5 3D Printing Machines and Pharmaceutical Process Design
6. 3.6 Development of SPRITAM®
7. 3.7 Conclusion
8. Acknowledgments
9. References
4 Manufacturing of Biomaterials via a 3D Printing Platform
1. 4.1 Additive Manufacturing and Bioprinting
2. 4.2 Bioinks
3. 4.3 3D Bioprinting Systems
4. 4.4 Applications
5. 4.5 Steps Necessary for Broader Application
6. References
5 Bioscaffolding: A New Innovative Fabrication Process
1. 5.1 Introduction: From Bioscaffolding to Bioprinting
2. 5.2 Scaffolding
3. 5.3 Bioprinted Scaffolds
4. 5.4 Applications of Bioscaffolder and Bioprinting Systems
5. 5.5 Conclusion
6. References
6 Potential of 3D Printing in Pharmaceutical Drug Delivery and Manufacturing
1. 6.1 Introduction
2. 6.2 Pharmaceutical Drug Delivery
3. 6.3 Conventional Manufacturing vs 3D Printing
4. 6.4 Advanced Applications for Improved Drug Delivery
5. 6.5 Instrumentations
6. 6.6 Location of 3D Printing Manufacturing
7. 6.7 Regulatory Aspects
8. 6.8 Summary
9. References
7 Emerging 3D Printing Technologies to Develop Novel Pharmaceutical Formulations
1. 7.1 Introduction
2. 7.2 FDM 3D Printing
3. 7.3 Pressure‐Assisted Microsyringe
4. 7.4 SLA 3D Printing
5. 7.5 Powder Bed 3D Printing
6. 7.6 SLS 3D Printing
7. 7.7 3D Inkjet Printing
8. 7.8 Conclusions
9. References
8 Modulating Drug Release from 3D Printed Pharmaceutical Products
1. 8.1 Introduction
2. 8.2 Pharmaceutically Used 3D Printing Processes and Techniques
3. 8.3 Modifying the Drug Release Profile from 3D Printed Dosage Forms
4. 8.4 Conclusion
5. References
9 Novel Excipients and Materials Used in FDM 3D Printing of Pharmaceutical Dosage Forms
1. 9.1 Introduction
2. 9.2 Biodegradable Polyester
3. 9.3 Polyvinyl Polymer
4. 9.4 Cellulosic Polymers
5. 9.5 Polymethacrylate‐Based Polymers
6. 9.6 Conclusion
7. References
10 Recent Advances of Novel Materials for 3D/4D Printing in Biomedical Applications
1. 10.1 Introduction
2. 10.2 Materials for 3DP
3. 10.3 Rheology
4. 10.4 Ceramics for 3D Printing
5. 10.5 Polymers and Biopolymers for 3D Printing
6. 10.6 4D Printing
7. 10.7 3D and 4D Printed Bone Scaffolds with Novel Materials
8. 10.8 Future and Prospects
9. References
11 Personalized Polypills Produced by Fused Deposition Modeling 3D Printing
1. 11.1 Introduction
2. 11.2 Polypharmacy and Polypills
3. 11.3 FDM 3D Printing of Pharmaceutical Solid Dosage Forms
4. 11.4 Key Challenges in the Development of FDM 3D Printed Personalized Polypills
5. 11.5 Conclusions and Future Remarks
6. References
12 3D Printing of Metallic Cellular Scaffolds for Bone Implants
1. 12.1 Introduction
2. 12.2 Metal 3D Printing Techniques for Bone Implants
3. 12.3 Biometals for Bone Implants
4. 12.4 Cellular Structure Design
5. 12.5 Outlook
6. References
13 3D and 4D Scaffold‐Free Bioprinting
1. 13.1 Introduction
2. 13.2 3D Scaffold‐Free Bioprinting
3. 13.3 4D Bioprinting
4. 13.4 4D Scaffold‐Free Bioprinting
5. 13.5 Conclusion
6. Acknowledgments
7. References
14 4D Printing and Its Biomedical Applications
1. 14.1 Introduction
2. 14.2 3D Printing Technologies with Potential for 4D Printing
3. 14.3 Soft Active Materials for 4D Printing
4. 14.4 Biomedical Applications of 4D Printing
5. 14.5 Conclusion and Outlook
6. References
15 Current Trends and Challenges in Biofabrication Using Biomaterials and Nanomaterials: Future Perspectives for 3D/4D Bioprinting
1. 15.1 Introduction
2. 15.2 Biofabrication as a Multidisciplinary to Interdisciplinary Research Field
3. 15.3 Biofabrication as a Multifaceted Approach
4. 15.4 Biofabrication Beyond Biomedical Pharmaceutical Applications
5. 15.5 The Diversity of Techniques Used in Biofabrication
6. 15.6 Natural Resources as Sources of Biomaterials Useful for Biofabrication
7. 15.7 Nanomaterials as Much More Than Just New Building Blocks for Biofabrication
8. 15.8 3D Bioprinting as the New Gold Standard for Biofabrication
9. 15.9 When 3D Bioprinting Is Not Sufficient for Bioconstruction: 4D Bioprinting
10. 15.10 An Overview About Current Bottlenecks in Biofabrication
11. 15.11 Conclusion
12. References
16 Orthopedic Implant Design and Analysis: Potential of 3D/4D Bioprinting
1. 16.1 Orthopedic Implant Design with 3D Printing
2. 16.2 Analysis of 3D Printed Orthopedic Implants
3. 16.3 3D Printed Orthopedic Implant Installation and Instrumentation
4. 16.4 Orthopedic Implants Manufactured with 4D Printing
5. 16.5 Summary
6. References
17 Recent Innovations in Additive Manufacturing Across Industries: 3D Printed Products and FDA's Perspectives
1. 17.1 Introduction
2. 17.2 Current Widely Used Processes Across Industries
3. 17.3 Emerging 3D Printing Processes and Technologies
4. 17.4 Industry Uses of Additive Manufacturing Technologies
5. 17.5 Material and Processes for Medical and Motorsport Sectors
6. 17.6 Medical Industry Usage and Materials Development
7. 17.7 3D Printing of Medical Devices: FDA's Perspectives
8. 17.8 Conclusions
9. References
Index
End User License Agreement

List of Tables

Chapter 01
1. Table 1.1 Examples of smart or responsive materils suitable for biomedical purposes.
2. Table 1.2 Variables that can affect mechanical properties of printed materials.
Chapter 02
1. Table 2.1 Material properties of ABS and PLA.
Chapter 06
1. Table 6.1 Features and limitations of conventional manufacturing vs 3D printing.
2. Table 6.2 Exemplary instrumentation for pharmaceutical 3D printing using additive manufacturing (fused deposition modeling).
Chapter 07
1. Table 7.1 Summary of research papers utilizing FDM 3D printing for the production of pharmaceutical formulations.
Chapter 08
1. Table 8.1 Three‐stage formulation strategy according to Zhang et al. [13].
Chapter 09
1. Table 9.1 Cases of FDM 3D printing based on various polymers.
2. Table 9.2 Physicochemical properties of pharmaceutical polymers in FDM 3D printing.
3. Table 9.3 Chemical structure, glass transition temperature, and thermal degradation temperature of AquaSolve™ HPMCAS.
4. Table 9.4 Molecular weight, T _g measured at 20 °C min⁻¹ heating rate, T _max for functional groups at a residence time of 4.5 minutes, and extrusion temperature of Eudragit® polymers.
Chapter 10
1. Table 10.1 Raw ceramic materials with particle size and mechanical strength used in the 3D printing process.
2. Table 10.2 Materials used for 3D printing of particle‐reinforced polymer composites and their property improvements.
3. Table 10.3 Materials used for 4D printing with potential of applications to biomedical engineering and their characteristics.
4. Table 10.4 Intelligent materials type and their actions.
5. Table 10.5 Glass transition temperatures of some selected polymers used in 3D/4D printing.
6. Table 10.6 3D printed materials with binders for bone tissue engineering.
Chapter 11
1. Table 11.1 Potential advantages of 3D printing in drug manufacturing.
2. Table 11.2 Summary of the CPPs that could affect a FDM 3D printing process.
3. Table 11.3 Summary of polymer blends using pharmaceutical grand excipients.
Chapter 12
1. Table 12.1 A comparison on various metal 3D printing techniques [8].
2. Table 12.2 A comparison between SLM and SEBM processes [7, 8].
3. Table 12.3 A comparison of mechanical properties between bone tissue and some popular biometals [3, 12, 14, 16, 17].
Chapter 16
1. Table 16.1 Cellular structures for compression testing [12].
2. Table 16.2 Femoral stems with cellular structures for 3D printing.

List of Illustrations

Chapter 01
1. Figure 1.1 Schematic of 1D, 2D, 3D, and 4D printing dimensions. In a 4D system, a 3D printed object undergoes time‐dependent deformations when exposed to various stimuli.
2. Figure 1.2 (A) Schematic diagram illustrating the reversible self‐folding of soft microgrippers in response to temperature. (B) Self‐tightening of a PLA staple. (I) Concept. (a) Original shape of a staple; (b) after programming; (c) after being fired into tissue; (d) after heating for tightening; (II) experimental result (Insorb® staple). Top: shrinking of staple upon heating; bottom: tightening of staple upon heating to bring two pieces of tissue closer. (C) Schematic of soybean‐oil‐epoxidized acrylate fabrication process from raw material through resin fabrication and application. (D) Schematic diagram illustrating the proposed soft microrobot, which can move freely by magnetic fields. Trapping and releasing of drug microbeads at the destination target by folding and unfolding motions is triggered by different pH values. (E) Schematic diagram illustrating the osmotic‐pressure‐driven deformation. Side view schematic of the three basic PEG bilayer photo‐crosslinking steps (a–c) and examples of self‐folded hydrogel geometries (d–i). (Source: Jamal et al. 2013 [20]. Reproduced with permission of John Wiley & Sons.)
3. Figure 1.3 Overview of material types used with specific layer building methods in 3D/4D printing.
4. Figure 1.4 Schematic of FFF process.
5. Figure 1.5 (a) Hot melt extrusion of hydroxypropylcellulose (HPC) filaments suitable for FFF. (b) Polymer relaxation (die swell) of HPC after leaving the extrusion die. (c) HPC filaments varying in diameter (<1.8 mm).
6. Figure 1.6 Schematic illustration of 3D printing by PBP.
7. Figure 1.7 Schematic illustration of SLA process: (a) bottom‐up process and (b) top‐down process.
8. Figure 1.8 Schematic of SLS process using a CO₂ laser to locally fuse powder particles on the surface of a preheated build chamber that is incrementally lowered as the process progresses.
Chapter 02
1. Figure 2.1 Mechanism of an SLA 3D printer.
2. Figure 2.2 Mechanism of powder‐based 3D printing: (a) powder bed system; (b) powder jetting system.
3. Figure 2.3 Mechanism of selective laser sintering (SLS).
4. Figure 2.4 Mechanism of fused deposition modeling (FDM) and Makerbot Replicator 2X, a dual‐extruder FDM 3D printer.
5. Figure 2.5 Mechanism of semisolid extrusion (EXT) 3D printing.
6. Figure 2.6 Schematic diagram of thermal inkjet printing.
7. Figure 2.7 Hot melt extrusion process [33].
8. Figure 2.8 4D printed stent [45].
9. Figure 2.9 Linear stretching primitive. Assembly of rigid disks with expanding materials in the middle. Adjusting the ratio of expanding materials to the rigid disks can control the length of stretching. Linear expansion in the presence of water over time [49].
10. Figure 2.10 Ring stretching. Expansion of a ring shape into a bar. Stretching length can be adjusted by controlling the radius of the ring [49].
11. Figure 2.11 Folding action of the structure [49].
12. Figure 2.12 Biomimetic 4D printing.
13. Figure 2.13 Additive manufacturing of polymer‐derived ceramics.
14. Figure 2.14 4D printed flower that self‐opens upon heat stimulation.
Chapter 03
1. Figure 3.1 Dose loading of active ingredients for prescription ODTs in the US market.
2. Figure 3.2 Illustration of dose loading and total mass in ZipDose units as compared to the largest prescription ODTs in the USA.
3. Figure 3.3 Simplified process schematic for pharmaceutical manufacturing using 3D printing as the forming step.
4. Figure 3.4 Photo of dosage forms after printing and drying (contrast enhanced).
5. Figure 3.5 Photo of dosage forms after harvesting.
6. Figure 3.6 Side view schematic of Aprecia's 3D printing process.
7. Figure 3.7 Top view schematic of Aprecia's “M0” 3D printing machine.
8. Figure 3.8 Photo of Aprecia's “M0” 3D printing machine.
9. Figure 3.9 Photo showing the top view of all the four strengths of SPRITAM.
Chapter 04
1. Figure 4.1 Printability. Several factors can influence the characteristics of a printed filament. These characteristics include the filament diameter, uniformity, overall shape, and behavior at directional changes and in proximity to other filaments. Translation rate and printing pressure are two factors that can have an effect on the resulting filament properties. For example, a too slow translation rate or high pressure can result in a nonuniform filament that is wider than anticipated. In contrast, a fast translation rate and low pressure can result in a noncontinuous filament. In particular, manipulation of the translation rate can be utilized to control filament diameter while keeping the pressure constant. However, at faster translation rates, the fidelity of the printed structure to printing commands can suffer. The physical and chemical characteristics of the bioinks can also have an effect on printability. Although ideally a deposited filament would have a cylindrical shape, in more realistic cases, a deposited filament will form a hemispherical shape on the surface. Bioinks with too low viscosity exhibit poor fidelity and are unstable. Additionally, the shape of the bioink filament immediately after extrusion through a nozzle can exhibit good or poor nozzle fidelity and nonuniformity in shape because of an improper nozzle or overly gelled or nonhomogeneous bioink. Understanding printability is important for minimizing the deposition of irregular filaments that can result in poor printed structures. It is a paramount that the printability of a bioink is well characterized to allow the fabrication of structures comprising of multiple bioinks that have distinct printing characteristics.
2. Figure 4.2 Bioink cross‐linking. Bioinks can be cross‐linked through several different modalities, including ionically, photochemically, and through intrinsic properties such as self‐assembly. Cross‐linking is necessary to impart stability on a deposited filament so that complex structures can be bioprinted and remain stable during culture and tissue development.
3. Figure 4.3 Bioprinting modalities. The several prevalent additive bioprinting modalities include filament extrusion‐based techniques, droplet deposition‐based techniques such as microsphere deposition and inkjet printing, and laser‐assisted bioprinting.
4. Figure 4.4 Bio X diagram. The Bio X bioprinter system contains several advanced features that facilitate the fabrication of multifaceted structures. Modular printheads allow flexibility in the types of bioinks that can be printed and the use of more precise printing parameters that allows better control over printability. The incorporation of printbed that can be either heated or cooled allows optimization of the post‐deposition environment to better maintain filament fidelity or facilitating stabilization through cross‐linking. The incorporation of dual‐layer HEPA filters in conjugation with the closed front allows for the preservation of sterility and the maintenance of a clean chamber environment for bioprinting of cells on the benchtop or ensuring the minimization of particulates into the bioprinted construct. Finally, intelligent software that can adjust printing parameters as fabrication is occurring to result in better optimized constructs is necessary for quality control and better reproducibility between prints.
5. Figure 4.5 Modular printheads. Modular printheads allow the use of multiple printing techniques and diverse bioinks within a singular construct. Each printhead has advantages and disadvantages in its use to fabricate a construct. Heated pneumatic printheads allow the printing of thermosensitive bioinks such as gelatin, GelMA, agar, and pluronics and also allow the maintenance of bioink temperature at physiological levels to improve cell viability during printing. A printhead that can heat up to high temperatures such as 250 °C allows the printing of thermoplastics such as biocompatible materials such as PCL, PLGA, and PVA. Alternatively, one could utilize a printhead such as a heated filament extrusion head that mimics traditional 3D printing. A cooled pneumatic printhead allows the deposition of thermosensitive bioinks such as collagens and decellularized ECMs such as Matrigel that self‐assemble at room temperature but can be printed at a low temperature. A mechanical extrusion‐based printhead can be utilized to deposit very small volumes such as those necessary for droplets or fluid dispensing. An inkjet printhead may be utilized for the deposition of thin layers of bioinks. Finally, other printheads could be developed that do not print materials but aid in cross‐linking of other materials or facilitate analysis of printed structures such as through optical imaging.
6. Figure 4.6 Multimaterial filaments. Specially designed printheads and nozzles permit the formation of filaments that can contain several types of bioinks in specific arrangements. These specialized nozzles can generate filaments more complicated than the single‐material filaments, with structures such as dual or triple material, block structure arrangements, core sheath, or gradient arrangements. These multimaterial filaments can enhance constructs or enable gradients that can better recapitulate native tissue architecture.
7. Figure 4.7 Patterning (a) and vascular structures (b). Bioprinting can be utilized to fabricate complicated structures that better mimic native tissue microarchitecture. Advanced bioprinter systems can fabricate constructs that can contain both patterned extracellular matrix and cells along with conduits that can guide the formation of a vascular network. The generation of these advanced microarchitectures within a bioprinted construct is necessary for the development of mature tissues. Additionally, the incorporation of sacrificial bioinks can be utilized to generate vascular networks that can either be used to perfuse the construct or act as a base for vasculogenesis or angiogenesis through continuous or noncontinuous channels and branched networks.
8. Figure 4.8 Personalized medicine. The maturation of the bioprinting field will permit the technology's use as a tool for the fabrication of constructs for personalized medicine applications. One such application may be the use of bioprinting to fabricate patient‐specific constructs based on clinical data such as biologically active bone grafts or constructs that reverse scarring of cardiac tissue.
Chapter 05
1. Figure 5.1 Automated printing process of a 3D structure of a human ear‐mimicking target tissue obtained from a CAD model developed from medical image data.
2. Figure 5.2 3D plotted scaffolds in clinically relevant dimensions with metabolically active (MTT staining, dark violet) hMSC, encapsulated in alginate–methyl cellulose bioink, compared to an empty non‐cell‐laden scaffold (upper left), bar = 1 mm.
3. Figure 5.3 Alginate–methyl cellulose–laponite blend as a versatile bioink for the fabrication of constructs of varying shape and of clinically relevant dimensions (a). Cubic scaffolds of 30, 20, and 10 strand layers (b), with open macropores, bar = 2 mm (c).
4. Figure 5.4 GeSiM BioScaffold Printer 3.2: Printhead with different tools for multimaterial scaffolds.
5. Figure 5.5 Multimaterial scaffold. Schematic scaffold design of alternating CPC (gray) and cell‐laden hydrogel strands (red) (a). MTT 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide staining for metabolically active cells inside the hydrogel strands, bar = 3 mm (b). Viability of encapsulated hMSC after 21 days of cultivation (>90%), viable cells labeled green (Calcein AM), dead cells labeled red (ethidium homodimer‐1), green autofluorescence of CPC strands, bar = 3 mm (c).
6. Figure 5.6 Schematic representation illustrating core–shell scaffold fabrication model. (a) Cross section of the coaxial needle. (b) Extruded core–shell strand. (c) Fabrication of a core–shell scaffold.
7. Figure 5.7 3D printed scaffolds of alginate/HAP core–shell scaffolds. (a) Scaffolds from left to right; mineralized alginate (pH 9.5), mixed alginate/HAP, and pure alginate. (b) Mineralized alginate with an inset showing core–shell morphology of cross‐sectional view. (c) Mixed alginate/HAP. Scale bars: a, millimeters and b–e, 500 µm [55].
8. Figure 5.8 Technical equipment used during 3D printing process for solidification/gelation processes. (a) Scaffold fabrication by core–shell nozzle with an aerosol spraying device of CaCl₂ solution [58]. (b) Diagram of a 3D printed system with a heating film on the nozzle and a cooling deposition platform to fix the extruded bioink [21]. (c) Deposition of partially cross‐linked alginate hydrogel being submerged into CaCl₂ bath to create better support for upcoming layers [59].
9. Figure 5.9 Piezoelectric pipet at GeSiM BS3.2 instrument: Twin‐tip pipet for mixing drops of two liquids (a); single‐tip pipet (b).
10. Figure 5.10 CT data extraction and translation to a STL file (a) to design and additively fabricate a human scaphoid bone from pasty CPC in actual physiological dimensions (b) after using open source software. Fabrication via layer‐by‐layer strand deposition, bar = 2 mm (c) [74].
11. Figure 5.11 Illustration of thermoresponsive self‐folding capsule. (A) A scheme of a star‐shaped polymer bilayer containing cells that fold upon swelling at a lower temperature. (B) The self‐folding capsules (dark field optical microscopy). Capsules containing cells are folded because of swelling at low temperature (b,d). Upon heating, unfolding of capsule and release of cells take place (a,c).
Chapter 06
1. Figure 6.1 Therapeutic aspects and personal preferences by the patient, which can be considered in an individual printed drug delivery system.
2. Figure 6.2 Example for a conventional and printing process.
3. Figure 6.3 Two scenarios for 3D printing on demand.'
Chapter 07
1. Figure 7.1 (a) and (b) Rendered images (Autodesk® 3DS Max) of shell–core designs with increasing shell thicknesses (0.17, 0.35, 0.52, 0.70, and 0.87 mm). (c) Images of 30% completed shell–core designs with theophylline core and increasing Eudragit L100‐55 shell thickness.
2. Figure 7.2 (a) Schematic illustration concept of perforating square‐sectioned channels. The perforating channels were at right angle with the long axis with 3D max rendered images of frontal, side, and top view of channeled tablet designs. (b) Rendered images of tablet designs with decreasing channel size with 18‐short channels. (c) Photographs of tablets with decreasing channel size of 18‐short channels.
3. Figure 7.3 (a) Makerware®.stl model of 3D PVA‐PLA three‐compartment hollow cylinder formulation with inner binding PLA ring. (b) Design depicting characteristic dimensions (h, r ₀, r ₁) of 3D PVA‐PLA formulations, (c) 3D printed three‐compartment PVA‐PLA printed dosage form. (d) Half‐constructed 3D printed three‐compartment PVA‐PLA dosage form with inner binding PLA ring.
4. Figure 7.4 Illustration of the polypill structural design, incorporating the aspirin and hydrochlorothiazide in the immediate release compartment, and atenolol, pravastatin, and ramipril in the sustained release compartments.
5. Figure 7.5 Illustration of the layers forming the breakaway tablet.
6. Figure 7.6 Images of inkjet printed tablets with honeycomb patterns. (a) Photographs illustrating various honeycomb cell sizes between 0.20 and 1.83 mm. (b) µCT images of the honeycomb configuration 58.
Chapter 08
1. Figure 8.1 Common modified release approaches for solid oral dosage forms.
2. Figure 8.2 The release profiles of printed disks with a diameter of 10 mm and a height of 2 mm over 45 days (a) and planktonic growth inhibition over seven days induced by printed disks (b). Samples with 30%, 20%, and 10% nitrofurantoin are shown as solid diamonds, squares, and circles. Samples containing the same amount of nitrofurantoin and an additional 5% of hydroxyapatite are shown as the corresponding open symbols. Phosphate‐buffered saline pH 7.4 at 37 °C; n = 3, mean ± SD.
3. Figure 8.3 Extrudates (a), FFF printed hollow cylinders in side view (b), and fluorescence microscopic images of printed cylinders from the top (c).
4. Figure 8.4 Dissolution curves of hollow cylinders consisting of 5% quinine and Eudragit RS (a), PCL (b), PLLA (c), and EC with additional 35% of triacetin (d). Phosphate‐buffered saline pH 7.4 at 37 °C, sink conditions; n = 3, mean ± SD.
5. Figure 8.5 Dissolution profiles of 3D printed tablets (3DP), tablets compressed from milled extrudates (EXT), and physical mixtures (PM). The composition is shown in Table 8.1. Simulated intestinal fluid without pancreatin, pH 6.8 at 37 °C; n = 3, mean ± SD.
6. Figure 8.6 Dissolution profiles of tablets prepared by SLS. Tablets contained 5%, 20%, and 35% of paracetamol, 3% of Candurin gold sheen, and Kollicoat IR. In the legend, K stands for Kollicoat IR and the number for the API percentage. pH was adapted according to the red line at 37 °C. n = 3, mean ± SD.
7. Figure 8.7 SLA printed tablets containing approximately 5% API with decreasing amounts of PEG diacrylate and increasing amounts of PEG 300 (left to right) with paracetamol (a) and 4‐aminosalicylic acid (b).
8. Figure 8.8 CAD designs of printed objects.
9. Figure 8.9 Dissolution profiles of printed geometries with constant surface area (a) and constant surface‐to‐volume ratio (b). Phosphate buffer pH 6.8, 37 °C, sink conditions. n = 3, mean ± SD.
10. Figure 8.10 DoD 3D printed tablets with different infill patterns. The diameter of the honeycomb cells is indicated in the top left corner of every image.
11. Figure 8.11 Drug dissolution profiles of printed tablets according to their cell diameter (a) and fit of the developed numerical model (b).
12. Figure 8.12 API release from DoP printed dosage forms with increasing amounts of polymer content. 0.1 N HCl for 1 h followed by a medium change to pH 7.5 phosphate buffer at 37 °C.
13. Figure 8.13 Compartmentalized tablet design (a) and dissolution curves of powder‐printed tablets (b). 0.1 N HCl for 1 h followed by a medium change to pH 7.5 phosphate buffer at 37 °C.
14. Figure 8.14 DDD design (a) and dissolution profiles of DDDs with increasing aperture diameters from F1 = 0.5 mm to F4 = 2.0 mm (b). Phosphate buffer pH 6.8; n = 6, mean ± SD.
15. Figure 8.15 Core–shell design (a) and dissolution profiles of tablets containing acetaminophen in the shell and caffeine in the inner core (b). pH was adapted according to the red line at 37 °C. n = 3, mean ± SD.
16. Figure 8.16 Renders of shell–core design with increasing shell thickness (a,b), images of tablets after printing 30% of the dosage forms (c), SEM images of tablets surfaces (d), and release profiles of theophylline (e). n = 3, mean ± SD; 2 h at pH 1.2 followed by 4 h at pH 6.8 at 37 °C.
17. Figure 8.17 Design of five‐in‐one dosage form with modified release properties (a) and the dissolution profiles (b). Phosphate buffer pH 6.8 at 37 °C. n = 3, mean ± SD.
Chapter 09
1. Figure 9.1 Schematic illustration of a FDM 3D printer.
2. Figure 9.2 Filament properties during 3D printing process. (a) Filaments very brittle; (b) filaments good for printing; and (c) filaments very soft.
3. Figure 9.3 Chemical structure of PLA.
4. Figure 9.4 Chemical structure of PCL.
5. Figure 9.5 Chemical structure of PVA.
6. Figure 9.6 3D representation of the printed solid dosage forms and the corresponding Raman mapping: (middle‐up) sectioned multilayer device and (middle‐down) sectioned DuoCaplet (caplet in caplet).
7. Figure 9.7 Chemical structure of EVA.
8. Figure 9.8 Chemical structure of PVP.
9. Figure 9.9 Chemical structure of Soluplus®.
10. Figure 9.10 Chemical structure of HPC.
11. Figure 9.11 Chemical structure of HPMC.
12. Figure 9.12 Chemical structure of HPMCAS.
13. Figure 9.13 Chemical structure of Eudragit® RL/RS (R₁ = H, R₂ = C₂H₅, R₃ = C₂H₅N(CH₃)₃Cl⁻; RL: n ₁:n ₂:n ₃ = 1 : 2 : 0.2; RS: n ₁:n ₂:n ₃ = 1 : 2 : 0.1).
14. Figure 9.14 Chemical structure of Eudragit® L100‐55 (n ₁:n ₂ = 1 : 1).
15. Figure 9.15 Chemical structure of Eudragit® EPO (R₁ = CH₃, R₂ = C₄H₉, R₃ = C₂H₅N(CH₃)₂, n ₁:n ₂:n ₃ = 1 : 1 : 2)
Chapter 10
1. Figure 10.1 Multishape memory effect from 2D to 3D by self‐bending in a smart trestle [56].
2. Figure 10.2 Multishape memory effect from 2D to 3D by self‐bending in an active helix shape [56].
3. Figure 10.3 The typical programming steps for SMPs and the desired response [56].
4. Figure 10.4 Mechanical spectra of k‐carrageenan/AAm pre‐gel solution at a constant frequency of 1 Hz (a) temperature ramp from 70 °C to 20 °C; (b) the elastic and the viscous modulus; and (c) complex viscosity as a function of time and temperature.
5. Figure 10.5 A 4D‐printed, thermoresponsive stent, which is able to reversibly change its diameter and height [62].
Chapter 11
1. Figure 11.1 Illustration of an example of personalized polypills produced and dispensed by FDM 3D printing at the point of care.
2. Figure 11.2 (a) Illustration of the Fuster‐CNIC‐Ferrer CV Polypill (Trinomia®, Sincronium®, and Iltria®) technology and (b) challenges faced by the development of polypills containing multiple drugs.
3. Figure 11.3 (a) Schematic of FDM 3D printing. (b) Illustration of FDM layer by layer building of a printed object.
4. Figure 11.4 The 3D design of layered disks FDM 3D printed using different levels of infills.
5. Figure 11.5 The effects of printing temperature (a–c), build plate temperature (d–f), and the head speed (g–i) on the layer thickness of triple‐layered FDM 3D printed disks. x‐Axes are temperature (°C) for a–f and head speed (mm s⁻¹) for g–i; y‐axes are the printed layer thickness (μm). The blue data points are the height of the printed strips and the red data points are the width of the printed strips (A. Brochard, M. Alhijjaj, S. Qi, unpublished lab report data, 2015).
6. Figure 11.6 Illustration of the effect of printing resolution on the precision of the edges of the printed products.
7. Figure 11.7 Schematic illustration of FDMe fabrication process of solid dosage forms.
8. Figure 11.8 The light microscopy images of FDM 3D printed triple‐layered patches with 50% infill using ABS. (a) Bottom layer, (b) middle layer, (c) top layer, and (d) the cross section of the patch containing all the three layers (A. Brochard, M. Alhijjaj, S. Qi, unpublished lab report data, 2015).
Chapter 12
1. Figure 12.1 Essential requirements for bone implants.
2. Figure 12.2 Schematic of an SLM system.
3. Figure 12.3 Schematic of an Arcam EBM system.
4. Figure 12.4 Structural density design of cellular topology in scaffolds.
5. Figure 12.5 Scaffold design for bone implants.
6. Figure 12.6 Classification of cellular structure in terms of cellular forms and their deformation behavior.
7. Figure 12.7 CAD models (a–d) of SEBM‐fabricated bone implant prototypes with gradient in porosity from inside to outside.
Chapter 13
1. Figure 13.1 Schematic overview of biomaterial‐free cardiac 3D bioprinting process. (a) Cells (CMs, FBs, and ECs) are aggregated in ultralow attachment 96‐well plates to form cardiospheres. (b) The desired 3D structure to be bioprinted is designed using computer software. (c) The 3D bioprinter picks up individual cardiospheres using vacuum suction and loads them onto a needle array. (d) Cardiospheres are allowed to fuse. The 3D bioprinted cardiac tissue is then removed from the needle array and cultured further to allow the needle holes to be filled in by the surrounding tissue (Reproduced from [5]).
2. Figure 13.2 Cell type, number, and ratio determine the cardiosphere integrity. (a,b) hiPSCs (100%) (a) and hiPSC‐CMs (100%) (b) do not form spheroids after 48 hours in ultralow attachment 96‐well plates (top 10 000 cells/well; bottom 40 000 cells/well). (c,d) hiPSC‐CM:FB:EC ratio 70 : 15 : 15 (c) and 45 : 45 : 10 (d) cardiospheres form in 24 hours and start beating in 48 hours. Scale bar panels: a–d : 400 µm. (e–g) The beating rate of cardiospheres composed of hiPSC‐CM:FB:EC ratio of 45 : 40 : 15 (e), 70 : 15 : 15 (f), and 85 : 0 : 15 (g) at various cell numbers per cardiosphere, in beats per minute (bpm). (h,i) The mean diameter (µm) of cardiospheres of various cell ratios (hiPSC‐CM:FB:EC) and various cell numbers, after 3 days (h) and 5 days (i) of culture (Reproduced from [5]).
3. The establishment of appropriate culture conditions for generating a large number of liver budlike spheroids. (a) Microscopic observation of spheroid formation at various ratios of hHeps and HUVECs. hHeps, black; HUVECs, red. (b,c) The morphological analysis of heterospheroid formation at various ratios of hHeps and hMSCs. (b) The microscopic observation of spheroid formation. The addition of hMSCs dramatically promoted hepatocyte aggregation and a single spheroid was generated in two days. (c) The roundness of the heterospheroid at various ratios of hHeps and hMSCs. The results represent mean ± SD; n = 12. (d) The ratios of the spheroids that had a roundness of ≥ 60% at various ratios of hHeps, HUVECs, and hMSCs; n = 16. (e) The secretion of albumin into the culture medium was measured by ELISA. LBSs containing hHeps, HUVECs, and hMSCs at a ratio of 10 : 7 : 3 showed the significantly highest level of albumin secretion. The results represent the mean ± SD; n = 8. (f) The profiles of the optimized spheroid (hHeps:HUVECs:hMSCs at 10 × 10³ : 7 × 10³ : 3 × 10³ cells). Changes in the diameters and roundness of the spheroids and the ratios of the spheroids that had the roundness of ≥ 60%. The results represent the mean ± SD; n = 16. (g) The microscopic observation of spheroid formation using mixtures of the three cells types (hHeps: black; HUVECs: red; and MSCs: green). Scale bar, 300 µm (Reproduced from [9]).
4. Figure 13.4 Cardiosphere dimensions and the degree of cardiosphere overlap determines the structural properties of 3D bioprinted cardiac patches. (a–c) Representative images of 3D bioprinted cardiac patches (CM:FB:EC 70 : 15 : 15) with overlap at least 50 µm (a), some overlap, 1 to 50 µm (b), and no overlap (c), immediately after printing, after decannulation, and after maturation. Scale bar: 1000 µm. (d) Cardiosphere diameters immediately before printing for 3D bioprinted cardiac patches in panels (a) (504.6 ± 30.6 µm) (n = 81), (b) (413.1 ± 21.6 µm) (n = 81), (c) (382.4 ± 16.1 µm) (n = 65) respectively (Reproduced from [5]).
5. Figure 13.5 A phase‐contrast microscopy shows the spheroid morphology of an MCS (a). Spindle to polygonal cells are mixed in the MSC (b). Masson's trichrome staining reveals the extensive collagenous extracellular matrix (ECM) as blue (c). vWF, CD31, and CellTracker Red‐positive vascular endothelial cells are distributed to all parts of the MCS (d–f). SMA and desmin‐positive HASMC intermingle with the other cell types (g,h) (Reproduced from [4]).
6. Figure 13.6 (a) The predesigned 3D tubelike structure. The green spheres represent homogeneous multicellular spheroids that were developed using only human normal dermal fibroblasts. (b) The bio 3D conduit according to the predesigned 3D model. The conduit was cannulated via an 18‐gauge intravenous catheter (SURFLO: NIPRO, Osaka, Japan). Scale bar = 10 mm (Reproduced from [10]).
7. Figure 13.7 (a) The system of lamination of the MCS (Bio‐3D printer) that (b) skewers the MCSs into needle array according to a three‐dimensional structure predesigned on a computer system. (c) It is possible to design a 3D tube‐shaped structure, such as that plotted in green on the workstation computers (Reproduced from Itoh et al., PLOS ONE [4]).
Chapter 14
1. Figure 14.1 Common 3D printing technologies. (a) Fused deposition modeling (FDM), (b) direct ink writing (DIW), (c) inkjet, and (d) projection stereolithography.
2. Figure 14.2 Schematics of FDM 3D printing technology.
3. Figure 14.3 Schematics of Polyjet 3D printing technology of liquid photopolymer, which is jetted on a build tray and then UV cured.
4. Figure 14.4 pSLA 3D bioprinting of a hydrogel‐based hepatic bioconstruct.
5. Figure 14.5 A typical thermomechanical loading–unloading cycle in a SMP application.
6. Figure 14.6 (a) A printed strip in its original shape and results of thermomechanical programming with differing fiber architectures. (b) 3D folding structures mimicking the United States Postal Service (USPS) mailbox. Upon heating, the sheet folds into a box with a self‐locking mechanism [19]. (c) A smart hook consisting of two SMPs with different T_g s [69].
7. Figure 14.7 (a) 3D printed shape memory (SM) Eiffel Tower. (b) 3D printed SM stents. (c) Multimaterial grippers were fabricated with different designs. (d) Demonstration of the transition between as‐printed shape and temporary shape of multimaterial grippers. (e) Snapshots of the process of grabbing an object [71].
8. Figure 14.8 Demonstrations of 4D printing presented by the Skyler Tibbits' research group [20]. (a) The self‐assembly process from a strand to the “MIT” pattern. (b) The design of a folding joint consisting of a layer of white elastomer providing elasticity and a layer of hydrophilic material that swells after water diffusion and causes the bending of the joint. (c) Deformation of a grid into a sinusoidal wave. (d) Deformation of a grid into a hyperbolic surface [20].
9. Figure 14.9 Biomimetic 4D printing (Gladman et al.) [18]. (a) Schematic of the shear‐induced alignment of cellulose fibrils during direct ink writing and subsequent effects on anisotropic stiffness E and swelling strain α. Print path (b), printed structure (c), and resulting swollen structure (d) of a flower demonstrating a range of morphologies inspired by a native orchid. (e) Based on the print path, this orchid architecture exhibits four different configurations: bending, twisting, and ruffling corolla surrounding the central funnel‐like domain (scale bars, 5 mm).
10. Figure 14.10 (a) The direct 4D printing approach exploits the ability to print controlled multimaterial composites to integrate the five steps into a single one (modified from [33]). (b) A buckyball directly transformed from a planar rod mesh upon heating [79]. The buckyball in conventional 3D printing from (c) isometric view and (d) top view needs to be supported by a large amount of the sacrificial material [79].
11. Figure 14.11 Examples of biomedical applications of shape memory polymers. (a) Shape recovery behavior of a poly(D,L‐lactide‐co‐trimethylene carbonate) (PLMC) scaffold fabricated by electrospinning. (b) Compression–heating–compression cycles of a PLA‐based hydroxyapatite (HA) porous scaffold fabricated by FDM 3D printing technology. (c) Recovery of a cardiovascular stent fabricated from PEGDMA by photopolymerization.
12. Figure 14.12 Shape memory cycle of the smart scaffold printed from soybean‐oil‐epoxidized acrylate [93].
13. Figure 14.13 Soft robot assembly printed by DIW technology. (a–f) Fabrication steps of the assembly, including loading a prefabricated microfluidic soft controller into a mold and printing hydrogel inks. (g) The fabricate robot is removed from the mold and inverted to reveal a fully soft, autonomous robot.
Chapter 15
1. Figure 15.1 A word cloud representing the 100 most common terms in the titles and journal names of the 500 works cited in the references section of this chapter.
2. Figure 15.2 Growth in the number of documents available in Google Scholar (including papers, patents, and citations) that were published with the topic query “biofabrication” for 18 years. The line‐fitting shows an exponential growth.
3. Figure 15.3 New proposals of categorized strategies to perform biofabrication processes using different techniques.
4. Figure 15.4 Number of documents available until 5 May 2018 in Google Patents (excluding nonpatent literature) with the topic queries “biofabrication” or “bioprinting” or “tissue printing” or “organ printing.”
5. Figure 15.5 Growth in the number of documents available in Google Scholar (including papers, patents, and citations) that were published with the topic queries “biofabrication” or “bioprinting” or “3D bioprinting” or “4D bioprinting” for 18 years.
6. Figure 15.6 Illustration representing the use of biomaterials and nanomaterials for the biofabrication of human organs. Image: Ella Maru Studio.
Chapter 16
1. Figure 16.1 Cortical and cancellous bone in the proximal femur.
2. Figure 16.2 A 3D printed customized pelvic implant (Suzhou Kangli Orthopedics Instrument).
3. Figure 16.3 Insertion of the 3D printed customized pelvic implant (Suzhou Kangli Orthopedics Instrument).
4. Figure 16.4 Total hip replacement stem with cellular structures.
5. Figure 16.5 (a) 3D printed femoral stem, (b) sectional view showing the internal cellular structures, (c) proximal section of a conceptual fully porous stem [12].
6. Figure 16.6 CoCrMo cellular structures for compression tests [12].
7. Figure 16.7 Micrograph of 0.5 mm struts of a cellular structure with 82.5% volumetric porosity [12].
8. Figure 16.8 Compressive stress and strain curves for cellular structures [12].
9. Figure 16.9 3D printed CoCrMo femoral stems manufactured for experimental tests [12].
10. Figure 16.10 Experimental bending test of a 3D printed femoral stem [12].
11. Figure 16.11 Load–displacement curves from the bending tests [12].
12. Figure 16.12 Finite element model used for analyzing a 3D printed porous femoral stem [12].
13. Figure 16.13 Von Mises stress (MPa) in the proximal femur: results from a fully dense femoral stem (a) and a fully porous stem (b). [12].
14. Figure 16.14 Femoral distal end personal specific instrumentations for knee joint replacement.
15. Figure 16.15 Tibial proximal end personal specific instrumentations for knee joint replacement.
Chapter 17
1. Figure 17.1 PC pipe section made with FDM process.
2. Figure 17.2 SLA tray section, slightly translucent in its natural state.
3. Figure 17.3 Nylon SLS impeller.
4. Figure 17.4 MJF process illustration.
5. Figure 17.5 Mating part examples built with HP MJF technologies.
6. Figure 17.6 Market projection of 3D printing across the industries.
7. Figure 17.7 The Ethereal Halo and sample component.
8. Figure 17.8 Design and prototype prints. Dimensions engraved were the base thicknesses.
9. Figure 17.9 Graphite water outlet and carbon SLS brake duct.
10. Figure 17.10 SR30 “Washout mandrel”.
11. Figure 17.11 3D scaffold prints in PLA material.
12. Figure 17.12 Digital manufacturing suite at North Manchester General Hospital.
13. Figure 17.13 The new Objet 30 3D printer in action.
14. Figure 17.14 3D printed mouthguard.
15. Figure 17.15 Flowchart of 3D printing manufacturing process.

3D and 4D Printing in Biomedical Applications

Process Engineering and Additive Manufacturing

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Dedication