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Journal Article•DOI•

3D printing: Principles and pharmaceutical applications of selective laser sintering.

30 Aug 2020-International Journal of Pharmaceutics (Elsevier)-Vol. 586, pp 119594

TL;DR: The current state-of-the-art in SLS 3D printing is reviewed, including the main principles underpinning this technology and the diverse selection of materials and essential parameters that influence printing are highlighted.

Abstract: Pharmaceutical three-dimensional (3D) printing is a modern fabrication process with the potential to create bespoke drug products of virtually any shape and size from a computer-aided design model. Selective laser sintering (SLS) 3D printing combines the benefits of high printing precision and capability, enabling the manufacture of medicines with unique engineering and functional properties. This article reviews the current state-of-the-art in SLS 3D printing, including the main principles underpinning this technology, and highlights the diverse selection of materials and essential parameters that influence printing. The technical challenges and processing conditions are also considered in the context of their effects on the printed product. Finally, the pharmaceutical applications of SLS 3D printing are covered, providing an emphasis on the advantages the technology offers to drug product manufacturing and personalised medicine.

Topics: 3D printing (54%), Selective laser sintering (51%)

Summary (5 min read)

1. Introduction

  • Currently, the majority of commercially available SLS printers employ carbon dioxide (CO2) lasers, which provide higher power at lower cost, permitting the use of a wide array of powdered thermoplastic materials.
  • In the pharmaceutical sector, therapeutic products can be fabricated using SLS printing if the feedstock material is a powder blend of a drug and thermoplastic polymer.
  • As such, it has been anticipated that SLS is more amenable for pharmaceutical use.
  • Whilst other 3D printing technologies, such as binder jetting, are also based on powdered materials, being a solvent-free process makes SLS a faster process, wherein the need for additional drying steps to evaporate any residual binder is avoided.

2. Technological stratification

  • Of these printing technologies, SLS is most well suited for use within pharmaceutical research, because it is able to sinter pharmaceutical-grade powders.
  • Thus, it offers a novel and versatile approach for the rapid tailoring of medications.

3. Fundamentals

  • The printing process entails raising the building platform to its uppermost position, whereupon a fresh layer of powder is spread and flattened by the roller (Gokuldoss et al., 2017) .
  • This is followed by the activation of the laser beam, which scans across the powder and sinters it by following the pattern from the 3D file.
  • The building platform is then lowered, creating enough space for a new powder layer.
  • The process repeats until the printing job is finished (Sillani et al., 2019) .
  • In some cases, the final object may require post-processing (e.g. coating, polishing or surface finishing) to improve its mechanical properties (e.g. tensile strength and hardness) or appearance (e.g. dimensions and surface precision).

4.3. Laser scanning speed

  • Generally, lowering the laser scanning speed induces in a high laser energy density and increases the contact time between the powder bed and the laser beam (Fred et al., 2014) .
  • This allows higher energy transmission to the powder bed, resulting in a higher degree of sintering and producing denser objects.
  • A greater laser scanning speed results in a low energy density and less energy being transmitted to the powder and thus leads to less sintering and so more porous objects.

4.4. Scan spacing

  • Scan spacing, which is also known as hatch distance or line offset, refers to the distance between two consecutive scanning vectors.
  • The optimum scan spacing should be set with respect to the laser beam diameter and energy density.
  • If the scan space is too large, the layers might undergo incomplete sintering, wherein the layers would not be connected, leaving unsintered parts in between and yielding objects with low mechanical strength.
  • Like the slice thickness, the scan spacing is proportionate to the printing time.
  • Decreasing the scan spacing lengthens the fabrication process, but it is best for creating thin and intricate structures.

4.5. Particle Size and Shape

  • To achieve optimum sintering, a balance between optimum size and shape of the powder particles should be achieved.
  • If the particles are too big, they would require more energy for proper sintering.
  • More importantly, bigger particles will leave larger empty spaces between each other, resulting in poor mechanical properties, which cannot always be overcome with higher laser energy.
  • On the other hand, the flow properties of very small particles are often hindered by high electrostatic forces, resulting in their agglomeration (Schulze, 2008) .
  • More importantly, the particle size distribution should be narrow to ensure even absorption of energy.

4.6. Layer thickness

  • Due to the complex nature of SLS 3D printing, there are other parameters that also contribute to the final outcome of the process.
  • This includes the flow of inert gas (e.g. argon or nitrogen) inside the printing chamber, which prevents oxidation by removing condensates produced during printing.
  • Another important factor is the dwell time, which refers to the cooldown time required at the start and end of each layer.
  • The building orientation (e.g. horizontal, vertical or diagonal) controls the physical properties and mechanical performance of the final object (Kundera and Kozior, 2016, 2018) .
  • Another dominating factor is post-treatment (e.g. coating, annealing or surface finishing), which could significantly affect the tensile strength, surface hardness, dimensional accuracy and precision (Dizon et al., 2018; Gibson and Shi, 1997; Nelson and Vail, 1991) .

6. Industrial applications

  • Typically, the use of 3D printing within industrial production helps streamline a more sustainable and efficient manufacturing process.
  • As an example, SLS has been widely applied for the manufacturing of electronics, substituting traditional micro-patterning methods (Theodorakos et al., 2015) .
  • Within the automotive and aviation industries, SLS has been utilised to create lightweight parts whilst cutting down energy consumption during production (Hettesheimer et al., 2018) .
  • The military has investigated the potential of utilising SLS to generate explosives in a harmless manner (Jiba et al., 2019) .
  • In the medical field, SLS has been utilised to fabricate implants specifically tailored to the patient (Williams and Revington, 2010) and for surgical tooling (George et al., 2017) .

7. Pharmaceutical applications

  • The United States (U.S.) Food and Drug Administration (FDA) approval of the first 3Dprinted tablet (Spritam ® ) marked an important milestone in the history of 3D printing, setting a benchmark for manufacture of pharmaceuticals (Aprecia Pharmaceuticals, 2018).
  • Since then, 3D printing has continued to evolve rapidly, with cutting-edge research showing the many novel prospects the technology can offer.
  • This has led researchers to investigate and explore more 3D printing technologies to evaluate their suitability for pharmaceutical applications.
  • Compared with some of the other 3D printing technologies, SLS has had a slow-moving journey within pharmaceutical research.
  • This is primarily due to initial fears of drug and excipients degradation caused by the laser beam (Alhnan et al., 2016) and absence of pharmaceutically approved materials that are commercialised for SLS use.

7.1. Adapting the technology

  • Depending on the selected polymer and the laser type of the SLS printer, some powder blends may require the addition of an absorptance enhancer.
  • The type of absorptance enhancer will depend on the wavelength of the laser.
  • Pre-processing the polymer powder could improve the particle morphology.
  • Grinding and milling could reduce the particle size, spray drying could improve particle morphology (Maa et al., 1997; Vehring, 2008) , whilst sieving could aid in controlling the size distribution (Awad et al., 2019) .
  • Likewise, the inclusion of flow enhancers (e.g. magnesium stearate, talc and colloidal silica) could improve the flow characteristics of the powder (Vasilenko et al., 2011) .

7.2. Historical perspectives

  • Two pharmaceutical grade polymers, Eudragit L100-55, having prolonged release properties, and Kollicoat IR, with immediate release characteristics, respectively, were successfully utilised to create paracetamol 3D printed tablets, termed Printlets TM .
  • With drug degradation from the diode laser being a major concern, degradation studies showed that no drug degradation has occurred.
  • It was evident, however, that no sintering can be achieved using the polymer and drug mixture on their own.
  • This is because the diode laser absorbs in the visible light region and with most pharmaceutical powders being white, no absorption will occur.

7.3. New opportunities

  • Previous studies have shown that SLS is more cost effective for the production of personalised parts when compared to other 3D printing technologies (e.g. FDM and SLA) and conventional production processes (e.g. injection moulding) (Awad et al., 2018; Hopkinson and Dicknes, 2003) .
  • Moreover, printed objects can be stacked on top of one another, increasing the capacity of the build platform and enhancing productivity, making it highly amenable for scale up and mass production.
  • Additionally, SLS offers the option of recycling and reprocessing feed material, reducing waste and supporting green pharmaceuticals.

7.4. Novel designs

  • SLS is an adaptable technology suitable for printing a variety of dosage forms with unique properties.
  • SLS offers a wide selection of materials with different inherent properties.
  • By selecting a suitable polymer and fine-tuning the processing parameters, an array of drug release modes could be achieved.

7.4.1 Orally-disintegrating Printlets

  • SLS is capable of forming 3D objects solely by loosely binding powder particles on the surface, resulting in very porous and fast-dissolving Printlets.
  • As such, once dispersed in water, the water molecules quickly penetrate into the Printlets, leading to their rapid disintegration.
  • This effect is intensified by increasing the laser scanning speed used for sintering.
  • On this basis, Printlets incorporating Kollidon VA64, a vinylpyrrolidone-vinyl acetate copolymer, were fabricated .

Insert Figure 4

  • In another study, 30% diclofenac sodium was incorporated into the formulation, reducing the disintegration rate and changing the mechanical properties of the Printlets (Barakh Ali et al., 2019) .
  • This required the addition of lactose monohydrate to help modulate the mechanical characteristics and disintegration time of the Printlets.
  • The partial least squares (PLS) concentration images of the Printlets displayed a uniformity in colour, indicating that the drug is uniformly distributed within Printlets .

7.4.4 Multi-reservoir systems

  • Due to the high resolution of the laser beam, SLS can be utilised for the fabrication of complex and precise objects, such as multi-reservoir systems, enabling controlled drug delivery (Salmoria et al., 2013b) .
  • The systems are designed to contain a PCL shell and a vacant core, and the device can be fabricated to contain the drug in both reservoirs or solely within the core.
  • By varying the content of the reservoirs, different progesterone release patterns, extending up to 290 days, were achieved (Salmoria et al., 2012c) .

7.4.5 Implants for tissue and bone regeneration

  • PCL implants incorporating ibuprofen have been exploited for tissue and bone regeneration (Salmoria et al., 2016) .
  • It was shown that the addition of ibuprofen increased the intensity of sintering.
  • Likewise, 5-fluorouracil implantable systems composed of either a PE (Salmoria et al., 2017b) or PCL (Salmoria et al., 2017c) matrix were fabricated for cancer therapy.
  • Both systems showed an initial drug release burst followed by sustained delivery, wherein the PE implants had longer-lasting effect.
  • By combining these concepts within a single device, dual drug therapy systems could be created.

7.5. Undesirable pitfalls

  • As such, posing restrictions on the suitability of materials and drugs.
  • Furthermore, in terms of technical aspects, to ensure consistent layer height and suitable flow of powders, the printing requires large quantities of powder, which might not be feasible in all cases (Telenko and Seepersad, 2010) .
  • This is particularly important in the case of expensive drugs or those with limited quantities.
  • In addition, whilst any unsintered powders can be recycled, they can only be reused for a limited number of prints due to concerns relating to chemical stability and physical changes (Dotchev and Yusoff, 2009) .
  • Similarly, as the process sometimes might require post-treatment (e.g. the sieving and brushing of printed dosage forms), it may need an extra time-consuming step and impart additional costs (Thomas and Gilbert, 2014) .

7.6. Regulatory aspects

  • Another technique could involve the use of NIR hyperspectral imaging for the quantification of drugs within the Printlets and assessing their spatial distribution (Vakili et al., 2015) .
  • Collectively, these findings further facilitate and support the integration of SLS 3D printing within practice, providing suitable solutions to some of the existing QC challenges.

8.0. Conclusion

  • Since its introduction, 3D printing has been forecast to pave the way for a new pharmaceutical revolution.
  • Of all the 3D printing techniques, SLS is the most capable of being scaled up for mass production and with its starting materials holding the closest resemblance to current pharmaceutical production technologies, it is potentially highly amenable for adoption as a novel and versatile manufacturing tool for pharmaceutical fabrication.
  • Due to the high resolution of its laser beam, SLS enables the engineering of intricate and delicate dosage forms that could be tailored to meet the needs of certain patient groups.
  • Unlike other technologies, complex dosage forms can be attained without the need for additional support material or processes.
  • Whilst technical and QC restraints have been the principal hinderance for the adoption of such innovative technologies, preliminary results appear promising.

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1
3D printing: principles and pharmaceutical applications of selective laser
1
sintering
2
3
4
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Atheer Awad
1
, Fabrizio Fina
1
, Alvaro Goyanes
2,3*
, Simon Gaisford
1,2
and Abdul W.
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Basit
1,2*
8
9
1
UCL School of Pharmacy, University College London, 29-39 Brunswick Square,
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London, WC1N 1AX, UK
11
2
FabRx Ltd., 3 Romney Road, Ashford, Kent, TN24 0RW, UK
12
3
Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, R + D
13
Pharma Group (GI-1645), Universidade de Santiago de Compostela, 15782, Spain
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15
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*Correspondence: a.basit@ucl.ac.uk (Abdul W. Basit)
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a.goyanes@fabrx.co.uk (Alvaro Goyanes)
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19
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21

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Abstract
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Pharmaceutical three-dimensional (3D) printing is a modern fabrication process with
23
the potential to create bespoke drug products of virtually any shape and size from a
24
computer-aided design model. Selective laser sintering (SLS) 3D printing combines
25
the benefits of high printing precision and capability, enabling the manufacture of
26
medicines with unique engineering and functional properties. This article reviews the
27
current state-of-the-art in SLS 3D printing, including the main principles underpinning
28
this technology and highlights the diverse selection of materials and essential
29
parameters that influence printing. The technical challenges and processing
30
conditions are also considered in the context of their effects on the printed product.
31
Finally, the pharmaceutical applications of SLS 3D printing are covered, providing an
32
emphasis on the advantages the technology offers to drug product manufacturing and
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personalised medicine.
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35
Keywords:
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Powder bed fusion; 3D printed drug products; printlets; additive manufacturing;
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personalized medicines; digital health; gastrointestinal drug delivery systems.
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39

3
1. Introduction
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Three-dimensional (3D) printing is a type of additive manufacturing technology that
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has provided fresh opportunities to rethink manufacturing paradigms in various sectors
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which require the design and fabrication of products (Basit and Gaisford, 2018; Capel
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et al., 2018; Ong et al., 2020); its use in preparing medicines is particularly promising
44
(Charoo et al., 2020; Hsiao et al., 2018; Liang et al., 2019; Tan et al., 2018; Trenfield
45
et al., 2019) and it has the potential to be a disruptive technology, moving the
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pharmaceutical sector away from mass production of fixed-dose units towards the
47
flexible manufacture of individual units with dose or other properties tailored to the
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patient (personalised medicine) (Alhnan et al., 2016; Capel et al., 2018; Goole and
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Amighi, 2016; Goyanes et al., 2019b; Melocchi et al., 2020; Zhang et al., 2018). In
50
addition, because objects are fabricated in a layer-by-layer manner from a computer-
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aided design (CAD) model, 3D printing permits the creation of constructs which would
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otherwise be impossible to produce with conventional manufacturing processes (Chen
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et al., 2020; Ghosh et al., 2018; Goyanes et al., 2019a; Pandey et al., 2020). In the
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pharmaceutical sector, this allows the design and evaluation of novel drug-eluting
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devices which were not previously able to be created (Aho et al., 2019; Gioumouxouzis
56
et al., 2019; Liang et al., 2019; Mohammed et al., 2020; Mohtashami et al., 2020; Xu
57
et al., 2020).
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Many types of 3D printing process have been developed (JamrĂłz et al., 2018;
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Mukhopadhyay and Poojary, 2018; Trenfield et al., 2018a). Each technology has its
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own distinct attributes, so a unique range of applications (Jennotte et al., 2020), and
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each requires specific feedstock materials. The American Society for Testing and
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Materials (ASTM) classifies 3D printing technologies in seven main categories; vat
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4
polymerisation, binder jetting, material jetting, direct energy deposition, sheet
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lamination, material extrusion and powder bed fusion (ASTM International, 2016).
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Within these categories, there are subsets of printer types, broadly grouped in terms
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of the method they use to consolidate the printer feedstock into a solid object.
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One of these, selective laser sintering (SLS), is a subset of powder bed fusion 3D
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printing; it uses a laser beam to create solid objects by heating powder particles, fusing
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them together at their surfaces (Fina et al., 2018a). The SLS technology was
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developed by Carl Deckard in 1984, and was based on a neodymium-doped yttrium
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aluminum garnet (Nd:YAG) laser, which had a power of 100 W (Beaman and Deckard,
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1990). The printer feedstock material was a powder of acrylonitrile butadiene styrene
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(ABS), a thermoplastic polymer used in many prototypes (Shellabear and Nyrhilä,
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2004).
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Currently, the majority of commercially available SLS printers employ carbon dioxide
79
(CO
2
) lasers, which provide higher power at lower cost, permitting the use of a wide
80
array of powdered thermoplastic materials. As such, applications of SLS span many
81
fields, including the aerospace, automotive, military, medical, dentistry, engineering
82
and electronics industries (Di Giacomo et al., 2016; George et al., 2017; Hettesheimer
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et al., 2018; Jiba et al., 2019; King and Tansey, 2003; Revilla-LeĂłn and Ă–zcan, 2017;
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Theodorakos et al., 2015; Williams and Revington, 2010). In the pharmaceutical
85
sector, therapeutic products can be fabricated using SLS printing if the feedstock
86
material is a powder blend of a drug and thermoplastic polymer. This means that,
87
compared with other 3D printing technologies, the feedstock material of SLS printing
88
has the closest resemblance to that of traditional tabletting. As such, it has been
89

5
anticipated that SLS is more amenable for pharmaceutical use. Whilst other 3D
90
printing technologies, such as binder jetting, are also based on powdered materials,
91
being a solvent-free process makes SLS a faster process, wherein the need for
92
additional drying steps to evaporate any residual binder is avoided.
93
94
This article reviews the current state-of-the-art in SLS 3D printing, including the main
95
principles underpinning the technology. The technical challenges and processing
96
conditions are considered in the context of their effects on the printed product. Finally,
97
pharmaceutical applications of SLS 3D printing are highlighted, providing an emphasis
98
on the advantages the technology offers to drug product manufacturing and
99
personalised medicine.
100
101
2. Technological stratification
102
Powder bed fusion is one of the seven main 3D printing classifications assigned by
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the ASTM (Chatham et al., 2019). It refers to the selective consolidation of powder
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particles into 3D objects using a heat source focused onto specific areas. Powder bed
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fusion currently has four subset technologies; SLS, selective laser melting (SLM),
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electron beam melting (EBM) and multijet fusion (MJF) (Gibson et al., 2015). The
107
technologies differ by the type of materials they employ and by the type and amount
108
of light utilised to transmit energy to the powder bed. In all cases, objects are built
109
layer-by-layer through the use of thermal energy resulting from the combination of
110
increased temperature and the use of a light source (Goodridge and Ziegelmeier,
111
2017) and all use powders as their feedstock materials. One immediate benefit of this
112
is that it permits fabrication of overhanging and/or intricate structures, without the need
113

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Journal Article•DOI•
TL;DR: This paper identifies essential structural characteristics and the pre-requisites for fabrication techniques that can yield scaffolds that are capable of directing healthy and homogeneous tissue development and compares the advantages and limitations of the SFF techniques.
Abstract: Most tissue engineering (TE) strategies for creating functional replacement tissues or organs rely on the application of temporary three-dimensional scaffolds to guide the proliferation and spread of seeded cells in vitro and in vivo. The characteristics of TE scaffolds are major concerns in the quest to fabricate ideal scaffolds. This paper identifies essential structural characteristics and the pre-requisites for fabrication techniques that can yield scaffolds that are capable of directing healthy and homogeneous tissue development. Emphasis is given to solid freeform (SFF), also known as rapid prototyping, technologies which are fast becoming the techniques of choice for scaffold fabrication with the potential to overcome the limitations of conventional manual-based fabrication techniques. SFF-fabricated scaffolds have been found to be able to address most, if not all the macro- and micro-architectural requirements for TE applications. This paper reviews the application/potential application of state-of-the-art SFF fabrication techniques in creating TE scaffolds. The advantages and limitations of the SFF techniques are compared. Related research carried out worldwide by different institutions, including the authors' research are discussed.

974 citations


01 Jan 2012
Abstract: Selective laser melting (SLM) and electron beam melting (EBM) are relatively new rapid, additive manufacturing technologies which can allow for the fabrication of complex, multi-functional metal or alloy monoliths by CAD-directed, selective melting of precursor powder beds. By altering the beam parameters and scan strategies, new and unusual, even non-equilibrium microstructures can be produced; including controlled microstructural architectures which ideally extend the contemporary materials science and engineering paradigm relating structure-properties-processing-performance. In this study, comparative examples for SLM and EBM fabricated components from pre-alloyed, atomized precursor powders are presented. These include Cu, Ti-6Al-4V, alloy 625 (a Ni-base superalloy), a Co-base superalloy, and 17-4 PH stainless steel. These systems are characterized by optical metallography, scanning and transmission electron microscopy, and X-ray diffraction.

922 citations


Journal Article•DOI•
Abstract: Selective laser melting (SLM) and electron beam melting (EBM) are relatively new rapid, additive manufacturing technologies which can allow for the fabrication of complex, multi-functional metal or alloy monoliths by CAD-directed, selective melting of precursor powder beds. By altering the beam parameters and scan strategies, new and unusual, even non-equilibrium microstructures can be produced; including controlled microstructural architectures which ideally extend the contemporary materials science and engineering paradigm relating structure-properties-processing-performance. In this study, comparative examples for SLM and EBM fabricated components from pre-alloyed, atomized precursor powders are presented. These include Cu, Ti-6Al-4V, alloy 625 (a Ni-base superalloy), a Co-base superalloy, and 17-4 PH stainless steel. These systems are characterized by optical metallography, scanning and transmission electron microscopy, and X-ray diffraction.

908 citations


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The selective laser sintering ( SLS ) is a subset of powder bed fusion 3D printing ; it uses a laser beam to create solid objects by heating powder particles, fusing them together at their surfaces this paper.