Development of AM Technologies for Metals in the Sector of Medical Implants

Additive manufacturing (AM) processes have undergone significant progress in recent years, having been implemented in sectors as diverse as automotive, aerospace, electrical component manufacturing, etc. In the medical sector, different devices are printed, such as implants, surgical guides, scaffolds, tissue engineering, etc. Although nowadays some implants are made of plastics or ceramics, metals have been traditionally employed in their manufacture. However, metallic implants obtained by traditional methods such as machining have the drawbacks that they are manufactured in standard sizes, and that it is difficult to obtain porous structures that favor fixation of the prostheses by means of osseointegration. The present paper presents an overview of the use of AM technologies to manufacture metallic implants. First, the different technologies used for metals are presented, focusing on the main advantages and drawbacks of each one of them. Considered technologies are binder jetting (BJ), selective laser melting (SLM), electron beam melting (EBM), direct energy deposition (DED), and material extrusion by fused filament fabrication (FFF) with metal filled polymers. Then, different metals used in the medical sector are listed, and their properties are summarized, with the focus on Ti and CoCr alloys. They are divided into two groups, namely ferrous and non-ferrous alloys. Finally, the state-of-art about the manufacture of metallic implants with AM technologies is summarized. The present paper will help to explain the latest progress in the application of AM processes to the manufacture of implants.


Introduction
Nowadays, industry is undergoing the 4th industrial revolution, which involves a lot of different fields such as nanotechnology, Internet of Things (IoT), and Artificial Intelligence (AI), among others. It also includes additive manufacturing (AM), which is the technology that builds 3D objects from successive layers. In recent years, the use of 3D printed parts in the medical sector has increased. According to the Wohlers report [1], the medical sector was the third most important one in the US in 2014 ( Figure 1).
Additionally, the planet's population is increasing every year, along with life expectancy. It is therefore not difficult to imagine the different medical problems that can arise. For example, the appearance of new diseases or more people in need of surgery for organs transplantation as well as body parts' replacements such as knees or hips. Additionally, the planet's population is increasing every year, along with life expectancy. It is therefore not difficult to imagine the different medical problems that can arise. For example, the appearance of new diseases or more people in need of surgery for organs transplantation as well as body parts' replacements such as knees or hips.
According to the current technological development, it is possible to think about personalized medicine, for instance, the customization, design and fabrication of patient-particular products using AM technologies. Moreover, this technology could offer several significant advances: • Creation of ideal products. Polymers are common in different medical applications such as tissue engineering [2], and the manufacture of surgical planning prototypes [3][4][5][6][7] and scaffolds [8]. Ceramic materials have also been employed in scaffolds [9]. However, in recent years the use of metals has increased in medicine. They can be found in several applications, such as surgical guides [10], prostheses [11], implants [12], etc. (Figure 2). Polymers are common in different medical applications such as tissue engineering [2], and the manufacture of surgical planning prototypes [3][4][5][6][7] and scaffolds [8]. Ceramic materials have also been employed in scaffolds [9]. However, in recent years the use of metals has increased in medicine. They can be found in several applications, such as surgical guides [10], prostheses [11], implants [12], etc. (Figure 2).
Most metallic parts used in the medical sector have complex shapes, in many cases combined with porous structures that favor their fixation in the body by means of osseointegration. AM can provide these shapes without excessively increasing costs. In addition, it allows customized parts to be produced from the DICOM (Digital Imaging and Communications in Medicine) files obtained, for example, in radiology tests.
The present paper focuses on the recent advances in AM of metallic implants, which are tissues or prostheses that are placed inside or on the surface of the body. Prostheses are artificially made parts of the body that replace a part that is missing, either internal or external.
First, the main AM technologies for metals are explained: binder jetting (BJ), selective laser melting (SLM), electron beam melting (EBM), direct energy deposition (DED), and fused filament fabrication (FFF). Next, the main properties of the metals that are used to manufacture prostheses and implants are summarized. Then, the recent advances regarding applications of AM metallic implants are presented. Finally, the main conclusions of the paper are summarized.
Most metallic parts used in the medical sector have complex shapes, in many cases combined with porous structures that favor their fixation in the body by means of osseointegration. AM can provide these shapes without excessively increasing costs. In addition, it allows customized parts to be produced from the DICOM (Digital Imaging and Communications in Medicine) files obtained, for example, in radiology tests.   [24][25][26].

Advantages Disadvantages
No need to design nor use supports Limited success in producing metallic parts Unused powder can be reused Worse mechanical properties than powder bed fusion processes Wide range of materials Low density Fast process Large build size Requirement of post processing (sintering/infiltration) Although this technique is mainly used for ceramic materials, for example to obtain sand molds and cores in the sand casting process [27], it is also employed for metal matrices [28]. For example, iron parts with enhanced strength are obtained by means of bronze infiltration [29]. However, the high density of metals makes them less stable than other materials, and the fine particles can be prone to oxidation [26]. Different materials such as titanium [30], stainless steel [20], CoCr alloys [31], or Inconel [21] have been manufactured with binder jetting. In addition, since this technology does not require the use of an energy beam for processing metals, it is a good choice for reflective and thermally conductive metals, which can be challenging to be processed by powder bed fusion technologies [32].

Powder Bed Fusion by Selective Laser Melting (SLM)
Powder bed fusion by selective laser melting (SLM) using metallic powder is an AM process that is similar to selective laser sintering (SLS). Unlike SLS, in which the particles are only sintered, the SLM technique uses a high power-density laser in order to melt and fuse the metallic powders together. Other common names for this powder bed fusion technology for metals are DMLS (direct metal laser sintering) and DMP (direct metal printing). The process starts by the spreading of a thin layer of the metal powder. Then, a high power-density laser is used in order to melt and fuse the metallic powders together. After this, the build platform is lowered in the Z direction and the process is repeated again until the 3D printed required part is built. SLM takes place in a chamber with inert gas atmosphere, using, for instance, argon or nitrogen.
Two examples of machines using this technology are the SLM 125 and SLM 280 2.0 of SLM Solutions Group AG, Lübeck, Germany [33]. On the one hand, SLM 125 has a build volume of 125 × 125 × 125 mm 3 and a printing speed of 25 cm 3 /h. On the other hand, SLM 280 2.0 has a build volume of 280 × 280 × 365 mm 3 and a printing speed of 113 cm 3 /h. These latter values depend on the materials and part geometry.
The main advantages and disadvantages of SLM can be seen in Table 2. Although ideal materials are pure metals, different alloys can also be used in the SLM process, such as stainless steel, CoCr alloys, titanium alloys, and aluminum [41].

Powder Bed Fusion by Electron Beam Melting (EBM)
Powder bed fusion by electron beam melting (EBM) is a type of 3D printing process for metals in which the object material, normally in the form of powder, is manufactured by melting layer-by-layer with an electron beam at high temperature in a high vacuum atmosphere.
Firstly, a layer of metal powder is distributed onto the build platform, and melted by the electron beam. Then, the build platform is lowered, and another layer of metal powder is subsequently coated on top.
One example of a machine of this technology is the Arcam EBM Q20plus, from GE Additive, Boston, MA, USA [42]. It has an electron beam power of 3 kW and a build volume of 350 mm in diameter and 380 in heigtt. Additionally, EBM takes place in a vacuum and at high temperatures.
The main advantages and disadvantages of EBM can be seen in Table 3. Table 3. Advantages and disadvantages of EBM [41,43].

Advantages Disadvantages
Possibility of working at elevated temperatures High fatigue Better protection against contamination Danger for electrostatic charge of the powder Low level of residual stresses Absence of shrinkage, no thermal post-processing Freedom of design, because of fewer supports Allows stacking parts and obtaining meshes Only conductive alloys can be obtained Rough finish that requires polishing (depending on process conditions) Titanium alloys, CoCr alloys, stainless steel and Inconel are frequently employed in EBM processes [41].

Direct Energy Deposition (DED)
Direct energy deposition (DED) is an additive manufacturing process in which an energy source such as an electron, laser beam or electric arc, is aimed at the material (in the form of powder or wire), Metals 2020, 10, 686 6 of 30 in order to fuse the materials by melting while they are being deposited. Due to the use of four-or five-axis machines, the material can be deposited from any angle onto the existing surfaces of the object and then melted. The process requires a chamber with inert gas to control the material properties and to avoid oxidation of the material.
Two examples of machines using this technology are the INTEGREX i-400 AM and the DMD 503D/505D, from Yamazaki Mazak Corporation, Oguchi, Japan. On the one hand, INTEGREX i-400 AM is a five-axis multi-tasking machine and it is used for 3D printing of materials which are difficult to be machined [44]. On the other hand, DMD 503D/505D has a build volume of 1590 × 1400 × 1470 mm 3 and a position accuracy of 0.03 mm [45].
The advantages and disadvantages of DED can be seen in Table 4.

Material Extrusion by Fused Deposition Modelling (FDM) or Fused Filament Fabrication (FFF)
In the FFF or FDM technique, a filament is melted, extruded through a nozzle and subsequently deposited on a printing bed layer-by-layer. Once a layer it deposited, the build platform is lowered (in low-cost machines, the build platform does not lower after each layer is deposited). Finally, when the piece is completed, it is placed into a sintering furnace to remove the plastic and sinter the metal particle together. Both debinding and sintering processes are required after extrusion, which cause material shrinkage.
One example of a machine of this technology is the Metal X of Markforged, Watertown, MA, USA. It has a build volume of 300 × 220 × 180 mm 3 and a Z resolution of between 50 and 125 µm [50].
The main advantages and disadvantages of FFF can be seen in Table 5. Table 5. Advantages and disadvantages of FFF with high metallic content [51][52][53].

Advantages Disadvantages
Simple technology Low accuracy Wide range of materials Shear stress on nozzle tip wall Possibility to use low cost machines Bad resolution Reliable Poor mechanical properties, although enhanced with respect to polymers Thermal postprocess (associated with shrinkage) Although it is associated with plastic materials such as polylactic acid (PLA) or acrylonitrile butadiene styrene (ABS), the filament can be filled with a high percentage of metallic particles in order to print metallic parts. Some of the metals used are copper [54], stainless steel [55], and titanium [56].

Comparison of the AM Technology Process for Metals
Before any object is 3D printed several factors must be considered. In other words, depending on the objective of the product, the material used, etc., it might be better to use one technology or another. Therefore, it is important to compare different aspects of the AM technologies (Table 6).  [26,37,[73][74][75] Regarding the manufacturing costs, the following values are the printing costs per unit [76]: (1) $ 2.50-4 for laser powder bed, (2) $ 1.33-3 for e-beam powder bead, (3) $ 0.33-1.5 for powder DED, (4) $ 0.25-0.6 for wire DED, and (5) $ 0.08-1.5 for binder jetting. Thus, among the studied processes, the most expensive one is laser powder bed (SLM) followed by e-beam powder bed (EBM).

Metals Used in the Medical Sector
Different metals and alloys are currently used in the medical sector. They can be divided into two categories: ferrous and non-ferrous ( Figure 3).  Ideally, an alloy used for implants should be biocompatible and have good mechanical properties, i.e., high tensile, compressive and shear strength, high fatigue strength to prevent failure under cyclic loading, and low elastic modulus comparable to that of bone. They should also have high corrosion resistance, high wear resistance, and a low price. Another important factor to be considered is the possibility to obtain porous structures, because they influence both the mechanical strength and the biological properties of the tissues. On the other hand, the osseointegration of bones depends on both biomechanical interlocking and biological interactions, which are related to the surface roughness of the implants. These properties are in more depth in Section 4.10.

Metals
Among the ferrous alloys, the most frequently employed one to manufacture implants is stainless steel due to its high corrosion resistance. However, it has low fatigue strength and undergoes deformation. Consequently, it is mainly used for non-permanent implants. Regarding the non-ferrous materials, some of them are bio tolerant like CoCr alloys, gold, niobium and tantalum, while pure titanium and titanium alloys are bio inert [77]. Ion release is one of the main disadvantages of CoCr alloys, titanium, and titanium alloys, although they provide high corrosion resistance. In addition, differences in mechanical properties between the bone and the implant can lead to stress shielding problems, with either a loosening of implants or the growth of soft fibrous tissue [78]. Figure 4 provides a comparison of metals by focusing only on the material price. This does not include the manufacturing costs, and prices are related to the market price. According to their price, metals can be divided into three categories. The green area corresponds to the cheap ones, the yellow area to the medium ones, and the red area to the expensive ones, in this case tantalum, with a price above 110 €/kg.  The manufacturing costs can be divided into two groups: fixed and recurring [62]. On the one hand, the fixed costs correspond to the manufacturing tools, dies, machines, etc. These costs are amortized over time and, therefore, the more the 3D printing machines are used, the lower the costs per printed piece are. On the other hand, the recurring costs include the material price and labor. Regarding the materials, it is important that they are easily 3D printed and have good physical and mechanical properties, but without excessive cost.
The following paragraphs present the main characteristics of the metals that are employed to manufacture metallic implants by means of AM processes.

Ferrous
A ferrous metal contains iron in its composition, as well as carbon. They can be divided into two categories, namely (a) alloys such as stainless steel and (b) iron.

Stainless Steel
It is an iron alloy containing at least 10.5% of chromium and 1.2% of carbon. Chromium offers the stainless steel the benefit of being resistant to corrosion thanks to the chromium oxide layer, unlike the regular steel. Additionally, stainless steel can have other materials but in lower proportions such as molybdenum or nickel [80]. Some examples of stainless steel are SAE 304, SAE 316 and SAE 316L Boron-titanium modified stainless steel, defined by the Society of Automotive Engineers (SAE). SAE 316 L has been used in recent years for biomedical applications. Sintering of the material in a nitrogen atmosphere helps to retain the nickel ions in the stainless steel [81], which would otherwise be released from implants due to local corrosion [82]. Additionally, it is necessary to carry out cell culture studies, such as cytotoxicity assays or cells imaging [83], to verify its biocompatibility. As for SLM manufactured stainless steel, biocompatibility increases when the material is coated with hydroxyapatite [84].
The main advantages and disadvantages of stainless steel can be seen in Table 7.  The manufacturing costs can be divided into two groups: fixed and recurring [62]. On the one hand, the fixed costs correspond to the manufacturing tools, dies, machines, etc. These costs are amortized over time and, therefore, the more the 3D printing machines are used, the lower the costs per printed piece are. On the other hand, the recurring costs include the material price and labor. Regarding the materials, it is important that they are easily 3D printed and have good physical and mechanical properties, but without excessive cost.
The following paragraphs present the main characteristics of the metals that are employed to manufacture metallic implants by means of AM processes.

Ferrous
A ferrous metal contains iron in its composition, as well as carbon. They can be divided into two categories, namely (a) alloys such as stainless steel and (b) iron.

Stainless Steel
It is an iron alloy containing at least 10.5% of chromium and 1.2% of carbon. Chromium offers the stainless steel the benefit of being resistant to corrosion thanks to the chromium oxide layer, unlike the regular steel. Additionally, stainless steel can have other materials but in lower proportions such as molybdenum or nickel [80]. Some examples of stainless steel are SAE 304, SAE 316 and SAE 316L Boron-titanium modified stainless steel, defined by the Society of Automotive Engineers (SAE). SAE 316 L has been used in recent years for biomedical applications. Sintering of the material in a nitrogen atmosphere helps to retain the nickel ions in the stainless steel [81], which would otherwise be released from implants due to local corrosion [82]. Additionally, it is necessary to carry out cell culture studies, such as cytotoxicity assays or cells imaging [83], to verify its biocompatibility. As for SLM manufactured stainless steel, biocompatibility increases when the material is coated with hydroxyapatite [84].
The main advantages and disadvantages of stainless steel can be seen in Table 7. Table 7. Advantages and disadvantages of stainless steel [80,85].

Advantages Disadvantages
High corrosion resistance Sometimes difficult to handle Heat resistance Release of chromium and nickel Biocompatible Prone to deformation Excellent mechanical properties Low fatigue strength when subjected to oxidation Easy fabrication Non-porous

Iron
It is only the most common element on Earth by mass, and also in the human body. It can be classified into three categories depending on the carbon content: wrought iron (less than 0.08% C), carbon steel (between 0.08 and 1.76% C) or cast iron (more than 1.76% C). Additionally, cast iron can be divided into smaller groups such as white, grey, malleable and nodular graphite.
The advantages and disadvantages of wrought iron can be seen in Table 8. Table 8. Advantages and disadvantages of wrought iron [86].

Advantages Disadvantages
Tough Cannot be hardened Excellent mechanical properties Sometimes difficult to handle Corrosion resistance High cost Excellent weldability Weldability is an important factor to be taken into consideration when a part needs to be joined to another of either a similar or dissimilar material [87], e.g., in implants. If cracks are easily avoided, the materials are 'weldable'.
Fe-Mn alloy has been used to produce bone scaffolds by SLM [88]. Mn is added to control the high degradation of Fe. Moreover, in another study, a Fe-HA (iron-hydroxyapatite) composite was manufactured using different particles sizes [89]. Not only were better corrosion rates obtained than for pure iron, but also with the addition of HA closer mechanical properties to those of bone are also obtained. For example, pure iron tensile strength is 215 MPa, for Fe + 2.5 wt% HA (1-10 µm) it is 117 MPa and the strength of the human femur bone is 135 MPa (longitudinal tension) [90].
The advantages and disadvantages of carbon steel can be seen in Table 9. Table 9. Advantages and disadvantages of carbon steel [86].

Advantages Disadvantages
Excellent mechanical properties Ductility decreases with carbon content Good weldability Susceptible to rust and corrosion Good formability Hard and tough Low stress concentration Resistant to oxidation The main advantages and disadvantages of cast iron can be seen in Table 10. Table 10. Advantages and disadvantages of cast iron [86].

Excellent mechanical properties High brittleness Biocompatible
Low machinability Cytocompatibility Good castability Low stress concentration Resistant to oxidation Machinability is measured by focusing in the machinability index. The value of 100 is the average, with carbon steel 1212 being the average. Therefore, a value lower than 100 means that the machinability is more difficult and, therefore, the production time is lower; while with a value higher than 100 it is easier. In terms of cast iron, it ranges from 36 to 78 [91].

Non-Ferrous
Non-ferrous metals do not contain iron in appreciable amounts and are generally more costly than ferrous metals due to their desirable properties. They can be divided into different categories: (a) alloys, (b) light metals, (c) rare metals, and (d) white.

CoCr Alloys
Cobalt-chromium alloys are alloys composed mainly of cobalt and chromium. They are used in aerospace engineering amongst other applications. However, taking into account their excellent properties, they have been used in dentistry for decades [85]. Most employed CoCr alloys in medical applications are Co-Cr-Mo, Co-Ni-Cr-Mo, and Co-Cr-W-Ni [92]. Using this metal alloy has a major drawback, which is the ion release, which could lead to adverse effects such as toxicity, metallic taste, mucosities, etc.
The advantages and disadvantages of the CoCr alloys can be seen in Table 11. Table 11. Advantages and disadvantages of the CoCr alloys [68,92].

Advantages Disadvantages
Excellent mechanical properties Wear and corrosion can lead to the release of metal ions Excellent corrosion resistance High cost Biocompatibility Limitations on component complexity

Nickel Alloys
Nickel (Ni) alloys are metals made from a combination of nickel as the primary element and another material such as Ni-Al alloy, Ni-Cr alloy or Ni-Ti alloy. Although nickel is very toxic, a titanium oxide layer is formed that prevents from nickel oxidation [92]. An example of Ni-Ti alloy is Nitinol, which contains approximately 50% of Ni and 50% of Ti. Nitinol is a shape memory alloy, which retains its original shape after severe deformations. It is used for hard tissue implants and in dentistry. In recent years, the behavior of SLM printed Ni-Ti alloys has been addressed [93,94].
The advantages and disadvantages of the nickel alloys can be seen in Table 12. The low thermal conductivity of nickel complicates its manufacture; for example, in machining or high temperature AM processes, because heat cannot be easily removed from the working area, thus increasing working temperatures. Titanium (Ti) is the ninth-most abundant chemical element in the Earth's crust and it can be combined with other elements in order to form the known titanium alloys. It is widely used in several applications such as dental implants, but during the last few years, it has assumed greater importance in the biomedical applications such as hip prostheses, especially due to its biocompatibility and high fracture resistance. These two parameters are important in prostheses for two reasons: (1) biocompatibility so that the host tissue does not reject the implant: (2) high fracture resistance so that the implant does not fracture. Commercial pure titanium (CP-Ti) has an excellent biocompatibility because of a stable oxide layer that forms spontaneously on its surface [96].
Regarding the use of SLM, Taniguchi et al. [97] investigated the bone ingrowth of different pore sizes of titanium implants manufactured by SLM. Finding the best titanium implant for osseointegration is essential, so that the implant integrates as quickly as possible with the bone.
The advantages and disadvantages of the titanium can be seen in Table 13. Titanium alloys contain titanium and other chemical elements. Different alloys are used in medical applications, such as α + β alloys, Ti-Al-Nb and β-Ti alloy [92]. However, the most typical example is Ti-6Al-4V which is an α-β titanium alloy containing a 6% aluminum and 4% vanadium. A specific alloy Ti6Al4V ELI (extra-low interstitial) alloy provides higher ductility and fracture toughness than the conventional alloy [100].
The three most developed techniques for additively manufacturing titanium alloy structures are direct energy deposition (DED), selective laser melting (SLM) and electron beam melting (EBM) [65,101]. For example, porous parts implants can be manufactured using SLM technology and they can achieve a mimicking of the human bone at a 60% of porosity [102].
The advantages and disadvantages of the titanium alloys can be seen in Table 14. Other titanium alloys, such as Ti-6Al-7Nb [104,105], have been used for printing implants as well as others such as Ti-24Nb-4Zr-8Sn [106] or Ti-33Nb-4Sn [107]. A typical niobium alloy used for prostheses is Ti-42Nb.

Magnesium
Magnesium (Mg) is a light material with a relatively high mechanical strength that can replace aluminum in some applications. However, its accelerated corrosion rate in physiological environments reduces its potential use in implants [108]. Nevertheless, magnesium-based biodegradable materials are promising candidates, making a second surgery for implant removal unnecessary [109,110]. Magnesium powder is flammable and should be handled with care [111].
The main advantages and disadvantages of magnesium can be seen in Table 15. Magnesium scaffolds have been prepared with the purpose of bone regeneration [113].

Tantalum
Tantalum (Ta) is a very chemically resistant metal and, consequently, it is widely used in biomedical applications. Additionally, it is inert to practically all the organic and inorganic compounds. Tantalum has been printed with the SLM technique [114].
The main advantages and disadvantages of the tantalum alloys can be seen in Table 16. Zinc (Zn) is one of the most indispensable trace elements in the human body and it is often employed in industry for the surface treatment of steel, for example in galvanization or electroplating processes. In medical applications, it has been used in cardiovascular stents and dental implants, amongst others.
The strength of zinc can be improved by alloying with elements such as Mg, Ca, Sr, Li, and Cu [117]. On the other hand, inorganic Zn compounds such as Zn-hydroxyapatite [118] or ZnO [119] can be used to manufacture implants.
The main advantages and disadvantages of zinc can be seen in Table 17.

Other Metals and Alloys
There are other metals that are not as commonly used in the medical sector, except in a few biomedical applications. For instance, copper (Cu) is the third most important trace element in the human body. Some commercially available copper alloys are Cu-Al-Ni and Cu-Al-Mn [92]. However, it has been proved that it is both difficult and expensive to print copper [120].
Pure Tungsten (W) powder has also been used in SLM processes [121], as well as pure Niobium (Nb) [122]. Neodymium (Nd) has been added to the Mg-5Zn-0.35Zr-0.13Y, improving the mechanical strength and corrosion resistance of the alloy [108].
Although aluminum is not a suitable material for implants because of its easy oxidation, it is found in many titanium alloys like Ti-6Al-4V [85].
Gold alloys were used in the past for dental implants [92]. However, they are not commonly used nowadays because of their high price.

Comparison of the Metals
A comparison of the different metals was made, regarding their most important properties (Table 18).

Applications
Metals have been widely used in different applications in recent last years. Not only can they be used in the automotive or aeronautical sectors, but also in the medical field. Within medicine, they can be employed for several purposes: scaffolds, implants, surgical guides, fixation guides, etc. The main applications of 3D printed metals in the manufacture of implants are presented in the following subsections.
Nowadays, many implants such as the hip or knee prostheses are manufactured in metallic materials. This is due to their high mechanical and fatigue strength and the easiness to manufacture them with conventional machining processes. Some authors have attempted to print prostheses by means of AM technologies. Unlike other manufacturing processes such as casting, AM technologies allow customized prostheses to be manufactured in serial batches without incurring excessive costs.
Several kinds of implants are available: cranial, maxillofacial, spinal, hip, knee, or skeletal reconstruction implants [12] among others. The ISO 5832 standard summarizes the characteristics, as well as the test methods, of the material to be used in metallic implants. For example, ISO 5832-1 [137] corresponds to wrought stainless steel, ISO 5832-3 to wrought titanium 6-aluminium 4-vanadium alloy [138], and ISO 5832-4 [139] corresponds to cobalt-chromium-molybdenum alloys.
The following subsections present the recent advances in metallic implants manufactured by AM methods, for cranial implants, maxillofacial implants, spinal implants, upper & lower limb implants, and dental implants.

Applications
Metals have been widely used in different applications in recent last years. Not only can they be used in the automotive or aeronautical sectors, but also in the medical field. Within medicine, they can be employed for several purposes: scaffolds, implants, surgical guides, fixation guides, etc. The main applications of 3D printed metals in the manufacture of implants are presented in the following subsections.
Nowadays, many implants such as the hip or knee prostheses are manufactured in metallic materials. This is due to their high mechanical and fatigue strength and the easiness to manufacture them with conventional machining processes. Some authors have attempted to print prostheses by means of AM technologies. Unlike other manufacturing processes such as casting, AM technologies allow customized prostheses to be manufactured in serial batches without incurring excessive costs.
Several kinds of implants are available: cranial, maxillofacial, spinal, hip, knee, or skeletal reconstruction implants [12] among others. The ISO 5832 standard summarizes the characteristics, as well as the test methods, of the material to be used in metallic implants. For example, ISO 5832-1 [137] corresponds to wrought stainless steel, ISO 5832-3 to wrought titanium 6-aluminium 4-vanadium alloy [138], and ISO 5832-4 [139] corresponds to cobalt-chromium-molybdenum alloys.
The following subsections present the recent advances in metallic implants manufactured by AM methods, for cranial implants, maxillofacial implants, spinal implants, upper & lower limb implants, and dental implants.  Jardini et al. [12] manufactured cranial implants with direct metal laser sintering (DMLS, same technology as SLM)). The Ti-6Al-4V alloy was used (Figure 2a).

Maxillofacial Implants
Suska et al. [142] used EBM of Ti-6Al-4V alloy to manufacture a jaw prosthesis, which was individually designed and implanted, with a good aesthetic outcome ( Figure 6). They added diamond-like porous structures to the upper and lower parts of the implant to favor the fixation of the prosthesis by means of osseointegration. The strut size employed was 0.3 mm and the pore size was 0.8 mm. Yan et al. [143] employed Ti-6Al-4V titanium alloy to manufacture a mandibular prosthesis with a 3D mesh by means of EBM. The mesh porosity was 81.38% and the strut size, Jardini et al. [12] manufactured cranial implants with direct metal laser sintering (DMLS, same technology as SLM)). The Ti-6Al-4V alloy was used (Figure 2a).

Maxillofacial Implants
Suska et al. [142] used EBM of Ti-6Al-4V alloy to manufacture a jaw prosthesis, which was individually designed and implanted, with a good aesthetic outcome ( Figure 6). They added diamond-like porous structures to the upper and lower parts of the implant to favor the fixation of the prosthesis by means of osseointegration. The strut size employed was 0.3 mm and the pore size was 0.8 mm. Yan et al. [143] employed Ti-6Al-4V titanium alloy to manufacture a mandibular prosthesis with a 3D mesh by means of EBM. The mesh porosity was 81.38% and the strut size, 0.7 mm.
Moiduddin et al. obtained a titanium zygomatic implant with the EBM technique, using Ti-6Al-4V ELI (extra low interstitial) powder [144]. The same author [145] compared different kinds of Ti-6Al-4V ELI mandibular implants for goats: EBM plate with mesh, EBM titanium plate without mesh and a commercial reconstruction plate. They found that the reconstructed plates with mesh showed a better fit than the other ones. They obtained a very good fit with titanium alloy mandibular implants [146].  [144]. The same author [145] compared different kinds of Ti-6Al-4V ELI mandibular implants for goats: EBM plate with mesh, EBM titanium plate without mesh and a commercial reconstruction plate. They found that the reconstructed plates with mesh showed a better fit than the other ones. They obtained a very good fit with titanium alloy mandibular implants [146]. Ciocca et al. [147] built DMLS titanium alloy meshes for the regeneration of atrophic maxillary arches. They used a 0.6 mm thickness mesh. Jardini et al. [148] manufactured Ti-6Al-4V parts for maxillofacial implants, using the DMLS technology. The same technology and material was used to obtain customized parts for upper maxillary implants [149].

Spinal Implants
Yang et al. [150] used the EBM technique to obtain Ti-6Al-4V vertebral bodies of sheep. Xu et al. [151] manufactured vertebral implants with the EBM technique and Ti-6Al-4V material, and Li et al. [152] tested porous artificial vertebral bodies in vivo, manufactured with the same material and technique. Choy et al. [14] printed titanium porous vertebral prostheses and performed in vivo spinal surgery. Siu et al. [153] applied EBM to obtain Ti-6Al-4V interbody cages for the lumbar area, in a case study with a deformity caused by osteoporotic fractures.
Hollander et al. [154] used direct laser forming (DLF) to obtain Ti-6Al-4V alloy vertebral bodies (Figure 7). They manufactured meshes with nominal pore sizes of 500, 700, and 1000 μm, which were reduced by 300 μm after the process. The prostheses' surfaces allowed the growth of human osteoblasts. Ciocca et al. [147] built DMLS titanium alloy meshes for the regeneration of atrophic maxillary arches. They used a 0.6 mm thickness mesh. Jardini et al. [148] manufactured Ti-6Al-4V parts for maxillofacial implants, using the DMLS technology. The same technology and material was used to obtain customized parts for upper maxillary implants [149].

Spinal Implants
Yang et al. [150] used the EBM technique to obtain Ti-6Al-4V vertebral bodies of sheep. Xu et al. [151] manufactured vertebral implants with the EBM technique and Ti-6Al-4V material, and Li et al. [152] tested porous artificial vertebral bodies in vivo, manufactured with the same material and technique. Choy et al. [14] printed titanium porous vertebral prostheses and performed in vivo spinal surgery. Siu et al. [153] applied EBM to obtain Ti-6Al-4V interbody cages for the lumbar area, in a case study with a deformity caused by osteoporotic fractures.
Hollander et al. [154] used direct laser forming (DLF) to obtain Ti-6Al-4V alloy vertebral bodies (Figure 7). They manufactured meshes with nominal pore sizes of 500, 700, and 1000 µm, which were reduced by 300 µm after the process. The prostheses' surfaces allowed the growth of human osteoblasts.
McGilvray et al. [99] compared the performance of polyetheretherketone (PEEK), titanium-coated PEEK and 3D printed porous titanium alloy with regard to the manufacture of interbody fusions of the lumbar area of sheep. They reported higher cell ingrowth in titanium implants than in PEEK or titanium-coated PEEK cages. McGilvray et al. [99] compared the performance of polyetheretherketone (PEEK), titaniumcoated PEEK and 3D printed porous titanium alloy with regard to the manufacture of interbody fusions of the lumbar area of sheep. They reported higher cell ingrowth in titanium implants than in PEEK or titanium-coated PEEK cages.

Upper Limb Prostheses
Zou et al. [155] obtained customized macro-porous shoulder Ti-6Al-4V prostheses with the EBM technique, implanted them and observed good short-term follow-up effects. In 2017, the same process was used for the first time to manufacture a mold to cast a titanium first metacarpal hand implant [156].

Chest Implants
In 2013, Turna et al. reported the first 3D-printed chest implant [157]. It consisted of a plate for sternum and ribs. Aranda et al. obtained a more advanced implant in 2015 [158]. Aragón and Méndez manufactured a more flexible implant [159]. In 2017, a titanium chest implant was manufactured with the EBM technique, and further fixed [160], showing the versatility of the 3D-printing processes to obtain complex shapes. A clavicle was reconstructed in pure Ti by means of EBM [161].

Pelvic Implants
A pelvic specific implant was manufactured in Ti-6Al-4-V with EBM and subsequently implanted [162].
Another pelvic patient-specific implant was manufactured with a laser powder bed fusion technology [163].

Upper Limb Prostheses
Zou et al. [155] obtained customized macro-porous shoulder Ti-6Al-4V prostheses with the EBM technique, implanted them and observed good short-term follow-up effects. In 2017, the same process was used for the first time to manufacture a mold to cast a titanium first metacarpal hand implant [156].

Chest Implants
In 2013, Turna et al. reported the first 3D-printed chest implant [157]. It consisted of a plate for sternum and ribs. Aranda et al. obtained a more advanced implant in 2015 [158]. Aragón and Méndez manufactured a more flexible implant [159]. In 2017, a titanium chest implant was manufactured with the EBM technique, and further fixed [160], showing the versatility of the 3D-printing processes to obtain complex shapes. A clavicle was reconstructed in pure Ti by means of EBM [161].

Pelvic Implants
A pelvic specific implant was manufactured in Ti-6Al-4-V with EBM and subsequently implanted [162].
Another pelvic patient-specific implant was manufactured with a laser powder bed fusion technology [163].

Lower Limb Prostheses
Cronskar et al. [42] produced Ti6Al4V hip stems by means of EBM. They reported a reduction of the fatigue limit using the rough surfaces obtained by 3D printing when compared to conventional machining. Murr [164] reported a Ti-6Al-4 V porous acetabular cup, manufactured with the EBM technique ( Figure 8).
Weiβmann et al. [165] manufactured titanium alloy porous acetabular cups with the SLM technique. They tested three types of cells: twisted, combined and combined open, and found that their mechanical strength depends on the geometry of the unit cell employed, its dimensions and the volume and porosity responsible for the press fit of the prosthesis. A custom-made component of a hip implant endoprosthesis was obtained in titanium alloy with the same technique. The implant matched the anatomical features of the patient, with porous structures to favor osseointegration, and with good mechanical properties [166].

Lower Limb Prostheses
Cronskar et al. [42] produced Ti6Al4V hip stems by means of EBM. They reported a reduction of the fatigue limit using the rough surfaces obtained by 3D printing when compared to conventional machining. Murr [164] reported a Ti-6Al-4 V porous acetabular cup, manufactured with the EBM technique ( Figure 8). Weiβmann et al. [165] manufactured titanium alloy porous acetabular cups with the SLM technique. They tested three types of cells: twisted, combined and combined open, and found that their mechanical strength depends on the geometry of the unit cell employed, its dimensions and the volume and porosity responsible for the press fit of the prosthesis. A custom-made component of a hip implant endoprosthesis was obtained in titanium alloy with the same technique. The implant matched the anatomical features of the patient, with porous structures to favor osseointegration, and with good mechanical properties [166].
Croitoru et al. [168] printed porous Ti6Al4V femoral stems for a hip replacement using powder bed fusion technology (laser sintering). They found that large fenestrations confer an elastic behavior to the structure while also contributing to enhance osseointegation. Arabnejad et al. [16] manufactured a titanium alloy stem taper-wedge implant with selective laser melting (SLM) ( Figure  2e). They reported high mechanical strength with reduced stress-shielding, while the implant respected bone in-growth. Femoral implants have also been obtained with SLM in CoCrMo alloys [169].
Ruppert et al. [170] compared the performance of femoral implants manufactured by both the EBM and the SLM methods. Osseointegration was evaluated by means of mechanical testing. Coarse EBM implants showed higher removal torque than fine DMLS implants.
Murr et al. [171] made EBM porous structures for knee replacement, with Co-29Cr-6Mo alloy as the femoral and Ti-6Al-4V as the tibial component of the knee prostheses. Liu et al. used the same technique with titanium alloy as material to manufacture porous knee prostheses [172].

Dental Implants
Dental restorations have been obtained with the SLM technology [173]. Tolochko et al. used the combination of SLS and SLM to obtain titanium dental implants [174]. CoCrMo alloys have also been employed for the same purpose, with SLM processes [175][176][177]. Croitoru et al. [168] printed porous Ti6Al4V femoral stems for a hip replacement using powder bed fusion technology (laser sintering). They found that large fenestrations confer an elastic behavior to the structure while also contributing to enhance osseointegation. Arabnejad et al. [16] manufactured a titanium alloy stem taper-wedge implant with selective laser melting (SLM) (Figure 2e). They reported high mechanical strength with reduced stress-shielding, while the implant respected bone in-growth. Femoral implants have also been obtained with SLM in CoCrMo alloys [169].
Ruppert et al. [170] compared the performance of femoral implants manufactured by both the EBM and the SLM methods. Osseointegration was evaluated by means of mechanical testing. Coarse EBM implants showed higher removal torque than fine DMLS implants.
Murr et al. [171] made EBM porous structures for knee replacement, with Co-29Cr-6Mo alloy as the femoral and Ti-6Al-4V as the tibial component of the knee prostheses. Liu et al. used the same technique with titanium alloy as material to manufacture porous knee prostheses [172].

Dental Implants
Dental restorations have been obtained with the SLM technology [173]. Tolochko et al. used the combination of SLS and SLM to obtain titanium dental implants [174]. CoCrMo alloys have also been employed for the same purpose, with SLM processes [175][176][177].
Ortorp et al. [178] compared four different manufacturing techniques to obtain CrCo dental prostheses: lost wax casting, lost wax with milled wax, milling, and direct laser metal sintering (DLMS). The best fit was reported for the DLMS technique.

Implants in General
The binder jetting technology was used to manufacture stainless steel bone scaffolds [179]. Four different lattices were studied, and it was observed that mechanical strength depends on the type of lattice. Sintering time and temperature also influence mechanical strength. Porous titanium parts have been characterized in order to use them as implants [180].
The DED technique has been employed, for example, to obtain functionally graded structure in Ti-Mo alloys [181].
As an example of the extrusion processes (FFF or FDM), polylactic acid (PLA) and polyethene terephthalate (PET) polymeric filaments mixed with stainless steel 316L and copper alloy Cu-10Sn allowed for the printing of multi-material parts [182].  Fused Filament Fabrication (FFF) 1 [182] As can be observed in Table 19, the largest number of references in the present paper corresponds to titanium alloys, firstly with the EBM technique and secondly with the SLM technique. They are followed by far by other technologies like BJ, EBM and FFF. Both EBM and SLM are powder bed fusion technologies. According to Table 6, both technologies have in common high dimensional accuracy and high corrosion resistance of the parts, because of the use of inert atmospheres. SLM provides higher resolution and part complexity than EBM. However, printing speed of EBM is higher than that of SLM, and it is cheaper. In EBM, only conductive alloys are used. On the contrary, SLM can be used for different alloys such as Inconel, stainless steel, etc.

Comparison of the AM Techniques and Materials Used for Metallic Implants
In the following paragraphs, the impact of EBM and SLM techniques on biocompatibility, porosity, mechanical performance, and biodegradability of the implants is addressed.
Nowadays, the concept of biocompatibility means not only that a metal should be non-toxic but also that it should have a positive effect when interacting with living cells [183]. The three most employed materials for implants, Ti alloys, CoCr alloys and stainless-steel show high biocompatibility with the human body. However, high temperature AM processes such as EBM and SLM modify the physical, chemical and mechanical properties of the alloys, which are related to biocompatibility. In this line, Wang et al. found good haemocompatibility, no dermal irritation and no skin allergic reaction of Ti-6Al-4V alloy with both EBM and SLM processes [184]. In another comparative study between EBM and SLM processes, it was observed that SLM manufactured commercially pure titanium (CP-Ti) scaffolds presented higher cell viability and cell adhesion than EBM manufactured Ti-6Al-4V (Ti64) scaffolds [185]. The surface finish of the printed parts is an important factor influencing biocompatibility, since it affects the cell attachment, proliferation and differentiation [38]. Low roughness values below 2.0 µm were reported to improve bone regeneration in titanium implants [186]. However, SLM and EBM lead to higher roughness values of 5-20 µm and 20-50 µm respectively [187]. In order to reduce roughness and improve cell adhesion along with cell proliferation, for example, the laser polishing operation can be applied [177].
The porosity of implants is directly related to cell growth. For example, the porosity of the cancellous bone ranges from 50% to 90% [77]. As for pore size, a certain variability is required, with small pores to improve cell attachment and large pores that favor nutrient transport [78]. For example, pore size values between 200 and 1000 µm are desirable in trabecular structures [117,188]. In addition, pores should be interconnected, in order to favor permeability and nutrient transport [80]. Regarding porosity, EBM combined with hot isostatic pressing achieved density values that were higher than 99%, while SLM did not exceed 97% [189]. Heinl al. manufactured different Ti-6Al-4V porous structures with interconnected porosity for bone implants, using selective electron beam melting (SEBM) [190]. Xue et al. used laser engineered direct shaping (LENS, a DED AM technology) to manufacture titanium porous implants for bone replacement [191]. Similar structures to those of the cancellous bone have been printed in titanium with the SLM technique [192].
High mechanical strength is important to protect patients with implants from fractures [193]. Titanium and some of its alloys have good mechanical properties, including high strength, a quite suitable elastic modulus, high fracture toughness and high fatigue strength [194]. However, additive manufacturing processes affect the properties of the material. For example, the compression strength of titanium aluminides obtained with the EBM technique, with preheating of the material and vacuum surrounding, were similar to those of the wrought material [189]. The higher the preheating, the lower the residual stresses are in EBM. Excellent wear properties were also reported in EBM processes in the transverse direction [189]. SLM manufactured titanium alloys also presented good mechanical properties [104]. On the other hand, metal implants should mimic the elastic modulus of bones. However, usually titanium alloys have higher elastic modulus values (around 112 GPa) [195] than those of the cortical bone, ranging from 7.7 to 21.8 GPa [196,197]. For this reason, porous structures can be built that reduce the elastic modulus of solid materials [198].
Biodegradability is another important property of the metallic implants. Alloys can be divided into two groups with regard to their biodegradability: materials with high mechanical properties but lower biodegradability such as stainless steel, titanium and CrCo alloys, and metals or alloys with higher biodegradability but lower mechanical strength such as zinc, magnesium and iron [117]. For example, Ti and stainless steel structures do not degrade significantly with time, remaining in the body as a foreign object [195]. This can lead to several diseases such as infections, physical irritation, inflammatory reaction, etc. [199].

Conclusions
In recent years, additive manufacturing has been successfully incorporated into the manufacture of metallic implants, thanks to the possibility to obtain customized parts with porous structures that favor cell growth and osseointegration. The main conclusions are summarized next: (1) The most-used metals in AM manufactured implants are titanium, titanium alloys, CoCr alloys, and stainless steel, mainly because of their high mechanical properties and biocompatibility. In addition, as a general trend, they maintain their properties when the parts are additively manufactured (2) The most popular techniques to obtain AM metallic implants are EBM and SLM. Both technologies belong to the powder bed fusion group, and both of them provide high dimensional accuracy and high corrosion resistance. EBM uses higher printing speed than SLM, and it is cheaper. On the contrary, SLM allows higher resolution, better surface finish and higher part complexity than EBM.
(3) Several examples are available in the literature of cranial, mandibular, spinal, and upper & lower limb titanium alloy implants, among others, manufactured with EBM and/or SLM techniques.
(4) The use of BJ, DED, or FFF to manufacture metallic implants is still at an early stage, in which metallic structures have been obtained and characterized, but with few in vivo tests. Further research is required in order to use these technologies in implants.
The application of AM technologies to the manufacture of metallic implants is still under development. Both the improvement of the printing technologies and the research investigating new alloys will help to consolidate the use of AM technologies for this purpose. Funding: This project was co-financed by the European Union Regional Development Fund within the framework of the ERDF Operational Program of Catalonia 2014-2020 with a grant of 50% of total cost eligible, project BASE3D, grant number 001-P-001646.

Conflicts of Interest:
The authors declare no conflict of interest.