3D printing metal implants in orthopedic surgery: Methods, applications and future prospects

Abstract

Background

Currently, metal implants are widely used in orthopedic surgeries, including fracture fixation, spinal fusion, joint replacement, and bone tumor defect repair. However, conventional implants are difficult to be customized according to the recipient's skeletal anatomy and defect characteristics, leading to difficulties in meeting the individual needs of patients. Additive manufacturing (AM) or three-dimensional (3D) printing technology, an advanced digital fabrication technique capable of producing components with complex and precise structures, offers opportunities for personalization.

Methods

We systematically reviewed the literature on 3D printing orthopedic metal implants over the past 10 years. Relevant animal, cellular, and clinical studies were searched in PubMed and Web of Science. In this paper, we introduce the 3D printing method and the characteristics of biometals and summarize the properties of 3D printing metal implants and their clinical applications in orthopedic surgery. On this basis, we discuss potential possibilities for further generalization and improvement.

Results

3D printing technology has facilitated the use of metal implants in different orthopedic procedures. By combining medical images from techniques such as CT and MRI, 3D printing technology allows the precise fabrication of complex metal implants based on the anatomy of the injured tissue. Such patient-specific implants not only reduce excessive mechanical strength and eliminate stress-shielding effects, but also improve biocompatibility and functionality, increase cell and nutrient permeability, and promote angiogenesis and bone growth. In addition, 3D printing technology has the advantages of low cost, fast manufacturing cycles, and high reproducibility, which can shorten patients' surgery and hospitalization time. Many clinical trials have been conducted using customized implants. However, the use of modeling software, the operation of printing equipment, the high demand for metal implant materials, and the lack of guidance from relevant laws and regulations have limited its further application.

Conclusions

There are advantages of 3D printing metal implants in orthopedic applications such as personalization, promotion of osseointegration, short production cycle, and high material utilization. With the continuous learning of modeling software by surgeons, the improvement of 3D printing technology, the development of metal materials that better meet clinical needs, and the improvement of laws and regulations, 3D printing metal implants can be applied to more orthopedic surgeries.

The translational potential of this paper

Precision, intelligence, and personalization are the future direction of orthopedics. It is reasonable to believe that 3D printing technology will be more deeply integrated with artificial intelligence, 4D printing, and big data to play a greater role in orthopedic metal implants and eventually become an important part of the digital economy. We aim to summarize the latest developments in 3D printing metal implants for engineers and surgeons to design implants that more closely mimic the morphology and function of native bone.

Graphical abstract

1. Introduction

With the progressive aging of the world's population, many elderly populations are prone to orthopedic diseases such as fractures due to advanced age and metabolic diseases, resulting in pain or loss of function [1]. By 2050, it is expected that the population aged 65 or elder will increase to about 20% of the global population [2]. This increase in the elderly population, coupled with changes in work and lifestyle, has also led to an increasing number of young people suffering from degenerative diseases such as osteoarthritis and osteoporosis. Solving these diseases usually requires replacement or repair of the body's skeleton, so the demand for orthopedic implants is growing rapidly [3].

Orthopedic implants can be made of metal, bioceramic, biopolymer, or composite biomaterials [4]. With the mechanical strength requirements of orthopedic surgical implants, surgeons often choose implants made of metal to provide support which enables early movement of the patient and prevents complications [5]. Although metal implants have been used in surgeries such as fracture fixation, spinal fusion, joint replacement, and bone tumor defect repair, traditional methods of implant fabrication have many limitations that make it difficult to meet the individual needs of patients [3,4]. It is important to match the mechanical properties between the metal implant and the bone, as higher elastic modulus tends to produce stress shielding, leading to subsequent bone resorption and eventual implant failure [6].

Precision, intelligence, and personalization are the future direction of orthopedics [7]. After fulfilling all the requirements for an ideal orthopedic implant, the diseased area can produce healthy and functional bone with the help of metal biomaterials [2]. To obtain such ideal biomaterials, advanced manufacturing techniques are required that can precisely fabricate complex geometries, reduce excessive mechanical strength, increase cell and nutrient permeability, and promote angiogenesis and bone growth [8,9]. Three-dimensional (3D) printing technology, also known as additive manufacturing (AM), or rapid prototyping (RP), has revolutionized the biomedical field as an advanced digital manufacturing technology [10]. In the clinic, physicians can use the patient's medical imaging data, such as computed tomography (CT)/magnetic resonance imaging (MRI), to individually design and fabricate patient-specific orthopedic implants to fit the patient's surgical requirements [1,2,5]. With the development of digital technology, computer-aided design (CAD) techniques, and surgical technology, there is an increasing interest in patient-specific metal implants with similar structural and functional properties to natural bone [1,11]. Furthermore, 3D printing technology has the advantages of low cost, fast manufacturing cycle, and high reproducibility, shortening the time of patient surgery and hospitalization [5,12]. In this paper, we review the characteristics of 3D printing methods and biometals and summarize the properties of 3D printing metal implants and their clinical applications in orthopedic surgery. Based on this, we systematically discuss the potential possibilities for their further promotion and improvement.

2. Metal 3D printing methods

Metal 3D printing methods have been available for at least 20 years and are widely used in the biomedical field [5]. Traditional manufacturing methods are limited to the fabrication of complex bone implants, and it is difficult to simulate the structure of cortical and cancellous bone in real bone tissues [2]. Compared to traditional manufacturing methods, metal 3D printing methods have unparalleled advantages in terms of high production accuracy, the ability to print controlled microporous structures, and achieving perfect replication of real bone tissue [8,11]. The process of fabricating 3D printing metal implants can be divided into four parts (Fig. 1). (1) Personalized acquisition of patient imaging data, such as CT or MRI. (2) The orthopedic surgeon and engineer use CAD software to create a data model of the implant based on the patient's needs, which is converted into a series of 2D layer slices and saved as stereolithography (STL) data. (3) Computer-controlled fabrication of the appropriate 3D printing technology melts the metal material layer by layer to print the molded model, and (4) Final finishing of the implant, such as grinding, coating, and surface oxidation techniques. In this section, the currently used methods for metal 3D printing are introduced and summarized in Fig. 2 and Table 1.

Figure 1.

The process of 3D printing metal implants (A) Personalized acquisition of patient imaging data, such as X-rays, CT, or MRI, (B) The orthopedic surgeon and engineer use CAD software to create a data model of the implant based on the patient's needs, which is converted into a series of 2D layer slices and saved as stereolithography (STL) data, (C Computer-controlled fabrication of the appropriate 3D printing technology melts the metal material layer by layer to print the molded model, and (D) Final finishing of the implant, such as grinding, coating, and surface oxidation techniques.

Figure 2.

Metal additive manufacturing (A) selective laser sintering [13], (B) selective laser melting [14], (C) electron beam melting [15], (D) laser direct metal deposition [16], (E) laser induced forward transfer [17], (F) atomic diffusion additive manufacturing [18], reproduced with permission.

Table 1.

The detailed classification of 3D printing methods for biometals.

Technique types	Description	Materials	Cost	Advantages	Limitations
Selective laser sintering (SLS) [2]	The laser selectively scans and melts a layer of material powder at a set speed and energy density	Titanium (Ti) alloys; cobalt-chromium (Co–Cr); stainless steel (SS); nickel (Ni)–Ti alloys	$$	1Fast print speed, up to 25.4 ​mm/h;	1Powdery surface finish
				2High material utilization, no sintered powder can be recycled repeatedly;	2Requiring post-printing process
				3No significant need for support structures	3Process with odor generation
Selective laser melting (SLM) [19]	Using a high-powered laser to completely melt each layer of metal powder, rather than just sinter it, results in a very dense and strong printed object	Almost all metal alloys	$$$	1Higher accuracy than SLS (0.02 ​mm);	1Low speed
				2Variety of materials;	2Possible delamination and porosity
				3Smooth surface	3High temperature gradients can lead to stress and misalignment within the final product
				4Suitable for complex internal structures
Electron beam melting (EBM) [20]	Similar to SLM, it is capable of producing a dense metal structure. The difference between these two techniques is that EBM uses an electron beam rather than a laser to melt the metal powder	Ti alloys; Co–Cr	$$$	1High forming efficiency;	1Less accurate
				2High product strength and less impurity due to vacuum melting;	2Poor surface finish and requires the post-printing process
				3Fabrication of brittle materials due to reduced cooling rate	3Expensive equipment
					4Long printing time
Laser direct metal deposition (LDMD)[21]	During the process, a nozzle aggregates powder on its working plane, while its laser beam centers to a point. The laser solidifies the powder which it shines on, creating a stacked entity at that position	Almost all metal alloys	$$	1Localized heat input and consequently, low distortion, allowing printing of metal with high melting point;	1Poor surface roughness
				2Fabricate functional gradient materials and parts	2Uncontrollable composition and microstructure
				3Perform surface defect repair of parts	3Complex residual stress
Laser-induced forward transfer (LIFT) [22]	The laser is exposed to a thin layer of metal material, resulting in a thermal stress wave or evaporation that subsequently yields the ejection of a liquid micron-sized droplet onto a transparent substrate	Chromium, tungsten, gold, Ni, aluminum	$$	1Very small-scale part processing;	1Small-batch production
				2Easy operation and without vacuum environment or cleanroom;	2Small size and thin layers
				3Wide range of printed materials;	3Weak structural support
				4High accuracy
Atomic diffusion additive manufacturing (ADAM) [23]	Processes use a wire which is made of metal powders enclosed in a thermoplastic polymer that works as a binder for the metallic particles	Sinterable metal powder: SS, Ti alloys	$	1The density of parts can reach about 95–99%;	Longer lead time to a strong part
				2Low cost;
				3High-quality surface;
				4Precise-complex structure;
				5Excellent isotropic performance;
				6Batch production

2.1. Selective laser sintering

Selective laser sintering (SLS) is a type of powder bed melting technology, patented in 1989 [2,13]. In this process, the powder is first preheated to a temperature below the sintering point so that the powder does not melt completely. Then the powder is evenly distributed and dispersed using a powder spreading roller, which focuses the laser beam precisely on the powder layers and scans the cross section of the part. Lower the print platform and repeat the process until all layers are sintered [24]. The outstanding feature o f SLS is that the powder can be used as support without laser sintering, so there is no need to print additional support materials [25]. Furthermore, SLS has the advantage of a wide selection of molding materials [26]. Although it can reduce the heat of material molding to a certain extent, it directly leads to the problems of porousness, low density, high surface roughness, and insufficient mechanical properties of the implant due to the presence of solid-phase particles, which require post-printing treatment [27]. In addition, odors are generated during the production process. Li et al. [28] found that the microstructure and mechanical properties of Ti alloy bone scaffolds fabricated by SLS technology were more similar to cancellous bone without significant stress shielding, and could be more effective in achieving early stability after implantation in vitro and in vivo. In addition, Kawaguchi et al. [29] used the SLS technique to fabricate a bone scaffold for implantation into the dog femur and found it could promote bone formation and vascularization at the site of the bone defect.

2.2. Selective laser melting

Selective laser melting (SLM) is also a type of powder bed melting technology and was first proposed in 1995 [2,14]. The technology was developed based on SLS, so the basic principles of both are similar. The difference is that the laser temperature of SLM is higher and will completely melt all the metal powder unformed. Therefore, the entire printing process in SLM needs to be carried out in a chamber protected by an amorous gas to avoid oxidation of the metal [19]. Compared to metal products fabricated with SLS, SLM has better molding properties, higher density, better mechanical properties, and higher dimensional accuracy [30]. The subsequent processing required in conventional processes such as casting and machining is not required. At the same time, this technology allows the processing of a wide range of medical metals, such as stainless steels (SS), titanium (Ti) alloys, and cobalt-based alloys, to form implants with complex structures [31]. Because of these, SLM has become an ideal method for fabricating complex or functional gradient structures with precise dimensions. This encourages its use in the preparation of metallic implants and scaffolds. However, it has some disadvantages. The process parameters of SLM are complex and the manufacturing speed is very low. Thinner layer thicknesses are required for greater accuracy, especially when faced with complex parts that require a large number of support structures, the printing cost and time for SLM will increase significantly, making it difficult to be used in large-scale manufacturing [32]. Residual stress is the common phenomenon that may cause interlayer debonding and stress cracking. These cracks may decrease the mechanical properties and dimensional accuracy [33]. The heating/cooling rate of the SLM process is high, which leads to high residual stress in final products. It is difficult to deposit metallic powder on the former layer uniformly, which may lead to delamination and porosity. Thus, it is important to minimize the balling effect, such as increasing laser power or reducing scan speed. SLM has been utilized to fabricate orthopedic implants such as replacements for zygomatic bone and finger [34]. Wang et al. [35] designed a novel trabecular acetabular cup by SLM technique and performed compression tests. The results showed that the compressive strength and elastic modulus were consistent with the mechanical properties of human cortical bone. Przekora et al. [36] found that SLM-fabricated mesh Ti6Al4V cages have all the characteristics of an optimal spinal implant, such as a low risk of implant subsidence and providing good osseointegration at the bone-implant interface.

2.3. Electron beam melting

Similar to SLS and SLM, electron beam melting (EBM) is a common 3D printing technique for metal implants that uses a high-energy, high-speed electron beam to bombard metal powders, melt the powdered material and form the product [20,15]. EBM is one of the most common 3D printing techniques applied for orthopedic metal implants, such as acetabular cups with outer porous mesh structure regions, femoral knee implants, and intramedullary rods [2]. The electron beam is controlled by a set of electromagnetic coils that precisely point the electron beam at the area to be melted. The electron beam selectively moves as it melts the powder, leaving the metal powder unfused. Since EBM uses electron beam heating to produce higher temperatures, it is mostly used to print Ti and cobalt-chromium (Co–Cr) alloys [20]. Moreover, compared to laser beam melting of metal powders, EBM can create a vacuum environment very well by the properties of the high-energy electron beam itself, without having to set up an environment specifically for isolating the material powder from the outside air. The electron beam has the advantages of a high energy utilization rate, a high material absorption rate, better stability, and low operation and maintenance costs. This also allows EBM to print parts with high density, high strength, and low risk of deformation [37]. However, the processing time of EBM could be longer than SLM in order to cool down the implants to room temperature. EBM-built implants also exhibit rough surfaces because of the attachment of a large amount of partially melted particles, which is similar to SLM [38]. What's more, it still has deficiencies that need to be improved such as low accuracy and expensive equipment. Liu et al. [39] prepared personalized porous bone plates by EBM and coated them with tantalum (Ta) metal. The bone plates exhibited a similar elastic modulus to cortical bone and did not generate stress shielding. Notably, EBM has many unique clinical applications in the field of bone repair, ranging from a simple acetabular cup to the fifth toe, from the hand–wrist complex to the shoulder, and from vertebral replacement to cranio-maxillofacial reconstruction [39]. Implants manufactured by EBM, such as acetabular cups, are also approved by the U.S. Food and Drug Administration (FDA) and were CE certified in 2010 and 2007, respectively [34].

2.4. Laser direct metal deposition

Laser direct metal deposition (LDMD) is a metal 3D printing technology developed on the basis of laser cladding technology combined with SLS [16]. It was first proposed by Sandia National Laboratories in the 1990s [21]. Many universities and institutions have independently studied LDMD, leading to various names for the technology, such as laser engineered net shaping (LENS), directed energy depositioin (DED), laser rapid forming (LRF), etc. Similar to SLS, the laser system is also the heating element, but the difference is that the LDMD heats and melts the metal substrate [40]. Due to the large laser focused spot, the printing accuracy is generally above 1 ​mm. Although the molding efficiency is greatly improved, the dimensional accuracy and surface finish are not ideal, and further mechanical processing is required before actual use. LDMD requires thermal cycling of the metal several times at melting and lower temperatures, and this thermal behavior leads to complex microstructural changes. As a result, it is difficult to control the composition and structure of the part [41]. At the same time, during implant fabrication, the metal experiences rapid heating and cooling, which can easily generate complex residual stress distributions that can lead to cracking and deformation of the metal implant. This high residual stress also affects the mechanical properties and corrosion resistance [42]. The uncontrollability of composition and microstructure, and the formation of residual stresses are two major disadvantages of LDMD technology [43]. In 2007, Krishna et al. [44] fabricated Ti hip stems by LENS technology, which improves the machining flexibility of complex shaped implants and reduces the stiffness of load-bearing implants. Balla et al. [45] successfully deposited a Ta coating on Ti using LENS to enhance the osseointegration properties. Samuel et al. [46] described the corrosion resistance of bone implants made of laser-deposited Ti–Nb–Zr–Ta alloys as superior to Ti–6Al–4V alloys with enhanced cell differentiation properties.

2.5. Laser induced forward transfer

For most of the cases, metal printing has been limited to materials with low melting points. Until now, 3D printing of metals such as copper or gold has proven to be very difficult or extremely expensive [17]. For this reason, laser induced forward transfer (LIFT) was developed [22]. It is a direct printing method that deposits various metals after laser interaction. The technique does not require metal powders and works differently from conventional metal 3D printing techniques. The method has been successfully applied to print chromium, gold, Ti, nickel (Ni), and aluminum [47]. However, LIFT also has some disadvantages, such as the inability to generate overhanging large 3D implants, weak structural support, and the inability to carry out mass production [48]. These limitations stem from the nature of LIFT and may require the sacrifice of support material.

2.6. Atomic diffusion additive manufacturing

The principle of atomic diffusion additive manufacturing (ADAM) is almost identical to the fused deposition 3D printing technology of the extrusion molding process [18]. The plastic binder can be removed in a sintering furnace after printing, and the metal powder is sintered with a density of 95–99%. Only the raw materials used in this technology are not plastics and thermoplastic resins for fused deposition, but metal materials such as Ti, aluminum, and iron (Fe) [23]. The Matel X metal 3D printer from Markforged is a prime example of this technology [18]. The main advantages of ADAM are as follows: 100 times faster than traditional machining methods, one-tenth the cost of traditional metal 3D printing, produces high-quality part surfaces without post-processing, creates precise, complex structures, has excellent isotropic properties, and is suitable for mass production. However, ADAM has the problem of long time to manufacture parts.

3. Metal materials

Although metals have been used in medicine since ancient times, metal implants were largely unsuccessful until the development of aseptic surgical techniques in the 1860s, which facilitated the use of metals in implants [3,11]. In 1896, Ni-plated steel screws were used for the treatment of bone dissection. In the 1920s, SS was developed with characteristics resistant to corrosion by body fluids. In the 1930s, Co–Cr alloys, originally developed for the aerospace industry, were first used in medical implants. Pure Ti implants were introduced in the mid-1950s, followed decades later by Ti alloys with superior mechanical properties [49]. In the 1970s, the clinical application of nickel-titanium (Ni–Ti) shape memory alloys (SMA) spurred further development of biomedical metals. As metal printing technology and materials science continue to mature, more and more metals can be safely implanted in the human body, and metal materials are receiving more and more attention.

In orthopedic surgery, the surgeon selects different types of biometal depending on the patient's clinical requirements [3,50]. Among the inert biometals, SS 316L, Co–Cr alloys, and Ti alloys are the most commonly used metals for fracture fixation and bone remodeling [5,[51], [52], [53], [54]]. This is mainly due to their long-term stability under highly reactive in vivo conditions and their excellent mechanical properties [55]. However, it is known that during the process of wear and slow erosion, the implants release metal ions, which may induce local tissue damage and inflammatory response [56,57]. Degradability is the preferred choice for temporary implant support in bone healing, such as plates and screws, thus eliminating unnecessary surgical risks and excessive costs for a second surgery [58]. Currently, magnesium (Mg), Fe, and zinc (Zn) alloys are the best biodegradable metals for orthopedics because they have good in vivo biocompatibility, controlled degradation profiles, and sufficient mechanical strength to support bone during regeneration [[59], [60], [61], [62]]. The mechanical properties of biomedical metal materials and natural human bone are listed in Fig. 3 and Table 2.

Figure 3.

Properties of 3D printing metal materials (A) Stainless steel [51], (B) Titanium alloy [52], (C) Cobalt-chromium alloy [53], (D) Tantalum alloy [52], (E) Shape memory alloy [54], (F) Zinc alloy [60], (G) Iron alloy [61], (H) Magnesium alloy [62], reproduced with permission.

Table 2.

Mechanical properties of biomedical metal materials and natural human bone.

Material	Yield strength (Mpa)	Modulus of elasticity (Gpa)	Biocompatibility	Applications	Reference
Stainless Steel	220–260	∼190	High biocompatibility	Acetabular cups, bone screws, bone plates, pins, etc.	[63]
CP-titanium (Ti)	240–550	100	High biocompatibility	Bone screws, bone plates, etc.	[64,65]
Ti–6Al–4V	950	112	High biocompatibility		[66]
Cobalt-chromium (Co–Cr) alloy	450–660	∼210	Low biocompatibility	Bone screws, bone plates, femoral stems, total hip replacements, etc.	[5]
Tantalum	205–480	3	High biocompatibility	Socket cups, pads, rods, and intervertebral fusion devices	[67]
Nickel (Ni)–Ti	195–690 (austenitic phase); 70–140 (martensitic phase)	48	High biocompatibility	Intervertebral fusion devices	[68,69]
Magnesium based alloy	160∼200	10–45	High biocompatibility, H2 evolution	Bone screws, bone plates (non-load bearing parts), etc.	[70,71]
Iron based alloy	100–200	188–215	Low biocompatibility	Bone screws, bone plates, etc.	[72,73]
Zinc based alloy	150–180	—	Cytotoxicity, no gas production, high biocompatibility	Bone screws, bone plates (load-bearing parts), etc.	[74,75]
Cortical bone	188–222	15–35	Natural skeleton	Natural skeleton	[1,11]
Trabecular bone	2–70	0.01–3	Natural skeleton	Natural skeleton	[1,11]

3.1. Stainless steel

SS remains one of the most commonly used alloys for the manufacture of surgical implants and instruments, and at least half of all orthopedic implants in the U.S. are made of it [63]. SS implants are inexpensive, simple to fabricate, and affordable for many patients, but they are gradually being replaced by other alloys, particularly Co-Cr and Ti [76,77]. Because of its general biocompatibility and corrosion resistance, SS is used in fracture treatment in the form of screws and plates to provide temporary support in anticipation of complete bone tissue regeneration, which can be surgically removed again after the bone tissue has healed [78]. Compared to other methods, the SLM method solidifies faster and therefore produces 316L parts with a fine honeycomb dendritic structure for higher strength.

The antioxidation and anti-corrosion properties of SS are gained from the addition of Cr and Ni [63]. Most orthopedic implant applications of SS 316L consist of reduced carbon (less than 0.03%), Cr (16–18%), and Ni (10–14%) with additions of molybdenum (2–3%), manganese (Mn) (approximately 2%) and minor additives of sulfur, silicon, phosphorus, and nitrogen [79]. Cr forms a protective oxide membrane on the surface of SS implants, and this membrane provides protection from implants and does not interfere with the metabolic processes occurring in vivo [80]. However, we should consider that SS 316L is prone to stress cracking and is susceptible to corrosion by chlorides [63]. Therefore, SS 316L is probably only used for implants that do not require long-term placement in the body, such as steel plates [81]. It should be mentioned that Cr and Ni are apparently harmful to human cells due to their presence in SS. If released due to corrosion, it may irritate tissues and cause an immune response that can seriously lead to cancer. Nitrogen is typically alloyed with Ni-free SS to maintain a low Ni content [82,83]. Wang et al. [84] manufactured cubic, octahedral, and triple-period minimum surface (TPMS) gyroscopes of SS316L at a relative density of 40/50/60% with appropriate Young's modulus and excellent biocompatibility for use in implants.

3.2. Titanium alloy

Ti has been known since the late 19th century for its ideal mechanical capacity and ability to bond with the adjacent bone, improving the stability of the implant [85]. Moreover, Ti has a monopoly in the orthopedic implant market because it has the remarkable advantage of not interfering with MRI [86]. The excellent biocompatibility of Ti is mainly due to the reaction of their surface with oxygen to form a dense TiO2 oxide membrane. In this family, Ti–6Al–4V was identified as one of the most useful Ti alloys [66]. Since the 1970s, Ti and its alloys have been widely used in artificial joints, bone trauma products (intramedullary nails, fixation plates, screws, etc.), and orthopedic internal fixators of the spine because of their excellent biocompatibility, good corrosion resistance, and high specific strength [87].

The first generation of Ti alloys: Commercially pure Ti (CP–Ti), Ti–3Al-2.5V, Ti–6Al–4V. In the 1940s, CP-Ti was first used for non-load-bearing, corrosion-resistant applications. Subsequently, Ti–3Al-2.5V was gradually used as an orthopedic implant material, but its use in orthopedics was limited due to its poor wear resistance [64,65]. Ti–6Al–4V was successfully developed in the United States in 1954 and has a high strength [88,89]. Compared to CP-Ti, Ti–6Al–4V has a 50% increase in mechanical strength, which allows Ti–6Al–4V to be used in load-bearing implants such as fracture fixation plates, hip stems, and screws [90]. The highest relative density reported for SLM Ti6Al4V is 99.80% and fully dense parts for Ti6Al4V by EBM were obtained by Arcam AB. The difference between EBM and SLM in processing Ti6Al4V lies in the final microstructure which in turn, affects the mechanical properties [91]. However, there are some concerns because Ti contains cytotoxic aluminum and vanadium. In addition, CP-Ti and Ti–6Al–4V have a much higher modulus of elasticity than human bone, which may lead to stress shielding and bone resorption [85].

With the finding that metal allergy can cause damage to the respiratory system, nervous system, gastrointestinal tract, and hematopoietic system, long-term use has potentially harmful effects on the human body [92]. The development of low or non-toxic Ti alloys became the next hot spot, that is, Nb, Fe, and other elements instead of toxic vanadium elements, which is called the second generation of medical Ti alloys, with Ti–5Al-2.5Fe, Ti–6Al–7Nb (TC20) as representatives [93]. However, the second-generation Ti alloy performance of Ti–6Al–4V is not significantly improved, the elastic modulus and human bone elastic modulus gap are still large, easy to produce stress shielding [87].

The third generation of Ti implants is β-type Ti alloys with high strength, low elastic modulus, and corrosion resistance, which are more suitable as internal human implants [94]. For instance, Parthasarathy et al. [95] found that Ti–35Nb–7Zr–5Ta alloy exhibited good bioactivity and low elastic modulus for use as orthopedic metal implants by EBM methods. In addition, Hein et al. [96] developed Ti–24Nb–4Zr–8Sn by the SLM method with an elastic modulus of only 50 ​GPa, a tensile strength of 706 ​MPa, and excellent corrosion resistance. FDA has approved the 3D printing Ti implants, which are known as emerging implant technologies (EIT) cellular Ti produced by a German medical device manufacturer, for spinal applications [5].

3.3. Cobalt-chromium alloy

Co–Cr alloys are high-strength alloys with Co and Cr as the main components, with high-temperature oxidation resistance and good biocompatibility [5]. An example of an alloy classification for medical purposes is ASTM F75 Co–Cr alloy [97]. Compared to SS and Ti alloys, Co–Cr alloys have higher wear resistance and corrosion resistance because of high content of Co and Cr [81]. Since the 1930s, Co–Cr alloys have been ideal for weight-bearing implants and are widely used in artificial joints (hip and knee joints), etc. [34,98,99]. Vitallium introduced one of the most popular CoCrMo alloys for joint replacements in 1939 [100]. Compared to bone, Co–Cr alloys have a higher modulus of elasticity, density, and hardness, and suffer from stress shielding and bone resorption problems [99]. 3D printing can help reduce the elastic modulus of Co–Cr alloys and minimize the stiffness difference between the alloy and bone [101]. Currently, EBM has been successfully used to create Co–Cr implants with desired macro-geometry and bulk interconnected pore architecture [102]. Compared to Ti alloys, Co–Cr alloys are less biocompatible and osseointegrated than Ti [103]. Therefore, in clinical practice, they are the material of choice for implants that do not come into contact with the bone interface (e.g., rods in spinal fixation) [104]. Besides, Co–Cr alloys are still associated with wear and corrosion problems after implantation in the human body [105]. In surgeries such as total hip replacement, knee implantation, and spinal fixation, the resulting release of metal ions can lead to various medical complications that greatly limit the application of the implant [5]. When prepared by the SLM method, the strong temperature gradient during melting leads to a fine cellular microstructure of the Co–Cr implant, which enhances the corrosion resistance of the implant [106]. Currently, the direction of Co-based alloy development is further alloy strengthening (such as the addition of hydrogen and tungsten elements) to obtain higher-strength alloys.

3.4. Tantalum alloy

Since 1940, Ta was first used in orthopedics, it has been used in clinical applications for more than 80 years. Ta has excellent biological inertness, corrosion resistance, and biocompatibility, with properties similar to cancellous bone [67]. In the field of bone and joint, porous Ta technology, such as socket cups for primary hip replacement, pads for hip and knee defect sites, and porous Ta rod implantation for the treatment of early femoral head necrosis, has been used extensively and has been reported to be safe and effective in long-term follow-up [[107], [108], [109]]. There are also reports of good results with Ta as an intervertebral fusion instrument [110]. Ta can be used as a coating on SS and Ti implants to enhance corrosion resistance and osseointegration [39]. However, the high density and melting temperature of Ta make it difficult to process using conventional techniques and the inventory costs are high. 3D printing technologies such as directed energy deposition make it possible to fabricate Ta. Recently, Bandyopadhyay et al. [111] demonstrated the feasibility of processing porous Ta structures using LENS to maintain processing parameters close to those of Ti64. 30% porous Ta structures showed in vivo biological properties similar to those of 30% porous Ti64 nanotube surface modifications. Computational fluid dynamics (CFD) analysis proved that 3D printing porous Ta scaffolds with pore sizes of 400–600 ​μm hold appropriate permeability and surface area, which facilitated cell adhesion and proliferation [112]. These findings provide new evidence for further application of porous Ta scaffolds for bone defect repair.

3.5. Shape memory alloy

The shape memory effect is a unique phenomenon in which deformed materials can be restored to their original shape and dimensions by heating in a certain temperature range or by reversible martensitic transformation [113]. Ni–Ti alloys are the most promising SMA because of their mechanical stability, low stiffness, and thermoelectricity [114,115]. Although the Young's modulus of Ni–Ti is higher than that of natural bone, it can be reduced to 11–20.5 ​GPa for porous NiTi implants using 3D printing techniques [116]. The 3D printing porous Ni–Ti skeletal fixation device provides adequate fixation stiffness over a 6–9 month healing period and has the flexibility to return to normal stress distribution after the bone is fully remodeled [117]. Based on the properties of SMA, Ni–Ti alloys are used in orthopedic implants such as spinal implants, intramedullary nails, scoliosis correction devices, and spinal spacers [68,69]. In addition to the interesting shape memory effect, Ni–Ti SMA has good corrosion resistance, wear resistance, and ideal biocompatibility due to the formation of a Ti oxide layer on its surface [118]. This protective membrane prevents the toxic and allergenic effects of Ni release, so we wanted to increase the formation and thickness of TiO2 [119]. Typically, SLM methods are commonly used to print SMA [120,121]. Intervertebral fusion devices are one of the recently identified applications for porous Ni–Ti in spine surgery, with one commercial product commercially available since 2002 under the trade-name Actipore (from Biorthex, Canada) for lumbar and cervical interbody devices [122]. Assad et al. [123] proved that porous Ni–Ti provides higher bone ingrowth stimulation (which further increases with time), due to its cellular, bone-like architecture, and a bone apposition rate two orders of magnitude higher, but still performs similarly to traditional Ti–6Al–4V fusion cages, without the need of bone grafting.

3.6. Absorbable metal materials

The use of inert metals in orthopedic surgery may require secondary implant removal if unexpected clinical complications occur, such as pain or impaired function [2]. Also, the diagnostic accuracy of X-ray and CT images is severely compromised by imaging artifacts produced by metals. Currently, the most widely studied biodegradable metals include Mg, Fe, and Zn and their alloys. During the early stages of bone defect regeneration, the entire mechanical support is dependent on the implant. The mechanical integrity of the implant should be maintained for approximately 3–12 weeks to support the healing process in the upper extremity, while the lower extremity requires approximately 12–24 weeks [124]. As the regenerated bone slowly regains its strength, the implant material can gradually degrade. Therefore, the rate of biodegradation of metal implants should be controlled so that the loss of load-bearing capacity of the resorbable metal material is balanced by the increase in structural integrity of the bone [125].

3.6.1. Magnesium alloy

Mg and its alloys are widely favored by researchers in the field of bone regeneration because of their good biocompatibility, suitable mechanical strength, and biodegradability [70]. The density and natural modulus of elasticity of Mg-based metals are very similar to human bone, with a modulus of elasticity of 45 ​GPa and a density as low as 1.74 ​g/cm³ [71]. Compared to Ti and SS, the stress shielding effect of Mg-based metals is negligible [126]. It can be used to make screws and rods that, when implanted, provide mechanical support and gradually degrade to provide space for growing bone tissue [127]. Ultimately, the implant degrades completely, thus minimizing the incidence of metal allergy to permanent implants [128].

The greatest advantage of Mg is its biodegradability [129]. Among the cations in the human body, Mg ranks fourth and is mainly stored in bone tissue, involved in many metabolic processes in the body [130]. In vivo, Mg is degraded to Mg²⁺, which can be excreted through urine [71]. More importantly, there is growing evidence that Mg ions released from implants can promote bone regeneration and accelerate the healing of bone disease [129]. In the treatment of challenging bone diseases, it may have a significant advantage over non-Mg-based counterparts [124]. However, due to rapid degradation after implantation, Mg and its alloys cannot maintain sufficient mechanical strength and are now mainly alloyed with other elements to modify their properties [126,130]. For example, Mg–Mn alloys have improved corrosion resistance, and Mg–Zn alloy has higher strength [131,132]. Yang et al. [133] prepared novel Mg–Ti composites by 3D printing and subsequent acid treatment, which significantly improved the morphology of MC3T3-E1 cells, reduced the apoptosis rate, and enhanced osteogenic activity. Rapid degradation of Mg releases large amounts of hydrogen, which may lead to the separation of tissues and tissue layers, delayed repair of bone defects and tissue necrosis [71,130,134]. According to recent studies, the new degradable Mg alloy ZEK100 and tricalcium phosphate coated Mg alloy AZ31 both have good biocompatibility and biodegradability [135,136]. Xie et al. [137] fabricated a porous 3D-printed Mg-Nd-Zn-Zr implant using SLM technology and the implant exhibited cytocompatibility and excellent osteoinductivity in vitro. Furthermore, the implant demonstrated excellent antibacterial ratios of 90.0% and 92.1% for methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli, respectively.

3.6.2. Iron alloy

Fe is one of the essential trace elements and is involved in many physiological reactions. It was shown that Fe is biocompatible and has excellent mechanical properties close to those of SS 316L, making it a good candidate for implants that require high structural strength, such as bone defect repair [71]. In addition, Fe is relatively easy and affordable to obtain and does not release hydrogen during biodegradation after implantation [72]. Currently, Fe-based materials are considered to be promising candidates for the manufacture of biodegradable implants due to their excellent mechanical properties and degradability [73].

Among the biodegradable metals, Fe has the lowest tendency to dissolve. Although the superior mechanical properties and the slow corrosion process are positive attributes, they may also have some undesirable consequences [72]. For orthopedic applications, too slow a degradation rate may impede tissue regeneration, limit force transfer to growing bone, and result in stress shielding [138]. More importantly, the recommended human intake of Fe is 6–20 ​mg daily, too excessive concentrations can produce toxicity, including inflammation, increased free radicals, and damage to lipid membranes, proteins, and DNA [139,140]. An increase in surface to volume ratio may also increase the degradation rate of this metal, keeping it in line with the respective regeneration rates of bone and vascular tissues [139]. Therefore, research efforts have focused on the development of porous structures made of Fe-based compounds to maximize surface area, reduce stress shielding, improve degradation rates, and promote natural tissue growth [141]. Yang et al. [142] showed that 3D printing Fe scaffolds with hydroxyapatite (HA) coatings achieved compressive mechanical properties in the range of those of natural bone and significantly improved the survival and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) on the scaffolds. Putra et al. [143] demonstrated that 3D printing Fe Mn-akermanite scaffolds could fulfill all the requirements for bone substitution in vitro, namely, adequate biodegradation rate, mechanical properties in the range of bone trabeculae even after 4 weeks of biodegradation, paramagnetic properties, cytocompatibility, and most importantly, osteogenic properties.

3.6.3. Zinc alloy

Similar to Fe, Zn is one of the essential trace elements in the human body and plays an important role in many physiological activities (e.g. growth, immunity, and wound healing) and is essential for the catalytic function of more than 300 enzymes [144]. Approximately 85% of Zn is reported to be found in muscle and bone, making Zn essential for bone development and growth [74]. To maintain normal body requirements for Zn, the recommended daily intake of Zn is 15–40 ​mg [75]. Although there is still concern about whether the utilization of Zn metal in the human body can lead to adverse effects, studies have shown that zinc has negligible toxicity [145]. A series of studies in vitro have shown that Zn ions can promote stem cell osteogenesis, increase mineralization capacity, as well as promote osteoblast adhesion, proliferation, and differentiation [146]. In addition, Zn has been shown to have antibacterial activity [147].

However, due to the soft texture and low mechanical strength of pure Zn, there are few reports on the use of pure Zn scaffolds for bone tissue engineering. Zn alloys prepared by adding other metal elements (e.g. Mg, Ca, and Sr) show significant improvements in mechanical properties and biocompatibility compared to pure Zn [148,149]. Zn and Zn alloys are being investigated for fracture fixation, and the Mg–Zn–Ca alloy scaffold prepared by Kim [150] et al. has good corrosion resistance and osteogenic properties and has shown satisfactory bone repair. Li et al. [151] proposed a novel bone repair bioscaffold by adding Zn submicron particles to PLGA/β-TCP using 3D printing technology. A series of in vitro and in vivo experiments demonstrated that the scaffold has no adverse effect on the viability of BMSCs and promotes their adhesion and osteogenic differentiation, as well as higher osteogenic and anti-inflammatory properties compared with PLGA/β-TCP scaffolds without Zn particles.

3.7. Limitations of metal materials and enhancement strategies

3D printing porous implants can reduce stress shielding effects and reduce implant loosening and fractures [152]. However, with the increased demand for metallic implants, the currently available materials and techniques cannot meet the needs of modern orthopedic implants, and scholars have begun to experiment with various enhancement strategies to improve the osteogenic capacity, osteoconductivity, bacterial inhibition, and biocompatibility of bone implants to varying degrees [[153], [154], [155]].

One of the challenges that plague metal implants is corrosion [156]. When in contact with tissue, due to the oxygen diffusion limit contributed by the fast leakage of metal ions in the body, these ions create a high toxicity level, thereby causing adverse effects on the cells [9]. The accumulation of heavy metals in the cells over time can lead to toxicity and death, called metallosis, which can lead to the development of sarcoma [25,83]. Incorporating elements that self-passivate (Ti, Cr, Al) is the most common method to prevent corrosion [157]. One method of AM that has garnered much attention for its capability in producing compositionally complex materials, as well as its ability to modify existing surface microstructure is LENS. Laser surface modification (LSM) using LENS of Ti–6Al–4V to modify granular structure thereby changing the hardness while creating a passive oxide layer that significantly reduces the in vivo wear when compared to as-received Ti–6Al–4V samples [158]. In studies by Roy et al. [159], the LENS processing technique was again used to create compositionally gradient Ti/HA and Ta/MgO implants. The studies showed that differences in microstructure can be elicited by varying the processing parameters such as laser scan speed and thickness of the gradient layer.

Another key challenge is the inability to interact with the surrounding tissue, called bioinert. Without proper implant-host tissue interaction, a thin fibrotic lining, or scar tissue, forms at the interface and the implant tends to loosen over time [160,161]. It has been found that osteoblasts prefer to aggregate on rough surfaces, while non-osteoblasts prefer smooth surfaces. Zhang et al. [162] showed the 3D printing Ti6Al4V implant presented a distinct fluctuant macroscale rough surface and relatively better hydrophilicity which enhanced the adhesion, proliferation, osteogenic differentiation, and angiogenetic factor expression of BMSCs. However, the most desirable surface roughness has not been determined. In addition, Zhang et al. [163] introduced submicron-scale pits on the original surface by acid etching to obtain a hierarchical micro/submicro-textured surface and the results suggested the adhesion, proliferation, and osteogenic differentiation of BMSCs were significantly improved. EBM and SLM have less inherent surface roughness compared to laser sintering or powder bed printing [39,164]. These processes have been utilized to print microscale porous structures while achieving stiffness and strength values in between that of trabecular and cortical bone [9]. Nano-scale topography has been shown to improve wettability, which increases the adhesion of cells [165]. However, it must be noted that these changes to surface topography may also have a direct effect on the nature of the interaction between pathogenic microorganisms and surfaces [166]. The beneficial effects of nano-pattering shown in in vivo studies comprise increased hydrophilicity, fast neovascularization at the bone implant site, early osseointegration, and as well osseointegration in compromised bone compared to micro rough surfaces [167,168]. Zhang et al. [169] successfully constructed a hierarchical micro-/submicro-/nanostructured surface feature of Ti6Al4V implants by 3D printing. The microscale topography and sub-micro pits increased the space for the cell growth and mechanical stability of implants, while the modification of nanotubes dramatically improved the surface hydrophilicity, protein adsorption, and biomineralization.

In particular, 3D printing is one of the most promising methods for introducing complex interconnected architectures and curved channels with controlled distribution into metal materials [170]. Adequate porosity with interconnecting pores allows the formation of vascularization as a transport pathway for nutrient diffusion and metabolic waste, which help functional key cellular activities and tissue survival. High surface-area-to-volume ratio, pore shape, and pore size are essential for cell attachment and growth. However, with the increase in porosity, the mechanical strength is jeopardized in terms of compressive strength. 3D printing has provided flexibility for designers and engineers to adapt the mechanical behavior of bone tissue accordingly [171].

Despite the fact that the bulk of the implant is made from metal material, the coating layer exhibits a bioceramic component that forms on the metal surface. For materials such as Ti, readily forming a passive layer alone is not enough for tissue integration. For this reason, HA coating has been extensively researched and is known for its ability to match bone mechanical strength, hence preventing osteoclasts, and its chemical bonding to bone, and has shown clinical success in inducing bone-growth fixation rather than fibrous connective tissue formation [172]. In addition, the bone support capabilities of biomolecules are being investigated, including peptides, bone morphogenetic protein (BMP) growth factors, non-BMP growth factors, collagens, and other extracellular matrix-related components (e.g. hyaluronic acid). Chitosan is a cationic polysaccharide that demonstrates excellent characteristics namely biocompatibility, non-toxicity, biodegradability, antimicrobial characteristics, and availability. Chitosan scaffolds enhance cell adhesion, proliferation, osteoblast differentiation, and mineralization [173]. Next to these groups, the effects of antiresorptive drugs (zoledronic acid, alendronic acid), osteoanabol drugs (teriparatide), chemotherapeutic agents (selenium), and different antibacterial agents (vancomycin, gentamicin) are explored [174]. Wang et al. [175] fabricated a polydopamine coating on a 3D-printed implant surface via the in situ polymerization method, which improved the hydrophilicity and osteogenic capacity of the implants.

4. Clinical applications

Many orthopedic conditions require implants to restore function at the site of the lesion. In clinical practice, metals are the preferred implant material due to their excellent biomechanical properties, but there is still the problem of unacceptable failure rates [176,177]. The availability of metal implants for patient is dependent on two main factors: mechanical stability and biological response to host bone [50]. Computational methods such as CAD, finite element analysis (FEA), and CFD can be used for the mechanical testing of implants by simulating tension, compression, bending, shear, torsion, and biomechanical/physiological loading conditions in vivo [178]. Compression is the most common loading condition for bone design, so among the various mechanical properties, the elastic modulus is the most important and frequently found in the literature. Ribeiro et al. [179] found that the prediction of the FEA showed a good agreement with conventional mechanical test results, revealing the areas more affected under compression load. Kang et al. [180] designed a multi-segment artificial vertebral implant by optimizing parameters such as pore diameter and porosity, and FEA showed that the optimized implant was about 2 times to trussed implant in terms of the maximum compression load and compression stiffness per unit mass and achieved good results in subsequent clinical trials. After the implant was fabricated by 3D printing, the mechanical properties such as unidirectional compression testing, strain energy density, and flexural performance or behavior of the material were evaluated by comparing the strength and strain energy density of the implants in four-point bending test or three-point bending test [181]. Extensive testing and evaluation are performed during the pre-market phase, often including mechanical testing such as fatigue and wear studies [182].

3D printing metal implants can be personalized to suit the different disease states and surgical conditions of the patient in order to balance the contradiction between porosity and stiffness [183]. The biological response to the host bone, on the other hand, is usually achieved by monolithic or surface modification of such implants [9]. In just the past few years, metal 3D printing technology in the medical field, especially the application of orthopedics has been highly valued, and its innovative potential and application prospects are more generally favored [50,108,[184], [185], [186], [187], [188]]. Several metal 3D printing orthopedic implant applications are shown in Fig. 4. However, will it bring disruptive changes to the future of orthopedics, as many colleagues expect? It is important to truly understand and objectively evaluate the value of metal 3D printing technology in orthopedics. To date, research on the clinical application of patient-specific implants has focused on bone tumor surgery, joint replacement surgery, spinal implants, and traumatic fracture fixation and reconstruction as listed in Table 3, Table 4, Table 5, Table 6.

Figure 4.

Clinical application of metal 3D printing orthopedic implants (A) Radial head prosthesis [184], (B) Porous scaffolds in femoral defect [108], (C) Total talus implant [185], (D) Spine fusion device [186], (E) Trabecular acetabular cup [187], (F) Cones in total knee arthroplasty [188], reproduced with permission.

Table 3.

The main clinical application of spinal surgeries.

Year	Authors	Journal	Case	Type of surgery	Results
2016	Spetzger et al. [189]	Eur Spine J	1	3D-printed cervical fusion titanium (Ti) cage	The improved load-bearing surface will lower the rate of implant dislocation and subsidence
2018	Thayaparan et al. [190]	J Clin Neurosci	3	Atlantoaxial transarticular screw fixation	No screw malposition and no neural or vascular injuries were observed
2018	Siu et al. [191]	World Neurosurg	1	A minimally invasive lateral lumbar interbody fusion at L2-3 and L3-4	Postoperative CT scan confirmed excellent implant-end plate matching and restoration of lost disk space
2019	He et al. [192]	Oper Neurosurg	1	3D printed microporous prosthesis (3D-PTMP) for the anterior column of the cervical spine between C1 and T1	The patient had an uneventful recovery, regaining ambulatory status 3 ​wk after the 2 operations without ventilator support or other severe complications
2020	Thayaparan et al. [193]	J Clin Neurosci	1	3D printed patient-specific implant (PSI) for occipitocervical fixation	There were no intraoperative or postoperative complications
2020	Arts et al. [194]	Spine J	49	Anterior cervical discectomy with an interbody cage (ACDF)	3D printed porous Ti cervical implants resulted in significant clinical improvement after surgery
2020	Wei et al. [195]	Ann Transl Med	9	3D printed vertebral body for spinal reconstruction with primary tumors involving C2.	The tailored shape matching with the contact surfaces and the porous structure conducive to osseointegration provide both short- and long-term stability to the implant
2021	Thayaparan et al. [196]	Eur Spine J	1	3D-printed lumbosacral fixation implant secured by L2-L5, S2, and iliac screws	No evidence of implant dysfunction was observed on radiography.
2021	Fang et al. [197]	Med Sci Monit	12	3D-printed artificial vertebral body in repairing bone defects for single-level anterior cervical corpectomy and fusion (ACCF).	The 3D-printed artificial vertebral body helps maintain intervertebral height and cervical physiological curvature and is a good candidate for ACCF
2021	Tang et al. [198]	Orthop Surg	27	3D printed modular prosthesis for spinal reconstruction after multilevel thoracolumbar total en bloc spondylectomy (TES)	At the latest follow-up, in 23 alive patients, 19 can walk independently and two can achieve outdoor activities by walking aid
2022	Sun et al. [199]	Orthop Surg	8	3D printed artificial vertebral body for multilevel total en bloc spondylectomy (TES)	X-rays showed that the 3D printed artificial vertebral body of all cases matched well, and the fixation was reliable. Hardware failures such as loosening, sinking, breaking, and displacement weren't observed during the follow-up period
2022	Hu et al. [200]	Int J Bioprint	8	3D printed artificial vertebral body for multilevel total en bloc spondylectomy (TES)	Combined with neoadjuvant and adjuvant therapy, these patients had excellent postoperative outcomes, long-term normal spinal function, and associated low local recurrence probability
2022	Girolami et al. [201]	J Clin Med	2	3D-printed personalized implants for reconstructing the anterior column	Three dimensional printing allowed the reported authors to design patient-specific solutions, not only for shape and size of the implants but also for the method to achieve proximal fixation
2022	Zhou et al. [202]	J Neurosurg Spine	23	3D printed artificial vertebral body for spinal reconstruction after en bloc resection of thoracolumbar tumors	The low incidence of prosthesis subsidence of 3D-printed endoprostheses can provide good stability instantly.

Table 4.

The main clinical application of joint surgeries.

Year	Authors	Journal	Case	Type of surgery	Results
2013	Colen et al. [203]	Acta Orthop Belg	8	A modified custom-made triflanged acetabular reconstruction ring (MCTARR) for revision hip arthroplasty	None of the reconstructions failed or had to be revised. Clinical results were satisfactory. Radiographs showed good screw positioning.
2015	Mao et al. [204]	Int Orthop	23	Customized cage with a hook, crest, and flange or braids for severely compromised acetabulum in revision THA	The mean Harris hip score improved from 39.6 pre-operatively to 80.9 ​at the final follow-up. There were no instances of deep infection, severe venous thrombosis, and nerve palsy.
2016	Li et al. [205]	Clin Orthop Relat Res	26	Custom acetabular cages for revision THA with severe bone defects	Individualized custom cages resulted in the generally reliable restoration of the hip center. No revisions have been performed.
2017	Wang et al. [206]	Exp Ther Med	17	3D printing hip arthroplasties in THA	The 3D printing approach provides a better short-term curative effect that is more consistent with the physiological structure and anatomical characteristics of the patient.
2020	Geng et al. [187]	J Orthop Surg Res	92	3D printing porous trabecular acetabular cup for primary total hip arthroplasty (THA)	The satisfaction rate (prevalence of satisfied or very satisfied) was 91.3%. No acetabular cup failures occurred. The overall survival rate of implantation is 99.1% (cup survival rate 100%).
2020	Tetreault et al. [207]	Bone Joint J	139	3D printed metaphyseal cones in revision total knee arthroplasty (TKA)	Survivorship free of cone revision for aseptic loosening was 100% and survivorship free of any cone revision was 98%
2020	Wang et al. [208]	J Int Med Res	1	3D printed porous tantalum (Ta) prosthesis for TKA	The surgery went smoothly and the patient achieved a satisfactory recovery after surgery.
2020	Faldini et al. [209]	J Orthop Traumatol	1	3D printed ankle prosthesis for total ankle arthroplasty (TAA)	The complete customization process for total ankle arthroplasty provided accurate and reliable implant positioning, with satisfactory short-term clinical outcomes.
2021	Macák et al. [210]	Acta Chir Orthop Traumatol Cech	3	3D printed titanium acetabular component of THA	The three-point fixed 3D printed acetabular component combined with impaction grafting of the acetabular base is a good alternative in managing the advanced bone defects of acetabulum after the failure of THA
2022	Ao et al. [188]	Front Bioeng Biotechnol	6	3D printed porous Ta cones in TKA	Radiological examination at the final follow-up showed that cones implanted into the joint were stable and bone defects were effectively reconstructed
2022	Zhang et al. [211]	ACS Omega	7	3D printed revision prostheses for ankle osteoarthritis	For complex bone defects and revision prostheses, matching implants can be printed individually, which could realize the personalized precise treatment.

Table 5.

The main clinical application of bone tumor surgeries.

Year	Authors	Journal	Case	Type of surgery	Results
2017	Liang et al. [212]	Bone Joint J	12	3D-printed pelvic endoprostheses after resection of a pelvic tumour	The application of 3D-printing technology can facilitate the precise matching and osseointegration between implants and the host bone
2017	Luo et al. [213]	Med Sci Monit	4	3D printed tibia block for treating giant cell tumors (GCT) of the proximal tibia.	No sign of prosthesis fracture, loosening, or other relevant complications were detected.
2019	Lu et al. [214]	BMC Surg	1	3D printed porous implant for GCT in the proximal tibia	At the last follow-up at 29 months postoperatively, the patient had satisfactory limb function and no further damage was seen to the subchondral area and articular surface.
2019	Feng et al. [215]	Yonsei Med J	1	3D printed prosthesis replacement for limb salvage	During the follow-up, the presence of bone ingrowths on the porous surface of some segments of the prosthesis suggested good outcomes for long-term biological integration between the prosthesis and host bone.
2020	Chen et al. [216]	J Int Med Res	1	3D printed implant for reconstruction of the pelvic bone	The patient recovered with significant pain relief and good functional recovery after the surgery. No implant-related complications occurred during the 12-month follow-up.
2021	Wu et al. [217]	J Surg Oncol	28	3D-printed pelvic endoprostheses after resection of a pelvic tumour	The mean follow-up period was 32.2 months, during which 16 patients had disease-free survival, 3 survived with the disease, and 9 died. The prostheses were stable, and the mean offset of the center of rotation was 5.48 ​mm.
2021	Park et al. [218]	J Orthop Sci	12	3D-printed bone-cutting guides and implants n pelvic bone tumor surgery	In all patients, independent gait was recovered except for a patient who underwent hindquarter amputation 4 months postoperatively because of local recurrence.
2021	Zhang et al. [219]	J Orthop Surg Res	8	3D printed porous implants for GCT in the proximal tibia	No degeneration of the knee joint was found. Osseointegration was observed in all patients.

Table 6.

The main clinical application of trauma surgeries.

Year	Authors	Journal	Case	Type of surgery	Results
2017	Mai et al. [220]	Zhonghua Wai Ke Za Zhi	8	3D printed acetabular wing-plate for complex acetabular fractures	Surgical management of complex acetabular fracture via lateral-rectus approach combined with 3D printing personalized acetabular wing-plate can effectively improve reduction quality and fixation effect
2018	Zhang et al. [221]	Medicine	6	3D printed titanium metal trabecular bone reconstruction systems for osteonecrosis of the femoral head	Hip-preserving rates were 100% for IIA, 100% for IIB, and 50% for IIC. The effect of TMTBRS treatment for early ONFH in ARCO IIA and ARCO IIB is satisfactory.
2019	Zhao et al. [222]	Orthop Surg	1	Porous tantalum (Ta) metal plates in the treatment of tibial fracture	The resulting porous Ta metal exhibited excellent mechanical and biological properties and improved the therapeutic effects for the treatment of a tibial fracture nonunion.
2020	Luenam et al. [223]	J Orthop Surg	1	3D printed implant for severe open distal humerus fracture	Due to the favorable result at a 2-year follow-up, this modality is a potentially viable surgical option in treating the severe open distal humeral fracture associated with entire lateral condylar damage.
2020	Wang et al. [224]	BMC Musculoskelet Disord	15	3D printed patient-specific (3DPPS) Ti–6Al-4 V plates to treat complicated acetabular fractures	The 3DPPS Ti-6AL-4 V plate is a feasible, accurate, and effective implant for acetabular fracture treatment.
2020	Hou et al. [225]	J Mater Sci Mater Med	3	3D printed micro-porous prosthesis for large metaphyseal segmental femoral bone defect	X-ray demonstrated good osseous integration of the implant/bone interface. No complications occurred such as implant loosening, subsidence, loss of correction, and infection.
2020	Kadakia et al. [226]	3D Print Med	4	3D printed implants in complex lower extremity reconstruction	This technology provides surgeons with tools to better tackle some of the more challenging clinical cases, especially within the field of foot and ankle surgery.
2020	Steele et al. [227]	J Foot Ankle Surg	11	3D Printed spherical Implants for tibiotalocalcaneal arthrodesis	Custom 3D printed sphere implant is safe in patients with severe bone loss undergoing TTC arthrodesis with a retrograde intramedullary nail and may result in improved rates of successful arthrodesis.
2021	Hussain et al. [228]	J Foot Ankle Surg	1	3D Printed total talus replacement	At the 12-month mark the foot function index (FFI) score improved from 95.9% pre-op to 4.7% post op and the American orthopedic foot and ankle score was 0 pre-op to 94 post-op
2022	Wu et al. [108]	J Orthop Surg Res	9	3D printed porous Ta scaffolds for infective segmental femoral defect	The 3D-printed porous Ta prosthesis was an acceptable alternative treatment, that could achieve satisfactorily reconstruct an infective broad bone defect in the femur when other biological techniques were not suitable.
2022	Liu et al. [229]	J Mater Sci Mater Med	10	3D printed porous Ti6Al4V scaffolds for diaphyseal defects of lower limbs	The implantation of a 3D printed Ti6Al4V scaffold was feasible and effective to reconstruct critical bone defects of lower limbs without additional bone grafting.
2022	Grau et al. [230]	J Foot Ankle Surg	1	3D Printed talus for the treatment of a chronic infection of the ankle	After a 2-year follow-up, a good clinical evolution was achieved, with no signs of reactivation of the infection, no pain, good skin condition, and optimal functionality

4.1. Spinal surgeries

Recently, 3D printing implants have become of interest in the manufacture of internal fixation implants, spinal cages for interbody fusion procedures, vertebral body replacements (VBR), and disc implants for total disc replacement (TDR) [231,232]. In the atlantoaxial spine due to the complex anatomy, surgical accuracy is crucial. Thayaparan et al. [190] designed a 3D printing manufactured Ti posterior fixation implant by SLS printer to cure three female patients with unilateral atlantoaxial osteoarthritis. No screw malposition and no neural or vascular injuries were observed. What's more, Thayaparan et al. [193] described a novel method for occipitocervical fixation using a 3D printing Ti patient-specific implant by SLM method. At 6-month follow-up, the patient reported resolution of symptoms and demonstrated satisfactory occipitocervical alignment without evidence of implant dysfunction.

Current spinal cages for interbody fusion procedures may lead to endplate fractures and collapse. Due to the particular usefulness of 3D printing in reconstructing complex geometries, they can be used in areas where current implants are not suitable to replace local anatomical structures [233]. In anterior cervical discectomy fusion (ACDF), 3D printing cages could significantly relieve symptoms, restore the curvature of the cervical spine, effectively maintain the intervertebral height for a long time, and prevent complications related to postoperative subsidence [234]. Arts et al. [194] found that 3D printing porous Ti cervical implants by SLM resulted in significant clinical improvement after ACDF. The fusion rate of porous Ti compared with polyetheretherketone (PEEK) with autograft at 12 months was similar, although porous Ti resulted in faster consolidation. Spetzger et al. [189] performed a pilot project of the first implantation with an anterolateral standard approach of a custom-designed cervical Ti cage, made of trabecular Ti and manufactured with direct metal printing. The improved load-bearing surface will lower the rate of implant dislocation and subsidence. Siu et al. [191] performed a minimally invasive lumbar interbody fusion on a 74-year-old woman with osteoporotic fractures at L2 and L3. The design was converted to implantable Ti cages through AM. At surgery, a tight fit between the implants and the targeted disk space was achieved. For revision lumbar fusion surgery, Thayaparan et al. [196] chose an EIT Cellular Ti interbody cage using an SLS printer to replace the existing PEEK interbody cage at L5–S1. No evidence of implant dysfunction was observed on radiography.

For the reconstruction of irregular vertebral body defects in special locations, 3D printing artificial vertebral bodies also had unique advantages [235,236]. In single-level anterior cervical corpectomy and fusion (ACCF), the 3D printing artificial vertebral body performs better in maintaining intervertebral height and cervical physiological curvature compared with the Ti mesh cage [197]. For reconstruction of bone defects after multilevel total en bloc spondylectomy (TES), 3D printing artificial vertebral bodies could greatly reduce the risk of prosthesis collapse and loosening, and its advantages were more significant [199,198]. Combined with neoadjuvant and adjuvant therapy, these patients had excellent postoperative outcomes, long-term normal spinal function, and associated low local recurrence probability [200]. A 3D printing Ti microporous prosthesis was designed by He et al. [192] to reconstruct the anterior column of the cervical spine between C1 and T1 for stability. A postoperative CT scan indicated a good position of the 3D printing construct between the endplates with no sign of tumor recurrence or implant subsidence. The location of spinal tumors in the spine provides challenges both for tumor excision, since satisfactory exposure is difficult to achieve, and reconstruction, especially for proximal fixation [201]. For C1/C2 chordoma, Mobbs et al. [237] discovered that the use of 3D printing individualized prostheses was easy to put into the required position, facilitates surgery, shortens the operative time, and avoids further complex reconstruction. In 9 patients with primary tumors involving C2, Wei et al. [195] found that the 3D printing vertebral bodies using an EBM printer were all stable with no sign of displacement or subsidence, evidence of implant osseointegration was observed in the imaging studies. Zhou et al. [202] considered that the use of a 3D printing artificial vertebral body for anterior reconstruction after en bloc resection of the thoracolumbar spinal tumor is useful. The low incidence of prosthesis subsidence of 3D printing endoprostheses can provide good stability instantly.

Along with interbody and vertebral body cages, the feasibility of manufacturing disc implants for TDR by means of 3D printing technologies has been recently studied. Intervertebral disc end plates were successfully designed by De Beer and colleagues and the end plate geometry of disc implants reduced the risk and potential for subsidence into the vertebral bone end plate [238]. Domanski et al. [239] have recently conducted preliminary research on 3D printing intervertebral disc implants. The endoprosthesis prototype was made of CoCrMo alloy with the use of selective laser technology. FEA demonstrated restoration of full range of motion of the spine in all anatomical planes and restoration of the normal height of the intervertebral space and curvature of the anterior spinal convexity.

4.2. Joint surgeries

In joint surgery involving the shoulder, hip, knee, and ankle, the use of 3D-printed articular prostheses to reconstruct joint function has yielded good therapeutic results. When treating severe bone defects in the joint after total shoulder arthroplasty, the 3D printing shoulder glenoid prosthesis with its porous structure fills the bone defect well and the additional threaded holes in the component allow for conversion to a reverse structure, achieving good functional scores at an average follow-up of 2.5 years [240].

Personalized patient prostheses have been reported to be a valuable option for total hip arthroplasty (THA), with high-precision printed cancellous bone structures that aid bone growth and fixation strength and improve surgical success [241,242]. Geng et al. [187] analyzed 92 consecutive patients and found that 3D printing porous trabecular Ti acetabular cup by EBM method may provide good initial stability and secondary fixation because of its highly interconnected, porous structure. Wang et al. [206] assessed the use of 3D printing hip replacements with Ti alloys in THA. In 17 patients, the time to postoperative weight bearing and the Harris scores were better than the traditional method. Colen et al. [203] reported on the use of a modified custom-made triflanged acetabular reconstruction ring in 6 patients with severe acetabular bone defects with acceptable to good results in all. Revision hip arthroplasty is conducted when a primary THA fails due to a variety of reasons, such as aseptic loosening (50%), instability (16%), infection (15%), debilitating pain, periprosthetic fractures, or component failure [243]. Macák et al. [210] concluded that the implantation technique of a three-point fixed custom-made 3D printing acetabular component combined with impaction grafting of the acetabular base is a good alternative in managing the advanced bone defects of acetabulum with pelvic discontinuity after the failure of THA. Li et al. [205] found that individualized custom cages by the SLS method appeared to provide stable fixation and improved hip scores in 26 patients with a massive acetabular defect. Mao et al. [204] designed a customized cage with a hook, crest, and flange or braids, and then utilized it to reconstruct severely compromised acetabulum in revision THA. The mean Harris hip score improved from 39.6 pre-operatively to 80.9 ​at the final follow-up. There were no instances of deep infection, severe venous thrombosis, and nerve palsy.

Total knee arthroplasty (TKA) is potentially difficult when using historical designs of cones [244]. The patient-customized 3D-printed metaphyseal cone is a useful technique for reconstructing massive proximal tibial bone defects, with encouraging clinical and radiological outcomes in TKA [245]. Tetreault et al. [207] found that 3D-printed Ti cones, with a reamer-based system, yielded excellent early survivorship and few complications in patients with severe bone loss undergoing difficult revision TKA. Hua et al. [109] treated patients with Charcot arthropathy by preparing 3D printing porous Ta implants, which could effectively restore the range of motion of the knee joint, and lower extremity alignment, and eventually achieve good functional results of walking without crutches after surgery. Ao et al. [188] demonstrated that 3D-printed porous Ta cones could effectively reconstruct bone defects and offer anatomical support in TKA revision. Radiological examination at the final follow-up showed that cones implanted into the joint were stable and bone defects were effectively reconstructed. The bone defect left by infection after artificial knee arthroplasty is large and irregular, and the prognosis for revision surgery is poor. Wang et al. [208] found that the 3D printing porous prosthesis can be used to reconstruct tibial bone defects in patients with chronic inflammation after joint replacement surgeries. The surgery went well and the patient achieved a satisfactory recovery after surgery. Yin et al. [246] used a uniquely shaped and highly porous 3D printing knee prosthesis during revision surgery. The porous structure of the tibia and femur provided micro-anchoring of the host bone and induced bone ingrowth, with mechanical strength (35.8 ​MPa) similar to cancellous bone and low modulus of elasticity (0.74 ​GPa) reducing the risk of stress masking. The 6-month postoperative follow-up showed better knee function.

Total ankle arthroplasty (TAA) has been proposed in an effort to improve functional outcomes. However, the outcomes of TAA are generally unsatisfactory compared to other arthroplasties, such as those of the hip and knee. Based on this, Faldini et al. [209] reported the metal prosthesis components using Co–Cr powders and immediate postoperative X-rays showed good implant positioning and alignment. Zhang et al. [211] found that 3D printing porous Ta has good histocompatibility, and its interface structure and porosity are more conducive to bone ingrowth for ankle osteoarthritis.

4.3. Bone tumor surgeries

In bone tumor surgery, 3D printing implants may be an ideal option to accurately reconstruct the unique anatomy of patients with specific bone defects [247]. The traditional treatment for osteosarcoma is amputation, but patients have a low long-term postoperative survival rate and accompanying limb dysfunction [248]. 3D printing metal implants significantly improve the treatment of bone tumors, restoring bone appearance and function [249]. Vitiello et al. [250] evaluate the application of 3D printing custom-made prostheses in different sites. The prosthesis was printed using the EBM method, by sintering Ti powder (Ti–6Al–4V). They found that preoperative and postoperative quality of life were comparable. The patients preserved their autonomy on daily life activities with no functional impairment and they were able to carry out normal activities and work.

Due to the lack of individual design, high incidence of prosthetic mismatching, and loosening were reported in pelvic reconstruction surgery with conventional modular prostheses [251]. Liang et al. [212] found that the use of 3D printing pelvic prostheses for the reconstruction of the bony defect was safe, without additional complications, and gave good short-term functional results. Additionally, 28 pelvic tumor patients were enrolled by Wu et al. [217] and achieved good early postoperative efficacy and functional recovery. Park et al. [218] filled cavitary bone defects with structural allobone graft precisely trimmed by the 3D printing allograft-shaping guide and 3D-printed mesh-style Ti spacer using EBM technology. The patient's independent gait was recovered. Chen et al. [216] described a 29-year-old woman with giant chondrosarcoma treated with a personalized 3D Ti implant. The surgery was successful, and the patient recovered with significant pain relief and good functional recovery after the surgery.

In patients with tibial plateau osteomegaloblastoma, the conventional hinged knee prosthesis has some problems, such as poor mobility, stress concentration, susceptibility to prosthesis fracture, loosening, and sinking. If the replacement is performed with a surface prosthesis, it cannot handle the large bone defect that occurs after the lesion is scraped away, and the joint stability is poor when the tumor segment is removed and then replaced with a conventional surface knee joint [252]. Based on the above considerations, Luo et al. [213] designed a 3D printing block made of Ti alloy (Ti–6Al–4V) through the use of the EBM method for semi-limited knee replacement after tumor resection. In all 4 cases, the 3D printing block fitted the bone defect precisely. In cases of giant cell tumour (GCT) of theproximal tibia, the application of 3D printing porous prosthesis combined autograft could supply enough mechanical support and enhance bone ingrowth [253]. Lu et al. [214] fabricated a personalized porous implant by the EBM method to mechanically support the graft and subchondral area and help avoid degenerative changes and mechanical failure. At the last follow-up at 29 months postoperatively, the patient had satisfactory limb function and no further damage was seen to the subchondral area and articular surface. Feng et al. [215] reported a case of radical resection of ameloblastoma in the mid-distal tibia combined with limb salvage using a Ti alloy prosthesis replacement. Computer-assisted 3D-printing technology allowed for more volume and structural compatibility of the prosthesis, thereby ensuring a good operation and initial prosthetic stabilization.

4.4. Trauma surgeries

The treatment of complex post-traumatic skeletal defects and deformities can benefit from 3D printing technology [254]. The application of 3D printing prostheses to repair bone defects and deformities in areas such as the extremities and pelvis can lead to excellent restoration of limb function, thus enabling patients to perform normal daily activities [255]. For patients with open fractures of the distal humerus with severe loss of articular surfaces and bony structures, Luenam et al. [223] used the SLM method to print metal powders to make prostheses. At the 24-month follow-up, radiographs showed good radiocapitellar and ulnar articular spaces.

Fractures involving the acetabulum require repair of the articular surface and anatomy to achieve a satisfactory clinical outcome. However, surgery involving the acetabulum has been challenging due to the complexity of the peripelvic anatomy and neurovascular structures [256,219]. The use of a personalized 3D printing dynamic anterior plate-screw system for the quadrilateral area (DAPSQ) Ti plate has potential advantages in reducing the operation time and blood loss during the treatment of double-column acetabular fractures [257]. Wang et al. [224] found that patient-specific Ti–6Al-4 V plate by SLM method is a feasible, accurate, and effective implant to treat complicated acetabular fractures involving quadrilateral plate (QLP) disruption. Mai et al. [220] reported 8 cases with complex acetabular fractures. The acetabular wing-plate was designed and printed with Ti. Postoperative X-ray and CT examination showed an excellent or good reduction of anterior and posterior column, without any operation complications.

The use of 3D printing metal implants is feasible and effective for reconstructing critical bone defects of the femur [229]. For early osteonecrosis of the femoral head (ONFH), especially in young patients, hip preservation becomes an important therapeutic principle. Zhang et al. [221] applied a new 3D printing Ti trabecular bone implant by the EBM method to replace the necrotic bone of patients with early ONFH. The results show that 3D printing Ti metal trabecular bone may be effective in delaying ONFH progression. For segmental irregular bone defects of the femur, Hou et al. [225] treated all patients with 3D printing micro-porous prosthesis by EBM method combined with intramedullary nail. No complications occurred such as implant loosening, subsidence, loss of correction, and infection. For infective segmental femoral defect, Wu et al. [108] combined the 3D printing porous Ta prosthesis and Masquelet's induce membrane technique to reconstruct bone defect for 9 patients. There were no deep infections, refractures, sensorimotor disorder, vascular injury, ankylosis and recurrence of infection occurred in all cases.

Fractures of the tibia represent a common class of injuries in orthopedics. The blood supply to the tibia is poor due to the small subcutaneous muscle tissues inside. Consequently, the tibia is prone to delayed fracture healing and nonunion of the fracture after surgery. Zhao et al. [222] used a porous Ta metal plate to treat nonunion of a tibial fracture. The resulting porous Ta metal exhibited excellent mechanical and biological properties and improved the therapeutic effects for the treatment of a tibial fracture nonunion. Hamid et al. [258] reported a 46-year-old woman who sustained a left open distal intra-articular tibia fracture with substantial distal tibia bone loss at the scene of the injury. The implant was made of Ti–6Al–4V with patented truss structure and roughened texture of the cross members to facilitate osteointegration. Plain radiographs and CT scans demonstrated successful bone incorporation of the talus, calcaneus, and 3 of 4 cortices of the tibia. Tibiotalocalcaneal (TTC) arthrodesis in the setting of a large bony defect remains a significant challenge for orthopedic surgeons. Yao et al. [259] found that personalized plates (P-Plates) could provide improved clinical outcomes in joint fusion by enabling perfect geometric matching between irregular bone and implants. Steele et al. [227] demonstrated that the use of a custom 3D printing sphere implant is safe in patients with severe bone loss undergoing TTC arthrodesis with a retrograde intramedullary nail and may result in improved rates of successful arthrodesis.

Total talar arthroplasty is a viable treatment option for talar injuries and pathologies. Hussain et al. [228] reported that the patient underwent surgical resection of the pathologic talus with implantation of the custom talar prosthesis. The current results are very favorable. In a patient with a chronic ankle infection, Grau et al. [230] implanted a custom Ti talus with an articular fixation nail. After a 2-year follow-up, a good clinical evolution was achieved, with no signs of reactivation of the infection, no pain, and good skin condition. Kadakia et al. [226] described that the 3D printing cage was used to provide structural support and match the anatomy of the patient with a collapsed native talus with a large bone defect. They also presented a case of total talus arthroplasty in the setting of talar avascular necrosis. This implant is designed based on CT images of the talus from the contralateral limb. The implant is made from cobalt chrome and is smooth to allow for gliding at adjacent articulations.

4.5. Adverse events

Postoperative monitoring of patients with 3D printing implants revealed that adverse events were mainly divided into material issues and implant design issues [260]. Chung et al. [261] reported a case of vertebral reconstruction with 3D printing implants, and the patient had increased eosinophils after surgery without further clinical symptoms, which was postulated to be an allergic-type hypersensitivity response to Ti powder particles. Hence, post-print processing to ensure the removal of powder particles may be important for surgeons of 3D printing implants to consider, as suggested by the FDA [260]. Li et al. [262] used Ti implants for the reconstruction of orbital defects and removed the implants in two patients after implant exposure due to infection. This suggests that orthopedic surgeons should take fully into account the patient's age, health status, medical history, localized infections, location and extent of bone defects, and remaining soft tissue volume when using metal implants. In addition, implant insertion may be difficult due to the complex anatomy of the surgical approach [263]. A few surgeons failed to achieve the midline union of the two-piece interbody cage and intraoperative discrepancy to the anticipated defect geometry and relative positioning of the posterior rods [261]. Therefore, multiple implant heights/sizes can be required to accommodate for variable resection defects and dimensions of the surgical insertion-window mandate consideration during design-rendering.

5. Advantages, limitations, and future

A serious analysis of the process characteristics of metal 3D printed implants reveals the following significant advantages in the field of orthopedic applications: 1) Personalization. By taking the CT or MRI scan data of the patient's patient's bones, the clinician personalizes the product according to the characteristics of the native bones and manufactures a product that exactly matches the native bones, thus reducing the impact of the implant on the human body and restoring the normal function of the human bones to the maximum extent. 2) Osseointegration. It is well known that bone fusion is one of the most important topics that has been highly focused and intensively studied in orthopedics ever. 3D printing technology can print rough mesh structures. The ability of the bone tissue adjacent to the implant to grow into the micropores means direct fusion of the patient's bone with the endosseous implant, which was previously unattainable with most endosseous implants. In addition, the density, strength, and elastic modulus of the implant is adjusted by adjusting the pore size and porosity to make the implant shape and mechanical properties similar to the natural cancellous and cortical bone of the human body. 3) The short cycle time and high material utilization. 3D printing technology can take a product from design to fabrication in as little as 24 ​h, significantly reducing delivery time, and the printing process is usually carried out under vacuum or inert gas protection, making the material recyclable.

However, it is important to realize that, at least at this stage, there are still some problems limiting the use of 3D printed metal implants. First, most orthopedic surgeons are unfamiliar with the various software and equipment used to make 3D printed implants, and expensive equipment purchases, maintenance costs, consumable costs, as well as incompatibility of printing software, severely limit the popularity and development of 3D printing technology. An integrated and unified computer platform should be developed to facilitate communication among different professions such as radiologists, orthopedic surgeons, and engineers.

Next, 3D printing requires more high-quality metal materials. Materials for clinical use have extremely stringent requirements. Currently, only a few mature materials are available for 3D metal printing, such as Ti, SS, and Co–Cr alloys. Safety, biocompatibility, degradation properties, and bioactivity of materials before and after printing need to be considered to meet the requirements for industrialization and clinical use. For example, for medical implants made from Ti alloys, the printing process and product properties should be evaluated before and after printing to ensure that they are not teratogenic and carcinogenic after implantation. The strict sterilization of 3D printing implants is one of the key aspects to ensure a successful placement. Incorrect sterilization processes can negatively affect the surface properties of orthopedic implants and joint prostheses, which can lead to implant failure. Therefore, it is critical that metal materials can withstand the effects of sterilization.

In addition, as the use of 3D printing implants becomes more widespread, appropriate laws and regulations need to be put in place to regulate the use of customized implants. In the U.S., 3D printing implants generally fall under the same regulatory class as similar orthopedic implants, most of which belong to the class III category [264]. Regardless of the manufacturing method, implants must pass regulatory standards based on the class of device (class I, II, or III) in order to come to market. For custom devices, the FDA may offer exemptions under section 520(b) of the Food, Drug, and Cosmetic Act (Fd & C Act) which allows for the distribution of devices which are “not generally available”, “modified to fit the order of the physician”, and related to “special need” or for “sufficiently rare conditions or unique pathology” [265]. In 2014, the FDA held a public working group that summarized best practices for quality control and safety in AM. On January 1, 2020, China officially implemented the "Regulations on the Supervision and Administration of Customized Medical Devices " to regulate 3D printing devices under the filing system. However, an international standard assessment system for such issues is not yet in place, and there are still some outstanding ethical issues [12]. In summary, those who chose to manufacture customized implants are held to the same standards as every other manufacturer of metallic implants.

Despite these limitations to the use of 3D printing metal implants in orthopedics, 3D printed metal implants will offer unprecedented opportunities as the metal materials industry and 3D printing technology continue to evolve and improve. Smart stimulus-responsive biomaterials have attracted increasing attention from researchers over the past 5 years [266]. They differ from conventional biomaterials in their ability to respond to external physical triggers (e.g., light irradiation, electric and magnetic fields, ultrasound, appropriate mechanical stimulus) or endogenous disease microenvironments (e.g., overexpressed ROS, mild acidity, endogenous electric fields, specific ionic concentrations, secreted enzymes or specific immune environments), or a combination of the above. Artificial intelligence, 4D printing, big data, and other digital technologies are constantly being updated, making metal orthopedic implants increasingly personalized and intelligent.

6. Conclusion

Precision, intelligence, and personalization are the future directions of orthopedics. 3D printing is an exciting technology which is considered to revolutionize patient-specific orthopedic implants. With the help of 3D printing techniques and advanced biometals, orthopedic implants can precisely fabricate complex geometries, reduce excessive mechanical strength, increase cell and nutrient permeability, and promote angiogenesis and bone growth. It is reasonable to believe that 3D printing technology will be more deeply integrated with artificial intelligence, 4D printing, and big data to play a greater role in orthopedic metal implants and eventually become a major part of the digital economy.

Declaration of competing interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.