Mechanical properties of magnesium alloys for medical application: A review

Mechanical properties of magnesium alloys for medical application: A review

Journal of the Mechanical Behavior of Biomedical Materials 87 (2018) 68–79 Contents lists available at ScienceDirect Journal of the Mechanical Behav...

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Journal of the Mechanical Behavior of Biomedical Materials 87 (2018) 68–79

Contents lists available at ScienceDirect

Journal of the Mechanical Behavior of Biomedical Materials journal homepage: www.elsevier.com/locate/jmbbm

Mechanical properties of magnesium alloys for medical application: A review ⁎

Junxiu Chena,b, Lili Tana, , Xiaoming Yua, Iniobong P. Etima,b, Muhammad Ibrahima,b, Ke Yanga, a b

T ⁎

Institute of Metal Research, Chinese Academy of Sciences, Shenyang 110016, China School of Materials Science and Engineering, University of Science and Technology of China, Shenyang 110016, China

A R T I C LE I N FO

A B S T R A C T

Keywords: Biodegradable magnesium alloy Mechanical properties Medical application

Magnesium alloys as a class of biodegradable metals have great potential to be used as implant materials, which attract much attention. In this review, the mechanical properties of magnesium alloys for medical applications are summarized. The methods to improve the mechanical properties of biodegradable magnesium alloys and the mechanical behaviors of Mg alloys in biomedical application are illustrated. Finally the challenges and future development of biodegradable magnesium alloys are presented.

1. Introduction Biodegradable metals are breaking the current knowledge in biomaterials by the development of corrosion resistant metals. The role of biodegradable implants is to support tissue regeneration, heal the specific trauma and finally disappear through degradation in biological environment. In recent years, biodegradable magnesium (Mg) and its alloys are showing great potential to be used as a new class of materials and are attracting much attention owing to their characteristics of biodegradation (Staiger et al., 2006; Tan et al., 2013; Zhao et al., 2017), anti-inflammatory (Mazur et al., 2007; Peng et al., 2013), antitumor effect (Li et al., 2014a, 2014b; Qu et al., 2013; Wang et al., 2014), antibacterial (Li et al., 2014a, 2014b; Ren et al., 2011; Robinson et al., 2010), osteogenesis inductivity (Chen et al., 2014a, 2014b, 2014c, 2014d; Cheng et al., 2016; Liu et al., 2016; Zhai et al., 2014) and some other biofunctional properties (Guo et al., 2013; Wan et al., 2013; Zeng et al., 2013). Mg was first reported for medical application in 1878 as ligatures. the physician Edward C. Huse used Mg wires to stop the bleeding vessels of three patients in 1878 (Huse, 1878). He observed that the corrosion of Mg in vivo was slower and the degradation period was dependent on the size of the Mg wire (Huse, 1878). However, pure Mg wire was too brittle to knot easily; therefore some elements were alloyed into Mg to increase its ductility. In 1900, the physician Erwin Payr introduced the idea of using Mg plates and sheets in animal joints to regain or preserve the joint motion. The Mg sheets were implanted in the knee joint of dogs and rabbits, and then the materials completely corroded after 18 days or few weeks, depending on their thickness



(Rostock, 1937). From the end of last century, a new round of study on Mg and its alloys as biodegradable materials has gained much progress. In 2013, the Biotronic Company in Germany obtained the CE mark on a biodegradable Mg alloy's coronary stent and led the development of biodegradable metal coronary stents. In 2013, the Syntellix Co. in Germany obtained the CE mark on a biodegradable Mg alloy's screw after the clinical trial to treat the hallux valgus surgery (Plaass et al., 2016; Windhagen et al., 2013). In December 2016, MAGNEZIX® continued to make its mark: with 25,000 MAGNEZIX® implants, more implants were placed on the market within just 12 months than in the previous 2.5 years. The MAGNEZIX® CBS with 3.5 mm diameter can be used in children, young people and adults as a temporary load-bearing device for bone fixation ("MAGNEZIX® implants"). MAGNEZIX® compression screws have different sizes (MAGNEZIX® CS 2.0, MAGNEZIX® CS 2.7, MAGNEZIX® CS 3.2, MAGNEZIX® CS 4.8) for different treatment (Seitz et al., 2016). Besides, Magmaris (Biotronik AG, Bulach, Switzerland) stent has also received the CE mark in 2016. Magmaris stent is a sirolimus-eluting bioresorbable magnesium scaffold that has better deliverability, radial support and a fast resorption time (Kang et al., 2017). In 2015, the Ministry of Food and Drug Safety of South Korea announced an approval to the K-MET biodegradable metallic screw for osteosynthesis or fixing a broken bone made in U&I Corporation, and 53 cases of hand and wrist fractures fixed by MgCaZn alloy screws were also reported (Lee et al., 2016). Zhao et al. (2016) in China used pure Mg screw for hip-preserving surgery with vascularized bone graft implantation and have finished more than 100 cases of clinical trials. From the clinical applications till present, we can see that the Mg alloy

Corresponding authors. E-mail addresses: [email protected] (L. Tan), [email protected] (K. Yang).

https://doi.org/10.1016/j.jmbbm.2018.07.022 Received 24 April 2017; Received in revised form 23 September 2017; Accepted 13 July 2018 1751-6161/ © 2018 Published by Elsevier Ltd.

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2.1. Alloy development

screws were mainly used at unload-bearing positions, such as hallux valgus, hand and wrist fractures, and femoral head bone graft fixation. It has been proved (Windhagen et al., 2013) that degradable magnesium-based screws are equivalent to titanium screws for the treatment of mild hallux valgus deformities. Although the Mg alloy screws in clinic at present are mainly used for unload-bearing positions, they still suffer some mechanical functions, since the function of a surgical bone screw is to clamp together the bone and a bone plate or to fix bone fragments, which is achieved by generation of a tensile stress along the length of the screw, arising from the torsional moment to be introduced into the screw during the implantation process (Hughes and Jordan, 1972). After implantation, the screws need to fix the fracture and suffer the shear strength of the bone, so for the Mg alloy screws, during the degradation in vivo the mechanical fixation is still needed to meet the healing process of the broken bone. Therefore the mechanical property and mechanical integrity of the Mg alloy implants in the physiological environment are of vital importance in effective fracture fixations and cardiovascular surgeries. The existent permanent metal implants such as titanium alloy, stainless steel and cobalt-chromium alloy in the human body can cause stress shielding because of their higher Young's modulus (Shi et al., 2011). Polymer materials such as poly-L-lactic acid are limited in some clinical applications due to their lower mechanical properties (Chiu et al., 2007). The mechanical properties of Mg alloys compared with some medical materials currently used in clinic are shown in Table 1, in which we can see that the Young's modulus of Mg alloy is much closer to human bone than those of bio-inert medical metals, such as Ti and its alloys, stainless steel and Co-based alloys, however the strength is lower than those of bio-inert metals, but higher than those of biodegradable polymers. This is the reason Mg alloy implants are only applied in unload-bearing position at present, and the mechanical properties of Mg alloys need further improvement to broaden their applications. In this review, the mechanical behaviors and potential medical application of some representative biodegradable magnesium alloys (Mg-Ca based alloys, Mg-Zn based alloys, Mg-Sr based alloys and Mg-RE based alloys…) in a time span of ten years were summarized.

Alloying is one of the most effective methods to improve the mechanical properties of metals. It has been known that solid solution strengthening and second phase strengthening are the two main ways for improving mechanical properties of magnesium alloys. In addition, to achieve good biocompatibility of the alloys, some nutrient elements have been considered as the first choice to be used as alloying elements, which can form biocompatible Mg alloys and can also improve the strength, which would be different from the engineering designed Mg alloys. Besides, adequate processing has an enormous impact on the mechanical properties of Mg-alloys. For example, heat treatment and plastic deformation. The degradation products have effects on tissue and human metabolism. The corrosion products could promote the bone healing (Witte et al., 2005) and histopathological evaluation of lung, liver, intestine, kidneys, pancreas, and spleen tissue samples showed no abnormalities (Waizy et al., 2014). Ca is one of the main metal elements in human bone and can improve the bone healing process (Jung et al., 2012; Li et al., 2008; Renkema et al., 2008; Yin et al., 2013). In the Mg-Ca alloy, Mg2Ca plays a crucial role in the mechanical properties of the alloy with distribution along the grain boundaries (Seong and Kim, 2015a). The addition of Ca to Mg can both increase the strength and the elongation rate due to the grain refinement (Du et al., 2016; Erdmann et al., 2011). However, excessive addition of Ca in magnesium will deteriorate the corrosion resistance. Therefore, Ca concentration in Mg alloys should be less than 1% (Ding et al., 2014). Seong et al. (Seong and Kim, 2015b) revealed that a high volume fraction of Mg2Ca particles could lead to a deterioration effect on ductility even though they were well refined and dispersed. This was because the interface between Mg and Mg2Ca was not coherent and the interfacial bonding was weak, thereby easily causing cavities and micro-cracks at the interfaces during plastic deformation. The results showed that the Mg-0.4Ca alloy had the highest tensile ductility (21.9%). However, Zeng et al. (Zeng et al., 2015) found that the Mg-0.79Ca alloy had the highest hardness (58.3 HV) and ultimate tensile strength (~200 MPa) in comparison with the Mg-0.54Ca and Mg-1.35Ca alloys due to the uniform distribution of Mg2Ca particles. Zn is one of the important trace elements in human body and a cofactor for optional enzymes in bone and cartilage (Brandão-Neto et al., 1995; Nagata and Lönnerdal, 2011) and Mg-Zn alloys have good biocompatibility (He et al., 2009; Peng et al., 2012; Zhang et al., 2010a, 2010b). Zn has a relatively high solubility in magnesium (6.2 wt%) and can play dual roles in both solid solution and precipitation strengthening (Li et al., 2008; Rosalbino et al., 2013). Zn also can increase age hardening response as it produces intermetallic compounds and refine the grain size (Li and Zheng, 2013; Su et al., 2013). The microstructure of binary as-cast Mg-Zn alloy consists of primary α-Mg matrix and MgZn intermetallic phase distributing along the grain boundary (Kubasek and Vojtech, 2013; Kubasek et al., 2012). It has been proved (Cai et al., 2012) that the strength of Mg-Zn alloy increased with increase of Zn content until 5%. However, the elongation decreased with increase of Zn content. When the content of Zn was over 5%, many MgZn phases would precipitate from Mg matrix along grain boundaries, which could enhance the strength of Mg-Zn alloy due to the dispersion

2. Methods to improve the mechanical properties of biodegradable Mg alloys Magnesium (Mg) is one of the lightest of metals; its alloys have been studied widely. In engineering Mg alloys possessing high specific strength, ductility and creep resistance (Zhu et al., 2015; Yuan et al., 2001). However as a biodegradable material Mg alloys are expected to possess good biocompatibility, high initial mechanical strength and delayed mechanical property decay when implanted in vivo. So for the improvement of mechanical properties of biodegradable Mg alloys, the biocompatibility and degradation properties should also be considered. Requirement to obtain such properties necessitates the alloy development, heat treatment and plastic deformation; all these three aspects are summarized here in this review.

Table 1 Mechanical properties of medical metals (Chen et al., 2014a, 2014b, 2014c, 2014d; Middleton and Tipton, 2000; Yang et al., 2001). Metals

Young's modulus (GPa)

Density (g/cm3)

YS (MPa)

UTS (MPa)

Elongation (%)

Stainless steel(SS316L, annealed plate, ASTM F138) Co–Cr alloys (ASTM F90) Tantalum (annealed) Pure iron (99.8 wt%) Mg-based alloy (WE43, ASTM B107/B107M) DL-PLA

193 210 185 200 44 1.9

8 9.2 16.6 7.87 1.84 –

190 310 138 150 170 –

490 860 207 210 220 27–41

40 20 – 40 2 3–10

69

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Fig. 1. BSE-mode SEM micrograph of surface morphologies of pure Mg (a), Mg-1Zn (b), Mg-5Zn (c) and Mg-7Zn (d) (Cai et al., 2012).

elongation (Gu et al., 2012; He et al., 2013). Brar et al. (Brar et al., 2012) systematically investigated the mechanical properties of Mg-Sr and Mg-Zn-Sr alloys. The optimized alloy for both mechanical and degradation behaviors were Mg-2.0Zn-0.5 Sr and Mg-4.0Zn-0.5 Sr with ultimate tensile strength of 142 MPa and 169 MPa, respectively. Si is regarded as an essential mineral in human body. It plays an important role in the bone healing process and helps to build the immune system. It may also be good for the growth and development of bone and connective tissue (Zhang et al., 2010a, 2010b). Si addition into Mg alloys leads to the formation of Mg2Si precipitates (Gil-Santos et al., 2017) and Mg-Si alloy showed a low ductility due to the presence of coarse Mg2Si. Due to the low corrosion resistance and mechanical properties there are only few reports about Si-containing magnesium alloys. It was found that Zn is very effective alloying element to improve the mechanical properties of the Mg-Si alloys (Ben-Hamu et al., 2008; Zhang et al., 2010a, 2010b). The addition of 1.6% Zn to Mg-0.6Si can modify obviously the morphology of Mg2Si phase from course

strengthening (in Fig. 1). Sr is another nutrient element in the biodegradable magnesium alloys and it's good for the growth of osteoblasts (Atkins et al., 2009; Landi et al., 2008; Marie, 2005; Marie, 2004). Strontium ranelate (SR) can improve the bone strength and bone mineral density, and is used in the treatment for osteoporosis. Furthermore, SR has shown to decrease the osteoblast activity and increase the replication of pre-osteoblast cells, thus decreasing the bone resorption while stimulating bone formation (Dahl et al., 2001). The typical metallographic microstructure of the Mg-Sr binary alloys mainly consists of α-Mg grains, and the second phase Mg17Sr2 precipitated along the grain boundaries as shown in Fig. 2 (Aydin et al., 2013). Sr has the effect of grain refinement, the refined eutectics lead to strong dispersion strengthening. However more than 3% Sr addition will deteriorate the mechanical properties of Mg-Sr alloy due to less formation of intermetallic with weaker dispersion strengthening. As-rolled Mg-2 Sr alloy showed the best combination of strength and ductility, with values of 213 MPa for UTS and 3.2% for

Fig. 2. Cross-sectional microstructures of as-cast samples; Mg-0.5 Sr (a), Mg-2.5 Sr (b) and Mg-6 Sr (c) (Aydin et al., 2013). 70

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eutectic structure to a small dot or short bar shape. As a result, tensile strength, elongation and bio-corrosion resistance were all improved significantly; especially, the elongation improved by 115.7%. The ultimate tensile strength and elongation could be reached 182 MPa and 14%, respectively. The above mentioned alloying development with nutrient alloying elements is one way to improve the mechanical properties of Mg alloys. In order to reach higher mechanical properties, Al, RE (rare earth) and other elements that have less biocompatibility or unknown biological properties, were also studied to develop biodegradable Mg alloys. Though one idea about these alloys is that one can accept lower contents of these elements, enough research is still needed to prove the biosafety. Feyerabend et al. (Feyerabend et al., 2010) evaluated the in vitro cytotoxicity of Y, Nd, Dy, Pr, Gd, La, Ce, Eu, Li and Zr and revealed that the cytotoxicity of these elements appear to be related to their ionic radii. La and Ce showed the highest cytotoxicity of the elements analyzed. Most interestingly the only Mg alloys in the market with CE marks are based on WE43 not the nutrient elements alloys. The reason can be explained as following: the corrosion resistance of alloys with nutrient elements is undesirable and high degradation rate is not good for the biocompatibility. However, MgYREZr (WE43) alloy has good corrosion resistance (Kalb et al., 2012) and mechanical properties (Windhagen et al., 2013) due to the RE (rare earth) addition and good processing technology. Therefore, MgYREZr used as implants is successful. These alloys are introduced as below. Al is an effective alloying element in Mg alloys for improving the mechanical properties and corrosion resistance (Alvarez-Lopez et al., 2010; Song et al., 1998; Abidin et al., 2011), which is studied a lot in structure materials filed. In recent years, many researchers have studied on AZ series magnesium alloys, e.g., AZ31 and AZ91, for potential biodegradable implant applications (Alvarez-Lopez et al., 2010; Kannan, 2010; Sunil et al., 2016; Song et al., 2008; Tian et al., 2016; Wen et al., 2009; Witte et al., 2005). When the content of Al is over 2%, the main second phases are Mg17Al12 or Mg4Al3. Mg17Al12 distributes along grain boundaries in the form of continuous network that enhances the mechanical properties and corrosion resistance of the Mg alloy. But Al can cause nerve toxicity and elevated concentration of Al3+ in the brain are related to Alzheimer's disease (Bakhsheshi-Rad et al., 2014), so the potential toxicity of Al-containing Mg alloys need to be studied in further, which is also a limitation for Mg-Al alloys as biodegradable Mg alloys. Adding rare earth metal elements is a useful way to improve the mechanical properties of Mg alloys, which has been proved by much research in structure materials field (Chang et al., 2008; Peng et al., 2010; Wu and Xia, 2007; Zhang et al., 2008). Rare earth metals can refine the grains and enhance the mechanical properties of Mg alloys due to solid solution and precipitation strengthening. Here we summarized three important rare earth elements studied for biodegradable Mg alloys, including Gd, Nd and Y (Aghion et al., 2012; Feyerabend et al., 2010; Willbold et al., 2015; Zhang et al., 2012a). The strength of Mg-Gd alloy can be increased by the solid solution in α matrix with the increment of Gd, icosahedral quasicrystalline phase (I-phase) was also introduced to the reinforcement of Mg-1.50Zn0.25Gd (at%) alloy, the LPSO (long period stacking ordered) structure had a great effect on the mechanical properties of Mg-5Gd-1Zn-0.6Zr alloy, the yield strength and elongation of which reached to 214 MPa and 30.7%, respectively (Zhang et al., 2016a, 2016b). Nd is another commonly used element to improve the mechanical properties of Mg alloys. The tensile strength and creep resistance were improved due to the formation of the intermetallic of Mg12Nd as shown in Fig. 3 (Zhang et al., 2012c). Zong et al. (Zong et al., 2012) explored Mg-(2–4.0)Nd(0.1–0.5)Zn-(0.3–0.6)Zr alloy which exhibited excellent mechanical properties with tensile yield strength and elongation in the range of 200–380 MPa and 8–32%, respectively. Y has high solubility (12.5%) in magnesium and has good aging hardening response. Hänzi et al. (Hänzi et al., 2009) found that after extrusion Mg-Y-Zn alloy exhibited high

Fig. 3. Microstructure of as-cast JDBM alloy (Zhang et al., 2012c).

ductility (uniform elongation: 17–20%) and considerable strength (ultimate tensile strength: 250 −270 MPa). However, it is reported that rare earth elements have certain toxic effects (Feyerabend et al., 2010; Myrissa et al., 2017). Therefore, the uncertain toxicity of rare earth elements needs further investigation. Finally, alloying is a useful way to improve the mechanical properties of Mg alloys. For biodegradable Mg alloys, the alloying elements are expected not only to improve the initial mechanical properties, but also to keep the mechanical integrity for longer time in vivo through improving the corrosion resistance of the alloys. 2.2. Heat treatment Heat treatment is used to improve the mechanical properties of Mg alloys under the condition that solubility of certain alloying element changes with temperature. Compared with other processing techniques, heat treatment generally does not change the shape or the chemical composition of the materials, but changes the microstructure of the materials. Fine grain strengthening and second phase strengthening are the two main ways for improving mechanical properties of Mg alloys. The commonly used heat treatments to Mg alloys are solid solution treatment (T4), aging treatment (T5) and solid solution + aging treatment (T6) (Blake and Caceres, 2005; Maier et al., 2016; Yu et al., 2017). The mechanical properties of Mg-Zn alloys usually were improved by heat treatment due to a high solubility of Zn in magnesium (Chen et al., 2009, 2016, 2011; Yuan et al., 2016). Lotfabadi et al. (Lotfabadi et al., 2016) found that T4 treatment at 340 °C for 6 h slightly increased the strength and elongation of Mg-1.5Zn alloy while it significantly improved the strength and elongation of Mg-9Zn alloy, as shown in Fig. 4, because of the presence of residual Mg51Zn20 and Mg12Zn13 second phases at grain boundaries. Rare earth (RE) metal-containing Mg alloys are oversaturated solution after heat treatment at 500–530 ℃. Then the alloys will have significant aging strengthening effect through aging treatment (T5) at temperature of 150–250 ℃. In the middle aging stage, the RE-containing Mg alloys can obtain the highest strength. Zhang et al. (Zhang et al., 2012b) found that the mechanical properties of the extruded Mg3Nd-0.2Zn-0.4Zr alloy after aging at 200 ℃ for 10 h could be greatly improved, which could be mainly attributed to the precipitation strengthening (in Fig. 5). The ultimate tensile strength, yield strength and elongation increased to 243 MPa, 189 MPa and 21%, respectively. Maier et al. (Maier et al., 2016) found that the mechanical properties of Mg-Y-Nd alloy could be enhanced by T6 treatment due to the precipitation hardening with yield strength of 133.3 MPa, ultimate tensile strength of 235.5 MPa and elongation of 15.4%. All in all, heat treatment is an effective method to improve the mechanical properties and biodegradable properties of magnesium alloys. The microstructure and the second phases distribution will be 71

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Fig. 6. Tensile properties of as-cast Mg-1Ca alloy, as-cast Mg-2Ca alloy, as-cast Mg-3Ca alloy, as-rolled Mg-1Ca alloy and as-extruded Mg-1Ca alloy samples at room temperature (Li et al., 2008).

Fig. 4. Effect of 6 h of solid solution treatment on the yield and tensile strength of Mg-1.5Zn and Mg-9Zn alloys (Lotfabadi et al., 2016).

1Ca alloy (71 MPa and 1.9%) were largely improved after hot rolling (167 MPa and 3%) and hot extrusion (239.63 MPa and 10.63%) due to the microstructure refinement as shown in Fig. 6, which also indicated that hot rolling presented less effect on mechanical improvement of Mg1Ca than hot extrusion. Moreover, Wang et al. (Wang et al., 2007) found that rolling could also enhance the fatigue properties of AZ31 alloy. The squeeze cast (SC) AZ31 alloy exhibited the lowest fatigue strength, with endurance limit (the stress amplitude at 107 cycles) of about 40 MPa, and hot rolling (HR) improved the fatigue strength of the SC AZ31 alloy and the endurance limit of the HR AZ31alloy (95 MPa) was more than twice as high as that of the SC alloy, and even somewhat higher than that of ECAP (equal-channel angular pressing) alloy. Considerable interests have developed recently in the methods of processing metal materials using severe plastic deformation (SPD) which can offer the possibility of refining the grain size to levels that are significantly smaller than those produced by using conventional thermo mechanical processing technique (Yamashita et al., 2001), including high pressure torsion (HPT), twist extrusion (TE), multi-directional forging (MDF), equal-channel angular pressing (ECAP), accumulative roll bonding (ARB), cyclic extrusion and compression (CEC), and repetitive corrugation and straightening (RCS) (Valiev et al., 2006). Here three SPD methods used for biodegradable Mg alloys processes were summarized, ECAP, HPT and CEC, respectively. ECAP is the most studied method for Mg alloys among all the SPD methods, during the ECAP process, a bulk sample is pressed through a die, and a strain is induced without any change in the cross-sectional dimension of the work-piece. After ECAP, grain refinement from a starting size of 46 µm (as-cast) to a grain size distribution of 1–5 µm was successfully achieved after the 4th pass. The corrosion resistance and mechanical properties were improved obviously (Gzyl et al., 2015; Sunil et al., 2016). The grain refinement on LAE442 alloy led to a decrease of the average grain size to ~1.7 µm after the final step of ECAP (Minárik et al., 2016a, 2016b). The ductility of ZK60 alloy after ECAP increased two times compared with the initial (unprocessed) alloy due to the grain refinement and texture evolution, as shown in Fig. 7 (Dumitru et al., 2016). The effect of grain refinement, dislocation density increase and especially texture evolution, on the mechanical properties of AE21, AE42 and LAE442 magnesium alloys processed by ECAP was thoroughly studied by Peter Minárik et al. (Minárik et al., 2016a, 2016b), the results of which showed that micro hardness evolution was correlated to grain size according to Hall-Petch relation and to the evolution of dislocation density, the yield stress in the tensile and compression uni-axial deformation tests was determined mainly by the texture, and by tailoring the c/a ratio the typical texture development

Fig. 5. Optical micrograph of JDBM (E250 + Aging) showing tiny grains and distribution of Mg12Nd phase (Zhang et al., 2012b).

changed after heat treatment which are closely related to the mechanical properties of magnesium alloys.

2.3. Plastic deformation In the process of plastic deformation, the dislocation density of Mg alloys increases and the grain refinement effect is obvious (Chen et al., 2014a, 2014b, 2014c, 2014d; Lu et al., 2015). As a result, the strength of Mg alloys is improved due to the resistance to dislocation movement. Usually, the mechanical properties of magnesium and its alloys can be greatly improved by plastic deformation such as extrusion, rolling, drawing and forging. Extrusion is the most commonly used plastic deformation to improve the mechanical properties of Mg alloys. Zhang et al. (Zhang et al., 2012) studied the extrusion ratio on the mechanical properties of MgNd-Zn-Zr alloy. The results showed that the lower extrusion ratio resulted in fine grains and higher strength (ultimate tensile strength of 312 MPa), but lower elongation (2.2%), while the higher extrusion ratio resulted in coarse grains and lower strength (ultimate tensile strength of 233 MPa), but higher elongation (25.9%). The mechanical properties of ZK series magnesium alloys could also be improved greatly after extrusion (Fereshteh-Saniee et al., 2016; Qiu et al., 2016). Rolling is another way, widely used to improve the mechanical properties of Mg alloys by grain refinement. Li et al. (Li et al., 2008) found that the ultimate tensile strength and elongation of as-cast Mg72

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structures in AZ31 and ZK60 alloys (Chen et al., 2008; Lin et al., 2010). Wu et al. (Wu et al., 2012; Zhu et al., 2013) prepared Mg-Zn-Y-Nd alloy with ultra-fine microstructure and nano-sized particles homogeneously distributed by CEC for fabrication of coronary stents (Fig. 9). The elongation of CEC treated samples (30.2%) was about 2 times higher than that of as-cast alloy and was about 1 time higher than that of extruded alloy. CEC processing was also adopted to refine grains of MgNd-Zn-Zr alloy, the yield strength and ultimate tensile strength of the ECEC are much higher than those of E (with the improvement of ~71% and ~28% respectively), and as shown in Fig. 10 (Zhang et al., 2012d), indicating that the CEC processing plays a significant role on strength improvement. During CEC, the microstructure of the Mg-1.5Zn-0.25Gd (at%) alloy was greatly refined by dynamic recrystallization, large numbers of I-phase particles precipitated and then grew up, the texture of the alloy was obviously weakened. These changes in microstructure improved the mechanical properties of the alloy significantly and the alloy processed by 8 passes CEC exhibited outstanding plasticity of 31.4% and moderate yield strength of 161 MPa (Tian et al., 2015). Other processing methods such as drawing and forging can also change the microstructures of magnesium alloys, resulting in the improvement of mechanical properties. According to the study of Oishi et al. (Oishi et al., 2003) the ultimate tensile strength and yield strength of the drawn wire were 1.4 and 1.9 times higher than those of the extruded wire, respectively. But the elongation of the drawn wire was less than that of the extruded wire. Seitz et al. (Seitz et al., 2010; Seitz et al., 2011) found that ZEK100 filament showed the finest microstructure having grains of 1.2 mm in diameter. ZEK100 had good mechanical properties with high tensile strengths (up to 550 MPa for monofilament) and fracture strains (up to 30% for poly-filament), which are comparable to those of conventional polymer-based suture materials. Bai et al. (Bai et al., 2014) prepared three kinds of Mg alloy fine wires containing 4%RE(Gd/Y/Nd) and 0.4%Zn with the diameter less than 0.4 µm through casting, hot extruding and multi-pass cold drawing combined with intermediated annealing process. In comparison with the corresponding as-extruded alloy, the final fine wire had significantly refined grain with an average size of 3–4 µm, and meanwhile showed higher yield strength but lower ductility at room temperature. Forging has many advantages such as high production efficiency, good dimensional stability and good mechanical properties (Kang and Ostrom, 2008). Harandi et al. (Harandi et al., 2011) found that forging could improve the Vickers hardness of Mg-1Ca alloy. The highest hardness of more than 47HV was obtained at 350 ℃ with forging rate of 65 spm (stock per minute). In order to fabricate high mechanical properties magnesium alloys, the three methods alloying, heat treatment and plastic deformation are usually adopted together. Fig. 11(Chen et al., 2014a, 2014b, 2014c, 2014d) demonstrated the mechanical properties of some representative biodegradable Mg alloys with different condition. In this review, only some representative magnesium alloys which are widely studied by researchers were summarized. The mechanical properties of the above alloys are summarized in Table 2. It can be seen that although Ca, Sr and Si elements have good biocompatibility, their mechanical properties are not desirable due to their lower solubility in magnesium alloys compared with Zn element. Their second phases are usually thick and distributing along the grain boundary, it's not good for the improvement of the mechanical properties of magnesium alloys. For Mg-Ca, MgSr and Mg-Si alloys, new processing technologies (ECAP, HPT and CEC) have to be adopted in order to improve their mechanical properties except alloying method. Zn has a relatively high solubility in magnesium (6.2 wt%) and can play dual roles in both solid solution and precipitation strengthening, Mg-Zn based magnesium alloys usually have good mechanical properties. Besides, RE-containing magnesium alloys usually also exhibit good mechanical properties due to the solid solution and precipitation strengthening. In order to explore new biodegradable magnesium alloys with good mechanical properties, the combination of Zn and RE may be the best choice as the alloying

Fig. 7. Tensile engineering stress-strain curves of extruded ZK60 magnesium alloy processed by ECAP at 523 K for different passes (Dumitru et al., 2016).

could be effectively suppressed in magnesium alloys processed by ECAP and in such way the negative effect of texture on strength can be avoided. In HPT process, a sample is subjected to torsion straining under a high pressure. After HPT, the mechanical properties and corrosion resistance of magnesium alloys can be improved greatly (Kulyasova et al., 2015; Lukyanova et al., 2016; Zhang et al., 2016a, 2016b). The Mg-ZnCa alloy gained ultrafine grained structure (1 µm), numerous dispersive second-phase nanoparticles were found in the grain interiors rather than grain boundaries, and the micro hardness of the alloy increased around 3 times compared with that of as-cast alloy, as shown in Fig. 8 (Guan et al., 2012). After hot extrusion, the mechanical properties and corrosion resistance of Mg-2.5 wt%Zn-1 wt% Ca alloy are enhanced. The alloy with hollow tubes is well suited for subsequent stent manufacturing (Liu et al., 2015). Besides, AZ31 alloy processed by HPT exhibits high ductility with a maximum elongation of ~400% at the relatively low testing temperature of 423 K (Xu et al., 2015). The strength of the magnesium alloys after HPT processed could be further improved by aging (Dobatkin et al., 2016). The disadvantages of ECAP and HPT are only small portions of material can be obtained. Therefore, significant effort is still needed to develop cost effective Mg grain refinement techniques. CEC process, in which sample with diameter D0 is pressed through two similar cylindrical channels with the same diameter connected via a reduced cross section neck d, can obtain ultra-fine grain and nanoparticles uniformly distributed in grains. Recently, CEC was successfully used to produce a variety of metallic materials with ultra-fine grain

Fig. 8. Local micro hardness distance from the center of the disk for HPT treated alloy and as-cast alloy samples (Guan et al., 2012). 73

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Fig. 9. Microstructures of Mg-Zn-Y-Nd alloy: as-cast (a); hot extruded alloy at 543 K with an extrusion ratio of 25:1 (b); CEC 2 passes at 543 K (c) (Wu et al., 2012).

elements.

3. The mechanical behaviors of Mg alloys in biomedical application Magnesium and its alloys have good potential to be used as biomaterials. Fig. 12 demonstrated some real/possible application of biodegradable magnesium implants (Chen et al., 2014a, 2014b, 2014c, 2014d). Nowadays, biodegradable magnesium and its alloys are mainly used in stent and orthopedic application. There are many factors that accelerate the degradation rate of Mg alloys and also affect the variation of mechanical properties during degradation: (1) impurities (Fe, Ni, Cu) (2)aggressive ions such as chlorides, carbonates, phosphates, and sulphates (Xin et al., 2008; Yamasaki et al., 2007); (3) the presence of proteins and glucose (Choudhary and Singh Raman, 2015); (4) the galvanic corrosion; (5) stress corrosion (Gu et al., 2010; McCormack et al., 1998), etc.

Fig. 10. Tensile curves of the Mg-2.73Nd-0.16Zn-0.45Zr alloy (Zhang et al., 2012d).

3.1. Mg-Ca based alloys Mg-Ca alloys have good potential to be used as bone screws for internal fracture fixation. Erdmann et al. (Erdmann et al., 2011) investigated the biomechanical behavior and degradation MgCa0.8 alloy screws in rabbit hind legs. After different implantation time, uniaxial pull-out tests were carried out. No significant differences could be noted between the pull-out forces of MgCa0.8 and S316L 2 weeks after surgery. Six weeks after surgery the pull-out force of MgCa0.8 decreased slightly. In contrast, the S316L pull-out force increased with time. They also observed that greater degradation occurred in the screw parts in close contact with blood vessels and body fluid than in those located in cortical bone. With the degradation of MgCa0.8 alloy, bone formation and integration by the surrounding tissue were observed.

3.2. Mg-Zn based alloys

Fig. 11. Typical yield strength and elongation at failure of representative biodegradable Mg alloys Mg-Al-based alloys include as-cast and extruded AZ31, asextruded AZ61 and AZ91; Mg-Zn-based alloys include as-cast Mg-xZn-1Ca (x = 1–6), as-cast and extruded Mg-1Zn-1Mn, as-extruded Mg-6Zn, ZK30 and ZK60; Mg-Si-based alloys include as-cast Mg-0.6Si-(0.2, 0.4, 1.5)Ca and asrolled Mg-1Si; Mg-Zr-based alloys include as-cast Mg-0.5Zr-(1, 2)Ca, Mg-1Zr-(1, 2)Ca and as-rolled Mg-1Zr; Mg-RE-based alloys include as-extruded WE43, ascast and extruded Mg-3Nd-0.2Zn-0.4Zr, as-cast Mg-10Gd and Mg-15Dy, as-extruded Mg-11.3Gd-2.5Zn-0.7Zr and Mg-8Y-1Er-2Zn (Chen et al., 2014).

Mg-Zn based alloys have a good potential to be used in orthopedic application (Singh et al., 2015). Sun et al. (Sun et al., 2012) found that the mechanical properties of extruded Mg-4Zn-0.2Ca alloy, with initial peak strength of 297 MPa, yield strength of 240 MPa, elongation of 21.3% and elastic modulus of 45 GPa, degraded to 220 MPa, 160 MPa, 8.5% and 40 GPa accordingly after 30 days immersion in SBF solution. A stimulatory effect on cells proliferation was observed when they are cultured with the extraction of ZK30 and ZK60 alloys by indirect contact. Hemolysis and adhesion of cells display good biocompatibility of Mg-Zn alloy in vitro (Huan et al., 2010; S. Zhang et al., 2009). Besides, Mg-Zn alloys have good potential to be used as suture materials and intestinal tract and bile repairing materials (Chen et al., 2014a, 2014b, 2014c, 2014d; Seitz et al., 2011; Yan et al., 2013). 74

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Table 2 Mechanical properties of some representative biodegradable magnesium alloys. Alloys

Condition

Ultimate tensile strength (MPa)

Yield strength (MPa)

Elongation (%)

References

Mg-(2, 3)Ca Mg-(4, 6)Zn Mg-(1, 2, 3, 4)Sr Mg− 0.6Si Mg-Y (MgYREZr) Mg-Nd (JDBM) Mg-Gd

Rolled Extruded Rolled Cast Extruded Extruded Extruded

– 240–315 110–213 166 > 275 194–240 ~260

136–162 100–235 80–148 60 > 250 90–189 ~210

1.9–2.4 8–17 2.8–3.2 6.62 > 10 12–25 ~30

(Seong and Kim, 2015a;) (Hradilová et al., 2013; Huan et al., 2010) (Gu et al., 2012) (Zhang et al., 2010a, 2010b) (Windhagen et al., 2013) (Zhang et al., 2012b) (Zhang et al., 2016a, 2016b)

Fig. 12. Real/possible applications of biodegradable magnesium implants: (a) cardiovascular stents (BIOTRONIK, Berlin, Germany, under clinical trial), (b) MAGNEZIX screw (received CE mark in Europe), (c) microclip for laryngeal microsurgery (pure magnesium), (d) biodegradable orthopedic implants, (e) woundclosing devices (WZ21) (Chen et al., 2014). Table 3 Mechanical behaviors of Mg and its alloys implants in vivo. Implants

Implantation site

Period / weeks

Strength loss

References

Pure Mg (99.99) screw Pure Mg (99.99%) +HA/screw AZ31B/extruded, screw AZ31B + Si coating/extruded, screw Mg− 0.8Ca + MgF2/extruded, rod WE43/extruded, plate WE43 + plasma electrolytic coating/extruded, plate ZEK100/extruded, rod AX30/extruded, rod

Tibia, rabbit Tibia, rabbit Femoral diaphysis, rabbit Femoral diaphysis, rabbit Marrow cavity, rabbit Nasal, minipig Nasal, minipig Marrow cavity, rabbit Marrow cavity, rabbit

12 12 21 21 26 24 24 26 26

50% (tensile) 10% (tensile) 42.4% (bending) 29.9% (bending) 55% (bending) 13% (bending) 8% (bending) 58.7% (bending) 70.3% (bending)

(Kim et al., 2014) (Kim et al., 2014) (Tan et al., 2014) (Tan et al., 2014) (Thomann et al., 2010) (Imwinkelried et al., 2013) (Imwinkelried et al., 2013) (Huehnerschulte et al., 2011) (Huehnerschulte et al., 2011)

3.3. Mg-Sr based alloys

potential to be used in skeletal applications. The optimal Sr content was 2 wt%. Sr concentrations below 2 wt% improved the strength and corrosion resistance of Mg, whereas excessive Sr addition resulted in poorer mechanical properties as well as increased the corrosion rate of the as-rolled Mg-Sr alloys and in vivo tests (implanted into the mice

Sr is chemically and physically closely related to Ca it is a natural bone seeking element that accumulates in the skeleton, preferably in new trabecular bone (Dahl et al., 2001). Binary Mg-Sr alloys have good 75

Journal of the Mechanical Behavior of Biomedical Materials 87 (2018) 68–79

(Ding et al., 2014; Erbel et al., 2007; Plaass et al., 2016) Stent and screw

(Ding et al., 2014; Mao et al., 2015; Mao et al., 2013; Niu et al., 2016)

(Bakhsheshi-Rad et al., 2014; Ding et al., 2014; Tan et al., 2014) Orthopedic application; screw

Stent and screw

(Ben-Hamu et al., 2008; Gil-Santos et al., 2017; Zhang et al., 2010a, 2010b) Orthopedic application; promote the bone healing

Helps to build the immune system; good for the growth and development of bone and connective tissue Causes nerve toxicity and elevated concentration of Al3+ in the brain are related to Alzheimer's disease Good biocompatibility; promote the bone healing process.

WE43 and Mg-Nd-Zn-Zr (JDBM) alloys have been widely studied for medical application. WE43 alloy has been used in clinic as stent and screw (Erbel et al., 2007; Plaass et al., 2016). Mg-Nd-Zn-Zr alloys were explored by Shanghai Jiao Tong University. They have tried to apply these alloys in many medical applications. Mao et al. (Mao et al., 2015; Mao et al., 2013) fabricated a cardiovascular stent using Mg-Nd-Zn-Zr and performed in vivo long-term assessment via implantation of this stent in an animal model. The results confirmed the reduced degradation rate in vivo, excellent tissue compatibility and long-term structural and mechanical durability. Liao et al. (Liao et al., 2013) fabricated polyporous magnesium alloy scaffolds. The polyporous scaffold possessed similar elastic modulus and compressive strength to those of human cancellous bone, and CaHPO4-coated JDBM foam maintained mechanical integrity whilst non-coated scaffolds disaggregated over 8 weeks. CaHPO4-coated JDBM scaffold possesses great potential in vivo applications. Besides, JDBM alloy fabricated as screw were implanted into rabbit mandible bones (Niu et al., 2016). At 18 months, the screw volume has been reduced by ∼90% exhibiting good osteointegration. Most of the magnesium alloys are used as screw for internal fracture fixation. The mechanical behaviors of some other alloys in vivo were summarized in Table 3. With the increase of implantation time, the strength of the magnesium alloys decreased and most of them had good biocompatibility. Finally, the mechanical behaviors, biocompatibility and potential biomedical applications of some representative magnesium alloys were summarized in Table 4.

Good biocompatibility; promoting the bone healing

(Brandão-Neto et al., 1995; Chen et al., 2014a, 2014b, 2014c, 2014d; Li et al., 2008; Nagata et al., 2011; Rosalbino et al., 2013; Seitz et al., 2011; Yan et al., 2013) (Atkins et al., 2009; Gu et al., 2012; Landi et al., 2008; Marie, 2005; Marie, 2004) Orthopedic application; suture materials; intestinal tract and bile repairing Orthopedic application; skeletal applications Important trace elements in human body and a co-factor for optional enzymes in bone and cartilage. Promotes osteoblast maturation; good for the bone formation

3.4. Mg-RE based alloys

4. Challenges and future development Up to now, several cases using magnesium and its alloys in clinic have been conducted. All the results showed the feasibility of using magnesium screws in clinic to treat diseases. However, magnesium and its alloys are mainly used as unload-bearing implants in clinic, and due to the complex stress state, plate and screw systems were only carried out in animal tests (Chaya et al., 2015), the use of combination of magnesium plate and screw is not realized in clinic. Because the solubility of alloying elements in magnesium is limited, and the biocompatibility and biodegradation must be considered for the design of new biodegradable material, the possibility to improve the mechanical properties is much restricted. Higher mechanical properties of magnesium alloys are expected to be reached by more attention on combination of new alloy design, heat treatment and plastic deformation techniques, and furthermore, an approach is introduced recently that combines the strengthening benefits of nanocrystallinity with those of amorphization to produce a dual-phase material that exhibits near-ideal strength of 3.3 GPa at room temperature and without sample size effects (Wu et al., 2017), which provides a new way to improve the mechanical properties for the biodegradable Mg alloys. In addition, with the development of magnesium alloys in medical area, many different potential products are being investigated, not only the strength, but also the ductility, corrosion fatigue, stress corrosion cracking, etc., should be emphasized for some medical implants, which will further broaden the research on mechanical properties of magnesium alloys.

Significantly enhances tensile strength and tensile yield strength with increasing addition of Y; improves elongation with the Y concentration below 3%. Improves the tensile strength and creep resistance due to the formation of the intermetallics of Mg12Nd; Nd content less than 6%.

(Du et al., 2016; Erdmann et al., 2011; Jung et al., 2012; Li et al., 2008; Renkema et al., 2008; Yin et al., 2013). Orthopedic application; screw Essential element of the human body; promote bone healing process

Increase the strength and the elongation rate; excessive Ca deteriorate the corrosion resistance; Ca concentration should be less than 1 wt% Enhance the tensile strength; solid solution strengthening and aging strengthening; the elongation decreased when Zn concentration was over 5 wt% The strength and corrosion resistance improved when Sr concentration below 2 wt%; excessive Sr decreased mechanical properties Mg-Si alloy showed a low ductility due to the presence of coarse Mg2Si; the addition of 1.6% Zn, tensile strength, elongation and bio-corrosion resistance improved significantly. Significantly improve ultimate yield strength and ductility at a concentration below 6%.

femur) showed that as-rolled Mg-2 Sr alloy promoted bone mineralization and peri-implant new bone formation without inducing any significant adverse effects (Gu et al., 2012).

This work was supported by the National Natural Science Foundation of China (Ref. 81401773, 31500777), the National Key Research on Development Program of China (No. 2016YFC1101804), National High Technology Research and Development Program of China (863 Program, No. 2015AA033701) and Institute of Metal

Mg-Nd alloys (JDBM)

Mg-Y alloys (MgYREZr)

Mg-Al alloys

Mg-Si alloys

Mg-Sr alloys

Mg-Zn alloys

Mg-Ca alloys

Acknowledgements

Alloys

Table 4 The mechanical behavior biocompatibility and potential biomedical application of some representative magnesium alloys.

References Potential biomedical application Biocompatibility Effects on mechanical properties

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Research, Chinese Academy of Sciences (No. 2015-ZD01).

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