Alloying elements

There are many reasons to alloy Mg. Improving mechanical and corrosion properties is the main one. Although the formation of secondary phases with a more noble character than Mg does, in principle, not improve the corrosion behaviour, they can improve the mechanical strength and the ductility. This is desirable for load bearing implant applications. Up to now, currently investigated alloying elements for biomedical applications are: aluminium, zinc, manganese, silicon, calcium, strontium, lithium, silver, bismuth, zirconium; and rare earth elements (REE) such as gadolinium, yttrium, neodymium, cerium, or dysprosium. Below, the state of the art of gadolinium and silver is shown as they are the selected alloying elements for this doctoral thesis, although some of the currently investigated elements are also mentioned (Al, Ca, Zn, Sr, Si, Mn).

a) Gadolinium

Rare earth elements (REE), such as Gd, Dy, Y, Nd and Ce are strong candidates to alloy Mg because they can improve mechanical properties and facilitate control of the degradation properties [91-93]. For example, the

‘‘scavenger effect” of REE on Mg-alloys improves the corrosion resistance by the formation of intermetallic compounds with impurities, which deteriorate Mg degradation properties [86, 94]. Gadolinium (Gd) is a promising alloying element due to its large solubility limit in Mg (23.49 wt.%) (Fig. 9a) [95]. This large solubility allows the adjustment of mechanical properties by precipitation and solid solution strengthening. The formation of intermetallic phases, such as Mg₅Gd, is proven to improve the mechanical properties [91]. In literature it is stated that the corrosion behaviour of Mg-Gd binary alloys improves with an increasing amount of Gd of up to 10 wt.% (Fig. 9b) [91, 93]. Furthermore, Guo et al. found Gd(OH)3

in the degradation layer, which can also contribute to the corrosion protection [96].

Figure 9. (a) Mg-Gd phase diagram from Ref. [97] and (b) degradation rates of Mg-Gd binary alloys with 2, 5, 10 and 15 wt.% of Gd [91]. Figures are edited and reprinted with permission.

Cuboid shaped particles have been reported in Mg-Gd [91, 92] and in Y containing alloys [98-100] (Fig. 10). These cubes could be GdH₂ and YH₂ particles formed during the casting or even during storage due to the contact of the material with hydrogen sources. The main source of hydrogen is the H2O molecules present in the air. Qiuming et al. observed by TEM GdH2

cubic particles in Mg-Gd alloys proving that hydrides can form [101].

Moreover, the presence of DyH₂ has also been proven in Mg20Dy alloys [102] which indicates that these cubic shaped hydride particles can precipitate with many REEs.

Figure 10. Cuboid shaped particles found in Mg-Gd alloys in: (a) Mg-15Gd alloy from Ref. [91]; (b) Mg-5Gd alloy from Ref. [92]; and (c) Mg-15Gd alloy. Qiuming et al. showed experimental proof of the existence of GdH₂ in cuboid shape [101]. Figures are edited and reprinted with permission.

Cytotoxicity tests of Gd with osteoblast cells indicated that Mg-Gd based implant material could be acceptable for medical applications [103].

Although many authors state that gadolinium is highly toxic, the acute toxicity is only moderate [91]. Grillo et al. reported cytotoxic effects of a mixture of La and Gd at concentrations lower than 200 μM while DNA damage was detected for 1600 μM of Gd [104]. In toxicology, the median lethal dose (LD50) is a measure of the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the dose required to kill half the members of a tested population after a specified test duration. The intraperitoneal LD50 dose of GdCl₃ was 550 mg kg^-1 in mice, while GdNO₃ induced acute toxicity at a concentration of 300 mg kg^-1 in mice and 230 mg kg^-1 in rats, respectively [105, 106]. However, there is an increasing evidence that many REE exhibit anticarcinogenic properties [107] and Gd-based elements are used as magnetic resonance contrasts [108-110]. However, there are indications that Gd ions released by transmetallation can induce nephrogenic systemic fibrosis in patients with renal failure, although not in healthy patients [111]. Finally, Gd has also been observed to have a certain retention rate in bone prior to redistribution to spleen and liver [112].

b) Silver

An option to achieve faster degradation rates is to add elements which can decrease the corrosion properties. Silver (Ag), for instance, is considered as an impurity with a low tolerance limit and accelerates resorption (see Ref.

[78] and page 471 in Ref. [79]). On the one hand, Ag is one of the most noble metals with a standard potential (E_o) in water at 25°C of +0.80 V vs SHE. On the other hand, the E_o of Mg in water at 25°C is -2.37 V vs SHE, which makes it one of the less noble metals. Thus, the combination of Ag and Mg in contact with an electrolyte is expected to accelerate the Mg-Ag corrosion process by creating many microgalvanic couples.

Although magnesium metal by itself has shown in vitro antibacterial properties against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus [113], Ag can also be added to Mg to enhance the antibacterial properties of implant material [114]. Tie et al. [61] demonstrated that the killing rate of Mg-Ag alloys against Staphylococcus aureus and Staphylococcus epidermidis, famous ‘superbugs’ that cannot be killed by most antibiotics, exceeded 90%. Moreover, metallic silver was proven to pose minimal risk to health [115]. Metallic and alloyed silver did not show any cytotoxicity in silver-containing medical devices [116]. A small amount of silver content in alloys or coatings was also reported to improve cytocompatibility and cell viability [116, 117] although elementary silver exhibits a dose-dependent cytotoxity. When 2 wt.% of Ag is added in Mg-Ag binary alloys the degradation rate of the material is already increased, although additions of 4 and 6 wt.% of Ag were also analysed finding similar results [61]. These additions of Ag are expected to be safe for the human body.

Tie et al. also reported silver rich secondary phases which are Mg₄Ag or perhaps partially it could be Mg₅₄Ag₁₇ [61]. However, the Mg-Ag binary diagram, calculated by Pandat software (from Computherm) using the database PanMg_2016, includes Mg3Ag and Mg4Ag as intermetallic phases.

Zheng reported the solid solubility of Ag in Mg as 3.83 at.% (15.14 wt.%) [118], while the calculated diagram indicates a solubility of 3.5 at.% (13.78 wt.%).

Figure 11. Mg-Ag binary phase diagram from Pandat software (by Computherm) using the database PanMg_2016 (image provided by Andrea Gil-Santos).

c) Aluminium

As mentioned above, the selection of the alloying elements can be critical for the biodegradation behaviour. Although aluminium (Al) is one of the common alloying elements of Mg alloy due to the appearance of the β Mg₁₇Al₁₂ phase, it is considered unfavourable to the human body since it could cause Alzheimer’s disease. It has been demonstrated that aluminium ions can easily combine with inorganic phosphates, leading to a lack of phosphate in the human body, which induces dementia [119-121]. Whilst being environmentally abundant, aluminium is not essential for life. On the contrary, aluminium is a widely recognized neurotoxin that inhibits more than 200 biologically important functions and causes various adverse effects in plants, animals, and humans [121]. Thus, well-known Al containing commercial alloys, such as AZ31 or AZ91, are no longer considered as implant candidates. AZ31 and AZ91 are Mg alloys with 1wt.% of Zn and 3wt.% and 9 wt.% of Al respectively.

d) Calcium

Calcium is the main component of human bone in the hydroxyapatite structure and improves bone healing because Ca ions are essential in cellular signalling [122]. In addition, Ca seems to better incorporate into bones in the presence of Mg ions [123].

In magnesium metallurgy, calcium can act as a deoxidant in the Mg melt during casting or in subsequent heat treatment, preventing the material from igniting [79]. In Mg alloys it promotes grain refinement improving corrosion and mechanical properties. The Mg₂Ca secondary phase in the Mg-Ca binary alloys can decrease corrosion resistance and increase the yield strength with increase in Ca content [124].

e) Zinc

Zinc is considered a crucial trace element for the human body and it is necessary for many biological functions [125, 126]. As an alloying element in Mg, it positively influences bone healing and cell reactions [127, 128].

Metallurgically, Mg-Zn alloys are known to increase the age hardening response as Zn produces intermetallic compounds and these refine the grain size [100, 129]. Mg₇Zn₃ can form as a secondary phase in the Mg-Zn binary alloy.

f) Strontium

Strontium (Sr) has been determined as a potential element for use in medical applications [73] of magnesium alloys. Sr is a component of human bone and it has been known to promote the growth of osteoblasts and prevent bone resorption [130]. Moreover, its role in bone, heart and muscle function was shown in the 1950's and 1960's [131].

As a grain refiner for Mg alloys, Sr can improve the mechanical properties of some Mg alloys, as well as improve the corrosion resistance of Mg [132-134]. Mg₁₇Sr₂can form in the Mg-Sr binary system [69, 73]. Tie et al.

recently showed promising corrosion and biocompatible properties of Mg-1Sr alloy, which stimulated new bone formation and showed no adverse effects after 16 weeks of implantation in New Zealand White Rabbits [135].

The biocompatibility and suitable biodegradability of Mg-1.0Ca-0.5Sr also have recently been reported in rat tibiae [136].

g) Silicon

Silicon can be tolerated in the human body and a small content of Si has been reported to be essential in mammals [137]. Moreover, it may be important for the growth and development of bone and connective tissue [138]; and it also helps to build the immune system [139].

However, as-cast Mg-Si alloys showed low ductility and strength because of the large Mg₂Si particle size and the brittle eutectic phase [140]. Srinivasan et al. found that fine and evenly distributed Mg₂Si intermetallic with polygon shape effectively inhibited the corrosion compared to the Chinese-script shaped Mg₂Si [141].

h) Manganese

Manganese also plays an important role in the metabolic cycle of, e.g., amino acids and carbohydrates [142].

Mn has the function of refining the grain size [143], and improving the tensile strength and corrosion properties of magnesium alloys [3, 144]. Mn also decreases the corrosion rate of Mg via transforming iron and other metal elements to harmless intermetallic compounds [80].