Effect of the addition of low rare earth elements (lanthanum, neodymium, cerium) on the biodegradation and biocompatibility of magnesium
Graphical abstract
Introduction
One of the actual and much-needed demands in orthopaedics is the clinical availability of biodegradable implants [1], [2], [3], [4], [5]. In some clinical applications, such as fracture treatment, permanent metal implants are not necessary or even disadvantageous and a temporary implant concept would be much more suitable. Temporary implants made of biodegradable materials are destined to corrode and dissolve postoperatively and hence a second surgery for implant removal is not necessary, eliminating surgery and accompanied additional costs and unnecessary health risks for the patients. The requirements for such temporary implants are multi-fold and depend upon the site of their utilization. However, some properties are essential: (i) the material should provide a controlled and adequate degradation profile, whilst allowing (ii) necessary spatial and temporal mechanical stability. (iii) The biodegradable material or its components should not only be biocompatible [6], [7], but moreover, (iv) it should at best assist specific and desired biological effects such as stimulating regeneration, healing processes or supporting anti-inflammatory mechanisms. (v) Finally and optimally, the biodegradable material should be completely replaced by host tissue. Amongst other candidates, magnesium-based alloys are very promising materials for such temporary implants [4], [8], [9]. These alloys offer some remarkable physico-chemical properties [10], [11], [12], [13], [14] while they disintegrate gradually up to complete dissolution in physiological environments. Magnesium and its alloys show high degrees of biocompatibility [15], [16], [17], [18], [19] and very interestingly, an increased bone growth has been repeatedly reported in the vicinity of corroding magnesium implants or its corrosion products [20], [21], [22], [23]. Actually, a drug-eluting magnesium stent [24] and a magnesium screw consisting of MgYREZr (a material similar to WE43) that contains >90 wt.% magnesium [25] are already in clinical use.
Despite the remarkable progress which was achieved in the development of Mg-based alloys, the important issues of corrosion resistance, gas formation, biocompatibility and mechanical stability need more research effort. In our search of suitable alloying elements for biomedically usable magnesium alloys, we concentrated on cerium (Ce), lanthanum (La) and neodymium (Nd), three rare earth elements (REEs). REE are widely used in different commercially available alloys such as AE, QE, WE or ZE series alloys [26], [27], [28]. The addition of REEs has significant effects on the high temperature strength and creep resistance [29] and they improve magnesium corrosion resistance [30]. For engineering applications, REEs are usually added as a mischmetal of various compositions commonly rich in Ce, La and Nd; however, this mischmetal can vary in its composition depending on its source. For biomedical applications a more defined approach is desirable, since reproducibility is a major requirement for medical devices. In a first approach, we focused on the collectivity of eligible REEs on these commonly occurring three elements and we prepared Mg–Ce, Mg–La and Mg–Nd alloys to observe the in vitro and in vivo effects. The alloy compositions were used at a concentration which was determined from an average of the most common representatives of Mg–REE alloys, e.g. 2.0–2.5% neodymium was used for WE43A alloy, according to ASTM B275-04 [31], [32]. We expected these concentrations to be toxicologically noncritical but sufficient enough to influence positively the mechanical properties of the alloy matrix architecture.
This study investigated the microstructures, the in vitro corrosion behaviour and the cytotoxicity of low concentrations of REE in Mg alloys. To observe the effects of these different Mg–REE alloys on the reactions of bone tissue, they were implanted, within the limits of a pilot study, into rabbit femur condyles. General biocompatibility as well as changes in the surrounding tissues using histomorphological analysis was investigated.
Section snippets
Preparation of Mg–REE alloys and microstructure observation
Three binary Mg–REE alloys (Mg–Ce: 1.27 wt.% cerium; Mg–La: 0.69 wt.% lanthanum; Mg–Nd: 2.13 wt.% neodymium) were melted and cast in pure Mg (99.95%) and commercially pure REE under a mixed gas atmosphere of SF6 and CO2 using a mild steel crucible. The chemical compositions of Mg–REE alloys were measured by inductively coupled plasma atomic emission spectrometry (Profile ICP-AES, Leeman Labs, Husdon, USA). The cylindrical samples (3 mm diameter and 5 mm height) were cut from casting ingots and
Microstructures of Mg–REE alloys
The typical microstructures of the as-cast Mg–Ce (Fig. 1a), Mg–La (Fig. 1b) and Mg–Nd (Fig. 1c) alloys showed coarse grains and bright intermetallic phases. The intermetallics distributed at the grain boundaries and inner grains, identified as RE-rich precipitate by EDS analysis (Fig. 1d). XRD examination indicated that the intermetallic phases in Mg–Ce, Mg–La and Mg–Nd alloys were identified as Mg12Ce, Mg17La2 and Mg12Nd (data not shown). The intermetallic volume percentage of the three alloys
Discussion
In this study, the three Mg–REE alloys exhibited quite different corrosion behaviours in the corrosion tests, both in vitro and in vivo. The typical microstructures of the as-cast Mg–REE alloys showed coarse grains and bright intermetallic phases identified as REE-rich precipitates. Similar results were obtained in previous studies referring to as-cast binary Mg–Ce and Mg–Nd alloys [11], [37], [38]. However, the intermetallic in Mg–La was identified as Mg17La2, which was different from the
Conclusion
This paper demonstrates that Mg–La exhibits the highest corrosion rate in vitro, followed by Mg–Ce and Mg–Nd alloys. The Mg–Nd alloy also appears to have the lowest corrosion rate in vivo. In addition, Mg–Ce showed more severe cytotoxicity to MC3T3-E1 cells than Mg–La and Mg–Nd. All tested Mg–REE (Mg–Ce, Mg–La and Mg–Nd) corroded slowly in vivo without enhancing bone growth in a 750 μm broad tissue area around the implant.
Disclosures
The authors declare no conflicts of interest.
Acknowledgements
This work was supported by the National Basic Research Program of China (973 Program) (Grant Nos. 2012CB619102 and 2012CB619100), National Science Fund for Distinguished Young Scholars (Grant No. 51225101). We thank Michael Schwarze for help with statistical analysis, Sean Lynch for critical reading of the manuscript and Maike Haupt, Sophie Müller, and Mattias Reebmann (all from Hannover Medical School) for excellent technical support.
References (50)
- et al.
Developments in metallic biodegradable stents
Acta Biomater
(2010) How smart do biomaterials need to be? A translational science and clinical point of view
Adv Drug Deliv Rev
(2013)- et al.
Magnesium and its alloys as orthopedic biomaterials: a review
Biomaterials
(2006) The history of biodegradable magnesium implants: a review
Acta Biomater
(2010)- et al.
Biodegradable metals
Mat Sci Eng R
(2014) - et al.
A comparison of corrosion behavior in saline environment: rare earth metals (Y, Nd, Gd, Dy) for alloying of biodegradable magnesium alloys
JMST
(2013) - et al.
Structural and corrosion characterization of biodegradable Mg–RE (RE = Gd, Y, Nd) alloys
Trans Nonferrous Met Soc China
(2013) Biocompatibility of rapidly solidified magnesium alloy RS66 as a temporary biodegradable metal
Acta Biomater
(2013)In vitro and in vivo evaluation of biodegradable, open-porous scaffolds made of sintered magnesium W4 short fibres
Acta Biomater
(2013)- et al.
Long-term in vivo degradation behaviour and biocompatibility of the magnesium alloy ZEK100 for use as a biodegradable bone implant
Acta Biomater
(2013)
In vivo corrosion of four magnesium alloys and the associated bone response
Biomaterials
Magnesium hydroxide temporarily enhancing osteoblast activity and decreasing the osteoclast number in peri-implant bone remodelling
Acta Biomater
Bone-implant interface strength and osseointegration: Biodegradable magnesium alloy versus standard titanium control
Acta Biomater
Magnesium alloys for temporary implants in osteosynthesis: in vivo studies of their degradation and interaction with bone
Acta Biomater
Evaluation of short-term effects of rare earth and other elements used in magnesium alloys on primary cells and cell lines
Acta Biomater
Magnesium alloys as implant materials – principles of property design for Mg-RE alloys
Acta Biomater
How useful is SBF in predicting in vivo bone bioactivity?
Biomaterials
In vitro and in vivo corrosion measurements of magnesium alloys
Biomaterials
Histology and research at the hard tissue–implant interface using Technovit 9100 New embedding technique
Acta Biomater
On the corrosion of binary magnesium–rare earth alloys
Corros Sci
Structure, mechanical properties, corrosion behavior and cytotoxicity of biodegradable MgX (X = Sn, Ga, In) alloys
Mater Sci Eng C Mater Biol Appl
Improvement of corrosion resistance of magnesium metal by rare earth elements
Electrochim Acta
Interference of magnesium corrosion with tetrazolium-based cytotoxicity assays
Acta Biomater
Effect of cerium chloride application on fibroblast and osteoblast proliferation and differentiation
Arch Oral Biol
Magnesium biomaterials for orthopedic application: a review from a biological perspective
J Biomed Mater Res B Appl Biomater
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These authors contributed equally to this work.
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Present address: Julius Wolff Institute and Center for Musculoskeletal Surgery, Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.