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Biomaterials 27 (2006) 17281734 www.elsevier.com/locate/biomaterials

Review

Magnesium and its alloys as orthopedic biomaterials: A review

Mark P. Staigera, Alexis M. Pietaka,, Jerawala Huadmaia, George Diasb
b

Department of Mechanical Engineering, University of Canterbury, Private Bag 4800, Christchurch, New Zealand Department of Anatomy & Structural Biology, University of Otago Medical School, P.O. Box 913, Dunedin, New Zealand Received 20 June 2005; accepted 3 October 2005 Available online 24 October 2005

Abstract As a lightweight metal with mechanical properties similar to natural bone, a natural ionic presence with signicant functional roles in biological systems, and in vivo degradation via corrosion in the electrolytic environment of the body, magnesium-based implants have the potential to serve as biocompatible, osteoconductive, degradable implants for load-bearing applications. This review explores the properties, biological performance, challenges and future directions of magnesium-based biomaterials. r 2005 Elsevier Ltd. All rights reserved.
Keywords: Magnesium; Orthopedic implant

Contents 1. 2. 3. 4. Introduction: the exciting potential of magnesium-based implants . . . . . . . . . . . . . . . . Biological performance of existing magnesium-based orthopedic implants. . . . . . . . . . . Suggested biological activity of magnesium metal . . . . . . . . . . . . . . . . . . . . . . . . . . . . Improvement of corrosion resistance, mechanical properties and biological performance 4.1. Alloying and surface treatments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Porous magnesium microstructures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1728 1729 1731 1731 1731 1732 1733 1733 1733

1. Introduction: the exciting potential of magnesium-based implants Metallic materials continue to play an essential role as biomaterials to assist with the repair or replacement of bone tissue that has become diseased or damaged [1]. Metals are more suitable for load-bearing applications compared with ceramics or polymeric materials due to their combination of high mechanical strength and fracture toughness. Currently approved and commonly used metallic biomaterials include stainless steels, titanium and
Corresponding author. Tel.: +64 3 389 8207.

E-mail address: alexis.pietak@gmail.com (A.M. Pietak). 0142-9612/$ - see front matter r 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.biomaterials.2005.10.003

cobaltchromium-based alloys. A limitation of these current metallic biomaterials is the possible release of toxic metallic ions and/or particles through corrosion or wear processes [26] that lead to inammatory cascades which reduce biocompatibility and cause tissue loss [2,413]. Moreover, the elastic moduli of current metallic biomaterials are not well matched with that of natural bone tissue, resulting in stress shielding effects that can lead to reduced stimulation of new bone growth and remodeling which decreases implant stability [14]. Current metallic biomaterials are essentially neutral in vivo, remaining as permanent xtures, which in the case of plates, screws and pins used to secure serious fractures, must be removed by a second surgical procedure after the tissue has healed sufciently

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M.P. Staiger et al. / Biomaterials 27 (2006) 17281734 Table 1 Summary of the physical and mechanical properties of various implant materials in comparison to natural bone Properties Density (g/cm3) Elastic modulus (Gpa) Compressive yield strength (Mpa) Fracture toughness (MPam1/2) Compiled from references [1619; 20]. Natural bone 1.82.1 320 130180 36 Magnesium 1.742.0 4145 65100 1540 Ti alloy 4.44.5 110117 7581117 55115 CoCr alloy 8.39.2 230 4501000 N/A Stainless steel 7.98.1 189205 170310 50200 Synthetic hydroxyapatite 3.1 73117 600 0.7 1729

[15]. Repeat surgery increases costs to the health care system and further morbidity to the patient. Magnesium is an exceptionally lightweight metal. With a density of 1.74 g/cm3, magnesium is 1.6 and 4.5 times less dense than aluminum and steel, respectively [16]. The fracture toughness of magnesium is greater than ceramic biomaterials such as hydroxyapatite, while the elastic modulus and compressive yield strength of magnesium are closer to those of natural bone than is the case for other commonly used metallic implants (Table 1). Moreover, magnesium is essential to human metabolism and is naturally found in bone tissue [2126]. It is the fourth most abundant cation in the human body, with an estimated 1 mol of magnesium stored in the body of a normal 70 kg adult, with approximately half of the total physiological magnesium stored in bone tissue [21]. Magnesium is a co-factor for many enzymes, and stabilizes the structures of DNA and RNA [26]. The level of magnesium in the extracellular uid ranges between 0.7 and 1.05 mmol/L, where homeostasis is maintained by the kidneys and intestine [21]. While serum magnesium levels exceeding 1.05 mmol/L can lead to muscular paralysis, hypotension and respiratory distress [22], and cardiac arrest occurs for severely high serum levels of 67 mmol/L, the incidence of hyper-magnesium is rare due to the efcient excretion of the element in the urine [21,22,24]. The major drawback of magnesium in many engineering applicationsits low corrosion resistance, especially in electrolytic, aqueous environmentsbecomes an intriguing property for biomaterial applications, where the in vivo corrosion of the magnesium-based implant involves the formation of a soluble, non-toxic oxide that is harmlessly excreted in the urine. Moreover, due to functional roles and presence in bone tissue, magnesium may actually have stimulatory effects on the growth of new bone tissue [2730]. Thus, it is projected that magnesium and its alloys be applied as lightweight, degradable, load bearing orthopedic implants, which would remain present in the body and maintain mechanical integrity over a time scale of 1218 weeks while the bone tissue heals, eventually being replaced by natural tissue [31,32]. The unfortunate complication is that pure magnesium can corrode too quickly in the physiological pH (7.47.6) and high chloride environment of the physiological system, loosing mechanical integrity before the tissue has sufciently healed and producing hydrogen gas in the corrosion process at a rate

that is too fast to be dealt with by the host tissue [31,33,34]. It is likely that in spite of some early successes with magnesium-based implants [33,35,36], the metal was abandoned due to the production of gas during the in vivo corrosion process when stainless steels became available [31]. Several possibilities exist to tailor the corrosion rate of magnesium by using alloying elements and protective coatings, processes that of course must lead to a non-toxic, biologically compatible material. This work reviews the biological performance of different magnesium-based materials that have been used as orthopedic biomaterials, reports on the safety of magnesium in the body, hypothesizes upon various biologically active features of magnesium-based implants, explores possible routes to improve limiting factors such as the corrosion resistance and improve integration of the implant with tissue, and ultimately highlights the need for further research. 2. Biological performance of existing magnesium-based orthopedic implants Magnesium-based materials were rst introduced as orthopedic biomaterials in the rst half of the century. The rst use of magnesium was reported by Lambotte in 1907, who utilized a plate of pure magnesium (actual purity level unknown) with gold-plated steel nails to secure a fracture involving the bones of the lower leg [33]. The attempt failed as the pure magnesium metal corroded too rapidly in vivo, disintegrating only 8 days after surgery and producing a large amount of gas beneath the skin [33]. In an attempt to slow the corrosion process and increase the mechanical integrity of the implants, future in vivo works have investigated various magnesium alloys [34,31,3540]. Troitskii and Tsitrin, in 1944, reported on 34 cases where magnesium, alloyed with small levels of cadmium, was fashioned into plates and screws and used to secure various fractures [34]. Of the 34 cases, 9 were unsuccessful; these failures were attributed to infection, or difculties arising with the mounting of a plaster cast, which presumably did not allow for treatment of gas cysts [34]. In all patients, no increase in serum levels of magnesium was observed. No distinct inammatory reactions to the implant were observed [34]. The material is reported to have stimulated the development of a hard callous at the fracture site [34]. Hydrogen gas was given off in the corrosion process,

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however, was easily treated by drawing off the gas with a subcutaneous needle [34]. While the sizes of the implants used were not given, it is reported that the mechanical integrity of most were maintained for 68 weeks, with complete resorption occurring in 1012 months [34]. On the contrary however, it was also reported that some implants only survived 35 weeks, which was attributed to increased acidity in the environment of some fractures [34]. Similar results were reported by Znamenski in 1945, where magnesium alloy containing 10 wt% aluminum was used to treat gunshot wounds in two young men [37]. In both cases, fractures fused in 6 weeks, with the magnesium plate no longer detectable after 6 weeks, and the pins no longer detected after 4 weeks [37]. McBride reports on the use of screws, pegs, plates and bands prepared from magnesiumaluminummanganese alloys to secure 20 fractures and bone grafts [35]. Consistent with other reports, no systemic reactions to the use of magnesium alloys or inammatory reactions adjacent to the implant are observed [35]. While no effect on the cancellous bone tissues is observed, a positive effect on the periosteal tissue and deposits of the osseous callous are reported [35]. McBride reports that while the absorption rate is higher for traumatized bone tissue, a typical magnesiumaluminiummanganese 1 gm screw would completely absorb in 120 days [35]. These early examples imply that magnesium-based materials are non-toxic and may actually stimulate bone tissue healing. However, the rate of corrosion of pure magnesium, or these simple alloys, occurs at a rate that is too rapid to allow sufcient time for healing as it is desirable to have the implanted xture present for at least 12 weeks [31]. In an effort to improve the corrosion resistance of magnesium, more complex alloying compositions may be necessary, with the addition of small levels (o4%) of rare earth elements having the most signicant effect. Stroganov et al. report that magnesium alloyed with 0.44 wt% rare earth metal, 0.051.2 wt% cadmium, 0.051.0 wt% calcium or aluminum, and variable, trace (o0.8%) levels of manganese, silver, zirconium or silicon had a slowed

corrosion rate, with pins 3 mm in diameter present for 5 months, and pins 8 mm in diameter present for 11 months in vivo [40]. No information was given as to how long the mechanical integrity of the implants survived or if the potentially toxic effects of the alloying elements were considered [40]. More recently, Witte et al. explored the in vivo degradation of magnesium-based alloys, comparing two alloys containing only aluminum and zinc, and two alloys with rare earth element combinations [31,39]. The aluminumzinc alloys contained 3 wt% aluminum and 1 wt% zinc (AZ31), and 9 wt% aluminum and 1 wt% zinc (AZ91). The rst rare-earth alloy was composed of 4 wt% yttrium and 3 wt% of a rare earth metal mixture consisting of neodymium, cerium and dysprosium (WE43). The nal rare-earth alloy consisted of 4 wt% lithium, 4 wt% aluminum and 2 wt% of a rare earth element mixture of cerium, lanthanum, neodymium and praseodymium (LAE442). The implants consisted of rods 1.5 mm in diameter and 20 mm in length, inserted into the femur of guinea pigs. A rod of polylactide of the same dimensions was used as a control. Radiographs were taken frequently, and implants were harvested at 6 and 18 weeks. Synchrotron-radiation-based microtomography was used to characterize the degradation of the implants, for which complete degradation was observed in 18 weeks [39]. Signicantly increased (Po0:05) bone area was observed in all groups with magnesium-based implants at weeks 6 and 18, in comparison to the polymer control [31]. Fig. 1 illustrates the increased bone area to magnesium implants [31]. Subcutaneous gas pockets were observed after 1 week, which were removed using a syringe, and were not observed after 23 weeks [31]. Adverse effects due to the formation of subcutaneous gas were not observed [31]. The slowest rate of corrosion was noted for LAE442, while AZ31, AZ91 and WE43 degraded at similar rates [31]. Energy dispersive X-ray analysis (EDX) was used to form elemental maps of the corrosion layer and new bone tissue [31]. The rare earth elements were shown to be localized in the corrosion layer, and were not detected in the

Fig. 1. Flouroscopic images of cross-sections of a degradable polymer (a) and a magnesium rod (b) with in vivo staining of newly formed bone resolved using calcein green. Bar 1.5 mm. I Implant residual; P periosteal bone formation; E endosteal bone formation. Reproduced from Witte et al. [31].

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surrounding bone [31]. The corrosion layer also contained high levels of calcium and phosphorous, and X-ray diffraction analysis suggested that an amorphous calcium phosphate had formed at the surface of the material in vivo [31]. While magnesium is a prevalent ion in the body, and magnesium-based implants have been used in vivo without signs of adverse reactions, more information is required to conrm its safe use. Li et al. have conducted a preliminary in vitro assessment of the cytotoxicity of pure and surfacetreated magnesium metal using bone marrow cells of mice [24]. The results show positive cell proliferation and viability after 72 h of incubation with the magnesium metals, with no sign of growth inhibition. While further investigation into the non-toxicity, biocompatibility, mechanical integrity, in vivo degradation processes and bone response is clearly necessary, the above examples support the viability of magnesium-based materials as lightweight, degradable, biologically compatible and possibly biologically active orthopedic implants. 3. Suggested biological activity of magnesium metal Osteoconductive bioactivity in magnesium-based metals is suggested by observations of increased bone apposition about magnesium-based implants compared to PLA controls [31] and a decreased time for hard callous formation when magnesium-based structures were used to support fractures in humans [34,37]. While investigations of bone cell response to pure magnesium metal are scarce, a number of studies have investigated the effect of enriching the surface of a biomaterial such as hydroxyapatite with magnesium ions and suggest a biochemical role for magnesium in the bone system [2730,41]. Revell et al. observed increased interfacial strength for implants with hydroxyapatite surfaces enriched with magnesium [27]. Zreiqat et al. report signicantly increased bone cell adhesion on magnesium-enriched alumina [28]. Cells grown on magnesium enriched substrates expressed a signicantly enhanced level of a5b1 integrin receptor, in addition to increased expression of collagen I extracellular matrix protein, thus suggesting a role of magnesium in the cell attachment process [28]. Two studies conducted by Yamasaki et al. using magnesium-enriched apatites or collagen materials report similar benecial effects of magnesium-enriched materials on bone cell attachment and tissue growth [29,30]. On the contrary, Serre et al., working with collagen sponges and magnesium-enriched apatite, report a toxic effect of higher magnesium levels on bone cells in vitro [41]. From these results, the biological activity of magnesium is an intriguing prospect, but as of yet the potential remains largely unexplored. Preliminary observations indicate that magnesium promotes precipitation of calcium phosphate in an in vitro environment, a feature that may be exploited to induce or enhance osteoconductivity, while also improving the in situ corrosion resistance [42,43]. It is now widely recognized

that the osteoconductive activity of many materials is highly dependent on the precipitation of a biologically equivalent apatite in a physiological electrolytea coating method referred to as a biomimetic process [4453]. The biomimetic precipitation of a calcium phosphate coating on titanium implants has been shown to impart osteoconductive capacity to otherwise biologically neutral material, enhancing osteoblast response and early bone apposition to the implant [5457]. The method of biomimetic precipitation is favored over other coating methods such as plasma spraying due to the low temperature processing which allows for incorporation of biological moieties such as RGD proteins, the capacity to evenly deposit the coating onto complex porous forms, increased coating adhesion and a greater similarity to the apatite crystals of natural bone which imparts a greater biological activity to the resulting surface [45,53]. The precipitation of amorphous calcium phosphate or magnesium calcium apatite ((Ca1xMgx)10(PO4)6OH2) coatings has been observed on the surface of magnesiumbased metals incubated in physiological electrolyte [42,43]. A similar coating is observed in the corrosion layer of magnesium-based metals implanted in vivo [31]. In addition to the possible enhancement of cell attachment and growth, the precipitation of calcium phosphates at the surface may slow the corrosion process of magnesium [42,43]. Given the recent success in the improvement of the biological response to titanium metals through the induction of a biomimetic calcium phosphate coating, the potential feature of magnesium metals is an intriguing possibility, certainly worthy of further exploration. 4. Improvement of corrosion resistance, mechanical properties and biological performance 4.1. Alloying and surface treatments The rapid corrosion rate of magnesium in the electrolytic physiological environment is one of the greatest limitations for its use in orthopedic applications. Unprotected magnesium exposed to a typical atmosphere will develop a gray oxide lm of magnesium hydroxide (Mg(OH)2) which slows corrosion [58]. These lms of Mg(OH)2 are slightly soluble in water, however severe corrosion occurs in aqueous physiological environments where chloride ions are present at levels on the order of 150 mmol/L, as Mg(OH)2 reacts with Cl to form highly soluble magnesium chloride and hydrogen gas [58]. Pitting of magnesium is observed for Cl concentrations exceeding 30 mmol/L [58]. The following reactions summarize the corrosion reactions of magnesium: Mgs 2H2 O-MgOH2 s H2 g; Mgs 2Cl aq-MgCl2 ; MgOH2 s 2Cl -MgCl2 : (1) (2) (3)

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Alloying is an essential step to improve mechanical properties and corrosion resistance of magnesium [58,59]. Protective coatings and surface treatments [60] can also be applied to improve the corrosion resistance and potentially improve biological compatibility and biological activity of magnesium-based implants. An appropriate alloying composition can improve the corrosion resistance, mechanical properties and the ease of manufacture of magnesium-based materials. Two primary groups of magnesium-based alloys are those that contain 210 wt% aluminum with trace additions of zinc and manganese, with products that demonstrate moderate corrosion resistance and improved mechanical properties [58]. The second group uses a mixture of rare earth elements in combination with another metal such as zinc, yttrium, or silver, and a small amount of zirconium which imparts a ne grain structure and enhanced mechanical properties [58]. Little is known about the in vivo corrosion characteristics of these metals, however the work of Witte et al. suggests that some magnesium-rare earth alloys have a slightly enhanced corrosion resistance [31]. As these materials are used in the body, care must be taken to choose alloying elements that are non-toxic. For orthopedic applications, protective coatings for magnesium must be non-toxic, and aim to improve the biocompatibility/bioactivity of the implant. Simple but effective options include alkali-heat treatments, which may induce a biomimetic precipitation of calcium phosphate at the implant surface [42]. Li et al. have demonstrated that incubation of 99.9% pure magnesium in an alkaline solution of NaHCO3MgCO3 at a pH of 9.3 for 24 h, followed by a 773 K 10 h heat treatment results in no mass loss from materials incubated for 14 days in simulated body uid (SBF), compared to untreated, or only alkali treated controls which completely degraded in this incubation period [42]. Li et al. also note that for high purity magnesium (99.99%) no mass loss was observed after 180 days of incubation in SBF [42]. A calcium phosphate phase was observed at the surface of the treated samples and was attributed as a possible inhibitor of further corrosion [42]. In a similar study, magnesium (99.9% purity) was reported to be heat treated at 743, 773 and 803 K for 125 h in an ambient atmosphere [43]. Mass losses were not observed for materials heat treated at 803 K compared with treatments at 743 or 773 K where near complete loss of the material was observed after 29 days of incubation in SBF [43]. Incubation of the 803 K heat treated material in SBF resulted in the precipitation of magnesium-apatite at the surface (at an approximate composition of (Ca0.86Mg0.14)10(PO4)6(OH)2) which is thought to reduce the corrosion of the material [43]. The authors do note that MgO is observed in their samples after heat treatments under ambient conditions [43], however the effect of the oxidation of magnesium on its mechanical properties was not evaluated by these authors.

4.2. Porous magnesium microstructures A microstructure of interconnected pores in the solid matrix results in an implant with lower density and considerably altered mechanical properties and deformation behavior [17]. Appropriate choice of pore size can result in signicantly improved integration of the implant with natural tissue [61]. An example of a magnesium material with a porous microstructure appropriate for an orthopedic application is shown in Fig. 2, reproduced from the work of Wen et al. [62]. In contrast to monolithic materials, porous materials under a compressive load are characterized by a shortened region of linear elasticity ending at the yield strength which is followed by a long plateau exhibiting a constant ow stress to large strains [17]. The number, size, shape and connectivity of pores have signicant effects on the Youngs modulus and yield stress [17]. Cancellous bone is an interconnected, porous structure, and consequentially it exhibits deformation mechanisms that are typical of such materials [18]. The porosity of cancellous bone varies considerably from 30% to 95%, which signicantly inuences the resulting mechanical propertiesyield stresses of cancellous bone are reported to range from 3 to 20 MPa, with corresponding Youngs moduli from 10 to 40 GPa [18]. Thus, the inclusion of porosity can benet the material by increasing biological integration and by adjusting the mechanical properties to comply with the natural bone system at hand. On the other hand, too many large pores will compromise the mechanical properties of the implant making it unsuitable for a load bearing applications. A number of techniques are available to produce an open porous metallic structure [63], however to ensure the biocompatibility of the resulting material, one must be careful when selecting the reagents or methods used for the generation of the pores [64]. Porous magnesium metal

Fig. 2. SEM micrograph of a magnesium material with porous microstructure produced using space-holding particles. Reproduced from Wen et al. [62].

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implants suitable for biomaterial applications have been prepared using argon gas injection to molten magnesium [64] a plaster casting method using a polyurethane foam [65], a powder metallurgy techniques using space-holding particles [32,62,66]. While plaster casting and powder processing using space-holding particles produced viable products [32,62,65,66], production using foaming by injection of argon gas to the molten metal did not produce a product with consistent morphology and this approach has been abandoned [64]. Pore volume and size signicantly affect the mechanical properties of porous magnesium materials [32,62,65]. In all cases, the inclusion of porosity results in a material with reduced yield strength and modulus, corresponding with the lower range of mechanical properties of natural bone [18,32,62,65]. In fact, as monolithic magnesium metals are already in the appropriate mechanical range for the bone system [16,17], and using the lower limit of 3 MPa reported for natural bone strength [18] as the design guideline, the inclusion of porosity can quickly compromise the mechanical strength. For instance, magnesium foams produced using the plaster casting method with porosities of 97.5% and macroscopic pore diameters of 4.5 mm would be unsuitable for load bearing orthopedic applications as compressive yield stresses are reduced to 0.1 MPa [65]. Similarly magnesium samples with porosities of 50% and pore sizes in the range of 100400 mm have compressive strengths of only 0.35 MPa [32]. In a more comprehensive study conducted by Wen et al. the yield stress and modulus of porous magnesium materials are found to decrease with both the pore volume and size [62]. Samples with suitable compressive strengths between 12 and 17 MPa were obtained with 3550% porosity and xed pore size of 250 mm, or by xing the porosity at 45% and varying the pore size between 100 and 400 mm [62].

with bone tissue of porous magnesium-based implants are also topics requiring further investigation. Acknowledgements One of the authors (MPS) would also like to acknowledge the Brian Mason Scientic & Technical Trust for their nancial support. References
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5. Conclusions While a substantial number of reports generate intrigue regarding the use of magnesium and its alloys as possibly osteoconductive, degradable orthopedic implants for loadbearing applications, a great deal of research is still necessary to appropriately evaluate magnesiums potential. As a rst step, it is clear that modulation of the corrosion rate of magnesium-based materials in the physiological environment must be accomplished, possibly through the use of high purity magnesium or experimenting with alloying composition and surface treatments. The nontoxicity of magnesium materials and more corrosionresistant variations must also be thoroughly evaluated. The possibility that magnesium is an osteoconductive metal is a feature which calls for investigations of in vitro bone cell attachment, differentiation towards an osteoblast phenotype, proliferation and formation of a mineralized matrix and studies of bone apposition and tissue in-growth in vivo. The development, performance and integration

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