Review of Magnesium-Based Biomaterials and Their Applications

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Journal of Magnesium and Alloys 6 (2018) 23–43

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Review
Review of magnesium-based biomaterials and their applications
Nurettin Sezer a, Zafer Evis b,∗, Said Murat Kayhan b, Aydin Tahmasebifar b, Muammer Koç a
a Sustainable Development Divison, Hamad Bin Khalifa University, Qatar Foundation, Education City, Doha, Qatar
b Engineering
Sciences, Middle East Technical University, PO Box 06800, Ankara, Turkey
Received 15 June 2017; received in revised form 25 February 2018; accepted 27 February 2018
Available online 16 April 2018
Abstract
In biomedical applications, the conventionally used metallic materials, including stainless steel, Co-based alloys and Ti alloys, often times
exhibit unsatisfactory results such as stress shielding and metal ion releases. Secondary surgical operation(s) usually become inevitable to
prevent long term exposure of body with the toxic implant contents. The metallic biomaterials are being revolutionized with the development
of biodegradable materials including several metals, alloys, and metallic glasses. As such, the nature of metallic biomaterials are transformed
from the bioinert to bioactive and multi-biofunctional (anti-bacterial, anti-proliferation, anti-cancer, etc.). Magnesium-based biomaterials are
candidates to be used as new generation biodegradable metals. Magnesium (Mg) can dissolve in body fluid that means the implanted Mg
can degrade during healing process, and if the degradation is controlled it would leave no debris after the completion of healing. Hence, the
need for secondary surgical operation(s) for the implant removal could be eliminated. Besides its biocompatibility, the inherent mechanical
properties of Mg are very similar to those of human bone. Researchers have been working on synthesis and characterization of Mg-based
biomaterials with a variety of composition in order to control the degradation rate of Mg since uncontrolled degradation could result in
loss of mechanical integrity, metal contamination in the body and intolerable hydrogen evolution by tissue. It was observed that the applied
methods of synthesis and the choice of components affect the characteristics and performance of the Mg-based biomaterials. Researchers
have synthesized many Mg-based materials through several synthesis routes and investigated their mechanical properties, biocompatibility
and degradation behavior through in vitro, in vivo and in silico studies. This paper is a comprehensive review that compiles, analyses and
critically discusses the recent literature on the important aspects of Mg-based biomaterials.
© 2018 Published by Elsevier B.V. on behalf of Chongqing University.
This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Peer review under responsibility of Chongqing University
Keywords: Mg-based biomaterials; Mechanical properties; Implant; Biomedical applications; Biodegradation.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2. Magnesium (Mg)-based biomedical implants and recent applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3. Fabrication of Mg-based implants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
4. Characteristics of Mg alloys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
4.1. Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
4.2. Microstructural characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
4.3. Surface characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
4.4. Mechanical properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
∗ Corresponding author.
E-mail address: [email protected] (Z. Evis).
https://doi.org/10.1016/j.jma.2018.02.003
2213-9567/© 2018 Published by Elsevier B.V. on behalf of Chongqing University. This is an open access article under the CC BY-NC-ND license.
(http://creativecommons.org/licenses/by-nc-nd/4.0/) Peer review under responsibility of Chongqing University
24 N. Sezer et al. / Journal of Magnesium and Alloys 6 (2018) 23–43
4.5. Biological properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

4.6. Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
5. Computational studies on Mg alloys and its fabrication into implants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5.1. Manufacturing processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.2. Degradation behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
5.2.1. Degradation behavior of implants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
5.2.2. Degradation behavior of stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
6. Mg-based composites for potential biomedical implant applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
6.1. Mg-polymer composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
6.2. Mg-ceramic composites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
7. Summary, conclusions and recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
1. Introduction
Mg and its alloys differ from other biomaterials by pre-
From materials science point of view, biomaterials can be senting compatible mechanical and physical properties to hu-
man bone. Their densities and elastic modulus are fairly close
classified into four different groups as metals, ceramics, poly-
mers and composites. Among these groups, ceramics such to each other which remove elastic mismatches between im-
plants and the bone [5,6]. Moreover, Mg is naturally present
as calcium phosphates are widely used as a coating mate-
in bone composition, and it is one of the required metals
rial since they exhibit non-toxicity, good biocompatibility and
osteoconductivity [1]. However, they possess poor mechani- for the metabolism [7]. However, the fundamental problem
of Mg-based implants is their low corrosion resistance re-
cal properties and high corrosion rate in acidic environment,
sulting undesirably fast and unexpected degradation within
which restrict their usage as bone implant in load bearing
areas [1]. a living system. Research investigations have been aimed to
enhance the corrosion resistance and to offer industrially ap-
Polymeric biomaterials are widely used for bone tissue en-
gineering applications since they are formable into complex plicable Mg-based biodegradable implants. Furthermore, it is
shapes, and their surface properties can be easily modified. projected that Mg-based biodegradable implant will shift the
direction of medical sector in near future as their commercial
Additionally, chemical and mechanical properties of polymers
can be altered to certain degrees during sterilization. However, products start to appear in the market.
application of polymers is limited due to their unsatisfactory Implant material is desired to have very similar mechan-
ical properties with the bone. However, in the current prac-
mechanical properties. Moreover, some toxic additives such
as plasticizers, antioxidizers or stabilizers used in synthesis tice, most of the metals used in biomedical applications ex-
of polymers can be harmful to the host tissue causing leach- hibit significantly higher mechanical properties than the bone.
This causes well-known phenomenon of stress shielding, the
ing in body fluid [2].
Metal implants are usually preferred to repair bone fracture results of which are bone-matter decomposition and loss of
its strength. Stress shielding occurs when the implant carries
owing to their outstanding mechanical properties [3]. Stain-
higher proportion of the applied load, so the adjacent bone is
less steel-, Co- and Ti-based alloys are well-known exam-
ples for the commercially available bone implants. Metals exposed to a reduced load and loses its density in response
[8,9]. Among various metal implants, Mg alloys stand out
are favored for long-term, durable and load bearing implants
to have Young’s modulus most similar to cortical bone (Mg:
since they exhibit high strength and outstanding ductility that
lead to high resistance to fracture [3]. In addition, metal im- 40–45 GPa, Cortical bone: 10–27 GPa) whereas the Young’s
modulus of Ti-based and 316L stainless steel are 110 and
plants with complex architecture can be produced through
193 GPa, respectively [8,9].
various available production methods such as casting, machin-
ing and powder metallurgy (PM) [3]. Their biocompatibility Biodegradable metal implants are new generation of metal
implants that exhibit improved corrosion resistance in body
and matching mechanical properties to bone are two impor-
tant factors for implants [3]. Biocompatibility of metallic im- fluid during healing process of host tissue [10]. The main duty
plants is affected by corrosion and wear. In metallic implants, is to support the host tissue with a slow corrosion rate in the
body fluid, and then dissolve completely after healing of the
harmful metal ions arising from corrosion and wear may lead
to inflammation, cell apoptosis and other destructive tissue host tissue with no implant debris [10,11]. Among biodegrad-
reactions [3,4]. It was reported that release of Cr (Co–Cr al- able metal implants, Mg, Fe and Zn, which are also known as
smart implants, have been widely investigated in recent years.
loys), Nb, V and Ni (Ti-based) ions may cause detrimental
tissue reaction by exceeding the concentration limit of these The most significant challenge with such biodegradable im-
elements in tissue or body fluid [3,4]. Ni, as an example, plants is to maintain their mechanical integrity during heal-
ing period of the host tissue [12]. Mg- and Fe-based implants
is a highly cytotoxic, genotoxic, carcinogenic and mutagenic
element. exhibit good mechanical properties as hard tissue implants.
However, high corrosion rate of Mg-based materials and very
N. Sezer et al. / Journal of Magnesium and Alloys 6 (2018) 23–43 25
low corrosion rate of Fe-based materials limit their applica- GT1TM (Abbott Vascular, Temecula, CA), DESolve® (Elixir
tion as biodegradable implants. Thus, degradation rate of pure Medical Corporation, Sunnyvale, CA) and the Magmaris®
Mg should be improved via alloying and surface engineering (BIOTRONIK AG, Bülach, Switzerland). The Absorb GT1TM
to use as biodegradable metal implants [12,13]. and DESolve® are made of polymers whereas Magmaris®
This study aims to present a comprehensive and criti- is an Mg-based PLLA coated stent. They were success-
cal review of recent research and technological advances on fully approved in clinical trials [17]. According to the tests,
Mg-based biomedical implants. The following section briefly Magmaris® expanded quickly and it was more stable in terms
summarizes the most recent Mg-based biomedical implant of mechanical performance. Although all the stents had suffi-
products to give readers clear idea about where industry and cient radial strength, metallic one had the highest. Windhagen
commercialization fronts have been heading in this field. The et al. conducted a comparison study between Magnezix® and
third section focuses on synthesis and fabrication of Mg-based Ti screws in 26 patients to assess their difference regarding
biomedical implants. Section four is more on characteristics patience comfort and biological effect during an implantation
of Mg-based biomedical implants presenting microstructural, period of six months. It was reported that there was no sta-
surface, mechanical, biological and degradation characteristics tistically significant difference between two types of screws
of various Mg alloys. Fifth section provides a summary about in terms of human comfort and poor biological reaction. All
computational aspects of Mg-based biomedical implants from patients were satisfied with the Magnezix® except one pa-
fabrication and degradation points. Section six discusses po- tient who had suffered from long-last wound problem [18]. It
tentials for Mg-based composites including Mg-ceramics and showed that there was no distinct difference in terms of func-
Mg-polymers composites. Final section provides a summary tionality but second surgical operation for implant removal
of this paper along with critical and comparative discussions was abolished for Mg based material.
ending with a list of recommendations for future studies.
3. Fabrication of Mg-based implants
2. Magnesium (Mg)-based biomedical implants and
recent applications This section presents the synthesis of Mg alloys and fabri-
cation of implants based on these alloys. Ball milling in PM
The commercially available Mg-based biodegradable im- encompasses mechanical alloying of two or more alloy pow-
plants have been new in the market dating back to 2010s. ders with hardened steel balls for extended periods of time.
Magnezix® (brand name of Mg-based implant in the market) This process consists of welding, fracturing and rewelding re-
is the first approved and CE-certified biodegradable screw that sulting in fine microstructure, small grain size and alloying of
has been manufactured using PM route [14]. It has been ap- the powder particles [19]. There are many factors that influ-
proved for bone fixation and fragments [15]. It has more ap- ence the characteristics of the end-product powders including
propriate mechanical properties than commercially available ball-to-powder ratio, milling time, turning speed, preventive
Ti. For instance, owing to its close elastic modulus to natural atmosphere and temperature.
bone, it hinders stress shielding that could even cause implant The effect of milling time (15, 30 and 37.5 h) on the mix-
loosening. Moreover, it is free of Aluminum (Al), therefore, it ture of Mg and Fe powders was investigated [19]. The ball-
is less likely to show any allergenic or toxic side effect [15]. to-powder ratio and rotation speed were kept the same as
Magnezix® has a yield strength (YS) greater than 260 MPa, a 10:1 and 350 rpm, respectively. More than 37.5 h ball milling
ultimate tensile strength (UTS) greater than 290 MPa and an caused to decrease in peak height in the XRD referring that
elastic modulus about 45 GPa. It has an ability to elongate as longer milling time decreases crystallinity of the alloyed pow-
high as 8%. After material and product design study started der. Additionally, grain size continuously decreased to the
in 2009 for Magnezix® , preclinical studies were conducted size of 13–30 nm by increasing milling time. Chaubey et al.
between the years 2010 and 2012 [14]. The Magnezix® was also investigated the effect of milling time on grain size and
approved by CE certification for 30 days in May 2013. It was shape at room temperature (RT) for 100 h. It was reported
put first in EU market and then the rest of the world. It has that an heterogeneous microstructure including two types of
been reported that more than 4000 Magnezix® screws were clustering (Mg and Mg–Al areas) was observed. The average
sold around the world since then. The company continued to particle size was 600 μm due to cold welding until 20 h of
expand their product range with different screw sizes. milling whereas sizes of Mg (< 450 μm) and Al (< 44 μm)
Commercially available Mg-based implants have been powders were smaller than the 20 h alloy. The average par-
compared with other biodegradable and non-Mg implants. ticle size decreased to 70 μm after milling for 40 h due to
They have been tried by in vivo studies as well. They have fracturing [20]. During the cold welding stage, grain size was
been implanted in 33 mini-pigs and 20 humans [16]. No even higher than the sizes of starting powder. However, the
toxicity or allergenic reactions were observed. They pre- grain size started to decrease with start of fracture process of
served mechanical integrity themfor six months that could ball milling.
be regarded as long-term for fixation implants. After that, Ball milling is not used to alloy only the metals but ce-
three generations of absorbable metal stents have successfully ramics as well. Mg and hydroxyapatite (HAp) mixtures were
been implanted into animals and humans [16]. Schmidt et synthesized through ball milling for 4 h under protective argon
al. compared three biodegradable stents namely: The Absorb atmosphere [21]. The optical images of ball-milled mixture
showed a uniform Ca and P distribution in the microstruc- homogenous microstructure than other two methods. It was
ture. It was a successful study since it uniformly distributed also detected that there is more secondary phase formation in
Ca and P that suppresses corrosion. Non-uniform distribution the extruded and as-cast alloys. Compatible with these find-
could lead localized corrosive attack on the end-product. ings, the extruded and as-cast alloys had lower corrosion re-
An effort has been put forward to overcome enormous sistance than the powder-processed alloy due to higher sec-
cold welding in milling by using lubricant agents. It is es- ondary phase formation that acts as a kind of galvanic cell.
pecially vital for materials which are ductile and with low Although, YS and UTS of as-cast and extruded alloys did
melting temperature. Feng et al. used stearic acid (5%) in or- not differ from each other, PMed alloy had a YS of 292 MPa
der to limit cold welding in ball milling of Mg, Al and Zn for and an UTS of 346 MPa due to its fine and homogenous mi-
20 h with 30:1 ball-to-powder ratio [22]. After ball milling, crostructure. It could be said that PM improved WZ21 alloy
MgO was homogenously distributed with nano-level particle not only mechanically but also electrochemically. It was also
size. It showed that ball milling could improve microstructural investigated how secondary phase (MgO) affects microstruc-
characteristics and consequently mechanical properties of tural chracteristics of Mg in the presence of HAp. Compatible
Mg–Al–Zn alloy. with the study of Cabeza et al., the addition of MgO decreased
Speaking of magnesium, ball milling could be hazardous the corrosion resistance and compressive strength [34]. Be-
due to its explosive nature [23]. Because of that, Mg was yond that, Mg-HAp without MgO exhibited the best mechan-
mixed with other metal elements in the absence of the hard- ical integrity. MgO acts as a galvanic cell in the microstruc-
ened balls. An alternative solution was proposed to circum- ture that accelerates degradation. Accordingly, the corrosion
vent the high flammability of Mg [23]. Mg, Al and Zn pow- resistance of the Mg-HAp with MgO diminished. It can be
ders were mixed for 1 h at 2500 rpm in a wet atmosphere to deduced that secondary phase existence in the microstructure
reduce the heat generation. The manufactured alloy without could worsen the mechanical and electrochemical properties.
the balls was successfully subjected to extrusion that shows In a different study, porous Mg–Zn alloy was manufactured
reliability of this method. Moreover, Yang et al. also mixed by PM route under an applied pressure of 100 MPa and heat
Mg, Al and CaCO3 for 72 h to produce Mg alloy foam [24]. treatment temperature of 500–580 °C. It was found that there
They manufactured a well-structured porous Mg alloy. Due to was an inverse correlation among porosity and compression
low ignition of Mg, it was also a safer way than ball milling. strength and elastic modulus [30]. The highest compression
Kang et al. obtained a mixture of Mg and NaCl as space strength and elastic modulus were observed at 550 °C so it
holder to use in PM [25]. This mixture was exposed to spark was chosen as the optimum heat treatment temperature. Tah-
plasma sintering (SPS) successfully under an applied pressure masebifar et al. investigated the effect of compaction pressure,
of 20 MPa. The space holder was used to create pores as well sintering temperature and surface conditions on relative den-
as to prevent excessive cold-welding. sity, bending strength, corrosion resistance and cell viability
In Mg-based alloy studies for biomedical implants, inves- of powder-processed AZ91D through design of experiment
tigators tend to purchase Mg and its alloy powders. However, (DOE) [35]. It was stated that increasing compaction pres-
Mg–Zn–Al alloy powders were manufactured by argon atom- sure (150–250 MPa) improved the relative density and bend-
ization and sieved to obtain particles smaller than 150 μm ing strength. On the other hand, sintering time did not signif-
[26]. The atomization results in spherical grain that offers icantly affect the material properties of AZ91D. It was also
uniform microstructure. The alloy is then powder processed revealed that the micro-patterned/textured surface with open
successfully. Manufacturing porous Mg implants with spher- pores showed higher cell viability than the smooth surface.
ical powders offers samples with more predictable material The study specifically showed that it was feasible to manu-
properties. Zhou et al. also used rapid solidification to manufacture Mg alloy with open pores on the surface with a struc-
facture Mg–Zn and Mg–Zn–Ca [27]. Powders were produced ture via PM. A similar study was carried out by Kayhan et
by melting of constituent powders and rapidly cooling by splat al. by manufacturing highly porous Mg alloy at lower com-
quenching under noble gas atmosphere. paction pressures (25 and 40 MPa) [36]. The relative density
PM offers to produce biodegradable Mg implants that can and hardness decreased as compaction pressure increased. In-
have controlled interconnected porous structure for enhanced creasing the sintering time (30–150 min) did not increase rela-
biological interaction with the environment of the host tis- tive density but hardness due to the formation of intermetallic
sue or bone. However, the degree of porosity is critical for phase. A surface with one-way channels was designed with
corrosion type (aggressive localized attacks such as pitting or a specific aspect ratio (1.25) to increase cell viability. Aspect
galvanic corrosion) and rate (mm/year) [28]. Due to nega- ratio is important not only for cell viability but also for cell
tive effect of pores that weaken materials mechanically and attachments. The study showed that a surface with the chan-
electrochemically, it is important to optimize porosity level as nels of 200 μm width and 160 μm height was biocompatible
well as the distribution and shape of the pores. Therefore, PM and favorable for biomedical applications [36]. Bi et al. in-
studies have been intensively focused on production of con- vestigated the relation between ultimate compressive strength
trolled or designed porous biodegradable implants [29–32]. (UCS) and porosity of pure Mg manufactured by powder pro-
The virtue of PM over other biodegradable implant man- cessing (compacted under 300 MPa, heat-treated 400 °C and
ufacturing methods including extrusion and casting was in- then 550 °C for 2 h each). It was found that increasing poros-
vestigated [33]. The PMed WZ21 alloy had finer and more ity to 40% with space holder decreased the UCS from 170
to 25 MPa [29]. Xia et al. have also reported that the YS resistance [42]. Similar to previous study, MgO peaks were
of AZ31 Mg alloy scaffolds decreased as porosity increased observed in the XRD analysis in the presence of 20 wt%
from 60% to 75% [37]. Pore size also affected energy absorp- HAp. However, the researchers reported formation of MgO
tion and consequently the UCS of the alloy. Pore sizes were during the SPS process which is contrary to the results of
1.2, 1.5, 1.8 and 2.0 mm but 1.5 mm differed from others due Sunil et al. Xiong et al. succeeded to fabricate Mg/HAp com-
to the ratio between specimen and pore sizes. posite with low porosity after 10 min sintering in microwave
Organic and inorganic materials such as PMMA, ammo- sintering furnace. In this method, a homogenous distribution
nium hydrogen carbonate, PE-VA, PPco1PB, PP, CaCO3 “so- of Mg and HAp particles was achieved. Furthermore, XRD
called as space holder” were used to produce interconnected results revealed that there was no incidence of any interaction
porous specimens [24,29,38,39]. A suitable space holder in between Mg and HAp during heat treatment [21].
terms of material properties is required to avoid its negative Metal injection molding (MIM) is another PM method
effect during manufacturing process. For instance, some space used in economical manufacturing of near net shape prod-
holder materials can react with matrix and affect negatively ucts. Some researchers have tried to manufacture Mg-based
the porosity characteristics. Porosity and pore structure can be implants by MIM. Wolff et al. carried out a study on pro-
controlled by manipulating the content and particle shape of ducing biodegradable implant from Mg–0.9Ca alloy powders
space holder. The more space holder content results in more through MIM method. The Mg alloy powders compacted un-
interconnected porosity [39]. Similarly, it was reported that der 100 MPa and heat-treated at 630–645 °C for up to 64 h
the sintered density is inversely proportional to the content under vacuum. An organic polymer binder was also used for
of space holder (PMMA) as in pure Mg. Besides, PMMA stocking in the injection process. It was reported that a min-
had poor affinity to Mg [29]. Thus, it does not easily react imum of 8 h sintering time is required for necking between
with Mg. Yang et al. also used CaCO3 to create pores in Mg- particles. It was also found that elastic modulus decreased as
Al alloy foam with various concentrations of Al from 15 to porosity increased. An interesting finding was about vacuum
50 wt%. They emphasized that if the required conditions and during sintering. Vacuum at elevated temperature, such as the
processes, such as high pressure of compaction, at 620 °C of sintering temperature, led to evaporate Mg alloy towards the
foaming temperature and 150 s of foaming time, are provided internal surface of the furnace. Thus, vacuum is recommended
then the uniform pores can be obtained [24]. for the first half an hour of sintering [39]. The manufactur-
SPS has been used to create porous biodegradable implants ing of porous biodegradable implants through cold isostatic
from Mg alloy powders. It has been developed to prevent pressing prior to the extrusion of Mg-HAp powder mixture
problems arising from sintering for longer times [40]. Due is another research which is still being investigated [32].
to its shorter time for sintering at relatively low tempera- Table 1 summarizes the results of available literature on
ture, oxidation or secondary phase formation were substan- porous Mg-based biodegradable materials.
tially hampered. Mg powders with the addition of Al2 O3 (up Apart from metallic alloying elements, Mg was mixed
to 5 vol%) and 60% NaCl as space holder were exposed with other elements or compounds to produce satisfactory
to SPS while uniaxially-compacted under 20 MPa. Uniformly biodegradable implant materials. For example, Mg was al-
distributed 3D interconnected porous structure with average loyed mechanically with nano-sized diamond powders, and
pore size of 240 μm and porosity of around 60% were ob- then were cold-pressed-and-sintered under 1 GPa at 600 °C
served in the microstructure. Moreover, no significant sec- for 30 min [44]. The addition of nano-sized diamond particles
ondary phase formation or reaction among existing phases into Mg powders increased corrosion resistance by creating a
was observed in the XRD analysis referring that sintering was protective layer on the implant surface. However, the relative
accomplished properly [41]. Sunil et al. carried out SPS on density decreased due to high hardness of nanodiamonds that
Mg/HAp powder mixture after 20 h ball milling to make more do not easily deform. The undeformed diamond particles pos-
uniform distribution in the mixture [40]. The mixture sintered sibly caused more pore formation in the microstructure. They
for 10 min under 50 MPa compaction pressure at 450 °C. Al- deduced that Mg with nano-sized diamond manufactured by
though secondary phase formation is not expected in SPS, PM is a suitable candidate for porous biomedical implant.
MgO peaks were found at the XRD analysis. The researchers Kowalski et al. also manufactured Mg–4Y–5.5Dy–0.5Zr alloy
estimated that it was formed just after ball milling before with HAp addition by powder processing [45]. Compaction
sintering was not started. Moreover, it is expected that in- under 600 MPa followed by sintering at 550 °C for 2 h caused
creasing the bioceramics (HAp in this case) amount increases formation of the secondary phase. HAp addition enabled to
hardness. On the contrary, Mg with the highest HAp addition produce implant samples with average porosity of 48% and
had the lowest hardness that could be related to low sintering elastic modulus of 7.1 GPa. HAp also helped to the forma-
temperature of SPS. Sintering at low temperature could not tion of protective F− layer that inhibits corrosion rate [45].
be sufficient for proper bonding between Mg-HAp and HAp- Furthermore, bioactive glasses were coated to increase corro-
HAp particles. Thus, sintering temperature and time should sion resistance and mechanical performance of PMed alloys.
be carefully designed in SPS process in order not to suf- Yazdimamaghani et al. coated Mg alloy (compacted under
fer from mechanical performance. In another study, Mg-HAp 400 MPa and sintered at 175 °C and then 600 °C for 2 h)
mixture was exposed to SPS at 475 °C under 40 MPa pressure with PCL and a silica-based bioactive glass mixture. Addi-
after 2 h ball milling with the purpose of enhancing corrosion tional to the contribution of coating to mechanical stability,
Table 1
Investigations on porous Mg-based implant through various PM methods.
Material Info Reference

Porous Mg/5 vol% Al2 O3 SPS (585 °C for 2 h under uniaxial pressing of 20 MPa), app. 60% porosity app. [43]
240 μm grain size.
Porous pure Mg scaffolds 0–40% porosity, increasing PMMA content from 0% to 30%, conventional PM [29]
(compacted under 300 MPa, heat-treated 400 °C and then 550 °C for 2 h)
Mg scaffolds with increasing PCL-BG 35–40% porosity, ammonium hydrogen carbonate as space holder, conventional [38]
addition PM (compacted under 400 MPa and sintered at 175 °C and then 600 °C for 2 h)
Suture anchor screws Mg–0.9Ca screw (metallic one) by Metal injection molding (MIM) [39]
the coated alloy was degraded less than the uncoated sample moderate corrosion rates. Zn is one of the common alloying
[38]. The mixture of ball-milled pure Mg with various amount elements for Mg. Presence of 6% Zn in Mg alloy is reported
of 45S5 bioactive glass from 5 to 15 wt% was developed to improve the corrosion resistance [55]. Ca is another well-
and manufactured under PM conditions [46]. The ball-milled known alloying element which accelerates the bone growth.
powders were pressed under 10–15 MPa and heat treated in a Mechanical properties and corrosion behavior of Mg–Ca al-
microwave furnace at 600 °C for less than 25 min. The addi- loys can be adjusted by controlling the Ca content [54]. REEs
tion of bioactive glass improved both hardness and corrosion are other common incorporating elements of Mg alloys. Ad-
resistance continuously. Less hydrogen evolution of Mg alloy dition of REEs into Mg–Al–Zn alloys is reported to further
with 15 wt% contribute the corrosion resistance. However, improve the corrosion resistance [28].
the highest flexural strength and UCS were statistically found Incorporating Ca in Mg alloy can improve the corrosion
in the alloy with 10 wt% bioactive glass addition. The au- resistance [56]. Li et al. fabricated binary Mg–Ca alloy at
thors commented that the result arouse from the redundant varying Ca contents from 1 to 20 wt% to investigate its
secondary phase formation related to the amount of bioactive biodegradability within bone. Alloys of high Ca content in-
glass and internal microcracks which were deeper and larger. cluding Mg–5, 10 and 20Ca were found to be very brittle. The
mechanical properties and biocorrosion behavior of Mg–Ca
4. Characteristics of Mg alloys alloy are adjustable by controlling Ca content. The YS, UTS
and elongation for as-cast Mg–Ca alloy samples decreased
4.1. Contents with increasing Ca content. Cytocompatibility evaluation re-
sults indicated that Mg–1Ca alloy induces no toxicity to cells.
Alloying is one of the methods in which different metals at Both the in vitro and in vivo evaluations showed formation of
varying concentrations can be added to improve the ductility, a mixture of Mg(OH)2 and HAp layer on the surface of Mg–
strength and corrosion properties of pure Mg. Improvements 1Ca alloy during immersion and implantation periods [54].
in strength and corrosion are primarily linked to modification A similar study by Rad et al. suggested Mg–0.5Ca alloy as
of microstructural characteristics; particularly a reduction in a promising candidate for biodegradable implants due to its
grain size compared to pure Mg. The majority of research in- high corrosion resistance [57].
vestigating Mg alloys has focused on improving all of these Knowing that incorporating Ca reduces the degradation
characteristics for commercial purposes. Hence, most of the rate, Ca-containing Mg alloys have been investigated for their
research on biomedical Mg alloys are conducted with alloys degradation behavior and mechanical integrity. Addition of
that are originally developed for aerospace, defense and au- Ca was noticed to improve the corrosion behavior of Mg al-
tomotive industries [47]. loys. Immersion test of AZ91Ca into modified simulated body
Generally, Mg alloys contain aluminum (Al) or rare earth fluid (SBF) showed only a marginal decrease in the UTS by
elements (REEs) [54]. Al is well-known as a neurotoxicant 15% and elongation to fracture by 20% [58]. Addition of
and its accumulation is associated to various neurological dis- Zn was also reported to improve the corrosion resistance of
orders as Alzheimer, dementia and senile dementia diseases. Mg alloys. The in vivo degradation behavior of Mg–Al–Zn
On the other hand, severe hepatotoxicity was noticed after alloy implanted intramedullary into the femora of rabbits was
the implementation of REEs such as praseodymium, cerium investigated by Jingjing et al. After a nine-week period, mi-
and yttrium. Thus, researchers recently concentrated on inves- croscopic evaluations showed formation of a thin layer of
tigation of biologically safe Mg alloys, comprising non-toxic calcium phosphate around the implants. In vivo degrada-
elements such as Ca, Zr, Zn and Mn. Other alloying compo- tion rate of Al–Zn containing Mg alloys AZ31B was slower
nents that are being investigated include Sr, Li, Sn, Si, Bi, than the pure Mg [59]. Another zinc containing Mg alloy
Cd, and Ag. Alloys of Mg can be binary, ternary or more. Mg–6Zn was investigated [55] and very similar results with
The components and the composition of the alloys contribute the previous research of Huang et al. were obtained.
to various mechanical properties as well as the corrosion be- The mechanical and corrosive characteristics of the Mg-
havior of Mg. based alloy (MgNd2) were investigated by Seitz et al. The
Alloying with Al enhances the corrosion resistance of Mg. study suggested that Nd2 can be used as an adequate alloy-
AZ31, AZ61, and AZ91 are common Mg–Al–Zn alloys with ing element for resorbable applications in low loaded tissue
[60]. A new Mg-based alloy (LANd442) containing 90 wt% sion rate inhibiting the growth of Mg matrix grains. During
Mg, 4 wt% Li, 4 wt% Al, and 2 wt% Nd was developed by solidification, Al–Ce phases form and distribute along grain
Hampp et al. Biocompatibility of this alloy was investigated boundaries which prevent the sliding of the boundaries at the
in a rabbit model for a duration of 26 weeks. In this period, a course of deformation. The Al–Ce particles also reported to
relatively slow degradation was observed with the LANd442 have a pronounced effect on the corrosion rate of Mg–Al–Ce
alloy. Formation of an additional bone at the implant’s lo- alloys. When the Ce content of the alloy is high, Al11Ce3
cation as well as accumulation of small amount of subcu- acicular particles reduce the corrosion rate of Mg alloys by
taneous gas was observed. The LANd442 Mg alloy lead to forming a network on Mg matrix [69].
considerable non-inflammatory bone remodeling processes in Most of the research studies reported promising results for
which new growth of bone in the periosteal region predom- the application of Mg alloys as implant material. Their desir-
inated. For this reason, the study suggested that LANd442 able mechanical properties, biocompatibility, and biodegrad-
appears to be a less suitable degradable implant material for ability are attractive features to be selected for implants. It
cortical bone applications [61]. After this study, Hampp et al. is believed that Mg and Mg alloys are a new generation of
investigated the earlier times of healing process since it could biomaterials and they will play an important role in revo-
represent possible early incidence of bone remodeling phase. lutionizing orthopedic, cardiovascular and dental applications
They investigated the biocompatibility of two Mg-based al- [70].
loys LAE442 and LANd442 and compared them with tita-
nium in the first 4 and 8 weeks of implantation. The study 4.2. Microstructural characteristics
identified interesting changes in the bone structure in the very
early stage of implantation of Mg alloys and Ti. The investi- The microstructure, such as the grain size, grain boundary
gated Mg alloys also revealed a good clinical tolerance which and phase distribution significantly affect the corrosion per-
allows for their assessment as suitable osteosynthetic materi- formance of Mg alloys. Grain refinements lead to changes in
als. However, compared to the studies with longer implanta- the density of grain boundaries and distribution, which alter
tion periods, this short-term biocompatibility cannot conclude the mechanical properties as well as the corrosion behavior
on long term effects. Thus, it was suggested that for a com- of Mg alloys [69]. The alloying elements, applied metallur-
plete conclusion, implant materials should be investigated for gical processes and process conditions have influence on the
at least 6 months period of implantation [62]. microstructure of Mg alloys [71–75].
Studies showed that Sr significantly improves the os- Cheng et al. [71] investigated the corrosion performance
teoblastic activity and bone formation in vivo [63]. Therefore, of as-cast and as rolled Mg–6Bi–2Sn alloys. Compared to the
it was considered as one of the promising biocompatible al- as-cast alloy, significant grain refinement and uniform distri-
loying element in Mg alloys [64]. Li et al. [63] investigated bution of second phase particles were achieved after rolling.
the biodegradable Mg–Zr–Sr alloys in vitro and in vivo. The Therefore, as-rolled alloy exhibited a higher corrosion resis-
study revealed that the addition of more than 2% Sr in Mg– tance than the as-cast one. The remarkably deceased corrosion
Zr–Sr alloys results in rough boundaries distributed by a sec- rate of as-rolled Mg–6Bi–2Sn alloy is credited to refined grain
ondary phase of Mg17Sr2. This phase may trigger galvanic size, finely dispersed particles of secondary phase, favorable
effects in the Mg–Zr–Sr alloys, leading to accelerated corro- crystal orientation and the formation of a passivity film on
sion of the Mg matrix. The study reported that addition of less the surface.
than 2% Sr ensures a significantly reduced corrosion rate for Lu et al. [72] investigated the corrosion behavior of Mg–
Mg–Zr–Sr and Mg–Sr alloys. The combined effects of Sr and 3Zn–0.3Ca alloy in SBF. Heat treatment was applied to mod-
Al on corrosion behavior of Mg alloys were studied by Nam ify grain size and secondary phase volume fraction and its
et al. [65] with various Sr contents. Addition of Sr to Mg–5Al effect on the corrosion behavior was then determined. The
alloy significantly influenced the grain boundaries, corrosion study revealed that fraction of secondary phases and grain size
resistance and surface film. The precipitation of Mg–Sr and are the two key factors which control the corrosion rate. The
Al–Sr phases was inhibited by the formation of Mg17Al12 sample with the smallest grain size but the largest fraction of
phase at the grain boundaries. In addition, Sr addition con- secondary phase has the lowest corrosion resistance, because
tributed to the formation of an Al(OH)3 protective film on the secondary phase causes the galvanic corrosion which sur-
the surface. The study by Bornapour et al. [66] demonstrated passes the favorable influence of fine grain size. Similarly,
that a Sr–HAp layer was formed on the surface of the binary the sample with the lowest secondary phase fraction but the
Mg–Sr alloy after immersion in SBF. This surface layer also largest grain size also has a low corrosion resistance because
improved the corrosion resistance. the large grain size accelerates the corrosion rate. The mini-
Addition of Ce improved the corrosion resistance of Mg mum corrosion rate was reported with the alloy heat-treated
alloys [66], such as Mg–Zn–Zr alloys [67] and Mg–Al–Zn at 420 °C for 24 h since it balanced the grain size and fraction
alloys [68]. Mg12Ce and Mg17Ce2 phases precipitate and of secondary phase.
distribute along the grain boundaries which effectively de- Addition of Zr reduces the grain size of Mg which re-
crease the grain size of Mg–Zn–Zr alloys. During solidifi- sults in improved ductility, smoothened grain boundaries and
cation process of Mg–Al–Ce alloys, Ce particles aggregate enhanced corrosion resistance. The ability of 1 wt% Zr–Mg
at the solid–liquid interface which reduces the atomic diffu- alloy to absorb high loads is better than that of pure Mg [73].
It was reported that Sr has a high Mg alloying efficiency 4.3. Surface characteristics
and refines the grain size in Mg alloys [52]. Mg–Sr alloy com-
posed of α-Mg as a main phase and Mg17 Sr2 and the amount Hierarchical structure of bone should be considered in
of intermetallic phase increase with increasing Sr content [76]. bone implant designs [82,83]. For instance, human compact
Additionally, Sr increases the compressive strength, improves bone is a composite material with a hierarchical architecture
biocompatibility and bone formation. However, Sr > 2% in from macro-scale to nano-scale. Human compact bone can be
Mg–Zr–Sr alloys leads to Mg17 Sr2 phase precipitation in the explained as follows. Osteons are fibers with 200 μm diameter
grain boundary and this intermetallic phase decreases the cor- that are composed of parallel lamellae and pores. The lamel-
rosion resistance. Thus, the level of Sr should be less than lae are built of fibers which are built from fibrils. Mineral
2%. Sr enhances the replication of preosteoblastic cells, and HAp and collagen type I formed a composite at nano-scale.
stimulates bone formation. In Mg–Si–Sr ternary alloys de- Thus, the wide range of scale should be taken into account to
pend on different composition of alloys four intermetallic achieve a high grade of compatibility with host tissue [83].
phase can be formed which are Mg17 Sr2 , MgSrSi, MgSi2 Sr There are important factors that should be considered to
and Mg2 Si. It was proved that high amount of (more than improve biocompatibility of implants such as corrosion rate,
14 wt%) intermetallic phase has negative effect on corrosion strength, wear resistance, flexibility and solubility in water
resistance of Mg alloys. The most effective factor in Mg–Si– [83]. Moreover, porosity, cavities or channels at micro scale
Sr ternary alloys degradation is Mg17 Sr2 intermetallic phase play an important role in cell proliferation and ingrowth
amount [77]. into the implant [83]. As explained, individual surface pa-
Mg–Ca–Si alloys are suitable candidates as biomedical im- rameters such as roughness, chemical composition, electrical
plants because Ca and Si are naturally present in human charge, wettability and crystallinity perform an important role
body, involved in crucial body functions and essential for the in terms of compatibility [83]. The most important factor to
bone regeneration processes. Apart from their duties in the attain a high degree of compatibility of an implant with host
body, presence of Ca resulted in formation of intermetallic tissue is surface property of the implant. Also, surface prop-
phase due to low solubility of Ca in Mg [78]. This inter- erties have a significant effect on stress shielding, wear resis-
metallic phase plays an important role in grain refinement tance and fatigue failure. Moreover, implant surface is a pre-
when they are located in front of grain boundaries. The in- dominant factor on success or rejection of implanted material
termetallic phases of Mg–Ca–Si alloys are MgCaSi, Mg2 Si because it is in direct contact with the host tissue surface.
and Mg2 Ca and their presence depends on composition of al- Surface roughness is a key factor for osseointegration rate
loy. It was proved that three different phase combination can and mechanical fixation of implant to bone [84]. It was proved
be seen in Mg–Ca–Si ternary alloys. The phase can be pre- that surface roughness at micro-scale range improves the new
dicted by considering the Ca/Si ratio. The phases for alloys bone formation rate due to an increase in protein adsorption
of lower than 1.4 Ca/Si ratio are α-Mg + Mg2 Si + MgCaSi. and cellular activity [84]. van Tol et al. showed that shear
If Ca/Si ratio is located between 1.4 and 1.7, the phases are strength of bone-implant was increased by increasing surface
α-Mg + MgCaSi and for Ca/Si higher than 1.7, they are α- roughness from 0.058 to 4.25 μm [85]. In another study, the
Mg + Mg2 Ca + MgCaSi [79]. bonding strength was increased (0.38–9.70 MPa) by increasing
The main phases for the Mg–Zn alloys are α-Mg, MgZn2 , Ra (0.2–4 μm) values [86]. Ra values of Mg plates were mea-
MgZn3 , Mg7 Zn3 and MgZn. Previous studies showed that sured between 5.66 and 6.44 μm. Previous studies showed that
addition of Al into Mg–6Zn alloy resulted in formation of the optimum surface roughness improves the bone-implant
other intermetallic phases such as Mg32 Al49 , Mg32 Zn49 and bonding strength. Rønold et al. investigated the effect of sur-
Mg17 Al12 , and formation of these phases are highly depen- face roughness on bone-implant integrity. They showed that
dent on the amount of Al [80]. Addition of Al up to 3 wt% the best bone-implant integrity was achieved at Ra = 3.90 μm
resulted in formation of eutectic phase while addition of Al and there is a significant decline in bone-implant integrity by
more than 5 wt% changes morphology from eutectic to lamel- increasing Ra value from 5.07 to 11.03 μm [87]. In another
lar phase by formation of Mg17 Al12 secondary phase. Thus, study, there was a significant increase in bone cell activity by
it can be concluded that Zn/Al ratio has significant role on increasing surface roughness from 0.37 to 3.29 μm [88].
the formation and morphology of phases [81]. Pore size and pore morphology have a significant effect
Zhang et al. [74] investigated a biodegradable Mg–Nd– on cell attachment and proliferation. It was proved that pores
Zn–Zr (denoted as JDBM) alloy extruded at 320 °C at 8 with hexagonal morphology increase cell attachment more
and 25 extrusion ratios. The results show that the lower ex- than the pores with spherical shape. Also, in vivo studies
trusion ratio leads to a better corrosion performance with showed that the risk of infection decreases by increasing pore
finer grains and higher strength, but lower elongation. Their size after implantation (0.1 mm). On the other hand, increas-
study at various extrusion temperatures revealed that the grain ing pore size negatively affected the mechanical properties of
size increases with the increasing extrusion temperature due implants. Implants show brittle behavior when the pore size
to the growth of recrystallized grain at a higher extrusion was increased from 100–200 to 350–450 μm. Thus, increasing
temperature [75]. the pore size declines elastic modulus, shear and compaction
strength [89].
Combination of random macro, micro and nano-scale that Y (2.5 wt% to 7.5 wt%) and Nd (1–4.2 wt%) content in
roughness on implant surface improves the integrity between extruded WE alloy caused a decrease in ductility while an in-
implant and host tissue. Roughness on surface of an implant crease in strength [95]. Hence, it can be said that their alloy
increases the protein accumulation and as a result improves is more appropriate for orthopedic implants than cardiovas-
cell attachment [90]. Thus, mimicking the bone surface with cular applications due to its low ductility. Homayun and Af-
micro and nano-texture may promote osteointegration due to shar investigated the effect of Al addition on the mechanical
increase in mineral deposition [91]. Prodanov et al. manufac- properties of as-cast Mg–4Zn–0.2Ca alloy. Though Al and Zn
tured three different pattern surfaces (150, 300 and 1000 nm). increase YS and UTS by solid solution and grain refinement
In vitro results proved that the best mechanical integrity was strengthening, more than 3 wt% Al addition caused secondary
achieved on the surface with 300 nm roughness [90]. phase (Al12 Mg17 ) formation at grain boundaries and reduced
Branemark et al. modified the implant surface by using elongation and UTS [97]. However, compressive strength was
laser technology. It was reported that the rate of new bone not affected as same as UTS by increasing amount of Al.
formation at contact region increases due to bone bonding at The authors explained that tensile and compression stresses
nano-level. Also, pore size has a significant effect on in vivo have different crack mechanism. The compressive strength in-
behavior of implant. Shear stress was increased by increasing creased due to the formation of secondary phase. Similarly,
pore size from 100 to 200 μm while by increasing pore size the Mg–Al binary alloy foam with 2% Al could withstand
from 200 to 300 μm, it was declined [92]. higher stress in compression test than the binary alloy with
The optimum surface roughness should be found to in- higher Al addition. It was related to the abundant secondary
crease cell attachment but it is not predominant factor in cell phase formation between Mg and Al that reduced mechani-
integration. The optimum size for roughness may depend on cal integrity [24]. Compatible with previous study, Zhou et
actual size of cell used in vitro studies. Mirhosseini et al. al. manipulated Nd content in the extruded Mg–1Mn–2Zn
investigated the effect of laser patterning on cell attachment to make microstructure finer and to increase UTS and duc-
for Ti6Al4V implant. The patterned surfaces improve 2T3 tility. Increase in Nd content increased UTS and elongation;
osteoblast cell growth and uniform cell attachment. While, however decreased compressive strength since the Mg7 Zn3 af-
smooth surface cells accumulate on the implants in region fected uniformity in the microstructure [27]. The effect of Mn
which is near to the center of seeding [93]. addition to as-cast and heat-treated Mg–2Zn–0.5Ca alloy was
also investigated by Yandong et al. Mn addition has a peak
4.4. Mechanical properties value of 1 wt% for the highest UTS and elongation [98]. They
also reported that addition of Mn higher than 1 wt% caused
It is vital to have sufficient and appropriate mechanical the formation of brittle Mg–Zn intermetallic phase and re-
properties for biomedical implants during their life cycle. duced UTS and ductility. Shi et al. tried to optimize me-
Durability in the implanted structure is a top priority issue chanical properties of Mg–Gd–Ca–Zr alloy by manipulating
for patient safety because the role of an implant is to sup- Ca addition up to 1.2 wt% [101]. Ca addition increased YS as
port physically the damaged tissue during healing process. well as compressive strength but decreased the ductility. They
Moreover, biodegradable implants that have the highest me- stated that Ca and Zr are good at grain refinement and helped
chanical properties do not necessarily mean that they will to increase mechanical performance of the alloy for orthope-
represent the best performance. For instance, an enormous dic applications. Yan et al. reported that YS and UTS had
difference between elastic moduli of implant and damaged their highest values as Zn addition reached to 14.5 wt% due
bone may lead elastic mismatches and cause stress shielding to uniform dispersion of Mg–Zn intermetallic phase in the
especially in metallic biomaterials that are used for orthope- microstructure. It was found that the extruded Mg–Zn binary
dic applications. There are many ways to boost mechanical alloy with Zn addition more than 14.5 wt% caused formation
performance of biodegradable implants. At least but not less, of coarser and strike-like grains that decreased the YS and
two main routes can be named in order to enhance mechan- UTS. However, elongation was affected from the increase in
ical properties of Mg alloys that are alloying and combined Mn addition differently. Addition of more than 14.5 wt% Mn
manufacturing methods. continuously increased the ductility that made the alloy suit-
From mechanical point of view, Mg-based alloys have able for stent applications [100].
faced two challenges which are stress shielding for bone im- Mn was added to Mg–3Sn alloy to increase mechanical
plants and “ductility and bendability” limitation for cardio- performance by the formation of intermetallic phases for stent
vascular stent applications [94]. applications [94]. Zhen et al. found that Mg–3Sn–0.5Mn al-
In many studies, researchers have tried to improve mechan- loy (23%) was more ductile than WE43 and AZ31 Mg alloys
ical properties of Mg by alloying it with various elements (12–21%) while their UTSs were at the same levels [102].
such as Ca, Al, Zn, Zr and REEs. Mg has ability to cre- Intermetallic Mg2 Sn phase helped to improve mechanical per-
ate solid solution with many elements including Al, Zn, Ca formance of the alloy due to the fact that Sn is an effective
and Sr due to its atomic size (about 320 nm) and hexagonal strengthening element because of intermetallic phase. It can
close-packed system [15]. The amount of alloying element be concluded from previous studies that basic mechanisms
was also tuned up to obtain the best mechanical performance in alloying that improves mechanical performance are solid
as a biomedical implant [27,95–101]. Wang et al. reported
solution, precipitation hardening and grain refinement 2Zn–Ca alloy containing 1 wt% β-TCP (789 HV) had higher
strengthening [15]. hardness than as-cast alloy (539 HV) [110]. Accordingly, Gui
Increasing simultaneously the concentration of Sr and Ca et al. also reported the hot extruded Mg–Gd–Zn–Zr–Mn al-
decreased the mechanical properties due to secondary brittle loy had about 1 time more YS and UTSs [105]. It was also
Mg phase formation of those elements in Mg–Si–Sr–Ca al- more ductile (18 to 21.3%) than as-cast and heat-treated coun-
loy [103]. As in previous studies, secondary phase formation terparts. Zhang et al. also emphasized that ECAP increased
without a uniform distribution in the microstructures led to UTS (161–267 MPa) and YS (85 to 217 MPa) of Mg–Gd–
weaken the mechanical performance including UTS, YS and Nd–Zn–Zr alloy as well as the hardness due to the fact that
elongation. Brittle secondary formation that causes the lack ECAP helped formation of β 1 phase which hinders disloca-
of uniformity helped crack initiation. tion movements [111]. Mechanical properties of Mg-based
Solution and aging treatments are two heat treatment pro- biodegradable implants are compiled in Table 2.
cesses to adjust mechanical properties in biomedical appli-
cations. Solution treatment increases ductility as it decreases 4.5. Biological properties
strength. However, aging treatment causes a total opposite.
Therefore, aging treatment could be suitable for bone im- Mg is one of the most important element constructed
plants whilst solution treatment or solution treatment followed within the human body where it is involved in high number
by aging treatment for cardiovascular stent applications [104]. of enzymatic reactions. It was reported that Mg takes place in
A study supported that aging treatment to the extruded Mg– synthesis processes of protein and nucleic acid, stabilization
3Nd–0.2Zn–0.4Zr alloy increased UTS. However, elongation of plasma membrane and many other cellular activities [47].
remained as high as 26% without aging treatment [75]. Ex- Amount of Mg in an average adult human body is around
trusion is regarded as more preferable manufacturing method 21–28 g and more than 50% of which is present in bone tis-
for Mg alloys than casting due to its work hardening occur- sue. Soft tissues contain 35–40% of this content and less than
rence and solid solution strengthening mechanism inducing in 1% is sequestered in serum [47]. Mg element, which is se-
the microstructure [27,105]. It was shown in multiple stud- questered in bone, acts as a reservoir for acute change in Mg
ies by comparing powder extrusion with other manufactur- levels of serum.
ing methods. For instance, Sun et al. compared mechanical Mg2+ bivalent ions play an important role in determining
properties of the as-cast and extruded Mg–4.0Zn–0.2Ca al- bone fragility. Also, it is known that Mg2+ ion takes place in
loy. The extruded ternary Mg alloy showed better mechan- transformation process of immature bone into a mature bone.
ical properties due to the formation of secondary phases of Mg ion content in bone mineral is around 6 mol% but this
Ca and solution hardening effect of Zn [106]. Wu et al. con- content decreases during maturation process of bone. Carti-
ducted a comprehensive comparison between as-cast, extruded lage and immature bone tissues contain high concentration of
and cyclic extrusion compressed (CECed) Mg–Zn–Y–Nd al- Mg2+ ion but this concentration changes depending on the ag-
loy for cardiovascular stent applications. The hot extruded ing. Moreover, presence of Mg in bone composition increases
Mg alloy exhibited higher YS and UTS. However, the CECed the elasticity of bone [47].
Mg alloy showed 1 and 2 times higher ductility. The authors Effect of Mg on bone formation was investigated in pre-
explained higher ductility, lower YS and UTS with smaller vious studies. Presence of Mg has significant effect on os-
grain size (about 1 μm), precipitation of secondary phases at teoblastic cell differentiation. Bone formation around and over
grain boundaries and dislocation density by the cyclic plastic degraded Mg implants proved its effect on accelerating of
deformation in the microstructure [107]. The effect of three bone healing. Mg degradation led to the release of Mg2+ ions
manufacturing methods (CEC, ECAP and hot extrusion) for to surrounding tissue which resulted in stimulation of local
cardiovascular applications on the tensile properties and duc- cells to bone formation. Also, it was proved that the hydro-
tility has been analyzed [108]. Contrary to Wu et al., the gen gas which is released during degradation process of Mg
CECed alloy had the highest UTS and YS. The formation of and its alloys can be tolerated by human body. However, high
intermetallic phase of Mg–Nd in the CECed alloy increased amount of hydrogen gas release can result in complication at
the tensile properties due to grain refinement and precipitation healing period. Thus, the corrosion rate of Mg should be con-
strengthening. However, it was noted that the ECAPed alloy trolled to decrease risk of gas accumulation. The amount of
had large grains than CECed alloy’s in spite of the fact that gas cleared from the implantation site also depends on the
their UTSs are close to each. Thus, the authors concluded that implanted region and available blood flow [48].
UTS is not only affected by grain size but also by dislocation Besides improving the mechanical properties and corro-
density [108]. sion resistance, since Zn takes part in a wide range of phys-
Fan et al. emphasized the positive effect of hot extrusion on iological functions such as the regulation of immune system
mechanical properties of Mg–1.5Y–1.2Zn–0.44Zr alloy due and enzymatic reactions, it was also reported that presence
to LPS structure of secondary phase (Mg12 ZnY). Similar to of Zn in composition of Mg alloys increases osteoblastic
previous study, the hot extruded alloy had superior strength cell proliferation. However, high concentration of Zn resulted
and ductility than as-cast and heat-treated alloys due to the in cytotoxic effect in vitro. Hong et al. showed ZK40–Mg
grain size refinement effect and uniform secondary phase dis- and AZ31–Mg increase cell proliferation in comparison to
tribution [109]. Similarly, it was reported that ECAPed Mg– pure Mg. High concentration of corrosion products leads to
Table 2
Mechanical properties of powder processed Mg-based alloys.
Tensile strength Yield strength Elongation Young’s Compression Bending

Mg alloy (MPa) (Mpa) (%) Modulus (Gpa) strength (Mpa) strength (Mpa) Reference
Mg–4.0Zn–0.2Ca (extruded) 297 240 21.3 45 – – [106]
Mg–Zn–Y–Nd (hot-extruded) 316 183 15.6 – – – [107]
Mg–Zn–Y–Nd (CECed) 303 185 30.2 – – – [107]
Mg–1.5Y–1.2Zn–0.44Zr 236 178 28 – 471 501 [109]
(hot-extruded)
Mg–3Sn–0.5Mn 240 150 23 – – – [102]
Mg–3Al–4Zn–0.2Ca 198 – 10.3 44.1 – 347 [97]
Mg–2Zn–0.5Ca–Mn (heat-treated) 205 – 15.7 – – – [98]
Mg–5.3Zn–0.6Ca + 1.0Ce/La 202 – – – – – [99]
(extruded)
Mg–1Mn–2Zn–1.5Nd (extruded) >285 – >14 – >395 – [27]
Mg–Gd–Zn–Zr–Mn (extruded) 341 315 21.3 – – – [105]
Mg–Gd–Nd–Zn–Zr (extruded) 267 217 – – – – [111]
Mg–Zn–Y–Nd (ECAP) 239 96 30.1 – – – [108]
Mg–Zn–Y–Nd (CEC) 280 194 29.4 – – – [108]
Mg–Zn–Y–Nd (extruded) 242 170 20.9 – – – [108]
cytotoxic effect in human body due to osmotic shock effect

on surrounding cells [49]. In another study, Mg implant which
is alloyed with different amount of Al did not show any cy-
totoxic or neurotoxic effect up to 9 wt% of Al. Moreover,
osteoblastic activity was increased with increasing amount of
Al up to 9 wt% so the release of Al ions can be tolerated with
human body at low levels [50].
Addition of Zr was also reported to improve the biocom-
patibility in vivo. Gu et al. showed that Zr higher than 5% led
to unalloyed Zr phase in the alloy [51]. Unalloyed Zr phase
led to a decrease in corrosion resistance so subsequently re-
sulted in poor biocompatibility. As a result, the recommended
content of Zr in Mg–xZr–ySr alloys was below 5% [52]. It
was proved that the addition of Ca and Zr to Mg-based im-
plants improve osseointegration rate and implant stabilization
in host tissue [53].
4.6. Degradation
Fig. 1. Degradation mechanism of Mg in vivo [114].
The corrosion of Mg and its alloys is an electrochemical
process [112]. It is known that this process in aqueous envi-
ronment is different than oxidation process in air [113]. The
corrosion mechanism of Mg in aqueous environment can be
these protective layers are not strong enough. Therefore, they
explained with the following reactions [112–114].
break down before starting of anodic polarization [115].
Mg → Mg2+ + 2e− (Anodic reaction) (1) Degradation behavior of Mg and its alloys are affected by
different parameters such as aqueous environment, composi-
2H2 O + 2e− → H2 + 2OH− (Cathodic reaction) (2) tion, structure, surface structure, alloying elements, impurities,
secondary phase and manufacturing method [28,114].
2H2 O + O2 + 4e− → 4OH− (Cathodic reaction) (3) Mg and its alloys show unpredictable behavior in physio-
logical environment due to the presence of dissolved oxygen,
Mg2+ + 2OH− → Mg(OH)2 (Product formation) (4) proteins, amino acids, chloride and hydroxide ions (Fig. 1)
[114,116]. Adsorption of amino acids, proteins and lipids over
High amount of hydrogen gas evolution during anodic the surface alters the degradation rate of Mg and its alloys
reaction resulted in decline of the speed of cathodic reac- [114,116]. Also, Mg(OH)2 acts as a protective layer which
tion which is known as negative difference effect phenomena results in an increase in corrosion resistance. However, high
[35,115]. The formation of moderately protective layer during concentration of chloride ions in physiological environments
cathodic reaction decreases cathodic reaction rate. However, break down the protective layer of Mg(OH)2 which leads to
pitting corrosion [10,117,118]. The corrosion mechanism of with different corrosion potentials at the same electrolyte. One
Mg in presence of chloride ions is explained as follows: of the metals acts as anode and the other one acts as cathode
and form a galvanic couple [82]. Thus, anode metal is cor-
Mg (OH)2 + 2Cl− → MgCl2 (5) roded due to electropotential difference between two metals.
Probability of galvanic corrosion is high for Mg implants in
Mg + 2H2 O → Mg(OH)2 + H2 (6)
physiological environment. The presence of different alloying
Mg + 2Cl− → MgCl2 (7) elements and phases usually cause micro galvanic corrosion
[124].
Formation of MgCl2 layer on the surface decreases the cor- Pitting corrosion is commonly observed in environments
rosion resistance since it is known that MgCl2 is moderately with aggressive ions such as chloride ions in body fluid [125].
soluble [10,117,118]. However, it is biocompatible and does Pitting corrosion is occurred at regions adjacent to second
not show any cytotoxic effect [10]. Furthermore, high con- phases in presence of chloride ions [125]. Fretting corrosion
centration of hydroxyl ions in the environment increases the occurs on the contact surfaces of metals. This type of cor-
alkalinity and presence of calcium and phosphate ions leads rosion causing a mechanical wear should be considered for
to precipitation of calcium phosphate protective layer on the Mg-based metal implants [82]. The mechanism of crevice cor-
surface [114,119,120]. rosion is similar to pitting corrosion and results in localized
The presence of buffering agents such as HCl–Tris and corrosion on the Mg implant surface. Microcracks can trigger
Hepes which are used to neutralize pH value of SBF, accel- crevice corrosion [82].
erate corrosion rate of Mg-based implants by consuming OH− Corrosion resistance of Mg significantly changes by alloy-
ions [10]. Thus, consumption of OH− ions leads to a decrease ing element. Ca increases the corrosion resistance and de-
in corrosion product formation and an increase in corrosion creases the grain size of the Mg alloys. Mg–Ca alloys con-
rate. In contrast, protein (Fetal Bovine Serum) adsorption on taining different amounts of Ca are synthesized and it was
the surface of Mg implants improves the corrosion resistance proved that Mg alloy containing 0.6 wt% Ca gives better re-
[10]. It is known that insoluble salts precipitate on the sur- sults in terms of corrosion resistance than other Ca com-
face of Mg in presence of protein which form an insoluble positions. Increasing the amount of Ca causes the forma-
dense layer on the surface. This protective layer improves the tion of Mg2 Ca phase which lowers the corrosion resistance
corrosion resistance [28,114]. [126].
It was reported that impurities and secondary phases play REEs are widely used in alloying of Mg to improve mi-
important role in corrosion resistance of Mg and its al- cro structure, mechanical properties and corrosion resistance.
loys. There is a difference between reference electrode po- It was proved that REEs such as La and Gd improve cor-
tential of Mg and impurities/secondary phase which create rosion resistance of biodegradable Mg alloys. However, the
micro-galvanic cell [28,35,113,117]. Corrosion rate of pure toxicity of the elements should be considered since good bio-
Mg increases in presence of impurities such as Fe, Ni, Cu compatibility of the elements released by Mg alloys during
and Co due to their higher standard electrode potentials degradation is essential for their use in an implant [127]. It
[28]. It was accepted that secondary phase has significant was showed that mechanical properties of Mg alloys were
effect on galvanic corrosion resistance of Mg and its al- improved by the addition of REEs due to the formation of
loys. Secondary phase can act as corrosion barrier or acts metastable REEs containing phases along the grain bound-
as a galvanic cathode [76,121,122]. Secondary phase amount, aries [121]. Gd higher than 10% increases the mechanical
grain size, precipitation side and reference electrode poten- strength because of noble behavior of Mg5 Gd precipitated in
tial should be taken into account to decide about its ef- grain boundaries. Moreover, for Mg alloys containing 15%
fect on corrosion rate [76,121,122]. It was reported that sec- Gd, an increase in corrosion rate was observed. Addition of
ondary phase with finer grain size precipitated along grain La to Mg alloys improves the corrosion resistance by forming
boundaries improve corrosion resistance while high corro- a passive film [127]. However, there is no in vitro or in vivo
sion potential of secondary phase increases the corrosion investigation present on this alloy, which shows the lack of
rate [122,123]. studies in this subject.
Corrosion behavior of Mg and its alloys is significantly
affected by the microstructural defects such as dislocations 5. Computational studies on Mg alloys and its
and deformation twins [115]. An increase in residual stress fabrication into implants
as a result of microstructural defect, led to an increase in
corrosion rate [115]. The corrosion rate of Mg and its alloys Computational models can be utilized to predict the me-
is increased due to an increase in population of dislocations, chanical function of biodegrading implants under physiolog-
twins and grain boundaries. Also, mechanical stress has con- ical loading conditions as well as to understand interaction
siderable effect on corrosion resistance. of implants with surrounding tissues. Design and manufac-
Different types of corrosion are likely to occur in physio- turing of Mg alloys are the other fields where computational
logical environment [82]. Galvanic, intergranular, pitting and models can be used to improve implant and stent designs
crevice corrosions are the most common types of corrosion. as well as to optimize the operational parameters. Finite ele-
Galvanic corrosion is caused by the presence of two metals ment models (FEM) have been used to predict deformation of
implants and their interaction with the surrounding tissues behaviors of high-speed cutting. A 2D FEA of plane strain
[128]. To determine the life-time and to assess the functional- orthogonal cutting was implemented using ABAQUS. Exper-
ity of an implant, it is required to include extra modeling con- imental and numerical studies revealed the same rake and
siderations e.g., corrosion behavior and change in mechanical relief angles of the rigid PCD tool. The predicted peak tem-
strength of implant during healing period. Such models are peratures of the chips and machined surfaces were 600 and
still under development stage. For optimum design and func- 400 °C, respectively. The surface temperature was sufficient to
tionality, existing empirical models for surface erosion and contribute to the formation of flank build-up. Predicted tem-
the related mass loss rate as well as mechanical characteristics peratures at the tool/chip interfaces were close to the melting
under multi-axial load can be incorporated in computational temperature of the Mg–Ca0.8 alloy (650 °C) [133]. In another
models to predict biodegradation and change in mechanical study, Split-Hopkinson pressure bar (SHPB) test was applied
strength of implants during healing. The following chapters on Mg–0.8Ca alloy to observe the mechanical behavior of the
review the literature related to computational studies of Mg biodegradable Mg–0.8Ca alloy under high strain rate loadings
alloys in an order consistent with the fields that they can be which is typical in metal cutting processes. Then the inter-
implemented. nal state variable (ISV) plasticity model was employed to
model the material behavior under cutting regimes. A finite
5.1. Manufacturing processes element (FE) analysis model was developed to study the chip
formation during high speed dry cutting of MgCa0.8 alloy.
Computational models have been developed to investigate Continuous chip formation predicted by FE simulation was
different aspects of manufacturing processes of Mg and Mg verified by experimental results [134].
alloys. This could ease optimizing the process parameters as Another computational model was developed by Lin and
well as predicting the mechanical characteristics of Mg-based Scott to determine the factors that contribute to the pull-out
biomaterials. strength of the screws made of Mg and Mg alloy AZ31 im-
One of the potential applications of Mg alloy can be in planted in a rabbit mandible. Holding strength of the screws,
surgical threads. However, Mg alloys have low plasticity at compared to the stainless steel screws, was measured in an
RT, making the cold wire drawing process difficult. An ex- in vitro pull-out test. Later, to simulate the pull-out test, a
perimental observation showed that the fracture of Mg alloys custom FE code was developed. All the screws that made
occurs in grain boundaries. Based on this, a mathematical of pure Mg, AZ31 and stainless steel exhibited very simi-
damage model was developed [129]. Later on, a micro-scale lar pull-out strength of around 40 N. Simulated pull-out force
numerical model was developed by Milenin et al. using the profiles indicated that for a constant diameter of the screw
boundary element method (BEM) for the drawing process of with similar interfacial conditions (e.g. depth of penetration,
MgCa0.8 alloy to optimize the deformation parameters based thread profile) the pull-out strength remains essentially con-
on the fracture in grain boundaries. The BEM model was then stant. Then, the effect of the interfacial strength on the pull-
coupled with the authors’ FEM code in order to model the out strength was examined keeping all the other model pa-
wire drawing process at the macroscale. The developed wire rameters constant. Predicted pull-out strength was increased
drawing model can be used for both optimizing the parame- with increasing interfacial strength. The study concluded that
ters of the drawing process and predicting the ductility of the pull-out strength is highly sensitive on the interfacial strength
material [130]. between the screw and the bone, and it is insensitive to the
In the cold production of Mg, low formability is one modulus of the screw material [135].
of the drawback. Combining the casting and forming pro- Burnishing can be applied to improve the corrosion be-
cesses within the horizontal twin-roll casting method can be havior of biodegradable MgCa0.8 alloy. An FE model was
a promising solution. This method involves feeding the molten developed by Salahshoor and Guo to simulate contact me-
Mg alloy between two counter rotating rolls which are water- chanics in ball burnishing of MgCa0.8 biomaterial. The ISV
cooled internally. The horizontal twin-roll casting of the Mg plasticity model successfully predicted the mechanical behav-
alloy AZ31 was numerically investigated using CFD model ior of MgCa0.8. The developed 2D axisymmetric FEM ac-
[131]. According to this study, cryogenic machining reduces curately predicted the dent geometry as well. Results of the
the grain size of Mg alloy effectively and this grain refinement study showed that the developed model is successful in pre-
improves the corrosion resistance significantly. A preliminary dicting the large amount of compressive layers produced by
study on modeling the microstructural changes of AZ31B Mg small amount of shallow deformation which is the unique
alloy during dry and cryogenic machining was conducted by characteristics of ball burnishing [136].
Pu et al. using FE method and a user subroutine which is In the reviewed literature, a variety of manufacturing
based on the dynamic recrystallization mechanism of Mg al- processes such as drawing, casting, forming and burnish-
loys. The model accurately predicted the experimental results ing have been numerically investigated for Mg-based ma-
[132]. terials. The developed models were successful in predict-
The surface integrity in high-speed dry milling of ing the experimental results and optimizing the production
biodegradable Mg–0.8Ca alloy was numerically investigated parameters. These models help design and manufacturing
by Guo and Salahshoor. An internal state variability (ISV) of biodegradable Mg materials with desirable mechanical
model was used to model the inherent dynamic mechanical characteristics.
5.2. Degradation behavior 5.2.2. Degradation behavior of stents

A new design concept of Mg alloy stent was proposed by
Uncontrolled degradation of biomaterials could result in Wu et al. and a shape optimization method with FE analysis
loss of their mechanical integrity, metal contamination in the on 2D stent models was applied considering four different
body and intolerable hydrogen evolution by tissue. Computa- Mg alloys namely; AZ80, AZ31, ZM21, and WE43. The op-
tional studies on degradation behavior of Mg-based implant timized designs were compared with an existing Mg alloy
and stent materials provide researchers with a clear infor- stent design by 3D FE analysis. The results showed that the
mation of the relevance of several factors to corrosion rate, optimized design with alloy WE43, compared to the existing
significant parameters for a reliable in vitro testing, and gen- Mg alloy stent, had an increased strut width by approximately
eral corrosion behavior of biodegradable stents and implants. 48%, improved safety properties (reduced the maximum prin-
These could also contribute saving time and energy required cipal stress after recoil with tissue by 29%, and reduced the
for the experimental research. maximum principal strain during expansion by 14%) and im-
proved scaffolding ability by 24%. Accordingly, the degrada-
tion time can be expected to extend. The applied methodology
was suggested to provide a convenient and practical way to
develop novel Mg alloy stent designs [142].
5.2.1. Degradation behavior of implants The first computational study to predict the interaction be-
Mg-based glasses are reported to offer extended solubility tween Mg alloy stent and arterial tissue was carried out by
period for alloying elements and a homogeneous single-phase Wu et al. Due to short degradation time, Mg alloy stents ex-
structure, both of which can contribute improving corrosion hibit insufficient scaffolding to the target vessels. Aiming to
behavior of the biomaterial significantly. The reduction of hy- improve the design and degradation behavior of Mg alloys,
drogen evolution in biodegradable Zn-rich MgZnCa glasses Wu et al. developed a degradable FEM for Mg alloy stents. A
was studied by Zberg et al. It was observed that above a par- three dimensional FEM was combined with degradable ma-
ticular Zn-alloying threshold (28 wt%), a Zn- and oxygen-rich terial model of AZ31 and applied to stents of conventional
passivating layer forms on the surface of the alloy which pre- and optimized designs. These designs were implanted through
vents rapid corrosion of the material. A model was developed simulation into a vessel model and degraded by changing in-
based on the calculated Pourbaix diagram of Zn in SBF using teractions between outer stent surface and the vessel. The 3D
corrosion analyzer software [137]. The relevance of several model was suggested to provide a proper design and testing
parameters to the corrosion rate of biodegradable Mg was in- tool for novel Mg alloy stents [143]. Following the develop-
vestigated by Willumeit et al. through artificial neural network ment of FEM for degradable Mg alloy stents, the model was
(ANN) analysis. The results showed that the most significant experimentally validated with twelve Mg alloy stents by Wu
parameters to be included for reliable in vitro tests are CO2 et al. Six samples were designed according to the developed
and NaCl [138]. Another study investigated the degradation degradation model and the other six samples were conven-
of Mg due to the presence of impurities and the thickness of tionally designed. The experimental results showed that the
electrolyte using the FE method. The results showed that Mg samples of the optimized design had better corrosion resis-
implant covered by a thick layer of electrolyte suffers severe tance than those of the conventional design. The degradation
corrosion attack, but this is significantly reduced when a thin process of the samples was dominated by uniform and stress
enough layer is formed on Mg [139]. corrosion [144]. This experimental work was the first valida-
Preliminary in silico assessment of the degradation rate of tion of the computational approach, which can be utilized to
Mg implant would save the time required for in vitro analy- design, test and improve Mg alloy stents.
sis. A new partial differential equation (PDE) model for the Another computational model was developed to predict
chemistry of corrosion was developed by Bajger. He used degradation rate of Mg that can be utilized in bioresorbable
the hydrogen evolution rate data obtained from an immer- stent design. Continuum damage mechanics (CDM) model
sion test of pure Mg in SBF to calibrate the PDE model was used to model the loss of mechanical strength of the ma-
[140]. Another mathematical model for the corrosion behav- terial by occurrence of geometrical discontinuities. For that
ior of Mg was developed by Bajger et al. to aid the design purpose, a scalar field was defined to quantify the damage
of biodegradable implants with suitable geometries. Level-set distribution. The developed model was then implemented in
method was employed to track complicated geometries as it FE framework. Two mechanisms were considered for corro-
is the case of porous implants. The study provided a frame- sion of Mg; stress corrosion and galvanic corrosion. Galvanic
work for the assessment of the corrosion rate of Mg including corrosion was used to describe mass loss when the material
the formation and dissolution processes of the protective film is exposed to an aggressive environment, even in a stress-free
[141]. The corrosion rate of Mg–Zn–RE–xCa alloy with Ca zone. On the other hand, stress corrosion accounted for the
contents varying from 0 to 6 wt% was experimentally and damage due to the localization of the corrosion attack in the
theoretically evaluated by Bakhsheshi-Rad et al. and the ex- zones of concentrated stress [145].
perimental results were compared with the simulation results. The influence of degradation on the mechanical integrity of
Good agreement in terms of corrosion rate was found between Mg stents was numerically modeled by Grogan et al. In order
experimental and predicted results [120].
to analyze the corrosion in complex 3D geometries, a phe- 6.1. Mg-polymer composites

nomenological corrosion model was developed and applied
within an FE framework. An element-specific dimensionless Expecting the polymer matrix to benefit from the higher
pitting parameter was introduced to include the heterogeneous strength and modulus of the Mg particles as well as Mg to
or pitting corrosion to the modeling framework. Results of the benefit from the surrounded protective polymer matrix that
study suggested that the developed model can be used to pre- can improve the corrosion resistance, Cifuentes et al. devel-
dict the performance of a bioabsorbable stent placed in an oped a poly-L-lactic acid (PLLA)/Mg composite. Compos-
artery [146]. Development of an implicit FE solution method ite specimens were prepared by combining solvent casting of
allowed to reduce the simulation time and extend the appli- PLLA loaded with 30 wt% Mg particles and further mold-
cability of degradation models of Mg stents. The developed ing by compression. Reinforcing the polymer matrix with
strategy was successful in predicting the localized corrosion Mg particles improved Young’s modulus up to 8 GPa, YS
of stent struts for progressively more complex vessel-stent up to 100 MPa and hardness up to 340 MPa [151]. In or-
patterns [147]. der to test the suitability of different methods to fabricate
The expanding rates, Poisson’s ratio and deformation be- PLLA/Mg composites, hot extrusion was employed. Extrusion
havior of self-expanding auxetic stents of different geome- distributed Mg particles uniformly within PLLA matrix. Ad-
tries were modeled and simulated by Carneiro and Puga. The dition of Mg up to 5% increased the degradation rate slightly,
results of the study indicated that Reentrant and Chiral ge- but significant increment was observed at 7%. Similarly, me-
ometries exhibit low Poisson’s ratio and high expanding rates. chanical strength of the specimen increased by addition of
Moreover, the observed deformation behavior implied a less Mg up to 5%, but it dropped drastically after the Mg content
axial deformation [148]. A computational test-bed for stent reached to 7% [152].
angioplasty was developed by Boland et al. to simulate stent To improve the mechanical properties of PLLA polymer
tracking, balloon expansion, recoil and in vivo loading in an and to prevent its inflammatory response in biomedical ap-
atherosclerotic artery model. A corrosion model was also de- plications Kum et al. developed a hybrid composite by in-
veloped to simulate uniform and pitting corrosion of Mg stent corporating oligolactide-grafted magnesium hydroxide (Mg-
as well as its interaction with arterial tissue. The study re- OLA) in a biodegradable polymer matrix (PLLA). Mg-OLAs
vealed a growth of new arterial tissue around the stent struts were synthesized using ring opening polymerization method.
that has a significant influence on the mechanical behavior of The measured UTS and modulus of PLLA/Mg80-OLA20 (0–
the degrading stent [149]. 20 wt%) were higher than PLLA/magnesium hydroxide. In-
Compared to the implants, stents typically have more com- creasing the amount of Mg80-OLA20 from 0 to 20 wt% in-
plex geometries. In the discussed literature, extended stent creased the cell viability by 100% that appeared to have a
degradation periods have been attained with the proposed positive effect on cytotoxicity as well as inflammatory re-
models that allow shape optimization for stent design. More- sponse of the composite [153].
over, these models bring about improved mechanical strength Reinforcement of poly lactic-co-glycolic acid (PLGA) by
and improved scaffolding ability of stents. Additional models Mg alloy AZ31 was studied by Wu et al. Addition of AZ31
have been proposed to observe the interaction of Mg alloy fibers significantly enhanced the UTS and elongation of the
stent with arterial tissue as well as to predict the degradation composite. The acid degradation products of PLGA were neu-
rate and performance of Mg stents. tralized by the alkaline corrosion products of AZ31 Mg al-
loy fibers. Direct cell attachment test showed that all the
cells exhibi a healthy morphology and the cells adhesion
and proliferation on the specimen surface were observable
6. Mg-based composites for potential biomedical implant [154]. Brown et al., for the first time, developed a metallic
applications Mg particle/PLGA composite scaffold using a solvent cast-
ing, salt leaching method to enhance bone regeneration after
Biodegradability of Mg alloys makes them suitable for or- tooth extraction. By addition of Mg into the PLGA scaffolds
thopedic implants. Many studies indicated that designing Mg the compressive strength and modulus were increased, and
alloys with controllable degradation rates is highly demanded. a suitable porous structure was obtained for cell infiltration.
Development of new composites based on Mg alloys with Combining basic-degrading Mg with acidic-degrading PLGA
other systems could be a promising solution to meet this led to an overall pH buffering effect and a long-term release
demand [150]. Researchers have incorporated different type of Mg over the period of 10-week degradation assay. Degra-
of ceramic and polymer materials with Mg and Mg alloys dation products of Mg/PLGA composite scaffolds increased
to form Mg-based composites through various manufacturing the proliferation of bone marrow stromal cell in vitro. His-
routes and investigated their effect on corrosion resistance, tological analysis indicated that the composite is biologically
mechanical properties and biocompatibility. In ceramic com- safe [155].
posites, Mg and Mg alloys are used as the matrix and the It is apparent from the discussed literature that reinforcing
matrix is reinforced by ceramics whereas in polymer com- Mg enhances mechanical properties of the biopolymer ma-
posites Mg and Mg alloys are usually added to reinforce the trix. Also, the corrosion resistance of Mg improves when it
polymer matrix. forms composites with polymer matrix. However, the resulting
mechanical strength of the composites is usually below that of the Mg–nHAp composite. The composite exhibited a su-
of Mg. Thus, more research can be conducted to develop and perior cell adhesion [159].
identify composites of Mg with biopolymers within a range Microwave assisted sintering method was used Xiong
of acceptable mechanical strength. et al., for the first time, to prepare HAp-reinforced Mg
composites. Microscopic evaluations showed a homogenous
distribution of HAp particles in Mg matrix. Significantly im-
6.2. Mg-ceramic composites proved mechanical properties (flexural strength and modulus
and compressive strength and modulus), enhanced corrosion
Composites made up of various Mg alloys as matrix and resistance, superior cytocompatibility and bioactivity were
various ceramics as reinforcements, with different fabrication achieved with HAp/Mg compared to that of the pure Mg. It
routes have been extensively investigated to assess their vi- was concluded that the HAp content has control over mechan-
ability in biomedical applications. A group of biomaterials ical properties, corrosion resistance and biological behavior of
which have similar characteristics with the mineral parts of HAp/Mg composite [21].
bone seems very promising for hard tissue engineering appli- Mg alloy (ZK60A) matrix composites reinforced with
cations. This group includes calcium phosphates, especially varying contents of calcium polyphosphate particles were fab-
HAp, beta-tricalcium phosphate (β-TCP) and bicalcium phos- ricated by Feng and Han through PM. A uniform particle
phate (BCP) which is the combination of HAp and β -TCP distribution of polyphosphate in the ZK60A matrices without
[150]. Calcium phosphates induce adsorption of ions and de- voids were observed in the composites containing 2.5 wt%
position of calcium phosphate minerals on the composite sur- and 5 wt% calcium polyphosphate. Mechanical properties
face which stimulate the bone growth. However, their mechan- (UTS, YS and elastic modulus) and corrosion rate of the com-
ical properties cannot compete with that of bone. A possible posite were adjustable with the control of calcium polyphos-
solution to this could be procured through development of phate content. Mg(OH)2 formation on the composite surface
calcium phosphates composites with Mg and Mg alloy ma- was observed after immersion of the samples into physiolog-
trix. Research groups evaluated the incorporation of HAp into ical saline solution [160]. An MMC of HAp/Mg–Zn which is
pure Mg and Mg alloys such as AZ91D and MgCa. A metal composed of Mg alloy Mg–Zn as matrix and different con-
matrix composite (MMC) composed of Mg alloy AZ91D ma- centrations of thermal-treated HAp particles as reinforcements
trix and HAp reinforcements was fabricated by Wittea et al. was fabricated by Liu et al. The addition of HAp particles
through hot extrusion. Mechanical properties of the compos- altered the corrosion mechanism of Mg matrix. During the
ite were found to be very similar to that of the natural bone. corrosion process, HAp particles adsorbed PO3 – 4 and Ca2+
HAp particles stabilized the corrosion rate and exhibited more ions efficiently and Ca-P compounds were deposited on the
uniform corrosion attack in artificial sea water and cell so- surface of composites. HA slowed down the corrosion rate
lutions. During immersion test, the bone cells were able to of Mg matrix composites in SBF. It is also indicated that Zn
adhere, proliferate and survive on the surface of MMC-HA addition improves the corrosion behavior of HAp/Mg compos-
composite [156]. Chen et al. used AZ91 Mg alloy and porous ites [161]. A Mg MMC was synthesized by Ye et al. using
HAp to prepare AZ91/HAp composite through squeeze cast- Mg–2.9Zn–0.7Zr alloy as the matrix and 1 wt% n-HAp parti-
ing method. A significantly higher compressive strength was cles as reinforcements. The composite exhibited a lower rate
observed with AZ91/HAp composite compared to HAp. AZ91 of corrosion and more favorable in vitro cytocompatibility in
alloy exhibited a lower corrosion resistance in comparison comparison with the Mg–Zn–Zr alloy. Composite surface was
with HAp. Therefore, it can lead recurrence of the porous covered with white Ca–P precipitates. Electrochemical test re-
HAp and promote bone cell adhesion and proliferation [157]. sults revealed that the addition of n-HAp particles increases
Compared to casting methods, PM is reported to be a the corrosion potential. An adhesion and proliferation of cells
more suitable method to obtain homogeneous distribution of on the surface of the composite was observed. The results
ceramic particles in Mg matrix [150]. Hence, PM method of Mg–Zn–Zr/n-HAp composite were promising to be con-
was employed by Gu et al. to fabricate Mg/HAp compos- sidered as biodegradable bone fixation material [162]. Nano-
ites of varying HAp content (10 wt%, 20 wt% and 30 wt%). fluorapatite-reinforced AZ91 Mg alloy composite was syn-
Mg/10HAp composite showed a uniform HA particle distri- thesized by Razavi et al. through blending–pressing–sintering
bution. Compared to the as-extruded bulk pure Mg, an en- method. The addition of fluorapatite nanoparticles to Mg al-
hanced YS but reduced UTS and elongation was observed loys enhanced the mechanical properties and corrosion resis-
with Mg/10HAp composite. Increasing HAp content also in- tance, and accelerated the formation of an apatite layer on the
creased the corrosion rate of the composite. The cytotoxicity surface, which contributed to the protection of AZ91 matrix
evaluation showed that Mg/10HAp is compatible to L-929 and enhanced osteoconductivity of Mg alloys for biomedical
cells [158]. Friction stir processing method was employed applications [163,164].
by Sunil et al. to synthesize n-HAp-reinforced Mg compos- β-TCP (Ca3 (PO4 )2 ) is another calcium phosphate used in
ite Mg–nHAp. The applied method refined grain size from bone substitution. Compared to HAp, it is bioresorbable in
1500 μm to as low as 3.5 μm. Addition of nHA and the re- biological environment and it shows osteoinductive proper-
fined grain size improved biomineralization in SBF. Cytotox- ties. Despite the rapid dissolution of β -TCP and Mg, their
icity study indicated only a marginal increase in cell viability composites revealed favorable degradation rates. He et al.
added β-TCP particles into Mg–Zn–Zr alloy to improve its cytotoxicity evaluation showed Mg/10HAp composite extrac-
microstructure and properties through hot extrusion process. tion medium did not induce toxicity to L-929 cells [169].
Mg–Zn–Zr/β-TCP composite grains were considerably re- Composites of Mg with silica and silicate materials also
fined. Addition of β-TCP as well as the obtained fine grain exhibited enhanced mechanical properties and bioactivity as
size enhanced the UTS and the elongation of the composite. well as reduced degradation rate. A semi-solid high pres-
The corrosion resistance of the composites was considerably sure casting process was applied by Huan et al., for the
improved compared to that of Mg–Zn–Zr alloy [165]. Suction first time, to incorporate bioactive glass (BG, 45S5) parti-
casting method was employed by Wang et al. to fabricate β- cles into Mg alloy (ZK30). The bioactive glass particles were
TCP/Mg–Zn–Mn composite through infiltrating Mg–Zn–Mn observed to distribute uniformly in ZK30 matrix. Compared
alloy into porous β-TCP. A compact structure and a good in- to the ZK30 alloy, the composites had an improved ability to
terfacial bonding between Mg–Zn–Mn alloy and β-TCP scaf- induce the formation of a bone-like apatite layer on the sur-
fold were obtained. An UTS of 140 ± 20 MPa similar to the face, indicating an enhanced surface biocompatibility [170].
bone and 1000-fold higher than porous β-TCP scaffold was The composite showed a lower rate of degradation and hy-
attained. The composite possessed an improved corrosion re- drogen evolution than the matrix alloy. In vitro cytotoxicity
sistance compared to the Mg–Zn–Mn alloy. The corrosion evaluation of the composite revealed ionic products of degra-
products (Mg(OH)2 , Ca3 (PO4 )2 and HAp) on the composite dation have superior ability to support the survival, prolifera-
surface were desirable compounds for bone growth [166]. tion, and osteoblastic differentiation of bone marrow stromal
A β-TCP /Mg–Zn composite was fabricated by Yu et al. cells to those of the ZK30 alloy [171].
using PM. The density and elastic modulus of the β-TCP A bioceramic-based composite was fabricated by mix-
/Mg–6%Zn composite matched well with those of natural ing HAp and bioactive glass (64SiO2 –26CaO–5MgO–5ZnO
bone, and the strength was approximately double that of nat- (based on mol%)) powders through sintering method. Main-
ural bone. 10% β-TCP/Mg–Zn exhibited a favorable corro- taining the sample for 14 days in SBF decreased its com-
sion resistance and the in vitro cytotoxicity evaluation re- pressive strength by 65%. In addition to its cytocompatibility
vealed a cytotoxicity grade of 0–1 against L929 cells meaning confirmed through in vitro biological evaluation, significant
the composite is safe for cellular applications. β-TCP/Mg– release of silicon ions in SBF was interpreted as the sign
Zn composite also exhibited a good biocompatibility with of osteoinductivity [172]. In another study, an MMC made
the tissue and visceral organs. The composite was found to up of pure Mg as the matrix and bioceramic calcium silicate
have a proper degradation rate and improved healing of a (CS) as the reinforcement was synthesized by Huan et al.
pre-broken leg. The corrosion products were Mg(OH)2 and using SPS method. The addition of calcium silicate particles
Ca5 (PO4 )6 (OH)2 which are known to advance the biocompat- improved the compressive strength of Mg matrix by 30%. Im-
ibility [167]. Yu et al. also fabricated Mg–6%Zn–15% β-TCP mersion test in SBF showed that the corrosion resistance of
composite again through PM and investigated its biocompat- Mg was improved owing to the accelerated precipitation of
ibility and biodegradation in vivo. The composite was im- HAp on the composite surface. Release of Si ions from the
planted to the pre-broken femoral shaft of a rabbit model. calcium silicate phase enhanced the ability of the composite
Throughout the experiment Mg2+ , Zn2+ , Ca2+ ion concentra- to stimulate the ALP expression of osteoblast-like cells com-
tions were in the normal range in animal’s blood. Inspections pared to pure Mg [173]. An Mg matrix composite reinforced
of the visceral organs during composite degradation showed by bredigite was developed by Dezfuli et al. A 67% higher
no anomaly signifying good biocompatibility. Biodegradation ultimate compressive strength and an improved ductility by
of the composites induced growth of the bone tissues [168]. 111% were achieved through incorporating 20 vol% bredig-
The results of these studies suggested that owing to its good ite particles in Mg matrix. The in vitro degradation rate of
biocompatibility and suitable biodegradation characteristics, the Mg-20% bredigite composite was observed as 24 times
the optimum composition of the Mg–Ca3 (PO4 )2 composite lower than that of monolithic Mg. Therefore, after 12 days of
could be a good candidate for implant materials. immersion in the cell culture medium, the mechanical proper-
An ideal biodegradable material should gradually dissolve ties of the composite were still comparable to those of cortical
concurrently with the process of newly forming bone. Bipha- bone [174].
sic calcium phosphate (BCP) can be a promising choice which Many researches were performed to investigate the Mg
is a biomaterial comprising different proportions of HAp and composites reinforced by MAX phases. The “MAX phases”
β-TCP. An appropriate proportion can allow obtaining desir- are applied to a family of more than 60 ternary nitrides and
able degradation rates. Despite excellent biocompatibility and carbides that share a layered structure. The term “MAX” rep-
degradation rates, BCP lacks required mechanical strength resents the formula Mn +1 AXn , where n = 1, 2, or 3, M is
[150]. The strength of bicalcium phosphate (BCP) scaffold an early transition metal, A is an A-group element (specifi-
was enhanced as much as 200-fold, corresponding to the cally, the subset of elements 13–16) and X is carbon and/or
half of the strength of bulk MgCa alloy, by forming MgCa- nitrogen. The Mn +1 AXn layers are characterized by strong co-
HAp/TCP composite through incorporation of MgCa alloy. valent M–X bonds interleaved with A layers through weaker
Slower corrosion rate was obtained with MgCa-HAp/TCP M–A bonds. This inherent nano-layered structure provides a
composite compared to the bulk MgCa alloy. In addition, the unique combination of metal-like and ceramic-like properties
[175]. They are elastically rigid (Young’s moduli > 300 GPa)
with low density (4 g/cm3 ), chemically inert, good thermal and Alloying of Mg, and forming of Mg composites with ce-
electrical conductors, and have relatively low thermal expan- ramics and polymers by using several synthesis methods have
sion coefficient. They are relatively soft and most are read- been studied to enhance the mechanical properties and cor-
ily machinable, resistant to fatigue and thermal shock [176]. rosion resistance of Mg. Mg has been alloyed with different
Yu et al. [175] fabricated Ti2AlC-reinforced AZ91D com- metals at different concentrations. Researchers have reported
posites by stir casting method. After reinforcement, higher that there are certain concentration limits for the alloying el-
values of YS, UCS and Young’s moduli were obtained and ements, above which they are toxic to the biological environ-
these values increased with increasing Ti2AlC volume frac- ment and they can adversely affect mechanical properties of
tion. The Amini and Barsaum [175] achieved a very high UCS the materials.
value of 800 MPa with MAX phase reinforced Mg composites Low ductility of Mg is the limitation since usually the
(Mg/Ti2AlC 50:50 vol%) made through hot pressing. Despite surgeon needs to bend the fixture to fit it to the hard tis-
many potential advantages of MAX phases reinforced Mg ma- sue properly. In addition, the stent material should be ductile
trix composites, to the best of authors’ knowledge, there is enough to allow forming of complex structure. Researchers
no published work in the literature which investigate their have identified alloying elements that improve the ductility of
application in biomedical field. Thus, this field requires fur- Mg without having a significant effect on mechanical strength.
ther studies including synthesis and characterization of MAX Synthesis processes and degradation behavior of Mg-based
phases-reinforced Mg matrix composites for their biocompat- biomaterials have been studied in silico. The developed mod-
ibility and biodegradation performance. els allow to improve implant and stent design by optimizing
In the above discussed literature several ceramic reinforce- the process parameters. The models also accurately predict
ment phases with different methods of production have been the degradation rate of biomaterials and their interaction with
proposed for synthesis of Mg matrix composites in order to surrounding tissues.
achieve the required enhancements in Mg-based implant mate- Enhanced corrosion resistance, biocompatibility and me-
rials. These composites have exhibited characteristics of high chanical properties have been attained by the composites of
strength, low corrosion rate and enhanced bioactivity com- Mg and Mg alloys. The corrosion resistance of Mg improves
pared to that of available Mg alloys, making them promising when it forms composites with polymer matrix. Also, Mg re-
candidates to be used as biomaterials. inforcement enhances the poor mechanical properties of poly-
mers. However, mechanical properties of the resultant com-
7. Summary, conclusions and recommendations posites are insufficient for hard tissue applications. On the
other hand, several ceramic reinforcement phases with differ-
The present paper is a comprehensive, comparative and ent methods of production have been proposed for synthesis
critical review of the recent literature on synthesis and perfor- of Mg matrix composites in order to achieve the required en-
mance evaluation of various types of Mg-based biomaterials. hancements in Mg-based biomaterials. These composites have
Mg degrades in physiological environment without dissipat- exhibited characteristics of high strength, low corrosion rate
ing any toxicity. Therefore, it eliminates the need of a sec- and enhanced bioactivity compared to that of available Mg
ondary surgical operation for implant removal provided that alloys, making them promising candidates to be used as bio-
its degradation rate is harmonized with the tissue healing rate. materials. Knowing the potential advantages of MAX Phases
Several synthesis methods have been implemented to synthe- reinforced Mg matrix composites, they should be investigated
size Mg-based biomaterials with different type of material for biomedical applications.
components. The main target was to achieve a controllable Previous investigations proved that the main drawback of
degradation. In this regard, after synthesis, in vitro and in pure Mg and its alloys is corrosion rate and unpredictable be-
vivo studies have been conducted. In addition, performances havior in body fluid. In vivo tests are a must for further un-
of the materials and synthesis processes have been evaluated derstanding of their behavior in a living system. A systematic
through computational studies. and comprehensive approach to achieve well-controlled and
Among the available synthesis methods, PM appears as durable material properties is needed to compensate unpre-
the most favorable method. It could produce interconnected dictable nature of living systems. Also, the morphology and
porous microstructures with desired pore size and distribution hierarchical structure of bone should be taken into account in
which is essential for an enhanced biological interaction of design of implants to improve bone and implant integrity. As
the materials and implanted environment. PM also produces explained above, surface roughness is one of the most sig-
finer grain size and suppresses the formation of secondary nificant factors in cell attachment and corrosion rate of Mg
phase during synthesis. Besides, it is required to optimize and its alloys. However, there is not sufficient number of in-
the PM process parameters to synthesize biomaterials with vestigations on it. Thus, the effect of surface roughness on
desired characteristics. corrosion behavior should be comprehensively investigated in
Beside the microstructure, the role of materials surface silico, in vitro and in vivo conditions. Furthermore, the ef-
characteristics is vital for biocompatibility. Textured surfaces fect of surface morphology and porosity on degradation rate
improve the cell attachment and proliferation. Thus, mim- of Mg implants in living systems has not been completely
icking the natural bone surface with both nano- and micro- investigated. Also, the manufacturing method plays impor-
textures is suggested to promote osteointegration. tant role in final properties of Mg-based implant. There is a
need to select a method to achieve desirable surface rough- [28] X. Li, X. Liu, S. Wu, K.W.K. Yeung, Y. Zheng, P.K. Chu, Acta Bio-
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Review of Magnesium-Based Biomaterials and Their Applications

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Journal of Magnesium and Alloys 6 (2018) 23–43

Keywords: Mg-based biomaterials; Mechanical properties; Implant; Biomedical applications; Biodegradation.

4.5. Biological properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Material Info Reference

Tensile strength Yield strength Elongation Young’s Compression Bending

cytotoxic effect in human body due to osmotic shock effect

5.2. Degradation behavior 5.2.2. Degradation behavior of stents

to analyze the corrosion in complex 3D geometries, a phe- 6.1. Mg-polymer composites

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