Review Chiu, Y.; et al.

Biodegradable magnesium alloys for

orthopaedic applications
Yu Lu1, Subodh Deshmukh2, Ian Jones1, Yu-Lung Chiu1,*

Key Words:
biodegradability; magnesium alloys; mechanical behaviour; microstructure; orthopaedic application

From the Contents

ABSTRACT
Introduction 214 There is increasing interest in the development of bone repair materials
The Role of Magnesium in the 219 for biomedical applications. Magnesium (Mg)-based alloys have a natural
Human Body ability to biodegrade because they corrode in aqueous media; they are thus
Performance Testing 225 promising materials for orthopaedic device applications in that the need for
a secondary surgical operation to remove the implant can be eliminated.
Future Perspectives 227 Notably, Mg has superior biocompatibility because Mg is found in the human
body in abundance. Moreover, Mg alloys have a low elastic modulus, close
to that of natural bone, which limits stress shielding. However, there are
still some challenges for Mg-based fracture fixation. The degradation of Mg
alloys in biological fluids can be too rapid, resulting in a loss of mechanical
integrity before complete healing of the bone fracture. In order to achieve an
appropriate combination of bio-corrosion and mechanical performance, the
microstructure needs to be tailored properly by appropriate alloy design, as
well as the use of strengthening processes and manufacturing techniques.
This review covers the evolution, current strategies and future perspectives of
Mg-based orthopaedic implants.

*Corresponding author:
Yu-Lung Chiu,
Introduction fulfilling the mission of assisting with tissue
[email protected]. A biomaterial is defined as a material intended healing while leaving no implant residues.3 The
to interface with biological systems to evaluate, materials should be non-toxic or made up of
http://doi.org/10.12336/
biomatertransl.2021.03.005 treat, augment or replace any tissue, organ or metallic elements which can be metabolised by
How to cite this article: function of the body.1, 2 Commonly, pacemakers, the human body. Therefore, magnesium (Mg)-
Lu, Y.; Deshmukh, S.; stents, sutures, bone plates and screws, based biodegradable alloys are a promising
Jones, I.; Chiu, Y. material for clinical applications.
Biodegradable magnesium
needles, knee joints and catheters all constitute
alloys for orthopaedic biomaterials. Biomaterials are used across a wide Extensive research so far suggests a bright
applications. Biomater Transl. range of applications and have become a major future for biodegradable Mg-based orthopaedic
2021, 2(3), 214-235.
industry in the 21st century. The traditional implants. However, new fabrication approaches,
metallic biomaterial requires that metals are updated design strategies and enhanced clinical
as inert as possible in order to minimise the requirements are emerging. Thus, up-to-date
immune response and reduce the corrosion of the progress and development of biodegradable
material itself in the physiological environment Mg alloys over recent decades are presented in
of the body. Typically, these biomaterials this review paper by searching google scholar.
are stainless steels, titanium (Ti) alloys and Firstly, we summarise orthopaedic applications
cobalt–chrome-based alloys. After decades and principles, traditional implant components
of developing improved corrosion-resistant (especially Ti), potential use of Mg in real
metallic biomaterials, the design and application clinical applications, degradation mechanisms
of biodegradable metals are currently under the and role of Mg in the human body. Monolithic
spotlight. A biodegradable material is expected Mg alloy components are comprehensively
to degrade gradually in vivo, with an appropriate discussed focusing on the effects of alloying
host response elicited by released corrosion elements, microstructural evolution (grain size,
products, and then to dissolve completely upon second phases, twins, texture, dislocations etc.),

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Biodegradable magnesium for orthopaedic application Biomaterials Translational

mechanical and bio-corrosion performance testing, in vitro and necessary to fix the bone when a fracture occurs. Orthopaedic
in vivo evaluation and biocompatibility assessment. Moreover, implants are medical devices which can be used to replace or
recent novel structural developments are indicated, including provide fixation of bone, or replace the articulating surfaces of
Mg-based bulk metallic glasses (BMGs), Mg metal matrix a joint. Typically, orthopaedic implants include plates, nails and
composites (MMCs) and porous structure. The fabrication screws. Fracture fixation is used to reduce interfragmentary
methods, mechanical properties, biodegradation performance, movement.
and in vitro and in vivo behaviours of these Mg materials There are several types of plates: compression plates, buttress
are introduced. Finally, this review discusses the future plates, neutralisation plates and bridging plates. Compression
perspectives and challenges for designing the next generation plates are used to bring the two fracture ends of the bones close
of biodegradable Mg-based alloys for orthopaedic applications. to each other and provide sufficient stability using dynamic
The smart tailoring of alloys, novel manufacturing techniques pressure between the fragments, which promotes bone
and relatively innovative three-dimensional model design, healing. Buttress plates are especially used around joints (such
mathematical modelling and effective transformation from as knees and ankles) to hold together fractures at the ends of
designed Mg materials to safe clinical applications are long bones; preventing axial forces from distorting the initial
emphatically proposed for future developments. reduction.7 These plates can be moved with the body because
they are contoured. Neutralisation plates are a category of plate
Design of orthopaedic implants which bridges the fracture and protects the screws or other
Bone is a hard biological tissue formed of cells embedded in a devices from bending and torsional loading.8 Bridging plates
matrix, which consists of an organic (90% collagen and 10% are designed to provide stability when multi-fragmentary
amorphous) ground substance reinforced by a mineral phase. long bone fractures occur; they can offer the correct length
Calcium phosphate (Ca3(PO4)2) and calcium carbonate (CaCO3) and alignment and promote secondary bone healing.8 This
are the main constituents of bone mineral. Bone serves as a is because they preserve the blood supply to the fragments
protector for organs and provides mechanical stability to the without disrupting the damaged area.
body, making movement possible. There are two types of The principle of meticulous anatomical reduction of each
bone, cortical (compact or Haversian) and cancellous (spongy fracture fragment by direct fracture exposure and subsequent
or trabecular) bone.4, 5 fixation by compression plating, as practised by surgeons
Bone remodelling is a continuous process of bone resorption through the 1980s,9 required extensive soft tissue intervention.
and formation, to provide maximum strength with minimum The application of locking plates coincided with the
mass. Bone has a strong capability to regain its lost strength development of minimally-invasive fracture fixation, which has
through the healing process. However, the internal fixation resulted in important changes in fracture management.6, 10 The
of broken bones only became possible via aseptic techniques most common treatment options for the fixation of fractures
for open fracture reduction and direct fixation with metallic are locking compression plates and interlocking nails, as
hardware.6 Thus, supportive orthopaedic implants are shown in Figure 1.11, 12

A B C D

Figure 1. (A) Locking compression plate. (B) Radiograph of distal tibial fracture treated with a locking plate. Reprinted
from Bastias et al.11 Copyright 2014 European Foot and Ankle Society. (C) Interlocking nail. (D) Radiograph of femoral
fracture treated with locking nail. Reprinted from Hsu et al.12 Copyright 2019, with permission from Elsevier.

1 School of Metallurgy and Materials, University of Birmingham, Birmingham, UK; 2 Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK

Biomater Transl. 2021, 2(3), 214-235 215

 Review Chiu, Y.; et al.

The principles of locking compression plates, nails and screws the bones. Lag screws are used to achieve interfragmentary
are illustrated in Figure 2.8 A locking plate provides fixation compression, which protects the fractured bone from bending,
with absolute stability for two-part fracture patterns, where being rotated and from trivial loading forces. The interlocking
the bone fragments can be compressed.13 Furthermore, the nail is basically an intramedullary pin, providing absolute
addition of an orthopaedic screw across the fracture and stability to maintain alignment and position, including the
through the plate enhances the stability. Orthopaedic screws prevention of rotation.14 The mechanical properties of an
are used to tighten up damaged areas, which are one of the implant significantly affect the stability of fracture fixation
tenets of orthopaedic fixation. They reduce the gap between provided by orthopaedic implants/devices.

A B

Figure 2. (A–C) Principles of locking compression plate (A), intramedullary nailing (B), and screw (C).8

Common metallic alloys for orthopaedic application femoral hip stems. Ti alloys have excellent corrosion resistance,
Ti, stainless steel and cobalt–chromium (Co-Cr) alloys have good biocompatibility and high mechanical strength, but poor
been employed as permanent implants. Stainless steel and Co- wear resistance, poor bending ductility and come at a high
Cr alloys are the first generation of inert metallic implants. cost.15 The objective of orthopaedic implants is to produce
Stainless steel has been used to manufacture bone plates,
absolute stability, abolishing all interfragmentary motion. The
screws and pins, which have excellent mechanical properties
but high modulus and poor wear resistance. Co-Cr alloys have implant material must have adequate mechanical properties.
good mechanical properties and superior corrosion resistance, The mechanical performance characteristics of unalloyed Ti,
but high modulus and are difficult to machine. Ti alloys are stainless steel and Co-Cr alloys for surgical implant applications
‘second generation’ and are used for fracture fixation and are listed in Table 1.16-18

Table 1. Mechanical performance of commercial pure (CP) titanium, stainless steel and cobalt–chromium alloys for
surgical implant application.
Yield strength (MPa) Ultimate tensile strength (MPa) Elongation (%)
CP Ti
Grade 1 170 240 24
Grade 2 275 345 20
Grade 3 380 450 18
Grade 4 483 550 15
Stainless steel
18Cr-14Ni-2.5Mo
Annealed 190 490 40
Cold-worked 690 860 12
Co-28Cr-6Mo
Annealed 517 897 20
Hot-worked 700 1000 12
Note: Superscript a indicates a different grade of CP Ti which often means a different oxygen content. Data are from ASTM
International.16-18

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Biodegradable magnesium for orthopaedic application Biomaterials Translational

Bone is a living tissue which undergoes constant remodelling Possible use of magnesium in surgical applications
under imposed stress. If the load supported by the implant is A more promising material for use in orthopaedic
too large, the bone beneath will bear a reduced load and will application is required and one example is biodegradable Mg
become less dense and weaker because the stimulation and alloys. Natural cortical bones have a volume density ranging
continual remodelling which maintain bone mass are absent or from 1.0 g/cm3 to 2.1 g/cm3 and an elastic modulus ranging
reduced, leading to the so-called stress-shielding phenomenon. from 3.0 GPa to 20.0 GPa.27 Mg has a very low density of
Although Ti alloy plates (e.g. Ti–6Al–4V, CP Ti) provide less 1.74–2.0 g/cm3, which is significantly lower than that of
stress-shielding than stainless steel (e.g. 316L)19 because of Ti alloys (~4.5 g/cm3) and stainless steel (~8 g/cm3).28 Mg
their lower moduli,20, 21 the moduli are still much higher than alloys have a relatively low elastic modulus of 41–45 GPa,
that of human cortical bone (around 20 GPa).22 Thus, the stress compared with other traditional biomaterials (Ti-6Al-4V
shielding effect caused by the mismatch in the elastic modulus alloys: 110–117 GPa; 316L stainless steel: 205–210 GPa;
between human bone and Ti implants is still an issue. Co-Cr alloys: 230 GPa).29 A comparison of Mg alloys and
To address this problem, alloys such as Co-Cr-Mo and Ti-6Al- natural bones is shown in Table 2.27, 30, 31 Mg2+ is the fourth
4V have been manufactured as a scaffold to reduce the modulus most abundant cation in the human body and is an essential
mismatch with natural bone.23 Conventionally-sintered element for the human body (the daily intake of Mg2+
metals, however, are often very brittle. Other fabrication for a normal adult is about 300–400 mg).32-34 It has been
techniques (such as foaming agents or molten metal) also have reported that moderate Mg2+ ion supplementation released
some drawbacks, such as contamination, impurity phases, directly from the prosthesis itself will bring significant
limited control of size and shape, and distribution of porosity.24 benefits after implant surgery, diminishing the chance of
Noticeably, mechanical wear and corrosion are associated with infection.35 A number of in vivo and in vitro experiments
a long period of implantation in the body, which results in have shown that Mg alloys have good biocompatibility.36-38
the release of some toxic ions (Cr, Ni, Co, etc.) and triggers The chief attraction of Mg alloys as orthopaedic materials,
undesirable immune responses, consequently reducing the however, is biodegradability. Mg alloys can be biodegraded
implant’s biocompatibility.25 Moreover, difficulty in removing in the human body, which can eliminate the need for a
locking head screws made of Ti has been reported:26 the screws second round of surgery for implant removal. Some in
cannot be removed with a normal screw driver and purpose- vivo studies have confirmed that the degradation of Mg is
built devices are required. harmless.37, 39, 40

Table 2. Summary of the physical and mechanical properties of magnesium alloys in comparison with human bone.
Density (g/cm3) Elastic modulus Tensile strength Fracture toughness Total elongation (%)
(GPa) (MPa) (MPa1/2)
Cortical bone 1.8–2.1 3–20 35–283 3–6 1.07–2.10
Cancellous bone 1.0–1.4 NA 1.5–38 NA NA
Magnesium alloys 1.74–2.0 41–45 150–400 15–40 2–20
Note: Different values are due to differences in ethnicity, age, testing conditions, etc. NA: not applicable. Data are from Maehara et al.26-28

In order to replace permanent metallic implants for requires sufficient ductility.43 Materials with higher elastic
orthopaedic applications, Mg alloys need to target both modulus can absorb more energy and hold their shape better,
mechanical requirements and an appropriate degradation and are therefore less likely to ‘cut’ into the bone.44 In addition,
rate. Figure 3 shows a schematic of the optimal relationship although fast corrosion kinetics can be generally beneficial in
between provision of mechanical support and biodegradation biodegradable alloys, there is a balance to be struck and Mg
behaviour. Initially, it is essential that the implants are strong alloys can have a significant problem if the corrosion rate is
enough to provide sustained fixation, support the injury and too high. Current Mg alloys degrade too quickly in the human
carry the load to give adequate time for the damaged bone body and lose function before the tissue heals.
tissues to heal. The implant should gradually and slowly
degrade and transfer the load to the bone over time.41 Before Magnesium biodegradation in the physiological
the injury heals, the implant has constantly to sustain the environment
injury and provide mechanical support until the tissue regains The corrosion of Mg in the aqueous environment is
sufficient mechanical strength. A period of 3–4 months is an electrochemical phenomenon. The electrochemical
generally required for new bone formation and recovery of degradation mechanism of Mg in aqueous solution can be
most of the bone’s original strength.42 The different healing described as follows and produces Mg hydroxide (Mg(OH)2)
periods relate to the different ages of the patients. and hydrogen gas (H2):
For load-bearing applications, the implant material has to Anodic reaction/dissolution: Mg→Mg2++2e– (1)
have suitable mechanical properties to withstand various Cathodic reaction: 2H2O+2e–→2OH–+H2 (2)
biomechanical forces. The mechanical properties of interest Hydrolysis: Mg+H2O→MgOH++H+ (3)
for the implant are elastic modulus, yield strength, ultimate Product formation: Mg2++2OH–→Mg(OH)2 (4)
tensile strength and ductility. To bend fixtures to fit properly Obviously, the hydrolysis reaction consumes H2O and

Biomater Transl. 2021, 2(3), 214-235 217

 Review Chiu, Y.; et al.

Bone fracture Implantation Implant degradation Heal

Small←Mechanical properties→Large

Large←Degradation rate→Small
Implantation time
Increase

Figure 3. Optimal degradation behaviour of a magnesium-based implant in bone fracture healing. The blue and yellow
lines indicate the mechanical integrity and biodegradation rate, respectively.

produces H+, and thus reduces the pH value in the solution. The processes of equations (1–4) are vividly demonstrated
The precipitation of Mg(OH)2 and stabilisation of the passive in Figure 4A. The dissolution of Mg and the formation
film tend to occur because of pH increases due to the cathodic of hydrogen and Mg hydroxide are the main features. The
reaction. Alkalisation of the solution occurs over time, which aggressive ion Cl– reacts with Mg(OH)2 and forms more soluble
is caused by the cathodic reaction and the balance between the MgCl2 (equation (5)).
anodic and cathodic reactions. Each Mg2+ formed produces Mg(OH)2+2Cl–→MgCl2+2OH– (5)
two OH– and generates one H+. Therefore, the overall reaction Further corrosion of Mg is promoted by the dissolution of
results in a pH increase, which must be paid attention to when Mg(OH)2 due to the disappearance of the protected areas.46 Cl–
monitoring the biodegradation rate. Figure 4 illustrates the catalyses the dissolution of Mg and directly produces MgCl2,
corrosion mechanism of Mg in an aqueous environment.45 exposing the bare Mg to the solution47, 48 (Figure 4B).

A H2 B Cl– Cl–
2H2O+2e–→2OH–+H2
Mg(OH)2+2Cl–→MgCl2+2OH– Mg2++2Cl–→MgCl2
Mg(OH)2

Mg2++H2O+2e–↔MgOH++H+
Intermetallic
particle

Mg(OH)2 Mg→Mg2++2e–
Mg→Mg2++2e–

Magnesium alloy substrate Magnesium alloy substrate

Figure 4. Schematic illustration of the corrosion of magnesium in an aqueous environment:45 (A) The dissolution of
magnesium via the anodic reaction. The cathodic reaction increases the pH and produces H2, while hydrolysis reduces
the pH. Intermetallic particles act as cathodic sites and consume the electrons produced by the anodic reaction. (B)
Chloride ions in the solution attack and dissolve the Mg(OH)2 film.

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Biodegradable magnesium for orthopaedic application Biomaterials Translational

Following the reaction of Mg in the physiological cells through the enhancement of bone morphogenetic
environment, it must be mentioned that hydrogen evolves protein receptor recognition and Smad signalling pathways.55
during the reaction according to the cathodic reaction. Gas The mitogen-activated protein kinase/extracellular signal-
cavities composed of generated hydrogen have been observed regulated kinase pathway is one of the signalling pathways
around Mg alloy implants because of insufficient diffusion.49 which controls the osteogenic differentiation of stem cells, and
The formation of these gas pockets happens during the early Mg2+ can selectively activate the mitogen-activated protein
implantation stage (7–30 days); the gas is then gradually kinase/extracellular signal-regulated kinase pathway.56 The
absorbed by the surrounding tissue.50 It has been reported biphasic mode of Mg2+ in bone repair has been recently reported
that gas formation does not have any negative effects on bone by Qiao et al.57 Mg-induced osteogenesis has been observed,
healing.51 However, the rapid corrosion of Mg causes the quick suggesting the therapeutic potential of Mg2+ in orthopaedics.58-60
formation of gas cavities and subcutaneous bubbles, which In addition, Mg2+ ions affect the seeded calcium phosphate
may reduce its mechanical strength. Thus, in order to slow crystallisation rate and subsequent hydroxyapatite growth.61
hydrogen generation, the degradation rate of Mg-based alloys The total body stores of Mg are between 21 g and 28 g in the
must be carefully controlled. average 70 kg adult. Normal serum usually has a Mg range
of 1.7 mg/dL to 2.5 mg/dL. Most of the body’s Mg is in the
skeletal bone mass, which accounts for more than 50% of the
The Role of Magnesium in the Human Body body’s stores. The remainder is located in soft tissues, of which
Mg is a nutrient that the body needs to stay healthy and is only 0.3% is located extracellularly. Of the total Mg consumed,
important for many processes. Mg is primarily found within approximately 30% to 50% is absorbed.62 Too much Mg from
the cells and is a cofactor in more than 300 enzymatic reactions, food does not pose a health risk because the kidneys eliminate
which are essential for the human body.52 The presence of Mg excess amounts via the urine.63 However, a very high dose of
is vital for transmission and storage of energy to be used by Mg via, for example, dietary supplements or medications can
cells.53 It also has a central role in cell growth and the structure result in diarrhoea that can be accompanied by nausea and
and permeability of their membranes.52, 54 It has been reported abdominal cramping.64 The daily intake allowances of Mg are
that Mg2+ ions are able to aid the growth of bone marrow summarised in Table 3.65

Table 3. Intake allowances for magnesium.

Recommended dietary allowances for Tolerable upper intake levels for supplemental
magnesium (mg) magnesium (mg)
Age (year) Male Female Male Female
19–30 400 310 350 350
31–50 420 320 350 350
51 or more 420 320 350 350
Note: Data are from Office of Dietary Supplements, National Institutes of Health.
65

Application of magnesium-based alloys in orthopaedic to the biomedical field, the alloys should also be designed
applications with nutriology and toxicology in mind, to give a superior
In the past, a number of investigations have been carried balanced performance. The alloying design, element selection,
out on potential Mg-based implants for use in orthopaedic processing history and heat treatments significantly affect the
applications. Windhagen et al.66 reported that compression microstructure and lead to different mechanical and corrosion
screws made of MgYREZr alloy showed good biocompatibility behaviours.
and osteoconductive properties. Cortical bone screws
machined from AZ31 (Mg-3Al-1Zn) alloy have been implanted Alloying elements
into hip bone,67 while intramedullary nails made of LAE442 Suitable alloying elements need to be tailored to design and
(Mg-4Li-4Al-2RE) have been implanted into the marrow improve the mechanical and bio-corrosion properties of
cavity of tibiae.68 However, very few monolithic Mg-based biomedical Mg alloys. Table 4 shows a brief summary of the
components are used in load-bearing applications (such as various alloying elements used in Mg biomaterials.3, 38, 69-85
compression plates, bridging plates etc.) because of their too- Alloying elements can strengthen the Mg alloys by solid
rapid biodegradation rate. Thus biodegradable Mg implants solution strengthening, precipitation hardening and grain
need to be further explored. Moreover, Mg-based bioceramics, refinement strengthening. These alloying elements must
bioglasses, biocomposites and 3D-printed scaffolds need to be have high and temperature-dependent solubility in Mg.
carefully designed. High solubility of an alloying element can lead to significant
precipitation hardening of Mg alloys, such as Mg-Al alloys, Mg-
Design strategies for biodegradable magnesium alloys Zn alloys and Mg-rare earth (RE) alloys. Both solid solution
Biodegradable Mg alloys require suitable mechanical and strengthening and precipitation strengthening improve the
biodegradation performance in a physiological environment strength, but generally cause deterioration in the ductility of
and, most importantly, biosafety with regard to the human Mg alloys. However, grain refinement strengthening improves
body. Rather than simply applying commercial Mg alloys both strength and ductility. It is widely acknowledged that

Biomater Transl. 2021, 2(3), 214-235 219

 Review Chiu, Y.; et al.

Table 4. The physical properties and influence of alloying elements on properties and biological impact of
magnesium-based alloys.
Element Solubility Growth Effects on Effects on corrosion Biological impact Maximum
limits restriction mechanical behaviour daily
(wt%) factor properties allowable
dose (mg)
Aluminium 12.7 4.32 Improves strength Decreases corrosion Neurotoxic; 14
(Al) and ductility rate Decreases osteoclast viability
Grain refinement
Increases
castability
Calcium 1.34 11.94 Improves strength Decreases corrosion Most abundant mineral in the 1400
(Ca) Grain refinement resistance human body;
Increases Is tightly regulated by
castability homeostasis
Zinc (Zn) 6.2 5.31 Improves strength Essential trace element 15
Reduces ductility (immune system, co-factor);
at high Neurotoxic at higher
concentration concentration
Manganese 2.2 0.15 Improves strength Decreases corrosion Essential trace element; 5
(Mn) and ductility rate by removing iron Important role in metabolic
Grain refinement and other heavy metal cycle and for the immune
elements into relatively system;
harmless compounds Neurotoxic at higher
concentration
Lithium (Li) 5.5 Reduces strength Reduces corrosion Possible teratogenic effects
Improves ductility resistance
Zirconium 3.8 38.29 Improves strength
(Zr) and ductility
Grain refinement
Silicon (Si) ~0 9.25 Reduces ductility Reduces corrosion Essential mineral in human
and castability resistance body
Helps to build the immune
system
Strontium 0.11 3.51 Improves strength Deceases corrosion rate Trace element in human 5
(Sr) and ductility; body;
Grain refinement Stimulates bone formation
Yttrium (Y) 12.4 1.7 Improves strength Same standard May exhibit anti-carcinogenic 0.016a
electrochemical properties
potential as Mg;
Decreases corrosion
rate by purifying the
alloy and forming a
passive film
Neodymium 3.6 Improves strength Decreases corrosion May exhibit anti-carcinogenic 4.2a
(Nd) rate by creating less properties
noble intermetallic
phase (‘scavenger effect’
on impurities)
Copper Increases strength Causes hypotension, jaundice,
(Cu) etc.
Note: Superscript a indicates that the total amount of rare earth elements (Ce, La, Nd, Pr, Y) should not exceed 4.2 mg/day. Data are
from Zheng et al.3, 38, 69-85

the refinement efficiency of the alloying elements can be segregate strongly in the melt and cause intense constitutional
determined by their growth restriction factor.86-88 The growth supercooling in a diffusion layer ahead of the advancing
restriction factor is a measure of the segregation power of an solid/liquid interface, consequently promoting nucleation
element during solidification. It is calculated from binary phase and restricting grain growth. Therefore, these elements can
diagrams and equals ΣimiC0,i (ki–1), where mi is the slope of the significantly refine the grains, which benefits both strength
liquidus line (assumed to be straight), ki is the distribution and ductility.
coefficient and C0,i is the initial concentration of element i.89 If The second aspect to be considered is the effects of alloying
an element has a large growth restriction factor (such as Zr, Ca, elements on the bio-corrosion behaviour. The addition of
Zn) this means that the growth-restricting effect on the solid- some alloying elements can improve corrosion resistance
liquid interface of the new grains is strong, thus preventing by reacting with impurities. For example, Mn and Zn can
new grains from growing into the melt.90 These elements overcome the harmful corrosion effects of impurities (such

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Biodegradable magnesium for orthopaedic application Biomaterials Translational

as Fe and Ni) by transforming impurities into harmless elements (Ce, La, Nd, Pr, Y) should be carefully controlled
intermetallic compounds.91 Alloying Mg with Y can enhance (below 4.2 mg/day).
the corrosion resistance, because of the formation of a stable Commercially-available Mg alloys can be divided into four
and less chemically-reactive hydroxide protective film.75, 92 major groups: 1) Al-containing Mg alloys, such as AZ31 (Mg-
Moreover, alloying elements which form secondary phases 3Al-1Zn),94 AZ61 (Mg-6Al-1Zn), AZ91 (Mg-9Al-1Zn) and
with a similar corrosion potential (Ecorr) can reduce internal AM60 (Mg-6Al-0.3Mn); 2) Al-free Mg alloys, such as ZK30
galvanic corrosion. (Mg-3Zn-0.6Zr),95 ZK60 (Mg-3Zn-0.6Zr) and Mg-Mn-Zn;96 3) RE-
The third consideration is the biocompatibility of alloying containing alloys, such as WE43 (Mg-4Y-3RE-0.5Zr),94, 97 LAE442
elements. The released metallic ions resulting from the (Mg-4Li-4Al-2RE), WZ21 (Mg-2Y-1Zn)98 and Mg-Y;38, 99 and
degradation of Mg alloys need to be non-toxic or to be tolerated 4) nutrient element-containing alloys, such as Mg-Zn,100-102
at low concentrations, below the threshold level. Elements can Mg-Ca,103 Mg-Zn-Ca,45, 104, 105 Mg-Si106 and Mg-Sr.107 The
be categorised into different groups: 1) nutrient elements: Ca, large range of mechanical properties of Mg alloys is shown
Zn, Si, Sr; 2) allergic elements (elements likely to cause severe in Figure 5.45, 84 An appropriate amount of Al, Ca and Zn
hepatotoxicity or other allergic problems): Al, Co, V, Cr, Ni, can increase both the strength and ductility concurrently. Zr
Ce, La, Cu, Pr; and 3) toxic elements: Cd, Be, Pb, Ba, Th. It has restricts grain growth and benefits the mechanical properties.
been reported that some RE elements (such as Y, Nd, Ho, Dy Among these Mg-based alloys, Mg-RE-based alloys normally
and Gd) have little influence on cell viability and haemolysis have a superior combined strength and elongation. Mg-Zn
rates, but that other RE elements (such as La, Ce, etc.) need based-alloys are also very promising and exhibit good strength
to be carefully controlled.93 Notably, the total amount of RE and elongation compared with other systems.

A B
Tensile yield strength (MPa)
Tensile strength (MPa)

Elongation (%) Elongation at failure (%)

Figure 5. The tensile strength and elongation of various magnesium alloys. (A) Reprinted from Lu.45 (B) Reprinted from
Chen et al.84 Copyright 2014, with permission from Acta Materialia Inc.

The in vitro and in vivo corrosion rates of Mg-based alloys are reduced corrosion rate.109
shown in Table 5.36, 38, 39, 94, 99, 100, 103, 108-117 The in vivo corrosion In summary, amongst these Mg-based alloys, Mg-Zn-based
rates of Mg-1.2Mn-1Zn,36 Mg-0.8Ca115 and WE43115 alloys alloys are very promising, not only exhibiting good strength
have been reported and compared.118 These alloys have a low and elongation compared with other systems, but also showing
in vivo corrosion rate. Corrosion resistance can be modified
enhanced corrosion resistance. Moreover, Mg-Zn alloys have
by thermal–mechanical processing: for example, as shown
good biocompatibility, because Zn is an essential trace element
in as-cast and as-extruded AZ31 alloy, as-cast and as-rolled
in the human body.
Mg-1Zn, as-cast and as-rolled Mg-1Zr. The Mg-RE-based
alloys generally show good corrosion resistance, especially Mg-Y and Mg-Nd-based alloys normally have an excellent
after thermal–mechanical processing, for example Mg-Nd- combination of strength and elongation, and good corrosion
Zn-Zr, WE43 and Mg-Gd-Zn-Zr alloys (shown in Table 5). resistance. Regarding biosafety, the amount of Y and Nd
Note that Witte et al. have reported that the in vivo (animal should be controlled to be below a threshold level. It is
model) degradation of AZ91D and LAE442 alloys was very generally accepted that the total amount of Nd and Y should
different from the in vitro corrosion.109 The major reason not exceed 4.2 mg/day.83, 84 Assuming that a Mg alloy implant
for the differing corrosion behaviours is the dynamic nature degrades within 3 months, the total released amount of Nd and
of the in vivo environment and the static nature of the in Y needs to be below 380 mg. For example, if the total weight
vitro environment. In addition, the covering of proteins on of an implant is 6.9 g (calculated from the locking compression
implants, the remodelling of bones and possibly a protective plate (LCP3.5-423.621)), then the total wt% of Nd and Y would
corrosion layer in the in vivo environment may lead to a need to be controlled to lie below 5wt%.

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 Review Chiu, Y.; et al.

Table 5. Bio-corrosion properties of magnesium-based alloys.

Alloy Condition In vitro corrosion rate In vivo corrosion rate Reference
(mm/year) (mm/year)
Mg-0.8Ca As-extruded – 0.5 115
Mg-1Ca As-cast – 1.27 103
Mg-1Al As-cast 2.07 – 38
Mg-1Zn As-cast 1.52 – 38
Mg-1Zn As-rolled 0.92 – 38
Mg-1Zr As-cast 2.2 – 38
Mg-1Zr As-rolled 0.91 – 38
Mg-1Sn As-cast 2.45 – 38
Mg-2Sr As-rolled 0.37 1.01 116
Mg-3Zn Solution treated 1.53 – 100
Mg-6Zn As-extruded 0.07 2.32 117
Mg-8Y As-cast 2.17 – 99
AZ31 As-cast 2 1.17 39
AZ31 As-extruded 0.21 – 94
AZ61 As-cast 0.73 – 108
AZ91D As-cast 2.8 1.38 109
WE43 As-cast 0.26 1.56 39, 94
Mg-1.2Mn-1Zn As-cast – 0.45 36
Mg-1Zn-1Ca As-cast 2.13 – 110
Mg-3Zn-0.3Ca Solution treated 0.81 – 111
Mg-6Zn-1Ca As-cast 9.21 – 110
Mg-4Zn-0.5Ca-0.4Mn As-cast 0.25 – 112
Mg-3.09Nd-0.22Zn-0.44Zr As-extruded 0.13 – 94
Mg-2Zn-1.53Y As-extruded 0.7 – 113
Mg-11.3Gd-2.5Zn-0.7Zr As-extruded 0.17 – 114

Microstructure with low to passive corrosion rates and therefore a fine grain
Besides alloying, the microstructure can be further tailored structure is more corrosion resistant. Song and StJohn 126
to meet the requirements of orthopaedic applications by indicated that the skin of the die-cast AZ91D alloy exhibits
adjusting the grain size, second phases and their distribution, better corrosion performance than the interior, because of the
twins, texture etc. Different processing techniques, such as more continuous Mg17Al12 phase formed around finer α-Mg
heat treatment and thermo-mechanical processing, can be grains. If the grains are small and the volume fraction of the
applied to achieve this. Mg17Al12 phase is not too low, then the Mg17Al12 phase forms
continuously like a net, and is difficult to undercut because
Grain size corrosion development cannot easily progress through
The corrosion behaviour of Mg alloys is closely related to their numerous Mg17Al12 precipitates. The Mg17Al12 phase is exposed
grain size. Grain refinement is an effective way to improve the and the α-Mg phase corrodes preferentially. Eventually, the
corrosion performance of Mg alloys.48, 119-122 For example, Lu final surface of the sample has large amounts of Mg17Al12 which
et al.111 found that the bio-corrosion rate of Mg-3Zn-0.3Ca is are more corrosion resistant than the α-Mg phase, thus the
a function of grain size and the volume fraction of secondary corrosion resistance is enhanced.91, 127
phase. Birbilis et al.122 proposed that the corrosion rate increases
as the logarithm of average grain size increases in pure Mg. Second phase
Ralston et al.123 also described a relationship between corrosion Second phases have a significant impact on the performance
rate and grain size: icorr=(A)+(B)·GS–0.5 (where A is a constant of Mg alloys.128, 129 A homogenous microstructure is desirable,
and a function of the environment; B is a material constant because a difference in corrosion potential between the α-Mg
and is determined by the composition and impurity level of and the second phase causes micro-galvanic corrosion. In
the material; GS is grain size and icorr is the corrosion rate). AZ alloys, the Mg17Al12 phase (–1.20 V) is nobler than the
Corrosion resistance can be linearly enhanced by reducing α-Mg matrix (–1.65 V)46 and therefore acts as a cathode and
the grain size. It has been reported that the reason why grain aggravates the corrosion of Mg.91, 130 Some researchers have
refinement causes a decreased corrosion rate is because of the proposed that the Mg17Al12 phase can act as a corrosion barrier
improved passive film.124, 125 A high grain boundary density and have a positive effect on corrosion resistance.128, 129, 131 The
promotes a better oxide film conduction rate on surfaces fraction and distribution of Mg17Al12 phases are important

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Biodegradable magnesium for orthopaedic application Biomaterials Translational

factors in determining which effect dominates. A finely- and Glassy structures

continuously-distributed β-phase serves as a corrosion barrier Mg-based BMGs display a uniform corrosion performance
and inhibits corrosion;119 otherwise, the β-phase promotes due to their single phase structure and chemical homogeneity.
corrosion. Song et al.126 proposed that more continuous second An increased corrosion resistance, uniform corrosion
phases can benefit the corrosion resistance of the Mg-RE-Zr morphology and better cytocompatibility of Mg66Zn30Ca4 BMG
alloy (MEZ alloy). The morphology of the second phase also have been reported by Gu et al.139 The glassy Mg60+xZn35–xCa5
affects the corrosion behaviour of Mg alloys. Srinivasan et al.132 (0 ≤ x ≤ 7) alloys exhibited a distinct reduction in hydrogen
reported that Mg with a coarse Chinese script Mg2Si phase evolution.140 A wide range of in vitro electrochemical corrosion
shows a weaker corrosion performance than that with evenly- rates of BMGs has been shown, for example 11.2 µA/cm2 for
distributed polygonal-shaped Mg2Si phases. The reduction Mg70Zn25Ca5139 and 0.02 µA/cm2 for Mg65Cu20Y10Zn5.141 The
and refinement of Mg2Si phases also lead to better corrosion Mg67Zn28Ca5 BMG shows good tensile strength: 675–894
behaviour of Mg-Si(-Ca) alloys.91 The rod-shaped nano-scale MPa,142 while the Mg66Zn30Ca4 BMG shows good compressive
β’www1 precipitates which form during aging strengthen the strength: 716–854 MPa.140 However, the manufacturability
Mg-3Zn alloy, but decrease its corrosion resistance.101 Mao and application of BMGs is limited by their glass-forming
et al.133 have reported that different thermal–mechanical ability which is very sensitive to the fabrication methods
processing treatments result in differences in mechanical and the purity of the components. Moreover, the brittleness
and bio-corrosion performance. The yield strength (YS), of BMGs needs to be carefully considered: they normally fail
ultimate tensile strength (UTS) and elongation of Mg-3.1Nd- without, or with limited, macro-plasticity. Nevertheless,
0.2Zn-0.4Zr (JDBM) alloy significantly improved after hot significant elongations of BMGs have been reported: 1.6%
extrusion, thanks mainly to precipitation strengthening.94, 134 for Mg65Cu15Ag10Y2Gd8,143 0.5% for Mg63Cu16.8Ag11.2Er10144 and
The corrosion rate of extruded JDBM (0.13 mm/year) was 0.9% for Mg65Cu7.5Ag5Ni7.5Gd5.143 The structural relaxation at
much lower than that of AZ91 (1.02 mm/year), because of a 20°C and 37°C for Mg95–xZnxCa5 BMG has been examined. The
homogeneous distribution of nano-scaled Mg12Nd phase.135 relaxation time increased from 10 to 30 days at 20°C, combined
Mg-2.2Nd-0.1Zn-0.4Zr (JDBM-2) alloy after double extrusion with a dramatic reduced hydrogen evolution.145 Yu et al.146
showed a high strength (276 MPa) and elongation (34%) and a reported that the addition of Yb (2at% and 4at%) significantly
good corrosion rate (0.37 mm/year) in artificial plasma for 120 improved the ductility of MgZnCa BMGs.
hours, caused by the presence of nanoparticles and by grain The fabrication method and processing parameters significantly
refinement.133 The finely dispersed nano-scale precipitates affect the alloying composition and microstructure of Mg-
not only improve the mechanical properties but also lead to based BMGs. The current development of Mg-based BMGs
homogeneous degradation and a reduced corrosion rate. for clinical applications is still focused on the forming ability
and formation mechanism. A simple fabrication process and
Other factors production of reasonably large sized BMGs need to be further
Several researchers report that twins, texture and dislocations developed. It has been reported that Mg-based BMGs have
all have influences on the corrosion performance. Aung and higher yield stress than their crystalline counterparts due to
Zhou120 reported that the existence of twins can accelerate the the absence of the crystallographically-defined slip systems
corrosion of Mg alloys. After equal channel angular extrusion, in polycrystalline metallic materials.147 However the ductility
a higher density of dislocations and twins appeared and a of Mg-based BMGs needs to be further improved because
more severe dissolution of the anode resulted.121 Andrei et they are extremely brittle. In addition, while some Mg-based
al.136 reported that the equilibrium potential in the vicinity BMGs possess good biocompatibility, other Mg-based BMGs
of the dislocations is locally reduced, thus causing accelerated contain toxic alloying elements (such as transition metals and
dissolution of the anode. According to Xin et al.137 extruded RE elements) because of their good glass-forming ability. Thus
AZ31 sheet showed better corrosion resistance because of the the alloying design of Mg-based BMGs needs to be carefully
initial basal texture. Schmutz et al.138 reported that filaments tailored.
of corrosion propagated at twin boundaries; this corrosion
took place on a plane near the basal plane and then propagated Composite structures
down the prismatic planes. Mg MMCs show a wide range of mechanical and corrosion
In order to meet the biomedical requirements of Mg alloys, behaviours because of the wide range of reinforcements
therefore, a desirable microstructure needs to be achieved: and their content, distribution and size. The manufacturing
refined grains increasing strength and ductility, a homogenous methods are usually powder metallurgy or stir casting. The
distribution of second phase resulting in homogenous bio- matrix materials are biomedical Mg alloys such as Mg-Ca, Mg-
corrosion, a reduced density of boundaries (such as twin Al, Mg-Zn and Mg-RE. Calcium phosphate-based ceramics
boundaries) limiting the propagation of corrosion and a small- (like calcium polyphosphate, hydroxyapatite and tri-calcium
scaled second phase reducing galvanic corrosion. phosphate), calcium, bioactive glass and zinc oxide have all
been used to reinforce Mg MMCs. The amount, distribution
Novel structure development and size of reinforcements are very important for the
So far we have been describing traditional monolithic metallic alloy mechanical and bio-corrosion properties of Mg MMCs. For
components. There are, however, more adventurous possibilities example, fluorapatite nanoparticles (up to 20%) have been used
which may have a significant impact on implanted components. to improve the mechanical properties of AZ91/FA MMC.148

Biomater Transl. 2021, 2(3), 214-235 223

 Review Chiu, Y.; et al.

Mg/ZnO MMCs (20wt% ZnO nanoparticles) have been pore structure encourages tissue ingrowth and survival of the
prepared using powder metallurgy and confer improved tensile vascular system required for continuing bone development.158, 159
strength, hardness and corrosion resistance but with reduced Such interconnected pore networks facilitate the delivery of
elongation.149 ZK60/CPP (calcium polyphosphate particles) oxygen and nutrients to the cells and the removal of products
MMCs have been produced with a compressive strength of stemming from cell metabolism and from degradation of
495 MPa.150 Gu et al.151 developed Mg-hydroxyapatite (10wt%, the scaffold.160, 161 Moreover, the material’s modulus can be
20wt% and 30wt%) composites using powder metallurgy. controlled via the porosity, which enables the design of implant
Mg/10HA composites showed higher YS, lower UTS and materials with a modulus close to that of human bone.162 Other
elongation, reduced corrosion resistance and no toxicity. An mechanical properties of Mg scaffolds can also be adjusted by
MMC was fabricated using Mg-2.9Zn-0.7Zr as the matrix changes to the porosity and pore size.163 Razavi et al.164 have
and 1wt% nano HA particles as reinforcement; it had a specifically proposed that Mg-based alloys can be employed
corrosion rate of 0.75 mm/year.152 A nano-sized β-tricalcium as biocompatible, bioactive, and biodegradable scaffolds for
phosphate/Mg-3Zn-Ca composite was produced and showed orthopaedic applications.
a UTS of 125 MPa and elongation of 2.85%.153 Poly (L-lactic) Powder metallurgy, laser additive manufacturing, the metal/gas
acid-Mg65Zn30Ca5 composites were studied as potential eutectic unidirectional solidification process and the negative
orthopaedic implant candidates; they showed high corrosion salt-pattern moulding method have all been used to produce
resistance and good antibacterial properties.154 A collagen a porous Mg scaffold. Porous WE43 scaffolds were fabricated
(10%)-hydroxyapatite (80%)-Mg (10%) composite scaffold by laser-powder bed fusion and their in vitro performance was
was developed as a bone substitute and showed favourable first reported by Li et al.165 The diamond lattice was adopted
bone healing and regeneration.155 A novel Mg nanocomposite to construct a porous scaffold cylinder with a diameter of 10
scaffold was fabricated and demonstrated that a Mg cationic mm and a height of 11.2 mm, as shown in Figure 6A. Geng
microenvironment promotes cell viability and osteogenic et al.166 reported that the pore size and porosity (48%) of a
differentiation properties in vitro leading to effective bone honeycomb-structured Mg scaffold (shown in Figure 6B167)
defect repair.156, 157 can be controlled by the laser perforation technique. Witte et
Mg-based composites can provide combined properties. For al. reported an open porous AZ91 alloy scaffold with porosity
example, composites made of bioactive ceramics can claim ranging from 72% to 76% and a pore size varying between 10
two important features: mechanical strength and bioactivity. and 1000 µm, which was created by infiltrating molten Mg
Currently, calcium phosphate ceramics are mainly used into a NaCl preform and then washing out the salt preform in
for bone defect filling (in dental and orthopaedic surgery). NaOH solution.40, 168 Gu et al.169 produced a lotus-type porous
Hydroxyapatite is adopted to enhance the bonding of hip pure Mg using a metal/gas eutectic unidirectional solidification
joint prostheses because of excellent biological behaviour, lack method, which showed a slower decay in compressive YS than
of inflammation and the absence of fibrous immunological that of pure Mg during immersion in simulated body fluid.
reactions. It has been stated that the scaffold structure provides three-
In summary, the strength and elongation of currently-studied dimensional space for cell adhesion and ingrowth, giving
Mg-based composites need to be further improved. As things good biocompatibility.170 More importantly, the laser additive
stand at the moment, the alloying/reinforcement needs to be manufacturing technology used to build the scaffold has
further optimised to satisfy the requirements for practicable significant advantages in the fabrication of complex porous
orthopaedic implants. structures and customised implants addressing specific clinical
needs. However, the pore structure (including pore size, shape,
Porous structures connectivity, etc.) needs to be carefully controlled, because this
Porous implants (also called scaffolds) are under the spotlight is one of the key factors determining the mechanical properties
for orthopaedic applications, because their interconnected of porous Mg.

A B

1 mm 1 mm

Figure 6. (A) As-built WE43 scaffold with diamond lattice fabricated by selective laser melting. Reprinted from Li et al.40
Copyright 2017, with permission from Acta Materialia Inc. (B) Honeycomb-structured magnesium scaffold produced
by laser perforation. Reprinted from Tan et al.167 Copyright IOP Publishing. Reproduced with permission. All rights
reserved. Scale bars: 1 mm.

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Biodegradable magnesium for orthopaedic application Biomaterials Translational

Besides the traditional techniques such as melting and casting, be used for material comparison, quality control and alloy
other fabrication methods have been developed to obtain development. Standard tensile tests can follow ASTM B557172
biomedical Mg implants, including powder metallurgy, metallic and ISO 6892-1.173 In clinical applications the Mg implant is
glass forming and laser additive manufacturing. The different continuously under the load in a physiological environment.
fabrication processes directly affect the microstructure and Fatigue-corrosion testing is also necessary because of the
relevant biological performance, mechanical properties and specific requirements of orthopaedic applications. Here the
bio-corrosion behaviour.118, 171 In particular, the accurate ASTM testing standard WK61103174 can be employed.
regulation of alloying elements, microstructure design,
biocompatibility tailoring, machinability and precise control In vitro testing
of porous structure need to be considered and further In vitro experiments are convenient and can provide quick
investigated. Moreover, the in vitro and in vivo testing needs to and reasonable feedback on efficacy as compared with in
be carefully studied. vivo testing. The simulated body fluid method is popular; it
is an aqueous solution with ion concentrations and pH value
equal to those of human body fluids. The corrosion of Mg in
Performance Testing simulated body fluid increases the pH because of alkalisation,
Mechanical testing which affects the biodegradation rate. In order to minimise the
A tensile test machine with tensile grips and extensometer can pH variation of simulated body fluid, the solution needs to be
be obtained to measure the characteristics of alloys. Tensile refreshed every 24 hours and the ratio of sample surface to the
tests are simple, inexpensive and standardised and measure volume of solution kept high. Table 6 shows several solutions
the YS, UTS and elongation. Results from tensile testing can used in in vitro tests.175

Table 6. The concentration of ions and pH values in blood plasma and in different solutions.
Ion Blood plasma Ringer’s solution Earle’s balanced Hank’s balanced Kokubo’s simulat-
salt solution salt solution ed body fluid
Na+ (mM) 142.00 130.00 143.60 138.00 142.00
K+ (mM) 5.00 4.00 5.37 6.14 5.00
Ca2+ (mM) 2.50 1.40 1.80 1.26 2.50
Mg2+ (mM) 1.50 NA 0.81 0.81 1.50
Cl– (mM) 103.00 109.00 125.30 144.8 147.80
HCO3– (mM) 27.00 NA 26.2 4.2 4.20
HPO42– (mM) 1.00 NA 1.00 0.78 1.00
SO 4
2–
(mM) 0.50 NA 0.81 0.81 0.50
Ca/P (mM) 2.50 NA 1.80 1.62 2.50
Buffer (mM) NA NA NA NA Tris
pH 7.4 6.5 6.7–6.9 6.7–6.9 7.4
Note: NA: not applicable. Data are from Gu et al.
147

Several methods are used to measure the degradation rates accepted by many researchers.10, 42, 59, 106, 107, 178-181 The mechanism
of Mg alloys: mass loss, hydrogen evolution, electrochemical of this measurement is simple and easy to understand, and is
techniques and micro-computed tomography measurement. based on the reaction below:
1) Mass loss is the simplest method for degradation testing, Mg+2H2O→Mg(OH)2+H2↑ (7)
with mass loss rates depending on the test duration. The The evolution of one mole of hydrogen gas corresponds to
degradation rate determined by mass loss can be calculated the dissolution of one mole of Mg metal. Thus, the volume of
using the following equation. evolved hydrogen gas is equal to the weight loss of the alloys,
degradation rate (mm/year)= k×weight change (6) and they can be converted into the same units (mm/year).
surface area×immersion time×density
(k is a constant, 8.76 × 10 )
4 3) Electrochemical measurement is widely used to measure
the in vitro degradation behaviour of Mg alloys.106, 148, 183-185
The tested Mg specimen is placed in the corrosion medium for The greatest advantage is that it can be used to obtain the real-
a period of time, at the end of which the Mg alloy is taken out time corrosion rate. Changes in corrosion behaviour can be
and washed with a cleaning solution (such as dilute chromic instantaneously observed. Generally, the Mg sample is used as
acid) to remove all corrosion products and then the resultant the working electrode, platinum as the counter electrode and
mass change is measured. This classic method has been used by a saturated calomel electrode as the reference electrode. Using
a number of researchers.117, 176-181 this method, more corrosion information can be accessed, such
2) A hydrogen evolution method has been developed by as the relative rates of the anodic and cathodic reactions over a
Song et al.182 based on the collection of hydrogen gas during range of potentials.186 A number of investigations indicate that
degradation of Mg in aqueous solutions. The hydrogen the corrosion rate of Mg alloys measured by electrochemical
evolution measurement is currently very popular and is widely testing agrees with that by hydrogen evolution and helps to

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 Review Chiu, Y.; et al.

increase the understanding of how corrosion takes place.119, 186, 187 losses of the samples can be calculated and then converted to
4) Micro-computed tomography (a non-destructive technique) the same units (mm/year). Lu et al.105 reported the corrosion
has been demonstrated to be a powerful technique to monitor morphology and degradation rate of Mg-3Zn-0.3Ca alloys
in vitro degradation.105, 188-190 The evaluation of the bio- using three-dimensional reconstructions, as shown in Figure
corrosion rate depends on a comprehensive observation of the 7. The as-cast Mg-3Zn-0.3Ca has been severely attacked by
Mg specimen before and after immersion testing. The volume corrosion and has lost 34.3% of its initial volume.

A B

Figure 7. Micro-computed tomographic three-dimensional images of as-cast Mg-3Zn-0.3Ca alloy. (A) Before immersion
test. (B) After immersion test. Scale bars: 2 mm. Reprinted from Lu et al.105 Copyright 2018, with permission from Acta
Materialia Inc.

In vivo testing into the spines of sheep.192 The first comprehensive in vivo study
The in vivo assessment of the compatibility of biomaterials and on Mg alloys was carried out by Witte et al.39 on four different
medical devices with tissue is important for the development Mg alloys (AZ31, AZ91, WE43 and LAE442), and these four
and implementation of implants for human use. Many in vivo Mg alloys were implanted into the femurs of guinea pigs. A
studies have been conducted to understand the degradation newly-formed mineral phase was observed on the surface of
process and the associated mechanisms. Animal models are the Mg implants during implant degradation, which stained
adopted in order to determine the response to the biomaterials with calcein green under fluorescent light (Figure 8A).39 The
or medical devices, such as the interactions of various cell types
in vivo bio-corrosion morphology of the remaining Mg alloy in
with the implants, endocrine factors acting on cells around
the implant and interactions with blood-borne cells and the guinea pig femora is shown in Figures 8B and C.109 It can
proteins. In vivo studies have mainly been performed on small be seen that the AZ91D rod was almost completely corroded,
animals, such as guinea pigs, rats and rabbits. Heublein et al.191 while the LAE442 rod was corroded more uniformly. Both of
investigated a cardiovascular stent (AE21 alloy) in domestic these Mg alloys exhibited good biocompatibility as evidenced
pigs. There is a report describing the implantation of Mg chips by the direct contact with newly-formed bone.

A B C

Figure 8. (A) Fluoroscopic image of cross-section of magnesium rod in a guinea pig femur. E: endosteal bone formation;
I: implant residual; P: periosteal bone formation. (B) Three-dimensional reconstruction of remaining AZ91D in the
femur of a guinea pig. (C) Three-dimensional reconstruction of remaining LAE442 in the femur of a guinea pig. Scale
bars: 1.5 mm. A–C were reprinted from Witte et al.39, 109 Copyright 2005 & 2006, with permission from Elsevier Ltd.

226 www.biomat-trans.com
Biodegradable magnesium for orthopaedic application Biomaterials Translational

Recently, some in vivo studies were carried out on large Future Perspectives
animal models. A goat was used to study the clinical capability Mg is an essential ion in metabolism and can encourage bone
of osteosynthesis of a lean Mg alloy (Mg-0.45Zn-0.45Ca) growth, which helps the proper fixation of an implant into the
screw.51 In vivo transformation experiments on high-purity host bone and potentially allows full healing of bone defects
weight-bearing Mg screws were also carried out on goats.193 after degradation.186, 214 Importantly, biomaterials need to be
Small animals (rats) and large animals (sheep) have been used designed to be bioactive and/or bioresorbable to improve
to compare the biodegradation rate, bone formation and in- tissue growth. Therefore, a biodegradable Mg alloy with great
growth of bone into Mg-0.45Zn-0.45Ca implants.194 A pig biocompatibility can make an ideal implant for load-bearing
model was designed to evaluate the in vivo performance of a orthopaedic applications. Complex and/or customised shapes
Mg-4Zn-0.1Sr anastomosis ring.195 A miniature pig has been consistent with specific patient needs are required in real clinics
employed to perform pre-clinical testing of human-sized Mg nowadays. Thus, additive manufacturing is assuming greater
implants at multiple implantation sites.196 and greater importance for implant manufacture, including
for Mg. In addition, the influence of local pH changes on the
Cytotoxicity adjacent tissue, evolution of hydrogen gas and the concentration
Cytotoxicity testing is one of the biological evaluation and of released metallic ions caused by bulk Mg-based implants can
screening tests that uses tissue cells in vitro to observe the be reduced by adopting Mg scaffolds due to the smaller volume
effects of medical implants on cell growth, reproduction of implant. Furthermore, a material with porosity changing
and morphology.197 It is an important indicator for quickly across the volume (a functionally-graded material) is currently
evaluating the biocompatibility of implants because it is believed to improve osseo-integration.215 This can be achieved
fast, simple and highly sensitive. Three types of cytotoxicity by an additively-manufactureld scaffold. These unique features
test are specified in ISO 10993:198 extract, direct contact and suggest that additively-manufactureld Mg scaffolds with bone-
indirect contact tests. The extract test is suitable for evaluating mimicking characteristics will become promising orthopaedic
the toxicity of soluble substances released from implants. implants, possessing sufficient mechanical strength and
The direct contact test is the most sensitive and can be used ductility, low elastic modulus, excellent biocompatibility, and
to measure even weak cytotoxicity.199 The indirect contact a complex shape.
test is used on implants with high toxicity and/or small
molecular weight.200, 201 Bone marrow-derived mesenchymal Over recent decades, new types of biodegradable Mg alloys
stromal cells, murine fibroblast cells (L-929) and murine have mainly been developed by casting because it is easy to
calvarial preosteoblasts (MC3T3-E1) are commonly used for regulate the alloying elements. However casting generally
cytotoxicity studies.202-207 The cytotoxicity assay includes cell leads to large grains, which need subsequent deformation
adhesion, cell viability and proliferation assessments. Cell (such as extrusion, rolling and forging) to reduce their size.
morphology can be viewed by fluorescence staining under an In particular, severe plastic deformation has been widely
inverted fluorescence microscope. In order to investigate cell used to obtain fine grains and therefore further tailor the
adhesion, samples seeded with MC3T3-E1 pre-osteoblasts mechanical and corrosion performance. In contrast, additive
were rinsed with phosphate-buffered saline (PBS).207 manufacturing involves rapid melting and solidification which
MC3T3-E1 cells were directly seeded onto Mg alloy to study results directly in a fine microstructure. This technique also
the cell proliferation behaviour.208 A standard MTT assay was shows an ability to regulate the second phase distribution and
adopted to measure cell viability.202 composition, because the alloy elements mainly dissolve in the
matrix due to the fast advanced solid/liquid frontier (‘solute
The degradation rate of Mg alloys determines the ion release capture effect’).216 The reduced second phase caused by the
rate in the physiological environment. The amount of released extended solid solution of alloying elements may result in
elements significantly affects the biocompatibility of the Mg improved corrosion resistance because of the reduced galvanic
alloys. An evaluation of the biosafety of Mg implants must corrosion effect.
be performed. Currently, preparation of the extracts from
medical devices for cytotoxicity testing needs to follow Parts However, it needs to be noticed that the additive manufacturing
5 and 12 of ISO 10993.198, 209 However, Mg alloys can react of Mg is still challenging. Unlike Ti or Fe alloys, the melting
with an aqueous environment, release Mg ions and produce a point (~650°C) of Mg is quite close to its boiling point
higher pH value and osmolality in the surrounding medium,186 (~1091°C) which limits the range of process parameters. In
which is significantly affected by the constituents of the addition, Mg is easily ignited during laser processing, because
medium.210 In order to mimic an in vivo environment, a cell of its low boiling point, high vapour pressure, low surface
culture medium supplemented with serum is recommended.211 tension and density. The formability of Mg is hard to control
Wang et al.212 proposed a modified cytotoxicity testing because it is easily oxidised due to its active chemical properties.
standard for biodegradable Mg-based materials: a minimum The densification of Mg (reduction of processing pores)
6-fold to a maximum 10-fold dilution of extracts from Mg needs to be improved to enhance the formability. Therefore,
implants for cytotoxicity tests. It has been reported that the test the fundamental mechanisms of processing as it affects the
conditions can significantly influence the cytotoxicity testing fabricability of Mg need to be further studied, like its residual
of biodegradable metallic materials, which further suggested stress control, processing stability, interaction between laser
that the test conditions need to be carefully specified and beam and Mg, internal defect formation mechanism and so on.
different studies need to be cautiously compared.213 Alloying is still the critical factor determining the

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 Review Chiu, Y.; et al.

biocompatibility, mechanical properties and biodegradation investigated, including changes in the implant shape, variations
behaviour of orthopaedic implant materials. Firstly, the toxicity in the mechanical strength and elastic modulus, pH variation,
of alloying elements in the biological environment needs to be the release of corrosion products, the amount of released
carefully considered. Some nutrient alloying elements are good metallic ions, hydrogen gas and the changed biocompatibility.
candidates. For example, Zn is recognised as a nutritionally- In addition, the related modelling, which can accurately
essential element in the human body. Ca is a major component simulate the dynamic physiological–chemical–mechanical
of human bone and is an important element in cell signalling; variation during the biodegradation process along with bone
released ions are beneficial for bone healing.217 Sr belongs to healing, needs development.
Group IIA of the periodic table (the same as Mg) and shares In summary, the following aspects are in the spotlight for
similar chemical, biological and metallurgical properties, designing the next generation of biodegradable Mg-based alloys
which can stimulate bone cell differentiation and inhibit for orthopaedic applications: 1) Mg-based alloys with excellent
bone resorption.218 Zr is known to be of low toxicity to living biocompatibility, especially incorporating nutrient elements
organisms and to have a stimulating effect on bone cells, which (such as Ca, Zn, or Sr) along with controlling elements such as
can improve bone integration.219 Nd and Y below the threshold level; 2) development of novel
Secondly, in order to achieve suitable mechanical properties fabrication techniques to satisfy the complex shape and various
(UTS: ~200 MPa, elongation: ~20%) and service life-time (3–4 size requirements, for example additive manufacturing, to build
months for orthopaedic application),133 the alloying design, the best processing window (suitable selection of processing
processing history, heat treatment and impurity control (like parameters); 3) innovative three-dimensional model design
Fe, Ni, Cu and Co) need to be carefully considered and tailored with changing porosity across the volume, resulting in a
properly. For orthopaedic applications, the fatigue-corrosion superior ability of Mg implants to mimic bone/tissue growth);
behaviour in an aqueous environment also must be taken 4) mathematical modelling and simulation, which can predict
into account. The mechanical properties can be improved by the dynamic mechanical and biodegradation variation of a Mg
various strengthening mechanisms, such as grain refinement implant during implantation; and 5) effective application of
strengthening, solid solution strengthening and precipitate in vivo testing on the basis of initial in vitro evaluation, finally
strengthening. translating to safe clinical application.
Thirdly, for bone implants, 3–4 months is required from
fracture callus formation to new bone formation and eventually
Author contributions
solid bone healing to restore most of the bone’s original Concepts, literature search, statistical analysis and manuscript preparation:
strength. For example, when the dimensions of a locking YL; manuscript editing: YL, IPJ; manuscript review: SD, IPJ, YLC. All authors
compression plate (locking compression plate 3.5–423.621 discussed the results and contributed to the final manuscript.
from Depuy Synthes220) are 163 mm × 10 mm × 2 mm (volume Financial support
None.
of 3.84 cm3 determined by micro-computed tomography), Acknowledgement
the degradation rate needs to be controlled to be below 0.97 None.
mm/year which would correspond to complete degradation Conflicts of interest statement
in 3 months according to equation (6). The biodegradation The authors declare that they have no known competing financial interests
or personal relationships that could have appeared to influence the work
properties can be tailored by adjusting the alloying treatment, reported in this paper.
grain refinement, the formation of a passivation film, reduction Open access statement
in the cathode–anode potential difference and secondary phase This is an open access journal, and articles are distributed under the terms
amount and distribution. The elements Nd and Y are good of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
License, which allows others to remix, tweak, and build upon the work non-
candidates which can significantly improve the mechanical commercially, as long as appropriate credit is given and the new creations are
performance of Mg alloys by grain refinement strengthening, licensed under the identical terms.
solid solution strengthening and precipitate strengthening.221
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