Journal of

Materials Chemistry B
View Article Online
REVIEW View Journal | View Issue

Nutrient alloying elements in biodegradable

Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

metals: a review
Cite this: J. Mater. Chem. B, 2021,
9, 9806
Huafang Li, *ab Guicai Lin,a Pengyu Wang,a Jinyan Huanga and Cuie Wen c

As a new generation of biomedical metallic materials, biodegradable metals have become a hot research
topic in recent years because they can completely degrade in the human body, thus preventing secondary
surgery, and reducing the pain and economic burden for patients. Clinical applications require biodegradable
metals with adequate mechanical properties, corrosion resistance, and biocompatibility. Alloying is an
important method to create biodegradable metals with required and comprehensive performances. Since
Received 8th September 2021, nutrient elements already have important effects on various physiological functions of the human body, the
Accepted 15th November 2021 alloying of nutrient elements with biodegradable metals has attracted much attention. The present review
DOI: 10.1039/d1tb01962g summarizes and discusses the effects of nutrient alloying elements on the mechanical properties,
biodegradation behavior, and biocompatibility of biodegradable metals. Moreover, future research directions
[Link]/materials-b of biodegradable metals with nutrient alloying elements are suggested.

1. Introduction biodegradable metals do not meet clinical requirements.8 What’s

more, the slow corrosion rate of Fe-based biodegradable metals
Biomedical metallic materials have been widely used in ortho- triggers an inflammatory response,9 while the fast corrosion rate of
pedic implants, cardiovascular stents, and many other fields due Mg-based biodegradable metals leads to early failure of the
to their high mechanical strength and adequate fracture tough- implant and generates large amounts of hydrogen gas which
ness. However, traditional bioinert metallic materials cannot be forms bubbles around or under the skin of the implant and
absorbed by the human body, which can be a barrier to bone hinders tissue/organ healing.10,11 Compared to these biodegrad-
healing and lead to side effects such as long-term endothelial able metals, zinc (Zn)-based biodegradable metals have a more
dysfunction, in-stent restenosis, and chronic inflammation. appropriate corrosion rate, and there is no hydrogen evolution.8
Furthermore, they need a second operation to remove the However, the mechanical properties of pure Zn do not meet
implant, thus increasing medical costs and pain for the patients. clinical requirements: for as-cast pure Zn, the ultimate tensile
Based on these reasons, in recent years researchers have begun to strength (UTS) is 33.6 MPa, yield strength (YS) is 29.3 MPa, and the
conduct in-depth research on biodegradable metals.1 elongation is 1.2%, all of which are far from meeting clinical
As a newly developed biodegradable material test standard, requirements.12–16 The shortcomings and applications of each of
ASTM-F3160, launched in 2016, defines an absorbable metallic the three biodegradable metals are summarized in Table 1.
material as ‘an initially distinct foreign material or substance To improve the comprehensive properties of biodegradable
that either directly or through intended degradation can pass metals, researchers have adopted various methods and alloying
through or be metabolized or assimilated by cells and/or tissue’.2 has been proven to be an effective method in recent studies.
In orthopedic applications, biodegradable implants would Among various alloying elements, nutrient alloying elements,
allow the load to be gradually transferred to the healing bone as due to their good biocompatibility, biological safety, and physio-
the implants degrade, thereby reducing the stress-shielding logical functions of the human body, are favored by researchers.17
phenomenon,3 and a further advantage of biodegradable materials In the present review, the effects of nutrient elements alloying on
is their ability to adapt to growth in young patients.4–7 the mechanical properties, biodegradable behavior, and bio-
However, biodegradable metals still have certain disadvantages. compatibility of biodegradable metals are analyzed and future
The degradation rates of iron (Fe)- and magnesium (Mg)-based development directions are suggested.

a
2. Physiological roles of nutrient
School of Materials Science and Engineering, University of Science and Technology
Beijing, Beijing, 100083, China. E-mail: huafangli@[Link] alloying elements
b
State Key Laboratory for Advanced Metals and Materials, University of Science
and Technology Beijing, Beijing, 100083, China During the degradation process, elements in the matrix of the
c
School of Engineering, RMIT University, Melbourne, Victoria 3001, Australia implant are released as metal ions, which then participate in

9806 | J. Mater. Chem. B, 2021, 9, 9806–9825 This journal is © The Royal Society of Chemistry 2021
 View Article Online

Review Journal of Materials Chemistry B

Table 1 Comparative summary of biodegradable metals

Type System Disadvantages Applications Ref.

Fe Fe–Mn, Fe–Mn–Si, Too slow corrosion rate Medical sutures, the IBS Angel Fe-based absorbable 18 and 19
Fe–Mn–Zn stent system (IBS Angel)
Mg Mg–Ca, Mg–Zn, Mg–Sr, Too fast corrosion rate; generates Biotronik’s Dreams 2G Mg stents, Magnezixs 20–25
Mg–Mn, Mg–Cu, Mg–Si large amounts of hydrogen gas Mg-based bone screws, a 99.99% high-purity
Mg orthopedic internal fixation implants
Zn Zn–Mg, Zn–Ca, Zn–Cu, Insufficient mechanical properties Zinc alloy biodegradable bone plates 26–34
Zn–Sr, Zn–Li
Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

tissue healing in a positive, neutral, or negative manner. Therefore, mineral nutrients and belong to the macroelement family.
in addition to the matrix elements, the ideal main alloy compo- Among these, Ca has the highest content with around 1000 g
nents of biodegradable metals would be essential nutrient elements of Ca in the human body for the bodyweight of a 70 kg
for the human body. Many essential nutrient elements found in the reference man.36 Several physiological functions in the body
human body can be used as alloying elements to improve the require the participation of Ca. The majority (B99%) of Ca
in vitro and in vivo properties of biodegradable metals.35 present in the body is found in bone, with a smaller amount
Fig. 1 shows the nutrient alloying elements used in bio- found in teeth. The remainder (o1%) is found in soft tissues
degradable metals. Nutrient alloying elements can be defined and body fluids.40 Diets containing insufficient amounts of Ca
as elements that are essential to life and health, and are used by lead to low bone mineral density, which may have implications
an organ of the human body to survive, grow, and reproduce; for bone health, notably the risk of osteoporosis, in later life.40
these elements can be alloyed with pure biodegradable metals Na is essential to health and resides in the extracellular fluid,
to improve the overall properties of the alloys and can release regulating plasma volume as well as cellular transport. It serves
bio-functional ions as the alloys degrade in the body. At a host of physiological functions, including nutrient absorption
present, more than 10 kinds of nutrient alloying elements have and maintaining fluid balance.41 Mg plays a significant role in
been applied to biodegradable metals.36 Among these, calcium many physiological functions.42 The normal adult human body
(Ca), sodium (Na), and Mg belong to the macroelements family contains approximately 1000 mmol of Mg (22–26 g). About 60%
and account for more than 0.01% of the total mass of the body. of this Mg is present in bone, 20% is in skeletal muscle, 19% in
Fe, Zn, copper (Cu), manganese (Mn), strontium (Sr), silicon other soft tissues, and less than 1% in the extracellular fluid,
(Si), tin (Sn), lithium (Li), and germanium (Ge) belong to the and hypomagnesemia is the main disease related to Mg.
microelement family37 and are less than 0.01% of body mass Fe, Zn, Cu, Mn, Sr, Si, Sn, Li, and Ge belong to the micro-
with their daily intake o100 mg per day.38,39 element family. Microelements have several significant functions
The physiological functions of these nutrient alloying ele- in the human body. For example, Fe can bind, transport, and
ments are summarized in Table 2. Ca, Na, and Mg are essential release oxygen in the human body.43 The content of Sr is related to

Fig. 1 Nutrient alloying elements in biodegradable metals.

This journal is © The Royal Society of Chemistry 2021 J. Mater. Chem. B, 2021, 9, 9806–9825 | 9807
 View Article Online

Journal of Materials Chemistry B Review

Table 2 Physiological roles of nutrient elements

Normal
concentration
Ele. (man of 70 kg) Daily intake Results of excessive intake Physiological processes involved Ref.
Ca 1000 g 700–800 mg Hypercalcemia disorder Mineralization of bone; muscle contraction, 36 and 49
neurotransmitter secretion, digestion, and blood
coagulation; playing a structural role outside of the skeleton
Na 100 g 1500 mg Hypernatremia Regulating plasma volume; cellular transport; nutrient 36 and 41
absorption; maintaining fluid balance
Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

Mg 21–28 g 280–350 mg Hyporeflexia, muscular paralysis, A cofactor in hundreds of enzymatic reactions; be required 50 and 51
respiratory arrest, and cardiac for protein and nucleic acid synthesis, the cell cycle,
arrest (5–15 mmol l1) cytoskeletal and mitochondrial integrity for the binding of
substances to the plasma membrane
Fe 5g 15–20 mg Toxicity; generation of reactive Oxygen transportation; DNA synthesis; electron transport, 36, 46, 52
oxygen species etc. and 53
Zn 2g 8–11 mg Abdominal pain, nausea, and Nucleic acid and protein metabolism; cell growth, 36, 54
vomiting division, and function and 55
Cu 100 mg 2 mg Neurodegeneration. Various enzymatic reactions; particularly as an electron 36 and 52
donor and for enzymes that are important to our ability to
use oxygen actively; formation of connective tissue
Mn 16 mg 3.5 mg Parkinsonism Metabolism; regulation of cellular energy; reproduction; 36 and 56
growth of bone and connective tissue
Sr 0.32 g 2–4 mg Ricket Antiosteoporotic; osteopromotive element; activating 57 and 58
osteoblastic cell replication and suppressing bone
resorption
Si 30–50 mg 21–46 mg Supra nutritional amounts pro- Bone matrix formation and bone mineralization; 59 and 60
mote bone and connective tissue protection from atherosclerotic vascular alterations and
health and may have a modula- lowering plasma lipids
ting effect on the immune or
inflammatory response
Sn 20 mg 0.3 mg Skin rashes, stomach complaints, Maintaining properly growth; maintaining the balances of 36, 37 and 47
nausea, vomiting, diarrhea, essential metals
abdominal pain, headache, and
palpitations
Li 350 mg 0.65–3.1 mg Confusion and speech impair- Mildly toxic; embryonic development; glycogen synthesis; 36 and 61
ment; risk of death hematopoiesis; may influence metabolism.
Ge 0.9 mg 0.3–3.4 mg Excessive or long-term exposure to A unique metalloid in the carbon group; a dietary trace 48 and 62
Ge has toxicological effects and element; might be necessary for ensure normal functioning
damages to the kidneys, nervous of the body; stimulating the hematopoietic function;
system, and lungs inhibiting bacterial growth; Ge can prevent pigmentation
and inhibit production of melanocytes

the prevalence of caries,44 and among the trace metals present in Pure Fe and Fe-based alloys usually have improved mechanical
human bone, Sr is the only element that related to the compression properties, but need better biomechanical compatibility and
strength of bone.45 Li is found in all organs and tissues. Human Li reduced magnetic susceptibility in clinical applications.29
deficiency diseases have not been observed; however, some obser- Alloying is one of the most effective ways to improve the
vations have shown that low Li intake causes behavioral defects.46 mechanical properties of biodegradable metals. It is well
Animal experiments have proved that Sn is an essential nutrient for known that second-phase strengthening and solid-solution
the growth of rats and that lack of Sn can cause reduced feeding strengthening are the two main ways to improve the mechanical
efficiency, alopecia, and slower growth. Studies have proved that strength of alloys. In addition, to achieve excellent biocompati-
lack of Sn in the human diet leads to an imbalance of essential bility and bio-functionality of an alloy, certain nutrient elements
metals, such as increased levels of Ca and decreased concentra- are considered to be the first choices as alloying elements. Table 3
tions of Mn, Cu, and Zn.47 Ge has many important biological summarizes the effects of the nutrient alloying elements on the
effects, such as antiviral, anti-microbial, anticancer, anti- mechanical properties of biodegradable metals.
inflammatory functions, and other functions, as well as regulation Schinhammer et al.9 have reported that the mechanical
of immunity, elimination of free radicals, prevention of cell aging.48 properties of Fe-based alloys improve as the Mn content in
Fe–Mn alloys increases. During the sintering process, the Mn
element can solid-solve with Fe to form a solid solution for
3. Effects of nutrient elements on the solid solution strengthening. However, due to different manu-
mechanical properties of facturing processes, the solid solution strengthening theory
biodegradable metals does not explain the mechanical properties of all Fe–Mn alloys.
For example, in porous structures, the strength of Fe–Mn alloys
The mechanical properties of biodegradable metals, especially increases with increasing Mn content; however, their elonga-
Zn- and Mg-based alloys, often fail to meet clinical requirements.28,63 tion also increases, probably due to a change in the crystal

9808 | J. Mater. Chem. B, 2021, 9, 9806–9825 This journal is © The Royal Society of Chemistry 2021
 Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

Table 3 Effects of nutrient elements on the mechanical properties of biodegradable metals

Mechanical properties
Tensile yield Ultimate tensile
Review

strength TYS strength UTS

Ele. Material Phases Strengthening mechanism Impact results (MPa) (MPa) Ref.
Ca Zn–0.8Mn–0.4Ca Zn + CaZn13 + MnZn13 Ca addition causes prominent refinement of microstructure; Effectively improved As-cast: As-cast: 120.3  27
MnZn13 particles attach to CaZn13 particles, resulting in mechanical properties. 112.2  3.4 6.3
CaZn13/MnZn13 compound structure As-extruded: As-extruded:
253.4  1.3 343.2  1.6
Ca Zn–1Ca Zn (hcp) + CaZn13 Zn–1Ca is mainly composed of Zn with a hexagonal close Significantly improved 119.12  7.01 164.57  13.92 30
packed (HCP) crystal structure, besides CaZn13 TYS, UTS, elongation,
and microhardness
Na As-cast a-Mg + Mg2Sn Diffusion of micro-alloyed Na into Mg2Sn phase. Increased mechanical — — 64
Mg4.6Sn2.4Zn0.07Na properties
and as-extruded
Mg6Sn5Zn0.3Na
Mg Zn–3Cu–xMg (x = 0.1, Zn matrix, CuZn5 and With increasing Mg content, dendrites are restrained and Increased TYS and UTS Zn–3Cu–1Mg: Zn–3Cu–1Mg: 32
0.5 and 1.0 wt%) Mg2Zn11 grain size of substrate decreases gradually but decreased elongation 426.7 440.5
Mg Zn–1Mg Zn (hcp) + MgZn2 Zn–1Mg is mainly composed of Zn with an HCP crystal Significantly improved 127.98  10.72 184.84  20.91 30
structure and MgZn2 TYS, UTS, elongation,

This journal is © The Royal Society of Chemistry 2021

and microhardness
Zn Mg–6 wt% Zn Matrix a-phase Zinc has a solution hardening effect on Mg alloys Effectively improved 169.5  3.6 279.5  2.3 13
mechanical properties
Cu Zn–0.8Mn–0.4Cu Zn + MnZn13 Mn addition causes prominent refinement of microstructure Effectively improved As-cast: As-cast: 117.3  27
mechanical properties. 113.1  0.2 3.2
As-extruded: As-extruded:
191.3  4.1 308.3  0.6
Cu Zn-x Cu (x = 2, 3, Primary Zn matrix and With increasing Cu concentration, volume fraction of Significantly improved Zn–4Cu: Zn–4Cu: 270.7 31
and 4 wt%) the dendritic secondary CuZn5phase increases and area of fine grain region expands TYS and UTS 227.0  5.0  0.5
CuZn5 phase gradually
Mn Fe–20Mn g-Phase, e-phase, a 0 e phase is harder and denser, which is responsible for Highest TYS among the 421  27 702  11 65
phase strengthening alloys and a 0 phase allows stress relaxation Fe–Mn alloys
Fe–25Mn g-Phase and e-phase e phase is harder and denser which is responsible for Highest UTS among the 361  33 723  19
strengthening alloys Fe–Mn alloys
Fe–30Mn g-Phase Only the g-phase is found in Fe30Mn and Fe35Mn speci- Higher ductility but 239  13 518  14
mens; contains relatively larger grains lower strength
Fe–35Mn g-Phase Only the g-phase is found in Fe30Mn and Fe35Mn Highest elongation 234  7 428  7
specimens; contains relatively larger grains among the Fe–Mn alloys
Mn Zn–0.1Mn, Zn–0.4Mn, Zn and MnZn13 — — Zn–0.4Mn: Zn–0.4Mn: 215 33
and Zn–0.8Mn 163  8 6
Sr Zn–1Mg–0.1Sr; Matrix Zn; SrZn13 and Zn and Sr exist predominantly in laminar eutectic structures Effectively improved As-rolled Zn– As-rolled Zn– 28
Zn–1Mg–0.5Sr MgZn2 mechanical properties 1Mg–0.1Sr: 1Mg–0.1Sr:
196.84  13.20 300.08  6.09
Sr Zn–1Sr Zn (hcp) +SrZn13 Zn–1Sr is mainly composed of Zn with an HCP crystal Significantly improved 120.21  6.08 171.40  14.13 30
structure and SrZn13 TYS, UTS, elongation and
microhardness
Si Fe30Mn5Si g-Austenite e- Si lowers stacking fault energy of austenite in Fe–Mn–Si Improved biomechanical 171  15 290  10* 66
martensite alloys, which favors martensite formation compatibility
Sn Mg–5Sn a-Mg; Mg2Sn (1) Hall–Petch (H–P) hardening; (2) solid-solution hardening; Improved mechanical 120  2 134  4 67
(3) hardening by secondary Mg2Sn and eutectic particles properties
Li Zn–Li Zinc phase and LiZn4 Large volume fractions of the LiZn4 phase Improved TYS, UTS, and 274  61 116  13
hardness but decreased
ductility
Ge Mg–xGe (x = B1.38, 2.53 a-Mg and Mg2Ge Second-phase strengthening of Mg2Ge; morphology of Higher mechanical prop- Mg–3Ge: 175.1 Mg–3Ge: 35
and 3.26 wt%) eutectic structures might also have impact on alloy strength erties than many other  5.1 236.4  0.7
View Article Online

J. Mater. Chem. B, 2021, 9, 9806–9825 | 9809

Journal of Materials Chemistry B

biodegradable alloys
* Compressive test.
 View Article Online

Journal of Materials Chemistry B Review

structure of Fe from a body-centered cubic (BCC) to a denser (wt%) alloy was solid-solution treated at 350 1C for 2 h, followed
face-centered cubic (FCC) or hexagonal dense – filled (HCP) by quenching in water, denoted as-heat treated. The heat-
structure as a result of the addition of Mn.56 Hermawan et al.65 treated alloy samples were hot-extruded at an extruding ratio
found that the mechanical properties of Fe–Mn specimens were of 8 : 1 at B250 1C, denoted as-extruded. It can be seen from
strongly influenced by the phase composition. Fe30Mn and Fig. 2a that there were two main phases in the as-cast Mg–6Zn
Fe35Mn specimens contained relatively larger grains that could samples, i.e., the matrix a phase and the second g-MgZn phase,
explain their superior ductility and lower strength. Moreover, in precipitating along the grain boundaries. The grain size of the
Fe20Mn and Fe25Mn specimens two g + e phases coexisted, as-extruded Mg–6Zn samples was markedly finer than those of
Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

whereas only the g phase was found in Fe30Mn and Fe35Mn its as-cast and heat-treated counterparts, indicating that hot
specimens. The e phase, which is harder and denser than the g working refined the microstructure. Neither precipitates nor
phase,68 is responsible for strengthening the alloys. Therefore, bulk impurities were observed, suggesting a uniform micro-
one could expect a decrease in strength and an increase in structure in the as-extruded Mg–6Zn samples. In addition, the
ductility as Mn content increases. An exception was found with grain size of the as-extruded pure Mg was similar to that of the
the specimens of Fe20Mn alloy where its ductility was slightly as-extruded Mg–6Zn alloy. The XRD patterns also show clear
higher than that of Fe25Mn specimens. This could be explained g-MgZn peaks in the as-cast Mg–6Zn, while after extrusion the
by considering the stress-relaxation mechanism produced by g-MgZn peaks disappeared in the as-extruded alloy, which is
the formation of a new phase and deformation twinning. consistent with the optical microstructural observation.11
During the tensile test, the e phase was formed in both alloys, Bian et al.35 reported the development of Mg–xGe (x = 1.5,
but in Fe20Mn the a0 phase was also formed. The formation of the 2.5, 3) alloys for biodegradable orthopedic implant applications;
a0 phase allowed stress relaxation in Fe20Mn which extended its Ge is a dietary trace element. All of the Mg–xGe alloys were
elongation. composed of two phases, i.e., a-Mg and intermetallic compound
Liu et al.64 revealed that Mg6Sn5Zn0.3Na demonstrated 106%, Mg2Ge with an FCC crystal structure (Fig. 2b). As-cast Mg–Ge
17%, and 15% higher hardness than pure Mg, Mg4.6Sn2.4Zn0.07Na, alloys consisted of dendrites of the a-Mg matrix (bright white
and Mg6Sn5Zn, respectively, due to the diffusion of micro- dendrites) and eutectic phases (a-Mg + Mg2Ge, brown rod-like/
alloyed Na into the Mg2Sn phase. Seong et al.69 found that in network-shaped) in the interdendritic regions. Area fractions of
an Mg–Ca alloy, Mg2Ca distributed along the grain boundaries, the eutectic phases increased from 17.0  1.3% in Mg–1.5Ge to
which observably affected the mechanical properties of the alloy. 24.3  2.9% in Mg–2.5Ge and then to 33.9  2.5% in Mg–3Ge.
The addition of Ca to Mg can increase both the strength and the The average size of the eutectic phase continuously increased
elongation rate due to grain refinement.70,71 Zhang et al.13 found with increasing Ge addition. The a-Mg dendrites in Mg–2.5Ge
that the mechanical properties of an Mg–6Zn alloy met the and Mg–3Ge were markedly refined compared to Mg–1.5Ge.
standards for medical implants after solid solution treatment Shi et al.73 reported their results from a study of as-cast
and thermal processing, which resulted in grain refinement and Zn–0.8Mn, Zn–0.8Mn–0.4Cu, and Zn–0.8Mn–0.4Ca alloys, and
a uniform single phase. The tensile yield strength (TYS) and the optical microstructures of these alloys are given in Fig. 2c.
elongation reached about 279.5 MPa and 18.8%, respectively. It can be seen that the eutectic structure was distributed
This indicates that the addition of Zn can improve the mechan- between neighboring Zn dendrites. The eutectic structure con-
ical properties of Mg. Gu et al.72 found that the addition of Si, Sn, sisted of MnZn13 and Zn. EDS analysis revealed that the second
and Zn improved the TYS and UTS of an Mg alloy, although there phase was a binary Zn–Mn phase containing B7.07 at% Mn,
is almost no solubility of Si in Mg and only 1 wt% Si addition led which agrees with MnZn13 with a stoichiometrical Mn content
to the formation of a Mg2Si phase. Kubásek et al.67 found that Sn of 7.14 at%. In an as-cast Zn–0.8Mn–0.4Cu alloy, the eutectic
addition increased in the TYS, UTS, and hardness of an Mg alloy. structure of Zn and MnZn13 were also distributed between
Three strengthening mechanisms were involved in the Mg–Sn neighboring Zn dendrites. However, in the as-cast Zn–0.8Mn–
alloys: Hall–Petch (H–P) strengthening, solid solution streng- 0.4Ca alloy, CaZn13 and MnZn13 were detected. CaZn13 exhibited
thening, and second-phase strengthening by Mg2Sn and eutectic a dendritic or blocky morphology, the contrast of which was less
particles. bright than that of MnZn13 since Ca is about 27% lighter than
Shi et al.27 investigated the properties of biodegradable Mn. MnZn13 particles were attached to CaZn13 particles, result-
Zn–0.8Mn alloy and revealed that all alloying elements of Ca, ing in a CaZn13/MnZn13 compound structure. A typical dendritic
Cu, and silver (Ag) notably strengthened a Zn–0.8Mn alloy in an CaZn13/MnZn13 compound structure is shown as an insert in the
as-extruded state, and the strengthening effect was ranked upper-right corner of Fig. 2d. Comparing Fig. 2a with Fig. 2d, it is
Ca 4 Cu 4 Ag. The addition of Ca led to significant refinement clear that the Ca addition caused a notable refinement of the
of the microstructure, which reduced the average length of Zn microstructure, resulting in a decrease in the average length of
dendrites from 637.2  103.1 mm to 289.2  98.7 mm, while the Zn dendrites from 637.2  103.1 mm to 289.2  98.7 mm.
strong adverse effect of Ca on ductility was due to the formation Tang et al.31 reported that Cu addition observably improved
of coarse CaZn13 particles, which are difficult to crush into the tensile properties of Zn–xCu alloys. With increasing Cu
smaller pieces during hot extrusion. content, both the strength and elongation increased dramati-
Fig. 2 shows the optical microstructures and corresponding cally as the secondary CuZn5 phase contributed to compatible
XRD patterns of several Mg-based alloys. An as-cast Mg–6Zn deformation and grain refinement during hot extrusion. Due to

9810 | J. Mater. Chem. B, 2021, 9, 9806–9825 This journal is © The Royal Society of Chemistry 2021
 View Article Online

Review Journal of Materials Chemistry B

Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

Fig. 2 Microstructures of Mg-based alloys: (a) as-cast Mg–6Zn, as-extruded Mg–6Zn and Mg, and XRD patterns of Mg–6Zn;11 (b) as-cast Mg–xGe
(x = 1.5, 2.5, 3) and corresponding XRD patterns;35 (c) as-cast Zn–0.8Mn, Zn–0.8Mn–0.4Cu and Zn–0.8Mn–0.4Ca.27

solid-solution strengthening, Zn–1Cu exhibited a much higher mechanical properties in different biodegradable metals in
TYS (148.7 MPa) than the as-extruded pure Zn (about 45 MPa). different ways. Fig. 3a(1) shows the microhardness of as-cast
Jia et al.33 investigated Zn–Mn alloys with the addition of small pure Zn and Zn–1X (Mg, Ca, Sr) binary alloys. It is clear that the
amounts of Mn (0.1, 0.4, and 0.8 wt%). The addition of Mn as-cast pure Zn had extremely low microhardness, only 38.24 
enhanced the mechanical properties of the Zn alloys, especially 1.06 Hv, but after alloying with Mg, Ca, and Sr, the microhard-
the elongation, which reached 83.96  2.36% for a Zn–0.8Mn ness was significantly increased to 78.26  2.84 Hv for as-cast
alloy. Other researchers investigated the effects of alloying Zn–1Mg, 73.00  7.43 Hv for as-cast Zn-1C, and 61.88  6.72 Hv
ternary nutrient elements on the mechanical properties of the for as-cast Zn–1Sr. Fig. 3a(2) shows the tensile properties of
alloy. Liu et al.28 reported that the TYS, UTS, and hardness of as-cast pure Zn and Zn–1X (Mg, Ca, Sr) binary alloys. It can be
Zn–Mg–Sr alloys were 108.93  14.30 MPa, 132.72  9.57 MPa seen that the YS, UTS, and elongation of as-cast pure Zn were
and 93.70  6.81 Hv for Zn–1Mg–0.1Sr, and 129.08  5.07 MPa, low, only 10.14  2.32 MPa, 18.25  2.99 MPa, and 0.32 
144.15  14.97 MPa and 109.33  8.43 Hv for Zn–1Mg–0.5Sr, 0.08%, respectively. After alloying with Mg, Ca, and Sr, the YS,
which are significantly higher than those of pure Zn, suggesting UTS, and elongation of as-cast Zn–1X binary alloys were signifi-
the effectiveness of alloying Mg and Sr on the improvement of cantly improved to 127.98  10.72 MPa, 184.84  20.91 MPa,
mechanical properties. Nevertheless, the elongation of samples and 1.82  0.23% for Zn–1Mg; 119.12  7.01 MPa, 164.57 
deteriorated from 2.60  0.54% for pure Zn to 1.38  0.42% for 13.92 MPa, and 2.10  0.23% for Zn–1Ca; and 120.21  6.08
Zn–1Mg–0.1Sr and 1.06  0.12% for Zn–1Mg–0.5Sr due to the MPa, 171.40  14.13 MPa, and 2.03  0.22% for Zn–1Sr.
presence of more eutectic mixtures along the grain boundaries. Fig. 3a(3) shows the compressive yield strength of the as-extruded
Tang et al.32 found that compared with Zn–3Cu, with increasing pure Zn and Zn–1X binary alloys. The compressive yield strength
Mg content the UTS of the Zn–3Cu–xMg ternary alloys was also improved from 102.92  6.73 MPa for pure Zn to
increased dramatically, whereas the elongation decreased due 284.50  16.90 MPa for Zn–1Mg, 280.70  20.72 MPa for
to the increase in the Mg2Zn11 phase. Kafri et al.77 compared Zn–1Ca, and 340.98  17.70 MPa for Zn–1Sr, suggesting the
the mechanical properties of pure Zn and Zn–1.3 wt% Fe and effectiveness of the alloying elements of Mg, Ca, and Sr on the
found that the addition of Fe resulted in increases in the TYS improvement of the mechanical properties of Zn.30
and UTS, but a decrease in the ductility of the Zn alloy. Fig. 3(b) shows the mechanical properties of pure Mg and
Fig. 3 shows the mechanical properties of Zn-based, Mg-based, Mg-based alloys.57 It can be seen that the addition of gallium
and Fe-based alloys as compared to pure Zn,50 Mg,57 and Fe.56 (Ga) and Sn leads to an increase in TYS, UTS, and hardness.
It can be observed that the nutrient elements influenced the However, in the case of Ga, the hardening effect is more

This journal is © The Royal Society of Chemistry 2021 J. Mater. Chem. B, 2021, 9, 9806–9825 | 9811
 View Article Online

Journal of Materials Chemistry B Review

Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

Fig. 3 (a) Mechanical properties of pure Zn and Zn–1X (Mg, Ca, Sr) binary alloys: (1) microhardness of as-cast samples, (2) tensile properties of as-cast
samples, (3) compressive yield strength (YS) of as-extruded samples;30 (b) mechanical properties of as-cast Mg-based alloys: (1) TYS – tensile yield
strength, UTS – ultimate tensile strength, (2) El– elongation, HV5 – Vickers hardness;67 (c) Compressive stress–strain curves of Fe23Mn5Si, Fe26Mn5Si,
and Fe30Mn5Si alloys and commercially pure Fe.66

pronounced, as the hardness, TYS, and UTS of Mg–4Ga are Mg-based alloys, because the Mg–4Ga showed the highest
higher than those of Mg–5Sn. Three hardening contributions elongation of 7.2% among all the tested alloys (Fig. 3b(2)).
can be expected in the Mg–4Ga and Mg–5Sn: (1) H–P hard- Plasticity in Mg-based alloys is influenced by the slip systems
ening; (2) solid-solution hardening; and (3) hardening by the available in the Mg lattice. Liu et al.74 reported that small Ga
secondary eutectic phases of Mg2Sn and Mg5Ga2 particles. The atoms introduced into the hexagonal lattice of Mg caused a
H–P hardening contribution is similar for both alloys because decrease in the c/a ratio, leading to the activation of additional
of the observed similarity in dendrite dimensions. Solid- slip planes and improvement in the plasticity.
solution hardening is caused by elastic stress induced by Fig. 3(c) shows the compressive stress–strain curves for
substitution atoms introduced into the Mg lattice which is Fe23Mn5Si, Fe26Mn5Si, Fe30Mn5Si, and commercially pure Fe.56
proportional to the atomic size mismatch between Mg and The Young’s modulus values of the Fe-based alloys determined
the alloying elements. The atomic radii of Mg, Sn, and Ga are from the unloading branch of the stress–strain curves were 145,
0.160, 0.158, and 0.135 nm, respectively.67 Ga atoms are smaller 133, and 118 GPa for Fe23Mn5Si, Fe26Mn5Si, and Fe30Mn5Si,
than Mg atoms by 16%, inducing higher elastic stress in the Mg respectively. These values are much lower than that of the
lattice than Sn atoms, whose radius is close to that of Mg commercially pure Fe (B226 GPa) and comparable with that of
atoms. The hardness and strength of the Mg alloys were also commercially pure Ti (B110 GPa), which is one of the most
influenced by the volume fractions of the secondary eutectic commonly used implant metals. An increase in Mn in the
phases. The volume fraction of the Mg5Ga2 phase in the Fe-based alloys leads to a decrease in Young’s modulus, which
Mg–4Ga alloy was observed to be slightly higher than that of is a significant mechanical property for bone-implant applications,
the Mg2Sn phase in the Mg–5Sn alloy, caused by the higher where a bone-mimicking Young’s modulus is required to avoid
solid solubility of Sn in Mg.67 In addition to the hardening and stress shielding. The compressive yield stress (s0.2) values
strengthening effects, Ga also improved the plasticity of the were 198, 211, and 171 MPa for Fe23Mn5Si, Fe26Mn5Si, and

9812 | J. Mater. Chem. B, 2021, 9, 9806–9825 This journal is © The Royal Society of Chemistry 2021
 View Article Online

Review Journal of Materials Chemistry B

Fe30Mn5Si, respectively, which were close to that of cortical the deep corrosion pits in both alloys, indicating that severe local
bone tissue measured in the longitudinal direction (B205 MPa) corrosion occurred in both the as-cast and as-rolled Mg–1.5Ge.
and higher than the value measured in the transverse direction However, as the Ge concentration increases, the boundary of the
(B131 MPa).75 Comparing the mechanical properties of the Mg–Ge matrix becomes smoother and more regular. The thick-
three Fe-based alloys, Fe30Mn5Si appeared to be the most ness of the corrosion product layer decreased with the increase in
suitable material for bone-implant applications in terms of Ge content, which indicated that local corrosion was suppressed
biomechanical compatibility. and the corrosion resistance of the alloy was improved. This is a
As mentioned above, nutrient element alloying has made typical example of how alloying can affect the corrosion behavior
Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

certain achievements in improving the mechanical properties of a substrate by forming a corrosion product layer.
of biodegradable metals, but the effects of different nutrient The slow in vivo corrosion rate of pure Fe limits its clinic
alloying content on the mechanical properties of alloys vary. application as a potential biodegradable metal. Therefore, the
Seong et al.76 revealed that a high volume fraction of Mg2Ca research on Fe-based alloys has focused on increasing the
particles could lead to deterioration in the ductility of Mg–Ca corrosion rate of pure Fe. At present, the most extensively
alloy sheets with Ca content r1 wt% even though they were studied Fe-based alloys are the Fe–xMn alloys. However, there
well refined and dispersed. This was because the interface is still controversy about the effect of Mn on the corrosion
between Mg and Mg2Ca was not coherent and the interfacial resistance of Fe–Mn alloys. Drynda et al.82 found that when the
bonding was weak, thereby easily causing cavities and micro- Mn content was less than 10 wt%, a Fe–Mn alloy exhibited
cracks at the interfaces during plastic deformation. Zeng et al.77 excellent corrosion resistance. Hermawan et al.65 found that all
found that an Mg–0.79Ca alloy had the highest hardness Fe–Mn alloys had a higher corrosion current density (Icorr) than
(58.3 HV) and UTS (B200 MPa) in comparison with Mg–0.54Ca that of pure Fe. In general, the Icorr increased with decreasing
and Mg–1.35Ca alloys due to the uniform distribution of Mg2Ca Mn content and the corrosion rate was higher for double g + e
particles. phase alloys than for single g phase alloys.
Shi et al.27 found that the addition of Ca decreased the
corrosion resistance of a Zn–0.8Mn alloy in simulated body
4. Effect of nutrient alloying elements fluid (SBF). The Zn–0.8Mn alloy showed a high corrosion
on corrosion and degradation behavior potential (Ecor) value of 1.07 V, which was lowered by the
of biodegradable metals addition of Ca, indicating a tendency to corrode more easily.
Zhao et al.34 found that the earlier degradation of Zn–Li alloy
Pure Mg degrades too quickly in the physiological environment, wire was a little slower than that of 4 N Zn (99.99% pure Zn) and
which causes insufficient mechanical integrity of the implant the benchmark for ideal degradation (0.02 mm per year) of
metal before tissue healing.78 On the contrary, the degradation medical implants; however, the degradation of the Zn–Li alloy
rate of Fe-based alloys is low, which makes it difficult to apply was accelerated to 0.019 mm per year at 9 months and
to the clinic, and the long-term retention of the degradation 0.046 mm per year at 12 months, which is twice as high as
residues of the materials in the human body will cause long- that of the 4 N Zn sample. This acceleration in the later stage
term complications.8,79 The corrosion rate of Zn is the most was preferred in stent applications because the alloy dissolved
suitable, but its mechanical properties need to be improved. quickly in the body after completing its supporting function.
The addition of nutrient alloying elements to biodegradable Kafri et al.86 compared the degradation behaviors of pure Zn
alloys can regulate the degradation and corrosion behaviors of and Zn–1.3 wt% Fe and found that the addition of Fe acce-
the alloys. Table 4 lists the effects of nutrient element alloying lerated the corrosion rate of Zn. Fig. 5 shows SEM images of the
on the degradation behavior of biodegradable alloys. corrosion morphologies of Zn–1.3 wt% Fe after 10 days of
Hermawan et al.85 reported the corrosion behaviors of exposure to phosphate-buffered saline (PBS). The macro view
Fe–Mn alloys with different Mn content. The corrosion attack reveals a uniform corrosion attack on the external surface
of Fe25Mn was slightly deeper than of Fe35Mn. Fe25Mn was (Fig. 5a). This phenomenon is in line with the basic degrada-
composed of e and g phases, which formed micro galvanic sites tion requirements for biodegradable implants, i.e., to maintain
susceptible to corrosion initiation, while Fe35Mn exhibited their mechanical integrity during the critical initial phase of
only a g phase. It was also found that intergranular corrosion, implantation and then to degrade without the risk of prema-
which preferentially attacks grain boundaries, was more evident in ture implant fracture. At higher magnification (Fig. 5b), intact
Fe25Mn than Fe35Mn. Zn11Fe particles are seen in the vicinity of the corroded matrix.
Bian et al.35 reported the corrosion behavior of Mg–xGe This is presumed to be due to the accelerated degradation of
alloys (x = 1.5, 2.5, and 3.0 wt%). Fig. 4(a) shows the typical Zn11Fe particles as the cathodic phase (0.87 Vsce for Zn11Fe vs.
corrosion morphology of Mg–Ge alloys after immersion in 1.03 Vsce for pure Zn87) through the micro galvanic effect.
Hanks’ solution for 3 and 30 days. A layer of corrosion products This mechanism can explain the higher corrosion rate of the
forms on the surface of the alloy sample, which appears as a Zn–1.3 wt% Fe alloy compared to pure Zn as quantified by
white lumpy or granular deposit. Fig. 4(b) shows the corres- immersion testing.
ponding cross-section morphologies of the alloys. It can be Tang et al.31 found that with increasing Cu concentration,
seen that a thick layer of corrosion products was formed above the corrosion rates of Zn–xCu alloys generally exhibited little

This journal is © The Royal Society of Chemistry 2021 J. Mater. Chem. B, 2021, 9, 9806–9825 | 9813
 View Article Online

Journal of Materials Chemistry B Review

Table 4 Effects of nutrient alloying elements on degradation behavior of biodegradable metals

Corrosion rate (in vitro)

Corrosion
Corrosion rate
Ele. Alloys Corrosion medium Method rate Mechanism (in vivo) Ref.
Ca Zn–0.8Mn–0.4Ca SBF Electrochemical m — 27
tests
Ca Mg–x wt% C (x = 0.5, Hank’s solution Electrochemical m Higher electrochemical activity of — 80
1.25, 2.5, 5 and 10) tests Mg2Ca than a-Mg
m
Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

Ca Zn–1Ca Hank’s solution Electrochemical Ecorr = 1019 mV, lower than that of _ 30
tests pure Zn (—988 mV)
Na As-cast Hank’s solution Electrochemical k The even diffusion of Na in Mg2Sn and k 64
Mg4.6Sn2.4Zn0.07Na tests the solid soluble Zn in Mg contributed
and as-extruded reduced galvanic effects of the alloys
Mg6Sn5Zn0.3Na
Mg Mg SBF Electrochemical 0.20 (3 — Corrode 13
measurements days) rapidly
Mg Zn–3Cu–0.1Mg; Hank’s solution Immersion tests m Increase in Mg concentration led to — 32
Zn–3Cu–0.5Mg; decrease in protection of oxide film
Zn–3Cu–1.0Mg
Mg Zn–1Mg Hank’s solution Electrochemical m Ecorr = 999 mV, lower than that of — 30
measurements pure Zn (988 mV)
Fe Pure iron SBF Immersion tests 0.2 mm — Corrodes 81
per year slowly and
82
Zn Pure zinc as extruded SBF Immersion tests 0.6 mm — Corrodes 81
per year moderately and
fast 83
Zn Mg–6Zn SBF Electrochemical k Zn addition led to enhanced corrosion k 13
measurements potential of Mg alloys and improved
corrosion resistance
Cu Zn–0.8Mn–0.4Cu SBF Electrochemical m Highest Ecor of 1.07 V for Zn–0.8Mn; — 27
tests addition of Cu or Ca led to a decrease
in Ecor
Mn Fe–30Mn Modified Hank’s Immersion tests m Fe30Mn composed of g + e phases, — 65
solution (H1387, leading to micro galvanic sites
Sigma Aldrich,
Canada)
Mn Zn–0.1Mn, Zn–0.4Mn, SBF Electrochemical m — — 33
and Zn–0.8Mn tests
Sr Zn–1.5Mg–0.1Sr Hank’s solution Immersion tests m More active secondary phase resulted — 84
in galvanic corrosion
Sr Zn–1Sr Hank’s solution Electrochemical m Ecorr of Zn–1Sr = 1031 mV, lower than — 30
measurements that of pure Zn (988 mV)
Si Fe30Mn5Si SBF Electrochemical m SiO2 formed on surface, acting as — 66
measurements cathodic sites, facilitating cathodic
reaction that limited overall corrosion
process
Sn Mg–5Sn SBF Electrochemical k Sn addition caused reduction of anodic — 67
measurements current density
Li Zn–Li SBF Electrochemical k Precipitates acting as an anodic barrier m 34
measurements and formation of a layer of corrosion
product inhibited overall corrosion
rate.
Ge Mg–xGe (x = 1.38, Hank’s Electrochemical k A thin corrosion product layer on alloy k 35
2.53, and 3.26 wt%) measurements surface strongly bonded to substrate
and provided protection

increase compared with pure Zn. Liu et al.28 found that all the Mg2Zn11 eutectic phase. The standard potential of Mg2Zn11 was
corrosion potentials (Ecorr) of Zn–Mg–Sr alloys were lower than reported to be lower than that of the Zn matrix. With increasing
that of pure Zn. In addition, the Icorr and corrosion rate (Vcorr) of Mg content, the volume fraction of Mg2Zn11 increased and the
Zn–Mg–Sr alloys were significantly improved compared to those Mg addition contributed to weakening the oxide film on
of pure Zn, which may be linked to the formation of galvanic the alloys. Thus, Zn–3Cu–xMg alloys corroded faster than the
micro-cells between Zn and SrZn13 or Zn and MgZn2, leading to Zn–3Cu alloy.
accelerated corrosion of the substrate.88 Tang et al.32 found that Zhang et al.13 found that Zn caused an increase in the
with increasing Mg content, the in vitro degradation rate of corrosion potential of an Mg–Zn alloy and the in vitro degrada-
Zn–Cu–Mg alloys increased. This might be explained by the tion rate of an Mg–6Zn alloy was slower than that of high-purity
difference in standard potential between the Zn matrix and the Mg in SBF. A protective layer of hydroxyapatite (HA) and other

9814 | J. Mater. Chem. B, 2021, 9, 9806–9825 This journal is © The Royal Society of Chemistry 2021
 View Article Online

Review Journal of Materials Chemistry B

Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

Fig. 4 SEM images of Mg–Ge alloys after immersion in Hanks’ solution for 3 and 20 days: (a) surface morphologies; (b) cross-sections (CP: corrosion
products).35

Mg/Ca phosphates formed on the surface of Mg–6Zn when Fig. 6. There are two mechanisms for modulating the corrosion
immersed in SBF. Kubásek et al.67 found that the addition of Sn performance of biodegradable metals. (1) The mechanism by
improved the corrosion resistance of an Mg–Sn alloy in SBF and which alloying inhibits the corrosion rate of the matrix is illu-
1 wt% of Sn was enough to reduce the corrosion rate. The strated in the left part of Fig. 6. The formation of a compact
corrosion potentials of Mg–Sn alloys were shifted to positive corrosion product layer on the surface of biodegradable alloys by
values in comparison with pure Mg because the standard adding nutrient elements can inhibit the progression of corro-
potentials of Mg and Sn are 2.38 V and +0.15 V, respectively. sion. (2) The mechanism by which alloying accelerates the corro-
The potentiodynamic curves of Mg–Sn alloys also demonstrated sion rate of the matrix is illustrated in the right part of Fig. 6. The
a reduction in anodic current density caused by the addition intermediate phase forms electrochemical corrosion. In such a
of Sn. Liu et al.64 found that micro-alloyed Na along with case, electrochemical microcells form between the matrix and the
its homogenous distribution helped to reduce the corrosion second phase, and the corrosion potential of the second phase is
potential difference between the a-Mg matrix and second higher than that of the matrix, leading to an accelerated corrosion
phase, resulting in a doubled corrosion resistance compared rate of the matrix. For Fe-based alloys, the introduction of
to Mg6Sn5Zn due to a reduced galvanic effect. This study electrochemical microcells due to secondary phases can increase
demonstrated that the distribution of Na in Mg2Sn was critical the corrosion rate of the alloys, thus solving the problem of
to the corrosion resistance. Gu et al.72 found that the addition low degradation in the physiological environment. In addition,
of Mn and Si improved the corrosion potential of as-cast nutrient elements can regulate the corrosion behavior of bio-
Mg–Mn and Mg–Si alloys, and the addition of Ag, Si, or Y degradable metals by combining with impure elements and thus
increased the corrosion current densities of as-cast Mg–Ag/Si/Y reducing defects.
alloys in both SBF and Hanks’ solution.
The mechanism of the role of nutrient elements in regulating
the corrosion performance of biodegradable metals is shown in
5. Effects of nutrient alloying elements
on biocompatibility of biodegradable
metals
5.1 In vitro and in vivo studies on alloying of nutrient
elements
Once the material is implanted in the body, a local chemical
reaction occurs with the host cell/tissue at the interface and all
implanted stents and prostheses induce an immediate host
response. Only metallic alloys with ideal biocompatibility and
biodegradability can be a suitable candidate as potential biode-
Fig. 5 SEM images of cross sections showing corrosion attack on Zn–1.3 wt%
gradable metals.2,89
Fe alloy after 10 days of exposure to phosphate-buffered saline (PBS): (a) macro Implantation of biodegradable metals into a living host can
view; (b) close-up view.86 interact with tissue in four ways:90 (i) toxic: the implantation of

This journal is © The Royal Society of Chemistry 2021 J. Mater. Chem. B, 2021, 9, 9806–9825 | 9815
 View Article Online

Journal of Materials Chemistry B Review

Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

Fig. 6 Corrosion mechanism of biodegradable metals containing nutrient elements.

biological materials into the human body will have adverse indispensable to evaluate the biocompatibility of its corrosion
effects on surrounding tissues, such as inflammation, immune products. Virtanen et al.109 showed that the alkaline pH shift, as
response, and cell death, etc.; (ii) bioinert (biologically inactive, well as H2 gas evolution on corroding Mg-based alloys surface,
non-toxic): the material has no interaction with surrounding could drastically affect in vitro cell viability. Therefore, the study
tissues, or only a small amount interaction. However, adverse of the biocompatibility of the corrosion products of Mg-based
reactions may still occur when implanted in the human body alloys should be focused on. Li et al.98 reported that cytocom-
(fibrous tissue may coat the device and cause the device to fail); patibility evaluation using L-929 cells revealed that an Mg–1Ca
(iii) bioactive (non-toxic): the material can form a close relation- alloy did not induce toxicity to cells and high activity of
ship with the surrounding tissue; (iv) bioabsorbable: the mate- osteoblasts and osteocytes was observed around Mg–1Ca alloy
rial (non-toxic) gradually dissolves In the body, the implant pins after implantation into rabbit femoral shafts for 1, 2, and 3
(such as a stent) only works temporarily, and the surrounding months. Radiographic examination revealed that the Mg–1Ca
tissue eventually replaces the material. alloy pins gradually degraded in vivo within 90 days and newly
Table 5 summarizes the effects of nutrient elements on the formed bone was clearly seen at month 3. Wang et al.106
biocompatibility of different biodegradable metals. Recent reported that the corrosion products of Mg65.2xZn30Ca4Mn0.8Srx
studies have shown that most alloys containing nutrient elements (x = 0, 0.3, 0.5, and 0.8) were Zn(OH)2, HA, and phosphate, which
possess the fourth tissue response: they are bioabsorbable. To promote bone growth. Evaluation of the cellular behavior demon-
date, Mg and Fe alloys have been extensively investigated.3,91–96 strated that a Sr-0.5 alloy showed well in vitro cytocompatibility,
Certain Mg-based alloys have already been successfully tested and the cell viability observed by optical microscopy indicated that
in vivo and clinical studies. Fe-based degradable metals possess the osteoblast cells had a growing tendency in 30% and 50%
good biocompatibility, and the most common Fe-based alloys are Sr-0.5 extraction mediums (Fig. 7).
the Fe–Mn alloys.29 Zn is an essential element in the human body Zn-based alloys have an antibacterial property and Zn alloy
and plays a significant role in metabolism, such as being involved implants generally possess good biocompatibility in the human
with many enzymes for protein and transcription factor syn- body. For example, Zhao et al.34 implanted 10 mm long Zn–Li
thesis;97 therefore, the release of Zn ions during degradation wire segments into the abdominal aorta of rats and found
can participate in normal metabolism with no toxicity or side excellent biocompatibility of this material in the arterial
effect.84 environment, as wide-open arterial lumens and low neointimal
Mueller et al.107 found that when soluble ferrous ions were growth around the implant are evident from the images, although
added to the culture medium, the growth rate of the smooth inflammation and neointima thickness appeared to be slightly
muscle cell declined, which indicates that the degradation higher for Zn–Li compared with high-purity zinc (Fig. 8).
products of Fe stent could possess positive effects on the
control of neointima proliferation; the inhibition of neointima 5.2 Clinical effects of nutrient elements
proliferation was probably due to the toxicity of Fe(II) on 5.2.1 Clinical application cases of nutritional elements.
smooth muscle cells. Hermawan et al.108 demonstrated that Many of the nutrient elements have been diffusely used in
pure Mn showed the highest metabolic inhibition effect on 3T3 various biodegradable implants in clinical applications. As the
fibroblast cells and Fe35Mn showed a lower inhibitory effect. most abundant mineral in the human body, Ca has a variety of
Mg, as an essential mineral element in the human body, has cellular functions and is essential for the formation and main-
good biocompatibility, but due to its rapid corrosion rate, it is tenance of bones and teeth. There are many clinical cases of Ca.

9816 | J. Mater. Chem. B, 2021, 9, 9806–9825 This journal is © The Royal Society of Chemistry 2021
 View Article Online

Review Journal of Materials Chemistry B

Table 5 Effects of nutrient elements on the biocompatibility of biodegradable metals

Biocompatibility
In vitro In vivo
Ele. Materials Cell type Biocompatibility Animals Biocompatibility Ref.
Ca Mg–1Ca L-929 Healthy morphology with a flattened Rabbis Observed periosteal reaction 98
spindle shape
Ca Zn–0.8Mn–0.4Ca L929 Addition of Ca alleviated cytotoxicity — — 27
Ca Zn–1Ca MG63 Significantly increased MG63 viability Mice No inflammation observed around 30
Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

and promoted MG63 proliferation implantation site; no mouse died after

operation
Na As-cast MC3T3-E1 Good biocompatibility Mice Enhanced bone regeneration 64
Mg4.6Sn2.4Zn0.07Na; cells
as-extruded
Mg6Sn5Zn0.3Na
Mg Zn–3Cu–0.1Mg; EA. hy926 Only Zn–3Cu–0.5Mg and Zn–3Cu– — — 32
Zn–3Cu–0.5Mg; 1.0Mg meet the cytotoxicity standard
Zn–3Cu–1.0Mg for biodegradable metals
Mg Zn–1Mg MG63 Significantly increased MG63 viability Mice No inflammation observed around 30
and promoted MG63 proliferation implantation site; no mouse died after
operation
Fe Iron SMCs and ECs Good biocompatibility. NMRI No inflammatory response or 4
mice neointimal proliferation; no systemic and
toxicity 82
Zn, Mg–5.25 wt% Zn–0.6 MG63 Grade 0–1 cytotoxicity for 2 and 10 Mice No systemic effects 99
Ca wt% Ca times dilution extracts
Zn Mg–6Zn L-929 Good biocompatibility Rabbits Good biocompatibility 13
Zn Pure Zn as extruded — Good biocompatibility Rabbits No severe inflammation, platelet 83
aggregation, thrombosis formation,
or obvious intimal hyperplasia
Cu Zn–3Cu EA. hy926 Good biocompatibility — — 32
cells
Mn Zn–0.1Mn, Zn–0.4Mn, MC3T3-E1 Mn addition significantly improved Mice Desirable in vivo biosafety and no ion 33
and Zn–0.8Mn cytocompatibility of pure Zn accumulation in organs
Mn Fe–25Mn 3T3 Low inhibition to fibroblast viability — — 100
Fe–30Mn L929 Mild local irritant; no systemic adverse — — 101–
reaction 103
Sr Mg–xSr (x = 1, 2 wt%) MG63 Grade 1 cytotoxicity Mice Increased bone thickness 104
Sr Zn–1Mg–0.1Sr; Zn– PRP No significant destructive effect on — — 28
1Mg–0.5Sr erythrocyte
Sr Zn–1Sr MG63 Significantly increases MG63 viability; Mice No inflammation observed around 30
promoted MG63 proliferation implantation site; no mouse died
after operation
Si Fe30Mn5Si MC3T3-E1 No significant cytotoxicity derived — — 105
from Si ions for Mg2Si extract
Sn Mg–1Sn Human osteo- Cells were viable even after 5 days at — — 67
sarcoma cells r163 ng mL1 Sn
(U-2 OS)
Li Zn–Li — — Mice Excellent biocompatibility 34
Ge Mg–xGe (x = 1.38, 2.53, Osteoblasts Osteoblast cells showed growth — — 106
and 3.26 wt%) tendency

Calcium carbonate (CaCO3) and Calcium gluconate are diffusely zinc oxide–zinc citrate tablets, zinc gluconate tablets, etc. are all
used as dietary supplements.110 Najeeb et al.102 showed that local drugs that have been used clinically. In addition, Zn has been
Ca delivery in the form of hydroxyapatite enhanced osseointegra- intensively studied as a biodegradable metal in recent years but
tion in dental implants. The results from this clinical study also has not yet been clinically used.
suggested that Zn supplementation may possess a positive effect The main clinical example of Na is sodium alginate (SA),
on healing and osseointegration around implants.111,112 Calcium which is a polyanionic polysaccharide extracted from brown
sulfate has been used as an antibiotically impregnated bone algae that combines the structures of b-D-mannose-hyaluronic
substitute in a variety of clinical constellations.113 Calcium hydro- acid and a-L-glutamine hyaluronic acid.114 Due to its high
xide paste, which is mainly used for pulp protection and base hydrophilicity, good biodegradability and biocompatibility,
material, and as a pulp-capping agent or sealing agent for root and low cost, SA has been diffusely used in wound dressings
canal filling, is managed according to the three types of medical and scaffolds for tissue engineering.115
devices. Other microelements used in biodegradable metals are also
Zn is also one of the essential nutrients in the human body supported by relevant examples. Sr is considered a significant
and has a variety of clinical applications; zinc sulfate tablets, trace element for the osteogenic formation and strontium

This journal is © The Royal Society of Chemistry 2021 J. Mater. Chem. B, 2021, 9, 9806–9825 | 9817
 View Article Online

Journal of Materials Chemistry B Review

Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

Fig. 7 Optical microscopy images and cell viability of osteoblasts cultured onto Mg alloy substrates with different Sr content for 72 h.106

ranelate has been diffusely used as an oral prescription against of pharmacological effects, such as enhancement of osteoblast
osteoporosis.116 Xu et al.117 found that Li was also incorporated activity, prevention of mineral decomposition in elderly osteo-
into Ti implants118,119 and greater bone mass and bone density porosis, a variety of immunological effects, antitumor activity,
were observed in patients.120,121 Li incorporated with sand- and antiviral activity.131 Tin, as traditional Chinese medicine,
blasted, large-grit, and acid-etched Ti implants via a hydro- has the reported effects of clearing heat and detoxifying the
thermal treatment enhanced osteogenesis by stimulating the body, dispelling decay, and regenerating muscle. It can be used
Wnt/b-catenin signaling pathway, inhibiting the formation of for boils and swellings, prune sores, and malignant wind sores.
osteoclasts, and controlling the balance between osteoblasts In addition, organotin has been diffusely studied as a potential
and osteoclasts.118 Cu has been found to possess an antibacterial anti-tumor substance.132
property since 1885.122 Nowadays, Cu is added into implant 5.2.2 Clinical applications of biodegradable metals for
materials to give antimicrobial properties to stainless steels,123,124 biomedical applications. Mg-based orthopedic implants date
Ti-based alloys,125 and cobalt-based alloys.126 Previous studies have back more than a century. In February 2016 Biotronik’s Dreams
demonstrated the biocompatibility and osteogenic promotion 2G Mg stent became the first CE-approved absorbable metal
effect of Mg–Cu alloys as a biodegradable bone implant.127,128 stent to be marketed in Europe.21 To date, the clinical use of
Mn is critical for antitumor immune responses via cGAS-STING Magnezix (Magnezixs Mg-based bone screws manufactured and
and improves the efficacy of clinical immunotherapy. More impor- sold by Neoteric in Germany) series screws has been extended to
tantly, a completed phase 1 clinical trial in patients with advanced over 50 countries/regions. Mg–Y–RE–Zr alloy screws were applied
metastatic solid tumors provided encouraging evidence of the to treat a mild hallux valgus fracture in thirteen patients, with
manageable safety profile and antitumor effects of Mn2+.129 Impor- a 6-month follow-up for observation and assessment.129 The Mg-
tantly, clinical observations suggested that Mn2+ administration based screw had an equivalent outcome compared to the Ti
triggered type I IFN induction and manageable suspected cytokine- control group based on the American Orthopaedic Foot and
release syndrome, augmenting and/or reviving patient responses to Ankle Society clinical rating score for the thumb, a visual analog
immunotherapy. The results of this phase 1 study, therefore scale for pain assessment, and the range of motion of the first
warranted its potential in future clinical applications.129 Silicon metatarsophalangeal joint (Fig. 9a).129 The South Korea U&I
nitride has been used for over 30 years in clinical applications company developed K-MET screws made of a MgCaZn alloy
for porous intervertebral spacers in spinal fusion surgery with- (Fig. 9b) for distal radius fracture repair.20 Fractures healed
out showing any undesirable long-term effects.130 Organic completely 6 months after surgery and the Korea Food and Drug
Ge compound (poly-trans-[(2-carboxyethyl)germasesquioxane], Administration approved the MGCAZN screw for clinical use in
Ge-132) is a low-toxic compound that possesses a wide range April 2015.20

9818 | J. Mater. Chem. B, 2021, 9, 9806–9825 This journal is © The Royal Society of Chemistry 2021
 View Article Online

Review Journal of Materials Chemistry B

Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

Fig. 9 Clinical use of Mg-based screws in orthopedics: (a) Mg–Y–RE–Zr

Fig. 8 Hematoxylin and eosin (H&E) staining of arterial explants of Zn–Li alloy screws applied to treat mild hallux valgus fracture in thirteen patients;
wire after implantation in abdominal aorta of rats for 11 months: (a) high- (b) Mg–Ca–Zn alloy screws used to fix distal radius fracture;22 (c) high-purity
purity zinc; (b) Zn–Li; (c) locally enlarged image of green asterisk position Mg (99.99%) screws used to fix vascularized bony flap for hip-preservation
in (a); (d) locally enlarged image of green asterisk position in (b); (e) locally treatment in 23 patients.20,133
enlarged image of red asterisk position in (a); (f) locally enlarged image of
red asterisk position in (b). ‘‘L’’ is the luminal opening of the artery. ‘‘W’’
identifies the wire cross section in (a). The black star in the right column available, filling an international gap in the treatment of
identifies the wire location, which became dislocated during histological
pulmonary vascular stenosis in children.
staining of the specimen.34
On October 19, 2020, a biodegradable zinc alloy cranio-
maxillofacial internal fixation system was applied in the
Department of Maxillofacial Trauma of the Air Force Military
A 99.99% high-purity Mg orthopedic internal fixation Medical University Stomatology Hospital. This is the first
implant was fabricated by Eontec in Guangdong, China.23 international application of zinc alloy biodegradable material
These high-purity Mg screws were used to fix the autologous in the medical clinical field, which is an important break-
vascularized bone flap in the treatment of avascular necrosis through and innovation in the medical field and marks the
of the femoral head in a patient (Fig. 9c) and were shown to upcoming ‘‘zinc’’ era in the medical field.
possess a 12-month long effect.24 These screws were also
successfully used for fixation of vascularized iliac grafts in
the treatment of displaced femoral neck fractures in young 6. Outlook and future research
adults, providing better results than a control group with directions of nutrient alloying elements
conventional implants and reducing complications such as in biodegradable metals
vascular necrosis and non-connection.25 The Mg screws were
officially approved by the National Medical Products Admin- Considering their good mechanical properties, biodegradation
istration of China (NMPA) for multicenter clinical trials in the behavior, and biocompatibility, nutrient-containing biodegrad-
treatment of steroid-induced osteonecrosis in 2019. able metals have great potential as future biomedical materials
Fe-based biodegradable metals have been used to manu- and devices, including orthopedic implants, cardiovascular
facture medical sutures since the 17th century.18,19 It is worth stents, and biliary stents, as shown in Fig. 10.
noting that Fe-based biodegradable stents have recently made a As shown in Fig. 11, future research directions for biodegrad-
major breakthrough. Life-tech Scientific recently announced able metals containing nutrient alloying elements can be focused
that its subsidiary, Yuanxin Technology, has independently on the following three main aspects: (1) exploring new alloy
developed an innovative product, the IBS Angel Fe-based absorb- systems, especially for Zn-based and Fe-based biodegradable
able stent system (IBS Angel), which has received registration metals; (2) investigating the effects of nutrient alloying elements
from the Malaysian Drug Regulatory Authority and is the first and their concentrations on the in vitro and in vivo properties of
Fe-based absorbable vascular scaffold to be commercially biodegradable metals; and (3) applying new processing technology

This journal is © The Royal Society of Chemistry 2021 J. Mater. Chem. B, 2021, 9, 9806–9825 | 9819
 View Article Online

Journal of Materials Chemistry B Review

Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

Fig. 10 Potential clinical applications of biodegradable metals containing nutrient alloying elements.

(2) The addition of nutrient elements improves the mechan-

ical properties of the base alloys through three main mechan-
isms: Hall–Petch strengthening, solid-solution strengthening,
and second-phase strengthening. In summarizing the results of
recent studies, we have found that alloying with nutrient
elements can effectively improve the mechanical properties of
biodegradable metals.
(3) The corrosion rates of Mg-based alloys are usually too
fast but can be slowed down by adding high-potential elements
such as Zn and Si to increase the corrosion potential of Mg alloys.
(4) As for Fe-based alloys, studies have shown that the
addition of nutrient elements can generally increase the corro-
sion rate effectively; for example, Mn forms a second phase
Fig. 11 Future research directions for nutrient alloying elements in bio- different from the electronegativity of the matrix, increasing the
degradable metals. galvanic corrosion caused by the difference in electronegativity.

to further improve the comprehensive properties of biodegradable Conflicts of interest

metals containing nutrient alloying elements containing such as
3D printing and 4D printing processes. There are no conflicts to declare.

7. Summary Acknowledgements
This work is supported by the National Natural Science Foundation
Ideal medical implants require materials with adequate mechan-
of China (No. 31700819), the Young Elite Scientists Sponsorship
ical properties, suitable corrosion resistance, and good biocompat-
Program by CAST (YESS, No. 2018QNRC001), the Fundamental
ibility. The present review has discussed the effects of nutrient
Research Funds for the Central Universities and the Youth Teacher
alloying elements on the mechanical properties, corrosion resis-
International Exchange & Growth Program (No. QNXM20210021).
tance, degradation behavior, and biocompatibility of biodegrad-
able metals and alloys. The main conclusions are as follows:
(1) All biodegradable metals including Mg alloys, Fe alloys, References
and Zn alloys with the addition of nutrient elements show good
biocompatibility; however, the addition of different types of 1 Y. Zheng, B. Liu and X. N. Gu, Research Progress in
nutrient elements and their concentrations should be carefully Biodegradable Metallic Materials for Medical Application,
designed to prevent toxicity of high doses. Mater. Rev., 2009, 23, 1–6.

9820 | J. Mater. Chem. B, 2021, 9, 9806–9825 This journal is © The Royal Society of Chemistry 2021
 View Article Online

Review Journal of Materials Chemistry B

2 Y. Liu, Y. Zheng, X. H. Chen, J. A. Yang, H. Pan, D. Chen, 17 K. Soetan, C. Olaiya and O. Oyewole, The importance of
L. Wang, J. Zhang, D. Zhu and S. Wu, Fundamental theory mineral elements for humans, domestic animals and
of biodegradable metals—definition, criteria, and design, plants-A review, Afr. J. Food Sci., 2010, 4(5), 200–222.
Adv. Funct. Mater., 2019, 29(18), 1805402. 18 J. M. Seitz, M. Durisin, J. Goldman and J. W. Drelich,
3 M. Ulum, A. Arafat, D. Noviana, A. Yusop, A. Nasution, M. A. Recent advances in biodegradable metals for medical sutures:
Kadir and H. Hermawan, In vitro and in vivo degradation a critical review, Adv. Healthcare Mater., 2015, 4(13),
evaluation of novel iron-bioceramic composites for bone 1915–1936.
implant applications, Mater. Sci. Eng., C, 2014, 36, 336–344. 19 D. Xia, F. Yang, Y. Zheng, Y. Liu and Y. Zhou, Research
Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

4 H. F. Li, Y. F. Zheng and L. Qin, Progress of biodegradable status of biodegradable metals designed for oral and
metals, Prog. Nat. Sci.: Mater. Int., 2014, 24(5), 414–422. maxillofacial applications: A review, Bioact. Mater., 2021,
5 U. Kamachimudali, T. Sridhar and B. Raj, Corrosion of bio 6(11), 4186–4208.
implants, Sadhana, 2003, 28(3), 601–637. 20 J.-W. Lee, H.-S. Han, K.-J. Han, J. Park, H. Jeon, M.-R. Ok,
6 J. S. Temenoff and A. G. Mikos, Biomaterials: the intersec- H.-K. Seok, J.-P. Ahn, K. E. Lee and D.-H. Lee, Long-term
tion of biology and materials science, Pearson/Prentice Hall, clinical study and multiscale analysis of in vivo biodegra-
Upper Saddle River, NJ, USA, 2008. dation mechanism of Mg alloy, Proc. Natl. Acad. Sci. U. S.
7 Y. Yun, Z. Dong, N. Lee, Y. Liu, D. Xue, X. Guo, J. Kuhlmann, A., 2016, 113(3), 716–721.
A. Doepke, H. B. Halsall and W. Heineman, Revolutionizing 21 L. Hongwei, Y. Han, W. Juanjie and X. Liang, Research
biodegradable metals, Mater. Today, 2009, 12(10), 22–32. Progress of Bioresorbable Stents, China Med. Devices, 2021,
8 J. Cheng, B. Liu, Y. Wu and Y. Zheng, Comparative in vitro 36(1), 171–174.
study on pure metals (Fe, Mn, Mg, Zn and W) as biodegrad- 22 H. Windhagen, K. Radtke, A. Weizbauer, J. Diekmann,
able metals, J. Mater. Sci. Technol., 2013, 29(7), 619–627. Y. Noll, U. Kreimeyer, R. Schavan, C. Stukenborg-
9 M. Schinhammer, A. C. Hänzi, J. F. Löffler and P. J. Colsman and H. Waizy, Biodegradable magnesium-based
Uggowitzer, Design strategy for biodegradable Fe-based screw clinically equivalent to titanium screw in hallux
alloys for medical applications, Acta Biomater., 2010, 6(5), valgus surgery: short term results of the first prospective,
1705–1713. randomized, controlled clinical pilot study, Biomed. Eng.,
10 R. Zan, W. Ji, S. Qiao, H. Wu, W. Wang, T. Ji, B. Yang, 2013, 12(1), 1–10.
S. Zhang, C. Luo and Y. Song, Biodegradable magnesium 23 D. Zhao, F. Witte, F. Lu, J. Wang, J. Li and L. Qin, Current
implants: a potential scaffold for bone tumor patients, Sci. status on clinical applications of magnesium-based ortho-
China Mater., 2021, 64(4), 1007–1020. paedic implants: A review from clinical translational per-
11 S. Zhang, X. Zhang, C. Zhao, J. Li, Y. Song, C. Xie, H. Tao, spective, Biomaterials, 2017, 112, 287–302.
Y. Zhang, Y. He and Y. Jiang, Research on an Mg–Zn alloy 24 D. Zhao, S. Huang, F. Lu, B. Wang, L. Yang, L. Qin, K. Yang,
as a degradable biomaterial, Acta Biomater., 2010, 6(2), Y. Li, W. Li and W. Wang, Vascularized bone grafting fixed
626–640. by biodegradable magnesium screw for treating osteone-
12 D. Zhu, I. Cockerill, Y. Su, Z. Zhang, J. Fu, K. W. Lee, J. Ma, crosis of the femoral head, Biomaterials, 2016, 81, 84–92.
C. Okpokwasili, L. Tang, Y. Zheng, Y. X. Qin and Y. Wang, 25 X. Yu, D. Zhao, S. Huang, B. Wang, X. Zhang, W. Wang and
Mechanical Strength, Biodegradation, and in Vitro and in X. Wei, Biodegradable magnesium screws and vascularized
Vivo Biocompatibility of Zn Biomaterials, ACS Appl. Mater. iliac grafting for displaced femoral neck fracture in young
Interfaces, 2019, 11(7), 6809–6819. adults, BMC Musculoskeletal Disord., 2015, 16(1), 1–6.
13 S. X. Zhang, X. N. Zhang, C. L. Zhao, J. A. Li, Y. Song, 26 X. X. Shao, X. Wang, Y. P. Liu, J. Y. Bai and G. Y. Zhou, Zinc
C. Y. Xie, H. R. Tao, Y. Zhang, Y. H. He, Y. Jiang and alloy degradable bone plate, CN210056199U, 2020.
Y. J. Bian, Research on an Mg-Zn alloy as a degradable 27 Z.-Z. Shi, J. Yu, X.-F. Liu, H.-J. Zhang, D.-W. Zhang, Y.-X.
biomaterial, Acta Biomater., 2010, 6(2), 626–640. Yin and L.-N. Wang, Effects of Ag, Cu or Ca addition on
14 W.-D. Mueller, M. L. Nascimento and M. F. L. De Mele, microstructure and comprehensive properties of biode-
Critical discussion of the results from different corrosion gradable Zn-0.8 Mn alloy, Mater. Sci. Eng., C, 2019, 99,
studies of Mg and Mg alloys for biomaterial applications, 969–978.
Acta Biomater., 2010, 6(5), 1749–1755. 28 X. W. Liu, J. K. Sun, Y. H. Yang, F. Y. Zhou, Z. J. Pu, L. Li
15 H. Bakhsheshi-Rad, E. Hamzah, H. Low, M. Kasiri- and Y. F. Zheng, Microstructure, mechanical properties,
Asgarani, S. Farahany, E. Akbari and M. Cho, Fabrication in vitro degradation behavior and hemocompatibility of
of biodegradable Zn-Al-Mg alloy: mechanical properties, novel Zn-Mg-Sr alloys as biodegradable metals, Mater.
corrosion behavior, cytotoxicity and antibacterial activities, Lett., 2016, 162, 242–245.
Mater. Sci. Eng., C, 2017, 73, 215–219. 29 R. Gorejová, L. Haverová, R. Oriňaková, A. Oriňak and
16 R. J. Guillory, P. K. Bowen, S. P. Hopkins, E. R. Shearier, M. Oriňak, Recent advancements in Fe-based biodegrad-
E. J. Earley, A. A. Gillette, E. Aghion, M. Bocks, J. W. Drelich able materials for bone repair, J. Mater. Sci., 2019, 54(3),
and J. Goldman, Corrosion characteristics dictate the long- 1913–1947.
term inflammatory profile of degradable zinc arterial 30 H. Li, X. Xie, Y. Zheng, Y. Cong, F. Zhou, K. Qiu, X. Wang,
implants, ACS Biomater. Sci. Eng., 2016, 2(12), 2355–2364. S. Chen, L. Huang and L. Tian, Development of biodegradable

This journal is © The Royal Society of Chemistry 2021 J. Mater. Chem. B, 2021, 9, 9806–9825 | 9821
 View Article Online

Journal of Materials Chemistry B Review

Zn-1X binary alloys with nutrient alloying elements Mg, Ca 47 F. Cima, Tin: environmental pollution and health effects,
and Sr, Sci. Rep., 2015, 5(1), 1–14. Encyclopedia of Environmental Health, 2011, pp. 351–359.
31 Z. Tang, J. Niu, H. Huang, H. Zhang, J. Pei, J. Ou and 48 L. Li, T. Ruan, Y. Lyu and B. Wu, Advances in effect of
G. Yuan, Potential biodegradable Zn-Cu binary alloys devel- germanium or germanium compounds on animals—a
oped for cardiovascular implant applications, J. Mech. Behav. review, J. Biosci. Med., 2017, 5(7), 56–73.
Biomed. Mater., 2017, 72, 182–191. 49 G. Cormick and J. M. Belizán, Calcium intake and health,
32 Z. B. Tang, H. Huang, J. L. Niu, L. Zhang, H. Zhang, J. Pei, Nutrients, 2019, 11(7), 1606–1622.
J. Y. Tan and G. Y. Yuan, Design and characterizations of 50 A. Ismail and N. A. Ismail, Magnesium: A mineral essential
Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

novel biodegradable Zn-Cu-Mg alloys for potential biode- for health yet generally underestimated or even ignored,
gradable implants, Mater. Des., 2017, 117, 84–94. J. Nutr. Food Sci., 2016, 6(2), 1–8.
33 B. Jia, H. T. Yang, Y. Han, Z. C. Zhang, X. H. Qu, Y. F. 51 A. E. Kirkland, G. L. Sarlo and K. F. Holton, The role of
Zhuang, Q. Wu, Y. F. Zheng and K. R. Dai, In vitro and magnesium in neurological disorders, Nutrients, 2018,
in vivo studies of Zn-Mn biodegradable metals designed 10(6), 730–753.
for orthopedic applications, Acta Biomater., 2020, 108, 52 J. Jiang, S. Lu, H. Zhang, G. Liu, K. Lin, W. Huang, R. Luo,
358–372. X. Zhang, C. Tang and Y. Yu, Dietary intake of human
34 S. Zhao, J.-M. Seitz, R. Eifler, H. J. Maier, R. J. Guillory II, essential elements from a Total Diet Study in Shenzhen,
E. J. Earley, A. Drelich, J. Goldman and J. W. Drelich, Zn-Li Guangdong Province, China, J. Food Compos. Anal., 2015,
alloy after extrusion and drawing: structural, mechanical 39, 1–7.
characterization, and biodegradation in abdominal aorta 53 N. Abbaspour, R. Hurrell and R. Kelishadi, Review on iron
of rat, Mater. Sci. Eng., C, 2017, 76, 301–312. and its importance for human health, J. Res. Med. Sci.,
35 D. Bian, W. R. Zhou, J. X. Deng, Y. Liu, W. T. Li, X. Chu, 2014, 19(2), 164–174.
P. Xiu, H. Cai, Y. H. Kou, B. G. Jiang and Y. F. Zheng, 54 L. M. Plum, L. Rink and H. Haase, The Essential Toxin:
Development of magnesium-based biodegradable metals Impact of Zinc on Human Health, Int. J. Environ. Res. Public
with dietary trace element germanium as orthopaedic Health, 2010, 7(4), 1342–1365.
implant applications, Acta Biomater., 2017, 64, 421–436. 55 N. Parveen, M. O. Ansari, M. F. Ahmad, S. Jameel and
36 M. A. Zoroddu, J. Aaseth, G. Crisponi, S. Medici, M. Peana G. Shadab, Zinc: An element of extensive medical impor-
and V. M. Nurchi, The essential metals for humans: a brief tance, Curr. Med. Res. Pract., 2017, 7(3), 90–98.
overview, J. Inorg. Biochem., 2019, 195, 120–129. 56 M. S. Dargusch, A. Dehghan-Manshadi, M. Shahbazi,
37 M. Aliasgharpour, Trace elements in human nutrition (II)– J. Venezuela, X. Tran, J. Song, N. Liu, C. Xu, Q. S. Ye and
an update, Int. J. Prev. Med., 2020, 11, 2. C. E. Wen, Exploring the Role of Manganese on the
38 M. Guo, Chemical composition of human milk, Human milk Microstructure, Mechanical Properties, Biodegradability,
biochemistry and infant formula manufacturing technology, and Biocompatibility of Porous Iron-Based Scaffolds,
2014, pp. 19–32. ACS Biomater. Sci. Eng., 2019, 5(4), 1686–1702.
39 F. S. Al-Fartusie and S. N. Mohssan, Essential trace ele- 57 H. Pan, K. Pang, F. Z. Cui, F. Ge, C. Man, X. Wang and
ments and their vital roles in human body, Indian J. Adv. Z. Y. Cui, Effect of alloyed Sr on the microstructure and
Chem. Sci., 2017, 5(3), 127–136. corrosion behavior of biodegradable Mg-Zn-Mn alloy in
40 H. E. Theobald, Dietary calcium and health, Nutr. Bull., Hanks’ solution, Corros. Sci., 2019, 157, 420–437.
2005, 30(3), 237–277. 58 I. Coelho, I. Castanheira, J. M. Bordado, O. Donard and
41 N. R. Cook, F. J. He, G. A. MacGregor and N. Graudal, J. A. L. Silva, Recent developments and trends in the
Sodium and health-concordance and controversy, BMJ, application of strontium and its isotopes in biological
2020, 369, 369–375. related fields, TrAC, Trends Anal. Chem., 2017, 90, 45–61.
42 R. Swaminathan, Magnesium metabolism and its disor- 59 F. H. Nielsen, Update on the possible nutritional impor-
ders, Clin. Biochem. Rev., 2003, 24(2), 47–66. tance of silicon, J. Trace Elem. Med. Biol., 2014, 28(4),
43 F. H. Nielsen and J. R. Hunt, Trace elements emerging as 379–382.
important in human nutrition, Proceedings of the four- 60 M. Arora and E. Arora, The promise of silicon: bone
teenth national databank conference. Univ. Iowa, Iowa regeneration and increased bone density, J. Arthrosc. Jt.
City, 1989, pp. 135-143. Surg., 2017, 4(3), 103–105.
44 M. Curzon, M. Ashrafi and P. Spector, Effects of strontium 61 B. Shahzad, M. N. Mughal, M. Tanveer, D. Gupta and
administration on rat molar morphology, Arch. Oral Biol., G. Abbas, Is lithium biologically an important or toxic
1982, 27(8), 667–671. element to living organisms? An overview, Environ. Sci.
45 J. Jensen, H. Stang, B. Kringsholm, G. Pritzl and Pollut. Res., 2017, 24(1), 103–115.
O. Sørensen, Relationship between trace element content 62 L. S. Keith, O. M. Faroon, N. Maples-Reynolds and
and mechanical bone strength, Bone, 1997, 20(Suppl 4), B. A. Fowler, Germanium, Handbook on the Toxicology of
104. Metals, Elsevier, 2015, pp. 799–816.
46 C. P. Gupta, Role of Iron (Fe) in Body, IOSR J. Appl. Chem., 63 J. Chen, L. Tan, X. Yu, I. P. Etim, M. Ibrahim and K. Yang,
2014, 7, 38–46. Mechanical properties of magnesium alloys for medical

9822 | J. Mater. Chem. B, 2021, 9, 9806–9825 This journal is © The Royal Society of Chemistry 2021
 View Article Online

Review Journal of Materials Chemistry B

application: A review, J. Mech. Behav. Biomed. Mater., 2018, 78 V. K. Bommala, M. G. Krishna and C. T. Rao, Magnesium
87, 68–79. matrix composites for biomedical applications: A review,
64 Y. Liu, H. Li, J. Xu, J. TerBush, W. Li, M. Setty, S. Guan, J. Magnesium Alloys, 2019, 7(1), 72–79.
T. D. Nguyen, L. Qin and Y. Zheng, Biodegradable metal- 79 Y.-X. Yin, C. Zhou, Y.-P. Shi, Z.-Z. Shi, T.-H. Lu, Y. Hao,
derived Magnesium and Sodium enhances bone regenera- C.-H. Liu, X. Wang, H.-J. Zhang and L.-N. Wang, Hemo-
tion by angiogenesis aided osteogenesis and regulated compatibility of biodegradable Zn-0.8 wt% (cu, Mn, Li)
biological apatite formation, Chem. Eng. J., 2020, 127616. alloys, Mater. Sci. Eng., C, 2019, 104, 109896.
65 H. Hermawan, D. Dube and D. Mantovani, Degradable 80 H. R. B. Rad, M. H. Idris, M. R. A. Kadir and S. Farahany,
Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

metallic biomaterials: Design and development of Fe-Mn Microstructure analysis and corrosion behavior of biode-
alloys for stents, J. Biomed. Mater. Res., Part A, 2010, 93(1), gradable Mg–Ca implant alloys, Mater. Des., 2012, 33,
1–11. 88–97.
66 R. Drevet, Y. Zhukova, P. Malikova, S. Dubinskiy, 81 H. Hermawan, Updates on the research and development
A. Korotitskiy, Y. Pustov and S. Prokoshkin, Martensitic of absorbable metals for biomedical applications, Prog.
transformations and mechanical and corrosion properties Biomater., 2018, 7(2), 93–110.
of Fe-Mn-Si alloys for biodegradable medical implants, 82 A. Drynda, T. Hassel, F. W. Bach and M. Peuster, In vitro
Metall. Mater. Trans. A, 2018, 49(3), 1006–1013. and in vivo corrosion properties of new iron-manganese
67 J. Kubásek, D. Vojtěch, J. Lipov and T. Ruml, Structure, alloys designed for cardiovascular applications, J. Biomed.
mechanical properties, corrosion behavior and cytotoxicity Mater. Res., Part B, 2015, 103(3), 649–660.
of biodegradable Mg–X (X= Sn, Ga, In) alloys, Mater. Sci. 83 H. T. Yang, C. Wang, C. Q. Liu, H. W. Chen, Y. F. Wu,
Eng., C, 2013, 33(4), 2421–2432. J. T. Han, Z. C. Jia, W. J. Lin, D. Y. Zhang, W. T. Li, W. Yuan,
68 F. Trichter, A. Rabinkin, M. Ron and A. Sharfstein, A study H. Guo, H. F. Li, G. X. Yang, D. L. Kong, D. H. Zhu,
of g - e phase transformation in FeMn alloys induced by K. Takashima, L. Q. Ruan, J. F. Nie, X. Li and
high pressure and plastic deformation, Scr. Metall., 1978, Y. F. Zheng, Evolution of the degradation mechanism of
12(5), 431–434. pure zinc stent in the one-year study of rabbit abdominal
69 J. Seong and W. Kim, Development of biodegradable Mg– aorta model, Biomaterials, 2017, 145, 92–105.
Ca alloy sheets with enhanced strength and corrosion 84 X. Liu, J. Sun, K. Qiu, Y. Yang, Z. Pu, L. Li and Y. Zheng,
properties through the refinement and uniform dispersion Effects of alloying elements (Ca and Sr) on microstructure,
of the Mg2Ca phase by high-ratio differential speed rolling, mechanical property and in vitro corrosion behavior of
Acta Biomater., 2015, 11, 531–542. biodegradable Zn–1.5 Mg alloy, J. Alloys Compd., 2016, 664,
70 Y. Du, X. Qiao, M.-Y. Zheng, D. Wang, K. Wu and 444–452.
I. Golovin, Effect of microalloying with Ca on the micro- 85 H. Hermawan, A. Purnama, D. Dube, J. Couet and
structure and mechanical properties of Mg-6 mass% Zn D. Mantovani, Fe–Mn alloys for metallic biodegradable stents:
alloys, Mater. Des., 2016, 98, 285–293. degradation and cell viability studies, Acta Biomater., 2010,
71 N. Erdmann, N. Angrisani, J. Reifenrath, A. Lucas, 6(5), 1852–1860.
F. Thorey, D. Bormann and A. Meyer-Lindenberg, Biome- 86 A. Kafri, S. Ovadia, J. Goldman, J. Drelich and E. Aghion,
chanical testing and degradation analysis of MgCa0. 8 The Suitability of Zn-1.3% Fe Alloy as a Biodegradable
alloy screws: a comparative in vivo study in rabbits, Acta Implant Material, Metals, 2018, 8(3), 153–168.
Biomater., 2011, 7(3), 1421–1428. 87 H. Lee and D. Hiam, Corrosion resistance of galvannealed
72 X. N. Gu, Y. F. Zheng, Y. Cheng, S. P. Zhong and T. F. Xi, steel, Corrosion, 1989, 45(10), 852–856.
In vitro corrosion and biocompatibility of binary magne- 88 D. Vojtěch, J. Kubásek, J. Šerák and P. Novák, Mechanical
sium alloys, Biomaterials, 2009, 30(4), 484–498. and corrosion properties of newly developed biodegrad-
73 Z.-Z. Shi, J. Yu and X.-F. Liu, Microalloyed Zn-Mn alloys: able Zn-based alloys for bone fixation, Acta Biomater., 2011,
from extremely brittle to extraordinarily ductile at room 7(9), 3515–3522.
temperature, Mater. Des., 2018, 144, 343–352. 89 J. Yang, G. L. Koons, G. Cheng, L. Zhao, A. G. Mikos and
74 H. Liu, G. Qi, Y. Ma, H. Hao, F. Jia, S. Ji, H. Zhang and F. Cui, A review on the exploitation of biodegradable
X. Zhang, Microstructure and mechanical property of Mg– magnesium-based composites for medical applications,
2.0 Ga alloys, Mater. Sci. Eng., A, 2009, 526(1–2), 7–10. Biomed. Mater., 2018, 13(2), 022001.
75 D. T. Reilly and A. H. Burstein, The elastic and ultimate 90 K. Feron, R. Lim, C. Sherwood, A. Keynes, A. Brichta and
properties of compact bone tissue, J. Biomech., 1975, 8(6), P. C. Dastoor, Organic bioelectronics: materials and bio-
393–405. compatibility, Int. J. Mol. Sci., 2018, 19(8), 2382–2403.
76 J. Seong and W. Kim, Mg-Ca binary alloy sheets with Ca 91 M. Heiden, E. Walker and L. Stanciu, Magnesium, iron and
contents ofr 1 wt.% with high corrosion resistance and zinc alloys, the trifecta of bioresorbable orthopaedic and
high toughness, Corros. Sci., 2015, 98, 372–381. vascular implantation-a review, J. Biotechnol. Biomater.,
77 R.-C. Zeng, W.-C. Qi, H.-Z. Cui, F. Zhang, S.-Q. Li and E.-H. 2015, 5(2), 1–9.
Han, In vitro corrosion of as-extruded Mg–Ca alloys—the 92 D. Vojtech, J. Kubasek, J. Capek and I. Pospisilova, Com-
influence of Ca concentration, Corros. Sci., 2015, 96, 23–31. parative mechanical and corrosion studies on magnesium,

This journal is © The Royal Society of Chemistry 2021 J. Mater. Chem. B, 2021, 9, 9806–9825 | 9823
 View Article Online

Journal of Materials Chemistry B Review

zinc and iron alloys as biodegradable metals, Mater. Tech- 109 S. Virtanen, Biodegradable Mg Alloys: Corrosion, Surface
nol., 2015, 49, 877–882. Modification, and Biocompatibility, Biomedical Applications,
93 J. Ma, N. Zhao and D. Zhu, Endothelial cellular responses Springer, 2012, pp. 101–125.
to biodegradable metal zinc, ACS Biomater. Sci. Eng., 2015, 110 M.-K. Kim, J.-A. Lee, M.-R. Jo, M.-K. Kim, H.-M. Kim, J.-M.
1(11), 1174–1182. Oh, N. W. Song and S.-J. Choi, Cytotoxicity, uptake beha-
94 H. Hermawan, Biodegradable metals: from concept to appli- viors, and oral absorption of food grade calcium carbonate
cations, Springer Science & Business Media, 2012. nanomaterials, Nanomaterials, 2015, 5(4), 1938–1954.
95 B. Liu and Y. Zheng, Effects of alloying elements (Mn, Co, 111 S. Najeeb, M. S. Zafar, Z. Khurshid, S. Zohaib and K. Almas,
Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

Al, W, Sn, B, C and S) on biodegradability and in vitro The role of nutrition in periodontal health: an update,
biocompatibility of pure iron, Acta Biomater., 2011, 7(3), Nutrients, 2016, 8(9), 530.
1407–1420. 112 S. Najeeb, M. S. Zafar, Z. Khurshid and F. Siddiqui, Appli-
96 C. Shuai, S. Li, S. Peng, P. Feng, Y. Lai and C. Gao, Bio- cations of polyetheretherketone (PEEK) in oral implantology
degradable metallic bone implants, Mater. Chem. Front., and prosthodontics, J. Prosthodont. Res., 2016, 60(1), 12–19.
2019, 3(4), 544–562. 113 D. Pförringer, N. Harrasser, H. Mühlhofer, M. Kiokekli,
97 H. Li, H. Yang, Y. Zheng, F. Zhou, K. Qiu and X. Wang, A. Stemberger, M. Van Griensven, M. Lucke, R. Burgkart and
Design and characterizations of novel biodegradable tern- A. Obermeier, Osteoinduction and-conduction through
ary Zn-based alloys with IIA nutrient alloying elements Mg, absorbable bone substitute materials based on calcium
Ca and Sr, Mater. Des., 2015, 83, 95–102. sulfate: in vivo biological behavior in a rabbit model,
98 Z. J. Li, X. N. Gu, S. Q. Lou and Y. F. Zheng, The development J. Mater. Sci.: Mater. Med., 2018, 29(2), 1–14.
of binary Mg-Ca alloys for use as biodegradable materials 114 S. A. Park, K. E. Park and W. Kim, Preparation of sodium
within bone, Biomaterials, 2008, 29(10), 1329–1344. alginate/poly (ethylene oxide) blend nanofibers with
99 X. Gu, F. Wang, X. Xie, M. Zheng, P. Li, Y. Zheng, L. Qin lecithin, Macromol. Res., 2010, 18(9), 891–896.
and Y. Fan, In vitro and in vivo studies on as-extruded 115 W. Yang, H. Xu, Y. Lan, Q. Zhu, Y. Liu, S. Huang, S. Shi,
Mg-5.25 wt.% Zn-0.6 wt.% Ca alloy as biodegradable metal, A. Hancharou, B. Tang and R. Guo, Preparation and
Science China, Materials, 2018, 61(4), 619–628. characterisation of a novel silk fibroin/hyaluronic acid/
100 H. Hermawan, Metallic biodegradable coronary stent: degrada- sodium alginate scaffold for skin repair, Int. J. Biol. Macro-
tion study, Biodegradable Metals, Springer, 2012, pp. 49–57. mol., 2019, 130, 58–67.
101 J. Capek, J. Kubasek, D. Vojtech, E. Jablonska, J. Lipov and 116 W. Querido, M. Farina and K. Anselme, Strontium ranelate
T. Ruml, Microstructural, mechanical, corrosion and cyto- improves the interaction of osteoblastic cells with titanium
toxicity characterization of the hot forged FeMn30(wt.%) substrates: Increase in cell proliferation, differentiation
alloy, Mater. Sci. Eng., C, 2016, 58, 900–908. and matrix mineralization, Biomatter, 2015, 5(1), e1027847.
102 J. He, F. L. He, D. W. Li, Y. L. Liu, Y. Y. Liu, Y. J. Ye and 117 N. Xu, J. Fu, L. Zhao, P. K. Chu and K. Huo, Biofunctional
D. C. Yin, Advances in Fe-based biodegradable metallic Elements Incorporated Nano/Microstructured Coatings on
materials, RSC Adv., 2016, 6(114), 112819. Titanium Implants with Enhanced Osteogenic and Anti-
103 M. Traverson, M. Heiden, L. A. Stanciu, E. A. Nauman, bacterial Performance, Adv. Healthcare Mater., 2020,
Y. Jones-Hall and G. J. Breur, In Vivo Evaluation of Bio- 9(23), 2000681.
degradability and Biocompatibility of Fe30Mn Alloy, Vet. 118 T.-b. Huang, Y.-z. Li, K. Yu, Z. Yu, Y. Wang, Z.-w. Jiang, H.-
Comp. Orthop. Traumatol., 2018, 31(1), 10–16. m. Wang and G.-l. Yang, Effect of the Wnt signal-RANKL/
104 X. Gu, X. Xie, N. Li, Y. Zheng and L. Qin, In vitro and in vivo OPG axis on the enhanced osteogenic integration of a
studies on a Mg–Sr binary alloy system developed as a new kind lithium incorporated surface, Biomater. Sci., 2019, 7(3),
of biodegradable metal, Acta Biomater., 2012, 8(6), 2360–2374. 1101–1116.
105 K. Hagihara, K. Fujii, A. Matsugaki and T. Nakano, Possi- 119 W. Liu, D. Chen, G. Jiang, Q. Li, Q. Wang, M. Cheng, G. He
bility of Mg-and Ca-based intermetallic compounds as new and X. Zhang, A lithium-containing nanoporous coating
biodegradable implant materials, Mater. Sci. Eng., C, 2013, on entangled titanium scaffold can enhance osseointegra-
33(7), 4101–4111. tion through Wnt/b-catenin pathway, Nanomedicine, 2018,
106 J. Wang, Y. Ma, S. Guo, W. Jiang and Q. Liu, Effect of Sr 14(1), 153–164.
on the microstructure and biodegradable behavior of 120 L. Tang, Y. Chen, F. Pei and H. Zhang, Lithium chloride
Mg–Zn–Ca-Mn alloys for implant application, Mater. Des., modulates adipogenesis and osteogenesis of human bone
2018, 153, 308–316. marrow-derived mesenchymal stem cells, Cell. Physiol.
107 P. P. Mueller, T. May, A. Perz, H. Hauser and M. Peuster, Biochem., 2015, 37(1), 143–152.
Control of smooth muscle cell proliferation by ferrous 121 P. Clément-Lacroix, M. Ai, F. Morvan, S. Roman-Roman,
iron, Biomaterials, 2006, 27(10), 2193–2200. B. Vayssière, C. Belleville, K. Estrera, M. L. Warman,
108 H. Hermawan, A. Purnama, D. Dube, J. Couet and R. Baron and G. Rawadi, Lrp5-independent activation of
D. Mantovani, Fe-Mn alloys for metallic biodegradable Wnt signaling by lithium chloride increases bone formation
stents: degradation and cell viability studies, Acta Biomater., and bone mass in mice, Proc. Natl. Acad. Sci. U. S. A., 2005,
2010, 6(5), 1852–1860. 102(48), 17406–17411.

9824 | J. Mater. Chem. B, 2021, 9, 9806–9825 This journal is © The Royal Society of Chemistry 2021
 View Article Online

Review Journal of Materials Chemistry B

122 P. Szymański, T. Fra ˛czek, M. Markowicz and E. Mikiciuk- implants with antibacterial activity for the treatment of
Olasik, Development of copper based drugs, radiopharma- osteomyelitis: in vitro and in vivo evaluations, Biomaterials,
ceuticals and medical materials, Biometals, 2012, 25(6), 2016, 106, 250–263.
1089–1112. 129 M. Lv, M. Chen, R. Zhang, W. Zhang, C. Wang, Y. Zhang,
123 L. Ren, K. Yang, L. Guo and H.-W. Chai, Preliminary study X. Wei, Y. Guan, J. Liu and K. Feng, Manganese is critical
of anti-infective function of a copper-bearing stainless for antitumor immune responses via cGAS-STING and
steel, Mater. Sci. Eng., C, 2012, 32(5), 1204–1209. improves the efficacy of clinical immunotherapy, Cell Res.,
124 H. Chai, L. Guo, X. Wang, Y. Fu, J. Guan, L. Tan, L. Ren and 2020, 30(11), 966–979.
Published on 29 November 2021. Downloaded by Politechnika Warszawska on 3/7/2022 [Link] PM.

K. Yang, Antibacterial effect of 317L stainless steel con- 130 R. B. Heimann, Silicon Nitride, a Close to Ideal Ceramic
tained copper in prevention of implant-related infection Material for Medical Application, Ceramics, 2021, 4(2),
in vitro and in vivo, J. Mater. Sci.: Mater. Med., 2011, 22(11), 208–223.
2525–2535. 131 H. Matsumoto, H. Iwafuji, J. Yamane, R. Takeuchi,
125 S. Wang, Z. Ma, Z. Liao, J. Song, K. Yang and W. Liu, Study on T. Utsunomiya and A. Fujii, Restorative effect of organic
improved tribological properties by alloying copper to CP-Ti germanium compound (Ge-132) on dermal injury, Wound
and Ti–6Al–4V alloy, Mater. Sci. Eng., C, 2015, 57, 123–132. Med., 2016, 15, 6–10.
126 Z. K. Ghouri, N. A. Barakat and H. Y. Kim, Influence of 132 S. A. A. Esmail, M. Shamsi, T. Chen and W. M. Al-asbahy,
copper content on the electrocatalytic activity toward metha- Design, synthesis and characterization of tin-based cancer
nol oxidation of Co w Cu y alloy nanoparticles-decorated chemotherapy drug entity: In vitro DNA binding, cleavage,
CNFs, Sci. Rep., 2015, 5(1), 1–12. induction of cancer cell apoptosis by triggering DNA
127 C. Liu, X. Fu, H. Pan, P. Wan, L. Wang, L. Tan, K. Wang, damage-mediated p53 phosphorylation and molecular
Y. Zhao, K. Yang and P. K. Chu, Biodegradable Mg-Cu docking, Appl. Organomet. Chem., 2019, 33(1), e4651.
alloys with enhanced osteogenesis, angiogenesis, and 133 J. L. Wang, J. K. Xu, C. Hopkins, D. H. K. Chow and L. Qin,
long-lasting antibacterial effects, Sci. Rep., 2016, 6(1), 1–17. Biodegradable magnesium-based implants in orthopedics—
128 Y. Li, L. Liu, P. Wan, Z. Zhai, Z. Mao, Z. Ouyang, D. Yu, a general review and perspectives, Adv. Sci., 2020, 7(8),
Q. Sun, L. Tan and L. Ren, Biodegradable Mg-Cu alloy 1902443.

This journal is © The Royal Society of Chemistry 2021 J. Mater. Chem. B, 2021, 9, 9806–9825 | 9825