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Advances in Fe-based biodegradable metallic

materials
Cite this: RSC Adv., 2016, 6, 112819
Jin He, Feng-Li He, Da-Wei Li, Ya-Li Liu, Yang-Yang Liu, Ya-Jing Ye
and Da-Chuan Yin*

Received 15th August 2016
Accepted 22nd November 2016
DOI: 10.1039/c6ra20594a
www.rsc.org/advances
In recent years, biodegradable metallic materials, such as Mg-, Fe-, Zn- and W-based materials, have been the
focus of many studies. As one of the two most studied types of biodegradable metallic materials, Fe-based
materials have aroused a great deal of interest because of their outstanding mechanical properties, which
are similar to stainless steel. The processing methods can directly affect the microstructure of the material
and influence the mechanical and degradation properties of the material. Furthermore, biocompatibility is
directly affected by the degradation properties. Therefore, the processing methods, mechanical properties,
degradability and biocompatibility are several of the main concerns in the study of biodegradable Fe-based
materials. Here, we systematically summarize recent studies on Fe-based materials and discuss these
findings in terms of their processing methods, degradability and biocompatibility.

material that has many advantages, such as excellent mechan-

1. Introduction
The use of metallic materials in the medical eld has a long
history. Traditional biomedical metallic materials, such as Ti
(Ti alloy), Co alloy and stainless steel,1–3 have excellent
biocompatibility and mechanical properties. Thus, they occupy
a dominant position in medical implant materials. Table 1 gives
a summary of the major merits and shortcomings of some
frequently studied biomedical metallic materials. Among these
materials, Ti (Ti alloy), Co alloy and stainless steel have already
been applied commercially. However, these materials are non-
degradable and permanently exist in the body as a foreign
object, which can cause negative effects.
In recent years, biodegradable metals have aroused a great
deal of interest because of their attractive properties, such as
the excellent mechanical properties that are similar to tradi-
tional biomedical metallic materials, superior biocompatibility
and degradability.4–11 Zheng et al.9 dened biodegradable
metals: biodegradable metals are metals expected to corrode
gradually in vivo, with an appropriate host response elicited by
released corrosion products, then dissolve completely upon
fullling the mission to assist with tissue healing with no
implant residues. Over the years, many types of biodegradable
metals have been studied, including Mg-,5,6 Fe-,8–10 W-12–15 and
Zn-based materials.16–19 Currently, the study of biodegradable
metals mainly focuses on two categories: Fe-based and Mg-
based materials. There is relatively less research conducted on
other biodegradable metals. Fe is a traditional engineering
Institute of Special Environmental Biophysics, Key Laboratory for Space Bioscience and
Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an
710072, PR China. E-mail: yindc@nwpu.edu.cn
ical properties, superior machinability and low price. These
inherent advantages make Fe-based materials a potentially
exceptional source of biodegradable metallic materials for the
medical eld.
2. Application of biodegradable
Fe-based materials
According to reported studies, the applications of biodegrad-
able Fe-based metallic materials mainly consist of three cate-
gories: intravascular stents, implant materials for bone surgery
and scaffolds for bone tissue engineering.
2.1 Stents
Stents have been widely used for the treatment of cardiovascular
disease. However, their applications can produce undesirable
complications.20 Restenosis can occur within the stent because
of inammation and neointimal proliferation. Furthermore,
stents implanted in children result in a xed vessel diameter,
and subsequent restenosis occurs due to vessel growth at the
stent site. Degradable stents can overcome these shortcom-
ings.20 This type of stent can eliminate the continuous inter-
ference process between the stent and the vessel wall, and its
use as a carrier for drugs can avoid re-dilatation surgery.
Another potential advantage of degradable stents is the avoid-
ance of subsequent surgeries on vessels with implanted stents.
An inherent advantage of iron is its excellent mechanical
properties, which make it an interesting candidate for use in
biodegradable stents.8 For example, the higher elastic modulus
of iron can produce a high radial strength of the stent, which is
benecial when producing stents with thinner struts.

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Table 1 A summary of the main merits and shortcomings of biomedical metallic materials1–3,5,6,8–10

Biomaterials Typical samples Merits Shortcomings

Fe-Based Pure Fe, Fe–Mn, Good mechanical properties, appropriate biocompatibility, Low degradation rates,
materials Fe–Fe2O3 various processing methods, biodegradable ferromagnetism
Mg/Mg alloys Pure Mg, Mg–Zn, Excellent biocompatibility, biodegradable, Too fast degradation rates,
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Mg–Zn–Ca similar mechanical properties with bone hydrogen evolution

Ti/Ti alloys Pure Ti, Ti–6Al–4V Good mechanical properties, excellent biocompatibility, Non-degradable,
high specic strength, good corrosion resistance toxicity elements (e.g., V)
Stainless steel 316L Excellent corrosion resistance, high mechanical properties, Non-degradable, toxicity elements
appropriate biocompatibility (e.g., Ni), too high modulus, poor
plastic workability
Co alloys Co–Cr–W–Ni, Excellent wear resistance, appropriate biocompatibility, Too high modulus, poor cold
Co–Cr–Mo high corrosion resistance workability, toxicity elements (e.g., Ni),
non-degradable

tissue regeneration. Moreover, scaffolds must have appropriate

Fig. 1 Photographs of a Fe stent (a) and Fe–35Mn alloy stents (b)
(reproduced with permission of Elsevier from ref. 20 and 21).
mechanical properties that match those of normal tissues and
organs.25 Because metallic materials have excellent mechanical
properties, the application of biodegradable metal porous
scaffolds is primarily used for the reparation of hard tissue,
such as bone. Thus, these novel scaffolds avoid the shortcom-
ings of traditional non-degradable metal scaffolds and over-
come the weaknesses of polymer scaffolds.

3. Manufacturing methods and

In addition, iron has high ductility, which can be useful when
the stent is plastically deformed during the implantation
procedure.3 Therefore, the development of degradable stents is
one of the main uses for degradable Fe-based materials. Fig. 1
shows examples of Fe and Fe–Mn alloy stents.
2.2 Implants for bone surgery
The non-degradable metal implants used in bone surgery, such
as screws22 and plates,23 can lead to adverse responses, such as
a toxic response to specic ions released from the materials due
to their long-term presence in the body. Although the implants
can be removed as a second operation, it can result in adverse
consequences, such as a second defect at the implantation site,
pain, and increased treatment costs. Fe-Based materials are
a good candidate to address these shortcomings. First, Fe-based
materials have excellent mechanical properties that are similar
to those of stainless steel and can satisfy the requirement of
high mechanical properties for bone repair. In addition, Fe-
based materials have good biocompatibility. Above all, Fe
corrodes in the body environment and is expected to be
completely dissolved during the lifetime.
2.3 Scaffolds for bone tissue engineering
Scaffolds play an important role in tissue engineering and
provide essential conditions for tissue repair. For example,
scaffolds provide a surface and space that allows for cell growth
and new tissue formation, thus aiding in the remodelling of
damaged tissue.24 An ideal scaffold must have reliable degra-
dation and resorption rates that are consistent with the rate of
mechanical properties
Many methods, including the manufacturing methods for raw
materials and post-treatment methods (Fig. 2), have been used
to manufacture biodegradable metallic materials; notably,
these methods are similar to those used with traditional metals.
The properties of the material, such as mechanical properties
and degradability, can be affected by the manufacturing
method. Indeed, mechanical properties are most vulnerable.
Table 2 summarizes the mechanical properties of the materials
aer processing with different methods. According to published
studies, the methods can be divided into ve types: casting,
sintering, electrodeposition, surface modication and other
methods. Except for surface modication, the other methods
refer to the manufacturing or processing of raw materials.
3.1 Casting
As a traditional manufacturing method of metals, the advantage
of casting is the convenience of adjustments to the alloy
components. A certain proportion of raw materials (powders or
blocks) are melted in a furnace and then cast to obtain alloys.
Many researchers prefer this method of preparing biodegrad-
able iron alloys. However, the poor properties of as-cast alloys
are induced by defects (such as segregation, blowholes and
shrinkages). Therefore, as-cast alloys must be further processed
by forging, rolling and/or heat treatment.
Liu et al.26 casted a Fe30Mn6Si ternary alloy with a shape-
memory function. The alloy consisted of martensite and
austenite and had a smaller grain size and higher ultimate
strength when compared with pure Fe. The recovery of this alloy

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austenite grain boundaries in Fe–Mn–Pd alloys were charac-

terized by site-specic atom probe tomography, and the mech-
anism of embrittlement and de-embrittlement have been
discussed.31
Schinhammer et al.32 discussed the design strategy of
biodegradable Fe-based alloys. The authors suggested that
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noble intermetallic phases improved the degradation rate and

increased the strength of the Fe matrix. For example, the
availability of Mn and Pd has been proven. The degradation
resistance of the newly developed Fe–Mn–Pd alloys is one order
of magnitude less than that of pure iron. Furthermore, both the
choice of alloying elements and changes in heat treatment can
be used to adjust mechanical properties.
The interaction of recrystallization and precipitation in
a biodegradable twinning-induced plasticity (TWIP) steel (Fe–
Mn–C–Pd) was studied by Schinhammer et al.33 The authors
found that the formation of a Pd-rich precipitate dramatically
Fig. 2 Diagram of the different manufacturing methods. Initial impeded recrystallization during the annealing treatment. The
methods refer to the production methods that transform raw materials impedance was caused by grain boundary pinning by the Pd-
into materials that can be used for device manufacturing. Post-pro- rich precipitates and reduced dislocation mobility due to
cessing refers to further treatments after the production of raw a solute drag effect from the Pd-enrichment of dislocation
materials. Note: surface modification is not an initial method, but it is
cores. These alloys showed high strength and superior ductility
one of the most studied manufacturing methods.
that exceeded other TWIP steels and the typical alloys used in
biomedical implants.
The mechanical properties and corrosion rate of alloys can
reached 53.7% (casting + solution treated). The authors also
be affected by the average grain size; thus, these parameters can
produced a series of binary Fe alloys (Fe–Mn/Co/Al/W/Sn/B/C/S)
be optimized by altering the grain size. Obayi et al.34 found that
by casting and rolling.27 Here, the addition of Mn, Co, Al, and W
thermo-mechanically treated (cold-rolled and annealed ingot)
had no obvious effect on the grain size of the Fe alloys; however,
pure iron had an optimum microstructure with an average grain
B notably decreased the grain size. Sn sharply decreased the
size of 20–25 mm. The authors also determined that the rolling
mechanical properties of the alloy. Mn, Co, W, B, C and S
direction affects the grain size and mechanical properties of
increased the yield and ultimate strength of Fe in the as-rolled
pure Fe.35 The grain orientation of unidirectional rolled pure Fe
alloys; furthermore, these elements increased the magnitude of
was obvious; however, this orientation was irregular for bi-
the difference between the yield strength and ultimate strength
directional rolled pure Fe. Moreover, the mean grain size and
of Fe.
the grain size distribution in bi-directional samples were larger
Except for casting followed by hot working, more complex
and broader, respectively, when compared with unidirectional
technology is typically needed to obtain alloys with specic
samples aer annealing. The yield strength and tensile strength
properties. A Fe–10Mn–1Pd alloy was produced by casting,
of unidirectional samples was larger than bi-directional
swaging, solution-heat-treatment and quenching, and the
samples. Aer annealing, the yield strength and tensile
hardening kinetics of a solution-heat-treatment were studied by
strength were markedly decreased.
Moszner et al.28 The authors suggested that the pronounced
Cast Fe–33Mn alloys were further processed with varying
strengthening was due to the thermally activated formation of
methods, including heavy cold-rolling, large-strain machining
coherent plate-like Pd-rich precipitates on 100 matrix planes.
(LSM) and annealing.36 The grain shape of the alloy using LSM
The new alloy was somewhat similar to maraging steel, e.g., the
resembled dendrite bands and was approximately 16 dendrite
initial microstructure, aging behaviour and precipitation; thus,
band diameters in length, which is less than that of samples
it represents a new high-strength, Ni-free maraging steel. To
processed with other methods. In order to improve the interface
demonstrate the composition of the Fe–Mn–Pd alloy precipi-
compatibility of implants with bone and orthopaedic so
tates, Fe–Mn–Pd alloys containing 10 wt% Mn with varying Pd
tissues, a cast Fe–30Mn alloy was further processed by a four-
concentrations (1, 3, and 6 wt%) were created by casting,
step dealloying process to create a nanoporous surface.37 This
solution-heat-treatment, quenching, isothermal aging and
surface was designed by the selective leaching of the less noble
quenching.29 The authors found that the precipitate was mainly
components (Mn and Zn) from the outer surface layer.
a face-centred tetragonal b1-MnPd phase that consisted of Mn
Aer casting and hot forging, the phase of FeMn30 was
and Pd. The alloys demonstrated remarkable age-hardening
mainly composed of g-austenite and 3-martensite. Its mechan-
aer isothermal aging at 500  C. The mechanism of reverse
ical properties were better than that of iron and 316L stainless
transformation from martensite to austenite in the Fe–Mn–Pd
steel.39 Manganese remains dissolved in g-Fe, thus stabilising
alloys and the inuence of prior precipitation on this process
the austenitic structure at room temperature and causing
were studied.30 The atomic-scale microstructures of prior
signicant solid-solution hardening and strengthening.40 Fe–

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Table 2 Summary of the manufacturing methods and the mechanical properties of different Fe-based materialsa

Mechanical properties
RSC Advances

Tensile Compress

Ultimate Yield Elasticity Elongation Yield Ultimate Elasticity

strength strength modulus at break strength strength modulus
Processing methods Components (MPa) (MPa) (GPa) (%) (MPa) (MPa) (GPa) Hardness Ref.

Casting + forging Fe–(0.5–6.9)Mn 353–1041 295–814 — 11.5–31.3 — — — — 38

Casting + forging + Fe–10Mn 1300–1400 650–800 — 14 — — — 374–428 (HV10) 32

112822 | RSC Adv., 2016, 6, 112819–112838

heat treatment Fe–10Mn–1Pb 1450–1550 850–950 — 2.0–11.0 — — — 376–437 (HV10)
Casting + forging + Fe–21Mn–0.7C(–1Pd) 1255 725 — 38 — — — — 33
heat treatment
(Armco ingot Fe) rolling + Fe-UD75% 600 593 — 3.5 — — — — 35
annealing Fe-BD75% 517 507 — 4.0 — — — —
Fe-UD + annealing 248–283 108–246 — 34.8–48.3 — — — —
Fe-BD + annealing 232–274 97–229 — 40.2–51.7 — — — —
Casting + forging Fe–30Mn 632 242 — 94 413 — — 175 (HBW) 39
Casting + forging Fe–30Mn 530 — — 15 — — — 175 (HV 5) 40
SPS Fe–5Pd — — — — 445 754 — — 41
Fe–5Pt — — — — 503 785 — —
Sintering Porous Fe — — — — 16.1–67.7 — 0.6–4 — 42
Sintering Fe–35Mn 20.2–30.1 — — 0.74–0.95 — — — 13.58–27.72 (HRH) 43
Sintering + cold rolling + Fe–35Mn 550 235 — 31 — — — 38 (Rockwell A) 44
sintering
Sintering + cold rolling Fe–(20–35)Mn 428–723 234–421 — 4.8–32 — — — 38–59 (Rockwell A) 45
Sintering Fe–HA — — — — 325 717 — — 46
Fe–TCP — — — — 312 708 — —
Fe–BCP — — — — 312 696 — —
Sintering Fe–TCP — — — — 696 — — — 47
Electroforming + Fe 169–292 130–270 — 18.4–32.3 — — — — 48
annealing
Electrodeposition Fe/Fe–W 4.01 — — — — — — — 49
alloy scaffold
3D-printing + sintering Fe–30Mn 115.53 106.07 32.47 0.73 — — — — 50
2
ECAP Fe 470 — — — — — — 444 kgf mm 51
Nitriding Fe 614.35 — — — — — — 287.06 (HV) 52
Magnetron sputtering Fe 343–638 267–612 — 1.3–20 — — — — 53
Vacuum inltration PLGA-inltrated — — — — 0.20–0.38 0.24–0.42 4.17–8.78 MPa — 54
and dipping porous Fe
PLGA–coated — — — — 0.27–0.65 0.30–0.71 6.15–14.22 MPa —
porous Fe
a
Note: pure Fe that served as a control is not listed in this table. The error values in the original data from the references are not shown. The values of the same materials manufactured using
different processes were expressed as a range.
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Mn alloys with lower Mn concentrations (0.5, 2.7, and 6.9 wt%
Mn) that were produced by casting and forging exhibited
superior mechanical properties.38
3.2 Sintering
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Spark plasma sintering (SPS)55 is the most advanced sintering
technique. SPS has obvious advantages over other sintering
techniques, such as lower sintering temperatures and shorter
holding times. The technique enables the sintering of nanosized
powders and can obtain a nearly full-densication of materials
with minimum grain. Cheng et al.56 reported that the grain size
of the pure iron processed by SPS was far smaller than that of as-
cast pure iron. W and CNT, which served as the second phase,
were added into the Fe matrix and clearly diminished the grain
size; furthermore, the decrease in grain size correlated with
increasing second phase fractions. The ultimate compressive
strength (UCS) of the Fe matrix composite is greater than pure
Fe, but the enhancement of yield strength (YS) for the composite
was not signicantly different from pure Fe. The YS and UCS of
the SPS of pure Fe may be greater than as-cast pure Fe due to the
smaller grain size of the former. Similarly, a Fe–Fe2O3 composite
prepared by SPS57 has a fast corrosion rate, good mechanical
properties and excellent biocompatibility. Huang et al.41
prepared Fe-5 wt% Pd and Fe-5 wt% Pt composites using SPS.
Because of the second phase strengthening effects, the
mechanical properties of the composites, including yield
strengths, ultimate compressive strength, rigidity and micro-
hardness, were much higher than that of pure Fe. Furthermore,
small grain size improves the mechanical properties of
composites. The low ductility of the composites may be due to
their relatively low density. Fe–Au and Fe–Ag were also prepared
by SPS.58 Fe-5 wt% Ag, Fe-2 wt% Au, and Fe-10 wt% Au
composites showed improved mechanical properties. This
improvement was attributed to the decrease in grain size and
second-phase strengthening effects. The enhanced strength of
the Fe–Au composite may be due to the ability of Au to partly
dissolve into iron and result in solid solution strengthening.
The sintering method is typically used for the manufacturing
of porous materials. A polyurethane sponge acted as a template,
and the replication method based on powder metallurgy was
used to produce an iron matrix composite (Fe–CNTs, Fe–Mg)
with open-cell foam structure.59,60 The pore size of the foam was
35–50 PPI with an apparent density of approximately 24 kg m 3.
However, there were many closed pores in the foam, which is
a disadvantage for tissue penetration. Ammonium bicarbonate
served as a space-holder, and porous iron was prepared by
vacuum sintering.42,61 The highest porosity of the samples was
82 vol%. Increased compression pressure decreased porosity,
while the use of a ner iron powder and more space-holder
material in the initial mixture led to an increase in porosity.
Increasing the porosity can decrease the mechanical properties
of the sample; however, the use of ner powder increased the
porosity and mechanical properties simultaneously. Further-
more, a higher compacting pressure enhanced exural and
compressive properties. The exural and compressive perfor-
mance of the sample was similar to that of human bone. A
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porous Fe–35Mn alloy with an open-cell porosity of 25–31% was
prepared by sintering with ammonium bicarbonate as a poro-
gen.43 The mechanical properties were decreased by increasing
the amount of porogen used.
The mechanical properties of sintered metals are typically
lower; however, they can be improved by rolling. Hermawan
et al.44 reported that the porosity of a Fe–35Mn alloy prepared by
cold-rolling and sintering cycles decreased by 0.3%, and the
mechanical properties of this allow were similar to those of 316L
stainless steel. This method can also change MnO particles into
much smaller particles, which are then distributed in the rolling
direction. Furthermore, Fe–Mn alloys with varying Mn content
(20, 25, 30, and 35 wt%) were prepared using this method.45 The
authors reported that alloys with lower Mn content existed
mainly in the g phase with some appearance of the 3 phase. The
yield strengths were between 234 MPa and 421 MPa, and the
elongations were between 7.5% and 32%. Next, the authors
processed Fe–35Mn alloy bulk materials produced from a similar
method into minitubes with a 1.80 mm outside diameter, 0.15
mm wall thickness and 40 mm length using wire-cut electrical
discharge machining and a programmable conventional turning
machine.21 The minitubes were transformed into stents using
laser cutting techniques. The mechanical properties of the stents,
including expansion performance and radial force, were satis-
factory. However, magnetic stents and those with too rough of
a surface were unfavourable.
Using sintering, other elements have also been added into
the iron matrix to form alloys. Wegener et al.62 prepared Fe–(C,
P, B, and Ag) alloys using powder metallurgy. The addition of B
and P had a notable effect on the microstructure of the alloy.
The addition of P signicantly decreased microporosity, while
the addition of Ag and B increased microporosity.
Bioceramics have excellent biocompatibility. Therefore, a Fe/
bioceramic composite is an interesting biodegradable metallic
material. Ulum et al.46 prepared Fe/bioceramic (hydroxyapatite
(HA), tricalcium phosphate (TCP), and biphasic calcium phos-
phate (BCP)) composites using sintering. The yield and
compressive strength was slightly more than pure Fe. Reindl
et al.47 prepared a Fe/b-TCP composite with 50 vol% b-TCP using
powder injection moulding combined with sintering; here, the
maximum compressive yield strength of the composite was
696 MPa, which is markedly greater than the 361 MPa
compressive yield strength of pure Fe.
3.3 Electrodeposition
Electrodeposition is a lm growth process that consists of the
formation of a metallic coating onto a base material via the
electrochemical reduction of metal ions in electrolytes.63 Elec-
troforming is an application of electrodeposition that is used
for the reproduction of moulds to directly form objects in their
nal shape.63 The electroforming technique is simple and does
not require complex equipment or a large amount of energy
consumption. Moravej et al.48 reported that electroformed iron
had a very ne texture and excellent mechanical properties.
Heat treatment decreased the strength of the electroformed
iron, whereas elongation was improved. The texture, grain size
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and grain shape of electrodeposited iron were markedly affected
by the current density. The microstructure of the iron lm was
altered by annealing at 550  C. This result was due to the
recrystallization induced during the annealing process.64 Elec-
trodeposition cannot be restricted by shape of substrate, and
can even occur on complex surfaces. He et al.49 prepared
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capable of homogeneous cell distribution; in addition, this
technique shows high precision and accuracy for creating
intricately-detailed biomimetic 3D structures.75 Fe–30Mn scaf-
folds were processed using inkjet 3D-printing combined with
sintering.50 The scaffolds had an open porosity of 36.3%. The
tensile mechanical properties were very similar to those of

a porous scaffold with a double-layer structured skeleton using natural bone. Equal channel angular pressing (ECAP) is a pro-
a two-step electrodeposition. The structure of the scaffold was cessing method for nanocrystalline (NC) metallic materials, and
similar to that of cancellous bone, and the tensile strength of it was used to obtain NC pure Fe.51,76 Aer eight passes, the
the scaffold was identical to that of cancellous bone. mean grain size decreased from approximately 50 mm to 80–
200 nm. Accordingly, the micro-hardness and tensile strength
3.4 Surface modication greatly increased, and these results conform to the Hall–Petch
rule. Furthermore, the contact angle of the NC pure Fe was
Surface modication is a method typically used to improve the
smaller than that of microcrystalline (MC) pure Fe. This result
biocompatibility or degradability of biodegradable metal. To
shows that NC pure Fe has a lower surface energy relative to MC
prevent the premature loss of mechanical stability of Fe stents
pure Fe. The surface roughness of NC-Fe is larger than MC-Fe,
by corrosion, oxide or nitride layers were prepared on the
which may be benecial for protein adsorption, cell spread
surface of pure iron using different methods. For example, a Fe–
and attachment. Magnetron sputtering was used for produce
O thin lm was prepared using plasma immersion ion
pure iron foils.53 The foils showed a preferential orientation,
implantation,65 a La2O3 lm was prepared with a metal vapour
a ne-grained structure and an enhanced mechanical strength
vacuum arc,66 and a nitride layer was created on the surface of
when compared with cast Fe. A series of biodegradable wires
pure Fe using plasma nitriding.67 Feng et al.52 modied a pure
composed of Fe, Mn, Mg and Zn were manufactured by cold
Fe stent with plasma nitriding. The Fe4N particles generated by
drawing technology.77 Because of the ne microstructures and
nitriding were uniformly dispersed in the Fe matrix, which
bre textures produced during cold drawing, these wires
enhanced its mechanical properties, including tensile strength,
demonstrated excellent mechanical properties. Among them,
microhardness, radial strength and stiffness. In addition, metal
an Fe35Mn–Mg composite wire showed more than a 7%
ions can be implanted in the pure Fe matrix. For example, Ag
increase in elasticity, a similar fatigue strength, an ultimate
ions were implanted into the surface of pure iron using a metal
strength of more than 1.4 GPa and a toughness exceeding 35 mJ
vapour vacuum arc (MEVVA) to form an approximately 60 nm
mm 3 when compared with 316L stainless steel. Vacuum
gradient layer that consisted of Ag2O in the outermost layer and
inltration and dipping methods were employed to prepare
Ag atoms in the inner layer of the Fe matrix.68 Zn was also
PLGA–porous pure iron composites, including PLGA-inltrated
implanted into the surface of pure Fe by MEVVA, and the
and coated pure porous iron.54 The compressive strength of
implantation depth reached to about 60 nm. In the outer layer,
PLGA–coated porous pure iron was higher than PLGA-inltrated
Zn element existed as ZnO, and Zn existed as Fe–Zn solid
porous pure iron and similar to that of cancellous bone.
solution beneath the ZnO layer.69 Some micro-patterned noble
metals arrays, such as Au70 and Pt,71 were coated on the surface
of pure Fe to improve its degradation performance. Lin et al.72 4. Degradation properties
designed a novel iron-based drug-eluting stent, which was
The corrosion rates of different Fe-based materials are
created by electroplating Zn and coating sirolimus-carrying
summarized in Table 3. An ideal biodegradable metal device
PDLLA on the surface of the stents. Nitride iron materials
should have an appropriate degradation rate that matches with
have outstanding comprehensive mechanical properties, thus
the repair rate at the implant site. For stents, a complete
stents made with this material show excellent device perfor-
degradation is expected to occur aer the vessel remodelling
mance. The Zn barrier layer of the stent allows for ultrathin
phase, which typically takes 90–120 days.9 During this phase,
struts, and the thick PDLLA coating maintains adequate scaf-
a very low degeneration rate provides sufficient mechanical
folding at 3 months aer implantation. A calcium phosphate/
support to the injured vessel. Depending on the clinical
chitosan coating was prepared on the surface of iron foam
conditions, the mechanical support from bone implants should
using electrophoretic deposition.73 Aer immersion in PBS and
be sustained for 12–24 weeks, as shown in Fig. 3.9 For biode-
m-SBF, apatite coatings were formed on the composite surface.
gradable Fe materials, a relatively low degradation rate is
Plasma polymerisation was employed to deposit an allylamine
currently a major problem. For example, pure iron stents were
coating onto pure Fe samples, and the results showed that an
implanted in blood vessels, and although there were signs of
ultra-thin, pinhole-free, polymer-like, and amine-rich layer with
degradation aer 1 year, a large portion of the stent remained
a thickness of 250 nm was completely and uniformly coated
intact, which can produce negative effects similar to those
on the samples.74
caused by permanent stents, such as restenosis.20 Thus,
improving the degradation rate of Fe is a problem that needs to
3.5 Other methods be resolved by further research into biodegradable Fe-based
Three dimensional (3D)-printing technology has been used to materials. A variety of methods have attempted to improve the
produce versatile scaffolds with complex shapes that are degradation performance of Fe, such as alloying, adding

112824 | RSC Adv., 2016, 6, 112819–112838 This journal is © The Royal Society of Chemistry 2016
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Table 3 Summary of the corrosion rates of different Fe-based materialsa

Corrosion rates from different methods

Corrosion Dynamic
Materials environment Electrochemical Static immersion immersion In vivo Ref.
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Fe (rolling) Modied Hank's 0.172–0.244 mm per 0.120–0.146 mm per — — 34

solution year year
Fe (rolling) Modied Hank's 0.209–0.243 mm per 0.115–0.144 mm per — — 35
solution year year
Electroforming Fe Modied Hank's 0.85 mm per year — — — 48
solution
Electroforming Fe, 0.51 mm per year — — —
annealed
Nanocrystalline Fe Hank's solution a
1.896 g m 2 d 1 — — — 51
Nanocrystalline Fe Gas-ow 0.009–0.100 mm per — — — 76
physiological saline year
Microcrystalline Fe 0.039–0.127 mm per — — —
year
Magnetron Modied HBSS 0.06–0.10 mm per — — — 53
sputtered Fe year
As-Electroformed Fe Hank's solution — 0.4 mm per year — — 83
E-Fe annealed — 0.25 mm per year — —
CTT-Fe annealed — 0.14 mm per year — —
Fe SBF — — f
4.896 g m 2 d 1
— 84
Fe Hank's solution 0.105 mm per year — — — 85
Fe–Mn/Co/Al/W/B/ Hank's solution 1.863–3.991 g m 2 0.028–0.361 g m 2 0.678–3.456 g — 27
C/S d 1 d 1 m 2d 1
Fe–30Mn HBSS 0.73 mm per year — — — 50
Fe–33Mn (LSM) Osteogenic media 0.8354 mm per year — — — 36
Hot forged Fe–30Mn SBF b
18.91 g m 2 d 1 0.028 mm per year — — 39
Fe–35Mn Modied Hank's 0.44 mm per year — — — 44
solution
Fe–(20–35)Mn Modied Hank's 0.4–1.3 mm per year — — — 45
quenched solution
Cold rolled 0.5–0.7 mm per year — — —
Fe–35Mn 5% NaCl and SBF 3.72–8.28 mm per — — — 43
year
Fe–20Mn (casting) Osteogenic media 0.9427 mm per year — — — 81
Fe–20Mn (cold 0.5397 mm per year — — —
rolling)
Fe–35Mn SBF 0.51 mm per year — — — 82
Fe–21Mn–0.7C–1Pd SBF — 0.21 mm per year — — 86
Fe–W Hank's solution 1.604–3.025 g m 2 0.560–0.663 g m 2 — — 56
d 1 d 1
Fe–CNT 2.108–2.419 g m 2 0.884–1.028 g m 2 — —
d 1 d 1
Fe–(2–50)Fe2O3 Hank's solution 0.107–2.407 g m 2 0.273–0.668 g m 2 — — 57
d 1 d 1
Fe–CNTs Hank's solution — c
0.009058 g m 2 d 1 — — 59
Fe–Mg — c
0.02362 g m 2 d 1 — —
Fe–HA SBF d
4.776 g m 2 d 1 d
1.008 g m 2 d 1 — — 46
Fe–BCP d
4.608 g m 2 d 1 d
1.488 g m 2 d 1 — —
Fe–TCP d
4.344 g m 2 d 1 d
2.16 g m 2 d 1 — —
Fe–TCP 0.9% NaCl — e
0.196 mm per year — — 47
HA/PCL–Fe SBF 0.002 mm per year — — — 87
HA–Fe 0.003 mm per year — — —
Nitrided Fe stent PBS 0.225 mm per year — — — 52
Ag ion implanted Fe Hank's solution b
1.01 g m 2 d 1 b
0.55 g m 2 d 1 — — 68
Micro-patterned Au Hank's solution 2.338–3.174 g m 2 1.134–1.417 g m 2 — — 70
arrays coated Fe d 1 d 1
Pt disc patterned Fe Hank's solution b
4.4285–4.7927 g b
3.4565–3.8324 g — — 71
m 2d 1 m 2d 1
Fe/Fe-W alloy Hank's solution — 0.149–0.264 g m 2 — — 49
scaffolds d 1

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Table 3 (Contd. )

Corrosion rates from different methods

Corrosion Dynamic
Materials environment Electrochemical Static immersion immersion In vivo Ref.
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PLGA–porous Fe PBS 0.42–0.72 mm per 0.76–6.42 mm per — — 54

composite year year
Fe–PPAam PBS 0.0386 mm per year — — — 74
Fe stent Descending aorta of — — — Aer 1 year, 20
minipigs a large
portion of the
stent remains
complete
Fe–10Mn–1Pd Femoral mid- — — — No 88
Fe–21Mn–0.7C–1Pd diaphyseal region of statistically
male Sprague- signicant
Dawley rat loss in
volume
Fe–(0.5–6.9)Mn Underneath the — — — No 38
subcutis of mice signicant
corrosion
aer 9
months
Fe wires Wall and luminal — — — Substantial 89
implant in biocorrosion
abdominal aorta of by 22 days in
male Sprague- wall and
Dawley rats minimal
biocorrosion
at 9 months
a
Note: pure Fe that served as a control is not listed in this table. The error values in the original data from the references are not shown. The
following units were changed to g m 2 d 1 or mm per year: a, mg m 2 h 1; b, mg cm 2 d 1; c, mg m 2 d 1; d, g m 2 h 1; e, mm per year; and
f
, mg cm 2 h 1.

a second phase, surface modication and other processing
methods. Fig. 4 summarizes the previous reports on the regu-
lation methods used to control the corrosion rate of Fe-based
materials.
4.1 Alloying
Alloying with other elements is a preferred method to improve
the corrosion rate of Fe. There are many alloying elements in
industrial steels; however, the effects of these elements on the
corrosion resistance of Fe can differ. To determine which
alloying elements could be used to produce biodegradable Fe
alloys, Liu et al.27 studied the feasibility of numerous elements,
including Mn, Co, Al, W, Sn, B, C and S. The authors reported
that the corrosion rates of pure Fe and its corresponding Fe–X
binary alloys were of the same order of magnitude. With regards
to mechanical properties, corrosion rates and biocompatibility,
the authors suggested that Co, W, C and S are feasible alloying
elements for biodegradable Fe alloys.
The standard potential of reaction for Mn / Mn2+ + 2e is
1.18 V, which is lower than the standard potential of reaction
for Fe / Fe2+ + 2e , which is 0.440 V.78 Because Fe and Mn
can form a solid solution that exists as a less noble state, the
standard potential of the Fe–Mn alloy was decreased by
increasing Mn content.32 Moreover, Mn is an essential trace
element that plays an important role in the growth, develop-
ment and maintenance of healthy bones.79 Therefore, Fe–Mn
alloy aroused a great deal of interest, and Mn was added into the
Fe matrix as a preferred alloying element. The corrosion prop-
erties of Fe–Mn alloys with varying Mn content, including
Fe20Mn,45,80,81 Fe25Mn,45,80 Fe30Mn,39,45,50,80 Fe33Mn,36
Fe35Mn 43–45,80,82
and lower Mn concentration Fe–Mn alloys (0.5,
2.7, and 6.9 wt% Mn),38 have been extensively studied.
Hermawan et al.45,80 found that the average corrosion rate of
Fe–Mn alloys was approximately 520 mm per year, which is two
times the rate of pure iron. In these alloys, the corrosion rate of
the double-phase (g + 3) alloys was higher than that of the single
phase (g) alloys. A similar result was reported for a 3D printed
Fe–30Mn alloy consisting of two phases (martensite and
austenite).50 Aer cold-rolling, the corrosion rate of Fe30Mn and
Fe35Mn slightly increased, whereas the rate for Fe20Mn and
Fe25Mn declined.45 The degradation products mainly consist of
Ca/P compounds and iron hydroxides. Because the degradation
products are not completely soluble, the release of iron and
manganese ions into solution was limited.80
Čapek et al.39 found that the free corrosion potential of the
hot-forged FeMn30 alloy was lower than that of iron, whereas
the corrosion rate was faster than that of iron. However, the
corrosion rate derived from a semi-static immersion test was
remarkably lower than that of iron. Heiden et al.81 reported that

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Fig. 3 The schematic diagram of degradation behaviour and changes
in the mechanical integrity of biodegradable metal implants during the
healing process: (a), vascular; and (b), bone (reproduced with
permission of Elsevier from ref. 9).
the oxidation layer formed on the surface of the Fe–Mn alloy
strongly inhibited the corrosion rate. Machining affected the
morphology of oxidation layer on the surface of the samples,
and the structure and morphology of oxidation layer impacted
the diffusion of metal ions and the corrosion rate of the alloy.
Compared with cast Fe–20Mn, the instantaneous corrosion rate
of cold-rolled Fe–20Mn was lower. Aer quenching, cast
samples have a ner grain and larger grain boundary, which
promotes corrosion. Aer large-strain machining (LSM), the
corrosion rate of the cast Fe–33Mn alloy showed a 140%
increase when compared with the cast alloy without LSM.36
Zhang et al.43 reported that the degradation rate of Fe–35Mn
prepared by sintering was remarkably increased when
compared with compact samples. The degradation rate of
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approximately 2–8 mm per year meets the required timeframe
for degradation. The degradation mechanisms include uniform
corrosion and crevice corrosion.43 A Fe–35Mn alloy prepared by
sintering-cold rolling-sintering included more dispersed MnO
ne particles and micropores, which provided more microsites
with a different potential and larger surface; thus, the corrosion
rate was greatly increased for this alloy.44 Because of the surface
alterations caused by the stent fabrication process, the degra-
dation rate of stent prototypes produced from a Fe35Mn alloy
was higher than that of the original alloy. The expanded stents
showed a lower polarisation resistance when compared with
nonexpanded stents, which highlights the effect of the expan-
sion procedure on degradation.82
Fe–Mn alloys with lower Mn content (0.5–6.9 wt%) showed
suitable in vitro corrosion properties. However, no remarkable
corrosion was observed during in vivo tests, which may be due to
the inhibition of corrosion by phosphate passivation layers.38
Moreover, different manganese concentrations had no detect-
able inuence on the biodegradation rate.
The addition of Si increased the content of austenite. The
electrical resistivity of martensitic is higher than that of
austenite; therefore, the Fe30Mn6Si alloy showed a higher
corrosion rate in electrochemical tests.26 However, immersion
tests revealed that the corrosion rate of Fe30Mn6Si was lower
than pure Fe because of the inuence of the corrosion products
on the surface. An in vivo study90 of 1.5Fe–Mn–Si implants
showed generalized corrosion, and the corrosion products
consisted of hydroxide layers on the surface. Except for
implants with basic elements, P, C, Ca, S and K compounds
were formed on the surface of subcutaneous implants, whereas
P, C, Ca and Na but not Mn compounds were found in tibia
implants.90
Small amounts of noble alloying elements added into the Fe
matrix can enhance its corrosion susceptibility. Moreover, the
addition of noble alloying elements can produce small and
nely dispersed intermetallic phases, which serve as cathodic
sites in the Fe matrix and cause microgalvanic corrosion.32
Therefore, noble elements, such as Pd32,86,88 and Ag,62 were
added to the Fe matrix to improve its corrosion rate. Schin-
hammer et al.32 reported that the addition of Pd decreased the
polarisation resistance and increased the degradation rate of
the alloy. Furthermore, heat treatment generated homoge-
neously distributed intermetallic phases, which facilitates
macroscopically homogeneous degradation behaviour in Fe–
Mn–Pd alloys. The authors also suggested that Pd deposited on
the metal surface and formed a macroscopic, short-circuited
primary cell that accelerated metal degradation. In vitro tests
showed that the addition of only 1 wt% of Pd to Fe–21Mn–0.7C
effectively improved the degradation rate.86 In vivo tests88 did
not produce similar results. Cylindrical Fe, Fe–10Mn–1Pd and
Fe–21Mn–0.7C–1Pd pins were implanted in the femurs of
Sprague-Dawley rats. The results showed that during the
implantation phase of 52 weeks and aer, the volume and
surface of all of the sample pins showed no obvious statistical
changes. The samples showed a slight, non-signicant decrease
in weight.88 A lower oxygen concentration at and near the
implant site produces a very slow degradation rate of the alloy.
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Fig. 4 Summary diagram of the regulation methods for the corrosion rates of Fe-based materials. Blue boxes represent regulation methods,
green boxes represent specific measures, and purple boxes represent the role of the specific measures.
In addition, degradation products can hinder oxygen diffusion
to the sample surface and limit further degradation. In Fe alloys
fabricated with powder metallurgy,62 the addition of C, Ag, P
and B increased the corrosion rate relative to pure Fe. However,
the C and P content as well as P and B content had no signi-
cant effect on corrosion rates.
4.2 Adding a second phase
Adding a second phase into the Fe matrix is another method
used to improve the corrosion rate of Fe composites. Cheng
et al.56,57 found that the addition of second phases led to
a decrease in corrosion potential; however, the corrosion
current densities increased. An immersion test showed that W
did not affect the long-term corrosion rate of the composite,
whereas the addition of CNTs and Fe2O3 markedly increased the
corrosion rate. A more uniform corrosion mode occurred on the
composite. Another study showed that the degradation rate of
Fe-based composite scaffolds decreased aer the addition of
112828 | RSC Adv., 2016, 6, 112819–112838
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CNTs and immersion in Hank's solution for 8 weeks, whereas
the addition of Mg greatly increased the degradation rate of the
scaffolds.59 A similar result for electrochemical measurements
was reported.60
Huang et al.41,58 selected noble metal elements (Pd, Pt, Ag
and Au) to serve as second phases in the Fe matrix. In Hank's
solution, Fe-5 wt% Pd and Fe-5 wt% Pt composites showed
uniform corrosion.41 Pd- and Pt-rich areas act as cathodes and
have a very high corrosion potential. The iron acted as an anode
and abundant small galvanic cells were formed, thus, markedly
enhancing the corrosion rate of the iron matrix. The corrosion
rate of Fe–Ag and Fe–Au composites was improved because pure
Ag and Fe–Au solid solutions, which have relatively high
corrosion potential, act as a cathode and the iron substrate acts
as an anode to form galvanic cells on the surface of the material
when immersed in Hank's solution.58
Bioceramics are frequently used for second phases. Bio-
ceramics (e.g., HA, TCP, and BCP) are soluble; therefore, the
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addition of bioceramics to the Fe matrix increased the corrosion

rate and enhanced the biocompatibility of the Fe matrix. Ulum
et al.46 reported that the corrosion rate of the Fe/bioceramic (HA,
TCP, BCP) composite tested with an electrochemistry method
was lower than pure Fe; however, the immersion test yielded
contrasting results. The authors suggested that the time
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required for the electrochemistry test procedure was shorter

than the immersion test, and the bioceramics did not have
enough time to go into solution. However, during the long
immersion period, bioceramics can enter the solution and form
a degradation layer. Immersion medium can also affect the
corrosion rate;47 for instance, the corrosion rate of the Fe/b-TCP
composite in a 0.9% NaCl solution was faster than that of SBF.
The corrosion rate of the Fe/b-TCP composite containing 40
vol% of b-TCP was 196 mm per year, which was 28% more than
pure Fe.

4.3 Surface modication

Surface modication can improve degradability and biocom-
patibility of implants during the initial implantation phase.
The oxide lm deposited on the surface remarkably
improved the corrosion resistance of pure Fe in SBF,65,66 and
a nitride layer improved the corrosion resistance of pure Fe in
a 0.9% NaCl aqueous solution.67 These layers may prevent the
premature loss of mechanical stability in Fe stents due to
corrosion. Feng et al.52 reported that the effect of nitriding on
corrosion potential is limited, but it markedly enhanced the
corrosion current density of pure Fe stents. Twelve months aer
implantation, the nitrided pure Fe stent showed severe corro-
sion with a visible bulk decline (Fig. 5), and the strut thickness
of the stent decreased from 120 mm prior to implantation to
approximately 60 mm. Lin et al.72 reported that nitrided iron-
based drug-eluting coronary stents had remarkably shortened
Fig. 5 Histological sections of nitrided iron stents at 3 (a), 6 (b), and 12
degradation periods, almost completely corroded by 13 months (c) months after implantation (reproduced with permission of Springer
aer implantation, and produced a small amount of degrada- from ref. 52).
tion products, as shown in Fig. 6.
Noble metal elements improved the degradability of the Fe
matrix when used as alloying elements or second phases. the degradation of composites. Daud et al.87 reported that the
Similar results were obtained when these elements were used degradation rate of porous iron scaffold coated with HA and HA/
for surface modication. Pure iron implanted with Ag ions PCL was approximately 10 times lower than samples without
showed faster and more uniform corrosion.68 Micro-patterned a coating. The coating may have inhibited the degradation of
noble metal arrays coated on the surface of pure Fe modu- the samples. Farack et al.91 reported that unmodied iron foams
lated the corrosion behaviour of pure Fe. Cheng et al.70 reported
that depositing a micro-patterned Au disc lm on the surface of
pure iron effectively increased the corrosion rate. Au served as
an anode and the iron acted as the cathode, thus micro-galvanic
corrosion occurred and accelerated the corrosion of the iron
matrix. Another advantage of the Au disc coating was macro-
scopically uniform corrosion. This was due to the wide and
uniform distribution of Au which formed numerous active sites
for corrosion reactions on the surface of the matrix. Similar
results were reported with the coating of the pure Fe surface
with Pt disc arrays.71
Fig. 6 The images of the nitrided iron-based drug-eluting coronary
PLGA–porous Fe composites showed a faster degradation stent after (a) 3 days, (b) 3 months, (c) 6 months, and (d) 13 months after
because of a stronger interfacial interaction between PLGA and implantation in the rabbit abdominal aorta (reproduced with permis-
the surface of porous Fe.54 The hydrolysis of PLGA accelerated sion of Elsevier from ref. 72).

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demonstrated the fastest corrosion rate and were accompanied
by high concentrations of H2O2. The iron foam coated with
a brushite layer was highly protected and showed almost no
corrosion. HA-coated iron foams showed signicant iron
release, hydrogen peroxide formation and oxygen depletion.
The brushite coating was a remarkably more effective means of
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corrosion control than the HA coating. Furthermore, the
corrosion behaviour was affected by the type of the incubation
medium. DMEM induced a more powerful corrosion when
compared with McCoy's medium.
A plasma allylamine polymerized coating remarkably
decreased the corrosion rate and the formation of biodegrad-
able Fe products.74 Polypyrrole lm was added to the surface of
an iron electrode using electrochemical polymerisation. This
lm increased the corrosion resistance of the iron. The redox
and electrical properties of the lm can be tailored by applying
appropriate potentials during synthesis.92 A phosphate coating
(CaZn2(PO4)2$2H2O) on the Fe surface effectively improved the
corrosion resistance of pure iron and provided effective
protection during the initial implantation stages.93 Because of
the inhibition of corrosion products, the corrosion rates of Fe/
Fe–W alloy double-layer scaffolds gradually decreased with
increasing immersion time, and the nal corrosion rates of
different samples were approximated during static
immersion.49
4.4 Degradation rate of pure Fe
The degradation rates of pure Fe fabricated by different
methods showed obvious differences. Typically, different
fabrication methods produce materials with different micro-
structures. Thus, the corrosion performance is changed.
Obayi et al.34 reported that the corrosion rates of cold-rolled
and annealed pure Fe slightly declined with a decrease of grain
size and grain size distribution. However, the authors also re-
ported that the effect of mean grain size on the corrosion rates
was not signicant.35 Annealing may reduce the corrosion rate
by reducing defect density. The corrosion rates decreased with
rising annealing temperatures due to more heterogeneity and
a higher dislocation density at lower annealing temperatures.
The corrosion rate of UD samples was slightly faster than BD
samples due to more residual stress. UD samples exhibited
more grain boundary corrosion than BD samples. This result
shows that the corrosion of cross-rolled samples is more
uniform.
Electroformed Fe showed uniform degradation with
a moderate rate,83 and the corrosion rate of this composite in
Hank's solution was faster than that of iron produced by casting
and thermomechanical treatment.48 The current density can
affect the corrosion rate of electrodeposited Fe lm.64 Because
of larger grains size and texture, electrodeposited Fe lm at 2 A
dm 2 presented with the lowest corrosion rate during electro-
chemical tests. Furthermore, the degradation morphology of
this lm showed uniform corrosion during a static immersion
test because of its strong texture. A degradation layer that
decreased the degradation rate was formed on the sample
surface; therefore, static degradation tests demonstrated lower
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corrosion rates for iron. Microscopic pits were found for Fe lm
with an electrodeposition at 1 A dm 2, 5 A dm 2 and 10 A dm 2.
Nie et al.51 reported that the corrosion rate of pure Fe grad-
ually decreased as ECAP times increased. Corresponding to the
decreased corrosion rate, the corrosion mode became milder, as
evidenced by the change of larger and deeper holes to only small
dimples on the corroded surfaces. Thus, the NC distinctly
reduced rigorous corrosion. This effect benets the design of
degradable stents. To simulate the corrosion of stents in the
body, electrochemical measurements for NC and MC pure Fe
were completed in physiological saline solutions with varying
dissolved oxygen concentrations.76 NC-Fe exhibited higher
corrosion resistance when compared with MC-Fe, and the
corrosion resistance was improved by decreasing the oxygen
concentration in the physiological saline. In an oxygen-free
solution, corrosion was attenuated by a hydrogen adsorption
mechanism. This mechanism was dominated by an oxygen-
consuming mechanism in oxygen-containing solutions.
The degradation properties of other pure Fe composites were
studied. Magnetron-sputtered pure iron foils showed a compa-
rable low degradation rate that could be increased by annealing
and grain coarsening.53 The in vivo corrosion behaviour of an
iron wire was assessed by Pierson et al.89 The iron wire wrapped
in the extracellular matrix of the arterial wall underwent
substantial corrosion by 22 days, but a large corrosion product
remained in the vessel wall for 9 months. However, iron wire
implanted in the artery lumen showed minimal corrosion. This
phenomenon was caused by a metallic surface that was
passivated in ion-rich blood and an inhibited corrosion reac-
tion; however, the wires placed in the artery wall may not be
protected due to minor levels of passivation. Zhu et al.84 re-
ported that pure iron showed uniform corrosion and no obvious
pitting corrosion during a dynamic corrosion test. The mean
corrosion rate was 20.4 mg (cm 2 h 1).
5. Biocompatibilities
5.1 In vitro
Table 4 shows the results of in vitro tests of Fe-based materials.
In general, the results of these in vitro tests were directly affected
by the ion concentration in the culture medium; furthermore,
the ion concentration correlated with the corrosion rate and
composition of the material.
Pure Fe consists of only one element; therefore, its biocom-
patibility is only affected by Fe2+, Fe3+, Fe hydroxide and Fe
particles. These products have been used in medical applica-
tions because of their advantageous properties, such as drug
loading and disease diagnoses.9 In vitro studies of pure Fe
showed excellent biocompatibility. Electroformed pure Fe did
not inhibit the metabolic activity of primary rat SMCs. When
used as a cardiovascular stent, electroformed Fe produced
a benecial inhibition of cell proliferation.83 Cheng et al.85 re-
ported that industrial pure Fe showed no signs of cytotoxicity on
L929 or ECV304 cells; in addition, the haemolysis percentage
was less than 5%, and platelets showed a normal round shape.
These results suggest that industrial pure Fe has excellent
biocompatibility and haemocompatibility. Eighth pass ECAPed
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Table 4 Summary of the results of in vitro biocompatibility studies on different Fe-based materials

Materials Methods Cells Results Ref.

Fe Extraction medium culture L929, ECV304 No signs of cytotoxicity 85

Nanocrystalline pure Fe Extraction medium culture L929, ECV304, VSMC Inhibited growth of VSMCs but promoted growth of 51
ECs and improved cytocompatibility with L929 cells
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Electroformed Fe Indirect contactb SMC No inhibition of metabolic activity or cell 83

proliferation
Ag-implanted pure Fe Extraction medium culture L929, VSMC, EA.hy926 Viabilities were decreased slightly 68
Phosphating pure Fe Extraction medium culture MSC Relative growth rate was higher than 90% and 93
exhibited no toxicity to cells
Nitride iron stent Extraction medium L929, SMC, EC Iron ions in high concentrations show no 94
culture/direct cell culture cytotoxicity to L929 cells
Fe–O lm Direct cell culture HUVEC Good adhesion and proliferation of HUVECs 65
Fe–30Mn Extraction medium MC3T3-E1 Direct culture did not show reduced cell viability, 50
culture/ direct cell culture and high live cell attachment; indirect cultures
show good cytocompatibility
Fe–Mn Indirect contacta 3T3 mouse broblast Low inhibition of broblasts' metabolic activities 80
cell line
Fe-30Mn Extraction medium culture L929 Metabolic activity is lower than iron but higher than 39
70% limit
Fe–Mn/Co/Al/W/Sn/B/ Extraction medium culture L929, ECV304, VSMC Except for the Fe–Mn alloy, no remarkable 27
C/S alloy cytotoxicity to ECV304 cells but reduced the viability
of L929 cells and VSMCs
Fe–21Mn–0.7C(–1Pd) Extraction medium culture HUVEC Cytocompatibility was related to degradation rate 96
Fe–(0.5–6.9)Mn Direct cell culture SMC, EC No signicant inhibition zones aer 24 and 72 h; 38
inhibition zones around the discs were observed for
all tested discs in both cell types aer 144 and 240 h
Fe–(C/P/B/Ag) Direct cell culture Fibroblast Monolayer cell culture test revealed cell death aer 62
24 h; dynamic perfusion chamber revealed
cytotoxicity was greatly reduced
Fe-Matrix wires Direct cell culture/metal EC, SMC Signicant EC attachment, good EC coverage and 97
chloride solutions proliferation; SMC migration differed depending
on ion species (Fe2+, Fe3+, Mn2+ and Mg2+)
Fe/Fe-W alloy porous Extraction medium culture MC3T3-E1 A higher corrosion rate led to lower cell viability 49
scaffolds
Fe–(2–50)Fe2O3 Extraction medium culture L929, VSMC, ECV304 Aer culturing for 4 days, the cell viabilities were 57
80–90% for L929 cells, decreased for VSMCs, and
approximately 90% for ECV304 cells
Fe–5Pd/Pt Extraction medium culture L929, VSMC, ECV304 Slight cytotoxicity to L929 and ECV304 cells and 41
inhibited VSMCs
Fe–Ag/Au Extraction medium culture L929, VSMC, HUVEC No cytotoxicity to HUVECs or L929 cells; suppressed 58
cell viability of VSMCs
Fe–W/CNTs Extraction medium culture L929, ECV304, VSMC Fe–W showed no signicant cytotoxicity to L929 56
and ECV304 cells; all composites showed mild
cytotoxicity to VSMCs
Fe–CNTs/Mg Direct cell culture Fibroblast, MC3T3 Fibroblasts died aer 24 h of incubation; nuclei 59
morphology in MC3T3 cells showed signicant and
changes and cell viability was inhibited 60
Fe–HA/BCP/TCP Direct cell culture/ RSMC Cellular activity increased compared to pure iron 46
extraction medium culture
(Fe, Fe–HA, Fe– Direct cell culture SaOs-2, hMSC Perfusion cell culture enhanced proliferation and 91
brushite) foams osteogenic differentiation of hMSCs
Fe–HA, Fe/HA–PCL Direct cell culture HSF1184, hMSC Cell viability was high; cells preferably attached and 87
grew actively
Pt disc patterned pure Extraction medium culture EA.hy926, VSMC No toxicity to human umbilical vein endothelial 71
Fe cells; inhibited the proliferation of VSMCs
PLGA–porous Fe Direct cell culture HSF1184 Accelerated degradation enhanced cell viability 54
composite during an early degradation period of up to 72 h
Plasma polymeric Direct cell culture HUVEC Enhanced EC attachment, spreading, and 74
allylamine coated Fe proliferation
Heparin modied Fe Extraction medium ECV304, VSMC Increased the viability and number of adhered 98
culture/direct cell culture VSMCs and ECV304 cells
a
Alloy powders. b Disc specimens.

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RSC Advances
bulk nanocrystalline pure Fe distinctly inhibited the growth of
VSMCs, markedly enhanced the growth of ECs and the cyto-
compatibility of L929 cells, and resulted in a haemolysis
percentage of less than 5%; thus, this material showed superior
haemocompatibility and biocompatibility.51 The in vitro cyto-
toxicity of nitrided iron stents was studied by Lin et al.94 These
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authors suggested that the extraction medium and available
oxygen are very important during the processes of extraction
and incubation. Extracts with high iron ion concentrations
showed no cytotoxicity to L929 cells. The in vitro cytotoxicity was
produced by the size effect of corrosion particles rather than the
material itself.
The biocompatibility of Fe alloys can be affected to varying
degrees due to the addition of alloying elements. A study on the
ltering of alloying elements used to create Fe alloys showed
that, except for the Fe–Mn alloy, the extracts of Fe–Co/Al/W/Sn/
B/C/S binary alloys showed no remarkable cytotoxicity to
ECV304 cells; however, these extracts reduced the cell viabilities
of L929 cells and VSMCs. The haemolysis percentage of the
alloys was less than 5%.27 A decrease in the metabolic activity of
L929 cells was caused by a hot-forged FeMn30 alloy; however,
the decrease was less than the tolerable 70% limit.39 The higher
release of ions from the Fe30Mn6Si alloy extracts decreased cell
viability.26 However, the viability of ECV304 cells began to
increase aer two days, and a visible inhibition of VSMCs was
observed. Moreover, the haemolysis percentage of the
Fe30Mn6Si alloy was less than 2%, thus showing no haemolysis.
Excess manganese can produce intoxication and neurotox-
icity;95 therefore, the biocompatibility of Fe–Mn alloys has been
extensively studied. Compared to pure manganese, the Fe–Mn
alloy showed a low inhibition effect on the metabolic activities
of 3T3 broblast cells. Increasing the alloy concentration in the
cellular medium increased the inhibition effect. A 50% inhibi-
tion effect was reported at a concentration of 6 mg ml 1, and
a 100% inhibition effect was reached with concentrations of
16 mg ml 1 or greater.80 In vitro cell cultures incubated with an
inkjet 3D printed Fe–30Mn extract showed a cell viability that
was 80% of control aer 3 days (cultured in cell culture media).
Aer direct culturing of the samples for 3 days, the attachment
level of live cells and the cell density was higher than culture day
1. This result demonstrates that the material had good in vitro
cytocompatibility and that the cells permeated through the
pores.50 SMCs and ECs were cultured on Fe–(0.5–6.9)Mn alloy
samples and showed excellent biocompatibility.38 Aer 24 and
72 h, no signicant inhibition zones were observed. Aer 144
and 240 h, inhibition zones were observed around the sample
discs for all of the tested samples in both cell types. For SMCs,
the inhibition zones decreased with increasing amounts of
manganese in the alloys, whereas this produced larger inhibi-
tion zones for ECs. Multicomponent Fe alloys were also studied.
Schinhammer et al.96 investigated the cytocompatibility of the
extract media of an Fe–Mn–C(–Pd) alloy with HUVECs. The
authors showed that cell viability and metabolic activity were
closely related to the concentration of the extract media. The
addition of Pd did not impact the cytocompatibility of the alloy.
The authors suggested that as long as the release rate of ions is
within tolerance level, Fe-based alloys will be cytocompatible.
112832 | RSC Adv., 2016, 6, 112819–112838
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Review
The release rate of ions depends on the degradation rate;
therefore, the degradation rate of Fe-based alloys can inuence
cytocompatibility. Cell viability closely correlated with the
corrosion rate of a Fe–W alloy.49 A higher corrosion rate led to
lower cell viability. In a monolayer cell culture test,62 cells died
aer 24 h. An in vitro study of Fe alloys performed cytotoxic tests
in a dynamic perfusion chamber and found a marked decrease
in cytotoxicity. This effect was likely due to the continuous
removal of cumulative cytotoxic agents within the dynamic
perfusion chamber. P in the Fe alloy did not signicantly
inuence cytotoxicity. A large number of ECs attached to Fe-
matrix wires, and all Fe-matrix wires showed good EC
coverage and proliferation.97 The migration of SMCs showed
different tendencies depending on the ion species (Fe2+, Fe3+,
Mn2+ and Mg2+).
Fe matrix composites prepared by SPS, including Fe–W, Fe–
CNT,56 Fe–Fe2O3,57 Fe–Pd and Fe–Pt,41 had no obvious cytotox-
icity on L929 or ECV304 cells, except for Fe–Pd and Fe–Pt. This
effect may be due to the faster corrosion rate of these two
composites, which led to a higher ion concentration in the
extract media.41 Pd showed mild cytotoxicity in eukaryotic cells,
and Pt showed a relatively higher cytotoxicity. However, their
content was very low in the extract media, which suggests they
had a negligible impact. All of the composites showed inhibi-
tion of VSMCs. The haemolysis percentage for all of the
composites was less than 5% and showed good haemo-
compatibility. These results suggest that the composites are
promising candidates for degradable stents. Fe–Ag and Fe–Au
composites showed almost no cytotoxicity to EA.hy926 and L929
cells; however, the cell viability of VSMCs was remarkably sup-
pressed.58 The haemolysis percentages of these composites were
lower than 5%, and a similar number of round platelets
adhered on the surface of the samples. Oriňák et al.59 studied in
vitro static cell cultures with porous Fe-based scaffolds and re-
ported that the broblasts died aer 24 h; furthermore, the
nuclei of MC3T3 cells showed signicant changes in
morphology, and cell viability was inhibited.60 However, the
scaffolds showed good blood compatibility. The authors suggest
that under the conditions of the static culture, the degradation
products of the scaffold inhibited the activity of the cell.
Therefore, the cytotoxicity assessment should be performed in
a dynamic system to avoid excessive accumulation of corrosion
products. Ulum46 et al. reported that Fe/bioceramic composite
increased the cell viability of RSMCs when compared with pure
Fe. The fast degradation of PLGA–porous pure Fe and its
interaction with PLGA resulted in good broblast cell viability
during the early and most active period of degradation.54
In general, biocompatibility at the beginning phases of
implantation can be improved by surface modication. This is
very important for the initial phase of implantation, which
requires good biocompatibility and slow corrosion rates. HA- or
HA/PCL-coated samples showed high viability for HSF cells and
hMSCs, which indicates that HA improves the cytocompatibility
of the surface.87 In comparison to uncoated specimens, plasma
polymeric allylamine-coated Fe resulted in higher cell viability,
as shown by the enhancement of EC attachment, spreading,
and proliferation.74 The oxide lms deposited on the surface of
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Table 5 Summary of the results of in vivo tests of different Fe-based materials

Implants Animals Site of implantation Results Ref.

Fe stent Minipigs Descending aorta No local or systemic toxicity 20

Fe stent New Zealand white rabbit Native descending aorta No thromboembolic complications or adverse 99
events
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Fe stent Juvenile domestic pigs Coronary arteries No stent particle embolisation or thrombosis; no 100
traces of excess inammation or brin deposition
Fe stent New Zealand white rabbit Abdominal aorta No adverse events or adverse effects to local tissues 72
Fe stent Juvenile pigs Iliac arteries Mild luminal loss and relative stenosis aer 12 52
months
Fe stent Mini-swine Coronary arteries Mild intimal hyperplasia and intimal coverage 101
appears more complete aer 28 days; did not cause
inammation or other adverse reactions
Fe wire Wistar rats Subcutaneous loose The Fe implant was encapsulated with granulation 102
connective tissue in the tissue; emigration of macrophages, neutrophils and
dorsal thoracic region multinucleated giant cells; dilation of blood vessels
Fe–21Mn(–0.7C)– Sprague-Dawley rats Femoral mid- All animals showed good general health; the 88
1Pd (cylindrical diaphyseal region implants were well-integrated and sheathed by
pins) a narrow capsule of connective tissue; no signs of
inammation or local toxicity
Fe–(0.5–6.9)Mn NMRI mice Underneath the No adverse effects or signs of infection 38
(cylindrical plate) subcutis resting on the
fascia of the gluteal
muscle
1.5Fe–Mn–Si (small Wistar rats Subcutaneous/tibia Subcutaneous implant showed very good 90
piece) crest biocompatibility; no local reaction of any kind;
adverse biological reactions were not induced by
bone implants
Fe–HA/BCP/TCP Indonesian thin tailed Below the radius Positive tissue response for up to 70 days 46
(small slice) sheep periosteum membrane
of radial forelegs on
medio proximal region
Fe–HA/BCP/TCP Indonesian thin tailed Radial bones of leg Minimal tissue response; normal dynamic change 103
(small slice) sheep in blood cellular response; no stress effects; lower
inammatory giant cell counts

pure iron reduced the number of adhered platelets and 5.2 In vivo
inhibited the aggregation and activation of platelets;65,66 in
In vivo testing is the most straightforward method to estimate
addition, these composites showed good adhesion and prolif- the biocompatibility and degradability of Fe-based materials.
eration of HUVECs.65 The anti-haemolysis properties and cell
Table 5 summarizes the results of in vivo tests of Fe-based
compatibility of pure iron coated with phosphate were notably
materials. Degradable stents are one of the most important
enhanced, whereas the anti-coagulant properties slightly
applications of Fe-based materials; thus, in vivo studies of stents
decreased.93 Aer modication with heparin, the hydrophilicity
were the rst to be completed. The rst in vivo testing of pure
of iron markedly increased. The blood clotting coagulation time
iron stents was published by Peuster et al.99 The authors
was extended; therefore, the risk of thrombosis was reduced.
implanted pure iron stents into the native descending aorta of
VSMC proliferation was reduced, whereas ECV304 cells were not
New Zealand white rabbits. During the follow-up of 6 to 18
dramatically affected.98 Ag ions implanted into pure Fe slightly months, no thromboembolic complications or adverse events
decreased the viabilities of L929 cells, EA.hy926 cells and
occurred. No remarkable neointimal proliferation, inamma-
VSMCs. The haemolysis percentage was lower than 2% and
tory response or systemic toxicity was observed (Fig. 7). Next, the
demonstrated good haemocompatibility; however, an increased
authors implanted pure iron stents into the descending aorta of
the risk of thrombosis was revealed by platelets adhesion tests.68
minipigs for 1–360 days. There was no occurrence of Fe overload
Pt patterned discs of pure iron showed almost no toxicity to
or Fe-related organ toxicity; in addition, there was no local
HUVECs, but exhibited a remarkable inhibition of VSMC
toxicity caused by corrosion products, as shown in Fig. 8.20
proliferation. The haemolysis percentage was lower than 1%.
In a short-term study, Fe stents were implanted into juvenile
The number of adhered platelets on the samples was less than pig coronary arteries for 28 days to assess safety and efficacy.100
that of the uncoated samples.71 Farack et al.91 suggested that the
No particle embolisation or thrombosis was observed, and
continuous supply of fresh medium and removal of cytotoxic
histomorphometry revealed no excess inammation or brin
corrosion products in perfusion cell cultures enhanced the
deposition at 28 days aer implantation. The tissue in close
proliferation and osteogenic differentiation of hMSCs on
proximity to the stent turned a brown colour, which was caused
calcium iron foams coated with phosphate.

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Fig. 7 Histological sections of degradable iron stent 18 months after

implantation in rabbit aorta. A stent strut is covered by neointima (N).
There is moderate infiltration of macrophages along the adventitial
side (arrows) (reproduced with permission of MBJ Publishing Group
Ltd from ref. 99).

by the absorption of the ferric salts generated during stent

degradation by adjacent tissue. In a similar study, nitrided Fe
Fig. 8 Histological sections of iron and 316-L (control) stent struts
stents were implanted into mini-swine coronary arteries.101
during the course of follow-up (reproduced with permission of
Twenty-eight days aer implantation, the Fe stent produced Elsevier from ref. 20).
intimal hyperplasia similar to that of the control Co–Cr alloy
stent, whereas the intimal coverage appeared more complete
Kraus et al.88 implanted Fe, Fe–10Mn–1Pd, and Fe–21Mn–
than the control. Furthermore, the degradation of the stent did
0.7C–1Pd pins into the femur of Sprague-Dawley rats. Over the
not lead to an inammatory response of the surrounding tissue
course of one year, the authors found that the animals showed
or remote organs. No other negative effects were observed,
no severe pathological characteristics. Aer surgery, the wound
suggesting that the Fe stent was safe and effective.
showed slight swelling for 1–2 days, which conforms with
Feng et al.52 implanted nitrided Fe stents into the iliac
clinical features, then showed no signs of inammation and
arteries of juvenile pigs. One month aer implantation, the
healed at the expected rate. All animals were healthy aer
stent was covered by endothelial cells, and the inammatory
surgery. The histological results showed that the Fe degradation
response had decreased. Aer 12 months, intimal hyperplasia
products in the tissue near the implants were mainly Fe3+ and
led to mild luminal loss; in addition, the piglets' growth resul-
a relatively low amount of Fe2+. No inammation or local
ted in stenosis of the vessel at the implanted stent site.
toxicity was observed, and the degradation process did not
Thrombosis or local tissue necrosis was not observed. The
harm the tissue adjacent to the implant, as shown in Fig. 9.
nitrided Fe stent showed acceptable biocompatibility. Next, the
Fe–(0.5–6.9)Mn cylindrical plates were implanted under-
nitrided iron stents were underwent Zn electroplating and were
neath the subcutis on the fascia of the gluteal muscle in NMRI
coated with a PDLLA carrying sirolimus.72 The drug-eluting
mice. During implantation, no adverse effects or signs of
coronary iron stents were implanted into New Zealand white
infection were observed. All animals survived the implantation
rabbits. No adverse events or adverse effects on the local tissue
procedure and reached the assigned follow-up period.38 The
were observed. Aer implantation for up to 13 months, there
1.5Fe–Mn–Si implants showed excellent biocompatibility, and
were no identied biological problems.

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Fig. 9 Detection of (a) Fe3+/Fe2+, (b) Fe2+ and (c) Fe3+ in consecutive
sections of pure Fe samples after 36 weeks (reproduced with
permission of Elsevier from ref. 88).
no local reactions were observed. Adverse biological reactions
were not induced by the bone implants.90
In so tissue implantation studies,102 Fe showed the least
toxicity when compared with the same concentration of Ni or
Cu. The damage to surrounding tissue caused by the Fe implant
was relatively minimal, and the implant was encapsulated by
granulation tissue.
Ulum et al.103 implanted Fe–bioceramic composites into the
medio-proximal region of the radial leg bones of male Indone-
sian thin tailed sheep to thoroughly investigate their bioactivity.
Inammation disappeared 35 days aer implantation. B-Mode
ultrasonography showed minimal tissue response during the
wound healing process. A normal dynamic change in blood
cellular response and no effects of stress were observed. The
number of inammatory giant cells was lower than that of
SS316L. The composites showed enhanced bioactivity and were
benecial to wound healing. X-ray radiography revealed that the
composite showed a consistent degradation progress and good
tissue response.46
6. Concluding remarks
As one of the main types of biodegradable metallic materials,
the Fe-based materials are remarkable because of their excellent
mechanical properties and biocompatibility. Previous
researches already proved that the Fe-based biomedical mate-
rials can be successfully manufactured by many techniques.
The biocompatibility studies, both in vitro and in vivo, together
with other studies like mechanical research, showed that the Fe-
based materials are potentially useful for applications in stents,
orthopedics and bone tissue engineering.
Nevertheless, on the way to practical applications, there are
still some problems to be solved. First, the degradation rate of
Fe-based materials and its effect on biocompatibility require
more researches. The degradation rate is relatively slow and
should be improved and controlled. The degradation rate can
impact the biocompatibility of the material. A lower degrada-
tion rate yields better biocompatibility and vice versa. The
excessive degradation products produced under higher degra-
dation rates can lead to a decline in biocompatibility. Therefore,
fast degradation rates are not necessarily better. The ideal
degradation rate is the one with sufficient biocompatibility and
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complete degradation by an expected time. Effort to make the
degradation rate controllable should be an important research
direction for these materials.
Second, corrosion mode is another important issue that
directly relates to safety and implant efficacy. Uniform corro-
sion is an ideal corrosion mode. Non-uniform corrosion (such
as point corrosion, intergranular corrosion, crevice corrosion,
and so on) can lead to the premature failure of implants.
Corrosion mode depends not only on the microstructure of the
materials, but also on the implantation environment. The two
factors need to be considered in the control of the corrosion
mode. For the Fe-based materials, a homogeneous phase and
ne microstructure are conductive for the corrosion to occur
uniformly. Some reports32,35,64 have shown that relatively
uniform corrosion can be attained by controlling microstruc-
ture of the Fe-based materials. The composition and the
distribution of the body uid can also affect the corrosion mode
of the implant, because they are different at different implant
positions. So far the effects of implantation position on corro-
sion mode of Fe-based materials have not been reported.
Therefore, a systematic research needs to be considered in the
future.
The above two problems, i.e., controlling the degradation
rate and corrosion mode, can be solved via controlling the
composition and structure of the materials. To realize the
controllability, the composition and structure of the materials
should be designed according to the specic requirements in
the applications. For example, the corrosion rate of the implant
should not be constant. On the contrary, it should be varying
against the time (as shown in Fig. 3). In the beginning aer
implantation, the corrosion rate should be slow, and the slow
degradation rate should remain for a period of time during
which remodelling or repair can happen. Aer that the mate-
rials should be degraded at an increasing rate so that
a complete degradation will nish within an expected period of
time. A multilayer structure may be a feasible solution to this
requirement. In the outer layer, a material with low corrosion
rate can be used to satisfy the requirement in the remodelling or
repair phase. In the inner layer, a material with high corrosion
rate can be used to make sure that the implant will be degraded
completely within expected time. More advanced materials for
different purposes can be similarly designed and
manufactured.
In summary, biodegradable Fe-based materials are very
promising and further researches on controlling the degrada-
tion process are key to promote the applicability.
Acknowledgements
This work was supported by the National Basic Research Program
of China (973 Program) (Grant No. 2011CB710905), the National
Natural Science Foundation of China (Grant No. 31170816,
31200551), the Fundamental Research Funds for the Central
Universities (Grant No. 3102014KYJD019, 3102016ZY039,
3102015ZY083), China Postdoctoral Science Foundation (Grant
No. 2013T60890), and the Natural Science Foundation of Shannxi
Province, China (Grant No. 2016JM3012).
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