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High nitrogen nickel-free austenitic stainless

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 SCIENCE CHINA
Technological Sciences
• RESEARCH PAPER • February 2012 Vol.55 No.2: 329–340
doi: 10.1007/s11431-011-4679-3

High nitrogen nickel-free austenitic stainless steel: A promising

coronary stent material
YANG Ke*, REN YiBin & WAN Peng
Institute of Metal Research, Chinese Academy of Sciences, Shenyang 110016, China

Received September 1, 2011; accepted October 30, 2011; published online December 14, 2011

Currently commercialized coronary stents are mainly made of the medical 316L stainless steel and cobalt-based alloy (L605)
due to their good combination of properties, especially excellent mechanical properties. However, the presence of high quanti-
ty of nickel and/or cobalt elements, the agents known to trigger the toxic and allergic responses, in these materials has caused
many clinic concerns. The potential adverse effect of nickel ions release has prompted the development of high nitrogen nick-
el-free austenitic stainless steels for medical application. Nitrogen in steel is not only to replace the nickel but also improve the
properties of steel. In this paper, the harmfulness and release of nickel from metallic stents, and the advantages in mechanical
properties and hemocompatibility of high nitrogen nickel-free stainless steels for coronary stents are reviewed. Apart from the
highlight of nickel-free, the superiority of high strength and better hemocompatibility of high nitrogen nickel-free stainless
steels can guarantee to manufacture thinner strut coronary stents with remarkable anticoagulation ability. High nitrogen nick-
el-free stainless steels as a promising coronary stents material will attract more and more clinical doctors and stents makers to
bring them into clinical application.

high nitrogen steel, nickel-free, biocompatibility, coronary stent, restenosis

Citation: Yang K, Ren Y B, Wan P. High nitrogen nickel-free austenitic stainless steel: A promising coronary stent material. Sci China Tech Sci, 2012, 55:
329340, doi: 10.1007/s11431-011-4679-3

1 Introduction sible for ISR after bare-metal stent (BMS) implantation,

such as migration and proliferation of vascular smooth
muscle cells, etc. [1, 2]. As a result, the restenosis and tar-
Coronary disease has become one of the most common rea-
get-vessel revascularization could be reduced to rates below
sons for death of mankinds in industrial countries. Since
10% after DES implantation, but the risks of late/very late
1986 when the metal vessel stent was first implanted into
stent thrombosis (ST) with DES become a new concern of
human bodies to prevent the vessel wall from collapsing,
coronary stents [3–5]. Human autopsy series have suggested
the coronary stent has become one of the most important
that the DES caused late/very late ST is partly attributed to
achievements in the area of surgical cardiology. However
the impairment of arterial healing characterized by incom-
in-stent restenosis (ISR) as a complication after surgery still
plete re-endothelialization, persistent fibrin deposition and
weakens the effectiveness and success rate of coronary
macrophage infiltration, compared with BMS [6, 7].
stents. Subsequent drug-eluting stents (DES) designed to
How to reduce the damage and stimulation of stents to
release the pharmacological agents after deployment were
the artery wall is always an issue of common concern from
developed to inhibit response to the injuries mainly respon-
the cardiovascular clinical doctors and stents maker. Obvi-
ously, more thinner or the optimized struts of stents can
*Corresponding author (email: kyang@imr.ac.cn)

© Science China Press and Springer-Verlag Berlin Heidelberg 2011 tech.scichina.com www.springerlink.com
330 Yang K, et al. Sci China Tech Sci
lessen the stimulation by reducing the contact area between
stents and neointima, and the role of stent design in the arte-
rial wall causing restenosis has been investigated by both
experimental and clinical work [8–12]. Many results
showed that stents with a thin-strut design could signifi-
cantly reduce the risk of angiographic and clinical restenosis,
and the patients implanted with a thin-strut coronary stent
had significantly less late luminal loss at follow-up than
those with a thick-strut stent. Thus the cobalt-chromium
(Co–Cr) alloy stents with thin-struts are becoming a main-
stay of contemporary metal stent implantations due to their
maintained radiopacity and radial strength compared with
stainless steel stents.
Except for thin-strut stents, the development of better
material for stents is also an aim pursued by biomaterials
scientists. At present, the majority of the commercially suc-
cessful coronary stents materials are the medical 316L
stainless steel and cobalt-based alloys such as L605 and
MP35N. However, the high nickel contents in these materi-
als are becoming a point of discussion owning to the possi-
bilities of allergic reaction and carcinogenicity caused by
nickel ions [13–15], and the relationship between in-stent
restenosis and inflammation or allergy induced by nickel
ions leaching from stents is still under controversy [16–21],
which needs further studies to reach a final conclusion.
Considering the potential risk of biomaterial containing
nickel, the experts suggested that the best way is to strictly
forbid or restrict the nickel content in biomedical alloys. For
the future stents materials with improved vascular compati-
bility, newly developed austenitic high nitrogen nickel-free
stainless steels, i.e., Fe-Cr-Mn-Mo-N steels, may offer an
alternative material. The high nitrogen nickel-free stainless
steel (HNNFSS) possesses better combination of strength
and ductility, as well as better corrosion resistance and bio-
compatibility, than those of 316L stainless steel, and espe-
cially, its high strength close to the cobalt-based alloy en-
sures it to be taken as a promising coronary stents material,
which can be used to make optimized thin-strut stents and
synchronously avoid the potential harmfulness of nickel
element.
2 Ideal coronary stents material
Most commercially available coronary stents are currently
made of an Fe-Cr-Ni-Mo stainless steel, i.e., AISI 316L.
Due to its steady austenitic structure, the steel shows a good
combination of strength, ductility and corrosion resistance,
and satisfactory biocompatibility. Other potentially used
materials can be cobalt (Co)­based alloy, platinum-iridium
(Pt–Ir) alloy, tantalum (Ta), nitinol (Ni–Ti), titanium (Ti)
and its alloy, pure iron (Fe), magnesium (Mg) alloys and
biodegradable polymers, etc [22, 23]. Pt–Ir alloy and Ta
alloy are not often used due to their expensive cost and poor
processing-ability. Despite the fact that Ti and its alloys
February (2012) Vol.55 No.2
have favorable properties such as high corrosion resistance
and good biocompatibility, they are still not used for mak-
ing stents because of poor working-ability, low X-ray radi-
oactivity, etc. Pure iron and Mg alloy as hopeful bio-ab-
sorbable stents materials are under study [24], and a large
number of animal tests and clinical trials are needed to
evaluate and verify their effectiveness.
Metals are always the main materials utilized for stents
because of their better mechanical properties and visibilities
under X-ray imaging. The characteristics of an ideal stent
have been described in numerous reviews [22, 23, 25]. In
general, it should have 1) low profile: ability to be crimped
on the balloon catheter supported by a guide wire; 2) good
expandability ratio: once a stent is inserted at the target area
and the balloon is inflated, the stent should undergo a suffi-
cient expansion and conform to the vessel wall; 3) sufficient
radial hoop strength and negligible recoil: once implanted, a
stent should be able to overcome the forces imposed by the
atherosclerotic arterial wall and should not collapse; 4) suf-
ficient flexibility: it should be flexible enough to travel
through even the smaller diameter atherosclerotic arteries;
5) adequate radiopacity/magnetic resonance imaging (MRI)
compatibility: to assist clinicians in assessing the in-vivo
location of the stent; 6) thrombo-resistivity: the material
should be blood compatible and not encourage platelet ad-
hesion and deposition; and 7) drug delivery capacity: this
has become one of the indispensable requirements for stents
of the modern era to prevent restenosis.
Nevertheless, due to its good properties combination
(strength, ductility, corrosion resistance, etc.), low cost and
easy production, whether it is a bare stent or with a coating
material, the supremacy of 316L steel for making stents is
still evident in clinic. But nowadays the high nickel content
in 316L steel has become a point of discussion because of
the possibility of allergic reactions. Therefore, only coro-
nary stents made of nickel-free stainless steels can really
reduce the concern over allergic reactions to nickel.
3 Harmfulness of nickel in biomedical alloys
3.1 Harmfulness of nickel
Nickel is a metallic element that is naturally present in the
earth’s crust. Due to unique physical and chemical proper-
ties, metallic nickel and its compounds are widely used in
modern industries. The most typical and commonly used
biomaterials in clinic that contain nickel element include
316L austenitic stainless steel with nominal composition of
Fe-18Cr-14Ni-2Mo, NiTi alloy and some cobalt-based al-
loys.
However, it has been known that exposure to nickel
compounds can have adverse effects on human health, and
nickel allergy in the form of contact dermatitis is the most
common and well-known reaction. The number of women
affected by nickel allergy has been doubled each of the last
 Yang K, et al. Sci China Tech Sci
few decades [26]. Dermatologists assume that about 20% of
young women and 4% of young men suffer from nickel
allergy [27]. The higher prevalence of nickel allergy in
women is thus not genetically determined, but is related to
the daily use of many nickel-containing utensils and jewel-
ries [26]. Moreover, the overall environmental pollution is
also proposed to be a significant reason for the ever-
increasing number of affected people.
The nickel element is also serving as a trace element
necessary for the normal function of the human organism,
but too high a concentration of nickel can also cause prob-
lems to health. Experiments with high nickel intake have
shown that nickel is teratogenic and has carcinogenic poten-
tial [13]. The International Agency for Research on Cancer
(IARC) evaluated the carcinogenicity of nickel in 1990 [28],
and all the nickel-containing compounds except for metallic
nickel were classified as carcinogenic to humans. Though
there have been different suggestions for the daily intake or
daily requirment on nickel in the human body, the limit is
generally much lower. For instance, the World Health Or-
ganization (WHO) reported that the daily physiological re-
quirement on nickel for an adault is 0.02 mg.
A nickel containing alloy is just a potential allergen or
carcinogen, but it is safe to us unless it corrodes and the
nickel ions of high dose interact with the body tissues. But
the corrosion of the nickel containing alloy is unavoidable
in the body fluid environment as long as we use the nickel
containing alloys for orthodontic, orthopedics and other
implants [29, 30]. It was reported that 316L orthopedic im-
plants corrode in body environment and release iron, chro-
mium and nickel [31–33]. In the tissues adjacent to 316 L
plates and screws, the Ni concentration ranges between 116
and 1200 mg/L [34]. The maximum rate of Ni release due to
corrosion in patients who have implants made of Ni con-
taining alloys is estimated to be 20 mg/kg/day [35]. 316L
stainless steel is still not resistant to the localized corrosions
such as pitting, crevice corrosion, and the stress corrosion
cracking when used as implants [31]. For example, the cor-
rosion products of 316L steel are toxic to the primary cul-
ture of vascular smooth muscle cells when the released
nickel concentration is higher than 11.7 ppm. The toxicity
effects include inhibiting the cells growth, changing the
cells morphology and inducing the cells necrosis [33, 36,
37]. The first report of an allergic reaction to an orthopedic
implant described an eczematous rash over a stainless steel
fracture plate [38]. After that, numerous reports documented
the similar observations, with symptoms of discomfort, er-
ythema, swelling and skin change in the general area of the
implant [39]. In addition, some patients reported general
malaise, fatigue, or weakness. The majority of reports in-
volved the implants manufactured from alloys containing
nickel and cobalt [40].
3.2 Nickel and restenosis of stents
Stainless steel implants can cause inflammatory hypersensi-
February (2012) Vol.55 No.2 331
tivity reactions and allergic reactions, which could lead to a
fibro-proliferative response around the implant [40]. The
fibro-proliferative and inflammatory response was also
characteristically seen in the restenotic tissues within coro-
nary stents [41]. Most cardiovascular and peripheral vascu-
lar stents are made of 316L stainless steel or cobalt-based
alloy which contains strongly sensitizing metals such as
nickel, cobalt and chromium. Nickel, cobalt and chromium
ions can be eluted from stainless-steel stents [42, 43], and
the actions of blood, saline, proteins and mechanical stress
can increase release of these ions [44]. Inflammatory and
allergic reactions to metal, particularly to nickel, have been
found to occur in patients with orthopaedic, dental and other
stainless-steel implants [45, 46]. These reactions were asso-
ciated with the formation of new tissue around the metal
[47]. Whether similar reactions occur around stents and
trigger restenosis in patients with allergy to metal is still not
well known.
Köster et al. supposed that allergic reactions to nickel
and molybdenum ions released from stainless steel coronary
stents may be one of the triggering mechanisms for the de-
velopment of in-stent restenosis. They investigated the cor-
relations between metal allergies and in-stent restenosis [16],
and concluded that patients with sensitivity to nickel and
molybdenum, based on a skin patch test, had a higher fre-
quency of in-stent restenosis than patients without sensitiv-
ity. Hence, the controversy of nickel and restenosis is main-
tained continuously [17–19, 43, 48]. While the investigators
recognized limitations in their studies, the work did raise
questions about the potential impact of metal ion release
from stainless steel or cobalt-based alloy which contains
more than 10% nickel element. Latterly, the research results
of Taro et al. strongly suggested that tissue reaction to the
metal component of 316L steel, especially nickel, may play
an important role in the CR-ISR (chronic refractory in-stent
restenosis) [48].
In-vitro studies have shown that very low concentrations
of nickel and cobalt ions which show no influence on cells
morphology, could cause significant expressions of endo-
thelial cells adhesion as well as adhesion of polymorphonu-
clear neutrophil granulocytes to endothelial cells in vitro [37,
49]. Similarly, they may activate through at least two endo-
thelial cell signal transduction pathways by up-regulating
cytokines, and induce expression of adhered molecules [50].
A recent study identified a molecular pathway by which
exposure of vascular smooth muscle cells to metal ions
from stainless steel caused stimulation of their synthetic
phenotype via an increase in the expression of thrombos-
pondin-1 combined with a dependant increase in transform-
ing growth factor-b activity, thus suggesting that corrosion
of the stent may be a key contributor to the mechanism of
IRS [51]. Corrosion of some retrieved stents is described to
lead to transfer of heavy metal ions into the surrounding
tissues, and the present report suggests that when a stent
corrodes in-vivo, it would generate an active microenvi-
332 Yang K, et al. Sci China Tech Sci February (2012) Vol.55 No.2

ronment possibly leading to ISR [43]. The contribution of
this metallic ion release to the mechanism of in-stent reste-
nosis as well as its effect on the mechanical properties of
stents is unknown and requires further investigation.
On the basis of the problem described above, the poten-
tial harmfulness of nickel ions release from stents contain-
ing nickel can not be neglected. Though the legislation has
been established to restrict the materials containing nickel
for applications in human body in many countries in the
world, considering the potential danger of nickel, attraction
in price and quality, and wide application of stainless steels
in medical field, nickel-free austenitic medical stainless
steel should be applied to coronary stents and other im-
plantable devices as soon as possible, which must meet the
following requirements: absence of nickel, absence of fer-
romagnetism, high corrosion resistance, good mechanical
properties including high plasticity, high fatigue endurance
and high wear resistance, as well as good biocompatibility.
4 Development of nickel-free medical stainless
steel
As nitrogen is an austenitic phase former element like nick-
el (Ni) in steels, it can be used to develop the Ni-free or low
Ni austenitic stainless steel. Nitrogen has been taken as an
alloying element in many industrially used stainless steels to
replace and save the expansive nickel element. This type of
nitrogen containing austenitic stainless steel possesses ex-
cellent combination of strength and toughness, better re-
sistance to corrosion, as well as high wear resistance, which
is intensely expected to be a possible material for an-
ti-nickel allergy in medical field.
The stainless steels used nowadays for medical and sur-
gical purposes still contain 13 wt% to 15 wt% Ni such as
316L stainless steel. Because of the potential hazards that
Ni can bring to humans, and the possibility of replacement
of Ni content by increase of nitrogen content in steels, ni-
trogen containing low-Ni and even though Ni-free austenitic
stainless steels have been developed for medical application.
This gradual improvement of surgical stainless steels can be
seen from the ASTM standards listed in Table 1. With the
development of new surgical stainless steel and the modifi-
cation of ASTM medical standard, the Nickel content is less
and less in new stainless steel, but the more and more Ni-
trogen content is added in new stainless steel, until the high
nitrogen nickel free stainless steel Fe-23Mn-21Cr-1Mo-1N
(ASTM F 2229, i.e., Biodur® 108 alloy of Carpenter Tech-
nology Corporation) and Fe-11Mn-17Cr-3Mo-0.5N (ASTM
F2581) are developed and listed in ASTM standard as se-
lected surgical stainless steel. Now the high nitrogen nickel
free Biodur® 108 alloy has been used in processing of
medical devices or instruments [52, 53].
Currently high nitrogen steels are usually produced by
means of pressuring melting techniques, for instance, pres-
sured electroslag remelting, counter-pressure casting, plas-
ma arc melting, powder metallurgy, etc. [54–56]. During the
development and preparation of high nitrogen nickel-free
stainless steels, manganese (Mn) is also added to supple-
ment the nitrogen content in stainless steels, additionally as
a nickel substitute alloying element. Then the properties and
related mechanisms of Fe-Cr-Mn-N and Fe-Cr-Mn-Mo-N
nickel-free stainless steels are usually studied and applied in
different industrial fields.
In 1995, at the Fourth International Conference on High
Nitrogen Steels (HNS95), Uggowitzer and Speidel et al.
from Switzerland introduced a new austenitic stainless steel
[57], which contained 15wt%–18wt% chromium, 3wt%–
6wt% molybdenum, 10wt%–12wt% manganese and about
0.9% nitrogen. Besides nickel free, the steel had excellent
corrosion resistance and outstanding mechanical properties.
They suggested that nickel allergy could be prevented by
using this new high nitrogen nickel-free stainless steel. At
the same conference, Menzel et al. [58] from Germany di-
rectly proposed high nitrogen containing Ni-free austenitic
steels for medical applications, and suggested to develop
Fe-15Cr- (10-15) Mn-4Mo-0.9N by reducing the Mn and Cr
contents and increasing the Mo content in the stainless steel.
From then a large number of studies were focused on the
properties of different Fe-Cr-Mn-Mo-N series medical nickel-
free stainless steels, especially corrosion and wear in body
fluid, in vitro and in vivo biocompatibilities, and so on.
In 1999, Uggowitzer and Thomann studied wear-corro-
sion behavior of a biocompatible high nitrogen nickel-free
austenitic stainless steel, P558 (Fe-17Cr-10Mn-3Mo-0.49N-
0.2C), in comparison with 316L (ASTM F138, ISO5832-1)

Table 1 Chemical compositions of selected stainless steels for application of surgical implants in the United States, wt%, showing trend of decreasing
nickel content in the steels

Steels C Cr Ni Mn Mo Cu Si N Others
F138, 139 ≤0.03 17–19 13.0–15.0 ≤2.0 2.25–3.0 ≤0.5 ≤0.75 ≤0.1 –
F745 ≤0.06 16.5–19.0 11.0–14.5 ≤2.0 2.0–3.0 ≤0.5 ≤1.0 ≤0.2 –
F1314 ≤0.03 20.5–23.5 11.5–13.5 4.0–6.0 2.0–3.0 ≤0.5 ≤0.75 0.2–0.4 V, Nb: 0.1–0.3
F1586 ≤0.08 19.5–22.0 9.0–11.0 2.0–4.25 2.0–3.0 ≤0.25 ≤0.75 0.25–0.5 Nb: 0.25–0.8
F2229 ≤0.08 19.0–23.0 ≤0.05 21.0–24.0 0.5–1.5 ≤0.25 ≤0.75 0.85–1.1 –
F2581 0.15–0.25 16.5–18.0 ≤0.05 9.5–12.5 2.7–3.7 ≤0.25 0.2–0.6 0.45–0.55 –
 Yang K, et al. Sci China Tech Sci
and Rex734 stainless steels (ASTM F1586, ISO5832-9,
Fe-21Cr-9Ni-3Mn-2Mo-0.41N) [59]. The result showed
that P558 alloy assembled outstanding mechanical proper-
ties and excellent corrosion resistance, and it was also
proved to have better resistances against dry wear, corro-
sion-wear and crevice corrosion than Rex734 and 316L.
At the same year of 1999, Carpenter Technology Corpo-
ration in the United States developed a new nickel-free
high-nitrogen austenitic stainless steel (Biodur®108 alloy,
Fe-23Mn-23Cr-1Mo-0.9N) [60–62], which can be consid-
ered as an alternative to replace some commonly used med-
ical austenitic stainless steels, such as 316L (ASTM F138)
and 734 (ASTM F1586). This high nitrogen nickel-free
stainless steel was listed in the ASTM standard in 2002
(ASTM F2229). Biodur® 108 alloy exhibits significantly
higher strength, in both annealed and cold worked condi-
tions, than any medical nickel-containing stainless steels.
Kraft et al. [63] from Germany in vivo comparatively stud-
ied the effect of Biodur® 108 alloy implant on the striated
muscle microcirculation, and showed that reduction of the
nickel content in stainless steel was associated with a con-
siderably lower inflammatory answer to the skeletal muscle
microvascular system, compared with the regular 316L
steel.
Mölder and Fischer et al. [64] from Germany assayed the
biocompatibility of a high nitrogen nickel-free austenitic
stainless steel, X13CrMnMoN18-14-3 brand name P2000),
by osteoblastic MC3T3-E1 cells, and the result indicated
that the cells growing directly on this steel were undistin-
guishable from the control cells culture with respect to
morphology and growth parameters during the cells test.
Montanaro et al. [65, 66] from Italy in vitro investigated the
mutagenicity and genotoxicity of a new nickel-free stainless
steel, P558, in comparison with 316L stainless steel. The
results of the cytogenetic effect and Ames test proved that
P558 alloy is devoid of genotoxicity and mutagenicity,
suggesting that this nickel-free stainless steel can be a better
altermative to the other conventional medical stainless
steels. Fini et al. [67–69] also in vitro and in vivo studied
effects of P558 on the primary osteoblasts and the bone im-
plantation in sheep tibia, and further demonstrated that P558
is a much biocompatible material. They believed that this
nickel-free stainless steel would be a good substitute bio-
material for the conventional 316L stainless steel and
Ti6Al4V alloy in orthopedics.
Kuroda et al. [70, 71] from Japan conducted the cytotox-
icity tests for Fe-Cr-Mo, Fe-Cr-Mo-N and 316L stainless
steels in both static and dynamic conditions to compara-
tively evaluate the biocompatibility of Fe-Cr-Mo-N, a nick-
el-free austenitic stainless steel produced by gaseous nitro-
gen adsorption. The results indicated that this Fe-Cr-Mo-N
steel had higher cytocompatibility than that of 316L steel,
which makes it a high possibility for application in medical
field. Alvarez et al. [72] from Japan investigated the bone
response to the lotus type porous nickel-free stainless steel
February (2012) Vol.55 No.2 333
implant by using Sprague-Dawley rats. The results clearly
indicated that the lotus-type porous structure allowed bone
cells and tissues to invade into the implant throughout the
existing superficial porous spaces, which would have an
efficient biological fixation responsible for the mechanical
stability at the implantation site. Therefore a lotus type po-
rous nickel-free stainless steel is potential to be used in
some special clinical applications.
In China, Yang and Ren et al. [73–87] from Institute of
Metal Research, Chinese Academy of Sciences, developed a
new high nitrogen nickel-free austenitic stainless steel
(BIOSSN4) for medical application, with nominal composi-
tion of Fe-18Cr-15Mn-2Mo-(0.45–1.0) N. BIOSSN4 steel
possesses excellent combination of strength and plasticity,
sufficient corrosion-fatigue strength, good wear-resistance,
better corrosion resistance, favorable biocompatibility, low
cost and good processability, compared with traditional
316L stainless steel [74].
It is expected that high nitrogen nickel-free stainless
steels with good combination of mechanical properties and
biocompatibility will be the next generation of stainless
steels as surgical implant materials, especially for applica-
tion in coronary stents.
5 Advantage of high nitrogen nickel-free stain-
less steel (NFSS) for stents
5.1 Development of materials for coronary stents
Currently over 40 different types of coronary stents are
commercially available or in development, which are made
of stainless steel, nitinol shape-memory alloy, cobalt-chro-
mium alloy, platinum, tantalum, gold, etc. [22, 23, 25]. In
the last decade, most of the studies were focused on the
materials biocompatibility and the reactions between stents
and tissues [25, 43], and some studies were made to im-
prove the mechanical properties of stents. However, the
bio-function and the properties of the materials themselves
have rarely been investigated. An ideal material for coro-
nary stents, as mentioned above, should be sufficient in ra-
dial strength, corrosion resistant, vascular compatible, fa-
tigue resistant, visible under standard X-ray and MRI, etc.,
which all depend on mechanical and physical properties of
the materials, i.e., strength, ductility, elastic modulus, corro-
sion resistance, density, and so on.
For balloon-expandable stents, an infinite elastic modu-
lus can prevent the recoil. Low yield strength is preferred to
allow the stent expansion at acceptable balloon pressures
and facilitate crimping of the stent on the delivery system.
High tensile properties after expansion help to achieve a
radial strength with thinner struts, thus improving the flexi-
bility, deliverability, and access to smaller vessels. A steep
work-hardening rate leads to a desirable rise in strength
during expansion. Finally, a high ductility is needed to
withstand the deformation during expansion. The above
334 Yang K, et al. Sci China Tech Sci
properties are interrelated and sometimes contradictory,
requiring careful compromise [12].
Early in the stents development, the flexibility was taken
as one of the principal requirements for a stent, in order to
easily track through the target vessel and cross through the
lesion. These features were significantly affected by thick-
ness of the struts, thinner struts leading to more flexible
devices and reducing cross-sectional profiles. There was
also a hypothesis that thinner struts would lead to reducing
restenosis rates [8–12, 88]. However, it was not until the
ground-breaking ISAR-STEREO clinical trial results were
released in 2001 that the data were available to prove this
theory [89].
With requirement of thinner struts stents, the moderate
yield strength of 316L stainless steel would not maintain the
compression strength of stents with thin flexible struts.
Search for high strength alloys with good X-ray radiopacity
resulted in the selection of the commercially available co-
balt-chromium based alloys, which subsequently resulted in
a new generation of thin-struts stents, such as Guidant’s
Multilink Vision stents (80 m with L605 alloy, Co-20Cr-
15W-10Ni) [90], Medtronic’s Driver Coronary stents (91
μm with MP35N, Co-20Cr-35Ni-10Mo) [91], B. Braun’s
Coroflex Blue stents (65 m) and AMG’s Archos Pico
stents (65 m) [92]. In summary, the introduction of these
higher strength materials facilitated the development of new
generation stents, with strut thicknesses in the region of
65–90 m, as compared to the strut thicknesses of 130–140
m for the earlier 316L steel devices.
Development of new materials for coronary stents with
high mechanical properties but without nickel or cobalt is
attracting both material scientists and clinical doctors,
among them the high nitrogen nickel-free austenitic stain-
less steel being a potential alternative material owing to its
better properties combination of strength, plasticity, corro-
sion resistance and biocompatibility [60–66]. Up to now all
the in vivo and in vitro studies strongly have supported that
high nitrogen nickel-free austenitic stainless steels would be
a class of promising biomaterials for stents manufacturing
[67–69, 83, 93, 94].
5.2 Biocompatibility of high nitrogen nickel-free stain-
less steel
The ideal biocompatible material for coronary stents is inert
and does not chemically react with vascular endothelial
cells. Stents which lack biocompatibility could induce many
complications, such as long-lasting chronic inflammation,
thrombosis, neointimal hyperplasia, restenosis, etc [95, 96].
According to the study results mentioned above, the high
nitrogen nickel-free stainless steel has good biocompatibil-
ity both in vitro and in vivo. Taking Biodur® 108 alloy for
example, which has been listed in ASTM standard in 2002
(ASTM F2229), the alloy has passed the standard biocom-
patibility assessments including the cytotoxicity test, irrita-
February (2012) Vol.55 No.2
tion test, acute systematic toxicity test, pyrogenicity test,
mutagenicity test, implantation with histopathology test and
hemocompatibility test by Toxikon Corporation of USA,
according to ISO 10993-3, 4, 5, 6, 10, 11, 12, 13 [60–62].
5.2.1 Hemocompatibility of high nitrogen nickel-free
stainless steel
Because the coronary stent is placed in the blood vessel for
a long time, its hemocompatibility must be principally con-
sidered. Metal stents implantated into the vascular system
would initiate a complex reaction between the blood com-
ponents and surface of the stents [96, 97]. Endotelialisation
of the implanted stents, i.e., covering the stent with endo-
thelium, is a slow process lasting for 2–3 months. The
greatest danger during this period is the process of blood
clotting on the implant surface, which is an effect of de-
crease in active cross-section of the blood vessel just at the
beginning of stents adaptation in the organism.
The high nitrogen nickel-free stainless steel must be bi-
ocompatible as a new class of stents material because of its
excellent hemocompatibility. Yang and Ren et al. [73, 75,
83–86] studied the platelet adhesion resistance of the newly
developed high nitrogen nickel-free stainless steel by the
blood platelet adhesion test, and the results indicated that
this high nitrogen nickel-free stainless steel possessed better
anti-platelet adhesion performance compared with 316L
stainless steel. Figures 1 and 2 show the number and mor-
phology of platelets on samples of both the high nitrogen
nickel-free steel and 316L steel that were dipped in PRP for
25 min and 3 hours, respectively [75]. The number of plate-
lets cling to the nickel-free steel samples were clearly less
than those to the 316L steel samples after long time dipping
in fresh human blood plasma, and the platelets on the nick-
el-free steel had few agglomeration and distortion, but they
were more on the 316L steel. Recently, they also studied the
numbers and morphologies of platelets on surface of the
316L steel, Co-28Cr-6Mo alloy and high nitrogen nick-
el-free stainless steel [85, 86], and similar results were
found (see Figures 3 and 4). Higher nitrogen content in the
nickel-free steel may improve the platelets adhesion re-
sistance of its own (see Figure 5 ), which further suggests
that the high nitrogen nickel-free stainless steel should have
better blood compatibility with a prospective application
potential for coronary stents.
Yang and Ren et al. [82] also studied the nickel-free steel
and showed the kinetic clotting time curves of the high ni-
trogen nickel free stainless compared with 316L steel and
Co-28Cr-6Mo alloy (see Figure 6). The results showed that
the initial clotting time of the high nitrogen steel was about
63 min, and that of Co-28Cr-6Mo alloy was shorter, about
45 min, but that of 316L steel was the shortest, about 40
min, which reveals that the high nitrogen nickel-free stain-
less steel should possess better thrombin resistance and be
suitable for making the coronary stents with anticoagula-
tion.
 Yang K, et al. Sci China Tech Sci February (2012) Vol.55 No.2 335

Figure 1 Blood platelets on BIOSSN4 nickel-free steel and 316L dipped in fresh human blood plasma for 25 minutes. (a) BIOSSN4; (b) 316L; (c) distri-
bution of blood platelets by dimension section.

Figure 2 Blood platelets on BIOSSN4 nickel free steel and 316L dipped in fresh human blood plasma for 3 hours. (a) BIOSSN4; (b) 316L; (c) distribution
of blood platelets by dimension section.

Figure 3 Blood platelets on 316L steel (a), Co-Cr-Mo alloy (b) and high nitrogen nickel-free steel (c) dipped in fresh human blood plasma for 30 min.

Figure 4 Blood platelets on 316L steel (a), Co-Cr-Mo alloy (b) and high nitrogen steel (c) dipped in fresh human blood plasma for 2 hours.

Figure 5 Platelets attachments on stainless steels after immersion in fresh blood for 2 h. (a) 316L SS; (b) high nitrogen nickel-free steel with 0.46wt%N;
(c) high nitrogen nickel-free with 0.64wt%N; and (d) high nitrogen nickel-free steel with 0.81wt%N.
336 Yang K, et al. Sci China Tech Sci February (2012) Vol.55 No.2

ated by cyclic diameter change of coronary arteries. The

Figure 6 Kinetic clotting time curves of 316L steel, Co-28Cr-6Mo alloy
and high nitrogen nickel-free steel, error bars are indicated at every point
(mean ± SD).
Figure 7 S-N curves of axial tensile/tensile fatigue of BIOSSN4 steel and
316L steel at ambient temperature and in 37°C 0.9% NaCl solution.
5.3 Mechanical properties of high nitrogen nickel-free
stainless steel
Besides good biocompatibility, the coronary stents have to
tolerate a distinctly inhomogeneous plastic deformation
during crimping and dilation, leading to residual stresses in
the material, which are superimposed on the stresses gener-
high nitrogen nickel-free stainless steel possesses superior
mechanical properties compared with medical 316L stain-
less steel, including greater strength and similar plasticity.
These properties make it possible to develop thinner struts
stents, offering increased flexibility and ease of delivery,
without compromising the radial strength. Therefore, be-
sides the advantage of nickel-free, the ability to make ul-
tra-thin struts can be another significant attraction for the
high nitrogen nickel-free stainless steel.
Mechanical properties of the presently used materials for
coronary stents are listed in Table 2. As expected, both yield
strength and ultimate strength of the high nitrogen nickel
free stainless steel are much higher than those of conven-
tionally used 316L stainless steel, 2–3 times higher in
strength and the same level of plasticity. Compared with the
cobalt-based alloy, for instance, L605 alloy, the high nitro-
gen nickel-free steel has similar mechanical properties. But
after 30% cold deformation, the ultimate strength of the
high nitrogen nickel-free steel is increased for about 50%,
the yield strength is double increased, the elongation is de-
creased visibly but still keeps a tolerance level, and the re-
duction in area almost maintains its initial level. Yang and
Ren et al. [79] also studied the fatigue property and erosion
resistance of the high nitrogen nickel-free austenitic stain-
less steel BIOSSN4, with comparison to 316L stainless steel,
at ambient temperature and in 37°C 0.9% NaCl solution, as
shown in Figure 7. Compared with 316L stainless steel,
BIOSSN4 steel showed higher fatigue strength even in the
medium of 37°C 0.9% NaCl solution.
The excellent mechanical properties of the high nitrogen
nickel-free stainless steel should be mainly attributed to the
high nitrogen content in the steel. Nitrogen dissolved in
austenitic stainless steels usually enhances their strength,
hardness, work hardening rate, wear resistance, corrosion
resistance, etc. [98, 99], and nitrogen alloying is generally
believed to be beneficial to fatigue resistance of stainless
steels [100–102]. Maruyama et al. [103] compared the fa-
tigue behavior in air and in a simulated body fluid (SBF) for
two high nitrogen nickel-free stainless steels, Fe-23Cr-1N
and Fe-24Cr-2Mo-1N. The result showed no difference
between the S-N (stress-number of cycles to failure) curves
in air and in SBF for each high nitrogen nickel-free stainless

Table 2 Comparison of mechanical properties among different stent materials (measured value) [60, 74, 92]

Materials Conditions Yield strength (MPa) Ultimate strength (MPa) Elongation (%) Reduction of area (%)
316L ASTM F138 Solution 225 555 64 72
L605 ASTM F90 Solution 380–780 820–1200 35–55 –
MP35N ASTM F562 Solution 414 930 45 –
BIODUR 108, Solution 586 931 52 75
NICKEL FREE 30% cold deformation 1227 1496 19 63
BIOSSN4, Solution 546 941 52 64
NICKEL FREE 30% cold deformation 1205 1245 24 58
 Yang K, et al. Sci China Tech Sci
steel. Therefore, it can be expected that as a medical im-
plantation material, the high nitrogen nickel-free austenitic
stainless steel should be suitable to make thinner-struts
coronary stents that will possess higher radial strength and
longer service cycle in the arteria.
5.4 Corrosion resistance of high nitrogen nickel-free
stainless steel
Corrosion of coronary stents generally occurs when the
protective oxide film on the surface breaks down [104].
This can be a result of local chemical/electrochemical attack
or mechanical damage of the surface. The damage of oxide
film on stents is perhaps formed during the pre-implantation
or post-implantation, and the dissolution rate of the oxide
film would be accelerated by the presence of amino acid,
proteins and chloride ions [105, 106].
Corrosion has been found on some metallic stents and the
stents can gradually corrode in the arteria of human body. It
was reported that corrosion of stents occurred in vivo and
would be associated with release of heavy metal ions into
the adjacent tissue [43]. The levels of metallic ions dis-
solved in the tissues (0.5–3.0 g/cm2 stents) near stents
were higher than those in the controls (0–0.30 g/cm2
stents). When enough tissue was available around the sig-
nificantly corroded stents, metallic ion levels were normal-
ized to the tissue weight and measured up to 39 g/g dry
tissue compared to the zero value measured from the
non-corroded stents.
Yang and Ren et al. [83] studied the anodic polarizations
of high nitrogen nickel-free stainless steel, 316L steel and
Co-28Cr-6Mo alloy in Hank’s solution at 37C, as shown in
Figure 8. It can be found that the anodic polarization of
316L steel was typical with a lower pitting potential, the
Co-based alloy showed a better corrosion resistance, and the
high nitrogen nickel-free stainless steel had the compara-
tively best corrosion resistance with the highest pitting po-
tential.
Figure 8 Anodic polarization curves of 316L, Co-Cr-Mo alloy and high
nitrogen nickel-free steel in Hank’s solution at 37C.
February (2012) Vol.55 No.2 337
Lots of experiments and industrial applications con-
firmed that the high nitrogen nickel-free stainless steels
possessed excellent corrosion resistances [98, 107–110]. For
the localized corrosion phenomena, for instance, pitting
corrosion and crevice corrosion, the beneficial role of ni-
trogen has been clearly identified, which in conjunction
with chromium and molybdenum can achieve 20 to 30
times of the effect of chromium. A formula for resistance to
pitting and crevice corrosions by different alloying elements
is: PREN=wt%C +3.3×wt%Mo+20×wt%N [110]. It is clear
that nitrogen provides significant contribution to the in-
crease of resistance to localized corrosion. However, for the
corrosion fatigue, in NaCl solution, for example, because
nitrogen strongly enhances the pitting corrosion resistance,
nitrogen alloying may also improve the corrosion fatigue
behavior of austenitic stainless steels without doubt.
Therefore, the excellent corrosion resistance of high ni-
trogen nickel-free austenitic stainless steel can keep coro-
nary stents at lower corrosion rate and lessen the release of
metal ions to avoid the complication of stents.
5.5 Surface properties of high nitrogen nickel-free
stainless steel
Surface properties are essential to the clinic performance of
coronary stents, including the surface energy, surface tex-
ture, surface potential, stability of surface oxide, etc [111].
Surface characteristics of a stent material can have influence
on thrombosis and neointimal hyperplasia, because platelets
and plasma proteins are negatively charged and can be at-
tracted to metals that have a positively charged surface. The
thrombogenicity of a material surface would increase with
increase of the surface energy which would affect the wet-
tability of the surface [112]. A polyurethane coating on Ta
and stainless steel reduced the surface energy, resulting in a
significant reduction of thrombosis [113, 114].
The net electrical charge on a material surface is also
critical to the success of a stent [22]. Zitter et al. [22, 115]
investigated the current densities of different metals in
in-vitro conditions and ranked the current densities in the
following order: Au>316L steel>Co-Cr alloy>Ti6Al4V
alloy>Ti>Nb>Ta. Ta has a net negative electrical charge
and thus has a theoretical advantage over other metals. Most
metals are electropositive while blood components tend to
be electronegative, which would accentuate the thrombo-
genicity problem [22].
The stability of surface oxide can directly affect the bio-
compatibility of a material as the surface layer acts as a bar-
rier to the release of ions from the bulk material. For exam-
ple, an atomic adsorption spectrophotometry analysis re-
vealed significant release of nickel and chromium ions from
stainless steel stents over 96 h in human plasma [42]. The
released metal ions may be considered as a potentially neg-
ative effect on endothelial cells [49].
Yang and Wan et al. [84, 86] studied the surface wetta-
338 Yang K, et al. Sci China Tech Sci
bility and surface free energy (SFE) of high nitrogen nick-
el-free stainless steel (BIOSSN4) compared with 316L
stainless steel and the results showed that BIOSSN4 was
more hydrophilic than 316L steel, and increase of nitrogen
content would enhance the hydrophilic character of
BIOSSN4. According to the potential of zero charge, they
also deduced that the surface of high nitrogen nickel-free
stainless steel behaved a net positive charge and the density
of surface net charge was decreased with increase of nitro-
gen content. Specially, the albumin adsorption that would
inhibit the adhesion of platelets was directly related to the
surface energy and then was promoted on the surface of
BIOSSN4. The influence of nitrogen on surface properties
further explains the better haemocompatibility of high ni-
trogen nickel-free stainless steel.
6 Development of high nitrogen nickel-free
stainless steel coronary stents
Most of coronary stents are made of the medical 316L
stainless steel, an Fe-Cr-Ni-Mo steel, due to its excellent
combined properties, but the potential allergen of nickel is
one of its obsessions. Other typically used materials such as
cobalt-based L605 alloy or tantalum have more or less
problems need to be overcome. Therefore, the newly de-
veloped austenitic high nitrogen nickel-free Fe-Cr-Mn-Mo-
N series stainless steels may offer an alternative to further
improve the performance of the current coronary stents.
Weiss et al. [94] comparably investigated the fatigue de-
formation through simulation and the microstructure char-
acteristic of stents with equal designs produced by 316L
steel and a high nitrogen nickel-free stainless steel (DIN EN
1.4452, similar to ASTM F2229­02), and they concluded
that this kind of high nitrogen nickel-free stainless steel
stents are suitable for clinical use, but further studies are
still needed. Their study gave a more comprehensive under-
standing of the influence of the stents material on the struc-
ture property relationship under monotonic and cyclic de-
formations, as a basis for ongoing development of new ma-
terials for stents optimization.
Premier coronary stents of Existent Company [116] are
designed to promote the low target vessel revascularization
rate (TVR) by pioneering the use of a superior strength
nickel-free alloy (Biodur 108 alloy) which enables the stent
to have the thinnest struts (starting from 0.045 mm), the
lowest surface coverage area (8%–9%) and significantly
less metal than any other coronary stents. Premier stents
have less than 4% recoil at nominal diameter, and are de-
signed to have two radiopaque markers at stents extremities
to enhance the angiographic visibility. Clinical results for 6
months implantation by Premier stents demonstrated excep-
tionally low MACE rates (3.51%, n=55 patients).
In China, precise tubes made of the high nitrogen nick-
el-free stainless steel (BIOSSN4) for manufacturing coro-
February (2012) Vol.55 No.2
nary stents have been produced in Institute of Metal Re-
search, Chinese Academy of Sciences [74], and a new type
of coronary stents made of BIOSSN4 with thinner struts are
being commercialized by Zhongkeyian Medical Technology
Company with technical support from the institute. At pre-
sent, the animal trial for these new stents is going to be
conducted on schedule.
7 Conclusions
The high nitrogen nickel-free stainless steels have been ap-
proved to be a new class of surgical implantable materials
with excellent mechanical properties, sufficient corrosion
resistance and satisfied biocompatibility, especially out-
standing hemocompatibility. Apart from the highlight of
nickel free in the steels, the superiority of high strength and
better hemocompatibility of high nitrogen nickel-free stain-
less steels can guarantee to manufacture thinner struts cor-
onary stents with remarkable anticoagulation ability, which
will attract more and more clinical doctors and stents mak-
ers to bring the new steels into clinical application.
This work was supported by the National Natural Science Foundation of
China (Grant No. 31000428) and the National Basic Research Program of
China (“973” Program) (Grant No. 2012CB619101).
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