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 quantity 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 nickel-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 nickel-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: 329340, doi: 10.1007/s11431-011-4679-3
1 Introduction Coronary disease has become one of the most common reasons for death of mankinds in industrial countries. Since 1986 when the metal vessel stent was first implanted into human bodies to prevent the vessel wall from collapsing, the coronary stent has become one of the most important achievements in the area of surgical cardiology. However in-stent restenosis (ISR) as a complication after surgery still weakens the effectiveness and success rate of coronary stents. Subsequent drug-eluting stents (DES) designed to release the pharmacological agents after deployment were developed to inhibit response to the injuries mainly respon-
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 target-vessel revascularization could be reduced to rates below 10% after DES implantation, but the risks of late/very late stent thrombosis (ST) with DES become a new concern of coronary stents [3–5]. Human autopsy series have suggested that the DES caused late/very late ST is partly attributed to the impairment of arterial healing characterized by incomplete re-endothelialization, persistent fibrin deposition and macrophage infiltration, compared with BMS [6, 7]. How to reduce the damage and stimulation of stents to the artery wall is always an issue of common concern from the cardiovascular clinical doctors and stents maker. Obviously, more thinner or the optimized struts of stents can
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lessen the stimulation by reducing the contact area between stents and neointima, and the role of stent design in the arterial 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 significantly 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 mainstay 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 successful 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 materials are becoming a point of discussion owning to the possibilities 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 compatibility, 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 biocompatibility, than those of 316L stainless steel, and especially, its high strength close to the cobalt-based alloy ensures 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.
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have favorable properties such as high corrosion resistance and good biocompatibility, they are still not used for making stents because of poor working-ability, low X-ray radioactivity, etc. Pure iron and Mg alloy as hopeful bio-absorbable 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 sufficient 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) sufficient 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 adhesion 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 coronary 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
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
Harmfulness of nickel
Nickel is a metallic element that is naturally present in the earth’s crust. Due to unique physical and chemical properties, 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 alloys. 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
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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 jewelries [26]. Moreover, the overall environmental pollution is also proposed to be a significant reason for the everincreasing 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 problems to health. Experiments with high nickel intake have shown that nickel is teratogenic and has carcinogenic potential [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 Organization (WHO) reported that the daily physiological requirement 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 implants corrode in body environment and release iron, chromium 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 containing 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 corrosion products of 316L steel are toxic to the primary culture 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, erythema, 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 involved the implants manufactured from alloys containing nickel and cobalt [40]. 3.2 Nickel and restenosis of stents Stainless steel implants can cause inflammatory hypersensi-
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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 coronary stents [41]. Most cardiovascular and peripheral vascular 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 associated 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 development of in-stent restenosis. They investigated the correlations 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 frequency of in-stent restenosis than patients without sensitivity. Hence, the controversy of nickel and restenosis is maintained 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 endothelial cells adhesion as well as adhesion of polymorphonuclear neutrophil granulocytes to endothelial cells in vitro [37, 49]. Similarly, they may activate through at least two endothelial 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 thrombospondin-1 combined with a dependant increase in transforming 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-
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ronment possibly leading to ISR [43]. The contribution of this metallic ion release to the mechanism of in-stent restenosis 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 potential harmfulness of nickel ions release from stents containing 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 implantable devices as soon as possible, which must meet the following requirements: absence of nickel, absence of ferromagnetism, 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 nickel (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 excellent combination of strength and toughness, better resistance to corrosion, as well as high wear resistance, which is intensely expected to be a possible material for anti-nickel allergy in medical field. The stainless steels used nowadays for medical and surgical 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, nitrogen 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-
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cation of ASTM medical standard, the Nickel content is less and less in new stainless steel, but the more and more Nitrogen 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 Technology Corporation) and Fe-11Mn-17Cr-3Mo-0.5N (ASTM F2581) are developed and listed in ASTM standard as selected 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, pressured electroslag remelting, counter-pressure casting, plasma 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 supplement 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 directly 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 nickelfree 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-corrosion behavior of a biocompatible high nitrogen nickel-free austenitic stainless steel, P558 (Fe-17Cr-10Mn-3Mo-0.49N0.2C), 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
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
9.0–11.0 ≤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
– –
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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 properties and excellent corrosion resistance, and it was also proved to have better resistances against dry wear, corrosion-wear and crevice corrosion than Rex734 and 316L. At the same year of 1999, Carpenter Technology Corporation 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 considered as an alternative to replace some commonly used medical 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 conditions, than any medical nickel-containing stainless steels. Kraft et al. [63] from Germany in vivo comparatively studied 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 considerably 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 undistinguishable 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 implantation 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 biomaterial for the conventional 316L stainless steel and Ti6Al4V alloy in orthopedics. Kuroda et al. [70, 71] from Japan conducted the cytotoxicity tests for Fe-Cr-Mo, Fe-Cr-Mo-N and 316L stainless steels in both static and dynamic conditions to comparatively evaluate the biocompatibility of Fe-Cr-Mo-N, a nickel-free austenitic stainless steel produced by gaseous nitrogen 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
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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 porous 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 composition 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 application in coronary stents.
5 Advantage of high nitrogen nickel-free stainless 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-chromium 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 improve the mechanical properties of stents. However, the bio-function and the properties of the materials themselves have rarely been investigated. An ideal material for coronary stents, as mentioned above, should be sufficient in radial strength, corrosion resistant, vascular compatible, fatigue 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, corrosion resistance, density, and so on. For balloon-expandable stents, an infinite elastic modulus 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 flexibility, 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
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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 thickness 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 cobalt-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-20Cr15W-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 stainless steel being a potential alternative material owing to its better properties combination of strength, plasticity, corrosion 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 stainless 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 biocompatibility 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 biocompatibility assessments including the cytotoxicity test, irrita-
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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 considered. Metal stents implantated into the vascular system would initiate a complex reaction between the blood components and surface of the stents [96, 97]. Endotelialisation of the implanted stents, i.e., covering the stent with endothelium, 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 decrease 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 biocompatible 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 morphology 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 platelets 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 nickel-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 nickel-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 resistance 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 nitrogen 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 stainless steel should possess better thrombin resistance and be suitable for making the coronary stents with anticoagulation.
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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) distribution 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.
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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-
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ated by cyclic diameter change of coronary arteries. The high nitrogen nickel-free stainless steel possesses superior mechanical properties compared with medical 316L stainless 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, besides the advantage of nickel-free, the ability to make ultra-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 conventionally 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 nitrogen 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 decreased visibly but still keeps a tolerance level, and the reduction 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 stainless 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 fatigue 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 316L ASTM F138 L605 ASTM F90 MP35N ASTM F562 BIODUR 108, NICKEL FREE BIOSSN4, NICKEL FREE
Conditions Solution Solution Solution Solution 30% cold deformation Solution 30% cold deformation
Yield strength (MPa) 225 380–780 414 586 1227 546 1205
Ultimate strength (MPa) 555 820–1200 930 931 1496 941 1245
Elongation (%) 64 35–55 45 52 19 52 24
Reduction of area (%) 72 – – 75 63 64 58
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steel. Therefore, it can be expected that as a medical implantation 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 dissolved 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 significantly corroded stents, metallic ion levels were normalized 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 37C, 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 comparatively best corrosion resistance with the highest pitting potential.
Figure 8 Anodic polarization curves of 316L, Co-Cr-Mo alloy and high nitrogen nickel-free steel in Hank’s solution at 37C.
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Lots of experiments and industrial applications confirmed 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 nitrogen 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 increase 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 nitrogen nickel-free austenitic stainless steel can keep coronary 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 texture, 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 attracted 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 wettability 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 thrombogenicity problem [22]. The stability of surface oxide can directly affect the biocompatibility of a material as the surface layer acts as a barrier to the release of ions from the bulk material. For example, an atomic adsorption spectrophotometry analysis revealed 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 negative effect on endothelial cells [49]. Yang and Wan et al. [84, 86] studied the surface wetta-
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bility and surface free energy (SFE) of high nitrogen nickel-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 nitrogen 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 nitrogen 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 developed austenitic high nitrogen nickel-free Fe-Cr-Mn-MoN 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 deformation through simulation and the microstructure characteristic 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 understanding of the influence of the stents material on the structure property relationship under monotonic and cyclic deformations, as a basis for ongoing development of new materials 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 designed to have two radiopaque markers at stents extremities to enhance the angiographic visibility. Clinical results for 6 months implantation by Premier stents demonstrated exceptionally low MACE rates (3.51%, n=55 patients). In China, precise tubes made of the high nitrogen nickel-free stainless steel (BIOSSN4) for manufacturing coro-
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nary stents have been produced in Institute of Metal Research, 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 present, 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 approved to be a new class of surgical implantable materials with excellent mechanical properties, sufficient corrosion resistance and satisfied biocompatibility, especially outstanding hemocompatibility. Apart from the highlight of nickel free in the steels, the superiority of high strength and better hemocompatibility of high nitrogen nickel-free stainless steels can guarantee to manufacture thinner struts coronary stents with remarkable anticoagulation ability, which will attract more and more clinical doctors and stents makers 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). 1
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