Shape Memory Materials for Biomedical Applications - Research

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Shape Memory Materials for Biomedical Applications By Fatiha El Feninat, Gaetan Laroche, Michel Fiset, and Diego Mantovani* Shape memory properties provide a very attractive insight into materials science, opening unexplored horizons and giving access to unconventional functions in every material class (metals, polymers, and ceramics). In this regard, the biomedical field, forever in search of materials that display unconventional properties able to satisfy the severe specifications required by their implantation, is now showing great interest in shape memory materials, whose mechanical properties make them extremely attractive for many biomedical applications. However, their biocompatibility, particularly for long-term and permanent applications, has not yet been fully established and is therefore the object of controversy. On the other hand, shape memory polymers (SMPs) show promise, although thus far, their biomedical applications have been limited to the exploration. This paper will first review the most common biomedical applications of shape memory alloys and SMPs and address their critical biocompatibility concerns. Finally, some engineering implications of their use as biomaterials will be examined.

1. Introduction Medical implants have undoubtedly made an indelible mark on our world during the last century. More than 100 millions humans carry at least one major internal medical device. The prosthesis industry has topped 50 billion US$ in annual sales, with approximately 150 universities throughout the world proposing an undergraduate program in bioengineering or biomedical engineering. Despite that, however, most medical devices have been constructed using a significantly restricted number of conventional metallic, ceramic, polymeric, and composite biomaterials. Medicine and improvisation hardly appear to be a likely pair, yet since ancient times, resourceful doctors have carried out difficult procedures, often having to work with materials on hand.[1] Wounds were sutured with plant fibers (animalderived materials by ancient Greeks, Chinese, and Egyptians), and prosthetic limbs were fashioned from wood. Metals were eventually introduced in dentistry, and early this past century, when stainless steel became available, corrosion-resistant alloys were used to make a variety of prostheses. As with their predecessors, today medical practitioners will often attempt to cure diseases or improve quality of life by replacing a defective body part with a substitute. While the designing process leading to the development of successful artificial organs has been improved over the years, bioengineers remain limited to fabricating devices with off-

ADVANCED ENGINEERING MATERIALS 2002, 4, No. 3

the-shelf materials which were not designed specifically for the application. The easy availability of industrial materials, along with the multiple specific and challenging constraints to which an artificial organ is submitted when implanted in the body, are the principal factors which may explain why today, only a dozen materials are routinely used to construct internal artificial organs. In this regard, motivated by the increasing need for custom-made materials for specific medical applications, materials scientists, metallurgists, chemists, mechanical and chemical engineers, as well as researchers in other disciplines, have progressively begun an interdisciplinary work in the hopes of creating high-performance biomate-

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[*] Prof. D. Mantovani, Dr. F. El Feninat Research Center, St. François d'Assise Hospital, Department of Mining, Metallurgy and Materials Engineering Laval University, Pouliot Building, Room 1745-E Quebec City, G1K 7P4 (Canada) E-mail: Diego.Mantovani@gmn.ulaval.ca Dr. M. Fiset Department of Mining, Metallurgy and Materials Engineering, Laval University Dr. G. Laroche Department of Surgery, Laval University

Ó WILEY-VCH Verlag GmbH, D-69469 Weinheim, 2002

1438-1656/02/0303-0091 $ 17.50+.50/0

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Mantovani et al./Shape Memory Materials for Biomedical Applications rials, or tailoring those industrial materials with specific properties into high-potential biomaterial candidates. Among the last industrial materials elected to the rank of biomaterials are shape memory alloys (SMA), which have

been proposed for use in a wide variety of internal applications, including orthopaedic, dental, surgical, and (only later) cardiovascular devices. The unique properties of SMA allow for a variety of applications in implantology. As it was pre-

Fatiha El Feninat received her M.Sc.A degree in chemical engineering from École Polytechnique de MontrØal. Recently, she obtained a Ph.D. degree in chemistry from the University of MontrØal, for her works on the characterisation of human dentin by atomic force microscopy. In November 2000, she joined the Department of Mining, Metallurgy and Materials Engineering at Laval University and the Research Center of the St-François d'Assise Hospital as Postdoctoral Fellow. Her research focus on surface modifications and characterisation of shape memory alloys in order to be used as long-term safe biomaterials, and atomic force microscopy.

GaØtan Laroche received both his B.Sc. (1986) and Ph.D. (1990) from the chemistry department at Laval University. He joined the Research Center of St-François d'Assise Hospital in 1992 and the Surgery Department at Laval University where he is professor since 1994. His main research interests are related to the physicochemical characterisation of biomaterials, molecular transport through biomaterials and surface engineering of biomaterials to improve their biocompatibility.

M. Fiset obtained a B.Sc. degree in physics and Ph.D. degree in metallurgy from Laval University. He joined the department of Mining, Metallurgy and Materials Engineering at Laval University in 1977 as professor of materials science. One of his major research interests has been the field of abrasive wear, with particular reference to alloy white cast irons, laser materials processing, as well as advanced alloys for biomedical applications.

Diego Mantovani obtained a B.Sc. degree in Bioengineering from the Politecnico di Milano, Italy, and a B.Sc. in Biomaterials and Artificial Organs from the UniversitØ de Technologie de Compigne, France. Then, he obtained a Ph.D. from Laval University in 1998 and a D.Sc. from the UniversitØ de Technologie de Compigne in 1999, for his studies on materials and biomaterials. He is professor at the Laval University department of Mining, Metallurgy and Materials Engineering and researcher at the Research Center of the St-François d'Assise Hospital in Biomaterials and Bioengineering since January 2000. With his team, he carries out project-oriented and multidisciplinary research in biomaterials, artificial organs and bioengineering. Focus is on functional materials for blood-contact applications, structure-properties relationships, micro-mechanics, surface properties modifications, and bioreactors design for reparative medicine.

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2. Shape Memory Alloys From a chronological point of view, in the thirties the pseudoelastic effect was already being observed in Au±Cd alloy.[4] This was followed in 1938 by the observation of the shape memory effect in Cu±Zn alloy.[5] It was, however, in the 1960s, that Buehler et al.,[6] at Naval Ordnance Laboratory, discovered the shape memory effect in nickel±titanium alloys, commonly known as Nitinol alloys (for nickel titanium Naval Ordnance Laboratory). From a more scientific point of view, there exists an exhaustive wide variety of metallic alloys which demonstrate shape memory and/or superelastic effects and which have been investigated in the past and are well reported in the literature.[4,7±18] These works focused on metallic alloys, including, for example, binary systems such as NiTi, CuZn, AuCd, CuSn, TiPd, NiAl, and InTi, as well as ternary systems such as NiTiCu,[19] and CuZnAl.[20,21] Moreover, it has been shown that introducing copper in a binary NiTi alloy increases its ability to change shape when heated (shape memory properties).[22±24] From a metallurgical point of view, nitinol is a nickel±titanium alloy of near-equiatomic composition, which implies that nickel represents approximately 50 % of its chemical


composition. This alloy is particularly interesting because of its significant mechanical properties, and above all, because of its ability to show high elastic deformation, or ªpseudoelasticityº, and ªshape memory effectº which are not present in other conventional metallic alloys. It has to be underlined that the terms pseudoelasticity and superelasticity are often used synonymously in the literature, even if the specific metallurgical mean and the proper use of these terms was previously discussed by Ostuka and Wayman.[25] Figure 1 shows the stress±temperature relation where the hysteresis describing the transformation of the SMA is presented. This hysteresis is characterised by four temperatures (Ms, Mf, As, and Af) which indicate the initial and final transformation temperatures. Two stable transformation phases are present at different temperatures: the martensite phase is stable at low temperature in contrast the austenite one which is stable at high temperature. These two transformations are reversible without inducing any diffusion between the existing phases. The most significant properties of the SMA are ruled by the phase transitions between the austenite (ªhigh temperatureº phase) and the martensite (ªlow temperatureº phase), and reciprocally. The phase transitions as a function of temperature are thus particularly important in order to control the properties. In a previous study,[2] we carefully described the five characteristic properties and proposed an integrated global overview of the various effects which can be observed on SMAs: l the one-way shape memory effect, where the change in shape is regulated by the transition from martensite to austenite, l the two-way shape memory effect, with the learning process by mechanical cycles and the one-way shape memory effect, where the changes in shape are regulated by the phase transitions (martensite±austenite followed by austenite±martensite), l the superelastic effect, where the deformations are regulated by the phase transitions (austenite±martensite, then martensite±austenite),

Fig. 1. Austenite transformation and hysteresis (H) following a temperature change. As = Austenite start, Af = Austenite finish, Ms = Martensite start, and Mf = Martensite finish.

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viously published in extensively reviews.[2,3] In general, each material used to fabricate industrial products designed to be implanted in the human body for small, medium or longterm periods must be tested to demonstrate its ªbiocompatibilityº. In vitro studies, followed by in vivo studies, and finally, clinical studies, are the three successive and general steps, with increased levels of scrutiny, required by the U.S. Food and Drug Administration (FDA) to authorise their use as implant. Consequently, only a few products developed by industrial R&D may effectively be used in implantology. Today, the use of endovascular stents, orthopaedic staples and dental braces are widely acknowledged world-wide, which is not the case for intra-cranial staples, which are not permitted by the FDA for use in the USA. The objective of this paper is first to review the most common applications of shape memory materials (SMMs), focusing on shape memory metallic alloys, which are widely used, and shape memory polymers (SMPs), for which strong R&D industrial efforts are ongoing. Secondly, this paper aim is to show the challenges facing their unique properties, while addressing some of the critical concerns with regard to the nature of the biological environment these materials will have to integrate. We will conclude by outlining some of the realistic implications such as societies expectations and the quality of life for the patient. The goal here is therefore not to categorise materials and biomaterials as being either ªbadº or ªgoodº, but rather to stimulate reader implication in a true interdisciplinary discussion towards an actual advancement of this ever-growing research field.

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Mantovani et al./Shape Memory Materials for Biomedical Applications the superthermic effect, where the material replaces the accumulated internal constraints during the learning process by the external constraints, l the rubber-like effect, observed in the repeated mechanical cycles of learning. The interconnections between temperature, force, and geometrical shape are complex, which make it difficult to predict the behaviour of SMA in each specific application. Most of the current applications use alloys that allow us to retain two of three parameters, with the third fixed by the choice of alloy elements and thermomechanical treatment. The NiTi general properties are primarily related to a temperature or stress that is induced by the martensitic transformation.[26] However, the mechanical properties of NiTi alloy depend more specifically on the transformation temperature of transition,[6] and the damping capacity of alloys which can reach 90 % for impact loads.[27] The properties of nickel±titanium alloys have been extensively investigated and reported by various authors.[25,28] The high mechanical properties of NiTi alloy may be helpful in self-expanding and self-compressing,[29] situations which make NiTi easily malleable when used in medical devices. This malleability is important, particularly in the case of alloys used in endovascular therapy. The instrument handles can be bent with enormous precision to the proper shape required for surgery, and recover their initial shape after heating.[30] From an industrial point of view, among the wide variety of shape memory metallic alloys available only those able to recover a substantial amount under strain (when the austenitic±martensitic phase change occurs) have been considered in the design of industrial products. Thus far, this signifies that only the equiatomic (or the near equiatomic) NiTi alloys and a few of the copper-based alloys have been largely commercialised. Moreover, only NiTi alloys have been introduced in the medical device industry and are currently overwhelmingly used as biomaterials through other potential metallic alloys, because the latter, while presenting similar properties, are at times expensive (such as gold-based alloys,[31,32]) or do not exhibit mechanical properties and thermal stability as competitively as do NiTi alloys.[33] Finally, in some other cases, they exhibit a far greater risk of toxicity.[34±36] The field of NiTi alloys is expanding rapidly: In 1998, TiNi Alloy Company reported that many devices of various sizes had been introduced for medical and others fields and that the sales of these devices had reached more than a hundred million USD per year.[37] We will therefore present a review of the various biomedical applications of NiTi-based SMA and its biocompatibility when used in the fabricating of biomedical devices. Since the discovery of NiTi alloy, and particularly in the early 1970s, many studies have exploited the potential of NiTi for medical applications.[38±41] However, it was not until the 1990s that adequate medical investigations led to a breakthrough with the development the first commercial stent.[42,43] Based on superelastic effect wires,[44] NiTi alloys were used in l

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orthodontic therapy because of their high flexibility in bending without kicking.[45±49] Studies emerged on the use of NiTi wires for the correction of malocclusions and impacted canines.[50] In 1978, Andreasen and Morrow[51] reported on the advantages of NiTi orthodontic wires over conventional orthodontic wire. During the early stages of orthodontic therapy, constant low stress to the dentition over time is required in order to minimise tissue destruction such as root resorption during tooth movement.[52,53] Superelastic NiTi wire easily gains these important forces, which are particularly favourable for large malaligned teeth. Another advantage of NiTi orthodontic wires is that it is possible to provide rapid orthodontic treatments, resulting in less patient discomfort because fewer adjustments and wire changes are required.[30,52] Other interesting medical applications of NiTi alloy have been reported in orthopaedic,[54] and other bone-related operations.[55] Nitinol has been to be more effective than others materials[56] in connecting broken bones. Staples made of NiTi SMAs have been used to fix small bone fragments.[57] In cervical anterior fusion, the NiTi staple was used in fifty patients; with successful results for 80 % of the cases (36 months).[58] Superelastic NiTi catheters facilitate access to areas in human body which are at times more difficult to reach using other materials. Because of its superelastic properties, NiTi alloy is exceptionally flexible, which enables its use in non-invasive surgery to reach narrow places. The NiTi wires are also shaped for use in prostheses, tissue anchoring and connection,[59] as well as stents.[60,61] When inserted into the human body, the superelastic NiTi-based stents are capable of self-expanding. This property allows us to use these stents in gastroenterology, cardiovascular and radiology fields. The U.S. Food and Drug Administration has accepted the vascular NiTi device reported by Simon and his research team.[41] This device, called Simon Nitinol Filter (SNF), is used for treating pulmonary embolism. Other applications in cardiovascular surgery have been reported.[62±64] In 1990, it was reported in Britain that 7.5 per 100 000 of the population develops oesophageal carcinoma[65] and only the palliation of oesophageal carcinoma was suitable by using self-expanding stents,[66] which offer the advantage of being easily implantable for providing effective malignant palliation. The follow-up in most of the studies on NiTi as implant material in humans may unfortunately have been limited in evaluating its toxicity which may arise after many years of implantation. When such a long-term application is not required, the use of this alloy may therefore be considered, as in the case of the preliminary bracket alignment stage of orthodontic treatment.[52] However, further investigations must to be envisaged prior to any long-term implantation of these materials in humans. If it is to be considered fully useful, the SMA must fulfil the requirements of both short and long-term biological (biocompatibility) and chemical (degradation, corrosion, and dissolution) reliabilities when used for human concerns.



Contrary to popular belief, shape memory is not a property known exclusively to metallic alloys. Nevertheless, it must to be emphasised that only metallic alloys are capable of showing shape memory properties because of a crystalline structure change, i.e., from austenite to martensite, or viceversa. Other materials exhibit similar properties, and therefore are defined as ªadaptive or smartº materials. Smart or adaptive are adjectives given to those materials that provide a specific response in a particular environment. For example, it means that they are able to assume pre-definite shapes and dimensions when their environment reaches at a determined temperature, or that they are capable of displaying a specific force at a particular temperature, etc. Therefore, it may be understood that those specific materials, namely, polymers with high, specific shape memory characteristics, have received early recognition as potential candidates as implant materials. In fact, the need for these new materials is well appreciated because of the controversy regarding the biocompatibility of nickel-containing SMAs (as will be discussed later in this paper), their difficult fabrication and/or their cost. The primary advantage of polymers over other materials in biomedical applications is their easier availability and their wide range of mechanical and physical properties.[67,68] As shown in Figure 2, the polymeric materials show the properties more closely to those of soft biological tissue, if compared to those of metals which are more similar to those of hard biological tissue. The international scientific community has therefore focused its attention on new polymeric materials offering the specific high advantage of returning to some previously defined shape under the appropriate thermal conditions. A variety of publications and patents have covered the development of polymers exhibiting these unusual properties.[69±76] The mechanism through which selected polymers demonstrate specific shape memory properties is related to their intrinsic non-crystalline molecular structure. As it is wellknown, the glass transition temperature (Tg) characterises polymers, making them unique in contrast to other materials such as metals or ceramics. However, polymers display dif-

ferent states depending on the temperature range within a few degrees of Tg. In fact, at this temperature, significant changes in the mechanical and thermodynamical properties may be observed[77] (Fig. 3): l above this temperature, the polymers are in their rubbery state, whereas at this stage, the polymers are elastic and soft,[78] l below the transition temperature, the polymeric materials become brittle and hard. At this point, the rubbery state is replaced by a glassy behavior, l across the glass temperature, the elastic modulus of polymers may exhibit a large, reversible change (Fig. 3). Through the shape memory effect shown in Figure 4, it may be possible to deform the polymers below Tg and return them to their original shape by heating the polymers to higher temperature than Tg. However, if the materials are deformed above their glass transition temperature under external force, the deformation will be fixed and maintained after removal of the external force. However, a subsequent heating of the material above its Tg will allow it to recover its original shape, thereby generating a lower force.[68] The shape memory and elastic properties make polymers highly interesting when used as smart (or adaptive) materials for industrial applications.[78] SMPs are basically characterised by a low temperature transition which is in the range of room temperature;[79] this feature makes the SMPs suitable for biomedical devices, as the latter are implanted at body temperature (37 C). Another advantage supporting the preferential use of polymers as biomaterials, is the potential to target specific complementary properties simply by copolymerising two or more monomers. For example, the copolymerisation of vinyl chloride (VC) with ethylene, allows us to combine some properties of polyethylene that is soft and elastic, and poly(vinyl chloride) (PVC) that is mostly hard. The copolymerisation of styrene and butadiene produces a styrene±butadiene copolymer with shape memory properties. In this case, the different temperature-dependent behaviours of the copolymerised styrene and butadiene moieties enable the copolymer to preserve its stiffness (styrene) while the butadiene segments help maintain its flexible character (butadiene), thereby leading to the shape memory capabilities.

Fig. 2. Schematic stress versus strain diagram for metals, polymeric materials, and biological tissues.

Fig. 3. Elasticity versus temperature of amorphous polymers.


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3. Shape Memory Polymers

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Fig. 4. Deformation at different temperatures obtained after external loading.

Polymers exhibit shape memory effects which completely differ from those of metallic alloys. Rubber is a typical SMP that is capable of expanding many times before returning to its original shape as a function of applied stress.[80] Contrary to the shape memory effects in metallic alloys, the effects in polymers are controllable not only by heating but also by exposure to light or through chemical reactions.[81,82] Indeed, crosslinking agents may be added to polymer formulations; these crosslinks are selected in reason of their potential to experience isomerisation under photo-irradiation. The most simple example is azobenzene which is used as a crosslinking agent for polymer fabrics. By isomerisation through the ultraviolet irradiation of azobenzene, the transformation from the cis to the trans form induces the shape change in the polymers.[83] As demonstrated by Hirai and his collaborators,[84] it is possible to introduce shape memorizing properties by crosslinking the polymer through chemical bonding. In addition to introducing the shape memory effect, this chemical crosslinking leads to a three-dimensional network which may significantly improve the physical properties such as acceptable elasticity and excellent strength. Of considerable interest is poly(vinyl alcohol) (PVA) crosslinked with glutaraldehyde. Without crosslinks, the use of the PVA gel is unfortunately limited in terms of thermal stability,[85] as heating this gel can in fact disrupt the hydrogen bonds and consequently the stability of the gel; this stability is also lost when the gel is placed in boiling water.[86] During the past 15 years, Nippon Zeon Co. and others[87±91] have developed a wide variety of SMPs. In the early 1997s, Liang et al.[92] developed new, easy-to-shape polymers. At Mitsubishi Heavy Industries in Japan, Hayashi developed

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shape memory segmented polyurethane (PU) copolymer which is characterised by two distinct elements: one, the hard, for the physical crosslinks and the other, the soft to introduce the shape memory effect. This material is capable of recovering the entire plastic deformation up to 400 % when heated above the glass transition temperature; however, this recovery is much lower than that of SMA (8 % at initial elongation). Unlike metal alloys,[80] polymers demonstrate a recovery stress, between 0.98 and 2.94 MPa (10 and 30 kg f/cm2) which is lower than that of metal alloys between 147 and 294 MPa (1500 and 3000 kg f/cm2). Therefore, despite the advantages of being relatively low-cost and easily processed, their application is often restricted because of their lack in recovering stress.[93] Shape memory polynorbornene, with a glass temperature of 35 C, has been used as an occluder device for patent ductus arteriosus (PDA) occlusion.[94] However, in vitro studies indicate that this technique requires that the temperature shape-changeable materials be easy introduced when used in intravascular surgery. Under this temperature, the occluder expands completely in the ductus and reduces the leak caused by the incomplete occlusion[95] at the PDA. However, because the compatibility of this material has not been tested, its ability to safely remain in contact with natural and living tissue cannot be predicted. Very recently, researchers have developed SMPs that are both compatible with the body and biodegradable upon interaction with physiological environment. These SMPs have been studied by Langer and Lendlein and their respective team[96] to produce scaffolds for engineering new organs and coronary stents. Such stents could be compressed and fed



4. Biocompatibility Concerns As discussed above, the development of metallic and polymeric adaptive (or smart) materials for biomedical applications is progressing rapidly because of their unique properties.[43] These materials are to be part of internal medical devices in intimate contact with tissue and body fluids, therefore particular attention must be given to the interface between the SMMs and the natural tissue upon implantation. Being synthetic (man-made), thus foreign to the body, these adaptive materials must first satisfy the basic criteria such as biofunctionality, biostability, and biocompatibility during implantation. This last element refers to the ability of the material to remain non-toxic while maintaining its initial functionality for the duration of implantation. Several studies have assessed the biocompatibility of the shape memory metallic alloys; however, thorough, more systematic studies of their biocompatibility when in contact with blood flow have only partially addressed the crucial question regarding their security, particularly in long-term applications, for which the biocompatibility of SMAs remains controversial, as we will present below. The rigorous investigation of the biocompatibility of biomaterials is of primary concern, because it will allow us to predict (albeit without certitude) their behaviour when implanted in humans. The objective being to guarantee the best possible quality of life for the patient, the biomaterialist's responsibility is to supply to the bioengineer with artificial organ materials which will remain stable for the rest of the patient life. Body fluids, such as blood, constitute an aggressive environment for a metallic implant.[98] Nitinol therefore represents the most widely used element in orthodontic and orthopaedic implants, and in stents. The clinical use of stents for intravascular application has been improved by studying their surface properties and characteristics.[99,100] Preliminary studies have concluded that NiTi-based devices for use as


peripheral arteries in human have led to interesting results.[101] Shih and his research group were the first to demonstrate the potential cytotoxicity of NiTi stent wires on rat aortic smooth muscle cells.[102] They observed cellular death following incubation of nitinol in cultured media and cell growth inhibition, and discussed that these phenomena were related to the concentration of nickel ions existing in NiTi stent as well as exposure time in the corrosive media. This finding is in agreement with several studies reporting that the release of the Ni ions from NiTi alloys has a significant effect, the dissolution of Ni may possibly contribute to the inhibition of cell replication[103] and proper cell function,[104±106] as these ions are considered both toxic and carcinogenic to cultured cells.[107±109] Each of these studies was consistent with the reports by Uo et al.[110] who observed the presence of severe tissue damage with inflammatory response around the Ni implants. When used to make catheters, or parts of catheters, NiTi alloys have a distinct advantage because of their properties, and particularly with regard to their easier insertion, which constitutes a very safe and justifiable choice for short-term (some hours) applications.[111] However, when the application requires longer periods of residence inside the body, a major question arises concerning its corrosion resistance, (particularly on the nickel presence) and its enormous potential to be cytotoxic, carcinogenic and eventually mutagenic. This potential must be further investigated and unequivocally stated: Appropriate procedures and rigorous standards have to be elaborated. Yet despite the many investigations,[112±114] the question is more complex than one would imagine. The possibility that nickel ions may react with the physiological environment is both realistic and theoretically possible. Each metal possesses its own intrinsic toxicity to cells, often depending on the concentration of its presence. Thus, the corrosion resistance of an alloy and the toxicity of individual metals (and their respective ions) in an alloy are the two principal factors that determine its long-term biocompatibility,[115] with results such as corrosion and other undesirable effects such as toxicity and carcinogenesis.[116±121] Moreover, this corrosive reaction may weaken the alloys mechanical properties.[122] Caution is therefore required when addressing the possibility that nickel is released into the human body and causes a potential risk when it is used long-term, as the dissolved Ni ions are capable of stimulating and activating natural tissue as well as adverse reactions.[123] It is for this reason, their applications have been sometimes limited.[124] Matsumoto et al.[125] reported that the subcutaneous implantation of nitinol rods in rabbits for 4 weeks led to the elution of Ni, causing a significant increase of the Ni concentration in the blood. Moreover, nitinol rods implanted intramedullary in rats exhibited significant surface corrosion after 60 weeks of implantation.[59] These studies identified the problem, which is a definite lack of evidence to support unequivocally the long-term biocompatibility of NiTi alloy. However, if the Ni dissolution

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through a tiny hole in the body into a blocked artery. Then, the warmth of body would trigger the polymer's expansion into original shape. Instead of requiring a second surgery for removing the SMPs, the polymer would gradually dissolve in the body over time. Others reported that the development of biodegradable materials suited for polymers will serve biomedical applications such as stents, catheters, and sutures.[97] As shown in this paper, polymers change their shape in 45 s at 65 C. The biodegradability of these materials will thus be an advantage in reducing the number of invasive surgeries.[93] Bernnan further explained that devices used for short-term endovascular applications will more readily degrade after successive tissue healing occurs. Therefore, follow-up surgery will be obligatory, which will mean less discomfort for the patient. In some cases, biodegradable polymers are the only solution in applications such as reconstruction and functionality of blood vessels.

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Mantovani et al./Shape Memory Materials for Biomedical Applications from alloy was significant enough to cause corrosion after 60 weeks, thereby affecting the natural tissue what are the effects if implanted for longer period of time (i.e., the rest of the patient's life)? Regardless, specific investigations of long-term implantation must therefore be carefully designed and methodically performed following rigorous procedures before the safety of nitinol can be absolutely started and certified. It therefore appears clear that today there are no available conclusive data on the biocompatibility of NiTi. Nickel is among those solid metals recognised as being potentially carcinogenic when used in human and animal models. In 1976, many investigations of nickel compounds reported that they may induce cancers in animals models.[126,127] Many type of cancers have been related to the exposure to nickel. Despite the advantages such as shape memory and superelasticity, the nickel released in the body may cause both toxic[128] and allergic[129] reactions. The implantation of nitinol alloy in rabbit paravertebral muscles[130] resulted in an inflammatory response which may have caused cell damage. In contrast to the above mentioned studies, several studies agree as to the safety of NiTi alloy.[131,132] Moreover, devices fabricated with SMAs are still present in the medical market. The controversy still continues. The use of this alloy in practical applications depends on the environment and the level of wear, specific to the application, as well as other factors. We are far from suggesting that NiTi alloys be banned from the medical market. For example, to overcome their potential and acknowledged Ni-leakage and the relative biocompatibility problems, devices made with NiTi alloys could be treated with various surface modifications to enhance their corrosion resistance and/or to prevent Ni leakage. However, the biocompatibility aspect of NiTi alloy must be rigorous by investigating so that we may precisely validate the long-term effects of the implant as well as eliminate any apprehension on the part of potential users. Orthopaedic and cardiovascular surgery remain the two major fields for the use of SMAs. However, they do impose a variety of constraints and environments on the implant which will require that validation studies seek out different approaches. As mentioned earlier in this review, SMPs may also be used as biomaterials because of their unusual and interesting properties. However, their short, medium and long-term biocompatibility have to be previously assessed. In fact, despite the fact that theoretically, polymers are well-recognised as high-potential biomaterials, because of their good biocompatibility, we must consider that large scale production (industrial) of polymers is very hard to achieve without additives, and that in many cases, the presence of these additives has resulted in biocompatibility problems in long-term implantation. Certain additives such as plasticizers, stabilisers and, sometimes, pigments are in fact often used in developing polymeric implants. These additives may show toxic effects under human constraints, such leaching by fluids, temperature, strain, stress and so on. The use of polymers as biomate-

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rials show some difficulties, for example, the ultra high molecular weight of polyethylene used in hip joint replacements led to the implant's failure after a long period (with the duration depending on each patient involved).[133,134] This failure was attributed to the loss of functionality of the implant and, the generating of wear debris from implant materials with osteolysis.[135,136] In fact, in vivo evaluation of polyethylene hip replacement sockets after 15 years of implantation, revealed a significant surface degradation.[137] The question therefore is this: Are polyethylene debris likely to be cyto-, muta-, and/or geno-toxic? In platelet retention experiments, it has been shown that some polymers from the PU family may be highly thrombogenic.[138,139] The authors concluded that the response of blood to PU surfaces depended on the PU surfaces and on the sequence of PU segments: In fact, the PU segmented copolymers displayed excellent blood compatibility only when the PU soft segment was polytetramethylene oxide, which suggests that a successful application is only possible by selecting the specific PU polymer for a particular application. On the other hand, following the introduction of polyethylene as a soft segment, a lack of biocompatibility was observed.[140] And although, the incorporation of carboxylate ion into PU reduced the deposition and activation of the adherent platelet,[141] Okkema and Cooper[142] demonstrated that the carboxylate ion had no statistically significant effect on platelet adhesion. Following the implantation of polyurethane foamcovered implants, some authors observed the presence of toluene diamine (TDA) in the patient's urine.[143±145] Exposure to TDA released from the coating was known to cause a cancer in animals, and for this reason this type of implant was taken off the market in 1991. In addition to the presence of additives, the issue chemical stability is of prime importance and must be carefully considered when designing a SMP which will be suitable for implantation. While some polymers are known to be chemically highly stable upon implantation in humans, (i.e., poly(tetrafluoroethylene), PTFE, and poly(ethyleneterephtalate)), others may be more susceptible to chemical degradation because of their intrinsic molecular structure. Indeed, several polymers contain chemical moieties which may be readily hydrolysed or oxidised within the aggressive, physiological environment of the human body. In other words, the chemical structure of an eventually perfect shape memory that polymer displays all of the appropriate mechanical characteristics must also meet the criteria for chemical stability to prevent the failure of the SMP-made biomedical device. Despite some success in biomedical applications, the use of polymers in acceptable permanent implants has yet to be reported, particularly in long-term applications. We must first keep in mind that biocompatibility of biomaterial depends on many parameters (both intrinsic and extrinsic) and that it cannot be easily assessed. In addition, as the expected duration of the implantation is directly related to the short or long-term material's ability to maintain its stabil-



5. Surface Engineering Concerns Although, the presence of nickel guarantees the mechanical performance of the NiTi alloy, the latter's biocompatibility has not been established beyond a reasonable doubt. In fact, despite numerous clinical applications of NiTi alloy,[146±150] its long-term biocompatibility has not been fully certified and has given rise to controversy. In short-term applications, Ryhänen demonstrated that the NiTi SMA has the same biocompatibility as stainless steel.[59] In long-term applications, it was proposed that the NiTi surface has to be treated or coated in order to inhibit any potential toxic effects.[151±154] The possibility of enhancing the corrosion resistance makes these materials attractive for biomedical applications as cardiovascular devices and others. In the present section, we will highlight some directions which could be successfully adopted to circumvent the potential toxicity of these Ni-containing alloys. In fact, a surface treatment would probably make nickel±titanium SMA more suitable for human implantation: the presence of nickel in the alloy would be masked, thus improving the corrosion resistance. In fact, surface treatment opens the door to many possibilities.[150,155,156] Results in laser treatment are exciting[157] and other surface treatments and coatings may lead to an improved sensitivity to corrosion. However, we believe that the changes of shape and dimension associated with nickel±titanium during the austenite±martensite transition may cause the film to delaminate. For this reason, the adhesion properties of any covering will have be extensively investigated. Because the long-term outcome is not fully understood, and/or due to the lack of biocompatibility or of shape memorising materials, many techniques to solve the problem of the biocompatibility have been developed to modify the material's surface. Surface modifications may change the surface tremendously but an excellent surface biocompatibility may be preserved. Various modification methods have previously been proposed to protect the surface of materials against corrosion and/or to prevent the release of toxic elements such as Ni ions. Among the available surface engineering techniques, those including thin film deposition,[155,158±160] and plasma surface treatment,[161,162] deserve an attention in the surface modification of biomaterials. Electropolishing has already been tested as a surface modification method to improve the corrosion behavior of NiTi.[163,164] The authors believe that this treatment allows the development of a layer of TiO2 on the surface of the alloy which may act a barrier against further Ni diffusion. TrØpa-


nier et al.[149] showed that nitinol surface treatments by electropolishing, nitric acid etching, or heating are helpful in improving the stent corrosion resistance. Another study demonstrated that mechanically polishing nitinol increases the Ti concentration which may in turn favour the development of a stable oxide Ti layer on the surface.[165] Another technique which consists in coating the NiTi alloy with a thin polymer film can be used to provide a protective barrier which will inhibit the diffusion of released Ni.[166] An overall protective polymer surface film may ensure outstanding corrosion resistance and biocompatibility. These findings are in agreement with other studies which indicate that the coating of nitinol by a polymeric film does in fact improve the corrosion resistance.[155,159] Moreover, the surface modification of stents with polymers would be an excellent means to achieve long-term local delivery of anti-thrombotic agent. Basically, a smooth metal surface is required to prevent the activation of the clotting process by trapped corpuscular blood components. Coating the NiTi with polymers, such as PTFE-like polymer[155] using plasma, has been known to improve the corrosion resistance. On the other hand, the implantation of nitinol stents coated by polyurethane in rabbit carotid arteries resulted in an increased inflammatory response.[167] Surface treatments may also be used to change the material surface topography, as shown by Kimura and Sohmura,[168] who unfortunately demonstrated that the coating of NiTi with bioceramics (TiN and CTiN) failed because of the cracking of the coating on a major deformation due to the memory effect. Therefore, as shown by many authors, the surface modification may induce the bulk material to alter in many materials during the sterilisation process.[169±171] Polymers are also good candidates to provide thin films to coat the surface of metallic biomaterials to inhibit the leakage of potentially toxic elements and improve their biocompatibility, or merely for the required sterilisation of the device. For example, this last process was shown to be beneficial in preventing the degradation of implant materials. The sterilisation by gamma-irradiation of polyethylene showed no surface oxidative degradation after 16 years of implantation.[137] In fact, the gamma-irradiation of polyethylene induced crosslinking, which is known to have a significant effect on both the mechanical as well as the physical properties. Thierry et al.[172] and others[78] showed that the sterilisation could chemically modify NiTi surface characteristics, however, the use of this technique remains uncertain, as the obtained results were not reproducible. The coating of nitinol devices with polymers by means of surface coating reactors (i.e., radio-frequency or microwave plasma systems) may represent a very promising alternative, although these new modified surfaces must to be thoroughly characterised and extensively studied. Despite their interesting properties, biomedical applications thus far of SMPs have been limited. We do believe, however, that these materials represent a valid choice in the new and exciting field of tissue engineering which has become a

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ity, the biocompatibility must be a priority when selecting biomaterials for specific applications. Ideally, biomaterials used as long-term medical implants must retain their properties and functionality for the remainder of the patient's life. Finally, we believe there is an urgent need for further systematic investigations on the biocompatibility of SMMs.

REVIEWS

Mantovani et al./Shape Memory Materials for Biomedical Applications serious alternative to the regeneration (rather than replacement) of diseased tissues, even organs, that require the use of innovative scaffolds for initial cell attachment and tissue development.[173±175] These scaffolds must be virtually biocompatible, at times bioresorbable, and they must create the three-dimensional network to which the cells will attach and grow. An extensive summary of polymeric scaffolds was presented by Agrawal and Ray,[176] in which various scaffolds made of synthetic biodegradable polymers such as poly(lactic acid)s (PLA), poly(glycolic acid) (PGA) and their copolymers (PLGA)[177±179] were investigated. PLA is considered scaffold material for the support of cell growth; however, it was found that this material was not chemically reactive enough. To overcome this problem, many authors proposed surface modification by introducing reactive groups.[174,180,181] Many other polymeric scaffolds have been developed for tissue engineering applications such as breast reconstruction,[182] as well as the replacement and regeneration of damaged bone[183] and cartilage.[184,185] For example, polyanhydrides have been used as successful scaffolds for orthopaedic implants[186,187] and tyrosine-derived polycarbonates have produced interesting results when used as scaffolds in tissue engineering. As shown by Choueka et al.,[188] these polymers exhibited an intimate contact with bone. Hydrogels have been developed as scaffolding materials for use either in biomedical[189,190] or tissue engineering applications,[191] such as peripheral nerve repair, because of their appropriate mechanical properties, as shown by Kuo and Ma.[192] In general, tissue engineering requires that synthetic materials display carefully tailored bulk and surface properties, and are specifically designed to function as scaffolds to promote tissue growth and organisation by providing a three-dimensional framework with characteristics that welcome favourable cell responses. More specifically, we believe that SMPs can provide new challenges by exhibiting the appropriate and required matching of their mechanical and micro-mechanical properties to those of hosting and surrounding cells and tissue.

6. Conclusions This review of medical applications of SMMs is perhaps not exhaustive, however, the objective was to show their obvious potential in the field of medicine. Shape memory ceramics, in particular which are a new exciting class of materials recently discovered and now being examined, have been voluntary emitted from this review, as their potential biomedical applications remain unexplored. In the coming years, as biology and material sciences evolve, we will most certainly witness true revolution in medicine. Challenging new concepts in conventional vascular surgery have begun in the field of endovascular surgery, and minimally invasive laparoscopy surgical interventions are now being combined with magnetic resonance imaging to push the science beyond the existing medical frontiers. New horizons must been opened,

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and clinicians, scientists and industrialists must quickly and truly work in close collaboration, as mastering such complex problems necessarily requires a multidisciplinary approach. As a result, numerous applications have been considered and many more are envisaged. This is undoubtedly the perspective by which the development of SMMs must be regarded and analysed. Because of their revolutionary properties, these alloys have been the stimulus for the most audacious applications since the 70's and have broken more than one some scientific barrier. However, as we deepen our knowledge, our criticism must become more rigorous. We must learn from past experience and adopt a more rational, and less emotional, approach if we are to face and overcome tomorrow's technological challenges. Received: June 25, 2001 Final version: October 23, 2001

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