2002 Feninat Shape Memory Materials

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ShapeMemoryMaterials

for Biomedical ApplicationsBy Fatiha El Feninat, Gaetan Laroche, Michel Fiset,and Diego Mantovani*

1. Introduction

Medical implants have undoubtedly made an indeliblemark on our world during the last century. More than100 millions humans carry at least one major internal medicaldevice. The prosthesis industry has topped 50 billion US$ inannual sales, with approximately 150 universities throughoutthe world proposing an undergraduate program in bioengi-neering or biomedical engineering. Despite that, however,most medical devices have been constructed using a signifi-cantly restricted number of conventional metallic, ceramic,polymeric, and composite biomaterials.

Medicine and improvisation hardly appear to be a likelypair, yet since ancient times, resourceful doctors have carriedout difficult procedures, often having to work with materials

on hand.[1] Wounds were sutured with plant fibers (animal-derived materials by ancient Greeks, Chinese, and Egyp-tians), and prosthetic limbs were fashioned from wood. Met-als were eventually introduced in dentistry, and early thispast century, when stainless steel became available, corro-sion-resistant alloys were used to make a variety of pros-theses. As with their predecessors, today medical practi-tioners will often attempt to cure diseases or improve qualityof life by replacing a defective body part with a substitute.While the designing process leading to the development ofsuccessful artificial organs has been improved over the years,bioengineers remain limited to fabricating devices with off-

the-shelf materials which were not designed specifically forthe application. The easy availability of industrial materials,

along with the multiple specific and challenging constraintsto which an artificial organ is submitted when implanted inthe body, are the principal factors which may explain whytoday, only a dozen materials are routinely used to constructinternal artificial organs. In this regard, motivated by theincreasing need for custom-made materials for specific medi-cal applications, materials scientists, metallurgists, chemists,mechanical and chemical engineers, as well as researchers inother disciplines, have progressively begun an interdisciplin-ary work in the hopes of creating high-performance biomate-

ADVANCED ENGINEERING MATERIALS 2002, 4, No. 3 91

[*] Prof. D. Mantovani, Dr. F. El FeninatResearch Center, St. Franois d'Assise Hospital,Department of Mining, Metallurgy and MaterialsEngineeringLaval University, Pouliot Building, Room 1745-EQuebec City, G1K 7P4 (Canada)E-mail: [email protected]. M. FisetDepartment of Mining, Metallurgy and MaterialsEngineering, Laval University

Dr. G. LarocheDepartment of Surgery, Laval University

Shape memory properties provide a very attractive insight into materials science, opening unexploredhorizons and giving access to unconventional functions in every material class (metals, polymers, andceramics). In this regard, the biomedical field, forever in search of materials that display unconven-tional 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 per-manent applications, has not yet been fully established and is therefore the object of controversy. Onthe other hand, shape memory polymers (SMPs) show promise, although thus far, their biomedicalapplications have been limited to the exploration. This paper will first review the most common bio-medical applications of shape memory alloys and SMPs and address their critical biocompatibilityconcerns. Finally, some engineering implications of their use as biomaterials will be examined.

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 specificproperties into high-potential biomaterial candidates.

Among the last industrial materials elected to the rank ofbiomaterials are shape memory alloys (SMA), which have

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

92 ADVANCED ENGINEERING MATERIALS 2002, 4, No. 3

Fatiha El Feninat received her M.Sc.A degree in chemical engineering from cole Polytechnique deMontral. Recently, she obtained a Ph.D. degree in chemistry from the University of Montral, for herworks on the characterisation of human dentin by atomic force microscopy. In November 2000, shejoined the Department of Mining, Metallurgy and Materials Engineering at Laval University and theResearch Center of the St-Franois d'Assise Hospital as Postdoctoral Fellow. Her research focus on sur-face modifications and characterisation of shape memory alloys in order to be used as long-term safe bio-materials, and atomic force microscopy.

Gatan Laroche received both his B.Sc. (1986) and Ph.D. (1990) from the chemistry department at LavalUniversity. He joined the Research Center of St-Franois d'Assise Hospital in 1992 and the SurgeryDepartment at Laval University where he is professor since 1994. His main research interests arerelated to the physicochemical characterisation of biomaterials, molecular transport through biomaterialsand 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. Hejoined the department of Mining, Metallurgy and Materials Engineering at Laval University in 1977 asprofessor of materials science. One of his major research interests has been the field of abrasive wear, withparticular reference to alloy white cast irons, laser materials processing, as well as advanced alloys forbiomedical applications.

Diego Mantovani obtained a B.Sc. degree in Bioengineering from the Politecnico di Milano, Italy, and aB.Sc. in Biomaterials and Artificial Organs from the Universit de Technologie de Compigne, France.Then, he obtained a Ph.D. from Laval University in 1998 and a D.Sc. from the Universit de Technolo-gie de Compigne in 1999, for his studies on materials and biomaterials. He is professor at the LavalUniversity department of Mining, Metallurgy and Materials Engineering and researcher at theResearch Center of the St-Franois d'Assise Hospital in Biomaterials and Bioengineering since January2000. With his team, he carries out project-oriented and multidisciplinary research in biomaterials, arti-ficial organs and bioengineering. Focus is on functional materials for blood-contact applications, struc-ture-properties relationships, micro-mechanics, surface properties modifications, and bioreactors designfor reparative medicine.


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viously published in extensively reviews.[2,3] In general, eachmaterial used to fabricate industrial products designed to beimplanted in the human body for small, medium or long-term periods must be tested to demonstrate its biocompat-ibility. In vitro studies, followed by in vivo studies, andfinally, 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 useas implant. Consequently, only a few products developed byindustrial R&D may effectively be used in implantology.Today, the use of endovascular stents, orthopaedic staplesand dental braces are widely acknowledged world-wide,which is not the case for intra-cranial staples, which are notpermitted by the FDA for use in the USA.

The objective of this paper is first to review the most com-mon applications of shape memory materials (SMMs), focus-ing on shape memory metallic alloys, which are widely used,and shape memory polymers (SMPs), for which strong R&Dindustrial efforts are ongoing. Secondly, this paper aim is toshow the challenges facing their unique properties, whileaddressing some of the critical concerns with regard to thenature of the biological environment these materials will haveto integrate. We will conclude by outlining some of the realis-tic implications such as societies expectations and the qualityof life for the patient. The goal here is therefore not to categor-ise materials and biomaterials as being either bad orgood, but rather to stimulate reader implication in a trueinterdisciplinary discussion towards an actual advancementof this ever-growing research field.

2.ShapeMemory Alloys

From a chronological point of view, in the thirties thepseudoelastic effect was already being observed in AuCdalloy.[4] This was followed in 1938 by the observation of theshape memory effect in CuZn alloy.[5] It was, however, inthe 1960s, that Buehler et al.,[6] at Naval Ordnance Laboratory,discovered the shape memory effect in nickeltitanium alloys,commonly known as Nitinol alloys (for nickel titanium NavalOrdnance Laboratory).

From a more scientific point of view, there exists anexhaustive wide variety of metallic alloys which demonstrateshape memory and/or superelastic effects and which havebeen investigated in the past and are well reported in the lit-erature.[4,718] These works focused on metallic alloys, includ-ing, for example, binary systems such as NiTi, CuZn, AuCd,CuSn, TiPd, NiAl, and InTi, as well as ternary systems suchas NiTiCu,[19] and CuZnAl.[20,21] Moreover, it has been shownthat introducing copper in a binary NiTi alloy increases itsability to change shape when heated (shape memory proper-ties).[2224]

From a metallurgical point of view, nitinol is a nickeltita-nium alloy of near-equiatomic composition, which impliesthat nickel represents approximately 50 % of its chemical

composition. This alloy is particularly interesting because ofits significant mechanical properties, and above all, becauseof its ability to show high elastic deformation, or pseudoe-lasticity, and shape memory effect which are not presentin other conventional metallic alloys. It has to be underlinedthat the terms pseudoelasticity and superelasticity are often

used synonymously in the literature, even if the specificmetallurgical mean and the proper use of these terms waspreviously discussed by Ostuka and Wayman.[25] Figure 1shows the stresstemperature relation where the hysteresisdescribing the transformation of the SMA is presented. Thishysteresis is characterised by four temperatures (Ms, Mf, As,and Af) which indicate the initial and final transformationtemperatures. Two stable transformation phases are presentat different temperatures: the martensite phase is stable atlow temperature in contrast the austenite one which is stableat high temperature. These two transformations are reversiblewithout inducing any diffusion between the existing phases.The most significant properties of the SMA are ruled by thephase transitions between the austenite (high temperaturephase) and the martensite (low temperature phase), andreciprocally. The phase transitions as a function of tempera-ture are thus particularly important in order to control theproperties. In a previous study,[2] we carefully described thefive characteristic properties and proposed an integratedglobal overview of the various effects which can be observedon SMAs:l the one-way shape memory effect, where the change in

shape is regulated by the transition from martensite toaustenite,

l the two-way shape memory effect, with the learning pro-

cess by mechanical cycles and the one-way shape memoryeffect, where the changes in shape are regulated by thephase transitions (martensiteaustenite followed by auste-nitemartensite),

l the superelastic effect, where the deformations are regu-lated by the phase transitions (austenitemartensite, thenmartensiteaustenite),


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


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l the superthermic effect, where the material replaces theaccumulated internal constraints during the learning pro-cess by the external constraints,

l the rubber-like effect, observed in the repeated mechani-cal cycles of learning.

The interconnections between temperature, force, and

geometrical shape are complex, which make it difficult to pre-dict the behaviour of SMA in each specific application. Mostof the current applications use alloys that allow us to retaintwo of three parameters, with the third fixed by the choice ofalloy elements and thermomechanical treatment. The NiTigeneral properties are primarily related to a temperature orstress that is induced by the martensitic transformation. [26]

However, the mechanical properties of NiTi alloy dependmore specifically on the transformation temperature of transi-tion,[6] and the damping capacity of alloys which can reach90% for impact loads.[27] The properties of nickeltitaniumalloys have been extensively investigated and reported byvarious authors.[25,28] The high mechanical properties of NiTialloy may be helpful in self-expanding and self-compres-sing,[29] situations which make NiTi easily malleable whenused in medical devices. This malleability is important, par-ticularly in the case of alloys used in endovascular therapy.The instrument handles can be bent with enormous precisionto the proper shape required for surgery, and recover theirinitial shape after heating.[30]

From an industrial point of view, among the wide varietyof shape memory metallic alloys available only those able torecover a substantial amount under strain (when the austeni-ticmartensitic phase change occurs) have been considered inthe design of industrial products. Thus far, this signifies that

only the equiatomic (or the near equiatomic) NiTi alloys anda few of the copper-based alloys have been largely commer-cialised. Moreover, only NiTi alloys have been introduced inthe medical device industry and are currently overwhel-mingly used as biomaterials through other potential metallicalloys, because the latter, while presenting similar properties,are at times expensive (such as gold-based alloys, [31,32]) or donot exhibit mechanical properties and thermal stability ascompetitively as do NiTi alloys.[33] Finally, in some othercases, they exhibit a far greater risk of toxicity.[3436]

The field of NiTi alloys is expanding rapidly: In 1998, TiNiAlloy Company reported that many devices of various sizeshad been introduced for medical and others fields and thatthe sales of these devices had reached more than a hundredmillion USD per year.[37] We will therefore present a reviewof the various biomedical applications of NiTi-based SMAand its biocompatibility when used in the fabricating of bio-medical devices.

Since the discovery of NiTi alloy, and particularly in theearly 1970s, many studies have exploited the potential of NiTifor medical applications.[3841] However, it was not until the1990s that adequate medical investigations led to a break-through with the development the first commercial stent.[42,43]

Based on superelastic effect wires,[44] NiTi alloys were used in

orthodontic therapy because of their high flexibility in bend-ing without kicking.[4549] Studies emerged on the use of NiTiwires for the correction of malocclusions and impactedcanines.[50] In 1978, Andreasen and Morrow[51] reported onthe advantages of NiTi orthodontic wires over conventionalorthodontic wire. During the early stages of orthodontic ther-

apy, constant low stress to the dentition over time is requiredin order to minimise tissue destruction such as root resorp-tion during tooth movement.[52,53] Superelastic NiTi wire easi-ly gains these important forces, which are particularly favour-able for large malaligned teeth. Another advantage of NiTiorthodontic wires is that it is possible to provide rapid ortho-dontic treatments, resulting in less patient discomfort becausefewer adjustments and wire changes are required.[30,52]

Other interesting medical applications of NiTi alloy havebeen reported in orthopaedic,[54] and other bone-relatedoperations.[55] Nitinol has been to be more effective thanothers materials[56] in connecting broken bones. Staples madeof NiTi SMAs have been used to fix small bone fragments. [57]

In cervical anterior fusion, the NiTi staple was used in fiftypatients; with successful results for 80% of the cases(36 months).[58] Superelastic NiTi catheters facilitate access toareas in human body which are at times more difficult toreach using other materials.

Because of its superelastic properties, NiTi alloy is excep-tionally flexible, which enables its use in non-invasive sur-gery to reach narrow places. The NiTi wires are also shapedfor use in prostheses, tissue anchoring and connection, [59] aswell as stents.[60,61] When inserted into the human body, thesuperelastic NiTi-based stents are capable of self-expanding.This property allows us to use these stents in gastroenterol-

ogy, cardiovascular and radiology fields. The U.S. Food andDrug Administration has accepted the vascular NiTi devicereported by Simon and his research team.[41] This device,called Simon Nitinol Filter (SNF), is used for treating pulmon-ary embolism. Other applications in cardiovascular surgeryhave been reported.[6264] In 1990, it was reported in Britainthat 7.5 per 100000 of the population develops oesophagealcarcinoma[65] and only the palliation of oesophageal carcino-ma was suitable by using self-expanding stents,[66] whichoffer the advantage of being easily implantable for providingeffective malignant palliation.

The follow-up in most of the studies on NiTi as implantmaterial in humans may unfortunately have been limited inevaluating its toxicity which may arise after many years ofimplantation. When such a long-term application is notrequired, the use of this alloy may therefore be considered, asin the case of the preliminary bracket alignment stage oforthodontic treatment.[52] However, further investigationsmust to be envisaged prior to any long-term implantation ofthese materials in humans. If it is to be considered fully use-ful, the SMA must fulfil the requirements of both short andlong-term biological (biocompatibility) and chemical (degra-dation, corrosion, and dissolution) reliabilities when used forhuman concerns.



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3.ShapeMemory Polymers

Contrary to popular belief, shape memory is not a prop-erty known exclusively to metallic alloys. Nevertheless, itmust to be emphasised that only metallic alloys are capableof showing shape memory properties because of a crystalline

structure change, i.e., from austenite to martensite, or vice-versa. Other materials exhibit similar properties, and there-fore are defined as adaptive or smart materials. Smart oradaptive are adjectives given to those materials that providea specific response in a particular environment. For example,it means that they are able to assume pre-definite shapes anddimensions when their environment reaches at a determinedtemperature, or that they are capable of displaying a specificforce at a particular temperature, etc. Therefore, it may beunderstood that those specific materials, namely, polymerswith high, specific shape memory characteristics, havereceived early recognition as potential candidates as implantmaterials. In fact, the need for these new materials is wellappreciated because of the controversy regarding the biocom-patibility of nickel-containing SMAs (as will be discussedlater in this paper), their difficult fabrication and/or theircost. The primary advantage of polymers over other materialsin biomedical applications is their easier availability and theirwide range of mechanical and physical properties.[67,68]

As shown in Figure 2, the polymeric materials show theproperties more closely to those of soft biological tissue, ifcompared to those of metals which are more similar to thoseof hard biological tissue. The international scientific commu-nity has therefore focused its attention on new polymericmaterials offering the specific high advantage of returning to

some previously defined shape under the appropriate ther-mal conditions. A variety of publications and patents havecovered the development of polymers exhibiting theseunusual properties.[6976]

The mechanism through which selected polymers demon-strate specific shape memory properties is related to theirintrinsic non-crystalline molecular structure. As it is well-known, the glass transition temperature (Tg) characterisespolymers, making them unique in contrast to other materialssuch as metals or ceramics. However, polymers display dif-

ferent states depending on the temperature range within afew degrees of Tg. In fact, at this temperature, significantchanges in the mechanical and thermodynamical propertiesmay 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 materialsbecome brittle and hard. At this point, the rubbery state isreplaced by a glassy behavior,

l across the glass temperature, the elastic modulus of poly-mers may exhibit a large, reversible change (Fig. 3).

Through the shape memory effect shown in Figure 4, itmay be possible to deform the polymers below Tg and returnthem to their original shape by heating the polymers to high-er temperature than Tg. However, if the materials are de-formed above their glass transition temperature under exter-nal force, the deformation will be fixed and maintained afterremoval of the external force. However, a subsequent heatingof the material above its Tg will allow it to recover its originalshape, thereby generating a lower force.[68]

The shape memory and elastic properties make polymershighly interesting when used as smart (or adaptive) materialsfor industrial applications.[78] SMPs are basically charac-terised by a low temperature transition which is in the rangeof room temperature;[79] this feature makes the SMPs suitablefor biomedical devices, as the latter are implanted at bodytemperature (37C). Another advantage supporting the pref-erential use of polymers as biomaterials, is the potential totarget specific complementary properties simply by copoly-merising two or more monomers. For example, the copoly-

merisation of vinyl chloride (VC) with ethylene, allows us tocombine some properties of polyethylene that is soft and elas-tic, and poly(vinyl chloride) (PVC) that is mostly hard. Thecopolymerisation of styrene and butadiene produces a sty-renebutadiene copolymer with shape memory properties. Inthis case, the different temperature-dependent behaviours ofthe copolymerised styrene and butadiene moieties enable thecopolymer to preserve its stiffness (styrene) while the buta-diene segments help maintain its flexible character (buta-diene), thereby leading to the shape memory capabilities.


Fig. 2. Schematic stress versus strain diagram for metals, polymeric materials, and bio-logical tissues. Fig. 3. Elasticity versus temperature of amorphous polymers.


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Polymers exhibit shape memory effects which completelydiffer from those of metallic alloys. Rubber is a typical SMPthat is capable of expanding many times before returning toits original shape as a function of applied stress.[80] Contraryto the shape memory effects in metallic alloys, the effects inpolymers 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 toexperience isomerisation under photo-irradiation. The mostsimple example is azobenzene which is used as a crosslinkingagent for polymer fabrics. By isomerisation through the ultra-violet irradiation of azobenzene, the transformation from thecis to the trans form induces the shape change in the poly-mers.[83] As demonstrated by Hirai and his collaborators,[84] itis possible to introduce shape memorizing properties bycrosslinking the polymer through chemical bonding. In addi-tion to introducing the shape memory effect, this chemicalcrosslinking leads to a three-dimensional network which maysignificantly improve the physical properties such as accept-able elasticity and excellent strength. Of considerable interestis poly(vinyl alcohol) (PVA) crosslinked with glutaraldehyde.Without crosslinks, the use of the PVA gel is unfortunatelylimited in terms of thermal stability,[85] as heating this gel canin fact disrupt the hydrogen bonds and consequently the sta-bility of the gel; this stability is also lost when the gel is placedin boiling water.[86]

During the past 15 years, Nippon Zeon Co. and others[8791]

have developed a wide variety of SMPs. In the early 1997s,Liang et al.[92] developed new, easy-to-shape polymers. AtMitsubishi Heavy Industries in Japan, Hayashi developed

shape memory segmented polyurethane (PU) copolymerwhich is characterised by two distinct elements: one, the hard,for the physical crosslinks and the other, the soft to introducethe shape memory effect. This material is capable of recover-ing the entire plastic deformation up to 400% when heatedabove 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 recoverystress, between 0.98 and 2.94 MPa (10 and 30 kg f/cm2) whichis lower than that of metal alloys between 147 and 294 MPa(1500 and 3000 kg f/cm2). Therefore, despite the advantages ofbeing relatively low-cost and easily processed, their applica-tion is often restricted because of their lack in recoveringstress.[93]

Shape memory polynorbornene, with a glass temperatureof 35C, has been used as an occluder device for patent duc-tus arteriosus (PDA) occlusion.[94] However, in vitro studiesindicate that this technique requires that the temperatureshape-changeable materials be easy introduced when used inintravascular surgery. Under this temperature, the occluderexpands completely in the ductus and reduces the leakcaused 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 livingtissue cannot be predicted.

Very recently, researchers have developed SMPs that areboth compatible with the body and biodegradable upon inter-action with physiological environment. These SMPs havebeen studied by Langer and Lendlein and their respectiveteam[96] to produce scaffolds for engineering new organs andcoronary stents. Such stents could be compressed and fed


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


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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 expansioninto original shape. Instead of requiring a second surgery forremoving the SMPs, the polymer would gradually dissolve inthe body over time. Others reported that the development ofbiodegradable materials suited for polymers will serve bio-

medical applications such as stents, catheters, and sutures.[97]

As shown in this paper, polymers change their shape in 45 sat 65 C. The biodegradability of these materials will thus bean advantage in reducing the number of invasive surgeries.[93]

Bernnan further explained that devices used for short-termendovascular applications will more readily degrade aftersuccessive tissue healing occurs. Therefore, follow-up surgerywill be obligatory, which will mean less discomfort for thepatient. In some cases, biodegradable polymers are the onlysolution in applications such as reconstruction and function-ality of blood vessels.

4. Biocompatibility Concerns

As discussed above, the development of metallic and poly-meric adaptive (or smart) materials for biomedical applica-tions is progressing rapidly because of their unique proper-ties.[43] These materials are to be part of internal medicaldevices in intimate contact with tissue and body fluids, there-fore particular attention must be given to the interfacebetween the SMMs and the natural tissue upon implantation.Being synthetic (man-made), thus foreign to the body, theseadaptive materials must first satisfy the basic criteria such asbiofunctionality, biostability, and biocompatibility during

implantation. This last element refers to the ability of thematerial to remain non-toxic while maintaining its initialfunctionality for the duration of implantation.

Several studies have assessed the biocompatibility of theshape memory metallic alloys; however, thorough, more sys-tematic studies of their biocompatibility when in contact withblood flow have only partially addressed the crucial questionregarding their security, particularly in long-term applica-tions, for which the biocompatibility of SMAs remains contro-versial, as we will present below. The rigorous investigationof 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 objectivebeing to guarantee the best possible quality of life for thepatient, the biomaterialist's responsibility is to supply to thebioengineer with artificial organ materials which will remainstable for the rest of the patient life.

Body fluids, such as blood, constitute an aggressive envi-ronment for a metallic implant.[98] Nitinol therefore repre-sents the most widely used element in orthodontic and ortho-paedic implants, and in stents. The clinical use of stents forintravascular application has been improved by studyingtheir surface properties and characteristics.[99,100] Preliminarystudies have concluded that NiTi-based devices for use as

peripheral arteries in human have led to interestingresults.[101] Shih and his research group were the first to dem-onstrate the potential cytotoxicity of NiTi stent wires on rataortic smooth muscle cells.[102] They observed cellular deathfollowing incubation of nitinol in cultured media and cellgrowth inhibition, and discussed that these phenomena were

related to the concentration of nickel ions existing in NiTistent as well as exposure time in the corrosive media. Thisfinding is in agreement with several studies reporting thatthe release of the Ni ions from NiTi alloys has a significanteffect, the dissolution of Ni may possibly contribute to the in-hibition of cell replication[103] and proper cell function,[104106]

as these ions are considered both toxic and carcinogenic tocultured cells.[107109] Each of these studies was consistentwith the reports by Uo et al.[110] who observed the presence ofsevere tissue damage with inflammatory response around theNi implants.

When used to make catheters, or parts of catheters, NiTialloys have a distinct advantage because of their properties,and particularly with regard to their easier insertion, whichconstitutes a very safe and justifiable choice for short-term(some hours) applications.[111] However, when the applicationrequires longer periods of residence inside the body, a majorquestion arises concerning its corrosion resistance, (particu-larly on the nickel presence) and its enormous potential to becytotoxic, carcinogenic and eventually mutagenic. This poten-tial must be further investigated and unequivocally stated:Appropriate procedures and rigorous standards have to beelaborated. Yet despite the many investigations,[112114] thequestion is more complex than one would imagine. The pos-sibility that nickel ions may react with the physiological envi-

ronment is both realistic and theoretically possible. Each met-al possesses its own intrinsic toxicity to cells, often dependingon the concentration of its presence. Thus, the corrosion resis-tance of an alloy and the toxicity of individual metals (andtheir respective ions) in an alloy are the two principal factorsthat determine its long-term biocompatibility,[115] with resultssuch as corrosion and other undesirable effects such as toxici-ty and carcinogenesis.[116121] Moreover, this corrosive reac-tion may weaken the alloys mechanical properties.[122] Cau-tion is therefore required when addressing the possibilitythat nickel is released into the human body and causes apotential risk when it is used long-term, as the dissolved Niions are capable of stimulating and activating natural tissueas well as adverse reactions.[123] It is for this reason, theirapplications have been sometimes limited.[124] Matsumoto etal.[125] reported that the subcutaneous implantation of nitinolrods in rabbits for 4 weeks led to the elution of Ni, causing asignificant increase of the Ni concentration in the blood.Moreover, nitinol rods implanted intramedullary in ratsexhibited significant surface corrosion after 60 weeks ofimplantation.[59]

These studies identified the problem, which is a definitelack of evidence to support unequivocally the long-term bio-compatibility of NiTi alloy. However, if the Ni dissolution



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from alloy was significant enough to cause corrosion after60 weeks, thereby affecting the natural tissue what are the ef-fects if implanted for longer period of time (i.e., the rest of thepatient's life)? Regardless, specific investigations of long-termimplantation must therefore be carefully designed and meth-odically performed following rigorous procedures before the

safety of nitinol can be absolutely started and certified.It therefore appears clear that today there are no availableconclusive data on the biocompatibility of NiTi. Nickel isamong those solid metals recognised as being potentially car-cinogenic when used in human and animal models. In 1976,many investigations of nickel compounds reported that theymay induce cancers in animals models.[126,127] Many type ofcancers have been related to the exposure to nickel. Despitethe advantages such as shape memory and superelasticity,the nickel released in the body may cause both toxic[128] andallergic[129] reactions. The implantation of nitinol alloy in rab-bit paravertebral muscles[130] resulted in an inflammatoryresponse which may have caused cell damage. In contrast tothe above mentioned studies, several studies agree as to thesafety of NiTi alloy.[131,132] Moreover, devices fabricated withSMAs are still present in the medical market. The controversystill continues.

The use of this alloy in practical applications depends onthe environment and the level of wear, specific to the applica-tion, as well as other factors. We are far from suggesting thatNiTi alloys be banned from the medical market. For example,to overcome their potential and acknowledged Ni-leakageand the relative biocompatibility problems, devices madewith NiTi alloys could be treated with various surface modifi-cations to enhance their corrosion resistance and/or to pre-

vent Ni leakage. However, the biocompatibility aspect of NiTialloy must be rigorous by investigating so that we may pre-cisely validate the long-term effects of the implant as well aseliminate any apprehension on the part of potential users.Orthopaedic and cardiovascular surgery remain the twomajor fields for the use of SMAs. However, they do impose avariety of constraints and environments on the implant whichwill require that validation studies seek out differentapproaches.

As mentioned earlier in this review, SMPs may also beused as biomaterials because of their unusual and interestingproperties. However, their short, medium and long-term bio-compatibility have to be previously assessed. In fact, despitethe fact that theoretically, polymers are well-recognised ashigh-potential biomaterials, because of their good biocompat-ibility, we must consider that large scale production (indus-trial) of polymers is very hard to achieve without additives,and that in many cases, the presence of these additives hasresulted in biocompatibility problems in long-term implanta-tion. Certain additives such as plasticizers, stabilisers and,sometimes, pigments are in fact often used in developingpolymeric implants. These additives may show toxic effectsunder human constraints, such leaching by fluids, tempera-ture, strain, stress and so on. The use of polymers as biomate-

rials show some difficulties, for example, the ultra highmolecular weight of polyethylene used in hip joint replace-ments led to the implant's failure after a long period (with theduration depending on each patient involved).[133,134] Thisfailure was attributed to the loss of functionality of theimplant and, the generating of wear debris from implant

materials with osteolysis.[135,136]

In fact, in vivo evaluation ofpolyethylene hip replacement sockets after 15 years ofimplantation, revealed a significant surface degradation.[137]

The question therefore is this: Are polyethylene debris likelyto be cyto-, muta-, and/or geno-toxic?

In platelet retention experiments, it has been shown thatsome polymers from the PU family may be highly thrombo-genic.[138,139] The authors concluded that the response of bloodto PU surfaces depended on the PU surfaces and on thesequence of PU segments: In fact, the PU segmented copoly-mers displayed excellent blood compatibility only when thePU soft segment was polytetramethylene oxide, which sug-gests that a successful application is only possible by selectingthe specific PU polymer for a particular application. On theother hand, following the introduction of polyethylene as asoft segment, a lack of biocompatibility was observed.[140]

And although, the incorporation of carboxylate ion into PUreduced the deposition and activation of the adherent plate-let,[141] Okkema and Cooper[142] demonstrated that the carbox-ylate ion had no statistically significant effect on plateletadhesion. Following the implantation of polyurethane foam-covered implants, some authors observed the presence of tol-uene diamine (TDA) in the patient's urine.[143145] Exposure toTDA released from the coating was known to cause a cancerin 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 consid-ered when designing a SMP which will be suitable forimplantation. While some polymers are known to be chemi-cally highly stable upon implantation in humans, (i.e., poly-(tetrafluoroethylene), PTFE, and poly(ethyleneterephtalate)),others may be more susceptible to chemical degradationbecause of their intrinsic molecular structure. Indeed, severalpolymers contain chemical moieties which may be readilyhydrolysed or oxidised within the aggressive, physiologicalenvironment of the human body. In other words, the chemi-cal structure of an eventually perfect shape memory thatpolymer displays all of the appropriate mechanical character-istics must also meet the criteria for chemical stability to pre-vent the failure of the SMP-made biomedical device.

Despite some success in biomedical applications, the useof polymers in acceptable permanent implants has yet to bereported, particularly in long-term applications. We mustfirst keep in mind that biocompatibility of biomaterialdepends on many parameters (both intrinsic and extrinsic)and that it cannot be easily assessed. In addition, as theexpected duration of the implantation is directly related tothe short or long-term material's ability to maintain its stabil-



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ity, the biocompatibility must be a priority when selectingbiomaterials for specific applications. Ideally, biomaterialsused as long-term medical implants must retain their proper-ties and functionality for the remainder of the patient's life.Finally, we believe there is an urgent need for further system-atic investigations on the biocompatibility of SMMs.

5. SurfaceEngineeringConcerns

Although, the presence of nickel guarantees the mechani-cal performance of the NiTi alloy, the latter's biocompatibilityhas not been established beyond a reasonable doubt. In fact,despite numerous clinical applications of NiTi alloy,[146150] itslong-term biocompatibility has not been fully certified andhas given rise to controversy. In short-term applications,Ryhnen demonstrated that the NiTi SMA has the same bio-compatibility as stainless steel.[59] In long-term applications, itwas proposed that the NiTi surface has to be treated or coatedin order to inhibit any potential toxic effects.[151154] The possi-bility of enhancing the corrosion resistance makes these mate-rials attractive for biomedical applications as cardiovasculardevices and others. In the present section, we will highlightsome directions which could be successfully adopted to cir-cumvent the potential toxicity of these Ni-containing alloys.In fact, a surface treatment would probably make nickeltita-nium SMA more suitable for human implantation: the pres-ence of nickel in the alloy would be masked, thus improvingthe corrosion resistance. In fact, surface treatment opens thedoor to many possibilities.[150,155,156] Results in laser treatmentare 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 asso-ciated with nickeltitanium during the austenitemartensitetransition may cause the film to delaminate. For this reason,the adhesion properties of any covering will have be exten-sively investigated.

Because the long-term outcome is not fully understood,and/or due to the lack of biocompatibility or of shape mem-orising materials, many techniques to solve the problem ofthe biocompatibility have been developed to modify thematerial's surface. Surface modifications may change the sur-face tremendously but an excellent surface biocompatibility

may be preserved. Various modification methods have pre-viously been proposed to protect the surface of materialsagainst corrosion and/or to prevent the release of toxic ele-ments such as Ni ions. Among the available surface engineer-ing techniques, those including thin film deposition,[155,158160]

and plasma surface treatment,[161,162] deserve an attention inthe surface modification of biomaterials.

Electropolishing has already been tested as a surface modi-fication method to improve the corrosion behavior ofNiTi.[163,164] The authors believe that this treatment allows thedevelopment of a layer of TiO2 on the surface of the alloywhich may act a barrier against further Ni diffusion. Trpa-

nier et al.[149] showed that nitinol surface treatments by elec-tropolishing, nitric acid etching, or heating are helpful inimproving the stent corrosion resistance. Another study dem-onstrated that mechanically polishing nitinol increases the Ticoncentration which may in turn favour the development of astable oxide Ti layer on the surface.[165]

Another technique which consists in coating the NiTi alloywith a thin polymer film can be used to provide a protectivebarrier which will inhibit the diffusion of released Ni. [166] Anoverall protective polymer surface film may ensure outstand-ing corrosion resistance and biocompatibility. These findingsare in agreement with other studies which indicate that thecoating of nitinol by a polymeric film does in fact improvethe corrosion resistance.[155,159] Moreover, the surface modifi-cation of stents with polymers would be an excellent meansto achieve long-term local delivery of anti-thrombotic agent.Basically, a smooth metal surface is required to prevent theactivation of the clotting process by trapped corpuscularblood components. Coating the NiTi with polymers, such asPTFE-like polymer[155] using plasma, has been known toimprove the corrosion resistance. On the other hand, theimplantation of nitinol stents coated by polyurethane in rab-bit carotid arteries resulted in an increased inflammatoryresponse.[167]

Surface treatments may also be used to change the materialsurface topography, as shown by Kimura and Sohmura,[168]

who unfortunately demonstrated that the coating of NiTiwith bioceramics (TiN and CTiN) failed because of the crack-ing of the coating on a major deformation due to the memoryeffect. Therefore, as shown by many authors, the surfacemodification may induce the bulk material to alter in many

materials during the sterilisation process.[169171]Polymers are also good candidates to provide thin films to

coat the surface of metallic biomaterials to inhibit the leakageof potentially toxic elements and improve their biocompat-ibility, or merely for the required sterilisation of the device.For example, this last process was shown to be beneficial inpreventing the degradation of implant materials. The sterili-sation by gamma-irradiation of polyethylene showed no sur-face oxidative degradation after 16 years of implantation.[137]

In fact, the gamma-irradiation of polyethylene induced cross-linking, which is known to have a significant effect on boththe mechanical as well as the physical properties. Thierry etal.[172] and others[78] showed that the sterilisation could chemi-cally modify NiTi surface characteristics, however, the use ofthis technique remains uncertain, as the obtained results werenot reproducible. The coating of nitinol devices with poly-mers by means of surface coating reactors (i.e., radio-fre-quency or microwave plasma systems) may represent a verypromising alternative, although these new modified surfacesmust to be thoroughly characterised and extensively studied.

Despite their interesting properties, biomedical applica-tions thus far of SMPs have been limited. We do believe, how-ever, that these materials represent a valid choice in the newand exciting field of tissue engineering which has become a



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serious alternative to the regeneration (rather than replace-ment) of diseased tissues, even organs, that require the use ofinnovative scaffolds for initial cell attachment and tissuedevelopment.[173175] These scaffolds must be virtually bio-compatible, at times bioresorbable, and they must create thethree-dimensional network to which the cells will attach and

grow. An extensive summary of polymeric scaffolds was pre-sented by Agrawal and Ray,[176] in which various scaffoldsmade of synthetic biodegradable polymers such as poly(lacticacid)s (PLA), poly(glycolic acid) (PGA) and their copolymers(PLGA)[177179] were investigated. PLA is considered scaffoldmaterial for the support of cell growth; however, it was foundthat this material was not chemically reactive enough. Toovercome this problem, many authors proposed surface mod-ification by introducing reactive groups.[174,180,181] Many otherpolymeric scaffolds have been developed for tissue engineer-ing applications such as breast reconstruction,[182] as well asthe replacement and regeneration of damaged bone[183] andcartilage.[184,185] For example, polyanhydrides have been usedas successful scaffolds for orthopaedic implants[186,187] andtyrosine-derived polycarbonates have produced interestingresults when used as scaffolds in tissue engineering. Asshown by Choueka et al.,[188] these polymers exhibited an inti-mate contact with bone. Hydrogels have been developed asscaffolding materials for use either in biomedical[189,190] or tis-sue engineering applications,[191] such as peripheral nerverepair, because of their appropriate mechanical properties, asshown by Kuo and Ma.[192]

In general, tissue engineering requires that synthetic mate-rials display carefully tailored bulk and surface properties,and are specifically designed to function as scaffolds to

promote tissue growth and organisation by providing athree-dimensional framework with characteristics that wel-come favourable cell responses. More specifically, we believethat SMPs can provide new challenges by exhibiting theappropriate and required matching of their mechanical andmicro-mechanical properties to those of hosting and sur-rounding cells and tissue.

6. Conclusions

This review of medical applications of SMMs is perhapsnot exhaustive, however, the objective was to show theirobvious potential in the field of medicine. Shape memoryceramics, in particular which are a new exciting class of mate-rials recently discovered and now being examined, have beenvoluntary emitted from this review, as their potential bio-medical applications remain unexplored. In the coming years,as biology and material sciences evolve, we will most cer-tainly witness true revolution in medicine. Challenging newconcepts in conventional vascular surgery have begun in thefield of endovascular surgery, and minimally invasive laparo-scopy surgical interventions are now being combined withmagnetic resonance imaging to push the science beyond theexisting medical frontiers. New horizons must been opened,

and clinicians, scientists and industrialists must quickly andtruly work in close collaboration, as mastering such complexproblems necessarily requires a multidisciplinary approach.As a result, numerous applications have been considered andmany more are envisaged. This is undoubtedly the perspec-tive by which the development of SMMs must be regarded

and analysed. Because of their revolutionary properties, thesealloys have been the stimulus for the most audacious applica-tions since the 70's and have broken more than one some sci-entific barrier. However, as we deepen our knowledge, ourcriticism must become more rigorous. We must learn frompast experience and adopt a more rational, and less emo-tional, approach if we are to face and overcome tomorrow'stechnological challenges.

Received: June 25, 2001Final version: October 23, 2001

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