Shape Memory Materials for Biomedical Applications

Shape Memory Materials
for Biomedical Applications
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By Fatiha El Feninat, Gaetan Laroche, Michel Fiset,andDiego 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 offthe-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-
±
[*] 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
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Mantovani et al./Shape Memory Materials for Biomedical Applications
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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 Compi›gne, France.
Then, he obtained a Ph.D. from Laval University in 1998 and a D.Sc. from the UniversitØ de Technologie
de Compi›gne 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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Mantovani et al./Shape Memory Materials for Biomedical Applications
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.
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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l 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] )ordo
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
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.
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3. Shape Memory Polymers
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 (T g ) characterises
polymers, making them unique in contrast to other materials
such as metals or ceramics. However, polymers display different
states depending on the temperature range within a
few degrees of T g . 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 T g and return
them to their original shape by heating the polymers to higher
temperature than T g . 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 T g 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.
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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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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
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/cm 2 ) which
is lower than that of metal alloys between 147 and 294 MPa
(1500 and 3000 kg f/cm 2 ). 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
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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.
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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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 biomaterials
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-
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Mantovani et al./Shape Memory Materials for Biomedical Applications
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.
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 TiO 2 on the surface of the alloy
which may act a barrier against further Ni diffusion. TrØpanier
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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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,
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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