Recent insights into the biomedical applications of shape-memory polymers

Review

Recent Insights Into the BiomedicalApplications of Shape-memory Polymers

Maria C. Serrano, Guillermo A. Ameer*

Shape-memory polymers (SMP) are versatile stimuli-responsive materials that can switch,upon stimulation, from a temporary to a permanent shape. This advanced functionality makesSMP suitable and promising materials for diverse technological applications, including thefabrication of smart biomedical devices. In thispaper, advances in the design of SMP are dis-cussed, with emphasis on materials investigatedfor medical applications. Future directions necess-ary to bring SMP closer to their clinical applicationare also highlighted.

1. Introduction

Shape-memory polymers (SMP) are polymeric materials

that have the ability to switch from a temporary to a

permanent shape due to an external stimulation. The

temporary shapes are stable until the appropriate stimulus

(i.e. shape memory-driving stimulus) is applied to the

material to induce the recovery of the permanent, original

shape.[1] The acquisition of shape-memory properties is a

combination of both a suitable polymer network architec-

ture and a tailored processing and programming techno-

logy, rather than an intrinsic property.[2] The first SMP,

polynorbornene, was developed by CdF Chimie Company

(France) in 1984.[3] One year later, this material was

Prof. G. A. AmeerChemistry of Life Processes Institute, Evanston, Illinois 60208,USAE-mail: [email protected]. M. C. SerranoInstituto de Ciencia de Materiales de Madrid, Consejo Superior deInvestigaciones Cientıficas, Cantoblanco, Madrid 28049, SpainProf. G. A. AmeerBiomedical Engineering Department, Northwestern University,Evanston, Illinois 60208, USAInstitute for BioNanotechnology in Medicine, NorthwesternUniversity, Chicago, Illinois 60611, USADivision of Vascular Surgery, Feinberg School of Medicine,Northwestern University, Chicago, Illinois 60611, USA

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commercialized by Nippon Zeon Company (Japan) under

the trade name of Norsorex.[4] A few more commercial

SMP came later, including Kurare TP-301 by Kurare

Corporation (Japan) and Asmer by Asahi Company

(Japan).[5] Polyurethane-based SMP developed by

Mitsubishi Heavy Industries[6] and others have been the

most relevant SMP commercialized for the past two

decades.

Shape-memory research was first built on the thermally-

induced dual-shape effect, where heat is directly driving the

shape change through a transition temperature (Ttrans) that

could be a melting temperature or a glass transition

temperature.[1] Melting temperatures are generally pre-

ferred over glass transitions as they induce a sharper

transition that is easier to predict and control. The heat-

induced shape-memory effect (SME) can also be indirectly

triggered by diverse stimuli, ranging from IR-light irradia-

tion,[7] electrical stimulation,[8] exposure to alternating

magnetic fields,[9,10] or immersion in water.[11] Further

investigation has also led to the synthesis of polymers with

a light-induced SME that is independent of tempera-

ture.[12,13] Additionally, and depending on the SME-driving

stimulus and the desired application, SMP can be triggered

by direct or indirect contact, the latter when remote

actuation is pursued. SME is conventionally quantified in

dynamic mechanical experiments in order to determine the

strain fixity rate (Rf), the strain recovery rate (Rr), and the

switching temperature for those thermally-induced (Ttrans),

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Guillermo A. Ameer, a native of Panama City,Panama, is Professor of Biomedical Engineeringand Surgery at Northwestern University. Hereceived his PhD in Chemical and BiomedicalEngineering from the Massachusetts Instituteof Technology. Dr. Ameer’s research interestsinclude biomaterials, tissue engineering, andbio/nanotechnology for improved therapeuticsand diagnostics. He has co-authored over100 peer-reviewed publications, conferenceabstracts and book chapters, 27 patents issuedand pending, and has co-founded severalmedical devices companies.

Marıa C. Serrano received her PhD in Biochem-istry and Molecular Biology from the UniversidadComplutense de Madrid in 2006 (Spain). After apostdoctoral training period in Dr Ameer’sresearch laboratory for over 2 years, she isnow a postdoctoral fellow Juan de la Cierva inthe Bioinspired Materials Group leaded by Pro-fessor del Monte in the Instituto de Ciencia deMateriales de Madrid (ICMM-CSIC). Her researchinterests are focused on biomaterials for cardi-ovascular, bone and neural tissue regeneration.

Figure 1. Example of a stress–strain-temperature diagram for athermoplastic SMP with thermally-induced SME. Reproducedwith permission.[60] Copyright 2011, American Chemical Society.

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M. C. Serrano, G. A. Ameer

all these parameters that define the particular SME of a

concrete material (Figure 1).[14]

From a practical point of view, SMP are considered

versatile stimuli-sensitive polymers,[15] with advanced

functionalities that make them suitable for diverse

applications such as self-deployable sun-sails or antenna

in spacecraft, wrinkle free fabrics, morphing wing struc-

tures, cell phones with active disassembly when obsolete,

and heat-shrinkable tubes for electric isolation or films for

packing.[16–19] For instance, polyurethanes have been

extensively explored for the development of materials

with tunable responsiveness and even patented for their

use as threads in fabrics to increase their crease resis-

tance.[20,21] More recently, SMP are being introduced in a

variety of new applications such as microfoldable vehicles

and microtags.[22]

In this article, the design of SMP will be discussed

from a biomedical perspective, with emphasis on those

materials with potential for medical applications.

Future directions necessary to bring these materials closer

to their clinical application will be also highlighted. For

further details on shape-memory composites, materials

with self-healing characteristics, and stimuli-responsive

systems not included herein, readers are referred else-

where.[23–39]

2. Introducing the Shape-memory Effect IntoMaterials

Since its discovery in alloys in 1932 by Chang and Read,[40]

the SME has been extensively investigated in metal alloys

for its potential use in medicine.[41] This phenomenon was

later observed in polymers,[42,43] thus introducing a variety

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of materials with stimuli responsiveness that represented a

cheaper and more efficient alternative to established shape-

memory alloys. More recently, the synthesis of SMP has

found inspiration in biological substances, as naturally

occurring bile acids have been used to fabricate amorphous,

thermoplastic polyesters with shape-memory proper-

ties.[44,45] Interestingly, these bioinspired polymers dis-

played rubber-like elasticity, glass transitions close to body

temperature, high strains at low temperatures, and low

systemic toxicity. Biodegradable polymers synthesized

by coupling amino acids and a-hydoxy acids, such as

polydepsipeptides, with poly(e-caprolactone) have also

demonstrated interesting shape-memory properties and

promise for biomedical applications.[46,47]

Shape-memory properties have also been incorporated

into polymer composites,[48–50] thus resulting in materials

that can generally recover from relatively large mechanical

strains by combining the advanced functionality of

stimuli-responsiveness with the benefits of using particles

embedded in the polymer network.[51] Five major objectives

are pursued when designing SMP composites: improving

shape recovery stress and mechanical properties,

speeding up shape recovery by increasing thermal con-

ductivity, fabricating novel formulations, tuning particular

properties in existing SMP, and designing materials with

additional responsiveness to electricity, magnetic fields,

light, or moisture.[27] For instance, Mohr et al. introduced

magnetic nanoparticles in thermoplastic polymers to

develop SMP composites able to be actuated by inductive

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heating slightly above body temperature in an alternating

magnetic field.[9]

3. Unraveling the Shape-memory Effectin Polymers

SMP contain actively moving polymer networks (i.e.

able to perform movements by themselves)[1] in which

the permanent shape is determined by netpoints that are

connected with stimuli-sensitive molecular switches.[52] In

general terms, SME requires three major stages: processing,

programming, and recovery. Conventionally, the polymer

network is formed into the initial, permanent shape.

Afterwards, programming leads to the deformation of

the polymer network into the temporary, fixed shape by the

action of an external stress. Finally, upon application of

the appropriate external stimulus, the polymer recovers its

original shape.[1] In these networks, a certain orientation of

the chain segments must be permitted in order to obtain

deformation when a stress is externally applied. Cross-

linking of either chemical or physical nature is responsible

for controlling the shape transitions in these materials.

When physical crosslinking is involved, domains with the

Figure 2. Scheme of thermally-induced shape-memory properties dsimplification, switch structures have been represented as diamondtemporary to a permanent shape is controlled by the transition tem2011, John Wiley and Sons.

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Macromol. Biosci. 2012, DOI: 10.1



highest thermal transition are conventionally the net-

points (hard domains) while the chain segments act as

switching domains.[2] By forming additional reversible

crosslinks driven by solidification, these molecular switch-

ing domains may fix the deformed temporary shape.

Figure 2 illustrates the shape memory properties of an

elastomeric SMP based on physical crosslinking. It is

believed that permanent shape recovery in SMP is mainly

lead by the entropic elasticity of the switching domains,[2]

although more complex, theoretical models are required to

interpret the behavior of some SMP.[2,53]

During the tailored processing and programming

required for the acquisition of the thermally-induced

shape-memory properties (also known as dual-shape

creation process) in elastomeric polymers, an external

stress is applied to the SMP in the amorphous state to

deform the material to a predetermined elongation em.

When cooling the material below the thermal transition

temperature Ttrans of the switching domains, these domains

solidify and form physical crosslinks. At this stage, these

additional physical crosslinks dominate the netpoints that

originally determine the permanent shape and then the

elongated shape is temporarily fixed. Reheating will drive

the recovery of the permanent shape.[2] On the basis of this

riven by physical crosslinking in citric acid-based elastomers. Fors and netpoints, as lines. As shown in the figure, transition from aperature of the material. Reproduced with permission.[77] Copyright

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one-way effect, further research has lead to the recent

development of triple-shape[54–56] and even quintuple

SMP.[57] Further details about suitable polymer network

architectures capable of a thermally-induced SME, as well

as strategies to obtain multifunctional SMP, are thoroughly

covered in recent reviews by Lendlein and coworkers.[1,2]

4. Designing Shape-memory Polymersfor Biomedical Use

SMP have emerged as an attractive and novel alternative to

conventional polymers, thus opening new opportunities

for innovation in the design of therapeutic strategies.

However, the peculiarities of specific biomedical applica-

tions introduce important restrictions in the design of SMP.

Some of the most relevant considerations, such as safety

requirements for actuation, biocompatibility, mechanical

properties, degradability, and sterilization capability, will

be further discussed in this section.

Firstly, the shape memory-driving stimulus needs to

meet safety requirements. In the particular case of

thermally-induced SMP, for instance, Ttrans should be in

the proximity of 37 8C. In this regard, diverse attempts have

been made to achieve successful shape recovery within a

safe temperature range. Choi et al. developed amorphous,

elastic and degradable block copolymer networks prepared

by photo-crosslinking of poly(rac-lactide)-b-poly(propylene

oxide)-b-poly(rac-lactide) dimethacrylate precursors with

Ttrans between 10 and 30 8C.[58] In a similar study, Zini et al.

fabricated bioresorbable (L-lactide-glycolide-trimethylene

carbonate) ter-polymers with glass transition temperatures

in the range of 38–42 8C when increasing the content in

L-lactide.[59] When considering other stimuli (IR, UV-light

irradiation, magnetic fields, etc.), similar safety concerns

apply in order to avoid damage to surrounding healthy

tissues. For example, Langer and coworkers designed SMP

containing cinnamic acid groups that were able to directly

respond to UV light illumination and recover their original

shape at ambient temperature.[12,13] However, the lower

strain-fixity rates obtained in these materials when

compared to thermo-responsive SMP might limit their

use for biomedical applications. As an attractive

alternative to UV radiation, thermally-induced SME indir-

ectly mediated by near infrared radiation could reduce the

risks associated with using high energy radiations.[1]

Another major consideration when designing SMP

for biomedical use is biocompatibility. The absence of

toxicity is a requirement in any biomedical context and an

extensive biocompatibility assessment, including both in

vitro cell culture experiments and in vivo studies in animal

models, must be performed. Significant progress has been

made in the past decades to this respect, thus providing a

wide repertoire of biocompatible SMP.[60–62] Neuss et al.




recently explored the behavior of L929 mouse fibroblasts

and mesothelial cells from human and rat when cultured

on shape-memory poly(e-caprolactone)dimethacrylate

networks for tissue engineering.[63] Cell adhesion, viability,

and proliferation were supported on these materials. The

authors further confirmed the differentiation of human

mesenchymal stem cells into osteoblasts and adipocytes on

these polymers and evaluated for the first time the effect

of the shape-memory actuation on cell cultures. Unfortu-

nately, significant reduction in cell number and detachment

of cell monolayers were detected after actuation at 54 8C for

10 s. Although no necrotic cells were observed in the culture,

a significant amount of cells were undergoing apoptosis due

to the mechanical forces created by the shape change and

the high temperatures required for actuation. These studies

pointed out the need to perform biocompatibility studies

to assess the usefulness of SMP. Migneco et al. synthesized

novel biocompatible polyesters, named as poly(glycerol-

dodecanoates), by esterification of glycerol and dodecane-

dioic acid in an equimolar ratio.[64] These polymers behaved

as stiff elastic-plastic materials at room temperature, while

showing a compliant non-linear elastic behavior at 37 8C.

Original shapes were recovered by heating the polymer at

temperatures equal or higher to 32 8C.

Besides the constraints of biocompatibility, tissue-

specific requirements must also be considered to ensure

the desired function in the target tissue. For instance, SMP

with potential application in cardiovascular tissue require

further compatibility studies with blood components in

order to avoid thrombogenicity issues. In these sense,

shape-memory polyurethanes such as MM-5520 have

demonstrated a reduced platelet adhesion compared to

regular polyurethanes, even when adsorption of certain

proteins was enhanced.[60] Adsorbed proteins on these

polymers were hypothesized to modify their structure and

subsequently mask RGD sequences needed for platelet

adhesion and activation.

Biodegradation is often a desirable characteristic

in biomedical applications. For instance, Nagata and

Yamamoto modified the degradation rate of photo-cross-

linked poly(e-caprolactone)-based SMP by adding pendant

coumarin groups and modulating the crosslinking degree of

the resulting polymers.[65] In a similar study, Kelch et al.

adjusted the hydrolytic degradation rate of SMP composed

of oligo[(e-hydroxycaproate)-co-glycolate]dimethacrylates

and butyl acrylate by modifying the glycolate and n-butyl

acrylate content.[66] However, tailoring the biodegradation

of polymers is not trivial, especially when trying to match

the formation rate of the native tissue.[67]

As most soft tissues in the body display an elastomeric

behavior, significant interest has been placed in the

design of elastomeric polymers.[68] Applying this concept

to SMP, Kelch et al. developed amorphous, elastic AB

copolymer networks by polymerizing acrylates and

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poly[(L-lactide)-ran-glycolide]dimethylacrylate using UV-

light.[69] In these studies, SMP with Ttrans varying from 9

to 45 8C were obtained depending on the choice of acrylate

monomer and the monomer ratio, with higher elasticity

than pure dimethylacrylate networks and potential to

show triple-shape functionality.

By controlling polymer composition and integrating

several single components to create multifunctional SMP,

additional properties can also be acquired and/or modu-

lated in SMP to benefit their biomedical application (e.g.,

permeability, electrical conductivity, mechanical proper-

ties, biodegradability, magnetic properties, transparency,

radio-opacity, etc).[2] For instance, Alteheld et al. described

amorphous and transparent copolyester-urethane net-

works with shape-memory properties and potential

applicability as devices for minimally invasive surgery

in ophthalmic applications.[70] Unfortunately, the Ttrans

(which varied from 48 to 66 8C depending on composition)

limited their biomedical use. More recent advances by

these authors have achieved a lower transition tempera-

ture range for these polymers (between 14 and 56 8C) by the

selection of the comonomer (e.g., p-dioxanone, diglycolide,

or e-caprolactone) and its content (wt%) without affecting

the elastic properties of the materials.[71] Finally, the effects

of standard sterilization methods on the SME must be

considered and assessed as these methods may modify the

switch mechanisms within the SMP.

5. Biomedical Applications of Shape-memoryPolymers

Since early attempts by Echigo et al. to occlude the cardiac

ductus arteriosus by using a thermally-activated SMP based

on polynorbornene,[72] significant experience has been

obtained in the design and application of SMP in biomedicine.

In this section, the most relevant advances in the biomedical

application of SMP are discussed, with special emphasis on

those works where evidence of functionality either in vitro or

in vivo has been obtained. Particularly, recent insights in the

use of SMP as drug delivery systems and medical devices

intended for minimally invasive surgery, including endo-

vascular clot removal, aneurysm occlusion, degradable

sutures, fasteners and removable stents, and orthodontic

appliances, are highlighted. All these approaches have been

summarized in Table 1. For further details about these and

other biomedical applications of SMP, readers are referred to

other comprehensive reviews.[28,39]

5.1. Drug Delivery Systems

Controlled drug delivery has been a major goal in the design

of smart materials for biomedical applications.[73] Neffe

et al. have recently developed degradable SMP networks





prepared by UV-curing oligo[(e-caprolactone)-co-glycolide]-

dimethacrylates precursors.[74] Ethacridine lactate and

enoxacin were loaded in the resulting polymer networks

by swelling and in situ incorporation as examples of

hydrophilic and hydrophobic test drugs, respectively. In

addition to achieving drug delivery and SME at relevant

temperatures (28–42 8C), further studies demonstrated the

accomplishment of three major requirements: mainte-

nance of shape-memory functionality after drug incorpora-

tion, diffusion-controlled release independent of polymer

biodegradation, and drug release profiles independent of

programming and recovery processes. The authors antici-

pated the potential use of this drug-releasing SMP for the

fabrication of ureter stents with bactericidal activity or

scaffolds for tissue engineering (Figure 3).

In a different approach, Nagahama et al. also used oligo(e-

caprolactone) by crosslinking with hexamethylene diiso-

cyanate to form SMP networks as interesting drug-eluting

polymers.[75] When loaded with theophylline (10 wt.-%),

the resulting SMP demonstrated a sustained release of the

compound for over a month in PBS at 37 8C, without initial

burst release. Aliphatic diisocyanates were also used by

Wischke et al. to create an amorphous copolyester urethane

network by crosslinking oligo[(rac-lactide)-co-glycolide]

with star-shaped tetrahydroxy telechelics.[76] The pre-

formed shape-memory networks were loaded with drugs

of different hydrophobicity (e.g., enoxacin, nitrofurantoin,

and ethacridine lactate) and demonstrated to maintain

shape-memory properties while acquiring drug delivery

abilities. A predictable controlled release of�90% of loaded

drug in 80 d was observed.

In our laboratory, we have recently developed a new class

of citric acid-based elastomers with shape-memory proper-

ties and capable of eluting drugs.[77] In these polymeric

materials, the SME is achieved with the choice of aliphatic

diol and the hydroxyl-to-carboxyl mole ratio during the

synthesis step. Particularly, the use of a hydrophobic diol,

such as 1,12-dodecanediol, and a small increase in the

hydroxyl-to-carboxyl mole ratio versus equimolar compo-

sitions (e.g., 4:3 versus 1:1) induced the formation

of hydrophobic prepolymer microdomains within the

elastomeric crosslinked network that induced and con-

trolled the shape memory properties by physical cross-

linking. When loading small hydrophobic compounds

in these poly(diol-co-citrates), a temperature-dependent

and slow release was observed. The mild operating

temperatures described for these materials support their

use for biomedical applications.

5.2. Medical Devices for Minimally Invasive Surgery

Technological advances in the past decades have led to an

increase in minimally invasive procedures in an attempt to

reduce complications of surgical interventions and post-

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Table 1. Shape-memory polymers (SMPs) explored for biomedical applications.

Authors Chemical

composition

Form Application Characteristics In vivo

studies

Highlighted results Ref.

Nagahama et al. e-CLþHMD Polymer network

Films

Drug delivery Biodegradable – Actuation at 37–42 8C [75]

Preserved shape-memory

after loading

Sustained release for 1 month

(no burst release)

Neffe et al. Oligo

(caprolactone-

co-glycolide)

dimethacrylates

Polymer network Drug delivery UV-cured – Actuation at 28–42 8C [74]

Biodegradable Diffusion-controlled release

independent from polymer

degradation and shape

properties use as bactericide

ureter stents

Serrano et al. Poly(diol-

co-citrate)

Polymer network

Films/sponges

Drug delivery Elastomeric

Biodegradable

Biocompatible

– Actuation at 37 8C

Temperature-controlled

release

[77]

Wischke et al. Oligo

(caprolactone-

co-glycolide)

dimethacrylate

Polymer network Drug delivery Biodegradable – Actuation at 23–52 8C [29]

Comparison of drug loading

techniques

More controlled loading and

extended release for drug

loading prior crosslinking

Wischke et al. Oligo(lactide-

co-glycolide)þaliphatic

diisocyanate

Polymer network

Films

Drug delivery Amorphous

Polyester urethane

Biodegradable

– Actuation at 34.5 8C (wet) or

47 8C (dry)

Preserved shape-memory

after loading

Sustained release of about

90% in 80 d

[76]

Hartman et al. PUþNiTi Electromechanical

microactuator

Clot removal – Rabbit Partial (2/5) or complete (2/5) [83]

blood flow restoration

Maitland et al. PU Microactuators (coil,

umbrella,

microgripper)

Clot removal Laser-activated – Actuation at 65–85 8C [79]

Indocyanine-doped Applicability demonstrated

in vitro

Small et al. PUþNiTi Electromechanical

microactuator

Clot removal Electro-resistive

Heat-activated

– Applicability demonstrated

in vitro

[30]

Local damage in close areas

Hampikian et al. PU (Calomer) Composite coil Aneurysm

occlusion

þ3% tantalum filler – Actuation at 32–35 8C [90]

Applicability demonstrated

in vitro

Visible by conventional

imaging

Metcalfe et al. PU CHEM foam Aneurysm

occlusion

Self-deployable

Biocompatible

Non-muagenic

Canine Successful occlusion of

carotid aneurysm

Cellular invasion and

reendothelialization

Minimal inflammatory

reaction

[95]

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Table 1. (Continued)

Authors Chemical

composition


studies


Rodriguez et al. PU Foam composite Aneurysm

occlusion

þ4% tungsten filler – Improved radio-opacity

by X-ray

[98]

Applicability demonstrated

in vitro

Minimal inflammation

Small et al. – Foam-augmented

stent

Aneurysm

occlusion

– – Applicability for

embolization of non-necked

fusiform and

wide-necked aneurysms

[96]

Maitland et al. HMDþHPEDþ TEA Foam Aneurysm

occlusion

Laser-activated

þEpolightTM 4121

– Applicability demonstrated

in vitro

Full expansion in the absence

of flow

[97]

Echigo et al. Polynorbornene Ring Ductus arteriosus

occlusion

Heat-activated – Successful occlusion in a

mock-circulation test of

large arteries

[72]

Lendlein and

Langer

Oligo(caprolactone)-

diolþ oligo(dioxaxon-

oligo(dioxaxone)-

diolþdiisocyanates

Monofilament Sutures Biodegradable

Biocompatible

400% deformation

Rat Chorioallantoic membrane

test

Wound closure after

actuation at 41 8C

[99]

Zhang et al. Styrene-butadiene Polymer blend in

filaments

Sutures Elastomeric – Actuation at 56–57 8C [100]

þPCL Automatic knotting within

10 s at 70 8C

Baer et al. PU MM5520 Stent Intravascular

stents

Laser-activated – Actuation at 40–45 8C [120]

Full expansion in the absence

of flow

Bellin et al. PEGþPCL Polymer network Fasteners and

stents

Triple-shape

memory

– Actuation at 40 and 60 8C [54]

Transitions among shapes A,

B, and C

Shape changes not

unidirectional

Chen et al. Crosslinked

chitosan

Helical strip-based

stent

Intravascular

drug-eluting

stent

Self-deployable

Biodegradable

Biocompatible

Heparin-coated

Sirolimus-loaded

Rabbit Nearly linear sirolimus

release

Neointima hyperplasia

reduction

Reduced inflammatory

response

[119]

Chen et al. Crosslinked chitosan

þethylene glycol

diglycidyl ether

Helical blend stent Intravascular

stent

Self-deployable

Biodegradable

Rabbit Full stent expansion in 150 s

100% patency, neither

migration nor thrombus

formation after 24 h

[118]

Xue et al. PCLþ PHBV Stent Intravascular

stents

Biocompatible – Self-expansion at 37 8C in 25 s [114]

Tm� 39 8C

and 142 8C

Yakacki et al. Butyl acrylateþPEGdimetracrylate

Perforated or solid

stents

Intravascular

stents

Elastomeric

Tg� 50 8C

– Higher crosslinking drives

faster recovery

Stent perforation initiates

sooner recovery

[105]


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Table 1. (Continued)

Authors Chemical

composition


studies


Lendlein and

Langer

Diverse composition Self-expanding

implant

Gastrointestinal

or urogenital

device

Diverse stimuli for

actuation

– Promise for curbing appetite

in obesity

[121]

or drug-delivery in other

pathologies

Patent

Marco Diverse composition Self-inflating

implant

Gastrointestinal

device

Actuated by acidic

pH or at 3.7 8C

– Promise for curbing appetite [122]

Patent

Mather et al. Diverse composition Ligatures, brackets,

modules, appliances

Orthodontic

therapy

Diverse stimuli for

actuation

– Promise to secure arch wire

to brackets, self-ligating

brackets, SMP-coated wire

springs to

display human teeth

[124]

Patent

Nakasima et al. Polynorbornene Appliances Orthodontic

therapy

Heat-activated – Promise to displace human

teeth

[123]

e-CL, oligo(e-caprolactone); HMD, hexamethylene diisocyanate; HPED, hydroxypropyl ethylenediamine; NiTi, nitinol (nickel-titanium

alloy); PCL, poly(e-caprolactone); PEG, poly(ethylene glycol); PHBV, poly(hydroxybutyrate-co-hydroxyvalerate); PU, polyurethane; TEA,

triethanolamine.

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surgery costs.[78] By using the dual-shape properties of

SMP, implants could be potentially delivered to the

desired target in a compressed, temporary shape and then

allowed to acquire the functional, permanent shape once

set in place and only after application of the appropriate

stimulus.[1] Metallic shape-memory alloys such as nitinol

(Ni–Ti alloy) are already used as cardiovascular stents,

guide wires, and orthodontic wires.[41] Unfortunately, these

alloys display important limitations, such as a limited

range of mechanical deformation (up to 8%) and a time-

consuming programming often with temperatures over

several hundreds of degrees Celsius,[14] thus opening new

opportunities for improvement by using SMP.

5.2.1. Microactuators for Endovascular Clot Removal

In the USA stroke is the primary cause of long-term

disability, with �730 000 cases annually. Their treatment

and rehabilitation costs exceed $40 billion per year.[79]

Intravenous recombinant tissue plasminogen activator

(tPA) is the only therapy currently approved for the clinical

treatment of acute ischemic stroke. Unfortunately, positive

outcomes are linked to the early administration of tPA (i.e.

within 3 h of the onset of symptoms), increasing the risk of

intracranial hemorrhage outside of this window.[80] In this

context, the design of microdevices to enable clot removal

has recently attracted significant attention in minimally

invasive surgery as an alternative to conventional clot-

dissolving drug treatments. However, critical engineering




of both the polymer and the resulting device is required to

satisfy actuation and clot removal under physiological

pressure and flow conditions.[80,81] Maitland and coworkers

designed an electromechanical microactuator composed of

a SMP and shape memory nitinol to remove stroke-causing

thrombus in brain blood vessels.[82] After delivery through a

catheter and penetration of the clot in a straight rod shape,

the device transformed to a corkscrew shape when actuated

with electro-resistive heating caused by an electrical

current that allowed clot grabbing and extraction. The

authors demonstrated the applicability of this prototype in

a water-filled silicone neurovascular model and found

potential thermal damage only localized in artery wall

areas adjacent to the device. When these endovascular

actuators were tested in vivo for the extraction of induced

thrombus that occluded the common carotid artery in

rabbits,[83] in four out of five cases partial or complete blood

flow restoration was confirmed by angiography. These

authors also reported on the design of optically-actuated

urethane-based SMP for the removal of neurovascular

occlusions causing ischemic strokes.[84] In an alternative

approach, this research group described a novel SMP

actuated by diode laser heating (A¼ 800 nm) as a

microactuator for endovascular thrombus removal.[85,86]

In vitro studies in a thrombotic vascular occlusion model

demonstrated the feasibility of its clinical use versus

conventional clot-dissolving drugs such as tPA. To guaran-

tee successful deployment, the microactuator was doped

with indocyanine green dye in order to increase adsorption

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Figure 3. Demonstration of the temperature-induced positioningof a shape-memory ureter stent made of UV-cured oligo[(e-caprolactone)-co-glycolide]dimethacrylates. Reproduced withpermission.[74] Copyright 2009, John Wiley and Sons.


www.mbs-journal.de

of laser light and delivered in its secondary straight rod

form. Further laser heating induced change to its primary

corkscrew shape and the subsequent capture of the

thrombus for posterior removal from the blood vessel.

5.2.2. Aneurysm Occlusion

It is estimated that two to six percent of the world

population is affected by intracranial aneurysms.[87] More

recent estimations anticipate that up to one out of 15 people

in the USA will develop a brain aneurysm during their

lifetime.[88] Even in industrialized countries, about half of

these cases will result in death and survivors will have a

50% probability of suffering from permanent neurological

damage. Nowadays, novel endovascular treatments such as

aneurysm embolization with balloon-assisted coils, flow-

diversion devices, open- and closed-cell stents, and embolic

materials (e.g., Guglielmi detachable coils, approved in 1995

by the FDA)[89] have become promising alternatives to

traditional invasive surgical techniques. Most of these

strategies rely on the total occlusion of the aneurysm by the

formation of a dense interconnected thrombus matrix and

scar tissue in the neck of the aneurysm.[90] Unfortunately,

treated aneurysms may re-canalize due to unorganized

thrombus, limited fibrous scar tissue and lack of endo-

thelialization in the entrance of the aneurysm.[91,92] Other

limitations such as intraprocedural rupture, occlusions

inferior to 50%, coil compaction, shifting, and migration of

the coil out of the aneurysm could also cause aneurysm





re-growth, rupture or stroke with damaging consequences

to the patients.[89]

Bioactive aneurysm coils have demonstrated promise,

versus traditional platinum-only coils, to facilitate perma-

nent aneurysm occlusion.[93,94] In 2003, Metcalfe et al.

tested cold hibernated elastic memory (CHEM) foams for

the treatment of lateral wall aneurysms in carotid arteries

by using an in vivo model in dogs.[95] These materials were

fabricated from polyurethane-based SMP in the form of

open cellular structures (foams) by Mitsubishi Heavy

Industry and Jet Propulsion Laboratory (California Institute

of Technology, Pasadena, CA, USA) and behaved as self-

deployable structures by means of the shape-memory

properties and the elastic recovery of the foam. After

confirming absence of both cytotoxic effects on L929

fibroblast cultures and mutagenicity with strains of

Salmonella typhimurium, in vivo aneurysm embolization

showed satisfactory occlusion with improved angiographic

results at 3 weeks (Figure 4). Furthermore, the inherent

porosity of these foams allowed for cellular invasion and

induced neointima formation. Unfortunately, residual

aneurysm necks and recurrences were observed when

incomplete lumen filling occurred. In a different study,

Hampikian et al. also reported the feasibility of using

a polyurethane-based polymer to replace platinum in

aneurysm coils.[90] In these studies, coils made of a shape-

memory block co-polymer named CalomerTM (The Polymer

Technology Group, Inc., CA, USA) were fabricated and

deployed inside a simulated aneurysm model (Figure 5). The

authors also introduced up to 3% tantalum metal filler in

the composition of these SMP fiber coils and observed that

the resulting composite material was opaque by using

conventional medical imaging techniques. In a different

approach, Small et al. reported on the development of a

prototype device based on SMP for the endovascular

treatment of nonnecked fusiform aneurysms.[96] The

actuator was composed of a stent augmented with

expandable foam, where the first was responsible for

maintaining the arterial lumen open and the foam expected

to embolize the aneurysms. This device demonstrated

efficacy in the embolization of fusiform aneurysms when

tested in an in vitro model. These authors fabricated

another SMP foam device for aneurysm occlusion by

crosslinking hexamethylene diisocyanate, hydroxypropyl

ethylenediamine, and triethanolamine.[97] The incorpora-

tion of the dye EpolightTM 4121 during processing

allowed for laser deployment of the prototype in an

in vitro basilar aneurysm model. Interestingly, when the

foam was deployed in the absence of flow, full expansion

with overheating at the aneurysm wall was detected.

However, deployment in low flow conditions (diastolic)

resulted in slow, full expansion with minimal temperature

increase. Incomplete foam expansion was detected under

conditions of high flow (systolic). More recently, these

002/mabi.201200097



Figure 4. Macroscopic and microscopic appearance of healed aneurysms after embolization with CHEM sponges in the lateral wall ofcommon carotid arteries at 3 and 12 weeks. (A–C) Aneurysms with a small crescent of neocanalization (arrows). (D–I) Aneurysms completelyhealed. Images of aneurysm necks (A, D, G) and axial sections (B, E, H). Microscopic views of axial sections (C,F,I). Reproduced withpermission.[95] Copyright 2003, Elsevier.

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authors published on the opacification of a similar

polyurethane-based SMP foam by incorporation of a

tungsten particulate filler (4 vol.-%).[98] This SMP composite

foams demonstrated improved radio-opacity in situ by

X-ray through a pig skull while maintaining their original

Figure 5. Deployment of two SMP coils for aneurysm occlusion under s2006, Elsevier.




mechanical, physical, and chemical properties. Additional

implantation studies confirmed minimal inflammation

caused by these tungsten-doped SMP. Further experimental

and computational simulation studies by Maitland and

coworkers emphasized the interest in SMP polyurethane-

imulated flow conditions. Reproduced with permission.[90] Copyright

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based foams as safe treatments for intracranial saccular

aneurysms in humans.[89] In these studies, oversized

shape memory foams were predicted as a better filling

for the entire aneurysm cavity while causing stresses below

those that induce rupture of aneurysm walls.

5.2.3. Degradable Sutures

Lendlein and Langer used the SME to develop smart

degradable sutures for biomedical applications.[99] Linear,

phase-segregated multiblock copolymers were synthesized

by ring-opening polymerization of macrodiols such as

oligo(e-caprolactone)diol and oligo(p-dioxanone)diol and

coupling with 2,2(4),4-trimethylhexanediisocyanate. Elon-

gations at break of 1 000% were obtained in the resulting

SMP, thus allowing deformations up to 400% between

permanent and temporary shapes. As the authors pointed

out, this finding represented a significant improvement

over traditional Ni–Ti alloys, where maximum deforma-

tions of only 8% could be achieved. Good tissue compat-

ibility of these materials was also confirmed when

investigated by using a chorioallantoic membrane test.

The authors further explored the use of these SMP as smart

degradable sutures by extruding the material in the shape

of monofilaments and using it to close an abdominal wound

involving muscle and skin tissue in a rat model. Fibers were

first stretched 200% of their original length and then set

in place. Subsequent thermal actuation at 41 8C allowed

recovery of the permanent shape, thus leading to wound

closure with an optimum force (Figure 6). In a different

approach, Zhang et al. developed a novel blend of styrene-

butadiene-styrene tri-block copolymer and poly(e-capro-

lactone) that was able to automatically knot within 10 s

in a water bath at 70 8C.[100] Although transition tempera-

ture adjustment for biomedical requirements is needed,

these shape-memory blends show promise for their use as

thermo-sensitive sutures.

5.2.4. Fasteners and Removable Stents

Since the first clinical application of a metallic stent in

1986 by Sigwart et al.,[101] intensive research has been

performed to improve the significant limitations of

these intravascular devices (e.g., limited flexibility, local

stiffness mismatch, compliance mismatch, thrombo-

Figure 6. In vivo application of a degradable shape-memory suture forthe temperature-induced shrinkage of the fiber suture (left to right). Refor the Advancement of Science.





genicity, impaired reendothelialization, etc.).[102] A com-

prehensive review of the recent progress in coronary stents

from a materials perspective can be found elsewhere.[103]

In this search for alternative materials in stent design,

the characteristic controlled shape change of SMP has

made them attractive candidates for the development of

a new generation of vascular stents.[104] Valuable advan-

tages of these devices might include their capability to

anchor devices during intravascular intervention by

expansion of their diameter,[105] as well as their ability to

be replaced if inadequately located by softening and

decreasing their diameter. Moreover, elastic and visco-

elastic memory in biodegradable stents have been pursued

as a pivotal property for the fabrication of self-expandable

stents.[106,107] For the new generation of stents with drug-

eluting capabilities,[108] recent advances in the develop-

ment of SMP with drug delivery abilities could benefit

stent therapy.[76,77,109,110]

Based on results from preliminary studies,[111] Yakacki

et al. evaluated the storage, deployment, and deformation

of several SMP-based stents synthesized by photo-

polymerization of tert-butyl acrylate and poly(ethylene

glycol) dimethacrylate to repair large blood vessels (4–5 cm

in diameter during aneurysms) (Figure 7).[105] The resulting

shape-memory polymeric networks showed Tg around

50 8C and rubbery modulus ranging from 1.5 to 11.5 MPa.

In these studies, the thermo-mechanical and recovery

properties of the stents were tailored by independently

varying the glass transition and rubbery modulus of

the SMP. Additionally, the crosslinking degree was also

demonstrated to significantly influence the recovery

properties of the stent, with higher crosslinking densities

driving faster recoveries. These authors further explored

the use of methyl methacrylate and poly(ethylene glycol)

dimethacrylate to develop strong, biocompatible SMP

networks for potential biomedical applications.[112]

Bellin et al. first described thermal triple-shape materials

as intelligent fasteners and removable stents.[54] These

polymer networks, composed of polyethylene glycol and

polycaprolactone, were able to experience three different

shapes (A, B, and C) controlled by two different melting

temperatures (Ttrans,B and Ttrans,A). An interesting feature of

these materials was their ability to be converted first from a

wound healing. An appropriate closure of the wound was achieved byproduced with permission.[99] Copyright 2002, American Association

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compressed shape A, which would facilitate their implan-

tation, to an expanded shape B to perform their expected

function, and finally to a contracted shape C, which would

assist the removal of the device if needed. Temperatures of

40 and 60 8C were required for inducing the transition from

shapes A to B and B to C, respectively. Although the

versatility of these triple-shape materials is promising,

transition temperatures need to be reduced in order to avoid

damage to functional tissues located around the implanted

device. Using the same precursors (i.e. polycaprolactone

and poly(ethylene glycol)) but 5-cinnamoyloxyisophthalic

acid as a chain extender, Nagata and Inaki recently

developed photocurable and biodegradable copolymers

with shape memory properties in the range of 37–60 8Cthat also showed promise for biomedical use.[113] In

a different study, Xue et al. also fabricated biodegradable

self-expandable stents based on block copolymers consist-

ing of hyperbranched three-arm poly(e-caprolactone)

as switching segment, but polyester poly[(R)-3-hydroxy-

butyrate-co-(R)-3-hydroxyvalerate] (PHBV) as hard seg-

ment.[114] These polymers demonstrated shape-memory

properties with two different Tm (39–40 8C and 142 8C) and

good biocompatibility when tested in vitro with L929

fibroblasts. When further investigated, stents containing

25 wt.-% of PHBV experienced complete self-expansion

at 37 8C within only 25 s, significantly improving the

expansion time of previously reported biodegradable self-

expandable stents made of poly(L-lactide) (Igaki-Tamai

stent, 20 min at 37 8C;[115] Meng et al., doubled diameter in

5 min at 37 8C[116]), poly(lactide-co-glycolide),[107] and

chitosan.[117]

In a different study, Chen et al. reported on the

fabrication of a novel biodegradable helical stent composed

of chitosan films crosslinked with ethylene glycol diglycidyl

ether and displaying shape-memory properties.[118] Blend-

ing with glycerol and poly(ethylene oxide) improved the

Figure 7. Shape recovery of an SMP stent delivered via an 18Fr.catheter into a 22 mm id glass tube containing water at 37 8C.Black rings were drawn to facilitate deployment visualization.Reproduced with permission.[105] Copyright 2007, Elsevier.




polymer ductility and the compressive strength of the

resulting stent. Complete expansion of the stent was

achieved by hydration after 150 s. Preliminary deployment

studies in the abdominal aorta of a rabbit in vivo model

demonstrated 100% patency and neither stent migration

nor thrombus formation in the explanted vessel 24 h

after implantation. In a more recent study, these authors

developed an alternative biodegradable version of a drug-

eluting stent made of chitosan-based strips fixed by an

epoxy compound and able to release the antiproliferative

drug sirolimus.[119] The resulting stent displayed shape-

memory properties and a nearly linear sustained release

of sirolimus. Further coating with heparin provided an

antithrombogenic surface. After confirming biocompat-

ibility with human foreskin fibroblasts and reduced platelet

adhesion to the stent, the released sirolimus was demon-

strated to arrest the cell cycle of smooth muscle cells. When

deployed in rabbit infrarenal abdominal aortas, a signifi-

cant reduction in neointima hyperplasia was observed,

while reducing macrophage infiltration and promoting

reendothelialization (Figure 8).

Finally, Baer et al. demonstrated the successful in vitro

deployment of a laser-activated SMP vascular stent made of

a thermoplastic polyurethane (MM5520, DiAPLEX Com-

pany, Ltd.).[120] When deployed in a water-filled mock artery

in vitro, the stents experienced incomplete expansion at the

physiological flow rate reported for the internal carotid

artery (180 ml �min�1), as convective cooling prevented

from correct photothermal actuation even at the maximum

laser power (8.6 W). However, when using endovascular

flow occlusion techniques regularly practiced in the clinic

(i.e., no flow conditions in the affected area), the stents

demonstrated satisfactory photothermal actuation and

complete expansion at lower laser powers (�8 W). The

shape recovery of these SMP-based materials was observed

to start at 40–45 8C, given the broad glass transition of the

soft phase in the original polyurethane (nominal Tg 55 8C).

5.2.5. Other Applications

The commercial use of SMP for biomedical applications

has achieved limited success to date. Some patents exist

reporting the use of SMP as biodegradable self-expanding

devices for curbing appetite.[121,122] In 1991, Nakasima et al.

envisioned the use of SMP based on polynorbornene to

displace human teeth in orthodontic therapy.[123] Mather

et al. recently patented fixed and removable orthodontic

appliances made of SMP and methods of making and using

those.[124] By using diverse chemical compositions (e.g.,

castable SMP, semicrystalline rubbers of crosslinked poly-

cyclooctene, thermoplastic polyurethanes, etc.), novel SMP-

based ligatures, self-ligating brackets, force modules,

torque modules, removable aligner appliances, arch wires,

and likes could be fabricated, thus providing improvements

to traditional orthodontic device materials.

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Figure 8. Photographs of a test stent after deployment in the rabbit infrarenal abdominal aorta (a) and patency test of the stent-implantedvessel at 4 weeks (b). Confocal fluorescence images show reendothelialization (c, top) and macrophage infiltration after stent implantation(c, bottom). Reproduced with permission.[119] Copyright 2009, Elsevier.


www.mbs-journal.de

6. Challenges and Future Perspectives

SMP present significant advantages when compared to

traditional shape-memory alloys, including lower density,

lightweight, lower cost of raw materials, lower cost of

fabrication and processing, and easy tailoring. Further-

more, the resulting materials have higher versatility in

shapes, higher recovery strains (>300%) and lower recovery

stresses (1–10 MPa). SMP also allow for the use of more

diverse stimuli for actuation, which could be remote, and

show ability to be converted on drug carriers. Moreover,

SMP are versatile to be combined with other materials to

form composites and blends for the acquisition of addi-

tional properties. Finally, their chemical stability, along

with biocompatibility and tunable biodegradability,

opens their use for biomedical applications, with a higher

potential for cheaper reuse and recycle. All these properties

have encouraged significant research on the use of SMP for

diverse biomedical applications. Particularly, as exten-

sively discussed in this article, minimally invasive surgery

may clearly benefit from SMP technology as it provides a

smart platform to deploy therapeutic devices through small

incisions and narrow conducts to reach the target in the

body. Although investigated for the fabrication of degrad-

able sutures or self-expanding stents, additional biomedical

applications for SMP could be further explored. For instance,

the design of ‘‘growth’’ stents[125] that could be deployed

in infant patients, whose blood vessels will grow after

implantation, could benefit from the progress in bio-

degradable SMP-based stents if designed as polymers with





the ability to be remodeled with the surrounding tissue.

Additionally, in the orthodontic practice, the application of

these actively moving materials show promise, as they

provide lighter materials and more constant forces that

may cause less pain to the patient, along with the esthetic

advantages that these materials offer (e.g., transparency,

colorable, and/or stain resistant). In some of these

applications, SMP with Tg slightly higher (e.g., 50 8C) would

be of interest, as they will resist hot beverages and

foods.[124]

Although promising, significant limitations still remain

when considering the long-term success of SMP in

biomedical applications. In the particular case of stenting,

for instance, larger radial strength is necessary to with-

stand vessel pulsation pressure at 37 8C, as well as broader

ranges of mechanical properties to completely fulfill the

vascular mechanical requirements (e.g., tensile stress

values of 0.069–1.17 MPa in different human vascular

conducts).[68] Hydration effects on material performance

should be addressed by tests in a physiological environ-

ment as the plasticization by water could significantly

affect network switching temperature at 37 8C and then

change polymer actuation.[76] Moreover, ageing after

implantation should also be carefully considered as it

can increase switching temperatures by more than

10 8C.[126] As the SME will occur under complex environ-

mental constraints generated by the surrounding tissues,

constitutive modeling studies might facilitate clinical

implementation of this technology by predicting impor-

tant limitations before clinical use.[127]

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The exploration of SMP in human trials is still rare and

their use in current clinical practice, negligible. For instance,

Pelissier et al. explored Polysoft1 patches for the surgical

repair of inguinal hernias allowing for reducing post-

operative complications and pain and shortening the

recovery time of the patients.[128,129] Although made of a

light monofilament polypropylene mesh, this patch con-

tained a recoil ring with shape memory properties to

facilitate the patch placement and spreading. The feasi-

bility of using this patch containing a memory coil is being

further investigated in humans.[130] In a different clinical

trial, SMP composites made of poly(lactide-co-e-caprolac-

tone) and b-tricalcium phosphate (chronOS Strips) are

currently under investigation as part of a synthetic bone

void filler.[131] The shape memory of these composites

facilitates site-specific placement as the strips conform the

specific peculiarities of the implant site of each patient.

Although diverse non-degradable thermally-induced

SMP are commercially available (e.g., thermoplastic and

thermoset polyurethanes DiAPLEX, Veriflex1, VerilyteTM,

VeritexTM, Tecoflex1, and TEMBO1, among others),[30]

none of these materials is available in medical grade

quality yet, thus limiting their translation in clinical

applications.

In summary, the main requirements for SMP envisioned

for biomedical use are: (i) actuation, preferentially remote,

within biologically safe ranges to avoid damage of

surrounding tissues, (ii) long-term stability that guarantee

durability of the outcome of the therapeutic procedure,

(iii) biocompatibility, (iv) compressed temporary shape to

facilitate minimally invasive deployment, (v) biodegrad-

ability by gradual erosion to avoid explantation, (vi) non-

toxicity, and (vii) non-immunogenicity. Multidisciplinary

research including efforts from chemists, physicians,

biologists, engineers, and clinicians will contribute to

significant advances in the biomedical use of SMP from

bench to bedside.

Acknowledgements: M. C. S. is greatly in debt with MINECO fora Juan de la Cierva fellowship.

Received: March 20, 2012; Revised: June 4, 2012; Publishedonline: DOI: 10.1002/mabi.201200097

Keywords: biomedical applications; minimally invasive surgery;poly(diol-co-citrates); polymers; shape-memory effect

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