CN 6162 ADVANCED POLYMERIC MATERIALS ASSIGNMENT 1 SHAPE MEMORY POLYMERS: A BRIEF OVERVIEW AND BIOMEDICAL APPLICATIONS SUBMITTED BY DEBIRUPA MITRA (A0123258)ii CONTENTS 1INTRODUCTION ............................................................................................................. 1 1.1Shape memory effect (SME) ....................................................................................... 1 1.2Shape memory polymers (SMP) ................................................................................. 2 1.3Characterisation of SME in polymers ......................................................................... 4 2Classification of SMPs ....................................................................................................... 5 2.1Classification based on polymer structure................................................................... 5 2.1.1Chemically cross-linked SMPs ..................................................................... 5 2.1.2Physically cross-linked SMPs ....................................................................... 6 2.2Classification based on external stimulus ................................................................... 8 3General mechanisms of SME in polymers ....................................................................... 12 3.1Dual state mechanism (DSM) ................................................................................... 13 3.2Dual component mechanism (DCM) ........................................................................ 14 3.3Partial Transition Mechanism (PTM)........................................................................ 16 4SMPs from a biomedical perspective ............................................................................... 17 4.1Design considerations in SMPs for biomedical applications .................................... 17 4.2Biomedical applications of SMPs ............................................................................. 18 4.2.1Drug delivery systems ................................................................................ 18 4.2.2Devices for minimally invasive surgery ..................................................... 21 5Conclusion ....................................................................................................................... 28 6References ........................................................................................................................ 29 iii LIST OF FIGURES Figure 1 One-way shape memory effect .............................................................................................. 2 Figure 2 Thermally induced SME in PTFE (I), PLA (II) and EVA (III). ............................................ 3 Figure 3 A typical thermo-mechanical shape response and the corresponding strain response .......... 4 Figure 4 Various molecular structures of SMPs .................................................................................. 5 Figure 5 The quintuple SME of poly(methyl methacrylate)/poly(ethylene glycol) ............................ 7 Figure 6 Light induced heating shape recovery of polyurethane SMP wire ........................................ 8 Figure 7 Synthesis of biodegradable multi-block polyester urethane .................................................. 9 Figure 8 Swellingshrinkage behaviour in ionic based hydrogel by changes in pH. ........................ 10 Figure 9 Retraction of polyurethane shape memory polymer stent in water. .................................... 10 Figure 10 Schematic illustration of the electro-triggered CNTs filled SMP ..................................... 11 Figure 11 Thermally induced shape recovery due to surface tension ................................................ 12 Figure 12 Basic working mechanisms for the heating-responsive SME ........................................... 13 Figure 13 The SME in silicone .......................................................................................................... 14 Figure 14 Thermo-responsive SME in EVA...................................................................................... 15 Figure 15 Concept of programming, shape recovery, and drug release ............................................ 19 Figure 16 Chemical Structure of Branched Oligo(-caprolactone) ................................................... 19 Figure 17 Molecular scheme of the polymer network of HD-polydiolcitrate elastomers ................. 20 Figure 18 Representative images illustrating the programming and recovery process. .................... 21 Figure 19 Temperature-controlled release kinetics of DCF from HD and EF polymers ................... 21 Figure 20 Schematic representation of SMP microactuator .............................................................. 22 Figure 21 Stent deployment ............................................................................................................... 23 Figure 22 Photographs exhibiting the self-expansion of the stent ..................................................... 24 Figure 23 CHEM processing cycle .................................................................................................... 25 Figure 24 Deployment of two SMP coils under simulated flow conditions ...................................... 25 Figure 25 In vivo application of a degradable shape-memory suture for wound healing. ................ 26 Figure 26 Schematic figures of the shape memory mechanism of polymer blends .......................... 27 Figure 27 An example for the recovery process of shape memory effect ......................................... 27 LIST OF ABBREVIATIONS EVA: Ethylene Vinyl Acetate IPN: Inter Penetrating Network PLA: Poly (Lactic Acid) PLGA: Poly (Lactic-co-Glycolic Acid) PTFE: Poly (tetrafluoroethylene) PCL: Poly (-caprolactone) PMMA: Poly (methyl methacrylate) PEG: Poly (ethylene glycol) PBS: Phosphate Buffered Saline SBS: Styrene-Butadiene-Styrene 1 1INTRODUCTION Materials science and technologyhas been one of the mostrapidlygrowing areas in the last century.Duringthistime,theworldhasseennumerousadvancedmaterialsoradvanced applications of various materials for use in almost every kind of industry; microelectronic and biomedical industries being two new industries which are heavily materials dependent as well asfastgrowing.Infact,advancesinmaterialshavealwayscharacterizedstagesofmankind development right from the stone age to the present age of polymers and composites. One of themostinterestingdiscoverieswasperhapsthediscoveryofShapememorymaterials. Shape memory materials (SMM) are those materials which can switch their shapes between a temporary shape and a permanent shape by the application and removal of some externally appliedstimulus.Possibly,thefirstshapememoryeffectwasobservedinGold-Cadmium alloy in the 1930s and since then these materials have been extensively investigated. Initially shape memory effects were being explored only in allows and ceramics and then in 1960s the first polymer reported to have a shape memory effect was a matrix of ethylene irradiated with gammaradiationwhichcouldmemorizeitsshape.Sincethen,Shape memory polymersor SMPsastheyarecalledhavebeeninvestigatedwidelyfortheirapplicationsinaerospace, electronics, textiles, biomedical and other fields. 1.1Shape memory effect (SME) Traditionally,SMEreferstowhatisknownas"onewayshapememoryeffect"i.e.,on applicationofastimulus,thepermanentshapeofamaterial(alsocalledthefixityphase) changes into a temporary phase which is retained as long as the stimulus is active. Oncethe stimulusisremoved,thefixityphaseisrecoveredfromthetemporaryphase.So,thereare essentially two steps in one-way SME: the "programming" step and the "recovery" step as shown in Figure 1. For example, if the external stimulus is temperature, the material changes fromitsfixitytotemporaryshapewhenheatedabovethetransitiontemperatureofthe material.So,thematerialissubjectedtosomekindofstrainduringtheprogrammingphase and the strain is recovered during the recovery phase. This is true for any SMM but the actual mechanisms by which the materials program and recover is different in alloys, ceramics and polymers.Therearematerialswhichalsoshow"multi-shapememoryeffect"i.e.,these materials can remember more than one shape. 2 Figure 1 One-way shape memory effect 1.2Shape memory polymers (SMP) Though the term SME was coined in the 1930s, polymers that can shrink in presence of heat or water have been known for ages. Polymers as materials are advantageous over alloys and ceramicsowingtotheireaseofprocessing,varietyoffunctionalitiespossessedbyawhole rangeofpolymersandcopolymers,easeofdesignandlowcost.Acomparisonbetween alloys,ceramicsandpolymersshowingSMEisshowninTable1.Thelargestrainrecovery observed in polymers is also a reason for choice of SMPs.The only drawback of polymers is itsweakmechanicalproperties;however,theirmechanicalstrengthcanbeincreasedbythe addition of fibers,fillers and nanoparticles. Table 1 Comparison between alloys, ceramics and polymer properties for use in SME 3 AmajorityoftheSMPsareactuallythermally-induced(externalstimulusistemperature), though some can be activated by other stimuli also as will be described later. This is because of the existence of the glass transition temperatureTg or the melt temperature Tm depending on whether the polymer is mostly amorphous or crystalline. Polymers can undergo relaxation oftheirchainsduetochangesintemperaturewhichismainlythereasonforitsthermally induced SME. The mechanisms will be described in more detail in. Figure 2 shows thermally induced SME in three very common engineering polymers. Figure 2 Thermally induced SME in PTFE (I), PLA (II) and EVA (III). (I) PTFE: (a) original shape; (b) after stretching at room temperature; and (cd) after gradually heating to 340 C in two steps (above the glasstransitiontemperatureandatthemeltingtemperature).(II)PLA:(a)originalshape;(b)after expansionathightemperatures;and(c)afterheatingforshaperecovery.(III)EVA:(a)originalstar shape; (b)afterexpansion into circular shape athigh temperatures; and (c)after heating for shape recovery. 4 1.3Characterisation of SME in polymers As mentioned before most polymers showing SME are thermally induced ones, so this report will mainlyfocus on that category; however others will be mentioned asand where needed. Ingeneral,therearenostandardwaysofcharacterizingalltypesofSMPs.Thermo-responsive SMPs can be characterised by temperature-programmed mechanical tests like the stress-strain and the bending tests just like their alloy counterparts. Microscopyanalysis can also reveal mechanisms in SMP.Stress-straintest:Thisisageneralfour-stepprocedurewhichisoftenusedtocharacterize SMEinpolymers.Firstthepolymerisheatedtoaboveitstransitiontemperatureandthen strain applied to deform it (the strain produced in this step is denoted by m). Then it is cooled downandwhenthetemporaryshapeisfixedthestressisremoved(theresidualstrainafter this step is u). Finally, if the polymer is heated again to above the transition temperature, it recovers its original shape (the strain after this is denoted p). The cycle is usually repeated to study the SME. A typical 3-axis diagram of stress-strain-temperature is shown below. Figure 3 A typical thermo-mechanical shape response and the corresponding strain response The parameters calculated are: Strain recovery % = {

} 100 (the ability of the polymer to return to its original shape) Strain fixity =

( the ability to hold the shape during switching) Bending test: This is similar to the above but here, the polymer is subjected to bending and theinitial(i)andfinalangles(f)ofdeformationaremeasured.Thisalsorecognizesthe polymer's ability to recover its shape.Bending recovery =

5 2Classification of SMPs SMPs can be broadly classified according to two different categories; one, on the basis of the polymer structure and the other based on type of external stimulus which induces the SME. 2.1Classification based on polymer structure The structure of a polymer depends on the type of cross-linking in the polymer. Based on the type of cross-linking, there may be the following types of SMPs described in the sub-sections below. Figure 4 shows the molecular structures of a SMP. Figure4VariousmolecularstructuresofSMPs.Astablenetworkandareversibleswitching transitionaretheprerequisitesfortheSMPstoshowSME.Thestablenetworkcanbemolecule entanglement, chemical cross-linking, crystallization, and IPN; the reversible switching transition can becrystallization-meltingtransition,vitrification-glasstransition,anisotropic-isotropictransition, reversible chemical cross-linking, and association-disassociation of supramolecular structures 2.1.1Chemically cross-linked SMPs TheseSMPscontaincovalentlycross-linkedpolymerchainsandthesecross-linksactasthe fixity phase. This means a permanent shape can be fixed by the activation of these cross-links 6 because a covalently cross-linked polymer chain cannot change its shape any further by chain relaxation.Thesecross-linkscanbeintroducedbyacross-linkingagentorthroughsome electromagnetic radiation. For example, the polymer can be heated in presence of a peroxide moleculewhichcancross-linkcertainpolymerchainsaboveaspecifictemperatureorthe polymer can be exposed to gamma or UV radiations in presence of a photo-initiator to cause cross-linking.Inthelattercase,theremustbefunctionalitiespresentinthesamemonomer which can becross-linked or there can be twoormore functional monomers or a functional monomer with an appropriate cross-linking agent.Anothertypeofchemicallycross-linkedSMPsareliquidcrystallinenetworksinwhich mesogens(moleculethatformsliquidcrystals)aregraftedontothepolymerchains.The SMEisobtainedwhenthemesogensinthepolymerbackboneundergophase transformations.Temperature-sensitivepolymerichydrogelnetworkscanalsoexhibitSMEbyvirtueoftheir solution critical temperature. Those exhibitingLower CriticalSolution Temperature(LCST) areswollenbelowLCSTandshrinkaboveit.ThoseexhibitingHigherCriticalSolution Temperature (HCST) exhibit the exactly opposite phenomena. 2.1.2Physically cross-linked SMPs In this type of SMPs, the fixity phase is governed byphysical interactions between polymer chains like formation of crystalline phases, hydrogen bonds or ionic interactions. Due to the physical forces involved, the fixity phase in these SMPs can be remoulded again unlike that of chemically cross-linked SMPs.Semi-crystalline polymers containing both amorphous and crystalline phases like PLA are examples of this type where the crystalline phase acts as the fixity phase.Polymerswithseparatedphasescanalsobeobtainedbyco-polymerisationwherethe monomer having the highest transition temperature acts as the fixity phase. Block copolymers showbetterSMEthanthehomopolymerofthesamekindduetoblendingofpropertiesof twodifferentmonomers(likeincreasedtoughnessorbiodegradability,etc).Forexample, PLA-PLGA co-polymer shows much better SME than PLA homopolymer.Polyurethanessynthesizedfromthermoplasticdiolshavebeenfoundtoshowgoodshape memoryproperties.Inthismethod,apolymericdiolreactswithdiisocyanatetoformapre- 7 polymer which then reacts further with low molecular weight diols to form oligoesters. Thus, the urethane groups form the fixity phase (by stabilization with the help of hydrogen bonding anddipole-dipoleinteraction)whereastheoligoestersactastheswitchingphase.Shape-memorypolyurethanescanalsobeobtainedbyblockco-polymerizationresultinginthe urethane linkages. Polymerblendingisaneasyandeffectivetechniquetoimprovethepropertiesofpolymers andmayleadtoshape-memoryproperties.Dependingonthetypeofpolymerblends,there maybemiscibleorimmiscibleSMPblends.MiscibleSMPblendsmaybeformedby blending of a semi-crystalline and an amorphous polymer like PCL and polydioxianone, PCL polyurethanewithphenolicresin,etcandexamplesofimmiscibleblendsmaybeSBS dispersed in a PCL matrix. Two miscible polymers whose networks can be inter mingled with oneanothercanformfullyInter-penetratingNetwork(IPN)orsemi-IPN.Thismayoccur whencross-linkingoftwopolymersoccursinstagesafterinitialblending.Inthesekindof IPNsthechainsactasthefixityphaseandthecross-linkednet-pointsofboththepolymers act as the switching phase. Figure 5 shows SME in a PMMA-PEG semi-IPN network. Figure5ThequintupleSMEofpoly(methylmethacrylate)/poly(ethyleneglycol)semi-IPNwitha broadened glass transition and a crystalline segment In manyapplications SMP composites have been shown toexhibitenhanced shape memory properties along with additional properties when compared with SMPs. The addition of fillers likenanoparticles,nanotubes,etccansignificantlyimprovethemechanicalpropertiesofa polymer.Inthiscase,thefixityphaseisoftentheinteractionbetweentheparticlesand polymers. 8 2.2Classification based on external stimulus Classification of SMPs can also be done based on the stimulus which induces the SME in the material.Externalstimulimaybedirectornon-direct:Directstimulifacilitatestheshape memoryinboththeprogrammingandrecoverystep,whereasindirectstimuliistheone which onlyacts on the recovery step. For indirect stimuli, usually temperature is used to fix the temporary shape.Temperature: Heat-inducedorthermo-responsiveSMPsarethemostcommonandwidelyinvestigated SMPs out of all due to the presence of suitable Tg or Tm in many of the polymers. Thus, this is also the most well understood category. The thermo-mechanical response has already been shownbeforeandthestructuralmechanismsarepresentedlaterforthisclassofSMPs.The temperaturerisecanbecausedbyJouleheating,inductiveheating,light-heatingandradio-heating. Figure6showsapolyurethaneSMPwirewhichafterprogrammingisstretchedand transparent but regains its length and transparency upon recovery. Figure 6 Light induced heating shape recovery of polyurethane SMP wire: Left: After programming; Right: After recovery Light: Light-induced or photo-responsive SMPs are those that can exhibit shape memory behaviour inthepresenceoflight,sotheymustcontainsomephoto-responsivemoleculesinthem. There can be 3 types of photo-responsive molecules: photoisomerizables (change from cis to trans in presence of light), molecules obtained by cationic induced polymerization and photo-responsive molecules like cinnamicacid. here, the covalent bonds in thepolymerchains act asthefixityphasewhilethephoto-responsivemoleculeactsastheswitchphase.This 9 categoryhasanadvantageofitsapplicationinbiomedicalengineeringasitdoesnotcause tissuedamagebyheating.However,successfulphoto-responsiveSMPsforsuchuseisstill limitedduetothepotentialtoxicityofthephoto-responsivemoleculesthemselves(like azobenzene). Figure 7 shows a photo-responsive polyurethane containing cinnamamide as the switch phase. Figure 7 Synthesis of biodegradable multi-block polyester urethane containing pendant photoactive cinnamamide groups from biodegradable soft diol (poly caprolactone diol), biodegradable hard diol (poly-(L-lactic acid) diol), and N,N-bis(2-hydroxyethyl) cinnamamide pH: pH-responsive SMPs are mostly polymeric hydrogels that can cause a change in their volume dependingonthepHduetothepresenceofchargedgroups/moleculesinthemwhichshow ph-induced ionization. Depending on the type ofionizing molecule therecan be polyacid or polybasebasedph-responsivehydrogel.PolyacidscanacceptprotonsatlowpHwhereas polybases donate protons at high pH. Many pH responsive hydrogels are commonly used for drugdeliveryanddeliveryapplications.However,oftenthismechanismiscoupledwith temperatureeffectsformoreeffectiveprogrammingandrecovery.Figure8showsthe shrinkage of gels due to change in pH. 10 Figure 8 Swellingshrinkage behaviour in ionic based hydrogel by changes in pH. Water and moisture: Some SMPs are stimulated by the presence or absence of water or moisture. This is governed bythepresenceofhydrophilic/hydrophobicmoietieswithinthepolymer.Forsome hydrophilicchemo-responsiveSMPs,itmaystretchwhenimmersedinwaterandshrink when immersed in ethanol. Plasticizing effects in water may cause shrinkage or expansion of apolymerinwater.Figure9showstheretractionofastentwhichcanbedeliveredtoa specificlocationbyacatheterafterwhichitcanexpandtoitspermanentshape.Moisture-inducedshaperecoveryalsoactsinasimilarwarethemoistureisslowlyabsorbedintothe polymer and this water acts as a plasticizer leading to a decrease in the transition temperature. Figure 9 Retraction of polyurethane shape memory polymer stent in water.

11 Electric/magnetic field: SMPsbythemselvesarerarelyelectro-sensitiveduetothenon-conductivenatureof polymers.HowevercompositeSMPsobtainedbytheadditionofconductingfillerslike Carbonnanotubescanrenderthepolymerelectro-responsive.Inmanycasestheelectro-responsive recovery is only indirect i.e., by virtue of electrical conductance if the temperature rises to the transition temperature, shape recovery occurs. In others, the electric field induces stresses due to the presence of conducting fillers, causing shape change as shown in Figure 10. Magnetic-field induced SME is also similar to the electric -field induced one; here, the active componentsaremagneticfillerslikemagnetitenanoparticles.Inthiscasealso,usuallythe magnetic field causes heating of the particles leading to shape recovery. Figure10Schematicillustrationoftheelectro-triggeredspatiallyandtemporallycontrolledshape recovery and the realization of multi-shapes on demand of CNTs filled SMP 12 3General mechanisms of SME in polymers Every different polymer exhibiting SME is governed by a specific mechanism and that too in responsetoaparticularstimulus.ItisunderstandablethatnotallSMPswillrespondinthe same way to a particular stimulus. Also, not every SMPs will show SME in response to more thanonestimulus.Thus,itsohappensthattheexact mechanism for individual SMPs in response to their corresponding external stimulus is different. For instance, shape memory is observed in thermo-responsive EVA-based melting glue droplet.In this case, the polymer droplet recovers its shape when heated due to a surface tension driving force which forces the polymer to revert back to its original surface (shown in Figure 11). However, there are some basicunderlyingprinciplesbyvirtueofwhichmanypolymersexhibitSME.Inthissection, somebasictheoriesofunderstandingSMEarediscussedwhichwereoriginallyderivedfor thermo-responsive SMPs but the idea can also be extended to others. Figure 11 Thermally induced shape recovery due to surface tension in an EVA-based melting glue droplet. (a) Original shape; (b) after indented for a line; and (c) after heating for shape recovery. Inthefollowingsub-sections,threetheoriesderivedfromunderstandingofthermally-induced SME are discussed. A majority of the SMPs are heat-induced and the mechanisms havebeenmoreclearlyunderstoodforthisclassofpolymersbyvirtueofmolecular mechanisms arising from transition temperatures in polymers. Although, these principles are applicable to heat-induced SME in polymers, they can be applied to understand SME in most other (if not all) polymers/ composites. Generally,theunderstandingisthatSMEisobservedinpolymerswhichhaveadual-componentsystem(likehardandsoftsegments,amorphousandcrystallinesegments,etc). Oneofthecomponentsiselasticinthetemperaturedomainofourinterestandtheother componentcandeformplasticallyinthelowstiffnessregions.Sotheplasticdomainbrings 13 about a change in the shape and the elastic domain stores the energy and provides the driving forceforshaperecovery.Thus,thesecondcomponentisactiveduringthe"programming" step and the first component is active during "recovery" step. The deformation occurs in the presenceoftherightstimulus.Forheat-inducedSMP,theglasstransitionandthemelting temperatures are utilized for causing these deformations. In the following mechanisms, time-dependentstraineffectsandviscositydependenteffectslikecreepingarenottakeninto account. The working mechanisms are pictorially represented in Figure 12. Most importantly, often a combination of the following mechanisms are said to work in most of the SMPs. Figure 12 Basic working mechanisms for the heating-responsive SME in polymeric materials. (I) Dual-statemechanism(DSM);(II)dual-componentmechanism(DCM);(III)partial-transitionmechanism (PTM). (a) Original sample at low temperatures; (b) upon heating and compressing; (c) after cooling and constraint removal; and (d) after heating for shape recovery 3.1Dual state mechanism (DSM) This theory is based on the existence of two states (hence the name) in polymers: the glassy stateandtherubberystate.Inthistheory,itisassumedtheSMPsareintheglassystate initiallyandthenheatedtoaboveitsTgfollowingwhichitisdeformed.Afterthe 14 deformation in the rubbery state, if the polymer is cooled to below its Tg while maintaining the deformed shape, the molecular motion is frozen and the polymer maintains the deformed shape. The original shape is recovered only when the molecular motion becomes active again byheatingthepolymertoaboveTg.So,accordingtothistheory,allelastomershaving achievableglass transition temperatures (corresponding to the application; like 30-40 Cfor applicationswithinthebody)canexhibitSMEtosomeextentnaturally.TwomainSMPs whose behaviour can be explained by this theory are PMMA and Silicone.In these kind of SMPs, the shape recovery phenomena is enhanced if there are net-points of cross-linkingpresentinthepolymermatrix.Thesecross-linkingjunctionscouldbe chemically cross-linked or physically cross-linked or tangled polymer chains. These junctions orpointscanefficientlystoretheenergyduringdeformationandserveasthedrivingforce during the recovery step. Figure13TheSMEinsilicone.aOriginalshape;bcooledinliquidnitrogen(abletomaintainthis shape in liquid nitrogen as stand-alone); c recovered at room temperature 3.2Dual component mechanism (DCM) Thistheoryexplainsshapememorybehaviourofpolymershavingtwocomponents:an elasticcomponentandanothertransitioncomponent.Oneofthedomains/segmentinthese SMPsishighlyelasticandtheotherdomain/segmentisresponsibleforreversiblephase transitions.Thisphasetransitionisglasstransitionormeltingforheat-inducedSMPs. Referringto,thematrixistheelasticsegmentandtheinclusionsconstitutethetransition segment.WhenthematerialisheatedaboveTg,theinclusionssoftenandthematrixis strainedanddeformed.IfthisstateismaintainedwhilethematerialiscooledbelowitsTg, the inclusions freeze/harden and prevents further deformation/recovery. The energy is stored in the elastic matrix and there is a residual strain observed. Upon heating again, the inclusions soften and pushes the matrix to come back to its original shape. 15 OneexampleofsuchaSMPisEthylene-vinylacetateorEVAcopolymercontainingdual segments. One component is highly elastic and the other component shows very low stiffness athightemperaturesandveryhighstiffnessatlowtemperatures.So,uponheatingand deformationaringofEVAexpands(showninFigure14)andtheexpandedringretainsits diameter once cooled due to the high stiffness of the transition component. Figure 14 Thermo-responsive SME in EVA. a After expansion; b after heating for (full) shape recovery AnotherwidelyexploredSMPofthiscategoryisPolyurethane(PU)anddifferent modifications/blends/compositesofPU.Inonework,twomisciblegradesofPUhaving differentmeltingtemperaturesledtotheformationofablendSMP.Whentheoperating temperatureisbetweenthesetwomeltingtemperatures,onecomponent(theonewiththe lowermeltingtemperature)cansoftenonheatingwhiletheother(theonewiththehigher melting temperature) maintains the elasticity. Thus this principle can be invariably applied to polymerblendsorpolymercompositeswithfillerscontainingsimilardual-component system.SomeexamplesofsuchSMPswhichhavebeeninvestigatedarePolyurethane-Polyvinyl chloride, acrylonitrile-butadiene-styrene (ABS) / Polycarbonate, etc. This DCM theory has also been extended to polymer-other component hybrid systems where theothercomponentcouldbeafattyacid,inorganicmolecules,metals,alloysetc.An exampleofashape-memoryhybridisthatofSilicone-paraffinwaxhybridcontaining30% by volume of paraffin wax. The circular wax droplets embedded in the Silicone matrix act as the transition component and become elliptical after programming. 16 3.3Partial Transition Mechanism (PTM) Thistheoryisquitelessmentionedintheliterature,thoughsohaveactuallyutilisedthis principletosomeextent.Accordingtothismechanism,thepolymerdoesnotcontain inclusions initially. During the programming step, a part of the polymer melts and behave as thetransitioncomponentandtheremainingpartbehavesastheelasticcomponent.So,after programming,thehardenedpartpreventstherestofthepolymerfromregainingitsshape. This mechanism is almost similar to DCM except for the fact that the two components do not separately co-exist in the original material and phase transition occurs for "partial" material. This mechanism can either act alone or in combination with the other two, which is the more frequent case. If it works alone, then the temperature control during the programming and the recovery steps become very important. 17 4SMPs from a biomedical perspective Thebiomedicalsectorisoneofthefastestgrowingresearchareasatpresentwithalotof emphasisontryingtotranslatetheresearchforcommercialapplications.Sincethemid-twentiethcenturytheuseofpolymersforbiomedicalapplicationshavebecomenotonly popular but almost indispensable. With the introduction of SMPs, research has now moved to thenextgenerationbiomaterials.However,applicationforbiomedicalpurposesrequire certaincharacteristicstobepresentwithinthematerial.TheSMPmustbebiocompatible, maybebiodegradabledependingonthespecificapplication,possesstransition temperaturesaroundthebodytemperature,showminimalcytotoxicityandhavesmall recoverytimes.Forspecificapplications,recenttrendhasbeentousepolymerblends, compositesaswellasShapememoryhybrids(SMH).Thefollowingtableprovidesa comparison between key properties of SMAs, SMPs and SMHs. 4.1Design considerations in SMPs for biomedical applications SMPsseemtobeaveryattractiveoptionforthedesignofbiomaterialsystemsforawide rangeofapplications.However,duetotherestrictionsimposedfortheiruseinbiomedical applications,onehastoverycarefullyselectanddesigntheSMPssuitablefordifferent purposes. Themostimportantpropertyisperhapsachievingthetransitiontemperature/otherproperty tobeinasaferangeforthebody.Forexample,thetransitiontemperatureforthermo-responsiveSMPsmustbaround37C.Forlight-inducedSMP,thetransitioncouldbe achieved by applying UV irradiation for a small time; however, thermally-induced SMPs are most efficient when it comes to use in physiological conditions. 18 BiocompatibilityoftheSMPsisalsoanotherimportantconstraintasanymaterialfor biomedical applications should not show even the slightest of toxicity. Extensive in vitro cell-cultureexperimentsfollowedbyinvivotestinginanimalsmustbeperformedforthis purpose. It is often not enough for the SMP to be just non-cytotoxic, it should also maintain proper functionality of the cells attached to it thus ensuring normal cell proliferation. A lot of workhasbeendoneinthisareaandSMPslikepoly(-caprolactone)dimethacrylate, poly(glycerol dodecanoates) among many others have been shown to be biocompatible. Some specific applications like use in cardio-vascular tissues may require good hemocompatibility. Someapplicationsrequirethematerialtobebiodegradableansometimestherateof degradation may be important such as in controlled release applications. So, while designing a SMP, the biodegradation rates can be tailored by adjusting ratios of copolymers or polymer blends or by the addition of a third component.So,byaproperchoiceofpolymericcompositionandtailoringofitscharacteristics, functional SMPs can be achieved which can find it use in biomedical applications. In addition tothebasiccharacteristicsofabiomaterial,specialpropertieslikemagneticbehaviour, electricalnature(conductingbehaviour),transparency,etccanbeintroducedintotheSMPs dependingontheirspecificuse,Lastlybutimportantly,sterilizationconsiderationsmustbe kept in mind if we are designing something for commercial biomedical uses. 4.2Biomedical applications of SMPs Useofpolymersforbiomedicalapplicationswasanimportantlandmarkinadvanced applicationsofpolymericmaterialsandnow,theadvanceddesignofmaterialshaveopened newapplicationstobeexploredandinvestigatedfurther.InvestigationofSMPsfor biomedical purposes became only after 1990s and since the early 2000 there have been a lot ofadvancementsinthisfield.Inthissub-section,themajorapplicationareasandafew examples to illustrate the application are discussed.4.2.1Drug delivery systems One of the major applications of SMPs is in fabrication on drug delivery systems. These are sodesignedthatonapplicationoftheexternalstimulus,therearechangesinthepolymer networkleadingtoreleaseofthedrug.ThisstimuluscouldbepHofthetargetarea, 19 externally applied magnetic field, body temperature, externally applied heat, etc. The concept of drug delivery using SMPs has been illustrated in the figure below and two recent examples are mentioned thereafter. Figure 15 Concept of programming, shape recovery, and drug release of drug loaded SMP devices for biomedical applications Nagahamaetal.,2009fabricatedabiodegradableSMPnetworkbythecross-linkingofbranchedoligo(-caprolactone)withhexamethylenediisocyanate(Figure16).Theshape-memorypropertieswerequantifiedusingthermo-mechanicaltensileexperimentsandstrain fixityrateshigherthan97%andstrainrecoveryratesof100%wereobserved.Theshape recovery to the permanent shape within 10 s at 42 C. A 10% theophylline-loaded SMPs was sufficientlysoftandflexibleforcomplexshapetransformationandalsoshowedhighfixity (98%) and recovery rates (99%). Sustained release of loaded theophylline was achieved over 1 month without initial burst-release in a phosphate buffer solution (PBS; pH 7.4) at 37 C. Figure 16 Chemical Structure of Branched Oligo(-caprolactone) and the Polymer Network Structure Formed by Cross-Linking Reactions 20 Recently, citric acid is being used to synthesize biodegradable polyester elastomers by virtue ofitspolymerizationwithsomediols.Atcertaincompositionswithspecificdiols,this polymerisfoundtoshowthermally-inducedSME.InaworkbySerranoetal.,2011, Hydroxyl-dominant(HD)polydiolcitratesweresynthesizedbyusing1,12-dodecanediol (DD).Byincreasingthemoleratioofhydroxyltocarboxylgroupsinthereactionmixture (4:3inHDpolymersvs1:1inequifunctional(EF)polymers)theesterificationofcarboxyl groupsfromcitricacidwithhydroxylgroupspresentinthealiphaticdiolsallowsforthe formationofhydrophobicmicro-domainsinthecross-linkedpolymernetworkthatare stabilizedbyintermolecularhydrophobicinteractions(Figure17).Byusinglong-chain aliphaticdiols,theintermolecularpackingisthermodynamicallyfavouredresultingina copolymerwiththermosensitivemechanicalandshape-memorypropertiesthatcanbe induced between room temperature (22 C) and body temperature (36.6 C). The polyester networkincludescovalentnetpointsresponsibleforthepermanentshapeandhydrophobic micro-domainsphysicallycross-linkedbyintermolecularhydrophobicinteractions,which behaveasswitchstructurestofixthetemporaryshape.TheSMEisillustratedinFigure18 and the drug release profiles are shown in Figure 19. Figure 17 Molecular scheme of the polymer network of HD-polydiolcitrate elastomers 21 Figure 18 Representative images illustrating the programming and recovery process in polymer films and porous 3D scaffolds, respectively. Polymer samples resemble capital letters A, B, and C as thepermanentshapeatroomtemperature(B13).3Dspongesbehaveastoughmatricesatroom temperature (C2), but become soft above T trans or with further post-polymerization (C3). Figure 19 Temperature-controlled release kinetics of DCF from HD and EF polymers 4.2.2Devices for minimally invasive surgery Minimallyinvasivesurgerymaybethekeytomoreefficientsurgeriesinthecomingyears duetoitsadvantagesovertraditionalsurgeries.Shape-memorymaterialscanbeutilizedfor this kind of application where the material is inserted when it is in the temporary shape and theninphysiologicalconditionsundergoshaperecoverytoobtaintheactualshapeofthe implant.Shape-memoryalloyofNi-Tiisalreadyinuseasorthodonticwiresandcardio-vascular stents. However, the alloys have limitations in processabilityand in achieving high strainrecoveryrateswhichcanbeovercomebyusingSMPs.Followingaresomeofthe examples illustrating this specific application of SMPs. 22 Microactuators for clot removal: Withrisingcasesofischemicstrokeworldwide,peoplearelookingfornewalternativesto conventional clot-dissolving drugs. The key concept is to use SMPs to facilitate clot removal under physiological pressures and flow conditions.A promising approach proposed by Maitland et al., 2002 for treating ischemic stroke can be the mechanical removal of thrombi using a novel microactuator device (shown in Figure 20). Thedeviceconsistsofaninjection-moldedlaser-activatedSMPmicroactuatorthatis delivered through a catheter distal to the thrombolic occlusion. The microactuator is mounted onadiffusingopticalfibreanddeliveredinitsstraightformthroughacatheterdistaltothe occlusion,whereitisdeployedviaopticalheatingintoitscoilshape.Oncethedeviceis deployed, both the microactuator and the thrombus are removed from the vessel. Figure20Left:SchematicrepresentationofSMP microactuatorusedin treatingischemicstroke. a: Theguidecatheterispushedthroughoraroundtheblockage.b:TheSMPdeviceispushedoutof theguidecatheterandactuated.TheSMPdevicemusthaveasmallenoughdiametertopass through an appropriate neurovascular guide catheter. Current design goals have set this diameter to be 0.01200 (300 mm) or less. c: The catheter, expanded device (coil depicted in this schematic), and clotarepulledinunisonproximallytorelievetheischemia;Right:Schematicrepresentationofan emboliccoilreleasemicrogripper.a:Thedeliverydevicewiththecoilloadedandreadyfor deployment. b: The delivery device after the SMP has been heated above its transition temperature. TheSMParoundthecoilhasmechanicallyrelaxed(expanded)toitsextrudeddiameter.TheSMP remains in its expanded state after the laser-coupled thermal energy is turned off and the SMP cools below its transition temperature 23 Stents: Using SPMs to fabricate different types of expandable stents has been one of the most widely exploredapplication.InaworkbyBaeretal.,2007,laser-activatedphotothermalSMPwas usedtodemonstratedeploymentofavascularstentinamockartery(Figure21).TheSMP stentwasfabricatedfromacommerciallyavailablethermoplasticpolyurethanehavinga segmented phase micro-structure (a hard phase and a soft phase). Figure 21 Stent deployment. Timeline of SMP stent deployment in the mock artery (zero flow) as the laser power was gradually increased. Laser duration was approximately 6.3 min InanotherworkbyXueetal.,2010,blockco-polymers(namedasPCTBVs)containing hyperbranchedthree-armpoly(3-caprolactone)(PCL)asswitchingsegmentandmicrobial polyester PHBV as crystallisable hard segment were designed as biodegradable SMP for fast self-expandablestent.PCTBVsshoweddesiredthermalproperties,mechanicalproperties, andductilenature.PCTBVcontaining25wt%PHBV(PCTBV-25)demonstratedexcellent shape-memory propertyat 40C (Figure22) and shape recovery within 25s. PCTBV-25 was also shown as a safe material with good biocompatibility by cytotoxicity tests and cell growth experiments. The stent made from PCTBV-25 film showed nearly complete self-expansion at 37 C within only 25sec making it a probable stent for future use. 24 Figure 22 Photographs exhibiting the self-expansion of the stent made from PCTBV-25 with original outerdiameterof3.45mm.(1)Thestentwasmechanicallydeformed,fixed onametallicrodwith diameter of 1 mm to give outer diameter of 1.43 mm, and removed the mechanical force; (2)e(4) the stentwas putin water bath at37C after 3s, 10s and 20s, respectively; (5)thestentwas taken out from water bath after 25s, with diameter of 3.35 mm. Viability of L929 cells after 3 days incubation in different concentrations of aqueous extracts of PCLBV and PCDBV films Aneurysm occlusion: An aneurysmisalocalized,blood-filledballoon-like bulge inthewallofa bloodvessel (Wikipedia)whichmayincreaseinsizeandleadtoarupture.Ingeneral,morethanhalfof thesecasesresultindeathandeventhosewhosurvivemaydevelopapermanentnerve damage. Nowadays, novel endovascular treatments like aneurysm embolization with balloon-assisted coils, flow diversion devices, open- and closed-cell stents, and embolic materials are viewedaspromisingoptionswhencomparedtotraditionalinvasivesurgicaltechniques. However,therearecertainlimitationstoowhichcanpossiblybeovercomebytheuseof SMPs.Metcalfeetal.,2002utilizedaSMPcalled"ColdHibernatedElasticMemory(CHEM)" polyurethane(whichisapolyurethanebasednetworkhavingafoamystructure)for endovascularinterventionsinvitroaswellasintrialstudiesondogs.Internalmaxillary articlesembolizedwithCHEMfoamwerehealedin3weeks.TheuseofSMEisdescribed by the figure below. 25 Figure23 CHEM processing cycle. Structures of any shape,madeof CHEM foam, are compacted to smallvolumesinaflexiblestateabovetheTgandlatercooledbelowTgtoaglassystate,tobe stowedforunlimitedperiodsbelowTg:ThestowedstructurecanbeheatedaboveTgtoaflexible state and the original shape will be precisely restored. A fully deployed structure can be rigidized by cooling below Tg to a glassy state. CommerciallyavailableSMPCalomer(blockco-polymerofpolyurethane)wasusedto fabricate coils to occlude blood flow for intracranial aneurysm in a work by Hampikian et al., 2006.CalomercoilswerefilledwithTantalumtoincreasetheradio-opacityofthecoil(for detectionusingX-rays)andthermo-mechanicalSMEwasevaluated.2SMPcoilsdeployed inside a simulated aneurysm model demonstrate (Figure 24) that typical hemodynamic forces do not hinder the shape recovery process and the coils remained stable. Figure 24 Deployment of two SMP coils under simulated flow conditions 26 Degradable sutures: Smart, degradable sutures may be the solution to minimally invasive and less painful wound repair where the sutures may tighten across the wound themselves and may degrade after the woundhasrepaired.Inonework,degradablesutureswerefabricatedfromSMPsofphase-segregatedmultiblockcopolymerslikethatgeneratedfromareactionbetweenoligo(-caprolactone)diol and 2,2(4),4-trimethylhexanediisocyanate. This specific SMP was found to have deformations upto 400% between their temporary and permanent shapes. The use of this SMP for wound closure was illustrated by using extruded fibers to act as sutures for closing abdominalincisiononaratmodel.Thesutureswerestretchedto200%oftheiroriginal length and then heated to 41C to thermally-induce shape memory for the suture to return to its original length and close the wound as depicted in Figure 25. Figure25Invivoapplicationofadegradableshape-memorysutureforwoundhealing.An appropriateclosureofthewoundwasachievedbythetemperature-inducedshrinkageof thefiber suture (left to right). Inadifferentapproach,Zhangetal.developedanovelblendofstyrene-butadiene-styrene tri-blockcopolymer(SBS)andpoly(-caprolactone)(PCL)thatwasabletoautomatically knotwithin10sinawaterbathat70C.Heretheshapememoryisduetothephase segregation of an elastomer SBS and a crystalline polymer PCL. It was found that PCL forms thecontinuousphaseabove30%ofthepolymer.ThemechanismisillustratedinFigure26 andtheshape-memorybehaviourfora50%PCLsample(PCL50)isshowninFigure27. Althoughtransitiontemperatureadjustmentforbiomedicalrequirementsisneeded,these shape-memory blends show promise for their use as thermo-sensitive sutures. 27 Figure26Schematicfiguresoftheshapememorymechanismofelastomer/switchpolymerblends concluded from SBS/PCL blend Figure 27 An example for the recovery process of shape memory effect when the PCL50 sample was placed in water of 70C Other applications: ExamplesfromthemajorapplicationareasofSMPinbiomedicalresearchhavebeen mentionedinthissection.Apartfromthesewell-establishedapplications,therearevarious others which utilize SMPs and some of these applications are rather new and just emerging. Some of the other examples not mentioned in this report but equally important are the use of SMPsasbonedefectfillers,celldifferentiationmanipulatingscaffolds,kidneydialysis needles,micro-tweezersforsurgicalapplications,micro-valvesinminiaturizedmedical devices,ophthalmicapplications,orthodonticwires,pharyngealmucosareconstruction, physiologicalmonitoring,shape-changingnanofibrousscaffolds,self-healingbiomaterials, shape-memory neuronal probes, wound dressings, self-expanding device for curbing appetite andmanymore.Thus,onecanimaginethebroadhorizonofapplicationsofSMPsin biomedical science and research. 28 5Conclusion From the overview presented in this report, it can be concluded that SMPs may turn out to be a promising approach to many of thecurrent research problems.Since there a large number of polymers available and one can perform a lot of modifications in their properties, a number of different SMPs can be designed according to specific needs. Thus, there exists an immense adaptability and versatility in this field.ThoughmostofthepresentSMPsarethermo-responsive,heatingmaynotalwaysbea desirable step for some applications like in some biomedical applications it can lead to tissue damage. Hence, there isa wide scope of research of other stimuli-responsive SMP which at presentarenotsoefficientastheheat-inducedones.Also,muchmoredetailed understanding of the molecular mechanisms of SMPs other than heat-induced ones are yet to beestablishedingreatdetail.Thegeneralmechanismspresentedinthisreportarethebest understoodonesbuttheymaynotapplyforsomeSMPslikethepH-responsiveones.Once the mechanisms are well grasped, it will provide a great help to design more SMPs. The use of SMPs is definitely not limited to biomedical applications, although this sector still accounts for the largest area of application till date. SMPs find applications in other areas like aerospaceengineering,defenceorganisations,textileandpaperindustryandmanymore. 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