Thermo-Responsive Toughening of Hydrogels

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Hui Guo

To cite this version:

Hui Guo. Thermo-Responsive Toughening of Hydrogels. Chemical Physics [physics.chem-ph]. Uni-versité Pierre et Marie Curie - Paris VI, 2015. English. �NNT : 2015PA066628�. �tel-01651344�

ED 397 : Physique et Chimie des Matériaux

Laboratoire Sciences et Ingénierie de la Matière Molle / Equipe Soft Polymer Networks

Thermo-Responsive Toughening of Hydrogels

Par Hui GUO

Thèse de doctorat de Chimie et Physico-chimie des Polymères

Dirigée par Dominique Hourdet, Alba Marcellan et Nicolas Sanson

Présentée et soutenue publiquement le 27 novembre 2015

Devant un jury composé de :

Christophe CHASSENIEUX

Professeur à l’Université du Maine - Le Mans

Rapporteur

Cécile DREISS

Senior Lecturer - King’s College London

Rapporteur

Loïc VANEL

Professeur à l’Université Claude Bernard - Lyon 1

Examinateur

Laurent BOUTEILLER

DR CNRS - Université P. et M. Curie - Paris 6

Examinateur

Alba MARCELLAN

MCF à l’Université P. et M. Curie - Paris 6

Co-encadrant

Nicolas SANSON

MCF à l’Université P. et M. Curie - Paris 6

Co-encadrant

Dominique HOURDET

Professeur à l’Université P. et M. Curie - Paris 6

Co-encadrant

I would like to express my gratitude to those who have given me the chance to complete this dissertation.

First, I would like to thank the Chinese Scholarship Council (CSC) and Centre National de la Recherche Scientifique (CNRS). Without their financial support, I am not able to realize my dream of studying in a foreign country.

Then, I feel like expressing my sincerely gratitude to my three supervisors, Dominique, Alba and Nicolas. Thank you for your generosity with your time and encouragement. I am deeply impressed with your profound knowledge in the field of polymer science. With your patience and support, countless difficulties have been overcome. You are always role models to me, which I wish to become if I could be a supervisor in the future.

I am enormously grateful to Costantino for the great help in the admission to France. In addition, thank you very much for your advice both in scientific research and career planning.

I would like to thank Christian Frétigny, the director of the lab SIMM of ESPCI, for accepting me as a PhD student and for all the things offered to me to carry out my thesis.

I would like to thank all the members in my jury: Professor Christophe Chassenieux, Professor Cécile Dreiss, Professor Loïc Vanel and Professor Laurent Bouteiller. I appreciate a lot for their interest in my work and their evaluations on my thesis.

I appreciate the support from Annie Brûlet of Laboratoire Léon Brillouin (CEA, Saclay) for her kindly help in my neutron experiments. Meanwhile, I thank Pattuparambil R. Rajamohanan, Szilvia Kaprati and Jean-Luc Genneisson for their help in my experiment. I feel privileged to have been able to work with all members in SIMM. Thank you for all your help. First, thank all the permanent staffs for your warm help. Especially, I would like to express my appreciation to Guylaine, who gives me great help in rheological test; Bruno, who helps me a lot in AFM support; Laurence, my “tuteur”; Ludovic, for the experimental setup, etc. I would like also to thank all the students in the lab for their discussion, help, encouragement, support, and great joy they brought to me. Especially, I wish to thank

Robert, Menghua, Jingwen, Thitima, etc.

I would like to thank Cécile Mussault, who works with me during the last period of my PhD study. With your help, tough experiments become easier.

At the same time, I feel like showing my gratitude to my Chinese friends in ESPCI. Thank you for strongly enriching my life in France.

Then, I would like to thank my parents for their full support and selfless love. As the only child in the family, I have received too much love from them. Without their help and encouragement, it is absolutely impossible to come to France and obtain my PhD diploma here. I shall feel forever in their debt. At the same time, I feel very guilty to stay so far away from them during these three years, especially my father, whom I have never seen upon my study here.

Thank you so much, Xiaolin. Thank you for your support, encouragement and patience all along these years. With your love, my life becomes much brighter in such a romantic country. Thank you, my little Shuya. You bring us too much happiness and delight upon your arrival, although occupy a lot of time which I should have spent in scientific research. I hope you have a precious memory for these days when you grow up.

NMR Nuclear Magnetic Resonance

SANS Small Angle Neutron Scattering

DSC Differential Scanning Calorimetry

SEC Size Exclusion Chromatography

DLS Dynamic Light Scattering

SLS Static Light Scattering

TGA Thermal Gravimetric Analysis

SEM Scanning Electron Microscopy

LCST Lower Critical Solution Temperature UCST Upper Critical Solution Temperature

Semi-IPN Semi-interpenetrated network

NC Nano-composite

DMA N,N-dimethylacrylamide MBA N,N’-methylene-bis-acrylamide

AMPS 2-acrylamido-2-methylpropanesulfonic acid

NIPA N-isopropylacrylamide

NAGA N-acryloyl glycinamide

SPP 3-[N-(3-methacrylamidopropyl)-N,N

-dimethyl] aminopropane sulfonate

SPE

3-[Dimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azaniumyl]propane-1-sulfonate

KPS Potassium Persulfate

APS Ammonium Persulfate

AIBN Azobisisobutyronitrile

SBS Sodium Metabisulfite

TEMED N,N,NĄ,NĄ-Tetramethylethylenediamine

DCC Dicyclohexylcarbodiimide NHS N-Hydroxysuccinimide

AET Cysteamine hydrochloride

PNIPA Poly(N-isopropylacrylamide) PDMA Poly(N,N-dimethylacrylamide)

PNAGA Poly(N-acryloyl glycinamide)

PSPP Poly(propylsulfonate dimethylammonium propylmethacrylamide)

PSPE Poly(propylsulfonate dimethylammonium ethylmethacrylate)

PAAH Poly(acrylic acid)

PAANa Poly(sodium acrylate)

PAMPS Poly(2-acrylamido-2-methyl-1-propanesulfonic acid)

E Elastic modulus

F Force

G Shear modulus

G’ Shear storage modulus

G” Shear loss modulus

Ð Dispersity

Mn Number average molar mass

Mw Weight average molar mass

Q0 Swelling ratio at preparation state

Qe Swelling ratio at equilibrium

R Ideal gas constant

R0 Radius

I(q) Scattering intensity

P(q) Form factor

S(q) Structure factor

S/V Surface Volume ratio

q Wave vector

Qexp Invariant

Icor(q) Scattering intensity normalized by Invariant

Nagg Aggregation Number

R Radius of the structure factor (Core-shell model)

HS

R2 Radius of globule (Core-shell model)

qpeak Peak position

I//

Scattered intensity in parallel direction to the elongation axis

(q)

IA

Scattered intensity in perpendicular direction to the elongation axis

(q)

t Time T 'T Temperature Temperature range V Volume  Strain  Stress U U

Scattering length density Contrast K Viscosity  Volume fraction 0 Wavelength Å Angstrom  Deformation ratio Gc Fracture energy

c Deformation ratio at break

c Strain at break

Tc Critical transition temperature

W Strain energy density

Generalintroduction

...1





Chapter1Introduction

...5



1. Hydrogels...7 1.1. Generalfeatures...7 1.2. Synthesis:swellingstateandinhomogeneities...8 1.3. Mechanicalshortcomingofchemicalgels...9 2. Reinforcedhydrogels...11 2.1. Hydrogelswithcovalentarchitectureimprovement...11 2.1.1. Slideringhydrogels...12 2.1.2. TetraPEGhydrogels...13 2.1.3. Doublenetworkhydrogels...14 2.2. Hydrogelsreinforcedbysecondaryphysicalinteractions...16 2.2.1. Ionicallycrosslinkedhydrogels...17 2.2.2. Nanocompositepolymerhydrogels...20 2.2.3. Microgelreinforcedhydrogels...22 2.2.4. Hydrogelswithhydrogenbonding...23 2.2.5. Hydrogelswithdipoledipoleinteraction...25 2.2.6. Hydrogelswithmetalligandcoordination...26 2.2.7. Hydrogelswithcrystallinedomains...26 2.2.8. Hydrogelswithhydrophobicinteractions...28 3. Thermoresponsivepolymersandhydrogels...30 3.1. Introduction...30 3.2. Thermoresponsivepolymers...31 3.2.1. CriticalSolutionTemperatureofpolymersinaqueousmedia...31 3.2.1. Poly(Nisopropylacrylamide)...33 3.2.2. Zwitterionicpolymers...35 3.2.3. Poly(Nacryloylglycinamide)...37 4. Objectiveofthedissertation...39

Chapter2LCSTbasedgraftcopolymers:influenceoftopologyonresponsive

assemblinginaqueousmedia

...53



1. Introduction...56 2. Experimentsection...58 2.1. Materials...58 2.2. Synthesisofthermosensitivelinearcopolymers...58 2.3. Sizeexclusionchromatography(SEC)...59 2.4. Nuclearmagneticresonance(NMR)...60 2.5. Rheology...60 2.6. DifferentialScanningCalorimetry(DSC)...60 2.7. DynamicLightScattering(DLS)...61 2.8. SmallAngleNeutronScattering(SANS)...61 3. Results...61 3.1. Synthesisandcharacterizationofgraftcopolymers...61 3.2. Thermothickeningbehavior:sol/geltransition...63 3.3. Phasetransition...64 3.4. Structurefromsmallangleneutronscattering...67 3.5. Concentrationdependence...71 3.6. Additionofsalt...72 3.7. Additionofsurfactant...74 3.8. Selfassemblingindilutesolution...76 4. Discussion...78 References...82 5. SupportingInformation...85 5.1. Synthesisofthermosensitivelinearcopolymers...85 5.1.1. SynthesisofAminoTerminatedTelomers...85 5.1.2. Synthesisoflinearmacromonomers...85 5.1.3. Synthesisofgraftcopolymers...86 5.2. Viscoelasticanalysis...86

structure/propertiesrelationships

...93



1. Introduction...98 2. Experimentalsection...101 2.1. Materials...101 2.2. Synthesisofpolymerprecursors...101 2.3. Synthesisofhydrogels...102 2.4. Gelcompositionandswellingexperiments...102 2.5. DifferentialScanningCalorimetry(DSC)...103 2.6. Rheology...103 2.7. Tensiletests...103 2.8. SmallAngleNeutronScattering(SANS)...104 3. Resultsanddiscussion...105 3.1. Grafthydrogels...105 3.1.1. Transitiontemperatureandswellingbehavior....105 3.1.2. Largestrainbehaviorandfractureproperties...109 3.1.3.Shapememoryproperties...110 3.1.3. Nanostructurefromsmallangleneutronscatteringanalysis...112 SANSunderstaticconditions...112 SANSunderuniaxialdeformation...118 Otherroutes,otherstories...124 3.2. SemiIPNhydrogels...126 3.2.1. Transitiontemperatureandswellingbehavior...126 3.2.2. Mechanicalproperties...128 3.2.3. Structurefromsmallangleneutronscattering...129 4. Conclusion...132 References...135 5. SupportingInformation...137 5.1. Shapememoryexperiments...137 5.2. SmallAngleNeutronScatteringunderstaticconditions...138



Chapter4Thermoresponsivetoughisochorichydrogels

...143



1. Introduction...145 2. Geldesignandsynthesis...146 3. Transitiontemperatureandswellingbehavior...147 4. Structureandlinearrheology...149 5. Largestrainbehaviorandfatigueresistance...150 6. Crackpropagationandfractureenergy...152 7. Conclusion...154 References...156 8. Experimentalsection...158 9. Supplementarydata...162 

Chapter5Thermoresponsivehydrogels:couplingbetweenUCSTandLCST

transitions

...167



1. Polysulfobetainehydrogels...169 1.1. Preparationofzwitterionichydrogels...170 1.2. Mechanicalpropertiesofzwitterionichydrogels...171 2. Poly(Nacryloylglycinamide)(PNAGA)...174 2.1. SynthesisofNAGAmonomer...174 2.2. InvestigationofPNAGAtypehydrogels...176 2.2.1. PNAGAhydrogels:preparationandswellingbehavior...177 2.2.2. SemiIPNbasedonPNAGAhydrogels...180 2.2.3. GraftPNAGAhydrogelswithdualthermosensitivity...185 3. Conclusion...192 References...194 

Generalconclusion

...195









Hydrogels are everywhere… As polymer networks that are expanded throughout their wholevolumebyaqueousfluid(IUPACdefinition),hydrogelscanbefoundinnature,likein algae,jellyfishorseacucumbersaswellasinoureverydaylifewheretheyareusedinvery different areas, such as agriculture, food science, oil recovery and cosmetic industry. Their high water content (typically 90 wt%), make hydrogels also very promising candidates in biology and medical applications like targeteddrug delivery systemsor tissue engineering for examples. With this concern, they have attracted considerable attention during the last fewdecades.

Innature,likeinplantsandtissues,hydrogelsrespondtospecificandcomplexphysiological functionalities including often sufficient mechanical stiffness and resistance in order to sustain mechanical loads from surrounding components. Unfortunately, in the case of synthetichydrogels,thehighwatercontentrespecttothepolymercompoundoftenleadsto weak mechanical properties in terms of elastic modulus and deformability. This fragility greatlylimitstheirpotentialapplications.

In order to overcome this problem, numerous strategies have come up for the mechanical reinforcement of hydrogels. For instance, the reduction of the crosslink heterogeneities, introducedduringsynthesis,isoneefficientoptionthatpermitstoprepare“ideal”networks with optimal cooperativity retarding the damage initiation. The interpenetration of a sacrificial rigid network within a ductile frame is another efficient way to obtain gels with veryhightoughness.However,alltheseapproachessufferfromcertainlimitations.Another interestingreinforcementstrategyformechanicalreinforcementinvolvestheimplementation of energy dissipation mechanisms. This can be done for example by introducing sacrificial interactions,eithercovalent(permanent)orphysical(reversible),intothecovalentnetwork. Nevertheless, even if these physical interactions are reversible by nature, they cannot be readilycontrolledexperimentallyinaqueousenvironmentandthiscanintroduceadditional stepsofsolventexchange.

An efficient way to getround the persistence of secondary interactions is the possibility to reversiblycommutethem.Toachievethis,stimuliresponsivepolymersclearlyappearasthe rightcandidatesastheirsolubilitycanbeeasilytunedinresponseofenvironmentalstimuli such as light, temperature, ionic strength, shear stress, pH… As a consequence, hydrogels

preparedwithstimuliresponsivepolymerscanexhibitlargemodificationsoftheirmolecular interactions that generally give rise to a large volume change when crossing the critical conditions for a chosen stimulus. This very specific feature opens a world of possible functionalities to gels that has already been considered as soft actuators, for fluidics or biomedicalapplications.

Fromapracticalpointofview,thetemperatureiscertainlythemoststudiedstimulusas1)it can be easily and reversibly handled, contrary to pH or ionic strength, 2) it can be used in manyapplications(frommedical eldtopetroleumindustry)and3)lastbutnotleast,there are many polymers with thermoresponsive properties in aqueous media. When hydrogels are prepared with such polymer sequences, characterized by a Lower Critical Solution Temperature(LCST)inwater,theirmacroscopicpropertiesaregenerallyrelatedtothelarge volume transition that the gel undergo above a critical temperature. This reversible transition,fromswollenstateatlowtemperaturetocollapsedstateathightemperature,has focused the current research with the huge potentiality to develop responsive actuators, valvesormedicaldevices.Whiletherearegreatapplicationsderivedfromthismacroscopic volume phase transition, like flow control in microfluidic channels, the main issue of this studyistobenefitfromthevolumetransitionofisolatedorconnecteddomainstoprovidea temperatureresponsive mechanical reinforcement. In order to tackle the question of mechanical reinforcement in covalent hydrogels, particularly when secondary forces are involved, the initial aim of this work was to use thermoresponsive polymers to drive reversiblyandinacontrolledmannerthephysicalinteractionsandthewholemacroscopic properties.Inthiswayitisexpectedtogetanewclassofcovalenthydrogelswithresponsive dissipationmechanism.Inordertosolvethekeyissueofthevolumetransition,copolymer networks have been designed withdifferent compositions and topologies (graftedor semi interpenetrated).Herein,wewillcombinetheresponsivebehaviorofoneofthepolymerand thehydrophilicandwatersolublecharacteroftheotherinordertokeepthevolumeofthe gelunchangedonthewholerangeinvestigated,typicallybetween5and60°C. Thefollowingmanuscriptisdividedintofivechapters,ofwhichchapter2,3and4willbe presentedintheformofpublications(thecontentofchapter2hasalreadybeenpublishedin Polymer2015,60,164175).Briefly,theoutlineisasfollows:

Chapter1isdevotedtoanoverviewofhydrogelsciencewherethemaincharacteristicsof hydrogels will be discussed along with their limitations. After a description of structural inhomogeneities at the origin of the weak properties of hydrogels, the different reinforcement strategies that have emerged during the last 15 years will be introduced. Finally, special attention will be paid to thermoresponsive polymers and hydrogels with theirspecificpropertiesandapplications.

Asanintroductiontochemicalgels,Chapter2isdedicatedtotheresponsiveassemblyof LCSTbased graft copolymers in aqueous solutions. Through the combination of poly(N,N dimethylacrylamide)andpoly(Nisopropylacrylamide)twograftcopolymerswithopposite topologies are synthesized. From complementary techniques of DSC, rheology and small angle neutron scattering (SANS) we will discuss the structure/properties relationships of thesetwocopolymersinaqueoussolutionwithaspecialemphasisontheirsimilaritiesand differences.

InChapter3,thesamemethodologypreviouslyappliedtocopolymersisnowextendedto 3D networks. Four dierent hydrogels, with grafted or semiinterpenetrated architectures withoppositetopologies,areinvestigatedbyDSC,SANS,rheology,tensiletestsandSANS at rest and under deformation. The relation between the network architecture, the nanostructure of hydrogels formed at high temperature and the large mechanical reinforcementobservedbyheatingisdiscussedaswellastheimpactofPNIPA.

Chapter4willmainlyfocuson3DnetworkspreparedwiththesamePNIPAcrosslinked backbone. The mechanical properties will be investigated in details in order to better understand the impact of network composition and topology on the mechanisms of mechanicalreinforcementathightemperature.

 In Chapter 5, the concept of thermoreinforced hydrogels is extended to UCSTtype polymers.AfteradescriptionofUCSTmonomersynthesisandnetworkdesign,theswelling and mechanical properties of semiIPN and grafted hydrogels will be investigated and compared to previous LCST networks. At the end of this chapter a dual responsive graft hydrogelwillbedesignedwithUCSTandLCSTpolymersanditspropertiesreported.









Chapter1

Introduction















Contents

1. Hydrogels...7 1.1. Generalfeatures...7 1.2. Synthesis:swellingstateandinhomogeneities...8 1.3. Mechanicalshortcomingofchemicalgels...9 2. Reinforcedhydrogels...11 2.1. Hydrogelswithcovalentarchitectureimprovement...11

2.1.1.



Slideringhydrogels...12



2.1.2.



TetraPEGhydrogels...13



2.1.3.



Doublenetworkhydrogels...14

 2.2. Hydrogelsreinforcedbysecondaryphysicalinteractions...16

2.2.1.



Ionicallycrosslinkedhydrogels...17



2.2.2.



Nanocompositepolymerhydrogels...20



2.2.3.



Microgelreinforcedhydrogels...22



2.2.4.



Hydrogelswithhydrogenbonding...23



2.2.5.



Hydrogelswithdipoledipoleinteraction...25



2.2.6.



Hydrogelswithmetalligandcoordination...26



2.2.7.



Hydrogelswithcrystallinedomains...26



2.2.8.



Hydrogelswithhydrophobicinteractions...28

 3. Thermoresponsivepolymersandhydrogels...30 3.1. Introduction...30 3.2. Thermoresponsivepolymers...31

3.2.1.



CriticalSolutionTemperatureofpolymersinaqueousmedia...31



3.2.1.



Poly(Nisopropylacrylamide)...33



3.2.2.



Zwitterionicpolymers...35



3.2.3.



Poly(Nacryloylglycinamide)...37

 4. Objectiveofthedissertation...39 Reference...42

1.

Hydrogels

1.1.

Generalfeatures

A macromolecular network is a three dimensional assembly of polymer chains that can be covalentlyorphysicallycrosslinked.Theresultingmaterialsarerespectivelycalledchemical orphysicalnetworks.Apolymergelisthenapolymernetworkswolleninaliquid,shownin

Figure 1.1. When the liquid considered is water, they are called hydrogels. Depending on

theirchemicalcomposition,hydrogelsareabletoabsorbvariousamountsofwaterthatcan reach several thousand times their initial dry weight.[12]_{ Because of their hydrophilicity,}

hydrogelsreadilyswellwhenbroughtincontactwithaqueoussolutions,butstillmaintain their solid form due to interchain crosslinks, which display either permanent features by covalent bonds or transient bonding by physical interaction. In addition, also due to their significantwatercontent,hydrogelsalsopossessahighdegreeofflexibilitysimilartonatural tissue. All these interesting properties make them useful for diapers, contact lenses, tissue engineering,[35]_{regenerativemedicineanddrugdelivery,}[69]_{orenvisagedassensorsorsoft}

actuators.[1011]_



Figure 1.1. Scheme presentation of polymer gel (from P.G. De Gennes[12])

Innature,hydrogelsinplantsandtissuesusuallyneedtobearsufficientlystiffnessinorder tosupportmechanicalloadsfromsurroundingcomponents.Similarly,manyapplicationsof artificialhydrogelsdemandthemtomaintainphysicalintegrityovertime,suchasincontact

lenses, wound dressings, drug delivery and coatings; other applications even require hydrogels to carry significant mechanical loads and/or accommodate substantial deformation, such as in artificial loadbearing tissues, oil field packers and hydrogelbased actuatorsandsoftmachines.



1.2.

Synthesis:swellingstateandinhomogeneities

Conventionally,hydrogelsaredefinedashighlyswollennetworks,ofwhichtheamountof water is typically above 90 wt%. However, they behave as solids. Indeed, although the dynamicsofthenetworkconstitutivepolymerchainsisdominatedbythermalfluctuations, likeinliquids,thegelssolidlikebehaviorarisesfromthefactthatnetworktopologyisfixed or“frozen”duringthesynthesis.Todefinethegel,itisthennecessarytoconsidertwostates: 1/ the conditions of preparation (concentration, good or poor solvent conditions, yield of reaction, etc.) and 2/ the situation at the moment of the study (solvent, swelling ratio, temperature,etc.).Hence,the“preparativeensemble”and“finalensemble”areambiguously defined.Themainsourceofinhomogeneitiesinhydrogelsderivesfromthesynthesisofthe networks. During the last few decades, with the development of advanced technologies, especially scattering techniques, the classification and characterization of inhomogeneities insidethehydrogelshavebeeninvestigatedindetail.AccordingtoShibayamaetal[1314]_the

inhomogeneitiesofhydrogelscanbeclassi edinto3groups(Figure1.2):

1) Spatial inhomogeneities, which are due to the nonuniform spatial distributions of crosslinks;

2) Topologic inhomogeneities, which derive from the state of topology of the network suchasloops,trappedentanglementsanddanglingchains;

3) Connectivityinhomogeneities,whichcomefromthesizedistributionandthespatial distributionofbranchedpolymerclusters.



Figure 1.2. Schematic representation of inhomogeneities in gels. Left: spatial

inhomogeneities. Middle: topological inhomogeneities. Right: connectivity inhomogeneities. (From Shibayama et al.[14])

Based on this classification, a number of factors can impact the homogeneity of hydrogels, suchastheconcentrationofmonomerorcrosslinkers,aswellastheintrinsicpropertiesof monomers and initiator systems. For instance, spatial inhomogeneities increase with the concentration of crosslinker in the reactive medium, which leads to strongly inhomogeneous structures. Thus, under large deformation, the extensibility is strongly restrictedbytheshortestchains.

1.3.

Mechanicalshortcomingofchemicalgels

Synthetic hydrogels are often described as “wet and soft” materials. Whereas versatile applicationsrelyonthehighwaterabsorptionability(wet),theirfurtherpotentialarestrictly restrainedbythecorrespondingweakness,i.e.softnessandfragility.

Chemical hydrogels are often compared to crosslinked elastomers (which are dried gels) andreportedtohavelowerstiness(10kPa),strength(100kPa)andfracturetoughness(10 J/m2_).[15]_{ As illustrated in Figure 1.3, from the basic picture of a network formed by a}

collectionoflongandflexiblechains,LakeandThomas[16]_{proposedatheoreticalestimateof}

thethresholdfractureenergyG0topropagateacrackinunfilledrubbers:

G0=JNc

where  is the surface density of chains crossing the fracture plane, Nc is the number of monomer units between crosslinks, and J is the energy required to rupture one covalent bond.



Figure 1.3. Schematic view showing a polymer chain lying across the plane of crack

propagation. (from Lake and Thomas[16])

Suchargumentisbasedontheassumptionthatthetransmittedloadthroughoutthenetwork bringseachbondinapolymerstrandcrossingtheinterfaceclosetoitsmaximalfreeenergy (i.e.thedissociationenergyoftheweakestbondinthemonomerunit).

Ofcourseinthecaseofhighlyswollennetworks,thetheoreticalvalueofthresholdfracture energy G0 decreases with polymer volume fraction and G0 values obtained for gels are

typicallya1 J/m2_{ while they are 10 times higher for un lled rubbers. Yet, experimentally,}

chemicallycrosslinkedelastomerscanexhibitfractureenergies,Gcthatareseveralordersof magnitude higher (around 110 kJ/m²) than the G0 prediction depending on crack

propagationvelocity. Indeed,fractureenergyinelastomerscanbewrittenasthecombinationoftwocontributions: aninterfacialtermandasecondcontributionrelatedtoviscoelasticlossesinavolumenear thecracktip.Thus,Gent[17]_{proposedthefollowingexpressionforthefractureenergy,Gc:} Gc=G0(1+f(aTv)) withG0beingmostlyrelatedtothechemistryoftheinterfaceandthesecondcontribution(1

+ f (aTv)), depending on the mechanical dissipation in the volume and related to the crack

velocityvandthetimetemperaturesuperpositionandshiftfactorv.

Asmentionedabove,inrubbers(i.e.,“dried”gels)thissecondtermcantypicallyenhancethe mechanical energy required to propagate a crack by two or three orders of magnitude. In contrast,chemicallycrosslinkedhydrogelsdonotseemtoexhibitsuchdissipativeprocesses

case, the fracture process is far away from the monomermonomer friction regime. As a result, besides gel’s softness, highly swollen gels demonstrate high fragility and particular sensitivitytodefectsorheterogeneities.

2.

Reinforcedhydrogels

Over the last two decades, due to tremendous demands for tough hydrogels in various applications, intensive research has been carried out to improve their mechanical strength. Manyhydrogelshaveshownsignificantenhancementoftoughnessovertheirconventional counterparts, such as hydrogels with crystalline domains, doublenetwork hydrogels, topological hydrogels and tetraarm polymer hydrogels, ionically crosslinked hydrogels, nanocomposite polymer hydrogels, selfassembled microcomposite hydrogels, hydrogels with hydrogen bonds and hydrogels with hydrophobic interactions. Basically, all these strategies aim at increasing homogeneity inside the network and/or introducing energy dissipation. Based on these points, tough hydrogels can be divided into two groups: hydrogels with covalent architecture improvement and hydrogels reinforced by physical interactions.

2.1.

Hydrogelswithcovalentarchitectureimprovement

Thereissufficientevidencefromhydrogelstudiestoverifythathomogeneouslycrosslinked networks are stronger, and more extensible than a heterogeneous network. Indeed, in a homogenousnetwork,theappliedloadisdistributedoveralargerfractionofchainswitha uniform strain distribution that decreases the number of sites for micro crack formation. Therefore, homogeneous networks are more stretchable than equivalent heterogeneous networksofthesameaveragecrosslinkdensity.

On this basis, different approaches have been investigated with the aim of improving the homogeneity, such as slide ring and tetraarm hydrogels. Meanwhile, by introducing sacrificial bonds, double network hydrogels have also demonstrated excellent mechanical properties.

2.1.1. Slideringhydrogels

Slide ring hydrogels, or “topological gels” (TP gels) were made from necklacelike macromolecules,wherethecrosslinkerscanslidealongapolymerchainandthusallowfor extensive stretching (Figure 1.4). In this case, the spatial inhomogeneities can be greatly reduced. Meanwhile, chain ends have stopper molecules (topological restrictions) that preventdissociationofthecyclicmoleculesfromtheaxis.Forexample, cyclodextrinrings were threaded onto linear polymer chains such as PEG and some of the rings were chemically paired forming sliding crosslinks between chains.[1820]_{ Thanks to its}

homogeneity,thegelcanswelltoabout500timesitsoriginalweightandcanbestretchedto nearly 20 times its original length. Later, the slide ring networks were also shown to be extremelyuniformbysmallangleneutronscatteringandlightscatteringmeasurements.[2122]_

Themechanicsofslideringgelsdifferfromthetraditionalpolymernetworksinthatthereis a “sliding state” where polymer chains are actively sliding through the links. This phenomenonaccountsforthemarkeddifferencesinmechanicalproperties.



Figure 1.4. Schematic drawing of a polyrotaxane with a) a polymer chain of PEG threading the cyclic molecules and end capped with bulky end groups b) after cross-linking of cyclic molecules to form the topological gels c) pulley effect of cyclic molecules and polymer chains under tension. (From Ito et al.[19])

Despitehighextensibilityandhomogeneity,themodulusremainsrelativelylow(around10 kPa) and tear properties have not been reported so far, probably due to weak energy

thePEGchainisrestrictedwithlimitedsolventconditions.Indeed,assoonastheringsstart toaggregate,theirmobilityisgreatlyreduced.

2.1.2.

TetraPEGhydrogels

Another set of polymer networks with high homogeneity is TetraPEG hydrogels (Figure

1.5).Theycanbeformedbycombiningtwostarshapedpolymerswithsymmetricalarmsof

the same size, where the tetrahedron macromonomers react with each other via the functionalgroupsontheendoftheirarms.[2324]_{Maximumcompressionstrengthof2.5MPa}

isobtainedforagelmadefromtwoPEGbasedtetrahedrallikemacromonomerswithamine and succinimidyl ester functional groups when the stoichiometric ratio of the two macromonomers is 1:1. Scaering studies show that these tetraPEG hydrogels are mostly homogeneouswithlowconcentrationfluctuationscomparabletothoseofthecorresponding solutions.[25]_{Iftheratioofthereactingmacromonomersisnotstoichiometric,heterogeneity}

developswiththeincreaseofstructuraldefects.[26]_{Inaddition,itturnsoutthatthegelsare}

verysensitivetofractures[27]_{astheydonotinvolveefficientdissipationprocess.}



Figure 1.5. Preparation and structure of PEG gels. TAPEG and TNPEG are

tetra-amine terminated PEG and tetra-NHS-glutarate terminated PEG, respectively. (From Chung et al[23-24])

2.1.3.

Doublenetworkhydrogels

In 2003, Gong et al.[28]_{ developed the first tough chemical gels by introducing a dissipation}

mechanism at the molecular level through the interpenetration of “strong” and “weak” polymer networks. These hydrogels were prepared in a twostep process: first forming a tightlycrosslinkednetwork,thenswellingthisgelinasolutionofasecondmonomerwitha lowratioofcrosslinkingagent,andfinallycarryingoutasecondpolymerization.Asaresult ofthehighdegreeofswellinginthemonomersolution,thefirstpolyelectrolytegelnetwork (PAMPS) is highly extended in the final material, while the second network (PAAm) is relaxed. Therefore, the first densely crosslinked network provides the hydrogel with high rigiditywhilethesecondlooselycrosslinkednetworkallowsforgoodextensibility.Under these circumstances, the double network hydrogels can achieve extremely high toughness withcompressivestrengthsupto17MPaat90%waterlevelaswellashighfractureenergy value of 1001000 J/m2_{ (Figure 1.6).}[2930]_{ Nevertheless, there isalways a disadvantage ofthe}

tough and double network gels: once covalent bonds of the first network are broken, the damageisirreversible.Aboveacriticalstress,thefirstnetworkfracturesandbuildsclusters thatcanslideandactascrosslinkers.



Figure 1.6. Photographs demonstrating how a DN gel sustains a high compression. a)

PAMPS-single network gel, b) PAMPS/PAAm-double network gel. (from Gong et al.[28])

Recently,amorehomogenoustoughgel[31]_{waspreparedbycombiningdoublenetworkwith}

tetraarmedgels. A nearly homogeneous first network structure basedon tetraPEG gels is formed via a molecular stent method, while PAAm is still applied as the second network. Thiskindofgelshowedessentiallythesametougheningbehaviorasthatoftheconventional doublenetworkgel,whichposestheroleofthehomogeneitywithinthefirstnetworkinthe toughening mechanism of double network gels. At the same time, for the reason of high homogeneity,themorehomogenousfirstnetworkgeldemonstratesmuchweakermodulus degradationthanconventionalones.

After the pioneering work of Jian Ping Gong, several theoretical studies have successfully proposed some interpretation of the toughness of hydrogels.[30, 3233]_{ Meanwhile, several}

double network hydrogels with structure modification have been reported, including hydrogelswithafirstphysicalnetwork,[34]_{involvingnaturalpolymers,}[35]_etc.[3637]_

2.2.

Hydrogels

reinforced

by

secondary

physical

interactions

Generally, crosslinkers formed by covalent bond are more stable than physical ones, as covalentbondenergyishigher(e.g.bonddissociationenergyforCCcovalentbondis347 kJ/mol[38]_{)thanthephysicalinteractions(e.g.bonddissociationenergyforhydrogenbonding}

835kJ/mol;Londondispersiontypehydrophobicinteractionsis48kJ/mol[39]_{).Inthiscase,}

secondary physical interactions can be applied into the hydrogels in order to serve as transient crosslinkers. Unlike pure chemical gels, where inhomogeneities are significant at high crosslink densities,[4041]_{ the polymer networks that are reinforced by secondary}

physicalcrosslinksdonotshowthisdisadvantage.Indeed,transientinterchainassociations allow mobility and chain rearrangements within the network, which may retard fracture propagation,[42]_{Atthesametime,therelativeweakerandmobilebondsalsocontributetothe}

highertoughnessaswellasextensibility,whilethereversibilityofcrosslinkerscontributes greatly to selfhealing. More importantly, thanks to the reversibility of the physical cross links, the energy dissipation involved during breaking and reformation processes can greatly increase the fracture resistance. Moreover, the responsive behavior of physical interactions towards environmental conditions opens the way to stimuli responsiveness of hydrogels.

Ingeneral,thephysicalinteractionsthathavebeenappliedtopreparetoughhydrogelsare versatile (Figure 1.7),[43]_{ such as hydrogen bonding, ionic interaction, crystallization,}

nanocomposite or microgels, dipoledipole interaction or hydrophobic crosslinks. Some representativeworkswillbepresentedinthefollowing.



Figure 1.7. Schematic representation of physically cross-linked hydrogels via. a ionic interactions, b hydrophobic interactions, c self-assembling of stereocomplex formation, d coiled coil interactions, e specific molecular recognition. (From Ebara et al[43])

2.2.1.

Ionicallycrosslinkedhydrogels



Tough,resilientandselfhealingmaterialshavebeendevelopedbyintroducingioniccross linkers, especially polyelectrolytes with cations. A couple of natural polymer or synthetic polyelectrolytescanbeusedforthispurpose,suchasAlginate,Chitosanorpoly(methacrylic acid) (PMAA), while the cations can be chosen from Zn2+_{, Ca}2+_{, Ni}2+_{, Al}3+_{ and Fe}3+_{ etc. It is}

proven that concentration, pH and the nature of the cation can significantly influence the mechanicalstrength.Forexample,followingtheIrvingWilliamsseries,[44]_{Cu(II)complexes}

aremorestablethantheCa(II)complexes.

AnexampleisgiveninFigure1.8whereaionicallycrosslinkedalginateCa2+_{frameisused}

to reinforce a covalently crosslinked PAAm network.[45]_{ Within this type of special double}

network,thePAAmnetworkisrelativelyextensiblebutweakwhiletheioniconeisrigidbut fragile. With this combination, under a certain deformation, the ionic alginateCa2+_{ cross}

linkscanbe“unzipped”anddissipateenergy.Afteracertaintime,theioniccrosslinkerscan be reformed upon unloading. Thus the energy dissipated during material deformation is “recoverable”.Atthesametime,thecovalentbondspreservetheinitialstateofthenetwork beforeandafterstretching.Mechanicaltestingresultsshowthatthegelcouldbestretchedto

gelcanretainafractureenergyover9000J/m2_{,whichsuggeststhatthefractureresistanceof}

hydrogels can be greatly increased by introducing effective energy dissipation mechanism. Nevertheless,thegelissomehowsoftwithtensilestrengthonlyaround160kPa.Extension ofthisworkhasbeenreportedlateronbyusingCa2+_{grapheneoxidecoordination.}[4647]_



Figure 1.8. Schematic representation of three types of hydrogels. a, an alginate gel with only ionic interactions b, a polyacrylamide gel with only covalent cross-links c, an alginate-polyacrylamide hybrid gel: the two types of polymer networks are intertwined, and joined by covalent cross-links (blue triangles) between amine groups on polyacrylamide chains and carboxyl groups on alginate chains. (from Suo et al.[45])

AnothertoughhydrogelwithionicinteractionsistheonedevelopedbyGongetalin2013.[39]_

Unliketheonedescribedpreviously,thispolyampholytenetworkwasformedonlybyionic bonds. Based on the experience on tough hydrogels, weak and strong bonds are randomly distributedinsidethehydrogel(Figure1.9).Thenetworkconnectivity,basedonionicbonds, is characterized by a wide distribution of strength: the strong bonds served as permanent crosslinks to maintain the shape of the gel, whereas the weak bonds perform several mechanical functions: increasing the fracture resistance by bond rupture; enhancing the

shockabsorbancebygeneratinghighinternalfrictionandimprovingthefatigueresistance, fracture resistance and selfhealing by bond reformation. Therefore, very high Young’s modulus (2.2 MPa) and fracture energy (4000 J/m2_{) are obtained. By comparison with the}

previousionicallycrosslinkedgelsinvolvingalginates,thispolyampholytegelshowsaself recoverybehavior:thestressstraincurvecompletelyrecoveredtotheoriginalloadingcurve after a waiting time of 2 h. In addition, excellent biocompatibility and antibiofouling propertiesaredemonstratedaswell.Nevertheless,itisworthnotingthatthewatercontent (5070%)isrelativelylow,atleastmuchlowerthaninconventionalhydrogels. Moreover,the mechanicalpropertiesofthegelsstronglydependonthechemicalstructure:replacementof relatively bulky and hydrophobic ion combinations (MPTC/NaSS) to hydrophilic combination(DMAEAQ/AMPS)cancompletelyhindertheformationofhydrogels.



Figure 1.9. Schematic representation of physical hydrogels composed of polyampholytes. a, an illustration of polyampholyte networks with ionic bonds of different strengths. The strong bonds serve as permanent cross-linking points whereas the weak bonds act as reversible sacrificial bonds that rupture under deformation. b, the chemical structures of monomers used in this work. Cationic monomers: MPTC; anionic monomers: NaSS. (from Gong et al.[39])

Very recently, Zhou et al[48]_{ reported the synthesis of novel dualcrosslinked hydrogel}

prepared by combining both covalent crosslinking and multivalence ion pairing of Fe3+_

reversible sacrificial bonds and rupture to dissipate energies. As a result, ultrahigh mechanicalstrength,excellentelongation,andgoodselfrecoverypropertiesareachieved. Whilethegelscanbestronglyreinforced,theioniccrosslinksarevulnerabletomobileions, which limit the hydrogel applications to some extent, especially under physiological and engineering conditions. For instance, the performance of certain ionically crosslinked hydrogelsdegrademarkedlyinelectrolytesolutions.[49]_

2.2.2.

Nanocompositepolymerhydrogels

Nanocomposite polymer hydrogels can be considered as polymer networks swollen with water in the presence of nanoparticles, which act as multifunctional crosslinkers with the polymer chains (Figure 1.10, left). The incorporated nanoparticles may impart mechanical toughness, deformability, and high swelling/deswelling rates of the polymer network.[5051]_

Since 2002, Haraguchi and coworkers have reported the formation of this type of ‘‘nanocomposite hydrogel” with a unique organicinorganic network structure by the introduction of exfoliated clay platelets in a polymer network of Nalkylacrylamide derivatives.[50,5255]_{Such transparenthydrogelsshowveryinterestingmechanicalproperties:}

extremely high deformability (up to 1000%) and tunable stiness by changing the ratio of inorganic nanoparticles (Figure 1.10, right). In addition, the fracture energy increases dramatically compared with conventional organic gels. Nevertheless for that system, a significant instantaneous residual strain is observed, mostly assigned to platelet residual alignment. Afterwards, the polymer/clay nanocomposite system has been systematically investigated and extended to other architectures. For example, by combining the clay nanoparticleswiththeidealstructureoftetraPEGhydrogels,[56]_{alargeenhancementofthe}



Figure 1.10. Left: Schematic representation of the structure of Haraguchi’s nanocomposite hydrogels, from [52]; Right: Stress-strain curves of nanocomposite PNIPA/clay hydrogels by varying the clay content (NC1 to NC9), in comparison to a corresponding organic hydrogel, from Haraguchi et al.[50]

Similarly,itwasshownthattheintroductionofsilicananoparticlesintopolymerhydrogels strongly impove their mechanical strength. Compared with clays, the spherical and well dispersed silica nanoparticles possess a number of advantages, such as commercial availability,stability,isotropyandfunctionality.Similartothepolymer/claynanocomposite system, the stiffness, strength and toughness can be remarkably enhanced by adding increasing amounts of silica nanoparticles in the polymer networks, especially poly(N alkylacrylamide).[5758]_{ For instance, a variety of mechanical properties are seen to be}

simultaneously enhanced by adding the silica nanoparticles into the poly(N,N dimethylacrylamide)network.Inaddition,theresultinghydrogelsshowtimedependenceof dissipative and recovery processes (Figure 1.11).[59]_{ Based on these hybrid interactions}

involving reversible bonding between polymer chains and silica surfaces, efficient gluing was simultaneously demonstrated by using aqueous nanoparticle suspensions in place of polymeradhesives.[60]_{Inthiscase,physicaladhesionbetweentwogelsurfacescanbereadily}

achievedbysimplyspreadingadropletofsilicananoparticleonthegelsurfaceandkeeping thecontactduringafewseconds.Theresultinggluinghasbeenshowntobeveryefficient, not only with hydrogels but also with human tissues with important applications in vivo organrepair.[6061]_

Following the important development of nanocomposite hydrogels, different mechanisms have been proposed to explain the reinforcement behavior, such as the formation of “clay brush particles”,[62]_{ particleinduced monomer enrichment}[63]_{ or silica/polymer hydrogen}

grapheme oxide,[6465]_{ surfactant particles,}[66]_{ hydroxyapatite nanocomposites or cellulose}

nanocrystals[67]_{)whichalsodemonstrateeffectivereinforcementinmechanicalbehavior.}

Figure 1.11. Left Schematic representation of hybrid hydrogels combining covalent cross-links (orange) and physical interactions sketched by polymer chains adsorbed at the surface of silica nanoparticles. Middle, Strain rate effect of hybrid hydrogel: loading-unloading cycles for varied strain rates. Right, Stress-strain curves of PDMA/Silica nanocomposite hydrogels by varying the silica content (from Marcellan et al.[59])

2.2.3.

Microgelreinforcedhydrogels

Inspired by carbon black reinforced rubbers, the introduction of a hard phase into a soft system seems to be an interesting way to increase the mechanical strength of gels. For instance, macromolecular microsphere composite hydrogels with 100 nm peroxidized microspheres as initiators and crosslinkers exhibit excellent compressive performances (Figure 1.12).[6869]_{ As they can effectively dissipate applied mechanical stress, some of the}

hydrogelscannearlycompletelyrecovertheiroriginalshapesevenafterastrainof99.7%in compression test. Meanwhile, no tensile and tearing properties that truly reflect the resistanceagainstcrackpropagationhavebeenreported.



Figure 1.12. Proposed mechanism for the formation of a macromolecular microsphere

composite hydrogel and a macromolecular microsphere composite hydrogel microstructure (from Wang et al.[68])

Later on, it was shown that the introduction of highly crosslinked microgels inside a hydrogel film is responsible for dramatic enhancement in mechanical strength and toughnessofthesinglenetwork.[70]_{Thehydrogelswerepreparedwithalooselycrosslinked}

continuousphasematrix(PAAm)andavirtuallydoublenetworkmicrogelsdispersephase. Byvisualizingtheembeddedmicrogelsunderstretching,itwasconfirmedthatthedisperse phase serve as sacrificial bonds under stretching and improve the mechanical strength. Whilethemechanicalpropertiesarecomparablewiththeconventionalbicontinuousdouble networks, the preparation of this kind of microgel reinforced hydrogel is easier to handle andfastertoprepare.[71]_

2.2.4.

Hydrogelswithhydrogenbonding

Ahydrogenbondisatypeofattractiveinteractionbetweenanelectronegativeatomanda hydrogen atom bonded to another electronegative atom. For a long time, this kind of interaction has been widely applied in the field of supramolecular chemistry[7273]_{ and}

biomedicinal science.[74]_{ In this case, the introduction of hydrogen bonding is another}

importantstrategyforhydrogelreinforcement.

For example, by simply copolymerizing vinyl4,6diamino1,3,5triazine or 3acrylamido phenylboronic acid inside a chain lengthmodulable polyethylene glycol PEG network, Liu et al. successfully introduced hydrogen bonds into the hydrogels.[75]_{ This gel demonstrates}

The content of hydrogen bonding significantly increases both the tensile and compressive strengthsofthehydrogels.Moreover,pHcanstronglyinfluencetheformationofthiskindof physical interactions,[76]_{ thus changing the macroscopic behaviors. However, fracture}

resistanceisquitelow.

Later on, a quadruple hydrogenbonding strategy has alsobeen developed to prepare self healing and highly deformable tough hydrogels. This kind of polyurethane hydrogel with functionalized PEG unit and 2(3(6methyl4oxo1,4dihydropyrimidin2yl)ureido)ethyl methacrylateunitinside,[77]_{whichhelptoformquadruplehydrogenbonds.Withthisstrong}

hydrogenbondinginteractions,thegelcanautonomouslyrepairoccurringcrackswithin10 minatambienttemperature,asthephysicalinteractionscanbereformedafterbeingcutoff. In addition, they exhibit relatively good elasticity, robustness and toughness as well: the tensile strength of the original polyurethane hydrogels is in the range from 134 to 382 kPa andtheirelongationatbreakexceeds1800%,whichmaybeassignedtothedisplacementof hydrogenbonds(Figure1.13).



Figure 1.13. Schematic model of self-healing and stretching of the hydrogel formed by polyurethane with hydrogen bonding interactions. (from Li et al.[77])

Fromtheabovedescription,hydrogelswithhydrogenbondingshowedgoodenhancement of mechanical behaviors. Meanwhile, unlike the case of rubbers, hydrogen bonds in hydrogelshaverelativelylowerassociationstrengthduetocompetitionofwaterforbinding sites.[78]_

2.2.5.

Hydrogelswithdipoledipoleinteraction

Dipoledipoleinteractionisanotherkindofattractiveforcebetweenthepositiveendofone polarmoleculeandthenegativeendofanotherpolarmolecule.Similartotheotherkindof physical interaction, it can be applied to form crosslinks inside the hydrogels. Liu et al prepared hydrogels by incorporating polyacrylonitrile inside the hydrophilic network by copolymerization.[79]_{ As the nitrile groups in the polyacrylonitrile can form dipoledipole}

interaction, the corresponding hydrogels exhibit an intriguing combination of properties such as several MPa tensile stress, tens of MPa of compressive strength, excellent fatigue resistance and no yielding in the course of stretching. Notwithstanding, relatively low extensibility (below 200% strain) is demonstrated, and no excellent fracture resistance is reported.



Figure 1.14. a, Molecule structure of hydrogel with dual physical interactions; b, schematic description of the destruction and reconstruction of dual physical cross-links in water (from Liu et al.[80])

Later, another type of reinforced gel combining dipoledipole interactions with hydrogen bonding[80]_{wassynthesizedbycopolymerizationofthreedifferentmonomers(Figure1.14a):}

acrylonitrile,inchargeofdipoledipoleformation;acrylamide,hydrogenbondingmonomer; and 2acrylamido2methyl1propanesulfonic acid, an anionic monomer which serves to absorbwater.Impressiveresultsareobtainedwiththehydrogelcomprisingbothhydrogen bonding and dipoledipole interactions: up to 8.3 MPa tensile stress, 4.8 MPa compressive stress and 716% elongation at break. Moreover, as the breakage and reformation of these

highfractureenergyof5500J/m2_{.Inaddition,excellentfatigueresistanceandshapememory}

effect are also demonstrated. However, the preparation of hydrogels is somehow inconvenient,assolventexchangeisneededafterinsitupreparation.

2.2.6.

Hydrogelswithmetalligandcoordination

The metalligand coordination is one of the most basic concepts in nature, which can be applied in medicinal science, metalbased organic synthesis and sensing elements. These kindsofinteractionsarenotonlythermodynamicallystablebutalsokineticallylabile,which makesitsuitableforhydrogelreinforcement.Moreover,theirreversibilityandstrengthcan befinelytunedbychoosingdifferentpairs.

A series of transition metal can form coordination with certain ligands. Beck et al.[81]_

demonstratedthepreparationofroomtemperatureselfhealablegelsviatheselfassemblyof ditopic ligands, consisting of a 2,6bis(1methylbenzimidazolyl) pyridine attached to either endofaPEGcore,inthepresenceoftransitionmetal.FustinandGohy[82]_{reportedthatthe}

formation of coordination interactions between poly(triethyleneglycol methylether methacrylate) and Ni(II) could help to prepare hydrogels with good rheological behavior. Inspired by mussels, histidinedivalent cation coordination bonds and 4nitrocatechol/3 hydroxy4pyridinonone cation complexes were developed by Messersmith[83] _and

Hawker,[84]_{respectively.Itprovesthatthemechanicalpropertiesshowastrongdependence}

on the nature of metals and ligands used. However, these physical gels with only metal ligandcoordinationseemtobetooweakfortractiontest.Inaddition,thepropertiesofthe resultinggelsareshowntobepHandionicsensitive.

2.2.7.

Hydrogelswithcrystallinedomains





Gelsreinforcedbycrystallizationareanotherfamilyofhydrogelswithexcellentmechanical properties and unique microstructures. Specially, when aqueous solutions of poly(vinyl alcohol) (PVA) with a high saponification ratio undergo a freezethawing or castdrying process, a strong and highly elastic gel is formed.[85]_{ Gel formation is ascribed to the}

formationofPVAcrystallites,whichserveasphysicalcrosslinkersinthenetwork.Whenthe numberoffreezethawingcyclesorcastdryingprocessgrows,thedegreeofcrystallinityof

reversible and stable with mobile ions, it makes them suitable to use under physiological environment. In this case, PVA has been widely used and extensively developed for biomedicalapplicationsduringthelastfewdecades.[8687]_

WangetalreportedthepreparationofPVAhydrogelswithanisotropicmicrostructurewith the directional freezingthawing method.[88]_{ Hence, the gels demonstrate significant}

anisotropy in their mechanical properties: their tensile strength, modulus and fracture energy being much higher in one direction compared with the other. Unfortunately, PVA hydrogelssynthesizedwiththismethodarebrittle.BesidesPVA,itwasfoundthatphysical gelscouldbeachievedwithpoly(2hydroxyethylmethacrylate).[89]_

A hybrid hydrogel involving chemical crosslinkers, hydrophilic interaction and crystalline polymernetworkshasbeenreportedrecently.[90]_{Inthesystem,alargenumberofcrystallites}

serve as physical crosslinks that are both stable and reversible; the covalently crosslinked hydrophilic polymer chains maintain the elasticity of the network during deformation and control the swelling of the hydrogel. In this case, the high crosslink density induced by crystallites is responsible for the remarkable stiffness of the material (Figure 1.15): the gels achieveanelasticmodulusof5MPa,astrengthof2.5MPa,andafractureenergyof14000 J/m2_{,whilemaintainingphysicalintegrityinconcentratedelectrolytesolutions.Meanwhile,}

itisworthnotingthatthewatercontent(67%)ismuchlowerthaninconventionalhydrogels.



Figure 1.15. Stress-strain curves of gels with (red) or without (green) freezing-thawing method (from Wang et al.[90])

2.2.8.

Hydrogelswithhydrophobicinteractions

With a large amount of water, hydrogels are basically hydrophilic. In this case, the introductionofhydrophobicmoietiesthatareabletoselfassociateinwatercandramatically increasetheextensibilityandresistancetocrackpropagation.

Forexample,bycopolymerizingasmallamountofhydrophobe(e.g.Nbutyl,Nhexyl,N octyl, N,Ndihexylacrylamides) with acrylamide and methylenebisacrylamide in the presence of sodium dodecyl sulfate (SDS), hydrophobically modified hydrogels were obtained with improved extensibility and resistance to crack propagation due to the deformationofhydrophobicassociationsunderstress.[91]_{However,largerhydrophobessuch}

as stearyl methacrylate (C18) or dococyl acrylate (C22) cannot be simply copolymerized insidethechemicalhydrogelofacrylamidesimplyduetotheirlowwatersolubility.

Later,thisproblemwaspartiallysolved,bycopolymerizingsmallamountsofhydrophobic monomers without chemical crosslinks[9296]_{ (e.g. stearyl methacrylate (C18) or dococyl}

acrylate(C22))withhydrophilicmonomers(e.g.PAAm,PDMA,PAA)inamicellarsolution ofsodiumdodecylsulfate(SDS).Withthisprocedure,Okayetal.havedevelopednewseries of physical hydrogels with unusual and intriguing properties. For instance, the hydrogels formed via hydrophobic interactions between C18 units exhibit good stiness (Young’s moduli 180600 kPa) and shape memory properties with a recovery ratio of 100%. Nevertheless, due to the lack of permanent crosslinks, the original length of this kind of physicalgelisnotrecoverableafterdeformation.



Figure 1.16. Illustration of the ternary stimuli responsive photonic hydrogel (from Gong et al.[97])

Another example of reinforced hydrogels with hydrophobic interactions is the anisotropic hydrogel with bilayer structures reported by Gong et al.[9798]_{ Inspired by cell membrane}

structure,hydrophobicsurfactantdodecylglycerylitaconatewassynthesizedinsideaPAAm matrix, which results in thousands of nanoscale lipidlike domains. Very interestingly, the unidirectional orientation of lamellar bilayers led to the onedimensional swelling of the network, and elastic modulus anisotropy with a 10fold difference. Later, by introducing a second network of poly(acrylic acid) (PAA), a photonic hydrogel is obtained (Figure 1.16). Besidesgoodtoughness,theresultinggelsaremultiplestimuliresponsive:temperature,pH, andstress/strain.Furthermore,thegelexhibitspositivethermochromaticbehavior,whichis attributedtothereversibleassociationanddissociationofhydrogenbondsbetweenPAAm andPAAinthesoftlayer.

Recently,itwasfoundthathydrophobicinteractionscouldalsoserveasthesecondnetwork of double network hydrogels. Simply using a onepot method, physically crosslinked Agar/hydrophobically associated polyacrylamide double network gel was synthesized by

Zheng et al.[35]_{ Similar to the conventional double network gels, this gel exhibits excellent}

mechanical strength and high toughness. More importantly, as the physically crosslinked second network can bear stress and reconstruct network structure, this gel demonstrates rapidselfrecovery,remarkablefatigueresistance,andnotableselfhealingpropertywithout any external stimuli at room temperature. All of these improvements greatly broaden the avenueoftheirpotentialapplications.



3.

Thermoresponsivepolymersandhydrogels

3.1.

Introduction

With the aforementioned examples, it is clearly shown that the mechanical behavior of hydrogels can dramatically rise by introducing secondary interactions in the covalent structure, but the reversibility of these interactions cannot be simply and finely controlled. Now, from a fundamental point of view as well as for specific applications, it could be desirable to switch on/off the association process through a simple environmental trigger. This also offers the possibility to prepare hydrogels in water and to tune the hydrophobic associations by a simple environmental switch contrary to hydrophobically modified hydrogels that generally require a solvent exchange procedure after being prepared in organic media. Moreover, such systems would offer the possibility to investigate the exact contribution of physical interactions on the mechanical properties of the swollen network and/ortodevelophydrogelswithresponsivetoughness.

In the past few years, the introduction of responsive stickers into macromolecular architectureshasopenedupthewayofreversibleassociationsandpromotedtheformation of physical networks using physical stimuli such as temperature, pH, ionic strength, shear stress,light,etc.[99104]_

From a practical point of view, temperature and light are two stimuli that are readily applicabletobulkhydrogels,andtheyhavedrawnconsiderableattentioninacademicand industry during the last few years, especially in drug delivery systems.[105107]_{ More}

3.2.

Thermoresponsivepolymers

3.2.1.

CriticalSolutionTemperatureofpolymersinaqueousmedia

Generally,thermoresponsivepolymersarematerialsthatshowavolumechangeatacertain temperaturewhereasharpmodificationofthesolvationstateoccurs.Asaslightchangein temperature can cause significant change of macroscopic properties, these polymers have potentialapplicationsinaverywiderangeofindustriesaswellasinbiomedicine.

Basedontheirresponsivebehaviors,thermoresponsivepolymerscanbeclassifiedintotwo main categories (Figure 1.17): Upper Critical Temperature Solution (UCST, positive temperature responsive) type and Lower Critical Temperature Solution (LCST, negative temperatureresponsive)type.



Figure1.17. A schematic plot of polymer/solvent binary mixture showing different phase transitions UCST or LCST.

UCSTisthecriticaltemperatureabovewhichthecomponentsofamixturearemisciblefor all compositions, while LCST is the opposite case. When the temperature of a solution is beyondthephaseseparationtemperature,interorintraaggregationsleadfromananotoa macro phase separation. Following the responsive behavior, thermoresponsive polymers canbedividedinto3types:

1) PolymersthatfollowtheclassicFloryHugginsbehavior:theirtransitionpointshifts uponchangingthepolymermolarmassorconcentration(e.g.:PNAGA,PEO);[108]_

2) Polymers/solvent binary systems where the transition temperature is hardly influencedbymolarmassorconcentration(e.g.:PNIPA);[109]_

3) Polymers that exhibit a bimodal phase diagram, presenting two critical points for low and high polymer concentrations corresponding to the Type 1 and Type 2 behaviors,respectively(e.g.:PMVE).[110]_

While the type 1 and 3 give a possibility for a large temperature range, type 2 is easier to handleforpracticalapplications.

EvenifUCSTistheregularbehaviorforbinarysystemsaccordingtoFloryHugginstheory, water is far from being a simple solvent and one can find much more LCST polymers in water than UCST polymers. As phase transition in aqueous media drives very important applications, LCST type polymers have generated much more interest than the UCST types.[111]_{ For example, since 2010, only 253 papers on UCST type polymer/water mixtures}

havecomeout(WebofScience),comparedwith1607equivalentLCSTmixtures.Whilealot of polymers show a thermoresponsive behavior in given conditions (temperature, solvent…),wearemoreinterestedhereinpolymershavingatransitiontemperatureinwater close to room or body temperatures. Focusing on their chemical structures, the UCST and LCSTtypesyntheticpolymerscanbeclassifiedintodifferentfamilies(Table1.12).



Table 1.1 Classification of UCST-type polymers in aqueous solution

Entry _{Category Example Transitiontemperature}

1 Zwitterionicpolymers PDMAPS 1532o_C 2 Poly(uracilacrylate) _{PAU 60}o_C 3 Poly(Nacryloylglycinamide) andderivatives PNAGA 1530 o_C 4 Ureidobasedpolymers poly(allylamineco allylurea) 1650oC 5 Polyelectrolytes _PEObP2VPH+_{S2O82 4070}o_C 6 Copolymersbasedon acrylamide poly(AAmcoAA) 25 o_C 7 Polymethacrylamide _{PMAAm 55}o_C