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PhD-Dissertation Chapter1.typ
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== Introduction<introduction>The crosslinking of polymers to create thermosets was a crucialinnovation in human history. The first polymer scientists, the ancientOlmec, were known to extract latex from _Castilla elastica_ trees and mixit with juice from the _Ipomoea alba_ vine to convert the latex intorubber as early as 1600 B.C.E. In fact, the name Olmec means \"rubberpeople\" in Nahuatl. Olmec derives from the Nahuatl Ōlmēcatl (singular)or Ōlmēcah (plural), which in turn is derived from ōlli, meaning\"natural rubber\", and mēcatl, meaning \"people.\"@coe2017Archaeologists applied this name to the ancient culture before it wasunderstood that the rubber people the Nahuas referred to were theircontemporary neighbors in the Gulf Lowlands since the time of the Aztecs(more properly the Mēxihcah), not the ancient Olmecs of 2000 yearsprior. The name stuck, and it wonderfully illustrates the ingenuity of theOlmecs.@diehl2004
#figure(image("Images/RubberBall.png", width: 80.0%), placement: auto, caption: [Mesoamerican people were the first polymer scientists. An image of a rubber ball preserved in soil, from El Manatí, 1600 BC.@perez2024])<fig:rubberball>
The Olmec used this rubber to fashion elastic balls as heavy as 9 lbsfor use in the mesoamerican ballgame. By varying the ratio of latex tojuice, rubbers of varying elasticity could be produced suited todifferent needs. In addition to making game balls (@fig:rubberball), they would also make rubber soled sandals, watertightcontainers, and waterproof fabrics by impregnating fabric with thelatex/juice mixture.@tarkanian2011@hosler1999@tarkanian2003@ricarte2024This technology would spread to later mesoamericans, and eventually benoted by colonists.
While this rubber was initially viewed as a curiosity by Europeans, somethree and a half millennia later, this class of materials and itscharacteristic liquid to solid transition would come to underpin manydevelopments in polymer science. Charles de la Condamine sent a sampleof rubber to the Académie Royale des Sciences from Ecuador in 1736. LaCondamine described rubber as originating from the milk, or as he calledit \"latex,\" a term still in use today, of Hévé trees. Joseph Priestleycoined the term \"indiarubber\" in 1770 after coming across a sample inan artist supply shop being sold to rub off pencil markings, eventuallybeing shortened to just rubber.@wake1983 In 1844 Charles Goodyearrediscovered and received a patent for the process of vulcanization ofnatural rubber.@fisher1939@guise-richardson2010 In 1907 Leo Baekelandintroduced the first commercial synthetic plastic, phenol-formaldehyderesin Bakelite, \"the material with a thousand uses.\"@baekeland1909 Themolecular underpinnings of these materials was put forward by the\"father of polymer chemistry\" Hermann Staudinger in his groundbreakingpaper \"On polymerization\" in 1920.@frey2020 Staundinger himselfunintentionally supported his macromolecular hypothesis withcyclopentadiene crosslinked by Diels-Alder reactions, which would not beunderstood until 1928.@bruson1926@veldman2009@diels1928 The concept ofgelation, the point at which polymers are crosslinked into a singlemolecule that spans a given volume element, was then firstquantitatively described by Paul Flory in 1941,@flory1941 as well as astatistical mechanical treatment of crosslinked polymers in1943.@flory1943@flory1943a
The years since have seen momentous developments in the field of polymerchemistry enabling the synthesis of polymers, and by extensionthermosets, by radical polymerizations with predictable molecularweights, low dispersity, and diverse functionality. Prior, free-radicalpolymerizations would produce \"dead\" polymers, those that cannotparticipate in further monomer addition, with heterogeneous degrees ofpolymerization. In 1956, Szwarc introduced the concept of a \"living\"polymerization,@szwarc1956 in which the propagating carbanion remainsactive even after all monomer is consumed. However, carbanions areeasily destroyed by impurities and cannot be regenerated after theirdestruction. In 1993, Georges _et al._ demonstrated a \"living\"free-radical polymerization with a narrow dispersity usingnitroxide-mediated polymerization (NMP).@georges1993 In 1995, Wang &Matyjaszewski and Kato _et al._ independently introduced atom transferradical polymerization (ATRP).@kato1995@wang1995 In 1997, the third ofthe three major reversible deactivation radical polymerizations (RDRP),reversible addition-fragmentation chain transfer (RAFT) polymerization,was introduced by Chiefari _et al._@chiefari1998 All three methods producepolymers with stable, dormant end groups that can subsequently bereinitiated. Suddenly chemists and engineers had several techniques attheir disposal for easily preparing well defined polymers with lowdispersity, a variety of functional groups, and with controlledarchitectures, enabling the production of ever more sophisticatedthermosets.
Polymer thermosets have since come a long way, rising to dominate muchof our world. By adjusting the crosslink density, as the ancient Olmecsdiscovered, and chemical structure the properties of the final materialcan be tuned to suit a whole host of applications. Additionally, thecrosslinked nature of thermosetting polymers impart solvent resistance,thermo-mechanical resistance, and chemical, wear, and creepresistance.@alabiso2020 The combination of these properties, as well astheir light weight, have made them irreplaceable in high performanceenvironments such as aerospace@ma2023 and renewable energy.@wang2024With applications further ranging the gamut from soft materials liketouch sensors,@reynolds2020 tissue mimicking hydrogels for cellculture,@jansen2022 re-processable pressure sensitiveadhesives,@arrington2018 to high-modulus materials like printed circuitboards,@lee2016 protective coatings,@kathalewar2014 structural compositematerials,@li2022 and many more too numerous to list, crosslinkedmaterials have become completely irreplaceable.
== Mechanoresponsive Thermosetting Materials<mechanoresponsive-thermosetting-materials>=== Introduction<introduction-1>Until recently, virtually all thermosetting materials have beencrosslinked, a.k.a. cured, by either temperature, radiation, or simplyspontaneous reactions upon mixing. These techniques generally induce theformation of covalent bonds between polymer chains or the polymerizationof small multifunctional molecules to form a three-dimensional networkstructure. Each approach to crosslinking has distinct advantages anddisadvantages. Thermal curing involves using high temperatures to driveforward crosslinking reactions that either occur very slowly at roomtemperature or not at all.@engels2004 Thermal curing is well suited forlarge samples, but is very energy intensive and requires anunderstanding of the thermal properties of the substrate to drive fullconversion.@abliz2013 Spontaneously thermosetting materials are cured bymixing, often by step polymerization, however this relinquishesspatiotemporal control over gelation and can make applying the mixturedifficult. Radiation-based curing, often achieved through free radicalpolymerization (FRP) with photosensitive radical initiators, can be veryfast and energy efficient, but the penetration depth of light orelectrons is limiting and the byproducts of radical initiators can betoxic. Reaching full cure is often not possible, and further thermalcuring is required in addition to radiation exposure.@raghavan2000Additionally, radiation curing cannot be conducted through opaquematerials, limiting their application space. As such, there is a need todevelop new methods of curing thermosets that can be conducted throughopaque materials, with lower energy cost, and with spatiotemporalcontrol.
Nature has had eons to develop and refine exquisite molecular machinerythat puts even the very best of modern chemistry and engineering toshame. Looking across the natural world, one will find it replete withstimuli responsiveness. Retinal based photosynthesis captures and storesthe energy of light through cis-trans isomerization coupled to ionpumps,@ernst2014 and chlorophyll based photosynthesis stores the energyof light through electron transfer.@vishniac1958 It's worth noting thatchlorophylls have been harnessed by polymer chemists to inducepolymerization with light.@shanmugam2015 Methods of sensing oxygencontent, temperature, and pH just to name a few more, are crucial forsurvival.@kumar2007@damaghi2013@tan2016 More rare in syntheticmaterials, but common in nature, is constructive responsive tomechanical forces.@eyckmans2011
Natural materials can respond to mechanical force constructively bypolymerizing under deformation, as is the case forfibronectin.@gee2008@gee2013@klotzsch2009@mao2005 Under stain, thetertiary structure of fibronectin partially unravels, exposing crypticbinding sites that then participate in mechanically-inducedpolymerization and fibril formation. Mechanical force can also changegene expression. Extracellular mechanical forces can be propagated fromfocal adhesions through the cytoskeleton and LINC complex directly tochromatin, causing chromatin stretching and mechanosensitive geneexpression.@dupont2022 Taking mechanically-induced unfolding of proteinsand protein complexes as inspiration, our lab and others have developedgels that stiffen in response to applied cyclic compression by forminginterchain disulfide bonds and thioethers.@lee2016a@tran2017@sonu2023However, these gels are not currently well suited for adhesives orcoatings due to the difficulties of applying solid materials tosubstrates. The development of liquid pre-cursor solutions that cancrosslink via mechanical perturbation for easy solution spread across achosen substrate would transform a range of industries where reliance onthermal, UV, and electron beam curing makes on-demand curing ofadhesives and post-crosslinking strengthening of coatings difficult.
=== Sonication as a tool for applying targeted force<sonication-as-a-tool-for-applying-targeted-force>Imparting force onto polymer chains is commonly achieved when thepolymer is in a fluid state, either as a melt, a glassy liquid, or asolution. When studying polymers, shear is most often applied, and shearis applied through the oscillations of parallel plates, extrusion, orultrasonic waves. In solution, linear polymers exist in a solventdependent coiled state (a Gaussian coil) in which the end-to-enddistance is much smaller than the contour length of the polymer (thelength of the polymer at maximum extension).@rubinstein2003 When polymersolutions flow rapidly near a surface (as in the case of parallel platerheology or extrusion through a narrow opening)@graham2011@boger1987 orare sonicated,@akbulatov2017 the shear forces cause this coiledstructure to be disrupted. Commonly, and perhaps intuitively, it isthought that tension along the polymer backbone reaches a maximum at thechain center, at which point enough force is accumulated along thebackbone such that mechanochemistry can occur. Models have been proposedbased on this, one suggesting polymers fully stretch, with theend-to-end distance reaching the contour length (overstretched chain),or there is only partial unfolding of the polymer coil based around thechain center (overstretched segment, @fig:dynamicchain).@diesendruck2023 More recent work has suggestedinstead that polymer unfolding in response to shear force may instead bea dynamic process in which chain unfolding begins at the polymer ends,with the overstretched segment propagating and growing along thebackbone until it is sufficiently strained to reactmechanochemically.@oneill2023
#figure(image("Images/DynamicChain.png", width: 80.0%), placement: auto, caption: [ Dynamic overstretched chain model. Overstretched segments of polymer (red) propagate and grow along the backbone in response to cavitations caused by ultrasound. ])<fig:dynamicchain>
In the case of polymers flowing near a surface, the shear forces aredriven by physically pushing a solution through an opening or moving asurface rapidly parallel to the liquid. In the case of sonication, forceis generated through the application of ultrasound, which has been knownto degrade polymer chains since 1939.@schmid1939 Ultrasound consists ofhigh frequency sound waves, with the 20 kHz to 2 MHz regime being\"destructive\" ultrasound necessary for for sonochemical andmechanochemical transformations. Sound waves compress and expand liquidsas they are ultrasonicated, in places causing distances that are largeenough to \"break\" the liquid and form cavitation bubbles. Thesebubbles expand over several cycles of compression and rarefaction untilthey grow large enough to become unstable, at which point it collapses.The collapse generates strong pressure gradients, causing a shear forceas the surrounding area is pulled towards the center of the implosion,affecting an area on a micrometer scale.@paulusse2006 These pressuregradients and resultant shear forces are commonly cited as the source ofmechanochemical transformations of polymers in response to sonication.Sonication as a means to drive chemical changes offers advantages overradiation and thermal curing. For one, sonication can be focused throughopaque materials.@kuang2023 Additionally, sonication consumes up to25,000 times less energy than thermal curing processes.@biswal2023However, sonication also generates heat, and the strong shear forcesgenerated can cause chain scission events.
=== Mechanophores<mechanophores>The field of polymer mechanochemistry has its origins in paperspublished by none other than Staudinger himself in the 1930s describingthe reduction in molecular weight of polystyrene samples after ballmilling.@staudinger1930a@staudinger1930@staudinger1934 The idea thatthis decrease in molecular weight was a direct result of shear forcescausing homolytic C--C bond cleavage was put forward by Kauzmann andEyring in 1940,@kauzmann1940 and then confirmed by Tabata _et al._ bystudying ultrasonicated polymers with electron paramagnetic resonance in1980.@tabata1980 That same year, Encina _et al._ demonstrated thatpolymers containing randomly distributed peroxide linkagespreferentially undergo scission at O--O bonds over C--Cbonds.@encina1980 In 2005, Berkowski _et al._ took the field a stepfurther from random cleavages to targeted cleavages by demonstrating thepreferential cleavage of chain-centered azo linkages.@berkowski2005Around this time at an Army Research Office workshop on polymermechanochemistry, Caster suggested the name \"mechanophore\" forfunctional groups that undergo chemical transformations in response tomechanical force.@li2015
The field grew after Hickenboth _et al._ published on biasing reactionpathways with mechanical force,@hickenboth2007 and while Woodward andHoffman may have been certain there would never and could never beexceptions to their pericyclic selection rules,@woodward1969 exceptionswould indeed arise. In this case, Hickenboth et al. conclusively showedthat both cis and trans isomers of polymer chain centered1,2-diacetoxybenzocyclobutene undergo a disrotary and conrotary,respectively, electrocyclic ring opening to form the E,E isomer ofortho-quinodimethide in response to mechanical force, in directviolation of the Woodward-Hoffman rules (@fig:HickenbothFig).This of course caused an explosion of interest in polymermechanochemistry, and mechanophores have since been developed forseveral applications including strain sensing,@raisch2018catalysis,@groote2013 and of course,crosslinking.@wang2015@groote2014@ramirez2013 Whereas previouslymechanochemical reactions resulted in the breaking and weakening ofpolymer chains, now there are ways to link chains together to formcrosslinked solids through mechanical force.@willis-fox2018@ghanem2021
#figure(image("Images/HickenbothFig.png", width: 100.0%), placement: auto, caption: [ Cartoon depiction of the predicted reaction pathways of 1,2-diacetoxybenzocyclobutene. Reproduced from Hickenboth et al. @hickenboth2007 ])<fig:HickenbothFig>
=== Limitations<limitations>A popular route to achieve mechanochemical transformation of polymericmaterials is to employ mechanophores. These motifs are speciallytailored weak bonds that can be incorporated into polymer chains thattransform into predictable products upon application offorce.@brantley2013@kean2013@kean2015@jung2021 However,mechanophore-mediated strengthening of polymeric materials remains achallenging approach for mechanical force curing of polymers for severalreasons. First, these moieties typically are restrained by limitedincorporation in polymer chains resulting in low crosslinking densitiesupon activation. Further, conversion of mechanophores is often low,resulting in poor activation even with good incorporation.@lloyd2023 Thechemistry necessary to implement mechanophores is complex in its designand execution, making the approach inaccessible. These moieties are notcommercially available. Typical means of mechanochemical activation tendto introduce significant and destructive bond scission, which one mustbe careful to avoid by selecting appropriate forceregimes.@grandbois1999@garnier2000 Chapter 2 describes my approach usingoff the shelf chemistries to produce materials that are constructivelysensitive to mechanical force with high conversions.
== Polymer architecture and bulk properties<polymer-architecture-and-bulk-properties>=== Introduction<introduction-2>Likely the first report of controlled polymer architecture and the first report of comb polymers arrived in the 1944 when Rehberg and Fisher prepared high $n$-alkyl polyacrylates.@rehberg1944 This was followed by Kaufman _et al_. 1948 who observed that higher $n$-alkyl polyacrylates show sidechain crystallization.@kaufman1948 These comb-like polymers were defined as polymers where each monomer bears its own polymer sidechain@plate1974, though in modern polymer science they can be defined as polymers were only some monomers bear their own polymer sidechains.
Another early example of controlled polymer architecture, block polymers,arrived in 1951 when Vaughn et al. published a study of new nonionicsurfactants, including block copolymers of poly(ethylene oxide) (a.k.a.poly(ethylene glycol) (PEG)) or poly(propyleneoxide).@vaughn1951@mankowich1954 Known commercially as poloxamers, thisparticular class of polymers remains highly studied and useful examplesof molecular design to this day.@surve2024 Living polymerizations wouldbe described just a few years later in 1956,@szwarc1956 which wouldsubsequently enable the facile preparation of whole new classes of blockpolymers as well as far more exotic examples of molecular architecture.
Living polymerizations would enable far more exotic examples of polymerarchitecture compared to linear polymers.@hadjichristidis2006 In theabsence of impurities, the carbanion active site remains intact even atfull monomer conversion, meaning a wealth of facile chain endmodifications were now within reach. In 1984, Rempp et al. published thefirst synthesis of macromonomers by modification of thecarbanion.@rempp1984@rempp1985 This would soon be followed up by thefirst publications on what are now called bottlebrush polymers byTsukahara et al. in 1989@tsukahara1989 through a combination of livinganionic polymerization and FRP, and then a more detailed investigationinto their physical properties in 1994.@tsukahara1994 At this pointhowever, the preparation of bottlebrush polymers was still quitedifficult. The free radical homopolymerization of $omega$-methacryloylfunctionalized polymers has several limitations, chiefly among them thedilute nature of the methacrylate functional group.@muehlebach2003 Itwould take further progress in polymer synthesis to unlock new routes tobottlebrush polymers, with ring opening metathesis polymerization andRDRPs in particular enabling the routine synthesis of cylindricalmolecular brushes with a huge array of monomers.
=== Comb polymers<comb-polymers>Polymer thermosets have several advantages over their small moleculecounterparts, including shortened gelation time due to less reactionsneeding to take place to achieve a volume spanning element, tunablearchitecture and phase behavior inherited from the polymer architecture,and the formation of stable one-pot latexes. Properties of the finalcrosslinked material are often inherited from the properties of theconstituent linked polymers. For example, the fibrillar structure ofcollagen I results in strain stiffening behavior,@motte2013 andsynthetic block copolymers exhibit microphase separation affectingvitrimer processing,@lessard2020 allowing for additional handles tocontrol the properties of these crosslinked networks.
Comb polymers are no exception to this, and the vast design space of these branched polymers allows for the preparation of polymers with interesting phase behavior and conformation. For example, synthesizing reactive comb polymers with easily crystallizable sidechains allows for the preparation of crosslinked thermosets containing crystalline domains in the cured product,@claesson2004@lorenzana2024 increasing it's toughness and modulus. Their high molecular weight allows for quickgelation times,@reynolds2020 consequently requiring less energy to cure. The low viscosity of comb polymer solutions and melts further reduces the energy needed to process polymer combs,@kong2021 and can be used to modify the viscosity of polymer blends.@2009 Moreover, by adjusting the composition and stiffness of the backbone, combs can be used as next-generation compatibilizers between immiscible polymerphases@dong2015 as well as tough networks and adhesives on their own.@zhang2016a@ohnsorg2024
=== Bottlebrush polymers<bottlebrush-polymers>Formally defined as a subset of comb polymers, bottlebrush polymers are a class of polymers characterized by thepresence of densely grafted side chains along a main backbone. Thesepolymers can be described using three variables: the degree ofpolymerization between each graft $(n_g)$, the degree ofpolymerization of the main backbone $(n_(b b))$, and the degree ofpolymerization of the side chains $(n_(s c))$. The crowding parameter$(ϕ)$ is defined by $n_g$ and $n_(s c)$, and provides a mathematicaldefinition for the transition from loosely grafted comb to denselygrafted bottlebrush polymer (@fig:BottlebrushPhases). Above a threshold $ϕ$, the intense sterics ofthe densely grafted side chains increase the rigidity of and createstension along@panyukov2009 the main backbone, causing the brush to adopta wormlike morphology, and preventing polymer chainentanglements.@reynolds2020@sheiko2019@xie2019 This lack of polymerentanglements, evidenced by the zero shear viscosity deviating from$eta_0 tilde.op N^3.4$,@dalsin2014 is most often exploited to createsuper soft additive free elastomers.
#figure(image("Images/BottlebrushPhase.svg", width: 100.0%), placement: auto, caption: [ Phase diagram for methacrylic bottlebrush polymers. Depending on $n_(s c)$, $n_(b b)$, and $n_g$ polymers with grafted sidechains can be categorized either as combs, bottlebrushes with rigid sidechains (RSC), stretched sidechains (SSC), or stretched backbones (SBB). ])<fig:BottlebrushPhases>
Perhaps owing to their recent discovery, bottlebrush polymers as a classof materials are relatively unexplored, and as a consequence poorlyunderstood. Models of describing the conformation of individualbottlebrushes@liang2018 and their melt behavior@liang2017 have been putforward, but these almost always describe bottlebrush polymers withhomopolymer side chains. Only recently has the self assembly ofbottlebrush block polymers in melt@dalsin2015 and solution@pan2021 beendescribed. Bottlebrush polymers with more complicated architecture, suchas block polymer sidechains (core-shell architecture) are poorlydescribed. Relatively well understood parameters of linear polymers suchas the Flory-Huggins polymer-solvent interaction parameter, $χ$, are farless well modeled for bottlebrush architectures, and only grow moredifficult to understand when secondary interactions like hydrogenbonding are taken into account.@bates2017 Predicting the Kuhn lengthsand persistence lengths of bottlebrush polymers as well remains achallenge, with experimental and theoretical studies offeringcontradictingconclusions.@dutta2019@lecommandoux2002@feuz2005@yethiraj2006@clarke2024Studies of bottlebrush polymers composed of reactive monomers capable ofparticipating in crosslinking are almost completely absent, and onlystudied as additives to other thermosetting resins.@moon2021 Somesamples of bottlebrush mechanochemistry have been published, thoughthese have very low functionality, only bearing mechanophores at thebackbone-arm junction.@noh2021@peterson2021 Given the unique morphology,lack of entanglements, large size, and potential for phase separationand microdomain formation, bottlebrush polymers present an opportunityto design high performance thermosetting materials. Already they havefound applications in fields such as touch sensors,@reynolds2020pressure sensitive adhesives,@arrington2018@maw2023 solvent freeelastomers,@daniel2016 nanocapsules for drug delivery,@huang2011 andantifouling coatings,@yoshikawa2022 but highly crosslinked bottlebrushes have not been studied to date.
=== Highly crosslinked combs<highly-crosslinked-combs>Chapter 3 details my work preparing robust, highly crosslinkedcomb polymers. When designing these materials, I imagined apolymer of extremely high molecular weight with a high density ofcrosslinkable sites. The final crosslinked material should be a highmodulus, insoluble solid. To achieve this, I selected GMA as thereactive monomer, which bears a pendent epoxide ring capable ofparticipating in nucleophilic additions to create intermolecularcrosslinks. To investigate the spatial effects of crosslinks ontoughness of the final thermoset, I identified BMA as an attractivecopolymer for GMA to act as a small spacer and internal plasticizer. Myapproach to identifying a highly crosslinkable, tough combs was tofirst synthesize a suite of polymers of different architectures: linearand comb, homopolymer and copolymer, and random and block. Then,I investigated crosslinking these polymers with succinic acid, a smalldi-carboxylic acid, to create a tightly crosslinked network. Finally, weinvestigated the toughness of the resultant materials. Comb polymerswith random sidechains produced crosslinked materials with highermodulus and toughness than polymers with block or homopolymersidechains.
== Hydrogel preparation<hydrogel-preparation>=== Introduction<introduction-3>Whereas the previously discussed thermosets are designed to be dispersedin organic solvents or used neat, polymers can also be designed to behydrophilic. When crosslinked, hydrophilic polymers form hydrogels that swell in the presence of water but do notdissolve. Mammalian, plant, and bacterial cells are known to synthesize, secrete, and assemble a mix of proteins, proteoglycans, and sugars tocreate extracellular matrices (ECM).@flemming2010@mouw2014@seifert2010The ECM in turn provides both chemical and mechanical cues tocells,@ringer2017 directing cell fate, morphology, andphenotype.@lantoine2016@wei2022@peyton2008@yeung2005 Hydrogels have fordecades attracted researchers due to their 3D network structure closelymimicking that of natural ECM, with the first cell encapsulation beingdemonstrated in 1980.@lim1980 Synthetic analogues in particular havebeen an area of intense focus as means to more precisely control theencapsulated cell environment compared to natural products, which oftenshow large lot-to-lot variability.@kozlowski2021
The first report of synthetic hydrogels as we currently know themappeared in 1958 in a publication by Danno in which poly(vinyl alcohol)in aqueous solution was crosslinked under gamma irradiation to form aninsoluble gel.@danno1958 This was soon followed up by Wichterle and Límwhen they polymerized 2-hydroxyethyl methacrylate in the presence ofethylene glycol dimethacrylate to create water swollen gels for use ascontact lenses,@wichterle1960 which is still the basis for many contactlens formulations to this day.@teichroeb2008@nicolson2001 In 1970 PEGhydrogels were prepared by irradiation with gamma and electronradiation,@stafford1970@king1970 and PEG gels started to attractattention due to their favorable biocompatibility and non-foulingproperties.@zhu2010 The chain end alcohols of PEG have since beenfunctionalized with methacrylates for the preparation of gels byFRP,@tanaka1977 isocyanates@graham1984 and succinimidylesters,@sakai2008 and a variety of chemistries capable of participatingin Michael-type additions.@jansen2018@buwalda2014@metters2005
=== Mixing and light<mixing-and-light>Cell encapsulation techniques within hydrogels must be both rapid enoughto prevent cell settling and cytocompatible.@caliari2016 Free radicalsand high energy UV light are well known to cause cellulardamage,@chen1999 though UV photoinitiators and vinyl monomers are usedto encapsulate cells. Michael-type reactions are commonly used asbio-orthoganol methods of crosslinking hydrogels, and are useful fortheir ability to incorporate bioactive peptides by exploiting Michaeldonors present in amino acids, such as the thiol incysteine.@peyton2006@galarza2020 Additionally, the A--B typecrosslinking by Michael-type reactions often produces highly homogenousgels.@sakai2008 However, the reaction kinetics vary amongst chemistriesused, and tuning the kinetics within the framework of physiologicalconditions can be a challenge, not to mention relative difficulties ofbiology labs synthesizing functional PEG not commerciallyavailable.@rizzo2023@paez2020 Moreover, Michael-type reactions mostoften do not allow for spatiotemporal control, meaning the homogeneityof the network is dependent on the reaction kinetics.@darling2016
=== Reversible deactivation radical polymerizations<reversible-deactivation-radical-polymerizations>RDRPs, by contrast, are rarely used in biomedical applications. Thereasons for this vary, though in general, RDRPs are slower than FRPs,are sensitive to trace oxygen and are traditionally thermallyinitiated. These aspects make them unsuitable for polymerization in the presence of living cells.ATRP most commonly requires cytotoxic metal halide salts among severalother reactants, although there are efforts to replace them withpowerful organic reducing agents capable of homolytically cleavingcarbon-halogen bonds.@corbin2022 NMP is traditionally extremelyslow@grubbs2011 and has serious challenges with monomercompatibility.@guegain2015 RAFT requires tuning of the chain transferagent to match the desired monomers@keddie2012 and is expensive tosource.
Despite all of this, RDRPs offer significant benefits over FRPs. FRPsproduce gels with heterogeneous networks due to unavoidable termination,slow initiation relative to propagation, and slow segmental relaxationrelative to chain growth in the gel phase.@lovestead2003@gu2020 FRPscommonly overcome inhibition from oxygen by overwhelming it with excessradical species, to the detriment of cytocompatibility. In contrast,RDRPs are able to produce highly homogenous gel networks due to theirhigh initiation relative to propagation rates and low radicalconcentrations which minimize irreversible termination events as well asminimizing cellular damage. Furthermore, the reversible nature of RDRPsenable living gels@peyton2023 by postpolymerization modifications ofgels.@bagheri2021 Chapter 4 of this dissertation will harness RDRPsusing the photoiniferter process to rapidly polymerize and crosslinkbiocompatible hydrophilic monomers.
== Hypothesis<hypothesis>Current methods of curing thermosets are limited in their applicationsand cannot be applied in all circumstances. This is particularly true ofbiomedical applications, where conditions must be kept within the strictconfines of physiological conditions. I hypothesize that graftingpendent PEG chains along the main polymer backbone will provide a facileway to install mechanosensitivity by sterically shielding reactivesites, enabling on demand gelation. Furthermore, I hypothesize denselygrafted bottlebrush polymers with reactive side chains can be preparedas high-modulus, tough thermosets by adjusting the sidechain architecture tofavor intermolecular crosslinking. Finally, I hypothesize that rapidfragmentation of xanthogen disulfides in response to visible light willenable rapid preparation and crosslinking of biocompatible hydrogels. Ipredict that that this work will enable new methods of bottom up designof thermosetting materials.
== Objectives<objectives>The following were the objectives for this dissertation:
+ Optimize a library of sparsely grafted copolymers carrying reactive pendent groups and methoxy poly(ethylene glycol) (PEG) grafts for use as mechanically activated crosslinkable materials;
+ Synthesize and characterize novel mechanically responsive core-shell bottlebrush polymers furnished with a high density of crosslinkable pendant groups;
+ Develop a method to rapidly crosslink hydrogels in response to light in the visible range.
== Significance<significance>I have identified a new path for easy installation ofmechano-responsiveness into synthetic polymers using off-the-shelfchemistries and materials. Further, I have developed strategies tocombat intramolecular crosslinking in densely grafted reactive polymers.Finally, I have designed a method of rapidly synthesizing andcrosslinking biocompatible hydrogels. Overall, this dissertationpresents easy and accessible approaches to designing strain sensitivepolymers as well as preparing hydrogels by reversible deactivationradical polymerization that will enable more rapid translation ofmechanosensitive polymers and tailor-made hydrogels. Additionally, thisdissertation provides new strategies for preparing tough thermosets fromhigh molecular weight resins.