*#align(center)[#smallcaps[@conclusions-limitations-and-future-directions[Chapter]]]* = #smallcaps[Conclusions, limitations, and future directions] == Conclusions This dissertation has presented novel methods to design mechanosensitive graft polymers, highly crosslinked bottlebrush polymers, and living hydrogels. Utilizing shielding PEG chains to provide a steric barrier to an otherwise efficient crosslinking reaction between amines or thiols and epoxides, I was able to produce mechanosensitive polymers that undergo a sol-gel transition in response to ultrasound. This approach to creating strain sensitive materials provides a facile route to creating strain responsive materials using commercially available monomers and simple techniques. I demonstrated, for the first time, a sol-gel transition accelerated under force using shielded reactive polymers. I synthesized novel thermosetting bottlebrush polymers containing both reactive glycidyl groups and rubbery butyl methacrylate. By adjusting polymer architecture I was able to suppress intermolecular crosslinks and increase the toughness of highly crosslinked bottlebrush polymers. In doing so I demonstrated a method for creating very high molecular weight thermosetting polymers with high toughness and modulus. Additionally, I demonstrated bis(xan)-mediated PI polymerizations to be tolerant to oxygen and produce telechelic polymers. Xanthate-capped hydrophilic polymers were shown to crosslink in the presence of a tri-functional crosslinker in $tilde.op$1.5 min. This approach provides a facile route to quick hydrogel fabrication using light in the visible spectrum, at physiological temperature, in air and water, and without radical initiators and their decomposition products. In all cases, careful design of initiator structure and polymer architecture enabled the production of novel materials. I foresee that this work will enable the development of new high performance coatings, adhesives, and biocompatible materials. == Materials and methods === Chemical sourcing Materials were purchased from Sigma-Aldrich unless otherwise mentioned. (APMA, 98%), Jeffamine ED-600, poly(ethylene glycol) (PEG) methyl ether methacrylate (950 g/mol, PEGMA950), 2-Hydroxyethyl methacrylate (HEMA, 98%), (CPA), (99%), pyridine (anhydrous, 99%), dichloromethane (DCM, anhydrous, 99%), dioxane (99%), CuBr#sub[2] (99%), 1,5,7-triazabicyclo\[4.4.0\]dec-5-ene (TBD, 98%), (EBPA, 97%), (, 99%), 1,1,3,3-tetramethylguanidine (TMG, 99%), and azobisisobutyronitrile (AIBN, 99%), were used as received. Glycidyl methacrylate (GMA, 99%), butyl methacrylate (BMA, 99%), 2-ethyhexyl methacrylate (EHMA, 98%), 2-methoxyethyl methacrylate (MEMA, 99%), and 2-(methacryloyloxy)ethyl methacrylate (AAEM, 95%) were passed through a column of basic alumina to remove inhibitors. CuBr (99.9%) was purified by stirring in glacial acetic acid. Tris(2-pyridylmethyl)amine (TPMA, 98%), tris 2-(dimethylamino)ethyl amine (Me#sub[6]TREN, 98%), cyclopentylmethyl ether (CPME, 99%), and 2-cyano-2-propyl dodecyl trithiocarbonate (CPDT, 97%) was purchased from TCI (Tokyo, Japan) and used as received. Methanol (99%), toluene (99%), dimethylformamide (DMF, 99%), isopropanol (99%), calcium chloride (99%) diethyl ether (anhydrous, 99%), tetrahydrofuran (THF, 99%), HCl (concentrated), reduced iron powder, copper turnings, basic alumina, and neutral alumina were purchased from Thermo Fisher (Waltham, MA) and used as received. === Synthesis of polyinitiator and vitrimers containing GMA Details of the synthesis of poly(BIEM), linear vitrimers, and bottlebrush vitrimers, and their formulation can be found in Chapter 3.2. === Representative PEG shielded and control polymer synthesis Poly(GMA_-co-_PEGMA950), poly(AAEM_-co-_PEGMA950), and of all molar ratios and degree of polymerization (DP) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Each reaction was fed 0.01 moles of monomer total. For example, 0.71 g (0.005 mol) GMA, 0.72 g (0.005 mol) MEMA, 0.0559 g CPA (0.2 mmol), 6.6 mg AIBN (0.04 mmol) (\[50\]:\[1\]:\[0.2\] \[M\]:\[CTA\]:\[I\], where \[M\]:\[CTA\] defines the DP), 4 mL of 1,4-dioxane, and a stir bar were added to a 20 mL scintillation vial. Polymers containing APMA were synthesized in 1:1 dioxane:water. The vial was sealed with a rubber septum and the solution was purged with N#sub[2] (g) for $tilde.op$20-30 min in an ice bath to prevent solvent and monomer evaporation (PEGMA solutions were bubbled in cool water to prevent PEG crystallization). Subsequently, the vial was placed in a thermostated aluminum reaction block at 60 °C on top of a magnetic stir/hot plate. The reaction was left to stir overnight, yielding a viscous liquid. The solution was removed from heat and exposed to air to terminate the polymerization. The solution was precipitated into cold (-20 °C) ether, the solid washed twice more with cold ether, and dried at 0.01 mbar overnight. Polymers containing APMA were poured into a small amount of cold ether, shaken, then isopropanol was added to precipitate the polymer. === Copolymer solution preparation Polymer solutions were initially prepared to be 50 wt% polymer. For example, 0.3 g of polymer was dissolved in 0.3 g of solvent, and crosslinker was added such that the nucleophilic functional group was equimolar with the total epoxide concentration. To control for the concentration of crosslinking points in solution, polymers were subsequently formulated to be 1 M of epoxide in solution. Each sample was vortexed for 5 sec to ensure complete mixing before proceeding with rheometry or sonication. For all experiments crosslinked with amines, reactions were conducted in a solvent system of 1:1 BuOH:DMF. Alcohols are known to catalyze the reaction between amines and epoxides through the formation of a trimolecular complex.@ehlers2007 Thiol-crosslinked reactions were conducted in MeCN with 10 µL of 2 M LiOH as a catalyst, necessary to deprotonate the thiols in order to perform a nucleophilic attack on the epoxide ring.@gadwal2015 Poly(APMA_-co-_MEMA) was first treated with pyridine to deprotonate the pendent amines. === Parallel plate rheology Gelation times and storage moduli ($G'$), and tanδ of polymer solutions/gels were determined on a Kinexus Pro parallel plate rheometer (Netzsch, Selb, Bayern, Germany). Measurements were run on a 20 mm plate with a 1 mm gap at 1 % strain and 1 -- 100 rad s#super[-1] frequency sweep. Each frequency sweep lasted approximately 5 min, and the entire measurement lasted approximately 15 hr. The gel point was defined using the Winter-Chambon criterion, for which the time of gelation is defined as the point at which tanδ becomes frequency independent at small frequencies.@winter1986@chambon1985@chambon1987 For samples with very high modulus, the elastic modulus was determined using compressive rheology by taking the slope of the stress strain curve of cured gels with a 4 mm diameter. Rheological experiments were analyzed using IRIS Rheo-Hub (IRIS Development, Amherst, MA).@poh2022 For samples treated with 30 % strain, single frequency measurements were conducted at 1 Hz and 30 % strain for 10 minutes in between each frequency sweep. === Time-temperature superposition measurements Time-temperature superposition was conducted by performing frequency sweeps at 30 °C intervals with a DMA 850 (TA Instruments) equipped with a tension clamp. Frequency sweeps were performed at 0.01 % strain with a preload of 0.01 N . == Limitations Thermosetting materials have come far from the crosslinked latex rubbers first developed by ancient Mesoamericans, and have transformed the world along the way. Polymer chemists have and continue to produce ever more sophisticated ways to prepare narrowly disperse polymers with diverse functionality enabling the synthesis of more and more exotic polymer architecture. Taking advantage of multiple methods of controlled/living polymerization enabled the bottom up molecular design of novel mechanosensitive comb polymers, highly crosslinked molecular bottlebrushes, and living hydrogels. While these materials do fill unmet needs for thermosetting resins and soft biocompatible materials, they still suffer from several drawbacks. Here I will detail the limitations of my approaches and how they might be overcome. === PEG-shielded polymers require high strain and/or strain rates to induce crosslinking Ultrasound is a convenient method for applying strong shear forces at high shear rates to polymers in solution on a laboratory scale. However, it is not necessarily a scaleable technique or easily accessible outside of laboratory environments. More relevant techniques involve parallel plate shear by forcefully spreading liquid on a solid substrate or extrusion of liquids through a narrow opening. To simulate these methods of straining polymer solutions, solutions pGMA_-co-_PEGMA950 and ethylene diamine were subjected to 30 % shear at 1 Hz on a parallel plate rheometer and extruded through a 27 Ga needled. Neither method showed any increase in the rate of gelation. Shear thinning was observed in the polymer solution, evidenced by a decrease in $G'$ after strain was applied (@fig:pegstrain). At a minimum, 20 kHz ultrasound at 10 % amplitude (50 W) was required to induce gelation of PEG shielded polymers. To enable more diverse applications, thermosetting polymers that are more sensitive to mechanical force should be developed. #figure(image("Images/C5F1.png", width: 100.0%), placement: bottom, caption: [ PEG shielded polymers are not activated by parallel plate shear. $G'$ evolution over time of pGMA_-co-_PEGMA950 at 1 % and 30 % strain. ] ) === Steric shielding by PEG is not generalizable to all crosslinking chemistries Although the PEG shielding groups are easily accessible and installed alongside reactive monomers on polymer backbones, they are not suitable for shielding all kinds of reactive monomers. Different applications demand different crosslinking chemistry. For example, ethylene diamine can be replaced with Jeffamines for decorative applications that require high clarity and transparency. Jeffamines are a class of amine terminated poloxamers developed specifically for preparing crosslinked epoxies, and their structure can be tuned to modulate the properties of the final crosslinked material. However, their large polymeric structure prevents them from diffusing to reactive sites flanked by large PEG shielding groups and forming crosslinks (@fig:jeffamineshield). #figure(image("Images/C5F2.png", width: 100.0%), placement: auto, caption: [ PEG shielding completely prevents gelation with Jeffamine. $G'$ evolution over time of pGMA_-co-_PEGMA950 in the presence of Jeffamine ED-900. ] ) Other applications require quicker crosslinking kinetics@zoller2016 or reversible crosslinks.@denissen2015 For such applications, acetoacetoxy functional polymers offer an attractive option, forming vinylogous urethane bonds in the presence of primary amines. However, the (acetoacetoxy)ethyl ester is quite large, and most likely significantly alters chain conformations, lessening the steric effects of pendent PEG. Additionally, the tendency of the acetoacetoxy pendent groups to self assemble through hydrogen-bonding@schlaad2004 likely preemptively brings reactive monomers into contact, increasing the apparent rate of crosslinking. As such, PEG shielding groups are insufficient to protect acetoacetoxy reactive groups (@fig:aaemshield). To overcome this, more aggressive shielding methods are required. #figure(image("Images/C5F3.png", width: 100.0%), placement: auto, caption: [ pAAEM_-co-_PEGMA950 rapidly gels in the presence of primary amines. $G'$ evolution over time of pAAEM_-co-_PEGMA950 in in the presence of pAPMA_-co-_MEMA. ] ) === Grafting-from produces unstable brushes One of the most important properties of thermosetting coatings and adhesives is shelf stability. The formulated resin should remain inert until the user desires the material to crosslink. To simplify application, one pot formulations are ideal. To produce highly shielded acetoacetoxy polymers, I turned to core-shell bottlebrush polymers composed of an inner core of crosslinkable AAEM and an outer shell of rubbery EHMA. These polymers were prepared by the \"grafting from\" method as it enables longer side chain lengths. Initially it was believed that ATRP of AAEM would be impossible due to the 1,3-dicarbonyl interfering with the copper complex. However, some reports have shown the controlled polymerization of AAEM through traditional ATRP mediated by CuBr.@mandal2018 To minimize the amount of copper halide required, poly(AAEM) was synthesized by SARA ATRP with Cu(0) as the reducing agent. This produced a polymer with a bimodal molecular weight distribution with the peak at shorter retention time being roughly double the molecular weight of the peak at longer retention time (@fig:saraaaem a). It is assumed that this is due to radical-radical coupling facilitated by chelation of coper bringing growing chains into close proximity. #super[1]H NMR clearly showed the presence of the acetoacetoxy group as well as the methacrylate backbone (@fig:saraaaem b). Replacing Cu(0) with Fe(0) as the reducing agent produced no polymer. This is to my knowledge the first SARA ATRP reported of AAEM. #figure(image("Images/C5F4.png", width: 100.0%), placement: bottom, caption: [ Characterization of pAAEM produced by SARA ATRP. (a) GPC chromatogram of pAAEM. (b) #super[1]H NMR of pAAEM. Spectra recorded at 500 MHz in CDCl#sub[3]. THF used as eluent. ] ) Still, bottlebrush polymers with AAEM and ethylhexyl methacrylate copolymer sidechains were prepared by the same technique. However, all copolymers prepared were extremely unstable, often forming insoluble gels instantaneously upon precipitation. Only a single sample, pBIEM-_g_-(AAEM-_b_-EHMA), could be analyzed by NMR and GPC. GPC of showed a small shoulder at shorter retention times, indicating some amount of radical-radical coupling @fig:aaembrush a). #super[1]H NMR clearly showed the successful sequential polymerization of AAEM and EHMA from the BIEM backbone (@fig:aaembrush b). #figure(image("Images/C5F5.png", width: 100.0%), placement: auto, caption: [ Characterization of pBIEM_-g-_(AAEM_-b-_EHMA) prepared by SARA ATRP. (a) GPC chromatogram of pBIEM_-g-_(AAEM_-b-_EHMA). (b) #super[1]H NMR of pBIEM_-g-_(AAEM_-b-_EHMA). Spectra recorded at 500 MHz in CDCl#sub[3]. THF used as eluent. ] ) Bottlebrush polymers prepared by ATRP \"grafting from\" are known to form C--C crosslinks at sidechain ends in the solid phase, even in the presence of ppm amounts of copper.@nese2011 Removal of copper from AAEM bottlebrushes was very difficult, presumably as a result of chelation between brush hairs, with copper being clearly visible even after passing through alumina. To make it easier to produce shelf stable bottlebrushes, AAEM was replaced with GMA, and EHMA was replaced with BMA. These bottlebrush polymers were able to be isolated as white solids after passing over alumina to remove the copper salts, but still were only stable for a few days at -20 °C. A different approach to synthesis would be required to produce highly shielded, reactive bottlebrush polymers with a long shelf life. === GMA is not suitable for transesterification based vitrimers Crosslinked bottlebrushes with GMA (co)polymer sidechains tend to have substantially lower elastic moduli compared to their linear counterparts. Controlling for total number of crosslinks possible, this suggests that not all crosslinking sites are being utilized. I hypothesized that the onset of vitrification during the cure process prevented the full conversion of epoxides by restricting chain mobility. In an attempt to overcome this and improve the elastic modulus of the bottlebrush polymers, I formulated vitrimers by incorporating a transesterification catalyst, TBD. Described in 2011 by Montarnal et al., vitrimers (sometimes referred to as covalent adaptable networks) are crosslinked thermosets with dynamic bonds that flow like glasses above a certain temperature.@montarnal2011 #figure(image("Images/C5F6.png", width: 100.0%), placement: auto, caption: [ pGMA_-b-_BMA performs well as a reprocessible adhesive. (a) Fragments of crosslinked pGMA_-b-_BMA are melt pressed into a homogeneous solid. (b) An image of a rheometer stage showing that the epoxy adhesive securing sandpaper to the bottom plate has failed, while pGMA_-b-_BMA is still adhering the bottom sandpaper and top plate. ] ) TBD is well understood to enable network topology rearrangement above its characteristic topology freezing temperature through bond exchange reactions at β-hydroxyl-esters. As a practical test, crosslinked pGMA_-b-_BMA was broken into pieces and pressed in a mold at 120 °C, reforming into a disk within minutes (@fig:gmavitrimer a). Remarkably, it even outperformed a commercial epoxy glue during parallel plate rheology at 155 °C (@fig:gmavitrimer b). To attempt to measure the activation energy of vitrimer flow, I employed time-temperature superposition measurements using DMA.@meng2022 However, we were unable to cleanly superimpose the elastic modulus data (@fig:tts a) and no such vitrimer flow was recorded by DMA, even at temperatures exceeding 180 °C (@fig:tts b). It remains unclear what exactly caused this behavior. Additionally, pGMA, pGMA_-co-_BMA, pBIEM_-g-_GMA, pBIEM_-g-_(GMA_-b-_BMA), pBIEM_-g-_(BMA_-b-_GMA), and pBIEM_-g-_(GMA_-co-_BMA) all failed to superimpose cleanly and showed no ability to be reformed by melt pressing. Different dynamic crosslinking chemistry is required to drive polymeric vitrimers to full conversion. #figure([#box(image("Images/C5F7a.png", width: 100.0%)) #box(image("Images/C5F7b.png", width: 100.0%)) ], placement: auto, caption: [ Time-temperature superposition of pGMA_-b-_BMA. (a) Time-temperature superposition of the elastic modulus of pGMA_-b-_BMA. (b) Time-temperature superposition of the loss factor of pGMA_-b-_BMA. ] ) == Future directions === Improving elastic modulus of thermoset bottlebrushes High-performance thermosetting resins are prized for their resistance to creep, temperature, and solvent, as well as their light weight. These same properties however make reprocessing and recycling impossible. Covalently crosslinked thermosets traditionally do not dissolve in solvent or melt at high temperature, unlike thermoplastics, meaning their shape is set at the onset of gelation. Additionally, the onset of gelation imposes vitrification on thermosetting resins whose $T_(c u r e) < T_g$, hampering further conversion of reactive sites. This is particularly problematic for bottlebrush polymers, whose large size produces already sluggish motion, making it very difficult to achieve full conversion and maximum modulus. I propose to introduce dynamic crosslinks to bottlebrush polymers in order to maximize the elastic modulus of bottlebrush thermosets by facilitating bond exchange through melt processing. #figure(image("Images/C5F8.png", width: 100.0%), placement: auto, caption: [ Proposed route to reactive bottlebrush polymers with labile side chains. ] ) Though there are many available chemistries used to prepare vitrimers, imine exchange is most commonly used for polymeric vitrimers. Imine crosslinked polymers can be prepared by reacting aldehyde functional polymers in the presence of primary amines. Copolymer vitrimers based on 2-(methacryloyloxy)ethyl vanillin, and aldehyde functional monomer, and plasticizing monomers have been demonstrated to undergo dynamic bond exchange.@stouten2023 Additionally, imine exchange requires no additional catalyst and occurs at lower temperatures. To prepare bottlebrush vitrimers in particular the use of styrenic monomers is preferred, both for their superior hydrolytic stability compared to (meth)acrylic monomers as well as for access to atom transfer nitroxide radical coupling reactions (ATNRC) for facile transformations of chain end halogens (@fig:bbpscheme).@teo2019 4-vinylbenzaldehyde (VBA) is an easily accessible monomer, though not commercially available. There are many reported routes to VBA, but I will relay two that give VBA in high yield, one by hydrolysis of p-(chloromethyl)styrene followed by oxidation to VBA (@fig:4vba a),@foyer2015 another by Wittig olefination of 4-(diethoxymethyl)benzaldehyde followed by deprotection (@fig:4vba b).@sun2007 RAFT polymerization of VBA has been reported,@sun2007 but not ATRP. #figure(image("Images/C5F9.png", width: 100.0%), placement: auto, caption: [ Proposed routes to aldehyde functionalized styrenic monomer for improved reactive bottlebrush polymers. ] ) === Mechanosensitive nanocapsule thermosets While the \"grafting from\" method excels at producing bottlebrush polymers with long side chains, it also produces ill-defined polymers. Residual initiating sites on side chain ends can also cause irreversible crosslinking in the solid phase, limiting their shelf life. Additionally, control over the final brush architecture is limited to only being able to adjust the sequence of the side chains, meaning the ends of the brush always presented exposed reactive groups to the environment, resulting in rapid crosslinking. Though it was not quantified, the initiation efficiency and monomer conversion for the bottlebrush side chains was likely quite low.@neugebauer2015 It's possible this could be avoided by an ATRP approach favoring deactivation of the propagating radicals.@xie2018 I propose to use the \"grafting through\" technique, by which olefin terminated macromonomers are polymerized into bottlebrushes, to create a new class of mechanosensitive \"nanocapsule\" bottlebrush thermosets that are able to crosslink in response to weak shear forces. While the \"grafting through\" technique is not able to prepare bottlebrushes with side chain lengths matching that of \"grafting from,\" it possesses several advantages of its own. Linear macromonomers are able to be easily characterized prior to polymerization into bottlebrush polymers, meaning the length of bottlebrush hairs can be precisely tuned. Different bottlebrush morphologies (comb, rodlike side chain, stretched backbone, stretched sidechain) can be precisely prepared. Bottlebrush block copolymers can be easily prepared by sequential addition of macromonomers. Additionally, bottlebrush polymers prepared this way possess a side chain on every monomer (if only macromonomers are polymerized). #figure(image("Images/C5F10.png", width: 100.0%), placement: auto, caption: [ Mechanosensitive nanocapsule thermosets expose a reactive core in response to shear forces. ] ) Steric repulsion between side chains of densely grafted bottlebrush polymers is known to induce significant tension along the polymer backbone, on the order of nanonewtons,@panyukov2009 the same or higher than the force required to break C--C bonds.@grandbois1999@willis-fox2018 These prestrained brushes may be easier to mechanochemically cleave, exposing the reactive core (@fig:nanocapsule). Indeed, it has been shown that the limiting contour length for bottlebrush polymers is dramatically shorter than linear polymers, and bottlebrush polymers approach this limit under sonication much more quickly.@li2016 Other methods of inducing strain, such as parallel plate shear or extrusion, may be able to \"activate\" molecular brushes with a reactive core more easily, particularly those in the stretched backbone regime or those adsorbed to surfaces, which can experience up to 100 nN of tension along the backbone. Scission at the hair-backbone junction will also generate unshielded reactive linear polymers.@peterson2019@peterson2021@noh2021 Further, the propensity for hairs to be released into solution can be tuned by weakening the alkoxyamine C--O bond with highly sterically hindered nitroxides (proposed structure #strong[1]),@pauly2025@jing2014 or by preparing bottlebrush polymers in the stretched side chain regime. #figure(image("Images/C5F11.png", width: 100.0%), placement: auto, caption: [ Proposed polymerization and chain-end chlorination of amine functional styrenes. ] ) Complementary amine functionalized bottlebrush crosslinkers should be prepared as well. Amine functional styrenes protected with trimethylsilane groups have been prepared by living anionic polymerization.@hirao2002 Carbanion chain ends of polymers prepared by living anionic polymerization can be easily converted to terminal chlorines for use in ATNRC (@fig:polymerchlor).@satoh2019 It's possible that protected amine functional styrenes could be directly polymerized by ATRP, though aryl amines (R = NH#sub[2]) will likely polymerize slowly if at all by increasing the dissociation energy of the chain end carbon-halogen bond and slowing propagation.@yoshioka2019 Choosing a strongly hydrogen bonding solvent may be able to overcome this by reducing the electron donating ability of the amine through intermolecular interactions. There are some reports of polymerization of unprotected 4-(vinylaniline) by ATRP.@rebelo2019 In any case, the amines should remain protected until use as they will both deactivate the ROMP catalyst preventing bottlebrush synthesis@sutthasupa2010 and the unprotected amines are unstable in air.@suzuki1989 Alternative reactive monomers include 4-vinylphenyloxirane, 4-vinylphenyl glycidyl ether, 4-vinylphenol, 4-vinylthiophenol, 4-(2-mercaptoethyl)styrene, and 4-vinylbenzoic acid. === Xanthogen disulfide optimization and hydrogel stereolithography The design and synthesis of chain transfer agents for the RAFT process has been much studied since the process was first introduced.@keddie2012 RAFT agents typically take the form of #strong[2] (@fig:waterxanth). The Z group (in this case O-ethyl) is generally responsible for modifying the rate of addition of propagating radicals and the rate of fragmentation of intermediate radicals in the main RAFT equilibrium. R is generally meant to act as an excellent homolytic leaving group capable of initiating polymerization. I use a symmetrical xanthogen disulfide, meaning modifications to the R group can be ignored. #figure(image("Images/C5F12.png", width: 100.0%), placement: auto, caption: [ Proposed xanthate structures. ] ) Xanthogens (Z = OR$'$) are chiefly used for the polymerization of less activated monomers. Xanthates have dramatically lower reactivity towards radical addition, qualitatively understood by the resonance contribution of the oxygen lone pair to the C=S double bond, meaning more activated monomers ((meth)acryloyl monomers) which produce less reactive radical species do contributing to lower transfer constants of the xanthate and poorer control. However, the C=S double bond can be made more reactive by lessening the contribution of the oxygen lone pair by installing electron withdrawing groups attached to the oxygen, lessening the contribution of the oxygen lone pair on the C=S double bond. Xanthates possessing the Z groups of #strong[3]@li2018a and #strong[4]@destarac2002 have shown superior control over polymerization of acrylic monomers, importantly with no change in polymerization kinetics, and should be explored as xanthogen disulfide photoiniferters. More pressingly for biomedical applications is the solubility of the chain transfer agent. My chosen xanthate is easy to synthesize, but is not water soluble, nor are #strong[3] or #strong[4]. Thus, I propose to develop zwitterionic xanthogen disulfides as photoiniferters. #strong[5] will likely provide excellent control of acryloyl functional monomers and excellent solubility. It should be cautioned however that while adding electron withdrawing Z (where Z is O--R' and R' is alkyl or aryl) groups to the RAFT agent will improve the control of certain monomers, it will also increase the susceptibility of it to aminolysis and hydrolysis, which will complicate cytocompatible polymerizations in water.@thomas2004@moad2005 Tertiary alcohols should be avoided such that Z does not become a good homolytic leaving group.@stenzel2003@coote2003 Additionally, I propose to utilize the dormant xanthogen chain ends to introduce and pattern hydrogels post polymerization. The 3D network structure of synthetic hydrogels nicely mimics the mechanical properties of the native cellular environment, but not the chemical properties. Synthetic materials, like PEG, tend to be both chemically inert and difficult to for cells to adhere to, long noted for their antifouling properties.@zhu2010 Hydrogels should be selectively functionalized by stereolithography with RGD adhesion points, as well as selectively increasing or decreasing the modulus of hydrogels. The necessary N-acryloyl functional oligopeptides are conveniently accessible by protease catalyzed peptide synthesis,@edson2023 and some work has been done polymerizing N-acryloyl amino acids.@bentolila2000@li2018