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Indiana University-Purdue University Indianapolis (IUPUI) / Stiffening and softening of extracellular matrix (ECM) are critical processes governing many aspects of biological processes. The most common practice used to investigate these processes is seeding cells on two-dimensional (2D) surfaces of varying stiffness. In recent years, cell-laden three-dimensional (3D) scaffolds with controllable properties are also increasingly used. However, current 2D and 3D culture platforms do not permit spatiotemporal controls over material properties that could influence tissue processes. To address this issue, four-dimensional (4D) hydrogels (i.e., 3D materials permitting time-dependent control of matrix properties) are proposed to recapitulate dynamic changes of ECM properties. The goal of this thesis was to exploit orthogonal enzymatic reactions for on-demand stiffening and/or softening of cell-laden hydrogels. The first objective was to establish cytocompatible hydrogels permitting enzymatic crosslinking and stiffening using enzymes with orthogonal reactivity. Sortase A (SrtA) and mushroom tyrosinase (MT) were used sequentially to achieve initial gelation and on-demand stiffening. In addition, hydrogels permitting reversible stiffening through SrtA-mediated peptide ligation were established. Specifically, poly(ethylene glycol) (PEG)-peptide hydrogels were fabricated with peptide linkers containing pendent SrtA substrates. The hydrogels were stiffened through incubation with SrtA, whereas gel softening was achieved subsequently via addition of SrtA and soluble glycine substrate. The second objective was to investigate the role of dynamic matrix stiffening on pancreatic cancer cell survival, spheroid formation, and drug responsiveness. The crosslinking of PEG-peptide hydrogels was dynamically tuned to evaluate the effect of matrix stiffness on cell viability and function. Specifically, dynamic matrix stiffening inhibited cell proliferation and spheroid formation, while softening the cell-laden hydrogels led to significant increase in spheroid sizes. Matrix stiffness also altered the expression of chemoresistance markers and responsiveness of cancer cells to gemcitabine treatment. markers and responsiveness of cancer cells to gemcitabine treatment.

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Additive manufacturing (AM) fabricates complex geometries inaccessible through other manufacturing techniques. However, each AM platform imposes unique process-induced constraints which are not addressed by traditional polymeric materials. Vat photopolymerization (VP) represents a leading AM platform which yields high geometric resolution, surface finish, and isotropic mechanical properties. However, this process requires low viscosity (<20 Pa·s) photocurable liquids, which generally restricts the molecular weight of suitable VP precursors. This obstacle, in concert with the inability to polymerize high molecular weight polymers in the printer vat, effectively limits the molecular weight of linear network strands between crosslink points (Mc) and diminishes the mechanical and elastic performance of VP printed objects. Polymer colloids (latex) effectively decouple the relationship between viscosity and molecular weight by sequestering large polymer chains within discrete, non-continuous particles dispersed in water, thereby mitigating long-range entanglements throughout the colloid. Incorporation of photocrosslinking chemistry into the continuous, aqueous phase of latex combined photocurability with the rheological advantages of latex and yielded a high molecular weight precursor suitable for VP. Continuous-phase photocrosslinking generated a hydrogel scaffold network which surrounded the particles and yielded a solid "green body" structure. Photorheology elucidated rapid photocuring behavior and tunable green body storage moduli based on scaffold composition. Subsequent water removal and annealing promoted particle coalescence by penetration through the scaffold, demonstrating a novel approach to semiinterpenetrating network (sIPN) formation. The sIPN's retained the geometric shape of the photocured green body yet exhibited mechanical properties dominated by the high molecular weight latex polymer. Dynamic mechanical analysis (DMA) revealed shifting of the latex polymer and photocrosslinked scaffold T_g's to a common value, a well-established phenomenon due phasemixing in (s)IPN's. Tensile analysis confirmed elastic behavior and ultimate strains above 500% for printed styrene-butadiene rubber (SBR) latexes which confirmed the efficacy of this approach to print high performance elastomers. Further investigations probed the versatility of this approach to other polymer compositions and a broader range of latex thermal properties. Semibatch emulsion polymerization generated a systematic series of random copolymer latexes with varied compositional ratios of hexyl methacrylate (HMA) and methyl methacrylate (MMA), and thus established a platform for investigating the effect of latex particle thermal properties on this newly discovered latex photoprocessing approach. Incorporation of scaffold monomer, N-vinyl pyrrolidone (NVP), and crosslinker, N,N'-methylene bisacrylamide (MBAm), into the continuous, aqueous phase of each latex afforded tunable photocurability. Photorheology revealed higher storage moduli for green bodies embedded with glassy latex particles, suggesting a reinforcing effect. Post-cure processing elucidated the necessity to anneal the green bodies above the T_g of the polymer particles to promote flow and particle coalescence, which was evidenced by an optical transition from opaque to transparent upon loss of the light-scattering particle domains. Differential scanning calorimetry (DSC) provided a comparison of the thermal properties of each neat latex polymer with the corresponding sIPN. Another direction investigated the modularity of this approach to 3D print mixtures of dissimilar particles (hybrid colloids). Polymer-inorganic hybrid colloids containing SBR and silica nanoparticles provided a highly tunable route to printing elastomeric nanocomposite sIPN's. The bimodal particle size distribution introduced by the mixture of SBR (150 nm) and silica (12 nm) nanoparticles enabled tuning of colloid behavior to introduce yield-stress behavior at high particle concentrations. High-silica hybrid colloids therefore exhibited both a shear-induced reversible liquid-solid transition (indicated by a modulus crossover) and irreversible photocrosslinking, which established a unique processing window for UV-assisted direct ink write (UV-DIW) AM. Concentric cylinder rheology probed the yield-stress behavior of hybrid colloids at high particle concentrations which facilitated both the extrusion of these materials through the UV-DIW nozzle and the retention of their as-deposited shaped during printing. Photorheology confirmed rapid photocuring of all hybrid colloids to yield increased moduli capable of supporting subsequent layers. Scanning electron microscopy (SEM) confirmed well-dispersed silica aggregates in the nanocomposite sIPN's. DMA and tensile confirmed significant reinforcement of (thermo)mechanical properties as a result of silica incorporation. sIPN's with relative weight ratio of 30:70 silica:SBR achieved maximum strains above 300% and maximum strengths over 10 MPa. In a different approach to enhancing VP part mechanical properties, thiol-ene chemistry provided simultaneous linear chain extension and crosslinking in oligomeric diacrylate systems, providing tunable increases to Mc of the photocured networks. Hydrogenated polybutadiene diacrylate (HPBDA) oligomers provided the first example of hydrocarbon elastomer photopolymers for VP. 1,6-hexanedithiol provided a miscible dithiol chain extender which introduced linear thiol-ene chain extension to compete with acrylate crosslinking. DMA and tensile confirmed a decrease in T_g and increased strain-at-break with decreased crosslink density. Other work investigated the synthesis and characterization of first-ever phosphonium polyzwitterions. Free radical polymerization synthesized air-stable triarylphosphine-containing polymers and random copolymers from the monomer 4-(diphenylphosphino) styrene (DPPS). ³¹P NMR spectroscopy confirmed quantitative post-polymerization alkylation of pendant triarylphosphines to yield phosphonium ionomers and polyzwitterions. Systematic comparison of neutral, ionomer, and polyzwitterions elucidated significant (thermo)mechanical reinforcement by interactions between large phosphonium sulfobetaine dipoles. Broadband dielectric spectroscopy (BDS) confirmed the presence of these dipoles through significant increases in static dielectric content. Small-angle X-ray scattering (SAX) illustrated ionic domain formation for all charged polymers. / Doctor of Philosophy / Additive manufacturing (AM) revolutionizes the fabrication of complex geometries, however the utility of these 3D objects for real world applications remains hindered by characteristically poor mechanical properties. As a primary example, many AM process restrict the maximum viscosity of suitable materials which limits their molecular weight and mechanical properties. This dissertation encompasses the design of new photopolymers to circumvent this restriction and enhance the mechanical performance of printed materials, with an emphasis on elastomers. Primarily, my work investigated the use of latex polymer colloids, polymer particles dispersed in water, as a novel route to provide high molecular weight polymers necessary for elastic properties in a low viscosity, liquid form. The addition of photoreactive molecules into the aqueous phase of latex introduces the necessary photocurability for vat photopolymerization (VP) AM. Photocuring in the printer fabricates a three-dimensional object which comprises a hydrogel embedded with polymer particles. Upon drying, these particles coalesce by penetrating through the hydrogel scaffold without disrupting the printed shape and provide mechanical properties comparable with the high molecular weight latex polymer. As a result, this work introduces high molecular weight, high performance polymers to VP and reimagines latex applications beyond 2D coatings. Further investigations demonstrate the versatility of this approach beyond elastomers with successful implementations with glassy polymers and inorganic (silica) particles which yield nanocomposites.

Vat photopolymerization's (VP) use in large-scale industrial manufacturing is limited due to poor scalability, and limited catalogue of engineering polymers. The challenges in scalability stem from an inherent process paradox: the feature resolution, part size, and manufacturing throughput cannot be maximized simultaneously in standard VP platforms. In addition, VP's inability to process viscous and high-molecular weight engineering polymers limits the VP materials catalogue. To address these limitations, the research presented in this work was conducted in two stages: (1) Development and modeling of new VP platforms to address the scalability and viscosity challenges, and (2) Investigating the influence of using the new processes on the cured polymer network structure and mechanical properties. First, a scanning mask projection vat photopolymerization (S-MPVP) system was developed to address the scalability limitations in VP systems. The process paradox was resolved by scanning the mask projection device across the resin surface while simultaneously projecting the layer as a movie. Using actual projected pixel irradiance distribution, a process model was developed to capture the interaction between projected pixels and the resin, and predict the resulting cure profile with an error of 2.9%. The S-MPVP model was then extended for processing heterogeneous UV scattering resins (i.e. UV curable polymer colloids). Using computer vision, the scattering of incident UV radiation on the resin surface was successfully captured and used to predict scattering-compensated printing parameters (bitmap pattern, exposure time , scanning speed). The developed reverse-curing model was used to successfully fabricate complex features using photocurable SBR latex with XY errors < 1.3%. To address the low manufacturing throughput of VP systems, a recoat-less, volumetric curing VP system that fabricates parts by continuously irradiating the resin surface with a movie composed of different gray-scaled bitmap images ( Free-surface movie mask projection (FreeMMaP)) was developed. The effect of cumulative exposure on the cure profile (X,Y,Z dimensions) was investigated and used to develop an iterative gray-scaling algorithm that generated a combination of gray-scaled bitmap images and exposure times that result in accurate volumetric curing (errors in XY plane and Z axis < 5% and 3% respectively). Results of this work demonstrate that the elimination of the recoating process increased manufacturing speed by 8.05 times and enabled high-resolution fabrication with highly viscous resins or soft gels. Then, highly viscous resins were made processible in VP systems by using elevated processing temperatures to lower resin viscosity. New characterization techniques were developed to determine the threshold printing temperature and time that prevented the onset of thermally-induced polymerization. The effect of printing temperature on curing, cured polymer structure, cured polymer mechanical properties, and printable aspect ratio was also investigated using diacrylate and dimethacrylate resins. Results of this investigation revealed increasing printing temperature resulted in improvements in crosslink density, tensile strength, and printability. However, presence of hydroxl groups on the resin backbone caused deterioration of crosslink density, mechanical properties, and curing properties at elevated printing temperatures. Finally, the lack of a systematic, constraint based approach to resin design was bridged by using the results of earlier process-structure-property explorations to create an intuitive framework for resin screening and design. Key screening parameters (such as UV absorptivity, plateau storage modulus) and design parameters (such as photoinitiator concentration, polymer concentration, UV blocker concentration) were identified and the methods to optimize them to meet the desired printability metrics were demonstrated using case studies. Most work in vat photopolymerization either deal with materials development or process development and modeling. This dissertation is placed at the intersection of process development and materials development, thus giving it an unique perspective for exploring the inter-dependency of machine and material. The process models, machines and techniques used in this work to make a material printable will serve as a guide for chemists and engineers working on the next generation of vat photopolymerization machines and materials. / Doctor of Philosophy / Vat Photopolymerization (VP) is a polymer-based additive manufacturing platform that uses UV light to cure a photo-sensitive polymer into the desired shape. While parts fabricated via VP exhibit excellent surface finish and high-feature resolution, their use for commercial manufacturing is limited because of its poor scalability for large-scale manufacturing and limited selection of engineering materials. This work focuses on the development of new VP platforms, process models and the investigation of the process-structure-property relationships to mitigate these limitations and enable fabrication of performance polymers. The first section of the dissertation presents the development of two new VP platforms to address the limitations in scalability. The Scanning Mask Projection Vat Photopolymerization (S-MPVP)) was developed to fabricate large area parts with high-resolution features and the Free-surface movie mask projection (FreeMMaP) VP platform was developed to enable high-speed, recoat-less, volumetric fabrication of 3D objects. Computer-vision based models were developed to investigate the influence of these new processes on the resultant cure shape and dimensional accuracy. Process models that can: (1) predict the cure profile for given input printing parameters (error < 3%), (2) predict the printing parameters (exposure time, bitmap gray-scaling) required for accurate part fabrication in homogeneous and UV scattering resins, and (3) generate gray-scaled bitmap images that can induce volumetric curing inside the resin (dimensional accuracy of 97% Z axis, 95% XY axis), were designed and demonstrated successfully. In the second portion of this work, the use of high-temperature VP to enable processing of high-viscosity resins and expansion of materials catalogue is presented. New methods to characterize the resin's thermal stability are developed. Techniques to determine the printing temperature and time that will prevent the occurrence of thermally-induced polymerization are demonstrated. Parts were fabricated at different printing temperatures and the influence of printing temperature on the resultant mechanical properties and polymer network structure was studied. Results of this work indicate that elevated printing temperature can be used to alter the final mechanical properties of the printed part and improve the printability of the high-resolution, slender features. Finally, the results of the process-structure-property investigations conducted in this work were used to guide the development of a resin design framework that highlights the parameters, metrics, and methods required to (1) identify printable resin formulations, and (2) tune printable formulations for optimal photocuring. Elements of this framework were then combined into an intuitive flowchart to serve as a design tool for chemists and engineers.

Ion-containing macromolecules continue to stimulate new opportunities for emerging electro-active applications ranging from high performance energy devices to water purification membranes. Progress in polymer synthesis and engineering now permit well-defined, ion-containing macromolecules with tunable morphologies, mechanical performance, ion conductivity, and 3D structure in order to address these globally challenged technologies. Achieving tailored chemical compositions with high degrees of phase separation for optimizing conductivity and water adsorption remains a constant synthetic challenge and presents an exciting opportunity for engineering sophisticated macromolecular architectures. This dissertation will introduce unprecedented charged polymers using conventional free radical and anionic polymerization to incorporate ionic functionalities based on phosphonium cations. This new class of copolymers offers unique properties with ionic functionality for tailorable electro-active performance. / Ph. D.

<p dir="ltr">Though vat photopolymerization-based Additive manufacturing (AM) technology shows potential in fabricating complex optical components rapidly, its poor surface quality and dimensional accuracy render it unqualified for industrial optics applications. The layer steps in the building direction and the pixelated steps on each layer’s contour result in inevitable microscale defects on the 3D-printed surface, far away from the nanoscale roughness required for optics.</p><p dir="ltr">To tackle the lateral stair-stepping issue caused by the pixelated projection pattern, we propose to defocus the curing image pattern by increasing the gap between the light source and the resin vat. This gap intentionally blurs the disconnected pixels to create a continuous and smooth projection pattern. Experiments verified that the smoothened image pattern led to an average 81.2% reduction in surface roughness, which was much more effective than grayscale pixels. The gap between the light source screen and the resin vat also enabled blowing air to dissipate the heat from the resin polymerization, reducing the part distortion and printing failure due to the thermal stress.</p><p dir="ltr">The precision spin coating process is reported to solve vertical stair-stepping defects. We establish a mathematical model to predict and control the spin coating process on 3D-printed surfaces precisely. In this work, a precision aspherical lens is demonstrated with less than 1 nm surface roughness and 1 µm profile accuracy. The 3D-printed convex lens achieves a maximum MTF resolution of 347.7 lp/mm.</p><p dir="ltr">Leveraging this low-cost yet highly robust and repeatable 3D printing process, we showcase the precision fabrication of multi-scale spherical, aspherical, and axicon lenses with sizes ranging from 3 mm to 70 mm using high clear photocuring resins. Additionally, molds were also printed to form multi-scale PDMS-based lenses. Following precision polishing, precision machining, and precision molding, we anticipate that precision spin coating will empower 3D printing as the fourth generation of lens making and unleash the power of 3D-printed lenses in rapid and massive customization of high-quality optical components and systems.</p>

Polymer synthesis and functionalization enabled the tailoring of polymer functionality for additive manufacturing (AM), elastomer, and biological applications. Inspiration from academic and patent literature prompted an emphasis on polymer functionality and its implications on diverse applications. Critical analysis of existing elastomers for AM aided the synthesis and characterization of novel photopolymer systems for lithography-based 3D printing. Emphasis on structure-processing-property relationships facilitated the attainment of success in proposed applications and prompted further fundamental understanding for systems that leveraged poly(dimethyl siloxane)s (PDMS), aliphatic polyesters, polyamides, and polyethers for emerging applications. The thiol-ene reaction possesses many desirable traits for vat photopolymerization (VP) AM, namely that it proceeds rapidly to high yield, does not undergo significant side reactions, remains tolerant of the presence of water or oxygen, and remains regiospecific. Leveraging these traits, a novel PDMS-based photopolymer system was synthesized and designed that underwent simultaneous chain extension and crosslinking, affording relatively low viscosity prior to photocuring but the modulus and tensile strain at break properties of higher molecular weight precursors upon photocuring. A monomeric competition study confirmed chemical preference for the chain-extension reaction in the absence of diffusion. Photocalorimetry, photorheology, and soxhlet extraction measured photocuring kinetics and demonstrated high gel fractions upon photocuring. A further improvement on the low-temperature elastomeric behavior occurred via introduction of a small amount of diphenylsiloxane or diethylsiloxane repeating units, which successfully suppressed crystallization and extended the rubbery plateau close to the glass transition temperature (Tg) for these elastomers. Finally, a melt polymerization of PDMS diamines in the presence of a disiloxane diamine chain extender and urea afforded isocyanate-free polyureas in the absence of solvent and catalyst. Dynamic mechanical analysis (DMA) measured multiple, distinct α-relaxations that suggested microphase separation. This work leverages the unique properties of PDMS and provides multiple chemistries that achieve elastomeric properties for a variety of applications. Similar work of new polymers for VP AM was performed that leveraged the low Tg poly(propylene glycol) (PPG) and poly(tri(ethylene glycol) adipate) (PTEGA) for use in tissue scaffolding, footwear, and improved glove grip performance applications. The double endcapping of a PPG diamine with a diisocyanate and then hydroxyethyl acrylate provided a urethane/urea-containing, photocurable oligomer. Supercritical fluid chromatography with evaporative light scattering detection elucidated oligomer molecular weight distributions with repeat unit resolution, while the combination of these PPG-containing oligomers with various reactive diluents prior to photocuring yielded highly tunable and efficiently crosslinked networks with wide-ranging thermomechanical properties. Functionalization of the PTEGA diol with isocyanatoethyl methacrylate yielded a photocurable polyester for tissue scaffolding applications without the production of acidic byproducts that might induce polymer backbone scission. Initial VP AM, cell viability experiments, and modulus measurements indicate promise for use of these PTEGA oligomers for the 3D production of vascularized tissue scaffolds. Similar review of powder bed fusion (PBF) patent literature revealed a polyamide 12 (PA12) composition that remained melt stable during PBF processing, unlike alternative commercial products. Further investigation revealed a fundamental difference in polymer backbone and endgroup chemical structure between these products, yielding profound differences for powder recyclability after printing. An anionic dispersion polymerization of laurolactam in the presence of a steric stabilizer and initiator yielded PA12 microparticles with high sphericity directly from the polymerization without significant post-processing requirements. Steric stabilizer concentration and stirring rate remained the most important variables for the control of PA12 powder particle size and melt viscosity. Finally, preliminary fusion of single-layered PA12 structures demonstrated promise and provided insight into powder particle size and melt viscosity requirements. / PHD / Additive manufacturing (AM) enables the creation of unique geometries not accessible with alternative manufacturing techniques such as injection molding, while also reducing the waste associated with subtractive manufacturing (e.g. machining). However, AM currently suffers from a lack of commercially-available polymers that provide elastomeric properties after processing. Poly(dimethyl siloxane)s (PDMS) possess distinctive properties due to their organosilicon polymer backbone that include chemical inertness, non-flammability, high gas permeability, and low surface energy. For these reasons, siloxanes enjoy wide-ranging applications from personal care products, contact lenses, elastomeric sealants, and medical devices. This dissertation focuses on the synthesis and functionalization of novel PDMS-, polyether-, polyester-, and polyamide-containing photopolymers or powders for improved performance in diverse applications that employ processing via vat photopolymerization (VP) or powder bed fusion (PBF) AM. Examples from this work include a novel photopolymer composition that undergoes simultaneous chain extension and crosslinking, affording low molecular weight and low viscosity precursors prior to VP-AM but the properties of higher molecular weight precursors, once photocured. Related work involved the characterization and VP-AM of siloxane terpolymers that suppress crystallization normally observed in PDMS, resulting in 3D printed objects that retain their elastomeric properties close to the glass transition temperature (Tg). Separate work leveraged the unique PDMS backbone for the melt polymerization of PDMS diamines in the presence of a chain extender and urea, yielding isocyanate-free PDMS polyureas in the absence of solvent or catalyst. This reaction creates ammonia as the only by-product and avoids the use of isocyanates, as well as their highly toxic precursors, phosgene. Finally, another research direction facilitates the understanding of observed differences in melt stability between commercially-available grades of polyamide 12 (PA12) powders for powder bed fusion. An anionic dispersion polymerization based in the patent literature facilitated further understanding of the polymerization process and produced melt-stable PA12 microparticles directly from the polymerization process, without requiring additional post-processing grinding or precipitation steps for powder production.

Photopolymerization is the basis of several multi-million dollar industries including films and coating, inks, adhesives, fiber optics, and biomaterials. The fundamentals of the photopolymerization process, however, are not well understood. As a result, spatial variations of photopolymerization impose significant limitations on applications in which a high spatial resolution is required. To address these issues, microrheology was implemented to study the spatial and temporal effects of free-radical photopolymerization. In this work a photosensitive, acrylate resin was exposed to ultraviolet light, while the Brownian motion of micron sized, inert fluorescent tracer particles was tracked using optical videomicroscopy. Statistical analysis of particle motion yielded data that could then be used to extract rheological information about the embedding medium as a function of time and space, thereby relating UV exposure to the polymerization and gelation of monomeric resins. The effects of varying depth, initiator concentration, inhibitor concentration, composition of the monomer, and light intensity on the gelation process were studied. The most striking result is the measured difference in gelation time observed as a function of UV penetration depth. The observed trend was found to be independent of UV light intensity and monomer composition. The intensity results were used to test the accuracy of energy threshold model, which is used to empirically predict photo-induced polymerization. The results of this research affirm the ability of microrheology to provide the high spatial and temporal resolution necessary to accurately monitor the photopolymerization process. The experimental data provide a better understanding of the photo-induced polymerization, which could lead to expanded use and improved industrial process optimization. The use of microrheology to monitor photopolymerization can also aid in the development of predictive models and offer the ability to perform in-situ quality control of the process.