We have used a molecular modeling of both random and blocky sequence hydrogel networks of poly(N-vinyl-2-pyrrolidone-co-2-hydroxyethyl methacrylate) (P(VP-co-HEMA)) with a composition of VP:HEMA = 37:13 to investigate the effect of the monomeric sequence and the water content on the equilibrium structures and the mechanical and transport properties by full-atomistic molecular dynamics (MD) simulations. The degree of randomness of the monomer sequence for the random and the blocky copolymers, were 1.170 and 0.104, respectively, and the degree of polymerization was fixed at 50. The equilibrated density of the hydrogel was found to be larger for the random sequence than for the blocky sequence at low water contents (< 40 wt %), but this density difference decreased with increasing water content. The pair correlation function analysis shows that VP is more hydrophilic than HEMA and that the random sequence hydrogel is solvated more than the blocky sequence hydrogel at low water content, which disappears with increasing water content. Correspondingly, the water structure is more disrupted by the random sequence hydrogel at low water content but eventually develops the expected bulk-water-like structure with increasing water content. From mechanical deformation simulations, the stress-strain analysis showed that the VP is found to relax more efficiently, especially in the blocky sequence, so that the blocky sequence hydrogel shows less stress levels compared to the random sequence hydrogel. As the water content increases, the stress level becomes identical for both sequences. The elastic moduli of the hydrogels calculated from the constant strain energy minimization show the same trend with the stress-strain analysis. Ascorbic acid and D-glucose were used to study the effect of the monomeric sequence on the diffusion of small guest molecules within the hydrogels. By analyzing the pair correlation functions, it was found that the guest molecule has greater accessibility to the VP units than to the HEMA units with both monomeric sequences due to its higher hydrophilicity compared to the HEMA units. The monomeric sequence effect on the P(VP-co-HEMA) hydrogel is clearly observed with 20 wt % water content, but the monomeric sequence effect is significantly reduced with 40 wt % water content and disappears with 80 wt % water content. This is because the hydrophilic guest molecules are more likely to be associated with water molecules than with the polymer network at the high water content. By analyzing the mean square displacement, the displacement of the guest molecules and the inner surface area, it is also found that the guest molecule is confined in the system at 20 wt % water content, resulting in highly anomalous subdiffusion. Therefore, the diffusion of the guest molecules is directly affected by their interaction with the monomer units, the monomeric sequence and the geometrical confinement in the hydrogel at a low water content, but the monomeric sequence effect and the restriction on the diffusion of the guest molecule are significantly decreased with increasing the water content. We also investigated the de-swelling mechanisms of the surface-grafted poly(N-isopropylacrylamide) (P(NIPAAm)) brushes containing 1300 water molecules at 275 K, 290 K, 320 K, 345 K, and 370 K. We clearly observed the de-swelling of the water molecules for P(NIPAAm) above the lower critical solution temperature (LCST) (~305 K). Below the LCST, we did not observe the de-swelling of water molecules. Using the upper critical solution temperature (UCST) systems (poly(acrylamide) brushes) for comparison purposes, we did not observe the de-swelling of water molecules at a given range of temperatures. By analyzing the pair correlation functions and the coordination numbers, the de-swelling of the water molecules occurred distinctly around the isopropyl group of the P(NIPAAm) brush above the LCST because C(NIPAAm) does not offer sufficient interaction with the water molecules via the hydrogen bonding type of secondary interaction. We also found that the contribution of the N(NIPAAm)-O(water) pair is quite small because of the steric hindrance of the isopropyl group. By analyzing the change in the hydrogen bonds, the hydrogen bonds between polar groups and water molecules in the P(NIPAAm) brushes weaken with increasing temperature, which leads to the de-swelling of the water molecules out of the brushes above the LCST. Below the LCST, the change in the hydrogen bonds is not significant. Again, the contribution of the NH(NIPAAm)-water pairs is insignificant; the total number of hydrogen bonds is ~20, indicating that the interaction between the NH group and the water molecules is not significant due to steric hindrances. Lastly, we observed that the total surface area of the P(NIPAAm) brushes that is accessible to water molecules is decreased by collapsing the brushes followed by the de-swelling of water molecules above the LCST.

The wettability of contact lenses has become an area of intense research, with the belief that the more "hydrophilic" or wettable the lens surface is, the more comfortable the lens may be, as the posterior surface of the eyelid will move more smoothly over it, hence increasing comfort. <br /><br /> There are many ways to assess the wettability of a given material, namely sessile drop,¹ captive bubble ² or Wilhelmy plate. ³ This thesis used the sessile drop method to determine the surface wettability of various hydrogel contact lens materials, by measuring the advancing contact angle made between the lens surface and a pre-determined volume of HPLC-grade water. This was followed by measuring the surface wettability following periods in which the lens materials were soaked in various contact lens care regimens. Further studies determined wettability of lens materials after various periods of in-eye wear and finally a study was undertaken to evaluate if a novel biological technique could be used to differentiate proteins that deposit on hydrogel lens materials that may affect wettability and cause discomfort. <br /><br /> A variety of hydrogel lenses, taken directly from their packaging and after soaking in various care regimens, were analyzed to determine their sessile drop advancing contact angles, in vitro. These studies indicated that poly-2-hydroxyethylmethacrylate (pHEMA)-based lenses are inherently more wettable than silicone-based lenses, unless they have a surface treatment that completely covers the hydrophobic siloxane groups. Additionally, certain combinations of lens materials and care regimens produce inherently more wettable surfaces when measured in vitro. <br /><br /> Suitable methods to assess contact lens wettability ex vivo, or after subjects had worn lenses for set periods of time, were developed. It was determined that using latex gloves to remove lenses had no impact upon the lens surface wettability and that rinsing of the lens surface after removal from the eye was required to determine the wettability of the underlying polymer. <br /><br /> The final wettability studies involved an analysis of various lens materials from clinical studies conducted within the Centre for Contact Lens Research (CCLR). These studies investigated differences in wettability between silicone hydrogel lenses manufactured from differing polymers and variations in ex vivo wettability of several combinations of lens materials and solutions, worn for varying periods of time. <br /><br /> A novel method to investigate proteins extracted from lenses using 2D-Difference in Gel Electrophoresis (DIGE) found that this technique could be used to analyze proteins extracted from contact lenses. The data obtained showed that there was no difference between a group of subjects who were symptomatic of lens-induced dryness or a control group, and that care solutions had a minimal influence on the pattern of deposition seen. <br /><br /> The overall conclusion of these studies is that hydrogel lens wettability is affected by the polymer composition and that care regimen components can modify the surface wettability.

A novel injectable hydrogel system for cell delivery in craniofacial bone tissue engineering was developed in this work. The hydrogel employs a dual solidification mechanism by containing units that gel upon temperature increase to physiological temperature and groups that allow for covalent crosslinking. The successful synthesis of macromers for hydrogel fabrication was demonstrated and structure-property relations were established. The hydrophilic-hydrophobic balance of the macromers was found to be an important design criterion towards their resulting thermal gelation properties. When tested with cells in vitro , macromers with different molecular compositions, molecular weights and transition temperatures were all found to be cytocompatible. The introduction of a chemically crosslinkable group in the macromers resulted in hydrogels with improved stability. The effect of the addition of these highly reactive groups on cell viability was evaluated and parameters that enable viable cell encapsulation in the hydrogels were determined. It was shown that there was a dose- and time-dependent effect of the macromers on cell viability. Increased degrees of modification were found to decrease the thermal transition temperature as well as the cytocompatibility of the macromers. Hydrogels were fabricated at physiological temperature upon physical gelation and chemical crosslinking with the addition of a thermal free radical initiator system. The swelling behavior of the hydrogels was characterized and it was found to be controlled by the chemistry of the macromer end group, the concentration of the initiator system used, the fabrication interval as well as the incubation temperature and medium. In order to evaluate the hydrogels as cell carriers, mesenchymal stems cells were encapsulated in the hydrogels over a 21-day period. Cells retained their viability over the duration of the study and exhibited markers of osteogenic differentiation when cultured with appropriate supplements. These findings hold promise for the use of these hydrogel systems for cell encapsulation in tissue engineering applications.

The wettability of contact lenses has become an area of intense research, with the belief that the more "hydrophilic" or wettable the lens surface is, the more comfortable the lens may be, as the posterior surface of the eyelid will move more smoothly over it, hence increasing comfort. <br /><br /> There are many ways to assess the wettability of a given material, namely sessile drop,¹ captive bubble ² or Wilhelmy plate. ³ This thesis used the sessile drop method to determine the surface wettability of various hydrogel contact lens materials, by measuring the advancing contact angle made between the lens surface and a pre-determined volume of HPLC-grade water. This was followed by measuring the surface wettability following periods in which the lens materials were soaked in various contact lens care regimens. Further studies determined wettability of lens materials after various periods of in-eye wear and finally a study was undertaken to evaluate if a novel biological technique could be used to differentiate proteins that deposit on hydrogel lens materials that may affect wettability and cause discomfort. <br /><br /> A variety of hydrogel lenses, taken directly from their packaging and after soaking in various care regimens, were analyzed to determine their sessile drop advancing contact angles, in vitro. These studies indicated that poly-2-hydroxyethylmethacrylate (pHEMA)-based lenses are inherently more wettable than silicone-based lenses, unless they have a surface treatment that completely covers the hydrophobic siloxane groups. Additionally, certain combinations of lens materials and care regimens produce inherently more wettable surfaces when measured in vitro. <br /><br /> Suitable methods to assess contact lens wettability ex vivo, or after subjects had worn lenses for set periods of time, were developed. It was determined that using latex gloves to remove lenses had no impact upon the lens surface wettability and that rinsing of the lens surface after removal from the eye was required to determine the wettability of the underlying polymer. <br /><br /> The final wettability studies involved an analysis of various lens materials from clinical studies conducted within the Centre for Contact Lens Research (CCLR). These studies investigated differences in wettability between silicone hydrogel lenses manufactured from differing polymers and variations in ex vivo wettability of several combinations of lens materials and solutions, worn for varying periods of time. <br /><br /> A novel method to investigate proteins extracted from lenses using 2D-Difference in Gel Electrophoresis (DIGE) found that this technique could be used to analyze proteins extracted from contact lenses. The data obtained showed that there was no difference between a group of subjects who were symptomatic of lens-induced dryness or a control group, and that care solutions had a minimal influence on the pattern of deposition seen. <br /><br /> The overall conclusion of these studies is that hydrogel lens wettability is affected by the polymer composition and that care regimen components can modify the surface wettability.

An ultrasonic nondestructive evaluation (NDE) technique has been developed to characterize the superficial layer of articular cartilage. The technique utilizes the unique properties of surface waves to detect changes in mechanical properties of the surface layer of the test sample. Experiments were performed first on poly(vinyl alcohol) (PVA) hydrogels, a material used to model articular cartilage, to examine repeatability and the ability of wave propagation parameters to reflect changes in material properties. Dynamic shear and compression tests were performed on 20% and 25% PVA by weight hydrogels to examine the difference in material properties. Ultrasonic NDE tests with longitudinal, shear and surface waves were performed on the hydrogels. Wave speeds in the 20% and 25% hydrogels were compared. Results showed that ultrasonic NDE with surface waves was repeatable and the technique was able to detect material property changes in hydrogels. Ultrasonic NDE tests with surface waves were then performed on healthy and damaged bovine articular cartilage. Wave speeds in the healthy cartilage were compared to speeds in enzymatically digested cartilage. Results showed that ultrasonic NDE with surface waves was repeatable and the technique was able to detect material property changes in the superficial layer of articular cartilage. Findings suggest that the technique has potential to be a tool in diagnosing diseases involving cartilage degeneration, such as osteoarthritis.

From medicine to aerospace, innovation in multiple fields will not occur without addressing current questions that still exist in polymer behavior and manipulation. This dissertation represents the research carried out over the course of three separate experiments using rheometry as the key technique to explore the behavior of polymer composites. In all three studies, polymer composites were investigated for changes to their known physical properties caused through the addition of a filler or functionalization. Chapter Two examines the possibility of enhancing poly(4-methyl-1-pentene) through the use of soluble carbon nanotubes. In this series of experiments, carbon nanotubes were covalently functionalized using reductive alkylation with a dodecyl group to render them easily soluble in the same organic solvents as low molecular weight poly(4-methyl-1-pentene). The polymer and the functionalized nanotubes were dissolved together in carbon tetrachloride then the solvent is removed leaving the functionalized nanotubes uniformly dispersed in the polymer matrix. The composites were then compression molded and the changes to the physical properties were explored. The functionalized nanotube filler generally acted to plasticize the samples producing transparent but colored polymers. The samples had a lower modulus and glass transition which was the opposite found by Clayton et al. using sonicated pristine carbon nanotubes. Polyurethanes have a growing significance in the biomedical field, and we explore the possibility fine tuning the properties of a polyurethane for such uses in Chapter Three. Here, self healing Polycarbonate polyurethanes (PCU) were synthesized with two different soft segments, Nippollan 964 and T-5652, and characterized with dielectric analysis (DEA), differential scanning calorimetry (DSC) and rheometry. The extra methyl group acted to produce a crystalline-like ordered hard segment that caused the 964 PCU to become Arrhenius in the glass transition region where the 5652 PCU had followed WLF behavior. Results showed the pendent methyl group acted to impart a crystalline-like character to the 964 PCU making it a candidate for applications that would be suited to a stiffer polymer. In Chapter Four we explore the possibility of increasing the wearability and comfort of contact lenses through increased hydration. The hydrogels 2-hydroxyethylmethacrylate (HEMA) and glycidyl methacrylate (GMA) solutions were created in three concentrations; neat, 50/50 and 60/40. Into these samples [Cu2({μ2-CO2}R)4(axial)2] (Cu(II) 4-hydroxybenzoic acid (MHBC) were dissolved 0.05% by weight. The samples were then polymerized via UV polymerization and compression molded. The experiments performed included penetration resistance , water absorption, micro hardness and glass transition. Addition of the MHBC acted to increase the water uptake of the samples but also reduced their ability to withstand mechanical penetration. With further study into crosslinking of the polymers, the MHBC could show promise in increasing hydration for commercial use.

Many important therapeutic agents are associated with significant undesired side effects which often limit treatment duration and dosing. Specifically, most major classes of antitumor chemotherapeutics have deleterious effects on cell division and DNA synthesis throughout the body due to systemic biodistribution. Engineering systems for controlled drug delivery allows for improved quality of life during treatment; as well as higher localized therapeutic concentrations by isolating toxic drugs used in many diseases to specific physiological compartments. An important drug delivery strategy for controlled release of therapeutics is based on responsive polymer matrices, which undergo swelling transitions in response to environmental stimuli. Biologically relevant factors which may trigger the release of therapeutics from responsive polymers include pH, ionic strength, and temperature. Temperature responsive polymers integrated into a composite system with metal nanoparticles allow for on demand drug release via an externally-applied optical or magnetic energy source. The intent of this work was to develop a temperature-responsive drug delivery platform for controlled therapeutic release, as well to expand the toolbox for rational design of responsive hydrogel nanoparticles intended for therapeutic delivery. Temperature-responsive hydrogels were synthesized and examined in the form of nanoparticles and bulk polymer networks. These materials are based on interpenetrating polymer networks (IPNs) of polyacrylamide (PAAm) and poly(acrylic acid) (PAA), which exhibit a positive volume swelling response with respect to temperature. Since this system responds to pH, ionic strength, and temperature, these IPNs were characterized over a wide range of solution conditions. Critical synthesis parameters needed to optimize thermal responses for specific solution conditions were identified, as were the specific effects of pH and ionic strength on network swelling and stability. The reverse emulsion process used to synthesize IPN nanoparticles was characterized to determine how particle growth proceeds during preparation. To enhance biocompatibility, IPN nanoparticles were surface-modified with a corona of poly(ethylene glycol) to reduce protein adsorption, a common strategy to improve in vivo performance. Due to the large amounts of surfactants employed in the preparation of IPN nanoparticles, purification methods needed to improve safety of IPN nanoparticles were optimized, and studied in vitro to ensure cellular compatibility. / text

A multitude of biophysical signals, including chemical, mechanical, and contact guidance cues, are embedded within the extracellular matrix (ECM) to dictate cell behavior and determine cell fate. To understand the complexity of the cell-matrix interaction and how changes to the ECM contribute to the development of tissues or diseases, three-dimensional (3D), culture systems that can decouple the effects of these cues on cell behavior are required. This dissertation describes the development and characterization of approaches based on multiphoton excitation (MPE) to control the chemical, mechanical, and topographical presentation of micro-3D-printed (μ-3DP) protein hydrogels independently. Protein hydrogels were chemically functionalized via the MPE-induced conjugation of benzophenone-biotin without altering the physical properties of the matrix. Complex, immobilized patterns and chemical gradients were generated within protein hydrogels with a high degree of spatial resolution in all axes. Hydrogel surfaces were also labeled with adhesive moieties to promote localized Schwann cell adhesion and polarization. Laser shrinking, a method based on MPE to manipulate the topographical and mechanical presentation of protein hydrogels after fabrication, is also presented. Topographical features on an originally flat substrate are created with depths approaching 6 μm. The Young’s modulus of protein hydrogels can also be increased by 6-fold (~15 – ~90 kPa) using laser shrinking, and parameters can be adjusted to create continuous gradient profiles for studying durotaxis. At determined scan conditions, the two properties can be adjusted independently of each other. Most importantly, the physical properties of the hydrogels can be manipulated in situ to study the effects of dynamic changes to the substrates on cells. As a potential tool to monitor cellular responses to presented cues, fluorescent probes that detect nitric oxide are characterized. Collectively, these technologies represent a key advance in hydrogel tunability, as the platforms presented offer independent, dynamic, and spatiotemporal control of the chemical, mechanical, and topographical features of protein hydrogels. The introduced technologies expand the possibilities of protein hydrogels to clarify underlying factors of cell-matrix interactions that drive morphogenesis and pathogenesis, and are broadly applicable to a multitude of physiological systems. / text

Advances in medical treatment are leading away from generalized care towards intelligent systems or devices which can sense and respond to their environment. With these devices, the burden of monitoring and dosing for treatment can be removed from the doctor (or the patient) and be placed on the device itself. Implicit closed-loop control systems will allow the device to respond to its environment and release therapeutic agent in response to a specific stimulus. Environmentally responsive hydrogels show great promise in being incorporated in such an intelligent device, such as pH-responsive hydrogels which can swell and deswell in response to changes in the pH of the media. Thus, pH changes can be exploited for controlled and intelligent drug delivery when used in combination with these pH-responsive hydrogels. In this work, heterogeneous, thermal-redox initiated free-radical polymerizations were developed to synthesize novel pH-responsive hydrogels, microparticles, and nanogels. The specific disease of interest was type I diabetes, which requires daily doses of insulin both at a basal amount and either a postprandial or preprandial bolus in order to maintain blood glucose levels within safe limits. To allow pH-responsive hydrogels to be sensitive to glucose, glucose oxidase was incorporated which oxidizes glucose to gluconic acid. A novel inverse-emulsion polymerization method was developed for the synthesis of poly[2-(diethylaminoethyl methacrylate)-grafted-polyethylene glycol monoethyl ether monomethacrylate] (P(DEAEM-g-PEGMMA)) nanogels (100-400 nm) for intelligent insulin delivery. The new polymerization method allowed the incorporation of hydrophilic components, such as glucose oxidase and catalase, as well as PEG surface tethers of lengths 400 Da up to 2000 Da. Surface tethers successfully decreased the surface charge of the nanogels. Insulin loading and release was determined for microparticles which were able to imbibe substantial amounts of insulin from solution when swollen, entrap the insulin when collapsed, and then release the insulin in response to either a pH or glucose stimulus. / text

Hyaluronic acid (HA) is a naturally occurring polymer that holds considerable promise for tissue engineering applications. Current cross-linking chemistries often require a coupling agent, catalyst, or photoinitiator, which may be cytotoxic, or involve a multistep synthesis of functionalized-HA, increasing the complexity of the system. With the goal of designing a simpler one-step , aqueous-based cross-linking system, we synthesized HA hydrogels via Diels-Alder “click” chemistry. Furan-modified HA derivates were synthesized and cross-linked via dimaleimide poly(ethylene glycol). By controlling the furan to maleimide molar ratio, both the mechanical and degradation properties of the resulting Diels-Alder cross-linked hydrogels can be tuned. Rheological and degradation studies demonstrate that the Diels-Alder click reaction is a suitable cross-linking method for HA. These HA cross-linked hydrogels were shown to be cytocompatible and may represent a promising material for soft tissue engineering.