Browsing by Subject "Hydrogel"
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Item Biodegradable microdevices for biological detection and smart therapy(2010-05) Snelling, Diana Kathryn; Peppas, Nicholas A., 1948-; Paul, Donald R.; Maynard, Jennifer; Sanchez, Isaac C.; Zaman, Muhammad H.Biodegradable, pH-responsive hydrogel networks composed of poly(methacrylic acid) crosslinked with varying mol percentages of polycaprolactone diacrylate were synthesized. These materials were characterized using NMR and FTIR. The equilibrium and dynamic swelling properties of these pH-responsive materials were studied. Also, the materials’ degradation was characterized using swelling studies and gel permeation chromatography. Methods were developed to incorporate these novel hydrogels as sensing components in silicon-based microsensors. Extremely thin layers of hydrogels were prepared by photopolymerizion atop silicon microcantilever arrays that served to transduce the pH-responsive volume change of the material into an optical signal. Organosilane chemistry allowed covalent adhesion of the hydrogel to the silicon beam. As the hydrogel swelled, the stress generated at the surface between the hydrogel and the silicon caused a beam deflection downward. The resulting sensor demonstrated a maximum sensitivity of 1nm/4.5E-5 pH unit. Sensors were tested in protein-rich solutions to mimic biological conditions and found to retain their high sensitivity. The existing theory was evaluated and developed to predict deflection of these composite cantilever beams. Another type of hydrogel-based microsensor was fabricated utilizing porous silicon rugate filters as transducers. Porous silicon rugate filters are garnering increased attention as components of in vivo biosensors due to their ability for remote readout through tissue. Here, the biodegradable, pH-responsive hydrogel was polymerized within the pores of a porous silicon rugate filter to generate a novel, completely degradable sensor. Silicon was electrochemically etched in hydrofluoric acid to generate the porous silicon rugate filter with its reflectance peak in the near infrared region. Poly(methacrylic acid) crosslinked with polycaprolactone diacrylate was polymerized within the pores using UV free radical photopolymerization. The reflectance peak of this sensor varied linearly with pH in the region pH 2.2 to 8.8. This work shows promise towards utilizing porous silicon rugate filters as transducers for environmentally responsive hydrogels for biosensing applications.Item Characterization and modeling of mixed-mode I+III fracture in brittle materials(2015-12) Pham, Khai Hong; Ravi-Chandar, K.; Landis, Chad M; Liechti, Kenneth M; Mear, Mark E; Marder, Michael PMixed-mode I+III fracture in brittle materials presents spectacular, scale-independent pattern formation in nature and engineering applications; and it is one of the last remaining puzzles in linear elastic fracture mechanics. This problem has received much attention in the literature over the past few decades both from experiments and analysis, but there are still open challenges that remain. Specifically, the existence of a threshold ratio of mode III to mode I loading below which fragmentation of the crack front (formation of daughter cracks) does not occur and the length scale associated with the spacing of the fragments when they do occur are still under debate. The continued growth of cracks under remote mode I + III loading is also of interest; it is observed that in some cases the fragmented cracks coalesce, while in others they maintain their independent development. We approach this problem through carefully designed experiments to examine the physical aspects of crack initiation and growth. This is then explored further through numerical simulations of the stress state that explore the influence of perturbations on the formation of daughter cracks. We show that a parent crack subjected to combined modes I+III loading exhibits fragmentation of the crack front into daughter cracks without any threshold. The distance between the daughter cracks is dictated by the length scale corresponding to the decay of the elastic field; this decay depends on the characteristic dimension of the parent crack from which the daughter cracks are nucleated. As the daughter cracks continue growing, they coarsen in spacing also through elastic shielding. As the daughter cracks grow farther, the parent crack, pinned at the original position, experiences increased stress intensity factor and the bridging regions begin to crack and the parent crack front advances towards the daughter cracks. This establishes a steady state condition for the system of parent crack with equally spaced daughter cracks to continue growing together. Finally, direct numerical simulation of crack initiation and growth is explored using a phase-field model. The model is first validated for in-plane modes I + II through comparison to experiments, and then used to explore combined modes I + III in order to study the above mechanism of mixed-mode I + III crack growth.Item Degradable poly(ethylene glycol) based hydrogels for pulmonary drug delivery and in vitro T cell differentiation applications(2013-08) Fleury, Asha Tarika; Roy, KrishnenduHydrogels, defined as three-dimensional, hydrophilic networks, offer extensive biomedical applications. The areas of application are heavily concentrated in drug delivery and tissue engineering because of the hydrogels’ ability to mimic extracellular matrixes of tissue while maintaining a high level of biocompatibility. Specifically, poly(ethylene glycol) (PEG) is a well-established biomaterial in hydrogel applications due to its high water-solubility, low toxicity, high biocompatibility, and stealth properties. This thesis discusses two applications of PEG-based degradable hydrogels. The first is the targeted, site-specific, controlled release of biologic drugs administered by inhalation. There are many challenges to designing a pulmonary delivery system for inhalation of biologic drugs such as low respirable fractions and short resident time in the lungs. In this report, the hydrogel microcarriers for encapsulated drugs were formed by cross-linked PEG and peptide sequences synthesized during a mild emulsion process. The microgels underwent freeze-drying in the presence of cryoprotectants and formulated for dry powder inhalation. The microgels displayed swelling properties to avoid local macrophage clearance in the lungs and exhibited triggered release and degradation in response to enzyme for disease specific release. Dry formulations were tested for aerosolization properties and indicated ability to be delivered to the deep lung by a dry powder inhaler. Lastly, microgels were successfully delivered to mice lungs via intratracheal aerosol delivery. This thesis also discusses the use of PEG-based hydrogel as a biomaterial microenvironment for encapsulated stem cells as a means of in vitro T cell differentiation. A 3D hydrogel system creates a biomimetic reconstruction of the cell’s natural microenvironment and allows us to adjust factors such as ligand density and mechanical properties of the hydrogel in order to promote cells differentiation. This report utilizes hydrogels of cross-linked hyaluronic acid and PEG to encapsulate mice bone marrow hematopoietic progenitor cells in the presence of notch ligands, displayed through stromal cells, magnetic microbeads, or immobilized within the hydrogel matrix. Mechanical properties of the hydrogels were tested and the release of encapsulated cells was performed by enzymatic degradation or dissolution. The differentiation data obtained indicated successful differentiation of stem cells into early T cells through the hydrogel system.Item Design of self-assembling nucleo-peptide hydrogels for molecular self-assembly study and functional biomaterials development(2019-04-26) Baek, Kiheon; Suggs, Laura J.; Ren, Pengyu; Zoldan, Janeta; Rosales, AdrianneSelf-assembling peptide-based biomaterials are promising for use in biomedical applications due to their inherent extracellular matrix-like structure, comparable nanofiber dimensions and responsiveness to cells and proteins. Among them, short peptides and their derivatives have been studied because of their ease of synthesis and bottom-up design for controlling fibrillar supra-structure. In this dissertation, nucleo-tripeptides which can self-assemble into a hydrogel form were designed based on considerations of their gelation conditions and applications to functional cell scaffolds and controlled drug release. From the result of Fmoc modified short depsipeptides study, showing functional potential but cytotoxicity upon degradation, nucleobases were evaluated as a replacement for the Fmoc group. A small library, composed of 16 nucleo-tripeptides, was constructed in order to control the self-assembly conditions and to identify a molecule which can form a hydrogel under physiologic conditions. The resulting supra-structures were analyzed experimentally and computationally. We found that nucleo-tripeptides can self-assemble into nano-fibers which then lead to hydrogel formation under physiologic pH. Self-assembled nano-fibers have DNA-like structures, exhibiting nucleobase stacking and Watson-Crick-like interactions. By using these DNA-like structures as well as the self-healing capability of the nucleo-tripeptide hydrogel, applications as functional cell scaffolds and controlled drug release were studied. The self-assembled nucleo-tripeptide hydrogel can be functionalized via mixing with a second molecule having a complementary nucleobase via Watson-Crick interactions. A molecule possessing arginine-glycine-aspartic acid (RGD), interacting with integrin located on the surface of cells, and a nucleobase was incorporated into the self-assembled nucleo-tripeptide hydrogel. This incorporation resulted in improved viability and cell attachment during 3D culture of fibroblasts. Nucleobase stacking structures were applied to the sequestration and controlled release of the doxorubicin, a cancer drug which exerts its action by intercalated DNA. The self-assembled nucleo-tripeptide hydrogel was able to load doxorubicin effectively through its DNA-like interactions, and in vitro and in vivo studies showed that controlled release of doxorubicin can inhibit tumor growth over a long-term period.Item Development and evaluation of enzymatically-degradable hydrogel microparticles for pulmonary delivery of nanoparticles and biologics(2012-12) Wanakule, Prinda 1985-; Roy, KrishnenduThe emerging class of biologic drugs, including proteins, peptides, and gene therapies, are widely administered by injection, despite potential systemic side effects. Rational design of targeted carriers that can be delivered non-invasively, with reduced side effects, is essential for the success of these therapies, as well as for the improvement of patient compliance and quality of life. One potential approach is to take advantage of specific physiological cues, such as enzymes, which would trigger drug release from a drug carrier. Enzymatic cleavage is highly specific and could be tailored for certain diseased tissues where specific enzymes are up regulated. Enzymatically-degradable hydrogels, which incorporate an enzyme- cleavable peptide into the network structure, have been extensively reported for releasing drugs for tissue engineering applications. These studies showed that a rapid response and corresponding drug release occurs upon enzyme exposure, whereas minimal degradation occurs without enzyme. Recently, Michael addition reactions have been developed for the synthesis of such enzymatically-degradable hydrogels. Michael addition reactions occur under mild physiological conditions, making them ideally suited for polymerizing hydrogels with encapsulated biologic drugs without affecting its bioactivity, as in traditional polymerization and particle synthesis. The focus of my research was to create enzymatically-degradable hydrogel microparticles, using Michael addition chemistry, to evaluate for use as an inhalable, disease-responsive delivery system for biologic drugs and nanoparticles. In this dissertation, I utilize bioconjugation and Michael addition chemistries in the design and development of enzymatically-degradable hydrogels, which may be tailored to a multitude of disease applications. I then introduce a new method of hydrogel microparticle, or microgel, synthesis known as the Michael Addition During Emulsion (MADE) method. These microgel carriers were evaluated in vitro, and found to exhibit triggered release of encapsulated biologic drugs in response to enzyme, no significant cytotoxic effects, and the ability the avoid rapid clearance by macrophages. Lastly, in vivo studies in mice were conducted, and microgels were found to exhibit successful delivery to the deep lung, as well as prolonged pulmonary retention after intratracheal aerosol delivery. In conclusion, a new class of enzymatically-degradable microgels were successfully developed and characterized as a versatile and promising new system for pulmonary, disease-responsive delivery of biologic drugs.Item The development of depsipeptides as tissue engineering scaffolds : synthesis, characterization, and self-assembly into hydrogels(2013-05) Nguyen, Mary Minh Chau; Suggs, Laura J.The development of novel, peptide based structures for tissue engineering materials has been widely researched, and its popularity can be attributed to advancements in technological analysis methods. Using principles based on protein structure and organization, this work describes the novel self-assembly of depsipeptides, which incorporate alternating esters within a native peptide backbone. Chapter 1 introduces and reviews peptide mimics for their utility for tissue engineering applications. Chapter 2 describes the methodology in synthesizing and characterization a depsipeptide library using both solution and solid phase methods. Chapter 3 discusses the effects of depsipeptide length, concentration, and sequence within a range of ionic concentrations and pH ranges on the self-assembly of depsipeptides into spherical nanostructures, fibers, or hydrogels. Chapter 4 describes proposed methods to increase the rate of gelation, followed by discussions of biocompatibility studies from other self-assembling peptide and modified-peptide systems in vitro and in vivo. The work described in this dissertation demonstrates that the synthesis and self-assembly of a depsipeptide family which alternates esters into a native peptide backbone does not disrupt the formation of higher order structures. This study illustrates the potential to synthesize a wide range of depsipeptides with variable side chains and hydrophobic character, as understanding these effects on self-assembly is imperative to the development of biomimetic materials for tissue engineering applications.Item Effect of shape on cell internalization of polymeric hydrogel nanoparticles(2013-05) Agarwal, Rachit, Ph. D.; Roy, KrishnenduRecent progress in drug discovery has enabled us to target specific intracellular molecules to achieve therapeutic effects. These next generation therapeutics are often biologics which cannot enter cells by mere diffusion. Therefore it is imperative that drug carriers are efficiently internalized by cells before releasing their cargo. Nanoscale polymeric carriers are particularly suitable for such intra-cellular delivery. Although size and surface-charge has been the most studied parameters for nanocarriers, it is now well appreciated that particle shape also plays a critical role in their transport across physiological barriers. Hence there is increasing interest in fabricating shape-specific polymeric nano and microparticles for efficient delivery of drugs and imaging agents. Nanoimprint lithography methods, such as Jet-and-flash imprint lithography (J-FIL), provide versatile top-down processes to fabricate shape-specific, biocompatible nanoscale hydrogels that can deliver therapeutic and diagnostic molecules in response to disease-specific cues. However, the key challenges in top-down fabrication of such nanocarriers are scalable imprinting with biological and biocompatible materials, ease of particle-surface modification using both aqueous and organic chemistry as well as simple yet biocompatible harvesting. Here we report that a biopolymer-based sacrificial release layer in combination with improved nanocarrier-material formulation can address these challenges. The sacrificial layer improves scalability and ease of imprint-surface modification due to its switchable solubility through simple ion exchange between monovalent and divalent cations. This process enables large-scale bio-nanoimprinting and efficient, one-step harvesting of hydrogel nanoparticles in both water- and organic-based imprint solutions. We also show that when shape is decoupled from volume, charge and composition, mammalian cells preferentially internalize disc-shaped nanohydrogels of higher aspect ratios over nanorods. Interestingly, unlike nanospheres, larger-sized hydrogel nanodiscs and nanorods are internalized more efficiently. Uptake kinetics, efficiency and internalization mechanisms are all shape-dependent and cell-type specific. Although macropinocytosis is used by all cells, epithelial cells uniquely internalize nanodiscs using caveolae pathway. On the other hand, endothelial cells use clathrin-mediated uptake along with macropinocytosis for all shapes and show significantly higher uptake efficiency compared to epithelial cells. We also study the effect of shape and surface properties for their tissue uptake and penetration using spheroids as a 3D tumor model and show that hydrophobic particles show no difference in penetration inside such models even after 125 fold reduction in volume. These results provide a fundamental understanding of how cell and tissue behavior is influenced by nanoscale shape and surface properties and are critical for designing improved nanocarriers and predicting nanomaterial toxicity.Item Fundamental, model-driven investigations of structure and physical properties of poly(vinyl alcohol) hydrogels and multi-arm poly(ethylene glycol) hydrogels : decoupling stiffness and solute transport(2022-07-29) Richbourg, Nathan R.; Peppas, Nicholas A., 1948-; Cosgriff-Hernandez, Elizabeth; Rausch, Manuel; Zoldan, Janet; Lynd, NateSynthetic hydrogels are advanced biomaterials frequently used in cutting-edge biomedical engineering research and clinical interventions. Their value is highly associated with their tunability and ability to mimic the extracellular matrix properties of a variety of tissues such as bone marrow and brain tissue, but many of the fundamental properties of hydrogels are overly generalized and under-investigated. Recent studies have shown that cells respond to both the stiffness and solute transport profile of their environment, but standard hydrogel synthesis methods cause those two properties to be highly correlated. New insight into structural control of hydrogel properties is needed to independently tune stiffness and solute transport in hydrogels. This dissertation combines fundamental modeling, the full capabilities of multi-arm poly(ethylene glycol) (PEG) hydrogel design, and high-throughput, standardized methods for measuring hydrogel swelling, stiffness, and solute transport to decouple stiffness and solute diffusivity in hydrogels without changing their chemical properties. First, we coordinated equilibrium swelling theory, rubberlike elasticity theory, and mesh transport theory into the fundamental predictive swollen polymer network model. From the model and prior studies relating hydrogel structure and function, we identified four structural parameters that could be independently controlled at synthesis. The swollen polymer network model predicted that simultaneously manipulating these four structural parameters would decouple stiffness and solute diffusivity. Poly(vinyl alcohol) (PVA) hydrogels were used to establish model-compatible, high-throughput measurement methods for swelling, stiffness, and solute transport. The eighteen PVA hydrogel formulations with variation in two of the four structural parameters also served as a control group for the multi-arm PEG hydrogels. The extensive validation studies with PVA hydrogels identified limitations of the swollen polymer network model not addressed by the following multi-arm PEG hydrogel studies, such as how solute diffusivity scales differently with solute size for different solute chemical profiles. Stiffness and solute transport were decoupled by the four structural parameters in multi-arm PEG hydrogels. However, the structure-property relationship that facilitated the decoupling was not predicted by the swollen polymer network model, highlighting an opportunity for further model development. The fundamental model-based hydrogel design approach described here provides a foundation for robust hydrogel design for biomedical applications.Item IGF-1 conjugated to a PEGylated-Fibrin hydrogel as a therapeutic modality for eccentric muscle damage in rats(2011-12) Treff, Jessica Caitlin; Farrar, Roger P.We evaluated the efficacy of treating eccentric muscle damage with IGF-1 PEGylated to a fibrin biomatrix. With one injection, delivered one hour after the induction of eccentric muscle damage we saw an attenuation of force loss early in recovery, maintenance of muscle weight, and progression to the repair/regeneration of the damaged fibers at a greater speed and magnitude in the first week of recovery. As opposed to introducing an unbound bolus of IGF-1, we believe the ability of the PEGylated-fibrin to stabilize and sustain delivery of the molecule results in significantly better recovery. Coupling IGF-1, which has multiple beneficial effects in tissue repair, with this system of delivery provides a simple and easy to administer treatment for eccentric muscle damage. With this form of damage being the most prevalent of all skeletal muscle damage types, since it is underlies all muscle strain, a simple and effective treatment is important for increasing functional recovery after injury.Item Investigating the stimuli responsiveness of reversible thia-conjugate addition crosslinked hydrogels(2022-12-01) FitzSimons, Thomas Miyamoto; Rosales, Adrianne M.; Bonnecaze, Roger T; Anslyn, Eric V; Lynd, Nathaniel A; Page, Zachariah ADynamic hydrogels have recently demonstrated utility as versatile biomaterials. Characterized by the spontaneous rearrangement of crosslinks at ambient conditions, dynamic hydrogels more closely mimic the native extracellular matrix better than their static hydrogel counterparts, and the wide parameter space allows for a high degree of control for drug release applications. Despite the promising applicability that these hydrogels demonstrate, the structure-property relationships that govern the effects of the hydrogel composition on the mechanics remain poorly understood. An ideal system for investigating both the relationship of crosslinking on hydrogel mechanics in addition to biomaterial applications are hydrogels crosslinked through reversible covalent crosslinks. A number of reversible covalent bonds have well defined mechanisms that allow for facile determination of their rate constants via kinetic model fitting. Oscillatory rheometry also provides a robust mechanical method to characterize both the overall stiffness and dynamics of the dynamic hydrogels. In order to investigate the structure-property relationships in reversible covalently crosslinked hydrogels, this work first incorporated a reversible thia-conjugate addition reaction into a hydrogel. Previous small molecule research established this reaction as a reversible covalent reaction under standard biological conditions, and the first part of this project functionalized macromers and analyzed how chemical changes to the functional groups influenced the kinetics and mechanics of the resulting hydrogel. The accepted mechanism of this reaction reveals a deprotonation step in the forward and reverse direction which lead to the second area of research, wherein pH values from 3 to 7 were used to alter the kinetics and mechanics of a reversible thia-conjugate addition crosslinked hydrogels. Additionally, a gastrointestinal molecular release study was performed to demonstrate the drug delivery applications of this hydrogel. Finally, the temperature dependence of the crosslinking reaction was analyzed, and reaction parameters were determined from the mechanical analysis. In summary, three stimuli; chemistry, pH, and temperature, were used to investigate the structure-property relationships in reversible thia-conjugate addition crosslinked hydrogels with additional focus placed on the biomaterial applications of these materials.Item Materials design and surface engineering of functional hydrogels for solar desalination and water purification(2021-07-28) Guo, Youhong; Yu, Guihua (Assistant professor); Johnston, Keith P; Li, Wei; Zheng, YuebingWater scarcity caused by the growing population and pollution in the wake of natural disasters or supply system damage is a severe threat to our society. Thermal and membrane-based technologies have been developed to deliver clean water via seawater desalination and wastewater recycling; however, the requirements of high energy consumption and frequent maintenance of infrastructures have raised a barrier for off-grid regions. Solar-powered distillation has regained attention as a potential solution to water shortage because solar energy dwarfs all other fossil-based energy resources in abundance and environmental benignity. A feasible solar-assisted water purification system not only requires scientific breakthroughs to enable efficient energy capture/conversion and a high rate of clean water production but also needs to be affordable for communities that suffer from economic water scarcity. Hydrogels are an emerging material platform for applications in sustainable water-energy-environmental nexus because gelation chemistry endows them with tunable physicochemical properties and ease of integration with versatile functionalities. This Dissertation focuses on designing hydrogel materials for solar desalination and water purification technologies. First, solar-absorbing nanoparticles are introduced into the hydrogel matrix to efficiently harvest and convert solar energy, powering water evaporation within molecular meshes. The energy utilization and water transport of the systems are investigated based on tuning polymer-water and polymer-particle interactions in hydrogel networks. Next, since evaporation occurs at the hydrogel-air interface, the surface property of hydrogels plays a vital role in the interfacial evaporation process. Taking advantage of intermolecular interactions between polymer chains and solvents, the surface topography of hydrogel evaporators can be tailored in nanoscale to achieve an enhanced water evaporation process. Furthermore, through chemical functionalization, surface wettability can be regulated to boost water evaporation performance. Last, by modifying the functional groups on polymer backbones and absorbers, heavy metal-ion adsorption, antibacterial, and anti-biofouling features are incorporated into hydrogel evaporators. It is anticipated that the studies presented can promote a better understanding of the water evaporation behavior at the hydrogel-air interface and inspire the future design of solar distillation devices/systems with higher clean water production and lower cost, overcoming the dependency on electricity supply to achieve decentralized water purification.Item Metal-polymer nanoparticulate systems for externally-controlled delivery(2010-12) Gran, Martin Luke; Peppas, Nicholas A., 1948-; Paul, Donald R.; Freeman, Benny D.; Johnston, Keith P.; Emelianov, StanislavMetal-polymer nanocomposites consisting of gold nanorods and temperature-responsive hydrogel nanoparticulates were investigated for use in externally-controlled drug delivery systems. Several different thermo-responsive hydrogels including poly(N-isopropyl acrylamide) (PNIPAAm) and poly(N-isopropryl acrylamide-co-acrylic acid) (P(NIPAAm-co-AA)) nanoparticles were synthesized for these nanocomposites using an aqueous dispersion polymerization method. In addition, nanoparticles of interpenetrating polymer networks (IPN) composed of poly(acrylamide) (PAAm) and poly(acrylic acid) (PAA) were synthesized using a water-in-oil emulsion polymerization. Temperature-responsive equilibrium swelling behavior of nanoparticles with varying crosslinking densities was characterized using dynamic light scattering. IPN systems exhibited a positive swelling response upon heating while PNIPAAm and copolymer systems collapsed upon increase in temperature above the transition point. Nanoparticles were characterized using scanning electron microscopy (SEM) and transmission electron microscopy (TEM) which demonstrated shape and morphology of polymer particles. Gold-polymer nanocomposites were formed by grafting gold nanorods to the surface of the polymer nanoparticles. Amine-functionalized gold nanorods were coupled to polymers using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and N-hydroxysulfosuccinimide (Sulfo-NHS) to activate carboxyl groups on the surface of the polymer nanoparticles. TEM confirmed successful formation of the metal-polymer nanocomposites. Loading and release of a model therapeutic were done to assess the potential use of the polymer component of the nanocomposite for drug delivery. Fluorescein, a model for chemotherapeutics, was loaded into P(NIPAAm-co-AA) polymer nanoparticulates. Loading of the compound was shown to be a function of crosslinking density in the polymer network. Maximum loading was achieved using nanoparticles synthesized with a 10 mol% crosslinker feed ratio with entrapment efficiencies of 80.0 % and loading capacities of 12.0 %. Cytotoxicity studies were performed using a NIH/3T3 mouse fibroblast cell model. Cell viabilities in presence of P(NIPAAm-co-AA) nanoparticles were comparable to (not statistically different than) controls at concentrations up to 4 mg/ml. Similarly, gold-polymer composite concentrations up to 0.5 mg/ml caused limited cell death.Item Modelling and simulations of hydrogels with coupled solvent diffusion and large deformation(2014-12) Bouklas, Nikolaos; Huang, Rui, doctor of civil and environmental engineering; Landis, Chad M.Swelling of a polymer gel is a kinetic process coupling mass transport and mechanical deformation. A comparison between a nonlinear theory for polymer gels and the classical theory of linear poroelasticity is presented. It is shown that the two theories are consistent within the linear regime under the condition of a small perturbation from an isotropically swollen state of the gel. The relationships between the material properties in the linear theory and those in the nonlinear theory are established by a linearization procedure. Both linear and nonlinear solutions are presented for swelling kinetics of substrate-constrained and freestanding hydrogel layers. A new procedure is suggested to fit the experimental data with the nonlinear theory. A nonlinear, transient finite element formulation is presented for initial boundary value problems associated with swelling and deformation of hydrogels, based on nonlinear continuum theories for hydrogels with compressible and incompressible constituents. The incompressible instantaneous response of the aggregate imposes a constraint to the finite element discretization in order to satisfy the LBB condition for numerical stability of the mixed method. Three problems of practical interests are considered: constrained swelling, flat-punch indentation, and fracture of hydrogels. Constrained swelling may lead to instantaneous surface instability. Indentation relaxation of hydrogels is simulated beyond the linear regime under plane strain conditions, and is compared with two elastic limits for the instantaneous and equilibrium states. The effects of Poisson’s ratio and loading rate are discussed. On the study of hydrogel fracture, a method for calculating the transient energy release rate for crack growth in hydrogels, based on a modified path-independent J-integral, is presented. The transient energy release rate takes into account the energy dissipation due to diffusion. Numerical simulations are performed for a stationary center crack loaded in mode I, with both immersed and non-immersed chemical boundary conditions. Both sharp crack and blunted notch crack models are analyzed over a wide range of applied remote tensile strains. Comparisons to linear elastic fracture mechanics are presented. A critical condition is proposed for crack growth in hydrogels based on the transient energy release rate. The applicability of this growth condition for simulating concomitant crack propagation and solvent diffusion in hydrogels is discussed.Item Multi-analyte biosensing : the integration of sensing elements into a photolithographically constructed hydrogel based biosensor platform(2005-05) Schmid, Matthew John; Willson, C. G. (C. Grant), 1939-The genome sequencing programs have identified hundreds of thousands of genetic and proteomic targets for which there are presently no ascribed functions. The challenge for researchers now is to characterize them, as well as identify and characterize their natural variants. Historically, this has meant studying each individual target separately. However, due to the recent development of multi-analyte microarray devices, these characterizations can be performed in a combinatorial manner in which a single experiment provides information on thousands of targets at a time. In the past decade, microarray technology has settled in on two major designs. The first entails spotting individual receptor types onto a functionalized glass substrate. This is a simple and inexpensive process; however, due to the limited resolution of the mechanical devices used to do the spotting, the densities of these arrays are relatively low. Moreover, receptor preparation requires substantial time and effort. The second variety of microarray uses photolithographic techniques adapted from the semi-conductor industry to chemically synthesize the receptor elements in situ on the sensing surface. Because lithographic patterning is spatially very precise, these arrays achieve very high densities, with as many as one million features per square centimeter. Although these arrays obviate the necessity for laborious "off chip" probe preparation, they are expensive to produce and are limited to two types of receptors (oligonucleotides and peptides). This dissertation presents the development work performed on a hydrogel-based biosensor platform which provides a high density and low cost alternative to the two aforementioned designs. The array features are fabricated lithographically from a liquid pre-polymer doped with biologically active sensing elements at sizes as small as 50[micrometer]. Each of the feature types is uniquely shaped, which enables the features to be mass-produced in batches, pooled together and then assembled into randomly ordered arrays using highly-parallelized self-assembly techniques. The three-dimensional hydrogel features accommodate a wide variety of sensing elements, such as enzymes, antibodies and cells, which cannot be deployed using the traditional designs. This dissertation presents methods developed to integrate cellular and oligonucleotide sensing elements into the hydrogel features which preserve their biological activity and optimize the sensor's performance.Item Multi-responsive microencapsulated nanogels for the oral delivery of small interfering RNA(2014-12) Knipe, Jennifer Marie; Peppas, Nicholas A., 1948-; Paul, Donald; Ellison, Christopher; Contreras, Lydia; Suggs, LauraMulti-responsive, anionic poly(methacrylic acid-co-N-vinyl-2-pyrrolidone) microscale hydrogels (microgels) encapsulating polycationic nanoscale hydrogels (nanogels) were synthesized with either degradable or nondegradable crosslinks. The pH-responsive volume phase transition of these formulations was consistent with the pH transition experienced during intestinal delivery, as the hydrogels swelled at pH values greater than pH 5. The physicochemical characteristics of the nondegradable formulations were evaluated by microscopy, potentiometric titration, Fourier transform infrared spectroscopy, and thermal gravimetric analysis. The nondegradable formulations successfully loaded and released a model protein in physiological buffers, but the ability of the microgels to release the nanogels upon exposure to intestinal conditions was inadequate. Therefore, microgels containing enzyme-degradable oligopeptide crosslinks were synthesized then characterized using Fourier transform infrared spectroscopy, electron microscopy, confocal microscopy, and ImageStream flow cytometry. Degradation of the microgels upon incubation in trypsin solutions, simulated gastric fluid, or simulated intestinal fluid was evaluated by measuring the change in relative turbidity over time. Microgels were degraded specifically by the enzyme trypsin, and the rate of degradation was dependent upon the microgel to trypsin concentration ratio; for all ratios tested, degradation was complete within 4 hours. The cytocompatibility of the enzyme-degraded microgels encapsulating nanogels was evaluated in both a human and a murine cell line; at microgel concentrations less than 0.4 mg/ml the cell viability was greater than 90%. Confocal microscopy was used to obtain Z-stack images of the cells following incubation with the microgels, confirming that nanogels were released from the degraded microgels and subsequently inteRNAlized by RAW 264.7 murine macrophage cells. The microencapsulated nanogels were able to load siRNA via electrostatic complexation with loading efficiencies ranging from 60-80%. Incubation of loaded microgels in simulated intestinal fluid with reduced trypsin concentrations or in rat intestinal fluid resulted in successful degradation of the microgel matrix and release of a detectable amount of viable siRNA. The degraded microgels with nanogels transfected the two different cell lines with up to 20% silencing efficiency. Though the knockdown efficiency is not as high as that of nanogels alone, the microgel results are consistent and reproducible across two cell lines.Item Natural biomaterials for enhanced oligodendrocyte differentiation and spinal cord injury repair(2014-08) Geissler, Sydney Amelia; Stachowiak, Jeanne Casstevens; Schmidt, Christine E.Spinal cord injury is a devastating source of suffering in the spectrum of human pathophysiology; advancement for clinical therapy in this area has been stagnant in comparison to modern medical development. Current treatments are palliative, and functional recovery is minimal. During the first two weeks after injury, dense glial scar forms that is impenetrable by regenerating axons. Intervention is imperative to minimize scar formation and provide a supportive environment for axonal regeneration. Oligodendrocytes are critical to maintain the health of growing axons during development and after injury. Obtaining these cells through differentiation of neural progenitor cells (NPCs) is a viable option, but current clinical trials involving stem cells are plagued by poor cell survival and undirected differentiation. Research indicates that local extracellular matrix (ECM) is vital to progenitor differentiation and tissue regeneration. During development, spinal cord ECM is comprised of high concentrations of laminin and hyaluronic acid (HA), which provide essential cues to direct NPC migration and differentiation. The purpose of this research is to create a biomaterial optimized to direct NPC differentiation to oligodendrocytes. Natural biomaterials were optimized from distinct combinations of collagen I, HA, and laminin I to model the native ECM signals found during oligodendrocyte maturation. Four material combinations (collagen, collagen-HA-laminin, collagen-HA, and collagen-laminin) were fabricated into injectable hydrogels to mimic the range of compressive and shear mechanical properties present in neonatal central nervous system (CNS) tissue. Differentiation was assessed by culturing rodent fetal NPCs in these materials without specific soluble factors to direct cellular behavior. The three-component hydrogel performed optimally and achieved a 66% oligodendrocyte differentiation rate compared to approximately 15% in the collagen alone hydrogel. An in vivo study was then conducted using a rat contusion model of spinal cord injury with intervention using the injectable, three-component hydrogel seeded with rat NPCs. Functional recovery was assessed using six behavioral tests. Significant recovery was observed using two behavioral tests six weeks post-treatment. Lesion size was measured and correlated well with behavioral outcomes. The data obtained in this research indicate that a multi-component hydrogel mimicking native, developmental CNS tissue may address problems associated with current clinical practice.Item Novel reactivity of materials from porphyrins, and highly conjugated scaffolds(2018-04-12) Lammer, Aaron David; Sessler, Jonathan L.; Ansyln, Eric; Que, Emily; Sean Roberts; Liu, BenThe study of photo responsive compounds is of immense importance to many fields of chemistry and materials development. As the need for green chemistry grows, light is an ever more attractive reagent. Light functions as a nondestructive, noninvasive implement in sensing systems. Light emitting materials have found extensive use in electric materials as devices are developed that require greater energy efficacy and flexibility. This dissertation covers the authors work in the synthesis and characterization of highly conjugated organic systems, and resulting interaction with light. Chapter 1 gives a brief overview of all projects explored in this dissertation. This summary includes the previous work and remaining challenges of each topic. Chapter 2 describes the development and utilization of texaphyrins as photo-catalysts in the break down of natural products. Chapter 3 describes our work toward photo activated hydrogels for targeted drug release. Chapter 4 describes the development of novel BODIPY systems for metal and fullerene binding. Chapter 5 describes the development of electroluminescent materials. Chapter 6 details the synthesis and characterization of compounds discusses in this dissertation.Item Novel templating of three-dimensional hyaluronic acid soft tissue scaffolds(2013-12) Thomas, Richelle Czarina; Sanchez, Isaac C., 1941-; Schmidt, Christine E.Effective tissue engineering scaffolds should mimic the physical and chemical attributes of native tissue. Native tissues have intricate patterns, a multitude of porosities, and large water contents that are each directly associated with their ability to regulate and support life function. Therefore, the physical architecture of scaffolds intended to mimic these tissues for engineering applications plays an important role in scaffold performance both in vitro and in vivo. Self-assembling molecules organize into intricate patterns with a complexity that resembles that of native tissue. Hyaluronic acid (HA) hydrogels are widely used in tissue engineering for a variety of applications but fail to offer physical architecture beyond the inherent hydrogel porosity. To address this issue, a novel method to impose architecture within thin HA-based films using crystal nucleation was developed in the Schmidt lab [1]. The work described herein extends this method for use in three-dimensional matrices, with the main vii goal being the creation of hydrogels with a complex macroarchitecture. Four in situ self-assembling molecules were used: glycine, guanidine, urea and potassium dihydrogen phosphate. The crystallization of each molecule creates a specific porous network within the hydrogel that is the negative imprint of the crystalline geometry. The novel restriction of aqueous polymer into the molecule interstitial crystalline space allows hydrogels to embody complex geometric lumen architectures. The hydrogels were characterized in terms of their internal architectures, swelling, bulk moduli, biodegradability, cytotoxicity and in vitro cellular response. The unique structure-property relationships displayed by hydrogels templated by each of the crystallizing molecules were characterized in regards to mechanical properties. The need for complex microscopic architecture is conserved over many tissue engineering applications and templated scaffolds were evaluated for two unique applications. Crystal-templated hydrogels were investigated for use as an artificial stem cell niche environment to expand undifferentiated neural progenitor cells. Additionally, the templated hydrogels were evaluated for the in vitro study of myelin expression from Schwann cells. A hydrogel that combines the biocompatible properties of HA and the architectural complexity of native tissue may prove beneficial for biomedical applications.Item pH-responsive polymer nanoparticles synthesized using ARGET ATRP(2013-12) Forbes, Diane Christine; Peppas, Nicholas A., 1948-Polycationic nanoparticles were synthesized with an activators regenerated by electron transfer for atom transfer radical polymerization-based (ARGET ATRP-based) emulsion in water method and investigated for their utility as biomaterials for drug delivery. The polycationic nanoparticles were composed of 2-(diethylamino)ethyl methacrylate (DEAEMA) for pH-responsiveness, poly(ethylene glycol) methyl ether methacrylate (PEGMA) for improved biocompatibility, tert-butyl methacrylate (tBMA) to impart hydrophobicity, and a tetraethylene glycol dimethacrylate (TEGDMA) cross-linking agent for enhanced colloidal stability. Dynamic light scattering demonstrated pH-responsive swelling, and cell-based assays demonstrated pH-dependent membrane disruption. The polycationic nanoparticles demonstrated low toxicity to cells. The polycationic nanoparticles were evaluated for use as drug delivery biomaterials by investigating the interactions with the drug and cells. Delivery remains a major challenge for translating small interfering RNA (siRNA) to the clinic, and overcoming the delivery challenge requires effective siRNA delivery vehicles. The polycationic nanoparticles demonstrated efficient siRNA loading. Evidence of siRNA-induced knockdown in cells was observed following transfection with the polycationic nanoparticle/siRNA complexes. Imaging techniques confirmed enhanced siRNA internalization using the polycationic nanoparticle/siRNA complexes compared to naked siRNA. An array of polycationic nanoparticles synthesized using ARGET ATRP or UV-initiated polymerization methods was characterized to examine the effect of polymerization method on material properties and the connection to molecular structure. An improved understanding of molecular structure, and its connection to polymerization method and material characteristics, may aid the design of advanced materials. The ARGET ATRP polycationic nanoparticles demonstrated increased nanoscale homogeneity compared to the UV-initiated polymerization polycationic nanoparticles; increased nanoscale heterogeneity in the UV-initiated polymerization polycationic nanoparticles was associated with broader transitions. The polycationic nanoparticles promoted cellular uptake of siRNA and induced knockdown, thus demonstrating potential as siRNA delivery vehicles. The ARGET ATRP method provides an alternative route to creating polycationic nanoparticles with improved nanoscale homogeneity.Item Polymer carriers with amphiphilic properties for the oral delivery of therapeutic agents for cancer treatment(2012-08) Schoener, Cody Alan; Peppas, Nicholas A., 1948-; Ellison, Christopher; Contreras-Martin, Lydia; Sanchez, Isaac; Roy, KrishnenduPolymer carriers composed of poly(methacrylic acid – grafted – ethylene glycol) (P(MAA-g-EG)) hydrogels modified with poly(butyl acrylate) (PBA) to form IPNs or photopolymerized in the presence of poly(methyl methacrylate) (PMMA) nanoparticles were investigated for their use in the oral delivery of therapeutic agents for cancer treatment. The P(MAA-g-EG) hydrogel provided pH-responsive and hydrophilic properties while PBA or PMMA polymers provided hydrophobic properties. An inulin- doxorubicin conjugate was also synthesized to provide local, direct targeting for the treatment of colon cancer. The pH-responsive behavior of these polymer systems was investigated using equilibrium and dynamic swelling experiments. In gastric conditions (low pH) all materials were in a collapsed state and in intestinal conditions (neutral pH) these material were swollen. The equilibrium swelling ratios decreased with increasing hydrophobic content for both IPNs and compositions of P(MAA-g-EG) containing nanoparticles. The loading efficiencies of doxorubicin, a chemotherapeutic drug, were as high as 56% for IPNs and the IPN structure and hydrophobicity influenced the loading efficiency values. The loading efficiency of doxorubicin using P(MAA-g-EG) containing nanoparticles was as high as 64% and increased with increasing weight percent of PMMA nanoparticles in the P(MAA-g-EG) hydrogel. In gastric conditions (low pH), IPNs released a majority of the encapsulated doxorubicin (up to 70%) as compared to the P(MAA-g-EG) containing nanoparticles (up to 27%). P(MAA-g-EG) containing nanoparticles was used to load and release the inulin-doxorubicin conjugate. Loading efficiency was 54% and release profiles behaved similarly as doxorubicin. Both polymer systems were biocompatible with Caco-2, HT29-MTX, and SW620 cell models over concentration ranging from 1 mg/mL to 5 mg/mL and exposure times lasting from 2 hr to 24 hr. The 75/25 IPN exhibited the highest degree of mucoadhesion and the P(MAA-g-EG)-5.0NP the lowest. Using the same cell lines and cytotoxicity assays, the inulin-doxorubicin conjugate was determined to be more toxic than free doxorubicin at equal doxorubicin concentrations. Doxorobuicin and inulin-doxorubicin conjugate were tested for transport across Caco-2/HT29-MTX cell monolayers with and without the presence of unmodified P(MAA-g-EG) or P(MAA-g-EG)-5.0NP microparticles. The presence of the microparticles did not increase transport across the cell monolayer which is advantageous for local, direct delivery to the colon.