Matching Items (12)
Description
Alzheimer's Disease (AD) is a progressive neurodegenerative disease accounting for 50-80% of dementia cases in the country. This disease is characterized by the deposition of extracellular plaques occurring in regions of the brain important for cognitive function. A primary component of these plaques is the amyloid-beta protein. While a natively unfolded protein, amyloid-beta can misfold and aggregate generating a variety of different species including numerous different soluble oligomeric species some of which are precursors to the neurofibrillary plaques. Various of the soluble amyloid-beta oligomeric species have been shown to be toxic to cells and their presence may correlate with progression of AD. Current treatment options target the dementia symptoms, but there is no effective cure or alternative to delay the progression of the disease once it occurs. Amyloid-beta aggregates show up many years before symptoms develop, so detection of various amyloid-beta aggregate species has great promise as an early biomarker for AD. Therefore reagents that can selectively identify key early oligomeric amyloid-beta species have value both as potential diagnostics for early detection of AD and as well as therapeutics that selectively target only the toxic amyloid-beta aggregate species. Earlier work in the lab includes development of several different single chain antibody fragments (scFvs) against different oligomeric amyloid-beta species. This includes isolation of C6 scFv against human AD brain derived oligomeric amyloid-beta (Kasturirangan et al., 2013). This thesis furthers research in this direction by improving the yields and investigating the specificity of modified C6 scFv as a diagnostic for AD. It is motivated by experiments reporting low yields of the C6 scFv. We also used the C6T scFv to characterize the variation in concentration of this particular oligomeric amyloid-beta species with age in a triple transgenic AD mouse model. We also show that C6T can be used to differentiate between post-mortem human AD, Parkinson's disease (PD) and healthy human brain samples. These results indicate that C6T has potential value as a diagnostic tool for early detection of AD.
ContributorsVenkataraman, Lalitha (Author) / Sierks, Michael (Thesis advisor) / Rege, Kaushal (Committee member) / Pauken, Christine (Committee member) / Arizona State University (Publisher)
Created2013
Description
The objective of this research is to investigate the relationship among key process design variables associated with the development of nanoscale electrospun polymeric scaffolds capable of tissue regeneration. To date, there has been no systematic approach toward understanding electrospinning process parameters responsible for the production of 3-D nanoscaffold architectures with desired levels quality assurance envisioned to satisfy emerging regenerative medicine market needs. , As such, this study encompassed a more systematic, rational design of experiment (DOE) approach toward the identification of electrospinning process conditions responsible for the production of dextran-polyacrylic acid (DEX-PAA) nanoscaffolds with desired architectures and tissue engineering properties. The latter includes scaffold fiber diameter, pore size, porosity, and degree of crosslinking that together can provide a range of scaffold nanomechanical properties that closely mimics the cell microenvironment. The results obtained from this preliminary DOE study indicate that there exist electrospinning operation conditions capable of producing Dex-PAA nanoarchitecture having potential utility for regenerative medicine applications.
ContributorsEspinoza, Roberta (Author) / Pizziconi, Vincent (Thesis advisor) / Massia, Stephen (Committee member) / Garcia, Antonio (Committee member) / Arizona State University (Publisher)
Created2013
Description
The objective of this research is to develop a biocompatible scaffold based on dextran and poly acrylic acid (PAA) with the potential to be used for soft tissue repair. In this thesis, physical and chemical properties of the scaffold were investigated. The scaffolds were made using electrospinning and cross-linked under high temperature. After heat treatment, Scanning Electron Microscope (SEM) was used to observe the structures of these scaffolds. Fourier transform infrared spectroscopy (FTIR) was used to measure the cross-linking level of scaffold samples given different times of heat treatment by detecting and comparing the newly formed ester bonds. Single-walled carbon nanotubes (SWCNT) were added to enhance the mechanical properties of dextran-PAA scaffolds. Attachment of NIH-3T3 fibroblast cells to the scaffold and the response upon implantation into rabbit vaginal tissue were also evaluated to investigate the performance of SWCNT dextran-PAA scaffold. SEM was then used to characterize morphology of fibroblast cells and rabbit tissues. The results suggest that SWCNT could enhance cell attachment, distribution and spreading performance of dextran-PAA scaffold.
ContributorsLiu, Chongji (Author) / Massia, Stephen (Thesis advisor) / Pizziconi, Vincent (Committee member) / Pauken, Christine (Committee member) / Arizona State University (Publisher)
Created2014
Description
In this work, a novel method is developed for making nano- and micro- fibrous hydrogels capable of preventing the rejection of implanted materials. This is achieved by either (1) mimicking the native cellular environment, to exert fine control over the cellular response or (2) acting as a protective barrier, to camouflage the foreign nature of a material and evade recognition by the immune system. Comprehensive characterization and in vitro studies described here provide a foundation for developing substrates for use in clinical applications. Hydrogel dextran and poly(acrylic acid) (PAA) fibers are formed via electrospinning, in sizes ranging from nanometers to microns in diameter. While "as-electrospun" fibers are continuous in length, sonication is used to fragment fibers into short fiber "bristles" and generate nano- and micro- fibrous surface coatings over a wide range of topographies. Dex-PAA fibrous surfaces are chemically modified, and then optimized and characterized for non-fouling and ECM-mimetic properties. The non-fouling nature of fibers is verified, and cell culture studies show differential responses dependent upon chemical, topographical and mechanical properties. Dex-PAA fibers are advantageously unique in that (1) a fine degree of control is possible over three significant parameters critical for modifying cellular response: topography, chemistry and mechanical properties, over a range emulating that of native cellular environments, (2) the innate nature of the material is non-fouling, providing an inert background for adding back specific bioactive functionality, and (3) the fibers can be applied as a surface coating or comprise the scaffold itself. This is the first reported work of dex-PAA hydrogel fibers formed via electrospinning and thermal cross-linking, and unique to this method, no toxic solvents or cross-linking agents are needed to create hydrogels or for surface attachment. This is also the first reported work of using sonication to fragment electrospun hydrogel fibers, and in which surface coatings were made via simple electrostatic interaction and dehydration. These versatile features enable fibrous surface coatings to be applied to virtually any material. Results of this research broadly impact the design of biomaterials which contact cells in the body by directing the consequent cell-material interaction.
ContributorsLouie, Katherine BoYook (Author) / Massia, Stephen P (Thesis advisor) / Bennett, Kevin (Committee member) / Garcia, Antonio (Committee member) / Pauken, Christine (Committee member) / Vernon, Brent (Committee member) / Arizona State University (Publisher)
Created2011
Description
Treatment of cerebral aneurysms using non-invasive methods has existed for decades. Since the advent of modern endovascular techniques, advancements to embolic materials have largely focused on improving platinum coil technology. However, the recent development of Onyx®, a liquid-delivery precipitating polymer system, has opened the door for a new class of embolic materials--liquid-fill systems. These liquid-fill materials have the potential to provide better treatment outcomes than platinum coils. Initial clinical use of Onyx has proven promising, but not without substantial drawbacks, such as co-delivery of angiotoxic compounds and an extremely technical delivery procedure. This work focuses on formulation, characterization and testing of a novel liquid-to-solid gelling polymer system, based on poly(propylene glycol) diacrylate (PPODA) and pentaerythritol tetrakis(3-mercaptopropionate) (QT). The PPODA-QT system bypasses difficulties associated with Onyx embolization, yet still maintains non-invasive liquid delivery--exhibiting the properties of an ideal embolic material for cerebral aneurysm embolization. To allow for material visibility during clinical delivery, an embolic material must be radio-opaque. The PPODA-QT system was formulated with commercially available contrast agents and the gelling kinetics were studied, as a complete understanding of the gelling process is vital for clinical use. These PPODA-QT formulations underwent in vitro characterization of material properties including cytotoxicity, swelling, and degradation behaviors. Formulation and characterization tests led to an optimized PPODA-QT formulation that was used in subsequent in vivo testing. PPODA-QT formulated with the liquid contrast agent ConrayTM was used in the first in vivo studies. These studies employed a swine aneurysm model to assess initial biocompatibility and test different delivery strategies of PPODA-QT. Results showed good biocompatibility and a suitable delivery strategy, providing justification for further in vivo testing. PPODA-QT was then used in a small scale pilot study to gauge long-term effectiveness of the material in a clinically-relevant aneurysm model. Results from the pilot study showed that PPODA-QT has the capability to provide successful, long-term treatment of model aneurysms as well as facilitate aneurysm healing.
ContributorsRiley, Celeste (Author) / Vernon, Brent L (Thesis advisor) / Preul, Mark C (Committee member) / Frakes, David (Committee member) / Pauken, Christine (Committee member) / Massia, Stephen (Committee member) / Arizona State University (Publisher)
Created2011
Description
Aqueous solutions of temperature-responsive copolymers based on N-isopropylacrylamide (NIPAAm) hold promise for medical applications because they can be delivered as liquids and quickly form gels in the body without organic solvents or chemical reaction. However, their gelation is often followed by phase-separation and shrinking. Gel shrinking and water loss is a major limitation to using NIPAAm-based gels for nearly any biomedical application. In this work, a graft copolymer design was used to synthesize polymers which combine the convenient injectability of poly(NIPAAm) with gel water content controlled by hydrophilic side-chain grafts based on Jeffamine® M-1000 acrylamide (JAAm). The first segment of this work describes the synthesis and characterization of poly(NIPAAm-co-JAAm) copolymers which demonstrates controlled swelling that is nearly independent of LCST. The graft copolymer design was then used to produce a degradable antimicrobial-eluting gel for prevention of prosthetic joint infection. The resorbable graft copolymer gels were shown to have three unique characteristics which demonstrate their suitability for this application. First, antimicrobial release is sustained and complete within 1 week. Second, the gels behave like viscoelastic fluids, enabling complete surface coverage of an implant without disrupting fixation or movement. Finally, the gels degrade rapidly within 1-6 weeks, which may enable their use in interfaces where bone healing takes place. Graft copolymer hydrogels were also developed which undergo Michael addition in situ with poly(ethylene glycol) diacrylate to form elastic gels for endovascular embolization of saccular aneurysms. Inclusion of JAAm grafts led to weaker physical crosslinking and faster, more complete chemical crosslinking. JAAm grafts prolonged the delivery window of the system from 30 seconds to 220 seconds, provided improved gel swelling, and resulted in stronger, more elastic gels within 30 minutes after delivery.
ContributorsOverstreet, Derek (Author) / Caplan, Michael (Thesis advisor) / Massia, Stephen (Committee member) / Mclaren, Alexander (Committee member) / Vernon, Brent (Committee member) / McLemore, Ryan (Committee member) / Arizona State University (Publisher)
Created2012
Description
Current treatment methods for cerebral aneurysms are providing life-saving measures for patients suffering from these blood vessel wall protrusions; however, the drawbacks present unfortunate circumstances in the invasive procedure or with efficient occlusion of the aneurysms. With the advancement of medical devices, liquid-to-solid gelling materials that could be delivered endovascularly have gained interest. The development of these systems stems from the need to circumvent surgical methods and the requirement for improved occlusion of aneurysms to prevent recanalization and potential complications. The work presented herein reports on a liquid-to-solid gelling material, which undergoes gelation via dual mechanisms. Using a temperature-responsive polymer, poly(N-isopropylacrylamide) (poly(NIPAAm), the gelling system can transition from a solution at low temperatures to a gel at body temperature (physical gelation). Additionally, by conjugating reactive functional groups onto the polymers, covalent cross-links can be formed via chemical reaction between the two moieties (chemical gelation). The advantage of this gelling system comprises of its water-based properties as well as the ability of the physical and chemical gelation to occur within physiological conditions. By developing the polymer gelling system in a ground-up approach via synthesis, its added benefit is the capability of modifying the properties of the system as needed for particular applications, in this case for embolization of cerebral aneurysms. The studies provided in this doctoral work highlight the synthesis, characterization and testing of these polymer gelling systems for occlusion of aneurysms. Conducted experiments include thermal, mechanical, structural and chemical characterization, as well as analysis of swelling, degradation, kinetics, cytotoxicity, in vitro glass models and in vivo swine study. Data on thermoresponsive poly(NIPAAm) indicated that the phase transition it undertakes comes as a result of the polymer chains associating as temperature is increased. Poly(NIPAAm) was functionalized with thiols and vinyls to provide for added chemical cross-linking. By combining both modes of gelation, physical and chemical, a gel with reduced creep flow and increased strength was developed. Being waterborne, the gels demonstrated excellent biocompatibility and were easily delivered via catheters and injected within aneurysms, without undergoing degradation. The dual gelling polymer systems demonstrated potential in use as embolic agents for cerebral aneurysm embolization.
ContributorsBearat, Hanin H (Author) / Vernon, Brent L (Thesis advisor) / Frakes, David (Committee member) / Massia, Stephen (Committee member) / Pauken, Christine (Committee member) / Preul, Mark (Committee member) / Solis, Francisco (Committee member) / Arizona State University (Publisher)
Created2012
Description
Following diagnosis of a glioblastoma (GBM) brain tumor, surgical resection, chemotherapy and radiation together yield a median patient survival of only 15 months. Importantly, standard treatments fail to address the dynamic regulation of the brain tumor microenvironment that actively supports tumor progression and treatment resistance. Moreover, specialized niches within the tumor microenvironment maintain a population of highly malignant glioblastoma stem-like cells (GSCs). GSCs are resistant to traditional chemotherapy and radiation therapy and are likely responsible for near universal rates of tumor recurrence and associated morbidity. Thus, disrupting microenvironmental support for GSCs could be critical to more effective GBM therapies. Three-dimensional (3D) culture models of the tumor microenvironment are powerful tools for identifying key biochemical and biophysical inputs that may support or inhibit malignant behaviors. Here, we developed synthetic poly(N-isopropylacrylamide-co-Jeffamine M-1000® acrylamide) or PNJ copolymers as a model 3D system for culturing GBM cell lines and low-passage patient-derived GSCs in vitro. These temperature responsive scaffolds reversibly transition from soluble to insoluble in aqueous solution by heating from room temperature to body temperature, thereby enabling easy encapsulation and release of cells in a 3D scaffold. We also designed this system with the capacity for presenting the cell-adhesion peptide sequence RGD for adherent culture conditions. Using this system, we identified conditions that promoted GBM proliferation, invasion, GSC phenotypes, and radiation resistance. In particular, using two separate patient-derived GSC models, we observed that PNJ scaffolds regulated self-renewal, provided protection from radiation induced cell death, and may promote stem cell plasticity in response to radiation. Furthermore, PNJ scaffolds produced de novo activation of the transcription factor HIF2α, which is critical to GSC tumorigenicity and stem plasticity. All together, these studies establish the robust utility of PNJ biomaterials as in vitro models for studying microenvironmental regulation of GSC behaviors and treatment resistance.
ContributorsHeffernan, John M. (Author) / Sirianni, Rachael W. (Thesis advisor) / Vernon, Brent L (Thesis advisor) / Mehta, Shwetal (Committee member) / Stabenfeldth, Sarah (Committee member) / Massia, Stephen (Committee member) / Arizona State University (Publisher)
Created2017
Description
The purpose of this study, which was done in conjunction with the Arizona Heart Foundation, was to evaluate whether pyridoxine accelerates ulcer wound healing in diabetic patients with ulcers in the lower extremities. In this study, 100 mg of pyridoxine per day was given to patients in the experimental group (while they receive normal wound treatment) while patients in the control group received normal treatment of wounds without the pyridoxine. Over time, wound healing was evaluated by photographing and then measuring the size of patients' ulcer wounds on the photographs. Results from the experimental group were compared with those of the control group to evaluate the efficacy of the pyridoxine treatment. In addition, comparisons of the healing rates were made with respect to whether the patients smoked, had hypertension or hypotension, and the patients' body mass indexes. It has been found that there was no statistically significant difference in the mean healing rates between the control groups and experimental groups. In addition, it has been found that smoking, BMI and blood pressure did not have a statistically appreciable effect on the difference in mean healing rates between the control and experimental groups. This is evidence that pyridoxine did not have a statistically significant effect on wound healing rates.
ContributorsHaupt, Shawn Anthony (Author) / Caplan, Michael (Thesis director) / Pauken, Christine (Committee member) / Pagan, Pedro (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2013-05
Description
Misfolding and aggregation of alpha-synuclein (a-syn) has been strongly correlated with the pathogenesis of Parkinson's disease (PD). Reagents such as single chain antibody fragments (scFv) that can interact with specific aggregate forms of a-syn can be very useful to study how different aggregate forms affect cells. Here we utilize two scFvs, D5 and 10H, that recognize two distinct oligomeric forms of a-syn to characterize the presence of different a-syn aggregates in animal models of PD.
ContributorsAlam, Now Bahar (Author) / Sierks, Michael (Thesis director) / Pauken, Christine (Committee member) / Williams, Stephanie (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor) / Harrington Bioengineering Program (Contributor)
Created2013-05