Browsing by Subject "PLGA"
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Item Design and development of an injectable, polymer-based immune priming center(2010-05) Singh, Ankur; Roy, Krishnendu; Kwak, Larry W; Peppas, Nicholas A; Schmidt, Christine E; Suggs, Laura J; Williams III, Robert OImmunotherapy, as a strategy to trigger immunity and eradicate a variety of chronic infectious diseases and cancers, has been explored for several decades with significant success in animal models. However, effective translation of these strategies into human clinical settings has proven elusive. Several cell-based anti-tumor therapies have progressed to clinical trials where antigen presenting dendritic cells (DCs) are isolated from patients, loaded with viral or tumor antigens and infused back in the patients. These ex-vivo “trained” DCs then present antigens to naïve T cells (adoptive therapy). However there exist several major limitations to this approach, including morbidity associated with patient cell isolation, high cost of ex vivo cell manipulation, time lag in “training” the immune cells, regulatory concerns, as well as the fact that ~ 90% of transplanted DCs die before they even home to lymph nodes. On the other hand, current immunotherapy approaches using recombinant proteins, synthetic peptides or nucleic acids, which "train" the immune cells in vivo to mount an immune response, have failed to address the tremendous challenge in generating efficient, sustained and protective immunity. There are two major challenges that must be overcome, (a) there exist relatively fewer numbers of immune cells at the sites of vaccine administration and given that these antigens themselves are weakly immunogenic, vaccine formulations must be tailored to attract large number of DCs to the immunization site and (b) immunologically, conventional nucleic acid or protein/peptide based vaccines do not elicit the required T helper type (Th) immunity along with a strong Cytotoxic T Lymphocyte (CTL) response against viral or tumor antigens and therefore new formulations must be able to “direct” the immune response towards a specific Th-type. Our goal was to design polymer-based sustained release formulations to addresses these challenges. Specifically, we have designed and developed delivery systems that can carry multiple biomolecules (nucleic acids, proteins, peptides, and chemoattractants) in a single injectable formulation. The delivery system promoted efficient migration of a large number of DCs to the site of injection and successful delivery of antigen resulting in activation of DCs. The multi-modal delivery system has the ability to bias or switch the immune response to the desired phenotype (e.g. Th1 or Th2) in a controlled manner. Using an infectious disease model against hepatitis B we have shown that co-encapsulation of Interleukin-10 (IL10) cytokine targeted siRNA within polymeric, surface-functionalized microparticles can further enhance DC activation and T cell proliferation in vitro as well as switch the hepatitis-specific immune response towards a strong Th1 phenotype in vivo. Further, in a weakly immunogenic A20 B cell lymphoma mouse model, a combination of microparticles and chemokine releasing in situ crosslinkable hydrogel provided significant Th1 type cellular immune response and delayed the onset of tumor development. Thus, the in situ crosslinkable hydrogel co-delivering microparticles and DC attracting chemokines creates an immune priming center with broad applications in a variety of disease models.Item Directing neuronal behavior via polypyrrole-based conductive biomaterials(2011-05) Forciniti, Leandro; Zaman, Muhammad H. (Muhammad Hamid); Schmidt, Christine E.; Sanchez, Isaac C.; Maynard, Jennifer A.; Bonnecaze, Roger T.The objective of my thesis is to explore the use of the conducting polymer, polypyrrole, in neural applications. In addition a supplementary aspect of dissertation will involves understanding the effects of external stimuli on nervous system cells, with the ultimate goal of designing therapeutic systems for nerve regeneration. In normal development and peripheral nervous system repair, nerves encounter naturally occurring chemical, physical, and electrical stimuli. Polypyrrole (PPy) has attracted much attention for use in numerous biomedical applications as it presents chemical, physical and electrical stimuli. In addition, PPy is particularly exciting because the extent by which chemical, physical, and electrical cues are presented to the injured nerve can be easily tailored. Thus, conducting polymers are excellent scaffolds for the exploration of how the cellular components of the nervous system (i.e., Schwann cells and neurons) interact with chemical, topographical, and electrical stimuli. This dissertation covers three main objectives and is supplemented by two additional topics. The two additional topics explore the effect stimuli present on the conducting polymer PPy have on neural interfaces. These fundamental studies use computational modeling to gain a better understanding of cellular motility on substrates containing different stimuli. Both topics are covered in the appendices of this dissertation. With regards to the three main objectives, I first characterized and optimized the electrochemical synthesis of the conducting polymer, PPy, for Schwann cell biocompatibility. Next, I investigated the effect the application of electrical cues through PPy has on Schwann cell migration. In addition to investigating the effect of the direct electrical current on Schwann cells I also considered the effect that electrical stimulation provided by PPy has on protein adsorption. Finally, I developed a hybrid PPy material that will provide advantageous properties for neural interfaces. Specifically, I describe the development of a polypyrrole:poly-(lactic-co-glycolic) acid blend for neural applications. In summary the three specific objectives covered in my thesis are: Specific Aim 1: Characterize and optimize the electrochemical synthesis of the conducting polymer, polypyrrole, for Schwann cell biocompatibility Specific Aim 2: Determine the effect of electrical stimulation on Schwann cell migration Specific Aim 3: Develop polypyrrole:poly-(lactic-co-glyolic) acid blends for neural engineering applications.Item Nanoencapsulation Strategies for Antimicrobial Controlled Release to Enhance Fresh and Fresh-Cut Produce Safety(2014-05-03) Hill, Laura EllenSpice essential oils and their constituents are powerful antimicrobials against foodborne pathogens. However, their low sensory threshold and low aqueous solubility make their application to fresh produce a challenge. Encapsulation within a biocompatible material has the potential to mask sensory attributes and increase aqueous solubility of the oils, thereby improving their applicability as antimicrobials onto fresh produce. Cinnamon bark extract (CBE), trans-cinnamaldehyde, clove bud extract, and eugenol were encapsulated in ?-cyclodextrin (BCD), poly(DL-lactide-co-glycolide) (PLGA), alginate, chitosan, and poly(N-isopropylacrylamide) (PNIPAAM) singly and in combination. All essential oil capsules were characterized for particle size and morphology, polydispersity index, entrapment efficiency, phase-solubility, and controlled release profile. Following physical and chemical characterization, the oils and their nanocapsules were analyzed for their antimicrobial activity against Salmonella enterica serovar Typhymirium LT2 and Listeria spp. using a microbroth dilution assay to determine minimum inhibitory and bactericidal concentrations at 35?C. The most efficacious antimicrobial nanocapsules during in vitro testing were BCD-CBE, PLGACBE, and chitosan-PNIPAAM-CBE, which were applied to fresh-cut romaine lettuce, along with free CBE, to determine their efficiency against L. monocytogenes in a food system. The chitosan-PNIPAAM-CBE yielded the greatest bacterial inhibition (P<0.05); therefore, it was subjected to a shelf-life study to determine if there were any effects of the particles on fresh-cut romaine lettuce quality over the course of storage. The antimicrobial nanoparticles did not significantly affect (P>0.05) overall product quality, making encapsulated essential oils a viable treatment for improving food safety without negatively impacting the product?s key attributes. This research project developed several natural antimicrobial delivery systems that each exhibited unique release properties and mechanisms, which improved the antimicrobial efficacy (P<0.05) of essential oils and their active compounds. This study sought to characterize and compare different nanoencapsulation systems based on their performance as controlled delivery systems for natural antimicrobials against foodborne pathogens, which has not been previously reported.