Thesis (Ph. D.)--Ohio State University, 2005. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2006 Apr 27.

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xxiii, 163 p.; also includes graphics. Includes bibliographical references (p. 118-123). Available online via OhioLINK's ETD Center

Thesis (Ph. D.)--Dept. of Chemistry and School of Computing and Engineering. University of Missouri--Kansas City, 2004. / "A dissertation in chemistry and software architecture." Advisor: Yan-Ching Jean. Typescript. Vita. Description based on contents viewed Feb. 27, 2006; title from "catalog record" of the print edition. Includes bibliographical references (leaves 205-218). Online version of the print edition.

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Currently, the most common route for vaccine delivery is by intramuscular injection with a needle and syringe. Injection has number of disadvantages, such as risk of infection at the i njection site, needle prick injuries, and needle phobia that leads to significant levels of patient non-compliance. Therefore, the focus of this thesis is the development of an alternative ultrasound-assisted transdermal vaccine delivery system. To do so, we target immunological Langerhans cells in the epidermal layer of the skin that efficiently provoke an immune response. The stratum corneum (SC) is a barrier that prevents conventional transdermal vaccine delivery. Methods such as microneedles, iontophoresis and thermal ablation are presented in literature for the permabilisation of this layer. Sonophoresis is the use of ultrasound to transport molecules through a medium. Previous studies have demonstrated that the key underpinning mechanism is inertial cavitation, which leads to permeabilisation of the SC and facilitates transdermal delivery. Most studies to date have pre-exposed the skin to ultrasound prior to delivery of a vaccine in liquid form as a droplet placed on the skin. This approach is not practical for widespread use, but more importantly fails to take advantage of the potential of cavitation-mediated micro streaming to enhance active transport of molecules beyond the permeabilised skin. The focus of the present work is the development of a complete system that enables storage of the vaccine in a readily useable gel form whilst promoting and monitoring cavitation activity to simultaneously permeabilise the skin and enhance transdermal vaccine transport. Through initial in vitro studies, we first demonstrated that inertial cavitation can be exploited to promote the active transport of molecular entities such as vaccine molecules from a gel into a biological medium. A gel vaccine dosage formulation is utilised in order to mimic current clinically approved and established clinical ultrasound coupling gel formulations. By comparing the effects mediated at two ultrasound frequencies (0.256 MHz vs 1 MHz) which preferentially promote cavitational microstreaming or acoustic streaming, ultrasound parameters most conducive to producing high levels of inertial cavitation were identified as 0.256 MHz and peak rarefactional pressures on the order of 1 MPa. Three vaccine loaded gels were then formulated with either micro- or nano-sized cavitation nuclei and assessed for the optimal acoustic and chemical characteristics at the predetermined ultrasound parameters. Nano-sized nuclei were shown to be most effective at lowering the inertial cavitation threshold, as well as instigating the highest and most sustained levels of inertial cavitation as indicated by broadband acoustic emissions at the ultrasound focus, without causing any structural damage to the vaccine molecules themselves. Ex vivo data has shown that nanoscale-nucleated inertial cavitation at the skin surface delivered a model vaccine Ovalbumin (OVA) to depths of 500 μm into porcine skin. Novel nanoparticles produced in-house used to enhance and instigate cavitation at lower pressures penetrated to depths of up to 700 μm, due to their small size and unique ability to self-propel. Delivery profiles were obtained using multi-photon microscopy of skin sections immediately after treatment. Analysis of acoustic emissions from the focus showed substantial correlation between high delivery dose and depth, and significant amounts of inertial cavitation (i.e. broadband acoustic emissions from the focus). In vivo studies showed that the delivery achieved to murine skin was significantly (p<0.05) higher in the nanoparticle-assisted ultrasound transdermal vaccination group than the chemical penetration enhancer (positive control) group, with delivery of doses up to 1 μg /treatment, compared to 400 ng in the positive control group. This dose was sufficient to trigger an antigen-specific immune response. Specific anti-OVA IgG antibody levels in the ultrasound-assisted vaccine delivery group were significantly (p<0.05) higher than in all other control groups, and substantially higher than the current gold standard in transdermal delivery – chemical penetration enhancers. Although a low level antibody response was observed transdermally compared to the subcutaneous injection group (indicative of 100% delivery response), it is believed that optimisation of this system will lead to a viable and non-invasive delivery platform for vaccines that can be used both in a primary care setting, and eventually for self-vaccination at home.

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Doctor of Philosophy / Department of Chemistry / Stefan Bossmann / A novel type of supramolecular aggregate, named "nanosponge" was synthesized through the interaction of novel supramolecular building blocks with trigonal geometry. The cholesterol-(K/D)[subscript n]DEVDGC)₃-trimaleimide unit consists of a trigonal maleimide linker to which homopeptides (either K or D) of variable lengths (n = 5, 10, 15, 20) and a consensus sequence for executioner caspases (DEVDGC) are added via Michael addition. Upon mixing in aqueous buffer, cholesterol-(K)[subscript n]DEVDGC)₃-trimaleimides, as well as a 1:1 mixture of cholesterol-(K/D)[subscript n]DEVDGC)₃-trimaleimides form stable nanosponges, whereas cholesterol-(D)[subscript n]DEVDGC)₃-trimaleimide is unable to form supramolecular aggregates by itself. The structure of the novel nanosponges was revealed through explicit solvent and then coarse-grained molecular dynamics (MD) simulations. The nanosponges are between 80nm and several micrometers in diameters and virtually non-toxic to monocyte/macrophage-like cells. Furthermore, the structure of novel binary nanosponges consisting of cholesterol-(K/D)[subscript n]DEVDGC)₃-trimaleimide units possessing a trigonal maleimide linker, to which either lysine (K)₂₀ or aspartic acid (D)₂₀ are tethered, has been elucidated by means of TEM. A high degree of agreement between these findings and structure predictions through explicit solvent and then coarse-grained molecular dynamics (MD) simulations has been found. Based on the nanosponges’ structure and dynamics, caspase-6 mediated release of the model drug 5(6)-carboxyfluorescein has been demonstrated. Moreover, the binary (DK20) nanosponges have been found virtually non-toxic in cultures of neural progenitor cells. Additionally, DK20 nanosponges were taken up efficiently by leucocytes (WBC) in peripheral blood within 3h of exposure. The percentage of live cells among the WBC was not significantly decreased by the DK20 nanosponges. Therefore, this novel material holds great promise for improved cell-mediated therapy. Two different nanosponges loaded with the anticancer agent perillyl alcohol (POH) were developed to test the suitability of nanosponges for cell-based cancer therapy. Drug-loaded nanoshuttles featuring trigonal supramolecular building blocks, type (D-POH)₁₀K₂₀ and (D-POH)₁₀R₂₀ were synthesized, purified, and characterized by Dynamic Light Scattering (DLS) and Atomic Force Microscopy (AFM). They were then tested in cell cultures of murine glioma cells (GL26) and murine neural progenitor cells (NPC). The two nanosponges exhibited significantly different biophysical properties (size distribution and zeta potentials). Consequently, different efficacies in killing GL26 and NPC were observed in both, serum free and serum containing culture media. The results from these experiments confirmed that type (D-POH)₁₀K₂₀ nanosponge is an excellent candidate for the cytotherapy of glioblastoma.

Human Resource Management is at the peak of discussion in most companies. This is after realising the importance on Human resource today’s competitive landscape. Human resource gives the organisation, competitive advantages as advanced technology and systems are easily copied. With focus on Human Resource Management, came the devolution of line managers. Line managers are not trained, nor experts on HRM, and as they take on the human resource role, the success of HRM depends on how well they can carry out their HR responsibilities. This research looks at factors that are detractors and enhancers of the effective Human Resource Management. Four factors are identified as having an impact on the HRM and these are Workload Pressures, Competency, Recognition and Management and HR staff support. The research methodology employed is a survey technique, which consisted of a survey questionnaire to identify, which ones are detractors and enhancers. The research identified some of these factors to fall as a detractor or enhancer depending on their positivist or negativity. / Dissertation (MBA)--University of Pretoria, 2010. / Gordon Institute of Business Science (GIBS) / unrestricted

Membrane sacs, known as vesicles and liposomes have been widely used as stores for bioactive materials both in vitro and in vivo. The vesicles are biocompatible and in vitro experiments often use them in conjunction with magnetic nanoparticles. The magnetic nanoparticles allow the liposomes to be magnetically located and act as a trigger for release of the encapsulated materials. However, these magnetic vesicles or 'magnetoliposomes' as they are also known have not mananged to cross the barrier into clinical use. The work in this thesis aims to develop a novel system of magnetoliposomes for use in a biological environment. Magnetoliposomes are created from phospholipid suspensions extruded to give a spherical bilayer membrane. This membrane is doped with biotinylated lipids. These lipids are key to allowing the system to work in vitro. The magnetic nanoparticles are formed from iron and are coated with a novel synthetic linker to allow them to interact with the liposomes. When the liposomes and the nanoparticles are mixed in the presence of the protein avidin, large heirarchacal structures are formed which are stable under physiological conditions. The magnetoliposomes are held in an alginate hydrogel scaffold which acts as a support for the liposomes and as an adherent cell scaffold for tissue culture. This work demonstrates that this system can be used to encapsulate and release a range of bioactive molecules such as nickel chloride as a mimic for cytotoxic cancer drugs, ascorbic acid-2-phosphate for the upregulation of collagen production in chondrocytes and SB 431542 for the differentiation of mouse embryonic stem cells. The results shown in this work demonstrate that it is possible to use this novel linking system to create a new form of magnetoliposomes which are stable, biocompatible and easy to form and use. This work also demonstrates a strong model for possible drug delivery in vivo.

El presente trabajo de investigación es una contribución intelectual para la implementación de buenas prácticas globales en gestión pública que permitan planificar, seguir y evaluar los resultados de las políticas públicas prioritarias de un país. Sobre el particular, la tendencia en el ámbito internacional, desde hace más de veinte años, ha consistido en instalar en el más nivel gubernamental delivery unit o unidades de cumplimiento que sirvan de mecanismo para el logro de objetivos prioritarios de un gobierno. En ese sentido, el documento tiene como objetivo general brindar un marco conceptual y metodológico para la implementación de un delivery unit (DU) en el gobierno peruano. Esto se podrá alcanzar mediante el cumplimiento de tres objetivos específicos que son conocer el marco conceptual de los DU, realizar un análisis situacional del marco general de las políticas públicas que resultan prioritarias para el Estado peruano, y proponer un marco metodológico para la implementación de un DU en el gobierno peruano.