Thesis (M.S.)--University of Oregon, 2006. / Includes bibliographical references (leaves 20-23).

Thesis (M.D.)--Boston University

Thesis (M.A.)--Boston University

There is a need for outcome measurement tools which are able to provide accurate and reliable information regarding the efficiency and efficacy of therapeutic intervention of soft tissue injury e.g. ligament tear. Electrical activity within the body tissues has been shown to be influenced by the tissue state, and following injury, bioelectric changes have been demonstrated for example in bone healing and nerve regeneration. This project considers the relationship between the electrical potentials recorded from the skin surface and clinical recovery following a soft tissue lesion. The measurement of the skin potential is not new but the application and approach used is novel in that a non invasive differential skin surface potential is used instead of the traditional and invasive transcutaneous potential. The differential potential was initially investigated in non injured subjects in order to gain an understanding of its character and behaviour. Simultaneous monitoring of environmental, physiological and psychological factors enabled evaluation of their influence on the generation mechanisms. In order to carry out the work, specialist instrumentation was designed and computer software developed. Injured subjects were recruited during two test series and the results compared with those obtained from the non-injured subjects. Differences in potential profiles were marked on occasions. However a significant percentage of injured subjects presented a profile which was very similar to the non injured subject potentials. The failure to demonstrate consistent differences between potentials from the groups may reflect the lability of tissue potentials or that their behaviour is not purely related to local tissue state. Psychological factors were shown to exert influences on the potentials and differences in environmental and physiological conditions may also be responsible for the variations seen. The refinement of the test apparatus and protocol which is discussed may facilitate more discriminative data collection.

Topical application of phorbol ester tumour promoter evoked the stimulated generation of hydrogen peroxide in the mouse skin in vivo, probably resulting from its action on an associated non-target population of infiltrating inflammatory cells. This formation was demonstrated indirectly by hydrogen peroxide dependent 3-amino-1,2,4-triazole catalase complex formation and confirms the hypothesis and findings of Goldstein et al. (1983). In the assay model discussed, n-alkanes representing the range C6-C14 caused stimulated production of hydrogen peroxide but in mouse skin already containing inflammatory cells. It is proposed that the known tumour-promoting activity of dodecane and tetradecane is free radical mediated, and that this activity is expressed when these alkanes cause an inflammatory state such as occurs upon repeated dermal application. Free radical generation and possible tumour-promoting activity of lower alkanes is latent, due to lower irritancy and high volatilization, unless these alkanes are encountered in combination with an irritant. Skin explant studies demonstrated a priming potential of the phorbol ester tumour promoter to the induction of skin catalase by oxygen. This dose-dependent induction is also seen in untreated skin and may represent a possible compensatory response to oxygen toxicity. Such induction may confound the interpretation of other air-incubation studies in vitro. The generation of hydrogen peroxide was stimulated as a consequence of abrasion, a known tumour promoting agent, and this indicates that irritation, (and possibly the immune response) has a role in tumour promotion and in the variation in strain susceptibility to tumour promoters. Current techniques for the assay of enzymic activities specific for cytochrome P-450 and cytochrome P-448 failed to detect these in mouse skin. The presence of these activities in mouse hepatic tissue was demonstrated. Preliminary data is presented for a novel skin irritation screening test based on phorbol ester-stimulated oxygen consumption by inflammatory cells responding to the applied test material. The technique may offer a more precise and convenient measure of irritancy than that provided by the currently used Draize test.

Dendrimers are characterized as synthetic, spherical macromolecules with tree- like branched structures. Their well-controlled sizes (3 - 10 nm), ease of functionalization, high water solubility, well-defined chemical structure, and biocompatibility make these nanomaterials attractive for a wide spectrum of promising biomedical applications. Peptide dendrimers and polyamidoamine (PAMAM) dendrimers have been used to date as effective transdermal or topical drug delivery systems, with the latest in a much greater extent. The structural characteristics of the aforementioned molecules guided us to design a novel repeating unit for dendrimers (monomer) possessing amino branching point and able to afford generation expanding through repeating amide bonds. The novel monomer, after appropriate modifications, was used to develop lower generations of polyamidoamino dendritic structures having amide groups and amino-branching points in their interior. The new dendrimers were isolated and fully characterized by typical spectroscopic technics. The final molecules will be used in human skin permeation experiments and will be evaluated for their effect on skin permeability.

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