The goal of this project is to develop and apply a new methodology that characterizes deployment of microbicidal formulations in women, and that elucidates biophysical mechanisms which govern deployment - the spreading and retention of formulations over the intra-vaginal epithelial surfaces. The precise nature of deployment that is sufficient for prophylaxis against STD pathogens is unknown, and there is little knowledge of deployment characteristics of any formulation in women. This project will thus obtain unprecedented knowledge and data. A new intravaginal optical sensing device, developed by our laboratory, will be employed to quantitate formulation coating thickness distributions in women, including their dilution with local fluids and pH. A series of studies will contrast important biological and biophysical factors, e.g. time and motion after formulation application, cycle phase and simulated coitus - for a set of contemporary formulations, used as vaginal lubricants, contraceptives, and/or being considered as potential STD prophylactic materials. The results will have immediate relevance to a broad spectrum of basic biological and clinical studies in microbicide development. This project will also employ objective biophysical analysis, experimental and theoretical, to develop relationships between formulation properties and deployment characteristics. At present there is virtually no such knowledge, nor methodology to obtain it. Our approach is to develop a set of integrated in vitro experimental simulations of salient bio-fluid mechanical processes that produce formulation flow and retention within the vagina. For each such process we will also develop fluid mechanical theory that predicts biologically important endpoints (e.g. formulation spreading rates, layer thicknesses and properties) using measured values of formulation properties as inputs. Correspondence between theory and experiment will provide a means of physical validation of the in vitro methods. The final goal of the project will be to link the in vitro methods with the in vivo results. This will be a cross validation analysis, in which measures of deployment in vivo are related to predictions in vitro, first from the simulations and then from the mathematical models themselves. To the extent that the latter link is established, we will have developed an objective and accurate means of relating formulation properties directly to microbicidal function. To the extent that our in vitro methodology is accurate, it will provide an extremely useful and cost effective means of evaluating current formulations and designing new and improved ones. It will also provide unprecedented biophysical data relevant to mechanisms of STD infection in women.
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