Mucus epithelia in the intestine, lung, mouth, eye, and vagina provide an effective and essential barrier against the entry of pathogens and toxins. Since these epithelia are readily accessible from outside the body, they also represent valuable sites for drug delivery. Here, the investigators propose to continue their bioengineering studies of the ability of molecules and cells to function in and penetrate the mucus layer that protects these tissues. In previous work, they demonstrated that the controlled delivery of antibodies (Ab) could provide passive immune protection against viral infection and contraception. Their present goal is to extend their findings to design methods for the controlled delivery of vaccinogens (Vg) directly to a mucus epithelium. Specifically, biocompatible polymeric controlled release devices will be designed to continuously deliver macromolecules to mucus layers over an extended period. The present studies will focus on 1) measuring the distribution and bioavailability of Vg following release from a polymer into the mucus secretions of the reproductive and intestinal tracts, and 2) determining the ability of Vg molecules to stimulate active immunity in the mucus secretions. By synthesizing Vg with a range of molecular characteristics, they will test the hypothesis that active mucosal immunity can be enhanced by local delivery of Vg with optimal physiochemical properties. Since macrophages and other phagocytic cells can transport pathogens and molecules across mucus layers, the ability of phagocytic cells to crawl in mucus will be studied, as well as the ability of mucus and external agents to interfere with phagocyte migration and adhesion to epithelial tissues. Mathematical methods will be used to correlate their results, to enhance the value of in vitro methods for optimizing devices for use in vivo. All of the information collected from these basic studies will be used to design improved controlled release polymers for the localized and extended delivery of proteins to the mucus secretions of mice and monkeys. Finally, these polymeric systems will be used to test the efficacy of delivery for sustained protection against unwanted pregnancy (immunocontraception).
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