The area of controlled release delivery systems has been a field of increasing interest in the past decade. However, relatively little attention has been focused on the development of such systems for macromolecular (M.W. greater than 1000) drugs such as polypeptides. Several years ago, we were able to develop the first such biocompatible polymeric systems for delivering these large molecular weight drugs. The principal findings of our work during the current period include 1) using microstructural analysis and kinetic modeling to show that release is diffusion controlled 2) showing little to no fibrous encapsulation occurs even after seven months in vivo, 3) showing that release rates in vitro and in vivo are the same, 4) developing experimental methods to produce systems that release macromolecules at zero order rates for several months, 5) using these systems to prevent calcification of heart valves and diabetes in animal models, 6) synthesizing a new class of surface erosion controlled bioerodible polymers-polyanhydrides, 7) characterizing critical release parameters from magnetically controlled systems. This grant renewal proposal will address three significant areas which are either important extensions of work initiated in the previous grant proposal, or new concepts which we feel will be significant in the future of controlled release systems for large or small molecules. The following are the specific aims of the present proposal: 1) non-erodible systems - to develop models, microstructural analysis techniques and computer simulations capable of predicting the kinetics of release of macromolecules; 2) bioerodible systems - to engineer a class of biocompatible polymers with controllable bioerosion rates and to characterize the release-related properties of these polymers; 3) magnetically controlled systems - to better understand the factors controlling modulation, and to initate the development of predictive models.
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