Controlled release of bioactive agents at the blood-polymer interface.

The research described in this dissertation was conducted to characterized and evaluate a novel approach towards the improvement of blood-material interactions by reducing the effects of foreign surface-induced thrombosis of the blood. This approach implemented the concept of controlled release of bioactive agents from a polymer matrix at the blood-polymer interface, in order to achieve maximal pharmacological effect at the desired site of activity with a minimum of general systemic effects. The hypothesis tested were to determine if known "platelet active" agents, specifically prostaglandins E1, D2 and I1, could be physically combined as a dispersion within hydrophobic polymers (polyether urethane and plasticized polyvinyl chloride) to provide sustained release. Studies were conducted to determine if the labile chemical structure and resultant biological activity of the prostaglandins could be sufficiently stabilized within the monolithically dispersed prostaglandin-polymer systems to produce the desired pharmacological response at the blood-polymer interface. Finally, efforts were directed towards determining if the prostaglandin-releasing polymer monolith could be effectively utilized towards the prevention of foreign surface-induced thrombus formation. Results of the in vitro experiments indicated that prostaglandins can be dispersed within the hydrophobic polymer matrix in loading doses of sufficient amount to provide sustained release for periods of two months without significantly altering the gross physical-mechanical properties of the polymers. Ex vivo blood studies were conducted to measure the inhibition of adenosine diphosphate induced platelet aggregation by prostaglandins released from monolithic polymers. The results suggest that sufficient amounts of these biologically active agents were released to significantly inhibit platelet aggregation when exposed to platelet-rich plasma, even after four weeks of storage of the monoliths. Finally, it may be interred from in vivo studies that when monolithically dispersed prostaglandin-polymer patches were implanted in the cardiovascular system of sheep, that the incidence and type of thrombus were reduced, the development of and organized endothelial structure was observed, and side effects of sever hypotension (as seen in systemic infusion of prostaglandin) were eliminated. Overall, it may be concluded from this research that the application of controlled delivery of biologically active agents to the problem of foreign-surface-induced thrombosis can exhibit adequate platelet-sparing activity, while under proper application (i.e. site of implantation, hemodynamic conditions, and duration of use), may significantly reduce and prevent thrombus formation.