PERIVASCULAR DELIVERY OF HEPARIN REGULATES MYOINTIMAL HYPERPLASIA

Heparin is the gold standard growth inhibitor for vascular smooth musc le cells, with chemistry and bioactivity similar to endogenous reparat ive compounds, such as heparan sulfate. Thus, heparin should be especi ally effective against proliferative arterial diseases that involve sm ooth muscle cells. Yet, at the systemic doses tolerated intermittent s ubcutaneous injections or intravenous infusion have, if anything, exac erbated rather than alleviated disease. We have demonstrated that far more beneficial effects are observed if one matches the delivery of he parin to the natural release of endogenous growth regulators; namely i n a continuous manner, administered directly to specific injured segme nts of the blood vessel wall. Local, perivascular controlled release o f heparin from polymeric matrices inhibited smooth muscle cell prolife ration following injury to vascular endothelium: for anticoagulant hep arin without the need for systemic anticoagulation; for anticoagulant heparin when administered from a site distant from the injured vessel; and in a manner more efficient than in systemic administration. Some heparin compounds only achieved a therapeutic response when delivered from polymeric devices in the perivascular position. These results lay the groundwork for examining the local control of the vascular respon se to injury and for investigating site specific means of modulating t hese processes. Polymeric drug delivery systems offer the potential fo r novel therapies and a means of investigating complex disease states. Future work on materials, formulations, and pharmacokinetics will aid immensely in these regards.