Perivascular delivery of heparin regulates myointimal hyperplasia

Abstract

Heparin is the gold standard growth inhibitor for vascular smooth muscle cells, with chemistry and bioactivity similar to endogenous reparative compounds, such as heparan sulfate. Thus, heparin should be especially effective against proliferative arterial diseases that involve smooth muscle cells. Yet, at the systemic doses tolerated intermittent subcutaneous injections or intravenous infusion have, if anything, exacerbated rather than alleviated disease. We have demonstrated that far more beneficial effects are observed if one matches the delivery of heparin to the natural release of endogenous growth regulators; namely in a continuous manner, administered directly to specific injured segments of the blood vessel wall. Local, perivascular controlled release of heparin from polymeric matrices inhibited smooth muscle cell proliferation following injury to vascular endothelium: for anticoagulant heparin 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 response to injury and for investigating site specific means of modulating these processes. Polymeric drug delivery systems offer the potential for novel therapies and a means of investigating complex disease states. Future work on materials, formulations, and pharmacokinetics will aid immensely in these regards.