The rush towards innovative technologies for the treatment of atherosclerotic vascular diseases has been accompanied by a sobering complication; the rapid recapitulation of initial cellular events in the months that follow. The accumulation of cells within a neointima can be so massive as to obstruct the arterial lumen and threaten tissue/organ integrity. The neointimal lesion involves loss of endothelial integrity, fibrin deposition and local alterations in thrombosis and hemostasis, infiltration of monocyte/macrophages, aberrant vasoconstriction, migration and proliferation of medial smooth muscle cells and proliferation of intimal smooth muscle cells. As a result a multitude of potent agents has been directed against one or more of these cellular events in hopes of halting this process. Unfortunately while many agents suppress smooth muscle cell growth in tissue culture, and a subset of these compounds reduce proliferation in animal models of vascular disease, the doses used would induce significant side effects if scaled up for human use. Moreover, at the doses tolerated, no agent has proven effective in inhibiting restenosis in the human. Thus, a second wave of enthusiasm has brought forth a number of alternatives for site-specific or local therapy. It is hoped that these modalities would allow for the utilization of potent compounds limited to a vascular bed or perhaps specific portions of the arterial wall without accompanying systemic side effects. We have demonstrated that polymer-based controlled release of drugs into the perivascular space of injured arteries is the most effective means of administering a number of mitogenic, antiproliferative and anti- thrombotic agents, and the only means of establishing a therapeutic effect for other compounds. The efficiency of this system extends to many forms of arterial injury/repair and for a number of parameters governing vascular healing. Others have infused drugs under high pressure directly into the arterial wall or transfected DNA directly or by way of transformed cells into blood vessels with variable success. What is not as yet clear is whether these modes of administration are effective simply because they provide heightened local drug concentrations, or whether there is a specific biological imperative for the placement of drugs at specific locations in and around the blood vessel. We now wish to investigate perivascular delivery of drugs in various states of vascular cell and tissue injury and repair in hopes of understanding the power of local forms of therapy. Our experiments will continue to utilize polymer based controlled drug delivery technology to provide precise release kinetics, tissue culture examination of cell growth to visualize the response of single cells or cells in co-culture, animal models of vascular injury to verify our in vitro results, and biochemical and immunohistologic identification and characterization of the cells and blood vessel wall to understand these effects. We will now: (A) examine whether one can control the release of vasoactive compounds in biologically active form, so that they will interact optimally with a unique and local segment of a blood vessel. (B) determine whether the blood vessel wall, in health and disease, will respond to the controlled local release of a compound, and define the resultant biological effects observed with different forms of administration. (C) study how the cells and elements within the perivascular space might modify vascular growth and repair, in particular when drugs are administered directly into this area.
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