Characterization and delivery of localized antithrombotics for treatment of restenosis

Rebecca A Scott, Purdue University

Abstract

Percutaneous coronary intervention (PCI) is an invasive cardiovascular procedure performed to mechanically widen narrowed coronary vessels using either balloon angioplasty or intracoronary stenting. While the number of percutaneous coronary interventions (PCI) performed in the United States has increased by 33%, thrombosis, intimal hyperplasia, and restenosis remain complications of this procedure and inhibit complete functional recovery of the vessel wall. The occurrence of these complications following PCI is attributed to trauma during the procedure, which triggers an array of mechanical and biological processes implicated in the healing process, including platelet activation, inflammation, smooth muscle cell (SMC) proliferation and migration, and extracellular matrix (ECM) synthesis. While some progress has been made via the local delivery of anti-restenotic therapeutics from drug-eluting balloons and stents, thrombosis has left room for therapeutic improvement. Towards this effort, our laboratory has designed an antithrombotic therapeutic, DS-SILY, which consists of type-I collagen-binding peptides bound to a dermatan sulfate backbone, and has been shown to specifically bind to type-I collagen, serving as a barrier to platelet adhesion and activation in vitro and in vivo. While DS-SILY appears to be a promising treatment for thrombosis, the ability of DS-SILY to limit intimal hyperplasia, in part by regulating vascular smooth muscle cells (SMC) activation, migration, and extracellular matrix (ECM) deposition, is another important avenue of exploration. The overall goal of my research is to determine the ability of DS-SILY to control SMC behavior, as well as to develop a means to deliver the therapeutic to the site of injury during PCI. In this dissertation, I address our findings regarding the ability of DS-SILY to modulate SMC behavior and the mechanisms of action utilized by the therapeutic. Furthermore, we correlate the impact of DS-SILY on SMC behavior in vitro with the onset of intimal hyperplasia and platelet interaction in vivo. Finally, as delivery of therapeutics via drug-coated balloons has proven to be a promising clinical endeavor, we explored the first steps towards delivering the mimic via fast-dissolving polymer film coated on an angioplasty balloon. These results advance our current understanding of DS-SILY and its role in limiting hyperplasia, and suggest that this therapeutic has the potential to be an effective therapy for restenosis.

Degree

Ph.D.

Advisors

Panitch, Purdue University.

Subject Area

Biomedical engineering|Immunology

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