Abstract
Stents are implanted during the percutaneous treatment of narrowed arteries. However, limitations and
unresolved questions remain how to achieve optimal stent patency and safety. Bare metal stent (BMS)
deployment remains limited by neointimal hyperplasia caused by vascular injury during stent implantation,
leading to in-stent restenosis. To reduce restenosis, a drug-eluting stents (DES), coated with anti-proliferative
and/or immuno-suppressive agents targeting neointimal hyperplasia, have been developed. However, recent
studies have revealed that the clinically used dose of sirolimus and its analogues for DES cause serious adverse
effects including 1) damage to the endothelium that delays re-endothelialization with impaired functions, and 2)
inflammation in response to the polymer coating that delivers sirolimus.
Another major issue in the stent industry is that outcomes from healthy animal model studies with or without
balloon injury do not adequately predict problems found when stents are used in a large number of patients.
Thus, there is a critical need to develop an innovative strategy for stent coating and stent evaluation in an
atherosclerosis model in order to address 1) adverse effects of clinical dose of sirolimus and 2) “overly optimistic”
findings when evaluating stents in a healthy rabbit model.
We have successfully developed the nitric oxide (NO) releasing prohealing multifunctional endothelium-
mimicking nanomatrix stent coating capable of providing the chemical and biological properties of the native
endothelium as demonstrated in vitro, ex vivo, and in a balloon injury healthy rabbit iliac artery model. Notably,
we recently found that NO has significant potential to salvage endothelial cell proliferation and migration from
the adverse effects of sirolimus while synergistically suppressing smooth muscle cell proliferation.
Therefore, we will develop the dual action NO and low-dose liposome-encapsulated sirolimus releasing
prohealing nanomatrix in Specific Aim 1. We will also develop novel Engineered Artery Sheets with
Atherosclerotic features (eASA) in Specific Aim 2. The efficacy of the dual action NO and sirolimus releasing
prohealing nanomatrix compared with commercial BMS and DES will be evaluated under atherosclerotic
conditions using the eASA in Specific Aim 2 and in a high fat diet rabbit model in Specific Aim 3.
If successful, this novel strategy, combining the unique features of NO and sirolimus will advance the field by
overcoming the current limitations of BMS and DES, and with the development of improved in vitro and in vivo
models for stent evaluation.
