The management of atherosclerotic vascular stenosis has undergone major advances over the pastdecades, yet challenges remain. Bare metal stents (BMS) were plagued by unacceptably high rates of in-stentrestenosis (ISR). Although drug-eluting stents (DES) were developed primarily to reduce neointimal hyperplasia(NIH), rates of ISR remain at least 5-15%. Furthermore, the use of stents remains controversial in certainsituations, including within vessels with small diameters, long lesions, bifurcations, repeated ISR, and insegments of peripheral artery disease (PAD). It is estimated that 8.5 million people in the U.S. alone have PAD,which can lead to further morbidities including life-style limiting claudication, amputation, and stroke. In certainlocations in the legs, stents carry a significant risk of stent fracture: stent fracture rates can approach 37%, oftenresulting in restenosis or total vessel occlusion. The use of drug-coated balloons (DCB) has emerged as anattractive alternative to treat both PAD and ISR lesions without leaving behind a permanent stent. DCB areangioplasty balloons coated with an anti-proliferative drug to prevent restenosis, usually paclitaxel. However,recent studies have called the safety of paclitaxel-coated balloons into question; thus, alternative anti- restenosisstrategies are needed. Furthermore, the drugs utilized on DCBs impair re-endothelialization, which can lead tolate thrombosis, inflammation, restenosis, and neoatherosclerosis. Ideally, the DCB would prevent neointimalproliferation and restenosis while encouraging endothelial cell growth and restoration of vascular function. Endomimetics, LLC has developed a novel dual-action coating for DCB that could reduce NIH and restenosisand enhance re-endothelialization and vascular healing. The coating consists of a nitric oxide (NO) releasingbionanomatrix composed of biocompatible peptide-based material along with liposome-encapsulated sirolimus.The liposome encapsulated sirolimus and bionanomatrix can be effectively transferred to the vessel wall andprovide sustained delivery to reduce NIH and restenosis. Additionally, the bionanomatrix provides sustainedrelease of NO from the multi-layered bionanomatrix to stimulate endothelialization and reduce inflammation. Thisdual- action strategy could overcome the limitations of current therapies for PAD and ISR by reducing NIH andrestenosis and enhancing re-endothelialization and vascular healing. In this Phase I SBIR, we propose to evaluate and optimize the dual-action DCB coating. This will includeevaluation of coating stability, release kinetics, and assessment of drug transfer and retention in an in vitrohydrogel vessel mimicking system as well as an ex vivo porcine artery bioreactor model under physiologicalconditions. We will then evaluate the novel dual-action DCB in vivo in a rabbit model. Development of a DCB coating that can reduce NIH and restenosis and enhance re-endothelialization andvascular function may have significant impact for treatment of patients with PAD and ISR. With successfulcompletion of Phase I, we plan to move forward in Phase II to larger animal studies and then to GLP evaluation.
Public Health Relevance Statement: Project Narrative
It is estimated that 8.5 million people in the U.S. have peripheral artery disease (PAD), which can lead to
further morbidities including life-style limiting claudication, amputation, and stroke. Up to 60% of patients who
receive percutaneous transluminal angioplasty with uncoated balloons experience restenosis, re-occlusion, and
recurrence of symptoms. Current drug-coated balloons (DCB) are associated with concerns about increased
risks, inflammation, and delayed endothelialization. Endomimetics, LLC has developed a novel dual-action
coating for DCBs that could reduce neointimal hyperplasia (NIH) and restenosis, and enhance re-
endothelialization and vascular healing.
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