Bioresorbable and customizable antioxidant drug-eluting stents

Cardiovascular disease including atherosclerosis leading to arterial blockages remains one of the primary causes of death in the US. Typical interventions for blocked arteries include bypass surgery or percutaneous coronary interventions (PCIs), either with or without stents. Typically PCIs will be used when possible as they are much less invasive and require less recovery time. Over the past decades, the use of stents has become commonplace, starting from initially bare-metal stents, which tend to suffer from high rates of intimal hyperplasia (IH). The next generation of drug-eluting stents achieved better results, yet problems have arisen due to late thrombosis, while in-stent restenosis still exists. FUrthermore, the permanent nature of the metallic stent is undesirable due to hampering natural vasomotion. More recently, biodegradable polymer stents (BDS) have been developed, which can provide temporary mechanical support after deployment, but eventually do not leave any synthetic material behind, which may allow for restoration of natural vasomotion and tissue remodelling, as well as limit IH. Despite this progress in stent technology, however, various issues still exist. BDS typically are limited in their design flexibility, are complicated to deploy and suffer from malapposition, partilly due to the inability to customize stent parameters. We therefore propose a novel strategy for regenerating a functional blood vessel wall after stenting following angioplasty by introducing a fourth generation stenting technology. Using a UV-light curable biodegradable biomaterial ink (B-Ink) we utilize additive manufacturing technology (projection microstereolithography) to synthesize a fully customizable 3D-printed stent. The B-Ink is an elastomeric polymer developed in our lab is based on citric acid, light-curable and possesses antioxidant properties. Our lab has extensive experience in citric-acid based polymers, which are hemocompatible and have been used for various cardiovascular applications including vascular graft coating. For this proposal, we aim to combine additive manufacturing, biomaterials science, and drug delivery to promote blood vessel regeneration after angioplasty. To add functionality to the 3D-printed stent, we aim to utilize all-trans retinoic acid (ATRA). ATRA, a vitamin A analog, is a known antiproliferative drug and we have recent show that it can reduce restenosis rates. Moreover, it is a UV-absorber and as such may be used as part of the UV-cured B-Ink make-up. For this proposal, our goals are to: 1) Incorporate ATRA releasing functionality into the 3D-printed stent and show successful incorporation, release and retaied bioactivity 2) Optimize B-Ink to allow for matching of mechanical properties to those of commercial degradable stents, allow for a strut design of 200 um or less to create acceptable material footprint and allow for balloon-guided deployment of printed stents 3) Show successful deployment of 3D printed B-Ink stents in and in vivo rabbit model. We will show survival, assess inflammation and neointimal hyperplasia (time points 3 days and 4 weeks) The proposed research is expected to result in big steps towards a 4th generation of stent technology. 3D-printed biodegradable stents potentially provide the advantages of fully customizable patient-specific stent design as well as the ability to print stents on-site in the operating room. Furthermore, the scalability will be much improved relative to current biodegradable stents on the market. Finally, this stent technology would also make for an