Hyaluronic Acid Nanoparticle Composite Films Confer Favorable Time-Dependent Biofunctions for Vascular Wound Healing

Vascular stent implantation is the primary treatment for coronary artery disease. Surface modification of coronary stents is a topic of interest to prevent thrombosis and restenosis and to promote endothelization. However, bioactive coatings on implants have not yet been fully developed for the time-ordered biological requirements of vascular stents. The first month after vascular stent implantation, the pathological changes in the injured vascular tissue are complex and time-ordered. Therefore, vascular stents possess time-dependent biofunctions with early phase anticoagulant and anti-inflammatory properties. In the later stage, inhibitory effects on smooth muscle cell proliferation and the promotion of endothelial cell adhesion might meet the requirements of vascular repair. We fabricated three types of hyaluronic acid nanoparticles (HA-NPs) by subjecting HA and poly(ether imide) to ethyl(dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide coupling reaction. The HA-NPs prepared by HA with a molecular weight of 100 kDa showed the best stability in a hyaluronidase environment. HA-NP composite films (HA-NCFs) were then fabricated by coimmobilizing selected HA-NPs (100 kDa) and HA molecules (100 kDa) through amide reaction on PDA/HD coated 316 L stainless steel surfaces. The detachment behavior of HA-NPs (100 kDa) in PBS for 20 days indicated that the HA-NPs (100 kDa) gradually detached from the surface. In vitro tests (anticoagulant and anti-inflammatory tests, endothelial cells, and smooth muscle cells seeding, and bacterial adhesion test) indicated that the newly fabricated HA-NCFs have inhibitory effects on the adhesion of fibrinogen, platelets, macrophages, bacteria, SMCs, and ECs. As the HA-NPs detached from the surface, the HA-NCFs showed excellent gradual comprehensive biocompatibility, which promoted adhesion and proliferation of ECs while still exerting inhibitory effects on the platelets, macrophages, and SMCs. Finally, in vivo SS wire implantation test (aortic implantation in healthy Sprague-Dawley rats) showed that HA-NCFs possessed anti-inflammatory properties, inhibited the proliferation of smooth muscle cells, and promoted re-endothelialization. In particular, HA-NCFs with time-dependent biofunctions showed better antirestenosis effects than those of surfaces modified with molecular HA, which exhibited constant biocompatibility. This study provides an important basis for the construction of HA-NP composite films with favorable time-dependent biofunctions for the time-ordered biological requirements of vascular stent.