Rosuvastatin- and Heparin-Loaded Poly(l-lactide-co-caprolactone) Nanofiber Aneurysm Stent Promotes Endothelialization via Vascular Endothelial Growth Factor Type A Modulation

Abstract

This study explored a new rosuvastatin calcium- and heparin-loaded poly­(l-lactide-co-caprolactone) (PLCL) scaffold for covered stents for treating aneurysms. The mechanism of rosuvastatin-induced endothelialization via vascular endothelial growth factor (VEGF)-A elevation was further explored. Rosu50, Rosu75, Rosu100, and phosphate-buffered saline (PBS) nanofibrous scaffolds were fabricated by coaxial electrospinning and observed by electron microscopy. Anticoagulation and pro-endothelialization properties were tested. Sixteen rabbits were selected for an in vivo assay and underwent microsurgery to establish a carotid aneurysm model. The animals were treated with covered stents and followed for 4 months using digital subtraction angiography (DSA), electron microscopy, and histology. Rosuvastatin-treated human umbilical vein endothelial cell (HUVEC) viability, function, and VEGF-A modulation were further studied to elucidate the pro-endothelialization mechanism of rosuvastatin. Our study demonstrates that rosuvastatin and heparin can be incorporated into PLCL nanofibers via electrospinning. Rosu100 nanofiber scaffolds exhibited significant anticoagulation properties. The viability of HUVECs transferred to Rosu100 nanofiber scaffolds was increased significantly. In vivo, DSA revealed that the Rosu100 group had better outcomes than the PBS group. In addition, the Rosu100 stents induced more integrated endothelialization. Further study demonstrated that rosuvastatin promoted HUVEC viability and function in vitro. The effects of rosuvastatin may be attributed to an elevation in VEGF-A. We demonstrated that rosuvastatin- and heparin-loaded PLCL-covered stents show favorable anticoagulation and pro-endothelialization properties in vitro and in vivo in a rabbit aneurysm model. VEGF-A elevation played a crucial role in rosuvastatin-promoted endothelialization. This work provides an additional option for treating cerebral aneurysms with covered stents.

Heparin- and Rosuvastatin- loaded Poly(L-lactide-co-caprolactone) Nanofiber Aneurysm Covered Stent Inhibits Inflammatory Smooth Muscle Cell in Reducing in-stent Stenosis and Thrombosis

“…Although the heparin coating reduced the thrombosis rate in animal experiments (22,23), it could not effectively improve late vascular patency and neointimal hyperplasia (24), suggesting that promoting the proliferation ability of ECs is crucial. In our previous study, we found that rosuvastatin-and heparin-coated stents could effectively promote early endothelialization and provide a basis for reducing long-term complications (25). Early endothelialization is the key to preventing in-stent stenosis and late thrombosis (26,27).…”

Two Sides of Electrospun Fiber in Promoting and Inhibiting Biomedical Processes

“…Adapted with permission. [261] Copyright 2018, American Chemical Society. B) Schematic image of cells cultured on a fibrous membrane covered with fibronectin.…”

“…To treat aneurysms, Liu et al used co-axial electrospinning to produce a series of novel rosuvastatin calcium-and heparin-loaded PLCL scaffolds. [261] The volume ratio of heparin to rosuvastatin calcium solution for three types of scaffolds was 450:50, 425:75, and 400:100 mL, respectively. Through SEM analysis of the RBCs on different scaffold mats and histograms analyses of the clotting time, kinetics, and clot strength, it was determined that the PLCL nanofibers incorporated with rosuvastatin and heparin at the volume ratio of 400:100 mL exhibited significant anti-coagulation properties.…”

Approaches to antithrombotic modification of vascular implants

“…Похожие результаты имплантации при разработке стентов для лечения аневризм были показаны Liu и соавт., которые для создания антитромботического покрытия использовали гепарин с гиполипидемическим препаратом розувастатином кальция [41]. Розувастатин относится к классу статинов и, кроме снижения уровня холестерина в крови, имеет свойство ингибировать пролиферацию гладкомышечных клеток кровеносных сосудов и активацию тромбоцитов, стимулировать эндотелизацию и подавлять реакцию воспаления.…”

“…Однако нановолокна получали коаксиальным электроспиннингом, в результате чего они имели в своей структуре полимерную оболочку и ядро, содержащее лекарственные препараты. Такой способ введения биоактивных веществ позволяет обеспечить их более пролонгированный выход из полимерных волокон по сравнению с эмульсионным электроспиннингом [41].…”