An electrospun fiber-covered stent with programmable dual drug release for endothelialization acceleration and lumen stenosis prevention

Abstract

Aneurysmal subarachnoid hemorrhage (SAH) causes high rates of mortality and morbidity. A covered stent is an effective endovascular treatment for complicated aneurysms intractable to endovascular coiling and surgical clipping. However, in-stent restenosis and delayed endothelialization are the main challenges contributing to its safety. In this study, we designed a biofunctional stent covered with dual drug-loaded electrospun fibers to achieve programmed vascular endothelial growth factor (VEGF) and paclitaxel (PTX) release for the early promotion of stent endothelialization and long-term inhibition of stenosis caused by smooth muscle hyperplasia. By encapsulating PTX-loaded mesoporous silica nanoparticles (MSNs) within electrospun polylactic acid (PLA) fibers, the release period of PTX was effectively extended. Furthermore, VEGF was conjugated onto the surface of the membrane by reacting with polydopamine (PDA) for quick release. The in vitro drug release profile revealed the sustained release of PTX, which persisted for 63 days without early burst release, while up to 87.05% of VEGF was rapidly released within 3 days. After 6 days of incubation, cell experiments demonstrated that the dual drug-loaded scaffold effectively prompted endothelial cell proliferation (488% vs. 386% in the control group, P = 0.001) and inhibited the proliferation of smooth muscle cells (SMCs) using the 21-day extracts (155% vs. 303% in the control group, P = 0.039). Animal studies showed that compared to bare stents, the drug-loaded covered stents improved the immediate- and mid-term complete aneurysm occlusion rates (P < 0.05). The drug-loaded covered stents also showed earlier endothelialization promotion and better lumen restenosis than normal covered stents (0% vs. 25%, P = 0.29) for 12 weeks. Overall, a programmed dual drug-loaded scaffold that effectively occluded the aneurysm sac was developed in this study, and the discrete release of VEGF and PTX promoted endothelialization and prevented in-stent stenosis. This study provided a new method to improve the biosafety of implanted covered stents for the treatment of intracranial aneurysms. STATEMENT OF SIGNIFICANCE: Aneurysmal subarachnoid hemorrhage (SAH) is one of the most common hemorrhage stroke resulted in a nearly 40% mortality and 33% morbidity due to sudden rupture of an intracranial aneurysm. Endovascular coil embolism is a popular treatment for aneurysm but this technique run high risk of bleeding, mass effect, low complete occlusion rate and higher recanalization rate due to its operation conducted within aneurysm sac. A bio-functional membrane knitted by dual-drug loaded electrospun fibers covered on a stent was designed to realize programed vascular endothelial growth factor and paclitaxel release for the early promotion of vascular endothelium and long-term inhibition of stenosis caused by smooth muscle hyperplasia. This study provides new method to improve the biosafety of covered stent insertion for the treatment of intracranial aneurysms.

Keywords: Covered stent; Drug elution; Endothelialization; Intracranial aneurysm; Restenosis.