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一种电纺纤维覆盖的支架,具有可编程双重药物释放功能,可加速内皮化和预防管腔狭窄。

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

机构信息

Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Shanghai 200233, PR China; Shanghai Institute of Traumatology and Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai 200025, PR China.

Department of Radiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, No. 600, Yishan Road, Shanghai 200233, PR China.

出版信息

Acta Biomater. 2019 Aug;94:295-305. doi: 10.1016/j.actbio.2019.06.008. Epub 2019 Jun 10.


DOI:10.1016/j.actbio.2019.06.008
PMID:31195144
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.

摘要

颅内动脉瘤性蛛网膜下腔出血(SAH)导致高死亡率和高发病率。覆膜支架是一种有效的血管内治疗方法,可用于治疗难以通过血管内线圈栓塞和手术夹闭治疗的复杂动脉瘤。然而,支架内再狭窄和内皮延迟是导致其安全性的主要挑战。在这项研究中,我们设计了一种带有双药物负载电纺纤维的生物功能支架,以实现血管内皮生长因子(VEGF)和紫杉醇(PTX)的程序化释放,从而早期促进支架内皮化并长期抑制平滑肌过度增生引起的狭窄。通过将负载紫杉醇的介孔硅纳米粒子(MSNs)封装在电纺聚乳酸(PLA)纤维内,有效延长了 PTX 的释放周期。此外,通过与聚多巴胺(PDA)反应,将 VEGF 接枝到膜表面,实现快速释放。体外药物释放曲线显示,PTX 的持续释放可持续 63 天,没有早期突释,而 VEGF 则在 3 天内迅速释放高达 87.05%。孵育 6 天后,细胞实验表明,双药物负载支架可有效促进内皮细胞增殖(与对照组相比为 488%,P=0.001),并抑制平滑肌细胞增殖(与对照组相比为 155%,P=0.039)使用 21 天提取物。动物研究表明,与裸支架相比,载药覆膜支架可提高即刻和中期完全动脉瘤闭塞率(P<0.05)。与普通覆膜支架相比,载药覆膜支架还表现出更早的内皮化促进和更好的管腔再狭窄(0%对 25%,P=0.29),持续 12 周。总之,本研究开发了一种有效的程序双药物负载支架,可有效闭塞动脉瘤囊,VEGF 和 PTX 的离散释放促进了内皮化并防止了支架内狭窄。这项研究为改善颅内动脉瘤治疗中植入覆膜支架的生物安全性提供了一种新方法。

声明:颅内动脉瘤性蛛网膜下腔出血(SAH)是最常见的出血性中风之一,约 40%的患者因颅内动脉瘤突然破裂而死亡,33%的患者因该疾病而致残。血管内线圈栓塞术是一种治疗动脉瘤的常用方法,但由于该技术在动脉瘤囊内进行操作,存在较高的出血、占位效应、低完全闭塞率和较高再通率的风险。本研究设计了一种由负载双药物的电纺纤维编织而成的生物功能膜,覆盖在支架上,以实现血管内皮生长因子和紫杉醇的程序化释放,从而早期促进血管内皮化,并长期抑制平滑肌过度增生引起的狭窄。本研究为改善颅内动脉瘤治疗中植入覆膜支架的生物安全性提供了一种新方法。

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