Introduction to Nanofiber Covered Stent

Fully expanded nanofiber covered stent

For bare metal stent, a main cause of failure is in-stent stenosis due to migration of smooth muscle cells into the lumen. A potential solution for this is to have a nanofibrous coating or covering on the bare metal stent. Several studies have shown favorable results for endothelial cell adhesion and proliferation on electrospun nanofibers. It is hypothesized that a nanofiber covered stent will present a barrier that prevents migration of smooth muscle cell into the lumen while encouraging endothelial cells to line the lumen. Avci-Adali et al (2023) showed the improvement of hemocompatibility of small-diameter stents with the application of electrospun polytetrafluoroethylene (PTFE) coating on the stent. The bare metal stent was wrapped internally and externally with 3 layers of electrospun PTFE membranes. The electrospun membrane covered stent demonstrated reduced adhesion of fibrinogen and platelet, and coagulation activation with similar performance to heparin coated ePTFE stents. An advantage of using membrane coverage without the need for heparin while having the same performance is that the hemocompatibility of the electrospun membrane is a material property unlike heparin which is released and transported away. As with any drugs, there is a risk of allergy reaction to heparin from the patient.

Coating nanofiber on the stent may be achieved by electrospinning directly over it. Due to the close proximity of the stent struts, the fibers are deposited on the outer surface of the stent. Researchers have explored the use of various materials for stent coating. Putzu et al (2018) used electrospun a co-recombinamer silk-elastin that combines both their properties. The electrospun fibrous material was found to be biocompatible with human umbilical vein endothelial cells (HUVECs). Electrospinning on angioplasty stent gave rise to a homogeneous fiber coating with thickness of 20 µm. However, having a biocompatible material coated over the stent is Insufficient. It is also important to determine whether the coated stent is able to function as intended and the coating integrity remains intact after stent deployment. Stent used for coating may be either be fully expanded or in its crimped form. In the former method, crimping is done after coating of the nanofiber. This minimizes any addition to the resistance to stent deployment as a result of the fiber coating. However, care must be taken not to disrupt the nanofiber coating during the crimping process. In the later method, fibers are coated on a crimped stent and it has to be verified that the coating is not torn during deployment. The fiber coating may also increase the resistance to stent deployment.

Almost complete endothelial coverage above struts for acetylsalicylic acid incorporated nanofiber covered stents at 2 weeks (A1) and 4 weeks (A2) [Lee et al 2014 International Journal of Nanomedicine 2014; 9: 311. This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License.]

To reduce the stent resistance to deployment when it is coated in its crimped form, Dong (2009) deposited aligned fibers along the long axis of the stent. Compared with randomly organized fiber coating, deployed coated stent with aligned fibers along its long axis maintained full coverage while stent with the randomly organized fiber coating ruptured at one end. The balloon pressure showed slight increase with the longitudinally aligned fiber coating. Following stent deployment, the nanofibers become disorganized. Another challenge faced by coating of stent in its crimped form is the prevention of fiber coating migration during insertion of the stent. Post deposition steps need to be carried out to ensure good adhesion between the nanofiber coating and the metal struts of the stent.

Several in vivo studies have been carried out with nanofiber covered (coated) stent. Drugs such as acetylsalicylic acid and heparin have been incorporated in the nanofiber to reduce thrombus formation. The nonwoven nanofibrous coating is formed by spinning on a fully expanded stent followed by crimping. Wu et al investigated the application of heparin loaded poly(L-lactide-co-caprolactone) covered stent to separate aneurysm dome from the blood stream in a rabbit model. The aneurysm was immediately cut-off upon stent deployment. 14 days follow up showed no obvious stenosis and no sign of the aneurysm. Bare metal stent covered with poly(D,L)-lactide-co-glycolide (PLGA) nanofibers containing acetylsalicylic acid was used in an in vivo rabbit model by Lee et al (2014). The results showed excellent endothelial coverage (99%) at 4 weeks for nanofiber coated stent loaded with 5 µg/mm² acetylsalicylic acid compared to nanofiber coated stent without drug (95% coverage). With acetylsalicylic acid released from the nanofiber, adhesion of platelets and monocytes to the stent were significantly reduced even at 4 weeks although in vitro drug release study showed sustained release of up to 3 weeks only. Vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor has been used to enhance endothelium-dependent vasodilatation in patients with diabetes and it is also known to reduce smooth muscle cell (SMC) hyperplasia and inflammatory reaction. Lee et al (2019) demonstrated the beneficial effect of using vildagliptin-loaded electrospun poly(D,L)-lactide-co-glycolide (PLGA) on stents in promoting re-endothelialization and reduce neointimal formation in diabetes. In vivo studies were carried out using rabbit model with the stents implanted in the abdominal aorta. After 2 months, endothelial coverage of the stent struts were more than 95% with vildagliptin loaded nanofibers while nanofibers without vildagliptin had 90% coverage. By 8 weeks, no intimal hyperplasia was observed in vildagliptin loaded nanofibers stents while around 200 µm intimal hyperplasia was observed in the group with nanofibers without drugs. Kuznetsov et al (2020) constructed an electrospun fiber coated drug eluting stent (DES) with a blend of polycaprolactone (PCL), human serum albumin and paclitaxel (PTX). The electrospinning was carried out over a crimped stent Due to the highly elastic nature of PCL, the deposited fibers did not break when the stent is fully expanded although they have undergone plastic deformation. The concentration of PTX loaded in the nanofibers was such that it was toxic for the vascular wall myocytes for at least 1-3 months. In the in vivo study using rabbit common iliac artery model, significantly thicker neointima were observed in the vessel of bare metal stent (BMS) compared to the electrospun DES after 6 months. With the DES, the PTX cytotoxic concentration was maintained for 1 month in the vessel but dropped to suboptimal concentration for the next two months. This release profile potentially helped to keep the lumen clear during the initial acute inflammation stage immediately after stent deployment. A dense tissue layer with connecting blood vessels was observed on the vessel with DES. Fibroblast and a surface endothelial cell layer was identified on the lumen. However for the BMS, the thicker neointima was composed of disorganized collagen fibers.

Another contribution to in-stent restenosis is tumor ingrowth. Coated stent with appropriate tumor-inhibiting drugs may be used to address this issue. Li et al (2013) coated polydioxanone weft-knitted stent with electrospun poly-L-lactide (PLLA) loaded with 5-fluorouracil to arrest and treat colorectal cancer tumor growth. In vivo studies on tumour-bearing BALB/c nude mice showed that drug loading dose of 12.8% was able to successfully retard tumor growth while pure PLLA did not show any inhibitory effect.

Electrospinning enables a thin layer of nanofibers to be coated on bare metal stent. Coupled with the ease of loading drug into the nanofiber matrix, it is possible to incorporate multiple drug loaded layers onto the stent without compromising its expansion mechanism. Janjic et al (2017) first coated a bare metal stent with rosuvastatin (Ros) loaded cellulose acetate nanofibers by electrospinning. Next they electrospun a second layer of cellulose acetate loaded with heparin over the initial nanofibrous layer. Statins are used to reduce cholesterol levels and also known for inhibiting the proliferation of vascular smooth muscle cells (VSMCs) and platelet activation, improving endothelial function, and reducing inflammation. Both drugs exhibit an initial burst release followed by gradual release through the degradation of cellulose acetate.

Electrospinning of nanofibers coating is not restricted to bare metal stents, coatings have also been applied to polymer stents. Chausse et al (2023) demonstrated the advantage of using electrospun nanofibers coated layer as the drug eluting carrier compared to using the polymer stent struts as the drug carrier. By using a solvent-cast direct writing method, everolimus-loaded poly-l-lactic acid (PLLA) and poly(l-lactic-co-ε-caprolactone) (PLCL) bioresorbable stents (BRS) were constructed. However, the drug release rate was too slow with less than 3% of total drug loading released after 8 weeks. To improve the drug release rate of the stent, electrospun PLCL fibers loaded with everolimus were coated onto the BRS. The drug release rate was much faster using the drug-loaded nanofibers with over 50% released in the first 6 h. Electrospinning was carried out with the printed BRS still on the metal rod. Unlike bare metal stents, the electrospun fibers were preferentially deposited on the metal rod surface between the non-conducting polymer struts before filling the gap and covering the struts.

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Content [Biomedical (Stent)]