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Key Findings: Implantation of the novel stent in venous system is safe and feasible.
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Take home Message: Alteration of stent length and increasing the skipped segments did not affect the development of neointimal formation and did not cause migration.
Abstract
Objective
Our study was a prospective in vivo study performed on an animal model to evaluate the safety and performance of a novel venous stent designed specifically for venous applications.
Methods
The novel stent were implanted in the inferior vena cava of 9 sheep. The stents were deployed with different distances between the closed cell rings to test for if the segments might migrate after being deployed at maximal distance. Three different total lengths were 9, 11 and 13 cm. After 1, 3 and 6 months, vascular injury, thrombus, neointima coverage, and stent migration were evaluated through CT venography and histopathology. Imaging, histology, and integration data were analyzed in each group.
Results
All stents were successfully deployed and all sheep survived until the time of harvesting. In all cases the native blood vessel sections were intact. The segmented stent parts showed a differently pronounced tissue coverage, depending on the duration of the implantation.
Conclusions
The new nitinol stent is safe and feasible to implant in the venous system with a rapid surface coverage. Alteration of stent length did not affect the development of neointimal formation and did not cause migration.
Chronic venous obstruction (CVO) can cause a wide spectrum of symptoms of venous hypertension ranging from edema of the lower extremities to venous claudication, skin changes and venous ulcers (
). Because it is minimally invasive and has a high safety profile, endovascular venous stenting is increasingly becoming the treatment of choice for patients with CEAP class 3-6 (
). According to a joint clinical practice guideline for the management of CVO published by the American Venous Forum (AVF) and Society for Vascular Surgery (SVS), stent placement is recommended for patients with symptomatic CVO due to iliac vein compression or obstruction, with the goal of improving symptoms and preventing recurrent venous thromboembolism (
De Maeseneer MG, Kakkos SK, Aherne T, Baekgaard N, Black S, Blomgren L, et al. Editor's Choice – European Society for Vascular Surgery (ESVS) 2022 Clinical Practice Guidelines on the Management of Chronic Venous Disease of the Lower Limbs. European Journal of Vascular and Endovascular Surgery. 2022;63(2):184-267.
). However, restenosis due to neointimal proliferation and wall thickening, thrombus formation, and negative remodeling continues to be the most common cause of stent failure, particularly in patients with extensive CVO (
Compared with arterial stents, research on venous stents is behind. There has been a significant increase in the number of dedicated venous stents manufactured in recent years. In terms of clinical utility or mechanical properties, each model has some differences comparing to competing models (
Despite persistent advancements in intervention techniques and stent design, there are still a noteworthy number of stent occlusions after venous interventions. The reported primary patency rates at one-year ranges from 59% to 87% in patients with post-thrombotic syndrome (PTS) (
Placement of closed-cell designed venous stents in a mixed cohort of patients with chronic venous outflow obstructions - short-term safety, patency, and clinical outcomes.
We designed a new tapered segmented laser-cut nitinol stent with adjustable length for more precise sizing and positioning. The more porose structure of the stent is theoretically less restrictive for the inflow through the tributaries and improves faster coverage of the stent struts. Its length adjustability and tapered design makes it suitable for being used in iliofemoral lesions, in which the vessel size differs. The purpose of this study was to test the accuracy of stent release in vivo, to investigate the risk of stent migration after elongation maneuver, to evaluate the time needed the stent struts to be covered and to assess the safety and performance of the stent in animals, providing a reference for further clinical trials.
Methods
The study was designed and performed in accordance with the Guide for the Care and Use of Laboratory Animals. Our institutional Animal Care and Use Committee and the relevant government authorities approved the experimental protocol.
Structural features of the stent and delivery system
The W-Stent is not currently available for commercial use. The stent's availability for clinical use depends on further testing, regulatory approval, and commercialization plans. The in length variable W-Stent (Venous Stent B.V., Maastricht, The Netherlands) is designed with a high porosity to improve fast coverage of the struts decreasing the necessity of anticoagulation, closed cell segments, to improve radial force, interconnections to improve flexibility and length adjustability and finally barbs to prevent migration after implantation.
The self-expandable nitinol stents used have a diameter of 18 mm with a proximal closed cell segment of 4 cm long with barbs, 2 segments in the middle of 1 cm length and a final stent of 2 cm with barbs again. The stent length can vary between 8 cm, intersegmental distance of 0 cm and max. 13 cm with an intersegmental distance of 1,5 cm (figure 1).
Figure 1W-Stent design; Illustrations demonstrate the three different total lengths of the stent relative to the degree of rotation during implantation: a 9 cm, b 11 cm and c 13 cm
The stent is mounted in a standard delivery system which can release the stent by retracting the sheet and deploying each individual segment. In between the segments the length can be increased by pulling and rotation. The stents will be deployed with different distances between the closed cell rings to test for if the segments might migrate after being deployed at maximal distance. Three different total lengths are used, 9, 11 and 13 cm 3 times in 9 sheep.
Animal models and experimental design
The study included 9 female sheep (type swifter, mean age 2 year) with a mean bodyweight of 44.3 kg (37-52 kg) divided in 3 groups (G1, n=3; G2, n=3; G3, n=3) all of which received a venous stent implantation in the inferior vena cava. After stent implantation the first group of 3 animals was followed and sacrificed at 4 weeks (G1), the second group at 12 weeks (G2) and the third group at 6 months (G3) post intervention.
During follow up duplex ultrasound (DUS) of the stent in the inferior vena cava was done at 3 days and 4 weeks after stent implantation for each group (G1, G2, G3), at 12 weeks for G2 and G3, and at 6 months only for G3. Each sheep underwent a CT scan prior to euthanasia and autopsy. This was for G1 at 4 weeks, for G2 at 12 weeks and for G3 at 6 months post intervention.
Stent placement and intraoperative protocol
All stents were implanted in the inferior vena cava (IVC) under general anesthesia. Intrajugular injection of Ketamine (10-20 mg/kg bodyweight) and inhalation of Isofluran 5% were used for sheep sedation anesthesia. General anesthesia was maintained through inhalation of Isofluran 2.5% after insertion of an endotracheal tube. An intravenous catheter was placed at the left hind leg to apply intravenous medication during surgery. Arterial access was gained via the right ear. Additionally, a gastric tube was placed.
Buprenorphine 10-20 mcg/kg, Meloxicam 0.5 mg/kg, Gentamicine 6.6 mg/kg and Penicilline 40000 IU/kg were given intravenously during surgery. After shaving the neck region, the surgical area was scrubbed with an iodium sponge followed by disinfection with isobetadine and braunol. The animals were draped with a sterile, impermeable covering to isolate the disinfected area. A 5-Fr sheath was placed in the right jugular vein. Heparin (5,000 IU) was administered after placement of the sheath intravenously.
Phlebography was performed using a pigtail and the iliocaval confluence was visualized. Dotarem 0.5 mmol/ml was used as contrast solution. The sheath was upsized to 10-Fr to facilitate stent placement. Via a stiff guidewire using the Seldinger technique, the 18 mm x 100 mm variable vein stent was positioned in the inferior vena cava (IVC) initiated at the iliocaval confluence up to the suprahepatic part of the IVC and deployed under fluoroscopy by retracting the covering sheath. After stent implantation, a control phlebography was obtained by using the pigtail catheter to document the patency and position of the stent. Then the vascular sheath was removed, and hemostasis was achieved by manual compression of the puncture site for 10 minutes. After the procedure Enoxaparin was given 3 mg/kg twice/day subcutaneously until termination (120-140 mg twice /day depending on availability of enoxaparin).
Follow-up and euthanasia
The follow-up examinations at the observation points (table 1) were performed by an independent researcher who was blinded to the animal groups.
All sheep underwent DUS of the stent in the inferior vena cava under sedation with Ketamine (10-20 mg/kg bodyweight), IV and inhalation of Isofluran 5% through a mask.
Postop 1 month
All sheep underwent DUS of the stent in the inferior vena cava under sedation with Ketamine (10-20 mg/kg bodyweight, IV) and inhalation of Isofluran 5% through a mask.
Three sheep underwent an additional CT scan under general anesthesia with Ketamine (10-20 mg/kg bodyweight, IV and inhalation of Isofluran 2.5% after placing an endotracheal tube. CT scans included plain scans, scans during inspiration and exspiration. Afterward, these three sheep were euthanized through application of Euthasol (Na-Pento Barbiturat 120 mg/kg) intravenously following autopsy.
Postop 3 months
Remaining six sheep underwent DUS of the stent in the inferior vena cava under sedation with Ketamine (10-20 mg/kg bodyweight) and inhalation of Isofluran 2.5% through a mask. Three sheep underwent a CT scan under general anesthesia according to the same protocol after placing an endotracheal tube. Afterward, these three sheep were euthanized through application of Euthasol (Na-Pento Barbiturat 120 mg/kg) intravenously following autopsy.
Postop 6 months
Last 3 sheep were undergoing a DUS of the stent in the inferior vena cava under sedation with Ketamine (10-20 mg/kg bodyweight, IV) and inhalation of Isofluran 2.5% through a mask. Afterwards, a CT scan was performed under general anesthesia following euthanasia and autopsy.
Autopsy and sampling
Autopsy was performed under general anesthesia by a median laparotomy (incision from the sternum to the udder, 40 cm) with exposure of the abdominal aorta and IVC. The IVC was prepared and fixed on a cork board to avoid axial shrinkage and inadvertent iatrogenic injury of the venous endothelium. The resected IVC was rinsed with a saline solution 0.9% until flushed contents become a clear solution. A total of nine slices of stented IVC were taken for each stent as well as skipped segment between the rings (figure 2).
Figure 2Schematic drawing showing the sampled segments acquired and investigated after stent explantation.
For the histological examination, the samples were processed with preparation of plastic slide stained with toluidine blue, according to a standard protocol. The toluidine blue stain serves as the standard stain for ground specimens to provide a histological overview and shows the structure of the specimen. A portion of connective tissue with fibrosis as well as intimal proliferation and tissue overgrowth of stent struts can also be visualized well. Six segment points in each section were analyzed and measured regarding the presence and thickness of the tissue proliferation and averaged, stating the minimum and maximum value (figure 3).
Figure 3Histological specimens of the stented segments showing the typical neo-intimal pattern over the stent.
The test samples were examined with a high-resolution digital microscope with software support (OLYMPUS digital microscope DSX-1000, Olympus Hamburg, Germany) to assess the surface structure. The digital microscopic examination was carried out on the native, unfixed test samples without further sample processing.
Statistics
Data are expressed as mean ± standard deviation. The endothelialization scores and the differences in neointimal thickness between the stents and animal groups were compared using Mann Whitney U test and one way ANOVA, respectively. A p value < .05 was considered statistically significant. All statistical procedures were computed with SPSS v25.0 software (SPSS, Chicago, IL, USA).
Results
Stent implantation
Nine stents were successfully deployed in nine sheep. All animals survived until the end of the study. DUS and CT scan were performed for all stents per protocol. The “release compensation” function of the new delivery system stabilized the tip of the stent during release. The novel stent did not exhibit obvious shortening during the release process. The operator was able to rotate the delivery system during the implantation to achieve a longer skipped segments and increase the total length of the stent as intended.
DUS and CT scan
Follow-up investigations were performed according to the predefined timetable. All stents remained patent and were normal in shape, without fracture, distortion, or migration. The CT scan prior to euthanasia showed no lumen stenosis in any group (figure 4). Review of follow up CT scans showed stable stent diameters, with no evidence of stent migration, undersizing or compression. Although the venous stent extended from the iliac vein confluence to the supra-hepatic IVC, potentially covering the renal veins, no evidence of obstruction or compromise of the renal veins was observed in any of the animals during the study period.
Figure 4Representative image from computed tomography angiography of 6-month animal showing the implanted W-stent in vena cava inferior (yellow arrow).
Macroscopic and microscopic (light and digital) findings
In all cases the native blood vessel sections were intact. The segmented stent parts showed a differently pronounced tissue coverage, depending on the duration of the implantation. No evidence of stent fracture, corrosion or degradation could be detected during the macro and microscopical evaluation (figure 5).
Figure 5Representative images of macroscopic, digital microscopic and light microscopic images of investigated segment after 1, 3 and 6 months.
The tissue covering was only partially developed and often consists of only a thin layer of cells. Tissue coverage of stents tended to increase distally up to 80%.
Postop 3 months
Comparing to the results after first month, both the percentage of tissue coverage as well as density of intraluminal tissue layer increased. A tissue coverage of 80% up to 100% was seen in all samples. The tissue coverage over nitinol rings and density of layers increased distally.
Postop 6 months
The nitinol rings of stents were almost completely covered with dense tissue layer (100%) with minor gaps in the area of vessel branches.
Analyses of endothelialization
Postop 1 month
The native blood vessel wall was intact. After 1 month of implantation, there was already a thin layer of tissue over the stents. The neointimal coverage of stents were essentially began from the distal segments (figure 6a). The tissue coverage tends to increase distally by up to 127 μm in S1, 378 μm in S2 and 439 μm in S3. In S4 there is less tissue covering with a maximum of 219 μm. The nitinol rings were covered by tissue up to a maximum of 419 μm in M1, 1125 μm in M2 and 695 μm in M3 (table 2). No significant differences were found between different length of stents.
Figure 6Overview of tissue coverage over stents with different lengths after 1, 3 and 6 months.
After 3 months of implantation, the stents were almost completely covered by thicker and denser layer of tissue (figure 6b). A small number of wires between the stent segments (M1 and M2) were not completely endothelialized. Through the neointima, the structure of the scaffold was visible. There was a distally increasing tissue coverage of a maximum of 217 μm in S1, 653 μm in S2 and 641 μm in S3. In S4 there is a maximum tissue covering of 721 μm. The nitinol rings were covered with tissue up to a maximum of 1176 μm in M1, 1297 μm in M2 and 1180 μm in M3 (table 3). No significant differences were found between different length of stents.
Table 3Endothelialization of stents after 3 months
After 6 months of implantation, the stents were completely covered by a dense tissue layer (figure 6c) with a distally increasing tissue coverage of up to 480 μm in S1, 1129 μm in S2 and 1278 μm in S3. Circumscribed stent sections were exposed only in the area of vascular branches. In S4 there was a maximum tissue covering of 1425 μm. The nitinol rings were covered by tissue up to a maximum of 1005 μm in M1, 1582 μm in M2 and 912 μm in M3 (table 4). No significant differences were found between different length of stents.
Table 4Endothelialization of stents after 6 months
Endovenous stenting is increasingly used to treat obstructive lesions of deep venous system. It is partly because of advancements in interventional technology and a better understanding of chronic iliac vein obstruction. Moreover, venous stent placement has shown good mid-term to long-term patency rates (
Iliac vein stenting as a durable option for residual stenosis after catheter-directed thrombolysis and angioplasty of iliofemoral deep vein thrombosis secondary to May-Thurner syndrome.
Editor's Choice - European Society for Vascular Surgery (ESVS) 2022 Clinical Practice Guidelines on the Management of Chronic Venous Disease of the Lower Limbs.
). The new generation of dedicated venous stents have a sufficient radial force with a greater flexibility than the arterial stents. Nevertheless, stent deployment injures the vein wall, activating a biological response to injury (
Effect of endothelial shear stress on the progression of coronary artery disease, vascular remodeling, and in-stent restenosis in humans: in vivo 6-month follow-up study.
). As major drawback remains in-stent stenosis due to excessive intraluminal narrowing caused by neointimal growth or thrombosis. Therefore, efforts are made to optimize the outcome of venous stenting by modifying the structural design of the stent and improving the implantation procedure. Several studies have investigated the mechanisms and factors that contribute to intimal hyperplasia in animal models. For example, a study by Kornowski et al. investigated the effect of stent design on intimal hyperplasia in the coronary arteries of sheep. The authors found that stents with a larger strut thickness and a smaller stent-to-artery ratio were associated with a higher degree of intimal hyperplasia (
). Another study that investigated the venous response to stent implantation in a sheep model found that a larger stent strut interval led to a lower neointima formation and a better long-term patency of venous stents (
Finding of current study shows that W-stent causes no inflammatory response or vascular injury to the native vein proximal and distal to stent. The tissue formation is tendential increasing from proximal to distal part of the stent but the NCP and NCD sections display after 3 and 6 months, with exception of a minor intima proliferation, no other vascular changes (table 3 and 4).
Stents with a closed-cell design have a high radial force but are less flexible comparing to the open-cell stents (
). Despite closed-cell design of W-stent, the special high porosity configuration and bigger length of its interconnecting struts provides a high longitudinal and also cross-sectional flexibility. A study on an ovine model investigating the neointima formation after venous stenting indicated that the longer “bare areas” and less metallic burden of a stent implanted in the venous system facilitates a faster and more complete endothelialization (
The hypothesis is that the endothelium behind the struts will die because of the mechanical pressure. The cells in between the struts stay alive and are able to cover the stent struts. Due to the large porosity of the W-stent the ratio between dead and living endothelial cells is more advantageous leading to a faster coverage of the struts. This effect may result in reduced time for therapeutic anticoagulation of the patients.
In the current study, endothelialization was almost complete 6 month after implantation in all study groups (figure 5). Small changes in intersegmental spaces in W-stent did not result in a significant impact on the stent endothelialization. Additionally, special attention was given to potential migration, especially in the longest configuration. But the evaluation of the stent geometry during placement and after euthanasia did not show any migration showing the efficacy of the barbs in the proximal and distal segment.
There are several limitations of this study. The sample size was small in this experiment due to the large-animal model used. Moreover, the follow up time was relatively short; long-term studies need to be carried out. In this experiment, the stent was placed in normal veins. Hence, the effect of the novel stent in the chronic venous occlusion in human still needs to be verified by clinical trials.
Conclusion
This study demonstrated the feasibility and safety of implanting W-stent in the venous system with a rapid surface coverage. Alteration of stent length and increasing the skipped segments did not affect the development of neointimal formation and did not cause migration.
ACKNOWLEDGEMENTS
The authors acknowledge the members of the Institute for Laboratory Animal Science KU Leuven, Leuven, Belgium, specially Mieke Ginckels and David Célis for their technical assistance. We express our appreciation to Merel Tewissen for her assistance during the follow up examinations.
References
Chaitidis N.
Kokkinidis D.G.
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Hasemaki N.
Attaran R.
Bakoyiannis C.
Management of Post-thrombotic Syndrome: A Comprehensive Review.
De Maeseneer MG, Kakkos SK, Aherne T, Baekgaard N, Black S, Blomgren L, et al. Editor's Choice – European Society for Vascular Surgery (ESVS) 2022 Clinical Practice Guidelines on the Management of Chronic Venous Disease of the Lower Limbs. European Journal of Vascular and Endovascular Surgery. 2022;63(2):184-267.
Placement of closed-cell designed venous stents in a mixed cohort of patients with chronic venous outflow obstructions - short-term safety, patency, and clinical outcomes.
Iliac vein stenting as a durable option for residual stenosis after catheter-directed thrombolysis and angioplasty of iliofemoral deep vein thrombosis secondary to May-Thurner syndrome.
Editor's Choice - European Society for Vascular Surgery (ESVS) 2022 Clinical Practice Guidelines on the Management of Chronic Venous Disease of the Lower Limbs.
Effect of endothelial shear stress on the progression of coronary artery disease, vascular remodeling, and in-stent restenosis in humans: in vivo 6-month follow-up study.
Single center prospective and observational experimental study
KEY FINDINGS:
Deployment of the new nitinol stent in 9 sheep resulted no mortality, no stent occlusion and no migration in 100% of animals.
TAKE HOME MESSAGE:
This new nitinol stent is safe and feasible to implant in venous system with excellent patency and no migration at 6 months.
Table of Contents Summary
The current animal study examined a new self expandable nitinol stent implanted in the venous
system in an in vivo experiment in sheep. This report shows that the novel stent is safe and feasible to implant in venous system with excellent patency and no migration at 6 months and suitable for clinical trials in humans.
FUNDING
This study was supported by a grant from Venous Stent B.V. (Maastricht, The Netherlands). The stents were supplied free of charge by Venous Stent B.V. (Maastricht, The Netherlands). The industry funder did not have any editorial input on the content of the manuscript.
The clinical relevance of our study titled "Evaluation of Safety and Performance of a New Prototype Self-Expandable Nitinol Stent in an Ovine Model" lies in its potential to advance the field of venous intervention. Stent implantation is a common procedure used to treat deep venous obstruction, and the use of self-expandable nitinol stents has been shown to be effective in improving the patency rates. However, the safety and efficacy of new stent prototypes must be evaluated thoroughly before they can be used in clinical practice. Our study contributes to the evaluation of a new prototype self-expandable nitinol stent by demonstrating its excellent mechanical properties, biocompatibility, and histopathological response in an ovine model. The results of our study may provide valuable insight for researchers and clinicians in developing and implementing new stent technologies, ultimately improving patient outcomes in the treatment of chronic venous obstruction.
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