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Original research
Safety and performance of the Penumbra Liberty stent system in a rabbit aneurysm model
  1. Rajendra Chavan1,
  2. Stephen Pons2,
  3. Vikas Gupta2,
  4. Delilah Hui2,
  5. Arani Bose3
  1. 1Department of Radiology, Jehangir Hospital, Pune, Maharashtra, India
  2. 2Department of Research and Development, Penumbra Inc, Alameda, California, USA
  3. 3Department of Medical Affairs, Penumbra Inc, Alameda, California, USA
  1. Correspondence to Dr R Chavan, Department of Radiology, Jehangir Hospital, Sassoon Hospital Road, Pune, Maharashtra 411001, India; dr_rajendrachavan{at}hotmail.com

Abstract

Background Endovascular treatment of wide necked and large/giant intracranial aneurysms is challenging. The goal of this study was to evaluate the Liberty stent system in the rabbit elastase aneurysm model for 30, 90, and 180 days.

Methods The Altes elastase model was used to create aneurysms in the right common carotid artery in New Zealand White rabbits. Safety was assessed by angiographic and histopathological data from treated wide necked aneurysms, treated subclavian arteries, and related vasculature immediately post-treatment and at scheduled end points.

Results In this study, stenting of wide necked aneurysms demonstrated excellent results in all 35 animals. The Liberty could be tracked to the final position across an aneurysm neck precisely, without changing microcatheter position. After device deployment, no significant changes in vessel contour and no stent migration were observed. Coil mass was well supported in all aneurysms and high packing densities were achieved. In addition, follow-up angiograms showed stable coil masses and persistent occlusion in all animals, without any recanalization of the neck or aneurysmal sac. Furthermore, there was no evidence of coil compaction or protrusion of coil loop through the stent struts. None of the immediate post-coiling angiograms revealed evidence of vasospasm, dissection, or in-stent thrombosis.

Discussion This animal study demonstrated promising results with the novel Liberty stent system. The Liberty showed consistent precise positioning and accurate deployment. The stent revealed good compatibility with embolic coiling procedures, while morbidity and mortality were negligible. In addition, persistent occlusion of aneurysms without recanalization or in-stent stenosis was observed at the 180 day follow-up.

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Background

Intracranial aneurysms are abnormal focal dilatations of vessel walls. The most common presentation of these aneurysms is subarachnoid hemorrhage (SAH). SAH secondary to intracranial aneurysm is a potentially lethal event, with a high mortality rate.1 Endovascular coiling of ruptured saccular small intracranial aneurysms was first performed with the Guglielmi detachable coil system. After publication of the International Subarachnoid Aneurysm Trial2 results, endovascular coiling was considered a safe and effective minimally invasive treatment option for aneurysms, and is presently a preferred treatment option in most countries.3 ,4

Aneurysms with necks measuring at least 4 mm5 or aneurysms with dome to neck ratios of <26 ,7 are classified as wide necked aneurysms. Wide necked aneurysms need special coil retention techniques to prevent prolapse of coil mass into the parent artery. Remodeling of aneurysm necks with inflation of intracranial balloons is a standard treatment option for ruptured aneurysms.8 Stent assisted coiling is preferred predominantly in unruptured wide necked aneurysms.9 ,10 However, physicians routinely face challenges in poor performance of these devices in tortuous anatomy, poor retrievability and visibility, acute vascular injury during deployment, and in-stent thrombosis.9–,13 Recanalization of the aneurysm neck and/or sac is another challenge,14–16 which warrants subsequent retreatment with coiling procedures or deployment of flow diverters.

We report results of a rabbit elastase aneurysm model study which was performed to evaluate the safety of the Penumbra Liberty stent device (Penumbra, Alameda, California, USA). Safety was evaluated by analysis of angiographic and histopathological data from treated wide necked aneurysms and related vasculature immediately post-treatment and at scheduled end points.

Materials and methods

The study was approved by an institutional animal care and use committee and conducted at Bio Assist Inc (Dixon, California, USA) in accordance with the US Food and Drug Administration Good Laboratory Practice (GLP) Regulations and institutional guidelines.

New Zealand White rabbits, weighing at least 4 kg, were divided into three study groups of 12 animals each, differing in the end time points: 30 days±5 days, 90 days±7 days, and 180 days±10 days. Each rabbit underwent three procedures under general anesthesia (ie, aneurysm creation, aneurysm treatment, and follow-up angiograms) after the respective time interval, prior to euthanasia. Blood was collected from all rabbits in the 90 day group for a complete blood count and serum chemistry, prior to aneurysm creation (baseline), prior to aneurysm treatment (pre-test), and at the time of the final procedure.

Test article

The Liberty stent system consists of three components: Liberty implant stent, an introducer sheath, and a delivery wire assembly (figure 1A). The implant is made of super elastic biocompatible nitinol tube with platinum radio-opaque markers on both ends. The Liberty is available with a helical twist in two orientations—primary (right-handed twist) and reverse (left-handed twist)—which allows it to conform to vessel curvature (figure 1B, C). Both helical variations are identical in terms of design, with the exception of the stent strut twist direction, which are mirror images. The introducer sheath is compatible with delivery catheters having a minimum inner diameter of 0.025 inches.

Figure 1

Illustrations of the Liberty stent system. (A) Schematic diagram shows the Liberty stent system, which is comprised of an implantable stent and delivery assembly. The self-expanding re-sheathable stent is composed of nitinol with radio-opaque markers on both ends. The introducer sheath is compatible with catheters having an inner diameter of 0.025 inches or greater. (B) Photograph shows the innovative design of the Liberty stent. Liberty's advanced nitinol technology provides robust radial force, while its hybrid cell structure and helical twist confer conformability to vessel curvature. (C) A Liberty device within a glass aneurysm model shows optimized coverage of the aneurysm neck, minimal foreshortening, and excellent wall apposition.

For this GLP study, Liberty devices with primary and reverse orientations were tested with two diameters, (3.5 and 4.0 mm) and two lengths (11 and 15 mm).

Aneurysm creation technique

The Altes elastase model was used to create aneurysms in the right common carotid artery in rabbits.17 A 5 F introducer/sheath was retrogradely inserted. Under roadmap guidance, a 3 F Fogarty balloon catheter was introduced through the sheath to the origin of the artery. A balloon was then inflated with 50% contrast in order to occlude blood flow in the artery. Fifty per cent elastase (mixed with an equal amount of contrast) was then infused slowly through the sheath, in the distal arterial stump. After 20 min, the elastase solution was gently aspirated until blood was noted in the syringe. Each aneurysm was allowed to stabilize for at least 14 days prior to treatment with a Liberty device.

At least 3 days prior to treatment, all animals were started on double antiplatelet drugs. Approximately 6 mg of Plavix (1.2 mg/kg based on 5 kg weight) and 24 mg of aspirin (4.75 mg/kg based on 5 kg weight) were mixed in animal feed until the end of the study.

Aneurysm treatment technique

A 5 F introducer was inserted into the right femoral artery, while a 4 F introducer was introduced into the left femoral artery. A 5 F H-1 Envoy guide catheter was introduced into the proximal brachiocephalic artery.

Acceptance criteria for these aneurysms were: (1) at least an 8 mm segment of subclavian artery with a diameter of 3–4 mm; and (2) aneurysm dome to neck ratio of 1–2. Aneurysms which fulfilled the acceptance criteria were then treated in the following manner.

An appropriately angled PX 400 Penumbra catheter, guided over a 0.014 inch microguidewire, was introduced into the aneurysm sac. A straight PX 400 catheter over a 0.014 inch guidewire was then introduced through the left 4 F femoral sheath and advanced into the right subclavian artery, distal to the origin of the right vertebral artery. Based on the dimensions of the aneurysm neck and subclavian artery, a Liberty device was selected. Alternate primary and reverse twist devices were studied. Device length was selected to provide adequate coverage of an aneurysm neck by the central portion of the device with relatively minimal risk of protrusion into the aorta. The distal end of the Liberty sheath was introduced into the hub of a straight PX 400 catheter. When the device reached the tip of the microcatheter, it was slowly advanced so as to deploy about 50% of the device. The partially deployed device was then re-sheathed, with advancement of the catheter, while holding the delivery wire in place. Partial deployment and re-sheathing was performed in every animal. Finally, the device was deployed across the neck of the aneurysm, minimizing device protrusion into the aorta. After deployment, the acute performance of the Liberty was recorded under the headings of trackability, pushability, re-sheathability, flexibility in tortuous vessel anatomy, radio-opacity, accuracy of deployment, and acute thrombus formation on the delivery system.

Coiling of the aneurysm was performed in accordance with standard neurointerventional practice using Penumbra coils. Coils were deployed until the operator achieved a high packing density. Post-treatment angiograms were acquired, and the WASID method was used to determine the patency of the subclavian artery, proximal and distal to the Liberty, as well as within the device.18 Aneurysm occlusion was assessed using the Raymond Scale.19 Coil prolapse through the Liberty device mesh and acute vessel trauma in the form of vasospasm and vessel dissection were evaluated. The number of operators evaluating acute performance parameters, compatibility with coiling, and vessel trauma was one each within the scope of this paper. Many of these parameters were evaluated further in a bench model and have since been evaluated in ongoing clinical trials.

Final angiography

Final angiograms were performed after predetermined time durations. Angiograms were acquired with the catheter held at the origin of the brachiocephalic artery. Using the WASID method, the patency of the subclavian artery was documented proximal to the device, within and distal to the device. Aneurysm occlusion was ranked using the Raymond Scale.

Histological analysis

After the final angiographic study, all rabbits were euthanized. The treated subclavian artery, aneurysm, and regional vasculature were resected for macroscopic and histological evaluation. Specimens were fixed with 10% neutral buffered formalin for at least 72 h. The musculature of the right forelimb (biceps and triceps), kidneys, liver, lung, heart, spleen, and brain were evaluated in the same manner for end organ tissue injury. Regional lymph nodes (thoracic/hilar/sternal) were also studied to examine evidence of device corrosion.

Results

Clinical data

After 14 days, aneurysms created with the Altes technique showed consistent necks, sizes, and shapes. Only one rabbit in the 30 day group was excluded from treatment as the aneurysm neck and subclavian artery dimensions were larger than the acceptance criteria. The subclavian artery was highly tortuous, and it was assumed these findings were due to leakage of elastase across the inflated balloon at the origin of the right common carotid artery. The rest of the animals in all three groups were treated successfully.

There were no early deaths of rabbits. All rabbits were followed to the expected study end points. None showed any sign or deficit related to deployed stent or treatment.

The 30 day group comprised 11 animals while the 90 day and 180 day groups had 12 animals each. There was no significant difference in age or weight in these groups at the time of aneurysm creation and treatment with a Liberty device. Blood counts and serum tests done in the 90 day group, at three different time points (baseline, pretreatment, final), did not reveal any significant alteration, except for a significant increase in creatine kinase levels at the pretreatment stage.

Test article randomization

Five devices with primary and six devices with reverse orientations were used in the 30 day group. In the 90 and 180 day groups, six devices of each configuration were used. The total number of devices with different diameters and lengths used in this study were as follows: diameter of 3.5 mm, 25; diameter of 4 mm, 10; device length of 11 mm, 20; length of 15 mm, 15.

Liberty performance

Performance was marked based on a scale which ranged from poor performance (1), needs to be improved (2), acceptable (3), good (4) to excellent (5). Performance ≥3 was considered as acceptable in this study.

Trackability, flexibility, and pushability of the Liberty

There was no difficulty in transferring these devices from the introducer sheath through the rotating hemostatic valve into the hub of the microcatheters. All devices could be easily pushed through the microcatheter without any friction, and trackability to the target vessels was precise. None of these devices led to significant straightening or displacement of the microcatheter. Performance of all devices was rated either good (4) or excellent (5), under all of these headings.

Device re-sheathability

Partial deployment and re-sheathing was possible in all Liberty devices. In none of the animals did this maneuver cause any vascular injury, abrupt change in the microcatheter or device position, or premature deployment of the stent.

Device deployment

All devices were deployed under continuous roadmap guidance across the neck of the aneurysms. Accurate device placement was possible in all animals, without any difficulty. There was no significant stent migration observed during, after deployment of the device, or on follow-up angiograms. None of the devices was seen protruding significantly into the arch of the aorta.

Device radio-opacity

Radio-opacity of proximal as well as distal platinum markers of the Liberty was good, not only in the collapsed state but also in the deployed state. The stent itself also demonstrated acceptable radio-opacity on routine fluoroscopy. We never encountered a problem in identifying the stent markers, stent, or catheter markers during deployment of the device or during the coiling procedure.

Compatibility of the Liberty with the coiling procedure

Coiling of aneurysms produced excellent results in all three groups of animals. There was no incidence of losing a microcatheter position once it was jailed with the Liberty. The entire coil mass was held within the aneurysm sac in all animals. There were no episodes of coil loop protruding into the parent vessel through the stent struts. At the end of the coiling procedure, the microcatheter could be withdrawn without any stent migration. In all animals, compatibility of the Liberty was rated either good or excellent. Furthermore, there was no evidence of coil compaction. In all aneurysms, high packing density was achieved.

Vessel trauma

Acute vessel trauma was assessed after the coiling procedure. Two parameters (vasospasm and vessel dissection) were used to assess vessel trauma at each time point. All subclavian arteries at the aneurysm site, as well as distally, were closely evaluated to observe any evidence of vasospasm or dissection. In none of the animals did we find any narrowing, intimal flap, or significant change in the vessel morphology to suggest vessel trauma.

Subclavian artery patency

The well established WASID method was used to assess the patency of the subclavian artery, immediately after the treatment and on final angiograms. The patency of the artery was assessed proximal to the Liberty, within the device, and distal to the device. None of the subclavian arteries showed less than 95% patency on immediate post-treatment angiograms. There was no appreciable change in the diameter of any of the subclavian arteries in any region on follow-up final angiograms.

Aneurysm occlusion

The Raymond Scale19 was used to rank occlusion of aneurysms on immediate post-treatment and final angiograms. Peak opacification images on the angiograms were used to assess this aspect (figures 2A, 3A, and 4A). None of the aneurysms showed recanalization on immediate post-treatment or final angiograms (figures 2B, 3B, and 4B).

Figure 2

A 30 day group animal. (A) A 3.5×15 mm Liberty test article with reverse (ie, left hand) twist was accurately placed across the neck of the aneurysm. A total of four soft Penumbra coils were deployed in the aneurysm sac. Post-treatment angiogram revealed total occlusion of the aneurysm without any residual neck, suggestive of Raymond Scale class 1. There was no evidence of coil loop prolapse. (B) Final angiography after 30 days. Persistent total occlusion of the aneurysm sac with Raymond Scale class 1. The distal subclavian artery and its branches were readily seen. (C) Histology image showing excellent stent position and stable aneurysm integrity. Compressed internal elastic lamina with expected normal inflammatory response is noted.

Figure 3

A 90 day group animal. (A) A 4.0×15 mm Liberty stent with left (ie, reverse) twist was used. The stent was deployed accurately without any protrusion into the aorta. Six curve extra soft Penumbra coils were deployed in the aneurysm. This post-treatment angiogram revealed a good angiographic result with Raymond Scale class 2 occlusion. There was no evidence of coil loop prolapse. (B) The 90 day final angiography revealed no residual neck opacification with Raymond Scale class 1. (C) Histology image showing excellent stent and coil placement. Very minor fibrin accumulation was seen around a coil at the neck. Normal fibrosis of the aneurysm with outstanding mechanical integrity was reported. The Schwartz Injury Score was 0, while the inflammatory/cellular reaction score was 1.

Figure 4

A 180 day group animal. (A) A 3.5×11 mm Liberty stent with primary twist was used for stent assisted coiling. One complex soft coil was deployed followed by four curve extra soft coils. The last 2×1 mm curve extra soft coil could not be deployed and hence was removed. Post-treatment angiogram revealed an excellent result with Raymond Scale class 1 occlusion. (B) The 180 day final angiography revealed a stable stent and coil mass. (C) Histology image reveals an aneurysm dome filled with mature fibrous tissue, indicative of good stability and structural integrity. Schwartz Injury and inflammatory/cellular reaction scores were 0.

Histopathological analysis

The vascular response to the Liberty was considered to be within normal limits (figures 2C, 3C, and 4C). The presence of the stent was associated with minor injury to the vessel wall. With rare exceptions, the stent struts were associated with compression of the internal elastic lamina and tunica media of the vascular wall (Schwarz Injury Score=0).20 Associated fracture of the internal elastic lamina with partial thickness laceration of the tunica media were rare occurrences. Full thickness strut perforation was not identified in any of the animals.

A normal degree of inflammatory cellular response was noted around the struts in all study animals. In most animals, it was generally minimal to mild in severity and typically characterized by modest numbers of aggregating histiocytes and fibrocytes without prominent nodular thrombus formation or disruption of the parent vessel architecture.

The average per cent stenosis (luminal narrowing) caused by neointimal proliferation averaged approximately 24% at the 30 day time point, 22.5% at the 90 day time point, and 17.1% at the 180 day time point. These morphometric results from all study groups are within the expected range for this application. The stent in the parent artery was consistently covered by a normal neointimal response. Normal endothelialization of the neointima across the neck of the aneurysm was noted in all animals. The shape of the neck of the aneurysm was typically either ‘concave’ or ‘flat’.

With one exception, the aneurysm was completely filled with mature organized fibrous connective tissue that integrated the coils and appeared to provide good structural integrity to the aneurysm sac. Findings indicated normal maturation and progression of organized fibrous tissue within the dome.

There was no evidence of thromboembolism or infarction in the right forearm musculature (ie, the vascular bed distal to the stent). Lymph node evaluation did not demonstrate evidence of device corrosion in any tested animals. Thus histopathological analysis of rabbits in an elastase aneurysm model demonstrated a normal vascular response to the Liberty stent, and normal maturation (fibrous integration) of the aneurysm dome through all time points tested.

Discussion

Endovascular treatment of wide necked and large/giant intracranial aneurysms is technically challenging. Although balloon assisted coiling is the most commonly used treatment for ruptured aneurysms, it does carry risks of complications from thromboembolism, intimal injury, or rupture of the parent vessel.21–24 The most important limitation of balloon assisted coiling procedures is that it only provides temporary protection.25 Frequently the morphology of the aneurysm is such that additional permanent protection is required.

Another method for endovascular treatment of wide necked aneurysms is the use of a stent to support the neck of the aneurysm. Balloon expandable stents meant for peripheral vessels were used initially and then replaced by self-expandable microstents, such as the Neuroform (Stryker, Kalamazoo, Michigan, USA).26 ,27 The earliest clinical report of stent assisted coiling of an intracranial ruptured cerebral aneurysm was by Higashida et al in 1997.28 Other self-expandable intracranial stents and flow diversion devices have been introduced in the past few years. Now stent assisted coiling is a well established treatment modality in cases with wide necked aneurysms.

Stent assisted coiling is showing consistently good results, with extensive publication about these treatment options in peer reviewed journals. Various issues such as premature or faulty deployment of the stent, stent migration during microcatheter placement into the aneurysm, stent herniation into the aneurysm, and prolapse of the coil loops through the struts of the stent have been discussed previously.9 ,10 ,29 ,30

Requirements of the ideal stent are that the stent should be flexible, atraumatic, and easily deployable, with sufficient radio-opacity. The stent should be retrievable, allow repositioning, and have adequate radial strength to maintain the patency of the vessel. The Liberty stent system has a self-expanding stent that is an adjunctive device to embolic coils for the treatment of wide neck, saccular, intracranial aneurysms. Its design optimizes coverage of the aneurysm neck with ease of delivery, no foreshortening, and excellent wall apposition and re-sheathability. The stent's neck coverage is maximized for superior coil retention, yet allowing for coil catheter penetration. In the USA, only the primary helix twist is available. In the European Union, both helix orientations are available. Initial stent placements should be conducted with the primary twist device. If additional stent coverage is necessary, the reverse orientation Liberty stent is recommended to create a uniform meshwork at the aneurysm neck.

It has been noted that many endovascular devices in current clinical use have never been reported in published preclinical studies.1 In the absence of randomized trials, the effectiveness of many devices remains unproven.

In this GLP study, a rabbit elastase aneurysm model was used to assess the performance of the Liberty stent in the treatment of wide necked aneurysms. The rabbit Altes aneurysm model is considered a reliable method to replicate features of intracranial aneurysms.1 This animal model is preferred over laboratory in vitro studies for evaluation of endovascular devices because it provides a morphologically more realistic experimental model.

Stenting of wide necked aneurysms demonstrated excellent results in all 35 animals. All 35 devices, including primary and reverse orientations, produced similar performance. In all aneurysms, coil mass was very well supported and high packing density was achieved with long term occlusion.

Even though follow-up angiograms and histopathological data were assessed, a limitation of this study is that the longest follow-up was 180 days. The performance of the Liberty over a longer duration remains to be addressed by a long term histopathological study. Another important limitation of this study is that the Liberty system was analyzed in the relatively smooth curvature of the animal vessel. How this system functions in the more tortuous diseased intracranial vessels of patients will need to be investigated.

In conclusion, this animal study demonstrated a promising performance of the novel Liberty stent system. The Liberty showed consistent and precise positioning, partial re-sheathing capability, and accurate deployment. The stent revealed good compatibility with embolic coiling procedures and excellent success rates, with vascular inflammatory response within an acceptable range. The morbidity and mortality rates were negligible. In addition, follow-up angiograms revealed persistent occlusion of aneurysms without recanalization or in-stent stenosis. In contrast with the hybrid cell design of the Liberty, the open cell design of the Neuroform/Treo stents provides conformability, kink resistance, and wall apposition but weak neck coverage and deployment properties, while the Enterprise stent closed cell design provides trackability, recapture, good neck coverage, and a higher rate of immediate aneurysm occlusion due to stronger radial forces, but not conformability, kink resistance, or delayed migration resistance.31–34 Symptomatic thromboembolic complications were significantly more frequent with the Enterprise versus the Neuroform stent.31

Acknowledgments

The authors would like to acknowledge and thank Dr Karen J Whitehair and Dr Jon G Whitehair for their support at Bio Assist Inc (Dixon, California, USA). The authors also thank Dr Sophia Kuo for her valuable assistance in manuscript preparation.

References

Footnotes

  • Contributors RC wrote and reviewed the manuscript, designed and conducted the study, and analyzed the data. SP, VG, and DH designed and conducted the study, and analyzed the data. AB reviewed the manuscript and analyzed the data.

  • Funding This work was supported by Penumbra Inc.

  • Ethics approval The study was approved by an institutional animal care and use committee and conducted at Bio Assist Inc in accordance with the US Food and Drug Administration Good Laboratory Practice Regulations and institutional guidelines.

  • Competing interests RC reports a consulting relationship with Penumbra. SP, VG, DH, and AB are employees of Penumbra. AB owns Penumbra equity, and SP, VG, and DH own Penumbra stock options.

  • Provenance and peer review Not commissioned; externally peer reviewed.