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. Author manuscript; available in PMC: 2020 Nov 1.
Published in final edited form as: J Biomed Mater Res B Appl Biomater. 2019 Feb 18;107(8):2466–2475. doi: 10.1002/jbm.b.34337

In vivo comparison of shape memory polymer foam-coated and bare metal coils for aneurysm occlusion in the rabbit elastase model

Scott M Herting 1,*, Yonghong Ding 2,*, Anthony J Boyle 1,3, Daying Dai 2, Landon D Nash 1,3, Solmaz Asnafi 2, Daniel R Jakaitis 2, Collin R Johnson 2, Lance M Graul 1, Chung Yeh 3, David F Kallmes 2, Ramanathan Kadirvel 2, Duncan J Maitland 1,3
PMCID: PMC7384583  NIHMSID: NIHMS1607967  PMID: 30775843

Abstract

Shape memory polymer (SMP) foam-coated coils (FCCs) are new embolic coils coated with porous SMP designed to expand for increased volume filling and enhanced healing after implantation. The purpose of this study was to compare chronic aneurysm healing after treatment with SMP FCCs to bare platinum coil (BPC) controls in the rabbit elastase aneurysm model. BPCs or SMP FCCs were implanted in rabbit elastase-induced aneurysms for follow-up at 30 days (n = 10), 90 days (n = 5), and 180 days (n = 12 for BPCs; n = 14 for SMP FCCs). Aneurysm occlusion and histologic healing, including a qualitative healing score, neointima thickness, collagen deposition, and inflammation were compared between the two groups. The mean neointima thickness was significantly greater in groups treated with SMP FCCs for all three time points. Histologic healing scores and collagen deposition quantification suggested that aneurysms treated with SMP FCCs experience more complete healing of the dome by 90 days, but the differences were not statistically significant. More progressive occlusion and recanalization were observed in aneurysms treated with SMP FCCs, but neither difference was statistically significant. Additionally, the SMP foam used in the FCCs was found to degrade faster in the rabbit elastase model than expected based on previous studies in a porcine sidewall aneurysm model. This study suggests that SMP FCCs can promote neointima formation along the aneurysm neck, and may lead to more complete healing of the dome and neck. These findings indicate potential benefits of this device for aneurysm occlusion procedures.

Keywords: shape memory polymer, embolization device, aneurysm healing, polyurethane foam

INTRODUCTION

Bare platinum coils (BPCs) have been used extensively for occlusion of intracranial aneurysms since the first versions, Guglielmi Detachable Coils, were cleared for clinical use by the FDA in 1995. These platinum microcoils promote the formation of a stable thrombus within the aneurysm, which is meant to be remodeled into connective tissue and covered by a neoendothelial layer across the ostium. The minimally invasive nature of BPC treatment has been beneficial for many patients; however, BPC-treated aneurysm recanalization rates have been reported from 17% to 34% in studies using 6- to 18-month follow-up schedules.1-3 Recanalization can lead to aneurysm rupture, and up to 30% of treated aneurysms require retreatment to prevent such adverse outcomes.4,5 Other endovascular devices and strategies have been developed to reduce these recanalization rates, including coated coils, stent-assisted coils, flow diverters, and liquid embolics.6-10 However, some additional issues remain to be resolved such as hydrocephalus induced by HydroCoils and coil compaction after deployment of matrix coils.2,11 The introduction of flow diverters has been beneficial in some cases, but coil embolization of intracranial aneurysms remains widely used. There is no need to use anticoagulation drugs after coiling, and occurrence of thromboembolic events in the parent artery is much lower than with flow diverter implantation.

One main concern with aneurysm coiling is incomplete occlusion, especially in large and wide-necked aneurysms.2 Shape memory polymer (SMP), foam-coated coils (FCCs) are a new type of coated coil that utilizes ultra-low density SMP foam to increase packing density, promote rapid thrombus formation, and encourage remodeling and connective tissue deposition within the aneurysm.12 The polyurethane SMP foam coating on these devices enables ~2.5× volume expansion upon thermal actuation at the glass transition temperature.13 This large volume expansion allows for increased packing densities, and increasing packing density has been reported to decrease recanalization rates.14-17 The porous foam also acts as a scaffold to support tissue healing, and previous studies in porcine sidewall aneurysms demonstrated increased connective tissue deposition within the domes and thicker neointimal formation at the necks of SMP foam-treated aneurysms.18,19 Previous studies utilized “foam only” devices, which were not deemed clinically viable due to limitations to device delivery through a 5–6F guide catheter. SMP FCCs are a new prototype device that utilizes the foam material in a more clinically relevant design that is deliverable through an 0.021″ ID (2.7F) microcatheter.

It has been hypothesized that dense collagen deposition and thick neointima formation, as has been observed after implantation of similar SMP foams, will lead to improved outcomes for endovascular aneurysm occlusion procedures by increasing the stability of the occlusion and preventing recanalization.20 This type of foreign body response is not often observed in aneurysms treated with BPCs. The goal of the research described here is to evaluate chronic aneurysm healing in the rabbit elastase aneurysm model after treatment with SMP FCC devices.

MATERIALS AND METHODS

Test devices

The SMP FCC devices consist of SMP foam cylinders adhered to the outside of platinum-tungsten coils as seen in Figure 1. A more detailed manufacturing process has been presented by Boyle et al.12 Briefly, platinum–tungsten wire wrapped in a tight, spring shape is formed into a helical secondary shape. Then, the SMP foam is synthesized using a three-step process that combines diisocyanates with polyols and water to form a highly crosslinked poly(urethane urea) foam as described previously.21 SMP foams are cut into cylinders using biopsy punches, then helical platinum–tungsten coils are pulled straight and threaded through the center axis of the foam cylinders. A mixture of the same diisocyanates and polyols used to synthesize the foam is applied to the assemblies, then heat-cured to act as a glue adhering the foam to the coil. The FCCs are attached to a delivery pushwire designed for electrolytic detachment of the coils when used with a separate detachment controller system. The devices are packaged in foil pouches and sterilized by electron beam irradiation at a minimum of 25 kGy before use.

FIGURE 1.

FIGURE 1.

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Shape memory polymer foam-coated coil device used in this study. The 0.750 mm diameter shape memory polymer foam coating is compressed to a 0.381 mm diameter (left) before implantation, then expands (right) when exposed to blood after implantation.

SMP FCC sizes available for this study included 2 × 2, 2 × 4, 4 × 6, 4 × 10, and 6 × 10 (helical diameter in mm × coil length in cm). The Barricade Coil System (Blockade Medical) was used as the BPC control device in this study. Available Barricade sizes included 1 × 2, 1.5 × 2, 1.5 × 3, 1.5 × 4, 2 × 1, 2 × 2, 2 × 3, 2 × 4, 2 × 6, 2 × 8, 2.5 × 3, 2.5 × 4, 3 × 4, 3 × 6, 3 × 8, 3 × 10, 4 × 6, 4 × 8, 4 × 10, 4 × 13, 5 × 8, 5 × 9, 5 × 10, 5 × 15, 5 × 17, 6 × 10, 6 × 11, 6 × 15, 6 × 16, 6 × 20, 7 × 13, 7 × 15, 7 × 20, 7 × 30 (helical diameter in mm × coil length in cm).

Aneurysm creation procedure

All the animal procedures were conducted according to Mayo Clinic AUP# A68514-15-R17. New Zealand White rabbits were anesthetized through intramuscular injection of ketamine/xylazine, intubated, and then anesthesia was maintained with 2.5–3% isoflurane carried by 100% oxygen. Aneurysms were created in rabbits with elastase incubation as described by Altes et al.22 Briefly, using sterile technique, the right common carotid artery (RCCA) was exposed and ligated distally, a five French sheath was advanced retrograde in the RCCA to a point approximately 3 cm cephalad to the CCA origin. Through this indwelling sheath, a three French Fogarty balloon was advanced to the origin of the right CCA at its junction with the right subclavian artery. The balloon was inflated with iodinated contrast just enough to achieve flow arrest in the RCCA. Porcine elastase (approximately 100 U/mL) mixed at a 1:1 ratio with iodinated contrast was incubated for 20 min in the dead space of the RCCA, above the inflated balloon. Following incubation of the elastase solution, the balloon was deflated and the sheath was removed and the RCCA was ligated below the sheath entry site. The skin was closed with running 4–0 Vicryl suture, and the rabbits were sent to recovery.

Embolization procedure

Aneurysms were embolized with BPC controls or SMP FCCs at least 3 weeks after aneurysm creation.23 The anesthesia procedure was the same as at the time of aneurysm creation. Using sterile technique, surgical exposure of the right common femoral artery was performed, and a five French sheath was placed in the right common femoral artery followed by 500 units heparin injection through the sheath. Using coaxial technique, with continuous heparinized saline flush, a Rebar-18 (SMP FCC Delivery) or Echelon-14 (BPC Delivery) microcatheter was advanced into the aneurysm cavity. The size of the aneurysm was assessed using direct comparison to radiopaque sizing devices during digital subtraction angiography (DSA) assuming the aneurysms were ellipsoids. Aneurysms were packed with multiple BPCs or multiple SMP FCCs and the packing density was calculated as the total volume of coils implanted divided by the aneurysm volume. The test device to be used for each aneurysm was chosen before initial DSA and measurement of the aneurysm. Two packing densities were calculated for SMP FCCs: (1) before and (2) after SMP foam expansion. The crimped and expanded foam volume values used in the calculations were measured in previous benchtop expansion experiments. Following coil placement and embolization, a final control DSA was performed. Aneurysm occlusion was evaluated using a three-point scale as follows: grade 1, complete occlusion; grade 2, near complete occlusion; and grade 3, incomplete occlusion. The catheters and sheath were removed, the femoral artery was ligated, and the incision was closed with 4–0 Vicryl suture.

Sacrifice/tissue harvest

Angiographic follow-up was performed 30, 90, or 180 days after coil embolization followed by sacrifice and tissue harvest. The same types of sheaths and catheters were used for the follow-up angiograms as were used for the treatment procedures. At the designated time point, animals were deeply anesthetized. DSA of the brachiocephalic artery was performed, and aneurysm occlusion was evaluated using the same three-point scale: grade 1, complete occlusion; grade 2, near complete occlusion; and grade 3, incomplete occlusion. After the follow-up, a comparative scale was used to compare occlusion scores at the time of sacrifice to occlusion scores immediately after treatment. The potential comparative scores included stable aneurysm occlusion, which indicates that the same grade was assigned at both time points; progressive aneurysm occlusion, which indicates that a better grade was assigned at follow-up; or aneurysm recanalization, which indicates that a worse grade was assigned at follow-up. The animals were then euthanized with a lethal injection of pentobarbital, and the aneurysms and parent arteries were harvested. Harvested tissue samples were immediately fixed in 10% neutral buffered formalin.

Gross evaluation

Gross images of each explanted tissue sample were acquired, and then each aneurysm’s neck orifice was exposed to acquire gross images of the tissue coverage at the neck. Tissue coverage was evaluated to assign the corresponding neck healing score for the ordinal scoring system.

Histologic evaluation

Formalin fixed tissues were processed as has been previously described.24 Briefly, samples were placed in alcoholic formalin followed by ascending alcohol concentrations from 70% to 100%. Next, specimens were placed in two changes of Xylene followed by three changes of liquid paraffin. Finally, specimens were embedded in paraffin blocks. The aneurysm was sectioned with an Isomet Low Speed saw at 1000-micron intervals in a coronal orientation, permitting long-axis sectioning of the aneurysm neck. Metal coil fragments were carefully removed with forceps under a dissection microscope. Following removal of all fragments, the slices were re-embedded in paraffin blocks. A microtome with disposable blades was used to section the blocks at 4-micron intervals. Sections were floated in a water-bath (42°C) then mounted on Superfrost Plus slides and dried overnight in an oven (37°C).

Slides were de-paraffinized and hydrated in water, followed by Hematoxylin & Eosin staining for histologic scoring or Masson’s Trichrome staining for collagen deposition evaluation. An ordinal grading system was used to evaluate histological healing.25 Briefly, neck healing score was calculated based on tissue coverage, coil micro-compaction at the neck was based on the shape of the coil mass across the neck, and the healing characteristics in the dome were categorized based on the density of cellular infiltration and area of organized tissue. The neck average, micro-compaction and healing scores were added together to obtain a total score representative of the aneurysm’s healing.

The degree of inflammation was scored for areas near the wall of the aneurysm and within the bulk of the dome of the aneurysm. These scores were defined as: 0 – no inflammatory cell infiltration; 1 – mild, scant, scattered inflammatory cell infiltration; 2 – moderate, patchy inflammatory cell infiltration; 3 – marked, attenuated, diffuse inflammatory cell infiltration.

Image Pro Plus 7.0 was used to view and measure neointima thickness with a calibrated measurement tool. The measurement method was adapted from Schwartz et al.26 The distance from the surface of the metal coils to the surface of the neointimal tissue was measured for each coil loop located at the necks of the aneurysms. Coil loops in the parent arteries were excluded because the tissue growth on coil loops extending into the parent artery is typically greater than coil loops within the aneurysm, and therefore would not be representative of the response to the devices at the neck interface. Tissue that extended from multiple adjacent coil loops was also excluded because it would not be representative of the response to individual devices.

The fibrosis ratio (collagen deposition) was calculated for each aneurysm as the total area of fibrosis within the aneurysmal cavity and neck divided by the total area of the aneurysmal cavity and neck. Photoshop was used to determine the number of pixels stained blue by Masson’s Trichrome, and this measurement was used as the total area of fibrosis. The aneurysmal cavity and neck were traced in Photoshop to obtain the total area.

In vivo degradation measurement

One H&E stained slide was selected from each animal near the midpoint of the aneurysm and scanned with an OLYMPUS Digital Microscope at a magnification of 100×. The scanned images were then evaluated using the OlyVIA Virtual Microscope. Using the virtual histology slides, the cross sectional area of the remaining polymer was measured at each time point to calculate the surface area loss of the polymer over time.

Statistical analysis

Data analysis was conducted using t-tests to compare parametric data and Mann–Whitney tests to compare nonparametric data. Two-tailed tests were used with a significance level < 0.05. Occurrence of recanalization and progressive occlusion between BPCs and FCCs were compared using Fisher’s exact test.

RESULTS

A total of 60 aneurysms were created and embolized using BPCs (n = 29) or SMP FCCs (n = 31). There were four unexpected fatalities. Two cases treated with FCCs for the 90-day group were sacrificed 1 day after treatment due to complications determined to be related to introducer sheath sizing. Two cases treated with BPCs for the 180-day group were sacrificed early: one at 11 days due to tracheal occlusion and one at 150 days due to an unknown cause. The number of animals that survived to the planned follow-up time point, mean aneurysm size, coil packing density, and the coil length used per aneurysm volume for each group are shown in Table I. The aneurysms in groups treated with SMP FCCs for 30 and 180 days were significantly larger than the aneurysms in groups treated with BPCs for the corresponding time points. Two values of packing density are listed for SMP FCC-treated aneurysms to indicate the packing densities pre- and post-polymer expansion. Packing densities after foam expansion for all three SMP FCC-treated aneurysm groups were significantly higher than packing densities in BPC-treated aneurysm groups. Packing densities before foam expansion in 30- and 180-day groups treated with SMP FCCs were significantly lower than corresponding BPC-treated aneurysm groups.

TABLE I.

Aneurysm Treatment Summary

Device Type Number of
Animals		 Aneurysm Size Before
Treatment (mm3)		 Packing Density (%) Coil Length per Aneurysm
Volume (cm/mm3)
Bare platinum coil
 30-day 10 51.2 ± 26.1  23.7 ± 7.8 0.438 ± 0.16
 90-day 5 119.3 ± 114.9  24.3 ± 7.8 0.417 ± 0.18
 180-day 12 39.8 ± 20.1  29.4 ± 9.7 0.515 ± 0.17
Foam-coated coil
 30-day 10 144.9 ± 106.2   Pre: 17.1 ± 4.2
 Post: 43.7 ± 10.8		 0.173 ± 0.04
 90-day 5 85.9 ± 63.1   Pre: 22.4 ± 10.5
 Post: 56.5 ± 28.1		 0.229 ± 0.11
 180-day 14 71.7 ± 31.9   Pre: 17.2 ± 3.6
 Post: 41.4 ± 8.7		 0.175 ± 0.06
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Neointima thickness

As shown in Figure 2, mean neointimal tissue thickness at the necks of aneurysms was significantly higher in FCC-treated aneurysms at all three follow-up time points (0.16 ± 0.06 vs 0.05 ± 0.04 mm at 30 days; 0.13 ± 0.02 vs 0.03 ± 0.01 mm at 90 days, 0.11 ± 0.05 vs 0.02 ± 0.01 mm at 180 days). The largest p value calculated was 0.000096 for the 30-day group. Representative en face images of the neointimal tissue coverage are provided in Figure 3.

FIGURE 2.

FIGURE 2.

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Angiographic and histologic follow-up at 30-day time point. From left to right, aneurysm before treatment, immediately after treatment, at sacrifice and histologic features (top row was treated with bare platinum coils; bottom row was treated with foam-coated coils). The black arrow identifies a SMP foam strut, which is staining bright red with H&E. The yellow star indicates one location where a metal coil was removed during processing for histology. BPC: bare platinum coil; FCC: foam-coated coil; SMP: shape memory polymer.

FIGURE 3.

FIGURE 3.

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Angiographic and histologic follow-up at 90-day time point. From left to right, aneurysm before treatment, immediately after treatment, at sacrifice and histologic features (top row was treated with bare platinum coils; bottom row was treated with foam-coated coils). BPC: bare platinum coil. FCC: foam-coated coil.

Collagen deposition

Collagen deposition was measured as the percent area positive for Masson’s Trichrome staining at 30, 90, and 180 days. Aneurysms treated with BPCs were observed to be filled with 0.77 ± 0.67% collagen at 30 days, 2.33 ± 3.04% collagen at 90 days, and 8.78 ± 2.98% collagen at 180 days. FCCs were observed to be filled with 1.68 ± 2.52% collagen at 30 days, 6.06 ± 2.77% collagen at 90 days, and 10.43 ± 2.28% collagen at 180 days. Representative sections stained with Masson’s Trichrome are shown in Figure 4 and a chart with these values is presented in Figure 5.

FIGURE 4.

FIGURE 4.

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Angiographic and histologic follow-up at 180-day time point. From left to right, aneurysm before treatment, immediately after treatment, at sacrifice and histologic features (top row was treated with bare platinum coils; bottom row was treated with foam-coated coils). BPC: bare platinum coil; FCC: foam coated coil.

FIGURE 5.

FIGURE 5.

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Histologic healing score comparison between the two groups at each time point. Error bars represent standard deviation.

Angiographic evaluation

Angiographic follow-up was performed at explant for all groups. Representative images are presented in Figures 6-8. Detailed outcomes for each time point and device type are listed in Table II. The observed differences were not statistically significant in any of the three time point groups.

FIGURE 6.

FIGURE 6.

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Gross images of BPC-treated aneurysms (top row) and FCC-treated aneurysms (bottom row) at 30- (left), 90- (middle), and 180-day (right) time points. BPC: bare platinum coil. FCC: foam-coated coil.

FIGURE 8.

FIGURE 8.

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Collagen deposition comparison between BPC-treated aneurysms (top row) and FCC treated aneurysms (bottom row) at 30- (left), 90- (middle), and 180-day (right) time points. The black arrow identifies a SMP foam strut, which is staining yellow with Masson’s Trichrome. BPC: bare platinum coil; FCC: foam-coated coil; SMP: shape memory polymer.

TABLE II.

Angiographic Outcomes at Follow-Up

Device Type Stable
Occlusion		 Progressive
Occlusion		 Recanalization
Bare platinum coil
 30-day 3 1 6
 90-day 3 0 2
 180-day 8 2 2
Foam-coated coil
 30-day 1 3 6
 90-day 1 0 4
 180-day 3 3 8
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Histological evaluation

Evaluation by an experienced pathologist indicated that there was no evidence of undesirable events related to thrombogenicity of the coils. In some cases, coil loops were present in the parent artery as a result of implantation, but the parent vessels remained patent at explant in all cases. This occurred in 11 cases treated with SMP FCCs and 4 cases treated with BPCs.

Histological evaluation of the aneurysm sacs showed a combination of loose connective tissue, thrombus, and inflammatory cells. Quantitative scoring using the method published by Dai et al.25 resulted in total histologic score means and standard deviations for BPC-treated aneurysms at 30, 90, and 180 days of 5.9 ± 2.2, 4.5 ± 2.4, and 7.2 ± 1.1, respectively. Total histologic scores for FCC-treated aneurysms were 5.5 ± 2.3, 7.8 ± 2.1, and 7.4 ± 1.2, respectively (Fig. 9).

FIGURE 9.

FIGURE 9.

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Collagen deposition comparison between the two groups. Error bars represent standard deviation.

Chronic inflammatory foci were observed to be associated with devices in both groups. These foci were primarily composed of macrophages and multinucleated giant cells. Inflammation scores among the two groups at the three follow-up time points are listed in Table III. The scores at the aneurysm wall were significantly higher in FCC-treated aneurysms at 30 days, but there were no statistically significant differences at later time points.

TABLE III.

Inflammation at Follow-Up

Device Type Dome Wall
Bare platinum coil
 30-day 0.90 ± 0.74 0.40 ± 0.84
 90-day 2.0 ± 0.0 0
 180-day 2.0 ± 0.58 0
Foam-coated coil
 30-day 1.7 ± 0.95 2.5 ± 0.97
 90-day 2.2 ± 0.45 0.80 ± 1.1
 180-day 2.0 ± 0.39 0
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In vivo degradation measurement

In the 30-day group (n = 10), polymer mass loss was estimated to be 13.57 ± 2.75% based on surface area analysis. In the 90-day group (n = 5), approximate mass loss was 98.61 ± 0.22%, and in the 180-day group approximate mass loss was 97.50 ± 2.81%.

DISCUSSION

Although BPCs have been widely used for intracranial aneurysm occlusion, limited tissue healing and high rates of incomplete occlusion persist as drawbacks, especially in large and giant aneurysms. Researchers have attempted to improve interventional outcomes by using either biostable or biodegradable polymers, less invasive procedures, higher volume filling of the aneurysm, and implant materials with mechanical properties that more closely match the native vessel properties.27 Hydrocoils, for example, are covered in a hydrogel designed to expand within the aneurysm to displace blood from the aneurysm lumen, resulting in better packing attenuation. However, researchers have reported that treatment success rates were not improved in a multicenter, clinical trial, which indicated less than 50% of aneurysms were completely occluded during follow-up.2 While PGA/PLA fiber coated Matrix coils are reported to promote tissue reaction after deployment, they were reported to be susceptible to coil compaction and have not decreased recanalization rates from those reported previously for BPCs.11 In this study, we tested a new generation of coils coated with porous SMP that physically changes shape to expand and more than double its volume after deployment. Similar to Hydrocoils, this expanding coating improves volume packing within aneurysms, but differs from hydrogels by providing a porous scaffold for full volume clot integration and guided tissue healing. The goal of this study was to evaluate the long-term tissue healing in the domes of aneurysms treated using these new SMP FCC devices.

Greater packing densities were achieved in aneurysms treated with SMP FCCs for all groups after foam expansion. The SMP foam coating passively expands upon implantation and exposure to body fluid and temperature. This allows the foam coating to fill the interstitial space between the implanted coils that cannot be filled with standard BPC devices. Additionally, this higher volume filling can potentially allow for treatment of aneurysms using less coils, as indicated by the use of significantly less coil length per aneurysm volume treated.

Both increased packing density and porous materials are expected to lead to tissue remodeling in the aneurysm dome and at the aneurysm neck.18,28-30 Our results indicated thicker neointima covering the aneurysm neck was achieved using FCCs by comparison with BPCs, and there was a trend toward earlier collagen deposition after treatment with FCCs. The average neointimal tissue thickness was two to three times higher in groups treated with SMP FCCs than in groups treated with BPCs. This is likely related to the scaffold provided by the highly porous SMP foam at the aneurysm necks. Both thicker neointima and increased collagen deposition have been hypothesized to improve the stability of aneurysm embolization.20 The increased thickness of the neointimal tissue may provide a barrier to prevent residual blood flow into aneurysms, while additional collagen or denser collagen within the aneurysm dome is believed to support the bulk tissue to resist compaction.

Ordinal scoring by an experienced pathologist indicated that healing in aneurysms treated with FCCs was not significantly different from healing in aneurysms treated with BPCs for any time point. The scores for BPC-treated aneurysms were similar to those previously reported in literature using this scoring system.25 There was a trend toward accelerated healing with FCCs. The 90-day scores were higher than the BPC group at that time point, but the difference was not statistically significant due to a small sample size.

In the 90-day group, it was noted that a large portion of the SMP foam material from FCC devices had degraded. Previous work using this material system has described the susceptibility of the foam to oxidative degradation.31 Analysis of foam explanted from a porcine sidewall aneurysm model has indicated that this SMP foam degrades slowly with exposure to reactive species produced by cells during the foreign body response.19,31 Using image processing techniques on images from a previous study, SMP foam mass loss in the porcine venous pouch sidewall aneurysm model was estimated to be 12.91 ± 3.10% at 90 days and 13.66 ± 2.70% at 180 days. The rate of degradation observed in this study using the rabbit elastase model was faster than expected based on the images analyzed from the porcine venous pouch sidewall aneurysm models.18 At 30 days (n = 10), we determined an approximate mass loss of 13.57 ± 2.75% for the FCC devices used in this study. However, at 90 days (n = 5) we observed mass loss of 98.61 ± 0.22%. About 180-day explants showed a similar level of degradation, with approximate mass loss values of 97.50 ± 2.81%. Other embolic devices, such as Matrix coils, have utilized a polymer coating that degrades by hydrolysis.6,32 The polymer used in the Matrix devices was observed to degrade at similar rates in different animal models and humans because the mechanism of degradation primarily depended on the presence of water in the environment. The inflammatory responses that produce reactive species, which are the primary cause for degradation of the proposed SMP foam, appear to differ depending on the animal model used. Recent research has described a spectrum of phenotypes for inflammatory cells that can range from pro-inflammatory to pro-healing, with pro-inflammatory phenotypes producing more reactive species.33 We hypothesize that cells in the rabbit elastase model produce more reactive species than in the porcine sidewall model due to differences in the transition between inflammatory phenotypes during the healing process, and therefore lead to accelerated degradation of oxidatively degradable polymers. Currently, it is not known which animal model most accurately depicts the reactive species production in human aneurysms.

In this study, qualitative scoring of inflammation indicated that FCCs elicited more inflammatory cell infiltration at the walls of aneurysms at 30 days than BPCs. This inflammation could be related to the high surface area of the porous SMP used in the implant. Anderson et al.34 state that implantation of materials with a high surface area to volume ratio such as the SMP foams used in SMP FCC implants is expected to result in higher numbers of macrophages and foreign body giants cells at the implant site. It is also reported that the specific cell types present at the implant site are important in determining the outcome of the foreign body response, and inflammatory cell presence is desired in a normal healing process.35 The inflammatory response also may be higher at the wall at this earlier time point because cell infiltration of coiled aneurysms typically initiates from the walls and progresses toward the center of the dome.20 The similar inflammatory responses observed between the two groups at the 90- and 180-day time points suggest that the degradation products from the SMP foam do not initiate a prolonged toxic local response.

In evaluating the treatment stability angiographically, we observed higher rates of recanalization in FCC-treated aneurysms for the 90- and 180-day groups relative to the BPC-treated aneurysms at the corresponding time points, but these differences were not statistically significant. The exact reason for recanalization remains unknown. It was noted that aneurysms treated with SMP FCCs were significantly larger for the 30- and 180-day groups, and it is known that larger aneurysms are more difficult to treat and more likely to recanalize.2 Additionally, the FCC devices used were prototypes with limited device sizes available. In some cases, this led to the use of device sizes that were not optimal for the treatment of the rabbit elastase aneurysms. While the final packing densities were higher in the FCC-treated groups after foam expansion, the device volume before foam expansion was lower than desired. Additional device designs and sizes could lead to the ability to consistently achieve packing densities greater than 24% before foam expansion, as is desired to reduce the likelihood of recanalization with other clinically used coils.14 Another potential factor is the accelerated degradation of the SMP foam material used in FCC devices. The material degraded at a rate faster than expected based on previous studies, which allows less time for tissue healing to provide a stable tissue matrix.19,31 Finally, some inflammatory responses may also be related to tissue contraction and coil compaction.

Limitations for this study include the small sample size in the 90-day treatment group (5 per time point) which limits the statistical comparisons that can be made. Additional limitations include non-ideal SMP FCC packing densities in some cases. Packing was stopped after the experienced interventional radiologist performing the implantations felt that the aneurysm was packed sufficiently for a clinical case or once they felt that the implantation of more devices would risk leaving coil loops in the parent artery. Limited device size availability of SMP FCCs also resulted in suboptimal packing. Finally, the method chosen to randomize the cases in this study was imperfect, and aneurysm sizes differed between groups. This is an inherent limitation to all studies using this animal model, as there is limited control of the size of aneurysms created using elastase.

The devices investigated in this study, SMP FCCs, were found to increase neointima thickness at the aneurysm neck in the rabbit elastase aneurysm model. Treatment with these devices was associated with higher packing densities after expansion of the foam coating, and additional device sizes and shaping procedures are being developed to further improve device packing. Additionally, oxidative degradation of polymeric materials likely differs between aneurysm animal models and should continue to be investigated to understand potential clinical impact. Overall, this study demonstrates that the SMP FCC device tested shows potential to enhance the healing response after endovascular treatment of aneurysms.

FIGURE 7.

FIGURE 7.

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Neointimal tissue thickness comparison between the two groups. Error bars represent standard deviation. ***p < 0.001. Largest p = 0.000096 in the 30-day group.

Acknowledgments

Contract grant sponsor: National Institute of Neurological Disorders and Stroke; contract grant number: U01-NS089692

Contract grant sponsor: U.S. Department of Defense

Footnotes

CONFLICT OF INTEREST

Shape Memory Medical, Inc. (SMM) owns the commercial license for clinical vascular embolization application of the technology shown in this work. The authors disclose that Duncan J. Maitland is a founder, board member, and shareholder of SMM. Anthony J. Boyle, Landon D. Nash, and Chung Yeh are or were employed by SMM at the time of this work.

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