Original Article

Comparative Biomechanical Behavior and Healing Profile of a Novel Thinned Wall Ultrahigh Molecular Weight Amorphous Poly-l-Lactic Acid Sirolimus-Eluting Bioresorbable Coronary Scaffold

Yanping Cheng, Pawel Gasior, Jing-Gang Xia, Kamal Ramzipoor, Chang Lee, Edward A. Estrada, Daniell Dokko, Jenn C. McGregor, Gerard B. Conditt, Thomas McAndrew, Greg L. Kaluza, Juan F. Granada
https://doi.org/10.1161/CIRCINTERVENTIONS.117.005116
Circulation: Cardiovascular Interventions. 2017;10:e005116
Originally published July 12, 2017

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Abstract

Background—Mechanical strength of bioresorbable scaffolds (BRS) is highly dependent on strut dimensions and polymer features. To date, the successful development of thin-walled BRS has been challenging. We compared the biomechanical behavior and vascular healing profile of a novel thin-walled (115 µm) sirolimus-eluting ultrahigh molecular weight amorphous poly-l-lactic acid-based BRS (APTITUDE, Amaranth Medical [AMA]) to Absorb (bioresorbable vascular scaffold [BVS]) using different experimental models.

Methods and Results—In vitro biomechanical testing showed no fractures in the AMA-BRS when overexpanded 1.3 mm above nominal dilatation values (≈48%) and lower number of fractures on accelerated cycle testing over time (at 21 K cycles=20.0 [19.5–20.5] in BVS versus 4.0 [3.0–4.3] in AMA-BRS). In the healing response study, 35 AMA-BRS and 23 BVS were implanted in 58 coronary arteries of 23 swine and followed-up to 180 days. Scaffold strut healing was evaluated in vivo using weekly optical coherence tomography analysis. At 14 days, the AMA-BRS demonstrated a higher percentage of embedded struts (71.0% [47.6, 89.1] compared with BVS 40.3% [20.5, 63.2]; P=0.01). At 21 days, uncovered struts were still present in the BVS group (3.8% [2.1, 10.2]). Histopathology revealed lower area stenosis (AMA-BRS, 21.0±6.1% versus BVS 31.0±4.5%; P=0.002) in the AMA-BRS at 28 days. Neointimal thickness and inflammatory scores were comparable between both devices at 180 days.

Conclusions—A new generation thinned wall BRS displayed a more favorable biomechanical behavior and strut healing profile compared with BVS in normal porcine coronary arteries. This novel BRS concept has the potential to improve the clinical outcomes of current generation BRS.

Introduction

WHAT IS KNOWN

  • Clinically available bioresorbable scaffolds (BRS) rely on strut dimensions and polymer crystallinity to achieve mechanical strength and display limited overexpansion capabilities and structural integrity when exposed to high-loading conditions.

  • Recent published randomized controlled trials suggest that thick-strut BRS is associated with an increased risk of late adverse clinical events, including scaffold thrombosis.

WHAT THE STUDY ADDS

  • A new generation thinner-strut ultrahigh molecular weight amorphous poly-L-lactic acid BRS demonstrated higher overexpansion capabilities and improved mechanical strength under stress conditions compared with first-generation BRS. Also, this novel device showed a favorable healing response and superior strut coverage compared with a thicker strut BRS control.

  • This novel BRS concept has the potential to improve the clinical performance of current generation BRS by providing a highly biocompatible and mechanically durable scaffold platform.

The Absorb everolimus-eluting bioresorbable vascular scaffold (BVS, Abbott Vascular, Santa Clara, CA) is currently the most studied poly-l-lactic acid (PLLA)-based bioresorbable scaffold (BRS).1–3 This first-generation BRS has an average strut thickness of 157 μm and relays on polymer crystallinity and a high vessel surface area to achieve stent-like mechanical strength. Bench data suggest that this current generation BRS displays limited overexpansion capabilities and structural integrity when exposed to high-loading conditions.4 Recent clinical reports suggest that mechanical BRS’ failure may be a potential mechanism for late clinical adverse events.5–7

Because of the inherent limitations of current generation PLLA, the reduction of wall thickness of clinically available BRS has been challenging. A novel ultrahigh molecular weight amorphous PLLA BRS (Amaranth Medical [AMA], Mountain View, CA) displays elongation at break points 10× higher compared with typical PLLA and promise to enhance the biomechanical properties of current generation BRS technologies.8,9 In this study, we evaluated the biomechanical behavior and vascular healing profile of a novel thin strut (115 µm) sirolimus-eluting BRS (APTITUDE, AMA-BRS) against the clinically available Absorb BVS using different experimental models.

Methods

Device Description

The APTITUDE AMA-BRS is manufactured using an ultrahigh molecular weight bioresorbable polylactide-based polymer with a strut thickness of 115 µm and incorporates 3 platinum radio-opaque markers at both ends to improve angiographic visualization. The AMA-BRS is coated with a matrix consisting of 1:1 polymer:drug ratio of sirolimus plus poly d-lactide polymer and has a sirolimus dosing of ≈96 µg/cm2. The core AMA-BRS technology involves a proprietary process of ultrahigh molecular weight polymer synthesis and processing designed to achieve a balance between strength, flexibility, and high resistance to fracture. Tube manufacturing is achieved by a proprietary multilayer deposition process. The biomechanical properties of the polymer are fully preserved throughout the manufacturing cycle with negligible reduction of molecular weight and no alteration of thermal properties from PLLA tubing fabrication to the final sterile device. In vitro studies showed that the reduction in molecular weight reaches ≈50% at 8 months and >85% at 18 months. Radial strength is maintained for ≈8 to 10 months. Vessel wall surface area coverage ranges from 21% to 25% depending on the scaffold diameter (2.50–3.50 mm). In this study, the APTITUDE AMA-BRS was compared with the Food and Drug Administration–approved, commercially available Absorb everolimus-eluting BVS (Abbott Vascular ). The Absorb BVS is a balloon-expandable, fully BRS that consists of a poly (l-lactide) backbone with strut thickness of 157 µm and a poly (d, l-lactide) coating in a 1:1 ratio with everolimus doses of 100 µg/cm2.

In Vitro Overexpansion and Cyclic Fatigue Testing

The mechanical behavior of the AMA-BRS and BVS after overexpansion was examined under static conditions. Both AMA-BRS (2.75 mm) and BVS (3.0 mm) were deployed in vitro at their rated burst pressure (16 atm for both BVS and AMA-BRS) after the recommended dilatation technique. The scaffolds were post-dilated using commercially available balloon catheters until strut fracture was observed. The scaffolds were additionally inspected at ≈0.5-mm diameter increments using conventional light microscope techniques (AmScope, Irvine, CA). Measurements were performed using a calibrated measurement gauge to measure the scaffold OD (Figure 1). In addition, mechanical stability overtime was tested under dynamic load conditions (AMA-BRS=4, BVS=4). In this study, fracture resistance was evaluated by applying identical multimodal cyclic loads to the scaffolds. The cyclic loads were similar to conditions present in physiological environments but with 50% to 100% greater amplitude to highlight mechanical properties of the scaffolds.

Figure 1.
Figure 1.

In the AMA (Amaranth Medical) 115-µm bioresorbable scaffold (BRS) group, the numbers of scaffold fractures were lower in both the overexpansion (A) and the cyclic fatigability (B) test conditions compared with 157-µm Absorb bioresorbable vascular scaffold (BVS); the expansion capacity of the AMA-BRS was 2.5-fold higher than BVS (AMA-BRS=91% [78, 107] vs BVS=33% [33, 35]). Values are expressed as median (25th–75th percentile).

In Vivo Porcine Healing Study

The Institutional Animal Care and Use Committee approved all studies, and all animals received care in accordance with the Guide to Care and Use of Laboratory Animals. All animals underwent endotracheal intubation and were maintained on a continuous inhalation of 1% to 3% isoflurane. Anticoagulation with heparin was achieved during the procedure (500–5000 U) to maintain an activated clotting time ≥250 seconds. In this study, either sirolimus-eluting AMA-BRS (n=35, size 2.50, 2.75, or 3.50×18 mm) or BVS (n=23, size 2.5, 3.0, or 3.5×18 mm) was implanted targeting a stent-to-artery ratio of 1.1:1 under intravascular ultrasound guidance in 58 coronary arteries of 23 swine. The implants were evaluated with in vivo weekly optical coherence tomography (OCT) analysis through the first month post-implantation in 9 animals (15 AMA-BRS and 9 BVS) to assess in vivo biomechanics and strut-vessel wall interactions. Longer term healing response was assessed by histological analysis at 28, 90, and 180 days.

Quantitative Coronary Angiography

Quantitative coronary angiography analysis was performed using QAngio XA Software TM 7.1.14.0 (Medis Medical Imaging System, Leiden, the Netherlands). The outer diameter of the contrast-filled catheter was used as the calibration standard, and the minimum lumen diameter was obtained from the single worst view while the reference vessel diameter was automatically calculated by the interpolation method. The percent diameter stenosis was calculated from the minimum lumen diameter and the reference vessel diameter. Acute absolute scaffold recoil was defined as the difference between mean diameter of the scaffold delivery balloon at the highest pressure at implantation (X) and mean luminal diameter of stented segment after implantation (Y). Percent acute recoil was calculated as (X−Y)/X×100.10

OCT Imaging

OCT images were recorded using the ILUMIEN PCI Optimization System (St. Jude Medical, St. Paul, MN), and the qualitative analyses were performed with the commercial software (ILUMIEN OPTIS, St. Jude Medical, St. Paul, MN). The following cross-sectional parameters were measured and calculated as previous described9: the lumen area, the inner and outer scaffold area, percentage area of stenosis, and neointimal thickness. Absolute late recoil was measured as the mean scaffold area at baseline (post-implant) minus the mean scaffold area at follow-up. Relative late recoil was calculated as [(absolute late recoil)/baseline mean scaffold area]×100.11

To determine the presence of strut tissue coverage in AMA-BRS, the thickness of the endoluminal bright border in 300 frames from 10 scaffolds struts located close to 12 o’clock position were measured. The threshold for coverage was 30 μm that corresponds to the average interobserver measurement of the endoluminal bright border of the strut (Figure 2A). Our results were similar to previously reported in BVS,12 therefore we decided to set the same threshold for both devices. Evaluated struts were assigned to 1 of the 3 following categories: covered with complete interstrut neoinitma (embedded), covered without complete interstrut neointima (protruding covered), and struts without evidence of coverage (uncovered; Figure 2B).

Figure 2.
Figure 2.

Evaluation of strut coverage using optical coherence tomography. A, The struts are classified as covered in the presence of a coverage thickness ≥30 μm for both Amaranth Medical (AMA) and bioresorbable vascular scaffold (BVS) scaffold struts. B, Evaluated struts were assigned to 1 of the 3 categories: embedded, protruding covered, and uncovered. BRS indicates bioresorbable scaffold.

Histological Analysis

An independent pathology laboratory (Alizee Pathology, LLC Thurmont, MD) conducted the histomorphometric analysis. All vessel segments were cut twice serially at ≈5 µm and stained with hematoxylin and eosin and elastin trichrome. The cross-sectional areas, including the external elastic lamina, the internal elastic lamina, and lumen area of each section, were measured. The neointimal thickness was measured and defined as the distance from the inner surface of the each strut to the luminal border. Neointimal area was defined as the difference of internal elastic lamina area minus lumen area. Percentage area of stenosis=[1−(lumen area/internal elastic lamina area)]×100. Vessel injury score was scored according to the method by Schwartz et al.13 Neointimal inflammation (0–4) and fibrin deposition (0–3) were semiquantitatively scored for each section as previously described.14 The neointima maturity was evaluated under the following semiquantitative score: 0=not present; 1=light dispersed smooth muscle population; 2=heavier population throughout less than the entire thickness of the neointima; and 3=dense population throughout the entire thickness of the neointima.

Statistical Analyses

Statistical analyses were performed using SAS statistical software (version 9.4; SAS Institute Inc, Cary, NC). Continuous variables were expressed as mean±SD with the median and interquartile range used for variables with non-normal distributions. A mixed model compared differences between the 2 treatments (AMA-BRS versus BVS) while accounting for dependent observation over time. Furthermore, this model contained a random effect to account for multiple scaffolds implanted in the same pig. The devices (AMA-BRS versus BVS), time (28, 90, and 180 days), and interaction between time and device were modeled as fixed effects. Scheffe post hoc test was applied to compare differences between time points and differences between treatments at each time point. A nonparametric test was used for those dependent variables with non-normal distributions. All tests were 2-tailed with a type I error held at 0.05.

Results

In Vitro Overexpansion and Cyclic Fatigue Study

In static conditions, none of the BRS devices tested presented signs of strut fracture when overexpanded at 0.5 mm above nominal pressure (≈17% overexpansion). However, in the BVS group, fracture occurred when expanded at ≈1.0 mm above nominal diameter (33% [33, 35] overexpansion); when expanded to the fracture point, 10.0 (6.0–11.5) fractures were observed. In contrast, no fractures were seen on the AMA-BRS group at 48% overexpansion (1.3 mm above nominal). In the AMA-BRS group, fractures did not occur until further dilatation up to 91% (78, 107) overexpansion (Figure 1A); 1.0 (1.0–1.5) fractures were observed on reaching the fracture point. Under accelerated cycle testing (dynamic conditions), the number of fractures progressively increased over time (at 21 K cycles=20.0 [19.5–20.5] in BVS versus 4.0 [3.0–4.3] in AMA-BRS; Figure 1B).

In Vivo Porcine Healing Study

Quantitative Coronary Angiography Analysis

At the time of device implantation, both BRSs were expanded to the calculated balloon-to-artery ratio and were angiographically apposed to the vessel wall. No post-dilatation was necessary in any of the implanted scaffolds. The mean balloon-to-artery ratios were comparable between AMA-BRS and BVS (1.16±0.11 versus 1.12±0.10; P=0.11). There were no differences in the post-implant minimum lumen diameter (AMA-BRS=2.93±0.28 mm versus BVS=2.96±0.45 mm; P=0.78) or reference vessel diameter (AMA-BRS=2.92±0.32 mm versus BVS=3.11±0.46 mm; P=0.10) between 2 devices. Post-implantation absolute (AMA-BRS=0.17±0.10 mm versus BVS=0.11±0.16 mm; P=0.24) and percent (AMA-BRS=4.9±6.3% versus BVS=3.1±5.2%; P=0.24) recoil rates were comparable between AMA-BRS and BVS. At 1 month, the AMA-BRS showed lower percent diameter of stenosis (AMA-BRS=12.0±8.7% versus BVS=26.8±12.2%; P=0.03) and late lumen loss compared with BVS (AMA-BRS=0.50±0.14 mm versus BVS=0.97±0.49 mm; P=0.02). There were no significant differences in any of the angiographic variables between both devices at 3 and 6 months (Table 1).

View this table:
Table 1.

Angiographic Data

In Vivo OCT Coronary Healing Analysis

Short-term OCT analysis was performed weakly for the first month to assess biomechanical behavior and short-term strut healing response (Figure 3A). The percentage of embedded struts was significantly higher at 14 days in the AMA-BRS group (AMA-BRS=71.0% [47.6, 89.1] versus BVS=40.3% [20.5, 63.2]; P=0.01; Figure 3B). Conversely, the presence of uncovered struts was more commonly seen in BVS at 7 days (25.9% [19.9, 43.3]) and persisted up to 21 days (3.8% [2.1, 10.2]; Figure 3C and 3D).

Figure 3.
Figure 3.

Comparison of serial optical coherence tomography variables at 7 to 28 d follow-up between Amaranth Medical (AMA)-bioresorbable scaffold (BRS) and bioresorbable vascular scaffold (BVS). There was higher percentage of embedded struts at 14 d in the AMA group while more uncovered struts were observed in the BVS group at 7 and 21 d. Variables are expressed as median (25th–75th percentile).

OCT evaluation at 1, 3, and 6 months indicated that the scaffold area did not significantly change in neither devices at any time point though BVS displayed significant higher late absolute recoil and percent recoil rates compared with AMA-BRS at 1 (AMA-BRS=0.80% [−5.00%, 4.00%] versus BVS=2.00% [−2.35%, 7.15%]; P=0.04) and 3 months (AMA-BRS=−0.30% [−6.00%, 2.25%] versus BVS=8.00% [−5.90%, 9.20%]; P=0.04; Figure 4). There was only 1 case in the BVS group showing discontinuities, stacked struts, and intraluminal strut protrusion 1 month after device implantation. Such discontinuities were present in the mid to distal sections of the scaffold at 1 month and extended to the proximal segment at 3-month follow-up.

Figure 4.
Figure 4.

Optical coherence tomography (OCT) analysis indicated that the lumen area, scaffold area, neointimal thickness, and area stenosis were similar between 2 groups; however, the bioresorbable vascular scaffold (BVS) had higher late percent recoil than Amaranth Medical (AMA)-bioresorbable scaffold (BRS) at 1- and 3-mo follow-up. Values are expressed as mean±SD or median (25th–75th percentile).

Histological Analysis

A summary of the histomorphometric analysis is shown in Table 2. Light microscopic assessment revealed that vascular responses to AMA-BRS were comparable with those to BVS at all time points (Figure 5). Neither AMA-BRS nor BVS showed evidence of luminal thrombosis of either the main or the side branch of coronary arteries. There was 1 case on the BVS group that showed strut discontinuities present at the proximal and distal sections at 3 months. Morphometric analysis showed no changes in internal elastic lamina or external elastic lamina area for both devices from 1 to 6 months. However, the AMA-BRS group showed less neointimal thickness, neointimal area, and percent area stenosis than BVS at 1 month (Table 2). The inflammatory scores were minimal to mild in both groups at all time points (Figure 6). Peri-strut inflammation was mostly composed of eosinophils, lymphocytes, histiocytes, and occasional foreign body giant cells oriented surrounding struts and within the media/adventitia. Foreign body giant cells lining the edges of scaffold struts were seen in both device groups; the number of these cells was small and did not meet the threshold level for peri-strut–associated inflammation. Injury scores were low for both devices, and no significant differences were seen in any of the tested time points. The neointima was described as immature with variable amounts of fibrin deposition (AMA-BRS=1.17 [1.00–1.42] versus BVS=1.50 [1.33–1.79]; P=0.73) at 1 month for both devices. At 3 months, there was no fibrin deposition in AMA-BRS group while small deposits of fibrin was observed in BVS group (0.33 [0.00, 0.69]; P=0.001; Table 2). At 6 months, all struts were covered by mature neointima, and no fibrin deposition or fibrin thrombi was found.

View this table:
Table 2.

Histological Data

Figure 5.
Figure 5.

Representative matched histological and optical coherence tomographic images of the Amaranth Medical (AMA)-bioresorbable scaffold (BRS) and bioresorbable vascular scaffold (BVS) in porcine coronary arteries at 1, 3, and 6 months after implantation.

Figure 6.
Figure 6.

Histological images (haematoxylin and eosin) show none to minimal inflammatory response around the scaffold struts (solid arrow). The neointima was immature with variable amounts of fibrin deposition (solid arrowhead) at 1 mo; by 3 mo, the neointima was much more mature and rarely contained small deposits of fibrin. AMA indicates Amaranth Medical; BRS, bioresorbable scaffold; and BVS, bioresorbable vascular scaffold.

Discussion

In this study, we aimed to evaluate the biomechanical properties and in vivo healing response of a novel thinned wall ultrahigh molecular weight amorphous PLLA BRS compared with the commercially available BVS. The major comparative findings of this study in regards to the AMA-BRS are (1) a higher (≈58%) acute overexpansion capacity and mechanical strength of the scaffold under stress conditions; (2) no in vivo scaffold recoil over time; (3) favorable inhibition of neointimal proliferation with superior strut coverage at early follow-up; and (4) comparable longer term healing and inflammatory responses as compared with BVS.

In current generation BVS, polymer crystallinity and strut thickness determine mechanical strength of the device. In turn, polymer crystallinity is a result of polymer’s molecular weight and manufacturing process of the polymeric tube. Current generation BRS has achieved an acute biomechanical performance comparable to metallic stents but at expenses of increasing strut’s dimension. Also, because of their inherent crystalline backbone structure, they display limited overexpansion capabilities.4

Decreasing wall thickness has been a challenging technological goal in the field of BRS technologies. New generation PLLA promise to improve the biomechanical properties of current generation devices. These polymers have been designed to improve the biomechanical behavior of PLLA by largely depending on the intrinsic material properties instead of purely polymer crystallinity. In this study, we demonstrated that ultrahigh molecular weight amorphous polymers dramatically improved resistance to fracture under static and dynamic conditions. In the bench study, the thin-walled (115 µm) AMA-BRS was effectively overexpanded up to 48% without evidence of mechanical failure. Also, the in vivo analysis demonstrated that the scaffold structure was better maintained overtime compared with BVS. These differences are critically important in clinical situations in which BRS overexpansion is clinically indicated (ie, side branch access).

One of the main challenges of BRS has been their limited ability to resist vessel recoil over time and under extreme loading conditions. Although clinically available BRS display acute radial forces comparable to metallic stents right after deployment, their ability to maintain lumen stability under specific biological conditions (ie, calcium) has been questioned.15 Optimal BRS design should ensure not only proper acute lumen gain but also preserve lumen patency as the vessel heals. Early clinical reports suggest that early scaffold dismantling resulting in intraluminal strut protrusion may be responsible for target vessel failures and scaffold thrombosis.16 In this study, there was only 1 case in the BVS group showing these rare findings of BRS failure, including strut discontinuities, leading to overlaid struts and intraluminal strut protrusion observed by OCT as early as 1 month and confirmed by histological evaluation. Finally, post-implantation acute scaffold recoil was comparable between AMA-BRS and BVS. In the AMA-BRS group, there was no scaffold area decrease at 6-month follow-up. Conversely, the BVS group displayed slightly higher late absolute and percent recoil rates at 1 and 3 months (Figure 4). Then, both ex vivo and in vivo results demonstrate that the BRS tested here showed not only superior periprocedural mechanical performance but also long-term architectural stability compared with BVS.

The optimal polymer resorption time length remains a topic of an ongoing debate. Clinical data suggest that rapid polymer resorption reduces radial force of the scaffold prematurely, potentially leading to late recoil and adverse clinical events.17 Moreover, in the clinical setting, a longer resorption period (6–9 months) may provide a more stable device dismantling process and better clinical outcomes. Ex vivo and in vivo degradation studies have shown that the device tested in this study maintains radial force for ≈8 to 10 months at which time the molecular weight is reduced by ≈50%. Also, because of the particular polymer characteristics of this device, the radial force values displayed over time were maintained at a significantly higher level compared with BVS. The mechanical limitations of all BRS have been partly compensated by increasing the scaffolds’ wall thickness and total surface area (26%–32% in BVS).18 It is expected that for devices using typical PLLA, the total surface area will increase aiming to compensate losses in radial strength. Conversely, the AMA-BRS technology has been able to miniaturize the scaffold’s wall thickness to the sub-100-micron without compromising the total vessel coverage area (21%–25%) in all devices ranges (2.50–3.50-mm).

The impact of strut thickness on stent’s surface coverage and healing has been well described.19 Several nonclinical and clinical studies suggest that BVS’ strut thickness may be associated with adverse clinical events. There is evidence that current wall thickness and geometric configuration induce laminar flow disruption20 and low shear stress regions around the struts’ area.21 Randomized controlled studies have demonstrated that in patients with stable coronary artery disease, Absorb BVS showed similar clinical outcomes as compared with Xience everolimus-eluting stent.2,3 However, a patient-level, pooled meta-analysis indicated that target vessel-related myocardial infarction was increased with BVS compared with everolimus-eluting stent due, in part, to nonsignificant increases in periprocedural myocardial infarction and late device thrombosis with BVS.22

As it happened in the drug-eluting stent field, it is expected that the scaffold thrombosis rates will decrease as the technology evolves and strut thickness decreases. An important objective of this study was the evaluation of the impact of strut thickness on early vascular healing by using OCT analysis on weekly basis over the first month. Our results showed that the thinned wall sirolimus-eluting AMA-BRS demonstrated favorable inhibition of neointimal proliferation with superior strut coverage in early phase of vessel healing compared with BVS. By OCT analysis, the AMA-BRS showed higher percentage of embedded struts (AMA-BRS=71.0% [47.6, 89.1] versus BVS=40.3% [20.5, 63.2]; P=0.01) at 14 days, whereas quantitative coronary angiography analysis and histopathology revealed less neointimal proliferation at 1 month. There was comparable injury and peri-strut inflammation responses between both devices at all time points. Similarly, small peri-strut fibrin deposits were initially observed in both BRS groups peaking at 1 month and rapidly decreasing to complete absorption at 3 months (Table 2). In general, the neointima was thin, immature, and encapsulated the peri-strut fibrin deposits in both BRS groups at 1 month. After that time point, drug releases slows down leading to fibrin deposit absorption, progressive neointimal maturation, and endothelial cell coverage.

The present study has some limitations that are important to discuss. First, the study was performed in healthy coronary arteries in the swine model of restenosis. All scaffolds were implanted in the main coronary artery segments avoiding large side branches (>2.0 mm). Therefore, although our data support the safety and biocompatibility of the device, our findings cannot predict the long-term biomechanical behavior among patients with high atherosclerotic burden. However, in vitro, animal, and First-in-Human post-deployment OCT data suggest that the BRS tested in this study displays an acute biomechanical behavior comparable to metallic stents. The long-term biomechanical behavior of this device is currently under evaluation in a multicenter First-in-Human clinical investigation. Finally, although the 6-month follow-up period presented in this study is sufficient to test the performance and safety of the device,23 a longer follow-up period is required to evaluate the impact of polymer resorption on vascular healing and remodeling. However, because of the similarities in sirolimus pharmacokinetics9 and superior mechanical performance of the AMA-BRS, the long-term results are not expected to be inferior compared with what has been already been published with BVS.

In conclusion, our data indicate that the novel thin strut sirolimus-eluting AMA-BRS used in the present study demonstrated enhanced biomechanical performance and favorable inhibition of neointimal proliferation with superior strut coverage to Absorb at early follow-up, maintaining vessel lumen stability during the 6-month follow-up period. Our study contributes to the BRS literature as introduces a novel thin-walled polymeric BRS platform and tests its biomechanical performance and vascular biocompatibility against a clinically available BRS control. These findings are also relevant because the enrollment and 9-month imaging follow-up of the multicenter RENASCENT-II trial (Restoring Endolumical Narrowing Using Bioresorbable Scaffolds–Extended Trial) using the APTITUDE scaffold have been already completed, and up to date, no major periprocedural complications have been reported (Granada JF, MD, TCT 2016). Finally, our findings suggest that the novel BRS tested in this study has the potential to improve the performance of current generation BRS by providing a highly biocompatible and mechanically durable platform with miniaturize the strut thickness.

Sources of Funding

This study was funded by Amaranth Medical, Inc.

Disclosures

Authors E.A. Estrada, K. Ramzipoor, C. Lee, and D. Dokko are employees of Amaranth Medical, Inc (Mountain View, CA). J.F. Granada is a scientific advisor of Amaranth Medical, Inc. The other authors report no conflicts.

  • Received February 10, 2017.
  • Accepted June 12, 2017.

References

  1. 1.↵
    1. Otsuka F,
    2. Pacheco E,
    3. Perkins LE,
    4. Lane JP,
    5. Wang Q,
    6. Kamberi M,
    7. Frie M,
    8. Wang J,
    9. Sakakura K,
    10. Yahagi K,
    11. Ladich E,
    12. Rapoza RJ,
    13. Kolodgie FD,
    14. Virmani R
    . Long-term safety of an everolimus-eluting bioresorbable vascular scaffold and the cobalt-chromium XIENCE V stent in a porcine coronary artery model. Circ Cardiovasc Interv. 2014;7:330–342. doi: 10.1161/CIRCINTERVENTIONS.113.000990.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Ellis SG,
    2. Kereiakes DJ,
    3. Metzger DC,
    4. Caputo RP,
    5. Rizik DG,
    6. Teirstein PS,
    7. Litt MR,
    8. Kini A,
    9. Kabour A,
    10. Marx SO,
    11. Popma JJ,
    12. McGreevy R,
    13. Zhang Z,
    14. Simonton C,
    15. Stone GW
    ; ABSORB III Investigators. Everolimus-eluting bioresorbable scaffolds for coronary artery disease. N Engl J Med. 2015;373:1905–1915. doi: 10.1056/NEJMoa1509038.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Serruys PW,
    2. Chevalier B,
    3. Dudek D,
    4. Cequier A,
    5. Carrié D,
    6. Iniguez A,
    7. Dominici M,
    8. van der Schaaf RJ,
    9. Haude M,
    10. Wasungu L,
    11. Veldhof S,
    12. Peng L,
    13. Staehr P,
    14. Grundeken MJ,
    15. Ishibashi Y,
    16. Garcia-Garcia HM,
    17. Onuma Y
    . A bioresorbable everolimus-eluting scaffold versus a metallic everolimus-eluting stent for ischaemic heart disease caused by de-novo native coronary artery lesions (ABSORB II): an interim 1-year analysis of clinical and procedural secondary outcomes from a randomised controlled trial. Lancet. 2015;385:43–54. doi: 10.1016/S0140-6736(14)61455-0.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Foin N,
    2. Lee R,
    3. Mattesini A,
    4. Caiazzo G,
    5. Fabris E,
    6. Kilic D,
    7. Chan JN,
    8. Huang Y,
    9. Venkatraman SS,
    10. Di Mario C,
    11. Wong P,
    12. Nef H
    . Bioabsorbable vascular scaffold overexpansion: insights from in vitro post-expansion experiments. EuroIntervention. 2016;11:1389–1399. doi: 10.4244/EIJY15M07_02.
    OpenUrlPubMed
  5. 5.↵
    1. Stone GW,
    2. Granada JF
    . Very late thrombosis after bioresorbable scaffolds: cause for concern? J Am Coll Cardiol. 2015;66:1915–1917. doi: 10.1016/j.jacc.2015.08.863.
    OpenUrlFREE Full Text
  6. 6.↵
    1. Felix C,
    2. Everaert B,
    3. Jepson N,
    4. Tamburino C,
    5. van Geuns RJ
    . Treatment of bioresorbable scaffold failure. EuroIntervention. 2015;11(suppl V):V175–V180. doi: 10.4244/EIJV11SVA42.
    OpenUrl
  7. 7.↵
    1. Capodanno D,
    2. Joner M,
    3. Zimarino M
    . What about the risk of thrombosis with bioresorbable scaffolds? EuroIntervention. 2015;11(suppl V):V181–V184. doi: 10.4244/EIJV11SVA43.
    OpenUrlPubMed
  8. 8.↵
    1. Vahl TP,
    2. Gasior P,
    3. Gongora CA,
    4. Ramzipoor K,
    5. Lee C,
    6. Cheng Y,
    7. McGregor J,
    8. Shibuya M,
    9. Estrada EA,
    10. Conditt GB,
    11. Kaluza GL,
    12. Granada JF
    . Four-year polymer biocompatibility and vascular healing profile of a novel ultrahigh molecular weight amorphous PLLA bioresorbable vascular scaffold: an OCT study in healthy porcine coronary arteries. EuroIntervention. 2016;12:1510–1518. doi: 10.4244/EIJ-D-16-00308.
    OpenUrl
  9. 9.↵
    1. Cheng Y,
    2. Gasior P,
    3. Shibuya M,
    4. Ramzipoor K,
    5. Lee C,
    6. Estrada EA,
    7. Dokko D,
    8. McGregor JC,
    9. Conditt GB,
    10. Kaluza GL,
    11. Granada JF
    . Comparative characterization of biomechanical behavior and healing profile of a novel ultra-high-molecular-weight amorphous poly-l-lactic acid sirolimus-eluting bioresorbable coronary scaffold. Circ Cardiovasc Interv. 2016;9:e004253. doi: 10.1161/CIRCINTERVENTIONS.116.004253.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. Onuma Y,
    2. Serruys PW,
    3. Gomez J,
    4. de Bruyne B,
    5. Dudek D,
    6. Thuesen L,
    7. Smits P,
    8. Chevalier B,
    9. McClean D,
    10. Koolen J,
    11. Windecker S,
    12. Whitbourn R,
    13. Meredith I,
    14. Garcia-Garcia H,
    15. Ormiston JA
    ; ABSORB Cohort A and B Investigators. Comparison of in vivo acute stent recoil between the bioresorbable everolimus-eluting coronary scaffolds (revision 1.0 and 1.1) and the metallic everolimus-eluting stent. Catheter Cardiovasc Interv. 2011;78:3–12. doi: 10.1002/ccd.22864.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Gomez-Lara J,
    2. Brugaletta S,
    3. Diletti R,
    4. Garg S,
    5. Onuma Y,
    6. Gogas BD,
    7. van Geuns RJ,
    8. Dorange C,
    9. Veldhof S,
    10. Rapoza R,
    11. Whitbourn R,
    12. Windecker S,
    13. Garcia-Garcia HM,
    14. Regar E,
    15. Serruys PW
    . A comparative assessment by optical coherence tomography of the performance of the first and second generation of the everolimus-eluting bioresorbable vascular scaffolds. Eur Heart J. 2011;32:294–304. doi: 10.1093/eurheartj/ehq458.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Nakatani S,
    2. Sotomi Y,
    3. Ishibashi Y,
    4. Grundeken MJ,
    5. Tateishi H,
    6. Tenekecioglu E,
    7. Zeng Y,
    8. Suwannasom P,
    9. Regar E,
    10. Radu MD,
    11. Räber L,
    12. Bezerra H,
    13. Costa MA,
    14. Fitzgerald P,
    15. Prati F,
    16. Costa RA,
    17. Dijkstra J,
    18. Kimura T,
    19. Kozuma K,
    20. Tanabe K,
    21. Akasaka T,
    22. Di Mario C,
    23. Serruys PW,
    24. Onuma Y
    . Comparative analysis method of permanent metallic stents (XIENCE) and bioresorbable poly-L-lactic (PLLA) scaffolds (Absorb) on optical coherence tomography at baseline and follow-up. EuroIntervention. 2016;12:1498–1509. doi: 10.4244/EIJY15M10_03.
    OpenUrl
  13. 13.↵
    1. Schwartz RS,
    2. Huber KC,
    3. Murphy JG,
    4. Edwards WD,
    5. Camrud AR,
    6. Vlietstra RE,
    7. Holmes DR
    . Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol. 1992;19:267–274.
    OpenUrlFREE Full Text
  14. 14.↵
    1. Kornowski R,
    2. Hong MK,
    3. Tio FO,
    4. Bramwell O,
    5. Wu H,
    6. Leon MB
    . In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol. 1998;31:224–230.
    OpenUrlFREE Full Text
  15. 15.↵
    1. Vetrovec GW,
    2. Rizik D,
    3. Williard C,
    4. Snead D,
    5. Piotrovski V,
    6. Kopia G
    . Sirolimus PK trial: a pharmacokinetic study of the sirolimus-eluting Bx velocity stent in patients with de novo coronary lesions. Catheter Cardiovasc Interv. 2006;67:32–37. doi: 10.1002/ccd.20565.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Azzalini L,
    2. L’Allier PL
    . Bioresorbable vascular scaffold thrombosis in an all-comer patient population: single-center experience. J Invasive Cardiol. 2015;27:85–92.
    OpenUrlPubMed
  17. 17.↵
    1. Tanimoto S,
    2. Bruining N,
    3. van Domburg RT,
    4. Rotger D,
    5. Radeva P,
    6. Ligthart JM,
    7. Serruys PW
    . Late stent recoil of the bioabsorbable everolimus-eluting coronary stent and its relationship with plaque morphology. J Am Coll Cardiol. 2008;52:1616–1620. doi: 10.1016/j.jacc.2008.08.024.
    OpenUrlFREE Full Text
  18. 18.↵
    1. Kawamoto H,
    2. Panoulas VF,
    3. Sato K,
    4. Miyazaki T,
    5. Naganuma T,
    6. Sticchi A,
    7. Figini F,
    8. Latib A,
    9. Chieffo A,
    10. Carlino M,
    11. Montorfano M,
    12. Colombo A
    . Impact of strut width in periprocedural myocardial infarction: a propensity-matched comparison between bioresorbable scaffolds and the first-generation sirolimus-eluting stent. JACC Cardiovasc Interv. 2015;8:900–909. doi: 10.1016/j.jcin.2015.02.011.
    OpenUrlCrossRef
  19. 19.↵
    1. Koskinas KC,
    2. Chatzizisis YS,
    3. Antoniadis AP,
    4. Giannoglou GD
    . Role of endothelial shear stress in stent restenosis and thrombosis: pathophysiologic mechanisms and implications for clinical translation. J Am Coll Cardiol. 2012;59:1337–1349. doi: 10.1016/j.jacc.2011.10.903.
    OpenUrlFREE Full Text
  20. 20.↵
    1. Dörler J,
    2. Frick M,
    3. Hilber M,
    4. Breitfuss H,
    5. Abdel-Hadi MN,
    6. Pachinger O,
    7. Liepsch D,
    8. Schwarzacher SP
    . Coronary stents cause high velocity fluctuation with a flow acceleration and flow reduction in jailed branches: an in vitro study using laser-Doppler anemometry. Biorheology. 2012;49:329–340. doi: 10.3233/BIR-2012-0617.
    OpenUrl
  21. 21.↵
    1. Gogas BD,
    2. King SB 3rd.,
    3. Timmins LH,
    4. Passerini T,
    5. Piccinelli M,
    6. Veneziani A,
    7. Kim S,
    8. Molony DS,
    9. Giddens DP,
    10. Serruys PW,
    11. Samady H
    . Biomechanical assessment of fully bioresorbable devices. JACC Cardiovasc Interv. 2013;6:760–761. doi: 10.1016/j.jcin.2013.04.008.
    OpenUrlFREE Full Text
  22. 22.↵
    1. Stone GW,
    2. Gao R,
    3. Kimura T,
    4. Kereiakes DJ,
    5. Ellis SG,
    6. Onuma Y,
    7. Cheong WF,
    8. Jones-McMeans J,
    9. Su X,
    10. Zhang Z,
    11. Serruys PW
    . 1-year outcomes with the Absorb bioresorbable scaffold in patients with coronary artery disease: a patient-level, pooled meta-analysis. Lancet. 2016;387:1277–1289. doi: 10.1016/S0140-6736(15)01039-9.
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Schwartz RS,
    2. Edelman ER,
    3. Carter A,
    4. Chronos N,
    5. Rogers C,
    6. Robinson KA,
    7. Waksman R,
    8. Weinberger J,
    9. Wilensky RL,
    10. Jensen DN,
    11. Zuckerman BD,
    12. Virmani R
    ; Consensus Committee. Drug-eluting stents in preclinical studies: recommended evaluation from a consensus group. Circulation. 2002;106:1867–1873.
    OpenUrlFREE Full Text
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  • Comparative Biomechanical Behavior and Healing Profile of a Novel Thinned Wall Ultrahigh Molecular Weight Amorphous Poly-l-Lactic Acid Sirolimus-Eluting Bioresorbable Coronary Scaffold
    Yanping Cheng, Pawel Gasior, Jing-Gang Xia, Kamal Ramzipoor, Chang Lee, Edward A. Estrada, Daniell Dokko, Jenn C. McGregor, Gerard B. Conditt, Thomas McAndrew, Greg L. Kaluza and Juan F. Granada
    Circulation: Cardiovascular Interventions. 2017;10:e005116, originally published July 12, 2017
    https://doi.org/10.1161/CIRCINTERVENTIONS.117.005116
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