Endovascular abdominal aortic aneurysm sealing: A systematic review of early outcomes

Abstract

Objectives

There has been a clear move towards endovascular repair of abdominal aortic aneurysms owing to better peri-operative outcomes compared with open surgical repair. However, follow-up has continued to reveal relatively high rates of endoleaks and re-interventions. Improvements in endovascular stent-grafts aim to decrease these complications. This systematic review aims to determine the early outcomes of abdominal aortic aneurysm sealing.

Methods

Standard PRISMA guidelines were followed. A literature search was performed with the aim to extract any publication related to the endovascular aneurysm sealing device.

Results

The total number of patients in this systematic review of 11 studies is 684, with a mean age of 73.2 years, and 587 (88.0%) males. The majority were undergoing elective procedures (n = 606, 91.0%), the remainder as emergencies (n = 30, 4.5% as ruptures, n = 30, 4.5% as symptomatic). Technical success rate including emergency cases was 99.1%. Thirty-day mortality rate was 2.6% (n = 17) including all cases, and 1.0% (n = 6) including elective cases only. Thirty -day endoleak detection rate was 4.7% (n = 31) including all cases, and 4.8% (n = 29) including elective cases only. Thirty-day aneurysm-related re-intervention rate was 5.7% (n = 38) including all cases, and 4.6% (n = 28) including elective cases only. There was no conversion to open surgery within 30 days post-op in the elective cases. There were three delayed conversions to open surgery within 30 days and one report of stent migration causing rupture in the emergency setting.

Conclusions

This novel endovascular aneurysm-sealing device for abdominal aortic aneurysm repair has shown respectable early outcomes. Good technical success rates, in both elective and emergency settings, low rates of all-type endoleaks and low re-intervention rates have all been demonstrated. It is proving to be a safe alternative to open and endovascular aneurysm repair; however, longer term follow-up results are needed to assess the safety and effectiveness of the device in the long term.

Keywords

Aneurysm EVAR EVAS Nellix

Introduction

Endovascular aneurysm repair (EVAR) is the gold standard treatment for abdominal aortic aneurysms (AAAs), due to the improved 30-day mortality.¹ A major caveat to this is anatomical suitability, as use of stent-grafts outside of the manufacturers’ instructions for use (IFU) can increase complication rates;² however, in an increasingly elderly population with multiple comorbidities, open AAA repair may not be appropriate. Stent-grafts have therefore been developed to treat differing aortic anatomy, outside of conventional IFU guidelines, e.g. with shorter aneurysm necks and increased angulation, to minimize endoleak rates.

The endovascular aneurysm sealing (EVAS) system is a novel device for AAA repair. The device aims to eliminate the aneurysm sac with the use of polymer-filled endobags which surround balloon–expandable stents to form a complete luminal seal. The device is currently being used in global vascular centers (having just reached the 5000 devices deployed mark) predominantly in the elective setting but also moving into emergency repair. Long-term outcomes are yet to be documented for EVAS; however, several recent publications have documented short-term outcomes following use of the endovascular sealing technique.^3–13 This systematic review of the available evidence aims to assess the technical success of EVAS and its early complications.

The aim of this systematic review and meta-cohort is to explore and analyze the short-term outcomes associated with the EVAS device in AAA repair, including technical success (defined as successful stent-graft placement resulting in complete sealing with no endoleak and without the need of conversion to open surgery), mortality, morbidity, endoleaks, open conversion rate and re-intervention rate.

Methods

The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 (PRISMA-P)¹⁴ guidelines were followed.

Literature search

A literature search was performed with the aim to extract any publication related to the EVAS device. A MEDLINE, Embase and Health and Psychosocial Instruments database search was performed on the 4th of April 2016 using Ovid online and repeated on the 21st of June 2016 separately by two researchers. The search included all studies relating to either “Nellix” or “EVAS.” Relevant papers were also searched for through manual reviewing of selected paper’s reference lists.

Study selection

All studies looking at EVAS were reviewed. Exclusions included in-vitro studies, case presentations, letters and commentaries and studies looking at alternative outcomes. Of those that were deemed relevant, two independent reviewers collected data from each paper looking at publication year, country of origin, number of patients, age, gender, aneurysm size and location, urgency of operation, study design, technical success, mortality, morbidity, endoleaks, graft occlusion, conversion rate, re-intervention and mean follow-up.

Statistical analysis

Data were interpreted as whole numbers and percentage. As no comparative data has been published, a formal meta-analysis was not possible.

Results

Literature search

The literature search returned 446 abstracts (Figure 1). After taking into account duplicates at an early stage, 362 abstracts remained, which were reviewed. In all, 350 articles were excluded due to non-relevant outcomes to this study, case reports, letters, conference abstracts or commentaries. It was not possible to get hold of one study.¹⁵ A total of 11 studies were included.^3–13

Figure 1.

PRISMA diagram for the systematic review.

Study selection

A total of four studies^3,4,9,11 were retrospective cohort studies, two of which were reviews from multiple centers,^3,4 and seven studies^{5–8,10,12,13} were prospective cohort studies, of which three were from multiple centers.^5,7,10 The 11 studies were published between 2011 and 2016 (Table 1).

Table 1.

Patient and study characteristics for all studies.

			Urgency of procedure				Aneurysm characteristics
Study	Number of patients	Country	Elective n (%)	Emergency n (%)	Rupture n (%)	Male (%)	Mean aneurysm size in mm	Infrarenal n (%)	Juxtarenal n (%)
Böckler et al.⁴	171	Europe, New Zealand	169 (99)	0 (0)	2 (1)	90	61	157 (92)	14 (8)
Boersen et al.⁸	27	Netherlands	27 (100)	0 (0)	0 (0)	93	55	27 (100)	0 (0)
Brownrigg et al.⁶	105	England	105 (100)	0 (0)	0 (0)	88	61	105 (100)	0 (0)
Carpenter et al.¹⁰	150	Worldwide	150 (100)	0 (0)	0 (0)	95	58	150 (100)	0 (0)
Donayre et al.⁵	21	Venezuela, Colombia, New Zealand, Latvia	21 (100)	0 (0)	0 (0)	90	57	21 (100)	0 (0)
England et al.¹³	18	UK	18 (100)	0 (0)	0 (0)	NS	57	18 (100)	0 (0)
Kīsis et al.¹²	20	Latvia	20 (100)	0 (0)	0 (0)	85	60	Ns	Ns
Krievins et al.⁷	34	Venezuela, Colombia, New Zealand, Latvia	34 (100)	0 (0)	0 (0)	91	58	Ns	Ns
McWilliams et al.¹¹	30	England	30 (100)	0 (0)	0 (0)	63	58	30 (100)	0 (0)
Reijnen et al.³	58	Europe, New Zealand	0 (0)	30 (52)	28 (48)	79	70	Ns	Ns
Zerwes et al.⁹	50	Germany	50 (100)	0 (0)	0 (0)	86	56	50 (100)	0 (0)

Ns: Not specified.

The data are primarily from prospective and retrospective quantitative studies, with one qualitative cohort study. At present there are no randomized controlled trials looking at the EVAS technique. To ensure the quality of the non-randomized studies included in this review, the Newcastle-Ottawa scale was exercised. All studies scored 6/9 or greater.

Patient characteristics

The total number of patients included in this systematic review is 684 (studies range from 18 to 171 participants). The mean age of the patient population was 73.2 years. The proportion of male participants was 88.0% (n = 587/666; Table 2). Where specified, the majority of aneurysms were infrarenal (97.0%), with an overall mean aneurysm diameter of 59 mm. The individual study patient and aortic characteristics are summarized in Table 2. The EVAS device was most commonly used in the elective setting (n = 606, 91.0%); however, there were 60 patients that presented as an emergency (n = 60, 9.0%). Of the emergency patients, half had presented as a rupture (n = 30) and half were symptomatic (n = 30) (Tables 3 and 4).

Table 2.

Patient and aneurysmal characteristics.

Study	Number of patients	Male (%)	Age (mean ± SD)	Aneurysm diameter (mm ± SD)	Aortic neck length	Proximal neck diameter (mm ± SD)	Infrarenal neck angulation (degrees ± SD)	Maximum common iliac diameter (mm ± SD)
Böckler et al.⁴	171	153 (89.5)	74 ± 7	61 ± 9	28 ± 15	25 ± 5	37 ± 22	20 ± 9
Boersen et al.⁸	27	25 (92.6)	73 ± 5	54.8 (range 35–80)	Ns	24.1 (range 19.3–28)^a	36.3	58.9 (range 32–100)^b
Brownrigg et al.⁶	105	92 (87.6)	76 ± 8	61 (range 58–67)	22 (range 14–33)	27 (range 24–30)	42 (range 30–58)	Ns
Carpenter et al.¹⁰	150	142 (94.7)	72	58 ± 6.2	31 ± 14	25 ± 3	30 ± 14	20 ± 6^b
Donayre et al.⁵	21	19 (90.5)	69.7 ± 8.3	57 ± 7	24.9 ± 14.3	25.7 ± 3.7	39 ± 15	Ns
England et al.¹³	18	10 (55.6)	80 ± 7	57 ± 5	30 ± 16	Ns	Ns	Ns
Kīsis et al.¹²	20	Ns	71 ± 8	60 ± 7	NS	Ns	Ns	Ns
Krievins et al.⁷	34	31 (91.2)	71 ± 8	58 (range 43–76)	22.1 (range 5–50)	23.5 (range 17.5–31.0)	37.4 (range 9.1–72)	Ns
McWilliams et al.¹¹	30	19 (63.3)	79 (IQR 73–83)	58 (IQR 57–60)	Ns	Ns	Ns	Ns
Reijnen et al.³	58	46 (79.3)	74 ± 9	70.1 ± 14.9	18.7 ± 13.0	25.9 ± 6.5	36.5 ± 20.5	20.3 ± 12.5^b
Zerwes et al.⁹	50	43 (86.0)	72 ± 7	56.2 ± 7.2	28.3 ± 12.8	23.7 ± 3.9	17.6 ± 23.4	19.9 ± 8.0^b

Ns: Not specified; IQR: interquartile range.

Measurement 100 mm below lowermost renal artery.

Reported as left and right, with largest mean and range stated.

Table 3.

Thirty-day outcomes.

Study	30-day any endoleak	30-day occlusions	30-day stenosis	Aneurysm related re-intervention within 30 days	30-day mortality	Technical success^a %	Conversion to open	Stent migration
Böckler et al.⁴	14	8	5	11	2	98.8	0	0
Boersen et al.⁸	0	0	0	0	0	100.0	0	0
Brownrigg et al.⁶	4	0	3	7	1	100.0	0	0
Carpenter et al.¹⁰	9	0	0	4	1	100.0	0	0
Donayre et al.⁵	1	0	0	0	2	95.2	0	0
England et al.¹³	NS	NS	NS	NS	NS	NS	NS	5
Kīsis et al.¹²	1	0	0	0	1	100.0	0	0
Krievins et al.⁷	2	0	0	0	2	100.0	0	0
McWilliams et al.¹¹	0	0	0	0	1	100.0	0	0
Reijnen et al.³	4	0	0	10	12	96.6	2	1
Zerwes et al.⁹	2	3	0	6	2	98.0	0	0
Total	37 (5.6%)	11 (1.7%)	8 (1.2%)	38 (5.7%)	24 (3.6%)	98.9%	2 (0.3%)	6 (0.9%)

Complete sealing with no endoleak or conversion.

Table 4.

Type of endoleak.

Study	Type 1a	Type 1b	Type 1 – not specified	Type 2	Unknown	Total
Böckler et al.⁴	5	4	0	4	1	14
Boersen et al.⁸	0	0	0	0	0	0
Brownrigg et al.⁶	4	0	0	0	0	4
Carpenter et al.¹⁰	1	0	0	8	0	9
Donayre et al.⁵	1	0	0	0	0	1
Kīsis et al.¹²	0	0	1	0	0	1
Krievins et al.⁷	1	1	0	0	0	2
McWilliams et al.¹¹	0	0	0	0	0	0
Reijnen et al.³	3	1	0	0	0	4
Zerwes et al.⁹	1	0	0	1	0	2
Total	16	6	1	13	1	37

Follow-up

All studies reported 30-day outcomes. All 10 studies’ participants underwent CT scanning within 30 days post-operatively, with further follow-up imaging being either ultrasound or CT at variable time points.

Technical success

Technical success was defined as successful stent-graft placement resulting in complete sealing with no endoleak and without the need of conversion to open surgery at the time of EVAS deployment. Overall technical success for all 10 studies (including Reijnen et al.³) was reported in 660 (99.1%) patients.

Mortality

In total, 17 deaths occurred within the 30-day post-op period, providing a 30-day mortality rate of 2.6%. After exclusion of emergency cases, the 30-day mortality rate was 1.0% (n = 6/608). Causes of death are listed in Supplemental Table 1. Only one case was believed to be aneurysm related which was following secondary rupture due to migrating stents. This was the only case to have reported a migration of stent. Another possible aneurysm-related death involved a case of sepsis where the cause had not been identified and sepsis from the graft had not been excluded.

Endoleak

The total 30-day endoleak rate for all 10 studies was 4.7% (n = 31); 2.0% (n = 13) of endoleaks were classified as a Type Ia, 1.5% (n = 12) as a Type II, 0.6% (n = 4) as a Type 1b and 0.3% (n = 2) as not specified. After exclusion of the emergency cases the 30-day endoleak rate was 4.8% (n = 29/608).

Migration

A single study has reported stent migration in a small (18 patient) series.¹³ All migration in their series was caudal. This was from a single stent in four cases from and both stents in one case. The migration rate was therefore 27.8%; however, after 1 year follow-up no significant sequelae had occurred. In addition, a single study³ reported a single-stent migration following emergency EVAS, which led to a secondary rupture.

Morbidity

Two important causes of morbidity associated with stent-graft insertion include limb occlusions and stenosis. In total there were 10 (1.5%) graft occlusions and 6 (0.9%) grafts stenoses detected within 30 days follow-up. No cases of graft occlusion or stenosis occurred in the emergency cases of Reijnen et al.³ in the 30-day post-op period. Other morbidities are detailed in Supplemental Table 2.

Re-interventions

In total there were 38 (5.7%) aneurysm-related re-interventions within 30-days. If we were to exclude the paper by Reijnen, the 30-day aneurysm-related re-intervention rate would be 4.6% (n = 28/608). These are detailed further in Supplemental Table 3. The most common re-intervention within 30 days of operation was the management of an endoleak (n = 9, 1.4%). Type Ia endoleaks were treated with a mixture of embolization with ONYX and coils (or liquid agent) and the Type Ib endoleak was treated by inserting a covered stent.

Open conversion rate

In total two patients were converted to open repair within 48 hours of surgery – due to persistent hemodynamic instability. One patient passed away on table. The second patient had a Type Ia endoleak. Another case underwent planned open repair 14 days later for a ruptured mycotic aneurysm, which was bridged by EVAS. The above three cases were all emergency presentations and therefore no elective cases were converted to open surgery within 30 days.

Discussion

This systematic review has shown that the EVAS device is a good alternative to EVAR techniques and may be perceived as at least equivalent, with lower rates of endoleaks and aneurysm-related re-interventions within the 30-day period. It has also proven to be a safe device to use with a high technical success rate.

Mortality

EVAR at present is the preferred treatment over open AAA repair for the elderly and those with multiple co-morbidities. It has a lower 30-day mortality rate and shorter hospital stay. Thirty-day operative mortality outcomes for EVAR are 1.3%, compared to 4.7% for open repair.¹ Our systematic review for the EVAS technique demonstrated a 30-day mortality rate of 1.0% in elective cases and 2.6% when including emergency cases, which at this early stage shows that EVAS repair has similar mortality rates compared to EVAR.

Endoleak

One of the novel ideas behind the Nellix device is the filling of the aneurysm sac with polymer-filled bags, aiming to prevent Type II endoleaks occurring. In this study, only 12 patients suffered a Type II endoleak (1.8%) within 30 days post-op. A systematic review of 32 non-randomized retrospective studies with a total of 21,744 patients determined a 30-day post-op incidence of Type II endoleaks to be 10.2% (n = 1515) in those undergoing EVAR.¹⁶ Therefore, the results are promising showing the EVAS system could reduce the number of Type II endoleaks.

Device migration

Device migration is an issue that can arise for typical EVAR repair, making the sealing zone vulnerable and results in Type Ia endoleak. Data from the EVAR Trials¹⁷ report a rate of rupture following EVAR of 3.2%. One theory is that the Nellix device would have a lower risk of migration due to the endobags providing anatomical fixation in the aneurysm sac. This systematic review identified only one case of distal migration leading to a complication, and this was in a patient who had a ruptured AAA repair;³, however, the series by England et al.¹³ also identified a significant rate of distal migration albeit in a small series of patients, with relatively short follow up. Due to the paucity of data it is difficult to draw conclusions regarding migration.

EVAS in the emergency AAA presentation

Reijnen et al.³ demonstrated that the EVAS system can be used in the acute setting. The study itself quoted a figure of 32.0% 30-day mortality rate (95% CI 18–51%), which is comparable to a recent randomized controlled trial¹⁸ comparing outcomes in the ruptured setting of open or endovascular repair, showing a mortality rate of 35.4% in the EVAR group. Further data are however required in this area, with comparisons between local, regional and general anesthetic techniques and multicenter studies on ruptured EVAS.

Technical success

Technical success was achieved in all but six cases. Boerson et al.⁸ detected one patient with an intraoperative Type Ib endoleak successfully treated, and one Type II endoleak which remains under surveillance. Donayre et al.⁵ reported a Type Ib endoleak seen at the time of implantation, for which treatment was attempted with iliac extension in both limbs. Reijnen et al.³ reported two Type-1a endoleaks, one from a patient presenting with rupture, who required a return to theatre to treat the endoleak, and one patient was a symptomatic patient who was reported to have an early complication of a Type-1a endoleak requiring treatment with ONYX and coils. Zerwes et al.⁹ reported one case of partial aneurysm sac rupture and Type-Ia endoleak following filling of the endobags, secondary to an uncontrolled secondary fill. Carpenter et al.¹⁰ reported an intraoperative iatrogenic disruption of the aortic aneurysm during the pre-fill step (presumed due to dropping in the patient’s blood pressure as the prefill was evacuated). The procedure however was completed uneventfully and therefore not included as a technical failure.

Stent-graft occlusions and stenosis

The risk factors or causes for stent occlusion or stenosis have been reported as high body mass index (endograft limb thrombosis), a “shaggy” aorta, deployment technique and cases occurring at the beginning of the “learning curve.”⁶ Keeping the balloons inflated during the polymer cure to maximize the stent lumen and performing post-dilatation with angioplasty balloons is felt to reduce stent-graft occlusions and stenosis.⁶

Quality of studies and limitations

This systematic review has taken place but recognizes that the quality of the data needs improvement. The studies included are all relatively small in sample size, and some studies identified that their cohort of patients undergoing the EVAS technique were some of the first cases in their centre.^4–6,9,11 Subsequent techniques were refined with increasing volume load. Donayre et al.⁵ for example modified their procedure after an early mortality to decrease the aortic occlusion time by immediate deflation after full endoframe expansion, rather than throughout endobag inflation.

Many studies report a selection bias for cases undergoing EVAS repair; however, there has been no documented reason as to why patients were selected in particular to undergo EVAS repair rather than EVAR. One possibility may be those with complex anatomy not suitable for conventional repair and high risk for open repair underwent EVAS. Therefore, as these are small studies with limited EVAS experience, the morbidity and mortality rates as well as re-intervention rates may come down with increasing experience and familiarity with the device.

An alternative reason for low endoleak rates and high technical success is the difficulty of determining small endoleaks in the presence of endobags, thus leading to an underdiagnosis. With increasing experience in this technique one would expect detection rates to improve, and longer follow-up durations may yield a more accurate endoleak rate.

Possible duplicate data

Two studies, Krievins et al.⁷ and Donayre et al.⁵ were included in this systematic review; however, a potential overlap of participants was noted. Krievins et al.⁷ investigated the Nellix device in the context of favourable and adverse aneurysm anatomy, whereas Donayre et al.⁵ presented their results following their initial clinical experience with the EVAS system. Both studies were performed around the same time period at the same centers; one study had 34 patients⁷ and the other 21.⁵ There was no way of determining which patients were reported twice and so all were included in this review.

Conclusion

This novel endovascular aneurysm-sealing device for AAA repair has shown very good early outcomes with good technical success rates, in both elective and emergency settings, low rates of endoleaks and low re-intervention rate. One of the risks that remains is the possibility of rupturing the aortic sac during the filling of the endobags and as such caution must be taken to follow the manufacturers’ guidelines on fill pressures. More studies are needed with a larger sample size to observe long-term outcomes and look specifically at outcomes in those with adverse anatomy undergoing EVAS. A comparison of EVAR v EVAS in those with suitable anatomy for both procedures would be prudent.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Stather

Sidloff

Dattani

. Systematic review and meta-analysis of the early and late outcomes of open and endovascular repair of abdominal aortic aneurysm. Br J Surg 2013; 100: 863–872.

Stather

Wild

Choke

. Endovascular aortic aneurysm repair in patients with hostile neck anatomy. J Endovasc Ther 2013; 20: 623–637.

Reijnen

MMPJ

de Bruin

Mathijssen

EGE

. Global experience with the Nellix endosystem for ruptured and symptomatic abdominal aortic aneurysms. J Endovasc Ther 2016; 23: 21–28.

Böckler

Holden

Thompson

. Multicenter Nellix endovascular aneurysm sealing system experience in aneurysm sac sealing. J Vasc Surg 2015; 62: 290–298.

Donayre

Zarins

Krievins

. Initial clinical experience with a sac-anchoring endoprosthesis for aortic aneurysm repair. J Vasc Surg 2011; 53: 574–582.

Brownrigg

JRW

de Bruin

Rossi

. Endovascular aneurysm sealing for infrarenal abdominal aortic aneurysms: 30-day outcomes of 105 patients in a single centre. Eur J Vasc Endovasc Surg 2015; 50: 157–164.

Krievins

Holden

Savlovskis

. EVAR using the Nellix sac-anchoring endoprosthesis: treatment of favourable and adverse anatomy. Eur J Vasc Endovasc Surg 2011; 42: 38–46.

Boersen

Schuurmann

RCL

Slump

. Changes in aortoiliac anatomy after elective treatment of infrarenal abdominal aortic aneurysms with a sac anchoring endoprosthesis. Eur J Vasc Endovasc Surg 2016; 51: 56–62.

Zerwes

Nurzai

Leissner

. Early experience with the new endovascular aneurysm sealing system Nellix: first clinical results after 50 implantations. Vascular 2015; 0: 1–9. PMID: 26486377.

10.

Carpenter

Cuff

Buckley

. Thirty-day results of the Nellix system investigational device exemption pivotal trial for endovascular aneurysm sealing. J Vasc Surg 2015; 63: 23–31.

11.

McWilliams

Fisher

England

. Observations on surveillance imaging after endovascular sealing of abdominal aortic aneurysms with the Nellix system. J Endovasc Ther 2015; 22: 303–306.

12.

Ķ īsis

Krieviņ š

Naškoviča

. Quality of life after endovascular abdominal aortic aneurysm repair: Nellix sac-anchoring endoprosthesis versus open surgery. Medicina (Kaunas) 2012; 48: 286–291.

13.

England A, Torella F, Fisher R, et al. Migration of the Nellix endoprosthesis. J Vasc Surg 2016; 64: 306–312.

14.

Moher

Shamseer

Clarke

. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015; 4: 1–1.

15.

Gossetti B, Malaj A, Alunno A, et al. Early and mid-term outcomes of a novel endovascular aneurysm sealing (EVAS) system in patients with infrarenal abdominal aortic aneurysms. J Cardiovasc Surg (Torino). 2015. Epub ahead of print. PMID: 26417934.

16.

Sidloff

Stather

Choke

. Type II endoleak after endovascular aneurysm repair. Br J Surg 2013; 100: 1262–1270.

17.

Wyss

Brown

Powell

. Rate and predictability of graft rupture after endovascular and open abdominal aortic aneurysm repair: data from the EVAR Trials. Ann Surg 2010; 252: 805–812.

18.

Improve Trial Investigators. Endovascular or open repair strategy for ruptured abdominal aortic aneurysm: 30 day outcomes from IMPROVE randomized trial. BMJ 2014; 248: f7661–f7661.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.58 MB