Abstract
Arterial aneurysms remain a significant public health problem because they often result in death when ruptured; therefore, they require immediate medical treatment. Endovascular aneurysm repair (EVAR) has recently become the primary treatment option, owing to the fewer side effects compared to those with open surgery. However, stents used for conventional EVAR often cause side-branch occlusion, which alters the perfusion of vital organs. Recently, multilayer flow modulator (MFM) stents have been used as a new treatment for arterial aneurysms. These stents appear to be feasible owing to their unique design consisting of an uncoated three-dimensionally braided multilayered structure. MFM stents generally remodulate laminar flow and reduce the flow velocity in the aneurysmal sac, leading to thrombosis, which causes the aneurysm to shrink over time. Thus, they reduce the risk of mortality. Moreover, they reduce morbidity by preserving the side-branch blood flow. They can be easily applied to complex aneurysms and are ready to use without customization, which shortens the waiting time for interventions. This study aimed to evaluate the role of MFM stents in the treatment of arterial aneurysms based on available data.
Introduction
An aneurysm is defined as a localized pathological dilation of an artery >50% of its diameter.1,2 Although aneurysms are often asymptomatic, they remain a significant public health problem, because they often result in death when ruptured; therefore, they require immediate medical treatment. 3 Aneurysms occur most frequently in the aorta, which is the central conduit artery of the body, particularly the abdominal aorta. 4 Additionally, they are observed in the peripheral arteries, mainly in the popliteal and femoral arteries. 5 Among the visceral arteries, aneurysms are most commonly found in the splenic, hepatic, and renal arteries, 1 and intracranial aneurysms are common. 6
Conventionally, aneurysms are treated via open surgery. However, this approach is associated with high morbidity and mortality.7,8 Recently, endovascular techniques (such as endograft and hybrid approaches for aortic aneurysms and endografts and visceral coils for peripheral aneurysms) have become the treatment of choice, owing to the significantly lower mortality and morbidity.1,7 Several devices are currently available for endovascular procedures. However,complex aneurysm anatomy, in which the main arterial branches are in close proximity to or originate from the aneurysm, may preclude conventional endovascular treatment. 9 The main drawback of endovascular treatment is that side branches, including vital side branches of the aneurysmal artery, are often occluded when a covered stent graft or coil is used. Additionally, covered stents have limited flexibility and require larger introducers, making them unsuitable for complex anatomies. 8
Various endovascular repair (EVAR) techniques using modified stent grafts, such as fenestrated EVAR, branched EVAR, and chimney-EVAR, have been developed to overcome this challenge. 3 These procedures are difficult to perform and occasionally require personalized stents because commercially available stents are not suitable for the patient’s arterial geometry. 10 Such situations cause vital delays because fenestrated and branched endografts are not available off the shelf and often take several weeks to manufacture. 9
Recently, multilayer flow modulator (MFM) stents have been introduced in clinical practice. With their unique design of an uncoated three-dimensional multilayer braided structure, MFMs easily adapt to the diameter, morphology, size, and course of the target artery. 8 MFM stents can usually restore laminar flow within the artery and reduce the flow velocity in the aneurysmal sac. Moreover, they allow the collateral branches to remain patent and the flow toward these branches to continue, allowing appropriate perfusion of vital organs. 7 Furthermore, they allow thrombosis to occur within the aneurysm sac and ultimately cause it to gradually shrink. 3 Unlike fenestrated and branched endografts, they are easier to place and do not require customization. 10
This study aimed to evaluate the general features, indications, and usefulness of MFM stents in aneurysm management based on the available data from literature review.
General characteristics of MFM stents
Influence on hemodynamic performance
Although EVAR is highly effective in isolating the aneurysmal sac, its main drawback is that side branches are often occluded after application. 8 In contrast, MFM stents maintain appropriate perfusion of vital organs by preserving side-branch flow.10,11
The MFM stent is a tubular three-dimensional self-expandable wire mesh composed of layers with a porosity of approximately 65%, which allows for laminar flow in the main artery while reducing the flow velocity within the aneurysm sac. 12 The porous design of MFM stents slows blood turbulence in the aneurysmal sac, remodels the main flow toward the lumen of the stent, and eventually reduces wall shear stress (WSS) and pressure within the sac.13,14 This modulation of the hemodynamic flow allows thrombosis to occur naturally in the aneurysm. 9 Furthermore, modulation of the hemodynamic flow into the stent lumen improves the flow to the side branches, which remain patent owing to the porous nature of the stent.15,16 Figure 1 shows the changes in blood-circulation dynamics within the aneurysmal sac, laminar aortic blood flow, and preservation of the side-branch flow after MFM stent implantation through computational fluid dynamics modeling. This decrease in flow velocity in the aneurysmal sac promotes the formation of thrombi inside the sac, and eventually, the aneurysm is excluded. Furthermore, it induces endothelial tissue formation in the artery wall.9,17
Simulated flow hemodynamics in an aortic aneurysm (a) before and (b) after placement of a Stena Multilayer Flow Modulator®.
Since stents placed in the aorta usually cover the side branches, it is very important to maintain branch perfusion. MFM stents, based on hemodynamic principles, promote flow to the main aorta and side branches. Thus, it provides perfusion to the organs supplied by the side branch and reduces the risk of rupture by reducing the stress on the aneurysm wall.18–21
Unique mechanical properties
Porosity, flexibility, and low-profile delivery systems are three important and unique properties of MFM stents. Unlike other grafted stents, uncoated MFM stents are three-dimensional interlocking porous stents. 2 A computational fluid dynamics study suggested that a stent with an overall porosity of 50%–70% will significantly decrease the flow velocity inside the aneurysmal sac. 22 Moreover, porous MFM stents overcome some of the inevitable disadvantages of conventional covered stents, such as the need for branch embolization to prevent type 2 endoleak. 2
Because of the flexible and low-profile delivery system of MFM stents, they can be applied even in small arteries, such as the renal and superior mesenteric arteries. Moreover, application of traditional stent graft to aortic aneurysms requires a delivery system with a diameter of 18–26 Fr. In contrast, uncovered stents can be compressed into a 6–10 Fr delivery system. 2 In previous studies, MFM stent application was advantageous because of its simple deployment and minimally invasive nature and showed good results in the splanchnic, renal, superior mesenteric, and cerebral arteries. 9 Owing to its availability without the need for customization, this technology can be used in urgent cases with complex aortic anatomy.9,10
Applications in aneurysms
Rather than the risk of rupture, peripheral aneurysms are associated with problems due to vessel blockage caused by the formation of a clot in the vessel, which grows and exerts pressure on the surrounding tissues. 5 The use of MFM stents for the treatment of peripheral aneurysms provides satisfactory outcomes in terms of technical success, aneurysm thrombosis and shrinkage, and branch vessel patency.8,9
MFM stents were originally used for intracranial aneurysm repair. 23 Intracerebral aneurysms usually do not rupture but can exert pressure on the nerves or brain as they grow. However, rupture is a medical emergency, as it may result in serious clinical conditions ranging from stroke to death.24,25 MFM stents significantly reduce intra-aneurysm WSS and WSS gradient. This is extremely important because, generally, higher pressure and abnormal WSS are predictors of aneurysm rupture, whereas the opposites are associated with thrombus formation. 24
Visceral artery aneurysms are relatively uncommon. 2 However, they are associated with the risk of rupture and, ultimately, mortality. Ruptures are more common in patients with hepatic, pancreatic, and superior mesenteric artery aneurysms. 1 Studies have reported that MFM stents are safe and reliable and can be used as an alternative approach for the treatment of anatomically suitable visceral artery aneurysms.7,8,26 Among the visceral arteries, MFM stents are mainly used to treat iliac- and subclavian-artery aneurysms. In these anatomical regions, important side branches, such as the internal iliac, genicular, and vertebral arteries, must be preserved. Among the peripheral arteries, MFM stents are frequently used to treat popliteal artery aneurysms. 9
MFM stents are commonly used to treat aortic aneurysms. This is important because the aorta is the central conduit artery and the main arterial branches that perfuse vital organs (such as the coronary, left common carotid, mesenteric, and renal arteries and the celiac trunk) originate from the aorta. 4 These aneurysms are difficult to manage because they can occur in any part of the aorta, even the main branch, and are quite complex in terms of shape, size, and extent. 27 Compared with EVAR techniques for the management of complex aneurysms, MFM stents offer a significant advantage because they are easier to apply and do not require customization. 26 Numerous studies evaluating MFM stents, including S-MFM, have reported satisfactory results in terms of technical success, aneurysm thrombosis and shrinkage, and branch vessel patency.1,3,9,26
Several MFM stents are available for use in arterial aneurysms. Some devices, such as the pipeline embolization device (ev3, Plymouth, MN, USA) and the SILK arterial reconstruction device (Balt Extrusion, Montmorency, France), have been used primarily in the treatment of intracranial aneurysms. 9 However, devices intended for use in different types of aneurysms, such as the S-MFM (INVAMED, Ankara, Turkey) and Cardiatis Multilayer Stent (Cardiatis, Isnes, Belgium), have been introduced.3,7–9
In general, MFM stents exhibit similar basic properties. The S-MFM (Figure 2), which is a relatively new product, is composed of a knitted 5-layer tubular network stent made of a superelastic biomedical metal alloy. The stent is made of a self-expandable alloy and has a high radial strength and shape memory. In addition to aortic aneurysms, S-MFM stents have been used for peripheral, intracranial, and vascular aneurysms. For example, the aortic stent is available in a wide range of lengths (80–200 mm) and diameters (25–45 mm), allowing treatment of aneurysms in different locations and of various shapes and sizes.
Schematic demonstration of the fundamental parts of the Stena Multilayer Flow Modulator® system.
Discussion
Dilation owing to thinning of the arterial wall caused by proteolytic damage to the extracellular matrix and destruction of smooth muscle cells constitutes the basic pathophysiology of aneurysms. As this damage progresses, the vortices within the sac become stronger, increasing the radial stress on the arterial wall, resulting in aneurysm rupture. 18 Therefore, the main goal of arterial aneurysm treatment is to prevent rupture and death. 12
Both aortic and other arterial aneurysms grow with time, and expansion of the aneurysm sac could be life-threatening owing to the risk of rupture. 26 Currently, specific guidelines for the treatment of arterial aneurysms are lacking. 21 Although EVAR significantly overcomes the adverse events associated with open surgery, in aneurysms adjacent to or involving a major arterial branch, covered stents or grafts occlude the branch.10,27 MFM stents, which were originally used to repair intracranial aneurysms, have been successfully implanted into aortic, visceral, and peripheral aneurysms. 23
The main goal of aneurysm treatment is to prevent aneurysm rupture. However, consensus on the best treatment strategy is lacking, and the choice of treatment varies depending on the type, location, and size of the aneurysm. Aneurysm treatment methods include open surgery, EVAR, endovascular coiling, microvascular clipping, and catheter embolization.1,2,28 Anatomical suitability and patient comorbidities play essential roles in the selection of surgical and endovascular interventions for the treatment of arterial aneurysms. 1 Anatomical factors can seriously limit the use of stent grafts for the treatment of arterial aneurysms. However, favorable outcomes have been obtained using MFM stents specifically designed to laminate blood flow in patients with difficult-to-treat aneurysms, not only in the aorta but also in the peripheral, visceral, and intracranial arteries.1,3,9,24,29 In previous studies, outcomes were generally evaluated according to the criteria of technical success, defined as successful stent placement, and clinical success, defined as maintenance of the circulation in vital collaterals while ensuring the exclusion of aneurysms. 29 Reduction in aneurysmal sac volume was considered clear evidence of clinical success. 9
As in some of the study examples summarized in Table 1, MFM stents reduce blood flow in the aneurysm sac and create stasis inside the sac, leading to gradual thrombosis and neointimal remodeling while maintaining blood flow in the side branches and perforators.3,7–9,26,30,31 In 2008, Henry et al. 12 documented the repair of renal artery aneurysms using a three-dimensional multilayer stent. They performed an angiogram of the artery after the procedure and observed an immediate and significant decrease in the blood flow inside the sac. Furthermore, the branches of the renal artery remained patent. Complete shrinkage of the aneurysm and patent renal artery branches were observed at the 6-month follow-up. 12 These findings are supported by thrombosis and shrinkage of aneurysmal sacs in an experimental aortic aneurysm. 10
The summarized outcomes of some selected studies used multi-flow modulator stents in arterial aneurysm.
AAA, abdominal aorta aneurysm; MFM, multilayer flow modulator; PAA, peripheral arterial aneurysm; TAA, thoracic aorta aneurysm; TAAA, thoracoabdominal aortic aneurysms.
In a 12-case study using S-MFM stents, Tanyeli et al. confirmed preserved blood flow in the aorta and side-branch arteries without significant adverse events or death at the 6-month follow-up. Furthermore, the technical success rate was 100%, and complete aneurysm thrombosis occurred in all patients. 3
The overall quality of existing studies using MFM is poor because long-term outcomes are lacking, the number of patients used in the study is quite small, patients are frequently lost to follow-up, and patient characteristics are highly diverse. Additionally, MFM is usually used only in patients who are unable to use both open and endovascular techniques, making it difficult to find an appropriate control group. 37 Furthermore, some studies also included off-label use, and some of these are not reported in detail.34,37
Sultan et al. 35 stated that deaths after MFM placement are mostly due to lack of experience. In addition, various serious complications after MFM placement are significant challenges to overcome. Despite the MFM stent, the expansion of the diameter and size of the aneurysm carries a significant risk of rupture, and ultimately mortality. Stent stenosis and side-branch occlusion can result in ischemia-related organ failure (e.g., renal failure), limb ischemia, and stroke. Migration and displacement of MFM, necessity of reintervention, and overlap are important adverse events.33,34,37
MFMs exhibit a three-phase mechanism of action. The first is the hemodynamic phase, which occurs immediately after stent placement and reduces blood flow from the main artery to the aneurysm. The second phase is the progressive thrombus formation phase, which lasts for days to weeks. The last phase is the endothelization phase, which can last from several months to years. 38 Although laminar flow within the aneurysmal sac is modulated and patency of the collaterals is ensured, thrombosis and endothelization of the aneurysmal sac over time does not eliminate the risk of rupture of the sac. 39 Delayed aneurysm rupture and thromboembolism are serious complications associated with MFM treatment. Both conditions are associated with poor prognosis, with an incidence of up to 6.9%. 38
Post-treatment evaluations generally show a decrease in the volume of flow into the sac, which is a positive sign of hemodynamic response. However, this does not parallel the expected decrease in aneurysm size and diameter in most studies, and in fact, the volume appears to increase.33,34 While the increase in volume maintains to increase in the risk of aneurysm sac rupture, it is predictable that the decrease in hemodynamic pressure into the sac will reduce this risk to some extent. In light of current knowledge, 40 we evaluate that the increase in aneurysm size and diameter is related to the continuation of the AAA pathophysiological process that triggers aneurysm formation and progression.
Open surgery remains the gold standard treatment for popliteal aneurysms, and few studies have reported MFM stent application for popliteal artery aneurysms.36,41 Ucci et al. 36 reported that primary patency was preserved in 70% of patients, and the limb salvage rate was >90% at the 2-year follow-up. In their study, reintervention was required in approximately one-quarter of the cases.
Although many people advocate their effectiveness, MFM stents have not been widely used for the treatment of visceral artery aneurysms because of the lack of quality evidence, similar to that in popliteal artery aneurysms. 1
Regarding aortic aneurysms, MFM stent application is technically feasible in emergency situations, with an acceptable 1-year survival rate. However, the incidence of aneurysm rupture after treatment of approximately 10%, the need for reintervention in one in four patients, and an increased/stable aneurysm sac diameter >60% of the arterial diameter have led to questioning the use of MFM stents for the treatment of aortic aneurysms.39,41
In addition to attracting attention due to its ease of placement and minimally invasive nature, MFM stents have shown good results in the cerebral arteries. 41 Therefore, MFM stents are important in neuroradiology. Unruptured complex aneurysms (including fusiform, large and/or giant, or wide-necked aneurysms), very small aneurysms, aneurysms with blood bubbles, and recurrences that cannot be treated with conventional coiling may be considered amenable to flow-diverter devices. In a large-scale meta-analysis of heterogeneous groups, Lv et al. 42 reported that MFM stents were associated with favorable clinical outcomes, complete or nearly complete aneurysm-occlusion rates, morbidity, and mortality in 88.2%, 84.4%, 3.3%, and 3.2% patients with intracranial aneurysms, respectively.
Limitations
This study had some limitations. First, this was a conventional review. MFM stent application is a relatively new strategy for the treatment of arterial aneurysms. Furthermore, aneurysms differ in some features such as anatomical location, size, and shape. Therefore, the available data cannot provide sufficient information to recommend a standard approach in terms of indications, effectiveness, and safety.
Conclusion remark
In conclusion, MFM stents were developed to isolate the aneurysmal turbulence from the laminar blood flow in the main artery. They are a viable alternative to surgery or EVAR for all arterial aneurysms because they reduce the size of the aneurysmal sac and preserve the blood flow in the side branch. Compared with other methods, MFM stents can be applied more easily in complex aneurysms and do not require customization, which significantly reduces the time to treatment, resulting in positive outcomes. The lack of quality evidence makes it difficult to consider MFM stents for some types of aneurysms such as visceral and popliteal aneurysms. However, they are a feasible and safe alternative in selected patients. More research and longer follow-ups are required to understand the effects on aneurysms located in different anatomical regions and with different structures in more detail.
