Surface-modified flow diverters for intracranial aneurysms: narrative review on mechanisms, evidence, and clinical implications

Introduction

Background

Endovascular treatment (EVT) for both ruptured and unruptured intracranial aneurysms, in particular coil embolization, has demonstrated a superior safety profile compared to surgical clipping, leading to its widespread adoption as the preferred treatment modality in the post-International Subarachnoid Aneurysm Trial (ISAT)/Barrow Ruptured Aneurysm Trial (BRAT) era (1-3). However, the long-term success of endovascular coiling remains highly variable with occlusion rates significantly influenced by factors such as aneurysm morphology, anatomical location, coil characteristics, and the operator’s skill. In addition, a subset of complex aneurysms (large, wide-necked, blister, fusiform and/or unfavorably located) remain challenging to treat with either endovascular therapy or surgical clipping (4). These limitations were addressed by the concept of flow diversion that employs mesh-like tubular implants as endoluminal scaffolds to reconstruct the parent vessel and redirect blood flow away from the aneurysm, rather than focusing only on aneurysm-sac occlusion. Flow diverters (FDs) have transformed the treatment of intracranial aneurysms by promoting intra-aneurysmal thrombosis through redirection of blood flow and subsequent endothelialization of the device over time (4,5).

Rationale and knowledge gap

FDs can achieve high aneurysm occlusion rates exceeding 80%, but the thrombogenicity from the high metal coverage poses risks (particularly during the endothelialization phase) of thromboembolic events in the tune of 6–15%, despite dual antiplatelet therapy (DAPT). This represents a compounded risk when DAPT usage itself exposes the patient to increased bleeding risk and related complications (6-8). Over the last decade, newer FD technologies that focus on reducing thrombogenicity through surface modifications have been introduced. These technologies can potentially broaden the safety profile and indications of flow diversion. If DAPT is not required, it would be even feasible to use these devices safely in patients with ruptured aneurysms, those with aspirin allergy, aspirin/clopidogrel non-responders, as well as in those with a history of nuisance bleed (e.g., erosive gastritis, hematuria) (7). Nevertheless, these technologies are still in varying stages of maturation, and clinical evidence on their superiority and safety over traditional devices is still emerging. To our knowledge, only a few published reviews currently describe the molecular mechanisms and/or compare the clinical data on different FD surface coating materials (9-11). Notably, a recent review by Zoppo et al. (12) provided a comprehensive overview of the preclinical and translational evidence underlying various FD surface modification strategies, including hydrophilic polymers, phosphorylcholine coatings, and CD31-mimicking peptides, emphasizing the delicate balance between thromboresistance and endothelialization.

Objective

This review aims to serve as an evidence-based synthesis of mechanistic, preclinical, and clinical data for neurointerventionalists by consolidating information on currently available FD coating technologies in clinical use, specifically Pipeline™ Flex and Vantage with Shield Technology™ (Medtronic, Irvine, California, USA), FRED™ with X Technology™ (MicroVention Inc./Terumo Corporation, Tokyo, Japan), p48/64 with HPC coating (phenox GmbH/Wallaby Medical, Shanghai, China), and Acandis DERIVO^® 2heal (Acandis GmbH, Pforzheim, Germany). We present this article in accordance with the Narrative Review reporting checklist (available at https://jni.amegroups.com/article/view/10.21037/jni-25-26/rc).

Methods

A literature review was conducted using international databases, including PubMed, Embase, MEDLINE, and Google Scholar, to gather detailed information on the coating technologies employed in major FDs currently in clinical use (Table 1, Appendix 1). The search utilized specific keywords related to both the surface modification materials: “phosphorylcholine”, “poly 2methoxyethyl acrylate”, “hydrophilic polymer coating”, and “fibrin-heparin”; as well as device-specific terms such as “Pipeline Shield”, “Pipeline Vantage”, “Flex Technology”, “FRED”, “FREDX”, “p64”, “p64-HPC” and “DERIVO 2heal”. Inclusion criteria encompassed studies that described the molecular mechanism of the coating, as well as preclinical evaluations and clinical evidence, including retrospective and prospective series or randomized trials involving these surface-modified FDs in the treatment of intracranial aneurysms.

Principles of surface modification and coating material design

The aim of FD surface modification/coating is to maintain hemocompatibility and to fine-tune the biological response to implanted FDs. Manufacturers have developed distinct surface modification strategies, each leveraging unique biomimetic principles. Rather than applying traditional thick coatings that risk degradation, these newer FDs feature ultra-thin, covalently bonded layers designed for long-term stability and biocompatibility. Thrombogenicity of endoluminal devices is largely driven by the adsorption of plasma proteins—particularly fibrinogen—onto the metallic surface, which initiates platelet adhesion, activation, and subsequent coagulation, as well as macrophage recruitment (13). With FDs covering 30–40% of the vessel lumen with metal, their thrombogenic potential contributes significantly to post-procedural complications (14). To mitigate this, surface modifications aim to reduce protein adsorption, thereby limiting platelet and immune cell attachment. At the same time, these enhancements play a critical role in promoting endoluminal healing through endothelial cell adhesion, migration, and neointima formation. The ultimate therapeutic challenge lies in striking a delicate balance—minimizing thrombogenicity to reduce early complications while simultaneously fostering endothelialization to ensure long-term aneurysm exclusion and vessel remodeling (15).

FDs using biopassive modifications

Pipeline™ Flex/Vantage FDs with Shield Technology™

Introduction and mechanism

The Pipeline Flex (3^rd generation) with Shield Technology (Medtronic, USA) was introduced to address the issue of thromboembolic complications associated with traditional FDs. Granted CE approval in 2015, the Pipeline Shield retains the mechanical design and deployment characteristics of the original Pipeline Flex device but distinguishes itself through the Shield technology™—addition of a 3-nm phosphorylcholine-based surface modification covalently bound to the FD metallic strands, that mimics the phospholipid membrane of red blood cells, aiming to enhance hemocompatibility by reducing protein adsorption, platelet adhesion, and subsequent thrombus formation (15). Phosphorylcholine features a hydrophilic head group while maintaining an overall zwitterionic (electrically neutral) charge, a structural characteristic that enhances both its biocompatibility and ability to reduce thrombogenicity. This biomimetic property closely resembles the outer surface of natural cell membranes, helping to minimize protein adsorption and subsequent platelet activation when used as a surface coating on FDs (16). The same shield technology was later employed in the 4^th generation of this device, Pipeline Vantage.

The surface modification using shield technology in Pipeline FDs has shown to reduce thrombogenicity and improve biocompatibility in both benchtop and animal studies compared to bare metal devices. In vitro blood loop models demonstrated lower thrombin and platelet activation, while animal models, such as baboon shunt and rabbit elastase aneurysm models, confirmed decreased thrombus formation, even under single antiplatelet therapy (SAPT) (17).

Phosphorylcholine coating has shown promise in enhancing endothelialization and reducing neointimal hyperplasia, though results vary across studies (9). Most recent in vivo animal study assessed the effect of longitudinal healing process between the phosphorylcholine-coated and uncoated Pipeline FDs in rabbit models showed no significant differences in average tissue growth thickness or endothelialization scores on optical coherence tomography (OCT) and scanning electron microscopy (SEM), with early tissue coverage evident by day 5 and near-complete endothelialization across all devices by day 30 (18). These findings suggest that phosphorylcholine surface modification does not delay vascular healing or endoluminal coverage (18).

Clinical data and outcomes (Table 2)

Despite the promises from in vitro benchtop and in vivo animal studies on phosphorylcholine surface coating, clinical outcomes have yet to consistently demonstrate a significant reduction in peri-procedural thromboembolic events, compared with prior studies using similar FDs without surface modification. Although not explicitly stated in the instructions for use (IFU) for Pipeline FDs with shield technology, there are reports on safe usage of the same with SAPT—mostly aspirin (21).

Multiple studies that used Pipeline FDs with shield technology in treating unruptured intracranial aneurysms (21) reported thromboembolic complication rates of 3–6% are almost similar to earlier case-control studies, e.g., PREMIER (27), IntrePED (28), which used similar FDs without surface modification. Occlusion rates and safety outcomes with the Pipeline Shield were comparable to those reported in earlier studies involving both traditional flow-diverter devices and earlier-generation Pipeline Embolization Device (PED) FDs, as shown in forest plots (Figures 1,2), suggesting that while surface modification may offer biological advantages, its clinical impact on efficacy and complication rates remains similar in the context of standard treatment protocols.

Figure 1 Forest plot of aneurysm occlusion rates by Pipeline Shield. Aneurysm occlusion rates in most studies using Pipeline Shield phosphorylcholine-coated FDs report high occlusion rates (above 80%), with the SCOPE-AUS study showing the highest (92.5%). FDs, flow diverters.

Figure 2 Forest plot of thromboembolic complication rates by Pipeline Shield. Thromboembolic complication rates remain relatively low across studies using Pipeline Shield phosphorylcholine-coated FDs, mostly under 5%, except for Manning et al., which included ruptured aneurysms and reported a higher rate (7.1%). FDs, flow diverters.

Notable ongoing clinical trials on phosphorylcholine-coated Pipeline Shield FDs include ELEVATE study (ClinicalTrials.gov ID: NCT04391803; slated to be completed in 2027), which investigates the safety and effectiveness of Pipeline Shield FDs in treating acutely ruptured intracranial aneurysms that are not amenable to clipping and coiling.

FRED™ with X Technology™

Introduction and mechanism

The FRED-X FD incorporates poly(2-methoxyethyl acrylate) (PMEA) surface modification covalently bonded to its nitinol braid. PMEA’s unique ability to retain “intermediate water” (29)—a hydration state that prevents protein adsorption which minimizes thrombogenic responses by repelling fibrinogen and inhibiting platelet adhesion. Crucially, while it limits fibrinogen-mediated thrombosis, PMEA allows fibronectin conformational changes essential for endothelial cell adhesion and vessel healing (30). Benchtop and in vitro models in pre-clinical studies show promising results by confirming reduced platelet activation, and a blood loop model demonstrated that FRED-X produced thrombin-antithrombin (TAT) complex and beta-thromboglobulin levels similar to Pipeline phosphorylcholine-coated FD and significantly lower than uncoated FRED. In vitro blood loop model study suggested better endothelial cell adhesion with PMEA compared to phosphorylcholine coatings, suggesting its potential to balance low thrombogenicity with favorable endothelialization (31).

Clinical data and outcomes (Table 3)

To date, FRESH study remains the largest published clinical study exclusively on the use of FRED-X FDs in treating intracranial aneurysms conducted across 9 centers (32). The study enrolled 161 patients, the majority of whom were treated for unruptured aneurysms, with only 11.2% involving ruptured cases. At a mean follow-up of 7 months, the study reported an aneurysm occlusion rate of 66.0% and a major adverse event rate of 3.2%, indicating favorable safety profile in clinical use. Of note, there is a suggestion of lower thromboembolic complications of 4.3% in the FRESH study (32) using PMEA-coated FRED-X FDs, compared to 6–7% in the previous 2 studies using uncoated FRED FDs, i.e., SAFE (n=103, published in 2019) (36) and US Pivotal Trial (n=145, published in 2022) (37).

Subsequent smaller multicenter and single-center series have supported these findings. Abbas et al. (33) reported on 44 patients (45 aneurysms) with an adequate occlusion rate of 89% at 6 months and 100% at 12 months, and a low complication profile (8% transient perioperative events, no mortality). A two-centre retrospective cohort study from Goertz et al. (34) on 34 patients (21% ruptured, 18% recurrent aneurysms) also reported an adequate occlusion rate of 89.3% at ~6 months with only 2.9% complications (symptomatic transient ischemic attacks).

The above findings were also corroborated by a prospective comparative study between FRED and FRED-X devices in 287 patients with 385 aneurysms published in 2025 (FRED used in 77.9% and FRED-X used in 22.1%) that suggested superior aneurysmal occlusion efficiency using FRED-X FDs (79.4% FRED-X vs. 59.3% FRED; P=0.022), and relatively better safety profile [complication rate of 10.4% (n=23) in FRED and 3.5%/n=2 in FREDX; P=0.166] to uncoated FRED FDs (35).

As illustrated in Figure 3, aneurysm occlusion rates reported in studies using the FRED-X FD vary considerably, ranging from 66.0% in the FRESH study (32) to 100.0% in Abbas et al. (33). Despite this variability, thromboembolic complication rates (Figure 4) remain consistently low and mostly under 5% across the literature, again likely due to the inclusion of ruptured aneurysm cases.

Figure 3 Forest plot of aneurysm occlusion rates by FRED-X. Aneurysm occlusion rates in studies using FRED-X FDs shows a wide range of occlusion rates, ranging from 66.0% (FRESH study) to 100.0% (Abbas et al.). FDs, flow diverters.

Figure 4 Forest plot of thromboembolic complication rates by FRED-X. Thromboembolic complication rates remain relatively low across studies using FRED-X, mostly under 5%, except for Manning et al., which included ruptured aneurysms and reported a higher rate (7.1%).

Notable ongoing studies on PMEA-coated FRED-X FDs include FRED/FRED Jr/FRED-X Intracranial Aneurysm Treatment Study (FRITS; ClinicalTrials.gov Identifier: NCT03920358).

p48/p64 MW HPC

Introduction and mechanism

The p48 and p64 FD were tailored for vessel sizes of ≤3 mm diameter (48 wires) and 3–5 mm diameter (64 wires) respectively. The p48 and p64 MW HPC FDs utilize a hydrophilic polymer coating (HPC) composed of a 3–10 nm thick glycocalyx-like glycan-based polymer biomimetic layer covalently bonded to the nitinol (NiTi) FD metallic wires to replicate the natural glycocalyx mesh (a carbohydrate-rich and gel-like lining) along vascular endothelial cells (35,38). These glycan-based coatings are carbohydrate polymers, setting them apart from the phospholipid-based polymers employed in Shield™ and X™ technologies. This fundamental chemical difference reflects a distinct biomimetic strategy: Shield™ and X™ mimic cell membranes to deter platelet adhesion, glycan-based coatings emulate the vascular glycocalyx to create a non-thrombogenic, hydrated interface that resists protein and cell attachment. Unlike the phospholipid-based coatings used in Shield™ and X™ technologies, this glycan coat reduces the surface availability of procoagulant factors such as fibrinogen and von Willebrand factor (vWF). In vitro and benchtop flow model studies showed significantly reduced platelet adhesion and activation, with lower thrombin generation compared to bare metal stents. These antithrombotic benefits were confirmed in animal models, where HPC-coated devices exhibited reduced clot burden and favorable biocompatibility (39,40). OCT and histopathological studies of these HPC-coated FDs further demonstrated no significant increase in inflammation or neointima formation (40-42).

Clinical data and outcomes (Table 4)

Current evidence suggests that HPC coating mitigates thrombogenicity more effectively than the uncoated variant and support use of SAPT (9).

In the largest series-to-date by Hellstern et al. published in 2022, 102 patients with 132 anterior circulation aneurysms were treated using HPC-coated p64 FDs under SAPT with prasugrel. Although 13.6% of patients had intraprocedural complications (i.e., 7 cases of foreshortening, 10 instances where the stent did not open properly/fish-mouthing that required adjunct device manipulation, as well as 1 case of internal carotid artery (ICA) dissection, they encountered no intraprocedural or periprocedural thromboembolic or hemorrhagic complications (52). However, between 1 and 30 days from implantation, 6 patients had symptomatic ischemic complications, all of them with MCA aneurysms. Three of these patients were non-compliant with SAPT medication. The overall aneurysm occlusion rate was good at 83.8% at 9 months follow-up.

Other studies that investigated the use of HPC-coated p48/p64 FDs with SAPT, published between 2020 and 2024, also demonstrated a favorable safety profile, including stent-patency and comparable aneurysmal occlusion efficacy (Table 4). As shown in Figure 5, studies evaluating p48/p64 HPC-coated FDs report a broad range of aneurysm occlusion rates, from approximately 33% to 86%, with lower rates often seen in early-phase or small cohort studies. In contrast, Figure 6 reveals a striking variability in thromboembolic complication rates ranging from 0% to 50%, reflecting heterogeneity in study design, patient selection (including ruptured vs. unruptured aneurysms), and antiplatelet therapy protocols.

Figure 5 Forest plot of aneurysm occlusion rates by p48/p64 HPC. Aneurysm occlusion rates in most studies using p48/p64 HPC-coated FDs show occlusion rates ranging from about 33% to 86%, with a few small or early-phase studies showing lower rates. FDs, flow diverters.

Figure 6 Forest plot of thromboembolic complication rates by p48/p64 HPC. Reported thromboembolic complications rate in p48/p64 HPC-coated FDs vary widely from 0% to 50% highlighting differences in study design, patient population (ruptured vs. unruptured), and antiplatelet regimens. FDs, flow diverters.

There are ongoing clinical trials on HPC-coated p48/p64 FDs, such as COATING trial (53) and COMATS study (ClinicalTrials.gov ID: NCT04305704). COATING is a randomized study directly comparing HPC-coated p64 FD under SAPT and uncoated p64 FD with DAPT in patients with unruptured/recanalized aneurysms, with primary endpoint of diffusion-weighted imaging (DWI) lesions on MRI within 48 hours as direct evidence of thromboembolic incidence, and secondary endpoints on overall safety as well as treatment efficacy. The COMATS observational registry assesses the safety of HPC-coated p48 and p64 FDs in anterior circulation aneurysms treated under DAPT.

FD using active drug modifications

DERIVO^® 2heal

Introduction and mechanism

The Acandis DERIVO^® 2Heal adopts an entirely different approach by using a biologically active fibrin-heparin nanocoating, designed not just to reduce platelet activity but to interfere directly with the coagulation cascade. These variations in surface chemistry reflect fundamentally different strategies—ranging from passive resistance to protein adhesion to active modulation of clotting pathways—all sharing the common goal of enhancing safety and enabling broader clinical use, including the potential for SAPT in high-risk patients.

Following the manufacturing of the bare flow-diverter, the device undergoes a specialized surface treatment called the “heal” coating, developed by Acandis. This multi-step process begins with the adsorption of fibrinogen onto the stent’s surface, followed by the attachment of thrombin to convert fibrinogen into fibrin, forming a mesh-like fibrin scaffold. The final step involves covalent bonding of activated heparin to the fibrin network, imparting anticoagulant properties and promoting compatibility with blood components. This fibrin-heparin structure mimics the end phase of the coagulation cascade, aiming to reduce thrombogenicity while encouraging endothelial cell adhesion and proliferation for enhanced neoendothelialization (54,55).

Clinical data and outcomes (Table 5)

One of the earliest published case reports described the use of DERIVO 2heal FD under SAPT in treating ICA pseudoaneurysm resulting from iatrogenic injury during sinus surgery, which reported no thromboembolic complications and complete aneurysm occlusion in five days (55). To date, 2 published retrospective study series analyzed and reported the outcomes of DERIVO 2heal FD usage.

In the smaller case series involving 9 patients (56), the Derivo^® 2heal^® FD was used to treat 10 aneurysms, which were technically successful in 9 cases and unsuccessful in 1 case due to microcatheter friction. Balloon angioplasty was required in 1 case to optimize wall apposition. Twelve arterial side branches were covered during the procedures and remained patent, with no thromboembolic events or clinical complications reported. Immediate postprocedural imaging showed contrast retention in 81% of aneurysms, and short-term follow-up indicated complete occlusion in 67% of treated cases.

In the largest retrospective multicenter study from 9 German neurovascular centers between February 2022 and December 2023 (57), 89 intracranial aneurysms were treated with 96 DERIVO 2heal FDs with a technical success rate of 99.0%. In-stent balloon angioplasty was needed in 6.0% of cases, and adjunctive coiling was used in 28.6%. Technical challenges occurred in 12.0% of procedures. Thrombotic events were reported in 4.8% of cases, all were asymptomatic. The study reported no mortality and a low morbidity rate of 1.2%. At a mean follow-up of 6.6 months, adequate aneurysm occlusion was achieved in 80.7% of patients.

Figure 7 demonstrates that aneurysm occlusion rates with DERIVO 2heal FDs range from 67.0% in the pilot study to 80.7% in a larger multicenter series, suggesting consistent efficacy across study scales. In Figure 8, the forest plot of thromboembolic complication rates reveals a variability between 0% and 11.9%, incorporating both symptomatic and asymptomatic events, highlighting potential differences in event classification and follow-up protocols.

Figure 7 Forest plot of aneurysm occlusion rates by DERIVO 2heal. The aneurysmal occlusion rate in studies using DERIVO 2heal FDs ranges from 67.0% in the pilot study to 80.7% in the larger multicenter study. FDs, flow diverters.

Figure 8 Forest plot of thromboembolic complication rates by DERIVO 2heal. Thromboembolic complication rate in studies using DERIVO 2heal FDs varies between 0% and 11.9%, including both symptomatic and asymptomatic events. FDs, flow diverters.

Ongoing clinical studies on DERIVO 2heal FDs include REHeal study (ClinicalTrials.gov ID: NCT05543447)—a prospective, single-arm, multicenter, open-label national study across approximately 15 sites in Germany post-market clinical follow-up (PMCF) investigation designed to align with EU Medical Device Coordination Group (MDCG) guidance with estimated enrollment of 158 patients and slated for completion in 2025–2026.

Discussion

The forest plots in Figures 9,10 provide a comparative overview of clinical performance across four surface-modified FD types. Figure 9 illustrates that Pipeline Shield consistently achieves high aneurysm occlusion rates, clustering above the overall mean, while FRED-X and DERIVO 2heal show moderate-to-high occlusion with narrower inter-study variability. In contrast, p48/p64 HPC-coated devices display a wider spread, with some studies reporting lower occlusion rates, particularly in smaller or early-phase cohorts. Figure 10 highlights the heterogeneity of thromboembolic complication rates, which remain generally low for Pipeline Shield and FRED-X, but vary widely for p48/p64 HPC—up to 50% in select studies—likely reflecting divergent antiplatelet regimens, inclusion of ruptured aneurysms, and differences in event classification. DERIVO 2heal studies report modest complication rates (0–11.9%), although further large-scale data are needed. Collectively, these plots underscore that while surface modifications may reduce thromboembolic risk and support high occlusion efficacy, device-specific performance is influenced by multiple clinical and methodological factors.

Figure 9 Forest plot of aneurysm occlusion rates by device type. Forest plot comparing the reported aneurysm occlusion rates from published clinical studies using four flow diverter types with surface modifications: Pipeline Shield (phosphorylcholine-coated), FRED-X (PMEA-coated), p48/p64 HPC (hydrophilic polymer-coated), and DERIVO 2heal (fibrin-heparin-coated). Each dot represents an individual study, grouped by device type. A vertical dashed line indicates the overall mean occlusion rate across all devices. FDs, flow diverters.

Figure 10 Forest plot of thromboembolic complication rates by device type. Forest plot illustrating the incidence of thromboembolic complications (symptomatic and asymptomatic) reported in clinical studies involving coated flow diverter devices. Device types are color-coded as in Figure 1. The variation highlights differences in antiplatelet strategies, patient populations, and aneurysm rupture status. The dashed line marks the overall mean thromboembolic complication rate.

Overall, the current generations of coated FDs from various manufacturers demonstrate clinical outcomes largely comparable to their uncoated counterparts, with only subtle differences observed thus far. Although definitive superiority has not been established, the potential for using these devices under SAPT could significantly broaden their clinical utility.

In acute aneurysmal subarachnoid hemorrhage (SAH), impaired aspirin responsiveness and sustained ADP–P2Y₁₂–GPIIb/IIIa pathway activation have been documented (58), supporting the preferential use of P2Y₁₂ inhibitor–based SAPT when considering coated FDs in this high-risk setting. In addition, hormonal status may influence aneurysm involution; estrogen, in particular, promotes endothelialization and attenuates vascular inflammation, whereas post-menopausal estrogen decline may delay healing (59). These findings underscore the potential value of tailoring both antiplatelet regimens and follow-up strategies to individual patient biology.

The safety data in terms of thromboembolic complications in clinical studies using phosphorylcholine-coated Pipeline Shield FDs under SAPT showed mixed results, with a more consistent safety profile under DAPT (15,60). PMEA-coated FRED-X had a lower thromboembolic complication rate of 4.3% in FRESH study (32) compared to 6–7% in uncoated FRED FD studies including SAFE (36) and US Pivotal Trial (37). PMEA-coated FRED showed superior aneurysmal occlusion efficiency (79.4% FRED-X vs. 59.3% FRED; P=0.022), and probably better safety profile (3.5% FRED-X complications vs. 10.4% FRED complications; P=0.166) than uncoated FRED FDs (33-35). Of note, these studies were conducted with patients on DAPT. There is early evidence to support the use of HPC-coated p48 and p64 FDs under P2Y12 inhibiting SAPT. Updated IFUs allow the DERIVO 2heal FDs to be considered under SAPT in selected cases, though evidence remains limited to retrospective studies and case series (60-62).

Two meta-analyses reported thromboembolic complication rates of 7–8% in patients treated with coated FDs under SAPT, which are somewhat higher than those in routine uncoated FDs studies (60,61). The variability in SAPT outcomes may stem from a predominant focus on aspirin SAPT rather than P2Y12 inhibitors SAPT (15). In the context of acute aneurysmal subarachnoid hemorrhage (aSAH), patients often exhibit variable responses to aspirin (sometimes requiring higher-than-usual doses to achieve effective platelet inhibition). Although the underlying cause remains unclear, SAH is known to activate platelets predominantly via the P2Y12-ADP-GPIIb/IIIa pathway (63), indicating that P2Y12 inhibitors acting on the upstream pathway may be more suitable as the SAPT choice for coated FDs in aSAH patients (43). Due to known resistance rates to clopidogrel, prasugrel is considered a safer option for SAPT, with ticagrelor as a possible alternative, though its shorter half-life presents certain limitations.

Apart from the technologies discussed earlier in this review, there are also other surface modification techniques in various stages of preclinical evaluation, e.g., Guardian and Biostealth surface modification from Stryker and P8RI coating from Balt. Additionally, promising preclinical evidence supports Stryker’s heparin-bonded Evolve FD and the P8RI peptide—a CD31 agonist, both aiming to enhance endothelialization while reducing thrombotic risk. These strategies reflect the ongoing innovation targeting safer, SAPT-compatible FDs (12).

Limitations of the current evidence

Despite encouraging early outcomes, the current body of evidence on surface-modified FDs is constrained by several important limitations. Most available clinical data are derived from single-arm registries, observational studies, or small retrospective cohorts, which are inherently prone to selection bias and lack control groups for meaningful comparison. Moreover, there is considerable heterogeneity in antiplatelet regimens across studies—ranging from aspirin-based to P2Y₁₂-based SAPT and DAPT—with inconsistent assessment of platelet function or resistance. This makes it challenging to draw definitive conclusions about optimal antiplatelet strategies for each device. Follow-up imaging protocols also vary widely in modality (DSA vs. MRA vs. CTA), timing, and completeness, further complicating outcome comparisons. Crucially, no head-to-head randomized controlled trials currently exist comparing coated vs. uncoated FDs or comparing different coating technologies against one another. As such, while the clinical potential of surface modification is compelling, definitive evidence for superiority or long-term benefit remains to be established.

Conclusions

Surface modification offers a promising means to reduce or eliminate the need for DAPT in neurovascular interventions and to minimize thromboembolic complications. These modifications generally fall into two categories: those aimed at decreasing device thrombogenicity through improved hemocompatibility or the incorporation of antithrombotic agents, and those designed to enhance vascular endothelial cell adhesion and proliferation, thereby promoting faster healing and reducing the duration of antiplatelet therapy. While both strategies aim to improve safety and efficacy, they may sometimes work in opposition—what minimizes thrombosis may also hinder endothelialization. Therefore, the most effective surface modification will need a careful balance of thromboresistance with neo-endothelialization, making this interplay a critical focus for ongoing translational and clinical research in neurovascular care.

With a sustained increase in interest in the science of surface modification among both industry partners and neurovascular specialists and early encouraging results, this technology is expected to become a mainstay and flourish in the short to intermediate term.

Acknowledgments

The authors would like to extend their sincere thanks to Karen Ang (MicroVention/Terumo Neuro APAC), Jason Wong (phenox/Wallaby Medical APAC), and Meghan Noh (Medtronic APAC) for their kind assistance in providing background information and materials.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Tufail Patankar, Ricardo Hanel, Jeremy Lynch) for the series “Intracranial Aneurysms Current Status and Future Prospects” published in Journal of Neurointervention. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jni.amegroups.com/article/view/10.21037/jni-25-26/rc

Peer Review File: Available at https://jni.amegroups.com/article/view/10.21037/jni-25-26/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jni.amegroups.com/article/view/10.21037/jni-25-26/coif). The series “Intracranial Aneurysms Current Status and Future Prospects” was commissioned by the editorial office without any funding or sponsorship. A.G. has received payments for lectures from Balt, Becton & Dickinson, Penumbra, Stryker Neurovascular & Medtronic with all payments made to the employer. S.Z.T. has received sponsorship to attend training workshop from MicroVention. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Molyneux A, Kerr R, Stratton I, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002;360:1267-74. [Crossref] [PubMed]
2. Spetzler RF, McDougall CG, Zabramski JM, et al. Ten-year analysis of saccular aneurysms in the Barrow Ruptured Aneurysm Trial. J Neurosurg 2020;132:771-6. [Crossref] [PubMed]
3. Wiebers DO, Whisnant JP, Huston J 3rd, et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003;362:103-10. [Crossref] [PubMed]
4. Wakhloo AK, Gounis MJ. Revolution in aneurysm treatment: flow diversion to cure aneurysms: a paradigm shift. Neurosurgery 2014;61:111-20. [Crossref] [PubMed]
5. Lieber BB, Sadasivan C. Endoluminal scaffolds for vascular reconstruction and exclusion of aneurysms from the cerebral circulation. Stroke 2010;41:S21-5. [Crossref] [PubMed]
6. Monteiro A, Cappuzzo JM, Aguirre AO, et al. Transradial versus Transfemoral Approach for Neuroendovascular Procedures: A Survey of Patient Preferences and Perspectives. World Neurosurg 2022;163:e623-7. [Crossref] [PubMed]
7. Kan P, Sweid A, Srivatsan A, et al. Expanding Indications for Flow Diverters: Ruptured Aneurysms, Blister Aneurysms, and Dissecting Aneurysms. Neurosurgery 2020;86:S96-S103. [Crossref] [PubMed]
8. Ihn YK, Shin SH, Baik SK, et al. Complications of endovascular treatment for intracranial aneurysms: Management and prevention. Interv Neuroradiol 2018;24:237-45. [Crossref] [PubMed]
9. White TG, Santhumayor BA, Turpin J, et al. Flow diverter surface modifications for aneurysm treatment: A review of the mechanisms and data behind existing technologies. Interv Neuroradiol 2026;32:109-25. [Crossref] [PubMed]
10. Dandapat S, Mendez-Ruiz A, Martínez-Galdámez M, et al. Review of current intracranial aneurysm flow diversion technology and clinical use. J Neurointerv Surg 2021;13:54-62. [Crossref] [PubMed]
11. Girdbas MG, Riedel T, Riedelová Z, et al. Comparison of the hemocompatibility of neurovascular flow diverters with anti-thrombogenic coatings. J Sci Adv Mater Devices 2024;9:100666.
12. Zoppo CT, Mocco J, Manning NW, et al. Surface modification of neurovascular stents: from bench to patient. J Neurointerv Surg 2024;16:908-13. [Crossref] [PubMed]
13. Kuchinka J, Willems C, Telyshev DV, et al. Control of blood coagulation by hemocompatible material surfaces—a review. Bioengineering (Basel) 2021;8:215. [Crossref] [PubMed]
14. Mutlu O, Olcay AB, Bilgin C, et al. Understanding the effect of effective metal surface area of flow diverter stent’s on the patient-specific intracranial aneurysm numerical model using Lagrangian coherent structures. J Clin Neurosci 2020;80:298-309. [Crossref] [PubMed]
15. Gawlitza M, Klisch J, Kaiser DPO, et al. A systematic literature review and meta-analysis of the treatment of ruptured intracranial aneurysms with hydrophilic polymer and phosphorylcholine-coated flow diverters under single antiplatelet therapy. World Neurosurg 2023;170:e791-e800. [Crossref] [PubMed]
16. Girdhar G, Andersen A, Pangerl E, et al. Thrombogenicity assessment of Pipeline Flex, Pipeline Shield, and FRED flow diverters in an in vitro human blood physiological flow loop model. J Biomed Mater Res A 2018;106:3195-202. [Crossref] [PubMed]
17. Lewis AL, Stratford PW. A Review on Phosphorylcholine-Coated Stents. J Long Term Eff Med Implants 2017;27:233-52. [Crossref] [PubMed]
18. Zoppo CT, Epshtein M, Gounis MJ, et al. Longitudinal healing flow diverting stents with phosphorylcholine surface modification. J Neurointerv Surg 2024;16:582-6. [Crossref] [PubMed]
19. Trivelato FP, Wajnberg E, Rezende MTS, et al. Safety and Effectiveness of the Pipeline Flex Embolization Device With Shield Technology for the Treatment of Intracranial Aneurysms: Midterm Results From a Multicenter Study. Neurosurgery 2020;87:104-11. [Crossref] [PubMed]
20. Martínez-Galdámez M, Lamin SM, Lagios KG, et al. Treatment of intracranial aneurysms using the pipeline flex embolization device with shield technology: angiographic and safety outcomes at 1-year follow-up. J Neurointerv Surg 2019;11:396-9. [Crossref] [PubMed]
21. Manning NW, Cheung A, Phillips TJ, et al. Pipeline shield with single antiplatelet therapy in aneurysmal subarachnoid haemorrhage: multicentre experience. J Neurointerv Surg 2019;11:694-8. [Crossref] [PubMed]
22. Atasoy D, Kandasamy N, Hart J, et al. Outcome Study of the Pipeline Embolization Device with Shield Technology in Unruptured Aneurysms (PEDSU). AJNR Am J Neuroradiol 2019;40:2094-101. [Crossref] [PubMed]
23. Rice H, Martínez Galdámez M, Holtmannspötter M, et al. Periprocedural to 1-year safety and efficacy outcomes with the Pipeline Embolization Device with Shield technology for intracranial aneurysms: a prospective, post-market, multi-center study. J Neurointerv Surg 2020;12:1107-12. [Crossref] [PubMed]
24. Chia GS, de Villiers L, Carraro do Nascimento V, et al. Safety and Clinical Effectiveness of Pipeline Shield Device for Intracranial Aneurysms in an Australian Cohort (SCOPE‐AUS). Stroke Vasc Interv Neurol 2022;2:e000292. [Crossref] [PubMed]
25. Goertz L, Hohenstatt S, Vollherbst DF, et al. Multicenter Experience with the Pipeline Flex and Vantage with Shield Technology for Intracranial Aneurysm Treatment. AJNR Am J Neuroradiol 2024;45:1488-94. [Crossref] [PubMed]
26. de Villiers L, Carraro do Nascimento V, Domitrovic L, et al. Vanguard study: initial experience with the new fourth generation pipeline vantage flow diverter (PVFD): 6-month results, technical and clinical considerations. J Neurointerv Surg 2025;17:e166-e171. [Crossref] [PubMed]
27. Hanel RA, Cortez GM, Lopes DK, et al. Prospective study on embolization of intracranial aneurysms with the pipeline device (PREMIER study): 3-year results with the application of a flow diverter specific occlusion classification. J Neurointerv Surg 2023;15:248-54. [Crossref] [PubMed]
28. Kallmes DF, Hanel R, Lopes D, et al. International retrospective study of the pipeline embolization device: a multicenter aneurysm treatment study. AJNR Am J Neuroradiol 2015;36:108-15. [Crossref] [PubMed]
29. Tanaka M, Sato K, Kitakami E, et al. Design of biocompatible and biodegradable polymers based on intermediate water concept. Polym J 2015;47:114-21.
30. Hoshiba T, Nikaido M, Tanaka M. Characterization of the attachment mechanisms of tissue-derived cell lines to blood-compatible polymers. Adv Healthc Mater 2014;3:775-84. [Crossref] [PubMed]
31. Yoshizawa K, Kobayashi H, Kaneki A, et al. Poly(2-methoxyethyl acrylate) (PMEA) improves the thromboresistance of FRED flow diverters: a thrombogenic evaluation of flow diverters with human blood under flow conditions. J Neurointerv Surg 2023;15:1001-6. [Crossref] [PubMed]
32. Vollherbst DF, Lücking H, DuPlessis J, et al. The FRESH study: treatment of intracranial aneurysms with the new FRED X flow diverter with antithrombotic surface treatment technology—first multicenter experience in 161 patients. AJNR Am J Neuroradiol 2023;44:474-80. [Crossref] [PubMed]
33. Abbas R, Lan M, Naamani KE, et al. First United States multicenter experience with the new-generation FRED X surface-modified flow diversion stent: feasibility, safety, and short-term efficacy. J Neurosurg 2024;140:1054-63. [Crossref] [PubMed]
34. Goertz L, Styczen H, Siebert E, et al. FRED X flow diverter for the treatment of intracranial aneurysms: Two-center experience and mini-review of the literature. Interv Neuroradiol 2024; Epub ahead of print. [Crossref]
35. Guimaraens L, Saldaña J, Vivas E, et al. Flow diverter stents for endovascular treatment of aneurysms: a comparative study of efficacy and safety between FREDX and FRED. J Neurointerv Surg 2024;17:e159-65. [Crossref] [PubMed]
36. Pierot L, Spelle L, Berge J, et al. SAFE study (Safety and efficacy Analysis of FRED Embolic device in aneurysm treatment): 1-year clinical and anatomical results. J Neurointerv Surg 2019;11:184-9. [Crossref] [PubMed]
37. McDougall CG, Diaz O, Boulos A, et al. Safety and efficacy results of the Flow Redirection Endoluminal Device (FRED) stent system in the treatment of intracranial aneurysms: US pivotal trial. J Neurointerv Surg 2022;14:577-84. [Crossref] [PubMed]
38. Lenz-Habijan T, Bhogal P, Peters M, et al. Hydrophilic Stent Coating Inhibits Platelet Adhesion on Stent Surfaces: Initial Results In Vitro. Cardiovasc Intervent Radiol 2018;41:1779-85. [Crossref] [PubMed]
39. Bhogal P, Lenz-Habijan T, Bannewitz C, et al. Thrombogenicity of the p48 and anti-thrombogenic p48 hydrophilic polymer coating low-profile flow diverters in an in vitro human thrombin generation model. Interv Neuroradiol 2020;26:488-93. [Crossref] [PubMed]
40. Martínez Moreno R, Bhogal P, Lenz-Habijan T, et al. In vivo canine study of three different coatings applied to p64 flow-diverter stents: initial biocompatibility study. Eur Radiol Exp 2019;3:3. [Crossref] [PubMed]
41. Lenz-Habijan T, Bhogal P, Bannewitz C, et al. Prospective study to assess the tissue response to HPC-coated p48 flow diverter stents compared to uncoated devices in the rabbit carotid artery model. Eur Radiol Exp 2019;3:47. [Crossref] [PubMed]
42. King RM, Langan ET, Ughi GJ, et al. Acute Thrombus Burden on Coated Flow Diverters Assessed by High Frequency Optical Coherence Tomography. Cardiovasc Intervent Radiol 2020;43:1218-23. [Crossref] [PubMed]
43. Bhogal P, Bleise C, Chudyk J, et al. The p48_HPC antithrombogenic flow diverter: initial human experience using single antiplatelet therapy. J Int Med Res 2020;48:300060519879580. [Crossref] [PubMed]
44. Aguilar-Perez M, Hellstern V, AlMatter M, et al. The p48 Flow Modulation Device with Hydrophilic Polymer Coating (HPC) for the Treatment of Acutely Ruptured Aneurysms: Early Clinical Experience Using Single Antiplatelet Therapy. Cardiovasc Intervent Radiol 2020;43:740-8. [Crossref] [PubMed]
45. Guzzardi G, Galbiati A, Stanca C, et al. Flow diverter stents with hydrophilic polymer coating for the treatment of acutely ruptured aneurysms using single antiplatelet therapy: Preliminary experience. Interv Neuroradiol 2020;26:525-31. [Crossref] [PubMed]
46. Petrov A, Rentsenkhuu G, Nota B, et al. Initial experience with the novel p64MW HPC flow diverter from a cohort study in unruptured anterior circulation aneurysms under dual antiplatelet medication. Interv Neuroradiol 2021;27:42-50. [Crossref] [PubMed]
47. de Castro-Afonso LH, Nakiri GS, Abud TG, et al. Aspirin monotherapy in the treatment of distal intracranial aneurysms with a surface modified flow diverter: a pilot study. J Neurointerv Surg 2021;13:336-41. [Crossref] [PubMed]
48. de Castro-Afonso LH, Nakiri GS, Abud TG, et al. Treatment of distal unruptured intracranial aneurysms using a surface-modified flow diverter under prasugrel monotherapy: a pilot safety trial. J Neurointerv Surg 2021;13:647-51. [Crossref] [PubMed]
49. Lobsien D, Clajus C, Behme D, et al. Aneurysm Treatment in Acute SAH with Hydrophilic-Coated Flow Diverters under Single-Antiplatelet Therapy: A 3-Center Experience. AJNR Am J Neuroradiol 2021;42:508-15. [Crossref] [PubMed]
50. Bhogal P, Petrov A, Rentsenkhu G, et al. Early clinical experience with the p48MW HPC and p64MW HPC flow diverters in the anterior circulation aneurysm using single anti-platelet treatment. Interv Neuroradiol 2022;28:266-76. [Crossref] [PubMed]
51. Aguilar Pérez M, Henkes E, Hellstern V, et al. Endovascular Treatment of Anterior Circulation Aneurysms With the p64 Flow Modulation Device: Mid- and Long-Term Results in 617 Aneurysms From a Single Center. Oper Neurosurg 2021;20:355-63. [Crossref] [PubMed]
52. Hellstern V, Aguilar Pérez M, Henkes E, et al. Use of a p64 MW Flow Diverter with Hydrophilic Polymer Coating (HPC) and Prasugrel Single Antiplatelet Therapy for the Treatment of Unruptured Anterior Circulation Aneurysms: Safety Data and Short-term Occlusion Rates. Cardiovasc Intervent Radiol 2022;45:1364-74. [Crossref] [PubMed]
53. Pierot L, Lamin S, Barreau X, et al. Coating (Coating to Optimize Aneurysm Treatment in the New Flow Diverter Generation) study. The first randomized controlled trial evaluating a coated flow diverter (p64 MW HPC): study design. J Neurointerv Surg 2023;15:684-8. [Crossref] [PubMed]
54. Kaplan O, Hierlemann T, Krajewski S, et al. Low-thrombogenic fibrin-heparin coating promotes in vitro endothelialization. J Biomed Mater Res A 2017;105:2995-3005. [Crossref] [PubMed]
55. Goertz L, Schoenfeld M, Zopfs D, et al. The DERIVO 2heal embolisation device: A technical report using single antiplatelet therapy for intracranial pseudoaneurysm treatment. Interv Neuroradiol 2024;30:170-4. [Crossref] [PubMed]
56. Goertz L, Zopfs D, Schönfeld M, et al. First clinical experience with the Derivo 2heal embolization device for the treatment of intracranial aneurysms. Interv Neuroradiol 2026;32:57-65. [Crossref] [PubMed]
57. Schwab R, Kabbasch C, Goertz L, et al. The DERIVO 2 Heal Embolization Device in the Treatment of Ruptured and Unruptured Intracranial Aneurysms: a Retrospective Multicenter Study. Clin Neuroradiol 2025;35:25-34. [Crossref] [PubMed]
58. Findlay MC, Kundu M, Nelson JR, et al. Emerging Treatments for Subarachnoid Hemorrhage. CNS Neurol Disord Drug Targets 2024;23:1345-56. [Crossref] [PubMed]
59. Segherlou ZH, Shakeri-Darzekonani M, Khavandegar A, et al. Hormonal influences on cerebral aneurysms: unraveling the complex connections. Expert Rev Endocrinol Metab 2024;19:207-15. [Crossref] [PubMed]
60. Senol YC, Orscelik A, Ghozy S, et al. The safety profile of single antiplatelet therapy with flow diverters: Systematic review and meta-analysis. Interv Neuroradiol 2023; Epub ahead of print. [Crossref]
61. Saber H, Kherallah RY, Hadied MO, et al. Antiplatelet therapy and the risk of ischemic and hemorrhagic complications associated with Pipeline embolization of cerebral aneurysms: a systematic review and pooled analysis. J Neurointerv Surg 2019;11:362-6. [Crossref] [PubMed]
62. Ma Y, Madjidyar J, Schubert T, et al. Single antiplatelet regimen in flow diverter treatment of cerebral aneurysms: The drug matters. A systematic review and meta-analysis. Interv Neuroradiol 2023; Epub ahead of print. [Crossref]
63. Perez P, Lukaszewicz AC, Lenck S, et al. Platelet activation and aggregation after aneurysmal subarachnoid hemorrhage. BMC Neurol 2018;18:57. [Crossref] [PubMed]