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New devices and techniques
Review
Surface modification of neurovascular stents: from bench to patient
Free
  1. Christopher T Zoppo1,
  2. J Mocco2,
  3. Nathan W Manning3,4,
  4. Alexei A Bogdanov, Jr1,
  5. Matthew J Gounis1
  1. 1 New England Center for Stroke Research, Department of Radiology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
  2. 2 Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  3. 3 The MIRI Centre, Ingham Institute for Applied Medical Science, Sydney, New South Wales, Australia
  4. 4 Department of Interventional Radiology, Liverpool Hospital, Sydney, New South Wales, Australia
  1. Correspondence to Professor Matthew J Gounis, New England Center for Stroke Research, Department of Radiology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; matthew.gounis{at}umassmed.edu

Abstract

Flow-diverting stents (FDs) for the treatment of cerebrovascular aneurysms are revolutionary. However, these devices require systemic dual antiplatelet therapy (DAPT) to reduce thromboembolic complications. Given the risk of ischemic complications as well as morbidity and contraindications associated with DAPT, demonstrating safety and efficacy for FDs either without DAPT or reducing the duration of DAPT is a priority. The former may be achieved by surface modifications that decrease device thrombogenicity, and the latter by using coatings that expedite endothelial growth. Biomimetics, commonly achieved by grafting hydrophilic and non-interacting polymers to surfaces, can mask the device surface with nature-derived coatings from circulating factors that normally activate coagulation and inflammation. One strategy is to mimic the surfaces of innocuous circulatory system components. Phosphorylcholine and glycan coatings are naturally inspired and present on the surface of all eukaryotic cell membranes. Another strategy involves linking synthetic biocompatible polymer brushes to the surface of a device that disrupts normal interaction with circulating proteins and cells. Finally, drug immobilization can also impart antithrombotic effects that counteract normal foreign body reactions in the circulatory system without systemic effects. Heparin coatings have been explored since the 1960s and used on a variety of blood contacting surfaces. This concept is now being explored for neurovascular devices. Coatings that improve endothelialization are not as clinically mature as anti-thrombogenic coatings. Coronary stents have used an anti-CD34 antibody coating to capture circulating endothelial progenitor cells on the surface, potentially accelerating endothelial integration. Similarly, coatings with CD31 analogs are being explored for neurovascular implants.

  • Aneurysm
  • Flow Diverter
  • Device
  • Stent
  • Technology

https://doi.org/10.1136/jnis-2023-020620

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    Introduction

    Flow diversion represents a major milestone in the treatment of cerebrovascular aneurysms. Flow diverters (FDs) were initially indicated only for specific challenging aneurysm morphologies previously difficult to treat.1 However, clinical studies have expanded indications and ‘off-label’ use has dramatically expanded at many centers.2–4 Flow diversion requires a large metal surface area to be effective. Consequently, FDs are thrombogenic, leading to ischemic complications and necessitating dual antiplatelet therapy (DAPT). Even with effective DAPT, ischemic events represent the majority of complications following FD treatment.5 6 Suppression of platelet function increases the risk of serious bleeding,7 and yet it does not always prevent thromboembolic complications.8 9 An FD that was safe and effective with single antiplatelet therapy (SAPT), preferably aspirin alone, would be of significant clinical value. Although a variety of solutions have been considered including bioabsorbable materials for stent struts,10 FD surface modification represents one of the attractive strategies for reducing thromboembolic ischemic complications and avoiding DAPT after implantation.

    Several potential modifications have previously shown good safety profiles but variable efficacy when studied in coronary stents. Over time, interest in surface modification faded as drug-eluting stents, particularly sirolimus, demonstrated high efficacy in reducing restenosis.11 Even with a robust body of literature surrounding many of these surface modifications for coronary applications, further work is needed to apply these concepts to FDs. Treating coronary atherosclerotic disease, which with exposed plaque components is thrombogenic by itself, is different from treating aneurysmal disease of the neurovasculature. Furthermore, the coronary circulation is driven by diastolic flow through larger vessels creating relatively low shear stress compared with the systolic flow through the neurovasculature.12–14 Although stent thrombosis has devastating consequences in both locations, there are unique considerations. Very small thrombi forming at jailed side branches and perforators are a specific concern after flow diversion, while stent restenosis is more problematic following coronary intervention.5 11 15 Finally, the eloquence of the two organs involved means that the neurovascular circulation is far less forgiving. These distinctions and the design differences between coronary stents and FDs demonstrate the need for further investigation of surface modifications for FDs.

    While there are conceptually different approaches to reducing DAPT-associated complications (figure 1, table 1), both strategies will also reduce thromboembolic complications. The first and most obvious is to directly decrease device thrombogenicity using mechanisms that reduce or eliminate the need for systemic therapies. An alternative strategy is to promote rapid device surface endothelialization, as normal endothelium is the best antithrombotic coating. While this may not eliminate DAPT, it may significantly decrease the duration of therapy. These two approaches conflict somewhat. Coatings that prevent the attachment of platelets may also delay endothelialization, while coatings designed to improve endothelial growth and adhesion may be a similarly attractive surface for platelet adhesion and activation, thereby potentially increasing the risk of thrombosis.

    Figure 1
    Figure 1

    Chart showing the approaches taken by various surface modifications to reduce or eliminate the need for dual antiplatelet therapy (DAPT). NiTi, nitinol; PMEA, poly(2-methoxyethyl acrylate).

    View this table:
    Table 1

    Summary of different surface modifications/coatings for flow diversion and intracranial stents

    Currently, only the p48 and p64 devices with a hydrophilic polymer coating (HPC; Phenox, Bochum, Germany) come with instructions for SAPT in some regions when DAPT is contraindicated; however, there are several different surface modifications designed to achieve a similar goal. This review will focus on currently available surface-modified FDs, concepts in translational stages showing great promise, and some research supporting their design and use.

    Surface modifications

    Biopassive coatings

    When exposed to the circulation, the surface of bare metal devices such as FDs is coated with proteins that can trigger undesirable reactions including inflammation, contact activation of the intrinsic coagulation cascade, and platelet activation.16 17 One way to avoid these reactions and their associated sequelae is to mask the device surface from circulating substrates such as platelets, fibrinogen, clotting factors, and leukocytes, among others. This can be accomplished by mimicking natural hydrophilic circulatory system components that do not induce these deleterious processes, or with non-interacting polymers that interrupt natural device surface interactions.18 Either strategy can impart reduced thrombogenicity while still allowing for normal neointima growth and proliferation.

    Phosphorylcholine

    Phosphorylcholine is a component of phosphatidyl choline headgroup and is the major constituent of all eukaryotic cell membranes, including red blood cells. Phosphatidyl choline headgroups do not induce platelet activation or allow for effective adhesion. It creates a hydrophilic boundary layer, discouraging protein conformational changes required for intrinsic pathway activation.19 It was perhaps the original coating proposed for vascular stents.20 It has been well studied on devices in the coronary vasculature; however, the vastly different cerebral vascular environment necessitates additional research and consideration. Medtronic (Irvine, California, USA) has built on coronary stent coating experiences to design a phosphorylcholine surface modification (Shield) for their Pipeline and Vantage FDs. It is a 3 nm thick chemically modified surface created from phosphorylcholine covalently linked to the devices’ braided wires.

    Early in vitro and ex vivo work showed that this surface modification resulted in significantly less prothrombin proteolytic activation and platelet deposition compared with uncoated devices. In vascular flow loops, the results were approximately the same as in the control group with no device.21–23 However, these model systems only test the intrinsic pathway for contact activation of blood products. In vivo modelling is required to study both the intrinsic and extrinsic pathways. More recently, rabbit model data showed that Shield-coated devices had significantly less thrombus formation than uncoated devices, as measured with intravascular optical coherence tomography, even in animals not treated with DAPT.24 25 It is worth noting that coated devices also had less side branch thrombus formation, an important consideration for implant sites in the distal cerebral vasculature.24 The coating does not negatively affect aneurysm occlusion rates and reduces neointimal hyperplasia, with earlier and more uniform neointimal growth compared with uncoated devices.26 27 In a rabbit model, the Shield modification did not interfere with longitudinal healing, which is a concern with many surface modification strategies.28

    With the efficacy and antithrombotic properties of the coating so well established, the next step is to evaluate whether this modification allows for SAPT, a particularly important question for patients with a ruptured aneurysm for whom DAPT carries significant risks.29 Early case reports demonstrate conflicting results,30 31 but some recent literature is promising.32–34 The largest multicenter retrospective study reported success in treating 14 ruptured aneurysms with Shield-coated devices and aspirin monotherapy with few ischemic and hemorrhagic complications.35 Continued work with larger patient populations and more standardized antiplatelet regimens is needed to completely understand the safety of this practice. The regulatory challenge has been to find the indication in which the risk–benefit ratio for SAPT would be acceptable. The ELEVATE trial (clinicaltrials.gov, NCT04391803) will test short-duration DAPT (48 hours) for acutely ruptured shallow intradural aneurysms treated with FDs having Shield technology.

    Glycans

    Glycans are another ubiquitous constituent of biological systems. Designed to mimic the glycocalyx and reduce hydrophobic interactions, HPC (Phenox) is a multilayer surface made of glycans covalently bonded to braids of the p48 and p64 FDs.

    Initial experiments in vitro showed that, based on immunohistochemistry, there is significantly less platelet adherence and activation with HPC-coated FD wires compared with similar uncoated wires.36 37 Given that the p48 device is designed for more distal circulation,38 it is important to consider side branch clot formation. In a porcine model investigating coated and uncoated devices with various antiplatelet regimens, both the HPC coating and systemic administration of aspirin were shown to significantly reduce thrombus formation over side branches, and the combination of the two eliminated 99.8% of side branch clots.15

    Although this is the only surface modification on the market that comes with instructions for SAPT after implantation in certain regions and when DAPT is contraindicated, results in the literature are mixed. A prospective study investigating these devices in the treatment of distal intracranial aneurysms with aspirin alone was stopped after eight patients were treated due to a very high rate of ischemic complications.39 Similar findings have also been reported in retrospective studies treating patients with ruptured aneurysms.40–42 Thromboembolic complications all occurred under SAPT with aspirin, and there is evidence that HPC-coated devices may be safe with SAPT when P2Y12 inhibitors are used.43–46 The COATING trial (clinicaltrials.gov, NCT04870047) is the first randomized clinical trial designed to test whether SAPT with prasugrel is as safe and effective as DAPT in the treatment of aneurysms with p64 HPC FDs. However, it is possible that the omission of aspirin, the weaker antiplatelet agent in the pairing, may limit the benefit of SAPT.

    Poly(2-methoxyethyl acrylate) (PMEA)

    PMEA belongs to a family of synthetic flexible biocompatible polymers including poly(ethylene glycol), poly(2-ethyl-2-oxazoline), poly(2-methoxyethyl acrylate) and others that disrupt normal interaction with circulating proteins and cells.47 48 PMEA is a thromboresistant polymer with years of medical device application evaluation, including extracorporeal membrane oxygenation machines. When any hydrophilic polymer coating is exposed to an aqueous environment it hydrates, forming a protective layer. PMEA attracts intermediate water molecules, which interact only weakly with the methoxy group of PMEA. When crystallizing and weakly associated, the dynamics of intermediate water appear to be involved in disrupting the interactions between the polymer and various proteins (eg, fibrinogen and factor XII). As a result, the proteins do not undergo conformational changes which would activate them and initiate the intrinsic pathway. Therefore, platelets are less likely to activate or adhere to the surface.49 Importantly, this coating does not seem to alter other binding interactions, such as those with endothelial and smooth muscle cells, because the cells use multiple simultaneous interactions between cell adhesion molecules and the surface-adsorbed proteins. This allows for normal endothelial growth over the device surface.

    X-technology covalently links PMEA to all surfaces of the dual-layer FRED device (FRED-X; Microvention, Aliso Viejo, California, USA) to impart thromboresistance. In vitro research shows superior hemocompatibility by reducing contact activation. Reported platelet counts, β-thromboglobulin (β-TG), and thrombin–antithrombin complex (TAT) levels were similar between Shield and FRED-X devices, and negative controls with no devices. Additionally, the β-TG and TAT levels of uncoated devices were significantly increased while platelet count was significantly decreased.50 On SEM analysis of the devices, the fewest platelet deposits were noted on the FRED-X device and immunohistochemistry findings suggest that the coating did not impede endothelial cell attachment.50 The multicenter FRESH study supported in vitro findings with results from 161 patients treated with FRED-X under several DAPT regimens depending on institutional standards. The study reported a low rate of thrombotic complications (4.3%) and major adverse events (3.1%), while 66% of the aneurysms were completely occluded at the study endpoint.51 These positive findings raise the possibility that the antithrombotic properties of the coating could make these devices safe with SAPT, but clinical validation is still required.

    Drug bound devices

    An alternative strategy for creating antithrombotic device coatings involves binding active drugs to the surface to reduce or eliminate the need for systemic drug therapy. In these examples, the drug is immobilized permanently to the surface of the device rather than eluted over time. The advantage of this approach is that it addresses the presence of the foreign material and the underlying damage to the intima during device deployment, which activates the extrinsic coagulation pathway. Data have shown that simple microcatheterization leads to endothelium denudation,52 which exposes thrombogenic subendothelial structures (figure 2). An active drug coating could theoretically limit thrombosis in this setting, or potentially lyse clots as they form.

    Figure 2
    Figure 2

    Scanning electron microscope image from a cross section of a canine anterior spinal artery after a microcatheter was passed through. Denudation of the endothelium on the vascular wall along the path of the microcatheter can be seen (arrowheads), as well as the path of the microwire (arrow).

    Immobilized heparin

    Heparin coating to reduce device thrombogenicity has been explored since the 1960s.53 54 A staple anticoagulant for 100 years, heparin enhances the natural antithrombotic mechanisms of the coagulation cascade. Specifically, it activates antithrombin III, which primarily inactivates factor V and thrombin, as well as other serine proteases.55 This, in turn, also inhibits platelet adhesion and activation.56 The decreased adhesion is likely due to reduced fibrinogen deposition, while the reduced activation is due to a reduction in platelet-stimulating factors like thrombin.54 57 These additional properties highlight the promise of using a heparin-coated neurovascular device without DAPT.

    Heparin coating was an exciting approach to prevent stent thrombosis in the coronary circulation before the ubiquity of drug-eluting designs. Although the larger registry studies are inconclusive,58 some have suggested heparin coatings to be safe and effective at reducing subacute stent thrombosis.59 Additionally, the HOPE trial demonstrated a 30-day stent thrombosis rate of 1% in 200 treated coronary arteries under aspirin monotherapy.60

    To build on this proven technology, Stryker recently entered a partnership with Carmeda (a wholly owned subsidiary of W.L. Gore Associates, Newark, Delaware, USA), seeking to improve their Evolve FD with a surface of covalently bonded heparin molecules (figure 3). Some early evidence supports the safety and efficacy of this surface modification in the neurovasculature,61 but it has yet to be applied to specific neurovascular devices. This coating has shown promise recently in a canine model. Both coated and uncoated FDs were implanted in the basilar artery. Animals in the coated stent group had fewer magnetic susceptibility artifacts on susceptibility weighted imaging than those in the bare stent group after 1 week, implying less thromboembolism. The coated devices also showed a trend to less acute thrombus formation on optical coherence tomography immediately following implantation compared with controls. These results suggest that the coating confers a reduced risk of thromboembolic events without a difference in efficacy.62 63 Future studies will look to build on these preliminary results.

    Figure 3
    Figure 3

    (A) The anticoagulant effects of freely soluble heparin systemically administered, which is dependent on concentration and molecular weight. (B) Heparin attached and immobilized on the surface of an implantable device which inhibits clotting factors by antithrombin at the material interface. (C) heparan sulfate proteoglycan of the endothelium which naturally binds antithrombin and inhibits clotting factors. (Figure from Advanced Drug Delivery Reviews 2017;112:12–23).54

    Fibrin nano-coating with bound heparin

    Fibrin-heparin coatings are being investigated to both decrease device thrombogenicity and improve endothelial ingrowth. Activated platelets aggregate and begin clot formation by binding fibrinogen through GPIIb/IIIa.55 Platelets also aggregate through GPIb and integrin-mediated interactions with fibrin. Unlike typical aggregation mechanisms, this alternative pathway depends on activated thrombin, the coagulation cascade’s final product.64 Heparin, which induces thrombin inactivation, can therefore be covalently bound to a fibrin coating, creating a surface that is highly conducive to endothelial growth and inert to coagulation.65 In vitro, foil sheets with this coating have significantly more bound endothelial cells compared with uncoated foil after incubation with a medium containing isolated endothelial cells. The fibrin-heparin-coated sheets were also found to be significantly less thrombogenic than plain fibrin-coated and bare metal sheets. This was reflected by platelet counts and SEM imaging after incubation with whole blood.66

    Acandis (Pforsheim, Delaware, USA) has used these principles to create a fibrin-heparin nanocoating for their DERIVO 2Heal embolization device. In a rabbit model, the device showed similar biocompatibility to bare stents with significantly less fibrin and platelet deposition. The endothelial growth over the device did not appear to be different between the coated and uncoated stents.67 To further investigate the long-term angiographic outcomes and safety of this coated device, Acandis is sponsoring the REheal observational trial (clinicaltrials.gov, NCT05543447), which will soon be enrolling patients. SAPT with this device appears promising,68 but larger studies are needed to corroborate the preliminary data.

    Immobilized FXa-GPIIb/IIIa inhibitors

    Another compelling drug choice is EP224238, which has the actions of both the antiplatelet drug tirofiban and the anticoagulant drug idraparinux. The combined antiplatelet and anticoagulant activity may reduce stent thrombosis substantially without systemic agents. Coated and uncoated discs showed similar results on platelet adhesion assays; however, qualitative platelet morphology analysis on SEM did demonstrate reduced platelet activation. Furthermore, drug-coated discs had good anti-FXa activity after exposure to whole blood, and human endothelial cell adhesion was unaffected.69 Theoretically, targeting FXa activation may also have advantages over heparin in certain patient populations as it does not require native antithrombin III activity. While we are not aware of any FD currently being developed with this coating, this concept is theoretically compelling.

    Modifications to improve endothelial growth

    While the previous surface modifications focused on reducing device thrombogenicity, another strategy for decreasing the requirement for DAPT is to increase the rate of implant endothelialization. Theoretically, DAPT should only be required for as long as the device is exposed to circulating blood.70 Accelerating endothelial ingrowth could theoretically decrease the amount of time patients spend on DAPT and the risk of thromboembolic complications.

    Anti-CD34 antibody

    Circulating CD34+ endothelial progenitor cells were shown to result in endothelization of implanted devices.71 Surface modification of FDs with covalently bound anti-CD34 antibodies should more efficiently bind circulating progenitor cells and may decrease the vasculature exposure time to a device. OrbusNeich has combined this antibody coating with a more traditional unidirectional drug-eluting polymer coating in their COMBO Plus coronary stent.

    Early work showed that the addition of the antibody surface modification allowed for the maintenance of the antiproliferative effects of sirolimus while also enhancing the endothelial growth over the device.72 The results of the REMEDEE registry further support this technology in the coronary circulation. Of the 1000 patients enrolled over the 5-year study, only 0.9% experienced stent thrombosis, with no cases reported after 3 years.73 These results are promising, and it may be worthwhile to consider the development of this technology on devices designed for the cerebral vasculature.

    UV-irradiated nitinol

    UV irradiation has been shown to alter the wettability of titanium dioxide surfaces.74 Building on these findings, another possible strategy for improving endothelial growth is through UV irradiation of nitinol. Electron transfer reactions via UV irradiation result in the conversion of Ti4+ to Ti3+, which has affinity for dissociative water adsorption.75 The UV-modified device surface led to increased albumin absorption, which is known to be inversely correlated with thrombogenicity. Endothelial cells were also shown to migrate over the surface more easily than on non-irradiated metal.75

    CD31 analogs

    CD31, also known as PECAM-1, is a transmembrane glycoprotein selectively expressed on platelets, leukocytes, and endothelial cells (figure 4).76 The molecule decreases the activation of leukocytes and platelets and may improve the healing of the vascular endothelium.77 Given this role, surface modification with an analog could conceivably improve device incorporation into the vessel wall, while also decreasing implant site inflammation and thrombosis.

    Figure 4
    Figure 4

    (A) Principal functions of CD31. CD31 is highly expressed at the surface of endothelial cells, platelets, and leukocytes. It plays key regulatory functions for circulation homeostasis on intercellular trans-homophilic binding. (B) Schematic of the P8RI peptide grafted onto the flow diverter strut. P8RI acts as a CD31 agonist by binding to a juxtamembrane CD31 domain. It aims at favoring endothelialization over the flow diverter while preventing thrombosis and inflammation. (Figure courtesy of Professors Aymeric Rouchaud and Jonathan Cortese).

    It has been shown that the P8RI peptide, an analog of the extramembrane portion of CD31, can be linked to the surface of Silk Vista Baby devices. In vitro, endothelial adhesion was improved and reaction with blood components was significantly decreased.78 In a rabbit model, endothelial ingrowth was improved and platelet activation decreased. Importantly, even though the coating stimulated neointimal growth, the vessels remained patent with adequate caliber.78 Surface modification with a CD31 analog is a promising approach to promote rapid endothelial coverage.

    Conclusions

    Surface modifications represent a powerful set of strategies to reduce or remove the requirement for DAPT with neurovascular implants as well as the most common ischemic complications resulting from thromboembolism. Most surface modifications can be divided into two broad categories: (1) those designed to decrease device thrombogenicity using hemocompatibility or bound drugs directly; and (2) technologies to spur vascular endothelial cell adhesion and proliferation on the surface of the device, decreasing the required duration of DAPT. Although these strategies share similar goals, they may counteract each other. The best surface modification will likely have to ensure a balance between these two approaches. As applied to the neurovasculature, this remains a critical topic for translational and clinical research.

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    References

    1. ↵
      2. Kühn AL ,
      3. Gounis MJ ,
      4. Puri AS
      . Introduction: history and development of flow diverter technology and evolution. Neurosurgery 2020;86:S3–10. doi:10.1093/neuros/nyz307
      OpenUrlPubMed
    2. ↵
      2. Patel PD ,
      3. Chalouhi N ,
      4. Atallah E , et al
      . Off-label uses of the pipeline embolization device: a review of the literature. Neurosurg Focus 2017;42:E4. doi:10.3171/2017.3.FOCUS1742
    3. ↵
      2. Brouillard AM ,
      3. Sun X ,
      4. Siddiqui AH , et al
      . The use of flow diversion for the treatment of intracranial aneurysms: expansion of indications. Cureus 2016;8:e472. doi:10.7759/cureus.472
    4. ↵
      2. Hanel RA ,
      3. Kallmes DF ,
      4. Lopes DK , et al
      . Prospective study on embolization of intracranial aneurysms with the pipeline device: the PREMIER study 1 year results. J Neurointerv Surg 2020;12:62–6. doi:10.1136/neurintsurg-2019-015091
      OpenUrlAbstract/FREE Full Text
    5. ↵
      2. Brinjikji W ,
      3. Murad MH ,
      4. Lanzino G , et al
      . Endovascular treatment of intracranial aneurysms with flow diverters: a meta-analysis. Stroke 2013;44:442–7. doi:10.1161/STROKEAHA.112.678151
      OpenUrlAbstract/FREE Full Text
    6. ↵
      2. Cagnazzo F ,
      3. Fanti A ,
      4. Lefevre P-H , et al
      . Distal anterior cerebral artery aneurysms treated with flow diversion: experience of a large-volume center and systematic review of the literature. J Neurointerv Surg 2021;13:42–8. doi:10.1136/neurintsurg-2020-015980
      OpenUrlAbstract/FREE Full Text
    7. ↵
      2. Diener H-C ,
      3. Bogousslavsky J ,
      4. Brass LM , et al
      . Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331–7. doi:10.1016/S0140-6736(04)16721-4
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      2. Wong GKC ,
      3. Kwan MCL ,
      4. Ng RYT , et al
      . Flow diverters for treatment of intracranial aneurysms: current status and ongoing clinical trials. J Clin Neurosci 2011;18:737–40. doi:10.1016/j.jocn.2010.10.011
      OpenUrlCrossRefPubMed
    9. ↵
      2. Pierot L
      . Flow diverter stents in the treatment of intracranial aneurysms: where are we? J Neuroradiol 2011;38:40–6. doi:10.1016/j.neurad.2010.12.002
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      2. Jamshidi M ,
      3. Rajabian M ,
      4. Avery MB , et al
      . A novel self-expanding primarily bioabsorbable braided flow-diverting stent for aneurysms: initial safety results. J Neurointerv Surg 2020;12:700–5. doi:10.1136/neurintsurg-2019-015555
      OpenUrlAbstract/FREE Full Text
    11. ↵
      2. Moses JW ,
      3. Leon MB ,
      4. Popma JJ , et al
      . Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–23. doi:10.1056/NEJMoa035071
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      2. Muller O ,
      3. Pyxaras SA ,
      4. Trana C , et al
      . Pressure-diameter relationship in human coronary arteries. Circ Cardiovasc Interv 2012;5:791–6. doi:10.1161/CIRCINTERVENTIONS.112.972224
      OpenUrlAbstract/FREE Full Text
    13. ↵
      2. Spaan JAE ,
      3. Piek JJ ,
      4. Hoffman JIE , et al
      . Physiological basis of clinically used coronary hemodynamic indices. Circulation 2006;113:446–55. doi:10.1161/CIRCULATIONAHA.105.587196
      OpenUrlAbstract/FREE Full Text
    14. ↵
      2. Cebral JR ,
      3. Putman CM ,
      4. Alley MT , et al
      . Hemodynamics in normal cerebral arteries: qualitative comparison of 4D phase-contrast magnetic resonance and image-based computational fluid dynamics. J Eng Math 2009;64:367–78. doi:10.1007/s10665-009-9266-2
      OpenUrlCrossRefPubMed
    15. ↵
      2. King RM ,
      3. Langan ET ,
      4. 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. doi:10.1007/s00270-020-02482-w
      OpenUrlCrossRefPubMed
    16. ↵
      2. Weber M ,
      3. Steinle H ,
      4. Golombek S , et al
      . Blood-contacting biomaterials: in vitro evaluation of the hemocompatibility. Front Bioeng Biotechnol 2018;6:99. doi:10.3389/fbioe.2018.00099
    17. ↵
      2. Liu X ,
      3. Yuan L ,
      4. Li D , et al
      . Blood compatible materials: state of the art. J Mater Chem B 2014;2:5718–38. doi:10.1039/C4TB00881B
      OpenUrl
    18. ↵
      2. Benetti EM ,
      3. Divandari M ,
      4. Ramakrishna SN , et al
      . Loops and cycles at surfaces: the unique properties of topological polymer brushes. Chemistry 2017;23:12433–42. doi:10.1002/chem.201701940
      OpenUrl
    19. ↵
      2. Campbell EJ ,
      3. O’Byrne V ,
      4. Stratford PW , et al
      . Biocompatible surfaces using methacryloylphosphorylcholine laurylmethacrylate copolymer. ASAIO J 1994;40:M853–7. doi:10.1097/00002480-199407000-00118
      OpenUrlPubMed
    20. ↵
      2. Hayward JA ,
      3. Chapman D
      . Biomembrane surfaces as models for polymer design: the potential for haemocompatibility. Biomaterials 1984;5:135–42. doi:10.1016/0142-9612(84)90047-4
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      2. Hagen MW ,
      3. Girdhar G ,
      4. Wainwright J , et al
      . Thrombogenicity of flow diverters in an ex vivo shunt model: effect of phosphorylcholine surface modification. J Neurointerv Surg 2017;9:1006–11. doi:10.1136/neurintsurg-2016-012612
      OpenUrlAbstract/FREE Full Text
    22. ↵
      2. Girdhar G ,
      3. Ubl S ,
      4. Jahanbekam R , et al
      . Thrombogenicity assessment of Pipeline, Pipeline Shield, Derivo and P64 flow diverters in an in vitro pulsatile flow human blood loop model. eNeurologicalSci 2019;14:77–84. doi:10.1016/j.ensci.2019.01.004
      OpenUrl
    23. ↵
      2. Girdhar G ,
      3. Andersen A ,
      4. 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. doi:10.1002/jbm.a.36514
      OpenUrlPubMed
    24. ↵
      2. Marosfoi M ,
      3. Clarencon F ,
      4. Langan ET , et al
      . Acute thrombus formation on phosphorilcholine surface modified flow diverters. J Neurointerv Surg 2018;10:406–11. doi:10.1136/neurintsurg-2017-013175
      OpenUrlAbstract/FREE Full Text
    25. ↵
      2. Starke RM ,
      3. Thompson J ,
      4. Pagani A , et al
      . Preclinical safety and efficacy evaluation of the pipeline vantage embolization device with shield technology. J Neurointerv Surg 2020;12:981–6. doi:10.1136/neurintsurg-2020-016043
      OpenUrlAbstract/FREE Full Text
    26. ↵
      2. Caroff J ,
      3. Tamura T ,
      4. King RM , et al
      . Phosphorylcholine surface modified flow diverter associated with reduced intimal hyperplasia. J Neurointerv Surg 2018;10:1097–101. doi:10.1136/neurintsurg-2018-013776
      OpenUrlAbstract/FREE Full Text
    27. ↵
      2. Matsuda Y ,
      3. Chung J ,
      4. Lopes DK
      . Analysis of neointima development in flow diverters using optical coherence tomography imaging. J Neurointerv Surg 2018;10:162–7. doi:10.1136/neurintsurg-2016-012969
      OpenUrlAbstract/FREE Full Text
    28. ↵
      2. Zoppo CT ,
      3. Epshtein M ,
      4. Gounis MJ , et al
      . Longitudinal healing flow diverting stents with phosphorylcholine surface modification. J Neurointerv Surg 2023:jnis-2023-020500. doi:10.1136/jnis-2023-020500
    29. ↵
      2. Luo C ,
      3. Jin L ,
      4. Dong J , et al
      . Clinical outcomes of pipeline embolization devices with shield technology for treating intracranial aneurysms. Front Neurol 2022;13:971664. doi:10.3389/fneur.2022.971664
    30. ↵
      2. Chiu AHY ,
      3. Ramesh R ,
      4. Wenderoth J , et al
      . Use of aspirin as sole oral antiplatelet therapy in acute flow diversion for ruptured dissecting aneurysms. J Neurointerv Surg 2017;9:e18. doi:10.1136/neurintsurg-2016-012657.rep
    31. ↵
      2. Hanel RA ,
      3. Aguilar-Salinas P ,
      4. Brasiliense LB , et al
      . First US experience with Pipeline Flex with Shield technology using aspirin as antiplatelet monotherapy. BMJ Case Rep 2017;2017:bcr2017219406. doi:10.1136/bcr-2017-219406
    32. ↵
      2. Pasarikovski CR ,
      3. Waggass G ,
      4. Cardinell J , et al
      . Pipeline embolisation device with Shield technology for the treatment of ruptured intracranial aneurysm. Neuroradiol J 2019;32:189–92. doi:10.1177/1971400919834692
      OpenUrlPubMed
    33. ↵
      2. Yeomans J ,
      3. Sandu L ,
      4. Sastry A
      . Pipeline Flex embolisation device with shield technology for the treatment of patients with intracranial aneurysms: periprocedural and 6 month outcomes. Neuroradiol J 2020;33:471–8. doi:10.1177/1971400920966749
      OpenUrlPubMed
    34. ↵
      2. Mohammaden MH ,
      3. English SW ,
      4. Stapleton CJ , et al
      . Safety and efficacy of ticagrelor as single antiplatelet therapy in prevention of thromboembolic complications associated with the Pipeline Embolization Device (PED): multicenter experience. J Neurointerv Surg 2020;12:1113–6. doi:10.1136/neurintsurg-2020-015978
      OpenUrlAbstract/FREE Full Text
    35. ↵
      2. Manning NW ,
      3. Cheung A ,
      4. Phillips TJ , et al
      . Pipeline Shield with single antiplatelet therapy in aneurysmal subarachnoid haemorrhage: multicentre experience. J Neurointerv Surg 2019;11:694–8. doi:10.1136/neurintsurg-2018-014363
      OpenUrlAbstract/FREE Full Text
    36. ↵
      2. Lenz-Habijan T ,
      3. Bhogal P ,
      4. Peters M , et al
      . Hydrophilic stent coating inhibits platelet adhesion on stent surfaces: initial results in vitro. Cardiovasc Intervent Radiol 2018;41:1779–85. doi:10.1007/s00270-018-2036-7
      OpenUrlCrossRefPubMed
    37. ↵
      2. Lenz-Habijan T ,
      3. Brodde M ,
      4. Kehrel BE , et al
      . Comparison of the thrombogenicity of a bare and antithrombogenic coated flow diverter in an in vitro flow model. Cardiovasc Intervent Radiol 2020;43:140–6. doi:10.1007/s00270-019-02307-5
      OpenUrlPubMed
    38. ↵
      2. Bhogal P ,
      3. Bleise C ,
      4. Chudyk J , et al
      . The p48MW flow diverter—initial human experience. Clin Neuroradiol 2021;31:135–45. doi:10.1007/s00062-019-00827-8
      OpenUrl
    39. ↵
      2. de Castro-Afonso LH ,
      3. Nakiri GS ,
      4. 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. doi:10.1136/neurintsurg-2020-017024
      OpenUrlAbstract/FREE Full Text
    40. ↵
      2. Aguilar-Perez M ,
      3. Hellstern V ,
      4. 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. doi:10.1007/s00270-020-02418-4
      OpenUrlCrossRefPubMed
    41. ↵
      2. Guzzardi G ,
      3. Galbiati A ,
      4. 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. doi:10.1177/1591019920950878
      OpenUrlPubMed
    42. ↵
      2. Lobsien D ,
      3. Clajus C ,
      4. 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. doi:10.3174/ajnr.A6942
      OpenUrlAbstract/FREE Full Text
    43. ↵
      2. Bhogal P ,
      3. Petrov A ,
      4. 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. doi:10.1177/15910199211029503
      OpenUrlPubMed
    44. ↵
      2. Hellstern V ,
      3. Aguilar Pérez M ,
      4. 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. doi:10.1007/s00270-022-03153-8
      OpenUrl
    45. ↵
      2. Bhogal P ,
      3. Bleise C ,
      4. Chudyk J , et al
      . The p48_HPC antithrombogenic flow diverter: initial human experience using single antiplatelet therapy. J Int Med Res 2020;48:300060519879580. doi:10.1177/0300060519879580
      OpenUrlCrossRefPubMed
    46. ↵
      2. de Castro-Afonso LH ,
      3. Nakiri GS ,
      4. 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. doi:10.1136/neurintsurg-2020-017262
      OpenUrlAbstract/FREE Full Text
    47. ↵
      2. Maitz MF ,
      3. Martins MCL ,
      4. Grabow N , et al
      . The blood compatibility challenge. Part 4: surface modification for hemocompatible materials: passive and active approaches to guide blood-material interactions. Acta Biomater 2019;94:33–43. doi:10.1016/j.actbio.2019.06.019
      OpenUrl
    48. ↵
      2. Viegas TX ,
      3. Bentley MD ,
      4. Harris JM , et al
      . Polyoxazoline: chemistry, properties, and applications in drug delivery. Bioconjug Chem 2011;22:976–86. doi:10.1021/bc200049d
      OpenUrlCrossRefPubMed
    49. ↵
      2. Tanaka M ,
      3. Sato K ,
      4. Kitakami E , et al
      . Design of biocompatible and biodegradable polymers based on intermediate water concept. Polym J 2015;47:114–21. doi:10.1038/pj.2014.129
      OpenUrl
    50. ↵
      2. Yoshizawa K ,
      3. Kobayashi H ,
      4. 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. doi:10.1136/jnis-2022-019248
      OpenUrlAbstract/FREE Full Text
    51. ↵
      2. Vollherbst DF ,
      3. Lücking H ,
      4. 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. doi:10.3174/ajnr.A7834
      OpenUrlAbstract/FREE Full Text
    52. ↵
      2. Gounis MJ ,
      3. Wakhloo AK ,
      4. Chueh J-Y
      . Preclinical investigations for thrombectomy devices--does it translate to humans? Stroke 2013;44:S7–10. doi:10.1161/STROKEAHA.111.000692
      OpenUrlFREE Full Text
    53. ↵
      2. Gott VL ,
      3. Whiffen JD ,
      4. Dutton RC
      . Heparin bonding on colloidal graphite surfaces. Science 1963;142:1297–8. doi:10.1126/science.142.3597.1297
      OpenUrlAbstract/FREE Full Text
    54. ↵
      2. Biran R ,
      3. Pond D
      . Heparin coatings for improving blood compatibility of medical devices. Adv Drug Deliv Rev 2017;112:12–23. doi:10.1016/j.addr.2016.12.002
      OpenUrl
    55. ↵
      2. Versteeg HH ,
      3. Heemskerk JWM ,
      4. Levi M , et al
      . New fundamentals in hemostasis. Physiol Rev 2013;93:327–58. doi:10.1152/physrev.00016.2011
      OpenUrlCrossRefPubMed
    56. ↵
      2. Stenach N ,
      3. Korn RL ,
      4. Fisher CA , et al
      . The effects of heparin bound surface modification (Carmeda bioactive surface) on human platelet alterations during simulated extracorporeal circulation. J Extra Corpor Technol 1992;24:97–102.
      OpenUrlPubMed
    57. ↵
      2. Weber N ,
      3. Wendel HP ,
      4. Ziemer G
      . Hemocompatibility of heparin-coated surfaces and the role of selective plasma protein adsorption. Biomaterials 2002;23:429–39. doi:10.1016/s0142-9612(01)00122-3
      OpenUrlCrossRefPubMedWeb of Science
    58. ↵
      2. Mehran R ,
      3. Nikolsky E ,
      4. Camenzind E , et al
      . An internet-based registry examining the efficacy of heparin coating in patients undergoing coronary stent implantation. Am Heart J 2005;150:1171–6. doi:10.1016/j.ahj.2005.01.027
      OpenUrlCrossRefPubMedWeb of Science
    59. ↵
      2. Gupta V ,
      3. Aravamuthan BR ,
      4. Baskerville S , et al
      . Reduction of subacute stent thrombosis (SAT) using heparin-coated stents in a large-scale, real world registry. J Invasive Cardiol 2004;16:304–10.
      OpenUrlPubMed
    60. ↵
      2. Mehran R ,
      3. Aymong ED ,
      4. Ashby DT , et al
      . Safety of an aspirin-alone regimen after intracoronary stenting with a heparin-coated stent. Circulation 2003;108:1078–83. doi:10.1161/01.CIR.0000086347.31341.F9
      OpenUrlAbstract/FREE Full Text
    61. ↵
      2. Parkinson RJ ,
      3. Demers CP ,
      4. Adel JG , et al
      . Use of heparin-coated stents in neurovascular Interventional procedures: preliminary experience with 10 patients. Neurosurgery 2006;59:812–21; doi:10.1227/01.NEU.0000232836.66310.46
      OpenUrlCrossRefPubMed
    62. ↵
      2. King R ,
      3. Anagnostakou V ,
      4. Peker A , et al
      . Active coating of flow diverters reduce the number of downstream magnetic susceptibility artifacts. SNIS 19th Annual Meeting Abstracts; BMA House, Tavistock Square, London, WC1H 9JR: BMA, 2022 doi:10.1136/neurintsurg-2022-SNIS.33
    63. ↵
      2. King RM ,
      3. Peker A ,
      4. Epshtein M , et al
      . Active drug-coated flow diverter in a preclinical model of intracranial stenting. J Neurointerv Surg 2023:jnis–2023 doi:10.1136/jnis-2023-020391
    64. ↵
      2. Soslau G ,
      3. Class R ,
      4. Morgan DA , et al
      . Unique pathway of thrombin-induced platelet aggregation mediated by glycoprotein IB. J Biol Chem 2001;276:21173–83. doi:10.1074/jbc.M008249200
      OpenUrlAbstract/FREE Full Text
    65. ↵
      2. Filová E ,
      3. Brynda E ,
      4. Riedel T , et al
      . Improved adhesion and differentiation of endothelial cells on surface-attached fibrin structures containing extracellular matrix proteins. J Biomed Mater Res A 2014;102:698–712. doi:10.1002/jbm.a.34733
      OpenUrl
    66. ↵
      2. Kaplan O ,
      3. Hierlemann T ,
      4. Krajewski S , et al
      . Low-thrombogenic fibrin-heparin coating promotes in vitro endothelialization. J Biomed Mater Res A 2017;105:2995–3005. doi:10.1002/jbm.a.36152
      OpenUrl
    67. ↵
      2. Mühl-Benninghaus R ,
      3. Fries F ,
      4. Kießling M , et al
      . Vascular response on a novel fibrin-based coated flow diverter. Cardiovasc Intervent Radiol 2022;45:236–43. doi:10.1007/s00270-021-03007-9
      OpenUrl
    68. ↵
      2. Goertz L ,
      3. Schoenfeld M ,
      4. Zopfs D , et al
      . The DERIVO 2Heal embolisation device: a technical report using single antiplatelet therapy for intracranial pseudoaneurysm treatment. Interv Neuroradiol 2022:15910199221104620. doi:10.1177/15910199221104620
    69. ↵
      2. Bricout N ,
      3. Chai F ,
      4. Sobocinski J , et al
      . Immobilisation of an anti-platelet adhesion and anti-thrombotic drug (EP224283) on polydopamine coated vascular stent promoting anti-thrombogenic properties. Materials Science and Engineering: C 2020;113:110967. doi:10.1016/j.msec.2020.110967
      OpenUrl
    70. ↵
      2. Sinnaeve PR ,
      3. Adriaenssens T
      . Dual antiplatelet therapy de-escalation strategies. Am J Cardiol 2021:S23–31. doi:10.1016/j.amjcard.2020.12.020
    71. ↵
      2. Marosfoi M ,
      3. Langan ET ,
      4. Strittmatter L , et al
      . In situ tissue engineering: endothelial growth patterns as a function of flow diverter design. J Neurointerv Surg 2017;9:994–8. doi:10.1136/neurintsurg-2016-012669
      OpenUrlAbstract/FREE Full Text
    72. ↵
      2. Granada JF ,
      3. Inami S ,
      4. Aboodi MS , et al
      . Development of a novel prohealing stent designed to deliver sirolimus from a biodegradable abluminal matrix. Circ Cardiovasc Interv 2010;3:257–66. doi:10.1161/CIRCINTERVENTIONS.109.919936
      OpenUrlAbstract/FREE Full Text
    73. ↵
      2. Kerkmeijer LSM ,
      3. Chandrasekhar J ,
      4. Kalkman DN , et al
      . Final five‐year results of the REMEDEE registry: real‐world experience with the dual‐therapy COMBO stent. Catheter Cardiovasc Interv 2021;98:503–10. doi:10.1002/ccd.29305
      OpenUrl
    74. ↵
      2. Wang R ,
      3. Hashimoto K ,
      4. Fujishima A , et al
      . Light-induced amphiphilic surfaces. Nature 1997;388:431–2. doi:10.1038/41233
      OpenUrlCrossRefWeb of Science
    75. ↵
      2. Tateshima S ,
      3. Kaneko N ,
      4. Yamada M , et al
      . Increased affinity of endothelial cells to NiTi using ultraviolet irradiation: an in vitro study. J Biomed Mater Res A 2018;106:1034–8. doi:10.1002/jbm.a.36304
      OpenUrl
    76. ↵
      2. Lertkiatmongkol P ,
      3. Liao D ,
      4. Mei H , et al
      . Endothelial functions of platelet/endothelial cell adhesion molecule-1 (CD31). Curr Opin Hematol 2016;23:253–9. doi:10.1097/MOH.0000000000000239
      OpenUrlCrossRefPubMed
    77. ↵
      2. Andreata F ,
      3. Syvannarath V ,
      4. Clement M , et al
      . Macrophage CD31 signaling in dissecting aortic aneurysm. J Am Coll Cardiol 2018;72:45–57. doi:10.1016/j.jacc.2018.04.047
      OpenUrlFREE Full Text
    78. ↵
      2. Cortese J ,
      3. Rasser C ,
      4. Even G , et al
      . CD31 mimetic coating enhances flow diverting stent integration into the arterial wall promoting aneurysm healing. Stroke 2021;52:677–86. doi:10.1161/STROKEAHA.120.030624
      OpenUrl

    Footnotes

    • Twitter @Chris_Zoppo, @DrPatchiz

    • Contributors CTZ: Literature review and drafting of the manuscript. JM, NWM, AAB, MJG (guarantor): Critical editing of the manuscript. All authors approved the final version of this manuscript to be published.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests CTZ and AAB declare no competing interests. JM: (1) Consultant for Viseon, Endostream, RIST, Synchron, Perflow, Viz.ai, CVAid, Imperative Care, and Mendaera. Investor in Endostream, Imperative Care, Echovate, Viseon, BlinkTBI, Serenity, NTI Managers, RIST, Viz.ai, Synchron, Songbird, Tulavi, Vastrax, Neurolutions, Sim&Cure, Neurolutions, Bend-it, Myra Medical, Q’Apel, Instylla, Viseon, Adona, Tulavi, Radical, E8, Borvo, and Spinaker; (2) Research funding from PCORI, Microvention, Penumbra, and Stryker Neurovascular; (3) President of SNIS. NWD: (1) Consultancy and speaker honoraria from Balt, Medtronic, Stryker and Microvention; (2) Research funding from Medtronic, Stryker and Microvention; (3) Proctoring for Microvention. MJG: (1) Consultant on a fee-per-hour basis for Alembic, Astrocyte Pharmaceuticals, BendIt Technologies, Cerenovus, Imperative Care, Jacob’s Institute, Medtronic Neurovascular, Mivi Neurosciences, phenox GMbH, Q’Apel, Route 92 Medical, Scientia, Simcerre, Stryker Neurovascular, Stryker Sustainability Solutions, Wallaby Medical; holds stock in Imperative Care, InNeuroCo, Galaxy Therapeutics, Kapto, Neurogami and Synchron; (2) Research support from the NIH, the United States–Israel Binational Science Foundation, Anaconda, ApicBio, Arsenal Medical, Axovant, Balt, Cerenovus, Ceretrieve, CereVasc, Cook Medical, Galaxy Therapeutics, Gentuity, Gilbert Foundation, Imperative Care, InNeuroCo, Insera, Jacob’s Institute, Magneto, MicroBot, Microvention, Medtronic Neurovascular, MIVI Neurosciences, Naglreiter MDDO, Neurogami, Q’Apel, Philips Healthcare, Progressive Medical, Pulse Medical, Rapid Medical, Route 92 Medical, Scientia, Stryker Neurovascular, Syntheon, ThrombX Medical, Wallaby Medical, the Wyss Institute and Xtract Medical; (3) Associate Editor of Basic Science on the JNIS Editorial Board.

    • Provenance and peer review Commissioned; externally peer reviewed.