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T. Darsaut, T. Darsaut, F. Bing, I. Salazkin, G. Gevry, Jean Raymond (2012)
Flow Diverters Can Occlude Aneurysms and Preserve Arterial Branches: A New Experimental ModelAmerican Journal of Neuroradiology, 33
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Darsaut TE, Bing F, Makoyeva A, Gevry G, Salazkin I, Raymond J (2014) Flow diversion of giant curved sidewall and bifurcation experimental aneurysms with very-low-porosity devices. World Neurosurg 82:1120–1126Darsaut TE, Bing F, Makoyeva A, Gevry G, Salazkin I, Raymond J (2014) Flow diversion of giant curved sidewall and bifurcation experimental aneurysms with very-low-porosity devices. World Neurosurg 82:1120–1126, Darsaut TE, Bing F, Makoyeva A, Gevry G, Salazkin I, Raymond J (2014) Flow diversion of giant curved sidewall and bifurcation experimental aneurysms with very-low-porosity devices. World Neurosurg 82:1120–1126
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Fahed R, Gentric JC, Salazkin I, Gevry G, Raymond J, Darsaut TE (2017) Flow diversion of bifurcation aneurysms is more effective when the jailed branch is occluded: an experimental study in a novel canine model. J Neurointerv Surg 9:311–315Fahed R, Gentric JC, Salazkin I, Gevry G, Raymond J, Darsaut TE (2017) Flow diversion of bifurcation aneurysms is more effective when the jailed branch is occluded: an experimental study in a novel canine model. J Neurointerv Surg 9:311–315, Fahed R, Gentric JC, Salazkin I, Gevry G, Raymond J, Darsaut TE (2017) Flow diversion of bifurcation aneurysms is more effective when the jailed branch is occluded: an experimental study in a novel canine model. J Neurointerv Surg 9:311–315
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Background: Flow-diverter stents (FDSs) have revolutionised the treatment of intracranial aneurysms. However, associated dual antiplatelet treatment is mandatory. We investigated the biocompatibility of three proprietary antithrombogenic coatings applied to FDSs. Methods: After Institutional Animal Care and Use Committee approval, four domestic juvenile female dogs (weight 19.9 ± 0.9 kg, mean ± standard deviation) were commenced on three different oral antiplatelet regimes: no medication (n = 1), acetylsalicylic acid (n = 2), and acetylsalicylic acid and clopidogrel (n =1). Four p64 FDSs were randomly implanted into the subclavian, common carotid, and external carotid arteries of each dog, including both uncoated p64 stents and p64 stents coated with three different antithrombogenic hydrophilic coating (HPC). Angiography and histological examinations were performed. Wilcoxon/Kruskal-Wallis and ANOVA were used with p value < 0.05 considered as significant. Results: Minimal inflammatory cell infiltration and no device-associated granulomatous cell inflammation were observed. No significant difference in adventitial inflammation (p = 0.522) or neointimal/medial inflammation (p = 0.384) between coated and uncoated stents as well as between the different stent groups regarding endothelial cell loss, surface fibrin/platelet deposition, medial smooth muscle cell loss, or adventitial fibrosis were found. Acute self-limiting thrombus formed on 6/16 implants (37.5%), and all of the thrombi were noted on devices implanted in the common or external carotid artery irrespective of the surface coating. Two of 12 p64 HPC-coated stents (16.7%) and 1/4 uncoated p64 stents (25%) showed severe or complete stenosis at delayed angiography. Conclusions: In these preliminary in vivo experiments, HPC-coated p64 FDSs appeared to be biocompatible, without acute inflammation. Keywords: Biocompatible materials, Disease models (animal), Intracranial aneurysm, Materials testing, Stents Key points Hydrophilic coated p64 flow-diverter stents appear to be biocompatible in initial in vivo tests. The hydrophilic coating (HPC) can be applied to p64 flow-diverter stents. Background The HPCs do not cause acute inflammation in the The introduction flow-diverter stents (FDSs) to the vessel wall. arena of interventional neuroradiology represented one of the most important breakthroughs for the specialty in recent times. These devices allowed not only the treat- * Correspondence: hhhenkes@aol.com ment of intracranial aneurysms but also the reconstruc- Rosa Martínez Moreno and P. Bhogal are joint first authors. 2 tion of the parent vessel. Similarly, these devices are also Department of Interventional Neuroradiology, The Royal London Hospital, Whitechapel Road, London E1 1BB, UK being used in the peripheral circulation [1]. Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Martínez Moreno et al. European Radiology Experimental (2019) 3:3 Page 2 of 13 Although the exact mechanism of action of FDSs is received DAPT (ASA 1.5 mg/kg/day and clopidogrel 1.5 unknown, it is believed they have a biphasic mechanism. mg/kg/day). The medication was commenced 72 h prior Initially, the FDS redirects flow away from the aneurysm to the planned intervention and continued for the dur- and promotes intra-aneurysmal stasis and thrombosis, ation of the study. The canine model was chosen as the which stabilises the aneurysm; subsequently, neointimal supra-aortic vessels have an appropriate diameter for clin- growth along the FDS struts remodels the vessel wall ically available stents and flow diverters. Furthermore, in and completes the exclusion of the aneurysm from the common with humans, dogs lack spontaneous endothelia- circulation [2]. A wide variety of FDSs exists with newer lisation and have a variable-enhanced coagulability that devices entering the marketplace designed to target spe- would allow a suitable assessment of the different FDSs cific problems. One issue that is yet to be conclusively and antiplatelet regimes. The canine model has been used resolved is the need for antiplatelet medication when previously to investigate the treatment of aneurysms with FDSs are implanted. This necessary medication is not FDSs [22–25]. without inherent risks. Similarly, there is hesitancy among the neuroradiological and neurosurgical community re- Flow-diverter implant procedure garding antiplatelet medication in the presence of acute All procedures were performed with the animals under subarachnoid haemorrhage. Therefore, an optimised FDS general anaesthesia with acepromazine (0.2 mg/kg, intra- would not require antiplatelet medication. muscularly), Telazol (5 mg/kg, intravenously), and main- Various stent coatings have been extensively tested for tenance with 2% isoflurane. The right common femoral stents used in the peripheral and cardiac circulation artery was surgically exposed and a 6-Fr introducer sheath since the early 2000s [3–7] with pre-clinical studies pub- inserted. Using a 5-Fr vertebral catheter and standard lished throughout the preceding decade [8–14]. Recently, 0.035-in. guidewire, angiography of the common carotid the pipeline embolisation device Shield (Medtronic, Dublin, arteries (CCAs), external carotid arteries (ECAs), and sub- Ireland) has entered the market. This device, the first FDS clavian arteries (SAs) was performed. After full heparinisa- with a thromboresistant coating, has a 3-nm-thick co- tion and activated clotting time 2–2.5 times the normal valently bound phosphorylcholine surface modification. value, a 0.027-in. Marksman microcatheter (Medtronic, Phosphorylcholine is a major component of the outer Dublin, Ireland) or Excelsior XT 27 (Stryker, Kalamazoo, membrane of erythrocytes and has demonstrated effi- USA) with 0.014-in. microwire was used to access the cacy in resisting platelet adhesion as well as intimal supra-aortic vessels. hyperplasia [15–17]. Although there is limited clinical information available regarding the clinical results of Flow-diverter stent characteristics this new technology [18–20], it is imperative to con- The p64 is a braided flow-diverting stent composed of tinue the development of antithrombogenic coatings 64 nickel-titanium (NiTi, nitinol) wires. Two platinum that would minimise or completely negate the require- wires wrapped around the shaft assist in radio-opacity. ment for antiplatelet medications. The 64 wires are grouped into 8 bundles proximally, We have recently shown that the hydrophilic coatings with each bundle consisting of 8 wires. A radio-opaque (HPCs) have antithrombogenic properties when tested marker is attached to the end of each bundle. The por- in vitro [21], but there is little known about the in vivo osity of the device is 51–60%. biocompatibility of these coatings. We sought to deter- mine the acute therapeutic efficacy and biocompatibility Surface HPCs of three different hydrophilic coatings. We present the The initial results of in vitro testing of the HPCs were results of in vivo testing of three different proprietary recently published [21]. In brief, it has been demon- HPCs (type 1, 2, and 3). We assessed the biocompatibil- strated that the coatings could be applied to both nitinol ity of uncoated and coated p64 FDSs (Phenox, Bochum, plates and nitinol wires that were subsequently used to Germany) without antiplatelet medication, single anti- construct p64 and p48 flow-diverter stents. The thick- platelet medication (acetylsalicylic acid (ASA)), and dual ness of the surface coatings is from 10 to 20 nm as de- antiplatelet medication (DAPT) (ASA and clopidogrel). termined by x-ray photoelectron spectroscopy analysis. The thin nature of the coatings has no influence on the Methods surface texture of the nitinol wires used to construct the Animal experiments and premedication flow-diverter stents [21]. In vitro testing showed a sig- After Institutional Animal Care and Use Committee ap- nificant reduction in the adherence of immunofluores- proval, four domestic male dogs, of similar age, were com- cent CD61-positive platelets when incubated with whole menced on three different oral antiplatelet medication blood from healthy volunteers compared to uncoated regimes. One dog did not receive antiplatelet medication, stents. Scanning electron microscopy also demonstrated two dogs received only ASA 1.5 mg/kg/day, and one dog minimal adherent platelets on the coated flow diverters Martínez Moreno et al. European Radiology Experimental (2019) 3:3 Page 3 of 13 compared to a thick layer of adherent platelets on un- photographed and radiographed using a LX-60 cabinet coated stents [21]. To summarise, the main differences radiography system (Faxitron, Arizona, USA). among HPC-1, HPC-2, and HPC-3 are the following: HPC-1 is a well-known polyethylene glycol (PEG)-based Histopathology preparation coating, HPC-2 is a newly developed glycan-based multi- After gross imaging, the excised arterial segments were layer polymer coating, and HPC-3 is a polyphosphazene dehydrated in a graded series of ethanol and embedded nanocoating. in Spurr’s epoxy resin. After polymerisation, the transverse section from the proximal, middle, and distal ends of the Implant location FDS were taken and the cross sections adhered to plastic A total of 16 p64 flow-diverter stents were implanted in 4 slides and prepared to a thickness of 32–88 μm (Exakt, animals with 4 stents implanted into each animal. In each Oklahoma City, USA). The slides were then polished and animal, an uncoated p64 and 1 each of the HPC-1 p64, stained with haematoxylin and eosin stain. HPC-2 p64, and HPC-3 p64 FDSs were randomly assigned and implanted into segments of the ECA, CCA, or SA. Two implants were placed in the SAs, and 2 implants Histological and morphological assessment placed in the CCAs or ECAs. The devices were deployed Morphometric analysis was performed on each segment under fluoroscopic guidance. The mean diameter of the by an independent, experienced (> 15 years) histopath- CCA was 3.7 ± 0.23 mm (mean ± standard deviation, the ologist (RV) using digital planimetry with a calibrated ECA 3.52 ± 0.45 mm, and the SA 3.79 ± 0.36 mm). The camera. For each prepared section, a morphometric ana- implant locations and medications are summarised in lysis was performed and included the luminal area of the Table 1. Control angiography was performed following vessel, the area of the internal and external elastic lam- implantation of the FDS and 45–60 min after the FDS inae (IEL and EEL, respectively), and the neointimal implantation. thickness that was calculated as the distance from the IEL to the luminal border. Semiquantitative data includ- Follow-up imaging ing surface platelet/fibrin deposition; injury; medial Sonographic imaging was performed to assess vessel pa- smooth muscle loss; neointimal, medial, and adventitial tency on days 7, 14, and 24 after the procedure. Angiog- inflammatory cell invasion; and medial plus adventitial raphy was performed on day 28 after the procedure via haemorrhage were recorded (Table 2). Histopathological the contralateral common femoral artery. Stents were analysis was conducted by an independent pathologist graded as patent (no stenosis), with minimal stenosis (1– (RV) blinded to the coatings. 29% lumen diameter reduction), with moderate stenosis The slides were stained with haematoxylin and eosin, (30–49% lumen diameter reduction), with severe stenosis and all sections were examined by light microscopy. In- (50–99% lumen diameter reduction), and occluded (100% flammatory cells were counted per area score as follows: lumen diameter reduction). All angiographic studies were 0/none (no inflammatory cells), 1/minimal (< 20 inflam- analysed by a single reader (AS) with over 15 years of matory cells per high power field in < 25% of area), 2/ experience in cerebral angiography. mild (21–100 inflammatory cells per high power field in 25–50% of area, 3/moderate (101–150 inflammatory cells Harvest and gross imaging per high power field in 51–75% of area, and 4/severe Euthanasia was performed by intravenous sodium pento- (> 150 inflammatory cells per high power field in > 75% of barbital overdose (100 mg/kg) at 28 days whilst the area). animals were under anaesthesia with isoflurane and Additionally, the media area (EEL area minus IEL area), following the final angiographic images. The arterial seg- neointimal area (IEL minus luminal area), and percent lu- ments with the implanted FDS were surgically removed minal stenosis (1 minus [luminal area/IEL area] × 100) were and fixed in 10% formaldehyde. All specimens were also calculated. Table 1 Test matrix of the canine models presenting the medication regimens and the locations of each stent Animal number Medication Right CCA/ECA Left CCA /ECA Right SA Left SA 1 None p64 HPC-1 p64 uncoated p64 HPC-2 p64 HPC 3 2 ASA p64 HPC-1 p64 uncoated p64 HPC-2 p64 HPC 3 3 ASA p64 HPC-2 p64 HPC-1 p64 HPC-3 p64 uncoated 4 ASA + clopidogrel p64 HPC-2 p64 HPC-1 p64 HPC-3 p64 uncoated ASA acetylsalicylic acid, CCA common carotid artery, ECA external carotid artery, SA subclavian artery Martínez Moreno et al. European Radiology Experimental (2019) 3:3 Page 4 of 13 Table 2 Description of semiquantitative histology scores 0 (none) 1 (minimal) 2 (mild) 3 (moderate) 4 (severe) Endothelium Endothelial loss None < 25% of the circumference 25–50% of the circumference 51–75% of the circumference > 75% of the circumference Tissue matrix Surface (fibrin/platelet deposition) None Minimal, focal Mild, multifocal Moderate, regionally diffuse Severe, marked diffuse, or total luminal occlusion Inflammation Intima/media None < 20 inflammatory cells/HPF 21–100 inflammatory cells/HPF 101–150 inflammatory cells/HPF > 150 inflammatory cells/HPF > 75% in < 25% of area in 25–50% of area >51–75% of area of area Adventitia None < 25% of area 25–50% of area > 51–75% of area > 75% of area Haemorrhage Media None Focal, occasional Multifocal and regional Regionally diffuse 100% red blood cells Adventitia None Focal, occasional Multifocal and regional Regionally diffuse 100% red blood cells Medial cell loss Medial smooth muscle loss (depth) None < 25% of medial thickness 25–50% of medial thickness 51–75% of medial thickness > 75% of medial thickness Medial smooth muscle loss (circumference) None < 25% of circumference 25–50% of circumference 51–75% of circumference > 75% of circumference Adventitial fibrosis Adventitial fibrosis None < 25% of the area 25–50% of the area 51–75% of the area > 75% of the area Medial injury/rupture Medial injury None Partial disruption involving the Complete medial disruption Complete disruption of the Complete disruption of the arterial wall medial wall (focal disruption with containment (intact arterial wall involving the media involving the media of the internal elastic lamina) external elastic lamina) HPF high-power field Martínez Moreno et al. European Radiology Experimental (2019) 3:3 Page 5 of 13 Fig. 1 Subtracted angiographic series of the left external carotid artery of subject number 2 (treated with ASA only), implanted with an uncoated p64 device. a The FDS immediately after its implantation. b The formation of multiple thrombus in the acute phase (white arrow), 30 min after implantation Biocompatibility, for the purpose of this study, was inflammation, medial and adventitial haemorrhage, and fi- defined as a non-significant difference in the degree of brin) were compared using the non-parametric Wilcoxon/ inflammation between the uncoated p64 stents and the Kruskal-Wallis (rank sums) test (Table 2). A p value lower HPC-coated p64 stents. than 0.05 was considered statistically significant. Statistical analysis Results For morphometric measurements, ANOVA was used for A total of 16 devices were implanted in 4 animals. There unpaired comparisons to calculate the significance of dif- was no morbidity or mortality during the intervention or ferences between the cumulative frequency distribution of after the procedure (mortality and overall morbidity 0%). coating groups. Semiquantitative (ordinal) data (including None of the dogs demonstrated any new neurological surface platelet/fibrin deposition, injury, medial smooth symptoms during the follow-up period (neurological muscle cell loss, neointimal/medial and adventitial morbidity 0%). Fig. 2 Subtracted angiographic series of the left external carotid artery of subject number 3 (treated with ASA only), implanted with an HPC-1 coated p64 device. a The FDS immediately after implantation. b The FDS 22 min after implantation, with a partial, acute in-stent thrombosis (white arrow) Martínez Moreno et al. European Radiology Experimental (2019) 3:3 Page 6 of 13 Fig. 3 Subtracted angiographic series of the right subclavian artery of subject number 2 (treated with ASA only), implanted with an HPC-2 coated p64 device. a The FDS immediately after implantation, b 12 min thereafter. After the waiting test, the implant was free from thrombus Intra-operative angiography results Single antiplatelet and dual antiplatelet medication No antiplatelet medication In the two animals given ASA only, four FDSs were im- Two p64 FDSs (one uncoated and one HPC-1) were im- planted in the CCA/ECA (animal 2, HPC-1 p64 stent planted in the CCA/ECA of animals that did not receive and uncoated p64 stent; animal 3, HPC-1 p64 stent and any antiplatelet medication. Transient small thrombi HPC-2 p64 stent). Transient small thrombi were seen were seen on both of these devices during the implant- on all the implants in the CCA/ECA. There were no ation procedure; however, in both cases, the thrombus thrombi seen on the FDSs implanted in the SAs (animal did not progress to complete occlusion of the vessel on 2, HPC-2 p64 stent and HPC-3 p64 stent; animal 3, the angiography performed at the end of the procedure. HPC-3 p64 stent and uncoated p64 stents) (Figs. 1, 2, 3). There were no thrombi seen on the HPC-2 p64 and There was no evidence of thrombus formation on any of HPC-3 p64 implants in the SAs. the FDSs implanted in the animal receiving DAPT. Fig. 4 Unsubtracted angiographic series of the right subclavian artery (a) and left subclavian artery (b) of subject number 2 (treated with ASA only), implanted with HPC-2 and HPC-3 coated p64 devices, respectively, at day 28 (final angiographic control). a The right FDS almost occluded by an extensive in-stent thrombosis. b Complete occlusion of the left-sided device Martínez Moreno et al. European Radiology Experimental (2019) 3:3 Page 7 of 13 Fig. 5 Unsubtracted angiographic series of the left subclavian artery of subject number 3 (treated with ASA only), implanted with an uncoated p64 stent, at day 28 (final angiographic control). It shows the occlusion of the stent lumen by moderate in-stent thrombosis (a) with subsequent impairment of the distal arterial flow (b) Overall acute self-limiting thrombus was seen to form No antiplatelet medication on 6/16 (37.5%) of the implants, and all of the thrombi A small thrombus was noted on the HPC-1 p64stents were noted on the FDSs implanted in the CCA/ECA ir- that had been implanted in the right CCA/ECA. There respective of the surface coating. were no thrombi seen on the other FDSs. Single antiplatelet and dual antiplatelet medication Delayed angiography outcome In animal 2 (treated with ASA only), both the FDSs in Angiography was performed in all animals on day 28 the CCA/ECA were patent. The HPC-2 p64 stent in the post-procedure. right SA was completely occluded, and the HPC-3 p64 Table 3 Summary of the end-procedural angiography results Animal number Medication Right CCA/ECA Left CCA/ECA Right SA Left SA 1 None p64 HPC-1 transient small thrombus p64 uncoated, transient, p64 HPC-2, patent p64 HPC-3, patent small thrombus 2 ASA p64 HPC-1, transient small thrombus p64 uncoated, transient p64 HPC 2, patent p64 HPC-3, patent small thrombus 3 ASA p64 HPC-2, small clot p64 HPC-1, small clot p64 HPC-3, patent p64 uncoated, patent 4 ASA + clopidogrel p64 HPC-2, patent p64 HPC-1, patent p64 HPC-, patent p64 uncoated, patent ASA acetylsalicylic acid, CCA common carotid artery, ECA external carotid artery, SA subclavian artery Martínez Moreno et al. European Radiology Experimental (2019) 3:3 Page 8 of 13 Table 4 Summary of the delayed post-procedural (day 28) angiography results Animal number Medication Right CCA/ECA Left CCA/ECA Right SA Left SA 1 None p64 HPC-1, minimal stenosis p64 uncoated, patent p64 HPC-2, patent p64 HPC-3, patent 2 ASA p64 HPC-1, patent p64 uncoated, patent p64 HPC-2, severe stenosis p64 HPC-3, complete stenosis 3 ASA p64 HPC-2, patent p64 HPC-1, patent p64 HPC-3, patent p64 uncoated, severe stenosis 4 ASA + clopidogrel p64 HPC-2, patent p64 HPC-1, patent p64 HPC-3, patent p64 uncoated, patent ASA acetylsalicylic acid, CCA common carotid artery, ECA external carotid artery, SA subclavian artery stent in the left SA was near-completely occluded on proximal markers on the HPC-2 p64 FDS implanted in angiography. In animal 3 (treated with ASA only), the the right SA of animal 2 was deflected into a bifurcation uncoated p64 stent in the left SA was near-completely branch (Fig. 6). occluded on angiography (Figs. 4 and 5). One device showed minimal (1–29%) stenosis, two devices showed se- Histopathological and morphological analysis vere (50–99%) stenosis, and one device showed complete All FDSs showed good apposition to the arterial wall stenosis on angiography performed at day 28. The cases of and virtually complete neointimal coverage along the severe and complete stenosis were seen in animals treated FDS strands. There was minimal inflammatory cell infil- with ASA only. There were no thrombi seen on any of the tration seen with no device-associated granulomatous implanted FDSs in animal 4 (treated with DAPT). cell inflammation (Fig. 8). Near-complete endothelialisa- The results of the end-procedural and delayed post- tion was noted for the patent FDSs (13/16 implants, procedural angiography are summarised in Tables 3 and 4. 81.3%). Neointimal growth was noted in the patent FDS segments. Morphologically, there was a significant differ- Gross and radiographic evaluation ence in the cross-sectional EEL area between the HPC-3 Mild dilatation of the arterial wall was noted correlating p64 and HPC-1 p64 (8.67 ± 0.99 mm versus 14.74 ± with the position of the implanted FDSs. There were no 0.64 mm , p = 0.013) and the IEL area between the un- grossly visible perforations, lacerations, or erosions of coated p64 and the HPC-3 p64 as compared to the 2 2 the arterial wall although small areas of haemorrhagic HPC-1 p64 (11.96 ± 0.61 mm , 11.49 ± 2.43 mm versus discolouration were noted and thought to be due to the 7.34 ± 0.69 mm , p = 0.009) (Fig. 9). The results are sum- resection procedure (Figs. 6 and 7). marised in Table 5. Radiography of the FDSs demonstrated them to be Histologically, there was no significant difference between generally well opposed to the vessel wall. One of the the different stent groups regarding endothelial cell loss, Fig. 6 Macroscopic and radiographic analysis of the explanted vessel segments of subjects number 1 and 2 Martínez Moreno et al. European Radiology Experimental (2019) 3:3 Page 9 of 13 Fig. 7 Macroscopic and radiographic analysis of the explanted vessel segments of subjects number 3 and 4 surface fibrin/platelet deposition, medial smooth muscle nitinol p64 FDS. Similarly, the coatings did not elicit a fi- cell loss, adventitial inflammation, or adventitial fibrosis. brotic reaction within the adventitia. Although there was Theresults aresummarisedinTable 6. no significant difference in the endothelialisation between the different coatings, the HPC-1 p64 had the lowest neoin- Discussion timal area suggesting that endothelialisation on this coating The results of this initial in vivo study demonstrate no sig- maybeimpairedrelativetothe otherstent coatings andthe nificant difference in the inflammatory response between uncoated p64. the three different stent coatings compared to the uncoated Kadirvel et al. [2] have previously shown that endothe- p64 FDSs. There was no evidence of a severe inflammatory lialisation of implanted FDSs is important for reconstruct- reaction or hypersensitivity reaction to either the HPC-1, ing the parent vessel and ultimately excluding the treated HPC-2, or HPC-3 coatings which suggests that all three aneurysm from the circulation. In this regard, a failure of coatings have a similar biocompatibility to the uncoated endothelialisation could ultimately lead to a failure to Fig. 8 Sections from explanted HPC-2-coated device from subject number 2 show luminal occlusion with re-canalised organising (mid-segment) to organised (proximal and distal sections) thrombus (a). Chronic inflammatory cells infiltration around the mesh wires are visible (b). Haematoxylin and eosin stain, × 100 magnification Martínez Moreno et al. European Radiology Experimental (2019) 3:3 Page 10 of 13 Fig. 9 Histomorphometric measurements (mean ± standard deviations) of the external elastic lamina area (left) and the internal elastic lamina area (right). Asterisks denote statistical significance using ANOVA: *p < 0.05, **p < 0.01 occlude the treated aneurysms. This finding has previously and aggregation promote the healing process through been reported for fusiform aneurysms treated with FDSs the release of growth factors and cytokines. [26], and inadequate neoendothelialisation has been sug- These observations strongly suggest that mural throm- gested as the underlying cause for the failure of FDSs to bosis with macrophage infiltration at the earliest stage after complete occlude some aneurysms [27]. stenting may be crucial in recruiting smooth muscle cells Therefore, the lack of endothelialisation seen on the sur- from the arterial wall. Indeed, platelet adherence and aggre- face of the HPC-1 p64 FDSs raises concerns regarding the gation promote the subsequent healing process through the potential use of this coating on FDSs. Conversely, the release of growth factors [28–30]. Interestingly, the HPC-3 HPC-3 FDS had a similar neointimal area compared to p64 FDS showed a non-significantly higher surface platelet/ the uncoated p64 FDSs (4.27 ± 3.97 mm versus 4.24 ± fibrin score, and it is possible that the HPC-3 coating allows 4.46 mm ) which would suggest that neointimal growth enough platelet adhesion to promote initiation of the on HPC-3 coated stents is similar to that on uncoated p64 neointima formation but insufficient platelet adhesion stents. to cause stent thrombosis. In the recent work of Matsuda In general terms, the initial event that leads to neoin- et al., [31] the pipeline embolisation device Shield showed tima formation is that of local thrombus formation, adja- a greater stent coverage ratio, defined as the number of cent to the stent struts. Gradually, there is an invasion struts covered with neointima/total stent struts, compared of cellular components such as macrophages and to the pipeline embolisation device Flex (Medtronic, α-actin-negative spindle-shaped cells accompanied by Dublin, Ireland) which is a similar device but without the the deposition of extracellular matrix components. This phosphorylcholine coating. Similarly, the authors noted eventually differentiates into a fibrocellular lesion con- that the endothelial growth on the pipeline embolisation taining α-actin-positive smooth muscle cells. Therefore, device Shield was faster than on the pipeline embolisation mural thrombus with a subsequent macrophage infiltra- device Flex, and the authors suggest that this could be due tion after stenting may be crucial in recruiting smooth to an effect of the coating. This is of interest since not muscle cells from the arterial wall. Platelet adherence only may this device reduce the risk of acute Table 5 Morphological measurements scoring 2 2 2 Coating group EEL area (mm ) IEL area (mm ) Lumen area Neointimal area Medial area (mm ) Stenosis (%) Thickness (mm) 2 2 (mm ) (mm ) Uncoated (n = 4) 13.59 ± 3.10 11.49 ± 2.43 7.24 ± 4.98 4.24 ± 4.46 2.11 ± 0.78 36.40 ± 36.54 0.20 ± 0.17 HPC-1 (n = 4) 8.67 ± 0.99 7.34 ± 0.69 6.03 ± 0.64 1.30 ± 0.24 1.34 ± 0.50 18.58 ± 2.42 0.11 ± 0.03 HPC-2 (n = 4) 10.57 ± 3.40 8.89 ± 2.37 5.68 ± 4.09 3.22 ± 2.15 1.67 ± 1.29 41.39 ± 39.47 0.14 ± 0.06 HPC-3 (n = 4) 14.74 ± 0.64 11.9 6 ± 0.61 7.69 ± 4.00 4.27 ± 3.97 2.78 ± 0.21 37.06 ± 33.07 0.28 ± 0.27 p value 0.013 0.009 (HPC-1 0.862 0.531 0.124 0.754 0.564 (HPC-1 versus versus HPC-3 HPC-3) + uncoated) Data are mean ± standard deviation EEL external elastic lamina, IEL internal elastic lamina Martínez Moreno et al. European Radiology Experimental (2019) 3:3 Page 11 of 13 Table 6 Histological scoring means, standard deviations, and Wilcoxon/Kruskal-Wallis results Coating group Endothelial cell loss Surface fibrin Neointimal/medial Medial smooth muscle cell loss Medial Adventitial Score Platelets score Fibrin score Inflammation score Depth Circumference Injury score Inflammation score Fibrosis score Uncoated (n = 4) 0.08 ± 0.17 0.58 ± 1.17 0.83 ± 1.67 2.50 ± 1.04 0.25 ± 0.50 0.58 ± 1.17 0.42 ± 0.42 0.92 ± 1.26 0.00 ± 0.00 HPC-1 (n = 4) 0.17 ± 0.33 0.50 ± 0.58 0.00 ± 0.00 1.75 ± 0.74 0.00 ± 0.00 0.00 ± 0.00 0.25 ± 0.32 0.25 ± 0.32 1.50 ± 1.82 HPC-2 (n = 4) 0.50 ± 0.64 0.58 ± 0.69 0.33 ± 0.67 2.25 ± 0.57 0.50 ± 0.43 0.83 ± 1.23 0.50 ± 0.43 0.42 ± 0.63 1.50 ± 1.91 HPC-3 (n = 4) 0.25 ± 0.50 0.83 ± 1.26 0.92 ± 1.83 1.58 ± 0.96 0.42 ± 0.32 1.33 ± 1.22 0.58 ± 0.17 1.17 ± 0.88 0.00 ± 0.00 p value 0.731 0.963 0.762 0.384 0.183 0.144 0.514 0.522 0.181 Martínez Moreno et al. European Radiology Experimental (2019) 3:3 Page 12 of 13 thrombogenic complications but it may also shorten the Author details 1 2 Hospital Universitario Virgen de las Nieves, Granada, Spain. Department of time that patients require antiplatelet medications. Al- Interventional Neuroradiology, The Royal London Hospital, Whitechapel though we have not conducted a similar experiment to 3 4 Road, London E1 1BB, UK. phenox GmbH, Bochum, Germany. Jacobs date, it is possible that a similar effect could be seen with School of Medicine and Biomedical Science, University of Buffalo, Buffalo, NY, USA. Clinica Sagrada Familia, ENERI, Buenos Aires, Argentina. the HPC-3 coating and further experiments are ongoing. 6 7 Neurozentrum, Klinikum Stuttgart, Stuttgart, Germany. Medical Faculty, We recognise that this study has limitations, and the University Duisburg-Essen, Essen, Germany. translation of its conclusions into clinical practice needs to Received: 6 August 2018 Accepted: 27 December 2018 be carefully considered. The follow-up period of the study was just 1 month, and therefore, the medium- and long- term effect of the device coatings is not known. Similarly, References FDSs are used to treat aneurysms, and in the current exper- 1. Mauri G, Sconfienza LM, Casilli F, Massaro S, Inglese L (2013) Cardiatis iments, aneurysms were not created so any impact of the multilayer stent for endovascular treatment of peripheral and visceral aneurysms: where do we stand? J Endovasc Ther 20:575–577 stent coating on aneurysm occlusion is unknown. Further- 2. Kadirvel R, Ding YH, Dai D, Rezek I, Lewis DA, Kallmes DF (2014) Cellular more, a limited number of subjects were used, and larger mechanisms of aneurysm occlusion after treatment with a flow diverter. cohorts would be necessary to prove the effect of the differ- Radiology 270:394–399 3. Sheiban I, Carrieri L, Catuzzo B et al (2002) Drug-eluting stent: the emerging ent coatings. The large number of variables and small sam- technique for the prevention of restenosis. Minerva Cardioangiol 50:443–453 ple size represent another major limitation of the study. 4. Sousa JE, Costa MA, Abizaid A et al (2001) Lack of neointimal proliferation In conclusion, HPC surface-modified p64 FDSs are after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular biocompatible in this animal study with no evidence of ultrasound study. Circulation 103:192–195 severe systemic allergic reaction, local inflammatory re- 5. Sousa JE, Costa MA, Abizaid AC et al (2001) Sustained suppression of action, or significant fibrosis. neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up. Circulation 104:2007–2011 Abbreviations 6. Sousa JE, Costa MA, Sousa AG et al (2003) Two-year angiographic and ASA: Acetylsalicylic acid; CCA: Common carotid artery; DAPT: Dual intravascular ultrasound follow-up after implantation of sirolimus-eluting antiplatelet medication; ECA: External carotid artery; EEL: External elastic stents in human coronary arteries. Circulation 107:381–383 lamina; FDS: Flow-diverter stent; HPC: Hydrophilic coating; IEL: Internal elastic 7. Sousa JE, Costa MA, Abizaid A et al (2003) Sirolimus-eluting stent for the lamina; SA: Subclavian artery treatment of in-stent restenosis: a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 107:24–27 8. Ozaki Y, Violaris AG, Serruys PW (1996) New stent technologies. Prog Availability of data and materials Cardiovasc Dis 39:129–140 There is no further data available to share at this time. 9. Violaris AG, Ozaki Y, Serruys PW (1997) Endovascular stents: a ‘break through technology’, future challenges. Int J Card Imaging 13:3–13 Funding 10. Whelan DM, van Beusekom HM, van der Giessen WJ (1998) Mechanisms of This study was funded by Phenox GmbH (Bochum, Germany; grant number drug loading and release kinetics. Semin Interv Cardiol 3:127–131 68.242,56 USD): animal lab and animals (Jacobs Institute, Buffalo, NY, USA) 11. Lincoff AM, Furst JG, Ellis SG, Tuch RJ, Topol EJ (1997) Sustained local delivery 39.998,77 USD; Histopathology (CVPath Institute, Gaithersburg, MD, USA): of dexamethasone by a novel intravascular eluting stent to prevent restenosis 16.718,00 USD; consulting and travel: 1.173,22 EUR + 3.500,00 EUR + 97,76 in the porcine coronary injury model. J Am Coll Cardiol 29:808–816 EUR + 4.914,56 EUR = 9.685,54 EUR (= 11.525,79 USD). 12. Park SH, Lincoff AM (1998) Anti-inflammatory stent coatings: dexamethasone and related compounds. Semin Interv Cardiol 3:191–195 Authors’ contributions 13. Gershlick AH (1998) Local delivery of glycoprotein IIb/IIIa receptor inhibitors RMM contributed to the data collection and manuscript preparation and using drug eluting stents. Semin Interv Cardiol 3:185–190 review. PB contributed to the data collection and manuscript preparation, 14. Aggarwal RK, Ireland DC, Azrin MA, Ezekowitz MD, de Bono DP, Gershlick editing, and review. TL-H contributed to the manuscript editing and review. AH (1996) Antithrombotic potential of polymer-coated stents eluting CB, AS, PL, RH, and HM contributed to the manuscript editing and review. platelet glycoprotein IIb/IIIa receptor antibody. Circulation 94:3311–3317 HH is the study guarantor and contributed to the manuscript editing and 15. Chen C, Lumsden AB, Ofenloch JC et al (1997) Phosphorylcholine coating of review. All authors read and approved the final manuscript. ePTFE grafts reduces neointimal hyperplasia in canine model. Ann Vasc Surg 11:74–79 Ethics approval and consent to participate 16. Chen C, Ofenloch JC, Yianni YP, Hanson SR, Lumsden AB (1998) All applicable international, national, and/or institutional guidelines for the Phosphorylcholine coating of ePTFE reduces platelet deposition and care and use of animals were followed. Institutional Animal Care and Use neointimal hyperplasia in arteriovenous grafts. J Surg Res 77:119–125 Committee approval was gained (Jacobs Institute, Buffalo, NY, USA). Consent 17. Campbell EJ, O’Byrne V, Stratford PW et al (1994) Biocompatible surfaces to participate: not applicable. using methacryloylphosphorylcholine laurylmethacrylate copolymer. ASAIO J 40:M853–M857 Consent for publication 18. Hanel RA, Aguilar-Salinas P, Brasiliense LB, Sauvageau E (2017) First US Not applicable. experience with pipeline flex with shield technology using aspirin as antiplatelet monotherapy. BMJ Case Rep. J Neurointerv Surg. BMJ Case Rep Competing interests 2017;2017:bcr-2017-219406. https://doi.org/10.1136/bcr-2017-219406. RMM has a proctoring agreement with Phenox until 2017. PB has a consulting Accessed 8 Jan 2018 and proctoring agreement with Phenox. TL-H and CB are employees of Phenox. 19. Orlov K, Kislitsin D, Strelnikov N et al (2018) Experience using pipeline AS declares that he has no competing interests. PL is a consultant of Phenox. RH embolization device with Shield Technology in a patient lacking a full and HM are CEOs of Phenox. HH is a co-founder and shareholder of Phenox. postoperative dual antiplatelet therapy regimen. Interv Neuroradiol 24:270–273 20. 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European Radiology Experimental – Springer Journals
Published: Jan 22, 2019
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