Hemodynamic Effect of Flow Diverter and Coils in Treatment of Large and Giant Intracranial Aneurysms

Accepted Manuscript Hemodynamic Effect of Flow Diverter and Coils in the Treatment of Large and Giant Intracranial Aneurysms Linkai Jing, MS, Jingru Zhong, MS, Jian Liu, MD, Xinjian Yang, MD, PhD, Nikhil Paliwal, MD, Hui Meng, MD, PhD, Shengzhang Wang, MD, PhD, Ying Zhang, MD PII:

S1878-8750(16)00167-4

DOI:

10.1016/j.wneu.2016.01.079

Reference:

WNEU 3683

To appear in:

World Neurosurgery

Received Date: 15 September 2015 Revised Date:

27 January 2016

Accepted Date: 27 January 2016

Please cite this article as: Jing L, Zhong J, Liu J, Yang X, Paliwal N, Meng H, Wang S, Zhang Y, Hemodynamic Effect of Flow Diverter and Coils in the Treatment of Large and Giant Intracranial Aneurysms, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.01.079. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Title page Title: Hemodynamic Effect of Flow Diverter and Coils in the Treatment of Large and Giant Intracranial Aneurysms Co-authors: Linkai Jing1, MS; Jingru Zhong2, MS; Jian Liu1, MD; Xinjian Yang1, MD, PhD; Paliwal Nikhil3,4, MD; Hui Meng4-7, MD, PhD; Shengzhang Wang8, MD,

E-mails:

[email protected],

[email protected],

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PhD; and Ying Zhang1, MD.

[email protected],

[email protected],

[email protected],

[email protected],

[email protected], [email protected]

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Affiliations: 1Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; 2Department of Biomedical Engineering, Capital

Engineering,

4

Department of Mechanical & Aerospace

Toshiba Stroke and Vascular Research Center, 6

Neurosurgery, 7

3

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Medical University, Beijing, China;

5

Department of

Department of Mechanical and Aerospace Engineering, and

Department of Biomedical Engineering, University at Buffalo, The State University

of New York, Buffalo, New York; 8Department of Mechanics and Engineering

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Science, Fudan University, Shanghai, China.

Key words: Aneurysm, Flow diverter, Coil, Computational fluid dynamics, Hemodynamics

Abbreviation list: CFD = computational fluid dynamics; DSA = digital subtraction

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angiographic; FD = flow diverter; ICA = internal carotid artery; LSA= low wall shear area; WSS = wall shear stress.

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Corresponding authors: Ying

Zhang,

MD,

Department

of

Interventional

Neuroradiology,

Beijing

Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, TiantanXili

6,

Dongcheng

Distict,

Beijing,

China,

100050.

Email:

[email protected]. Tel: +8610-67098852. Fax: +8610-67018349.

Shengzhang Wang, MD, PhD, Department of Mechanics and Engineering Science, Fudan University, 220 Handan Rd., Yangpu District, Shanghai, China, 200433. Email: [email protected]. Tel: +8621-65642737. Fax: +8621-65642737. 0

ACCEPTED MANUSCRIPT Abstract Background This study aimed to investigate the hemodynamic changes induced by the flow diverter (FD) and coils in treatment of internal carotid artery aneurysms, and to evaluate the effect of this treatment by using angiographic follow-up data.

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Methods Six large and giant aneurysms were treated by the Tubridge FD and loose packing coils between June 2013 and May 2015. Patient-specific models were constructed and analyzed by a computational fluid dynamics (CFD) method. The virtual FD deployment method was used to implant the Tubridge stent into a

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3D-digital subtraction angiographic image of the aneurysms and the coils were simulated by a porous medium model.

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Results Tubridge FD alone can significantly reduce the intra-aneurysmal flow velocity (0.17±0.05 to 0.11±0.06 m/s, P<0.001) and wall shear stress (WSS, 1.39±0.29 to 0.77±0.34 Pa, P=0.001), and increased the low wall shear area (LSA, 6.38%±1.49% to 34.60%±28.90%, P=0.047). Coils, as a supplementary measure, further reduced the velocity (0.11±0.06 to 0.08±0.05 m/s, P=0.03) and WSS

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(0.77±0.34 to 0.47±0.35 Pa, P=0.04), and increased the LSA (34.60%±28.90% to 63.33%±34.82%, P=0.044). Aneurysm with sustained strong inflow after treatment (case 3, 25% reduction in velocity, 12% reduction in WSS, and 16% increment in

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LSA) showed partial patency, whereas others with a weaker inflow jet (mean 56% reduction in velocity, 74% reduction in WSS and 1081% increment in LSA) showed

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complete occlusion at follow-up. Conclusions Based on CFD method, adjunctive coiling with the Tubridge FD placement may significantly reduce intra-aneurysmal flow velocity and WSS, promoting thrombosis formation and occlusion of aneurysms. Key words: Aneurysm, Flow diverter, Coil, Computational fluid dynamics, Hemodynamics

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ACCEPTED MANUSCRIPT Text Introduction Large and giant (≥10 mm) intracranial aneurysms have worse outcomes compared with small aneurysms when using conventional endovascular treatment. The flow

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diverter (FD) devices are increasingly used for treating these aneurysms (1-4). Rather than mechanically excluding the aneurysm from the circulation, the FD is designed to create a low flow hemodynamic state within the aneurysm that would favor its thrombosis and ultimate occlusion and remodeling. However, under the condition of

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inflow stream into the aneurysm, and when patients are under dual antiplatelet therapy, use of the FD barely provides immediate thrombosis and occlusion of the aneurysm .

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During this time, some clinical complications, such as delayed aneurysm rupture and flow persistency, have been reported (1-8). To avoid these complications, our medical center usually places a few coils in addition to the Tubridge FD in an attempt to further protect the dome and dampen the inflow effect on the aneurysmal wall. The Tubridge is a new type of FD device developed by MicroPort Medical

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Company (Shanghai, China). Animal experiments and preliminarily clinical experience have shown that the Tubridge FD is a safe and effective device for treatment of large and giant internal carotid artery (ICA) aneurysms (4, 9, 10).

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Understanding the hemodynamic effect within an aneurysmal sac after the Tubridge FD deployment is essential. Computational fluid dynamics (CFD) is an efficient method to understand how the FD affects aneurysmal hemodynamics for successful

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treatment, as well as the inevitable complications (11-13). This study evaluated the independent hemodynamic effect of the Tubridge FD, as

well as the combined hemodynamic effect of the Tubridge FD and loose packing coils in treatment of large and giant ICA aneurysms, using CFD simulations, the virtual Tubridge FD deployment method, and porous medium modeling. Materials and methods Patients Between June 2013 and May 2015, 10 patients were treated by a single Tubridge FD and loose packing coils (bare) in our department. All of these patients were enrolled in 1

ACCEPTED MANUSCRIPT a multicenter, randomized, and controlled clinical trial that aimed to assess the clinical safety and effectiveness of the Tubridge FD in treatment of unruptured large/giant ICA aneurysms (9). The Institutional Review Board of our hospital approved this study, and written informed consent was obtained from all of the patients. Among

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them, two patients’ 3D-digital subtraction angiographic (DSA) data did not have sufficient resolution for CFD analysis and two patients refused to participate in our hemodynamic study. Finally, this study included four women and two men with ages ranging from 42 to 57 years (mean: 51.50 years). The mean size of the aneurysms was

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18.15 mm (range, 12.15-25.61 mm) and the mean neck diameter was 9.39 mm (range 6.51-11.82 mm). The mean follow-up time was 8.5 months (range, 5-12 months). The

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angiographic results were classified according to the Raymond-Roy classification system . General information of the patients and characteristics of the aneurysms are shown in the Table 1.

Patients were administered with aspirin (300 mg/day) and clopidogrel (75 mg/day) at least 3 days before the procedure. Each patient received systemic heparin

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after the placement of the sheath. The same postoperative antiplatelet regimen was provided for 6weeks. Aspirin (100 mg/day) and clopidogrel (75 mg/day) were then provided between 6 weeks to 3 months after treatment, whereas aspirin (100 mg/day)

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was continued during the rest of the follow-up period (3-12 months). Platelet function testing was not applied. No thromboembolic complications were found in all patients Tubridge Flow Diverters and Loose Coiling

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The Tubridge FD is a braided, self-expanding mesh cylinder with flared ends,

specifically designed to produce hemodynamic flow diversion and to reconstruct laminar flow in the parent artery (4, 9) (Figure 2). It’s detailed structure has been compared with other FDs previously(4). In this study, the device was composed of 62 nickel–titanium alloy and two platinum-iridium radio-opaque microfilaments. The device was designed to provide approximately 30–35% metal coverage of the inner surface of the target vessel. Endovascular treatments were performed by two specialists, each of whom has more than 10 years of experience in intracranial stent placement. 2

ACCEPTED MANUSCRIPT When treating large-giant aneurysms with FD device, additional coil placement may prevent the risk of postoperative aneurysm rupture(2, 3, 14). But to our knowledge, there is no criterion to define the sufficient coil packing degree (15). Morales et al.(12) found that the first inserted coils (when packing density <12%) can

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significantly reduce intra-aneurysmal flow velocity by more than 50%. Damiano et al.(13) defined the low packing density as <11%. By reference to above two papers, we chose 12% as criterion for loose packing in this study. As presented in Table1, four cases (cases 1, 2, 3 and 4) have packing densities of 4%-5%. Case 5 has a wide neck

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which was located at a circuitous parent artery, so more coils ( with a 9% coil packing density ) were placed to help the microcatheter cross the neck and stabilize the FD

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during deployment. Case 6 has some prone-to-rupture symptoms (ie. dizziness, headache, nausea, and vomiting), we chose a 12% coil packing density. Computational modeling and CFD simulations

Patient-specific 3D-DSA data was obtained and imported into Geomagic studio software (version 12.0, Geomagic Inc., NC) to repair, cut, and smooth (16, 17). After

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this stage, surface geometries were saved as standard tessellation language format. Geometric models of the FD stents were created and placed within the vascular models using an in-house virtual stent-deployment technique that we previously

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developed (18) (Figure 2). Briefly, the virtual stent deployment consisted of three steps: pre-processing, simplex mesh expansion, and post-processing. Pre-processing prepared the 3D aneurysm geometry and initialized the simplex mesh within the

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parent vessel prior to its expansion. We obtained the parent vessel centerline and uniformed initial mesh with a small diameter along the centerline. Finally, using MATLAB (R2013a, The Mathworks, Natick, MA, USA), we extracted the maximum inscribed sphere diameter inside the parent vessel along its centerline and placed a series of circles. In the second step, the initialized simplex mesh was treated as a deformable simplex model and expanded inside the parent vessel in MATLAB. In post-processing, we determined the stent vertex coordinates on the deployed simplex mesh according to the stent pattern. We then connected the vertex coordinates into distinct wire curves, using an in-house python code based on FEM software 3

ACCEPTED MANUSCRIPT Abaqus/Explicit 6.12 (Simulia, Providence, RI, USA). Finally these wires curves were swept into 3D strut structures to generate a 3D solid stent in the CAD program Creo Parametric 2.0 (PTC, Needham, MA, USA). The 3D strut structures were placed inside the original untrimmed 3D aneurysm geometry and meshed together for CFD

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analysis. The aneurysmal sac with coils was modeled as porous medium as described by Wang et al. (19) and Mitsos et al. (20). The volume of the coil was calculated and the algebraic equation was as follows: volume of the coil = π × (diameter of coil/2)2× the

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length of the coil. Packing density was defined as the ratio between the volume of the coils and the volume of the aneurysms.

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The CFD simulations were as described previously (16, 17). Briefly, the deployed stent was merged with the aneurysm geometry in ICEM CFD version 14.0 (ANSYS, Inc., USA) to create finite volume tetrahedral elements for CFD simulation. The largest element size was 0.1 mm. The element size on the stent was set to 0.01 mm to sufficiently present geometry of the stent, which was approximately 1/3 of the

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width of the strut of the FD stent (21). Mesh sizes ranged between 3 and 5 million of the cases without a stent and from 20 to 40 million elements for cases with a stent. After meshing, ANSYS CFX 14.0 software (ANSYS, Inc., USA) was used for

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simulation of hemodynamics. The vessel wall was assumed to be rigid with a no-slip boundary condition. Blood was modeled as a homogenous, laminar, incompressible Newtonian fluid (attenuation = 1060 kg/m3, viscosity = 0.004 Pa/s). The governing

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equation underlying the calculation was the Navier–Stokes formulation. The pulsatile period velocity profile was obtained by transcranial Doppler from a normal subject and set as the inflow boundary condition. The flow waveforms were scaled to achieve a mean inlet WSS of 15 dyne/cm under pulsatile conditions (22). To reduce initial transients, we computed two complete cardiac cycles, and data of the second cardiac cycle were collected. Data collection and analysis Three models were constructed and simulated as follows: 1) pre-treatment; 2) post-treatment (single FD deployment); and 3) post-treatment (single FD and loose 4

ACCEPTED MANUSCRIPT packing coils). After CFD simulations, we calculated and compared the following hemodynamic variables related to aneurysms: (1) blood flow velocity at peak systole on a fixed cross-section of the aneurysm; (2) time- and spatial-averaged WSS; and (3) low wall shear area (LSA): the areas of low WSS (<0.4 Pa) was evaluated in the

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aneurysmal sac (22). Statistical analysis was performed with the SPSS 17.0 package (IBM, Chicago, IL, USA). The one-sample Kolmogorov–Smirnov test was used to test normal distribution. Two-way analysis of variance was used for approximately normally

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distributed parameters and Wilcoxon’s sign rank test was used for non-normally distributed parameters. Data are expressed as mean ± SD or median ± interquartile

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range. A value of p<0.05 was considered statistically significant. Results Angiographic results

Six aneurysms were treated by the Tubridge FD and loose packing coils. Immediate postoperative angiographic results showed residual aneurysm in all of the aneurysms.

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During follow-up, five aneurysms (cases 1, 2, 4 and 6) were completely occluded, one aneurysm (case 5) showed residual neck and one aneurysm (case 3) still showed residual aneurysm (Table 1, Fig. 1). None of the patients had any procedure-related

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morbidity or mortality. Hemodynamic results

Before treatment, aneurysmal flow patterns were similar in all cases, with a flow

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entering the aneurysm and directly impinging on the distal wall (Fig. 4A1, A2 and Fig. 5A1, A2). After aneurysms were treated by FD, some favorable flow patterns were observed, such as central diversion and peripheral stasis (Fig. 4B, C and Fig. 5B, C). All the hemodynamic parameters were significantly changed (Fig. 3). The FD markedly reduced the intra-aneurysmal flow velocity (0.17±0.05 m/s to 0.11±0.06 m/s, 37% reduction, P<0.001) and WSS (1.39±0.29 Pa to 0.77±0.34 Pa, 45% reduction, P=0.001), but markedly increased LSA (6.38%±1.49% to 34.60%±28.90%, 458% increment, P=0.047). Compared with treatment of the FD alone (Fig. 3), use of coils in conjunction 5

ACCEPTED MANUSCRIPT with FD significantly decreased intra-aneurysmal flow velocity (0.11±0.06 m/s to 0.08±0.05 m/s, P=0.03) and WSS (0.77±0.34 Pa to 0.47±0.35Pa, P=0.04), and increased LSA (34.60%±28.90% to 63.33%±34.82%, P=0.044). Then the total intra-aneurysmal flow velocity and WSS were decreased by 54% and 66%,

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respectively, whereas LSA was increased to 1001% of its pre-treatment value. During follow-up, one aneurysm with sustained strong inflow showed residual aneurysm after 12 months (case 3; Fig. 1D3 and Fig. 5). In this single case after treated by FD and coils, intra-aneurysmal flow velocity and WSS showed a slight

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reductions (0.25 to 0.19 m/s, 25% reduction; 1.24 to 1.09 Pa, 12% reduction; respectively), but LSA almost remained unchanged (6.73% to 7.83%, 16% increment).

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For the other cases, the intra-aneurysmal flow velocity and WSS were markedly reduced (0.16 to 0.07 m/s, 56% reduction; 1.42 to 0.37 Pa, 74% reduction, respectively), and LSA was greatly increased (6.30% to 74.42%, 1081% increment). Discussion

FD treatment for Large and giant aneurysms

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Large and giant ( 10 mm) aneurysms present a challenge for classic endovascular treatment. The FD device appears to be an effective therapeutic option, but large and giant size still represents added risks(1-3). A large multicenter study of pipeline FD

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therapy retrospectively studied 793 patients with 906 aneurysms in 17 centers and found that the complication rates with Pipeline treatment are comparable with those of other endovascular treatment options such as stent-assisted coiling(3). But Patients

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with large-giant aneurysms are still at higher risk of ischemic stroke and SAH compared with small aneurysms(3). Then additional coiling may be performed according to the treating physician’s judgment(1, 2, 15). Briganti et al.(1) reviewed 18 studies of endovascular treatment by FDs (Pipeline, Silk and Surpass) for a total of 1704 aneurysms in 1483 patients. 448 aneurysms (14%) were large or giant. Additional coiling was realized during the FD implantation in 134 procedures (7.8%) among 16 studies, with a variable rate from no case to 59%. Immediate aneurysm occlusion rate was 10.8%, and the mean final occlusion rate was 88.2% in eight Pipeline FD studies, 83% in seven Silk studies, and 75% for the unique Surpass 6

ACCEPTED MANUSCRIPT study(1). Alghamdi et al.(2) reviewed the Silk FD treatment and proposed that Silk FD seems to achieve lower occlusion rate than Pipeline FD (68 vs 88%) and higher rate of ischemic complications, aneurysm rupture, and mortality. Additional coiling is recommended in giant aneurysm and is usually considered in large aneurysms(2).

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Zhou et al. (4) prospectively collected and analyzed the data of 28 large/giant ICA aneurysms treated by Tubridge FDs. Seven of the 25 initially treated aneurysms and all of the 3 recanalized aneurysms were treated by using the Tubridge alone; the remaining 18 aneurysms were treated with the Tubridge FD and loose coiling. With a

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mean angiographic follow-up period of 9.9 months, they found that the overall complete occlusion rate was 72% (18/25), the neck remnant rate was 24% (6/25) and

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only one aneurysm remained unchanged(4). Similarly, the six aneurysms with Tubridge FD treatment and adjunctive coiling in the present study showed angiographic improvement during follow-up, including four complete occlusions, one residual neck and one residual aneurysm.

Hemodynamic effect of the Tubridge FD and loose packing coils

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Treating aneurysms with an FD can mechanically exclude the aneurysm from the flow stream and provide immediate protection for the aneurysm (6, 8, 11, 20, 23, 24). The healing process of aneurysms after placement of an FD depends on intra-aneurysmal

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flow modifications and the endothelialization process over the neck (10, 11, 21, 24, 25). CFD simulation is an effective tool to understand how FD affects aneurysmal hemodynamics (10, 11, 25). Kulcsar et al. (11) analyzed the hemodynamic changes in

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eight ICA aneurysms treated by a single Silk FD and found relative flow velocity and WSS reduction in the majority of cases. Of which only two cases were large or giant, and both of them had high aspect ratio (4.5 and 3.6) which indicated narrow necks. After a Silk FD deployment, their mean velocity decreased by 71% and 20%, and their mean WSS decreased by 75% and 60%, respectively (8). Xiang et al. (25) evaluated the flow modification effects of the Pipeline Embolization Device in four complex aneurysms. For a giant aneurysm of 20×16mm, the aneurysmal average velocity and average WSS decreased by 20.3% and 31.8% with a Pipeline FD deployment, respectively. Considering the strong inflow impingement, this patient 7

ACCEPTED MANUSCRIPT was treated with 2 FD devices and then the average velocity and average WSS decreased almost double—by 39.4% and 59.1%, respectively (25). Damiano et al. (13) assessed the hemodynamic effect of endovascular coiling and FD device in one patient-specific aneurysm model and found that the main role of FDs is to divert

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inflow, while that of coils is to create stasis in the aneurysm. In this study, using CFD simulations and the virtual Tubridge FD deployment method, we observed that intra-aneurysmal flow velocity and WSS were decreased by 37% and 45% with one Tubridge FD, respectively, whereas LSA was increased to 458% of its pre-treatment

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value. Currently, data about hemodynamic changes related to different FD Devices in treating large and giant aneurysms are still not too much. Further hemodynamic study

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with a larger sample size will help doctors to explain the discouraging prognosis. However, FD treatment alone may presente a potential for fatal rupture, especially in treating large and giant aneurysms (1, 2, 6). Chow et al. (6) observed the fatal delayed rupture of a large aneurysm at 20 days after FD treatment. They found that the flow stream pointed to the rupture site, aneurysmal dome, along the wall and

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speculated that thrombus may destabilize the aneurysmal wall (6). The possible reason is that, during the healing process, the aneurysmal wall is subject to pulsatile perfusion and biological processes related to the unstable red thrombus which is

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physiologically unstable and has a high content of proteolytic enzymes (5-8). Therefore, as a supplementary measure for FD placement, loose coil packing is sometimes considered to help accelerate the process of thrombosis and provide

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immediate protection of the dome during the initial non-thrombosed phase (5). Loose coil packing can lead to favorable effects in decreasing intra-aneurysmal

flow velocity(12). There coils slow washout of the aneurysmal wall and stabilize large, rapidly accumulated intra-aneurysmal thrombus by changing the morphology of the aneurysmal cavity. Coils, similar to a breakwater, may further mechanically buffer the intra-aneurysmal hemodynamic forces and decrease aneurysmal wall pulsation, which further promote thrombosis and protect the flimsy aneurysmal wall (23). In our study, coils and FD were complementary (Fig. 3), and coils further decreased intra-aneurysmal velocity (16% reduction) and WSS (22% reduction), and increased 8

ACCEPTED MANUSCRIPT LSA (542% increase). In addition, as the packing density increased, the reduction of intra-aneurysmal velocity and WSS, and the increase of LSA were more obvious in the present study, which was similar to the previous studies (12, 13). Adjunctive coiling with FD placement can help to create an environment that is favorable to

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thrombosis formation and may reduce the need for retreatment. Hemodynamic characteristics of aneurysm remaining residual aneurysm 12 months after treatment Comparison with the other aneurysms

the aneurysm (case 3) with residual aneurysm

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had slightly diminished intra-aneurysmal flow velocity and WSS, and almost an unchanged flow pattern (Fig. 5). Hemodynamic analysis showed that blood flow

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entered the aneurysm through the impingement region and formed a complex vortex inside (Fig. 5A1, A2). After placement of a single Tubridge FD, intra-aneurysmal velocity of the flow jet decreased, albeit its flow structure remained unchanged (Fig. 5B1, B2). Placement of coils further reduced velocity, although the impingement jet remained (Fig. 5C1, C2). Quantitative analysis showed that the reduction of

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intra-aneurysmal flow velocity and WSS may be not sufficient to promote the thrombosis formation compared with the other aneurysms (Fig. 3). The reason for this finding may be that individual anatomy with a sharp turn of the ICA at the base of the

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aneurysm decreased local porosity of the Tubridge FD, allowing the metallic wires to slip to accommodate the vessel curves (24). Because the blood flow cannot be markedly reduced at the neck of the aneurysm, the physiological high flow in the ICA

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directly impinged into the aneurysm, resulting in partial patency. Therefore, complex interactions in hemodynamics, the shape of the aneurysm, and the geometry of the parent artery should be considered. Additionally, the necessity of individualized flow-diverting treatment is not negligible. If an optimal hemodynamic state cannot be achieved by a FD and loose-packing coils, multiple overlapping FD layers or more coils may be beneficial. Limitations A limitation of the present study is the small sample size. A larger series is required to assess the clinical safety and effectiveness of the Tubridge FD. Our follow-up time 9

ACCEPTED MANUSCRIPT range is 5-12 months. Continued follow-up of the participants in this study will be helpful to further verify our results. To our knowledge, well defined data about the sufficient coil packing degree are not available, and the exact efficacy of ajunctive coilng in different FDs treatment of large and giant aneurysms still need further study.

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Similar to most CFD hemodynamic analyses, the assumption of rigid walls, Newtonian blood properties, and physiological but not patient-specific flow-boundary conditions, were used. Additionally, the geometrical structure of the Tubridge FD struts was simplified as an approximation of an actual stent in all of the cases.

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Furthermore, the porous media method was used to mimic ideal coil mass without actual configuration of the coils.

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Conclusions

Based on CFD method, adjunctive coiling with the Tubridge FD placement may significantly reduce intra-aneurysmal flow velocity and WSS, promoting thrombosis formation and occlusion of aneurysms. CFD simulations can help operators understand the variation in intra-aneurysmal hemodynamics and choose a safer

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treatment for patients. Further studies with refined CFD modeling and in vitro experiments are needed to confirm these results. Acknowledgments

Funding

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No.

This work was supported by the National Natural Science Foundation of China (grant

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No. 81301003, 81171079, 81471167, 81371315 and 81220108007), Special Research Project for Capital Health Development (grant No. 2014-1-1071), and Youth Fund of Beijing Neurosurgical Institute (grant No. 2014-001). Competing Interests

We declare that they have no conflict of interest. Author’s contribution LJ and JZ contributed equally to the preparation of the manuscript and data collection. JL performed statistical analysis. YZ, XY conceived and designed the research. SW did the CFD simulation. PN, HM, AS designed in-house software and developed 10

ACCEPTED MANUSCRIPT virtual stent-deployment technique. References

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endovascular coiling and flow diversion enables hemodynamic prediction of complex treatment strategies for intracranial aneurysm. J Biomech 48:3332-40, 2015. 14. Lubicz B, Collignon L, Raphaeli G, Pruvo JP, Bruneau M, De Witte O, Leclerc X: Flow-diverter stent for the endovascular treatment of intracranial aneurysms: a prospective study in 29 patients with 34 aneurysms. Stroke 41:2247-53, 2010. 15. Saatci I, Yavuz K, Ozer C, Geyik S, Cekirge HS: Treatment of intracranial aneurysms using the pipeline flow-diverter embolization device: a single-center experience with long-term follow-up results. AJNR Am J Neuroradiol 33:1436-46, 2012. 16. Luo B, Yang X, Wang S, Li H, Chen J, Yu H, Zhang Y, Zhang Y, Mu S, Liu Z, Ding G: High shear stress and flow velocity in partially occluded aneurysms prone to recanalization. Stroke 42:745-53, 2011. 17. Fan J, Wang Y, Liu J, Jing L, Wang C, Li C, Yang X, Zhang Y: Morphological-Hemodynamic Characteristics of Intracranial Bifurcation Mirror Aneurysms. World Neurosurg 84:114-20.e2, 2015. 18. Paliwal N, Yu H, Damiano R, Xiang J, Yang X, Siddiqui A, Li H, Meng H, editors. Fast Virtual Stenting With Vessel-Specific Initialization and Collision Detection. ASME 2014 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference; 2014: American Society of Mechanical Engineers. 19. Wang S, Zhang Y, Lu G, Yang X, Zhang X, Ding G: Hemodynamic performance of coil embolization and stentassisted coil embolization treatments: a numerical comparative study based on subject-specific models of cerebral aneurysms. Science China Physics, Mechanics and Astronomy 54:2053-63, 2011. 20. Mitsos AP, Kakalis NM, Ventikos YP, Byrne JV: Haemodynamic simulation of aneurysm coiling in an anatomically accurate computational fluid dynamics model: technical note. Neuroradiology 50:341-7, 2008. 21. Stuhne GR, Steinman DA: Finite-element modeling of the hemodynamics of stented aneurysms. J Biomech Eng 126:382-7, 2004. 22. Malek AM, Alper SL, Izumo S: Hemodynamic shear stress and its role in atherosclerosis. Jama 282:2035-42, 1999. 23. Boecher-Schwarz HG, Ringel K, Kopacz L, Heimann A, Kempski O: Ex vivo study of the physical effect of coils on pressure and flow dynamics in experimental aneurysms. AJNR Am J Neuroradiol 21:1532-6, 2000. 24. Darsaut TE, Bing F, Salazkin I, Gevry G, Raymond J: Flow diverters failing to occlude experimental bifurcation or curved sidewall aneurysms: an in vivo study in canines. J Neurosurg 117:37-44, 2012. 25. Xiang J, Damiano RJ, Lin N, Snyder KV, Siddiqui AH, Levy EI, Meng H: High-fidelity virtual stenting: modeling of flow diverter deployment for hemodynamic characterization of complex intracranial aneurysms. J Neurosurg 123:832-40, 2015.

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ACCEPTED MANUSCRIPT Figure Legends Figure 1. Angiograms of aneurysms at pre-treatment (A1-F1), post-treatment (A2-F2), and follow-up (A3-F3) were obtained in all of the patients. Figure 2. The geometry of model.

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Figure 3. The key hemodynamic changes at pre-treatment, post-Tubridge FD placement, and post-Tubridge FD & coils placement. Data are expressed as mean± SD. Tubridge FD alone can significantly reduce the intra-aneurysmal flow velocity and wall shear stress (WSS), and increased the low wall shear area (LSA). Coils can

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further strengthen these effect.

Figure 4. The aneurysm (case 4) showed complete occlusion at the 6 months’

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follow-up. Hemodynamic analysis (magnitude of intra-aneurysmal flow velocity on a cut plane [A1-C1] and streamline [A2-C2] at the systolic peak, and WSS [A3-C3]) was conducted. The high-speed inflow jet was decreased (A1 and C1), and the flow pattern was markedly changed (A2 and C2) by the Tubridge FD and coils. Additionally, the magnitude of WSS was significantly reduced with this treatment (A3

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and C3). Loose packing coils further reduced velocity and WSS (B and C). Figure 5. The aneurysm (case 3) remained patent 12 months after treatment. Hemodynamic analysis (A-C) was conducted. The high-speed inflow jet was slightly

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attenuated (A1 and C1), and the flow pattern almost remained unchanged (A2 and C2), and the magnitude of WSS was slightly reduced (A3 and C3) by the Tubridge FD and

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loose packing coils. Additionally, coils slightly reduced velocity and WSS (B and C).

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Age, y, Sex

Location

Aneurysm size, mm

Neck width, mm

Packing density, %

1

57, Female

L C4

25.61

11.82

4.01

2

49, Female

L C4

17.11

9.73

4.20

3

42, Male

L C6

21.53

10.46

5.16

4

49, Male

L C4

12.15

7.54

5.47

5

56, Female

L C4

19.52

10.27

9.36

6

56, Female

L C6

12.97

6.51

12.75

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Internal carotid artery, the Bouthillier classification: C4, cavernous; C6, ophthalmic.

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initial angiographic result

Follow-up result and time

Residual aneurysm

Complete occlusion at 5 months

Residual aneurysm

Complete occlusion at 10 months

Residual aneurysm

Residual aneurysm at 12 months

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Case

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Table 1. Characteristics of the patients and aneurysms

Residual aneurysm

Complete occlusion at 6 months

Residual aneurysm

Residual neck at 6 months

Residual aneurysm

Complete occlusion at 12 months

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AC C

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AC C

EP

TE D

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AC C

EP

TE D

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AC C

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TE D

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ACCEPTED MANUSCRIPT Conflict of interest: We declare that they have no conflict of interest. This work was supported by the National Natural Science Foundation of China (grant No. 81301003, 81171079, 81471167, 81371315 and 81220108007), Special Research Project for

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Neurosurgical Institute (grant No. 2014-001).

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Capital Health Development (grant No. 2014-1-1071), and Youth Fund of Beijing

ACCEPTED MANUSCRIPT Highlights: 1. Six aneurysms were treated by a novel Tubridge flow diverter (FD) and loose packing coils.

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2. Patient-specific models were constructed and analyzed by a computational fluid dynamics method.

3. FD markedly reduced velocity and wall shear stress (WSS), and increased low wall

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shear area (LSA). Coils further reduced velocity and WSS, and increased LSA.

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4. Aneurysm with strong inflow after treatment showed residual aneurysm. 5. Adjunctive coiling with FD placement may significantly promote the occlusion of

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aneurysms.