Numerical modeling is an effective tool for preoperative planning. The present work is devoted to a retrospective analysis of neurosurgical treatments for the occlusion of cerebral aneurysms using flow-diverters and hemodynamic factors affecting stent endothelization. Several different geometric approaches have been considered for virtual flow-diverters deployment. A comparative analysis of hemodynamic parameters as a result of computational modeling has been carried out basing on the four clinical cases: one successful treatment, one with no occlusion and two with in stent stenosis. For the first time, a quantitative assessment of both: the limiting magnitude of shear stresses that are necessary for the occurrence of in stent stenosis (MaxWSS > 1.23) and for conditions in which endothelialization is insufficiently active and occlusion of the cervical part of the aneurysm does not occur (MaxWSS < 1.68)—has been statistacally proven (p < 0.01).

We have designed a reinforced drug-loaded vascular graft composed of polycaprolactone (PCL) and polydioxanone (PDO) via a combination of electrospinning/3D printing approaches. To evaluate its potential for clinical application, we compared the in vivo blood compatibility and performance of PCL/PDO + 10%DY grafts doped with an antithrombotic drug (dipyridamole) with a commercial expanded polytetrafluoroethylene (e-PTFE) graft in a porcine model.
A total of 10 pigs (weight: 25-35 kg) were used in this study. We made a new 5-mm graft with PCL/PDO composite nanofiber via the electrospinning technique. We simultaneously implanted a commercially available e-PTFE graft (n = 5) and our PCL/PDO + 10%DY graft (n = 5) into the carotid arteries of the pigs. No anticoagulant/antiplatelet agent was administered during the follow-up period, and ultrasonography was performed weekly to confirm the patency of the two grafts in vivo. Four weeks later, we explanted and compared the performance of the two grafts by histological analysis and scanning electron microscopy (SEM).
No complications, such as sweating on the graft or significant bleeding from the needle hole site, were seen in the PCL/PDO + 10%DY graft immediately after implantation. Serial ultrasonographic examination and immunohistochemical analysis demonstrated that PCL/PDO + 10%DY grafts showed normal physiological blood flow and minimal lumen reduction, and pulsed synchronously with the native artery at 4 weeks after implantation. However, all e-PTFE grafts occluded within the study period. The luminal surface of the PCL/PDO + 10%DY graft in the transitional zone was fully covered with endothelial cells as observed by SEM.
The PCL/PDO + 10%DY graft was well tolerated, and no adverse tissue reaction was observed in porcine carotid models during the short-term follow-up. Colonization of the graft by host endothelial and smooth muscle cells coupled with substantial extracellular matrix production marked the regenerative capability. Thus, this material may be an ideal substitute for vascular reconstruction and bypass surgeries. Long-term observations will be necessary to determine the anti-thrombotic and remodeling potential of this device.

Stent-induced vascular injury is manifested by removal of the endothelium and phenotypic changes in the underlying medial smooth muscle cells layer. This results in pathological vascular remodelling primarily contributed to smooth muscle cell proliferation and leads to vessel re-narrowing; neointimal hyperplasia. Current drug-eluting stents release non-selective anti-proliferative drugs such as paclitaxel from the stent surface that not only inhibit growth of smooth muscle cells but also delay endothelial healing, potentially leading to stent thrombosis. This highlights the need for novel bioactive stent coating candidates with the ability to target key events in the pathogenesis of in-stent restenosis. Citric acid, a molecule with anti-coagulant properties, was investigated against L-ascorbic acid, an antioxidant molecule reported to preferentially promote endothelial growth, and paclitaxel, a typically used anti-proliferative stent coating. Citric acid was found to exhibit growth supporting properties on endothelial cells across a range of concentrations that were significantly better than the model stent coating drug paclitaxel and better than the ascorbic acid which inhibited endothelial proliferation at concentrations ≥100 μg/ml. It was demonstrated that a citric acid-paclitaxel combination treatment significantly improves cell viability in comparison to paclitaxel only treated cells, with endothelial cells exhibiting greater cell recovery over smooth muscle cells. Furthermore, cell treatment with citric acid was found to reduce inflammation in a lipopolysaccharide (LPS)-induced in vitro inflammation model by significantly reducing interleukin 6 expression. Thus, this study demonstrates that citric acid is a promising candidate for use as a coating in stents and other endovascular devices.

To evaluate the safety and feasibility of a modified poly(l-lactic acid) (PLLA) atrial septal defect (ASD) occluder.
Forty-five piglets were divided into two groups: an experimental group (n = 27) and a control group (n = 18). The experimental group underwent percutaneous implantation of a modified PLLA ASD device while the control group underwent percutaneous implantation of a widely used metal ASD device. X-ray imaging, transthoracic echocardiography (TTE), electrocardiogram (ECG), histopathology and electron microscopic examination were performed at 7 days, 1, 3, 6, and 12 months after implantation.
Twenty-seven experimental piglets and 18 control piglets were all successfully implanted with modified biodegradable and metal ASD devices, respectively. While both devices exhibited very good occluding effects, the modified PLLA ASD devices were completely endothelialized at 3 months after implantation, and the endothelialization appeared to be more complete compared to the control group. Degradation of the PLLA devices was noted at 12 months follow-up with no loss of integrity at the atrial septum.
This animal model with implanting of the occluders was effective and not associated with complications. The modified PLLA ASD devices are more controllable and practical than our previous devices. The implanted devices demonstrated good endothelialization and degradability in short and moderate term follow-up. Long-term studies are now underway to further evaluate the biodegradability of this novel device.

Endothelialization is an important process after stenting in coronary artery. Recovery of the injured site timely can reduce the neointima formation and platelet absorbance, leading to a lower risk of in-stent restenosis. Copper is known to be critical in vascular construction. Thus a combination of copper with stent materials is a meaningful attempt. A copper bearing L605-Cu cobalt alloy was prepared and its effect on human umbilical vein endothelial cells (HUVECs) was evaluated in vitro in this study. It was found that HUVECs attached and stretched better on the surface of L605-Cu compared with L605, and the apoptosis of cells was decreased simultaneously. The migration and tube formation of HUVECs were also enhanced by the extract of L605-Cu. Furthermore, L605-Cu increased the mRNA expression of VEGF in HUVECs significantly. However it had no effect on the secretion of NO or mRNA expression of eNOS. The result of blood clotting test indicated that L605-Cu had better blood compatibility. These results above have demonstrated that the L605-Cu alloy is promising to be a new stent material with function of accelerating endothelialization. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 561-569, 2018.

Dialdehyde carboxymethyl (DCMC) was select as an optimal crosslinking reagent for its excellent biocompatibility, appropriate degradable property and suitable chemical reactivity in our previous research. However, similar to other traditional crosslinking reagent, the endothelialization of biological vascular scaffolds fixed by DCMC was not sufficient enough. To overcome this limitation presented in DCMC-fixed arteries, a novel strategy was developed by introducing SCPP into arteries to investigate effects of strontium doped calcium polyphosphate (SCPP)-doping on the properties of DCMC-fixed arteries, especially on the endothelialization of fixed arteries. After modifying and crosslinking, their chemical structures, mechanical properties, stability, and cytocompatibility were examined. The result obtained from EDS analysis indicated SCPP was successfully introduced into DCMC-fixed arteries. Compared with purely DCMC-crosslinked ones, DCMC/SCPP modification has no significant effect on mechanical strength of fixed arteries, but a slight tend to improve the stability of fixed samples in D-Hanks solution. Moreover, MTT assay, SEM observation and live/dead assay implied that DCMC/SCPP modification could effectively stimulate HUVECs\' adhesion and proliferation, and thus promote endothelialization process of fixed arteries. In this study, micron-sized SCPP particles were firstly applied to modify DCMC-crosslinked porcine arteries, and the results demonstrated this method could improve the endothelialization of fixed arteries. Therefore, DCMC/SCPP-modified arteries with excellent physicochemical properties and biocompatibility should be a promising materials for fabricating vascular scaffolds.

Although flow-diverting devices are promising treatment options for intracranial aneurysms, jailed side branches might occlude leading to insufficient blood supply. Especially differences in the local stent strut compression may have a drastic influence on subsequent endothelialization. To investigate the outcome of different treatment scenarios, over- and undersized stent deployments were realized experimentally and computationally. Two Pipeline Embolization Devices were placed in the right common carotid artery of large white swine, crossing the right ascending pharyngeal artery. DSA and PC-MRI measurements were acquired pre- and post-stenting and after three months. To evaluate the stent strut endothelialization and the corresponding ostium patency, the swine were sacrificed and scanning electron microscopy measurements were carried out. A more detailed analysis of the near-stent hemodynamics was enabled by a realistic virtual stenting in combination with highly resolved Computational Fluid Dynamics simulations using case-specific boundary conditions. The oversizing resulted in an elongated stent deployment with more open stent pores, while for the undersized case a shorter deployment with more condensed pores was present. In consequence, the side branch of the first case remained patent after three months and the latter almost fully occluded. The virtual investigation confirmed the experimental findings by identifying differences between the individual velocities as well as stent shear stresses at the distal part of the ostia. The choice of flow-diverting device and the subsequent deployment strategy strongly influences the patency of jailed side branches. Therefore, careful treatment planning is required, to guarantee sufficient blood supply in the brain territories supplied those branches.

Local flow disturbance by arterial stent struts has been shown to play an important role in stent thrombosis. To reduce the local flow disturbance near a stent strut, we proposed a new concept of stent design with small holes in the stent struts. The present study evaluated the new design numerically by comparing it with the traditional stent in terms of local hemodynamic parameters such as flow velocity, flow recirculation area, time-averaged wall shear stress (TAWSS), oscillating shear index (OSI), and relative residence time (RRT). The results demonstrated that when compared with the traditional strut, the new design could significantly enhance flow velocity and reduce the flow recirculation zone in the vicinity of the strut. Moreover, the new design would significantly elevate TAWSS and remarkably reduce OSI and RRT along the host arterial wall. In conclusion, the new design of stent struts with punched holes is advantageous over the traditional one in the aspect of improving local hemodynamics, which may reduce thrombosis formation and promote re-endothelialization after stenting.

OBJECTIVE: To compare the long-term clinical safety between two drug-eluting stents with different healing characteristics in the Patient Related Outcomes with Endeavour (E-ZES) vs. Cypher (C-SES) Stenting Trial (PROTECT). At 3 years, there was no difference in the primary outcome of definite or probable stent thrombosis or in the other main secondary clinical outcomes consisting of the composite of death or myocardial infarction (MI). Prespecified 4-year clinical follow-up was analysed.
RESULTS: Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial was a prospective, open-label randomized-controlled superiority trial powered to look at differences in long-term clinical safety, including stent thrombosis. Dual antiplatelet therapy (DAPT) was prescribed for ≥ 3 months and up to 12 months based on current guidelines. Patient Related OuTcomes with Endeavour vs. Cypher Stenting Trial enrolled 8791 patients undergoing elective or emergency PCI to E-ZES or C-SES. There was no difference in DAPT usage between the two groups up to 4 years. At 4-year follow-up, the primary outcome occurred in 1.6% of E-ZES vs. 2.6% of C-SES patients [HR 0.63 (95% CI 0.46-0.85), P = 0.003]. The composite of all-cause death or large MI occurred in 6.7% of E-ZES vs. 8.0% of C-SES-treated patients [HR 0.84 (95% CI 0.71-0.98), P = 0.024].
CONCLUSIONS: Drug-eluting coronary stents with different healing characteristics demonstrated different late safety profiles: after 4 years, compared with C-SES, E-ZES reduced the risk of stent thrombosis and the risk of the composite endpoints of death or MI. Appropriately powered large-scale trials with long-term follow-up are critical to determine clinical safety and efficacy of permanently implanted coronary stents. This trial is registered with ClinicalTrials.gov, number NCT00476957.