In vivo comparison of braided (Accero) and laser-cut intracranial stents (Acclino, Credo): evaluation of vessel responses at subacute and mid-term follow-up in a rabbit model.

This study aimed to investigate in vivo two stent technologies, with particular emphasis on thrombogenicity and inflammatory vessel remodeling processes. The micro-stents tested in this study were developed for intracranial aneurysm treatment. In our study twelve, New Zealand white rabbits were divided into two groups: 18 laser-cut stents (LCS) and 18 braided stents (BS) were impanated without admiration of antiplatelet medication. Three stents were implanted into each animal in the common carotid artery, subclavian artery, and abdominal aorta. Digital subtraction angiography was performed before and after stent implantation and at follow-up for the visualization of occurring In-stent thromboembolism or stenosis. The Stents were explanted for histopathological examination at two different timepoints, after 3 and 28 days. Angiographically neither in-stent thrombosis nor stenosis for both groups was seen. There was a progressive increase in the vessel diameter, which was more pronounced for BS than for LCS. We detected a higher number of thrombi adherent to the foreign material on day 3 for BS. On day 3, the neointima was absent, whereas the complete formation observed was on day 28. There was no significant difference between both groups regarding the thickness of the neointima. The in vivo model of our study enabled the evaluation of blood and vessel reactions for two different stent technologies. Differences in vessel dimension and tissue around the stents were observed on day 28. Histological analysis on day 3 enabled the assessment of thrombotic reactions, representing an important complementary result in long-term studies.

Publisher Correction: In vitro investigation of chemical properties and biocompatibility of neurovascular braided implants.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

In vitro investigation of chemical properties and biocompatibility of neurovascular braided implants.

Braiding of Nitinol micro wires is an established technology for the manufacturing of fine-meshed neurovascular implants for tortuous vessel geometries. Electropolishing of wires before the braiding process has the potential to improve the in vitro behaviour in terms of thrombogenicity and endothelial cell proliferation. In this study, we present the first in vitro investigation of braided electropolished/blue oxide Nitinol samples in a blood flow loop, showing a significantly lower activation of the coagulation pathway (represented by the TAT III marker) and a tendency towards reduced platelet adhesion. Furthermore, we applied the same surface treatment on flat disks and measured protein adhesion as well as endothelial cell proliferation. We compared our results to non-electropolished samples with a native oxide surface. While platelet deposition was reduced on electropolished/blue oxide surface, a significant increase of endothelial cell seeding was observed. Investigation of inflammatory marker expression in endothelial cells provided divergent results depending on the marker tested, demanding closer investigation. Surface analysis using Auger electron spectroscopy revealed a thin layer mainly consisting of titanium oxynitride or titanium oxide + titanium nitride as a potential cause of the improved biological performance. Translated to the clinical field of intracranial aneurysm treatment, the improved biocompatibility has the potential to increase both safety (low thrombogenicity) and effectiveness (aneurysm neck reconstruction).

Combined local hypothermia and recanalization therapy for acute ischemic stroke: Estimation of brain and systemic temperature using an energetic numerical model.

Local brain hypothermia is an attractive method for providing cerebral neuroprotection for ischemic stroke patients and at the same time reducing systemic side effects of cooling. In acute ischemic stroke patients with large vessel occlusion, combination with endovascular mechanical recanalization treatment could potentially allow for an alleviation of inflammatory and apoptotic pathways in the critical phase of reperfusion. The direct cooling of arterial blood by means of an intra-carotid heat exchange catheter compatible with recanalization systems is a novel promising approach. Focusing on the concept of "cold reperfusion", we developed an energetic model to calculate the rate of temperature decrease during intra-carotid cooling in case of physiological as well as decreased perfusion. Additionally, we discussed and considered the effect and biological significance of temperature decrease on resulting brain perfusion. Our model predicted a 2 °C brain temperature decrease in 8.3, 11.8 and 26.2 min at perfusion rates of 50, 30 and 10ml100g⋅min, respectively. The systemic temperature decrease - caused by the venous blood return to the main circulation - was limited to 0.5 °C in 60 min. Our results underline the potential of catheter-assisted, intracarotid blood cooling to provide a fast and selective brain temperature decrease in the phase of vessel recanalization. This method can potentially allow for a tissue hypothermia during the restoration of the physiological flow and thus a "cold reperfusion" in the setting of mechanical recanalization.

In vitro, contrast agent-based evaluation of the influence of flow diverter size and position on intra-aneurysmal flow dynamics using syngo iFlow.

PURPOSE: Treatment of intracranial aneurysm with flow-diverting devices has become widespread in recent years. Despite that, intra-aneurysmal flow changes are yet not fully understood and can lead to different complications. Our aim was an in vitro contrast-based evaluation of the influence of flow diverter size and position on intra-aneurysmal flow dynamics. METHODS: Flow-diverting devices with different sizes (diameters 4.0, 4.5, and 6.0 mm) were deployed in seven silicone aneurysm models at different positions relative to the aneurysm neck (proximal, central, distal). Using syngo iFlow, we defined quantitative evaluation criteria based on contrast medium intensity and performed a flow evaluation. RESULTS: Intra-aneurysmal flows were heavily dependent on both size and position of flow-diverting devices at the aneurysm neck. We observed a higher peak intensity delay and intra-aneurysmal washout delay with the centrally placed 4.0- and 4.5-mm device, respectively, compared to the proximal and distal positions. Especially distally placed 4.0-mm devices led to an earlier filling of the aneurysm and increased intra-aneurysmal contrast agent intensity compared to the parent vessel, due to a potential endoleak. CONCLUSIONS: Not only size but also position of flow-diverting devices have a considerable impact on the intra-aneurysmal flow dynamics. The suggested evaluation criteria allowed a quantitative comparison of flow-diverting effect using syngo iFlow and could represent an efficient tool for predicting flow diversion pre-procedurally.

Evaluation of occurring complications after flow diverter treatment of elastase-induced aneurysm in rabbits using micro-CT and MRI at 9.4 T.

INTRODUCTION: Flow diverters are increasingly being used to treat intracranial aneurysms. This study evaluates occurring complications of flow-diverting devices in the treatment of experimental aneurysms, involving the use of micro-CT and small animal MRI at 9.4 T, in correlation to angiographic and histological findings. METHODS: We previously published two preclinical studies, in which we assessed two different flow diverters in the treatment of elastase-induced aneurysms. Devices have been implanted across the aneurysm neck as well as in the abdominal aorta. From these studies, a total of 65 devices (prototype FD (n = 30) and Derivo embolization device (n = 35)) additionally underwent micro-CT and MRI after angiographic follow-up and before being histologically examined. RESULTS: The different architectures of both devices were precisely comparable due to high-resolution micro-CT imaging. Micro-CT revealed wire fractures in nine cases (30 %) only with the prototype FD. In three cases (10 %), severe wire fractures correlated with an in-stent stenosis due to intimal hyperplasia. Other complications, like distal stent occlusions and post-stent stenosis, were seen in both groups and verified with both imaging techniques. Osseous metaplasia were correlated to calcifications seen with micro-CT. MRI enabled visualization of the position of the implanted devices relative to the aneurysm and revealed incomplete aneurysm neck coverage with the prototype FD in two cases (6.7 %). CONCLUSION: Micro-CT and 9.4-T MRI are valid to discover and understand occurring complications of flow diverters in the preclinical phase and can serve as evaluation tools to minimize complication rates of endovascular devices in the future.

An imprint-based approach to replicate nano- to microscale roughness on gelatin hydrogel scaffolds: surface characterization and effect on endothelialization.

Biologization of biomaterials with endothelial cells (ECs) is an important step in vascular tissue engineering, aiming at improving hemocompatibility and diminishing the thrombo-inflammatory response of implants. Since subcellular topography in the scale of nano to micrometers can influence cellular adhesion, proliferation, and differentiation, we here investigate the effect of surface roughness on the endothelialization of gelatin hydrogel scaffolds. Considering the micron and sub-micron features of the different native tissues underlying the endothelium in the body, we carried out a biomimetic approach to replicate the surface roughness of tissues and analyzed how this impacted the adhesion and proliferation of human umbilical endothelial cells (HUVECs). Using an imprinting technique, nano and micro-roughness ranging from Sa= 402 nm to Sa= 8 µm were replicated on the surface of gelatin hydrogels. Fluorescent imaging of HUVECs on consecutive days after seeding revealed that microscale topographies negatively affect cell spreading and proliferation. By contrast, nanoscale roughnesses of Sa= 402 and Sa= 538 nm promoted endothelialization as evidenced by the formation of confluent cell monolayers with prominent VE-cadherin surface expression. Collectively, we present an affordable and flexible imprinting method to replicate surface characteristics of tissues on hydrogels and demonstrate how nanoscale roughness positively supports their endothelialization.

Fabrication, characterization and numerical validation of a novel thin-wall hydrogel vessel model for cardiovascular research based on a patient-specific stenotic carotid artery bifurcation.

In vitro vascular models, primarily made of silicone, have been utilized for decades for studying hemodynamics and supporting the development of implants for catheter-based treatments of diseases such as stenoses and aneurysms. Hydrogels have emerged as prominent materials in tissue-engineering applications, offering distinct advantages over silicone models for fabricating vascular models owing to their viscoelasticity, low friction, and tunable mechanical properties. Our study evaluated the feasibility of fabricating thin-wall, anatomical vessel models made of polyvinyl alcohol hydrogel (PVA-H) based on a patient-specific carotid artery bifurcation using a combination of 3D printing and molding technologies. The model's geometry, elastic modulus, volumetric compliance, and diameter distensibility were characterized experimentally and numerically simulated. Moreover, a comparison with silicone models with the same anatomy was performed. A PVA-H vessel model was integrated into a mock circulatory loop for a preliminary ultrasound-based assessment of fluid dynamics. The vascular model's geometry was successfully replicated, and the elastic moduli amounted to 0.31 ± 0.007 MPa and 0.29 ± 0.007 MPa for PVA-H and silicone, respectively. Both materials exhibited nearly identical volumetric compliance (0.346 and 0.342% mmHg-1), which was higher compared to numerical simulation (0.248 and 0.290% mmHg-1). The diameter distensibility ranged from 0.09 to 0.20% mmHg-1 in the experiments and between 0.10 and 0.18% mmHg-1 in the numerical model at different positions along the vessel model, highlighting the influence of vessel geometry on local deformation. In conclusion, our study presents a method and provides insights into the manufacturing and mechanical characterization of hydrogel-based thin-wall vessel models, potentially allowing for a combination of fluid dynamics and tissue engineering studies in future cardio- and neurovascular research.

Investigation of tracer gas transport in a new numerical model of lung acini.

Obstructive pulmonary diseases are associated with considerable morbidity. For an early diagnosis of these diseases, inert gas washouts can potentially be used. However, the complex interaction between lung anatomy and gas transport mechanisms complicates data analysis. In order to investigate this interaction, a numerical model, based on the finite difference method, consisting of two lung units connected in parallel, was developed to simulate the tracer gas transport within the human acinus. Firstly, the geometries of the units were varied and the diffusion coefficients (D) were kept constant. Secondly, D was changed and the geometry was kept constant. Furthermore, simple monoexponential growth functions were applied to evaluate the simulated data. In 109 of the 112 analyzed curves, monoexponential function matched simulated data with an accuracy of over 90%, potentially representing a suitable numerical tool to predict transport processes in further model extensions. For total flows greater than 5 × 10-4 ml/s, the exponential growth constants increased linearly with linear increasing flow to an accuracy of over 95%. The slopes of these linear trend lines of 1.23 µl-1 (D = 0.6 cm2/s), 1.69 µl-1 (D = 0.3 cm2/s), and 2.25 µl-1 (D = 0.1 cm2/s) indicated that gases with low D are more sensitive to changes in flows than gases with high D.

Vascular Response on a Novel Fibrin-Based Coated Flow Diverter.

PURPOSE: Due to thromboembolic complications and in-stent-stenosis after flow diverter (FD) treatment, the long-term use of dual antiplatelet treatment (DAPT) is mandatory. The tested nano-coating has been shown to reduce material thrombogenicity and promote endothelial cell proliferation in vitro. We compared the biocompatibility of coated (Derivo Heal) and non-coated (Derivo bare) FDs with DAPT in an animal model. METHODS: Derivo® bare (n = 10) and Derivo® Heal (n = 10) FD were implanted in the common carotid arteries (CCAs) of New Zealand white rabbits. One additional FD, alternately a Derivo bare (n = 5) or Derivo Heal (n = 5), was implanted in the abdominal aorta (AA) for assessment of the patency of branch arteries. Histopathological examinations were performed after 28 days. Angiography was performed before and after FD implantation and at follow-up. RESULTS: Statistical analysis of the included specimens showed complete endothelialization of all FDs with no significant differences in neointima thickness between Derivo® bare and Derivo® Heal (CCA: p = 0.91; AA: p = 0.59). A significantly reduced number of macrophages in the vessel wall of the Derivo Heal was observed for the CCA (p = 0.02), and significantly reduced fibrin and platelet deposition on the surface of the Derivo Heal was observed for the AA. All branch arteries of the stented aorta remained patent. CONCLUSION: In this animal model, the novel fibrin-based coated FD showed a similar blood and tissue compatibility as the non-coated FD.

New Concept of Patient-specific Flow Diversion Treatment of Intracranial Aneurysms : Design Aspects and in vitro Fluid Dynamics.

PURPOSE: Current flow diverter (FD) designs limit the possibilities to achieve ideal functional parameters for intra-aneurysmal flow alteration in the implanted state. In this work, we evaluate the technical feasibility of a new patient-specific FD concept and the impact on intra-aneurysmal flow reduction compared to standard FD. METHODS: Based on a literature review, we defined functional requirements, followed by the design and manufacturing of two different prototypes, which we implanted in a patient-specific phantom model. Functional porosity distributions and contour parameters were evaluated in the implanted state and compared to standard FD. Subsequently, we carried out a series of particle image velocimetry (PIV) measurements, in order to assess the impact on intra-aneurysmal flow. RESULTS: With both patient-specific prototypes, it was possible to achieve stronger intra-aneurysmal flow reductions in terms of maximum and mean velocity and vorticity than a standard FD; however, one design showed a strong sensitivity against malpositioning. Overall, fluid dynamics parameters correlated with geometrical aspects such as the porosity and its grade of homogeneity. Beyond that, we found influences by the FD contour projection within the aneurysm, especially connected to the formation of in-jets. CONCLUSION: Our results show that there is a technically feasible concept, which enables a more specific adjustment of functional FD parameters and more effective intra-aneurysmal flow reduction. This could potentially lead to improvements in the efficacy of aneurysm occlusion in cases with challenging fluid dynamics.

Selective Brain Hypothermia for Ischemic MCA-M1 Stroke: Influence of Cerebral Arterial Circulation in a 3D Brain Temperature Model.

Acute ischemic stroke is a major health problem with a high mortality rate and a high risk for permanent disabilities. Selective brain hypothermia has the neuroprotective potential to possibly lower cerebral harm. A recently developed catheter system enables to combine endovascular blood cooling and thrombectomy using the same endovascular access. By using the penumbral perfusion via leptomeningeal collaterals, the catheter aims at enabling a cold reperfusion, which mitigates the risk of a reperfusion injury. However, cerebral circulation is highly patient-specific and can vary greatly. Since direct measurement of remaining perfusion and temperature decrease induced by the catheter is not possible without additional harm to the patient, computational modeling provides an alternative to gain knowledge about resulting cerebral temperature decrease. In this work, we present a brain temperature model with a realistic division into gray and white matter and consideration of spatially resolved perfusion. Furthermore, it includes detailed anatomy of cerebral circulation with possibility of personalizing on base of real patient anatomy. For evaluation of catheter performance in terms of cold reperfusion and to analyze its general performance, we calculated the decrease in brain temperature in case of a large vessel occlusion in the middle cerebral artery (MCA) for different scenarios of cerebral arterial anatomy. Congenital arterial variations in the circle of Willis had a distinct influence on the cooling effect and the resulting spatial temperature distribution before vessel recanalization. Independent of the branching configurations, the model predicted a cold reperfusion due to a strong temperature decrease after recanalization (1.4-2.2  °C after 25 min of cooling, recanalization after 20 min of cooling). Our model illustrates the effectiveness of endovascular cooling in combination with mechanical thrombectomy and its results serve as an adequate substitute for temperature measurement in a clinical setting in the absence of direct intraparenchymal temperature probes.

Selective intra-carotid blood cooling in acute ischemic stroke: A safety and feasibility study in an ovine stroke model.

Selective therapeutic hypothermia (TH) showed promising preclinical results as a neuroprotective strategy in acute ischemic stroke. We aimed to assess safety and feasibility of an intracarotid cooling catheter conceived for fast and selective brain cooling during endovascular thrombectomy in an ovine stroke model.Transient middle cerebral artery occlusion (MCAO, 3 h) was performed in 20 sheep. In the hypothermia group (n = 10), selective TH was initiated 20 minutes before recanalization, and was maintained for another 3 h. In the normothermia control group (n = 10), a standard 8 French catheter was used instead. Primary endpoints were intranasal cooling performance (feasibility) plus vessel patency assessed by digital subtraction angiography and carotid artery wall integrity (histopathology, both safety). Secondary endpoints were neurological outcome and infarct volumes.Computed tomography perfusion demonstrated MCA territory hypoperfusion during MCAO in both groups. Intranasal temperature decreased by 1.1 °C/3.1 °C after 10/60 minutes in the TH group and 0.3 °C/0.4 °C in the normothermia group (p < 0.001). Carotid artery and branching vessel patency as well as carotid wall integrity was indifferent between groups. Infarct volumes (p = 0.74) and neurological outcome (p = 0.82) were similar in both groups.Selective TH was feasible and safe. However, a larger number of subjects might be required to demonstrate efficacy.

In vitro investigation of an intracranial flow diverter with a fibrin-based, hemostasis mimicking, nanocoating.

Flow diversion aims at treatment of intracranial aneurysms via vessel remodeling mechanisms, avoiding the implantation of foreign materials into the aneurysm sack. However, complex implantation procedure, high metal surface and hemodynamic disturbance still pose a risk for thromboembolic complications in the clinical praxis. A novel fibrin and heparin based nano coating considered as a hemocompatible scaffold for neointimal formation was investigated regarding thrombogenicity and endothelialization. The fibrin-heparin coating was compared to a bare metal as well as fibrin- or heparin-coated flow diverters. The implants were tested separately in regard to inflammation and coagulation markers in two different in vitro hemocompatibility models conducted with human whole blood (n = 5). Endothelialization was investigated through a novel dynamic in vitro cell seeding model containing primary human cells with subsequent viability assay. It was demonstrated that platelet loss and platelet activation triggered by presence of a bare metal stent could be significantly reduced by applying the fibrin-heparin, fibrin and heparin coating. Viability of endothelial cells after proliferation was similar in fibrin-heparin compared to bare metal implants, with a slight, non-significant improvement observed in the fibrin-heparin group. The results suggest that the presented nanocoating has the potential to reduce thromboembolic complications in a clinical setting. Though the new model allowed for endothelial cell proliferation under flow conditions, a higher number of samples is required to assess a possible effect of the coating.

Hemocompatibility Testing of Blood-Contacting Implants in a Flow Loop Model Mimicking Human Blood Flow.

The growing use of medical devices (e.g., vascular grafts, stents, and cardiac catheters) for temporary or permanent purposes that remain in the body's circulatory system demands a reliable and multiparametric approach that evaluates the possible hematologic complications caused by these devices (i.e., activation and destruction of blood components). Comprehensive in vitro hemocompatibility testing of blood-contacting implants is the first step towards successful in vivo implementation. Therefore, extensive analysis according to the International Organization for Standardization 10993-4 (ISO 10993-4) is mandatory prior to clinical application. The presented flow loop describes a sensitive model to analyze the hemostatic performance of stents (in this case, neurovascular) and reveal adverse effects. The use of fresh human whole blood and gentle blood sampling are essential to avoid the preactivation of blood. The blood is perfused through a heparinized tubing containing the test specimen by using a peristaltic pump at a rate of 150 mL/min at 37 °C for 60 min. Before and after perfusion, hematologic markers (i.e., blood cell count, hemoglobin, hematocrit, and plasmatic markers) indicating the activation of leukocytes (polymorphonuclear [PMN]-elastase), platelets (ß-thromboglobulin [ß-TG]), the coagulation system (thombin-antithrombin III [TAT]), and the complement cascade (SC5b-9) are analyzed. In conclusion, we present an essential and reliable model for extensive hemocompatibility testing of stents and other blood-contacting devices prior to clinical application.

Accuracy of optical coherence tomography imaging in assessing aneurysmal remnants after flow diversion.

BACKGROUND: Optical coherence tomography (OCT) is an ultra-high resolution real-time intravascular imaging method that is gaining interest in cerebrovascular applications. OBJECTIVE: To compare, in a rabbit elastase aneurysm model, digital subtraction angiography (DSA) and OCT as diagnostic tools for the assessment of aneurysmal remnants and baseline characteristics of aneurysms after flow diverter (FD) implantation. METHODS: With Institutional Animal Care and Use Committee approval, saccular aneurysms were created in 28 rabbits and treated with Derivo FDs. DSA was performed before, and immediately after, stent implantation. As a follow-up, DSA and OCT were performed 28 days after device implantation. RESULTS: DSA and OCT were successfully performed in 23 cases. OCT could not be achieved in 5 cases owing to navigational difficulties in the stent lumen with the OCT catheter. Residual aneurysms were significantly more often visible with OCT (18/23 (78%) than with DSA 12/23 (52%), p = 0.031). CONCLUSION: OCT was more sensitive than conventional angiography for the assessment of residual aneurysms at 28 days after FD implantation in an animal model.

Corrigendum: Development of a Routinely Applicable Imaging Protocol for Fast and Precise Middle Cerebral Artery Occlusion Assessment and Perfusion Deficit Measure in an Ovine Stroke Model: A Case Study.

[This corrects the article DOI: 10.3389/fneur.2019.01113.].

Review of selective brain hypothermia in acute ischemic stroke therapy using an intracarotid, closed-loop cooling catheter.

In acute ischemic stroke patients, selective brain hypothermia is a promising concept aiming at a fast decrease of brain temperature and thus neuroprotection in the acute phase of ischemia. At the same time, the emergence of mechanical thrombectomy (MT) as an effective treatment in large-vessel occlusion opens the door for a combination of neuroprotective approaches in the frame of a neurovascular, catheter-based intervention. In this regard, intracarotid cooling is a very effective energetic approach, using the blood supply to the penumbra as a fast transport vector for heat exchange in affected brain regions. We review the state of development of a novel closed-loop cooling catheter, describing design-related as well as procedural aspects and presenting results from different theoretical and experimental studies. Finally, we compare the concept with two alternative methods: cold saline infusion and extracorporeal blood cooling. We focus on the combination with MT, considering the effect of different and variable perfusion rates on the final goal of a "cold reperfusion" at the time of blood flow restoration.