Juan Raul Cebral

The severity of ischemic strokes, the likelihood of successful endovascular treatment, and subsequent clinical patient outcomes are all strongly influenced by the degree of collateralization of the brain arterial network. Although several scoring systems based on different imaging modalities have been developed to assess brain collateralization, they are subjective and quite coarse and do not capture many nuances of the underlying collateral vessel distribution. This article introduces a methodology for quantitatively and objectively assessing the degree of collateralization of the brain. The strategy is based on a regional analysis of time‐density curves extracted from dynamic angiographic image sequences. To investigate the dependence of the extracted metrics on the underlying collateralization in a controlled manner, a computational study is carried out by generating virtual patients with prescribed collateralization characteristics and conducting blood flow and transport simulations to create virtual angiographic sequences. The virtual angiograms of patients with large vessel occlusions and different collateral vessel distributions are used to generate “angiographic signatures” reflective of the underlying collateralization. The results show that angiographic signatures created from virtual angiograms exhibit consistent characteristics with angiographic signatures of actual stroke patients with different levels of collateralization. These findings indicate that these angiographic signatures can be used to assess the underlying collateralization of the brain and identify patients and conditions associated with adverse treatment outcomes.

Background Although good long-term outcomes have been obtained in the treatment of intracranial aneurysms with flow-diverting devices, aneurysms are not immediately occluded, and many remain incompletely occluded for a long time necessitating re-treatment. Improving devices and treatment outcomes requires detailed understanding of the mechanisms leading to quick and complete aneurysm occlusion after device implantation. Methods In this work, a series of seven aneurysms with persistent high-speed flow after flow diverter deployment were analyzed with computational models that include fibrin production and adhesion to the device struts and subsequent flow alteration due to fibrin accumulation. Four of the seven aneurysms were completely occluded at 3 months despite having high-flow conditions immediately after treatment. The remaining three aneurysms were incompletely occluded for at least 6 months. Results Significantly more fibrin accumulation and neck coverage (P=0.0209) was observed in the aneurysms that were completely occluded at 3 months compared with those that remained incompletely occluded. This larger fibrin accumulation resulted in larger inflow jet disruption and mean aneurysm velocity reductions (p=0.0209), creating in these aneurysms hemodynamic environments more favorable for fast complete occlusions. Conclusions Fibrin production induced by high-flow shear stress and adhesion to the device wires can result in some cases with persistent high-speed flow after device deployment in neck coverage and substantial inflow jet obstruction that may explain why these aneurysms were quickly completely occluded.

Endoluminal flow diverters are increasingly used to treat cerebral aneurysms. Despite good aneurysm occlusion efficacy, delayed ischemic complications due to side branch or perforator occlusion remain a serious concern. However, the mechanisms leading to side branch occlusion are poorly understood. To investigate these mechanisms, a combination of animal and computational models was utilized. Flow diverters were deployed in four rabbit superior mesenteric artery (SMA) and studied with computational fluid dynamics (CFD) and a previously developed fibrin dynamics model. Subject‐specific vascular models were reconstructed from 3D rotational angiography images and flow conditions were derived from Doppler ultrasound velocity measurements. Flow diverting devices were virtually deployed within the vascular models under guidance from angiography images. Coupled flow and fibrin production, transport, and adhesion simulations were carried out and the effects of fibrin accumulation at the origin of jailed side branches after flow diverter implantation were analyzed. The results of the computational models suggest significant fibrin accumulation across the struts of all flow diverting devices jailing side branches. Larger accumulation was observed at the more distal branches. However, minor flow alterations were produced which were not detectable in angiography sequences. These results were in agreement with experimental observations. On the other hand, fibrin accumulation alone did not explain complete side branch occlusions, which are likely the result of the interaction between initial fibrin accumulation and subsequent cell migration from the peripheral parent artery.

The role of the vasa vasorum in the growth and rupture of intracranial aneurysms, as well as the conditions stimulating its local development along aneurysm walls are not completely clear and have not been studied on an aneurysm‐specific basis. In this study, the oxygen distribution throughout the wall of an intracranial aneurysm that underwent substantial thickening and developed an extensive adventitial vasa vasorum network was numerically modeled in order to elucidate the role played by the vasa vasorum. The computational model was constructed based on high‐resolution ex vivo micro computed tomography and multi‐photon microscopy images of a tissue sample of the aneurysm harvested during open surgery. The mathematical model was based on the transport equation including oxygen diffusion and consumption in the tissue and diffusion across the lumen in the intimal side, and the vasa vasorum in the adventitial side. The governing equation was numerically solved with a finite volume approach on a high‐resolution mesh containing approximately 48 million tetrahedra with an element size of 10 μm. The results demonstrate that the observed vasa vasorum plexus provided adequate oxygen supply to the outer layers of the thickened walls. Furthermore, the models show that without the vasa vasorum, due to consumption throughout the wall, the oxygen demand could not be met by diffusion from the luminal surface. These findings support the idea that local hypoxic conditions in regions of increased wall thickness stimulate the development of the vasa vasorum network on the adventitial surface.

Currently, it is unclear why some patients experience restenosis after carotid endarterectomy (CEA) and whether the closing procedure is linked to greater rates of restenosis. Here, the morphology and hemodynamics are compared for the carotid bulb of two patients post‐CEA. One carotid bulb was closed with a patch which later suffered a restenosis, while the other patient's bulb was treated using primary closure and did not. Contrast‐enhanced magnetic resonance angiography (CE‐MRA) was segmented to provide the domain for computational fluid dynamics (CFD). Flowrate waveforms measured with phase‐contrast MR were provided for the common carotid artery (CCA) and internal carotid artery (ICA), while only the mean flow rate was provided for the external carotid artery (ECA), requiring the ECA waveform to be calculated. A Womersley profile was applied to the CCA inlet and ECA outlet, with a traction‐free boundary condition applied to the ICA outlet. The patch patient who restenosed exhibited a nonphysiological hemodynamic environment that differed from the flow environment observed in the healthy, contralateral bulb. In contrast, the hemodynamics of the primary closure patient who underwent a successful CEA showed more favorable levels and trends of WSS as well as healthy mixing from vortices that were both present in the healthy, contralateral bulb. Changing model parameters such as flow rate, wall compliance, and flow waveforms did not alter these conclusions. Therefore, the geometry of the carotid bulb, as opposed to flow characteristics, seems responsible for the observed differences between these two cases in hemodynamic environments and subsequent outcomes.

As the number of cerebral aneurysms treated with flow diverters continues to increase, it is important to understand what factors influence not only thrombus formation within the aneurysm cavity but also fibrin accumulation across the device and its associated disruption and blockage of the inflow stream. Both processes contribute to the eventual occlusion of the aneurysm or its continued patency and incomplete occlusion which may require future re‐treatment. To investigate fibrin accumulation on flow diverters placed across the neck of cerebral aneurysms, a previously developed computational model that couples flow and fibrin dynamics is used in combination with experimental in vitro models of cerebral aneurysms treated with flow diverters. Fibrin accumulation was previously investigated in four glass models of cerebral aneurysms with varying parent artery geometries placed in a flow loop at different flow rates. Corresponding computational models were constructed and compared with the experimental findings. The computational model based on fibrin production stimulated from flow shear stress and subsequent adhesion to device wires was able to reproduce and explain the fibrin accumulation patterns observed in the experimental aneurysms treated with flow diverters. Specifically, these models indicated that increasing vessel curvature, flow rate, and thrombin concentration induced faster fibrin accumulation and associated aneurysm inflow disruption and blockage. The models described and tested in this paper are valuable to understand the detailed mechanisms leading to aneurysm occlusion and healing or incomplete occlusions after treatment with flow diverting devices.

The mechanisms leading to aneurysm occlusion after treatment with flow‐diverting devices are not fully understood. Flow modification induces thrombus formation within the aneurysm cavity, but fibrin can simultaneously accumulate and cover the device scaffold, leading to further flow modification. However, the interplay and relative importance of these processes are not clearly understood. A computational model of fibrin accumulation and flow modification after flow diversion treatment of cerebral aneurysms has been developed under the guidance of in vitro experiments and observations. The model is based on the loose coupling of flow and transport‐reaction equations that are solved separately by independent codes. Interaction or reactive terms account for thrombin production from prothrombin stimulated by thrombogenic metallic wires and inhibition by antithrombin as well as fibrin production from fibrinogen stimulated by thrombin and flow shear stress, and fibrin adhesion to device wires and already attached fibrin. The computational model was demonstrated and tested on idealized vessel and aneurysm geometries. The model was able to reproduce the salient features of fibrin accumulation after the deployment of flow‐diverting devices in idealized in vitro models of cerebral aneurysms. Namely, fibrin production in regions of high shear stress, initial accumulation at the inflow zone, and progressive occlusion of the device and corresponding flow attenuation. The computational model linking flow dynamics to fibrin production, transport, and adhesion can be used to investigate and better understand the effects that lead to fibrin accumulation and the resulting aneurysm inflow reduction and intra‐aneurysmal flow modulation.

The effectiveness of various stroke treatments depends on the anatomical variability of the cerebral vasculature, particularly the collateral blood vessel network. Collaterals at the level of the Circle of Willis and distal collaterals, such as the leptomeningeal arteries, serve as alternative avenues of flow when the primary pathway is obstructed during an ischemic stroke. Stroke treatment typically involves catheterization of the primary pathway, and the potential risk of further flow reduction to the affected brain area during this treatment has not been previously investigated. To address this clinical question, we derived the lumped parameters for catheterized blood vessels and implemented a corresponding distributed compartment (0D) model. This 0D model was validated against an experimental model and benchmark test cases solved using a 1D model. Additionally, we compared various off‐center catheter trajectories modeled using a 3D solver to this 0D model. The differences between them were minimal, validating the simplifying assumption of the central catheter placement in the 0D model. The 0D model was then used to simulate blood flows in realistic cerebral arterial networks with different collateralization characteristics. Ischemic strokes were modeled by occlusion of the M1 segment of the middle cerebral artery in these networks. Catheters of different diameters were inserted up to the obstructed segment and flow alterations in the network were calculated. Results showed up to 45% maximum blood flow reduction in the affected brain region. These findings suggest that catheterization during stroke treatment may have a further detrimental effect for some patients with poor collateralization.

Intracranial aneurysms (IAs) pose severe health risks influenced by hemodynamics. This study focuses on the intricate characterization of hemodynamic conditions within the IA walls and their influence on bleb development, aiming to enhance understanding of aneurysm stability and the risk of rupture. The methods emphasized utilizing a comprehensive dataset of 359 IAs and 213 IA blebs from 268 patients to reconstruct patient‐specific vascular models, analyzing blood flow using finite element methods to solve the unsteady Navier–Stokes equations, the segmentation of aneurysm wall subregions and the hemodynamic metrics wall shear stress (WSS), its metrics, and the critical points in WSS fields were computed and analyzed across different aneurysm subregions defined by saccular, streamwise, and topographical divisions. The results revealed significant variations in these metrics, correlating distinct hemodynamic environments with wall features on the aneurysm walls, such as bleb formation. Critical findings indicated that regions with low WSS and high OSI, particularly in the body and central regions of aneurysms, are prone to conditions that promote bleb formation. Conversely, areas exposed to high WSS and positive divergence, like the aneurysm neck, inflow, and outflow regions, exhibited a different but substantial risk profile for bleb development, influenced by flow impingements and convergences. These insights highlight the complexity of aneurysm behavior, suggesting that both high and low‐shear environments can contribute to aneurysm pathology through distinct mechanisms.

The mechanisms behind intracranial aneurysm formation and rupture are not fully understood, with factors such as location, patient demographics, and hemodynamics playing a role. Additionally, the significance of anatomical features like blebs in ruptures is debated. This highlights the necessity for comprehensive research that combines patient‐specific risk factors with a detailed analysis of local hemodynamic characteristics at bleb and rupture sites. Our study analyzed 359 intracranial aneurysms from 268 patients, reconstructing patient‐specific models for hemodynamic simulations based on 3D rotational angiographic images and intraoperative videos. We identified aneurysm subregions and delineated rupture sites, characterizing blebs and their regional overlap, employing statistical comparisons across demographics, and other risk factors. This work identifies patterns in aneurysm rupture sites, predominantly at the dome, with variations across patient demographics. Hypertensive and anterior communicating artery (ACom) aneurysms showed specific rupture patterns and bleb associations, indicating two pathways: high‐flow in ACom with thin blebs at impingement sites and low‐flow, oscillatory conditions in middle cerebral artery (MCA) aneurysms fostering thick blebs. Bleb characteristics varied with gender, age, and smoking, linking rupture risks to hemodynamic factors and patient profiles. These insights enhance understanding of the hemodynamic mechanisms leading to rupture events. This analysis elucidates the role of localized hemodynamics in intracranial aneurysm rupture, challenging the emphasis on location by revealing how flow variations influence stability and risk. We identify two pathways to wall failure—high‐flow and low‐flow conditions—highlighting the complexity of aneurysm behavior. Additionally, this research advances our knowledge of how inherent patient‐specific characteristics impact these processes, which need further investigation.