Aktuelle experimentelle Entwicklungen endovaskulärer Therapien intrakranieller Aneurysmen

Aktuelle Studien belegen, dass etwa 3% aller Erwachsenen Träger eines Aneurysmas sind, die Häufigkeit erhöht sich mit zunehmendem Lebensalter (117, 141). Viele Aneurysmen werden als Zufallsbefund diagnostiziert. Auch wenn die meisten, auf diese Weise entdeckten Aneurysmen nicht platzen (143), besteht dennoch Handlungsbedarf, da nicht vorhergesagt werden kann welche Aneurysmen platzen und welche nicht. Dabei spielen auch entsprechende Risikofaktoren wie beispielsweise Rauchen, Bluthochdruck oder Alkoholmissbrauch eine wichtige Rolle (35). Zur Behandlung von Aneurysmen stehen verschiedene Möglichkeiten zur Verfügung. Neben dem operativen Verschluss durch Clipping des Aneurysmas, können Aneurysmen auch interventionell verschlossen werden. Interventionell kann ein Aneurysma mittels Coil, Coil-Stent-Kombination, Flüssig-Embolysat oder auch durch einen Flow Diverter verschlossen werden. Gerade in den letzten Jahren kommen vermehrt Flow Diverter zum Einsatz. Ein Flow Diverter ist ein Stent mit einem sehr engen Maschengeflecht oder zum Teil verschlossenen Poren. Das Prinzip beruht auf der Flussumleitung des Blutes, wodurch das Aneurysma im Idealfall vom Blutstrom komplett abgetrennt wird und sich so ein Thrombus im Aneurysma bildet. Im Laufe der Zeit kommt es dann zu einem organisierten Thrombus im Aneurysma und einer Neubildung der Neointima über dem Aneurysmahals. In dieser Studie wurde ein neu entwickelter Flow Diverter (Derivo) sowohl in vitro als auch in vivo getestet und bezüglich seiner Wirksamkeit bewertet. Die durchgeführten Biokompatibilitätstests belegten eine gute Verträglichkeit des Materials. Es konnte gezeigt werden, dass der Flow Diverter weder die Zellviabilität beziehungsweise Zellproliferation beeinflusst, noch nekrotische Auswirkungen auf die ihn umgebenden Zellen hat. Das in vivo verwendete Tiermodell (Elastase-induziertes-Aneurysmamodell) in New Zealand White Rabbits wurde 1999 entwickelt und ist seit 2005 an unserem Institut etabliert. Die Handhabung des Flow Diverters erwies sich als unkompliziert und die Sichtbarkeit des Devices während den angiographischen Kontrollen war über den Verlauf des gesamten Versuchszeitraums gut. Den Tieren wurde sowohl ein Flow Diverter über das Aneurysma platziert als auch, um die Durchgängigkeit abgehender Gefäße beurteilen zu können, in die Bauchaorta. Der verwendete Flow Diverter zeigte schon nach drei Monaten bei 88% der Tiere einen kompletten Verschluss der Aneurysmen, lediglich bei 11% war ein Restfluss (Okklusionsrate Grad II) ins Aneurysma festzustellen. Bereits nach sechs Monaten waren alle Aneurysmen bis auf eins (Grad III) komplett verschlossen. Die histologische Auswertung zeigte in allen Aneurysmen teilorganisierte Thromben, nach sechs Monaten in fünf von neun Fällen sogar komplett organisierte Thromben. Die zusätzlich durchgeführten Mikro-MRT und Mikro-CT Untersuchungen belegten zum einen die histologischen Ergebnisse. Des Weiteren waren während des gesamten Versuchszeitraums, auch unter starker mechanischer Beanspruchung des Flow Diverters, keine Brüche von Stentstreben nachzuweisen. Der in dieser Studie getestete Flow Diverter (Derivo) stellt auf Grund der Ergebnisse gute Möglichkeiten für die Behandlung von nicht rupturierten Aneurysmen im Menschen in Aussicht.Current studies show that about 3% of all adults have an aneurysm; the frequency increases with age (117, 141). Many aneurysms are diagnosed as incidental findings. While most of these aneurysms don´t burst (143) there is need for action, because it is not possible to predict which aneurysms will burst and which ones won’t (143). Corresponding risk factors like smoking, high blood pressure or alcohol abuse also play an important role (35). For therapy there are different options. Besides operational occlusion by clipping of the aneurysm, it is possible to occlude the aneurysm interventionally. Interventional occluding can be performed with the help of coils, coil-stent-combinations, liquid embolization or with the help of a flow diverter. The latter have been used more and more over the past years. A flow diverter is a stent with a tight mesh web or partially closed pores. The principle is based on blood stream diversion, which ideally will completely cut off the aneurysm from the blood stream and a thrombus will form in the aneurysm. Gradually an organized thrombus will develop in the aneurysm and a new neointima will grow growth over the neck of the aneurysm. In this study a newly developed flow diverter (Derivo) was tested in vitro as well as in vivo and evaluated regarding its effectiveness. The biocompatibility tests performed showed a good compatibility of the material. It could be shown that the flow diverter does not influence the cell viability or the cell proliferation, nor does it have necrotic effects on the ambient cells. The in vivo animal model used (elastase induced aneurysm model) in New Zealand White Rabbits was developed in 1999 and has been established since 2005 in our institute. The handling of the flow diverter proved uncomplicated and the visibility of the device was good during the entire experiment. All animals received a flow diverter over the aneurysm as well as in the A. abdominalis for judging the patency of outgoing branches. The flow diverter used showed after 3 months already complete occlusion of the aneurysms in 88% of all animals, merely 11% showed a slight blood flow in the aneurysm (occlusion grade II). After 6 months all aneurysms except one (occlusion grade III) were completely closed. The histological analysis showed in all aneurysms partially organized thrombi, after 6 months even completely organized thrombi in 5 of 9 cases. The micro-MRT and micro-CT analyses performed in addition confirmed the histological findings. There were also no breaks found of the stent struts over the entire experiment, even under strong mechanical strain. On the basis of these results the flow diverter tested in this study offers a perspective of good therapy possibilities for unruptured aneurysms in humans

In-silico clinical trials for assessment of intracranial flow diverters

In-silico trials refer to pre-clinical trials performed, entirely or in part, using individualised computer models that simulate some aspect of drug effect, medical device, or clinical intervention. Such virtual trials reduce and optimise animal and clinical trials, and enable exploring a wider range of anatomies and physiologies. In the context of endovascular treatment of intracranial aneurysms, in-silico trials can be used to evaluate the effectiveness of endovascular devices over virtual populations of patients with different aneurysm morphologies and physiologies. However, this requires (i) a virtual endovascular treatment model to evaluate device performance based on a reliable performance indicator, (ii) models that represent intra- and inter-subject variations of a virtual population, and (iii) creation of cost-effective and fully-automatic workflows to enable a large number of simulations at a reasonable computational cost and time. Flow-diverting stents have been proven safe and effective in the treatment of large wide-necked intracranial aneurysms. The presented thesis aims to provide the ingredient models of a workflow for in-silico trials of flow-diverting stents and to enhance the general knowledge of how the ingredient models can be streamlined and accelerated to allow large-scale trials. This work contributed to the following aspects: 1) To understand the key ingredient models of a virtual treatment workflow for evaluation of the flow-diverter performance. 2) To understand the effect of input uncertainty and variability on the workflow outputs, 3) To develop generative statistical models that describe variability in internal carotid artery flow waveforms, and investigate the effect of uncertainties on quantification of aneurysmal wall shear stress, 4) As part of a metric to evaluate success of flow diversion, to develop and validate a thrombosis model to assess FD-induced clot stability, and 5) To understand how a fully-automatic aneurysm flow modelling workflow can be built and how computationally inexpensive models can reduce the computational costs

New Insight into Cerebrovascular Diseases

“Brain circulation is a true road map that consists of large extended navigation territories and a number of unimagined and undiscovered routes.” Dr. Patricia Bozzetto Ambrosi This book combines an update on the review of cerebrovascular diseases in the form of textbook chapters, which has been carefully reviewed by Dr. Patricia Bozzetto Ambrosi, Drs. Rufai Ahmad and Auwal Abdullahi and Dr. Amit Agrawal, high-performance academic editors with extensive experience in neurodisciplines, including neurology, neurosurgery, neuroscience, and neuroradiology, covering the best standards of neurological practice involving basic and clinical aspects of cerebrovascular diseases. Each topic was carefully revised and prepared using smooth, structured vocabulary, plus superb graphics and scientific illustrations. In emphasizing the most common aspects of cerebrovascular diseases: stroke burden, pathophysiology, hemodynamics, diagnosis, management, repair, and healing, the book is comprehensive but concise and should become the standard reference guide for this neurological approach

Development of a novel uncovered stent system for the management of complex aortic aneurysms

Endovascular aortic repair (EVAR) is a minimally invasive alternative to open surgery for the treatment of aortic aneurysms (AA). However, standard EVAR is not applicable to complex AA with involvement of vital branches, which could be occluded by the endograft. As an emerging technique, the concept of multiple overlapping uncovered stents (MOUS) have been proposed to manage complex lesions. MOUS was used to modulate the flow pattern inside the aneurysm sac, and promote the thrombus formation followed by the aneurysm shrinkage. In this dissertation, we sought to investigate the mechanism of MOUS-induced flow modulation and key factors associated with the success of this novel technique: - The mechanical behaviour of AA was characterised by uniaxial material tests (Chapter 4). A Bayesian framework was proposed for material constants identification. They were found correlated to the microstructure of tissue fibre network and were capable in differentiating tissue types. - Solid-to-solid interaction and one-way fluid-solid interaction (FSI) analysis was performed based on patient-specific computer tomography angiography (Chapters 5&6). Structural stress concentrations were observed within the landing zones, which increased with the number of stents deployed. In the parameter studies (Chapter 6), the overall porosity was identified as the dominant factor of the flow-diverting outcome, while cross-stent structures of MOUS had limited influence. - The pathological effect of structural stress concentration induced by an implanted device was further studied in rabbit models (Chapter 7). The wall structural stress and fluid shear stress were obtained from FSI analysis based on magnetic resonance imaging (MRI), and correlated to plaque characteristics. Both high structural stress and low fluid shear stress were found correlated to plaque initialisation and increased inflammation. Overall, MOUS modulates the blood flow with robust performance under different overlapping patterns. Image-based biomechanical analysis can optimise MOUS design and can contribute to personalised pre-surgery planning.Shuo Wang was sponsored by China Scholarship Council (2014-2018)

Verification of a novel rabbit model used in the study of human intracranial aneurysm

Coupling the hemodynamics with the pathophysiology of human intracranial aneurysm (IA) has been a subject of interest for eventually obtaining the reliable prediction of subarachnoid hemorrhage caused by aneurysm rupture. In recent works, the stability of flow patterns, regions of impingement, size of jets, wall shear stress (WSS), and the formation of vortices are considered to be the major causes of aneurysm rupture. A trending conclusion from the qualitative analysis of patient-specific cases is that aneurysms with simple stable flow patterns and large impingement region are safer than those with complex unstable flow pattern and small impingement region. When it comes to clinic, some physical experiments such as the testing of medical devices could not be operated on human body. Thus, preclinical animal models are introduced as surrogates. In the study of human IA, the most commonly used elastase-induced rabbit model has been found that it could only generate limited flow pattern due to the unrealistic retrograde flow condition inside the aneurysm. A novel method of creating bifurcation-like rabbit model for limiting retrograde flow was proposed recently and two new bifurcation-like rabbit aneurysms with different geometry were created in Mayo clinic. However, only the performance of the one with relative generalized geometry was testified. In this paper, the other novel bifurcation-like rabbit aneurysm model with irregular long sac was investigated and its hemodynamics performance has been extensively evaluated by using computational fluid dynamic (CFD) method. The methodology of creating this rabbit aneurysm model, the construction of geometric model in the computer and the setting of boundary conditions will be described in detail. The robustness of this rabbit model has also been investigated by modifying the essential geometric variables of the model. Additionally, quantitative analysis of flow pattern changes was given as supplement for the robustness study. The result showed that this rabbit model with irregular long sac is capable of generating interest-relevant flow types and robust enough under geometric perturbation. It could serve as an extra evidence that the novel bifurcation-like rabbit model is powerful and robust enough for extrapolating results of animal experiments into human study

Optimisation of a novel hydrogel for the treatment of cerebral aneurysms

Approximately 1-6% of adults have a cerebral aneurysm. Treatments include clipping and coiling; however, over 20% of coiled aneurysms recur. A novel bioactive glass-alginate hydrogel has been optimised to fill the aneurysm and prevent recurrence. For successful aneurysm embolization, the hydrogel must be injectable and set in situ, as well as meeting other design requirements, including; injectability, strength, adhesiveness, radiopacity and cytocompatibility. The hydrogel was optimised by examining the effect alginate concentration, chemical composition and molecular weight has on the hydrogel’s properties. The glass was acid washed which improved homogeneity of the hydrogel and reduced glass agglomeration. The glass and GDL content were optimised and resulted in a hydrogel with a higher compressive strength compared to in situ gelling alginates reported in the literature. The addition of EDC and NHS improved the adhesive strength of the hydrogel without the need for cell attaching peptides. In vitro analysis showed cells can adhere and proliferate in direct contact with the hydrogel and its eluent. Proliferation was dose dependent and likely caused by silica ions and gluconic acid released. Although endothelial cells attached to the surface of the hydrogel, this was minimal. Platelet adhesion to the hydrogel was also marginal. The hydrogel was sterilised and radiopacity was improved, but with a loss in compressive strength. In vivo analysis indicated that issues occur in delivering this material into an aneurysm, though this hydrogel can be effectively used as an embolization treatment that supports the formation of a neointima layer. This work highlights the influence each component has on the hydrogel’s properties. Although this hydrogel was optimised for the treatment of cerebral aneurysms, the hydrogel is highly tuneable and would be suitable for a range of embolic applications. This bioactive in situ gelling hydrogel would also be suitable for tissue engineering and therapeutic drug delivery