Project

Discipline

hydrogel; cerebral aneurysms; photopolymerization; embolization; endovascular; fiber optics; photoinitiators; coils; optical probe; liquid embolic agents; photosensitive

Lead
Le but de ce projet interdisciplinaire est la mise au point de nouveaux agents emboliques liquides photo-sensibles pour le traitement des anévrismes intracrâniens.
Lay summary
Les anévrismes intracrâniens représentent une cause de morbi-mortalité neurologique importante. Le traitement endovasculaire par embolisation s'est progressivement imposé comme la thérapie de référence pour cette pathologie. Les implants intra-saculaires les plus communément utilisés pour occlure les anévrismes sont les coils ou spires de platine. D'autres dispositifs intra-sacculaires (cages auto-expansibles) ont émergé ainsi que des implants extra-sacculaires tels que les stents à diversion de flux (flowdiverter). Le principe est d'induire une thrombose de l'anévrisme afin que celui soit exclu définitivement de la circulation. Au cours du temps, il arrive que les implants intra-sacculaires se compactent, que le thrombus se modifie et que l'anévrisme se reconstitue (recanalisation). De même, certains anévrismes traités par flowdiverter ne s'occluent pas. Comparés aux implants solides, les agents emboliques liquides ont le potentiel d'occlure tout le volume anévrismal et ne requièrent pas de médicaments anti-aggrégants. La maîtrise du processus de solidification et la toxicité des agents liquides actuels demeure cependant un obstacle majeur à leur utilisation dans la pratique courante. Notre objectif est de créer une nouvelle génération d'agents emboliques liquides photosensibles, polymérisant sélectivement au contact de la lumière, elle-même amenée à travers un microcatheter par un nouveau type de fibre optique ultra souple conçu par notre groupe. La toxicité, la thrombogénicité, l'aspect inflammatoire et la capacité à promouvoir la néo-endothelialisation seront évalués au niveau cellulaire et histologique sur différents substrats et modèles d'anévrismes ex vivo et in vivo. Le projet relève de la recherche fondamentale et requière une forte interdisciplinarité scientifique, impliquant ingénierie (physique, chimie, sciences des matériaux, mirotechnique), médecine vétérinaire et médecine humaine.

Direct link to Lay Summary

Last update: 05.02.2017

Natural persons

Active participation

Self-organised

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Title	Year

Start-ups

Cerebral aneurysm rupture is associated with a 65% risk of neurological deficit or death and represents an important socio-economic burden. Endovascular therapy (EVT) with platinum coil occlusion has become the gold standard compared to surgical clipping. Ideally, a treated aneurysm becomes isolated from its parent artery by neointimal bridging of the neck of the aneurysm, preventing blood flow into the sac and aneurysmal rupture. Current endovascular embolization techniques focus on occlusion with metallic implants that promote thrombosis within the aneurysm sac. Because an unorganized intra-aneurysmal thrombus may continue to interact with the aneurysm wall and blood flow, maintaining inflammatory conditions and proteolytic enzyme activity, clot remodeling and wall changes can lead to aneurysm recurrence and rupture. Long term durability of EVT, therefore, remains a major concern. Liquid embolic agents represent interesting alternatives to address these limitations but have shown disappointing results so far due to the risk of embolic migration related to poor control over their injection and solidification processes. Based on a photo-sensitive hydrogel recently developed at EPFL by the Laboratory of Applied Photonic Devices (LAPD) and two other groups, we aim to exceed the state of the art by developing a more controllable, durable and safer liquid embolic substance designed to be more than just another clot-forming space filler. Our main objective is to increase long term aneurysm occlusion by creating a light-triggered bio implant with reduced thrombogenic properties and enhanced healing features, capable of excluding blood from entering the sac permanently and attracting new cells, overcoming the underlying wall inflammation mechanisms and promoting stable neointimal growth at the neck. As a leader in photoinitiator synthesis, the Laboratory of Inorganic Chemistry (LIC) at ETHZ will develop new generations of photoinitiators that enable fast and homogenous photopolymerization within the challenging environment of aneurysms, where light is rapidly absorbed or scattered by blood. Moreover, surface modification molecules will be added to the photoinitiators to enable the cross-linked hydrogel to be as less thrombogenic as possible and to adhere tightly to the aneurysm wall as it photopolymerizes. As a certified “Good Laboratory Practice” facility experienced in animal aneurysm models, the Musculoskeletal Research Unit (MSRU) at UZH-VetSuisse will perform in vivo testing, provide animal care and carry out toxicity, imaging and biochemical and histological testing. The Interventional Neuroradiology team at Inselspital-Bern will provide the surgical endovascular expertise and drive the project by maintaining a clinically oriented overview of the consortium, while also actively collaborating throughout all stages of the project. The main research goal is to verify whether the implant can effectively lead to higher immediate and long term occlusion rates and promote better wall and neck healing compared to traditional coiling. To fulfil this objective, we aim to develop (1) an optimal formulation of photosensitive hydrogel that can be safely injected in normal arteries, rapidly triggered to photopolymerize selectively and remains inside the aneurysm; (2) a minimally invasive optical device capable of safely and efficiently delivering light into a brain aneurysm. Implementation will be incremental, using a step by step approach, both in vitro and in vivo. Once the desired characteristics of the hydrogel and light-delivery device will have been determined, toxicity studies will be conducted in rats, followed by hydrogel delivery and photopolymerization feasibility tests in Helsinki rat models before treating elastase-induced aneurysms in rabbits and evaluating the short and long term results.