In situ photopolymerizable hydrogels for intracranial aneurysms treatment

Intracranial aneurysm is a cerebrovascular disease characterized by an artery dilation in the brain. An aneurysm is prone to rupture, which causes a life-threatening subarachnoid hemorrhage. The major drawbacks of the current treatments, open surgical clipping and endovascular therapy, are the invasiveness of the surgery and the high recurrence and retreatment rates, respectively. In situ forming injectable hydrogels have emerged as a promising approach to overcome the current drawbacks. Ideally, the embolic agent should (1) permanently and completely occlude the aneurysm, (2) be implanted via a minimally invasive surgery, (3) be safe for the patient, and (4) promote the endothelialization at the aneurysm neck. In this thesis, in situ photopolymerizable hydrogels based on poly(ethylene glycol) dimethacrylate (PEGDMA) were developed for the treatment of intracranial aneurysms. First, PEGDMA hydrogels were characterized according to polymer molecular weight and concentration. Denser covalently cross-linked hydrogel networks were obtained by decreasing the molecular weight and increasing the polymer concentration. It was demonstrated that PEGDMA hydrogels of 6 kDa molecular weight at a concentration of 15 wt% meet the physical and mechanical requirements of aneurysm embolic agent. Their compressive elastic modulus and compliance cover the range of native tissue and their minimal swelling behavior avoids protrusion in the parent artery and limits stresses applied on the aneurysm wall. The fatigue-resistance of the hydrogels under pulsatile flow-induced loadings was subsequently evaluated. The hydrogels withstood the 5.5 million cycles and maintained their weight and elastic modulus. However, slight roughness due to erosion was noticed at the hydrogel surfaces. Second, the in vitro proof-of-concept of photopolymerizable hydrogels implementation into intracranial aneurysms models using the same microcatheters as in clinical practice was validated. The PEGDMA precursors exhibited a low viscosity allowing their injectability through 430 µm microcatheters. The addition of iodinated contrast agent as solvent enabled the precursors to be visible under fluoroscopy. Moreover, the precursors polymerized in a controlled manner within less than 8 minutes by visible light illumination using a customized light-conducting microcatheter. Then, the biocompatibility of the precursors was assessed in vitro and in an in vivo systemic toxicity study in rats. The obtained results revealed that the PEGDMA precursors did not trigger any acute or delayed toxicity and did not induce thrombus formation or inflammation. Additionally, the polymerized hydrogels did not affect the endothelial cells survival after one week of contact. Finally, the biofunctionalization of PEGDMA hydrogels with gelatin methacrylate (GelMA) was proposed as a strategy to promote the in situ endothelialization. The incorporation of GelMA into PEGDMA network significantly improved the endothelial cell migration, adhesion and spreading on the hydrogel surfaces and a cellular network was formed after one week of culture. The adherent cells on the hybrid hydrogels were then exposed to laminar flow in a microfluidic channel and withstood the shear stresses. The overall results showed that the photopolymerizable PEGDMA-based hydrogels possess the appropriate properties to be a promising candidate for intracranial aneurysms treatment. In vivo studies are required to confirm these promising results.