Chitosan-Doxycycline hydrogel: an MMP inhibitor/sclerosing embolizing agent as a new approach to endoleak prevention and treatment after endovascular aneurysm repair

Publication date: Available online 18 September 2017
Source:Acta Biomaterialia
Author(s): Fatemeh Zehtabi, Pompilia Ispas-Szabo, Djahida Djerir, Lojan Sivakumaran, Borhane Annabi, Gilles Soulez, Mircea Alexandru Mateescu, Sophie Lerouge
The success of endovascular repair of abdominal aortic aneurysms remains limited due to the development of endoleaks. Sac embolization has been proposed to manage endoleaks, but current embolizing materials are associated with frequent recurrence. An injectable agent that combines vascular occlusion and sclerosing properties has demonstrated promise for the treatment of endoleaks. Moreover, the inhibition of aneurysmal wall degradation via matrix metalloproteinases (MMPs) may further prevent aneurysm progression. Thus, an embolization agent that promotes occlusion, MMP inhibition and endothelial ablation was hypothesized to provide a multi-faceted approach for endoleak treatment.In this study, an injectable, occlusive chitosan (CH) hydrogel containing doxycycline (DOX)—a sclerosant and MMP inhibitor— was developed. Several CH-DOX hydrogel formulations were characterized for their mechanical and sclerosing properties, injectability, DOX release rate, and MMP inhibition. An optimized formulation was assessed for its short-term ability to occlude blood vessels in vivo.All formulations were injectable and gelled rapidly at body temperature. Only hydrogels prepared with 0.075M sodium bicarbonate and 0.08M phosphate buffer as the gelling agent presented sufficient mechanical properties to immediately impede physiological flow. DOX release from this gel was in a two-stage pattern: a burst release followed by a slow continuous release. Released DOX was bioactive and able to inhibit MMP-2 activity in human glioblastoma cells. Preliminary in vivo testing in pig renal arteries showed immediate and delayed embolization success of 96% and 86%, respectively. Altogether, CH-DOX hydrogels appear to be promising new multifunctional embolic agents for the treatment of endoleaks.Statement of SignificanceAn injectable embolizing chitosan hydrogel releasing doxycycline (DOX) was developed as the first multi-faceted approach for the occlusion of blood vessels. It combines occlusive properties with DOX sclerosing and MMP inhibition properties, respectively known to prevent recanalization process and to counteract the underlying pathophysiology of vessel wall degradation and aneurysm progression. After drug release, the biocompatible scaffold can be invaded by cells and slowly degrade.Local DOX delivery requires lower drug amount and decreases risks of side effects compared to systemic administration.This new gel could be used for the prevention or treatment of endoleaks after endovascular aneurysm repair, but also for the embolization of other blood vessels such as venous or vascular malformations.

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