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Injectable Shear-Thinning Hydrogels with Sclerosing and Matrix Metalloproteinase Modulatory Properties for the Treatment of Vascular Malformations

2023    Zehtabi, Fatemeh; Gangrade, Ankit; Tseng, Kaylee; Haghniaz, Reihaneh; Abbasgholizadeh, Reza; Montazerian, Hossein; Khorsandi, Danial; Bahari, Jamal; Ahari, Amir; Mohaghegh, Neda; Kouchehbaghi, Negar Hosseinzadeh; Mandal, Kalpana; Mecwan, Marvin; Rashad, Ahmad; de Barros, Natan Roberto; Byun, Youngjoo; Ermis, Menekse; Kim, Han-Jun; Khademhosseini, Ali

Sac embolization of abdominal aortic aneurysms (AAAs) remains clinically limited by endoleak recurrences. These recurrences are correlated with recanalization due to the presence of endothelial lining and matrix metalloproteinases (MMPs)-mediated aneurysm progression. This study incorporates doxycycline (DOX), a well-known sclerosant and MMPs inhibitor, into a shear-thinning biomaterial (STB)-based vascular embolizing hydrogel. The addition of DOX is expected to improve embolizing efficacy while preventing endoleaks by inhibiting MMP activity and promoting endothelial removal. The results show that STBs containing 4.5% w/w silicate nanoplatelet and 0.3% w/v of DOX are injectable and have a twofold increase in storage modulus compared to those without DOX. STB-DOX hydrogels also reduced clotting time by 33% compared to untreated blood. The burst release of DOX from the hydrogels show sclerosing effects after 6 h in an ex vivo pig aorta model. Sustained release of DOX from hydrogels on endothelial cells shows MMP inhibition (approximately an order of magnitude larger than control groups) after 7 days. The hydrogels successfully occlude a patient-derived abdominal aneurysm model at physiological blood pressures and flow rates. The sclerosing and MMP inhibition characteristics in the engineered multifunctional STB-DOX hydrogels may provide promising opportunities for the efficient embolization of aneurysms in blood vessels.

Combining occlusive, sclerosing, and MMP inhibitory properties enabled the development of a Gelatin-Laponite (STB) hydrogel loaded with Doxycycline (DOX) for abdominal aortic aneurysm sac embolization and endothelial ablation. Validated in a patient-derived aneurysm model, STB-DOX gels showed optimal injectability, strength, and aneurysm sac embolization. In vitro, MMP inhibition and endothelial removal are observed.image