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

Abstract

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.

Engineered Regenerative and Adhesive Hydrogel for Concurrent Sealing and Healing of Enterocutaneous Fistulas

“…Given the comparatively high death rate (46%) among patients with ECF due to intra-abdominal bleeding reported by Wu et al in their retrospective study, 47 a thorough evaluation of the biomaterial's impact on blood coagulation in the context of ECF is crucial. Laponite and gelatin are known for their ability to clot blood, 6,28 aligning with our observation of D5L4P0, which relatively reduced blood clotting time to 20% (Figure 3Cii). However, adding PRP reduced the hemostatic effects of D5L4P0 hydrogel, and D5L4P25 showed no significant reduction in blood clotting time.…”

“…The shear-thinning behavior of the DLP hydrogel aligns with previous reports on Laponite hydrogel. 6,28,29 Additionally, the addition of PRP did not alter this behavior (Figure 2F).…”

“…The bench test was performed as previously done with modification. 28 Briefly, water was systematically circulated within a closed circuit using a syringe pump. The circuit was established by connecting a 3D-printed silicone tube or pig skin with an 8 mm drilled hole to simulate a fistula tract.…”

“…Our chosen threshold for success, set at 300 mmHg, was based on the average systemic pressure of the human body (200−220 mmHg), 28 ensuring that the hydrogel's effectiveness was evaluated under clinically relevant pressures. The results revealed that the D5L4P0 hydrogel demonstrated a 100% success rate in occluding both the tube and porcine skin.…”

Development of an Injectable, ECM-Derivative Embolic for the Treatment of Cerebral Saccular Aneurysms

“…Recently, extensive research has been conducted on gelatin for the development of injectables aimed at treating hemorrhage. Gelatin has been explored as a shear-thinning, − semisolid, , and cross-linkable hydrogel. , These studies have been motivated by the various characteristics of gelatin, such as its ability to trigger clot formation, low immunogenicity, and support for cell attachment and proliferation. Among these approaches, injectables composed of gelatin and nanoclay have shown promising results in hemorrhage control and embolization. , However, it has been reported that silicate nanoplatelets can induce cytotoxicity through the generation of reactive oxygen species, damage to cell membrane interactions, and intracellular interaction mechanisms …”