Engineering Bioadhesive Polyvinyl Alcohol Hydrogels for Aneurysm Occlusion

Aneurysms pose a major health risk; 30,000 aneurysms rupture each year in the United States, causing stroke, permanent nerve damage, or subarachnoid hemorrhage. The current endovascular embolization method using platinum coils cannot treat wide-necked, large, or giant aneurysms. To create a new treatment paradigm, we synthesized photopolymerizable polyvinyl alcohol (PVA) gels to fabricate a space-filling material with engineered bioadhesion to inflamed endothelial cells. PVA was chosen for its low adhesiveness, non-degradability, and chemical tunability. PVA was modified to include methacrylate and amine side groups for photopolymerization and bioconjugation, respectively. We functionalized PVA surfaces with varying ratios of antibodies against cell adhesion molecules (CAMs) highly expressed on inflamed human umbilical vein endothelial cells (HUVECs). We validated gene expression profiles of endothelial leukocyte adhesion molecule-1 (ELAM) and vascular cell adhesion molecule-1 (VCAM) on HUVECs treated with interleukin-1α (IL-1α) to simulate an inflammatory environment. PVA gels were either modified with anti-ELAM only, anti-VCAM only, or a 1:1 ratio of anti-ELAM to anti-VCAM. HUVECs were stimulated with IL-1α before seeding onto the gels, and attachment was quantified after 2 and 24 hr. Cell adhesion was assessed by calculating the ratio of cells retained after centrifugation over cells retained after inversion. Preliminary results showed strong and reversible cell attachment to PVA gels conjugated with either anti-ELAM or anti-VCAM. Though anti-ELAM and anti-VCAM showed strong adhesion at early times, this adhesion was reversed as a function of time. Synergistic binding of both anti-ELAM and anti-VCAM showed stable adhesion at 24 hr post-seeding. Endothelial cells were retained on 1:1 anti-ELAM:anti-VCAM presenting surfaces at a centrifugal force of 300xg; adherence decreased steadily with increased centrifugation speeds. An in vitro microfluidic aneurysm was designed to evaluate in situ polymerization and adhesion at physiological shear stresses of up to 15 dynes/cm². Our findings suggest that cytokine-activated CAM expression may be used to engineer bioadhesive gels for the specific and effective adhesion of inflamed endothelial cells. Such materials have significant potential for use as an embolic agent for cerebral aneurysms as they may conform to any aneurysm geometry and maintain adhesion to prevent rupture and dislodging.