Long-Term Sustained Drug Delivery via 3D Printed Masks for the Development of a Heparin-Loaded Interlayer in Vascular Tissue Engineering Applications.

Abstract

Current approaches in small-diameter vascular grafts for coronary artery bypass surgeries fail to address physiological variations along the graft that contribute to thrombus formation and ultimately graft failure. We present an innovative interlayer drug delivery system that can be utilized for the sustained delivery of heparin through a graft with a high degree of temporal and spatial control. A heparin-loaded gelatin methacrylate (gelMA) interlayer sits within a biohybrid composed of decellularized bovine pericardium (dECM) and poly(propylene fumarate) (PPF), and its UV crosslinking is controlled via three-dimensional (3D) printed shadow masks. The masks can be readily designed to modulate the incident light intensity on the graft, enabling us to control the resultant gelMA crosslinking and properties. A high heparin loading efficiency was obtained in gelMA and was independent of crosslinking. We achieved sustained heparin release over the course of 2 weeks within the biohybrid material using the 3D printed mask patterns. High doses of heparin were observed to have detrimental effects on endothelial cell function. However, when exposed to heparin in a slower, more sustained manner consistent with the masks, endothelial cells behave similarly to untreated cells. Further, slower release profiles cause significantly more release of tissue factor pathway inhibitor, an anticoagulant, than a faster release profile. The heparin-loaded gelMA interlayer we have developed is a useful tool for the temporal and spatial control of heparin release that supports endothelial function and promotes an antithrombotic environment.