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.

Development of Biocompatible 3D-Printed Artificial Blood Vessels through Multidimensional Approaches

“…In another investigation, Megan Kimicata et al harnessed gelatin methacryloyl (gelMA) laden with heparin during the fabrication of artificial blood vessels. This strategic incorporation facilitated the continuous release of heparin, leading to a robust enhancement in endothelial functionality and the establishment of an anti-thrombotic microenvironment [137]. These compelling results substantiate the tremendous potential of the engineered artificial blood vessels, rendering them more suitable for transplantation and concurrently ameliorating associated side effects.…”

A personalized biomimetic dual-drug delivery system via controlled release of PTH1-34 and simvastatin for in situ osteoporotic bone regeneration

“…Additionally, a delivery system that serves as a local platform to sustainably release active substances should be considered. GelMA is an ideal platform for controlled drug release and cell adhesion ( Sun et al, 2018 ; Collins et al, 2021 ; Kimicata et al, 2021 ). The hydrogels establish a biomimetic microenvironment for bone tissue engineering ( Meng et al, 2022 ; Xue et al, 2022 ), but their biomechanical properties are slightly inadequate compared with those of hard bone tissue.…”

Oral administration microrobots for drug delivery

“…under UV light exposure with the presence of a photo-initiator) [ 55 , 58 , 59 ]. The concentration of reactants, light intensity can significantly affect the physical characteristic of the formed hydrogels [ 60 , 61 ]. GelMA hydrogels closely resemble some essential properties of native extracellular matrix (ECM), because of the presence of cell-adhesion and matrix metalloproteinase (MMP) responsive peptide motifs.…”

“…GelMA hydrogels closely resemble some essential properties of native extracellular matrix (ECM), because of the presence of cell-adhesion and matrix metalloproteinase (MMP) responsive peptide motifs. With the excellent biological properties and tunable physical characteristics, GelMA hydrogels have a wide range of biomedical applications, such as 3D bioprinting [ 60 , 62 ], tissue engineering [ 61 , 63 ], drug delivery [ 64 ], and biomedical microrobot [ 57 ] et al Additionally, lots of efforts have been devoted to combining GelMA-based hydrogels and functional nanomaterials, which aims to endow GelMA with enhanced physical-chemical and biological properties [ 63 ].…”